Tips and Tricks in Interventional Therapy of Coronary Bifurcation Lesions

Tips and Tricks in Interventional Therapy of

CoronaryBifurcation Lesions

Edited by Issam

D. Moussa Antonio Colombo

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Tips and Tricks in Interventional Therapy of Coronary Bifurcation Lesions

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Tips and Tricks in Interventional Therapy of Coronary Bifurcation Lesions Edited by Issam D. Moussa New York Presbyterian Hospital–Weill Medical College of Cornell University New York, New York, U.S.A.

Antonio Colombo San Raffaele Scientific Institute EMO-GVM Centro Cuore Columbus Milan, Italy

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c 2010 Informa UK Ltd
First published in 2010 by Informa Healthcare, Telephone House, 69-77 Paul Street, London EC2A 4LQ. Informa Healthcare is a trading division of Informa UK Ltd. Registered Office: 37/41 Mortimer Street, London W1T 3JH. Registered in England and Wales number 1072954. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. A CIP record for this book is available from the British Library. Library of Congress Cataloging-in-Publication Data Data available on application ISBN-13: 978-1-84184-726-9 Orders Informa Healthcare Sheepen Place Colchester Essex CO3 3LP UK Telephone: +44 (0)20 7017 5540 Email: [email protected]

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Foreword

Bifurcation PCI is not easy. The decision tree for the approach to bifurcations requires knowledge and experience to move through the procedure with minimal time, effort, and complications. In some cases, avoiding the bifurcation stenting altogether may be the best approach. Although the many ways to perform bifurcation PCI can be simplified into two major approaches—(i) stent with provisional side branch stent and (ii) planned stents from the start—there remains controversy as to the best approach for a particular lesion that has a wide variability of mother/daughter branch size ratio, angulation, ostial atherosclerotic involvement, and potential for extensive myocardial infarction if the technique fails. In the practice of PCI and especially bifurcation PCI, the old adage that there is no such thing as “simple” PCI has never been truer. Bifurcation lesions have the most complex anatomic configurations and hence potential for multiple individualized approaches. One only needs to recall the six or more bifurcation classification schemes, and understand and apply one of the more than eight stent techniques to the particular bifurcation anatomy for the best outcome. Unfortunately, understanding which technique is associated with best outcomes for bifurcation PCI is not that simple. Bifurcation PCI remains more of an art form, struggling to become science. It is here that Moussa and Colombo introduce logic and science into this rarified arena. While I, like many others, believe the simple approach is the best approach, in practice this is not always true. Complex interventions are required for some complex circumstances. The field of bifurcation PCI has taken on a life of its own in the recent years as evidenced in 2004 by the birth of the European Bifurcation Club (EBC), with sessions at scientific meetings dedicated to bifurcation PCI management. The “Tips and Tricks” book dedicated to bifurcation PCI is a unique offering, addressing this important clinical PCI subset. Its importance is supported by the industrial development of novel side branch stents and further emphasizes the common and difficult problem that side branch management represents. Drs. Moussa and Colombo have assembled a unique book dedicated to understanding and managing this critically challenging PCI problem. It is a first of its kind in the interventional world. Because of the numerous configurations of a bifurcation involving the aorto-ostia, the main branch and side branch relationship, as well as the distal left main, the PCI approach requires careful classification, categorization, and technique selection based on the best studies (randomized, multicenter, etc.). Validation of the outcomes from the studies reporting the numerous approaches to these treatments is hard to come by. Drs. Moussa and Colombo, experts in their own right, have assembled a stellar team of coauthors who cover the universe of bifurcation PCI. For example, in the first section, the reader will be introduced to the evidence and studies on which most initial decisions are based. Moussa and Colombo ask: Are the trials on which we have based our current approaches to this point satisfactory? Are they large enough? Is there enough detail and division of the types of bifurcations studied to appreciate outcomes related to therapy? These questions and more are addressed in detail. While one cannot generalize these introductory remarks to all bifurcation procedures, the subsequent chapters on the bifurcation anatomy by Drs. Costa, Russell, and Moussa set the groundwork for understanding classifications and hence techniques. The anatomy and physiology resulting in unique stress patterns of specific angulations of the side branches provide insight into the role of stenting and carina reconstruction. To understand the anatomy, the routine incorporation of the imaging modalities as well as physiologic assessment is warranted and addressed. Importantly, because obviously not all bifurcations are the same, the left main coronary artery bifurcation is discussed in a separate set of chapters later in the book.

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Foreword

Albiero and Boldi discuss stenting for non–left main coronary artery bifurcations, addressing the advantages and disadvantages of the provisional stent strategy. Drs. Lim and Koo expertly describe physiologic guidance for both provisional stenting and side branch jailing after stenting. Using fractional flow reserve to simplify the approach and demonstrate its longterm outcome for bifurcation lesions with stenting and kissing balloons is described by Dr. Koo, the world’s expert on the physiologic assessment of these jailed side branches using the pressure wire technique. In double stenting rather than provisional stenting, Drs. Favero, Pacchioni, and Reimers provide description of the most suitable anatomy, rationale for patient selection, and technique descriptions covering the complex double stenting nomenclature including T stenting, crush stenting, culotte stenting, and V stenting. The technique and execution of such methodologies is critical to procedure success. Those individuals interested in pursuing complex intervention will find this chapter highly stimulating. Left main coronary interventions are discussed in the third section of this book. Drs. Park and Kim present the evidence from numerous single and multicentered experiences, identifying outcomes for complex stenting of the different regions of the left main artery. Provisional stenting of the left main distal bifurcation constitutes a real challenge. The opinion provided from two of the most experienced interventionalists in the world in treating bifurcation left main stenoses is based on thousands of patients and is well reported in our major journals. Drs. Latib, Chieffo, and Colombo conclude Section 3 with a discussion of double-stenting of the left main coronary artery, providing detailed descriptions of stent technique, the simultaneous kissing strategy. Finally, in the fourth section, the reader will review bench testing and dedicated studies on focused technology, attempting to improve the delivery of existing stents and the manufacture and development of unique dedicated bifurcation stents. Observations gained from the testing involve insights into overlapping metal struts in the wide array of combined methods including crush, T, culotte, and V stenting. In the last chapter of the book, Drs. Latib, Sangiori, and Colombo speculate on the future of dedicated bifurcation stent systems and where our next steps will lead. An intriguing description and categorization of the staged development for many new stents that are soon to be available within the next few years are provided. The regulatory challenge of bringing these to the practicing interventional cardiologists is worth reading. I believe all levels of physicians interested in the practice of interventional cardiology will benefit by reading “Tips and Tricks” with its important lessons for their practice and patients. The Interventional cardiologists, fellow-in-training, the early career interventionalists as well as the seasoned expert can take heart in using this information to support current practice and identify future practices for his best outcomes, especially those regarding the left main coronary bifurcation. My compliments to Dr. Moussa and Dr. Colombo as they bring into focus one of the more difficult aspects of all coronary interventions, that of the bifurcated and branched lesion. Morton J. Kern, M.D., FSCAI, FACC, FAHA Chief Cardiology, Division of Cardiology Long Beach Veterans Administration Hospital Long Beach, California, U.S.A. Associate Chief Cardiology, Professor of Medicine Division of Cardiology University of California Irvine Orange, California, U.S.A.

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Preface

The mark of mediocrity in written material, whether it is literature, politics, or medicine, is to rely heavily on precedents; so whatever is previously written about a topic is written again and again propagating the same narratives. This statement may seem irrelevant to the topic of coronary bifurcation lesions, and to medical writing in general, because we are in the era of “evidencebased medicine” and written medical literature need to be supported by “evidence” and not merely reflect opinions and anecdotal experience. In reality, however, what is occasionally offered as “evidence” does not qualify as an undisputable guide for clinical or technical decision making. There is no topic in Interventional Cardiovascular Medicine where this “disconnect” is more relevant than that of interventional treatment of coronary bifurcation lesions. The narrative that has been propagated in the literature is that provisional stenting (stenting the main vessel, with additional stenting of the side branch only in the case of an unsatisfactory result) is better than elective double stenting of both branches. This narrative states no exceptions to the rule, as it applies to all patients with coronary bifurcation lesions irrespective of bifurcation anatomy. Advocates of this narrative base their supposition on the results of several prospective randomized controlled trials. This narrative, however, overlooks fundamental problems in the design of these clinical trials, which makes its generalizability to all patients with coronary bifurcation lesions problematic. The goal of this book is to present the reader with a patient-centered approach to technical decision making in the interventional treatment of coronary bifurcation lesions. In doing so, we relied on evidence when it was of high quality and relevant, and we relied on experts’ opinion and judgment when high-quality evidence was lacking. The first section of the book is devoted to the fundamentals of decision making with regard to interpretation of the existing evidence (chapter 1) and understanding the role of bifurcation anatomy in impacting technique choice and outcomes (chapter 2). The subsequent chapters are devoted to technical decision making with regard to tailoring technical approaches to bifurcation anatomy for patients with left main and non–left main coronary bifurcation lesions. A particular emphasis is placed on providing practical tips and tricks to optimize the results and deal with complications, all in the context of actual case presentations. The last section of the book is devoted to the role of in vitro bifurcation modeling and the current state of dedicated bifurcation stent systems. Ultimately, we hope that this book will be a useful resource for interventional cardiologists who thrive to treat their patients as unique individuals who may not fit the profile represented in a given randomized clinical trial. Technical decision making in these patients requires individualized judgment, utilizing pragmatic interpretation of the evidence and applying techniques tailored to the individual patient. Issam D. Moussa, MD Antonio Colombo, MD

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Contents

Foreword Morton J. Kern . . . . v Preface . . . . vii Contributors . . . . xi Section 1. Coronary Artery Bifurcation Lesions: The Fundamentals 1. Coronary Artery Bifurcation Interventions: Bridging the Gap Between Research and Practice 1

Issam D. Moussa and Antonio Colombo 2. Coronary Artery Bifurcation Lesions: Anatomy 101

14

Ricardo A. Costa, Hiroyuki Kyono, Marco Costa, Mary E. Russell, and Issam D. Moussa Section 2. Non–Left Main Coronary Artery Bifurcation Interventions 3. Provisional Stenting Technique for Non–Left Main Coronary Bifurcation Lesions: Patient Selection and Technique 48

Remo Albiero and Emiliano Boldi 4. Physiologic Guidance of Provisional Stenting in Coronary Bifurcation Lesions

67

Michael J. Lim and Bon-Kwon Koo 5. Elective Double Stenting for Non–Left Main Coronary Artery Bifurcation Lesions: Patient Selection and Technique 83

Luca Favero, Andrea Pacchioni, and Bernhard Reimers Section 3. Left Main Coronary Artery Bifurcation Interventions 6. Coronary Revascularization for Patients with Unprotected Left Main Coronary Artery Disease: Making Clinical Decisions in the Absence of Definitive Evidence 116

Issam D. Moussa and Ted Feldman 7. Provisional Stenting for Left Main Coronary Artery Bifurcation Lesions: Patient Selection and Technique 134

Seung-Jung Park and Young-Hak Kim 8. Elective Double Stenting for Left Main Coronary Artery Bifurcation Lesions: Patient Selection and Technique 149

Azeem Latib, Alaide Chieffo, and Antonio Colombo

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Contents

x

Section 4. Coronary Bifurcation Interventions: Bench Testing and Dedicated Bifurcation Stents 9. Bench Testing of Coronary Bifurcation Stenting Techniques: How Is It Done? Does It Help Technical Decision Making? 193

Yoshinobu Murasato 10. Current Status and Future of Dedicated Bifurcation Stent Systems

Azeem Latib, Giuseppe M. Sangiorgi, and Antonio Colombo Index . . . . 251

211

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Contributors

Remo Albiero Cath Lab, Clinica San Rocco di Franciacorta, Ome (Brescia), Italy Emiliano Boldi Cath Lab, Clinica San Rocco di Franciacorta, Ome (Brescia), Italy Alaide Chieffo Interventional Cardiology Unit, San Raffaele Scientific Institute, and Interventional Cardiology Unit, EMO-GVM Centro Cuore Columbus, Milan, Italy Antonio Colombo Interventional Cardiology Unit, San Raffaele Scientific Institute, and Interventional Cardiology Unit, EMO-GVM Centro Cuore Columbus, Milan, Italy Marco Costa Harrington-McLaughlin Heart and Vascular Institute, University Hospitals, Case Western Reserve University, Cleveland, Ohio, U.S.A. Ricardo A. Costa Instituto Dante Pazzanese de Cardiologia & Cardiovascular Research Center, S˜ao Paulo, Brazil Luca Favero Department of Cardiology, Mirano Hospital, Mirano, Italy Ted Feldman Cardiac Catheterization Laboratory, Cardiology Division, Evanston Hospital, Evanston, Illinois, U.S.A. Young-Hak Kim South Korea

University of Ulsan College of Medicine, Asan Medical Center, Seoul,

Bon-Kwon Koo Seoul National University Hospital, Seoul, South Korea Hiroyuki Kyono Harrington-McLaughlin Heart and Vascular Institute, University Hospitals, Case Western Reserve University, Cleveland, Ohio, U.S.A. Azeem Latib Interventional Cardiology Unit, San Raffaele Scientific Institute, and Interventional Cardiology Unit, EMO-GVM Centro Cuore Columbus, Milan, Italy Michael J. Lim

Saint Louis University, St. Louis, Missouri, U.S.A.

Issam D. Moussa Cardiac Catheterization Laboratory, New York Presbyterian Hospital–Weill Medical College of Cornell University, New York, New York, U.S.A. Yoshinobu Murasato Department of Cardiovascular Medicine, Heart Center, New Yukuhashi Hospital, Yukuhashi, Japan Andrea Pacchioni Department of Cardiology, Mirano Hospital, Mirano, Italy Seung-Jung Park University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea Bernhard Reimers

Department of Cardiology, Mirano Hospital, Mirano, Italy

Mary E. Russell Ascent Translational Sciences, Inc., Carlisle, Massachusetts, U.S.A. Giuseppe M. Sangiorgi Interventional Cardiology Unit, San Raffaele Scientific Institute, and International Cardiology Unit, EMO-GVM Centro Cuore Columbus, Milan, Italy

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Coronary Artery Bifurcation Interventions: Bridging the Gap Between Research and Practice Issam D. Moussa Cardiac Catheterization Laboratory, New York Presbyterian Hospital–Weill Medical College of Cornell University, New York, New York, U.S.A.

Antonio Colombo Interventional Cardiology Unit, San Raffaele Scientific Institute, and Interventional Cardiology Unit, EMO-GVM Centro Cuore Columbus, Milan, Italy

INTRODUCTION The mark of mediocrity in written material, whether it is literature, politics, or medicine, is to rely heavily on precedents; so whatever is previously written about a certain topic gets written again, propagating the same narratives over and over. Of course, this statement may initially seem irrelevant to our topic, and to medical writing in general, because we are in the era of “evidence-based medicine” and written medical literature need to be supported by “evidence” and not merely reflect opinions and anecdotal experience. In reality, however, what is occasionally presented as “evidence” does not qualify as an undisputable guide for clinical or technical decision making. There is no topic in interventional Cardiovascular Medicine where this “disconnect” is more relevant than that of interventional treatment of coronary bifurcation lesions. The narrative that has been propagated in the literature is that provisional stenting (PS) [stenting the main vessel (MV), with additional stenting of the side branch (SB) only in the case of an unsatisfactory result] is better than elective double stenting (EDS) of both branches. This narrative declares no exceptions to the rule and some perceive it as if it applies to “all” patients with coronary bifurcation lesions. Proponents of this narrative base their conclusion on the results of several retrospective registries (1–7) and randomized controlled trials (RCTs) (8–12). The purpose of this chapter is to present a counter perspective to this dominant narrative; namely, that neither approach should be the default strategy in all patients with bifurcation lesions and that a decision as to which approach to use should be based on the patient’s bifurcation anatomy. The majority of patients with bifurcation lesions will have anatomy that can be safely treated with PS (see chap. 3); however, some patients have “at risk” bifurcation anatomy where PS may be associated with high risk of side branch occlusion (see chap. 2). In this chapter, we will I. Critically appraise the “evidence-base” with regard to PCI of bifurcation lesions: 1. Review the evidence-base 2. Discuss the questions that clinicians should ask of the evidence-base to make an informed decision: A. Does the design of the RCTs appropriately address the questions that need to be answered? B. Are the current bifurcation classifications reliable vehicles to tell us what we need to know about bifurcation anatomy? C. How do we apply the results of the RCTs to patient-centered decision making? II. Discuss the “cost” of inappropriate generalizabilty of the results of the RCTs to all patients III. Summary

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MOUSSA AND COLOMBO

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CRITICAL APPRAISAL OF THE EVIDENCE-BASE Review of the Evidence-Base

Retrospective Studies Over the last decade, numerous retrospective studies compared PS with EDS using bare metal stents (BMS) and drug-eluting stents (DES) (1–7). Although a detailed discussion on this topic is beyond the scope of this chapter, all these studies were limited by the systematic bias, favoring the use of PS in less complex bifurcations and EDS in more complex bifurcations. This bias rendered the findings of these studies, namely, lower restenosis and thrombosis with PS, misleading. Despite the obvious limitations of these studies, the debate concerning the role of PS versus EDS has been errounously framed in a manner that ignores the importance of the specific bifurcation anatomy in determining technique choice. RCTs of PS Vs. EDS The conclusions of the above retrospective studies shaped the underlying hypothesis of the subsequent RCTs (8–12). The basic hypothesis was that one technique is better than the other technique in all patients with bifurcation lesions. This chapter addresses the largest RCTs that have been published in peer-reviewed journals, namely, the NORDIC, BBK, and CACATUS trials (10–12). As shown in Tables 1 and 2, these trials demonstrated the following:

r

There is no statistical difference between PS and EDS in main vessel (MV) restenosis or target vessel revascualrization (TVR).

Table 1

Clinical and Angiographic Outcomes in the RCTs of EDS Vs. PS NORDIC Elective (N = 206)

Clinical outcome Death (%) Nonfatal MI (%) Q-wave Non–Q-wave TVR (%) Any MACE (%) Stent thrombosis (%)

Table 2

Provisional (N = 207)

Elective (N = 101)

6 mo 1.5 0.5 0.5 18 1.9 3.4 0.0

Angiographic outcome Restenosis (%) MV SB

BBK Provisional (N = 101)

Elective (N = 177)

1 yr 1 0.0 0.0 8 1.9 2.9 0.5

1 2 NA NA 8.9 11.9 2

8 mo 5.1 11.5

CACTUS

6 mo 2 1 NA NA 10.9 12.9 1

0.0 10.7 1.7 9.0 7.3 15.8 1.7

0.5 8.6 1.1 7.4 6.3 15.0 1.1

9 mo 4.6 19.2

3.1 10.4

Provisional (N = 173)

6 mo 7.3 5.2

4.6 13.2

6.7 14.7

Procedural Details: RCTs of ES Vs. PS NORDIC

Cross over (%) Final kissing (%) Contrast volume (mL) Procedure time (min) Fluoroscopy time (min)

BBK

CACTUS

Elective (N = 206)

Provisional (N = 207)

Elective (N = 101)

Provisional (N = 101)

Elective (N = 177)

Provisional (N = 173)

5 74 283 + 117 76 + 40 21 + 10

4 32 233 + 93 62 + 51 15 + 9

3 100 203 + 109 51 + 23 15 + 9

18.8 100 204 + 86 56 + 25 13 + 7

1 92 NA NA NA

31 90 NA NA NA

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There is no statistical difference between PS and EDS in SB restenosis or TVR (10) [although in the NORDIC trial there was a trend towards higher SB restenosis in the PS arm (19% vs. 11%; p =0.06)]. There is no statistical difference between PS and EDS in stent thrombosis. The NORDIC trial showed increased procedure time and contrast use with EDS compared to PS (10), while other trials did not (11,12). The NORDIC trial showed higher rate of postprocedure cardiac biomarker elevation in the EDS arm but showed no difference in MI at follow-up (10).

These RCTs confirmed that the conclusions drawn from the retrospective studies—namely, that a one stent approach is associated with lower restenosis and thrombosis—are erroneous. Nonetheless, one can fairly propose that although both approaches are equally safe and effective, PS stenting should be the preferred startegy in patients with bifurcation lesions because it is simpler than EDS and uses less resources. Indeed, these were the conclusions made by the authors of the NORDIC study. So, are these conclusions consistent with the application of evidence-based medicine? We propose that they are not! Questions Clinicians Should Ask of the Evidence-Base to Make an Informed Decision? The application of evidence-based medicine findings to clinical practice does not imply the literal adaptation of the conclusions of a given study(s). Evidence-based medicine should be a dynamic process of intelligent decision making that involves critical appraisal of the “evidence” before adapting its results to treat patients. The disconnect between clinical research methodology and patient-centered decision making is undeniable and may even be unavoidable given the logistical difficulty and potential monetary cost involved if we attempt to tackle the complex clinical/technical questions facing the practice of Interventional Cardiology. As caregivers we should always aim to understand the reasons for this disconnect, how to narrow the gap in future evidence collection, and above all how to make sound clinical/technical decisions in the absence of absolute certainty. In that regard, the following are key questions that we need to ask of the RCTs before using them as basis for decision making regarding the treatment of coronary bifurcation lesions.

Does the Design of the RCTs Appropriately Address the Questions that Need to be Answered? The answer is absolutely not. The hypothesis underpinning the design of the RCTs was determined in isolation from clinical reality. The most effective approach to rationalize this answer is to compare the hypothesis underlying the relevant RCTs to the question(s) a physician would ask before making a decision on how to treat a bifurcation lesion: 1. What is the hypothesis underlying the design of the relevant RCTs? The hypothesis of these clinical trials states that one technique should be the preferred, compared to other technique(s), approach in all patients with bifurcation lesions? So what is wrong with this hypothesis? This hypothesis is disconnected from the clinical reality in that no physician would use EDS in all patients with bifurcation lesions but typically select this technique for more complex bifurcations. This hypothesis does not specify “which” bifurcations to be evaluated with the assumption that all bifurcations should similarly respond to various techniques, irrespective of individual variations in SB lesion severity and bifurcation morphology. The study design based on this hypothesis would allow, for example, a patient with a bifurcation lesion 1,1,0 (no SB disease) to be a candidate for randomization. This patient may end up with EDS, even though in clinical practice no rational physician would elect to use EDS in the absence of SB disease. This is just a simple example that illustrate the over simplistic study design underlying some of these clinical trials. 2. What are the question(s) a physician would ask before making a decision how to treat a bifurcation lesion? When a physician is planning to treat an individual patient with a bifurcation lesion, he or she would determine the various anatomic attributes of the bifurcation before deciding which technique to use: (a) How large is the SB (diameter, vessel length, and myocardial territory supplied)? (b) Is the SB ostium diseased? If yes, what is the severity and length of the lesion?

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MOUSSA AND COLOMBO

4

Medina Duke (modified)

D

C

F

G

A

B

E

Sanborn

I

-

-

III

IV

II

IV

Lefevre

1

2

-

4

3

4a

4b

Safian

IA

IB

IIA

IIIA

IIB

IIIB

IV

Movahed

L

S

2

1m

1s

V

T

Staico-Feres

3

2A

2B

2C

1A

1B

1C

Figure 1 Coronary bifurcation classifications.

(c) (d) (e) (f)

Is there severe disease in the SB beyond the ostium? What is the angle of the SB takeoff? Is it difficult to wire/rewire? What is the severity and distribution of the MV lesion? What will happen to the SB after stenting (mild or significant compromise or occlusion)? And what are the consequences of SB occlusion (depend on the territory supplied)? The answer to these questions would determine whether an operator uses PS or EDS (this topic will be extensively covered in the forthcoming chapters). The above discussion clarifying the gap between the design of the RCTs and the process of patient-centered decision making clearly illustrates that the available evidence-base is not sufficient to fill the current knowledge gap. Clinical research can only answer the questions that we pose to it. If we pose the wrong questions we cannot expect to get the right answers!

Are the Current Bifurcation Classifications Schemes Reliable Vehicles to Tell Us What We Need to Know About Bifurcation Anatomy? Unlike non-bifurcation lesions that can be fairly characterized by reference vessel diameter and lesion length, coronary bifurcations have complex anatomic attributes both in the MV and the SB that do not lend itself to simple classifications (see chap. 2). There have been multiple bifurcation classification schemes in an attempt to standardize reporting and guide PCI technique selection (Fig. 1). The most recent and widely used classification is the Medina classification (Fig. 2) (13).

1,1,1

1,1,0

1,0,1

0,1,1

1,0,0

0,0,1

0,1,0 0,1

MV (Distal)

, MV (Proximal)

, SB

0,1 0,1

Figure 2 Medina classification. The Medina classification divides the bifurcation lesion into three segments, the proximal MV, the distal MV, and the SB, and assign each segment a binary value (1, 0) according to the presence or absence of obstruction (DS > 50%). Source: Adapted from Ref. 13.

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Although the Medina classification is intuitive and much easier to remember, it has not added any descriptive elements beyond the other classifications (i.e., it continue to ignore the importance of the size of the SB, the severity and the length of the SB lesion, the SB angle, and the relationship between the SB ostial stenosis and the MV stenosis). A telling example of the limited ability of the Medina classification to provide an accurate anatomic description of bifurcations is found in Figure 3(A) and 3(B). It is clear from these figures that bifurcation lesions with similar Medina classification can significantly differ with regard to ostial SB lesion severity, ostial SB lesion length, SB angle, and most importantly SB size and its corresponding myocardial territory. These anatomic elements are critical to technique selection, procedural success, and the risk of SB occlusion, yet it is not reflected in any of the above classification. A recent classification was proposed by Movahed (14) to account for these elements, but this classification is difficult to remember and to use in everyday practice. The implications of this issue is that the current bifurcation classifications schemes are not reliable indicators of the complexity of bifurcations included in the RCTs, and therefore it can be fairly stated that the degree of bifurcation complexity in these trials remains a “black box”!

How Do We Apply the Results of the RCTs in the Context of Patient-Centered Decision Making? The most effective approach to provide guidance regarding the use of the results of the RCTs for decision making in individual patients is to simulate the process of technical decision making in patients with coronary bifurcation lesions. Patients in Figure 4(A) and 4(B) have ischemia producing coronary bifurcation lesions that require PCI. How would an interventionalist make a decision as to which technique to use in each of these patients? Currently, physicians prescribe to one of the two following distinct approaches: 1. One approach would advocate the literal application of the results of the RCTs choosing the methodology that was used in these trials (i.e., choose one technique to treat all patients). Hence, they would adapt universal PS for all patients with bifurcation lesions irrespective of the specifics of the anatomy of each bifurcation. The assumption being made is that all patients with bifurcation lesions were well represented in these trials, and therefore they would have similar outcome to the patients enrolled in these trials! 2. The second approach would advocate patient-centered decision making and therefore would not choose one technique to treat all patients with bifurcation lesions but rather match the technique to the individual bifurcation anatomy guided by the available data as well as by personal experience. The assumption being made is that the results of the RCTs cannot be generalized to all patients encountered in clinical practice, because patients with “complex” bifurcations were not well represented in these trials. These two divergent approaches illustrate the gap between the methodology and findings of clinical research as well as the dynamics of patient-centered decision making. Who is right? Is there anyone wrong? An approach that would satisfy both perspectives is to determine which patients are well represented in the RCTs and which patients are not. Surely, no one can argue for the application of the results of the RCTs in patients who were not well represented in these trials! For the purpose of this discussion, we will address the largest RCTs published in peerreviewed journals (NORDIC, BBK, and CACTUS) (10–12). The BBC trial will not be discussed because the angiographic and morphologic information are not yet available. As shown in Table 3, patients included in these RCTs had focal lesions of moderate severity in the SB ostium. This means that patients with long and/or severe stenoses in the ostial SB were largely excluded, although these anatomic variables were not prespecified as exclusion criteria. This may indicate a natural bias to exclude patients with “high-risk” bifurcation anatomy from randomization. Furthermore, no data were provided in these trials regarding other important anatomic features such as the myocardial territory supplied by the SB, the angle of the SB, and the presence or absence of distal SB disease. Therefore, when one contemplates how to apply the evidencebased knowledge derived from these RCTs to an individual patient, one should first ask the question whether the patient was well represented in these trials or not! For example, let us use this process for decision making for patients in Figure 4(A) and 4(B). It is clear that the patient in Figure 4(A) is representative of patients included in the above RCTs and therefore PS

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(B) Figure 3 Case examples illustrating the limitations of the Medina classification. (A) Coronary angiography in two different patients with Medina class 0,1,1 bifurcation lesions: (a) LCX/OM1 bifurcation lesion and (b) LAD/2nd diagonal bifurcation lesion. Note the difference in SB lesion length between the two patients. (B) Coronary angiography in two different patients with Medina class 1,0,1 bifurcation lesions: (a) LAD/2nd diagonal bifurcation lesion and (b) LCX/OM1 bifurcation lesion. Note the difference in SB size. It is clear from these examples that the Medina classification is not a sufficient descriptor of bifurcation anatomy.

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would be a safe and effective approach. On the other hand, patients in Figure 4(B) are not well represented in the RCTs, and PS may not be a safe and effective approach. WHAT IS THE COST OF INAPPROPRIATE GENERALIZABILITY OF THE RCTs TO ALL PATIENTS WITH BIFURCATION LESIONS? The primary reason why PCI of bifurcation lesions has been a challenge is the risk of SB occlusion (SBO) or compromise after treating the MV. Almost 25 years ago, Meier and colleagues (15) demonstrated that coronary angioplasty in coronary stenoses that involve a diseased SB results in SBO in 14% of patients. They also noted that CK-MB elevation (non–Q-wave MI in today’s terminology) occurred in 30% of these patients. These results were obtained in patients with small SBs because patients with large SBs were disqualified from undergoing PCI. These results were corroborated by Arora et al. (16) who evaluated 167 patients (181 bifurcations lesions) with SB occlusions during PCI of the MV. In this study, 14% of patients developed postprocedure myocardial infarction (MI) despite successful SB reopening in 16% of patients. Of course, one would be quick to note that antithrombotic therapy, PCI technology, and techniques have progressed so much that results are now much better. However, despite the significant aforementioned progress, SBO and/or compromise remains a problem particularly in patients with “at risk” bifurcations. In a study by Chaudhry et al. (17), 158 patients with bifurcation lesions with SBs ≥2 mm were treated with single stenting approach (MV stent). In this study, 16% of patients had SB compromise (TIMI flow <3 and/or ≥70% stenosis); SB compromise

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(A) Figure 4 Case examples demonstrating a wide range of bifurcation lesions to illustrate which lesions were, and which lesions were not, well represented in the RCTs of PS versus EDS. (A) Coronary angiography in the RAO cranial (a) and LAO cranial (b) projections, demonstrating two bifurcation lesions (proximal LAD/1st diagonal branch and mid-LAD/2nd diagonal branch), which are representative of bifurcation lesions included in the RCTs. Note that both bifurcation lesions have only moderate and focal stenosis in the SB ostium. (B) Case examples of bifurcation lesions that were not well represented in the RCTs: (a) LCX/large OM1 bifurcation lesion with subocclusive stenosis in both branches, (b) proximal LAD/large diagonal branch bifurcation lesion with aneurysmal dilatation at the SB ostium, (c) proximal LAD/large diagonal branch bifurcation lesion with focal but severe stenosis at the SB ostium, (d) Proximal LAD/very large diagonal branch bifurcation lesion with focal but severely stenosed and angulated SB, and (e) proximal LAD/diagonal branch bifurcation lesion with focal ostial SB lesion but with a 90-degree takeoff angle. (Continued on page 8 )

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Quantitative Angiographic Measurements: RCTs of ES Vs. PS NORDIC Elective (N = 206)

Main vessel Reference (mm) Lesion length (mm) Diameter stenosis (%) Side branch Reference (mm) Lesion length (mm) Diameter stenosis (%) Bifurcation morphology True bifurcations No SB disease Bifurcation angle

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CACTUS

Provisional (N = 207)

Elective (N = 101)

Provisional (N = 101)

Elective (N = 177)

Provisional (N = 173)

3.3 ± 0.41 7.5 ± 7.5 50 ± 25

3.3 ± 0.41 8 ± 8.3 52 ± 24

3.08 ± 0.40 21.7 ± 7.5 54.9 ± 24.3

3.08 ± 0.38 20.9 ± 8.2 54.9 ± 24.3

2.85 ± 0.33 15.8 ± 8.7 68 ± 12

2.74 ± 0.35 14.7 ± 8.2 69 ± 12

2.6 ± 0.3 6.4 ± 4.7 47 ± 26

2.6 ± 0.4 6.0 ± 4.8 46 ± 2

2.39 ± 0.31 10.4 ± 4.1 53.1 ± 23.5

2.38 ± 0.37 9.9 ± 4.2 54.4 ± 22.3

2.3 ± 0.31 5.9 ± 4.7 63 ± 12

2.16 ± 0.33 5.7 ± 4.2 61 ± 13

NA NA <70

75% 25% 48–50

94% 6% NA

was associated with large periprocedural MI (15% vs. 1.1%; p = 0.02). The rate of MI after SBO depends on the size of the myocardial territory supplied by the SB and the definition of MI, hence the wide variability in the reported rate of procedural MI after SBO (7–27%) (17–20). Furthermore, the concept of “threatened” SB morphologies is important because the incidence of SBO varies widely accordingly to varying morphologies that are also not reflected in the Medina classification (18,21). In the study by Aliabadi and colleagues (18), SBO occurred in 7.9% of patients without threatened SB morphology versus 80% of patients with threatened SB morphology [Fig. 5(A) and 5(B)]. The fact that the rate of SBO in the PS arms of the RCTs (10–12) was very low could mean one of two things: either that the operators, technology, and techniques have improved so much that the concept of “at risk” bifurcations have become irrelevant and does not impact SB occlusion rates or that the patients with “at risk” bifurcations were not well represented in these trials. We propose the latter possibility. In fact, a recent study by Gil et al. (22) have shown a functional occlusion rate of 17% in consecutive patients treated with PS despite the fact that only one-third of the study population had true bifurcations. Therefore, we think that PS should not be the default strategy in “at risk” bifurcations that involve a large SB. A case in point is the patient in Figure 6. This patient has a proximal LAD bifurcation lesion involving a moderate size diagonal branch. Provisional stenting of this lesion was adopted, although this patient does not fit the profile of those patients enrolled in the RCTs (SB with severe ostial lesion and approximately a 90-degree angulation). Despite a jailed wire technique, the SB occluded after deploying the MV stent and the operator was not able to salvage it despite prolonged attempts with several wires. The patient suffered an STEMI. In hindsight, did the evidence-base apply to this patient? The answer is no. SUMMARY The currently available evidence-base pertaining to treatment of bifurcation lesions is not adequate to inform decision making in all patients with bifurcation lesions, hence a gap still exists between the evidence-base and patient-centered decision making. Although meta-analyses of the existing RCTs improve the statistical power of the data, they do not solve the problem of trial design (23,24). The reason for the gap between “evidence-base” and patient-centered decision making is that the research methodology used in the RCTs does not simulate the questions asked in practice. This position should not be construed to the effect that clinical research is destined to be disconnected from clinical practice, but it meant to emphasize that clinical research can only provide answers to the questions that we pose and within the framework we apply. Physicians

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(B) Figure 5 The concept of “threatened” SB morphologies. (A) (Left panel ) threatened SB morphologies characterized by SBs with >50% ostial narrowing, where the origin is completely spanned by either the diseased segment of the index lesion (1a) or arises adjacent to, but is partially contiguous with, the diseased index lesion (1b). (Right panel ) Nonthreatened SB morphologies includes four subtypes: SBs without (2a) or with ostial narrowing (2b) that were incidentally covered by stents that extended beyond the diseased segment of the index lesion; disease-free SB arising just adjacent to the diseased segment of the parent vessel (2c); SBs without ostial disease arising from parent vessel lesion spanning the entire origin of the SB (2d). (B) Comparison of the incidence of SBO based on threatened versus nonthreatened morphology. The incidence of SBO was significantly higher in threatened morphologies (80%) than in nonthreatened morphologies (7.9%). Source: Adapted from Ref. 18.

initiate their inquiry for solutions from the demands of the patient’s particular condition and not from the demand for generalizable knowledge, and their goal is just as specific: to treat the patient’s illness, not to test the therapy. To generate an evidence-base that can be used to guide decision making in patients with “complex bifurcation lesions,” a RCT should (a) include patients with complex “at risk” bifurcations, that is, patients with true bifurcation lesions involving moderate-to-large side branches with severe SB ostial stenosis (not 50–60% stenosis) and/or complex bifurcation angles; (b) utilize a randomization strategy that simulate clinical practice, that is, on one hand, all patients will be allocated to PS; on the other hand, the operator will triage patients to PS or EDS based on predefined anatomic criteria. (c) Operators participating in these trials should possess familiarity and skills in performing a variety of double stenting techniques. Surely, this would be a complex trial design, but so is clinical decision making! Until such a RCT is performed, clinicians should individualize decision making based on the particulars of patient’s bifurcation anatomy.

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(D) Figure 6 Coronary angiography in RAO cranial (A) and LAO cranial (B) projections, illustrating a midLAD/diagonal bifurcation lesion (0,1,1). Note the severity and length of the SB ostial lesion; (C) a 3.0 mm × 28 mm DES deployed in the mid-LAD with a jailed wire in the diagonal branch; (D) coronary angiography in the RAO cranial projection poststent deployment demonstrating compromised flow in the diagonal branch (with chest pain and ST elevation); (E) failure to re-wire the diagonal branch after using multiple wires over 20 minutes; (F) diagonal branch occlusion (with chest pain and ST elevation); (G, H) five-month follow-up coronary angiography in RAO cranial (G) and LAO cranial (H) projections, illustrating persistent occlusion of the diagonal branch. (Continued on page 12 )

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REFERENCES 1. Yamashita T, Nishida T, Adamian MG, et al. Bifurcation lesions: two stents versus one stent: immediate and follow-up results. J Am Coll Cardiol 2000; 35:1145–1151. 2. Al Suwaidi J, Berger PB, Rihal CS, et al. Immediate and long-term outcome of intracoronary stent implantation for true bifurcation lesions. J Am Coll Cardiol 2000; 35(4):929–936. 3. Lefevre T, Louvard Y, Morice MC, et al. Stenting of bifurcation lesions: classification, treatments, and results. Catheter Cardiovasc Interv 2000; 49(3):274–283. 4. Al Suwaidi J, Yeh W, Cohen HA, et al. Immediate and one-year outcome in patients with coronary bifurcation lesions in the modern era (NHLBI dynamic registry). Am J Cardiol 2001; 87:1139–1144. 5. Cervinka P, Stasek J, Pleskot M, et al. Treatment of coronary bifurcation lesions by stent implantation only in parent vessel and angioplasty in side branch: immediate and long-term outcome. J Invasive Cardiol 2002; 14(12):735–740. 6. Assali AR, Teplitsky I, Hasdai D, et al. Coronary bifurcation lesions: to stent one branch or both? J Invasive Cardiol 2004; 16(9):447–450. 7. Costa RA, Moussa I. Percutaneous treatment of coronary bifurcation lesions in the era of drug-eluting stents. Minerva Cardioangiol 2006; 54(5):577–589. 8. Pan M, de Lezo JS, Medina A, et al. Rapamycin-eluting stents for the treatment of bifurcated coronary lesions: a randomized comparison of a simple versus complex strategy. Am Heart J 2004; 148:857–864. 9. Colombo A, Moses JW, Morice MC, et al. Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions. Circulation 2004; 109:1244 –1249. 10. Steigen TK, Maeng M, Wiseth R, et al. Randomized study on simple versus complex stenting of coronary artery bifurcation lesions: the Nordic bifurcation study. Circulation 2006; 114:1955–1961. 11. Ferenc M, Gick M, Kienzle RP, et al. Randomized trial on routine vs. provisional T-stenting in the treatment of de novo coronary bifurcation lesions. Eur Heart J 2008; 29:2859–2867. 12. Colombo A, Bramucci E, Sacc`a S, et al. Randomized study of the crush technique versus provisional side-branch stenting in true coronary bifurcations. The CACTUS (Coronary Bifurcations: Application of the Crushing Technique Using Sirolimus-Eluting Stents) study. Circulation 2009; 119:71–78. 13. Medina A, Suarez de Lezo J, Pan M. A new classification of coronary bifurcation lesions. Rev Esp Cardiol 2006; 59(2):183. 14. Movahed MR. Coronary artery bifurcation lesion classifications, interventional techniques, and clinical outcome. Expert Rev Cardiovasc Ther 2008; 6(2):261–274. 15. Meier B, Gruentzig AR, King SB, et al. Risk of side branch occlusion during coronary angioplasty. Am J Cardiol 1984; 53(1):10–14. 16. Arora RR, Raymond RE, Dimas AP, et al. Side branch occlusion during coronary angioplasty: incidence, angiographic characteristics, and outcome. Cathet Cardiovasc Diagn 1989; 18(4):210–212. 17. Chaudhry EC, Dauerman KP, Sarnoski CL, et al. Percutaneous coronary intervention for major bifurcation lesions using the simple approach: risk of myocardial infarction. J Thromb Thrombolysis 2007; 24(1):7–13. 18. Aliabadi D, Tilli FV, Bowers TR, et al. Incidence and angiographic predictors of side branch occlusion following high-pressure intracoronary stenting. Am J Cardiol 1997; 80:994–997. 19. Bhargava B, Waksman R, Lansky AJ, et al. Clinical outcomes of compromised side branch (stent jail) after coronary stenting with the NIR stent. Cathet Cardiovasc Intervent 2001; 54:295–300. 20. Paez L, Moreno R, Alcocer A, et al. Side branch occlusion during direct stent implantation. Incidence and related factors. Arch Cardiol Mex 2005; 75(3):252–259. 21. Furukawa E, Hibi K, Kosuge M, et al. Intravascular ultrasound predictors of side branch occlusion in bifurcation lesions after percutaneous coronary intervention. Circ J 2005; 69(3):325–330. 22. Gil RJ, Vassilev D, Formuszewicz R, et al. The Carina angle—new geometrical parameter associated with periprocedural side branch compromise and the long-term results in coronary bifurcation lesions with main vessel stenting only. J Interv Cardiol 2009; 22(6):E1–E10. Epub 2009 Aug 20. 23. Niccoli G, Ferrante G, Porto I, et al. Coronary bifurcation lesions: to stent one branch or both? A meta-analysis of patients treated with drug eluting stents. Int J Cardiol 2010; 139(1):80–91. Epub 2008 Nov 22. 24. Zhang F, Dong L, Ge J. Simple versus complex stenting strategy for coronary artery bifurcation lesions in the drug-eluting stent era: a meta-analysis of randomised trials [published online ahead of print July 29, 2009]. Heart 2009; 95(20):1676–1681.

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Coronary Artery Bifurcation Lesions: Anatomy 101 Ricardo A. Costa Instituto Dante Pazzanese de Cardiologia & Cardiovascular Research Center, S˜ao Paulo, Brazil

Hiroyuki Kyono and Marco Costa Harrington-McLaughlin Heart and Vascular Institute, University Hospitals, Case Western Reserve University, Cleveland, Ohio, U.S.A.

Mary E. Russell Ascent Translational Sciences, Inc., Carlisle, Massachusetts, U.S.A.

Issam D. Moussa Cardiac Catheterization Laboratory, New York Presbyterian Hospital–Weill Medical College of Cornell University, New York, New York, U.S.A.

INTRODUCTION PCI in coronary bifurcation lesions continue to be a focus of debate and interest because of its complexity with respect to obtaining an optimal result in the main vessel (MV) while maintaining adequate patency of the side branch (SB). This procedural complexity is responsible for the fact that bifurcation PCI is associated with higher incidence of procedural complications and worse clinical outcomes compared with non-bifurcation PCI. Even though several technical approaches have been advocated for bifurcation PCI, the risk of SB compromise is still a major concern that drives new innovations and new techniques in this space. Although angiographic SB compromise is not always hemodynamically significant when assessed physiologically (1), it can result in periprocedural myocardial infarction. The causes and consequences of SB compromise during bifurcation PCI depend on well-defined bifurcation anatomic characteristics (2–6), size of the territory supplied by the SB, and the physiologic severity of the flow compromise in the SB. Therefore, defining and understanding bifurcation anatomy is critical for the success of any bifurcation PCI strategy. This chapter reviews the following:

r r r r

Defining coronary bifurcation anatomy Bifurcation classification schemes: advantages and limitations The bifurcation anatomic features that affect the frequency and severity of SB compromise Novel imaging modalities of coronary bifurcations

DEFINING CORONARY BIFURCATION ANATOMY What is a Coronary Bifurcation Lesion? A coronary bifurcation encompasses three distinct anatomical segments: proximal MV (including the bifurcation carina), distal MV, and SB [Fig. 1(A)]. The bifurcation carina (or MV-SB “transition zone”) is considered to be the core of the coronary bifurcation anatomy and is delimited proximally by the inflection point of the MV and SB and distally by the takeoff of both distal branches. In general, each coronary bifurcation presents with an unique anatomy represented by (a) conical shape connecting proximal and distal segments; (b) different vessel diameters at each segment location, that is, larger proximal MV reference diameter compared with smaller reference diameter in distal branches; (c) negative remodeling at the SB ostium; (d) proximal to distal vessel diameter tapering; and (e) nonuniform geometrical distribution of

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(B) Figure 1 (A) Coronary bifurcation lesion (LAD/Diagonal). (B) (See color insert ) Representative histologic images of coronary plaque in a bifurcation lesion. (a) Longitudinal section of trifurcation (left main/LAD/Ramus intermedicus/CX). There are atherosclerotic plaques in the lateral wall, while the flow divider regions are spared (b). (c) Longitudinal section taken in the region of LCM/left obtuse marginal bifurcation. Note, severe luminal narrowing located at, and proximal to, the bifurcation. Low shear regions show atherosclerotic plaque development including necrotic core formation whereas flow divider regions show minimal intimal thickening (d, e). Source: Adapted from Ref. 7. Courtesy of Virmani R et al. (C) (See color insert ) Three-dimensional reconstruction of the lumen (red) and outer vessel wall (green) of the left main coronary artery, left main bifurcation, left anterior descending coronary artery (LAD), and circumflex coronary artery (a). Detailed view of the left main bifurcation (white box) demonstrating the blood flow pattern in the lumen with an area (arrow ) of disturbed slow recirculating flow on the side of the LAD (b), where lower values of computed endothelial shear stress (c) and increased plaque thickness (d) are found. Source: Adapted from Ref. 9. (Continued on page 16 )

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atherosclerotic plaque that can involve one, two, or all three anatomical segments, sparing the flow divider [Fig. 1(B)] (7). Histopathological studies had demonstrated greater deposits of elastic tissue surrounding the SB ostium compared to other locations in the coronary tree, which could partially explain the elastic recoil and spasm frequently seen at this location. Coronary bifurcation lesions are typically defined by the presence of a stenosis of at least 50% within 3 mm of a bifurcation carina and may be found in every segment of the coronary tree with a side branch involved. Atherosclerotic plaques are usually localized in vascular regions with low wall shear stress. In coronary bifurcations, it has been shown that the outer wall is exposed to low wall shear stress compared to the flow divider, where high wall shear stress is present [Fig. 1(C)] (8,9). Ex Vivo Characterization of Coronary Bifurcation Lesions A study by Russell et al. (10) reported an ex vivo characterization of coronary bifurcation lesions, evaluating the intersections of coronary bifurcations by measuring vessel diameters, angles, and shapes at the SB ostium in human coronary arteries with a combination of a microscope (Smartscope MVP100) and computer program (Gage-X metrology software) specifically calibrated for video-based inspection and measurement (34-fold magnification). In this experiment, retrograde polymer injection was performed to create casts of the human coronary tree in 23 human adult cadavers to characterize the anatomy of the SB vessels relative to the MV. This experiment demonstrated a complex and asymmetric geometry at the MV-SB transition zone (carina) of the bifurcation. The major forms of asymmetry included curvilinear junctions, tapering diameters, and an elliptical SB takeoff rather than spherical or round forms [Fig. 2(A)]. This study demonstrated the following: 1. Vessel tapering is more pronounced in the SB compared to the MV (2.5-fold greater). The relative reduction in vessel diameter within the bifurcation length in the MV (proximal to distal) was 17% compared to 30% in the SB [Fig. 2(B]).

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Figure 2 (A) Schematic illustration demonstrating different segments and/or spots within the bifurcations (derived from Russell et al.): a, region defined as carina (or MV–SB transition zone), delimited proximally by the MV–SB inflexion and distally (laterally) by the take-off of both distal branches; b, proximal MV axis or centerline, used as landmark to assess proximal angle or “take-off” angle (between b and d); c, distal MV axis or centerline, used as landmark to assess distal angle or “carina” angle (c and d); d, SB axis or centerline, used as landmark to assess both “take-off” and “carina” angles; e, point where all axis or centerlines from the three segments of the bifurcation meet (“point of bifurcation”), landmark for assessing bifurcation angles (intersection angles); f and g, proximal and distal transition angles (“obtuse” angles), defined as the initial angle in the MV–SB transition zone as measured from the MV; h, SB “ostium” diameter (defined as the distance between the inflection points of the MV and SB on the proximal and distal sides; i, SB ostium diameter typically measured by QCA and IVUS. (B) Cast of a human coronary bifurcation demonstrating the location for vessel diameter measurement. Overall, the mean vessel diameters at proximal MV, distal MV, and SB were the following according to each myocardial territory— LMCA: 4.46 ± 0.97 mm, 2.91 ± 0.44 mm, and 2.81 ± 0.46 mm; LAD/Diagonal (1st major branch): 3.06 ± 0.40 mm, 2.47 ± 0.31 mm, and 2.10 ± 0.22 mm; for LCx/OM (1st major branch): 2.95 ± 0.51 mm, 2.46 ± 0.38 mm, and 2.07 ± 0.25 mm; for RCA-PDA/PLSA: 2.58 ± 0.48 mm, 2.21 ± 0.41 mm, and 1.79 ± 0.11 mm. SB ostium: 2.45 ± 0.71 mm, 2.36 ± 0.54 mm, and 2.17 ± 0.37 mm; for the LAD, LCX and RCA locations, respectively. (C) Location of transitional and intersection angles at coronary bifurcations. (D) Plots of measurements of transitional and intersection angles at coronary bifurcations. (E) SB ostium geometry. Source: Adapted from Ref. 10. (Continued on page 18 )

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2. Transition and intersection angles [Fig. 2(C)]: a. Transition angles: The proximal and distal “transition” angles in non-LMCA locations were obtuse (150.1 ± 21.2 degrees and 111.3 + 29.6 degrees, respectively) [Fig. 2(D)]. b. Intersection angles: The proximal and distal “intersection” angles in non-LMCA locations were 136.4 ± 22.0 degrees and 57.5 ± 24.7 degrees, respectively [Fig. 2(D)]. The distal intersection angle in the LMCA location (i.e., between LAD and LCX) was 68.5 ± 13.5 degrees. 3. The shape of the SB takeoff segment had a curvilinear geometry. Also, the SB ostium had an actual elliptical shape in the majority of cases rather than a spherical shape [Fig. 2(E)]. The Intersection Between Anatomy and Physiology in Coronary Bifurcation Lesions The physiological pattern of biological fluid diffusion through a branching system was addressed in the classical work by C.D. Murray (11). The following are Murray’s assumptions regarding connecting large vessels to small vessels: (a) the cube of the radius of a mother vessel (proximal MV) should equal the sum of the cubes of the radii of the daughter vessels (distal branches); (b) the total flow of the system is carried by a set of vessels whose radii cubed sum to a constant value;

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(c) under optimum physiological arrangement, flow is achieved with the least possible biological work; and (d) a maintenance energy term is required for the volume involved. Considering bifurcation lesions, Murray’s law is a function of the size of the proximal MV and the distal branches and is represented by the following formula: D13 = D23 + D33 (+ . . . + . . .), where D1 is the mother vessel, and D2 and D3 are the daughter vessels. Importantly, Murray’s relation was found to be applicable to both symmetrical and asymmetrical branching systems; also, there was no effect of lesion angulation (11,12). A study by Hutchins et al. (13) evaluated the usefulness of the Murray’s law in predicting geometrical relationships between MV and SB in 95 branch-points (LM = 42) in postmortem human coronary arteriograms. Overall, the results validated measured diameters according to Murray’s law in angiographically normal coronary arteries. More recently, a study by Finet et al. (14) investigated the bifurcational fractal geometry in 59 patients (173 bifurcations) with angiographically normal coronaries. In this seminal work, quantitative coronary angiography (QCA) analysis was performed with a dedicated software where each reference diameter was located in an arterial segment adjacent to the bifurcation (mother vessel and two daughter vessels). In addition, intravascular ultrasound (IVUS) of the LM bifurcation, LAD, and LCx was performed in 27 patients. The angles between the mother and major daughter vessel (proximal angle) and between the two daughter vessels (distal angle) were 156 ± 29 degrees and 60 ± 28 degrees, respectively. For each bifurcation, the ratio between the sum of the daughter-vessel diameters and the mother-vessel diameter was calculated (ratio = Dm/Dd1+Dd2, where Dm was the diameter of the mother vessel, and Dd1 and Dd2 were the respective diameters of the two daughter vessels). Overall (n = 173), mean diameters were 3.34 ± 0.95, 2.71 ± 0.77, and 2.24 ± 0.69 for Dm, Dd1, and Dd2, respectively, and the mean ratio was 0.68 ± 0.066. Importantly, this ratio was constant across every scale of observation (mother vessel diameters ranging between ≤2.5 and ≥4.5 mm), and the relative reduction between the mother- and major daughter-vessel diameters was around 19%. Several studies have validated Finet’s law; its applicability includes determination of actual vessel size (diameter) for the three segments of the bifurcation including the mother vessel and two daughter vessels—if two diameters are known, it is possible to derive the diameter of the third vessel by using the formula (given above) [Fig. 3(A) and 3(B)]. This may be helpful for sizing devices (balloon, stent), defining PCI strategy, and preventing complications such as coronary dissection and perforation. Impact of Cardiac Motion on Coronary Bifurcation Lesions Another important concept that has been largely overlooked with regard to coronary bifurcations is the fact that this coronary segment is subject to constant motion. The constant movement and dynamic changes in the relationship between the MV and the SB occur continuously during the cardiac cycle (15,16). Basically, each vessel is moving in different directions and at different time delays as the electrical activation of the heart progresses. During the cardiac cycle, coronary arteries follow the movement of their corresponding wall. For example, the LAD artery follows the anterior wall, whereas the diagonal branches follow the lateral wall movement. Thus, attrition would be maximized at the bifurcation carina, where bending and twisting occur repeatedly. These constant movements may become clinically relevant if the stent is deployed through the MV to the SB. In addition, these sustained long-term repetitive stresses may cause stent fracture or recoil or may cause excessive injury to the vessel wall. Theoretically, this may influence long-term outcomes in this lesion subset, particularly if rigid stents are anchored in the MV, but have to follow the 3D movement path of the distal SB. CLASSIFICATION SCHEMES OF CORONARY BIFURCATION LESIONS Historically, several bifurcation classification schemes have been proposed in an attempt to standardize reporting and guide decision making [Fig. 4(A)]. However, all of the existing classifications either ignored key anatomic elements, that are essential for accurate description of bifurcation lesions (SB ostium lesion severity and length, SB size and the myocardial territory it supplies, angulation, tortuosity, and calcification) or were difficult to use. Although the Medina classification distinguished itself because it is easier to use and remember, it still did not address

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(a)

(c)

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Proximal MV reference diameter

SB reference diameter

Distal MV reference diameter

(A)

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(a)

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(B) Figure 3 Murray’s and Finet laws. Once the vessel diameter is known for two segments of a bifurcation, it is possible to calculate the diameter of the third segment. (A) QCA-measured diameters at the proximal MV, distal MV, and SB. (B) IVUS measured diameters at the proximal MV, distal MV, and SB.

the deficiencies of previous classifications (17). The Medina classification divides the bifurcation lesion into three segments: the proximal MV, the distal MV, and the SB, and assign each segment a binary value (1, 0) according to the presence of absence of obstruction [Fig. 4(B)]. A lesion is designated as a “true bifurcation lesion” when both the MV and the SB have a >50% stenosis (Medina types: 1,1,1; 1,0,1; 0,1,1) [Fig. 4(C)]. Although the Movahed classification did address some of the deficiencies of prior classifications, it remains difficult to use (18). Therefore, although the existing bifurcation classifications provide a basic description of bifurcation anatomy, it does not provide sufficient anatomic information to standardize reporting in clinical trials or to guide technical decision making. This point is clearly illustrated

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Medina type 1,0,0

Medina type 1,0,1

Medina type 1,1,0

Medina type 0,1,1

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Medina type 0,0,1

(C) Figure 4 (A) Current coronary bifurcation classifications. (B) Medina classification. (C) Examples of coronary bifurcation lesions according to each type of the Medina classification.

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(A)

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Figure 5 “True” coronary bifurcation lesions involving the proximal LAD/Diagonal location. Note that all lesions (A,B,C) are classified as Medina type 1,1,1; however, with different complexity and outcome: A – bifurcation lesion with a severe focal stenosis involving the SB ostium successfully treated with provisional (SB) stenting approach (A1); B – bifurcation lesion with SB diffusely diseased unsuccessfully treated (SB occlusion) with provisional (SB) stenting approach (B1); C – bifurcation lesion with SB diffusely diseased successfully treated with double stenting technique (“mini-crush”), (C1).

in Figure 5 that shows bifurcation lesions that have similar Medina classification but clearly different levels of complexity that require different techniques to treat. What Are the Bifurcation Anatomic Characteristics That Affect the Frequency and Severity of SB Compromise? Historically, it has been suggested that SB compromise during PCI [Fig. 6(A)] is the result of snowplowing of plaque over the SB ostium or simply “plaque shift.” However, pathologic evaluation and IVUS studies have demonstrated that although atherosclerosis develops frequently at the bifurcation, it is often located opposite to the flow divider, that is, opposite the origin of the SB. This led to the proposition that SB compromise after MV stenting is due to “carina shift” rather than plaque shift. Nevertheless, some patients do have plaque accumulation at the SB ostium and these patients are at high risk for plaque shift [Fig. 6(B)] (6). Although angiographic SB compromise, even when it is >50% stenosis, is not always hemodynamically significant when assessed physiologically (1), it can result in periprocedural ischemia or myocardial infarction when there is compromised flow. In any event, irrespective of the mechanism that led to SB compromise in bifurcation PCI, there are several bifurcation anatomic features that affect the frequency and severity of this event. These features are not well represented in the current bifurcation classifications and are as follows.

SB Size and Its Correspondent Myocardial Territory Although the size of the SB and its correspondent myocardial territory are the most important factors that would determine the clinical consequences of SB compromise during bifurcation PCI, neither of these anatomic elements are represented in any of the coronary bifurcation classifications. Furthermore, the effect of the size of myocardial territory supplied by the SB on patient outcomes has been neither quantified nor considered in any of the studies addressing PCI of bifurcation lesions. Although the effect of SB vessel size on procedural and long-term outcome after bifurcation PCI is not as well defined as it relates to MV intervention, there are several studies that did address this issue. In general, the cutoff values for SB vessel diameters that determine inclusion or exclusion from a specific bifurcation study has been arbitrary chosen in both retrospective registries (19,20) and randomized controlled trials (RCTs) (Table 1) (21–26). Of note, regardless of the technical

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(B) Figure 6 (A)—(a) coronary bifurcation lesion with mild SB stenosis; (b) stent implantation in the MV; and (c) SB compromise after stent implantation in the MV. (B) An example of side branches that were occluded after angioplasty of the parent vessel in a patient with acute myocardial infarction. (a) A severe stenosis (arrowhead ) at the bifurcation of the middle segment of the left anterior descending artery (LAD) and the diagonal branch (Dx) is shown in a left anterior cranial view. (b) After deployment of a stent, the diagonal branch was occluded. (c and d) Preintervention intravascular ultrasound (IVUS) images showing diffuse plaque around the ostium of the Dx. Source: Adapted from Ref. 7.

83%

3%

18.8%

• Flow limiting dissection, and/or • Residual stenosis ≥75% If after KB, SB with: • <TIMI 3, and/or • >70% stenosis at ostium, and/or • Threatened vessel closure, and/or • Dissection more than type A

31.2%

• Residual stenosis ≥50%, and/or • Dissection type B or worse, and/or • TIMI flow ≤2

4.3%

• TIMI flow = 0, after SB dilatation

NA

NA

<50% final diameter stenosis in both branches

NA

NA

<50% final diameter stenosis in both branches

b

Lesion length criteria for each vessel of the bifurcation lesion. Defined as ≥50% diameter stenosis in both MV and SB. c Unpublished data. BBCONE = British Bifurcation Coronary Study: Old, New, and Evolving Strategies. Abbreviations: BBK, Bad Krozingen Bifurcation study; CACTUS, Coronary Bifurcations: Application of the Crushing Technique Using Sirolimus-Eluting Stents; DES, drug-eluting stents; KB, kissingballoon; MV, main vessel; NA, not available/reported; SB, side branch; TIMI, Thrombolysis in Myocardial Infarction.

a

Bifurcation lesions requiring treatment

68% (17)

94% (17)

2.1%

51.2%

• Severe persistent stenosis (>60%), and/or • major flow-limiting dissection

• Residual stenosis >50%

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50% stenosis of the MV and/or SB

True bifurcation lesionsb

NA

86% (16)

NA

Angiographic success criteria

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CACTUS (24)

Any bifurcation lesion type according to Lefevre ` classification (16)

Significant stenosis in both MV and SB originb (diffuse SB lesion was excluded)

True bifurcation lesionsb

Actual rate

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• • • • • • • • • • • • • • • •

De novo bifurcation lesions Non-left main location TIMI flow ≥1 Vessel size 2.5–3.5 mm Lesion length ≤24 mma De novo bifurcation lesions Non-left main location MV: ≥2.5 mm SB: ≥2.25 mm De novo bifurcation lesion LM location allowed in a right dominant system MV: ≥2.5 mm SB: ≥2.0 mm De novo bifurcation lesions Non-left main location TIMI flow ≥1 (in both branches) MV: 2.5–3.5 mm SB: 2.25–3.5 mm Lesion length ≤28 mma De novo bifurcation lesions Non-left main location MV: 2.5–4.0 mm SB: ≥2.25 mm De novo bifurcation lesions Non-left main location MV: ≥2.5 mm SB: ≥2.25 mm

Criteria for SB stenting if:

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Pan et al. (22)

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Lesion type

Cross-over (from single to double stenting)

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Angiographic Criteria in Randomized Clinical Trials with DES in Bifurcations

Randomized series with DES

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Figure 7 Relationship between reference vessel diameter and SB restenosis rates in DES bifurcation series.

approach in treatment of bifurcations, smaller SBs appear to have increased risk of restenosis, even with DES (Fig. 7). More importantly, SB diameter also affects the risk of SB occlusion during bifurcation PCI, where even smaller SBs may be clinically relevant (2–5). A study by Arora et al. (2) reported a series of 167 patients including 181 bifurcations lesions presenting with SB occlusions during PCI of the MV. In this analysis, all SBs with diameter >1.00 mm in non-LM location were included, while lesions where the SB was protected with a wire or was treated with PCI were excluded. In this study, 14% of patients developed postprocedure MI (new Q-wave MI and/or three times increase in total CPK with elevated MB fraction within 24 hours post-PTCA) despite successful SB reopening in 16% of patients. In a study by Chaudhry et al. (5), 158 patients with bifurcation lesions with SBs ≥2.00 mm were treated with single stenting approach (MV stent). In this study, 16% of patients had SB compromise (TIMI flow <3 and/or ≥70% stenosis); patients with SB compromise had smaller SBs compared with those without SB compromise (2.29 ± 0.34 mm vs. 2.54 ± 0.55 mm; p = 0.03). Importantly, SB compromise was associated with a large periprocedural MI (15% vs. 1.1%; p = 0.02; large AMI defined as CK-MB >5 times the upper normal limit). Independent predictors of SB “compromise” were eccentric lesion morphology in the MV (OR, 2.92; 95% CI, 1.11, 7.63; p = 0.03), smaller SB vessel diameter (OR, 0.21; 95% CI, 0.06, 0.77; p = 0.02), and SB% diameter stenosis (OR, 1.02; 95% CI, 1.00, 1.04; p = 0.047).

SB Lesion Severity and Length Although the Medina classification makes a distinction between SBs with > or <50% stenosis at the ostium, it does not represent the importance of the increasing severity of the ostial SB lesion nor it represents the importance of lesion length or the presence of more distal lesions in the SB. Although the presence of large plaque burden at the bifurcation can be associated with SB ostial deterioration or even occlusion after stent implantation in the MV, even in the absence of baseline SB ostium obstruction (19) the presence of ostial SB obstruction certainly increases this risk. Aliabadi et al. (4) categorized bifurcation lesions according to the degree of obstruction in the SB ostium into (a) SB with minimal or no disease, where the chance of SB occlusion was 1% to 4%; and (b) SB with ostial stenosis >50%, where the risk of SB occlusion was 14% to 27%. Furukawa et al. demonstrated that the risk of SB deterioration (final TIMI flow ≤2) during bifurcation PCI is significantly more common in SBs with an ostial stenosis ≥50% compared to an ostial stenosis <50% (20.8% vs. 6.1%; p = 0.049) and in longer lesions compared to shorter lesions (Fig. 8) (6). Furthermore, Chaudhry et al. (5) demonstrated that the risk for SB

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p=0.003 35.0% Risk of SB occlusion

8.2%

SB stenosis due to MV plaque

SB stenosis due to SB ostium plaque

Figure 8 Frequency of SB occlusion as a function of SB ostium involvement. Source: Adapted from Ref. 6.

compromise increases with increased SB ostial stenosis severity (for every 10% increase in SB stenosis severity, the risk of SB compromised increased by 23%) and calcification (46% vs. 26%; p = 0.06). Therefore, it becomes clear that the lack of representation of ostial SB lesion severity and the length in the existing classifications are major limitations to its utility in standardizing reporting and guiding decision making.

The Bifurcation Angle None of the existing bifurcation classifications reflect the importance of the bifurcation angle. Although several studies have reported on measurements of bifurcation angles (19,27,28), there has been no standardized method, which makes comparisons between published series futile. Lansky et al. (29) proposed a methodology for angle assessment in the Consensus Statement from the European Bifurcation Group. This report proposed measuring two angles: (i) the “take-off angle” (proximal angle) between the proximal MV and the SB and (ii) the “carina angle” (distal angle) between the distal MB and the SB; to consider the widest angle in the least foreshortened view [Fig. 9(A)]. The majority of QCA analysis software includes a “digital caliper” tool to analyze angles and the new dedicated bifurcation QCA software has integrated automated contour-detectors that can derive angle calculation. A study by Ramcharitar et al. (30) reports the point of bifurcation (POB), which is defined as the point where all the centerlines from the three segments of the bifurcation meet (at the core of the carina); the centerlines being the lines (or axis) through the middle of the vessel. Measurement of bifurcation angles utilizing the angulations between the axes or the centerlines of the proximal and distal segments of the bifurcation has been widely accepted. The angle between the SB and the MV affects the outcome of bifurcation PCI on various levels:

r r r

Risk of SB compromise after MV stenting. The technical ease or difficulty with which SB wiring and stent delivery can be accomplished. Appropriateness of coverage of the ostium SB and the extent of geometric deformation of the SB stent.

In general, a shallow distal angle between the SB and the MV may be associated with higher incidence of SB occlusion, especially if the SB ostium is severely diseased. However, a shallow angle allows easier access for SB wiring and stent delivery during PCI. On the other hand, a wider distal angle (closer to 90 degrees) may be associated with lower chances of SB occlusion, but it may make SB wiring and stent delivery more challenging. Bifurcation lesions have also been categorized on the basis of the distal angle measurement as Y-shaped (<70 degrees) [Fig. 9(B)] or T-shaped (>70 degrees) [Fig. 9(C)]. A study by Lef`evre et al. (19) suggested that Y-shaped lesions are associated with increased risk for periprocedural complications compared with T-shaped lesions, including more “snow-plow” effect. Also, it is more difficult to accurately position a stent at the SB ostium in Y-shaped bifurcations when

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Angle a

Angle b

LAD

Diagonal

LAD

Diagonal

(A)

(a)

(b)

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(B) Figure 9 (A) Two-dimensional angulations between the MV (LAD in this case) and the SB (Diagonal in this case). Angle a (left ) is the “take-off” angle between the proximal MV to the SB. Angle b (right ) is the “carina angle” between the distal MV and the SB. (B) Coronary bifurcation lesions with distal anglesmeasured 70 degrees: (a, b) proximal LAD/Diagonal bifurcation with distal angle measured 53 degrees; (c, d) LCx/OM bifurcation with “sharp” angle measured 35 degrees. (C) Coronary bifurcation lesions with distal angles >70 degrees: (a, b) proximal LAD/Diagonal bifurcation with obtuse “distal” angle measured 112 degrees; (c, d) mid-LAD/Diagonal bifurcation with distal angle measured 89 degrees. (Continued on page 28 )

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(C) Figure 9 (Continued)

T-stenting is used. In these bifurcations the operator is often required to allow the SB stent to protrude into the MV to ensure appropriate SB ostium coverage. This typically would not be an issue in T-shaped bifurcations where stent positioning can be ensured without significant protrusion into the MV. Although the bifurcation angle clearly affects the procedural performance of various double stenting techniques, its effect on clinical outcome need more study. Dzavik et al. (27) reported that a bifurcation angle more than 50 degrees is an independent predictor of major adverse cardiac event (MACE) in patients treated with a crush stent strategy. In this study, 133 patients treated with crush stenting at a single institution had angiographic assessment including measurement of the distal bifurcation angle. The mean distal bifurcation angle was 51.1 ± 15.3 degrees, and patients were divided into two groups on the basis of the median bifurcation angle (50 degrees). At one year, MACE-free survival was significantly lower in patients with wider angle (76.2% vs. 93.8%; p = 0.005), including a nonsignificant trend towards high TLR (12.3% vs. 3.1%; p = 0.096). In this study, only 90 of 133 cases underwent final kissing-balloon (FKB) inflation, and both FKB and distal angle ≥50 degrees were identified as significant independent predictors for MACE (HR, 0.22; 95% CI, 0.08–0.56; p = 0.002; and HR, 5.72; 95% CI, 1.83, 17.96; p = 0.003; respectively). Importantly, a significant association between bifurcation angle and FKB for the occurrence of MACE was found (p < 0.0001). Whether these results reflect the primary role of bifurcation angles in determining the outcome or other associated factors (such as FKB) is unclear, more studies are needed to settle this issue.

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IMAGING OF CORONARY BIFURCTION LESIONS Quantitative Coronary Angiography (QCA) Accurate analysis of coronary lesions is entirely dependent on the quality of the angiographic image acquisition including adequate projections to ensure optimal visualization. Previous studies have attempted to identify the most favorable viewing angles that provide optimal diagnostic value in terms of assessing stenosis severity, and minimizing vessel foreshortening and overlap (31). However, such studies did not include bifurcations. Angiographic assessment of coronary bifurcation lesions is often difficult and incomplete because of vessel overlap, limited (and inaccurate) visualization of the lesion (especially the SB ostium), and the requirement for multiple views. Current recommended views for optimal bifurcation lesion visualization are based on heuristic experience and have not been scientifically studied. Optimal visualization of the SB ostium remains the most critical issue with obvious implications for lesion complexity assessment and technical decision making, especially for stent positioning when using double stenting techniques, as relatively high incidence of incomplete SB ostium coverage has been reported, which has been also associated with restenosis at this location. As with non-bifurcation lesions when using angiography to image bifurcations one should choose the views with best visualization of the target lesion including the most orthogonal view of the SB ostium with particular attention to avoid vessel overlap and foreshortening. Current standard image acquisition protocol for angiographic analysis in non-bifurcated lesions require at least two orthogonal views >30 degrees apart. Although optimal visualization of the bifurcation carina and the SB ostium is sometimes achieved in one single projection, which may be found in nonstandard views, two or more projections are often required. Table 2 displays angiographic views commonly utilized for optimal visualization of bifurcation lesions [Fig. 10(A) to 10(I)]. Historically, QCA analysis of bifurcation lesions lacked standarized methodology, and several pitfalls were identified when standard QCA packages (designed for standard QCA analysis) were adopted for bifurcation analysis. The major challenge in performing QCA in bifurcations is to determine the reference diameter at all distinct locations within the bifurcation segment; incorrect reference determination will lead to either overestimation or underestimation of the stenosis severity. Inconsistencies in QCA methods and reporting (including not reporting the exact restenosis location) have occasionally precluded the understanding of the differences between bifurcation studies (Table 3). Although there were significant differences in baseline angiographic characteristics, which could partially explain differences in outcomes among trials such as Nordic vs. CACTUS (CACTUS included smaller vessels with more severe obstruction), it is clear that a standardized methodology was needed in order to allow consistent comparisons of bifurcations trials. The consensus panel of the European Bifurcation Group provides several recommendations for bifurcation imaging acquisition, analysis, and reporting (Table 4) (29). In this algorithm, the three segments of the bifurcation are independently analyzed including a predefined subsegmental analysis on the basis of the areas of interest depending on the technique and/or device used during PCI (Fig. 11). Because of vessel tapering in bifurcation lesions, pre-, post-, and follow-up MLD may vary according to location, thus creating systematic under- or overestimation. Therefore, MLD and percent diameter stenosis postprocedure and at follow-up should be calculated at each subsegment, and the interpolated reference diameter generated at each predefined area of interest should be used at each study point (final and follow-up). Importantly, in patients with restenosis, location of recurrence would be documented. Currently, there are two dedicated commercial softwares for bifurcation QCA analysis: the Medis Medical Imaging Systems bifurcation application (QAngio XA V 7.2, Leiden, the Netherlands) and the CAAS 5 (Pie Medical Bifurcation Imaging software, Maastricht, the Netherlands). Angiography-based three-dimensional (3-D) vessel reconstruction systems are another development that may enhance visualization of coronary vessel anatomy. In bifurcation lesions, 3-D reconstructed images reduce vessel overlap and provide accurate measurements of bifurcation angles and degree of SB ostial involvement (Fig. 12). A preliminary study by Dvir et al. reported a series of 18 patients with serial pre- and postprocedure 3-D reconstruction analysis of bifurcation lesions treated with PCI and stenting. In this study, the authors used the CardiOp-BTM 3-D reconstruction system (CardiOp-BTM , Paieon Medical Inc., Rosh Ha’ayin,

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Recommended Angiographic Projections for Optimize Viewing of Coronary Bifurcations

Target bifurcation

Location

Common views

Proximal

a. RAO 25–35◦ /Cranial 30–45◦ b. Cranial 35–45◦ c. LAO 25–35◦ /Cranial 30–45◦ for LAD/Diagonalis: d. LAO 30–45◦ /Caudal 30–45◦ e. RAO 20–30◦ /Caudal 20–40◦

Mid/distal

a. RAO 25–35◦ /Cranial 30–45◦ b. Cranial 35–45◦ c. LAO 25–35◦ /Cranial 30–45◦

Proximal

a. RAO 20–30◦ /Caudal 20–40◦ b. LAO 30–45◦ /Caudal 30–45◦ c. LAO 25–35◦ /Cranial 30–45◦

Mid

a. AP 0◦ b. RAO 20–30◦ /Caudal 20–40◦ c. LAO 30–45◦ /Caudal 30–45◦

Distal

a. AP 0◦ b. RAO 20–30◦ /Caudal 20–40◦ c. Cranial 35–45◦

Ramus

Proximal

a. RAO 20–30◦ /Caudal 20–40◦ b. LAO 30–45◦ /Caudal 30–45◦ c. LAO 25–35◦ /Cranial 30–45◦

RCA

Mid (i.e., RCA/AM)

a. LAO >30◦ b. Cranial 20–40◦ c. RAO 25–45◦

Distal (i.e., PDA/PLSA)

a. LAO 30–45◦ b. LAO 20–45◦ /Cranial 20–40◦ c. Cranial 20–40◦

Distal (i.e., LAD/LCx)

a. AP 0◦ b. RAO 20–30◦ /Caudal 20–40◦ c. LAO 30–45◦ /Caudal 30–45◦

LAD/Diagonal

LCx/OM

LM

Abbreviations: AM, acute marginal; AP, antero-posterior; LAD, left anterior descending; LAO, left anterior oblique; LCx, left circumflex; LM, left main; OM, obtuse marginal; PDA, postero descending artery; PLSA, postero-lateral side artery; RAO, right anterior oblique; RCA, right coronary artery.

Israel) (32). This study showed significant reduction in the distal bifurcation angle from preto postprocedure (71 ± 17 degrees vs. 58 ± 18 degrees; p < 0.001), primarily when double stenting techniques were used. A previous study also suggested that angle changes from preto post-stent implantation predict late adverse events (28). Reasons for this observation are not clear, and the existing data are insufficient to make any actionable recommendations in this regard. Although standardizing methods of reporting of angiographic analyses of bifurcation interventions and development of new angiography-based imaging systems are welcome developments, it is critically important to remember that angiography, at its best, is limited in terms of providing accurate anatomic information at baseline and postprocedure. Therefore, there should always be a healthy degree of skepticism regarding insights provided by angiography and aim to confirm these observations with other imaging modalities.

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(B) Figure 10 Series of orthogonal views demonstrating optimized views for coronary bifurcations at different locations: (A) Proximal LAD bifurcation: poorly visualized in a (RA0 23◦ /CAU 20◦ ) and b (LA0 35◦ /CAU 33◦ ); best visualization achieved in cranial views, c (RA0 10◦ /CRA 38◦ ) and d (LA0 35◦ /CR 35◦ ). (B) Proximal LAD/Diagonalis bifurcation: not optimal assessment of bifurcation lesion, angle and SB ostium in a (RA0 29◦ /CAU 22◦ ), b (RA0 13◦ /CAU 41◦ ), C (LA0 48◦ /CAU 30◦ ); best visualization achieved in d (LAO 8◦ /CAU 36◦ ) and e (LA0 43◦ /CAU 29◦ ). (Continued on pages 32–34)

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(b)

(c)

(d)

(C)

(a)

(b)

(c)

(d)

(D)

Figure 10 (Continued) (C) Mid-LAD bifurcation: SB ostium best assessed in a (RA0 3◦ /CRA 39◦ ) and b (LA0 43◦ /CRA 32◦ ); poorly assessed in c (RA0 24◦ /CAU 20◦ ) and d (LA0 28◦ /CAU 42◦ ). (D) Distal LAD bifurcation: poorly assessed in a (RA0 20◦ /CAU 16◦ ) and d (LA0 36◦ /CAU 39◦ ); lesion best visualized in b (RA0 2◦ /CAU 42◦ ) and d (LA0 34◦ /CRA 32◦ ).

c02

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Specs: 7x10 tight

(a)

(b)

(c)

(d)

7in×10in

Char Count=

(E)

(a)

(b)

(c)

(d)

(F)

Figure 10 (Continued) (E). Proximal LCx bifurcation: bifurcation and SB ostium not visualized in a (RA0 18◦ /CRA 43◦ ) and b (LAO 35◦ /CRA 37◦ ); best visualization in c (RA0 20◦ /CAU 25◦ ) and d (LA0 36◦ /CAU 31◦ ). (F) Ramus bifurcation: a-–bifurcation not visualized (LAO 36◦ /CAU 32◦ ); b-–best visualization of bifurcation lesion and SB ostium (RAO 25◦ /CAU 27◦ ). Distal LCx (i.e., OM) bifurcation: c-–bifurcation not visualized (LAO 50◦ /CAU 29◦ ); D-–best visualization of bifurcation lesion and SB ostium (RAO 30◦ /CAU 25◦ ). (Continued )

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COSTA ET AL.

34 (b)

(a)

(c)

(G)

(a)

(b)

(H)

(a)

(b)

(c)

(I)

Figure 10 (Continued) (G) Mid-RCA bifurcation: SB ostium poorly visualized in a (RA0 33◦ /CAU 6◦ ) and b (LAO 85◦ /CAU 5◦ ), best visualized in c (LAO 58◦ /CRA 2◦ ). (H) Distal RCA bifurcation (i.e., RCA-PDA/PLSA): a (LAO 22◦ /CAU 2◦ ); SB ostium best visualized in b (LAO 12◦ /CRA 19◦ ). (I) LM bifurcation: SB ostium not visualized in a (RAO 20◦ /CAU 22◦ ) and b (LAO 85◦ /CAU 5◦ ), best visualized in c (LAO 38◦ /CAU 35◦ ).

− −

− −

−

2.19 − − − − −

0.61 −

− −

2.75 − − 10 − −

0.93 64

− −

2.66 − − 9 − −

0.85 65

− 2.5

− −

2.73 − − 13.0 − −

0.89 65.9

8.99 2.39

15.38 2.71 − − 0.93 − − 65.9 − −

− −

2.82 − − 5.9 − −

0.66 72.2

12.35 2.36

18.62 2.87 − − 0.88 − − 69.4 − −

− −

2.47 − − 14.4 − −

1.23 43.4

5.4 2.21

14.4 2.78 − − 1.01 − − 64.4 − −

− −

2.69 − − 13.9 − −

1.27 41.5

4.7 2.22

16.6 2.93 − − 0.94 − − 67.7 − −

SES‡‡ 68

− −

− 2.86 2.34 − 11 13

− −

− 3.04 2.50 − 7 11

1.22 47

6.4∗∗ 2.6∗∗

6.0∗∗ 2.6∗∗ 1.21 46

17.5∗∗ 3.3∗∗ 3.00 2.63 − 1.62 1.32 − 46 50

Double SES 206

18.0∗∗ 3.3∗∗ 2.93 2.41 − 1.43 1.18 − 40 52

Single SES 207

− −

2.75 − − 9 − −

1.00 60

7 2.42

19 3.0 − − 0.84 − − 72 − −

Single SES 103

− −

2.76 − − 8 − −

1.15 56

7 2.36

20 3.0 − − 0.80 − − 73 − −

Single PES 102

Pan et al. (2007)55

− 1.66

2.56 − − 14.7 − −

1.14 49.7

7.20 2.28

16.25 2.68 − − 0.90 − − 68.2 − −

“MiniCrush” SES/ PES 52

Galassi et al.77

− 1.1

2.58 − − 13 − −

0.83 61

5.7 2.16

14.7 2.74 − − 0.83 − − 69 − −

Single SES 177

− 1.47

2.71 − − 12 − −

0.84 63

5.9 2.30

15.8 2.85 − − 0.90 − − 68 − −

Double SES 173

CACTUS30

1.54 1.53

− 3.17 2.74 − 3.0 9.3

1.11 54.4

9.9 2.38

20.9 3.08 − − − 1.63 1.20 − 47.3 54.9

Double SES 101

(Continued )

1.69 1.48

− 3.22 2.77 − 2.5 7.6

1.13 53.1

10.4 2.39

21.7 3.08 − − − 1.53 1.28 − 50.3 53.4

Single SES 101

BBK31

7in×10in

2.66 − − 11.5 − −

0.88 56.8

1.14 46.2

− 2.5

− 1.99

− 2.9 − − 0.76 − − 74 − −

BMS‡‡ 58

NORDIC29

Specs: 7x10 tight

2.65 − − 11.7 − −

5.5 2.1

5.1 2.1

− 3.0 − − 0.74 − − 77 − −

− 2.64 − − 0.64 − − − − −

“Crush” SES 120

“Crush” Double Single Double SES/ SES SES SES PES 65 50 41 241

SCANDSTENT53

11:8

Final Parent Vessel MLD, mm Proximal stent Distal stent % DS Proximal stent Distal stent Acute gain, mm Proximal stent Distal stent

10.8 2.6 − − 0.99 − − 61.7 − −

12.2 2.6 − − 0.92 − − 64.7 − −

Moussa et al.36

Pan et al. (2004)28

Hoye et al.52

Tanabe et al.26

April 9, 2010

Baseline Parent Vessel Lesion length, mm RD, mm Proximal vessel Distal vessel MLD, mm Proximal vessel Distal vessel % DS Proximal vessel Distal vessel Side Branch Lesion length, mm Reference diameter, mm MLD, mm % DS

Double SES 63

Colombo et al.27

QCA Parameters Reported in DES Bifurcations Trials

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Stenting Technique Single and Device SES Number of Lesions 23

Studies

Table 3

c02 Char Count=

2.35 − − 17.3 − − 0.28

− −

1.59 29.4 0.50

− −

1.42 32.0 0.37

2.11 14.4 −

2.51 − − 13.1 − − 0.14

1.69 23.5 −

1.49 31.0 0.31

1.78 28 −

− −

2.50 − − 18 − − −

1.95 21 −

1.73 30 −

− −

2.30 − − 23 − − −

2.15 12 −

1.85 30.7 0.41

− −

2.43 − − 22.9 − − 0.30

2.26 15.5 −

− − 1.70 28.0 0.03

− − −

2.35 − − 20.7 − − 0.99

1.77 24.5 −

− −

− − − − − − −

2.20 10.8 −

BMS‡‡ 58

1.19 45.1 0.56

− −

1.68 − − 42.5 − − 0.12

1.73 26.1 −

SES‡‡ 68

1.52 31 −0.04

0.00 0.04

− 2.86 2.29 − 11 15 −

1.50 34 −

Single SES 207

1.86 24 0.20

0.10 0.10

− 2.94 2.38 − 10 15 −

2.05 16 −

Double SES 206

NORDIC29

1.74 29 0.20

− −

2.45 − − 20 − − 0.31

2.03 17 −

Single SES 103

1.58 33 0.36

− −

2.10 − − 29 − − 0.60

1.97 17 −

Single PES 102

Pan et al. (2007)55

1.63 28.4 0.35

− −

1.99 − − 29.8 − − 0.30

2.16 14.6 1.02

“MiniCrush” SES/ PES 52

Galassi et al.77

1.52 31 0.13

− −

2.19 − − 25 − − 0.06

1.65 27 0.81

Single SES 177

1.66 30 0.29

− −

2.24 − − 25 − − 0.14

1.94 16 1.41

Double SES 173

CACTUS30

1.93 18.3 0.03

−0.01 0.01

− 3.23 2.77 − 3.0 9.9 −

1.97 16.6 0.84

Single SES 101

1.98 23.4 0.32

−0.02 0.08

− 3.16 2.65 − 3.6 12.5 −

2.30 9.6 1.19

Double SES 101

BBK31

7in×10in

− −

2.07 − − 22.9 − − 0.12

1.80 − −

“Crush” SES 120

“Crush” Double Single Double SES/ SES SES SES PES 65 50 41 241

SCANDSTENT53

Specs: 7x10 tight

Angiographic FU Parent Vessel MLD, mm Proximal stent Distal stent % DS Proximal stent Distal stent Late lumen loss, mm Proximal stent Distal stent Side Branch MLD, mm % DS Late lumen loss, mm

Side Branch MLD, mm % DS Acute gain, mm

Double SES 63

Moussa et al.36

Pan et al. (2004)28

Hoye et al.52

Tanabe et al.26

11:8

Stenting Technique Single and Device SES Number of Lesions 23

Colombo et al.27

April 9, 2010

Studies

QCA Parameters Reported in DES Bifurcations Trials (Continued )

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Table 3

c02 Char Count=

− − −

− −

−

−

−

−

−

−

−

−

72 (34/47) −

−

−

−

−

77 (10/13) 77 (10/13) 0 (0/13)

0 (0/4) 0 (0/4)

−

100 (4/4) −

11.3 (13/115)# 3.5 (4/115) 8.7 (10/115)

−

−

−

−

−

−

−

−

−

−

−

−

−

−

−

43.4

14.8

−

28.3

−

4.9

−

100 (29/29)†† 38 (11/29)††

−

57 (4/7) 0 (0/7) 57 (4/7) 43 (3/7) 0 (0/7)

22.5 (34/151) 4.6 (7/151) 19.2 (29/151)

94 (17/18)†† 33 (6/18)††

−

13 (1/8)†† 38 (3/8)†† 40 (4/8)†† 25 (2/8)††

−

16.0 (25/156) 5.1 (8/156) 11.5 (18/156)

100 (4/4)†† 100 (4/4)†† −

67 (2/3)†† 33 (1/3)†† 33 (1/3)†† 33 (1/3)†† 0 (0/3)††

9.4 (5/53) 5.7 (3/53) 7.5 (4/53)

100 (10/10)†† 100 (10/10)†† −

73 (8/11)†† 27 (3/11)†† 46 (5/11)†† 27 (3/11)†† 0 (0/11)††

28.6 (16/56) 10.7 (6/56) 8.9 (10/56)

−

−

−

−

−

−

−

−

12.2 (6/49) 2.0 (1/49)

−

−

−

−

−

−

−

−

−

6.7 (10/150) 14.7 (22/150)

−

−

−

−

−

−

−

−

−

4.6 (7/152) 13.2 (20/152)

−

−

−

−

−

−

−

−

−

12.5 (12/96) 7.3 (7/96) 9.4 (9/96)

−

−

−

−

−

−

−

−

13.5 (13/96) 3.1 (3/96) 12.5 (12/96)

7in×10in

Percentage of overall population with angiographic follow-up. † Defined as ostium 5 mm plus balloon-treated area in the side branch. ‡ Number of lesions with angiographic success at index procedure and angiographic follow-up (angiographic success defined as attainment of <50% residual stenosis in both branches). § Overall 6.1% (N = 4) restenosis in PV including 1 in-stent, 2 proximal edge, and 1 distal edge.  No systematic angiographic FU available. # Clinical restenosis. ∗∗ By visual estimation. †† Some lesions had stenosis in more than one location. ‡‡ Double stenting technique used in 55% in SES and in 53% in BMS. BMS = bare metal stents; DS = diameter stenosis; FU = follow-up; MLD = minimum lumen diameter; PES = paclitaxel-eluting stents; RD = reference diameter; SES = sirolimus-eluting stents.

In-stent/injured segment† Distal edge

83 (5/6) 100 (6/6) 0 (0/6)

25 (1/4) 0 (0/4)

−

−

−

9.1 (17/186) 25.3 (47/186)

−

Specs: 7x10 tight

∗

−§

−§

Distal edge

92 (11/12) 92 (11/12) 8 (1/12)

−§

−§

Proximal edge

100 (3/3) 100 (3/3) −

−

−

Distal stent

−

−

10.0 (4/40) 15.0 (6/40)

−

11:8

Side Branch Ostium 5 mm

−

−

−

2 (1/?) 5 (2/?)

−

April 9, 2010

75 (3/4) −

22.7 (10/44) 9.1 (4/44) 13.6 (6/44)

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Proximal stent

18.7 28.0 (3/16‡ ) (14/50‡ ) Parent Vessel 4.8 5.7 (1/21) (3/53) Side Branch 14.2 21.8 (3/21) (12/55) Restenosis location, % (N = total number of restenosis in each vessel) Parent Vessel In-stent −§ −§

Restenosis, % (N)∗ Overall lesion

c02 Char Count=

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38 Table 4

Recommendations for Reporting of Bifurcation Analyses Standard reporting of bifurcation analyses

Item Angiographic views

Angulation

Restenosis

Segmental Analysis Additional reporting

Recommendation Acquire angiograms on at least three matching views at baseline, final intervention, and follow-up (attempt to: no vessel overlap, minimal target segment foreshortening, display widest bifurcation angle) Report two-dimensional angulations between MV and SB, including a. the “take-off” angle between the proximal MV to the SB, and b. the “carina angle” between the distal MV and the SB 1. A single restenosis rate should be provided for the MV and for the SB (suggestion to use the Medina classification (17) as primary endpoint for bifurcation trials) 2. An overall restenosis rate should be reported for the entire bifurcation lesion Describe QCA parameters in the subsegmental areas of the bifurcation (Figure 11) Results should further be reported based on the target lesion location, the Medina classification (17), and on the specific treatment strategy of the bifurcation PCI

Source: Adapted from Ref. 29.

Intravascular Ultrasound IVUS is routinely used to clarify angiographic ambiguity in many clinical scenarios. In general, IVUS is more useful in complex lesions where optimization of acute results is critical to improve long-term outcome (33). In bifurcation lesions, IVUS provides valuable baseline and iterative information regarding plaque distribution, particularly in relation to the SB ostium, vessel size, and appropriateness of stent expansion particularly at the SB ostium [Fig. 13(A) to 13(C)]. Furukawa et al. (6) demonstrated that the presence and severity of ostial SB plaque as observed by IVUS is the most important predictor of SB occlusion after bifurcation PCI. In

Figure 11 QCA analysis method proposed for coronary bifurcation including subsegmental analysis in three distinct locations at the proximal MV, distal MV, and SB. Source: Adapted from Ref. 29.

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39

After stenting

Before stenting

2-D

2-D

3-D

3-D

(A)

After stenting

(B)

Figure 12 Illustrations demonstrating distal angle measurements in 3-D reconstruction models of coronary bifurcations: (A) distal RCA bifurcation and (B) proximal LAD bifurcation.

this study, the SB ostium was assessed by an IVUS pullback from distal to proximal MV and was classified according to the IVUS findings into group 1, angiographic ostial stenosis due to atherosclerotic plaque visualized only in the MV (n = 61); and group 2, angiographic ostial stenosis due to atherosclerotic plaque involving the SB ostium. There were no differences in baseline SB reference diameter (1.75 ± 0.48 mm) and percent diameter stenosis between the groups. After MV stenting, group 2 had significantly higher frequency of SB deterioration (defined as final TIMI flow ≤2) compared to group 1 (35% vs. 8.2%, p = 0.003). Also, the presence of eccentric and diffuse plaque in the MV around the SB ostium significantly increased SB deterioration. The question whether IVUS pullback in the MV is sufficient to characterize the degree of SB ostium involvement, compared to an IVUS pullback from the SB, is important and the data suggest that it is not (Fig. 14). Van der Waal and colleagues (34) performed IVUS pullback in the MV and the SB in bifurcation lesions. They studied three segments: (a) distal segment, measured 3 mm distal to the bifurcation (MV and SB); (b) bifurcation carina, measured 3 mm starting at the first frame in which the distal branch (MV or SB) was visualized and ended where the LAD assumed a circular shape; and (c) proximal MV (LAD), measured 3 mm proximal to the bifurcation carina. This study showed the following: (i) IVUS measurements of the proximal MV differed significantly between the MV versus the SB pullback; (ii) the mean vessel area and mean vessel diameter at the carina were significantly larger during MV pullback compared to SB pullback; and (iii) there was no relationship between the IVUS measurements at different bifurcation segments and the 3-D bifurcation angle. Nonetheless, IVUS interrogation of bifurcation lesions may be challenging because the image in the carina usually appears oval or irregular in shape. Standardized IVUS methodology for bifurcation analysis has not been considered in previous IVUS and bifurcation consensus documents. Thus, the findings from van der Waal et al. study strengthen the recommendation for performance of IVUS pullbacks from both the MV and the SB for assessment of bifurcations rather than one pullback, as two pullbacks allow better understanding of the geometry of the bifurcation, especially the SB ostium. One of the authors of this chapter (Marco Costa, MD, personal communication) proposed an IVUS methodology for bifurcation lesions as depicted in Figure 15. It includes performance of quantitative analysis in four distinct segments including proximal MV, distal MV, SB, and carina. The carina was defined within 5 mm from the bifurcation point and calculated as the average of value obtained from IVUS pullbacks from both the MV and the SB.

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40

Virtual Histology and Optical Coherence Tomography Although IVUS has provided valuable insights into our understanding of bifurcation anatomy and its response to intervention, IVUS imaging does not have the required resolution to provide insights into bifurcation plaque vulnerability. Recent studies using virtual histology (VH) and optical coherence tomography (OCT) have shed light on these issues. A study by Gonzalo et al. (35) evaluated the in vivo frequency and distribution of high-risk plaques at bifurcations using a combined plaque assessment with IVUS-VH and OCT. IVUS-VH and OCT analysis of coronary bifurcations was performed in 30 patients (103 lesions). All lesions were considered nonsignificant by angiographic criteria and had a MLA >4.0 mm2 . The lesions were

(a)

(c)

LAD

(b)

(d)

(A) Figure 13 Examples of IVUS cross-sectional images assessing coronary bifurcations. (A)—(a, b) Angiograms demonstrating proximal LAD/Diagonal bifurcation lesion: SB ostium involvement not visualized in (a), better assessed in (b). (c) SB ostium (pullback from SB) demonstrating significant amount of plaque located opposite to the flow divider. (d) Distal reference of the SB. (B)—(a) angiogram demonstrating proximal LAD/Diagonal bifurcation lesion: Note that the MV has moderate stenosis by angiography. (b) MV proximal reference (IVUS). (c) MV minimum lumen area with large plaque burden (IVUS). (d) MV distal reference (IVUS). (e) SB ostium (IVUS). (f) SB distal reference (IVUS). (C) LAD/Diagonal bifurcation post-double stenting implant (“crush” technique). (a, b) Final angiograms demonstrating optimal angiographic result. (c) SB distal reference. (d) SB ostium minimum stent area with significant stent underexpansion compared to distal reference. (Continued on pages 41 and 42 )

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41

analyzed at three cross-section locations: (a) proximal rim of the ostium (first frame proximal to the SB take-off); (b) in-bifurcation (frame with the larger SB ostial diameter); and (c) distal rim of the SB ostium (first frame distal to the SB take-off) (Fig. 16). The authors predefined the following characteristics for identifying high-risk plaque morphology: (a) fibroatheroma (FA)-–the presence of more than 10% confluent necrotic core covered by a fibrous cap thicker than 65 ␮m; (b) calcified FA (CaFA)-–FA with more than 10% of confluent dense calcium; (c) IVUS-VH/OCT-derived thin capped FA (TCFA)-–more than 10% confluent necrotic core at the lumen covered by a fibrous cap <65 ␮m; and (d) IVUS-VH/OCT-derived calcified TCFA (CaTCFA)-–TCFA with more than 10% of confluent dense-calcium. Overall, the mean area of necrotic core and the mean percentage of necrotic core decreased from proximal to distal location. Conversely, the mean cap thickness was lower in the proximal rim and increased from proximal to distal location. The distribution of FA, CaFA, TCFA, and CaTCFA plaque components were 8.4%, 14.7%, 10.5%, and 5.3% in the proximal rim; 4.9%, 14.6%, 7.8%, and 5.8% in the in-bifurcation; and 5.3%, 13.7%, 3.2%, and 2.1% in the distal rim; respectively. In addition, thin caps (<65 ␮m) were more often located in the proximal rim

(f)

(e)

LAD (a)

f e b

c d

(b)

(d)

(c)

(B) Figure 13 (Continued) (Continued on page 42 )

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COSTA ET AL.

42

(a)

(c)

(b)

(d)

LAD

(C) Figure 13 (Continued)

(a)

(b)

(c)

MV

SB

MV

SB

Figure 14 Angiography of an LAD/diagonal bifurcation lesion (a), illustrating the observation that IVUS pullback in the main vessel (b) is not adequate for accurate imaging of the SB ostium compared to direct imaging of the SB (c).

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43

MT

Carina (5 mm) MB

Carina

MT SB MB

A SB

Carina

B

MT

Figure 15 Proposed IVUS methodology for evaluation of coronary bifurcation lesions.

Figure 16 (See color insert ) An illustration of the proximal rim, in-bifurcation, and distal rim of bifurcation cross-sections using virtual histology and optical coherence tomography. Source: Adapted from Ref. 35.

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44

(A)

(B)

(D)

(C)

(E)

(F)

Pericardial side

Myocardial side

Figure 17 Illustration of MSCT extraction of the cross-section of a LAD bifurcation analyzed from the 3-D dataset: (A) plane through the mother and side branches of the bifurcation of interest; (B) imaging plane; (C) plane magnification, star indicates the flow divides and the arrows (D and E) indicate the position of the cross-sections; (D) cross-section of the distal MV; (E) cross-section of the SB; (F) cross-section division into quadrants according to expected WSS level, as demonstrated in (D and E). Source: Adapted from Ref. 36.

compared to the in-bifurcation and distal rims (44.1% vs. 41.2% vs. 14.7%). Furthermore, highrisk lesions had significantly greater vessel area and plaque burden, but similar lumen area compared to non–high-risk lesions. Multislice Computed Tomography (MSCT) The introduction of MSCT presents a great opportunity to study and categorize the 3-D structure of coronary bifurcation anatomy (Fig. 17). A study by van der Giessen et al. (36) assessed the plaque distribution and morphology near bifurcations with 64-slice computed tomography in relation to wall shear stress distribution. In this analysis, plaque distribution was evaluated in two locations: distal LM-LAD/LCx and LAD/Diagonal. Analysis was performed at a plane where both the MV and the SB were visible and the distal angle was maximal. Overall, 28 patients (65 lesions) with suspected CAD underwent MSCT evaluation. Plaques were more often found in low wall shear stress regions (62–72%) compared to high wall shear stress regions (31–38%). Another study by Kawasaki et al. (37) investigated bifurcation angles in 209 patients undergoing 64-MSCT because of symptoms of angina. In this study, the prevalence of “steep” (proximal) angle (<110 degrees) was significantly higher in the LM (26%) compared to non-LM locations (p < 0.05), demonstrating that MSCT can clarify the 3-D structure of coronary bifurcation and may provide useful information for bifurcation PCI strategy. Finally, a study by Rodriguez-Granillo et al. (38), investigating the differences in plaque burden at different segments of the LM bifurcation and its relationship with the bifurcation angle in 50 patients undergoing 40-row MSCT analysis, demonstrated that >90% of plaques were located opposite to the flow divider, localized at the ostial LAD. Also, the median distal angle was 88.5 degrees (diseased LAD had significantly increased angle compared to nondiseased LAD; p = 0.018). THE LEFT MAIN CORONARY ARTERY BIFURCATION: A DIFFERENT ANIMAL The bifurcation anatomy of the distal left main coronary artery (LMCA) is different from that of non-LMCA bifurcations with respect to vessel size (larger) and proximal and distal angles. Although the MEDINA classification is also used to classify LMCA bifurcation lesions, it provides limited insight in terms of actionable information. The LMCA perfuse most of the

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CORONARY ARTERY BIFURCATION LESIONS

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45

(A)

(B)

Figure 18 MSCT imaging demonstrating plaque location within the LM bifurcation.

ventricular myocardium (68.8% of the cardiac muscle mass and 79% of the left ventricular cardiac muscle mass) (39). The anatomy of the LMCA has been described in detail by Reig and Petit (40). In this study, the average length of the LMCA was 10.8 mm. Short (<5 mm), medium length (>5 mm to <15 mm), and long (>15 mm) LMCA was observed in 7.4%, 73.7%, and 18.9% of the study population, respectively. The average diameter of the LMCA at midpoint was 4.86 mm. Although the LMCA often ends with a bifurcation (the LAD and the LCx), it does divide into three or more branches in more than one-third (38%) of the cases. The average angle between the LAD and the LCx is ∼90 degrees (86.7 degrees). Correlation between the angle and the length of LM, with the longest LM having the largest angle of division, has also been reported. Autopsy has also limitations in assessing bifurcation since it does not consider the natural dynamic of the bifurcation along the cardiac cycle. Recently, a 4-D (X, Y, Z axes + time) assessment by MSCT has been developed for assessing coronary bifurcation anatomy more quantitatively, considering the movement of the heart (Fig. 18).

SUMMARY The complexity of performing PCI in coronary bifurcation lesions is simply due to the operator efforts to maintain optimal patency of the SB while optimally treating the MV. These efforts are well justified because side branch compromise can lead to myocardial injury. The dominant viewpoint of relying exclusively on the Medina classification to characterize bifurcation anatomy in practice and clinical trials may be misguided! The Medina classification fails to capture key bifurcation anatomic elements (SB ostium lesion severity and length, SB angulation and SB size) that have been shown to increase the risk of SB compromise during bifurcation PCI. In other words, this classification is not designed to identify the “at risk” bifurcations where the chances of SB compromise during PCI is highest. Although improvements in angiographic methods of bifurcation anatomy characterization are important other imaging modalities are needed to further enhance our understanding of bifurcation anatomy. In clinical practice, physician operators should make individual judgments regarding technique choice based on comprehensive analysis of bifurcation anatomy that allow the identification of “at risk” bifurcations that may need tailored treatment techniques. With respect to the ongoing efforts to build a more relevant evidence-base for treatment of coronary bifurcation lesions more focus should be placed on inclusion of “at risk” bifurcations as defined by comprehensive anatomic analysis.

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REFERENCES 1. Koo BK, Park KW, Kang HJ, et al. Physiological evaluation of the provisional side-branch intervention strategy for bifurcation lesions using fractional flow reserve. Eur Heart J 2008; 29(6):726–732. 2. Arora RR, Raymond RE, Dimas AP, et al. Side branch occlusion during coronary angioplasty: incidence, angiographic characteristics, and outcome. Cathet Cardiovasc Diagn 1989; 18(4):210–212. 3. Fischman DL, Savage MP, Leon MB, et al. Fate of lesion-related side branches after coronary artery stenting. J Am Coll Cardiol 1993; 22(6):1641–1646. 4. Aliabadi D, Tilli FV, Bowers TR, et al. Incidence and angiographic predictors of side branch occlusion following high-pressure intracoronary stenting. Am J Cardiol 1997; 80(8):994–997. 5. Chaudhry EC, Dauerman KP, Sarnoski CL, et al. Percutaneous coronary intervention for major bifurcation lesions using the simple approach: risk of myocardial infarction. J Thromb Thrombolysis 2007; 24(1):7–13. 6. Furukawa E, Hibi K, Kosuge M, et al. Intravascular ultrasound predictors of side branch occlusion in bifurcation lesions after percutaneous coronary intervention. Circ J 2005; 69(3):325–330. 7. Nakazawa G, Yazdani SK, Finn AV, et al. Pathological findings at bifurcation lesions—the impact of flow distribution on atherosclerosis and arterial healing following stent implantation. J Am Coll Cardiol 2010. In press. 8. Ku DN, Giddens DP, Zarins CK, et al. Pulsatile flow and atherosclerosis in the human carotid bifurcation. Positive correlation between plaque location and low oscillating shear stress. Arteriosclerosis 1985; 5(3):293–302. 9. Papafaklis MI, Bourantas CV, Theodorakis PE, et al. Association of endothelial shear stress with plaque thickness in a real three-dimensional left main coronary artery bifurcation model. Int J Cardiol 2007; 115:276–278. 10. Russell ME, Binyamin G, Konstantino E. Ex vivo analysis of human coronary bifurcation anatomy: defining the main vessel-to-side-branch transition zone. EuroIntervention 2009; 5(1):96–103. 11. Murray CD. The physiological principle of minimum work: I. The vascular system and the cost of blood volume. Proc Natl Acad Sci U S A 1926; 12(3):207–214. 12. Sherman TF. On connecting large vessels to small. The meaning of Murray’s law. J Gen Physiol 1981; 78:431–453. 13. Hutchins GM, Miner MM, Boitnott JK. Vessel caliber and branch-angle of human coronary artery branch-points. Circ Res 1976; 38(6):572–576. 14. Finet G, Gilard M, Perrenot B, et al. Fractal geometry of arterial coronary bifurcations: a quantitative coronary angiography and intravascular ultrasound analysis. EuroIntervention 2007; 3:490–498. 15. Potel MJ, Rubin JM, MacKay SA, et al. Methods for evaluating cardiac wall motion in three dimensions using bifurcation points of the coronary arterial tree. Invest Radiol 1983; 18(1):47–57. 16. Husmann L, Leschka S, Desbiolles L, et al. Coronary artery motion and cardiac phases: dependency on heart rate—implications for CT image reconstruction. Radiology 2007; 245(2):567–576. 17. Medina A, Suarez de Lezo J, Pan M. A new classification of coronary bifurcation lesions. Rev Esp Cardiol 2006; 59(2):183. 18. Movahed MR. Coronary artery bifurcation lesion classifications, interventional techniques, and clinical outcome. Expert Rev Cardiovasc Ther 2008; 6(2):261–274. 19. Lef`evre T, Louvard Y, Morice MC, et al. Stenting of bifurcation lesions: classification, treatments, and results. Catheter Cardiovasc Interv 2000; 49(3):274–283. 20. Tanabe K, Hoye A, Lemos PA, et al. Restenosis rates following bifurcation stenting with sirolimuseluting stents for de novo narrowings. Am J Cardiol 2004; 94(1):115–118. 21. Colombo A, Moses JW, Morice MC, et al. Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions. Circulation 2004; 109(10):1244–1249. 22. Pan M, de Lezo JS, Medina A, et al. Rapamycin-eluting stents for the treatment of bifurcated coronary lesions: a randomized comparison of a simple versus complex strategy. Am Heart J 2004; 148(5):857– 864. 23. Steigen TK, Maeng M, Wiseth R, et al. Randomized study on simple versus complex stenting of coronary artery bifurcation lesions: the Nordic bifurcation study. Circulation 2006; 114(18):1955– 1961. 24. Colombo A, Bramucci E, Sacca S, et al. Randomized study of the crush technique versus provisional side-branch stenting in true coronary bifurcations: the CACTUS (Coronary Bifurcations: Application of the Crushing Technique Using Sirolimus-Eluting Stents) study. Circulation 2009; 119(1): 71–78. 25. Ferenc M, Gick M, Kienzle RP, et al. Randomized trial on routine vs. provisional T-stenting in the treatment of de novo coronary bifurcation lesions. Eur Heart J 2008; 29(23):2859–2867. 26. Hildick-Smith D. The British Bifurcation Coronary study: old, new and evolving strategies—a randomized comparison of simple versus complex drug-eluting stenting for bifurcation lesions.

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Paper Presented at: Transcatheter Cardiovascular Therapeutics (TCT) 2008; October 16, 2008; Washington, DC. Dzavik V, Kharbanda R, Ivanov J, et al. Predictors of long-term outcome after crush stenting of coronary bifurcation lesions: importance of the bifurcation angle. Am Heart J 2006; 152(4):762–769. Gil RJ, Vassilev D, Formuszewicz R, et al. The carina angle—new geometrical parameter associated with periprocedural side branch compromise and the long-term results in coronary bifurcation lesions with main vessel stenting only. J Interv Cardiol 2009; 22(6):E1–E10. Epub 2009 Aug 20. Lansky A, Tuinenburg J, Costa M, et al. Quantitative angiographic methods for bifurcation lesions: a consensus statement from the European Bifurcation Group. Catheter Cardiovasc Interv 2009; 73(2):258–266. Ramcharitar S, Onuma Y, Aben JP, et al. A novel dedicated quantitative coronary analysis methodology for bifurcation lesions. EuroIntervention 2008; 3(5):553–557. Garcia JA, Movassaghi B, Casserly IP, et al. Determination of optimal viewing regions for X-ray coronary angiography based on a quantitative analysis of 3D reconstructed models. Int J Cardiovasc Imaging 2009; 25(5):455–462. Dvir D, Marom H, Assali A, et al. Bifurcation lesions in the coronary arteries: early experience with a novel 3-dimensional imaging and quantitative analysis before and after stenting. EuroIntervention 2007; 3:95–99. Oemrawsingh PV, Mintz GS, Schalij MJ, et al. Intravascular ultrasound guidance improves angiographic and clinical outcome of stent implantation for long coronary artery stenoses: final results of a randomized comparison with angiographic guidance (TULIP study). Circulation 2003; 107(1):62–67. van der Waal EC, Mintz GS, Garcia-Garcia HM, et al. Intravascular ultrasound and 3D angle measurements of coronary bifurcations. Catheter Cardiovasc Interv 2009; 73(7):910–916. Gonzalo N, Garcia-Garcia HM, Regar E, et al. In vivo assessment of high-risk coronary plaques at bifurcations with combined intravascular ultrasound and optical coherence tomography. JACC Cardiovasc Imaging 2009; 2(4):473–482. van der Giessen AG, Wentzel JJ, Meijboom WB, et al. Plaque and shear stress distribution in human coronary bifurcations: a multislice computed tomography study. EuroIntervention 2009; 4(5):654– 661. Kawasaki T, Koga H, Serikawa T, et al. The bifurcation study using 64 multislice computed tomography. Catheter Cardiovasc Interv 2009; 73(5):653–658. Rodriguez-Granillo GA, Rosales MA, Degrossi E, et al. Multislice CT coronary angiography for the detection of burden, morphology and distribution of atherosclerotic plaques in the left main bifurcation. Int J Cardiovasc Imaging 2007; 23(3):389–392. Kalbfleisch H, Hort W. Quantitative study on the size of coronary artery supplying areas postmortem. Am Heart J 1977; 94(2):183–188. Reig J, Petit M. Main trunk of the left coronary artery: anatomic study of the parameters of clinical interest. Clin Anat 2004; 17(1):6–13.

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Provisional Stenting Technique for Non–Left Main Coronary Bifurcation Lesions: Patient Selection and Technique Remo Albiero and Emiliano Boldi Cath Lab, Clinica San Rocco di Franciacorta, Ome (Brescia), Italy

INTRODUCTION Bifurcation lesions are frequent in routine practice, accounting for up to 20% of all coronary disease treated by percutaneous coronary intervention (1). Compared to the left main coronary artery bifurcation, the size of the vessels in non–left main bifurcations is smaller and the angle between them is narrower (2). On the basis of the results of six randomized controlled trials (RCTs) (3–8) (Fig. 1), in true coronary bifurcations with a short side branch lesion length, a stepwise provisional side branch stenting strategy with drug-eluting stents is consensually considered the preferable technique compared to deliberate elective double stenting (9). It is critically important to emphasize the statement “with a short side branch lesion length” since all these trials included bifurcations with side branches that have short lesions of moderate severity. Hence, these data cannot be presumed to apply to patients with coronary bifurcations who are not well represented in these trials (i.e., those with large side branches that have severe stenoses which are long or have unfavorable angulation). For instance, patients in Figures 2 through 5 had true bifurcation lesions with features that would be inappropriate for the provisional stenting approach, so elective double stenting technique was performed. This chapter focuses on proper patient selection for the provisional stenting approach as well as on proper technique execution. WHO QUALIFIES FOR THE PROVISIONAL STENTING TECHNIQUE? Understanding the anatomical characteristics of coronary bifurcations is required to optimize the results of the provisional side branch stenting strategy. Although the Medina classification (10) of coronary bifurcation lesions has gained wide acceptance (11) because it is considered the most simple to understand and remember (Fig. 6), this classification does not consider several critical anatomic elements that are relevant to bifurcation intervention: (a) the angle between the two branches; (b) the side branch lesion length; (c) the observed/expected diameter; (d) the plaque distribution. Angle Between the Branches By angiography, bifurcations are classified according to the internal angle between the main vessel and the side branch (in the working view), with a Y-shaped lesion having an angle <70 degrees and a T-shaped lesion having an angle ≥70 degrees. The analysis of the natural distribution of bifurcation angles by MDCT (multidetector computed tomography) (2) reveals that left main bifurcations (LAD/LCx) are T-shaped with an average value of 80 degrees, while non–left main bifurcations (LAD/Diagonal; LCx/OM, PDA/PL) are mostly Y-shaped with an average angle of 46 to 53 degrees. The provisional side branch stenting strategy is more suitable for Y-shaped bifurcations with an internal angle <60 degrees, therefore is more suitable for non–left main bifurcations. Attempts to apply provisional stenting in true bifurcations with a severely angulated SB origin can result in SB occlusion (Fig. 7). Lesion Length Side branch lesions, specifically those enrolled in the RCTs, are mostly angiographically short (3,12)—on average less than 5 to 6 mm (Table 1). Procedural side branch occlusion is less common

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BBC ONE (8) Cactus (7)

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Figure 1 Low rate of reintervention with drug-eluting stents in six randomized trials comparing provisional T stenting versus elective double stenting in true bifurcation lesions with a short side branch lesion length (lesions suitable for both treatments).

in short compared to long side branch stenoses (8.2 vs. 35.0%; p = 0.003) (13). In bifurcations with a side branch lesion length less than 3 to 5 mm, the provisional side branch stenting strategy allows to obtain a good final result in both branches in the majority (>70–80%) of cases by stenting only the main branch and using a final kissing balloon inflation to optimally scaffold the side branch ostium. The provisional stenting approach is more suited to treat bifurcations with side branches that have short lesions rather than long stenoses. For example, the patient in Figure 3 underwent elective double stenting because the SB is large and has a severe long lesion at the ostium. Observed/Expected Diameter As demonstrated by Finet et al. (14) in 173 angiographically normal coronary bifurcations, there is an important mother/daughter-vessel mathematical relationship, first described by Murray (“Murray’s law”)—in particular, the constant ratio R = Dm/(Dd1 + Dd2) between the mothervessel diameter and the sum of the daughter-vessel diameters is 0.678. By using this simple

(A)

(B) Figure 2 Bifurcation that requires the elective implantation of a SB stent. (A) Baseline angiogram of the LAD-D1 bifurcation; (B) final result after drug-eluting stent (DES) implantation in the proximal and mid-LAD and one long DES at the ostium-proximal segment of the diagonal branch using the modified T stenting technique, and followed by final “kissing balloon” inflation.

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Figure 3 Bifurcation that requires the elective implantation of a SB stent. (A) Baseline angiogram of the LAD-D1 bifurcation; (B) final result after drug-eluting stent (DES) implantation in the proximal LAD and one long DES at the ostium-proximal segment of the diagonal branch using the modified T stenting technique, and followed by final “kissing balloon” inflation.

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Figure 4 Bifurcation that requires the elective implantation of a SB stent. (A) Baseline angiogram of the LAD-D1 bifurcation; (B) Final result after drug-eluting stent (DES) implantation in the proximal–mid-LAD and one long DES at the ostium-proximal segment of the diagonal branch using the modified T stenting technique, and followed by final “kissing balloon” inflation.

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Figure 5 Bifurcation that requires the elective implantation of a SB stent. (A) Baseline angiogram of the LAD-D1 bifurcation; (B) final result after drug-eluting stent (DES) implantation in the proximal LAD and one long DES at the ostium-proximal segment of the diagonal branch using the modified T stenting technique, and followed by final “kissing balloon” inflation.

Figure 6 Original Medina classification.

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Side Branch Lesions are Usually Angiographically Short

Patients (n) Reference (mm) Lesion length (mm) Stenosis SB (%)

TULIPE (12)

Sirolimus (3)

187 2.3 ± 0.5 3.7 ± 3.3 52 ± 17

85 2.1 ± 0.3 5.3 ± 4.2 52 ± 19

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Figure 7 Side branch occlusion after main branch stent implantation using the provisional stenting strategy. (A) Baseline angiogram in the LAO caudal view of the LCx-OM1 bifurcation showing the difficult SB take-off with an angle >70◦ ; (B) baseline angiogram in the RAO caudal view of the LCx-OM1 bifurcation; (C) main branch predilation; (D) side branch predilation; (E) angiogram after predilation of both branches; (F) final angiogram after main branch stenting showing side branch occlusion.

ratio, relating mother-vessel diameter (Dm) and the daughter-vessel diameters, by the formula Dm = 0.678 (Dd1 + Dd2), one daughter-vessel diameter can easily be calculated when the other daughter-vessel diameter and the mother-vessel diameter are known. Moreover, this formula can be very useful for evaluating the correct mother (proximal reference)-vessel diameter in a bifurcation lesion when both daughter-vessel diameters are known. Plaque Distribution Atherosclerotic plaque in human coronary arteries is localized almost exclusively on the outer wall of one or both daughter vessels at major bifurcations, where the flow is either slow or disturbed with the formation of slow recirculation and secondary flows and where Wall Shear Stress (WSS) is low. Pathologic studies in coronary arteries show that the atherosclerotic plaques are located mainly along the inner side of the curved coronary arteries, close to the areas of low shear stress. Regions exposed to the nonuniform low shear stresses develop early atherosclerotic lesions, whereas areas exposed to uniform high shear stresses are protected (15–22). Consequently, atherosclerotic plaque usually develops in both branches opposite the flow divider (23–26), which is almost always free of disease, due to the atheroprotective effect of high shear

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5.5 mm

(B)

L P

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(C) Figure 8 Carina is not involved by atherosclerosis. (A) Angiogram of the LCx-OM bifucation (Medina 1,1,0). (B) IVUS shows that the carina is the largest segment of bifurcation: arrow indicates the largest diameter (5.5 mm) between the outer wall of the main branch and the outer wall of the side branch ostium; (C) IVUS shows that the carina is minimally involved by atherosclerotic plaque (P), which is localized on the outer wall of the main branch. The two small arrows indicate the flow divider (carina). Abbreviations: P, plaque; L, lumen.

stresses (27–30). In an intravascular ultrasound (IVUS) study in left main bifurcations in 73 patients (31), angiography suggested that the flow divider (carina) was involved in 61%, while IVUS showed that the carina was spared in all 73 patients. Our personal IVUS observations (Figs. 8 and 9) confirm these findings. We have therefore modified the Medina classification on the basis of these results, removing the plaques at the level of the carina (Fig. 10). Understanding the pattern of plaque distribution in coronary bifurcations has led to technique modification that increased the likelihood of success with provisional stenting. PROVISIONAL SIDE BRANCH STENTING STRATEGY Provisional stenting consists of stenting the main branch first, followed, if necessary, by delivery of a second stent to the side branch through the main branch stent in a classic T (32), TAP (T And small Protrusion) (33), inverted Culotte (34,35), or Internal Crush configuration (36) (Fig. 11). The advantage of this approach is that the use of a second stent is only provisional. In the MADS classification (treatment description techniques of coronary bifurcation lesions published in a consensus paper from the first European Bifurcation Club meeting; Ref. 11), the acronym of this technique is A (Main Across side first).

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P

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5. 6. 7. Figure 9 Carina is not involved by atherosclerosis. (A) True bifurcation lesion (Medina 1,1,1) in the mid-LAD involving the ostium of diagonal branch; (B) IVUS performed before stenting shows that the flow divider (carina) (images 4. and 5.) is not involved by the atherosclerotic plaque (P), which is localized (C) on the outer wall of one or both daughter vessels, where wall shear stress (WSS) is low.

1,1,1

1,1,0

1,0,0

1,0,1

0,1,0

0,1,1

0,0,1

Figure 10 Modified Medina classification based on IVUS and pathologic observations: atherosclerotic plaque in bifurcations is distributed on the outer walls of the mother and daughter vessels, sparing the flow divider (carina). The plaques at the level of the carina have been removed.

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Figure 11 Procedure for treatment of bifurcations using a provisional stenting strategy. 1. Wires are advanced in both the distal main vessel and the side branch. 2. The main vessel is predilated if necessary. Predilation of the side branch is avoided when possible. 3. A stent is deployed in the main vessel, jailing the wire in the side branch. 4. Once the main vessel result is seen to be satisfactory, the side branch is rewired: this maneuver is performed using the main branch wire by pulling it back slowly from the main vessel (guidewires exchange) or by using a third wire and pointing the tip toward the side branch ostium with the intention to cross into the side branch through the distal strut closest to the flow divider. 5. The “jailed wire” is withdrawn from the side branch and pushed distally in the main branch. 6. A kissing inflation is systematically performed in order to open the stent struts to cover the ostium of the side branch, while preserving the result in the main vessel. 7. If at this point there is normal (Thrombolysis in Myocardial Infarction flow grade 3) flow in the side branch and <50% residual angiographic stenosis, this marks the end of the procedure; if this is not achieved, a second stent is deployed in the side branch. The side branch stent crosses the struts of the first stent and is deployed in a simple T configuration (7a). To achieve complete ostial side branch lesion coverage, especially after a proximal cross and kissing balloon, the second stent can be implanted slightly protruding into the main branch (T And Protrusion, TAP) (7b) or with internal crush configuration (7c), or by using an inverted culotte technique (7d) followed in all cases by a final kissing inflation to correct any possible main branch stent deformation.

Wiring Both Branches Provisional SB stenting strategy begins with wiring of both branches (Fig. 11,1), selecting guidewires with good torquability, steerability, and adequate support. The BMW 0.014 wire (Abbott) is our first choice. Polymer-coated guidewires, such as the Choice PT, PT2, and PT Graphics (Boston Scientific), can be used in the presence of tortuosity, calcifications, or difficult access to side branch. However, we do not recommend to leave polymer-coated guidewires “jailed” because of the possible risk of wire fracture during retrieval (a theoretical concern that has not been corroborated), especially when the distal tip is severely bended. When polymercoated wires are required to access the side branch, we recommend to use other polymer-coated wires such as Whisper (Abbott) or Fielder (Asahi), or they can be exchanged for a BMW after the first polymer-coated wire has modified the side branch angulation: in fact after wiring, a T-shaped can become a Y-shaped bifurcation.

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Predilation The main vessel is then predilated if required (Figure 11,2). Predilation of the side branch is avoided when possible and performed only in the presence of severe ostial stenosis, unfavorable extreme angulation of the side branch take off, severe calcification, or a long significant lesion (>3–5 mm). Data from the TULIP (12) and the SURF registry (37) have shown that predilation of the side branch is not a predictive factor for “strut rewiring” success and for side branch angiographic success.

Predilation is also dependent on the planned strategy after main branch stenting with regard to the performance of kissing balloon inflation.

r

r

When final kissing balloon inflation is planned, we recommend avoiding side branch predilation. The reason not to predilate the side branch with this strategy is that the plaque in coronary bifurcations (see above) is localized almost exclusively on the outer wall of one or both daughter vessels (23–26), with the flow divider (carina) almost always free of disease (27–30). After main branch stenting, the carina (free of disease) is displaced/shifted toward the side branch ostium facing the intact (not disrupted by predilation) plaque on the outer wall of the side branch. Therefore, during the subsequent step (rewiring the side branch), it would be much easier for the operator to cross into the side branch through the stent strut at the tip of the flow divider (distal cross) (Figs. 12 and 13). Rewiring the side branch through this point of the bifurcation will guarantee optimal side branch ostium scaffolding after subsequent kissing balloon inflation. On the other hand, if final kissing balloon inflation is not planned, a stepwise strategy is suggested with the first step being the systematic balloon angioplasty of the side branch followed by stenting of the main vessel (38). The drawback of this latter strategy is that predilatation of the side branch could create a dissection that could hamper guidewire recrossing through the main branch stent strut and increase the risk of crossing a proximal strut (proximal cross) (Fig. 14), which may lead to deformation of the main branch stent during subsequent kissing balloon inflation and increasing the odds of needing provisional stent implantation [Fig. 15(A) and 15(B)]. In this latter scenario, to optimally scaffold the side branch ostium, the provisional side branch stent typically protrudes into the main branch, creating a neo-carina in the main vessel [Fig. 16(D)], with potentially increased risk of stent thrombosis.

(A)

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Figure 12 Stent implantation in a true bifurcation (Medina 1,1,1) without side branch predilation. (A) Atherosclerotic plaque is located on the outer wall of the mother and daughter vessels; (B) after main branch stenting the flow divider (carina) is shifted (short arrow ). Side branch predilation should be avoided to take advantage of the carina shift, because the guidewire will cross the stent strut exactly at the tip of the flow divider (long arrow ).

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Figure 13 Stent implantation in a true bifurcation (Medina 1,1,1) without side branch predilation. (A) In the baseline angiogram, the atherosclerotic plaque is depicted as located on the outer wall of the mother and daughter vessels; (B) after 3.0 × 23 mm stent implantation at 12 atm with a jailed wire in the side branch the flow divider (carina) is shifted; (C) magnification of part B showing the carina shift (arrow ). During guidewire exchange (before kissing), the tip of the wire will cross through the stent into the side branch exactly at the tip of the flow divider (carina, shifted); (D) kissing balloon inflation; (E) final optimal angiographic result after single stent implantation and kissing balloon: the side branch ostium is optimally scaffolded by the struts of the main branch stent.

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Figure 14 Stent implantation in a true bifurcation (Medina 1,1,1) with side branch predilation. (A) Atherosclerotic plaque is located on the outer wall of the mother and daughter vessels; (B) side branch predilation dissects the atherosclerotic plaque; (C) after main branch stenting and carina shift (short arrow ), there is the possibility (induced by side branch predilation) to rewire the side branch through a proximal strut (arrow ; proximal cross).

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Figure 15 Proximal cross versus distal cross and result after kissing balloon inflation. (A) The case of proximal cross (arrow ); (B) after kissing balloon: poor side branch ostium scaffolding (short arrow ) associated with strut displacement inside the main branch stent (long arrow ). (C) The case of distal cross (arrow ); (D) after kissing balloon: good side branch ostium scaffolding (short arrow ) associated with expansion of the main branch stent at the carina level (long arrow ).

The Role of Adjunctive Devices Rotational atherectomy (Rotablator) or the “Cutting Balloon” can be used in calcified or severely fibrotic ostial side branch lesions to reduce the likelihood of side branch compromise after main branch stenting. Directional atherectomy can be helpful in debulking the main branch lesion before stenting in order to decrease the risk of excessive carina shift or occlusion, especially for large branch-ostial lesions.

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Figure 16 The case of “proximal cross” with and without the use of a spherical balloon during provisional T stenting. (A) Final result with the use of the spherical balloon postdilation strategy. (B) If an additional stent is required in the side branch, T stenting without neo-carina can be performed. (C) Risk of final result without the use of the spherical balloon post-dilation strategy. (D) In case of provisional T stenting, the TAP (T And Protrusion) with a neo-carina should be done to completely cover/scaffold the side branch ostium. This could increase the risk of subsequent restenosis and/or stent thrombosis.

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Figure 17 The case of false bifurcation (Medina 0,1,0). (A) Atherosclerotic plaque is mainly located on the outer wall of the mother vessel; (B) after main branch stenting the carina is shifted (short arrow ) and there is the possibility (due to the absence of disease in the side branch ostium) to rewire the side branch through a proximal or a distal strut (proximal cross vs. distal cross).

Stenting the Main Branch The next step is stenting the main branch across the side branch by using a moderate inflation pressure (on average 12–14 atm) (Figure 11,3). The stent diameter should be chosen based on the distal main branch size in order to decrease the risk of excessive carina shift or side branch occlusion, leaving the side branch wire outside the stent (“jailed” guidewire technique). We use the “jailed wire” technique in nearly all cases even when the side branch has a stenosis <50%, because (a) this technique favorably modifies the angle between both branches by converting a T-shaped to a Y-shaped angle; (b) this technique helps splinter the side branch open; (c) this technique is a good marker of the side branch origin in case of branch occlusion after main branch stenting; and (d) in this technique a “jailed wire” can be used to treat an occluded/dissected large side branch by passing a balloon under the main branch stent and crushing it (crush conversion). The design of the main branch stent should allow side branch access and offer optimal plaque scaffolding: A drug-eluting stent with an open cell design is the best option—for example, the TAXUS Libert`e (Boston Scientific), the Xience V (Abbott), and the Endeavor (Medtronic) stents are “bifurcation-friendly.” On bench testing, they provide good scaffolding of the side branch ostium while opening the strut of the stent placed in the main branch. This phenomenon has been called “stenting of both branches with the main branch stent.” Unfortunately, opening the strut of the main branch stent toward the side branch causes secondary stent deformation that results in the nonapposition of the main branch stent to the vessel wall opposite to the entry of the side branch. The final kissing balloon is therefore recommended in order to correct this deformation and restore adequate stent apposition of the stent on the main branch wall while optimal opening of the stent strut toward the side branch is obtained simultaneously (Figure 11,6). Stent diameter selection depends on the stent maximal diameter that we want to achieve in the mother-vessel (Dm) according to the Murray’s law by the formula Dm = 0.678 (Dd1 + Dd2). We recommend selecting stent diameter according to the main branch distal reference in order to decrease the risk of side branch occlusion due to excessive carina shift. The stent design should also allow further expansion in the mother-vessel (proximal to the carina) after kissing balloon or using a larger (short) balloon inflation. The size of stent cells is another important design parameter that influences the resulting wall coverage. The stent cell circumference varies considerably between stents with different design, as demonstrated by Mortier et al. (39). The maximal expandability of the stent cells should preferably be as large as the side branch ostium circumference to allow vessel wall opposition after kissing balloon inflation.

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SB Rewiring After Stenting the Main Branch As previously discussed, after main branch stent implantation with a “jailed wire” in place, a decision need to be made regarding the need for kissing balloon inflation. If the angiographic results in the main vessel and in the SB are satisfactory with normal flow and with residual diameter stenosis less than 50% to 75% (5,6,40), the jailed SB wire is removed and the procedure is completed (38). If the result at the side branch ostium is not satisfactory or if the operator determines that there is a need for final kissing balloon inflation, then the side branch should be rewired. Side branch rewiring can be performed by using the main branch wire by pulling it back slowly from the main vessel or by using a third wire, and pointing the tip toward the side branch ostium with the intention to cross into the side branch through the distal strut closest to the tip of the flow divider (Figure 11,4). As previously mentioned, this “distal cross” is facilitated in bifurcations with a side branch lesion (Medina 1,1,1 or 0,1,1 or 1,0,1) when the side branch is not predilated (Figs. 12 and 13). Thereafter, the “jailed wire” is withdrawn from the side branch and pushed distally in the main branch trying to advance with the wire tip bended (Figure 11,5). Pulling back the jailed wire should be performed with caution because it almost always lead to the guide being pulled deep into the coronary artery, potentially resulting in proximal coronary dissection. For most operators who do not perform a systematic kissing balloon inflation after main branch stenting, the treatment of bifurcations with minimal or no disease at the ostium of the side branch (Medina 1,0,0 or 1,1,0 or 0,1,0; also called “pseudo-bifurcations”) seems easier compared to the treatment of bifurcation with a side branch lesion (Medina 1,1,1 or 0,1,1 or 1,0,1; also called “true bifurcations”) because they stop the procedure after main branch stenting, without dilating the side branch ostium. On the contrary, more expert operators who adopt the strategy of systematic kissing balloon after main branch stenting (9,11,41) are faced with the problem of a “proximal cross” versus “distal cross” during guidewire exchange before kissing balloon (Fig. 17). In other words, although side branch rewiring is done taking care to pull back slowly the wire from the main vessel and pointing the tip toward the side branch ostium with the intention to cross into the side branch through the distal strut closest to the tip of the flow divider, this is not certain. To assist operators in identifying a wrong “proximal cross” versus a correct “distal cross” in pseudo-bifurcations, we are currently using a new tool: a spherical oversized balloon inflated at the carina after guidewire exchange and before the kissing balloon inflation (Fig. 18). This spherical balloon is sized 0.5 mm larger than the proximal reference main branch diameter and 1 mm larger than the distal main branch diameter, as illustrated in Figure 18(B). After inflation of this spherical balloon with the central marker positioned 1 mm proximal to the flow divider [Fig. 19(D)], we perform two tests: (a) a check of the free movement of the guidewire in the side branch and (b) a check of the free passage into the side branch of the balloon selected for the kissing [Fig. 19(F)]. If one or both the tests fail, we still have the chance to rewire the side branch. During the next side branch rewiring, the probability to rewire the wrong proximal strut (proximal cross) is minimized because with the prior spherical balloon inflation the proximal stent strut was apposed against the outer wall of the side branch. We have therefore a very high probability to cross into the side branch through the “right” distal strut (distal cross) [Fig. 19(G)].

Final Kissing Inflation (FKI) The final step in the provisional stenting strategy is kissing balloon inflation (Figure 11,6). Some operators perform final kissing balloon inflation systematically in all patients while others do so only if required to correct the main branch stent deformation that results from side branch dilatation. The final kissing balloon inflation, when done correctly after rewiring the side branch using “distal cross,” not only corrects the main branch stent deformation but also provides a better scaffolding of the side branch ostium and facilitates future access to the side branch (12,42). Kissing balloon inflation is usually performed with two balloons that are matched in diameter and length to the respective vessels. To perform safe kissing balloon inflation, the position of the two balloons should be adjusted in order to avoid a barotrauma (and a possible late restenosis) outside the proximal edge of the main branch stent (geographical miss). A subanalysis of the provisional stenting group in the CACTUS trial has shown that final kissing balloon was

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Figure 18 Utility of a very short (spherical) oversized, postdilation balloon to discover a proximal cross. (A) The case of proximal cross (arrow ); (B) inflation of the spherical oversized balloon (with a diameter 0.5 mm larger than the proximal reference and 1 mm larger than the distal reference diameter) with the central marker positioned 1 mm proximal to the flow divider. After spherical balloon inflation, the guidewire will be jailed and the balloon used for the subsequent kissing inflation will not cross easily in the side branch. (C) Due to protrusion of struts into the side branch ostium induced by the spherical balloon inflation, it will be easy to reposition the wire between distal struts where the wire will cross now on a wide front.

associated with better angiographic results and lower MACE rate (7). Furthermore, the final kissing balloon inflation in Medina (0,1,0) lesions guarantees a good vessel wall apposition of the proximal stent segment (Fig. 20). However, before reaching general consensus on the need for systematic final kissing balloon inflation in the provisional stenting strategy, we should wait for the results of the randomized NORDIC-KISS trial, which is evaluating this issue. Provisional Side Branch Stenting Side branch stenting is not necessary in almost 70% to 80% of bifurcations that are suitable for this technique. This is related to the concept of “stenting both branches with the main branch stent,” which is feasible in clinical practice because side branch lesions are usually short (Table 1) and for the fact that the flow divider (carina) is free of disease and only shifted after main branch stent (Figs. 12 and 13). Therefore, a provisional side branch stent is required on average in 20% of patients [between 2% and 51% of cases in five RCTs (3–7)] when results in the side branch are unsatisfactory after final kissing balloon inflation (>75% residual stenosis, dissection, TIMI flow grade <3 in a SB ≥2.5 mm or fractional flow reserve (FFR) <0.75) (40,43). Optimal stent positioning is crucial to scaffold the ostium of the side branch to avoid an ostial gap that will predispose to ostial side branch restenosis. Additional final kissing balloon inflation is then performed to correct any possible main branch stent deformation. The T technique is the most frequently used for side branch stenting (6): (a) “simple T” (without protrusion in the main vessel) (Figure 11,7a), this technique is appropriate when the final kissing balloon inflation flares the main branch stent struts to cover/scaffold the side branch ostium (the case of “distal cross”); (b) “T And Protrusion” (TAP) (33) (Figure 11,7b), this technique is used when side branch rewiring occurred through “proximal cross” and some operators use it in all patients. A balloon inflated at low pressure (2–3 atm) placed in the main branch can help side branch stent precise positioning. Provisional side branch can also be performed using the internal crush (36) (Figure 11,7c) or the inverted Culotte (35) (Figure 11,7d) techniques to be sure to provide

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(G) Figure 19 Stent implantation in a false bifurcation (Medina 1,1,0). (A) Baseline angiogram of the LCx-OM bifurcation; (B) 3.0 × 23 mm drug-eluting stent implantation at 12 atm with a jailed wire in the side branch; (C) the flow divider (carina) is mildly shifted; guidewire exchange is performed trying to cross into the side branch through the more distal strut closest to the carina (short arrows); (D) spherical 3.5 mm balloon inflation at 18 atm with the central marker of the balloon positioned 1 mm proximal to the flow divider; (E) angiogram after spherical balloon inflation; (F) a 2.0 × 15 mm new Maverick balloon failed to cross into the side branch; (G) the side branch guidewire (probably jailed after the prior proximal cross) was removed and easily repositioned in the distal struts where it crossed on a wide front; (H) final kissing balloon; (I) final result after kissing balloon with good side branch ostium scaffolding associated with expansion of the main branch stent at the carina level.

complete stent coverage of the side branch ostium in case of a proximal cross or systematically (independently from the main branch strut crossed: proximal or distal cross). The drawbacks of the inverted Culotte technique are excess of metal (double layer) covering of the mother vessel (proximal main branch) and the complexity of the procedure that requires many steps, each potentially at risk of complications. PROVISIONAL SIDE BRANCH STENTING STRATEGY: WHAT CAN GO WRONG? The primary concern with provisional side branch stenting is side branch occlusion. Although this is an uncommon event with the current techniques in the hands of experienced operators, it still can occur particularly when this technique is used in complex bifurcation anatomy (severely angulated side branches and/or severe ostial involvement). Although an occluded side branch after main branch stenting can often be salvaged by proper technique, this is not always the case. When the side branch is small and does not supply large myocardial territory its occlusion in inconsequential. However, occlusion of large side branches can result in myocardial infarction. The cases in Figures 21 and 22 illustrate two different scenarios of side branch occlusion during provisional stenting technique.

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Figure 20 The role of final kissing balloon inflation in 0,1,0 and 0,1,1 bifurcations. (A) After main branch stent implantation in a 0,1,0 or 0,1,1 lesion, the proximal stent segment is not apposed to the vessel wall; (B) after final kissing balloon inflation the proximal stent segment is well apposed to the vessel wall (short arrows) with additional scaffolding of the side branch ostium (long arrow ).

TAKE HOME MESSAGE 1. A stepwise provisional side branch stenting strategy with drug eluting stents in suitable bifurcation lesions is preferable to elective double stenting (almost 70–80% of cases). 2. The provisional stenting strategy consists of stenting the main branch first, followed, if necessary, by stenting the side branch through the main branch stent in a classic T, TAP (T And small Protrusion), inverted Culotte, or Internal Crush configuration.

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Figure 21 Side branch occlusion after main branch stent implantation using the provisional stenting strategy. (A) Baseline angiogram of the PDA-PL bifurcation in the distal RCA. The angle PDI-PL is >70◦ ; (B) drug-eluting stent implantation in the distal RCA toward the PDA without a jailed wire in the PL branch due to the unfavorable SB take-off; (C) final angiogram after stenting showing side branch occlusion.

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Figure 22 Side branch subocclusion after main branch stent implantation using the provisional stenting strategy. (A) Baseline angiogram of the OM1-OM2 bifurcation; (B) drug-eluting stent implantation with a jailed wire in the side branch; (C) angiogram after main branch stenting; (D) guidewire exchange: the tip of the main branch guidewire was pulled-back and directed towards the SB ostium to cross through the stent into the side branch; (E) the guidewire crossed into the SB but was subintimal due to a proximal cross; (F) final angiogram showing ostial dissection and subocclusion.

3. Patient selection for provisional stenting is essential for success. There are four anatomic elements to evaluate: (a) the angle between the two branches, (b) the side branch lesion severity and length, (c) the observed/expected diameter, and (d) the plaque distribution. 4. The design of the main branch stent should allow side branch access and offer optimal plaque scaffolding. 5. The “jailed wire” technique should be used in all cases of provisional stenting. 6. When final kissing balloon inflation is planned, we recommend avoiding side branch predilation. 7. A new adjunctive tool (a spherical oversized balloon inflated at the carina after guidewire exchange and before the kissing balloon inflation) can be used to assist operators in identifying a wrong “proximal cross” versus a correct “distal cross” in pseudo-bifurcations. 8. Performing provisional side branch stenting in “unsuitable bifurcation anatomy” carries the risk of side branch closure. REFERENCES 1. Tsuchida K, Colombo A, Lefevre T, et al. The clinical outcome of percutaneous treatment of bifurcation lesions in multivessel coronary artery disease with the sirolimus-eluting stent: insights from the Arterial Revascularization Therapies Study part II (ARTS II). Eur Heart J 2007; 28(4):433–442. 2. Pflederer T, Ludwig J, Ropers D, et al. Measurement of coronary artery bifurcation angles by multidetector computed tomography. Invest Radiol 2006; 41(11):793–798. 3. Colombo A, Moses JW, Morice MC, et al. Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions. Circulation 2004; 109(10):1244–1249. 4. Pan M, de Lezo JS, Medina A, et al. Rapamycin-eluting stents for the treatment of bifurcated coronary lesions: a randomized comparison of a simple versus complex strategy. Am Heart J 2004; 148(5):857– 864.

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5. Steigen TK, Maeng M, Wiseth R, et al. Randomized study on simple versus complex stenting of coronary artery bifurcation lesions: the Nordic bifurcation study. Circulation 2006; 114(18):1955–1961. 6. Ferenc M, Gick M, Kienzle RP, et al. Randomized trial on routine vs. provisional T-stenting in the treatment of de novo coronary bifurcation lesions. Eur Heart J 2008; 29(23):2859–2867. 7. Colombo A, Bramucci E, Sacca S, et al. Randomized study of the crush technique versus provisional side-branch stenting in true coronary bifurcations: the CACTUS (Coronary Bifurcations: Application of the Crushing Technique Using Sirolimus-Eluting Stents) Study. Circulation 2009; 119(1):71–78. 8. Hildick-Smith D. The British Bifurcation Coronary Study: old, new and evolving strategies (BBC ONE study). Paper Presented at: Transcatheter Cardiovascular Therapeutics (TCT)2008; Washington, DC. 9. Legrand V, Thomas M, Zelisko M, et al. Percutaneous coronary intervention of bifurcation lesions: state-of-the-art. Insights from the second meeting of the European Bifurcation Club. EuroIntervention 2007; 3(9):44–49. 10. Medina A, Suarez de Lezo J, Pan M. A new classification of coronary bifurcation lesions. Rev Esp Cardiol 2006; 59(2):183. 11. Thomas M, Hildick-Smith D, Louvard Y, et al. Percutaneous coronary intervention for bifurcation disease. A consensus view from the first meeting of the European Bifurcation Club. EuroIntervention 2006; 2(6):149–153. 12. Brunel P, Lefevre T, Darremont O, et al. Provisional T-stenting and kissing balloon in the treatment of coronary bifurcation lesions: results of the French multicenter “TULIPE” study. Catheter Cardiovasc Interv 2006; 68(1):67–73. 13. Furukawa E, Hibi K, Kosuge M, et al. Intravascular ultrasound predictors of side branch occlusion in bifurcation lesions after percutaneous coronary intervention. Circ J 2005; 69(3):325–330. 14. Finet G, Gilard M, Perrenot B, et al. Fractal geometry of arterial coronary bifurcations: a quantitative coronary angiography and intravascular ultrasound analysis. EuroIntervention 2008; 3 (12):490– 498. 15. Kassab GS, Fung YC. The pattern of coronary arteriolar bifurcations and the uniform shear hypothesis. Ann Biomed Eng 1995; 23(1):13–20. 16. Kimura BJ, Russo RJ, Bhargava V, et al. Atheroma morphology and distribution in proximal left anterior descending coronary artery: in vivo observations. J Am Coll Cardiol 1996; 27(4):825–831. 17. Peacock J, Jones T, Tock C, et al. An in vitro study on the effect of branch points on the stability of coronary artery flow. Med Eng Phys 1997; 19(2):101–108. 18. Perktold K, Hofer M, Rappitsch G, et al. Validated computation of physiologic flow in a realistic coronary artery branch. J Biomech 1998; 31(3):217–228. 19. Doriot P, Dorsaz P, Dorsaz L, et al. Accuracy of coronary flow measurements performed by means of Doppler wires. Ultrasound Med Biol 2000; 26(2):221–228. 20. Weydahl ES, Moore JE. Dynamic curvature strongly affects wall shear rates in a coronary artery bifurcation model. J Biomech 2001; 34(9):1189–1196. 21. Jin S, Yang Y, Oshinski J, et al. Flow patterns and wall shear stress distributions at atheroscleroticprone sites in a human left coronary artery—an exploration using combined methods of CT and computational fluid dynamics. Conf Proc IEEE Eng Med Biol Soc 2004; 5:3789–3791. 22. Fabregues S, Baijens K, Rieu R, et al. Hemodynamics of endovascular prostheses. J Biomech 1998; 31(1):45–54. 23. Mallus MT, Kutryk MJ, Prati F, et al. Extent and distribution of atherosclerotic plaque in relation to major coronary side-branches: an intravascular ultrasound study in vivo. G Ital Cardiol 1998; 28(9):961–969. 24. Wahle A, Lopez JJ, Olszewski ME, et al. Plaque development, vessel curvature, and wall shear stress in coronary arteries assessed by X-ray angiography and intravascular ultrasound. Med Image Anal 2006; 10(4):615–631. 25. Papafaklis MI, Katsouras CS, Theodorakis PE, et al. Coronary dilatation 10 weeks after paclitaxeleluting stent implantation. No role of shear stress in lumen enlargement? Heart Vessels 2007; 22(4):268– 273. 26. Banks J, Bressloff NW. Turbulence modeling in three-dimensional stenosed arterial bifurcations. J Biomech Eng 2007; 129(1):40–50. 27. Montenegro MR, Eggen DA. Topography of atherosclerosis in the coronary arteries. Laboratory investigation. Lab Invest 1968; 18(5):586–593. 28. Caro CG, Fitz-Gerald JM, Schroter RC. Atheroma and arterial wall shear. Observation, correlation and proposal of a shear dependent mass transfer mechanism for atherogenesis. Proc R Soc London B Biol Sci 1971; 177(46):109–159. 29. Schwartz CJ, Mitchell JR. Observations on localization of arterial plaques. Circ Res 1962; 11:63–73. 30. Asakura T, Karino T. Flow patterns and spatial distribution of atherosclerotic lesions in human coronary arteries. Circ Res 1990; 66(4):1045–1066.

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31. Oviedo C, Maehara A, Mintz G, et al. A critical intravascular ultrasound appraisal of the angiographic classification of bifurcation lesions: where is the plaque really located? J Am Coll Cardiol 2008; 51(Poster 2902–2916): B23–B98. 32. Lefevre T, Louvard Y, Morice MC, et al. Stenting of bifurcation lesions: a rational approach. J Interv Cardiol 2001; 14 (6):573–585. 33. Burzotta F, Gwon HC, Hahn JY, et al. Modified T-stenting with intentional protrusion of the sidebranch stent within the main vessel stent to ensure ostial coverage and facilitate final kissing balloon: the T-stenting and small protrusion technique (TAP-stenting). Report of bench testing and first clinical Italian-Korean two-centre experience. Catheter Cardiovasc Interv 2007; 70 (1):75–82. 34. Chevalier B, Glatt B, Royer T, et al. Placement of coronary stents in bifurcation lesions by the “culotte” technique. Am J Cardiol 1998; 82(8):943–949. 35. Kaplan S, Barlis P, Dimopoulos K, et al. Culotte versus T-stenting in bifurcation lesions: immediate clinical and angiographic results and midterm clinical follow-up. Am Heart J 2007; 154 (2):336–343. 36. Porto I, van Gaal W, Banning A. “Crush” and “reverse crush” technique to treat a complex left main stenosis. Heart (Br Card Soc) 2006; 92 (8):1021. 37. Darremont O, Lefevre T, Brunel P, et al. Treatment of bifurcation lesions with Paclitaxel-eluting stents. Insights from the SURF registry. Eur Heart J 2006; 27 (Abstract Suppl):765–766. 38. Pan M, Suarez de Lezo J, Medina A, et al. A stepwise strategy for the stent treatment of bifurcated coronary lesions. Catheter Cardiovasc Interv 2002; 55 (1):50–57. 39. Mortier P, De Beule M, Van Loo D, et al. Finite element analysis of side branch access during bifurcation stenting. Med Eng Phys 2008; 31(4):434–440. 40. Koo BK, Kang HJ, Youn TJ, et al. Physiologic assessment of jailed side branch lesions using fractional flow reserve. J Am Coll Cardiol 2005; 46 (4):633–637. 41. Ormiston JA, Webster MW, Ruygrok PN, et al. Stent deformation following simulated side-branch dilatation: a comparison of five stent designs. Catheter Cardiovasc Interv 1999; 47(2):258–264. 42. Ormiston JA, Webster MW, El Jack S, et al. Drug-eluting stents for coronary bifurcations: bench testing of provisional side-branch strategies. Catheter Cardiovasc Interv 2006; 67 (1):49–55. 43. Koo BK, Park KW, Kang HJ, et al. Physiological evaluation of the provisional side-branch intervention strategy for bifurcation lesions using fractional flow reserve. Eur Heart J 2008; 29 (6):726–732.

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Physiologic Guidance of Provisional Stenting in Coronary Bifurcation Lesions Michael J. Lim Saint Louis University, St. Louis, Missouri, U.S.A.

Bon-Kwon Koo Seoul National University Hospital, Seoul, South Korea

INTRODUCTION The treatment of bifurcation lesions utilizing a technique of provisional side branch (SB) stenting fundamentally requires the operator to make bedside decisions regarding specific treatments within the SB after the stent is placed in the main vessel (MV). For the most part, current practice dictates careful evaluation of the angiogram obtained after MV stenting to look for SB ostial narrowing, reduced flow down the SB, or dissection. Although clear-cut evidence of decreased flow or dissection mandates further therapy to preserve the patency of the SB, the majority of cases do not possess these definitive findings. Within the protocol of the NORDIC bifurcation study, operators were only allowed to further dilate the SB in the provisional group if there was angiographic evidence of impaired TIMI flow (1). Furthermore, stenting of the SB (in addition to the MV) was allowed only for complete occlusion of that branch. This randomized study showed that there was no clinical advantage seen for a more complex strategy of stenting both the MV and the SB in patients enrolled in this trial (patients with moderate and focal lesions at the SB ostium). However, many operators may be less comfortable leaving more subtle abnormalities without angioplasty or stent treatment despite preserved TIMI flow, especially ostial SB angiographic stenoses that appear significant. Operators are also faced with the urge to utilize an upfront two-stent strategy because of significant plaque burden within the MV and SB on the diagnostic angiogram. This chapter discusses the utilization of fractional flow reserve to guide decision making in the cath lab for patients with bifurcation disease. Invasive physiologic assessment of coronary stenoses utilizing fractional flow reserve (FFR) has proven to be an extremely useful tool in determining coronary stenoses that require stenting versus those that can be treated with medical therapy alone. These same tenets for intermediate epicardial coronary lesions can be extrapolated for use in bifurcation lesions. BACKGROUND ON FRACTIONAL FLOW RESERVE Invasive physiologic assessment of a coronary artery stenosis with FFR has been verified as a tool for the interventional cardiologist to address the question whether performing an angioplasty (PCI) in an intermediate coronary lesion is necessary. An intermediate lesion, usually reported in the range between 40% and 70% narrowing, is the most frequently encountered stenosis in patients with CAD and its treatment in the cardiac catheterization lab is highly variable. Ultimately, PCI has the potential to remove the burden of myocardial ischemia and subsequent anginal symptoms as a result of a coronary stenosis. Multiple studies have shown that an FFR of >0.75 translates into low subsequent cardiovascular event rates. Furthermore, performance of PCI on these non–ischemia-producing lesion did not lower event rates for these patients (2–4). Most of the data supporting the utilization of FFR in patients have been in single-vessel stable disease. Recently, the FAME trial evaluated the utility of FFR in patients with multivessel disease and PCI utilized drug-eluting stents (5). Utilizing an FFR threshold of <0.80 to signify an ischemia producing lesion, this study confirmed the lack of benefit in performing PCI for non– ischemia-producing lesions in over 1000 randomized patients. Specifically, this study utilized

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the FFR-guided decision-making approach to stenting (i.e., stents only placed in lesions with an FFR <0.80) as compared to an approach relying only on angiography (i.e., stents placed in lesions with a >50% stenosis). After one year of follow-up, the FFR-guided group had a significantly lower MACE rate. Thus, even in complex patients, FFR can be used to direct decision making in the cath lab. Besides confirming previous studies showing low subsequent event rates in those patients in whom PCI was not performed, the FAME study gave considerable credence for defining the ischemic threshold for performing PCI as an FFR of 0.80 or less. Previous to this study, validation studies had shown that a value of 0.75 was highly correlative with ischemia detection in noninvasive studies, but there was a “gray-zone” that allowed for ischemia to be present up to an FFR of 0.80 if the patient had significant left ventricular hypertrophy. FAME has shown that an operator can implement an FFR ischemic cut-off of 0.80 to ensure that no false-negative FFR lesions are undetected and still have a dataset supporting excellent clinical outcomes. That being said, the best pure cut-off value to correlate with an ischemic-producing lesion remains an FFR <0.75. DETERMINING THE SIGNIFICANCE OF SB OSTIAL LESIONS The precise determination of ostial lesion severity by angiography has proven to be difficult due to angulation, branch overlap, and imaging artifacts. This difficulty is demonstrated by the need for additional angulated radiographic views, and at times, cannot be resolved despite the angiographer’s best efforts. Fundamentally, angiographic guidance for percutaneous treatment of a bifurcation involves at least the ostium of the SB and, in the case of a distal left main, the ostia of the LAD and LCx. Studies have also evaluated the utility of intravascular ultrasound (IVUS) to help guide decision making in the cath lab. Given the previously stated limitations of the ability to fully visualize bifurcation lesions with angiography alone it is not surprising that IVUS has proven useful in providing high-quality quantitative and qualitative measures of plaque burden at bifurcation lesions. A recent case series showed that the extent of plaque burden at the SB ostium (as determined by IVUS) predicts the incidence of SB closure as compared to those bifurcations in which the plaque was exclusively in the MV (6). This finding suggests that if the operator suspects a high probability that the SB will eventually require stenting anyway, then why not elect for a two-stent strategy at the start? Diverting from the provisional SB stent approach could be considered if the patient would be left with significant angina following the procedure. Although IVUS can show the location of plaque, its ability to assess the physiologic significance of the plaque has only been shown in the proximal or mid segments of main epicardial vessels (7). Furthermore, seeing larger plaque burdens within the coronary tree before stenting a bifurcation lesion may prompt more operators to utilize a dual-stenting approach and increase the overall complexity of the procedure. Increasing the complexity of an intervention would be warranted if proven to provide improved outcomes, and as discussed in other chapters of this text, this is yet to be proven. Physiologic assessment of the SB with FFR would alert the operator to the presence of an ischemia causing SB lesion and potentially influence the treatment by preferentially utilizing a two-stent strategy, especially when there appears to be angiographic disease in the SB. We have previously shown (8) that the angiographic specificity is quite poor in predicting the significance of ostial SB lesions as compared to FFR. These data showed that ostial angiographic lesions of less than 70% were never associated with an ischemic FFR. For those ostial lesions of 70% or greater, 20% were associated with a physiologically significant lesion which would be responsible for ischemia. Prebifurcation assessment in this manner may allow the operator to maximize the opportunity to treat bifurcations with a provisional strategy. FFR UTILITY IN ASSESSING THE NEED TO TREAT AN OSTIAL SB LESION A 64-year-old woman presents to the hospital with recurrent atypical chest discomfort. She has a nondiagnostic electrocardiogram, showing no T-wave or ST-segment abnormalities consistent with ischemia, and has negative troponins. She undergoes an adenosine perfusion stress test that revealed normal left ventricular function and a small, mild anterior reversible perfusion

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Figure 1 Coronary angiography in the RAO caudal (A) and LAO (B) projections demonstrating a lesion in the ostium of the circumflex coronary artery.

defect consistent with ischemia. She then underwent diagnostic angiography to evaluate her coronary anatomy. Angiograms [Fig. 1(A) and 1(B)] showed no angiographic stenoses within the LAD or RCA, but suggested a narrowing in the ostium of the circumflex. Although the patient does have atypical chest discomfort and, at worst, single-vessel disease, the question of whether this lesion is responsible for her symptoms remains unclear. To answer this question, FFR was performed by advancing a pressure wire into the circumflex through a guide catheter after intravenous anticoagulation was given. Intravenous adenosine (140 ␮g/kg/min IV) was infused and the FFR of the circumflex was found to be 0.89. This value is clearly above the ischemic threshold and, thus, the lesion was left untreated and the patient was discharged. FFR-Guided Provisional Stenting: Why This Approach Should Be Routinely Used? A provisional stent strategy remains the preferable approach for most patients with bifurcation lesions who are similar to those enrolled in the clinical trials (patients with moderate and focal lesions in the SB ostium). However, the steps that follow the placement of the stent in the MV are not universally agreed upon. Basically, the operator must make a decision regarding the need for dilation of the ostium of the SB and, subsequently, whether the SB needs to be stented. This decision process revolves around whether the ostium of the SB is compromised, much like the discussion in the previous section. The operator relies on the angiogram of the bifurcation to make this decision, but the angiographic ability to define significance of an obstruction in a “jailed” SB is more challenging because the metal stent struts provide more distortion to the picture. This decision appears strikingly similar to the discussion of the significance of an ostial SB—one in which the angiogram was not as helpful as one would want. Furthermore, the overall goal for treating the patient remains the same: to abolish all coronary stenoses responsible for ischemia. Thus, it is only logical that FFR could be utilized at this step to guide further therapy or allow the operator to end the procedure with confidence. The best collection of data to support the assessment of FFR in “jailed” SBs is that collected by Koo et al. (9). In a group of 94 “jailed” SBs, FFR was measured and compared to quantitative coronary angiographic assessment of the SB. Although there was a significant correlation between these two parameters (r = −0.41, p < 0.001), the variability of the points suggests little accuracy of QCA to predict a positive FFR (Fig. 2). Of those lesions that were 90% or greater, only 14 out of 25 had FFR values <0.75, demonstrating the inability of angiography to predict “jailed” SB lesion severity.

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The true mark of a useful strategy in coronary intervention, however, is not whether a lesion is physiologically or angiographically significant, but whether the clinical outcome is acceptable for a given strategy. The same group evaluated a strategy of MV stenting followed by assessment of the “jailed” SB by FFR (10). The SB was subsequently treated if an abnormal FFR (<0.75) was found. Ninety-one patients with bifurcation lesions were treated in this manner and then followed for six months. Only 30% of all “jailed” SB lesions were found to have an FFR <0.75 in this patient population with 96% of all SBs able to be accessed successfully with the pressure wire. The SB lesions that had an FFR <0.75 underwent further therapy with “kissing” balloon angioplasty, resulting in a follow-up FFR of these SBs >0.75 in 92% of them. Six-month follow-up in these patients found a 48% binary restenosis (defined as angiographic stenosis >75%) of the SBs. However, when these stenoses were assessed by FFR, only 8% had a value less than 0.75. Furthermore, TVR was only required in 5 of these 91 patients over the follow-up period. These data repeatedly demonstrate that angiography tends to overestimate the degree of stenosis present in ostial SB lesions. When further therapy of the SB is restricted to those patients with physiologically significant SB narrowing after MV stenting, excellent clinical outcomes are achieved. Thus, FFR-guided decision making regarding further treatment of the SB after the placement of an MV stent simplifies not only the decision-making process but also the interventional procedure for the patient while providing excellent discriminatory capability of FFR-guided provisional stenting. Limitations to Generalizability Although the use of FFR-guided decision making in treatment of bifurcation lesions is theoretically appealing, there are two issues that need to be addressed before this approach can be recommended for routine use: 1. Is the current FFR wire technology versatile enough to be used successfully in the majority of unselected patients with jailed SBs? Although Koo and colleagues (9) have reported a success rate of 97% in crossing jailed SBs with the FFR wire, patients in this study may represent a lower level of bifurcation lesions complexity. This is confirmed by the fact that two-third of patients in this report had a class (1–2) bifurcation morphology and the SB ostial lesions were focal (mean length

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6 mm) and only of moderate severity (%DS = 45%). Success in wiring these lesions cannot be generalized to more severe lesions with more complex morphology. 2. Is the clinical outcome of patients undergoing FFR-guided provisional stenting better than that of patients undergoing angiography-guided provisional stenting? Although the FAME study demonstrated that FFR-guided multivessel intervention is superior to angiography-guided multivessel intervention, this data cannot be automatically generalized to intervention on side branches. The current data certainly does not support this generalization. In the first report by Koo et al. (9), there was no comparative control arm. In the second Koo report the outcome of patients undergoing FFR-guided provisional stenting was not better than a historical group of patients who underwent angiographyguided provisional stenting (10). Moreover, the NORDIC study, which included similar patients to the study by Koo (i.e., bifurcations with moderate and focal disease in the side branches), showed very low rate of crossover to stenting in the angiography-guided provisional stenting arm and equivalent outcome to double stenting. On the basis of these data, how can we justify adding the time and the cost of using FFR to guide provisional stenting without proving that it provides superior outcome to angiographicguided provisional stenting? Until a randomized trial proves this point, this approach should only be used selectively. CASE EXAMPLES Case #1 A 58-year-old man presents to the catheterization lab after being admitted to the hospital with unstable angina. He undergoes a precatheterization stress test, which showed anterior ischemia, and was found to have an LAD lesion, which was deemed to be significant [Fig. 3(A)]. The LAD is treated with a stent, “jailing” the diagonal branch that arises in the same region as the lesion. After the stent was placed, routine angiography shows a “pinch” to the ostium of the diagonal branch [Fig. 3(B)]. The operators weigh the option of wiring the diagonal and performing kissing balloon angioplasty but instead, opt to wire the diagonal with a pressure wire and measure FFR.

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Figure 3 (A) Coronary angiography in the RAO cranial projection showing a significant lesion in the LAD involving a diagonal branch. (B) Coronary angiography following stent placement in the LAD showing impingement of the diagonal branch.

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With intravenous adenosine hyperemia, the FFR of the diagonal branch was 0.85. The operators then removed the wires, and the patient was sent back to the floor without further angioplasty. Case #2 A 70-year-old man undergoes diagnostic angiography secondary to unstable angina. He is found to have serial lesions in his LAD, one before and one after a sizeable diagonal branch [Fig. 4(A)]. Baseline FFR is performed in the LAD and diagonal to get more data for planning of the interventional strategy, and it is found that the FFR in the LAD is 0.71 and in the diagonal it is 0.78. This FFR data indicates that the two serial lesions in the LAD are in fact physiologically significant (FFR = 0.71). However, the diagonal FFR of 0.78 is most likely reflective of the LAD lesion prior to the take-off of the branch and, therefore, the operator elects to stent the LAD with a long stent covering both lesions and “jailing” the diagonal (this stent is deployed over

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Figure 4 (A) Coronary angiography in the RAO cranial projection demonstrating serial LAD lesions before and after a large diagonal branch. (B and C) Follow-up angiography in the RAO and LAO projections, showing that the diagonal branch has an angiographic “pinch” after it is jailed and a pressure wire in the diagonal. (D) Final RAO angiography.

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the pressure wire used to FFR the LAD). Subsequent angiography demonstrates a “pinch” in the ostial diagonal that did not seem to be present prior to the stent placement [Fig. 4(B)]. Repeat FFR assessment [Fig. 4(C)] is performed by advancing a pressure wire through the LAD stent struts and into the diagonal. With adenosine-induced hyperemia, the diagonal FFR is 0.71. The LAD–diagonal bifurcation is then treated with the inflation of balloons in a “kissing” fashion over the two pressure wires that are in the LAD and diagonal. Follow-up FFR is then performed in the LAD (0.87) and the diagonal (0.83) and proves that there is no physiologically significant obstruction to coronary blood flow left at the site [Figure 4(D) shows the final angiogram]. This case shows not only the ability of the ostial “pinch” seen on the post-stent angiogram to sometimes be physiologically significant, but also the ability for an operator to perform a bifurcation procedure working over the coronary pressure wire (in this case, two pressure wires). Of note, however, because of the pressure sensor housed within the wire and the hydrophilic coating that is now on the shaft of commercially available pressure wires, it is not recommended to entrap one of these wires left in a side branch with a main branch stent. The preferred technique would be to leave a workhorse wire in the branch instead of the pressure wire or to remove the pressure wire before deploying the main branch stent. One may ask about finishing the case with a diagonal FFR of only 0.83? While this value represents that there indeed is a residual stenosis within the diagonal branch, it is above the ischemic threshold and, therefore, should not result in symptoms for the patient. However, operators are acutely aware of the potential for restenosis of the ostial side branch, especially when it has been treated by a balloon inflation. So, is the likelihood of restenosis of this diagonal branch higher with an FFR of 0.83 than it would be if the value was greater or the side branch was stented? There is no available data to answer this question and it becomes an operator decision, weighing the increased complexity of a two-stent procedure with the available data supporting the benefit of stenting the side branch. Case #3 A 73-year-old woman is found to have a lesion in her circumflex, just after a large OM branch [Fig. 5(A)]. FFR assessment of the OM branch was performed initially, indicating that there was no baseline physiologic gradient (FFR = 0.98). The LCx was then wired and stented in a manner that “jailed” the large OM branch [Fig. 5(B)]. The OM branch was then rewired with the original pressure wire (which was removed while the LCx was treated) and FFR was measured and found to be 0.98, identical to the baseline value. No further treatment was performed, and the final angiogram is shown in Figure 5(C). This case demonstrates that the plaque burden in this bifurcation was likely confined distal to the OM branch and the stenting of this vessel did not change the geometry of the OM take-off enough to cause any physiologic affect on blood flow. In our experience, it is an extremely rare occurrence that a jailed side-branch cannot be accessed with a pressure wire. We place a double-bend on the pressure wire (a distal 50–60 degrees bend and a more proximal 40 degrees bend), wire the main vessel so that the tip of the wire is beyond the side branch, and then pull the wire back while torquing the tip toward the ostium of the side branch. Occasionally, subtle changes in the bend are necessary when the initial curvature does not access the branch vessel. Case #4 A 57-year-old man is found to have a complex series of lesions within his LCx and large first OM branch [Fig. 6(A)]. The mid-OM lesion is seen at a branch point in the vessel that the operator intends to stent and then there is an irregular nature to the LCx–OM bifurcation that the operator also intends to stent. Working distal to proximal, the OM lesion is stented and the side branch off of the main OM is felt to be too small to require subsequent treatment. The proximal OM is then stented, with the stent starting in the LCx proper, thereby “jailing” the AV-LCx. Subsequent angiography [Fig. 6(B)] demonstrates a “pinch” in the ostium of the AV-LCx. A pressure wire is then directed through the stent struts and into the distal AV-LCx, intravenous adenosine is given, and the FFR of this branch was found to be 0.83. Although not normal, this value is above the ischemic threshold and the operator elected to perform a final angiogram and end the procedure at this point with a successful result [Fig. 6(C)]. As in previous cases, the reader should note that lesions that occur in “jailed” side branches are

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(C) Figure 5 (A) Coronary angiography in the RAO caudal projection demonstrating a severe stenosis in the circumflex artery that appears to arise distal to a large OM branch. (B) Follow-up angiography after the circumflex is stented, showing a change in the take-off angle of the branch without severe stenosis. (C) Final angiography prior to the completion of the procedure.

not usually associated with a physiologically significant stenosis, despite their disconcerting angiographic appearance. Case #5 A 53-year-old man is found to have a subtotal occlusion of the proximal LAD [Fig. 7(A)]. The operator elects to wire the LAD, which is accomplished easily with a hydrophilic wire, and the vessel is subsequently ballooned and stented [Fig. 7(B)]. Subsequent angiography demonstrates that there is a moderately sized diagonal branch that was “jailed” by the LAD stent, and the ostium appears to be significantly obstructed by angiography [Fig. 7(C)]. As previously described, a pressure wire is placed into the LAD and across the stent struts into the diagonal branch [Fig. 7(D)]. FFR is performed and is found to be 0.76. At this point, the operator

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Figure 6 (A) Coronary angiography in the RAO caudal projection demonstrating multiple lesions within the circumflex and first obtuse marginal branch. (B) Angiogram after stenting across the AV-circumflex and into the OM branch. (C) Final angiography.

decides to further treat the bifurcation with kissing balloons in the LAD and in the diagonal (over the pressure wire). After removal of the balloons, follow-up FFR of the diagonal branch becomes 0.93 and the procedure is completed [Fig. 7(E)]. This case shows that even when a side branch is not readily apparent on initial angiograms, its appearance after main branch stenting can be handled in a similar manner. Performing kissing balloon inflations over a pressure wire does not require any special techniques and does not compromise the wire to be able to perform subsequent FFR measurements. Follow-up FFR in the side branch becoming nonphysiologically significant is a finding that we utilize to avoid stenting the side branch. In our experience, the inability to “normalize” an FFR above the ischemic threshold is most often related to dissections arising in the ostia of the side branch and is the sign that a side branch stent needs to be placed. Additional case examples that illustrate how FFR can be utilized in bifurcation stenting are shown in Figures 8–11. The combination of IVUS and FFR to treat an LAD lesion is shown in Figure 8. The case in Figure 9 shows an example of patient with a left main lesion treated with

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(E) Figure 7 (A) Coronary angiography in the RAO caudal projection showing a subtotal occlusion of the LAD. (B) Stent placement in the LAD. (C) LAO cranial angiogram demonstrating a stenosis in a “newly discovered” diagonal branch. (D) Pressure wire in the diagonal branch before measuring FFR. (E) Final angiogram.

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Figure 8 (See color insert ) (A) A 57-year-old man was admitted due to the abnormality in a radionuclide scan (left ). Angiogram showed the stenoses located at the mid-LAD and proximal LAD bifurcation segments. By intravascular ultrasound, minimal lumen area was 3.0 mm2 at mid-LAD and 3.1 mm2 at LAD ostium. (B) FFR at distal LAD was 0.69. A significant pressure step up was found only at a LAD ostial lesion in a pressure pull-back curve (green line). Therefore, additional stent was implanted at the LAD ostium. (C) A radioisotope scan six months after stent implantation shows no perfusion defect.

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Figure 9 FFR-guided left main stenting in an ambiguous distal left main–LAD ostial lesion. (A) In an angiogram of a 65-year-old male, intermediate stenosis at the distal left main–LAD ostium was found. (B) (See color insert ) FFR measured at mid-LAD was 0.69. Pulling back the pressure wire from mid-LAD to left main ostium revealed a significant pressure step-up across the lesion. (C) (See color insert ) Crossover stenting from left main to proximal LAD was performed. FFR was measured at a jailed left circumflex artery and found to be 0.67 (left ). FFR was measured again after kissing balloon inflation, and it was 0.83 (right ). (D) (See color insert ) Despite a physiologically negative FFR, the operator felt that the LCx result was suboptimal and an additional stent was implanted followed by kissing balloon inflation. Final FFR was 0.95 and 0.90 at LAD and LCx, respectively. (E) Two years after stenting, follow-up angiography shows no significant restenosis.

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(B) Figure 2.1B Representative histologic images of coronary plaque in a bifurcation lesion. (a) Longitudinal section of trifurcation (left main/LAD/Ramus intermedicus/CX). There are atherosclerotic plaques in the lateral wall, while the flow divider regions are spared (b). (c) Longitudinal section taken in the region of LCM/left obtuse marginal bifurcation. Note, severe luminal narrowing proximal and at the bifurcation. Low shear regions show atherosclerotic plaque development including necrotic core formation whereas flow divider regions show minimal intimal thickening (d, e). Source: Adapted from Ref. 7. Courtesy of Virmani R et al.

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(C) Figure 2.1C Three-dimensional reconstruction of the lumen (red) and outer vessel wall (green) of the left main coronary artery, left main bifurcation, left anterior descending coronary artery (LAD), and circumflex coronary artery (a). Detailed view of the left main bifurcation (white box) demonstrating the blood flow pattern in the lumen with an area (arrow ) of disturbed slow recirculating flow on the side of the LAD (b), where lower values of computed endothelial shear stress (c) and increased plaque thickness (d) are found. Source: Adapted from Ref. 9.

Figure 2.16 An illustration of the proximal rim, in-bifurcation, and distal rim of bifurcation cross-sections using virtual histology and optical coherence tomography. Source: Adapted from Ref. 35.

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Figure 4.8A A 57-year-old man was admitted due to the abnormality in a radionuclide scan (left ). Angiogram showed the stenoses located at the mid-LAD and proximal LAD bifurcation segments. By intravascular ultrasound, minimal lumen area was 3.0 mm2 at mid-LAD and 3.1 mm2 at LAD ostium.

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Figure 4.8B FFR at distal LAD was 0.69. A significant pressure step up was found only at a LAD ostial lesion in a pressure pull-back curve (green line). Therefore, additional stent was implanted at the LAD ostium.

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A radioisotope scan six months after stent implantation shows no perfusion defect.

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Figure 4.9B FFR measured at mid-LAD was 0.69. Pulling back the pressure wire from mid-LAD to left main ostium revealed a significant pressure step-up across the lesion.

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Figure 4.9C Crossover stenting from left main to proximal LAD was performed. FFR was measured at a jailed left circumflex artery and found to be 0.67 (left ). FFR was measured again after kissing balloon inflation, and it was 0.83, which is below the successful angioplasty criterion of 0.9 (right ).

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TAXUS 3 × 12mm KBI: 3.5 × 10 & 3 × 10 (D) Figure 4.9D Additional stent was implanted at a circumflex artery followed by kissing balloon inflation. Final FFR was 0.95 and 0.90 at LAD and LCx, respectively.

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(A) Figure 4.10A A case with multiple jailed branches after left main to LAD crossover stenting. By angiogram, left circumflex ostium and the os of three diagonal branches seem to have significant stenosis. FFR was 0.82 for LCx ostium and 0.94 for 1st diagonal, 0.77 for the 2nd diagonal, and 0.82 for the 3rd diagonal branches.

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(B) Figure 4.10B A radioisotope scan after stenting shows no reversible perfusion defect at the territories of LCx and diagonal branches.

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Figure 4.11 Functional outcome of a nontreated jailed circumflex artery. Just after stenting, FFR was 0.87 at a jailed circumflex artery (left ). Nine months after stenting, FFR at LCx is still 0.85 (right ). There was only a minimal functional late loss of 0.02 in this nontreated jailed circumflex artery.

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Distal LM Figure 8.17I We assessed the severity of LCX and RI lesions by IVUS and fractional flow reserve (FFR); both the lesions were functionally significant with an FFR of 0.73 in the RI and 0.77 in LCX.

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Figure 9.5 Overlap of the balloons in the distal LMCA. Visual inspection of the LAD (red ) balloon located over the LCX (blue) balloon (A, upper panel), and the reverse relationship (B, upper panel). Fluoroscopic inspections in the anterior–posterior caudal (middle panels), and spider (lower panels) views. The arrows indicate the guidewire advanced from the LMCA into the LCX. The wire is visible on the myocardial side of the distal LMCA when the LAD balloon is positioned over the LCX balloon (A, middle and lower panels), and on nonmyocardial side when the overlapping is reversed (B, middle and lower panels). Source: From Ref. 12.

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Figure 9.16 MFCT images of T-stenting and protrusion (TAP) in the 3-D LMCA bifurcation model. Experiments were performed using Driver (upper panels) and Bx Velocity stents (lower panels) for the MV. (A, E) Long axis 3D image. (B, F) Cross-sectional view at the distal LMCA. Blue and red lines indicate the LCX and the LAD stents, respectively. Wide opening of the orifice of the LCX stent was observed in the panel (B), whereas the restriction of the stent expansion was observed in the panel (F). (C, G) Cross-sectional view corresponding to the line “a” in the 3-D image. The squeezing of the LCX stent at the strut where the LCX stent was protruded into the LMCA was small in the panel (C), whereas it was apparent in the panel (G) (arrows). (D, H) Cross-sectional view corresponding to the line “b.” There was a gap at the distal carina in the panel (H) (arrow ).

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(B) Figure 10 (See color insert ) (A) A case with multiple jailed branches after left main to LAD crossover stenting. By angiogram, left circumflex ostium and the ostia of three diagonal branches seem to have significant stenosis. FFR was 0.82 for LCx ostium and 0.94 for 1st diagonal, 0.77 for the 2nd diagonal, and 0.82 for the 3rd diagonal branches. (B) A radioisotope scan after stenting shows no reversible perfusion defect at the territories of LCx and diagonal branches.

a stent into the LAD that an operator electing to place a provisional stent in the LCx despite knowing that the lesion was associated with a negative FFR. The case in Figure 10 illustrates that nuclear perfusion scans may not be sensitive enough to define ischemia in sidebranches that were found to be physiologically significant by FFR. The case in Figure 11 demonstrates that a physiologically negative FFR in a jailed ostial LCx lesion remains durable, even after 9 months of follow-up.

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Figure 11 (See color insert ) Functional outcome of a nontreated jailed circumflex artery. Just after stenting, FFR was 0.87 at a jailed circumflex artery (left ). Nine months after stenting, FFR at LCx is still 0.85 (right ). There was only a minimal functional late loss of 0.02 in this nontreated jailed circumflex artery.

SUMMARY The treatment of bifurcation lesions is complex in that it not only involves two vessels, but multiple decision-making points are encountered during the procedure that have significant implications. Angiography, unfortunately, remains a poor tool to guide decision making in lesions involving the ostia of a vessel or the ostium of a “jailed” side branch. Intravascular ultrasound has a significant role in helping the operator in the treatment of bifurcation disease, but FFR provides real-time ability to determine ischemic significance of these lesions. More importantly, FFR guidance as a strategy has been shown to be something that can be performed frequently in bifurcation lesions and provide good clinical results. TAKE HOME MESSAGES 1. FFR provides operators with an ability to determine the physiologic significance of any coronary stenosis, and this information can be incorporated into decision making when treating bifurcation lesions. 2. Performing FFR to interrogate ostial side-branch lesions that appear to be significant from angiography may prove that some of these lesions are not physiologically significant. 3. Assessing angiographic abnormalities in side branches that are “jailed” by main vessel stents have been proven to be a useful strategy to determine the physiologic significance of these abnormalities. 4. “Jailed” side branches that are found to have an FFR >0.75 have been shown to have a very low clinical event rate without further balloon or stent therapy to the side branch.

REFERENCES 1. Steigen TK, Maeng M, Wiseth R, et al. Randomized study on simple versus complex stenting of coronary artery bifurcation lesions: the Nordic Bifurcation Study. Circulation 2006; 114:1955–1961. 2. Bech GJW, De Bruyne B, Pijls NHJ, et al. Fractional flow reserve to determine the appropriateness of angioplasty in moderate coronary stenosis: a randomized trial. Circulation 2001; 103:2928–2934.

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3. Bech GJW, Pijls NHJ, De Bruyne B, et al. Usefulness of fractional flow reserve to predict clinical outcome after balloon angioplasty. Circulation 1999; 99:883–888. 4. Rieber J, Schiele TM, Koenig A, et al. Long-term safety of therapy stratification in patients with intermediate coronary lesions based on intracoronary pressure measurements. Am J Cardiol 2002; 90:1160–1164. 5. Tonino PAL, De Bruyne B, Pijls NHJ, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Eng J Med 2009; 360:213–224. 6. Furukawa E, Hibi K, Kosuge M, et al. Intravascular ultrasound predictors of side branch occlusion in bifurcation lesions after percutaneous coronary intervention. Circ J 2005; 69:325–330. 7. Abizaid AS, Mintz GS, Mehran R, et al. Long-term follow-up after percutaneous transluminal coronary angioplasty was not performed based on intravascular ultrasound findings: importance of lumen dimensions. Circulation 1999; 100:256–261. 8. Ziaee A, Parham WA, Herrmann SC, et al. Lack of relationship between imaging and physiology in ostial coronary artery narrowings. Am J Cardiol 2004; 93:1404–1407. 9. Koo BK, Kang HJ, Young TJ, et al. Physiologic evaluation of jailed side branch lesions using fractional flow reserve. J Am Coll Cardiol 2005; 46:633–637. 10. Koo BK, Park KW, Kang HJ, et al. Physiological evaluation of the provisional side-branch intervention strategy for bifurcation lesions using fractional flow reserve. Eur Heart J 2008; 29:726–732.

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Elective Double Stenting for Non–Left Main Coronary Artery Bifurcation Lesions: Patient Selection and Technique Luca Favero, Andrea Pacchioni, and Bernhard Reimers Department of Cardiology, Mirano Hospital, Mirano, Italy

INTRODUCTION The randomized controlled trials (RCTs) comparing provisional stenting to elective double stenting (EDS) technique in patients with coronary bifurcation lesions (1–4) cannot be generalized to all patients with bifurcation coronary artery disease. In these trials, operators chose to randomize patients who are candidates for both techniques (see Chap. 1). This means that patients with complex coronary bifurcation anatomy (significant atherosclerosis of a large side branch and/or severely angulated side branch origin) were not well represented in these trials. Therefore, although provisional stenting can be successfully used in the majority of patients with bifurcation lesions, there are approximately 20% to 30% of patients where the EDS technique may be a safer approach (i.e., lower risk of procedural side branch compromise). The decision as to when to utilize the EDS technique depends on patient’s clinical risk profile, bifurcation anatomy, and operator experience. INDICATIONS FOR ELECTIVE DOUBLE STENTING Patient Selection The use of drug-eluting stents (DES) should be considered the default strategy for EDS techniques. Patients treated with a EDS strategy should undergo at least 12 months of dual antiplatelet therapy (5). Hence, EDS should be avoided in patients who are noncompliant with their medical regimen and who are at high risk for bleeding. Bifurcation Lesion Anatomy The decision to perform EDS technique depends primarily on bifurcation lesion morphology (Fig. 1). The most important bifurcation morphologic features that favor an EDS technique are (a) The presence of a true bifurcation lesion, defined as a bifurcation in which both the main branch (MB) and the side branch (SB) are significantly narrowed (≥50 diameter stenosis) (Medina classification 1:1:1, 1:0:1, and 0:1:1) (Fig. 2) (6). (b) The SB lesion is severe and/or long (Fig. 3): Side branches with longer lesions, compared to those with shorter lesions, have a significantly higher risk of occlusion after stenting (7). It is noteworthy to remind the reader that the SB lesion length in all the RCTs comparing provisional to EDS was ∼5 mm, reflecting the lower scale of bifurcation complexity in these trials. (c) The SB should supply a large amount of myocardium and it should be appropriate for stenting (diameter > 2.25–2.5 mm) (Fig. 4). (d) A wide angle between the MB and the SB that would be anticipated to increase the difficulty in recrossing into the SB after stenting the MB (Fig. 5). Of course, the combination of several of these features is what determines the need for EDS. Specifically, the presence of features (a, b, and c) or (a, c, and d) combined are probably

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Is the side branch disease beyond 5 mm from ostium ? YES

Elective double stenting Figure 1 Proposed flow chart for elective double stenting.

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(B) Figure 2 (A) Medina classification of bifurcation lesions. Source: Adapted from Ref. 6. (B) True bifurcation lesions according to the Medina classification.

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Figure 3 (A) Baseline angiography of a true bifurcation lesion involving the LAD and a large diagonal branch (Medina 0:1:1). The SB lesion is severe and extends beyond 5 mm from the SB ostium. (B) Final result after step crush stenting with DES. Abbreviations: LAD, left anterior descending; SB, side branch; DES, drug-eluting stents.

the strongest predictors for the need for EDS technique. Finally, EDS should not be performed in thrombotic bifurcation lesions. ELECTIVE DOUBLE STENTING: TECHNIQUE DESCRIPTION When a decision has been made to employ EDS, several questions need to be answered: (1) How to choose among the various techniques? (2) How to optimally perform the procedure? and (3) Is there an evidence-base for decision making? Over the last decade, several EDS techniques have been proposed and some of these techniques have undergone various modifications in an

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Figure 4 (A) Case example of true bifurcation lesion with large SB that is appropriate for EDS. (B) Case example of true bifurcation lesion with small SB that is not appropriate for EDS technique.

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(B) Figure 5 Case examples of true bifurcation lesion with narrow (A) and wide (B) angle between the MB and the SB. Abbreviations: MB, main branch; SB, side branch.

attempt to make them more “user friendly” and to optimize outcomes. Although each of these techniques has its “devotees” as well as its theoretical rational, strong evidence as to the superiority of one technique over others is lacking. Nonetheless, some techniques have been more rigorously studied (T-technique, crush technique, culotte technique) compared to others (Vstenting, kissing stent technique). The value of any given technique should be judged based on

r r r

ease of performance, bifurcation stent geometry (coverage, deformation), and clinical outcome.

In the absence of unequivocal evidence as to the superiority of one technique over others, the decision as to which technique to use should be driven by bifurcation anatomy, operator experience, and the relevant contemporary evidence-base. At the end, it may well be that optimization of final results, rather than which technique is used, is what determines clinical outcome.

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(G) Figure 6 Diagram of the T-stent technique. (A) Both branches are wired and predilated. (B) A stent is advanced in the SB, avoiding any stent protrusion into the MB. (C) The stent is deployed in the SB. (D) If the angiographic result in the SB is satisfactory, the wire is removed from the SB and a stent is positioned in the MB. (E) The stent is deployed in the MB. (F) The SB is rewired through the MB stent. (G) Final kissing balloon at high pressure is performed. Abbreviations: MB, main branch; SB, side branch.

T-Stenting Technique

Classical T-Stent Technique Definition This technique consists of implantation of a stent in the SB followed by implantation of a stent in the MB. The SB stent does not protrude into the MB. With this technique, there is no overlap between the MB and the SB stent struts (8). Step by step (Fig. 6) 1. Both the MB and the SB are wired. 2. Both the MB and the SB are adequately predilated. 3. The SB stent is advanced and positioned at the SB ostium, being careful to avoid stent protrusion into the MB. 4. The SB stent is deployed at nominal pressure. 5. The balloon is removed from the SB and a control angiogram is performed. If distal dissection or residual disease is present, a second stent is advanced and deployed in the SB. If the angiographic result is satisfactory, the wire is removed from the SB. 6. The stent is advanced and deployed in the MB at high pressure. 7. The SB is rewired through the MB stent layers. 8. Dilatation of the SB is performed, preferably using noncomplaint balloon at high pressure. 9. Final kissing balloon at high pressure is performed by using two noncomplaint balloons of the same size as that used to deploy the stents. Anatomic indication Bifurcation lesions with ∼90 degrees angle between the MB and the SB.

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Figure 7 Diagram of the modified-T stent technique. MB, main branch; SB, side branch. (A) Both branches are wired and predilated. (B) The stents are advanced in the MB and in the SB; the stent in the SB is slightly pulled back into the MB, just to ensure SB ostium coverage, avoiding marked protrusion into the MB. (C) The stent is deployed in the SB. (D) If the angiographic result in the SB is satisfactory, the wire is removed from the SB and the stent is deployed in the MB. (E) The SB is rewired through the MB stent. (F) Final kissing balloon at high pressure is performed.

Advantages This technique is easy and not technically demanding. Drawbacks An angle between the MB and the SB of ∼90 degrees is quite uncommon in non–left main coronary bifurcations. Moreover, even when the angle is ∼90 degrees, an attempt to position the SB stent exactly at the SB ostium without protrusion into the MB is often associated with missing the ostium. The risk of this occurrence is even higher if the angle is <90 degrees. An unstented segment at the SB ostium may increase the risk of restenosis at this site (1). For this reason, this technique has been largely replaced by the modified T-stenting technique.

Modified T-Stent Technique Definition This technique differs from the classical T-stent technique in that both the SB and the MB stents are positioned simultaneously and the SB stent is deployed with minimal protrusion into the MB. This technique guarantees the coverage of the SB ostium and is synonymous with the minicrush technique (9,10). Step by step (Fig. 7) 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Both the MB and the SB are wired. Both the MB and the SB are adequately predilated. The SB stent is advanced in the SB, and the MB stent in advanced in the MB. The SB is slightly pulled back into the MB to ensure SB ostium coverage with avoidance of marked protrusion into the MB. The SB stent is deployed at nominal pressure. The balloon is removed from the SB and a control angiogram is performed. If distal dissection or residual disease is present in the SB, a second stent is advanced and deployed in the SB. If the angiographic result is satisfactory, the wire is removed from the SB. The MB stent is deployed at high pressure. The balloon is removed from the MB and a control angiogram is performed. The SB is rewired through the MB stent at the distal part of the SB orifice. The SB stent is postdilated, preferably using noncomplaint balloon at high pressure. Final kissing balloon inflation at moderate pressure is performed by using two noncomplaint balloons of the same size as that used to deploy the stents.

Anatomic indication This technique can be used in almost all true bifurcation lesions but is preferable if the angle is close to 90 degrees (Fig. 8).

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(E) Figure 8 Case example of the modified T-stent technique (synonymous with the minicrush technique). (A and B) Baseline angiography showing a true bifurcation lesion of a large OM branch of a dominant LCx in the caudal RAO and in the cranial RAO view, respectively. Chronic total occlusion of the LAD is also present. (C) After predilatation of both branches and positioning of two stents, the stent of the SB, minimally protruding into the MB (closed arrow ), is deployed (Cypher 2.5 × 13 mm). (D) After angiographic confirmation of optimal result in the SB, the balloon and the guidewire are removed from the SB and the stent is deployed in the MB (Cypher 2.5 × 28 mm). (E) After rewiring of the SB, kissing balloon with 3.0-mm noncompliant balloon in the MB and with 2.5-mm noncompliant balloon in the SB branch is performed. (F and G) Final result in the caudal RAO and in the cranial RAO view, respectively. Abbreviations: LCx, left circumflex artery; OM, obtuse marginal; MB, main branch; SB, side branch; RAO, right anterior oblique. (Continued on page 90 )

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Advantages This technique guarantees the complete coverage of the SB ostium while ensuring the patency of both branches throughout the procedure. Compared to the culotte technique, there is need to rewire only the SB and not both branches. Drawbacks This technique results in excess metal (triple stent layer) at the proximal MB. This requires aggressive postdilatation at the proximal MB segment to guarantee stent apposition. Also, this technique requires rewiring of the SB and recrossing it with a balloon through three stent layers, which can be difficult, and time-consuming.

The TAP (T and Protrusion) Technique Definition Typically, this technique is used to stent the SB after a suboptimal result in a provisional stenting approach. However, some have used this approach in an EDS strategy (4). This technique differs from all other EDS techniques in that the MB stent is deployed first followed by rewiring and stenting of the SB, and kissing balloon inflation (11). Step by step (Fig. 9) 1. 2. 3. 4. 5.

Both the MB and the SB are wired. Both the MB and the SB are predilated, if needed. A stent is positioned and deployed in the MB with a jailed guidewire in the SB. Kissing balloon inflation after rewiring of the SB. The SB stent is positioned to fully cover the SB ostium with minimal protrusion into the MB, while an uninflated balloon is kept in the MB. 6. The SB stent is deployed with the uninflated balloon in the MB. 7. After SB stent deployment, the balloon of the stent is slightly retrieved and aligned with the MB balloon, and then final kissing balloon is performed. Anatomic indication This technique can be used in low-to-intermediate risk bifurcations with favorable angles (avoid extreme angles in either direction).

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Figure 9 Angiographic images of in vitro TAP stenting. (A) Stent positioning in the MV with jailed guidewire into the side branch (SB). (B) Deployment of MV stent. (C) Kissing balloon after rewiring of the SB. (D) SB stent positioning: the position of the SB stent is adjusted to fully cover the proximal (or upper ) part of the SB ostium (arrow ), while an uninflated balloon is kept into the MV. (E) SB stent is deployed with the uninflated balloon into the MV. (F) After SB stent deployment, the balloon of the stent is slightly retrieved and aligned to the MV balloon. The arrow indicates the protruding side branch stent’s struts within the MV only at the distal side of the SB ostium. (G) Final kissing balloon is performed by inflating simultaneously the SB stent’s balloon and the MV balloon. (H) After kissing balloon, the protruding side branch stent struts are reoriented resulting in a small, single stent struts, neocarina (arrow ). Source: Adapted from Ref. 11.

Advantages This technique guarantees the complete coverage of the SB ostium without large double or triple stent struts layers (thus differing from the culotte and the crush techniques). Drawbacks There are two drawbacks to this technique: (a) this technique assumes that the chances of SB occlusion after MB stenting are zero! It also assumes that the success rate in rewiring the SB and delivering a stent through the MB stent struts are 100%. Although these assumptions may be true in many bifurcations, they would clearly not apply to complex bifurcation lesions (severely angulated SB take-off, calcified vessels, severely stenosed SB ostium with high risk of occlusion); (b) this technique should be avoided in bifurcations with acute angles where the SB stent will need to significantly protrude into the MB to provide complete ostium coverage. Crush Stent Technique

Minicrush Stent Technique Definition The crush stent technique (12–16) consists of simultaneous advancement of the MB and the SB stents into the vessel, followed by sequential implantation of the SB stent and the MB stent. The SB stent is deployed first and then “crushed” by deployment of the MB stent. The minicrush technique has largely replaced the standard crush technique to minimize the amount of metal overlap proximal to the SB origin. Step by step (Fig. 10) 1. Both the MB and the SB are wired. 2. Both the MB and the SB are adequately predilated.

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Figure 10 Diagram of the crush stent technique. (A) Both branches are wired and predilated. (B) The stents are advanced in the MB and in the SB; the stent in the SB is pulled back 3 mm into the MB. (C) The stent is deployed in the SB. (D) If the angiographic result in the SB is satisfactory, the wire is removed from the SB. (E) The stent is deployed in the MB. (F) The SB is rewired through the MB stent. (G) Dilatation of the SB is performed by using noncomplaint balloon at high pressure. (H) Final kissing balloon at high pressure is performed. Abbreviations: MB, main branch; SB, side branch.

3. 4. 5. 6. 7. 8. 9. 10. 11.

The SB stent is advanced in the SB, and the MB stent in advanced in the MB The SB is pulled back 3 mm into the MB. The SB stent is deployed at nominal pressure. The balloon is removed from the SB and a control angiogram is performed. If distal dissection or residual disease is present in the SB, a second stent is advanced and deployed in the SB. If the angiographic result is satisfactory, the wire is removed from the SB. The MB stent is deployed at high pressure. The balloon is removed from the MB and a control angiogram is performed The SB is rewired through the MB stent at the distal part of the SB orifice. The SB stent is postdilated, preferably using noncomplaint balloon at high pressure. Final kissing balloon inflation at moderate pressure is performed by using two noncomplaint balloons of the same size as that used to deploy the stents.

Anatomic indication This technique can be used in almost all true bifurcation lesions but should be avoided in wide-angle bifurcation (Fig. 11). Advantages This technique guarantees the complete coverage of the SB ostium while ensuring the patency of both branches throughout the procedure. Compared to the culotte technique, there is need to rewire only the SB and not both branches.

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Drawbacks This technique leads to the formation of three stent layers in the MB proximal to the origin of the SB and two stent layers at the distal part of the SB ostium. This may lead to difficulty in rewiring the SB and advancing the balloon particularly if rewiring was attempted through the proximal aspect of the SB orifice. SB rewiring should be performed through the distal aspect of the SB orifice.

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Figure 11 Case example of the crush stent technique. (A) Baseline angiography showing a true bifurcation lesion of the distal RCA involving the origin of large PDA and PLB. (B) Wiring and subsequent predilatation of both branches. (C) Two stents are positioned. The stent in the PLB (SB) protrudes 3 mm into the distal RCA (proximal MB). The stent in the RCA-PDA (MB) is placed more proximally than the stent in the PLB (SB). (D) Deployment of the stent in the PLB (SB) (Cypher 2.5 × 13 mm). (E) After angiographic confirmation of optimal result in the PLB (SB), the balloon and the guidewire are removed from the PLB and the stent in the distal RCA-PDA (MB) is deployed (Cypher 2.5 × 18 mm). (F) After rewiring of the PLB, final kissing balloon with 3.5 mm balloon in the RCA-PDA and 2.5 mm balloon in the PLB is performed. (G) Final result of the index procedure. (H) Angiographic follow-up at nine months. Abbreviations: RCA, right coronary artery; PDA, posterior descending artery; PLB, posterolateral branch; MB, main branch; SB, side branch. (Continued on page 94)

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Figure 11 (Continued )

Potential Failure Modes of the Crush Technique and Suggested Solutions 1. Inability to rewire the SB a. Make sure that the wire is directed toward the distal part, and not the proximal part, of the SB orifice. b. If the primary work guidewires (BMW, Prowater, Abbott Vascular Devices) fail, try hydrophilic wires (careful manipulation). If they also fail, then consider stiffer tapered tip wires (Miracle wire series, Abbott Vascular Devices). 2. Inability to pass a balloon into the side branch a. Use a compliant monorail 1.5 mm balloon. b. If this balloon fails to cross, rewire the SB through a different part of the SB orifice and reattempt balloon crossing. c. If this also fails, then use a fixed wire balloon system.

Step Crush Technique Definition This is a variant of the crush technique which is used when the operator uses a 6-Fr guiding catheter (17). In this technique, the SB stent is deployed first and then “crushed” against the

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Figure 12 Diagram of the step crush stent technique. MB, main branch; SB, side branch. (A) Both branches are wired and predilated. (B) A stent is advanced in the SB and a balloon is advanced in the MB. (C) The stent is deployed in the SB. (D) If the angiographic result in the SB is satisfactory, the wire is removed from the SB. (E) The balloon is inflated in the MB. (F) The stent is deployed in the MB. (G) The SB is rewired through the MB stent. (H) Dilatation of the SB is performed by using noncomplaint balloon at high pressure. (I) Final kissing balloon at high pressure is performed.

vessel wall by inflation of a balloon and not by the MB stent deployment. This step is then followed by advancement and deployment of the MB stent. Step by step (Fig. 12) 1. Both the MB and the SB are wired. 2. Both the MB and the SB are adequately predilated. 3. The SB stent is advanced and positioned at the SB ostium, and a balloon is advanced and positioned in the MB. 4. The SB stent is pulled back 3 mm into the MB. 5. The SB stent is deployed at nominal pressure. 6. The balloon is removed from the SB and a control angiogram is performed. If distal dissection or residual disease is present in the SB, a second stent is advanced and deployed. If the angiographic result is satisfactory, the wire is removed from the SB. 7. The balloon in the MB is inflated at high pressure to crush the SB stent and is then removed. 8. The MB stent is advanced and deployed at high pressure. 9. The SB is rewired through the MB stent at the distal part of the SB orifice. 10. The SB stent is postdilated, preferably using noncomplaint balloon at high pressure. 11. Final kissing balloon inflation at moderate pressure is performed by using two noncomplaint balloons of the same size as that used to deploy the stents. Anatomic indication Similar to that of the minicrush technique, but only requires a 6-Fr guide catheter (Fig. 13).

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Figure 13 Case example of the step crush stent technique. (A) Baseline angiography showing a true bifurcation lesion of the mid-LCx involving the origin of a large OM branch. (B) After wiring and predilatation of both branches, a stent (closed arrow ) is positioned in the OM branch, minimally protruding into the LCx, and a deflated balloon (open arrow ) is positioned in the LCx. (C) Deployment of the stent in the OM branch (Cypher 3 × 23 mm). (D) After angiographic confirmation of optimal result in the OM branch, the balloon and the guidewire are removed from the OM branch and the balloon is inflated in the mid-LCx (Maverick 3 × 20 mm). (E) The balloon is removed and a stent is advanced into the mid-LCx. (F) The stent is deployed in the mid-LCx (Cypher 3 × 28 mm). (G) After rewiring of the OM branch, final kissing balloon with 3.0 mm balloon in the LCx and 2.5 mm balloon in the OM branch is performed. (H) Final result. Abbreviations: LCx, left circumflex artery; OM, obtuse marginal.

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(H) Figure 13 (Continued )

Advantages Similar to that of the minicrush technique, but can be performed through a 6-Fr guiding catheter. Drawbacks Similar to that of the minicrush technique.

Double Kiss Step Crush Technique (Sleeve Technique) Definition This is a variant of the Step Crush technique with the goal of increasing the chances of successful final kissing balloon inflation to further optimize the results. In this technique, the SB stent is deployed first, then “crushed” against the vessel wall by inflation of a balloon, and then postdilated with kissing balloon inflation prior to deployment of the MB stent. This step is then followed by advancement and deployment of the MB stent (18). Step by step (Fig. 14) 1. Both the MB and the SB are wired. 2. Both the MB and the SB are adequately predilated. 3. The SB stent is advanced and positioned at the SB ostium, and a balloon is advanced and positioned in the MB. 4. The SB stent is pulled back 3 mm into the MB. 5. The SB stent is deployed at nominal pressure. 6. The balloon is removed from the SB and a control angiogram is performed. If distal dissection or residual disease is present in the SB, a second stent is advanced and deployed. If the angiographic result is satisfactory, the wire is removed from the SB. 7. The balloon in the MB is inflated at high pressure to crush the SB stent. 8. The SB is rewired at the distal part of the SB orifice and the SB stent is postdilated, preferably using noncomplaint balloon at high pressure. 9. First kissing balloon inflation is performed, and the SB balloon and wire are removed. 10. The MB stent is advanced and deployed at high pressure. 11. The SB is rewired again through the MB stent at the distal part of the SB orifice. 12. The SB stent is postdilated, preferably using noncomplaint balloon at high pressure. 13. Final kissing balloon inflation at moderate pressure is performed by using two noncomplaint balloons of the same size as that used to deploy the stents.

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Figure 14 Diagrammatic outline of the sleeve technique. One, stenting of SB with the proximal segment of the stent protruding into MV. A balloon is already loaded in the MV, covering the protruding stent segment (A). Two, balloon inflation in the MV, crushing the SB stent against the MV wall (B). Three, rewiring of the SB through its own stent strut, followed by balloon dilatation of the SB ostium (C). Four, first kissing balloon inflation of the bifurcation. A new sleeve has been reconstructed (D). Five, stenting of the MV (E). Six, second rewiring of the SB through the MV stent strut, followed by second balloon dilatation of the SB ostium (F). Seven, second and final kissing balloon inflation of the bifurcation (G). Source: Adapted from Ref. 18.

Anatomic indication Similar to that of the minicrush technique but only requires a 6-Fr guide catheter. Advantages (a) Easier to rewire the SB and pass noncompliant balloons through the stent struts for final kissing balloon inflation; (b) leads to better stent expansion at the SB ostium. Drawbacks It involves an extra intermediate step of SB rewiring and dilatation. Culotte Stent Technique

Definition The culotte stent technique consists of sequential implantation of the SB and the MB stents as detailed below (19). Step by step (Fig. 15) 1. 2. 3. 4. 5. 6. 7. 8.

Both the MB and the SB are wired. Both the MB and the SB are adequately predilated. A stent is advanced to the more angulated branch (usually the SB). The stent in the more angulated branch (usually the SB) is deployed at nominal pressure. The wire in the straighter branch (MB) may be retrieved before SB stent deployment or may be jailed at operator’s discretion. The nonstented branch (MB) is rewired through the stent struts, and the wire is removed from the stented branch (SB). Dilatation of stent struts toward the nonstented branch is performed, preferably by using noncomplaint balloon. A second stent is advanced into the nonstented branch (MB) and deployed at nominal pressure. The first-stent branch (SB) is rewired through the second stent struts.

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Figure 15 Diagram of the culotte stent technique. (A) Both branches are wired and predilated. (B) A stent is advanced to the more angulated branch (usually the SB). (C) The stent is deployed in the SB (the wire in the MB is removed, as in the figure, or jailed, at operator’s discretion). (D) If the angiographic result in the SB is satisfactory, the wire is removed from the SB and the MB is rewired through the stent. (E) Dilatation of the MB is performed by using noncomplaint balloon at high pressure. (F) A stent is positioned in the MB. (G) The stent is deployed in the MB. (H) The SB is rewired through the MB stent. (I) Final kissing balloon at high pressure is performed. Abbreviations: MB, main branch; SB, side branch.

9. Final kissing balloon inflation at moderate pressure is performed by using two noncomplaint balloons of the same size as that used to deploy the stents.

Anatomic Indication This technique can be used in almost all true bifurcation lesions irrespective of bifurcation angle. We use this technique for treatment of bifurcations in which the MB and the SB have similar diameter and for LMCA bifurcation (Fig. 16). Advantages This technique guarantees the complete coverage of the SB ostium with DES. The angle between the MB and the SB does not constitute a problem using this technique. Drawbacks r This technique leads to a double stent layer at the proximal MB and at the level of the carina. r Open-cell stents are preferable to closed-cell stents because it permit a larger intrastrut opening toward both branches (see section Technique Execution). r This technique is not advisable when there is large discrepancy between the size of the proximal MB and the SB due to the risk of incomplete wall apposition of the SB stent in the proximal MB segment (see section Technique Execution). r This technique requires rewiring of both branches through the stent struts, which can be technically demanding and time-consuming.

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V-Stent and Kissing Stent Techniques

Definition The V and simultaneous kissing stent (SKS) techniques consist of implantation of the MB and the SB stents simultaneously (20,21). When the two stents protrude minimally into the proximal MB creating a new carina, the technique is called V-stent technique [Fig. 17(A)] (20), whereas when the two stents protrude more deeply into the proximal MB, then that technique is called SKS technique [Fig. 17 (B)] (21).

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Figure 16 Case example of the culotte technique. (A and B) Baseline angiography showing a true bifurcation lesion involving the LAD and a large diagonal branch. (C) Wiring and predilatation of both branches. (D) The stent in the diagonal branch (SB) is deployed (Cypher 3 × 23 mm). A jailed choice PT guidewire is left in the LAD (MB). (E) The guidewire of the diagonal branch (SB) is removed and the LAD (MB) is rewired through the stent struts. After dilatation of the stent struts, the stent is advanced and deployed in the LAD (MB) (Cypher 3 × 18 mm). (F) The diagonal branch (SB) is rewired, and kissing balloon inflation is performed with two 3.0 mm balloons (G and H). Final result. Abbreviations: LAD, left anterior descending; MB, main branch; SB, side branch.

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Figure 16 (Continued )

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Figure 17 (A) Positioning of stents in the V-stent technique. (B) Positioning of stents in the kissing stent technique.

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Figure 18 Diagram of the V-stent technique. (A) Both branches are wired and predilated. (B) The stents are simultaneously advanced in the MB and in the SB; both stents protrude into the MB. (C) The stents are deployed by inflating both balloons simultaneously (In case the proximal MB diameter is relatively small and a risk of proximal MB damage by simultaneous inflation of the two stents do exist, the operator may consider to deploy the single stent individually.) (D) Final kissing balloon at high pressure is performed. (E) Final result. Abbreviations: MB, main branch; SB, side branch.

Step by step (Fig. 18) 1. Both the MB and the SB are wired. 2. Both the MB and the SB are adequately predilated. 3. The stents of the MB and the SB are advanced and positioned at the lesion site. In V-stenting the stents are positioned such that they minimally protrude into the proximal MB, while in SKS the stents protrude deeply into the proximal MB. It is advisable to check stent positioning in at least two projections. 4. The stents are deployed by inflating both balloons simultaneously, or sequentially, up to at least 12 atm. Simultaneous stent deployment should be avoided if the proximal MB diameter is relatively small. 5. Postdilate the stents using simultaneous inflation of two noncomplaint balloons of the same size as that used to deploy the stents. We recommend postdilatation at high pressure but, if the proximal MB diameter is relatively small, moderate or low pressure should be used.

Anatomic Indication V-Stenting A (0,1,1) bifurcation with large proximal MB and a <90-degree angle between both branches. We reserve this technique to patients with very short LMCA free from disease and critical disease of both LAD and LCx ostia (Fig. 19). SKS Technique The authors of this chapter do not use this technique and believe that proximal stent overlap should always be kept to a minimum.

Advantages Access to both branches during the procedure is always preserved with no need for rewiring any of the branches. The technique is relatively easy and fast. Drawbacks This technique, particularly the SKS, leads to the creation of a metallic neocarina in the proximal MB with stent malapposition (Fig. 20). Theoretically, this technique raises several concerns: 1. The risk of proximal dissection after stent deployment, which would require converting the procedure to a crush technique. 2. The stent lumen area in the double barrel is often suboptimal and asymmetric.

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3. If reintervention becomes necessary at follow-up rewiring, the stented vessels may be complicated by wire passage behind stent struts. 4. If restenosis occur in the neocarina or at the proximal stent edge, it would require converting to the crush technique for treatment. ELECTIVE DOUBLE STENTING: TECHNIQUE EXECUTION Patient Preparation EDS is a complex coronary intervention that requires optimal antithrombotic pretreatment. Although the RCTs (1–4) did not demonstrate an increased risk of stent thrombosis after EDS

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Figure 19 Case example of the V-stent technique. (A and B) Baseline angiography, showing a true bifurcation lesion involving the distal LMCA, the ostial LAD, and the ostial LCx. The proximal LCx is occluded. (C to E) After wiring the LAD and recanalization of the proximal LCx, two stents are advanced simultaneously and correct positioning was checked using three different projections. (F) Deployment of the two stent by simultaneous inflation (Cypher 3.5 × 18 mm in the LAD, Cypher 3.0 × 18 mm in the LCx). (G and H) Final result after kissing balloon. (I) Angiographic follow-up at eight months. Abbreviations: LMCA, left main coronary artery; LAD, left anterior descending; LCx, circumflex coronary artery; MB, main branch; SB, side branch. (Continued on page 104)

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Figure 20 V-stent and kissing stent techniques. Cross-sectional view of the neocarina in the proximal MB. The arrows indicate the zones of the proximal MB in which malapposition may occur.

up to one-year follow-up, they did show higher postprocedure cardiac enzyme elevation. Furthermore, real world registries indicate that bifurcation intervention, irrespective of the technique, increases the risk of stent thrombosis (22–24). Therefore, optimal antiplatelet and antithrombotic therapies are mandated to minimize procedural complications and reduce stent thrombosis. Guide Catheter Selection When an operator decides to perform elective DS, a 7 or 8-Fr guide catheter (GC) is preferable. The utilization of an 8-Fr GC have several advantages: first, it reduces the friction among the multiple catheters that are simultaneously introduced into the vessel assuring easy manipulation; second, it allows adequate visualization that is particularly important for simultaneous stent positioning; and third, it provides optimal support for stent delivery particularly through tortuous and calcified vessels. If the operator chooses not to use an 8-Fr GC, the procedure can certainly be performed with a 6-Fr GC, but technique choices will be more limited (i.e., step crush or culotte techniques) and procedure execution potentially more challenging. Wire Introduction Although wiring the MB and the SB is considered a simple step and is often taken for granted, this is not always the case. Bifurcations with wide angulation and/or severe calcifications can present a challenge. One potential option that can be used in selected cases after failure to wire the SB is to perform low-pressure balloon dilatation of the MB using an undersized balloon which may modify the plaque geometry at the bifurcation site allowing access to the SB. Needless to say, if the operator fails to wire the SB (and if it is a large SB), then the procedure should be aborted rather than hope that the SB will remain patent after stenting the MB. Another potential problem when using two or more guidewires is wire crisscrossing, which may lead to difficulty (or inability) to advance balloons and/or stents into the vessel. A simple rule that can minimize the chances of this problem is to wire the branch with the more difficult access first, where prolonged wire manipulation and rotation is expected. Then the second wire aimed for the easier access vessel should be advanced with minimal rotation while keeping both wires separate on the table. Lesion Preparation Lesion predilatation (in the MB and SB) followed by intracoronary nitroglycerin administration should be performed in all patients undergoing EDS. This would allow (a) more accurate assessment of vessel diameter (particularly the SB) to optimize stent sizing; (b) facilitate advancement of stents into the bifurcation and optimize visualization during positioning; (c) identify difficult to dilate bifurcation lesions prior to stent implantation to avoid suboptimal stent expansion. Alternative techniques can then be used to properly prepare the lesion prior to stent deployment. Devices such as rotational atherectomy in severely calcified lesions, the cutting balloon

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or the angiosculpt balloon in fibrotic lesions are valuable in lesion preparation before stenting (Fig. 21) (25,26). One potential disadvantage of aggressive balloon predilatation prior to EDS are dissections; however, this represent a challenge only with the culotte technique where there is a need to rewire one of the branches to position a second stent. Therefore, when only the culotte technique is planned, gentle predilatation should be performed on the branch that needs to be rewired (the less angulated branch). Stent Implantation EDS, when indicated, must be carried out with DES. Numerous studies have demonstrated the superiority of DES over historical results obtained with BMS in coronary bifurcation lesions (1–4,27,28). The DES most extensively studied in RCTs of EDS is the sirolimus-eluting stent, but comparative data among the various DES in bifurcation lesions are limited and do not indicate significant differences in outcome (29).

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Figure 21 Case example of the step crush stent technique in a severely calcified true bifurcation lesion involving the LAD and a large diagonal branch. (A) Baseline angiography. (B) Lesion dilatation with noncompliant balloon at high pressure failed to dilate the stenosis. (C and D) Rotational atherectomy was first performed toward the diagonal branch and subsequently toward the LAD. Note that during rotablation the second guidewire was removed.

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Figure 21 (Continued ) (E) The stent is deployed in the diagonal branch (SB) (Cypher 2.5 × 13 mm). A deflated balloon was positioned in the LAD (MB). (F) The balloon and the wire are removed from the diagonal branch and the balloon is inflated in the LAD to crush the SB stent. (G and H) Positioning and deployment of the stent in the LAD (Cypher 3 × 23 mm). (I) Rewiring of the diagonal branch and dilatation at high pressure. (L) Induction of long dissection in the diagonal branch, distal to the first stent, requiring stent implantation (Cypher 2.5 × 28 mm). (M) Final kissing balloon inflation with 3.5 mm balloon in the LAD and 2.5 mm balloon in the diagonal branch. (N and O) Final result. (P) Angiographic follow-up at eight months. Abbreviations: LAD, left anterior descending; LCx, circumflex coronary artery; MB, main branch; SB, side branch. (Continued on page 108 )

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Figure 22 The culotte technique is not advisable when there is large discrepancy in vessel size between the proximal MB and the SB, because the proximal segment of the SB stent will not attain good apposition to the vessel wall of the proximal MB.

Stent sizing is of particular importance to optimize lumen dimensions and to avoid stent malapposition in all EDS techniques. In particular, careful attention should be paid to vessel size discrepancy between the SB and the MB when the culotte technique is being considered because this can lead to lack of apposition of the SB stent in the proximal portion of the MB (Fig. 22). Intravascular ultrasound (IVUS) can inform decision making and assist the operator in choosing the optimal stent size and postdilatation balloon for both the SB and the MB. Stent type (open vs. closed cell design) is also of particular importance, especially when using the culotte technique. The intrastrut space in closed-cell stents is limited to <3 mm, whereas it is >3 mm in open-cell stents (30). The Jailed Wire Technique Most of the EDS techniques (T-stent, modified T-stent, crush stent, V-stent) do not require jailing a SB wire. Only culotte stenting may require a jailed wire technique at operator’s discretion (see above). Most operators use nonhydrophilic wires as jailed wires: the rational of this preference is that jailing hydrophilic guidewires may lead to coating peeling upon retrival of the guidewire (31). In our practice, we routinely jail a hydrophilic guidewire (Choice PT, Boston Scientific) because it is much more easier to retrieve than nonhydrophilic guidewires after implanting the MB stent at nominal pressure. Using this technique, we never observed peeling or fracture of the guidewire. In either case there are several tips that need to be followed to avoid complications due to the jailed wire technique: (a) this technique should not be used when the “jailing stent(s)” covers a long segment proximal to the SB (the longer the stent, the higher the friction with the jailed wire); (b) prior to deployment of the jailing stent (typically the MB stent), the SB wire should be pulled back and positioned only few centimeters away from the SB ostium (no need to jail a long segment of the wire); (c) the jailing stent (typically the MB stent) should be deployed at nominal or intermediate pressure; (d) the jailed wire should not be removed until recrossing the SB with a second wire; (e) prior to removal of the jailed wire, the guide catheter should be pulled back into the aorta and be held with one hand while the jailed wire is removed. The reason for this maneuver is to avoid guide catheter “deep throating” into the coronary artery when the jailed wire is forcefully removed (an almost predictable event); (f) if attempts to remove the jailed wire fail using the above technique, one should load a monorail low profile 1.5 mm balloon (or smaller) over the jailed wire and embed this balloon behind the jailing stent (the MB stent) and reattempt wire removal. Rewiring the SB Across the MB Stent Struts All the EDS techniques, except for the V-stent and kissing stent techniques, require recrossing into the SB. Using the culotte technique, a double stent layer need to be recrossed, whereas using the modified T-stent (or minicrush) technique, three stent layers need to be recrossed.

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Figure 23 (A) Double curve of the tip of the guidewire. (B) The distal tip engages the SB ostium while the primary curve guarantees good back support to reenter the SB.

This step can be technically demanding and time-consuming, and failure to perform it is a common reason for the lack of performance of final kissing balloon inflation by operators who are not familiar with the technique. An optimal wire tip shape, double curve with long primary curve larger than the MB diameter and a short distal tip curve, is an essential element to rewire the SB. The distal tip engages the SB ostium, whereas the primary curve guarantees adequate support, by pushing against the MB wall, to re-enter the SB (Fig. 23). Often, the SB can be recrossed through the stent using nonhydrophilic guidewires such as BMW and Balance Universal (Abbott Vascular Devices). It is essential that one attempts to recross into the SB through the MB stent struts at the distal aspect of the SB orifice. In cases where rewiring of the SB fails after multiple attempts using nonhydrophilic guidewires and multiple angiographic projections, we suggest using hydrophilic guidewires (Choice PT, Boston Scientific Corporation; Pilot 50 and Pilot 150, Abbott Vascular Devices) or stiff tapered-tip guidewires (Miracle Bros, Abbott Vascular Devices). It is extremely important to point out that these guidewires can easily dissect the SB if not used carefully and expertly. If all attempted wires fail to recross into the SB, a fixed wire-balloon system can be attempted. In case of persistent inability to rewire the SB, postdilatation of the MB stent with noncompliant balloon could lead to more favorable stent strut geometry, allowing subsequent reentry of the wire into the SB. Stent Deployment Optimization

General Guidelines Final kissing balloon inflation using noncompliant balloons is a key element to optimize the results in all EDS techniques. Except for the V-stent and kissing stent techniques, the SB balloon needs to traverse the MB stent struts. This step can be difficult and time-consuming, especially in the presence of multiple stent layers such as the case with the crush and culotte techniques. We suggest that a low-profile monorail balloon (1.0 or 1.5. mm) is used first to predilate the struts. If the balloon does not cross, inflation of the balloon at high pressure while pushing it against resistance may help open the intrastrut space and allow the subsequent passage of a new low profile balloon. In case of persistent failure to cross the stent with a balloon, the operator should consider repositioning the wire and crossing the stent at another site. It is important to point out that in every instance where there are persistent difficulties in recrossing the MB stent with the balloon, the operator should make certain that there is no wire crisscrossing or that the

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SB wire has not traversed under the proximal MB stent. If in doubt, it is advisable to retrieve the wire from the SB and try to recross the stent toward the SB at the distal aspect of the SB orifice. After dilatation of the MB stent struts toward the SB with a small balloon, the next step should be postdilatation of the SB with a noncompliant balloon at high pressure (≥16 atm) to guarantee complete stent apposition and expansion. This is followed by final kissing balloon inflation using two noncompliant balloons with sizes similar to the respective stents at moderate inflation pressure. Care should be taken not to extend the balloons beyond the proximal edge of the MB stent to avoid dissections. Optimization of results during EDS techniques cannot be realized on the basis of angiography alone. As it has been demonstrated with nonbifurcation lesions, IVUS often provide insights that cannot be elucidated by angiography alone, irrespective of the experience of the operator.

Role of IVUS Suboptimal stent deployment in bifurcation lesions, particularly with EDS techniques, increase the risk of stent thrombosis and restenosis (particularly at the SB ostium) (16,32). As it has been discussed in Chapter 2, IVUS interrogation before intervention can inform technical decision making regarding true vessel size and plaque burden/composition, which may lead to better lesion preparation and stent sizing (especially in the SB). Postprocedure IVUS assessment of stent expansion and apposition, particularly at the carina level, is also important to guide optimal dilatation of the SB ostium and kissing-balloon dilatation. Although IVUS catheter advancement through stent struts into the SB can be challenging, particularly in severely angulated SBs, this can be accomplished in many patients with appropriate technique. Few studies have provided valuable insights into the problems and solutions associated with EDS techniques in bifurcation lesions. In an analysis of postprocedure IVUS in 25 patients undergoing EDS (crush technique) (Fig. 24) using sirolimus-eluting stent, Costa et al. (14) reported high frequency of localization of minimum stent area (MSA) at the SB ostium (68%)

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Figure 24 A schematic diagram of the in-stent segmental approach to intravascular ultrasound analysis after crush stenting. Abbreviations: MV, main vessel; SB, side branch. Source: Adapted from Ref. 14.

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Figure 25 Intravascular ultrasound (IVUS) minimum lumen diameter (MLD) versus quantitative coronary angiography (QCA). MLD in the main vessel (left ) and side branch (SB) ostium (right ). Source: Adapted from Ref. 14.

[SB-MSA <5.00 mm2 and <4.00 mm2 in 76% and 44% of patients, respectively] with significant SB stent under expansion compared to the MV. Only a moderate correlation between IVUS and quantitative angiography minimum lumen diameter was found both in the MV and in the SB (Fig. 25). Despite a good angiographic appearance after crush stenting, incomplete crush was noted in the majority of cases (>60%) (Fig. 26). In this study, incomplete crush was associated with lower postdilatation balloon inflation pressure in the SB and SB stent under expansion. The above observations were also corroborated in a larger study where serial IVUS analysis (Figs. 27 and 28) was performed postprocedure and at nine-month follow-up in 73 bifurcation lesions (42% LMCA) treated with the TAP technique (33). This study also demonstrated that the postprocedure MSA was located at the SB ostium in 42% of lesions and that there was significant SB stent under expansion compared to the MV. In addition, the SB ostium was not fully covered by stent struts in 8.2% of patients in whom a majority (5 of 6 lesions) had a distal angle <60 degrees. At follow-up, SB restenosis was found in 12.3% of patients and involved mainly the SB ostium (8 out of 9 lesions). The optimal cut-off value of postprocedure MSA at the SB ostium to predict “adequate” follow-up minimum lumen area (MLA) (>4.0 mm2 ) was 4.83 mm2 . Of course, larger body of evidence is needed to establish whether routine IVUS guidance of EDS in bifurcation lesions can improve outcome. In the meanwhile, however, IVUS should be

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Figure 26 (A) Intravascular ultrasound image showing complete crush (apposition) of the side branch (SB) stent; arrows indicate the three layers of stent struts. (B and C) Intravascular ultrasound images showing incomplete crush (apposition) of the SB stent struts (arrows). Source: Adapted from Ref. 14.

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Figure 27 Schematic diagram of intravascular ultrasound analysis and location of postprocedural minimum stent area in the main vessel (MV) and the side branch (SB). Source: Adapted from Ref. 33.

used whenever in doubt regarding the adequacy of the results because relying on angiography alone to determine optimal stent deployment is almost always inadequate. IS THERE AN EVIDENCE-BASE FOR CHOOSING AN OPTIMAL EDS TECHNIQUE? There has been only one RCT that compared one EDS technique with another, namely, the Nordic Stent Technique Study (34). In this study, 424 out of 2292 eligible patients with a bifurcation lesion were selected for randomization to crush (n = 209) and culotte (n = 215) stenting. At six-month follow-up, there were no significant differences in major adverse cardiac events rates between the groups (crush 4.3%, culotte 3.7%, p = 0.87). Procedure and fluoroscopy times and contrast volumes were similar in the two groups. The rates of procedure-related increase in biomarkers of myocardial injury were 15.5% in crush versus 8.8% in culotte group (p = 0.08). A total of 324 patients had a quantitative coronary assessment at the index procedure and after

Figure 28 The neocarina was observed, and the side branch (SB) stent was slightly pulled back into the main vessel. The SB ostium was fully covered, and stents were well apposed against the vessel wall. Abbreviations: D1, first diagonal branch; LAD, left anterior descending artery. Source: Adapted from Ref. 33.

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8 months. The angiographic end-points of in-segment and in-stent restenosis of main vessel and/or side branch after 8 months were found in 12.1% versus 6.6% (p = 0.10) and in 10.5% versus 4.5% (p = 0.046) in the crush and culotte groups, respectively. Although this is an important study that demonstrates the safety and efficacy of the tested techniques, several major limitations limit its generalizability to unselected patients with bifurcation lesions. The most important of these limitations is that only 18% of eligible patients with bifurcation lesions were recruited into this trial. Although the reasons for this selection are not clear, the most plausible scenario is that operators excluded patients whom they believe were not good candidates for one of the techniques. This issue is of prime importance in treatment of bifurcation lesions because the various EDS techniques are not interchangeable (i.e., it is unlikely that one technique is better than all other techniques in all lesions and across all ranges of operator experience). For the time being, the choice of technique should be driven by the bifurcation morphology and operator experience. REFERENCES 1. Colombo A, Moses JW, Morice MC, et al. Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions. Circulation 2004; 109:1244–1249. 2. Steigen TK, Maeng M, Wiseth R, et al. Randomized study on simple versus complex stenting of coronary bifurcation lesions: The Nordic Bifurcation Study. Circulation 2006; 114:1955–1961. 3. Colombo A, Bramucci E, Sacc`a S, et al. Randomized study of the crush technique versus provisional side-branch stenting in true coronary bifurcations: the CACTUS (Coronary Bifurcations: application of the Crushing Technique Using Sirolimus-Eluting Stents) Study. Circulation 2009; 119(1):71–78. 4. Ferenc M, Gick M, Kienzle RP, et al. Randomized trial on routine vs. provisional T-stenting in the treatment of de novo coronary bifurcation lesions. Eur Heart J 2008; 29:2859–2867. 5. Guidelines for Percutaneous Coronary Interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Eur Heart J 2005; 26(8):804–847. 6. Medina A, Suarez de Lezo J, Pan M. A new classification of coronary bifurcation lesions [in Spanish]. Rev Esp Cardiol 2006; 59:183. 7. Furukawa E, Hibi K, Kosuge M, et al. Intravascular ultrasound predictors of side branch occlusion in bifurcation lesions after percutaneous coronary intervention. Cir J 2005; 69:325–330. 8. Carrie D, Elbaz M, Dambrin G, et al. Coronary stenting of bifurcation lesions using “T” or “reverse Y” configuration with Wiktor stent. Am J Cardiol 1998; 82(11):1418–1421, A8. 9. Kobayashi Y, Colombo A, Akiyama T, et al. Modified “T” stenting. A technique for kissing stents in bifurcational coronary lesion. Catheter Cardiovasc Diagn 1998; 43:323–326. 10. Colombo A, Stankovic G, Orlic D, et al. Modified T-stenting technique with crushing for bifurcation lesions: immediate results and 30-day outcome. Catheter Cardiovasc Interv 2003; 60:145–151. 11. Burzotta F, Gwon HC, Hahn JY, et al. Modified T-stenting with intentional protrusion of the sidebranch stent within the main vessel stent to ensure ostial coverage and facilitate final kissing balloon: the T-stenting and small protrusion technique (TAP-stenting). Report of bench testing and first clinical Italian-Korean two-centre experience. Catheter Cardiovasc Diagn 2007; 70(1):75–82. 12. Ge L, Airoldi F, Iakovou I, et al. Clinical and angiographic outcome after implantation of drug-eluting stents in bifurcation lesions with the crush stent technique: importance of final kissing balloon postdilation. J Am Coll Cardiol 2005; 46(4):613–620. 13. Ormiston JA, Currie E, Webster MW, et al. Drug-eluting stents for coronary bifurcations: insights into crush technique. Catheter Cardiovasc Interv 2004; 63:332–336. 14. Costa RA, Mintz GS, Carlier SG, et al. Bifurcation coronary lesions treated with the “crush” technique: an intervascular ultrasound analysis. J Am Coll Cardiol 2005; 46:599–605. 15. Moussa I, Costa R, Lasic Z, et al. A prospective registry to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions using the “crush technique.” Am J Cardiol 2006; 97(9):1317–1321. 16. Hoye A, Iakovou I, Ge L, et al. Long-term outcomes after stenting of bifurcation lesions with the “crush” technique: predictors of an adverse outcome. J Am Coll Cardiol 2006; 47(10):1949–1958. 17. Collins N, Dzavik V. A modified balloon crush approach improves side branch access and side branch stent apposition during crush stenting of coronary bifurcation lesions. Catheter Cardiovasc Interv 2006; 68:365–371. 18. Jim MH, Ho HH, Miu R, et al. Modified crush technique with double kissing balloon inflation (sleeve technique): a novel technique for coronary bifurcation lesions. Catheter Cardiovasc Interv 2006; 67(3):403–409. 19. Chevalier B, Glatt B, Royer T, et al. Placement of coronary stents in bifurcation lesions by the “culotte” technique. Am J Cardiol 1998; 82:943–949.

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20. Schampaert E, Fort S, Adelman AG, et al. The V-stent: a novel technique for coronary bifurcation stenting. Catheter Cardiovasc Diagn 1996; 39:320–326. 21. Sharma SK. Simultaneous kissing drug-eluting stent technique for percutaneous treatment of bifurcation lesions in large-size vessels. Catheter Cardiovasc Interv 2005; 65:10–16. 22. Roy P, Torguson R, Okabe T, et al. Angiographic and procedural correlates of stent thrombosis after intracoronary implantation of drug-eluting stents. J Interv Cardiol 2007; 20(5):307–313. 23. Kuchulakanti PK, Chu WW, Torguson R, et al. Correlates and long-term outcomes of angiographically proven stent thrombosis with sirolimus- and paclitaxel-eluting stents. Circulation 2006; 113(8):1108– 1113. 24. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005; 293(17):2126–2130. 25. Moussa I, Di Mario C, Moses JW, et al. Coronary stenting after rotational atherectomy in calcified and complex lesions. Angiographic and clinical follow-up results. Circulation 1997; 96(1):128–136. 26. Ozaki Y, Suzuki T, Yamaguchi T, et al. Can intravascular ultrasound guided cutting balloon angioplasty before stenting be a substitute for drug eluting stent? Final results of the prospective randomized multicenter trial comparing cutting balloon with balloon angioplasty before stenting (Reduce III). J Am Coll Cardiol 2004; 43:(Suppl A):1138. 27. Al Suwadi J, Berger PB, Rihal CS, et al. Immediate and long-term outcome of intracoronary stent implantation for true bifurcation lesions. J Am coll Cardiol 2000; 35:929–936. 28. Yamashita T, Nishida T Adamian MG, et al. Bifurcation lesions: two stents versus one stent: immediate and follow-up results. J Am Coll Cardiol 2000; 35:1145–1151. 29. Latib A, Cosgrave J, Godino C, et al. Sirolimus-eluting and paclitaxel-eluting stents for the treatment of coronary bifurcations. Am Heart J 2008; 156(4):745–750. 30. Colombo A, Stankovic G. Ostial and bifurcation lesions. In: Topol EJ, ed. Textbook of Interventional Cardiology, Vol. 20. Philadelphia, PA: Saunders Elsevier, 2008:349–375. 31. Louvard Y, Lefevre T. Bifurcation lesion stenting. In: Colombo A, Stankovic G, eds. Problem Oriented Approach in Interventional Cardiology, Vol 4. London, U.K.: Informa Healthcare, 2007:37–57. 32. Costa RA, Mintz GS, Carlier SG, et al. Impact of final lumen dimensions on restenosis after crush drug-eluting stent implantation for bifurcation lesions. J Am Coll Cardiol 2005; 45:3A. 33. Hahn JY, Song YB, Lee SY, et al. Serial intravascular ultrasound analysis of the main and side branches in bifurcation lesions treated with the T-stenting technique. J Am Coll Cardiol 2009; 54(2):110–117. 34. Erglis A, Kumsars I, Niemela M, et al.; For the Nordic PCISG. Randomized comparison of coronary bifurcation stenting with the crush versus the culotte technique using sirolimus eluting stents: the Nordic Stent Technique Study. Circ Cardiovasc Intervent 2009; 2:27–34.

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Coronary Revascularization for Patients with Unprotected Left Main Coronary Artery Disease: Making Clinical Decisions in the Absence of Definitive Evidence Issam D. Moussa Cardiac Catheterization Laboratory, New York Presbyterian Hospital–Weill Medical College of Cornell University, New York, New York, U.S.A.

Ted Feldman Cardiac Catheterization Laboratory, Cardiology Division, Evanston Hospital, Evanston, Illinois, U.S.A.

INTRODUCTION A 63-year-old patient with progressive exertional angina on maximal medical therapy and no prior revascularization is admitted to your service. Coronary angiography demonstrated a 75% lesion in the distal unprotected left main coronary artery (ULMCA) extending to the ostium of the left anterior descending artery. The left circumflex and right coronary arteries were free of obstructive disease. The left ventricular systolic function was normal. The patient was otherwise healthy. How should this patient be treated? In the United States, the majority of cardiologists would affirm that this patient should undergo coronary artery bypass graft (CABG) surgery. On the other hand, if this patient was in South Korea, Italy, or Germany, it is likely that his treating physician would recommend PCI. Who is right? Is someone wrong? Supporters of the CABG recommendation would argue that CABG is the “standard of care” and is endorsed by Guidelines as a class I recommendation (1), whereas PCI is considered a class III recommendation (2). On the other hand, supporters of the PCI recommendation would argue that the underlying evidence for the practice guidelines recommendations is both weak and outdated, and that the emerging evidence does not support the superiority of CABG over PCI with respect to irreversible clinical endpoints. From this vantage point, physician judgment, expertise, and patient preference should drive clinical decision making on a case-by-case basis. The purpose of this chapter is to critically reevaluate current state of the art with respect to coronary revascularization of patients with ULMCAD who are acceptable surgical candidates. In doing so, we will 1. briefly discuss the divergence between clinical practice guidelines and clinical decision making. 2. critically appraise the “evidence” underlying the current practice guidelines recommendations. 3. review the emerging data regarding utility of CABG versus PCI in patients with ULMCAD. 4. Discuss the elements of a contemporary approach to clinical decision making in light of the current state of knowledge. CLINICAL PRACTICE GUIDELINES AND CLINICAL JUDGMENT In principle, the process of clinical practice guidelines development should be straightforward when “unequivocal evidence” is available. So why then do different physicians come out with different interpretations after scrutinizing the same “evidence?” The simple truth is that “unequivocal evidence” in the practice of medicine is rarely achievable. The word “evidence” has been overused to include not only randomized clinical trials (RCT) and well-organized registries but also almost any peer-reviewed publication. Although categorization of “evidence” to different classes (A, B, C) has been used to express its quality, this step has not been effective

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in reflecting the extent of uncertainty in the literature because at the end it is still promoted as “evidence.” Although it is true that RCTs are often the best we can do to increase scientific certainty, and do to an extent, the applicability of these trials, and by extension the clinical practice guidelines, to individual patients is fraught with uncertainty. This uncertainty stems from whether the patient was adequately represented in the trial, whether the choice of endpoints weighs events proportionally to its impact on patient well-being, whether the underlying power calculation assumptions reflect reality, and finally whether the technology and expertise used in the trial are similar to those at the time of patient’s encounter. In brief, despite the admirable role of clinical practice guidelines in attempting to provide a sense of certainty in making clinical decisions, we continue to practice medicine in an environment of inescapable uncertainty. This assertion is not meant to suggest that guidelines have no practical value in clinical decision making, but rather that the process has to allow for clinical and scientific judgment to be used by those who ultimately put the recommendations into clinical practice. In other words, framing a clinical decision as “evidence-based” does not absolve the physician from using clinical judgment. There are disclaimers in the guidelines that try to convey this sentiment, but are lost in the translation from print documents into practice. THE “EVIDENCE” UNDERLYING THE CURRENT CLINICAL PRACTICE GUIDELINES The American College of Cardiology/American Heart Association (ACC/AHA/SCAI) 2004 guidelines categorize the use of CABG surgery for ULMCAD as a class IA recommendation (1) while the 2006 guidelines categorize the use of PCI as class III recommendation (class IIb for patients with US/NSTEMI with hemodynamic instability) (1,2). The recently proposed appropriateness criteria for coronary revascularization reflect these recommendations (3). In the forthcoming discussion we will review the evidence underlying these recommendations and evaluate the extent of uncertainty of this “evidence” in light of current knowledge. The Evidence for CABG Vs. Medical Therapy in Patients with ULMCAD When one is asked about the role of CABG surgery in treatment of patients with ULMCAD, the most likely answer is that the superiority of CABG surgery over medical therapy was established over a quarter century ago by randomized controlled trials (4)! Along the same lines, the current ACC/AHA/SCAI guidelines state, “the benefit of surgery over medical treatment in patients with significant ULMCAD (greater than 50%) is little argued” (1). In the face of this unquestionable certainty one could raise eyebrows by “revisiting” the topic! Why waste time and discuss well-established facts? The reason is that the alleged “evidence” is not so certain, and it does merit a critical review since the standards for “evidence” today are not those of three decades ago. The evidence supporting CABG over medical therapy for treatment of patients with ULMCAD does not meet today’s standards and is outdated: In fact, it may be surprising to many that there is not a single dedicated prospective RCT that compared CABG to medical therapy for patients with ULMCAD. The current guidelines are based primarily on a meta-analysis (5) that summarized the results of four small and three moderate-sized trials of patients with stable angina and significant CAD conducted in the 1970s. Altogether, 2649 patients were randomized to CABG or to an initial strategy of medical therapy. Of note, patients with ULMCAD made up only 6.6% (150 patients) of the study population and the presence of ULMCAD was not a prespecified element for analysis. In this analysis, there was a significant relative risk reduction in mortality with CABG of about 66% at 5 years with the benefit extending to 10 years. However, this is not the whole story. One of the more frequently quoted studies in support of CABG over medical therapy is the CASS (Coronary Artery Surgery Study). CASS enrolled asymptomatic or minimally symptomatic patients. In this registry, 1484 patients with ULMCAD underwent CABG (n = 1153) or medical therapy (n = 331) and were followed for up to 16 years (6). Patients undergoing medical therapy in this registry were at higher risk than those undergoing CABG, and in this older era, CABG surgery may have been denied surgery due to older age and increased surgical risk. Although the overall median survival for CABG patients was 13.3 years versus 6.6 years for patients undergoing medical therapy, several subgroups did not have survival benefit from CABG. Patients who did not benefit from CABG included those with preserved systolic LV function, with nonobstructive RCA disease, and with ULMCAD between

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50% and 59%. The survival benefit of CABG extended only to the higher-risk subgroups of patients with symptomatic multivessel coronary disease and left ventricular dysfunction. Furthermore, both the medical therapy and surgical techniques used in these studies are outdated by today’s standards. In patients undergoing CABG, the internal mammary artery (IMA) grafts were used in less than 10% of patients. More importantly, pharmacological agents proven to reduce long-term mortality were not used in the medically treated patients. Specifically, only 66.1% of the patients in the medically treated arm were on a B-blocker, and only 18.8% were taking aspirin. Statins and angiotensin-converting enzyme inhibitors were not used at all. Whether the impact of an IMA graft on survival is as important as statins, ACEI, and aspirin is unknown. Nonetheless, the current guidelines advocate offering CABG to all patients with ULMCAD. The purpose of this discussion is not to suggest that CABG surgery is not beneficial to patients with ULMCAD but to highlight that there are many questions and uncertainties about this recommendation, which is considered by our guidelines as an undebatable gold standard! The “Evidence” for CABG Surgery Vs. PCI in Patients with ULMCAD

Current Guidelines The most updated ACC/AHA/SCAI clinical practice guidelines for revascularization of patients with ULMCAD who are candidates for surgery categorize CABG surgery as a class IA (1) and PCI as a class III indication (class IIb for patients with US/NSTEMI with hemodynamic instability) (2,7). According to these guidelines, elective stent implantation in a patient with ULMCAD who is a candidate for CABG surgery would be considered harmful. Let us review the evidence underlying these recommendations. Is PCI for ULMCAD Harmful? The evidence that was used to suggest that PCI is harmful at the time of guidelines synthesis consisted of the published literature between 1997 and 2005 (2). Discussion of the details of these studies is beyond the scope of this review, but its substance can be characterized by the following observations: 1. All these studies were retrospective and none included a comparative CABG arm. 2. All these studies were small and included a high proportion of high-risk surgical patients or surgical “turn-downs” (i.e., patients who have bad prognosis irrespective of the revascularization modality.) 3. The majority of patients in these studies were treated with bare metal stents (BMS), though several studies reported patient outcomes after DES implantation. One of the studies often quoted to highlight the shortcomings of PCI in patients with ULMCAD is the ULTIMA (Unprotected Left Main Trunk Intervention Multicenter Assessment) registry (8). This registry suggested a high early mortality (2% per month among hospital survivors over the first six months after hospital discharge). What is conspicuously absent from discussion of this study is the fact that 65% of patients were at high risk for surgery or inoperable and stents were only used in ∼50% of patients. So, how are these data relevant to clinical decision making for patients with ULMCAD, who are good surgical candidates, contemplating the choice between CABG surgery and stents? The answer is simple and clear. These data are not relevant because these patients were not represented in the above studies. Therefore, these data constitute an “absence of evidence” and it cannot form an evidence-base for recommendations for management of patients with ULMCAD and no special risks for either surgery or PCI. Absence of evidence should not be used to formulate “evidence” of harm, which a class III recommendation does. The “Evidence” Beyond the Current Guidelines Since the publication of the 2006 ACC/AHA/SCAI guidelines, many more publications on the topic of coronary revascularization in patients with ULMCAD have become available. The objective of this discussion is to review a representative number of these studies. These studies

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CORONARY REVASCULARIZATION FOR PATIENTS WITH UNPROTECTED LEFT MAIN CORONARY ARTERY DISEASE Table 1

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Studies of DES Vs. BMS in Patients with ULMCAD Cumulative long-term events

Study

Registry Tamburino et al.a (9) RCT Erglis et al. (10)

Patient no., DES/ BMS

High surgical risk (%), DES/ BMS

Urgent intervention (%), DES/ BMS

Distal location (%), DES/ BMS

611/238

60/79

NR

68/60

3

53/50

0

0

68/81

0.5

Cardiac death (%), DES/ FU (yr) BMS

MI (%), DES/ BMS

TVR (%), DES/ BMS

13/17

4.8/11.8b

8.6/19.3b

2/0

9/14

2/16b

High surgical risk defined by a Euroscore >6 or a parsonnet score >13–15. a Patients with acute coronary syndromes (long-term events are reported in the matched population of DES vs. BMS). b p < 0.05. Abbreviation: NR, not reported.

include registries of BMS or DES without a CABG arm for comparison, registries with a CABG comparison, and randomized trials of PCI compared to CABG:

Studies of DES and BMS Without a Comparative CABG Arm Table 1 lists few of the most recent studies that compared DES to BMS in patients with ULMCAD (9,10). The only randomized trial that compared DES to BMS in good-surgical candidates (10) included small number of patients and reported only six-month follow-up data. These studies indicate that (i) the short- to intermediate-term cardiac death and nonfatal MI in patients receiving DES is similar, or lower, than that in patients receiving BMS; (ii) the short- to intermediateterm rate of repeat intervention is lower in patients receiving DES compared to BMS; ( iii) there are no special procedure risks of death or MI for LM PCI; and ( iv) the risk of mortality due to stent thrombosis is low. Table 2 lists studies that reported on the use of DES in patients with ULMCAD (11–14). These studies share the limitations of previous reports in that they included high proportion of high-risk surgical patients and patients undergoing urgent interventions, thereby, limiting generalizability to good-risk surgical patients. Nonetheless, several noteworthy observations can be made: (a) When DES implantation is performed electively in patients with ULMCAD, it is associated with low rates of cardiac death (∼2–3% annually) and myocardial infarction (∼2–3% annually). (b) There is a wide variation in the rate of repeat intervention after DES implantation due to the multitude of factors that influence this event such as systematic angiographic follow-up, Table 2

Studies of DES in Patients with ULMCAD Cumulative long-term events

Price et al. (11) Chieffo et al. (12) SanMartin et al. (13) DELFT (14)

Patient no.

High surgical risk (%)

Urgent intervention (%)

Distal LM location (%)

50

58

34

94

0.8

147

39

0

0

100

46

19

358

50

20

FU (yr) Cardiac mean death (%)

MI (%)

TVR (%)

2

10

38a

2.4

3.4

3.4

5.4

53

1

7.0

6

3.7

74

3

9.2

8.6

21.4

High surgical risk defined by a Euroscore >6 or a parsonnet score >13–15. a Angiographically driven TVR.

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lesion location (ostial or body vs. bifurcation), and the concomitant need for multivessel intervention. The exceptionally high rate of repeat intervention (38%) at one year in the study by Price et al. (11) was due to the systematic angiographic follow-up that revealed a high rate of focal restenosis, particularly at the ostium of the left circumflex artery, which was often asymptomatic. The extensive use of kissing stent technique and low rate of kissing balloon inflation may have played a role as well. Similar trends were noted in the study by Valgimigli et al. (15), where serial surveillance angiography in a cohort of LM PCI patients with primarily bifurcation stenting revealed a 38% incidence of restenosis. In this study, however, clinically driven TLR at 600 days was noted in 15% of patients with distal LM intervention versus 3% of patients with ostial or body left main intervention. The favorable outcome of patients with ostial or body left main intervention was also confirmed by Chieffo and colleagues (12), where only 5.4% of patients needed reintervention at 2.5 years of follow-up. Whether one DES performs better than others in patients with ULMCAD awaits the results of the appropriate trials. As of this writing, the only randomized study available is the ISAR-LM trial, which compared SES to PES in patients with ULMCAD (16). In this trial, there was no difference in cardiac death, nonfatal MI, or repeat intervention at two-year follow-up. Since stent platforms, polymers, and drugs are steadily evolving, it is unlikely that studies comparing one product with another will ever be meaningful. Although the above studies provided reassuring data similar to the role of DES in patients with ULMCAD, the absence of a comparative CABG arm and the inclusion of high proportion of high-risk surgical patients limit their value with respect to informing clinical decision making for the choice between CABG and DES in good-risk surgical patients.

Registries Comparing DES to CABG Surgery for ULMCAD Although this category of studies provided new data regarding the comparative efficacy of DES to CABG surgery in patients with ULMCAD (Table 3), the majority of these studies (17–20) included a large proportion of high-risk surgical patients, except for the study by Seung and colleagues (21). Table 3

Studies of DES Vs. CABG in Patients with ULMCAD Cumulative long-term events

Registry Chieffo et al. (17) Bolognab (18) Lee et al. (19) SanMartin et al. (20) Seung et al. (21) RCT LE MANS (22) SYNTAX (23)

Patient no., DES/ CABG

High surgical risk (%), DES/ CABG

FU (yr)

Cardiac death (%), DES/ CABG

Distal location (%), DES/ CABG

MI (%), DES/ CABG

Stroke (%), DES/ CABG

TVR (%), DES/ CABG

107/142

32/29

81/NR

1

2.8/6.4

0.9/1.4

0.9/2.1

19.6/5.7%a

157/154 50/123 96/245

64/61 64/46 27/25

80/ NR 60/ NR 62/ NR

1.2 1 1.3

7.4/9.7 4/15 5.2/8.4

5.3/4.5 0/2 0/1.3

NR 0/8 0/0.8

22.3/2.6%a 13/5 5.2/0.8

396/396

3

61/61

3

9/7

NR

NR

9/2a

52/53

0/0

56/60

1

1.9/7.5

1.9/5.6

0/3.7

27/9.4a

357/348

0/0

NR

1

4.2/4.4

4.3/4.1

0.3/2.7a

12/6.7a

High surgical risk defined by a Euroscore >6 or a parsonnet score >13–15. a p < 0.05. b DES was used in 94 out of 157 patients (long-term events are for DES patients). Abbreviation: NR, not reported (MI and stroke not reported separately in the study by Seung KB).

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Compared to CABG surgery, DES use in patients with ULMCAD was associated with 1. Similar incidence of cardiac death and myocardial infarction. 2. Lower incidence of procedural strokes. 3. Higher incidence of repeat revascularization for PCI with significant variability among studies reflecting previously discussed factors. One of the largest and well-conducted registries comparing stenting in good surgical candidates to CABG surgery in patients with ULMCAD is the MAIN-COMPARE registry (21). In this registry, 1102 patients with ULMCAD who underwent stent implantation and 1138 patients who underwent CABG in Korea between January 2000 and June 2006 were evaluated. The majority of patients (97%) in this study were considered good surgical candidates. At threeyear follow-up, in the matched cohort, there was no significant difference between the stenting and CABG groups in the risk of death [hazard ratio for the stenting group, 1.18; 95% confidence interval (CI), 0.77–1.80) or the risk of the composite outcome of death, Q-wave myocardial infarction, stroke, and target-vessel revascularization (hazard ratio for the stenting group, 1.10; 95% CI, 0.75–1.62). The rates of target-vessel revascularization were significantly higher in the group that received stents than in the group that underwent CABG (hazard ratio, 4.76; 95% CI, 2.80–8.11). These studies demonstrate that PCI with DES is safe and results in acceptable shortand intermediate-term survival results compared with those seen with CABG surgery, even in patients with complex disease.

Randomized Clinical Trials Comparing PCI and CABG for ULMCAD To date there have been only two RCTs comparing CABG surgery to DES in patients with ULMCAD who qualify for both procedures. In the LE MANS study (22), 105 patients with ULMCAD were randomly assigned to PCI (52 patients) or CABG (53 patients). The primary end point was the change in left ventricular ejection fraction (LVEF) 12 months after the intervention. A significant increase in LVEF at the 12-month follow-up was noted only in the PCI group (3.3 ± 6.7% after PCI vs. 0.5 ± 0.8% after CABG; p = 0.047). Patients performed equally well on stress tests, and angina status improved similarly in the two groups. PCI was associated with a lower 30-day risk of major adverse events (MAE) (p = 0.006) and major adverse cardiac and cerebrovascular events (MACCE) (p = 0.03) and shorter hospitalizations (p = 0.0007). Total and MACCE-free one-year survival was comparable. Left main target vessel failure (TVF) was similar in the two groups. During the 28.0 ± 9.9 months follow-up, there were three deaths in the PCI group and seven deaths in the CABG group (p = 0.08). The largest randomized clinical trial to address the efficacy of DES versus CABG surgery in patients with ULMCAD who qualify for both is the SYNTAX (TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries) study (23). In this study, 1800 patients were randomized to CABG surgery versus PES. Patients were stratified by the presence of diabetes mellitus or ULMCAD. The primary clinical endpoint of the trial was the 12-month major cardiovascular or cerebrovascular event rate (MACCE). Among trial participants, 705 patients with ULMCAD were randomized to PES (n = 357) and CABG surgery (n = 348) (24). In patients with ULMCAD, the use of PES, compared to CABG surgery, resulted in similar MACCE rates at one-year follow-up (Fig. 1) and similar combined safety endpoints (death, MI, and stroke) (Fig. 2). For patients treated with PES compared to those undergoing CABG, there was similar mortality and myocardial infarction, lower stroke rate, and higher need for repeat revascularization at one-year follow-up (Fig. 3). The higher need for repeat revascularization in the PES group was significant only in patients with LM plus two- or threevessel disease (Fig. 4). In this trial, the SYNTAX score was used to stratify patients according to the angiographic complexity of coronary disease. Patients with low (Fig. 5) and intermediate complexity scores (Fig. 6) had similar MACCE rate at one-year irrespective of revascularization modality while patients with high complexity scores (Fig. 7) had higher MACCE event rate when treated with PES as opposed to CABG primarily due to higher rate of repeat revascularization. Interestingly, the rate of symptomatic stent thrombosis at one-year in the PES cohort was the same as the rate of symptomatic graft occlusion in the CABG cohort (Fig. 8).

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122 CABG LM, all (n = 705)

13.7

p = 0.44

15.8

8.5

LM only (n = 91)

LM + 1VD (n = 138)

PCI

13.2

7.1

p = 1.00

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Figure 1

Overall MACCE at 12 months in the left main subset of the SYNTAX trial. (ITT population.)

One criticism of the SYNTAX data is that the one-year safety data may look different after several years, with the potential for CABG to show a survival benefit as time passes. However, two recent meta-analyses of prior CABG versus PCI trials show no mortality differences between the two techniques between 5 and 10 years. One of these used pooled patient level data for the analysis (25,26). The subgroup data from SYNTAX are not definitive because this trial was powered for MACCE events in the total study population. Nonetheless, the value of the SYNTAX trial in informing clinical decision making cannot be underestimated. The trial included patients from 85 sites in the United States and Europe, and over 70% of the screened study population, and represents real world practice. This is in sharp contrast to prior randomized trials comparing PCI with either medical therapy or CABG, where fewer than 10% of screened patients were studied. The SYNTAX data should be considered as part of an increasing body of knowledge that consistently points to the safety and efficacy of DES in treatment of patients with ULMCAD. HOW SHOULD WE MAKE CLINICAL DECISIONS REGARDING REVASCULARIZATION OF PATIENTS WITH ULMCAD? Although the existing data regarding the utility of PCI (stents) versus CABG for revascularization of patients with ULMCAD who are good surgical candidates still lack important milestones, such as long-term follow-up, it is certainly of higher quality than the “evidence” that was used to categorize CABG as a class I and PCI as a class III recommendation in this important CAD subgroup in the current clinical practice guidelines. The most contemporary data regarding CABG LM, all

9.2

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p = 0.72 9.9 8.1

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Figure 2

Safety (death/CVA/MI) at 12 months in the left main subset of the SYNTAX trial. (ITT population.)

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93.3%

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Figure 3 (A) Freedom from death at 12 months in the left main subset of the SYNTAX trial. (B) Freedom from CVA at 12 months in the left main subset of the SYNTAX trial. (C) Freedom from MI at 12 months in the left main subset of the SYNTAX trial. (D) Freedom from revascularization (any revascularization PCI or CABG) at 12 months in the left main subset of the SYNTAX trial. Event rates are expressed as event rate ± 1.5 SE. ∗ Fisher exact test; calculated by core laboratory per ITT population.

the role of PCI (DES) versus CABG in patients with ULMCAD were not included in either the guidelines or the recent appropriateness document, and point to the following: 1. There is no difference in death or MI up to three-years follow-up. 2. CABG surgery is associated with higher perioperative stroke rate. 3. PCI is associated with higher frequency of repeat revascularization primarily driven by patients with combined ULMCAD and multivessel disease. Critics of this data point to two issues: first, the lack of long-term (beyond three years) follow-up after PCI; and second, the concerns about late stent thrombosis. Recent meta-analyses suggest no mortality differences between PCI and CABG up to five years (26). If anything, historical evidence points to the fact that revascularization efficacy is attenuated with long-term CABG LM, all

(n = 705)

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(n = 91)

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(n = 138)

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3.0

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Figure 4 Revascularization at 12 months in the left main subset of the SYNTAX trial.

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CABG (n = 103)

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100 92.3% 87.0% 80

p = 0.19*

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Figure 5 MACCE at 12 months in the left main subset of the SYNTAX trial by SYNTAX score tercile (low scores 0–22). Event rates are expressed as event rate ± 1.5 SE. ∗ Fisher exact test; calculated by core laboratory per ITT population.

CABG (n = 92)

PCI (n = 103)

Freedom from MACCE (%)

100

87.4% 84.5% 80

p = 0.54*

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Figure 6 MACCE at 12 months in the left main subset of the SYNTAX trial by SYNTAX score tercile (intermediate scores 23–32). Event rates are expressed as event rate ± 1.5 SE. ∗ Fisher exact test; calculated by core laboratory per ITT population. CABG (n = 150)

PCI (n = 135)

100 Freedom from MACCE (%)

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Figure 7 MACCE at 12 months in the left main subset of the SYNTAX trial by SYNTAX score tercile (high scores ≥33). Event rates are expressed as event rate ± 1.5 SE. ∗ Fisher exact test; calculated by core laboratory per ITT population.

follow-up due to progression of the disease. The benefit of CABG surgery over medical therapy in patients with ULMCAD in the CASS registry started to narrow down after seven years (6). This is not surprising given the failure rate of saphenous vein grafts, disease progression distal to the bypass conduits, and the acceleration of disease proximal to the bypass graft insertions. Although concern regarding the impact of delayed stent thrombosis after DES implantation on outcome of patients with ULMCAD is legitimate, the existing data are reassuring. Chieffo and colleagues (27) reported the rate of stent thrombosis in a multicenter registry that included 731 consecutive patients who had sirolimus- or paclitaxel-eluting stent implantation in patients with ULMCAD. At 29.5 + 13.7 months follow-up, 4 (0.5%) patients had a definite ST—three early (two acute and one subacute) and one late ST—and no cases of very late definite ST were recorded. All patients survived the event. Three patients had a probable ST. Therefore,

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Figure 8 Symptomatic graft occlusion and stent thrombosis at 12 months in the left main subset of the SYNTAX trial.

7/731 (0.95%) patients had a definite or a probable ST and all were on dual antiplatelet therapy at the time of the event. Recently, critics asserted that the ethics of a randomized controlled trial comparing CABG with DES for ULMCAD are questionable because there is a lack of equipoise between the proven “standard of care” and DES (4). In light of the current state of knowledge, this statement appears to be unjustified. The Neglected Surgical Endpoints The ongoing debate has thus far ignored the impact of many CABG surgery specific complications. These complications and their associated morbidity, patient suffering, and need for both prolonged hospital stay and readmissions have not been included as endpoints in any clinical trial. Our surgical colleagues suggest that these complications are self-limiting and of little consequence to the patient over the long term” (28). Let us review these problems and explore how relevant they are to our discussion.

In-Hospital Postoperative Complications Despite the significant improvements in perioperative care after CABG surgery, major complications remain common. Brown and colleagues (29) reported on the incidence of post-CABG complications in 114,233 Medicare beneficiaries who survived isolated CABG during a hospitalization for fiscal year 2005. The frequencies of seven complications were determined: hemorrhage or postoperative shock, reoperation, postoperative adult respiratory distress syndrome, new-onset hemodialysis, postoperative stroke, postoperative infection, and septicemia. After adjusting for patient demographics and comorbid conditions, 13.64% of Medicare beneficiaries experienced one or more of the study complications. These patients consumed significantly more hospital resources (incremental cost, $15,468) and had a longer length of stay (incremental stay, 5.3 days). This study did not address the issue of postoperative atrial fibrillation, which develops in ∼30% of patients, and its association with subsequent cognitive changes, renal dysfunction, infection, and greater resource utilization (30). Rehospitalization in the first month after CABG occurs in almost 17% of Medicare patients, mostly due to arrhythmias, infections, and heart failure (31). Furthermore, what has not been studied well is the impact of these complications on patient’s perception and quality of life. Postoperative Cognitive Decline Apart from stroke, which occurs in 1% to 3% of CABG procedures, patients undergoing CABG surgery can suffer from two distinct neurological disorders, delirium and delayed cognitive decline. Delirium is a well-recognized complication of any major surgery including CABG. It occurs in around 3% of patients and is associated with a fivefold increase in hospital mortality and length of hospital stay (32). Cognitive decline is not usually apparent on regular clinical examination and accurate diagnosis requires formal assessment on a battery of neuropsychological tests. Some patients recognize intellectual deterioration (classically with memory, proprioceptive skills, or intellectual tasks such as crosswords), while in others relatives may observe that things are “not quite the same.” The incidence of cognitive impairment varies widely. In a systematic review, van Dijk and colleagues (33) reported a 22% incidence of cognitive decline

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two months after CABG. Newman and colleagues (34) reported the incidence of cognitive decline to be 53% at discharge, 36% at six weeks, 24% at six months, and 42% at five years in 261 patients.

Durability of CABG When a patient is referred to undergo CABG surgery, one of the main attractions is its publicized durability to the extent that many patients believe it is a permanent cure! Although it is true that the internal mammary artery is a durable conduit, the same cannot be said for saphenous vein grafts. About 8% of LIMA grafts and one-fourth of vein grafts fail within one year of implantation (35), and this number approaches 50% at 10 years (36). Although there have been reports of good results with bilateral ITA grafting, this is not frequently performed. Data from the Society of Thoracic Surgery suggest that considerably fewer than 20% of patients receive this procedure at a first isolated CABG (37). Furthermore, it is not uncommon that when CABG surgery is performed, bypass conduits are attached at or proximal to severely diseased coronary segments or that some coronary segments is not bypassed at all. Moreover, surgical therapy significantly accelerates atherosclerotic progression in the grafted vessels, especially in the proximal portions (38). Proximal disease progression has been shown to result in adverse clinical events at follow-up (39). In brief, it is difficult to understand why these well-documented CABG-related complications have been excluded from the ongoing debate similar to the pros and cons of CABG versus PCI in patients with ULMCAD. Our surgical colleagues assert that “patients are influenced into making a preordained choice” and that cardiologists “instigate” patients in making the choice between PCI and CABG” (4). Although this may occur in a minority of cases, it is more concerning that surgeons rarely, if ever, review the full range of the well-documented complications and shortcomings of CABG surgery. Instead of declaring that “these complication are self-limiting with no long-term sequelae” (28), we all need to provide this information to patients and let them weigh the impact on their well-being. HOW SHOULD GOOD-RISK SURGICAL PATIENTS WITH ULMCAD BE COUNSELED ON REVASCULARIZATION OPTIONS IN THE YEAR 2009? Some physicians may choose to continue relying on the current guidelines and simply refer all patients with ULMCAD who are good surgical candidates to CABG surgery. We think that the existing data can inform clinical decision making beyond what the current guidelines offer. A few actual clinical scenarios illustrate the discussion with patients with ULMCAD who are good surgical candidates: Patient #1 A 45-year-old male with progressive exertional angina on medical therapy. Patient underwent ECG exercise stress test where he exercised for 11 minutes, developed angina, and ischemic ECG changes with concomitant drop in BP. CTA demonstrated obstructive disease in the LAD and RCA. Coronary angiography showed ULMCAD and three-vessel disease and normal left ventricular systolic function [Fig. 9(A)]. Subsequent management and followup are illustrated in Figure 9(B). Patient #2 A 58-year-old male with multiple cardiovascular risk factors and CAD status post-PCI on the LAD presents with recurrent progressive exertional angina while on medical therapy. Coronary angiography demonstrated ostial ULMCAD with no significant involvement of other territories. He had normal left ventricular systolic function and no comorbidities. Coronary angiography and subsequent management are shown in Figure 10. Patient #3 A 78-year-old male with end-stage renal disease underwent cardiac work-up prior to hemodialysis fistula construction. Pharmacological stress test showed anterior ischemia and an echocardiogram demonstrated a left ventricular ejection fraction of 35%. The patient did not have other comorbidities. Coronary angiography demonstrated ULMCAD with involvement of the ostial LAD and LCx. The coronary anatomy and subsequent management are shown in Figure 11.

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Counseling each one of these patients regarding options of coronary revascularization can take one of the following directions: Counseling option #1 You have a severe blockage in the left main coronary artery as well as in some of its branches. This is a serious condition and we need to restore blood flow to your heart as soon as possible. When you return to your room you will be seen by a cardiac surgeon to evaluate

(a)

(b)

(d)

(c) (A)

Figure 9 (A) Coronary angiography at baseline: (a) note the distal ULMCAD (white arrow ), moderate proximal LAD disease, severe distal LAD disease, and severe proximal LCx disease; (b) note the severe disease in the distal LAD as well as the collaterals from the septal branches to the right poster lateral branch; (c) note the distal LM and OM lesions; (d) note the proximally occluded RCA. The patient was counseled to undergo CABG surgery. The patient could not return to work before two months. The patient had recurrent angina six-month post-CABG with evidence of anterior ischemia, which was managed medically. Patient returned a year later with recurrent progressive angina while on medical therapy. (B) Coronary angiography after one year: (a) note occlusion of the mid-LAD; (b) note that the insertion site of the left internal mammary artery graft is proximal to a severely diseased segment; (c) note that the insertion of the SVG to OM1 is proximal to a severely diseased segment; (d) note patent SVG to OM2; (e) note the stenosed SVG to a small PDA. The large posterolateral branch was not bypassed. In retrospect, was it appropriate to perform CABG surgery considering the extent of distal coronary disease particularly in the LAD? Did CABG surgery provide complete revascularization in this patient? Did CABG accelerate progression of disease in the proximal LAD? (Continued on page 128 )

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Figure 10 (A) Note the ostial disease in the ULMCA; (B) note mild disease in the LAD and LCx artery; (C) note the moderate disease in the PDA. The patient was counseled by both the cardiac surgeon who offered him CABG surgery and the interventionalist who offered him PCI with DES placement. (D) The patient declined CABG and subsequently underwent ULMCAD PCI with DES. At one-year follow-up patient remains free of symptoms.

you for coronary bypass surgery because it is the standard of care for treatment of this condition. Counseling option #2 You have a severe blockage in the left main coronary artery as well as in some of its branches. This is a serious condition and we need to restore blood flow to your heart as soon as possible. When you return to your room I will visit you and explain to you how we can restore blood flow using a minimally invasive approach with a stent. Counseling option #3 You have a severe blockage in the left main coronary artery as well as in some of its branches. This is a serious condition and we need to restore blood flow to your heart as soon as

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Figure 11 (A) Note the distal LM disease extending to both the ostium of the LAD and the LCx artery; (B) note mild disease in the RCA. The patient was counseled by both the cardiac surgeon who offered the patient CABG surgery and the interventionalist who offered the patient PCI with DES placement. (C) The patient declined CABG and subsequently underwent ULMCAD PCI with DES. At six-month follow-up patient remains free of symptoms and with subsequent improvement in left ventricular function.

possible. There are two methods to restore blood flow to your heart: CABG surgery, which has been the “standard of care,” and angioplasty with stents, which is another option. When you return to your room, both the cardiac surgeon and I will visit with you and explain the pros and cons of both options! It is very likely that almost all of our surgical colleagues and many interventionalists in the United States would opt to use counseling option #1, while a minority of interventionalists would chose counseling option #2. A variation on option #2 is when a patient is referred to a surgeon and there is no offer to have an interventional consultant weigh in with an opinion. We argue to opt for counseling option #3. At the crux of deciding how to counsel patients are two basic question: first, should we as physicians execute clinical practice guidelines that were published several years prior to patient encounter or make a contemporary judgment that reflects the current knowledge at the time of patient encounter? And secondly are caregivers as well as patients obligated to accept the clinical trialist “tradition” of giving equal weight to the need for repeat intervention versus that of death, myocardial infarction, or stroke? Shouldn’t patients be consulted as to what they would accept as potential consequences of revascularization, stroke, and prolonged recovery or the need to undergo another PCI! As caregivers, the ethics of the practice of medicine calls on us to investigate the reliability of current knowledge as well as “standards of care” (40). In counseling patients with ULMCAD regarding coronary revascularization, three important facts need to be made clear: (i) the revascularization procedure, CABG, or PCI, is not a cure and there is a chance that they may need repeat interventions in the future (more so with the PCI compared to the CABG surgery in cases where the LM disease is associated with two or three vessel CAD); (ii) although CABG surgery is currently considered the “standard of care,” there is no evidence that CABG surgery is better than PCI for prevention of death and MI (up to 3–5 years) and; (iii) CABG surgery involves higher “up-front” risk of significant adverse events (including higher stroke rate) and a prolonged recovery. When the cardiac surgeon or the interventionalists offers their perspectives separately, it is likely that both would be conflicted in their presentation. To present patients with a balanced view, both the interventional cardiologist and the cardiac surgeon should provide an informed consent not solely based on the current guidelines but also on the individual data of each patient: (i) the extent of disease beyond the LMCA; (ii) the morphology of disease, particularly the presence of combined severe calcifications and torousity and CTOs; (iii) the projected number of stents that are needed; (iv) the presence of disease in the distal coronary segments that may affect the effectiveness of bypass grafts; (v) quality of arterial and/or venous conduits for grafting; and (vi) patient and/or referring physician preferences.

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Undoubtedly, there is pressing need for more high-quality data comparing CABG to PCI to enrich and further inform clinical decision making. However, the primary endpoint of future trials should focus on safety endpoints (death, MI, stroke). The need for repeat revascularization for PCI and the high frequency of CABG surgery–related complications should be considered secondary endpoints, as it is in the NHLBI-sponsored FREEDOM trial (41).

SUMMARY Although scientific and technological advances refine clinical insight and provide tools, physicians still work in an environment of uncertainty. This uncertainty leads many of us to use the term ‘‘Medicine is both a science and an art’’ to manage the gaps in our knowledge base. This paradoxical description of the practice of medicine is ‘‘convenient’’ because it is flexible enough to allow us to be empiric at times yet scientific at others. We rationalize that we are empiric when we do not have ‘‘evidence,’’ yet we are scientific when we have evidence. The problem is that the evidence is a moving target. Although no one knows what the “evidence” for management of patients with ULMCAD will be 10 to 15 years from now, it is likely that both PCI and CABG will have a role in the management of these patients. Of course, whatever the “evidence” is at the time, there will continue to be uncertainties because both CABG and PCI would have advanced beyond the existing evidence of the day. What will not change is our mission as physicians to always investigate the reliability of current knowledge as well as standards of care and treat individual patients using our best judgment. REFERENCES 1. Eagle KA, Guyton RA, Davidoff R, et al. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery). J Am Coll Cardiol 2004; 44:e213–e310. 2. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention—summary article: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (ACC/ AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol 2006; 47:216–235. 3. Patel MR, Dehmer GJ, Hirshfeld JW, et al. ACCF/SCAI/STS/AATS/AHA/ASNC 2009 appropriateness criteria for coronary revascularization. J Am Coll Cardiol 2009; 53(6):530–553. 4. Taggart DP, Kaul S, Boden WE, et al. Revascularization for unprotected left main stem coronary artery stenosis stenting or surgery. J Am Coll Cardiol 2008; 51(9):885–892. 5. S. Yusuf, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomized trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet 1994; 344:563–570. 6. Caracciolo EA, Davis KB, Sopko G, et al. Comparison of surgical and medical group survival in patients with left main equivalent coronary artery disease: Long-term CASS experience. Circulation 1995; 91:2335–2344. 7. King SB III, Smith SC Jr, Hirshfeld JW Jr, et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/ American Heart Association Task Force on Practice guidelines. J Am Coll Cardiol 2008; 51(2):172– 209. 8. Ellis SG, Tamai H, Nobuyoshi M, et al. Contemporary percutaneous treatment of unprotected left main coronary stenoses: initial results from a multicenter registry analysis 1994–1996. Circulation 1997; 96:3867–3872. 9. Tamburino C, Di Salvo ME, Capodanno D, et al. Comparison of drug-eluting stents and bare-metal stents for the treatment of unprotected left main coronary artery disease in acute coronary syndromes. Am J Cardiol 2009; 103:187–193. 10. Erglis A, Narbute I, Kumsars I, et al. A randomized comparison of paclitaxel-eluting stents versus bare-metal stents for treatment of unprotected left main coronary stenosis. J Am Coll Cardiol 2007; 50:491–497. 11. Price MJ, Cristea E, Sawhney N, et al. Serial angiographic follow-up of sirolimus-eluting stents for unprotected left main coronary artery revascularization. J Am Coll Cardiol 2006; 47:871–877.

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34. Newman MF, Kirchner JL, Phillips-Bute B, et al. Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med 2001; 344:395–402. 35. Alexander JH, Hafley G, Harrington RA, et al. Efficacy and safety of edifoligide, an E2F transcription factor decoy, for prevention of vein graft failure following coronary artery bypass graft surgery: PREVENT IV: a randomized controlled trial. JAMA 2005; 294:2446–2454. 36. Grondin CM, Campeau L, Thornton JC, et al. Coronary artery bypass grafting with saphenous vein. Circulation 1989; 79:124–129. 37. Data Analyses of the Society of Thoracic Surgeons Adult Cardiac Surgery Database, Spring 2007 Report: Isolated CAB Procedures. 38. Hwang MH, Meadows WR, Palac RT, et al. Progression of native coronary disease at 10 years: insights from a randomized study of medical versus surgical therapy for angina. J Am Coll Cardiol 1990; 16:1066–1070. 39. Chen L, Theroux P, Lesperance J, et al. Angiographic features of vein grafts versus ungrafted coronary arteries in patients with unstable angina and previous bypass surgery. J Am Coll Cardiol. 1996; 28(6):1493–1499. 40. Montgomery K, ed. How Doctors Think: Clinical Judgment and the Practice of Medicine. New York: Oxford University Press, Inc., 2006. 41. Lee TH, Hillis D, Nabel EG. CABG vs. stenting—clinical implications of the SYNTAX Trial. N Eng J Med 2009; 360(8):e10.

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Provisional Stenting for Left Main Coronary Artery Bifurcation Lesions: Patient Selection and Technique Seung-Jung Park and Young-Hak Kim University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea

INTRODUCTION Coronary artery stenting has made percutaneous coronary intervention (PCI) for revascularization of patients with unprotected left main coronary artery (LMCA) disease safer (1). Moreover, drug-eluting stents (DES), together with advances in periprocedural and postprocedural adjunctive pharmacotherapies, have improved outcomes of PCI for these patients (2–9). In fact, compared with bare-metal stents (BMS), DES reduced the incidence of angiographic restenosis and subsequently the need of repeat revascularization (2–4). In the early series of studies for unprotected LMCA stenosis, the one-year incidence of repeat revascularization after DES implantation was 2% to 19%, as compared with 12% to 31% after BMS implantation (2–4). However, despite the great benefit of DES, treatment of bifurcation lesions in an unprotected LMCA remains a challenge. Besides the technical complexity of the procedure, lesions located at bifurcations are at higher risk for restenosis and thrombosis after stenting compared with nonbifurcation location (5,10–14). Patients with bifurcation LMCA disease who require a two-stent strategy have higher incidence of restenosis compared to patients with bifurcation LMCA disease who require a single stent (11,12). Whether the cause of this difference is the more complex bifurcation anatomy in the two-stent strategy or the technique itself remains to be revealed. Therefore, until the appropriate RCTs comparing single- versus two-stent strategies in bifurcation LMCA disease are available, selection of the bifurcation stenting technique should be based on the individual lesion morphology. In patients with suitable anatomy, an initial strategy of provisional stenting, as opposed to “routine” side branch (SB) stenting should be attempted. With the provisional approach, stenting of the SB is reserved for suboptimal result or significant dissection in the SB after main branch (MB) stenting. This chapter reviews proper patient selection and preparation and technical execution of provisional stenting in patients with unprotected LMCA bifurcation stenosis. WHO QUALIFIES FOR THE PROVISIONAL STENTING APPROACH: ANATOMIC CONSIDERATIONS Plaque Distribution and Side Branch Lesion Severity and Length LMCA bifurcation stenoses Medina class (1,1,0 or 1,0,0) (i.e., plaque located in the MB alone) should be treated using the provisional stenting technique. By contrast, when LMCA bifurcation stenoses involving the MB and SB (true bifurcation lesions) are treated with the provisional stenting approach, they are more likely to result in SB deterioration (Table 1). For example, Figure 1 shows a patient with LMCA bifurcation stenosis not involving the SB (the LCX artery) treated with provisional stenting, in which a single stent was placed in the LMCA crossing the left circumflex artery (LCX). However, as shown in Figure 2, a patient with LMCA bifurcation stenosis involving the ostia of the LCX and LAD arteries was treated with elective double stenting technique. IVUS is very helpful in determining the extent of disease in the ostial LCX artery where angiography can over- or underestimate the extent of disease. Size of the SB (LCX Artery) In making a selection between provisional and elective double stenting of LMCA bifurcation stenoses, the size of the LCX artery and the size of the myocardial territory it supplies are

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Table 1 Favorable or Unfavorable Anatomical Features for Provisional Stenting in the Treatment of Unprotected Left Main Coronary Artery Stenosis Anatomical features

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Significant stenosis at the ostial LCX with MEDINA classification 1,1,0 or 1,0,0 Large size of LCX with ≥2.5 mm in diameter Right dominant coronary system Narrow angle with LAD No concomitant disease in LCX Focal disease in LCX Insignificant stenosis at the ostial LCX with MEDINA classification 1,1,1; 1,0,1; or 0,1,1 Diminutive LCX with <2.5 mm in diameter Left dominant coronary system Wide angle with LAD Concomitant disease in LCX Diffuse disease in LCX

Abbreviations: LAD, left anterior descending artery; LCX, left circumflex artery.

of prime importance. The size of the LCX artery does not only refer to the diameter of the vessel (which may appear smaller due to diffuse disease) but also to its length and number of branches (which indicate the amount of myocardium at jeopardy). Elective double stenting should be strongly considered if the LCX artery supplies large myocardial territory and has severe ostial/proximal disease (Fig. 2). On the other hand, provisional stenting should be the strategy of choice if the LCX artery is small (<2.5 mm and it supplies small myocardial territory), irrespective of the extent of disease in the ostium (Figs. 3 and 4).

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Figure 1 Provisional stenting in a 69-year-old man with unprotected LMCA bifurcation lesion and normal left ventricular ejection fraction. (A and B) Baseline coronary angiography showing distal LMCA stenosis involving the ostium of the LAD. (C) Preintervention IVUS image of the ostial LCX (dotted white circle). (D) Coronary angiography after stenting of the LMCA-LAD with a 3.5 × 28 mm Xience everolimus-eluting stent (Abbott Vascular, Santa Clara, CA). Note the angiographic compromise of the LCX ostium. (E) FKI after high-pressure balloon dilation of the LMCA stent with a 4.5 × 8 mm noncompliant balloon. (F and G) Final coronary angiography after FKI with two 3.5 × 15 mm noncompliant balloons. Note the improvement in the LCX ostium.

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Figure 2 Elective double stenting in a 38-year-old man with unprotected LMCA bifurcation lesion and normal left ventricular ejection fraction. (A–C) Baseline coronary angiography shows distal LMCA bifurcation stenosis involving both the LAD and LCX. (D) Preintervention IVUS image of the ostial LCX (dotted white circle). (E) Simulatneous kissing stents with two 3.5 × 33 mm (LAD) and 3.0 × 23 mm (LCX) Cypher sirolimus-eluting stents (Cordis Corp, Johnson & Johnson, Warren, NJ). (F and G) Final coronary angiography.

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Figure 3 Provisional stenting in a 63-year-old man with unprotected LMCA bifurcation lesion and normal left ventricular ejection fraction (A–C) Baseline coronary angiography. Note that although the LCX ostium is involved, the LCX artery is small. (D) Stenting of the LMCA into the LAD with a 3.5 × 33 mm Cypher sirolimus-eluting stent (Cordis Corp, Johnson & Johnson, Warren, NJ); (E and F) Final coronary angiography (no final kissing balloon inflation).

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Figure 4 Provisional stenting in an 82-year-old woman with unprotected LMCA bifurcation lesion and normal left ventricular ejection fraction. (A and B) Baseline coronary angiography. Note the small myocardial territory supplied by the LCX artery. (C) Stenting of the LMCA towards the LAD with a 4.0 × 28 mm Xience everolimus-eluting stent (Abbott Vascular, Santa Clara, CA); (D and E) Final coronary angiography. Note that despite the apparent angiographic compromise of the ostial LCX, final kissing balloon inflation was not performed because the patient was asymptomatic and the LCX artery supplies a small territory.

Angulation in the Distal LMCA Bifurcation By angiography, bifurcations are classified according to the internal angle between the main vessel and the side branch, with a Y-shaped lesion having an angle <70 degrees and a T-shaped lesion ≥70 degrees. A Y-angle allows easier wire access to the SB than a T-angle. On the other hand, precise stent placement at the ostial SB is more difficult in a Y-angle lesion compared to a T-angle lesion. The LMCA bifurcations (LAD/LCX) are often T-shaped with an average angulation of 80 degrees. Therefore, the potential difficulty in rewiring the SB after MB stenting is an important consideration in selecting the stenting strategy for LMCA bifurcation stenosis. Figure 5 shows an example of LMCA bifurcation stenosis with a wide angle between the LAD and LCX arteries, which has a moderate stenosis at the ostium. To avoid the potential failure of wire recrossing to the LCX (large vessel supplying large myocardial territory), an elective double-stenting technique (crush technique) was used. Concomitant Disease in the Distal Circumflex Artery Although DES has improved patient outcomes after PCI, diffuse disease remains an indicator of higher risk of unfavorable outcomes (15). IVUS studies have demonstrated that incomplete lesion coverage leaving significant plaque proximal or distal to DES is associated with worse outcomes (16,17); therefore, complete lesion coverage is an important factor for good long-term outcomes. Patients with bifurcation LMCA disease and diffuse coronary disease elsewhere in the coronary tree are a particularly high-risk group. We typically avoid performing elective double stenting on the LMCA bifurcation in combination with multiple stents to treat distal diffuse disease because of the additive procedural and long-term risk. Figure 6 shows a patient with LMCA disease and small LCX artery with diffuse disease. In this patient, provisional LMCA stenting was used and a decision was made not to implant multiple stents in the diffusely diseased LCX artery.

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Figure 5 Elective double stenting in a 66-year-old man with unprotected LMCA bifurcation lesion and normal left ventricular ejection fraction. (A and B) Baseline coronary angiography. Note the distal LMCA lesion involving the ostial LAD and LCX (wide angle). (C) Preintervention IVUS image of the ostial LCX (dotted white circle) showed significant plaque burden. (D) Based on these findings, the decision was to proceed with elective double stenting using the minicrush technique. Two sirolimus-eluting stents (Cordis Corp, Johnson & Johnson, Warren, NJ) were positioned and sequentially deployed in the LM/LAD (3.5 × 23 mm) and the LCX (3.0 × 18 mm). (E and F) Final coronary angiography after sequential high-pressure balloon dilation with a noncompliant balloon of 4.0 × 18 mm in LAD and a noncompliant balloon of 3.0 × 18 mm in LCX followed by kissing balloon inflation.

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Figure 6 Provisional stenting in a 72-year-old woman with unprotected LMCA bifurcation lesion and normal left ventricular ejection fraction. (A and B) Baseline coronary angiography. Note the distal LMCA lesion involving the ostial LAD and LCX (wide angle). (C) Stenting of the LMCA towards the LAD with two 3.5 × 23 mm sirolimus-eluting stents (Cordis Corp, Johnson & Johnson, Warren, NJ) with a jailed wire in the LCX (arrow ). (D) Angiography after stenting. Note the compromise of the LCX ostium. (E) Due to the large size of the compromised LCX artery, a decision was made to implant a stent using a provisional T-stenting approach with a 2.75 × 33 mm sirolimus-eluting stent; (F and G) Final coronary angiography after kissing balloon inflation.

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PROVISINAL STENTING OF LMCA BIFURCATION LESIONS Patient Preparation In general, the elements of patient preparation before the procedure are dependent on the clinical risk profile of the patient and the anatomic complexity of the lesion. Optimal antiplatelet and antithrombotic therapy is, of course, required in all patients, but we do not use IIb/IIIa receptor antagonists routinely. Although the femoral approach is the most widely used in LMCA bifurcation interventions, few studies have reported the feasibility of the radial approach (18,19). When the radial approach is used, a 6-Fr guiding catheter is often used, although a 7-Fr guiding catheter can be used in male patients. We think that the femoral approach is preferable when a complex LMCA bifurcation intervention is required. In addition, elective use of hemodynamic support is occasionally necessary. The frequency of elective use of intra-aortic balloon pump (IABP) with LM PCI varies widely. Recently, a study in 219 elective LMCA interventions evaluated the role of IABP (20). An elective IABP was used in a broad range of patients undergoing LMCA bifurcation interventions including patients with unstable angina, patients with left ventricular ejection fraction <40%, patients with critical RCA disease, and when debulking devices are used. In this study, although the patients receiving elective IABP had more complex clinical risk profile, the rate of procedural complications was lower than those not receiving an IABP (1.4% vs. 9.3%; p = 0.032). Old age, myocardial infarction, cardiogenic shock, severely reduced left ventricular ejection fraction, and occlusion of the right coronary artery are common conditions requiring elective or provisional hemodynamic support. Patients in Figures 1 to 6 underwent LMCA PCI using the femoral approach without IABP support and without IIb/IIIa receptor antagonists. On the other hand, the patient in Figure 7 who was presented with cardiogenic shock underwent LM PCI with elective use of IABP.

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Figure 7 Provisional stenting in a 60-year-old woman presenting with cardiogenic shock due to acute anterior wall ST-elevation myocardial infarction. (A and B) baseline coronary angiography. Note the severe stenosis in the body of the LMCA with the small caliber and diffusely diseased LCX artery. (C) an intra-aortic balloon pump was placed prior to intervention. (D) A 3.5 × 23 mm Cypher sirolimus-eluting stent (Cordis Corp, Johnson & Johnson, Warren, NJ) was deployed in the LMCA toward the LAD (provisional approach). (E and F) final coronary angiography without kissing balloon inflation.

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Other, more potent, hemodynamic support devices such as the Tandem-Heart (CardiacAssist, Pittsburgh, PA) or the Impella Recover LP 2.5 System (Impella CardioSystems, Aachen, Germany) may allow safe treatment of exceedingly high-risk patients. Technique Execution

Guide Selection For LMCA interventions, a guiding catheter with side holes is selected to maintain blood flow to the target lesion. Some operators use guide catheters without side holes, particularly in patients with renal insufficiency, to reduce the amount of contrast used. Selection of the size and shape of the guiding catheter is based on the complexity of procedure and lesion morphology. When debulking is planned (rotational or directional atherectomy), a large caliber guiding catheter and a strong support are required. Also, when elective double stenting is planned, an 8-Fr guiding catheter is necessary to facilitate stent delivery and optimize visualization. In terms of back-up force, XB (Extra-backup) or EBU (Extra Back Up) catheter has stronger back-up support than JL (Judkins left) catheter. However, caution need to be exercised while using catheters with strong support due to the possibility of damage to the LMCA. Thus, in the majority of LMCA interventions using provisional stenting, we use an 8-Fr JL guiding catheter. Lesion Preparation: Role of Debulking In the BMS era, debulking coronary atherectomy (DCA) before stenting was often used in an attempt to reduce restenosis by reducing plaque burden. However, the role of DCA has diminished after the introduction of DES because of the dramatic reduction of restenosis. Nonetheless, a study of 99 patients with LMCA lesions suggested a viable role for DCA even in the DES era (21). Of interest, DCA in the MB and SB for the LMCA stenoses allowed single-stenting in 60 out of 63 LMCA bifurcation stenoses. There were no serious adverse events at one-year follow-up. This study indicates that DCA may have a role in the treatment of LMCA bifurcation lesions to optimize the success of provisional stenting strategy. In the patient illustrated in Figure 8, DCA was used to remove the plaque in the LMCA, hindering advancement of the wire into the LAD. Also, rotational atherectomy remains a valuable technique in severely calcified LMCA lesions. Therefore, although data is limited, DCA or rotational atherectomy still plays a limited, but important, role even in the DES era primarily to reduce plaque shift and facilitate stent expansion. Main Branch (LMCA) Stenting There is no evidence that one DES is better than others in terms of reducing procedural or long-term complications. The only RCT that compared two different DES in the LMCA is the ISAR-LEFT MAIN (A Randomized Clinical Trial on Drug-Eluting Stents for Unprotected Left Main Lesions study) (22). In this trial, 607 patients with unprotected LMCA disease (distal LMCA disease was present in 63% of patients) were randomized to receive either a paclitaxeleluting stent (PES) or sirolimus-eluting stent (SES). Provisional stenting was used in ∼50% of patients. There was no difference in the primary endpoint at one year (MACE was 13.6% in PES vs. 15.8% in SES; RR = 0.85; 95% CI = 0.56–1.29). However, based on bench testing, tubular type stents seems to be better in achieving optimal lesion coverage in the SB and stronger radial force in the LMCA than the coil or hybrid type stents (23). In the provisional approach, the main branch (LMCA) stent should be directed towards the LAD. In cases where the ostial LCX is heavily diseased, elective double stenting should be considered. Provisional Approaches for the Management of the SB Final kissing balloon inflation (FKI) Provisional treatment of the SB (usually the LCX artery) with either balloon angioplasty or stenting is reserved for patients with suboptimal results. Despite the controversy, we do not routinely perform balloon angioplasty or FKI after MB stenting. As shown in Figure 9, angiographic narrowing at the ostial LCX is often caused by the MB stent strut, not by plaque shift. Therefore, to avoid unnecessary barotrauma to the ostial LCX artery, FKI is selectively

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Figure 8 Provisional stenting after debulking coronary atherectomy (DCA) in a 71-year-old man. (A and B) Baseline coronary angiography. Note the distal LMCA lesion extending to the ostial LAD. (C) DCA to the distal LMCA toward the LCX artery due to inability to wire the LAD. (D) Successful wiring of the LAD. (E and F) Final coronary angiography after three Cypher sirolimus-eluting stents (Cordis Corp, Johnson & Johnson, Warren, NJ), 3.5 × 18 mm, 3.0 × 23 mm, and 2.5 × 33 mm, in the LMCA toward the LAD without FKI (provisional approach).

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Figure 9 Provisional stenting in a 54-year-old woman with normal ejection fraction. (A and B) Baseline coronary angiography. (C) Baseline IVUS image showing normal ostial LCX (dotted white circle); (D) Baseline IVUS image showing diseased ostial LAD and normal ostial LCX; (E and F) Final coronary angiography after stenting the ostial LAD toward the LMCA with a 3.5 × 33 mm Cypher sirolimus-eluting stent (Cordis Corp, Johnson & Johnson, Warren, NJ) using a provisional approach. (G) Final IVUS image of the LAD ostium showing normal ostial LCX (arrow ). (H) Fractional flow reserve (FFR) after hyperemia in the LCX (FFR = 0.97).

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Figure 10 A diagram illustrating provisional T-stenting with minimal protrusion. (A) After main branch (MB) stenting; (B) stenting in the side branch (SB) with T-shape through the MB stent; (C) final kissing balloon inflation; (D) final result.

performed in lesions that develop true narrowing after MB stenting, as shown in Figure 1. When a decision is made to perform FKI, we use a standard guidewire to recross into the LCX artery. However, when a standard guidewire fails to recross due to a wide bifurcation angle or a severe stenosis, hydrophilic-coated or stiffer guidewires may be useful with the caveat that these wires can easily induce dissections if not used carefully. If all these techniques fail, recrossing with a small fixed-wire balloon should be attempted. Stenting of the SB Stenting of the LCX artery is only required provisionally in the case of suboptimal result or significant dissection after FKI. When SB stenting is required as a bailout procedure, we use provisional T-stenting or the reverse crush technique (24–28). The “provisional T-stenting” technique (Fig. 10) is a strategy of T-stenting in the LCX artery after MB stenting with minimal protrusion into the LMCA. FKI after T-stenting is a mandatory step for optimal final result. In the “reverse crush technique,” a LCX stent is implanted with also minimal protrusion into the LMCA, but the protruding LCX stent is crushed to the vessel wall by the MB balloon, after the removal of the LCX wire and balloon. Then the LCX artery is rewired and stent struts dilated with high-pressure noncompliant balloon. FKI of both branches should be performed with noncompliant balloons (Fig. 11).

Stent Deployment Optimization Role of IVUS IVUS is a useful modality to help in selecting treatment strategies as well as optimize stent deployment and outcomes even in the DES era (29–31). Although one study reported that the clinical impact of IVUS-guided stenting for LMCA with DES did not show significant clinical long-term benefit compared with angiography-guided procedure (32), this study was retrospective and underpowered. Recent registry data provide support for the concept that IVUS-guidance may reduce the long-term risk of restenosis and late mortality (33,34). IVUS interrogation in patients with unprotected LMCA bifurcation disease can provide unique and useful information that cannot be derived from angiography: 1. IVUS provide more accurate assessment of the LMCA stenosis severity and true vessel size—both are important elements to optimize stent deployment in the LMCA. 2. Coronary angiography is not accurate in discriminating between true and pseudostenosis in the ostial LCX artery. The degree of ostial LCX stenosis and plaque burden impacts the probability of LCX compromise after LMCA stenting. An IVUS confirmation of small

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Figure 11 A diagram illustrating reverse crush stenting. (A) After main branch (MB) stenting; (B) stenting in the side branch (SB) keeping the balloon in the MB; (C) crushing the SB stent with a MB balloon; (D) crushed SB stent; (E) wire recrossing into the SB; (F) balloon dilation of the SB stent; (G) kissing balloon inflation; (H) final result.

plaque burden at the LCX ostium makes provisional stenting success more likely, while a large plaque burden makes provisional stenting success less likely. 3. IVUS interrogation of the LCX ostium after LMCA stent placement is more accurate than angiography to make a determination as to the need for further intervention on the LCX. Figure 9 is an example of usefulness of IVUS examination after stenting. Angiographic haziness at the ostial LCX after MB stenting turned out to be the MB stent strut without flow limitation. Role of fractional flow reserve Fractional flow reserve is a reliable physiological measurement to assess the significance of lumen compromise in the SB after MB stenting. In a study comparing the discrepancy between angiographic severity and fractional flow reserve (FFR) of the SB for 94 coronary bifurcations, there was weak correlation between the two measurements (35). Of interest, only 27% of lesions with ≥75% angiographic stensosis had significant flow impairment as determined by FFR

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<0.75. Based on this finding, we occasionally measure FFR when the functional severity of the SB stenosis after LMCA stenting in not certain by visual evaluation. Figure 9 is an example showing the advantage of FFR measurement, in that no angioplasty or stenting was performed in the LCX because FFR was >0.75 despite the presence of moderate LCX stenosis. A detailed discussion on the role of FFR in guiding provisional stenting of bifurcation lesions can be found in chapter 4. TIPS AND TRICKS IN PROVISIONAL STENTING OF LMCA BIFURCATION LESIONS Although provisional stenting is the easiest technique to treat LMCA bifurcations lesions, several considerations are worth noting:

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Predilation of the LCX artery ostium before MB stenting is generally not recommended if the stenosis of the LCX is not significant because it may cause a flow limiting dissection that requires the operator to perform an unplanned stenting of the SB. The “jailed wire technique” is a very important element of the provisional stenting technique. It helps maintain SB patency during MB stenting, provides a marker of the SB origin in case of occlusion, and may change the angle from T- to Y-shape that may facilitate SB recrossing (Fig. 6). Careful preprocedural evaluation of ostial LCX lesion severity and angulation by angiography and IVUS are important to choose the appropriate technique as well as to anticipate potential problems. If the angle between a severely diseased ostial LCX and the LMCA is wide, it may be very difficult to recross into the LCX after MB stenting. As an example, the patient in Figure 12 underwent an elective two-stent strategy (kissing stenting) due to the concern about LCX compromise/occlusion after MB stenting.

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Figure 12 Simultaneous kissing stenting for a 69-year-old man with normal ejection fraction. (A and B) Baseline coronary angiography. Note the severe stenosis involving the distal LMCA, ostial LAD, and ostial and distal LCX; (C) deployment of a 2.75 × 18 mm Cypher sirolimus-eluting stent (Cordis Corp, Johnson & Johnson, Warren, NJ) in the distal LCX; (D) kissing stents (Cypher sirolimus-eluting stents) deployed in the ostial LAD (3.5 × 33 mm) and ostial LCX (3.0 × 23 mm) into the distal LMCA; (E and F) final coronary angiography.

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Figure 13 Simultaneous kissing stenting in a 46-year-old-man with severe in-stent restenosis of a bare metal stent placed in the LMCA across the LCX. (A–C) Baseline coronary angiography. Note the proliferative pattern of restenosis within a bare metal stent extending from the distal LMCA to the ostial LAD. (D) Simultaneous kissing stenting with two 3.5 × 24 mm (LAD) and 3.5 × 8 mm (LCX) Taxus paclitaxel-eluting stents (Boston Scientific, Natick, MA); (E and F) Final coronary angiography.

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Although restenosis remains an important limitation of the long-term efficacy of PCI for LMCA bifurcation lesions, it is relatively an uncommon event (<10%), particularly in patients with less-complex lesion morphology who are suitable for provisional stenting (12). Even in patients with restenosis, the majority have focal restenosis that can be easily treated with repeat PCI. As shown in Figure 13, repeat PCI with DES is a useful strategy for restenosis of BMS or DES.

ANTIPLATELET THERAPY IN PATIENTS UNDERGOING PROVISIONAL STENTING OF LMCA BIFURCATION LESIONS Although the reported incidence of stent thrombosis after DES implantation in LMCA lesions is very low (36), fear of stent thrombosis remains a major concern. Premature discontinuation of clopidogrel is strongly associated with stent thrombosis (13,37). Therefore, as generally recommended, dual antiplatelet therapy including aspirin and clopidogrel (or ticlopidine) should be maintained for at least one year. Furthermore, during the procedure, elective or provisional use of glycoprotein IIb/IIIa inhibitor may play a role in reducing procedure-related thrombotic complications. In a patient illustrated in Figure 12, prophylactic abciximab was administered before the procedure due to the complex lesion morphology. In some institutions in Asian countries, adjunctive administration of cilostazol has been used for the purpose of reducing thrombotic complications (38). However, the additive role of glycoprotein IIb/IIIa inhibitor, cilostazol, low-molecular-weight heparin, direct thrombin inhibitor, or other new drugs in DES treatment for LMCA lesions need to be investigated in future studies. Some operators recommend to continue dual antiplatelet therapy for more than one year in high-risk patients (diabetes mellitus, multiple stents, chronic renal failure, or presentation with myocardial infarction) (39).

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TAKE HOME MESSAGE 1. In percutaneous interventional treatment of patients with unprotected LMCA bifurcation lesions, provisional stenting should be the preferred technique in the following anatomic subsets: (a) Patients without ostial LCX involvement as assessed by angiography and IVUS. (b) Patients with diminutive LCX artery irrespective of the extent of disease in the ostium. 2. In patients with unprotected LMCA bifurcation lesions and severe involvement of the ostium of a large LCX artery, elective double stenting strategy should be considered. 3. In patients with complex unprotected LMCA bifurcation lesions, a large guiding catheter (8-Fr guiding) provides more options for optimal treatment. 4. Prophylactic IABP (or other hemodynamic support devices) should be considered in patients who are hemodynamically unstable or who have very complex coronary lesions. 5. Aggressive lesion preparation with debulking (excisional or rotational atherectomy) should be considered in very bulky or severely calcified LMCA bifurcation lesions. 6. Final kissing balloon inflation (FKI) should be selectively performed only when the ostium of the LCX artery is significantly compromised. 7. Provisional stenting of the LCX artery (using T-stenting, inverse crush technique, or culotte stenting) should be only performed after failure of FKI in obtaining an acceptable result in a large LCX artery. 8. Patients undergoing provisional stenting (DES) of unprotected LMCA bifurcation lesions should receive dual antiplatelet therapy (aspirin and clopidogrel) for at least one year or more. 9. Routine angiographic surveillance between 6 and 9 months is generally recommended after stenting of unprotected LMCA stenosis.

REFERENCES 1. Park SJ, Mintz GS. Handbook of Left main stem disease. Seoul, South Korea: Informa Healthcare, 2006. 2. Park SJ, Kim YH, Lee BK, et al. Sirolimus-eluting stent implantation for unprotected left main coronary artery stenosis: comparison with bare metal stent implantation. J Am Coll Cardiol 2005; 45(3): 351–356. 3. Chieffo A, Stankovic G, Bonizzoni E, et al. Early and mid-term results of drug-eluting stent implantation in unprotected left main. Circulation 2005; 111(6):791–795. 4. Valgimigli M, van Mieghem CA, Ong AT, et al. Short- and long-term clinical outcome after drugeluting stent implantation for the percutaneous treatment of left main coronary artery disease: insights from the Rapamycin-Eluting and Taxus Stent Evaluated At Rotterdam Cardiology Hospital registries (RESEARCH and T-SEARCH). Circulation 2005; 111(11):1383–1389. 5. Price MJ, Cristea E, Sawhney N, et al. Serial angiographic follow-up of sirolimus-eluting stents for unprotected left main coronary artery revascularization. J Am Coll Cardiol 2006; 47(4):871–877. 6. Palmerini T, Marzocchi A, Marrozzini C, et al. Comparison between coronary angioplasty and coronary artery bypass surgery for the treatment of unprotected left main coronary artery stenosis (the Bologna Registry). Am J Cardiol 2006; 98(1):54–59. 7. Lee MS, Kapoor N, Jamal F, et al. Comparison of coronary artery bypass surgery with percutaneous coronary intervention with drug-eluting stents for unprotected left main coronary artery disease. J Am Coll Cardiol 2006; 47(4):864–870. 8. Kim Y, Dangas G, Solinas E, et al. Effectiveness of drug-eluting stent implantation for patients with unprotected left main coronary artery stenosis. Am J Cardiol 2008; 101(6):801–806. 9. Buszman PE, Kiesz SR, Bochenek A, et al. Acute and late outcomes of unprotected left main stenting in comparison with surgical revascularization. J Am Coll Cardiol 2008; 51(5):538–545. 10. Chieffo A, Park SJ, Valgimigli M, et al. Favorable long-term outcome after drug-eluting stent implantation in nonbifurcation lesions that involve unprotected left main coronary artery. A Multicenter Registry. Circulation 2007; 116(2):158–162. 11. Valgimigli M, Malagutti P, Rodriguez-Granillo GA, et al. Distal left main coronary disease is a major predictor of outcome in patients undergoing percutaneous intervention in the drug-eluting stent era: an integrated clinical and angiographic analysis based on the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) and Taxus-Stent Evaluated At Rotterdam Cardiology Hospital (T-SEARCH) Registries. J Am Coll Cardiol 2006; 47(8):1530–1537.

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12. Kim YH, Park SW, Hong MK, et al. Comparison of simple and complex stenting techniques in the treatment of unprotected left main coronary artery bifurcation stenosis. Am J Cardiol 2006; 97(11):1597– 1601. 13. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005; 293(17):2126–2130. 14. Alfonso F, Suarez A, Perez-Vizcayno MJ, et al. Intravascular ultrasound findings during episodes of drug-eluting stent thrombosis. J Am Coll Cardiol 2007; 50(21):2095–2097. 15. Lee CW, Park K-H, Kim Y-H, et al. Clinical and angiographic outcomes after placement of multiple overlapping drug-eluting stents in diffuse coronary lesions. Am J Cardiol 2006; 98(7):918–922. 16. Sonoda S, Morino Y, Ako J, et al. Impact of final stent dimensions on long-term results following sirolimus-eluting stent implantation: Serial intravascular ultrasound analysis from the Sirius trial. J Am Coll Cardiol 2004; 43(11):1959–1963. 17. Fujii K, Carlier SG, Mintz GS, et al. Stent underexpansion and residual reference segment stenosis are related to stent thrombosis after sirolimus-eluting stent implantation: an intravascular ultrasound study. J Am Coll Cardiol 2005; 45(7):995–998. 18. Cheng CI, Wu CJ, Fang CY, et al. Feasibility and safety of transradial stenting for unprotected left main coronary artery stenoses. Circ J 2007; 71(6):855–861. 19. Ziakas A, Klinke P, Mildenberger R, et al. Comparison of the radial and femoral approaches in left main PCI: a retrospective study. J Invasive Cardiol 2004; 16(3):129–132. 20. Briguori C, Airoldi F, Chieffo A, et al. Elective versus provisional intraaortic balloon pumping in unprotected left main stenting. Am Heart J 2006; 152(3):565–572. 21. Tsuchikane E, Aizawa T, Tamai H, et al. The efficacy of pre drug eluting stent debulking by directional atherectomy for bifurcated lesions: a multicenter prospective registry (PERFECT Registry). J Am Coll Cardiol 2007; 49 (suppl 2)(9):15B. 22. Mehilli J, Kastrati A, Byrne RA, et al. Paclitaxel- versus sirolimus-eluting stents for unprotected left main coronary artery disease. J Am Coll Cardiol 2009; 53(19):1760–1768. 23. Ormiston JA, Webster MW, Ruygrok PN, et al. Stent deformation following simulated side-branch dilatation: a comparison of five stent designs. Catheter Cardiovasc Interv 1999; 47(2):258–264. 24. Ormiston JA, Webster MW, El Jack S, et al. Drug-eluting stents for coronary bifurcations: bench testing of provisional side-branch strategies. Catheter Cardiovasc Interv 2006; 67(1):49–55. 25. Ge L, Airoldi F, Iakovou I, et al. Clinical and angiographic outcome after implantation of drug-eluting stents in bifurcation lesions with the crush stent technique: importance of final kissing balloon postdilation. J Am Coll Cardiol 2005; 46(4):613–620. 26. Burzotta F, Gwon HC, Hahn JY, et al. Modified T-stenting with intentional protrusion of the sidebranch stent within the main vessel stent to ensure ostial coverage and facilitate final kissing balloon: the T-stenting and small protrusion technique (TAP-stenting). Report of bench testing and first clinical Italian-Korean two-centre experience. Catheter Cardiovasc Interv 2007; 70(1):75–82. 27. Colombo A, Moses JW, Morice MC, et al. Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions. Circulation 2004; 109(10):1244–1249. 28. Steigen TK, Maeng M, Wiseth R, et al. Randomized study on simple versus complex stenting of coronary artery bifurcation lesions: the Nordic bifurcation study. Circulation 2006; 114(18):1955–1961. 29. Sano K, Mintz GS, Carlier SG, et al. Assessing intermediate left main coronary lesions using intravascular ultrasound. Am Heart J 2007; 154(5):983–988. 30. Mintz GS. Features and parameters of drug-eluting stent deployment discoverable by intravascular ultrasound. Am J Cardiol 2007; 100(8, suppl 2):S26–S35. 31. Mintz GS, Weissman NJ. Intravascular ultrasound in the drug-eluting stent era. J Am Coll Cardiol 2006; 48(3):421–429. 32. Agostoni P, Valgimigli M, Van Mieghem C, et al. Comparison of early outcome of percutaneous coronary intervention for unprotected left main coronary artery disease in the drug-eluting stent era with versus without intravascular ultrasonic guidance. Am J Cardiol 2005; 95(5):644–647. 33. Roy P, Steinberg DH, Sushinsky SJ, et al. The potential clinical utility of intravascular ultrasound guidance in patients undergoing percutaneous coronary intervention with drug-eluting stents. Eur Heart J 2008; 29(15):1851–1857. 34. Hong MK, Kim YH, Kim WJ, et al. Impact of intravascular ultrasound guidance on long-term clinical outcomes in patients undergoing percutaneous coronary intervention for unprotected left main disease. J Am Coll Cardiol 2008; 51(suppl 2):B7. 35. Koo BK, Kang HJ, Youn TJ, et al. Physiologic assessment of jailed side branch lesions using fractional flow reserve. J Am Coll Cardiol 2005; 46(4):633–637. 36. Chieffo A, Park S-J, Meliga E, et al. Late and very late stent thrombosis following drug-eluting stent implantation in unprotected left main coronary artery: a multicentre registry. Eur Heart J 2008; 29(17):2108–2115.

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37. Park DW, Park SW, Park KH, et al. Frequency of and risk factors for stent thrombosis after drug-eluting stent implantation during long-term follow-up. Am J Cardiol 2006; 98(3):352–356. 38. Lee SW, Park SW, Hong MK, et al. Triple versus dual antiplatelet therapy after coronary stenting: impact on stent thrombosis. J Am Coll Cardiol 2005; 46(10):1833–1837. 39. Pinto Slottow TL, Waskman R. Overview of the 2006 Food and Drug Administration Circulatory System Devices Panel meeting on drug-eluting stent thrombosis. Catheter Cardiovasc Intervent 2007; 69(7):1064–1074.

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Elective Double Stenting for Left Main Coronary Artery Bifurcation Lesions: Patient Selection and Technique1 Azeem Latib, Alaide Chieffo, and Antonio Colombo Interventional Cardiology Unit, San Raffaele Scientific Institute, and Interventional Cardiology Unit, EMO-GVM Centro Cuore Columbus, Milan, Italy

INTRODUCTION Percutaneous coronary intervention (PCI) on the left main coronary artery (LMCA) has been a challenge since the inception of coronary angioplasty. In fact, in 1979, Andreas Gruentzig wrote, “We have not been too successful in dilating stenotic main stems of left coronary arteries” (1). Indeed the poor immediate and short-term outcome of the first attempts of PCI with balloon angioplasty led Gruentzig to list LMCA as an exclusion criterion for elective PCI. However, PCI for the LMCA has come a long way from those days and is currently associated with shortand medium-term survival rates similar to coronary artery bypass surgery (CABG) (2–6). This dramatic change and improved results are consequences of the evolution and development of PCI techniques, especially in regards to bifurcations, improvements in hemodynamic support during PCI, and the introduction of drug-eluting stents (DES). LMCA PCI has also become the object of randomized trials such as the Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) Study, which showed similar major adverse cardiac and cerebrovascular events at 12 months in the LMCA subgroup between PCI with DES and CABG (4). As a result these new data, the update current guidelines no longer consider PCI for unprotected LMCA as a Class III recommendation (contraindication) if the patient is eligible for CABG (7,8). The ACC/AHA/SCAI 2009 updated guidelines (9) have modified the class of recommendation for PCI to unprotected LMCA to Class IIb (Level of Evidence: B), explaining the recommendation as follows: “PCI of the left main coronary artery with stents as an alternative to CABG may be considered in patients with anatomic conditions that are associated with a low risk of PCI procedural complications and clinical conditions that predict an increased risk of adverse surgical outcomes.” A distinction needs to be made between lesions involving the ostium or midshaft and those involving the bifurcation. In nonbifurcation lesions, results are excellent and comparable to those seen with CABG (10). An important limitation to PCI is that the majority of LMCA lesions treated are located in the distal LMCA bifurcation, which has been shown to be associated with worse clinical outcomes (11) and for which we still do not have an ideal stenting approach. However, in LMCA bifurcation disease, results are very much dependent on patient selection and optimal technique. The next important distinction that needs to be made is that LMCA bifurcation intervention differs significantly from non-LMCA bifurcations in that there is a larger area of myocardium at jeopardy; there is less room for error during the procedure; the vessels are larger; the side branch (SB) is as important as the main branch (MB) regarding both the size and territory of distribution; and the operator is less likely to accept a suboptimal result in the SB. Current approaches may require two stents in about 30% of true non–left main bifurcations unless located on the LMCA where this percentage may go up to 50% (12). For purposes of nomenclature and clarity, we generally consider the left anterior descending artery (LAD) the MB, and the left circumflex artery (LCX) or ramus intermediate (RI) branch as the SB even though both branches may be of the same size and importance. At the outset, we should state that there are no randomized trials of bifurcation strategies specifically performed in LMCA disease. As with all bifurcation PCI, there is no single strategy that can be applied to every bifurcation. Bifurcations vary not only in anatomy (plaque burden, 1

There are no potential conflicts of interest or funding sources to disclose.

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location of plaque, angle between branches, diameter of branches, bifurcation site) but also in the dynamic changes in anatomy during treatment (plaque shift, dissection). Thus the most important issues in LMCA bifurcation PCI are in selecting the most appropriate strategy for an individual bifurcation followed by the optimal performance of the procedure. The latter is often not sufficiently stressed in current PCI, and we advise following the dictum that “the procedure has only started after the stents have been implanted.” This point will frequently be reiterated in this chapter. The decision to use one or two stents, or sometimes even three (in case of a trifurcation), should be made as early as possible. An appropriate and timely taken decision will affect the results, save time, lower costs, and lower the risk of complications. Whichever approach, strategy, or technique is chosen, we think that elective LMCA stenting should always aim for an optimal final result verified by IVUS (intravascular ultrasound) unless there are good reasons not to do so. In this chapter, we have used case examples to illustrate which patients and lesions should be selected for double stenting and when and how to perform the various double stenting techniques. WHO ARE THE PATIENTS WHO QUALIFY FOR ELECTIVE DOUBLE STENTING? Correct patient selection for double stenting requires accurate assessment of lesion severity, distribution, extension, and the presence of concomitant disease. This will result not only in the appropriate patients being selected for double stenting, which is more complex, timeconsuming, and labor intensive than provisional stenting, but also reduce the risk of complications. The major factors that need to be assessed and taken into account, when the operator is deciding between provisional stenting and elective double stenting, are described below. Although each of these factors is discussed separately, there is usually a combination of these factors present that dictates the decision to electively perform double stenting. Figure 1 demonstrates how to use these factors below to select patients for double stenting. Distribution of Disease In considering the distribution of disease (Fig. 2) in the LMCA bifurcation, the most important distinction is whether the disease at the bifurcation only involves one branch of the bifurcation (LAD or LCX), or if it extends into both branches or into three distal branches when the RI is present. In general, a double stenting approach from the outset would usually be appropriate when there is disease in both the LAD and LCX. However, this only holds true when the LCX Small LM LCX disease +

Diameter stenosis of LCX (%)

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Small LM LCX disease –

1

Large LM LCX disease –

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3

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6

Reference diameter of LMCA (mm) Provisional Crush, Culotte Crush, Culotte, V, Kissing Figure 1 The diagram demonstrates how to select among the different techniques based on LMCA size and LCX involvement. Source: Photo courtesy of Dr. Seung-Jung Park.

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is of a sufficiently large diameter with a large area of distribution and the disease extends more than a few millimeters beyond the ostium. If the LCX is small or the disease is localized to the ostium, a provisional approach is appropriate with a second stent reserved for a suboptimal result such as dissection or significant residual stenosis. When the LMCA disease extends to only one branch, the best strategy is to stent from the LMCA into the diseased branch with a provisional approach to the nondiseased branch. In this approach, the decision to place a second stent should be made only after having dilated the unstented branch and after having performed final kissing inflation (FKI). The threshold to place a second stent will be lower if the unstented vessel is the LAD (13).

(A)

(B) Figure 2 Selecting between elective double stenting and provisional stenting for the LMCA. In this figure, we demonstrate how we select patients for elective double stenting based on baseline anatomical factors (see text). (A) There is distal LMCA bifurcation disease involving the LAD but the LCX is undiseased. In this patient, we stented the LMCA toward the LAD with a provisional approach to the LCX. (B) Distal LMCA disease extending into both the LAD and LCX, and we would prefer stenting both branches. (C) There is severe distal LMCA disease involving the LAD ostium but not the large LCX. In this case, we would again favor a provisional approach and stent toward the LAD. (D) LMCA disease extends into the LAD and LCX. In particular the LCX disease extends quite a distance from the ostium and we would electively stent both branches. (Continued on page 152)

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(C)

(D) Figure 2 (Continued )

Size of Branch The diameter of the SB (LCX or RI) and territory of distribution will determine the operator’s decision whether to electively implant a stent or treat it with a provisional approach. However, when selecting a strategy for the LMCA, as with other lesion factors discussed here, the size of the branch (Fig. 2) is not considered in isolation but in combination with the severity and length of disease. In general, we would not stent SBs that are <2.5 mm unless it is long with a somewhat large territory of distribution or the branch is in danger of occlusion. In contrast, we would favor a double stenting technique from the outset when the LCX or RI are at least ≥2.5 mm in diameter with a relatively large territory of distribution and has significant disease extending from the origin to 10 to 20 mm or more millimeters distally. For example, in a nondominant LCX without large marginal branches, irrespective of its size, we would not favor elective double stenting. Similarly, in a large dominant LCX, we would not always stent the LCX if it has only focal disease localized to or not extending more than a few millimeters from the ostium. Angle of Branch For definition purposes, the angles between the LMCA–LCX, LCX–LAD, and LMCA–LAD are designated by the letters A, B, and C, respectively (Fig. 3). Proximal Angle A is defined as the

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Figure 3 This is an 82-year-old patient with a recent history of chronic renal dysfunction, acute myocardial infarction, repeated episodes of pulmonary edema, and episodes of seizures and confusion on the basis of embolization from a left ventricular apical thrombus. The patient was refused surgical revascularization on the basis of the patient’s poor general condition, and thus referred for LMCA stenting. (A) The baseline coronary angiography with severe distal LMCA stenosis and markedly angulated LCX. Angle A is the angle between the LMCA and the LCX, Angle B is between the LAD and the LCX, and angle C between the LMCA and LAD. Wiring and predilatation of the LAD and LCX, favorably modified Angle A, which was now less acute (B). We decided on double stenting due the severity of disease in the LMCA and the dissection of both the LAD and LCX after predilatation. We elected to perform a minicrush due to the instability of the patient and need to rapidly secure patency of both branches. A 3.0 × 18 mm Endeavor Resolute zotarolimus-eluting stent (Medtronic Vascular, Santa Rosa, CA) was implanted on the LAD with minimal protrusion into the distal LMCA (C) and crushed with an Endeavor Resolute 3.0 × 18 mm implanted from the LMCA to the LCX (D), followed by FKI with two 3.0 × 12 mm noncompliant balloons (E). The final result was excellent (F) and the entire procedure was performed with only 50 mls of contrast. (Continued on page 154)

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(F)

Figure 3 (Continued )

angle between the LMCA and the LCX, whereas distal Angle B is delineated between the LAD and the LCX (14–16). The LMCA bifurcation is designated as T-shaped (distal bifurcation angle B ≥70◦ ) or Y-shaped (distal bifurcation angle B <70◦ ). The degree of Angle A has an influence on the accessibility of the SB and can frequently be a reason for initially stenting the SB. When Angle A is <110 degrees, it may complicate guidewire insertion into the SB. This angle may also impede recrossing into the SB with a wire, balloon, or stent after MB stenting. However, the decision to electively implant a stent on the SB should be made only after wire insertion, which may favorably modify this angle. Angle B (between LCX and LAD) is a predictor of SB occlusion after MB stenting; that is, the more acute the angle, the higher the risk of plaque shift, compromise of the ostium, and SB occlusion (14–16). The wider the Angle A or the narrower the Angle B, the larger the SB ostium area, which would necessitate the operator to select a large-cell stent for the MB. As will be discussed below in detail, the bifurcation angles will also influence the operator’s decision as to which double stenting technique will be performed and may also have a negative effect on long-term outcomes. Angle B may impact the acute and long-term results. Indeed, very acute angles require the placement of a stent with optimal strut opening potential in the MB. Conversely, when the angle is 90 degrees, the crush technique is associated with a high risk of stent malapposition in the SB while T-stenting provides complete coverage of the SB ostium but should be avoided with more acute angles where the culotte or crush techniques are a better choice. Severity and Length of the Side Branch (LCX) Lesion As already discussed, the severity and length of disease in the SB (Fig. 2) is probably the most common reason for performing double stenting of the LMCA. If the SB is large (≥2.5 mm), supplies a relatively large territory of myocardium, and has significant disease that extends 10 to 20 mm or more from the ostium, then we prefer performing double stenting. In assessing the severity of disease at the ostium of the LCX, the operator needs to be aware that sometimes the angulation at the ostium and movement of the LCX may result in what appears angiographically to be a stenosis but may actually be a “pseudostenosis.” In this regard, IVUS is invaluable in making an accurate diagnosis as to whether there is large plaque burden resulting in stenosis (Fig. 4). Presence of Concomitant Distal Disease in the Side Branch (LCX Artery) The presence of concomitant distal disease affects the LMCA PCI strategy in two ways. First, if the ostium is nondiseased but there is distal disease close to the ostium that can be covered by

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Figure 4 In this patient, angiography (A) was misleading in that there appeared to be a significant stenosis at the ostium of the LCX (B: LMCA bifurcation magnified). Isolated LCX ostial stenosis before or after LMCA stenting is a situation that often leads to confusion and doubts. In this patient, we assessed the LCX with IVUS which demonstrated in panels (C) and (D) (corresponding to diastolic and systolic frames) that a significant stenosis was not present (minimum CSA = 5.7 mm2 ). This appearance of pseudostenosis was due to movement of the artery with a change in shape of the lumen from circular to eccentric.

a long stent from the LMCA, we would prefer double stenting. Second, if, however, the distal disease cannot be treated with the LMCA stent and requires a second stent to be implanted distally, we prefer implanting the distal stent first if possible and then treating the LMCA. This approach avoids difficulty later in passing a stent through stent struts in the LMCA. Obviously, this only holds true if the patient and LMCA lesion are stable. If not, the LMCA disease should be treated first. TECHNIQUES FOR ELECTIVE DOUBLE STENTING OF THE LMCA This section describes how to perform and select patients for all the currently utilized techniques for double stenting as an intention-to-treat. At present, there are insufficient data to determine which of these techniques is superior in regards to procedural and follow-up events. Although it is important for an operator performing LMCA intervention to have a good knowledge of all the techniques described below, the operator would not be amiss to know only one or two of these techniques and be able to perform them well. We would stress that it is not only the specific technique used but rather the meticulous attention to performing the procedure that is important in ensuring success and improving long-term results (12,17). When dealing with complex bifurcations involving large territories, where it is crucial to maintain optimal patency of both branches, we recommend the V-stent or crush techniques. In Figure 5, we have

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An approach for LMCA lesions when using 2 stents as intention to treat

Very short left main

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Figure 5 Demonstrates how we chose between the various double stenting techniques based on the anatomy of the LMCA.

summarized how we choose among the various double stenting techniques (described below) based on the LMCA bifurcation anatomy. The V-Stent and the Simultaneous Kissing Stent (SKS) Techniques The V-stent and the SKS techniques are performed by delivering and implanting two stents together (18,19). One stent is advanced into the SB and the other into the MB. Both stents are pulled back to create a new carina as close as possible to the original one. When the two stents protrude into the MB with the creation of a double barrel and a very proximal carina, the technique is called SKS (19). The main advantage of these techniques is that the operator will never lose access to any of the two branches. In addition when FKI is performed, there is no need to recross the side branch stent.

Technique Description—Requires an 8-Fr Guiding Catheter (Fig. 6) (a) Both branches are wired and fully predilated. It is important to perform adequate predilatation to facilitate full stent expansion. (b) Two stents are positioned into the branches with a slight protrusion of both stents in the LMCA. Different operators allow a variable amount of protrusion creating sometimes a rather long (5 mm or more) double barrel in the proximal MB (SKS). Although we recognize that it is impossible to be so accurate in positioning the stents exactly at the ostium of each branch, we generally try to limit the length of the new carina to less than 5 mm. Sometimes it is necessary to advance the first stent more distally into the vessel to facilitate the advancement of the second stent. This maneuver is essential when the kissing stent technique is used to stent a trifurcation using three kissing stents (need of a 9-Fr guiding catheter). Following accurate stent positioning, it is important to verify their correct placement in two projections before deploying the stents. (c) Each stent is deployed individually at high pressure of 12 atm or more. Some operators prefer deploying the stents simultaneously. When the stents are deployed simultaneously,

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the operator needs to be aware of the risk of LM dissection. This can be avoided by using lower deployment pressure. (d) Perform high-pressure sequential single stent postdilatation followed by medium-pressure FKI with short and noncompliant balloons. Balloon sizes are chosen according to the diameter of the treated vessels. In the event that the reference vessel size proximal to the bifurcation is relatively small, FKI should be performed using low-pressure inflation to avoid proximal dissection.

V-stenting

V-stenting

(A)

1. Wire both branches and predilate if needed.

3. Deploy one stent.

2. Position two parallel stents covering both branches and extending into the MB • V: minimal protrusion into MB • SKS: double barrel into the MB

4. Deploy the second stent.

(B) Some operators deploy the two stents simultaneously

V-stenting

5. Perform high-pressure single stent postdilatation and medium-pressure kissing inflation with short and noncompliant balloons.

(C) SKS stenting

SKS stenting

1. Wire both branches and predilate if needed.

(A)

(B)

2. Position two parallel stents covering both branches and extending into the MB • V: minimal protrusion into MB • SKS: double barrel into the MB

3. Deploy one stent.

4. Deploy the second stent.

SKS stenting

5. Perform final kissing inflation.

(C) Figure 6 A schematic representation of the V-technique and simultaneous kissing stents (SKS) technique.

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Specific Issues The V-stent technique is probably the easiest and the one that guarantees immediate patency and access to both branches. We prefer to apply this approach only when the disease does not extend proximal to the bifurcation (into the distal LMCA) and is the preferred technique when the LMCA is short or during emergencies. The V-stent technique is also suitable for other bifurcations, provided the portion of the vessel proximal to the bifurcation is free of disease and there is no need to deploy a stent more proximally. Proponents of the SKS technique assert that this technique can be performed even if the LMCA is long and has significant disease distally that extends into the bifurcation. They also suggest that the SKS is preferred when the LMCA is very large, resulting in a significant diameter mismatch with the LAD and LCX, as this technique will ensure apposition and full coverage of the large LMCA with drug. In our experience, we have found that we have not had difficulty in performing other two-stent techniques in large LMCA and ensuring good stent apposition with IVUS guidance and FKI. The SKS technique results in a new metallic carina quite proximally into the LMCA. We do not know at present what the long-term outcome risks are of leaving this exposed double stent layer in a vessel when utilizing DES. There have been case reports describing a thin diaphragmatic membranous structure at the new carina (at the level of the kissing struts), resulting in an angiographic filling defect (Fig. 7). Other than producing a very distressing angiographic appearance, the exact long-term significance and relation to adverse events of this membrane is not known. There are several limitations for this technique that need to be considered: (a) the possibility of balloon barotrauma to the LMCA body during stent deployment or postdilatation, which can lead to dissection, progression of disease, or edge restenosis in the ostium and/or shaft of the LMCA. This can be partially avoided by using short noncompliant balloons for FKI. (b) If a proximal stent becomes necessary to treat a proximal dissection, there is almost always the risk of leaving a small gap and the stent needs to be directed toward one of the two arms of the V. (c) If restenosis occurs in the proximal portion of one or both stents, this would require crushing one of the stents which would make recrossing into the branch covered by the crushed stent potentially challenging as four layers of stent struts will need to be traversed (Fig. 8). (d) If disease distal to the V-stenting or SKS site need to be treated at follow-up, advancing guidewires can be challenging, as the stent struts can be easily engaged or crisscrossed making

(A)

(B)

Figure 7 The figure demonstrates the angiographic (A) and IVUS (B) appearance of a thin tissue membrane that developed at the site of kissing struts of the new carina 18 months after SKS of the LMCA. Source: Photo courtesy of Dr. Young-Hak Kim and Dr. Seung-Jung Park.

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advancement of balloons and stents impossible. If additional guidewires need to be inserted during the procedure to treat distal disease (Fig. 9), we recommend using a dual access catheter such as the Twin-Pass catheter (Vascular Solutions, Minnesota). When previous V-stenting or SKS needs traversing at another PCI, we suggest passing through the stent with a loop on the radiopaque part of the guidewire to prevent the guidewire from passing through stent struts.

(A)

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(C)

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Figure 8 (A) Baseline angiography showing ostial LAD and proximal LCX disease (LM equivalent); (B) successful V-stenting with 3 × 20 mm (LAD) and 3 × 32 mm (LCX) Taxus paclitaxel-eluting stents (Boston Scientific, Natick, MA) with an excellent final angiographic result (C). The patient presented 11 months later with inducible ischemia on myocardial perfusion scintigraphy and angiography demonstrated focal restenosis at the ostioproximal segment of the LCX (D). We elected treat this restenosis after V-stenting by converting it into crush stenting of the distal LMCA. (E) Inflation of a Taxus 3.0 × 16 mm stent into the LAD while another stent (Taxus 3.5 × 16 mm) is in position from the left main toward the LCX. The LCX stent was then deployed crushing the LAD stent (F). Procedure was completed with two-step FKI by performing high-pressure SB dilatation (G), followed by FKI with 3.0 × 15 mm (LAD) and 3.5 × 15 mm (LCX) noncompliant balloons (H). The final angiographic result is shown in panel (I) and follow-up angiography after six months in panel (J). (Continued on page 160)

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(C) Figure 9 This patient underwent LMCA and multivessel stenting (LAD and LCX) with elective IABP hemodynamic support (A–C). In view of the short left main trunk, we elected to perform V-stenting with two 3.0 × 16 mm Taxus paclitaxel-eluting stents (Boston Scientific, Natick, MA). Both stents were positioned in the LMCA with their proximal markers overlapping (D); the LAD stent was inflated first (E); then both stents were inflated together (F); and FKI inflation was performed with a 3.5 × 12 mm (LAD) and 3.0 × 12 mm (LCX) noncompliant balloons (G). We then proceeded to treat the LCX and obtuse marginal (OM) bifurcation. We used a multifunction probing catheter (Boston Scientific, Natick, MA) in order to place another wire into the OM (before stent implantation and after for FKI) without crisscrossing the V-stenting struts in the LMCA; a 3.0 × 16 mm Taxus stent was placed on the proximal LCX (H); the OM was rewired and FKI was performed (I). The multifunctional probing catheter was again used to place another wire in the LAD in order to protect the first diagonal branch. Two 3.0 × 32 mm Taxus stents were placed on the mid to proximal LAD, and FKI was performed on the LAD/diagonal bifurcation (J–L). The final result was excellent (M and N). (Continued on pages 162 and 163)

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(J) Figure 9 (Continued )

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Figure 9 (Continued )

The Crush Technique (the SB Stent Crushed by the MB Stent) The main advantage of the crush technique is that immediate patency of both branches is assured, and therefore it should be applied in conditions of instability or when the anatomy appears complex (Fig. 10) (20). This objective is notably important when the SB is functionally relevant or difficult to be wired. In addition, this technique provides excellent coverage of the ostium of the SB. The main disadvantage is that in order to perform FKI, there is the need to recross multiple struts with a wire and a balloon. The crush technique has evolved and is nowadays performed with less stent protrusion into the MB (i.e., minicrush) and mandatory two-step FKI (21,22).

Technique Description—Requires a 7- or 8-Fr Guiding Catheter (Fig. 11) (a) Both branches are wired and fully dilated. (b) SB stent positioned in the SB and then MB stent is advanced. (c) SB stent is pulled back into the MB about 1 to 2 mm and is verified in at least two projections. (d) SB stent is deployed at least at 12 atm. The balloon is deflated and removed from the guiding catheter. An angiogram is taken to verify that the SB has an appropriate lumen, normal flow, and that no distal dissection or residual lesions are present. If an additional stent is needed in the SB, this is the time to implant it. Following this check, the wire is removed from the SB and the stent in the MB is fully deployed at high pressure, usually above 12 atm. An angiogram is taken following removal of the balloon from the MB. When we use this technique, we keep only a single indeflator on the table that is connected to the SB stent. This will prevent inadvertent deployment of the MB stent first, thereby crushing the undeployed SB stent. (e) Rewire SB. It is important to perform a two-step FKI. First, we suggest a dilatation of the stent toward the SB with a balloon appropriately sized to the diameter of this branch and inflated at high pressure (16 atm or more), then FKI with a second balloon in the MB with an inflation pressure about 8 to 14 atm in both balloons. Step Crush When there is the need to perform a two-stent technique as intention-to-treat and a 6-Fr guiding catheter as the only available approach (radial approach), the “step crush” or “the modified balloon crush” techniques can be used. The final result is basically similar to that obtained with the standard crush technique, with the only difference that each stent is advanced and deployed separately. Another modification of the step crush is when reverse crush stenting needs to be performed as a crossover from provisional SB stenting. The need for a 6-Fr guiding catheter is the only reason to utilize this technique.

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Technique description (a) Both branches are wired and fully dilated. (b) Stent is advanced in the SB protruding a few millimeters into the MB. A balloon is advanced in the MB over the bifurcation. (c) Stent in SB is deployed, the balloon removed, an angiogram is performed, and if the result is adequate the wire is also removed. (d) MB balloon is then inflated (to crush the protruding SB stent) and removed. (e) A second stent is advanced in the MB and deployed (usually at 12 atm or more). (f) The next steps are similar to those of the classical crush technique and involve recrossing into the SB, SB stent dilatation, and two-step final kissing balloon inflation. Specific issues An important change in the classical crush technique is that we now try to limit the area of crush stenting and multiple layering of stent struts by performing a minicrush. The minicrush may be associated with more complete endothelialization (and theoretically less stent thrombosis)

(A)

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Figure 10 This patient with a history of previous CABG and occluded bypass grafts (two vein grafts and left internal mammary artery) presented to us with an acute coronary syndrome. Baseline coronary angiography (A– C) demonstrated a severe stenosis of the distal LMCA bifurcation involving both the LAD and LCX; a subtotally occluded and diffusely diseased LAD; and severe stenosis of the first diagonal branch (D1). An IABP was electively inserted; wires were placed in the LAD, LCX, OM, D1; and the LAD, D1, LCX and LMCA were predilated. A 2.75 × 32 mm Taxus paclitaxel-eluting stent (Boston Scientific, Natick, MA) was placed on the mid-LAD. We then performed crush stenting of the LMCA with a Taxus 3.5 × 32 mm stent toward the LCX (D) and Taxus 3.5 × 32 mm stent toward the LAD (E). Two-step FKI was performed with two 3.5 × 15 mm noncompliant balloons, first only dilating the LCX ostium at high pressure (F) followed by conventional FKI (G). Although the angiographic result appeared good (G), IVUS demonstrated marked malapposition of the stent in the distal LMCA (H and I; arrows). We thus performed further postdilatation with noncompliant balloons: 4.0 × 15 mm at 18 atm toward LAD, 3.5 × 12 mm at 18 atm toward LCX, and 4.5 × 20 mm at 18 atm on the LMCA. Repeat angiography and IVUS confirmed good stent apposition (K–M). We then treated the LAD-D1 bifurcation by implanting a Taxus 2.5 × 16 mm stent with the reverse crush technique. The final angiographic result was excellent (N and O), which was maintained at angiographic follow-up performed seven months later (P and Q).

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Figure 10 (Continued ) (Continued on page 166 )

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(L)

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Figure 10 (Continued )

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Crush stenting

1. Wire both branches and predilate if needed

3. Deploy the SB stent

(A)

(B)

2. Advance the two stents. MB stent positioned proximally. The SB stent will protrude only minimally into MB.

4. Check for optimal result in the SB and then remove balloon and wire from SB. Deploy the MB stent

Crush stenting

5. Rewire the SB and perform high pressure dilatation

(C)

6. Perform final kissing balloon inflation

Figure 11 A schematic representation of the crush technique.

and easier recrossing of the crushed stent. Ormiston et al have reported bench testing with three different stent platforms (BX Velocity, Cordis, A Johnson & Johnson Company, Miami Lakes, FL; Express II, Boston Scientific, Natick, MA; and Driver, Medtronic, Minneapolis, MN) utilizing the crush technique (23,24). The authors stressed the importance of FKI and concluded that appropriate SB and MB postdilatation is needed to fully expand the stent at the SB ostium, to widen gaps between stent struts overlying the SB (facilitating subsequent access), and to minimize stent distortion. The importance of FKI with the crush technique has also been confirmed in a clinical study that demonstrated significant reductions in restenosis (11.1% vs. 37.9%) and late loss (0.32 mm vs.0.52 mm) of the SB in the group treated with final kissing balloon (17). It is very important to perform the so-called “two-step kissing inflation,” which consists of high-pressure balloon inflation in the SB before performing the true FKI at medium pressures. Ormiston et al. have recently demonstrated through imaging of bench deployments that (i) recrossing the crushed stent for kissing postdilation, the most difficult part of the procedure, is technically easier with minicrush than with classical crush; (ii) traditional one-step kissing postdilation leaves considerable residual metallic stenosis that may not be visible on angiography and may predispose to thrombosis because of eddy currents, stasis, altered shear stress, and foreign body presence; (iii) SB ostial coverage and residual stenosis by metal struts is significantly reduced by a two-step kissing inflation (Fig. 12) (25). Finally, the bifurcation angle may be an important factor to be considered when performing the crush technique. When the angle between the MB and the SB is closed to 90 degrees, it is possible to minimize the gap even without crushing the SB stent and utilizing the modified T-technique. Furthermore, a bifurcation Angle B ≥50◦ between the two branches has been suggested as an independent predictor of MACE after crush stenting (26). The Culotte Technique The culotte technique uses two stents and leads to full coverage of the bifurcation at the expense of an excess of metal covering the proximal end (27). The culotte technique will give the

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Figure 12 This figure demonstrates a bench model of a bifurcation treated with the crush stenting as seen from the SB directly after stenting and after normal FKI. Two-step FKI results in improved opening of and less obstruction by stent struts at the SB ostium. Source: Photo courtesy of Dr. John Ormiston.

best immediate angiographic result and theoretically it may guarantee a more homogeneous distribution of the struts and of the drug at the site of the bifurcation. It is for this reason that we prefer using this technique to treat restenosis of the LMCA bifurcation that occurs after Tor crush stenting. Important caveats about this approach are that with some closed cells stents such as the Cypher (Cordis Corp, Johnson & Johnson, Warren, NJ) stent, the opening of the struts toward the branches may only reach a maximum diameter of 3 mm. For this reason, the culotte technique should be only used with stents that have a design (open cells stents) allowing full opening of the struts toward both branches or when the expected size of the SB is ≤3 mm. This technique is suitable for all angles of bifurcations and provides near-perfect coverage of the carina and SB ostium. However, like the crush technique, it leads to a high concentration of metal with a double-stent layer at the carina and in the proximal part of the bifurcation. The long-term impact of this double dose of drug with DES on re-endothelialization is unknown. The main disadvantage of this technique is its complexity in that rewiring both branches through the stent struts can be difficult and time-consuming. The only anatomic limitation to the culotte technique is when there is a large mismatch in diameter between the distal LMCA and LCX.

Technique Description—Can Be Performed with a 6-Fr Guiding Catheter (Fig. 13) (a) Both branches are wired and predilated. (b) A stent is deployed across the most angulated branch, usually the SB. (c) The nonstented branch is rewired through the stent struts and dilated. (d) A second stent is advanced and expanded into the nonstented branch, usually the MB. (e) Finally, kissing balloon inflation is performed. When performing the kissing inflation, we prefer using noncompliant balloons and dilating each limb of the culotte (i.e., at the ostium of the LCX and LAD) at high pressure (≥16 atm) individually before simultaneously inflating both balloons at 8 to 12 atm (Fig. 14).

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Culotte stenting

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1. Wire both branches and predilate if needed.

3. Rewire the unstented branch and dilate the stent struts to unjail the branch (MB).

(B)

4. Place a second stent into the unstented branch (MB) and expand the stent leaving some proximal overlap.

2. Leave the wire in the more straight branch (MB) and deploy a stent in the more angulated branch (SB). Culotte stenting

(C)

5. Recross the second stent’s (MB) struts into the first stent (SB) with a wire and perform kissing balloon inflation.

Figure 13 A schematic representation of the culotte technique.

Specific Issues Although the culotte technique may be technically more challenging than other techniques, there are a number of factors that can facilitate its successful performance. When rewiring the other branch after stent placement, we always first place the guidewire distal into the stented branch to be sure that we have not passed under the stent struts before re-crossing into the branch. In performing the culotte technique, we recommend stenting the branch with the sharpest angle first, which is usually the LCX. This has the advantage that recrossing stent struts into the less angulated branch will be easier as will passing the second stent through stent struts into a less angulated branch. However, this conventional practice has recently been challenged by the Nordic PCI Study Group. In the Nordic Stent Technique Study, a randomized comparison of culotte and crush stenting of coronary bifurcations, the authors recommended stenting of the MB first to avoid acute closure of the MB (28). This approach guarantees patency of the MB, which in this case is the LAD, and may avoid one of the potential problems of performing the culotte technique where we always need to remove the wire from one of the two branches and where patency of this branch is not guaranteed (Fig. 15). In the Nordic Stent Technique Study, culotte stenting was associated with similar rates of procedural success as crush stenting and higher rates of protocol-mandated FKI (92% vs. 85%; p = 0.03) (28). The authors speculated that rewiring and balloon insertion through stent struts are more difficult in the crush technique, where three layers of stent have to be crossed versus only one layer in the culotte technique. Even though in our experience we have not had greater difficulty in recrossing stent struts with the crush versus culotte techniques, it is reassuring that in the Nordic Study the authors did not have difficulty in recrossing stent struts into the more angulated branch. Only 10% of the 424 bifurcation lesions included in this study involved the LMCA, thus limiting the generalizability of the results to this subgroup. However, this is the first study to randomly compare the two double stent techniques that result in complete coverage of the SB ostium. At six months, there were no significant differences in MACE rates between the groups (crush 4.3% vs. culotte 3.7%; p = 0.87). Procedure and fluoroscopy times and contrast volumes were similar in the two groups. Angiographically, there was a trend toward less in-segment restenosis (6.6% vs. 12.1%; p = 0.10) and significantly reduced in-stent restenosis following culotte stenting (4.5% vs. 10.5%;

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p = 0.046). The relevance of this angiographic finding is unclear and may be explained by the lack of two-step FKI in the crush group. T- and Modified T-Techniques The T-technique is most frequently utilized to crossover from provisional stenting to stenting the SB and is most suited to bifurcations where the angle between the branches is close to 90 degrees. This technique is less laborious than the crush or culotte technique. Unlike the V-technique, it can be used for the coverage of lesions located proximal to the bifurcation. In our view, the T-technique is associated with the risk to leave a small gap between the stent implanted in the MB and the one implanted in the SB. This gap may be a factor contributing

(A)

(B)

(C) Figure 14 This patient underwent crossover stenting with a 3.5 × 38 mm Taxus paclitaxel-eluting stent (Boston Scientific, Natick, MA) from the LMCA toward the LCX for a long lesion extending from the ostium to the midsegment of the LCX (A–C). A provisional approach was taken toward the LAD, which after FKI at the distal LMCA had a linear dissection proximally extending to its ostium (D). A 3.0 × 24 mm Taxus stent was then inserted from the LMCA to the LAD utilizing the culotte technique (E). High-pressure dilatation was performed toward to the LAD (F) followed by FKI with 3.5 × 12 mm and 3.0 × 12 mm noncompliant balloons at 14 atm (G). IVUS was performed to verify optimal stent deployment. Although, the angiographic result was good (H), IVUS demonstrated that the stent was well expanded in the LMCA and LAD, but there was suboptimal expansion of the stent at the ostium of the LCX (I). The stent CSA was 5.95 mm2 , which is well below the 8 mm2 that we accept as an optimal result for a 3.5 mm postdilatation balloon (see AVIO criteria in Table1). We then performed high-pressure dilatation with a 3.5 × 12 mm noncompliant balloon at 26 atm toward the LCX and repeated the FKI. Final angiography confirmed an excellent result (J). Repeat IVUS at the ostium of the LCX now demonstrated a marked improvement of the minimal CSA to 9.94 mm2 (K). At angiographic follow-up, the good final result was maintained (L and M). This case illustrates the importance of performing high-pressure dilatation toward both branches before FKI when performing the culotte technique.

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Figure 14 (Continued ) (Continued on page 172 )

to an uneven distribution of the drug, hence leading to ostial restenosis at the SB. This may have been a possible cause for the restenosis we noticed at the ostium of the SB when two stents were implanted in the Sirolimus bifurcation study (29). Currently, we rarely perform the classical T-technique in our practice, and in our opinion there are two reasons to perform the T-technique: (i) to place a stent at the ostium of a SB after placement of a stent in the MB because the result at the SB ostium was unsatisfactory (provisional SB stenting). In this situation, we have replaced the classical T-technique with the TAP. (ii) To perform stenting at the ostium of the SB when there is isolated SB ostial stenosis (e.g., T-balloon stenting).

Classical T-Technique Description (Figs. 16 and 17) (a) Position a stent first at the ostium of the SB, being careful to avoid stent protrusion into the MB while trying to minimize any possible gap. (b) Deploy the stent and remove the balloon from the SB (keep the wire in the SB). (c) Advance and deploy the MB stent. (d) Rewire SB and then remove the jailed wire. (e) SB balloon dilatation and FKI.

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(H)

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(L) Figure 14 (Continued )

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Figure 15 This is a patient who previously had a left mammary implantation on the LAD with graft failure who underwent culotte stenting on this unprotected LMCA stenosis (A and B). Following wiring of both branches and predilatation of the LCX, a 3.5 × 16 mm Taxus stent paclitaxel-eluting stents (Boston Scientific, Natick, MA) was deployed on the LCX (C). The LAD was then rewired and dilatation of the struts toward this vessel was performed without difficulties (Panel D). At that point a second Taxus stent was advanced towards the LAD during which the vessel abruptly closed and the patient had hemodynamic collapse (E). A Zeta stent (Guidant Corporation, Santa Clara, CA) was successfully advanced into the LAD reestablishing flow in this vessel (F). In addition, balloon counterpulsation was initiated. Following stabilization, the procedure was completed with implantation of a 3.5 × 16 mm Taxus stent from the LMCA toward the LAD (G). The stent was then crossed and dilated toward the LCX (H) and FKI was performed (I). The final result was excellent (G and I). This case illustrates one of the disadvantages of the culotte technique in comparison to the crush and V-techniques, both of which ensure patency of both branches without removing the wire. In this case, we were fortunate that the LAD occluded only after the LCX stent was recrossed and we thus had access to the LAD. (Continued on page 174)

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(J) Figure 15 (Continued )

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T-stenting

1. Wire both branches and predilate if needed.

(A)

(B)

3. Rewire the SB passing through the struts of the MB stent, remove the jailed wire and dilate toward SB.

Assuming that the result is suboptimal

4. Advance stent into the SB with no or minimal protrusion into the MB and deploy the stent.

2. Stent the MB leaving a wire in the SB. The stent in the MB can be deployed at high pressure.

T-stenting

(C)

5. Perform final kissing inflation following advancement of a balloon in the MB. If needed use a new balloon for the SB.

Figure 16 A schematic representation of the T-stenting technique.

The above description of T-stenting describes the situation in which the operator decides to stent the SB first. However, in majority of cases, the T-stenting technique is performed after MB and provisional SB stenting for a suboptimal result of flow-limiting dissection (Fig. 16).

Modified T-Technique Modified T-stenting is a variation performed by simultaneously positioning stents at the SB and MB when the angle between the branches is close to 90 degrees. The SB stent is deployed first, and then after wire and balloon removal from the SB, the MB stent is deployed. The procedure is completed with FKI. T-Stenting and Small Protrusion (TAP) The TAP is a simplified form of the reverse crush technique, which combines some features of the T- and crush technique (30). Unlike the classical T-technique, the TAP ensures complete coverage of the SB ostium while the absence of crushing facilitates recrossing into the SB. The TAP has become our technique of choice when having to implant a second stent in the SB for a suboptimal result after the provisional approach. Technique description (a) A second stent is advanced in the SB in a way to minimally protrude (1 or 2 mm) into the MB where a stent has been already implanted. (b) A balloon is advanced in the MB. (c) SB stent is deployed as usual (12 atm or more), and the MB balloon is simultaneously inflated at 12 atm or more. (d) Both balloons are deflated and removed. The technique is quite similar to the V-stenting technique with the only difference that one of the components of the system is a balloon, which is inflated inside a stent previously deployed in the MB. Despite some concerns about stent protrusion in the MB, in our experience we have been able to perform IVUS in both branches and, when needed, to advance additional stents distally in the MB and the SB.

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(A)

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Figure 17 This patient presented with multivessel disease involving a distal LMCA trifurcation, proximal LAD, and mid-LCX (A–C). An IABP was electively inserted, an 8-Fr EBU guide catheter utilized, and the mid-LCX was stented first (D) with a 2.5 × 12 mm Endeavor Resolute zotarolimus-eluting stent (Medtronic, Minneapolis, MN). Guidewires were placed in the LCX, RI, LAD, and the first two septal branches were also protected with guidewires. Our strategy for the LMCA trifurcation was to stent the LMCA toward the LAD with an initial provisional strategy to the LCX and RI. The LAD was predilated (E) and a 3.5 × 30 mm Endeavor Resolute stent implanted from the LMCA to LAD (F). The LCX and RI were rewired by recrossing the LAD stent struts; and the triple kissing inflation performed (G) on the distal LMCA trifurcation (LAD: 3.5 mm; LCX: 2.5 mm; RI: 2.0 mm). The angiographic result toward the LMCA was good, but the result on LCX and RI appeared angiographically suboptimal (H). We assessed the severity of LCX and RI lesions by IVUS and fractional flow reserve (FFR); both the lesions were functionally significant with an FFR of 0.73 in the RI and 0.77 in LCX (I; see also color insert ). Thus simultaneous T-stenting of the RI and LCX (Endeavor Resolute 2.5 × 30 mm in both) was performed. A 4.0-mm noncompliant balloon was placed in LMCA-LAD and used initially as a marker to guide accurate placement of the stents at the ostia of the LCX and RI (J). The stents and balloon were inflated simultaneously (K). The final angiographic result was excellent (L–O).

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(Continued on pages 178 and 179 )

Final Kissing Inflation (FKI) After Double Stenting A special mention needs to be made of the importance of FKI when implanting two stents in LMCA bifurcations. FKI has been repeatedly demonstrated to reduce late loss and restenosis, especially at the SB, and has now become standard in the performance of all double stenting techniques (17,20,31,32). FKI is not only important to correct stent distortion and expansion (23,33) but is especially important in fully expanding the stent in the distal LMCA where the diameter is usually much larger than the diameters of the LAD and LCX. The effective balloon diameter in the distal LMCA (which we calculate as the MB balloon diameter plus 1/3 of the SB balloon diameter) from the two balloons used for FKI is essential to fully expand the stent(s). As previously mentioned, our experience of bifurcation stenting utilizing two stents has taught us how important it is to perform the FKI in two steps: high-pressure inflation in the SB following wire recrossing and then FKI (17,20,34). This has now also been proven in a bench model (Fig. 12) (25). In performing FKI, it is critical to choose postdilatation balloons of appropriate size; that is, the kissing balloons should be the same size or larger than the deploying balloons to prevent stent distortion (23). When performing FKI, we inflate both balloons simultaneously and slowly which makes “melon seeding” less likely. We also deflate the balloons simultaneously to avoid distortion.

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The Challenge of Difficult Access to the SB Access to the SB is one of the greatest challenges in bifurcation PCI. Difficult access to the SB can occur either at the start of the procedure or after MB stenting in recrossing the stent struts into the SB with a guidewire or advancing a balloon through the stent struts.

At the Beginning of the Procedure After having attempted different types of wires with all sorts of curves and all personal tricks the operator may fail to advance a wire into the SB. At this point, few options are available: (i) to abort the procedure because the risk of losing the SB will be too high considering the size and distribution of the branch (typically an angulated circumflex artery), (ii) to perform directional atherectomy on the MB with the intent to remove the plaque which prevents entry towards

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the SB, (iii) to dilate the MB with a balloon with the rationale that the plaque modification and hopefully a favorable plaque shift will facilitate access toward the SB. Each of the three options has its rationale and the specific anatomical condition, the operator’s experience, and the clinical scenario may direct the selection of the best strategy. Usually, the third option is the one more frequently employed and most of the times effective. After the SB is wired, this SB wire should be “jailed” in the majority following deployment of the stent on the MB. This approach is important in protecting the SB from closure due to plaque shift and/or stent struts during MB stenting. The jailed SB wire also facilitates rewiring of the SB (if SB postdilatation/stenting or FKI is needed, or if the SB occludes) by widening the angle between the MB and SB (33,35); by acting as a marker for the SB ostium; and by changing the angle of SB take-off.

After Stenting the Main Branch The next challenge is often in rewiring the SB after MB stenting. In our experience, recrossing into the SB through the MB stent struts is usually possible using the Rinato-Prowater wire (Asahi Intecc Co Ltd, Nagoya, Japan/Abbott Vascular Devices, Redwood City, CA) and in extremely difficult cases the ACE fixed wire balloon (Boston Scientific). In difficult situations, we have also successfully used the Pilot 50 and 150 (Abbott Vascular Devices /Guidant Corporation, Santa Clara, CA) or the Miracle 3 or 4.5 g (Asahi Intecc Co Ltd /Abbott Vascular Devices) wires. The jailed wire in the SB should always be left in place as a marker until complete recrossing has been done. We are very cautious about using hydrophilic guidewires when recrossing into the SB due to the risk of wire-induced dissection and perforation. After having recrossed into the SB with a guidewire, there may subsequently be great difficulty advancing a balloon through the struts in order to dilate them. We frequently try first to cross through the stent struts into the SB with the smallest balloon we have on the table. If this balloon fails, we then use a Maverick (Boston Scientific) 1.5 mm diameter balloon to separate struts and allow a larger balloon to pass into the SB. If the 1.5 mm balloon cannot cross, we consider recrossing with a second wire while the first wire remains in place to traverse the stent struts in another spot. In cases of persistent failure, guidewires should be uncrossed (by retrieving and re-inserting the MB wire). If balloon insertion through the strut still proves impossible, the stent should be further dilated. Another attempt should be made with a 1.5-mm coaxial balloon. If the problem persists, we then try a fixed wire balloon, such as an ACE (Boston Scientific). Another tip that sometimes works is to advance the balloon as close as is possible to the stent struts, inflating the balloon, and while deflating the balloon to attempt advancing it further. Repeating this maneuver can often result in the balloon being slowly advanced through the stent struts. However, once the balloon is in the cell, it should not be inflated distal to the strut to avoid “balloon jailing.” It is important to perform a final dilatation on the stent toward the SB with a balloon appropriately sized to the diameter of this branch and inflated at high pressure (12 atm or more). PATIENT PREPARATION AND TECHNICAL PLANNING Patient Preparation

Antithrombotic Therapy The most important factor for us in regards to patient preparation is clopidogrel pretreatment. We prefer to have all patients pretreated for at least five days before the procedure with aspirin (at least 100 mg/day) and clopidogrel 75 mg/day. If a patient is not pretreated, we give a 600-mg loading dose of clopidogrel after performing the diagnostic angiography and the patient has consented to LMCA PCI. In our daily practice and considering that international guidelines give elective PCI for the LMCA a class IIb recommendation, we do not immediately perform LMCA stenting. Instead, we take the patient off the cath table, and together with the patient, family members, and cardiothoracic surgeon we discuss all revascularization options. In general, we only proceed with unprotected LMCA stenting if the patient refuses CABG or if based on the expertise of the surgeon the patient is considered to be excessively high risk for CABG. An attractive strategy that we have commenced prior to left main PCI is to perform a point-of-care assay such as the VerifyNow (Accumetrics Inc., San Diego, CA) for platelet responsiveness to

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clopidogrel. In patients who by VerifyNow are found to be low responders (i.e., PRU > 240) (36), we reload them with 600 mg of clopidogrel and continue a double maintenance dose of 150 mg/day. In patients with unprotected LMCA disease treated with DES, hyporesponsiveness to clopidogrel has been correlated with worse outcome (37). Although many operators give elective glycoprotein IIb/IIIa inhibitors to all patients undergoing double stenting of the LMCA as intention-to-treat, there is no evidence to support this approach. In view of some reports of intraprocedural and very early thrombosis when using two stents (31), we are not against a more liberal usage of glycoprotein IIb/IIIa inhibitors, especially when the preparation with clopidogrel is incomplete or there are uncertainties. Another approach, as an alternative to glycoprotein IIb/IIIa inhibitors and heparin, is the usage of bivalirudin.

Hemodynamic Support When dealing with unprotected LMCA lesions, the operator should take into account the 8% risk of acute hemodynamic instability, which almost always will need urgent IABP support (38). When performing double stenting, this risk may be even higher due to the complexity of the disease and the interventional strategy being performed. Thus, we would recommend that in double stenting of an unprotected LMCA, to always electively position an intra-aortic balloon pump (IABP) unless there is a specific contraindication. Indeed, Briguori et al. have demonstrated that elective IABP support seems to contribute to an uncomplicated and successful outcome, particularly in patients with distal left main stenosis and Euroscore > 6 (38). In cases, where the operator decides not to electively place an IABP, we would advise that vascular access be secured at the beginning of the procedure in case urgent hemodynamic support becomes necessary during the procedure. In general, if the PCI is completed without complication, we remove the IABP at the end of the procedure. An alternate option for hemodynamic support in high-risk patients is the Impella 2.5 system (Abiomed Inc., Danvers, Massachusetts). The Impella 2.5 device is a miniaturized 12-F rotary blood pump, minimally invasive LV assist device, which is placed retrogradely across the aortic valve via the femoral artery using conventional catheterization techniques. Using a miniaturized rotary pump, blood is drawn from the LV cavity and expelled into the ascending aorta, providing up to 2.5 L/min forward flow at its maximum rotation of 51,000 rpm. In the PROTECT I (A Prospective Feasibility Trial Investigating the Use of the IMPELLA RECOVER LP 2.5 System in Patients Undergoing High Risk PCI) multicenter trial, the Impella 2.5 was successfully implanted on 20 patients undergoing PCI of either an unprotected LMCA or the last patent coronary conduit (39). No patients developed hemodynamic compromise during PCI. The study demonstrated that the use of the Impella 2.5 system was safe and feasible during high-risk PCI, and based on these data a randomized clinical trial is underway to compare the efficacy of prophylactic circulatory support during high-risk PCI with the Impella 2.5 device versus conventional IABP counterpulsation (PROTECT II). Technical Planning

Guide Selection When the operator knows a priori that two stents will be implanted, we recommend an 8-Fr guiding catheter even if a 7-Fr is acceptable with some new generation DES. We think that the 8-Fr guide will give better visualization, will decrease friction during advancement of the stents, allow for all sizes of burr if rotablation required, and allow for IVUS to be performed in the presence of multiple guidewires. In general, even if an initial provisional strategy is chosen for the LMCA, we recommend utilizing an 8-Fr guide catheter, as this will give the operator the largest variety of options if a second stent needs to be implanted in the other branch. If two stents are needed and a 6-Fr guiding catheter is employed, some limitations need to be known. The two stents can only be inserted and deployed sequentially. The standard crush technique and the V or kissing stents technique cannot be performed unless a guiding catheter of 8-Fr is utilized. Furthermore, if implanting Xience V (Abbott Vascular Devices), Promus (Boston Scientific), or Endeavor and Endeavor Resolute stents (Medtronic), a 6-Fr guide will not allow simultaneous insertion of the stent and an angioplasty balloon. Thus with these stents, a 6-Fr guide catheter will prohibit the use of certain techniques such as the step crush technique, T-balloon stenting, or V-balloon stenting.

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Lesion Preparation: Role of Debulking Although lesion preparation should not be considered routine, it should be used when (a) there are diffuse and severe calcifications (Fig. 18); (b) the predilating balloon does not cross the lesion or fully expand; (c) it is difficult to cross the lesion with the stent. In these cases, we usually perform rotational atherectomy with a 1.25 or 1.5 mm burr. However, if the IVUS catheter crosses the lesion, we use information on the plaque morphology to determine our lesion debulking strategy in the following way: (i) superficial calcium extending more than 180◦ may demand lesion preparation with rotational atherectomy (Rotablator, Boston Scientific), (ii) severe fibrosis or moderate calcifications may demand for cutting balloon (cutting balloon Ultra and Flextome, Boston Scientific) or noncompliant balloons sized to the media-to-media diameter; (iii) the presence of soft plaque may permit direct stenting.

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Figure 18 (A and B) A severely calcified stenosis of the distal LMCA. This kind of severely calcified lesion should always undergo debulking with rotational atherectomy to allow for optimal stent expansion. We performed rotablation with a 1.5-mm burr and crush stenting with a 3.0 × 33 mm (LCX in panel C) and 3.5 × 18 mm (LAD in panel D) Cypher sirolimus-eluting stents (Cordis Corp, Johnson & Johnson, Warren, NJ). Panel (E) demonstrates the result after crush stenting and panel (F) demonstrates the result after FKI. At follow-up (G), there was no evidence of angiographic restenosis.

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Rotational atherectomy (Fig. 18) The role of rotablation is important to allow optimal stent expansion in lesions with severe superficial calcifications or when the balloon does not cross the lesion or fully expand. Rotablation is performed with the intent of modifying the plaque to allow a better stent expansion and not with the goal of debulking the lesion, which means that a single small burr (1.25 or 1.5 mm) is the most frequently utilized approach. Even if no published data are available regarding the role of this technology with DES in the LMCA, we think it is intuitive to aim for optimal stent expansion and symmetry. In a setting of a very calcific lesion, this goal can only be obtained with adequate lesion preparation. The main area of discussion is how frequently a calcific lesion should be pretreated with rotational atherectomy and when, conversely, a high-pressure balloon is sufficient. Except for information obtained with IVUS or in circumstances where no balloon would cross the lesion, we cannot provide additional objective guidelines to make a scientific decision. The operator’s judgment remains the most frequent tool dictating the choice of rotational atherectomy. Cutting balloon (Fig. 19) Bifurcation lesions with a fibrotic plaque at the SB ostium are an ideal setting for this device. The REDUCE III (Restenosis reduction by Cutting balloon Evaluation) randomized trial evaluated the role of cutting balloon dilatation before stenting versus standard balloon dilatation in a variety of lesions (40). This trial reported a lower restenosis rate (11.8% vs. 18.8%, p = 0.04) when lesions were predilated with the cutting balloon. The fact that the final postprocedure lumen diameter was larger in the cutting balloon arm and that the late loss was 0.74 mm for both strategies may make us assume that the main advantage was toward better stent expansion. As just discussed in the context of rotational atherectomy, it is difficult to demonstrate that a niche device has an advantage in every lesion. Cutting balloon may be considered when a noncompliant high-pressure balloon fails to fully expand. In some centers, cutting balloon is used at high pressures with good clinical outcome (Eulogio Garcia, written communication, March, 2009). Dr. Garcia reports that when treating very calcified lesions, he recommends undersizing the cutting balloon by 0.5 to 0.75 mm according to the reference vessel diameter obtained by IVUS and to inflate the cutting balloon at >14 atm (usually 16–18 atm). When using cutting balloons in noncalcified, high-plaque burden lesions, he suggests 12 atm. Directional atherectomy (Fig. 20) Directional coronary atherectomy (DCA) has been considered ideal for bifurcation lesions. The rationale for plaque removal in this setting is various and there are a number of positive anecdotal experiences. Unfortunately, the AMIGO trial (Atherectomy before Multi-Link Improves Lumen Gain and Clinical Outcomes) failed to support the original findings and hypothesis,

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even in the subgroup of lesions involving a bifurcation (41). However, it may be that such niche technology only has a favorable cost–benefit ratio when used selectively and appropriately as in the PERFECT (PrE Rapamycin-eluting stent FlExi-CuT) registry (42,43). In the PERFECT prospective multicentre registry, 99 patients underwent IVUS-guided DCA of coronary bifurcation lesions prior to DES implantation. Eighty-one percent of the lesions were located in the LMCA or at the ostium of the LAD or of the LCX. Atherectomy was performed mainly in the MB, with only three lesions treated in the SB as well and no complications occurred during the procedure. The primary endpoint, binary restenosis, occurred in one lesion on the

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Figure 19 This patient presented with distal LMCA disease involving the ostium of the LCX (A and B). The ostium of the LAD and LCX were not fully dilatable with conventional semicompliant and noncompliant balloons. The result after balloon angioplasty was suboptimal (C), and thus cutting balloons were utilized to dilate the ostium of the LCX [3.5 × 6 mm at 14 atm; (D)] and LAD (3.5 × 10 mm at 14 atm). The LMCA was then stented with the culotte technique by implanting a 4.0 × 23 mm Biomatrix biolimus A9-eluting stent (Biosensors Interventional Technologies Pte Ltd., Singapore) toward the LAD and a 3.5 × 18 mm Nobori biolimus A9-eluting stent (Terumo Corporation, Tokyo, Japan) toward the LCX. FKI was implanted with two 4.0 × 15 mm noncompliant balloons at 18 atm. (E and F) The final angiographic result.

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MB and in three lesions in the SB for a total restenosis rate of 4.5%. In the 63 patients with lesions located in the LMCA, there were no cases of angiographic restenosis.

Stent Choice We have no preference with respect to choice of DES. However, when performing double stenting with large branches of ≥3.5 mm in diameter, we prefer using stents with an open cell design. The only randomized data comparing DES in LMCA is the ISAR-LEFT MAIN (A Randomized Clinical Trial on Drug-Eluting Stents for Unprotected Left Main Lesions study), which was recently reported in the Late Breaking Clinical Trial Session at TCT 2008 Study (44). In the ISAR-LEFT MAIN, 607 patients were randomized to receive either a paclitaxel-eluting stent (PES) or sirolimus-eluting stent (SES). Distal LMCA was present in 63% of the patients, and Euroscore was 4.7 ± 3.5 and 4.4 ± 3.2 in the PES and SES groups, respectively. Two-stent techniques were used in 51% in PES versus 49% in SES (predominantly the “culotte” technique). The primary endpoint of noninferiority was met at one year (MACE was 13.6% in PES vs. 15.8% in SES; RR = 0.85; 95% CI = 0.56–1.29). Moreover, two-year results confirmed that MACE was comparable between PES and SES (RR = 0.99; 95% CI = 0.69–1.42). Also, no differences were observed in two-year mortality (RR = 1.14, 95% CI = 0.66–1.94, p = 0.64), ST rates (in PES definite ST 0.3%, probable ST 0.0%, in SES definite ST 0.7%, probable ST 0.3%), and TLR (in PES 9.2% vs. 10.7% in the SES; p = 0.47). There are currently no adequate published data on the outcomes of LMCA stenting with second-generation DES. Stent Deployment Optimization: Role of IVUS In our view, the most important part of LMCA PCI and where most attention needs to be given is in the optimal performance of double stenting techniques, particularly in optimizing stent implantation. Stent optimization in the era of DES is as important if not more so and the part of the procedure that still remains most undervalued. Suboptimal stent implantation (in particular stent underexpansion) has become recognized as an important risk factor not only for DES failure (restenosis) but also for the more serious and rare event of stent thrombosis (45,46). Indeed, one of the most important changes that have occurred in our practice during LMCA PCI has been in the use of IVUS in determining and optimizing stent deployment with noncompliant balloons at high pressure. We now always perform IVUS in LMCA intervention not only at the beginning of the procedure to assess plaque morphology and burden but more importantly after stent implantation to determine the need for postdilatation with appropriately sized (i.e., based on average media-to-media diameters) noncompliant balloons.

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Figure 20 (A and B) The baseline angiogram of this lesion involving the distal LMCA, with a sharp angulation of the LCX. The LAD is protected by a functioning left internal mammary artery graft. The first approach was to try to wire both, the diagonal branch coming off the proximal LAD, the RI and LCX. Due to sharp angulation of the LCX and despite numerous attempts with several different guidewires, we were not able to negotiate the wire into the LCX. Thus we elected to perform directional atherectomy on the distal LMCA toward the LAD (C) with a FlexiCut 3.0–3.5 mm (6 cuts). We felt that in this case some lesion debulking would not only allow better stent expansion but also facilitate an easier passage of the wire into the LCX. The result following atherectomy is shown in panel (D). Following atherectomy, we were able to advance a guidewire wire into the LCX and then dilated both vessels as shown in panels (E and F) (using a 3.0 × 6 mm cutting balloon for the LCX). (G) The result following lesion predilatation and cutting balloon. We then performed crush stenting on the distal LMCA with Taxus stent paclitaxel-eluting stents (Boston Scientific, Natick, MA), followed by FKI (H–K). The final result with preservation of all three major branches (L and M). We think that the approach to perform atherectomy to negotiate a wire into a branch when the anatomy is not favorable is quite unusual and this is one of the first cases in which we used this technique. Theoretically plaque removal in the MB may facilitate entry into the SB, as demonstrated in this case. An alternative would have been to predilate the LMCA toward the LAD in order to modify the plaque at the ostium of the LCX and thus allow wiring of the branch. However, it should be noted that both of these techniques may result in occlusion of the branch vessel.

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Current data on IVUS in bifurcation PCI is limited. In the crush technique, IVUS has provided us with valuable insights in that it demonstrated that conventional crush stenting was associated with incomplete crushing (i.e., incomplete apposition of the three layers of main and SB stent struts) and ostial SB stent underexpansion are common and often not suspected angiographically (47). As a result of this study and our own observations, we modified our technique by using noncompliant balloons to perform high-pressure SB inflation prior to FKI, thereby performing a two-step kiss (34). The authors have also undertaken a prospective registry (INSIDE 1) that enrolled 31 patients with 35 bifurcations in which IVUS-guided stenting was performed on the MB and/or SB. This study found that an optimal IVUS result at the end of the procedure was the main factor associated with the absence of restenosis on the MB or SB. We also noticed that the need for two stents was mainly confined to lesions with a large plaque burden at the baseline IVUS. An interesting finding from this early experience was that attaining an optimal angiographic result in the SB was frequently not supported by IVUS evaluation. An optimal IVUS result was finally obtained following dilation with a larger balloon and at higher pressure. These observations remain preliminary due to the small number of patients evaluated, and only a prospective study with predefined criteria may be able to fully evaluate this issue. The major obstacle to the widespread adoption of IVUS-guided DES implantation has been the fact that it is more time-consuming, the added cost of IVUS and additional postdilatation balloons, the lack of randomized data, as well as the lack of appropriate and easily applicable criteria for optimal stent deployment. The routine usage of IVUS in clinical practice is frequently impeded by the time needed to perform a complete pullback and the need of additional staff to control the IVUS console. We propose a clinical use of IVUS as if we are doing “fluoroscopy.” The operator manually advances the IVUS catheter to the area of interest without necessarily recording and then does the measurements online himself. Currently available integrated IVUS systems with the use of electronic catheters facilitate the performance of this approach. There are accumulating data, though not randomized, that suggest that IVUS may impact long-term adverse events. In a large registry of IVUS-guided PCI with DES, the outcomes in 884 patients (1296 lesions) who underwent IVUS-guided DES implantation to all treated lesions were compared with those in 884 propensity-score matched patients (1312 lesions) who underwent DES implantation with angiographic guidance alone (48). At 30 days and 12 months, a higher rate of definite stent thrombosis was seen in the No-IVUS compared to IVUS-guided group (1.4% vs. 0.5%; p = 0.046) and (2.0% vs. 0.7%; p = 0.014, respectively).There were no major differences in late stent thrombosis and MACE (14.5 vs. 16.2%; p = 0.33) at 12-month follow-up between the groups. Rates of death and myocardial infarction were similar. A trend was seen in favor of the IVUS group in TLR (5.1% vs. 7.2%; p = 0.07). IVUS guidance was an independent predictor of freedom from cumulative stent thrombosis at 12 months (adjusted hazard ratio = 0.5, 95% CI = 0.1–0.8; p = 0.02) (48). Specifically looking at LMCA intervention, in the MAIN-COMPARE (Revascularization for Unprotected Left Main Coronary Artery Stenosis: Comparison of Percutaneous Coronary Angioplasty versus Surgical Revascularization) registry, IVUS guidance was associated with a significant tendency to a lower risk of three-year mortality compared with angiographyguidance (6.0% vs. 13.6%, log-rank p = 0.063; HR = 0.54, 95% CI = 0.28–1.03, p = 0.061) (49). IVUS guidance, however, did not modify the risk of MI or repeat revascularization. Similarly, in our multicentre registry evaluating 731 LMCA lesions (76.5% involving the distal left main) undergoing DES implantation, IVUS guidance was associated with reduced cardiac death (OR = 0.93, CI 95% = 0.16–0.93; p = 0.03) at univariate exact logistic (unconditional) analysis (50). Until now, the criteria for IVUS optimization used in different studies have relied on distal vessel reference or on the mean reference vessel size for stent or postdilatation balloon sizing. This reduces the potential to optimally increase the lumen size in long lesions, overlapping stents and in vessels with distal tapering. In addition, these criteria do not take advantage of vessel remodeling, which may allow the operator to attain a larger final stent cross-sectional area (CSA). We have recently proposed new IVUS criteria based on vessel remodeling which is currently being utilized in an ongoing randomized study, the Angiographic Versus IVUS Optimization (AVIO) trial (51). The AVIO study criteria for IVUS optimization are based on the achievement of a CSA inside the stent corresponding to the area achieved in our preliminary experience, called the achievable optimal result (AOR) in Table 1. The AOR depends on the

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Table 1 AVIO Study Criteria for Optimal DES Implantation Based on Achievable Optimal Result (AOR), Which is the Target Minimum Stent Cross-Sectional Area (CSA) According to the Noncompliant Balloon Chosen for Postdilatation Balloon size (mm) 2.25 2.5 3 3.5 4 4.5

Achievable optimal result (mm2 ) 3.5 4 6 8 10 12

The diameter of the balloon is chosen on the basis of the average media-to-media diameters of the vessel at different points of the stented area (proximal, mid-lesion, distal, and any other points of interest such as the point of maximum underexpansion).

diameter of the optimal postdilatation balloon chosen on the basis of the vessel media-to-media size at different points. These criteria take into account the varying vessel size in overlapping stents and that multiple postdilations with different size noncompliant balloons may be needed. In Figure 10, we demonstrate a case of LMCA stent optimization utilizing the AVIO criteria. Despite the lack of randomized data, we strongly believe that IVUS guidance utilizing modern and feasible criteria should be utilized when implanting stents in bifurcation lesions involving a large amount of myocardium at jeopardy such as the LMCA. CONCLUSIONS Current guidelines still indicate CABG as the optimal treatment for LMCA lesions. However, data from worldwide registries and the left main subset of SYNTAX are encouraging toward a noninferiority of PCI with DES versus CABG in regards to MI, death, and cerebrovascular events at medium-term follow-up. We are particularly optimistic by the randomized SYNTAX data, which demonstrate that you have to do 19 CABGs to prevent just one repeat revascularization after left main PCI. Notwithstanding these positive results, we would stress that double stenting of the distal LMCA is more complex than provisional stenting and requires expertise and performance of an optimal procedure including double antiplatelet pretreatment, testing for clopidogrel hyporesponsiveness, elective hemodynamic support when needed, adequate lesion preparation, and IVUS-guided DES implantation, and postdilatation in all cases. Moreover, we would advise that this high-risk group should have good clinical follow-up assessing their clinical condition and re-enforcing adherence to dual antiplatelet therapy for at least 12 months. We also recommend routine angiographic follow-up at six months. TAKE HOME MESSAGE 1. The choice of stenting technique for LMCA bifurcations should be based on bifurcation morphology and operator experience. 2. The bifurcation anatomy, size of the side branch, and distribution of disease are the most important determinants of electively performing double stenting of the LMCA; that is, if the side branch is of a sufficiently large diameter (at least ≥2.5 mm), with a large area of distribution and the disease extends beyond the ostium, then elective implantation of two stents should be considered. 3. Elective implantation of two stents to treat LMCA bifurcation disease is required in approximately 50% of patients. 4. In complex bifurcations involving large territories or in unstable patients, where it is crucial to maintain optimal patency of both branches, we recommend the V- or crush techniques. 5. Double stenting of the LMCA is more complex, time-consuming, and labor intensive; optimal technique is mandatory to avoid complications and ensure favorable long-term results. 6. Final kissing inflation with appropriately sized noncompliant balloons is mandatory with all techniques of double stenting.

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7. Dual antiplatelet pretreatment, testing for clopidogrel hyporesponsiveness, and ensuring uninterrupted adherence to at least 12 months of dual antiplatelet therapy is essential. 8. Elective hemodynamic support is recommended in selected cases such as very complex anatomy, severe calcifications, or low ejection fraction. 9. Adequate lesion preparation is important in severely calcified lesions, or where the predilating balloon will not pass the lesion or fully expand. 10. IVUS-guided DES implantation and optimization should be performed in all cases. REFERENCES 1. Gruntzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med 1979; 301:61–68. 2. Migliorini A, Moschi G, Giurlani L, et al. Drug-eluting stent supported percutaneous coronary intervention for unprotected left main disease. Catheter Cardiovasc Interv 2006; 68:225–230. 3. Chieffo A, Morici N, Maisano F, et al. Percutaneous treatment with drug-eluting stent implantation versus bypass surgery for unprotected left main stenosis: a single-center experience. Circulation 2006; 113:2542–2547. 4. Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous coronary intervention versus coronaryartery bypass grafting for severe coronary artery disease. N Engl J Med 2009; 360:961–972. 5. Seung KB, Park DW, Kim YH, et al. Stents versus coronary-artery bypass grafting for left main coronary artery disease. N Engl J Med 2008; 358:1781–1792. 6. Buszman PE, Kiesz SR, Bochenek A, et al. Acute and late outcomes of unprotected left main stenting in comparison with surgical revascularization. J Am Coll Cardiol 2008; 51:538–545. 7. Silber S, Albertsson P, Aviles FF, et al. Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Eur Heart J 2005; 26:804–847. 8. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention—summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). Circulation 2006; 113:156–175. 9. Kushner FG, Hand M, Smith SC, Jr, et al. Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2009; 120:2271–2306. 10. Chieffo A, Park SJ, Valgimigli M, et al. Favorable long-term outcome after drug-eluting stent implantation in nonbifurcation lesions that involve unprotected left main coronary artery: a multicenter registry. Circulation 2007; 116:158–162. 11. Valgimigli M, Malagutti P, Rodriguez-Granillo GA, et al. Distal left main coronary disease is a major predictor of outcome in patients undergoing percutaneous intervention in the drug-eluting stent era: an integrated clinical and angiographic analysis based on the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) and Taxus-Stent Evaluated At Rotterdam Cardiology Hospital (T-SEARCH) registries. J Am Coll Cardiol 2006; 47:1530–1537. 12. Latib A, Colombo A, Sangiorgi G. Bifurcation stenting: Current strategies and new devices. Heart 2009; 95:495–504. 13. Colombo A, Chieffo A. Treatment of unprotected left main stenosis. In: Colombo A, Stankovic G, eds. Problem Oriented Approaches in Interventional Cardiology. London, UK: Informa Healthcare, 2007:21–35. 14. Louvard Y, Lefevre T, Morice MC. Percutaneous coronary intervention for bifurcation coronary disease. Heart 2004; 90:713–722. 15. Louvard Y, Thomas M, Dzavik V, et al. Classification of coronary artery bifurcation lesions and treatments: time for a consensus! Catheter Cardiovasc Interv 2008; 71:175–183. 16. Louvard Y, Lefevre T. Bifurcation lesion stenting. In: Colombo A, Stankovic G, eds. Problem Oriented Approaches in Interventional Cardiology. London, UK: Informa Healthcare, 2007:37–57. 17. Ge L, Airoldi F, Iakovou I, et al. Clinical and angiographic outcome after implantation of drug-eluting stents in bifurcation lesions with the crush stent technique: importance of final kissing balloon postdilation. J Am Coll Cardiol 2005; 46:613–620. 18. Schampaert E, Fort S, Adelman AG, et al. The V-stent: a novel technique for coronary bifurcation stenting. Cathet Cardiovasc Diagn 1996; 39:320–326.

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19. Sharma SK. Simultaneous kissing drug-eluting stent technique for percutaneous treatment of bifurcation lesions in large-size vessels. Catheter Cardiovasc Interv 2005; 65:10–16. 20. Colombo A, Bramucci E, Sacca S, et al. Randomized study of the crush technique versus provisional side-branch stenting in true coronary bifurcations: the CACTUS (Coronary Bifurcations: Application of the Crushing Technique Using Sirolimus-Eluting Stents) Study. Circulation 2009; 119:71–78. 21. Colombo A, Stankovic G, Orlic D, et al. Modified T-stenting technique with crushing for bifurcation lesions: immediate results and 30-day outcome. Catheter Cardiovasc Interv 2003; 60:145–151. 22. Galassi AR, Colombo A, Buchbinder M, et al. Long-term outcomes of bifurcation lesions after implantation of drug-eluting stents with the “mini-crush technique.” Catheter Cardiovasc Interv 2007; 69:976– 983. 23. Ormiston JA, Currie E, Webster MW, et al. Drug-eluting stents for coronary bifurcations: insights into the crush technique. Catheter Cardiovasc Interv 2004; 63:332–336. 24. Ormiston JA, Webster MW, El Jack S, et al. Drug-eluting stents for coronary bifurcations: bench testing of provisional side-branch strategies. Catheter Cardiovasc Interv 2006; 67:49–55. 25. Ormiston JA, Webster MWI, Webber B, et al. The “crush” technique for coronary artery bifurcation stenting: insights from micro-computed tomographic imaging of bench deployments. JACC Cardiovasc Interv 2008; 1:351–357. 26. Dzavik V, Kharbanda R, Ivanov J, et al. Predictors of long-term outcome after crush stenting of coronary bifurcation lesions: importance of the bifurcation angle. Am Heart J 2006; 152:762–769. 27. Chevalier B, Glatt B, Royer T, et al. Placement of coronary stents in bifurcation lesions by the “culotte” technique. Am J Cardiol 1998; 82:943–949. 28. Erglis A, Kumsars I, Niemela M, et al.; for the Nordic PCI Study Group. Randomized comparison of coronary bifurcation stenting with the crush versus the culotte technique using sirolimus eluting stents: The Nordic Stent Technique Study. Circ Cardiovasc Interv 2009; 2:27–34. 29. Colombo A, Moses JW, Morice MC, et al. Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions. Circulation 2004; 109:1244–1249. 30. Burzotta F, Gwon HC, Hahn JY, et al. Modified T-stenting with intentional protrusion of the sidebranch stent within the main vessel stent to ensure ostial coverage and facilitate final kissing balloon: the T-stenting and small protrusion technique (TAP-stenting). Report of bench testing and first clinical Italian-Korean two-centre experience. Catheter Cardiovasc Interv 2007; 70:75–82. 31. Hoye A, Iakovou I, Ge L, et al. Long-term outcomes after stenting of bifurcation lesions with the “crush” technique: predictors of an adverse outcome. J Am Coll Cardiol 2006; 47:1949–1958. 32. Adriaenssens T, Byrne RA, Dibra A, et al. Culotte stenting technique in coronary bifurcation disease: angiographic follow-up using dedicated quantitative coronary angiographic analysis and 12-month clinical outcomes. Eur Heart J 2008; 29:2868–2876. 33. Brunel P, Lefevre T, Darremont O, et al. Provisional T-stenting and kissing balloon in the treatment of coronary bifurcation lesions: results of the French multicenter “TULIPE” study. Catheter Cardiovasc Interv 2006; 68:67–73. 34. Latib A, Colombo A. Bifurcation Disease: What Do We Know, What Should We Do? JACC Cardiovasc Interv 2008; 1:218–226. 35. Weinstein JS, Baim DS, Sipperly ME, et al. Salvage of branch vessels during bifurcation lesion angioplasty: acute and long-term follow-up. Cathet Cardiovasc Diagn 1991; 22:1–6. 36. Price MJ, Endemann S, Gollapudi RR, et al. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J 2008; 29:992–1000. 37. Migliorini A, Valenti R, Marcucci R, et al. High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drug-eluting stenting for unprotected left main coronary disease. Circulation 2009; 120:2214–2221. 38. Briguori C, Airoldi F, Chieffo A, et al. Elective versus provisional intraaortic balloon pumping in unprotected left main stenting. Am Heart J 2006; 152:565–572. 39. Dixon SR, Henriques JPS, Mauri L, et al. A Prospective Feasibility Trial Investigating the Use of the Impella 2.5 System in Patients Undergoing High-Risk Percutaneous Coronary Intervention (The PROTECT I Trial): Initial U.S. Experience. JACC Cardiovasc Interv 2009; 2:91–96. 40. Ozaki Y, Suzuki T, Yamaguchi T, et al.; The REDUCE III Study Group. Can intravascular ultrasound guided cutting balloon angioplasty before stenting be a substitute for drug eluting stent? Final Results of the Prospective Randomized Multicenter Trial Comparing Cutting Balloon With Balloon Angioplasty Before Stenting (Reduce III) (abstract). J Am Coll Cardiol 2004; 43(suppl A):1138–1166. 41. Stankovic G, Colombo A, Bersin R, et al. Comparison of directional coronary atherectomy and stenting versus stenting alone for the treatment of de novo and restenotic coronary artery narrowing. Am J Cardiol 2004; 93:953–958.

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42. Colombo A. Directional coronary atherectomy and implantation of drug-eluting stents in selected bifurcation lesions: A logical combination waiting evidence. J Am Coll Cardiol 2007; 50:1946–1947. 43. Tsuchikane E, Aizawa T, Tamai H, et al.; for the PI. Pre drug-eluting stent debulking of bifurcated coronary lesions. J Am Coll Cardiol 2007; 50:1941–1945. 44. Mehilli J, Kastrati A, Byrne RA, et al. Paclitaxel- versus sirolimus-eluting stents for unprotected left main coronary artery disease. J Am Coll Cardiol 2009; 53:1760–1768 45. Cook S, Wenaweser P, Togni M, et al. Incomplete stent apposition and very late stent thrombosis after drug-eluting stent implantation. Circulation 2007; 115:2426–2434. 46. Windecker S, Meier B. Late coronary stent thrombosis. Circulation 2007; 116:1952–1965. 47. Costa RA, Mintz GS, Carlier SG, et al. Bifurcation coronary lesions treated with the “crush” technique: an intravascular ultrasound analysis. J Am Coll Cardiol 2005; 46:599–605. 48. Roy P, Steinberg DH, Sushinsky SJ, et al. The potential clinical utility of intravascular ultrasound guidance in patients undergoing percutaneous coronary intervention with drug-eluting stents. Eur Heart J 2008; 29:1851–1857. 49. Park SJ, Kim YH, Park DW, et al. Impact of intravascular ultrasound guidance on long-term mortality in stenting for unprotected left main coronary artery stenosis. Circ Cardiovasc Interv 2009; 2:167–177. 50. Chieffo A, Park S-J, Meliga E, et al. Late and very late stent thrombosis following drug-eluting stent implantation in unprotected left main coronary artery: a multicentre registry. Eur Heart J 2008; 29:2108– 2115. 51. Gerber RT, Latib A, Ielasi A, et al. Defining a new standard for IVUS optimized drug eluting stent implantation: The PRAVIO study. Catheter Cardiovasc Interv 2009; 74:348–356.

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Bench Testing of Coronary Bifurcation Stenting Techniques: How Is It Done? Does It Help Technical Decision Making? Yoshinobu Murasato Department of Cardiovascular Medicine, Heart Center, New Yukuhashi Hospital, Yukuhashi, Japan

WHY IS BENCH TESTING OF CORONARY BIFURCATION STENTING TECHNIQUES IMPORTANT? PCI for coronary bifurcation lesions has been associated with high restenosis rates in the bare metal stent (BMS) era (1); however, the introduction of drug-eluting stents (DES) have led to significant reduction in restenosis and target lesion revascularization in bifurcation lesions (2–7). However, the risk of acute compromise and/or delayed restenosis in the ostium of the side branch (SB) remains an issue particularly in the “at risk” bifurcations (i.e., true bifurcation lesions with severe ostial SB lesion and/or wide bifurcation angle, particularly when the SB supplies a large myocardial territory). Although the in vivo imaging modalities [angiography, intravascular ultrasound (IVUS), optical coherence tomography] that are used to guide bifurcation stenting are valuable in optimizing acute results, they provide limited insight into the relationship between bifurcation anatomy, stenting technique, and the ensuing stent configuration at the bifurcation. This information is critical to individualizing technique selection and refining technique execution [provisional vs. elective, fate of jailed SB, and necessity of kissing balloon inflation (KBI)]. Bench testing allows direct and detailed inspection of stent configuration at the bifurcation and its relationship to the simulated bifurcation anatomy and stenting technique. Imaging is typically performed with high-quality cameras, microscopy, and microfocus X-ray computed tomography (MFCT) with resolution of 0.06 mm (8–11). An example of the difference in the quality of information attainable with IVUS versus MFCT is shown in Figure 1(A) and 1(B). As shown in Figure 1(A), the proximal segment of the SB stent was crushed due to incorrect guidewire recrossing, and subsequent dilation, outside of the SB stent using the modified crush stenting technique. The three-dimensional (3-D) images of MFCT demonstrate a large gap at the proximal segment of the SB. In the cross-sectional views, the absence of struts on the carina side and the evidence of two layers of crushed stent at the opposite site were clearly observed [Fig. 1(A)]. As shown in Figure 1(B), the IVUS images also show the crushed stent and non– strut-covered area, but the image resolution is inferior to that of MFCT. This may be because of the uneven pullback speed due to the slack of the catheter in the corner of the bifurcation, as well as due to oblique projection from the lateral side of the SB sweeping to the MV. Using these high-quality imaging modalities, the previous bench testing studies have clearly demonstrated stent distortion, stent apposition, gap formation, metal overlapping, opening of jailed strut, and polymer damage in each bifurcation stenting technique (8–15). Many factors that can potentially affect the results of bifurcation stenting has been investigated by bench testing such as stent platform, bifurcation angle, 3-D structure, balloon size, inflation pressure, balloon overlapping, KBI, and guidewire position (8–15). HOW IS BENCH TESTING DONE? In previous reports, silicone tubes (8,9,11,12), polyvinyl acetate (PVA) tubes (13), and silicone blocks (10,14,15) have been used as phantom models. Although a silicon tube has elasticity that resembles the human coronary artery, it is not transparent enough to allow direct observation externally, and the removal of the implanted stent for observation without inadvertent damage is challenging. PVA tubes are soft and can be embedded in the vessel mold constructed by the silicon block. The implanted stent can then be removed easily because the PVA tube melts

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Figure 1 Comparison in the resolution for the analysis of complex stenting between MFCT and IVUS. The proximal site of the SB stent was crushed by the SB balloon and there was a large gap at the opposite site. (A) MFCT images. Each cross-sectional view corresponds to the line in the 3-D view. The absence of the struts (arrows) and the crushed stent at the opposite site (gray arrows) were clearly visualized. (B) IVUS images. Each view corresponds to the line in the 3-D view. Although the absence of the strut (arrows) and the crushed stent at the opposite site (gray arrows) were observed, their resolutions were inferior to the MFCT views so the problems were missed. Source: From Ref. 9.

in hot water immersion. Most studies were performed in the two-dimensional (2-D) model (10,11,13–16). However, it has been demonstrated that the 3-D structure of the bifurcation has a great impact on stent deformational behavior because of the various configurations of balloon overlapping (8,9,12). We used a 7.5-cm diameter column to reproduce the 3-D structure of the LMCA bifurcation. A 4-mm-diameter silicon tube, corresponding to the LAD, was glued and oriented vertically, while a 3-mm-diameter tube, corresponding to the circumflex artery (LCX), was glued in a transverse direction, with a 90-degree angle between both tubes. A tube corresponding to the LMCA was glued and oriented at a 135-degree angle with respect to the other two branches [Fig. 2(A)]. The 3-D structure of the model was inspected by fluoroscopy and confirmed to be similar to that of a human LMCA bifurcation [2(B–F)] (12).

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Figure 2 3-D model of left main coronary bifurcation. The LAD tube was attached along the longitudinal axis and the LCX tube was attached obliquely to create an angle between the LMCA and the LAD, which was equal to that between the LMCA and the LCX (A). Fluoroscopic inspection, in the right anterior oblique 30◦ (B), left anterior oblique 50◦ (C), anterior–posterior caudal 30◦ (D), and in the spider view (E), confirmed the similarity of the model to a human coronary angiogram. Source: From Ref. 12.

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The stenting procedure was performed under fluoroscopy or direct visualization. The magnified image of Charge Coupled Device (CCD) camera was useful for procedure execution such as guidewire recrossing through the target strut. The experiments were performed under a variety of factors, which were thought to affect stent configuration. Although in the initial studies fluoroscopy, CCD camera, and microscopy were used (12–16), MFCT has become the standard imaging technique in later investigations (8–11). This technique provides high-resolution images in the 3-D reconstruction model and any cross-sectional or longitudinal views can be obtained. WHAT ARE THE OBSERVATIONS GAINED FROM BENCH TESTING? Bench testing of bifurcation stenting techniques have revealed numerous observations and insights that can help in refining the technical execution of the various bifurcation stenting techniques. Insights into the Provisional Stenting Technique Provisional stenting can result in outcome similar to elective double stenting with lower use of resources in appropriately selected patients (2–6). However, there are several technical steps that need to be performed to produce optimal results (17).

The Ideal Site for Guidewire Recrossing into the SB Bench testing have demonstrated that the site of guidewire recrossing into the SB affects the scaffolding of the SB ostium after KBI. As shown in Figure 3, the ideal site of recrossing into the SB is the distal segment of the stent covering the ostium because that leads to scaffolding the SB ostium after SB dilation (black star in A[4]), whereas recrossing into the SB through the proximal segment (white triangles in C[4]) produces MV stent deformity without scaffolding the SB ostium.

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Figure 3 Relation between stent configuration and the position of recrossed guidewire in the procedure of crossover stenting followed by kissing balloon inflation (KBI). As the dotted arrows indicate, the wires were recrossed at distal (A), middle (B), and proximal (C) portions of the SB ostium [1]. Although the deformations of the MV stents were promoted by the SB ballooning (A[2], B[2]; arrows), the KBI [3] corrected these deformations (A[4], B[4]; white arrows). Finally, the SB ostium was scaffold by the protruded MV stent when the wire was recrossed through the distal portion (A[4]; black star ). However, distal MV stent was protruded into the MV when the wire was recrossed through the proximal portion (C[4], white triangles).

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The Importance of KBI Bench testing demonstrated the importance of KBI to correct the deformation of the MV stent. As shown in Figure 3 (arrows in A[2] and B[2]), the deformation of the MV stent opposite to the SB ostium after SB dilation was corrected after subsequent KBI (white arrows in A[4] and B[4]). Insights into the Double Stenting Techniques Elective double stenting is often necessary in true bifurcation lesions that involve a large SB with severe ostial stenosis. Final KBI is considered a critical step to optimize the results and some believe that it may reduce the need for repeat interventions (19).

The Effects of Bifurcation Angle on Balloon Overlapping Patterns and Proximal MV Expansion In elective double stenting techniques, two stents are deployed consecutively or simultaneously and KBI is performed to optimize the results. Therefore, understanding the 3-D pattern of stents/balloons overlap is important because the pattern of balloon overlapping affects the configuration of the proximal segment of the MV stent. As shown in Figure 4, the effect of bifurcation angle on the pattern of balloon overlapping was investigated in the simultaneous kissing stenting (SKS) technique using Multilink stents (Abbott Vascular, Santa Clara, CA). In narrow angle bifurcations [Fig. 4(A)], the two stents are aligned lateral to each other, whereas in wide-angle bifurcations the two stents are increasingly overlapped longitudinally according to the degree of the bifurcation angle [Fig. 4(B) and 4(C)] and the overlap pattern becomes

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(F) Figure 4 (A–C) Relation between bifurcation angle and style of stent overlapping during simultaneous kissing stenting (SKS). (Upper panels) position of the two stents before inflation. (Lower panels) During inflation. In the narrow angled bifurcation (A; 30◦ ), the two stents positioned laterally, whereas the stents overlapped longitudinally according to the degree of the bifurcation angle (B; 70◦ ) and the style finally changed to the x-shape (C; 80◦ ). (D) Long overlapping also led to the x-shape crossing of the two stents in the proximal MV. This overlapping style showed maximal dilation at the proximal end of the stents (black arrows) and minimal at the bifurcation point (white arrows). (E) Minimal overlapping in the same bifurcation model as shown in panel (D). This overlapping style showed maximal dilation at the bifurcation point (black arrows) and minimal at the proximal end of the stents (white arrows). (F) Plaque distribution in the bifurcation according to recent pathological study. Minimal overlapping is more effective for plaque compression compared to x-shape crossing, because it can provide maximal dilation at the lateral area where plaque burden is rich.

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x-shaped in the widest angle [Fig. 4(C)]. The proximal in-stent area for stents implanted in wide-angle bifurcations (x-shaped overlap pattern) is larger than stents implanted in narrow angle bifurcations. This finding suggests that when kissing stents are deployed in a wide-angle bifurcation, the x-shaped pattern of overlap may increase the risk of proximal overdilation after SKS and after KBI. Furthermore, the x-shaped pattern of overlap can lead to underdilation of the segment proximal to the carina in the transverse direction [Fig. 4(D), where most of the plaque is typically localized [Fig. 4(F)] (18). On the other hand, minimizing the extent of balloon overlapping (not x-shaped overlapping) leads to better plaque compression proximal to the carina [Fig. 4(E)]. We have previously demonstrated in a 3-D model that the wide bifurcation angle in the LMCA influences balloon overlapping patterns during KBI (8,9,12,13,20). Furthermore, we have illustrated that the various patterns of overlap (MV balloon located over SB balloon and SB balloon located over MV balloon) can be easily reversed by the manipulation of the guidewire (Fig. 5) (12). Crush stenting Although this technique secures immediate patency of both branches of the bifurcation, it can be associated with various stent deformities if used in improper anatomy and/or if not performed in an optimal fashion. Studies using IVUS (20) and animal experiments (21) have shown stent malapposition at the SB ostium, excessive metal overlapping, and incomplete crush at the proximal MV. Bench testing has demonstrated that the bifurcation angle had a significant impact on stent apposition to the SB ostium (8–10,12,14,15). Although final KBI improves SB ostium stent apposition in narrow-angled bifurcations, it does not do so in wide-angled bifurcations (persistence

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Figure 5 (See color insert ) Overlap of the balloons in the distal LMCA. Visual inspection of the LAD (red ) balloon located over the LCX (blue) balloon (A, upper panel), and the reverse relationship (B, upper panel). Fluoroscopic inspections in the anterior–posterior caudal (middle panels), and spider (lower panels) views. The arrows indicate the guidewire advanced from the LMCA into the LCX. The wire is visible on the myocardial side of the distal LMCA when the LAD balloon is positioned over the LCX balloon (A, middle and lower panels), and on nonmyocardial side when the overlapping is reversed (B, middle and lower panels). Source: From Ref. 12.

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of an unstented area at the distal carina site of the SB) (8,9,12,14). In a 3-D left main bifurcation model (Figs. 6 and 7), the cross-sectional images at the distal bifurcation clearly demonstrate a wedge-shaped gap between the stents [Fig. 6(B)] and the absence of struts [Fig. 7(C)]. In this model, when the LAD stent was located above the LCX stent, the stent was crushed on the myocardial side and the unstented area was observed on the nonmyocardial side. When this overlap was reversed, the LCX stent was crushed on the nonmyocardial side, and the unstented segment was located on the myocardial side (12). Although it has been suggested that the two-step balloon dilation technique (10), the minicrush technique (22), and the double kiss crush technique (DK crush) (23) lead to better SB ostium apposition and improved long-term outcome, bench testing of these techniques still reveals lack of complete apposition to the distal carina. There are several factors, which may be responsible for these observations: 1. The position at which the guidewire recrosses the MV stent into the stented SB has a major influence on ostial SB stent deformity. The ideal position for guidewire recrossing into the SB is the middle of the SB ostium. Guidewire recrossing into the SB through the proximal portion of the SB ostium leads to incomplete expansion of the balloon during postdilatation. On the other hand, guidewire recrossing into the SB through the distal portion of the SB ostium (from the outside of the SB stent) leads to partial crushing of the proximal part of the SB stent with the postdilatation balloon (Fig. 8). As shown in Figure 9(A), the 3-D MFCT images demonstrate a large gap on the carina side of the proximal segment of the LCX artery

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(B) Figure 6 MFCT images after crush stenting in the 3-D LMCA bifurcation model with the LAD stent positioned above the LCX stent. (A) The 3-D image shows the crushed proximal end of the LCX stent extending onto the lateral LMCA and the gap at the distal carina (dotted arrow ). (B) Proximal to distal (a–d) cross-sectional images of the carina. Each image was acquired at the level of the arrows in panel (A). In the proximal carina, the protruding strut of the MV stent into the LCX covered the ostium of LCX (b, dotted arrow ). However, in the distal carina, a gap between the two stents was observed along the nonmyocardial site (d, arrows). Source: From Ref. 8.

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Figure 7 (A) 3-D view of classical crush stenting using Express II stents in the 3-D LMCA bifurcation model. (B) Magnified view of the bifurcation. A relatively large gap was observed at the nonmyocardial site of the LCX ostium (B2, encircled area). (C) Cross-sectional views at the corresponding lines indicated in part (B1). The arrows indicate absence of the struts. Source: From Ref. 9.

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Figure 8 (A) 3-D view of the worst case of crush stenting that the guidewire was recrossed through the distal portion of the LCX ostium. The LCX stent was crushed more distally after kissing balloon inflation (dotted arrows). (B) Cross-sectional view at the corresponding lines in part (A). White arrows indicate the absence of the strut and the crushed stent was observed at the opposite site of the carina. (C) Mechanism of this phenomenon. The guidewire and balloon were advanced outside the proximal segment of the crushed stent (1) and the balloon was inflated (2). Finally, the proximal part of the LCX stent was recrushed more distally (3). Source: From Ref. 9.

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Figure 9 The style of the dilation of the cell for the SB after crush stenting followed by kissing balloon inflation. The dotted lines in the right panels indicate maximally dilated cells of the MV stent at the SB ostium. A case with good expansion of the cell (A) and that with poor position of the cell (B) using Bx Velocity stents are shown as well as a case with well-apposed expansion using an Express II stent (C). Source: From Ref. 9.

as well as two layers of a crushed stent at the opposite side. In the cross-sectional views, the absence of struts on the carina side and the evidence of two layers of crushed stent at the opposite site were also clearly observed [Fig. (9B)]. 2. The size of the reconstructed SB opening in the crush technique depends on the number of layers of jailed struts over the SB ostium and on stent design (9,11,15). Inflating a 3.5 mm balloon in the SB ostium, Ormiston demonstrated maximal stent cell size of 3.2 × 2.8 mm in the Bx Velocity stent (Cordis Corporation, Miami Lakes, FL), 3.3 × 3.3 mm in the Express II stent (Boston Scientific, Natic, MA), and 3.6 × 3.4 mm in the Liberte stent (Boston Scientific) (15). As shown in Figure 9, an adequate opening of the SB was not achievable even after highpressure KBI because of the numerous struts of the Bx Velocity stent over the SB ostium that restricted optimal balloon expansion. This observation is consistent with previous findings suggesting that stents with a smaller cell size (<3.5 mm) had smaller opening at the SB ostium compared to stents with larger cell size (>3.5 mm) (10). 3. Although the DK crush technique was advocated to improve the size of the SB ostium, opening its efficacy remains questionable. In the 3-D LMCA bifurcation model, the fully dilated SB stent strut rose up from the MV bed and deviated to one side by the LAD balloon (Fig. 10) (9). This complex configuration might be caused by balloon overlapping. The raised SB stent strut would be crushed again after MV stenting and the advantage of the DK crush technique would be lost.

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Figure 10 (A) 3-D view of the LCX stent from the nonmyocardial side after first kissing balloon inflation in DK crush stenting. (B) 3-D view from the LAD side. The dilated strut was raised up from the MV bed and deviated to one side by the LAD balloon. (C) The position of each balloon during kissing balloon inflation: dotted gray and solid gray lines indicate the LAD and LCX balloons, respectively. The overlapping of the stents had some effect on the expansion of the strut at the LCX ostium. (D) The second stent is advanced in the MV. (E) The raised strut (encircled part ) will be crushed again after MV stenting. Source: From Ref. 9.

The above observations cannot be discerned using traditional clinical imaging devices (IVUS, OCT) (Fig. 1) (9). Modified T-stenting In this technique, the SB stent is positioned with minimal protrusion into the MV in order to prevent or minimize the potential for a gap at the SB ostium. In the 3-D LMCA bifurcation model, the MFCT images showed minimal protrusion of the LCX stent and a short metallic carina-like overlap along the myocardial side of the proximal MV (8). The overlap was minimal as compared with other double stenting technique. However, the 3-D MFCT images revealed the absence of stent coverage on the nonmyocardial side [Fig. 11(B)] (8). This nonmyocardial unstented area was thought to be generated by the straightening of the SB stent during deployment caused the slippage of the proximal end to the outside of the MV stent, when the 3-D curvature of the SB is sharp. Modified T-stenting requires redilatation of the proximal SB stent orifice after MV stent deployment to ensure expansion of the SB ostium. This can be accomplished by guidewire recrossing into the SB through the proximal portion of the SB orifice instead of the stent struts, although distinguishing these two pathways on fluoroscopy may be challenging. If the guidewire recrosses into the SB through a stent strut, the outcome with respect to SB stent apposition to the vessel wall would be similar to that achieved with crush stenting. Although minimizing the protruded segment of the SB stent into the MV is desirable to ensure proper

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Figure 11 MFCT images after modified T-stenting in the 3-D LMCA bifurcation model. (A) Long axis 3-D image. (B) Proximal to distal (a–d) cross-sectional images of the carina. In the distal carina, a hole-like gap was observed on the nonmyocardial side of the vessel, which was generated by slippage of the proximal end of SB stent from the MV after straightening of the stent during inflation in the 3-D structure (d, arrows). (C) The plain horizontal image shows a metallic carina (dotted arrow ). Source: From Ref. 8.

passage of the guidewire when recrossing, this approach may increase the chances of missing the SB ostium (11,15). Culotte stenting Since this technique involves consecutive jailing of the SB and MV stents by the opposite stent, optimal dilation of these jailed struts is necessary. Therefore, open-cell stents are preferable because stent struts can be dilated to a larger diameter. As shown in Figure 12(A), the 3-D images of Bx Velocity stents (closed-cell design) demonstrate a “napkin ring” restriction of the ostium of the MV and the SB, because the maximal strut dilation diameter is 3.0 mm even if >3.00 mm balloon is used (9,11). On the contrary, the 3-D images of the Driver stent (Medtronic, Santa Rosa, CA) and Liberte stent (open-cell stents) show good apposition to the vessel wall [Fig. 11(B) and 12(C)]. In most segments of the bifurcation, the cross-sectional views also show good stent apposition; however, there remains a very small gap and small metallic carina at the distal bifurcation site (9). The density of metal overlapping in the proximal MV is one of the disadvantages of this technique. Simultaneous kissing stenting (SKS) With the SKS technique, two stents are deployed in the MV and SB simultaneously, therefore obviating the need for guidewire recrossing into either branch. Bench testing using the 3-D LMCA bifurcation model demonstrates that stent overlap in this technique creates a wedgeshaped gap beneath the site where the LCX stent crosses over the LAD stent, creating a substrate for restenosis at the LCX ostium (Fig. 13) (8,12,13). When the stent overlap extends deep into the proximal MV, two unfavorable configurations take place (Fig. 14): (i) “twisting” of the two stents, where the LCX stent extend to the opposite side of the LCX ostium; and (ii) asymmetric and often underexpanded lumen in one or both stents.

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Figure 12 MFCT images after culottes tenting. (A) Bx Velocity stents in the 2-D bifurcation model at 45◦ angle between the MV and the SB. The restriction of the stent expansion is observed in both ostium of the daughter branches after kissing balloon inflation using 3.5 mm balloons (arrows). (B) Driver stents in the 3-D LMCA bifurcation model. Middle and lower panels show the cross-sectional image corresponding the lines where the star and the circle are located at the upper panel, respectively. (C) Liberte stents in the LMCA bifurcation model. Both Driver and Liberte stents showed well-apposed configuration and a tiny gap was observed in the distal carina in the experiment using Driver stents (B, lower panel ). The image of (A) was provided by Yutaka Hikichi (Saga University, Japan).

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Figure 13 MFCT images after simultaneous kissing stenting in the 3-D LMCA bifurcation model. (A) The long axis 3-D image shows the proximal end of the LCX stent crossing the LAD stent in the distal LMCA, rather than being positioned lateral to the LAD stent. (B) Proximal to distal (a–c) cross-sectional images of the carina. Proximally, the LCX stent was compressed by the LAD stent (a, dotted arrow ). Distally, a gap is seen beneath the overlapped stents on the myocardial side (c, solid arrow ). (C) The plain cross-sectional image at level “a” also shows compression of the LCX stent. Source: From Ref. 8.

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Figure 14 MFCT images after simultaneous kissing stenting with long overlapping site in the LMCA. (A) Long axis 3D image. (B) Proximal to distal (a–e) cross-sectional images of the LMCA. The solid gray line indicates the LCX stent in both views. The LCX stent was located over the LAD stent at the bifurcation and extended proximally at the opposite side of the LCX ostium.

V-stenting With the V-stenting technique, two stents are also deployed in the MV and SB simultaneously, therefore obviating the need for guidewire recrossing into either branch. This technique, however, differs from the SKS technique in that there is minimal protrusion of both stents into the proximal MV (or no protrusion). This technique is favorable for lesions located at the ostia of both branches with nondiseased large proximal MV (such as ostial LAD and LCX disease sparing the distal LMCA). In bench testing using the 3-D LMCA bifurcation model, the proximal end of both stents oppose each other laterally. However, there is often asymmetry in stent expansion at the proximal edge based on the size and inflation pressure of the corresponding balloon (Fig. 15).

T-stenting and protrusion (TAP) This technique is only applicable to the provisional stenting approach when stenting of the SB becomes necessary due to a suboptimal balloon result. This technique does not require guidewire recrossing through a distorted SB stent orifice or a crushed SB stent. In bench testing using the 3-D LMCA bifurcation model, stent expansion and apposition at the LCX ostium were dependent on the ability of MV stent struts to maximally dilate. When an open-cell stent is used in the MV, optimal expansion of the SB stent at the ostium was possible [Fig. 16(A) to 16(D)]. On the other hand, when a close-cell stent is used in the MV, expansion of the SB stent at the ostium was not optimal and a residual unstented area around the proximal edge of the stent was observed [Fig. 15(E–H)]. The advantage of this technique is that there is minimal protrusion of the SB stent into the MV.

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Figure 15 MFCT images after V-stenting in the 3-D LMCA bifurcation model. (A) Long axis 3D image. (B) View from the LMCA. (C) Cross-sectional view at the distal LMCA. Lateral position of the two stents was maintained and the distortion of the proximal side of both stents was minimal.

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Figure 16 (See color insert ) MFCT images of T-stenting and protrusion (TAP) in the 3-D LMCA bifurcation model. Experiments were performed using Driver (upper panels) and Bx Velocity stents (lower panels) for the MV. (A, E) Long axis 3D image. (B, F) Cross-sectional view at the distal LMCA. Blue and red lines indicate the LCX and the LAD stents, respectively. Wide opening of the orifice of the LCX stent was observed in the panel (B), whereas the restriction of the stent expansion was observed in the panel (F). (C, G) Cross-sectional view corresponding to the line “a” in the 3-D image. The squeezing of the LCX stent at the strut where the LCX stent was protruded into the LMCA was small in the panel (C), whereas it was apparent in the panel (G) (arrows). (D, H) Cross-sectional view corresponding to the line “b.” There was a gap at the distal carina in the panel (H) (arrow ).

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Insights into “MV to SB” Stenting The failure of the classical T-stenting technique in assuring SB ostium coverage and the frequent incidence of restenosis at this site (24) led to the re-emergence of other stenting techniques. One of these techniques is the strategy of extending the stent from the MV to the SB to ensure SB ostium coverage with the main frame of the stent. However, recent data indicate that the anatomy of SBs varies from that of the main epicardial vessels in two ways: (i) the SB ostium is more often elliptical than round; and (ii) there is conical tapering of the proximal SB, and the ratio of tapering from proximal to distal is three times of that in the MV (25). Therefore, the SB ostium is much larger than its distal reference vessel. We investigated the 3-D configuration of the “MV to SB” stenting technique in two 3-D bifurcation models: a 90-degree bifurcation angle and a 45-degree bifurcation angle with the proximal MV (Figs. 17 and 18).

Gap Formation In the initial phase of stent balloon inflation, the stent dilated in a dumbbell shape where the stent expanded proximally first, then distally, and finally at the mid-portion (Fig. 16A[b], 17B[b]). When the stent was inflated with maximal pressure, the guidewire position remained at the outer side at both the proximal and distal stent segments but was positioned at the inner side of the SB ostium (Fig. 16A[d], 17B[d]). Since the wire is located in the central core of the balloon, this asymmetric position of the wire suggests nonuniform balloon expansion at the SB ostium. This led to gap (unstented area) at the distal carina in both the 90-degree and 45-degree angle bifurcations and the gap was larger in the 45-degree angle bifurcation (17A[c], 17B[c]).

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Figure 17 Experiment of the SB stenting from the MV. (A) Right-angled bifurcation. (B) Steeply-angulated bifurcation at 45◦ angle between the proximal MV and the SB. (a) Initial position of the guidewire is in the inner side at the middle portion (black triangle) and in the outer side at both ends of the stents (white triangles). (b) In the initial phase of the inflation, the middle portion was dilated finally (arrow ). The stent configuration was changed to the dumbbell shape. (c) There was unstented area at the distal carina even after full expansion of the stents. (d) The guidewire position had not been changed during the stent expansion. Note the biased position of the wire, which was in the central core in the balloon.

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Figure 18 MFCT images of the SB stents deployed from the MV (a: view from the inner side, b: anterior–posterior view, c: view from the outer side). Experiments were performed using Bx Velocity (A) and Driver stents (B). There were restrictions of the stent expansions in both stents (A[a], B[a]; arrows). The outer struts of the Bx Velocity stent were stretched (A[c]; dotted arrow ), whereas the Driver stent had the wide opening between the coils at its outer side (B[b], B[c]; white triangles).

Stent Distortion In this experiment, we used the Bx velocity stent [Fig. 18(A)] and the Driver stent [Fig. 18(B)] in the 45-degree angle bifurcation model. Restricted stent expansion was observed at the bifurcation in both stents (18A[a], 18B[a]; arrows). The stretch of the struts at the outer side and concentration of the struts at the inner side were also observed in both stents. The S-link of the Bx Velocity stent was extremely stretched (18A[c]; dotted arrow) and the distance between the coils of the Driver stent was widened to generate the gap at the outer side (18B[b], 18B[c]; white triangles). These experiments closely simulate the potential problems related to stenting from the LMCA to the LCX artery, namely, stent expansion is less uniform than that in a straight vessel; the restricted stent expansion at the LCX ostium leads to gap formation; and the hinge motion at this point may cause stent fracture (Fig. 19). ARE THE FINDINGS FROM BENCH TESTING APPLICABLE TO CLINICAL PRACTICE? The decision to use provisional stenting or elective double stenting technique should be based on a careful analysis of the patient’s bifurcation anatomy (as discussed in previous chapters). If a decision has been made to use elective double stenting, the choice of which technique to utilize has been largely based on the individual operator experience due to the lack of strong evidence favoring one technique over another. Anyhow, optimal technique is critical to ensure optimal results, particularly in LMCA bifurcation disease where elective double stenting is utilized in 20% to 50% of patients (26–28). Although bench testing cannot take into account all the potential anatomic variations that can be present in a given patient, it is the best method we have to gain better insights into the 3-D behavior of stents in bifurcation lesions.

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Figure 19 These experiments evoke the potential problem with stenting from the LMCA to the LCX. The guidewire remained in the inner side at the LCX ostium and in the outer side at both ends of the stents during the entire inflation (B). The stent expansion is less uniform than that of the straight vessel (comparison between A[b] and B[b]). The restricted stent expansion at the LCX ostium leads to a gap formation (B[b]; dotted arrows) and the hinge motion at this point may cause fracturing of the structure of the stretched struts.

Key findings from bench testing that proved useful for bedside technical decision making are as follows: 1. The effect of bifurcation angle on selection of the appropriate double stenting technique: We learned that the crush and culotte stenting techniques perform favorably (from stent configuration perspective) in Y-shaped bifurcations, whereas T-stenting is more favorable in T-shaped bifurcations. The effect of stent configuration on clinical outcome has been suggested (29), but a convincing proof requires more dedicated clinical studies to answer this specific question. 2. The importance of stent platform in optimizing the technical results: We learned that the maximal achievable strut diameter, conformability at angulations, and the degree of distortion after KBI are all important attributes for results optimization particularly at the SB ostium. 3. The importance of the site of guidewire recrossing into the jailed SB: With most double stenting techniques, guidewire recrossing should be through the distal portion of the SB ostium to provide the most optimal scaffolding of the SB ostium and least deformation of the MV stent. However, with crush stenting, the optimal recrossing site is the middle portion of the SB ostium. Recrossing through the distal portion of the SB ostium would lead to partial crushing of the proximal SB stent. 4. The importance of the pattern of balloon overlap during KBI on final configuration of the proximal MV stent: We learned that an x-shaped balloon overlap in wide-angle bifurcations is associated with the suboptimal stent configuration. Optimal balloon positioning for KBI involves advancing the two balloons distally and then pulling them back to where the proximal markers are in the same position. KBI should be performed with minimal overlap or with the balloons positioned lateral to each other. 5. The importance of the pattern of stent overlap during stent deployment on vessel wall coverage: We learned that when the plaque is primarily localized in the myocardial side of the SB

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ostium, the use of the crush or SKS technique with the SB stent overlapping the MV stent should be avoided because that will lead to a gap at the lesion site. On the other hand, when the plaque is located in the nonmyocardial side of the SB ostium, the use of these techniques with the MV stent overlapping the SB stent should be avoided for the same reasons. The most optimal stent positioning should involve minimal overlapping or lateral positioning. Of course, illustrating the value of these observations does not negate the need for significant improvement on the current bifurcation phantom models with regard to a variety of factors such as: bifurcation angle, 3-D structure, vessel size, tortuosity, vascular elasticity, and atherosclerotic changes. Also, the addition of physiological assessment parameters (coronary flow, wall shear stress, and the durability against the cardiac motion) will be a welcome development in future bench testing. TAKE HOME MESSAGE r Bench testing allows direct and detailed inspection of stent configuration in bifurcation phantom models using high-quality cameras, microscopy, and microfocus X-ray computed tomography (MFCT) with resolution of 0.06 mm. r Although significant insights have been gained through these techniques, one should not lose sight of the numerous limitations of these techniques resulting from the lack of good coronary bifurcation models. r The insights derived from bench testing can be summarized as follows: b Every double stenting technique has its own set of technical advantages and limitations. b Bifurcation angle is an important anatomic element in making a decision as to which double stenting technique to use. b In elective double stenting, excessive overlap should be avoided during simultaneous or consecutive stent deployment. b Guidewire recrossing into the jailed SB should take place through the distal portion of the SB ostium (except for the crush technique where recrossing should take place through the middle portion of the SB ostium). b Proximal balloon overlap should be minimized during KBI.

REFERENCES 1. Al Suwaidi J, Yeh W, Cohen HA, et al. Immediate and one-year outcome in patients with coronary bifurcation lesions in the modern era (NHLBI dynamic registry). Am J Cardiol 2001; 87:1139–1144. 2. Tsuchida K, Colombo A, Lef`evre T, et al. The clinical outcome of percutaneous treatment of bifurcation lesions in multivessel coronary artery disease with the sirolimus-eluting stent: insights from the Arterial Revascularization Therapies Study part II (ARTS II). Eur Heart J 2007; 28:433–442. 3. Steigen TK, Maeng M, Wiseth R, et al.; Nordic PCI Study Group. Randomized study on simple versus complex stenting of coronary artery bifurcation lesions: the Nordic bifurcation study. Circulation 2006; 114:1955–1961. 4. Ferenc M, Gick M, Kienzle RP, et al. Randomized trial on routine vs. provisional T-stenting in the treatment of de novo coronary bifurcation lesions. Eur Heart J 2008; 29:2859–2867. 5. Colombo A, Bramucci E, Sacc`a S, et al. Randomized study of the crush technique versus provisional side-branch stenting in true coronary bifurcations: the CACTUS (Coronary Bifurcations: Application of the Crushing Technique Using Sirolimus-Eluting Stents) Study. Circulation 2009; 119:71–78. 6. Hildick-Smith D. The British bifurcation coronary study: old, new and evolving strategies (BBC ONE). Transcatheter Cardiovascular Therapeutics (TCT) Conference. Lecture 2008. 7. Erglis A, Kumsars I, Niemel¨a M, et al. Randomized comparison of coronary bifurcation stenting with the crush versus the culotte technique using sirolimus eluting stents: The Nordic Stent Technique Study. Circ Cardiovasc Intervent 2009; 2:27–34. 8. Murasato Y, Horiuchi M, Otsuji Y. Three-dimensional modeling of double-stent techniques at the left main coronary artery bifurcation using micro-focus X-ray computed tomography. Catheter Cardiovasc Interv 2007; 70:211–220. 9. Murasato Y, Hikichi Y, Horiuchi M. Stent deformation and gap formation after complex stenting of left main coronary artery bifurcations using micro focus computed tomography. J Interv Cardiol 2009; 22:135–144.

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10. Ormiston JA, Webster MWI, Webber B, et al. The “crush” technique for coronary artery bifurcation stenting: insights from micro-computed tomographic imaging of bench deployment. JACC Cardiovasc Interv 2008; 1:351–357. 11. Hikichi Y, Inoue T, Node K. Benefits and limitations of Cypher sent-based bifurcation approaches: in vitro evaluation using micro-focus CT scan. J Interv Cardiol 2009; 22:128–134. 12. Murasato Y. Impact of three-dimensional characteristics of the left main coronary artery bifurcation on outcome of crush stenting. Catheter Cardiovasc Interv 2007; 69:248–256. 13. Murasato Y, Suzuka H, Suzuki Y. Incomplete stent apposition in a left main bifurcated lesion after kissing stent implantation. J Invasive Cardiol 2006; 18:E279–E284. 14. Ormiston JA, Currie E, Webster MW, et al. Drug-eluting stents for coronary bifurcations: insights into the crush technique. Catheter Cardiovasc Interv 2004; 63:332–336. 15. Ormiston JA, Webster MW, El Jack S, et al. Drug-eluting stents for coronary bifurcations: bench testing of provisional side-branch strategies. Catheter Cardiovasc Interv 2006; 67:49–55. 16. Louvard Y, Lef`evre T, Morice MC. Percutaneous coronary intervention for bifurcation coronary disease. Heart 2004; 90:713–722. 17. Louvard Y, Thomas M, Dzavik V, et al. Classification of coronary artery bifurcation lesions and treatments: time for a consensus! Catheter Cardiovasc Interv 2008; 71:175–183. 18. Nakazawa G, Joner M, Ladich E, et al. Pathologic findings of coronary bifurcation stenting: drugeluting stent vs. bare metal stent. American College of Cardiology & i2 Summit 2007. 19. Hoye A, Iakovou I, Ge L, et al. Long-term outcomes after stenting of bifurcation lesions with the “crush” technique: predictors of an adverse outcome. J Am Coll Cardiol 2006; 47:1949–1958. 20. Costa RA, Mintz GS, Carlier SG, et al. Bifurcation coronary lesions treated with the “crush” technique: an intravascular ultrasound analysis. J Am Coll Cardiol 2005; 46:599–605. 21. Murasato Y, Suzuka H, Kamezaki F. Vascular endoscopic and macroscopic observations after crush stenting of coronary artery bifurcations in pigs. Catheter Cardiovasc Interv 2005; 66:237–243. 22. Galassi AR, Tomasello SD, Capodanno D, et al. Mini-crush versus t-provisional techniques in bifurcation lesions: clinical and angiographic long-term outcome after implantation of drug-eluting stents. JACC Cardiovasc Interv 2009; 2:185–194. 23. Chen SL, Ye F, Zhang JJ, et al. DK crush technique: modified treatment of bifurcation lesions in coronary artery. Chin Med J 2005; 118:1746–1750. 24. Colombo A, Moses JW, Morice MC, et al. Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions. Circulation 2004; 109:1244–1249. 25. Russel ME, Konstantin E, Binyamin G. Main vessel to side branch transition zone in human coronaries; Unique geometric insights missed by QCA. 3rd European Bifurcation Club, 2007. 26. Meliga E, Garcia-Garcia HM, Valgimigli M, et al.; DELFT (Drug Eluting stent for LeFT main) Registry. Longest available clinical outcomes after drug-eluting stent implantation for unprotected left main coronary artery disease: the DELFT (Drug Eluting stent for LeFT main) Registry. J Am Coll Cardiol 2008; 51:2212–2219. 27. Vaquerizo B, Lef`evre T, Darremont O, et al. Unprotected left main stenting in the real world. Two-year outcomes of the French left main Taxus registry. Circulation. 2009. 28. Carri´e D, Eltchaninoff H, Lef`evre T, et al.; FRIEND. Twelve month clinical and angiographic outcome after stenting of unprotected left main coronary artery stenosis with paclitaxel-eluting stents—results of the multicentre FRIEND registry. EuroIntervention 2009; 4:449–456. 29. Collins N, Seidelin PH, Daly P, et al. Long-term outcomes after percutaneous coronary intervention of bifurcation narrowings. Am J Cardiol 2008; 102:404–410.

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Current Status and Future of Dedicated Bifurcation Stent Systems Azeem Latib, Giuseppe M. Sangiorgi, and Antonio Colombo Interventional Cardiology Unit, San Raffaele Scientific Institute, and Interventional Cardiology Unit, EMO-GVM Centro Cuore Columbus, Milan, Italy

IS THERE A NEED FOR DEDICATED BIFURCATION STENT SYSTEMS? Defining the clinical need for dedicated bifurcation stent systems is not a straightforward exercise. If one were to adopt the results of the randomized controlled trials (RCTs) (1–5) that evaluated provisional versus elective double stenting in bifurcation lesions as reflective of real world clinical practice, there would hardly be a compelling reason to develop expensive dedicated bifurcation stent systems! In these trials, provisional stenting appeared simple to use, carried minimal procedural risks, was associated with good long-term outcome, and was inexpensive! Considering all these attributes of a “simple” stenting technique, why would any operator need a dedicated bifurcation stent system? The simple answer to this question is that patients recruited into the RCTs had low-risk coronary bifurcation anatomy where investigators thought that a provisional approach would have high chances of success. Therefore, it would be inappropriate to generalize the results of these trials to patients with complex bifurcation coronary disease (Chaps. 1 and 2). In reality, PCI for coronary bifurcation disease remains technically challenging and is associated with lower procedural success rates and worse clinical outcomes than nonbifurcation lesions. A need does exist for coronary bifurcation stent systems in patients with “complex” coronary bifurcation lesions irrespective of the technique that will be utilized (provisional or elective double stenting) for the following reasons:

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r

Although provisional stenting has been conveyed as a simple and safe procedure, this may not be the case in complex bifurcations where several problems may arise. With this approach the most critical issue is to maintain adequate patency of the SB throughout the procedure. SB patency can be threatened after predilatation, after MB stent placement that may cause plaque or carina shift, and after attempts to rewire the SB. SB rewiring can be difficult in lesions with unfavorable angles and in cases where the SB flow is compromised. Furthermore, the SB ostium is often not fully covered and scaffolded. In fact, acceptance of a suboptimal result in the SB is almost inherent to the provisional strategy (6). Similarly, patients with complex bifurcation lesions who need double stenting (elective or provisional) have to undergo a complex procedure that is more time and resource intensive and end up with stent deformity at the carina irrespective of the technique used.

Therefore, novel devices that can enhance the safety of provisional stenting in complex lesions as well as reduce the complexity of two-stent approaches are certainly desirable. WHAT SHOULD AN IDEAL DEDICATED BIFURCATED STENT SYSTEM ACHIEVE? The ideal dedicated bifurcation stent system should make PCI of complex coronary bifurcation lesions simpler and should improve short- and long-term outcomes. To achieve this task, the device should have a low profile and be highly deliverable even in challenging anatomy. It should allow for an optimal coverage of the bifurcation carina while maintaining a versatile platform for various bifurcation anatomies and procedural scenarios (e.g., provisional vs. double stenting techniques). The device should be actively torqueable when alignment of the SB access is needed to accurately place the device. The dedicated bifurcation device should ensure and facilitate rapid SB access and protection during the procedure (7). The first generation of dedicated bifurcation stent systems were difficult to deploy, as they were stiff and accurate positioning of the stent at the SB ostium was tricky. Many also had larger

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crossing profiles and less flexibility compared with conventional stents, so they were difficult to deliver in tortuous or calcified arteries. Nonetheless, these devices have undergone rapid evolution from design and bench top testing a few years ago to clinical testing in First-In-Man (FIM) studies. One of the most important steps is the shift from bare metal to drug-elution platforms. There are now at least six devices that have CE mark and are commercially available in Europe, whereas in the United States none of these devices are FDA approved and are thus under investigational use only. The development of more drug-eluting platforms and larger studies with control groups demonstrating their clinical applicability, efficacy, and safety are required before they are widely incorporated into daily practice. CATEGORIES OF DEDICATED BIFUCRATION STENTS The currently available (or under investigation) dedicated bifurcation stents can be broadly divided into: 1. Stents that are implanted in both the MB and the SB at the same time; that is, complete bifurcation “Y” stents such as the Medtronic Bifurcation StentTM (Medtronic, Santa Rosa, CA). 2. Stents for provisional SB stenting that facilitate or maintain access to the SB after MB stenting and do not require recrossing of MB stent struts [e.g., PetalTM , former AST stent (Boston Scientific, Natick, MA); Invatec Twin-RailTM (Invatec S.r.l., Brescia, Italy); AntaresTM (Trireme Medical Inc, CA); Y-med SidekickTM (Y-med Inc, San Diego, CA); Nile CroCoTM (Minvasys, Genevilliers, France); Multi-link FrontierTM (Abbott Vascular Devices, Redwood City, CA/Guidant Corporation, Santa Clara, CA)]. These stents allow placement of a second stent in the SB if needed. 3. Stents that usually require another stent implanted in the bifurcation—for example, SideguardTM (Cappella Inc, MA); TrytonTM (Tryton Medical, MA); BiguardTM (Lepu Medical Ltd., Beijing, China); Axxess PlusTM (Devax Inc, Irvine, CA). The TrytonTM , SideguardTM , and BiguardTM are designed to treat the SB first and require recrossing into the SB after MB stenting for final kissing inflation. The AxxessTM is the exception, as it is implanted in the proximal MB at the level of the carina and does not require recrossing into the SB but may require the additional implantation of two further stents to completely treat some types of bifurcation lesions.

TECHNICAL CHALLENGES FACING DEDICATED BIFURCATION STENT SYSTEMS The stent delivery systems (SDS) of these dedicated bifurcation systems have a number of design features in common, which explain both their strengths and weaknesses: (a) Double balloon SDS has to be tracked over two wires, and thus wire wrap (twisting) is a common problem. However, the stent is implanted by simultaneous kissing inflation possibly resulting in shorter procedure times. In addition, these devices still tend to be bulkier than single balloon SDS requiring guide catheters larger than the standard 6F and limiting their use in calcified lesions and tortuous vessels. (b) Devices that track over two wires may be limited by wire wrap, wire bias, and atheroma (Fig. 1) that prevent device advancement and rotation to align with the SB (8). r Wire wrap or twisting is the most frequent problem and is recognized as resistance when advancing the device and is often visible on fluoroscopy. Wire wrap can be avoided by wiring the most difficult branch first, then wiring the second branch with minimal rotation, and avoiding wire wrap on the catheterization table. If wire wrap prevents advancement of the device, then the following can be tried to resolve the problem: pull back one wire up to the tip of the balloon or catheter and rewire with limited rotation; or place the SB wire into the MB, push the device up to the bifurcation, pull back the device slightly, and rewire the SB. r Wire bias results in the SB wire directing the SB component away from the SB and prevents rotational alignment with the SB. It is less of a problem in distal lesions and with shallower SB angles.

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Wrap (twisting)

Wire bias (wire directs stent away from the SB)

Atheroma/calcium prevents rotation and alignment

Figure 1 Delivery challenges for SB access dedicated bifurcation stents, particularly those that are delivered over two wires include wire wrap, wire bias, and atheroma that may prevent device advancement and rotation to align with the SB. Source: Photo courtesy of Dr. John Ormiston.

r

(c)

(d)

(e) (f) (f) (g)

Atheroma and/or calcium prevent rotation and alignment of the device. Adequate predilatation and lesion preparation of both branches is mandatory with all of these devices. Stents with a preformed SB aperture maintain access to the SB during MB stenting but successful implantation is dependent on accurate positioning with very little tolerance for incorrect placement. Also, an optimal view of the bifurcation is crucial for axial and longitudinal alignment and SB positioning. An SDS with a side hole needs to have axial and rotational self-positioning properties, that is, r Axial: SDS has a “stopper” to position the side cell at the SB level, closest to the carina. r Rotational: SDS automatically turns the side hole exactly towards SB. Rotation to align the device with the SB ostium may be passive (NileTM , Frontier/PathfinderTM , TwinRailTM , PetalTM , Medtronic Y-stentTM ) or active and torquable rotation may be possible (AntaresTM and SidekickTM ). The NileTM , FrontierTM , Twin-RailTM , SidekickTM , and StentysTM SDS have struts that only partially cover the ostium, and thus leave the potential for a gap and ostial restenosis. Stents that have struts that can be expanded into SB ostium (PetalTM , AntaresTM ) may be clinically advantageous, as they provide complete coverage of the SB orifice and offer the possibility of delivering drug to the SB ostium. SB specific stents commit the operator to stenting both branches. Unfortunately, most are still BMS but with DES currently under development in the majority.

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DEDICATED BIFURCATION STENT SYSTEMS: TECHNICAL DESCRIPTION AND STAGE OF DEVELOPMENT This section describes each of these devices in detail, including their unique design features and implantation technique, and where possible we have provided a case example. The main technical characteristics have been summarized in Table 1, and the available clinical results regarding their implantation in humans in Table 2. Medtronic Bifurcation Y-StentTM (Medtronic) The Medtronic bifurcated Y-stent is based on the Medtronic Driver stent cobalt alloy design and is essentially 3 Driver/MicroDriver stents fused into a trouser leg bifurcation design (Fig. 2) (9,10). This balloon expandable bifurcated stent is premounted on a dual monorail SDS, with a single inflation lumen, has a crossing profile of 0.062 inches, and an ostial marker band, which facilitates device placement. After adequate predilatation of both branches, the stent is tracked over two wires and advanced to the carina. The stent is deployed by simultaneous inflation of both balloons using a single indeflator, which also provides the final kissing inflation and potentially decreases the number of procedural steps. No recrossing of the SB is required with this device as access to both branches is maintained throughout the procedure. The first generation of this dual-branch stent should accommodate bifurcation angles from 0 to 70 degrees. This device is currently undergoing investigation in a 60-patient multicenter nonrandomized FIM BRANCH (Bare metal bifuRcAtion steNt Clinical trial in Humans) study. The primary endpoint of the study is a composite of cardiac death, target-vessel MI, and clinically driven TVR at 30 days. Preliminary data on the 60 patients enrolled showed acute device success in 83% with some of the failures being due to underrotation of the device (10). If the final results of the BRANCH study appear promising, Medtronic is expected to invest in a DES platform that will utilize the Endeavor Resolute technology, that is, the Biolinx biocompatible polymer and Zotarolimus. Y-med SidekickTM (Y-med Inc) The SidekickTM (Fig. 3) is a low profile 6F guide compatible SDS that integrates a MB fixedwire platform with a rapid exchange steerable SB guidewire designed to preserve SB access during bifurcation stenting. There are three models with different exit ports (proximal, mid, and distal) that are selected depending on the location of the disease in the bifurcation; for example, proximal exit port for a lesion distal to the bifurcation or an ostial lesion. When the device is close to the carina, a guidewire is passed through the SB exit port and MB stent struts into the SB, thus avoiding recrossing into the SB. This steerable SB wire enables torquability for optimal stent orientation axially and longitudinally without wire twist. The fixed MB wire becomes movable poststent deployment to preserve MB access. Various BMS designs and even a DES platform are currently under investigation. The only clinical data available for the SidekickTM is unpublished data from a First-InMan (FIM) study performed in 17 patients with 20 lesions presented at the 2007 Cardiovascular Revascularization Therapies (CRT) conference (11). The device success rate was 80% and an additional stent was required in 40% of cases. During the short follow-up period (68 ± 32 days), there was one major adverse cardiac event (MACE) due to a subacute stent thrombosis. Multilink FrontierTM and PathfinderTM (Abbott Vascular Devices/Guidant Corporation) The Multilink FrontierTM coronary stent system (Fig. 4) is a balloon-expandable 316 L stainless steel stent premounted on a dedicated delivery system with two balloons (monorail for MB and over-the-wire inner lumen for SB) and two guidewire lumens. To assist tracking and avoid wire wrap, the Multilink FrontierTM has an integrated tip design that allows single tip delivery—the MB balloon tip includes a pocket on the distal sleeve for joining the MB and SB balloon tips with a mandrel. The Multilink FrontierTM is advanced into the MB over a conventional wire. The joining mandrel is retracted, releasing the over-the-wire SB tip and a 300-cm exchange wire is inserted into the SB balloon lumen and into the SB. The system is advanced to the carina and simultaneous kissing inflation of the two balloons is performed, using a single indeflator, to expand the stent on the MB and SB.

5F

7F

SideKickTM

FrontierTM

Y-Med

Guidant/Abbott

6F

NileTM

Minvasys

Nile PaxTM

Balloonexpandable

Balloonexpandable

Cobalt chromium Cobalt chromium

Stainless steel

Double balloon, dual rapid exchange system, 2 independent catheters

Double balloon, dual rapid exchange system

±

±

± ±

±

± ±

+

+

+ +

+

+ + Polymer-free paclitaxel

–

–

EverolimusFluoropolymer –

–

–

+

+

–

(Continued )

Tracks over 2 wires; partial coverage of SB ostium; potential SB gap when placing second stent; no DES under development Tracks over 2 wires; partial coverage of SB ostium; potential SB gap when placing second stent that can be overcome by placing Nile Delta SB stent

Partial coverage of SB ostium; potential SB gap when placing second stent Partial coverage of SB ostium; Potential SB gap when placing second stent

Tracks over 2 wires

Comments

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Nile CroCoTM

6F

Invatec Twin-RailTM

Double balloon, single wire tracking, dual lumen tip, MB rapid exchange & SB over-the-wire

Double balloon, dual rapid exchange system Single rapid exchange system

SDS

Ostial SB coverage

SB protection

Drugeluted

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Invatec

Cobalt chromium Stainless steel

Stainless steel

Cobalt chromium

Cobalt alloy

Stent material

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Balloonexpandable

Balloonexpandable

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PathfinderTM

7Fr

Y-stent

GC

Medtronic

Stent type

Summary of the Main Characteristics of Current Dedicated Bifurcation Stents

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7F

6F

6F

5F

6F

7F

PetalTM

AntaresTM

SideguardTM

TrytonTM

Biguard

AxxessTM

Boston Scientific

Trireme Medical Inc

Cappella

Tryton Medical

Lepu Medical Ltd.

Devax

Stainless steel

Stent material

Self-expandable Nitinol

Single balloon, single wire rapid exchange system Single wire rapid exchange system

++

–

N/A

+

Sirolimus

BiolimusA9-PLA polymer

++

N/A

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Stainless steel

+

+

++

SB stent; Stenting of both branches mandatory SB stent; Stenting of both branches mandatory; No DES under development SB stent; MB stenting required to fully treat bifurcation Requires 3 stents for complete coverage of true bifurcation lesion

+

+

N/A

Torqueable and active rotation possible

±

No coverage of SB ostium; potential SB gap when placing second stent; no DES under development Partial coverage of SB ostium; potential SB gap when placing second stent Tracks over 2 wires

Comments

–

–

+

–

–

PaclitaxelTranslute polymer –

Paclitaxel-PESU polymer

–

Ostial SB coverage

SB protection

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Balloonexpandable

Platinum Double balloon, dual Chromium wire rapid exchange system BalloonStainless Single balloon, single expandable steel wire rapid exchange system Self-expandable Nitinol Single balloon, single wire rapid exchange system BalloonCobalt Single balloon, single expandable chromium wire rapid exchange system

Single wire rapid exchange system

Single balloon, dual over-the-wire system

SDS

Drugeluted

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Self-expandable Nitinol

Balloonexpandable

Mechanism of stent expansion

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Abbreviations: GC, guiding catheter size (French); SB; side branch; MB; main branch; SDS, stent delivery system; DES, drug-eluting stent. Source: Adapted from Ref. 7.

7F

StentysTM

Stentys

8F

SLK

viewTM

Advanced Stent Technology

GC

Stent type

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302

139

180

210

180

30 180 180 180

N/A

98.3

93.5

100 80 86 96.7

89.3

N/A

82/68

71/52

0/18 N/A – N/A

36/25

– 14/25 23/33 54/38

12.1

7.7

11.2

5.9e 12.5 10.8 9.9

11.5

– 31 25 33.3

3.3 5.8 17.1 14.3 19.4 13 10.7b 11.8d

9.1

4.3

6.0

5.9e 6.3 3.6 6.6

3.8

– 2.5 1 33.3

3.3 5.8 3.8 0 0 0 2.7 2

9.1

4.3

7.5

2.9e 12.5 6 6.6

3.8

– 21.3 22.5 16.7

0 0 13.3 14.3 17 14 6.7c 9.4

15

– 28.3 25 45.5

N/A N/A 29.9 N/A N/A 14 N/A N/A

0

1.0

2.2

6.9

3.6

4.8

2.9e N/A 0 N/A 3.2 2.5 0 4.3

0

– 1.3 0 N/A

0 5.8 0 0 0 0 N/A N/A

MB (%)

16.1

4.3

9.2

N/A N/A 14.5 0

10

– 37.7 14 54.5

N/A N/A 29.1 N/A N/A N/A N/A N/A

SB (%)

b

Not specified whether MB or SB. Follow-up data available only on 45 patients. c Study reports results for target vessel revascularization only and not TLR. d Follow-up data available only on 85 patients. e Follow-up data available only on 34 patients. Abbreviations: PI, principal investigator; FIM, First-In-Man study; MACE, major adverse cardiac event; MI, myocardial infarction; TLR, target lesion revascularization; ST, stent thrombosis; MB, main branch; SB, side branch; N/A, not available. Source: Adapted from Ref. 7.

a

Axxess-LMTM Hasegawa et al. (36,37)

Verheye et al. (35)

Multicenter Registry (AXXESS PLUS) Multicenter Registry (DIVERGE) Multicenter Registry (AXXENT)

39 20 83 30

180

– 97.6 95.5 92.3

N/A 40a 40/43 17/23 0/29 0/0 28/15 0/13

ST (%)

7in×10in

AxxessTM

TrytonTM

FIM Study (TOP) FIM Study (SG-1) Combined SG-1 & SG-2 FIM-Study

28

– 180 180 120

83 80 91 75 88 97 90.7 96

TLR (%)

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AntaresTM SideguardTM

FIM Study ongoing

100 81/84 40 13

FIM Study ongoing (BIPAX) Multicenter Registry FIM Study (OPEN I) FIM Study

30 68 ± 32 180 210 180 360 210 180

MI (%)

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60 17/20 105 15 41 30 75 93

FIM Study (BRANCH) FIM Study Multicenter Registry FIM Study (DESIRE) Single-center Registry RCT Multicenter Registry Multicenter Registry

Study type

Restenosis

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Minvasys NileTM

PI: I. Meredith (10) Solar et al. (11) Lefevre et al. (12) Lefevre et al. (14) Hoffman et al. (16) Cervinka et al. (17) NileTM Lefevre et al. (18) Nile CroCoTM Del Blanco et al. (19) Nile PaxTM PI: J. Fadajet Ikeno et al. (21) Verheye et al. (23,24) AST PetalTM Ormiston et al. (25) Taxus PetalTM PI: J. Ormiston Grube et al. (26) Di Mario et al. (28) Grube et al. (29) PI: E. Grube Kaplan et al. (31) and Onuma et al. (32) Grube et al. (34)

Study

Number Additional of Follow- Device stent in patients/ up success MB/SB MACE lesions (days) (%) (%) (%)

Summary of the Available Data and Trials of Current Dedicated Bifurcation Stents

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Device

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Figure 2 The Medtronic bifurcation Y-stent is mounted on a dual-wire double balloon SDS and is the only true complete bifurcation stent that has both a MB and SB components.

The safety and performance of the Multilink FrontierTM stent has been evaluated in a 105patient multicenter registry (12). Device success was 91% and procedural success 93%. Reasons for failure to deliver the device were vessel calcification in eight cases and wire wrap in one case. Two patients suffered an in-hospital myocardial infarction secondary to SB occlusion. The late loss for the Multilink FrontierTM was 0.84 ± 0.55 mm and the overall bifurcation restenosis rate (44.8%) was high (MB: 29.9%, SB: 29.1%). At six-month follow-up, the target lesion revascularization (TLR) and MACE rates were 13.3% and 17.1%, respectively. There were no cases of subacute or late stent thrombosis during the follow-up period. The acute device success but high restenosis rates of the Multilink FrontierTM formed the platform for the development of Abbott’s next generation bifurcation DES, called the Abbott PathfinderTM . The PathfinderTM utilizes the same unique SDS of the FrontierTM , but the stent is now chromium

(B)

(A)

Figure 3 The Y-med SidekickTM (upper panel ) is a fixed-wire main branch stent delivery system with different exit ports for the side branch protection wire located either proximally (A), mid (B), or distally. The torqueable shaft actively rotates the stent to allow alignment with the SB (lower panel ).

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219

(A)

(B)

(C)

(D)

Figure 4 The Multilink FrontierTM – PathfinderTM is a dual lumen, double balloon stent delivery system with the two balloons joined by a mandrel (A), thus allowing tracking of the device into the MB over a single wire to prevent wire wrapping (B); when the device is close to the carina, the joining mandrel is retracted releasing the over-the-wire SB balloon, a guidewire is then placed via this balloon into the SB, and the entire system is advanced to the carina (C); the stent is expanded into the MB and SB with simultaneous kissing inflation of the two balloons using a single indeflator (D).

cobalt with the Xience VTM DES platform (i.e., Everolimus on a nonerodable acrylic and fluoro polymer) (13). There are no clinical data currently available for the PathfinderTM . The Invatec Twin-RailTM (Invatec S.r.l.) The Invatec Twin-RailTM (Fig. 5) is a slotted tube, 316 L stainless steel stent premounted on double balloons in its proximal portion, and only on the MB balloon in its distal portion. The stent has a closed cell-type design with variable stent geometry. This 6F-compatible system consists of a single dual lumen catheter splitting into two distal balloons, with a central stopper that prevents further advancement of the SDS when the carina is reached. The stent is deployed by simultaneous kissing inflation with a single indeflator. The Twin-RailTM is similar to the Multilink FrontierTM double-balloon system except that in the latter the SB balloon is a short tapered balloon while in the Twin-Rail there is a full dilatation balloon. The Twin-RailTM double balloon SDS was evaluated in the unpublished DESIRE (DoublE vs. Single balloon stent delivery systems for bifurcation lesions) trial. This trial presented at the Transcatheter Cardiovascular Therapeutics (TCT) 2005 meeting compared the safety and efficacy of the Twin-RailTM double balloon SDS (15 patients) to a single balloon SDS (24 patients) (14). Although angiographic success was high, device success was only 75% with the Twin-RailTM ,

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(A)

(B)

(C)

(D)

Criss-cross

(E)

(F)

Figure 5 The Twin-RailTM (A) is a double balloon, dual lumen rapid exchange system that tracks over two wires. Panel (B) demonstrates an expanded Twin-RailTM stent. Baseline angiography (C and D) shows a true bifurcation lesion of the left circumflex (LCX) and a large obtuse marginal (OM). Both branches of the bifurcation were wired and then predilated. The Twin-Rail was then delivered over two wires through the guiding catheter but wire wrap prevented advancement to the bifurcation (E and F). A third protection buddy wire was placed in the OM before removing the twisted wire and rewiring the OM. Panel (G) confirms the absence of wire wrap. The device was then advanced to the carina and deployed by simultaneous dual balloon inflation (using a single indeflator) while pushing on the system (H). The system is retracted and access to both branches is preserved. Final kissing postdilatation was then performed (I). Panel (J) shows the final angiographic result. Source: Photos courtesy of Dr. Remo Albiero.

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(G)

(I)

221

(H)

(J)

Figure 5 (Continued )

and there was a high rate of guidewire crisscross with both devices. The TLR rate for the TwinRailTM was 14.3% at seven months. In this small pilot study, there was also a trend for higher device success and better safety profile with the Twin-RailTM compared to a single balloon SDS. The second-generation Twin-RailTM was then assessed in a single-center registry in Berlin, Germany, by Hoffman et al. in 41 patients between April and September 2005 (Table 2) (15,16). The Twin-RailTM was also assessed in a single-center randomized trial, which compared this dedicated stent to provisional stenting with a conventional bare-metal stent (Libert´eTM ; Boston Scientific) in 60 patients with de novo bifurcation disease (17). The use of the Twin-RailTM was associated with reduced procedure and fluoroscopy time (34 ± 9 vs. 46 ± 20 min, p = 0.004; and 9 ± 6 vs. 15 ± 9 min; p = 0.003, respectively) and lower contrast volumes (168 ± 86 mL vs. 199 ± 103 mL; p = 0.02). At 12-month follow-up, there were no statistically significant differences regarding TLR (14% vs. 13%) or MACE (13.7% vs. 13.3%; p = 0.9).

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222

Nile CroCoTM (Minvasys) The Nile CroCoTM (Fig. 6) is a double balloon SDS similar to the Multilink FrontierTM and Twin-RailTM but unlike these latter SDS’s that are a single catheter with single inflation port, the Nile CroCoTM has two independent yet joined catheters that require independent manipulation and pressure monitoring. The two parallel rapid exchange catheters are premounted with a chromium cobalt stent crimped on the MB balloon and the tip of the SB balloon. The MB balloon has three markers with the central marker indicating the position of the SB aperture. After the stent is deployed into the MB, the SB balloon is advanced into the SB and a final kissing inflation is performed with the deploying balloon and the tapered SB balloon to limit proximal overexpansion. The feasibility, safety, and efficacy of bifurcation stenting using the NileTM and Nile CroCoTM stent have been evaluated in two multicenter registries. Lefevre and colleagues evaluated the first-generation 316 L stainless steel NileTM stent in the multicenter (10 European centers) Nile Registry (18). Preliminary results of the first 75 patients showed a procedural success rate of 94.7% and a MACE rate of 10.7% in the 45 patients in whom follow-up was available at seven months. The second-generation Nile CroCoTM stent, made from a 605-L chromium cobalt alloy, was then assessed in the three-center Spanish-French Nile CroCo Registry (19). The promising acute and mid-term results of these first- and second-generation dedicated stents prompted the development of a drug-eluting version based on the chromium cobalt Nile CroCoTM platform. The Nile PaxTM is a polymer-free dedicated bifurcation stent coated only the abluminal surface with 2.5 ␮g/mm2 of paclitaxel. As a result of the polymer-free delivery of paclitaxel, all the drug is released within 45 days with complete reversion to a cobalt chromium stent (20). Minvasys have also developed a specific SB stent (Nile DeltaTM —BMS and Delta PaxTM —DES) designed to fit with their MB stent. The DeltaTM is a short 8 mm stent mounted on a conical shaped balloon, similar to the SB balloon of the Nile CroCoTM . Using the MB balloon with the

(A)

(B)

(C)

Figure 6 The Nile CroCoTM (A) is a double balloon, dual lumen rapid exchange systems that has two independent catheters (arrows) that can be manipulated and inflated separately to deploy the Nile CroCoTM SB access-MB stent (B). The Nile DeltaTM is an SB stent specifically designed to be implanted after the Nile CroCoTM and cover the SB ostium without leaving a gap (C). Baseline angiography of a 74-year-old male with a true bifurcation lesion of the posterior descending (PDA) and posterolateral (PL) arteries (D and E), who underwent bifurcation stenting with the Nile CroCoTM and Nile DeltaTM . Both branches of the bifurcation were wired and predilated. The Nile CroCoTM (3.5 mm MB/2.5 mm SB × 18 mm) was positioned at the bifurcation site with the middle marker of the MB (PDA) balloon aligned with the center of the SB (PL) ostium (F). The Nile CroCoTM was then deployed on the PDA (G) and the SB balloon was then advanced into the PL and positioned by aligning the proximal marker of the SB balloon with the middle marker of the MB balloon (H). Final kissing inflation with two indeflators was then performed (I). The Nile DeltaTM was then positioned and implanted with the proximal marker at the ostium of the PL (J), and final kissing inflation was repeated (K). The final angiographic result was excellent (L). (Continued on pages 223 and 224)

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(D)

(E)

(F)

(G)

(H)

(I)

Figure 6 (Continued )

Char Count=

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224

(J)

(K)

(L)

Figure 6 (Continued )

Nile DeltaTM or Delta PaxTM should avoid any potential gap when placing the additional stent in the SB. The safety and efficacy of the Nile PaxTM and Delta PaxTM is currently being assessed in a prospective, nonrandomized, multicenter BiPAX (Bifurcation Paclitaxel-Eluting Stent) trial. The BiPAX trial will enroll 100 de novo bifurcation lesions with the primary endpoint of binary angiographic restenosis of the MB and SB at nine months after the procedure. AST SLK-ViewTM (Advanced Stent Technologies, Pleasanton, CA) The SLK-ViewTM (Fig. 7) is a 316-L stainless steel flexible slotted tube stent with a side aperture located between the proximal and distal sections to facilitate access to the SB after deployment of the stent in the MB. The delivery system has a dual over-the-wire design with a proximal dual lumen shaft that separates into two catheters (a balloon and a side-sheath) at its distal segment. The stent is premounted on the distal segment of delivery system with the side-sheath

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Figure 7 The SLK-viewTM is a MB stent with a preformed aperture (A), without stent struts that scaffold the ostium, that has to be positioned accurately at the ostium; the stent is mounted on a dual over-the-wire stent delivery system that separates into a side sheath and balloon distally; the side sheath runs under the stent and positions the side hole at the ostium (B).

running under the proximal segment of the stent and exiting through the side hole. There are a total of three radiopaque markers on the balloon located at the center, proximal, and distal edges. The SLK-ViewTM system is placed over two wires simultaneously and advanced to the bifurcation until the center marker band is aligned to the branch vessel and the side sheath marker separates from the center marker. The SLK-ViewTM stent is then deployed on the MB leaving the preformed side hole positioned at the ostium. Unlike the PetalTM or AntaresTM stents, there are no stent struts protruding into and scaffolding the ostium. The SLK-ViewTM stent has been assessed in a multicenter nonrandomized study of 81 patients with 84 de novo bifurcation lesions (21). The study proved the feasibility of this stent with high procedural success rates (97.6%) while maintaining SB access in all treated lesions. However, the SLK-viewTM bare-metal stent was associated with a high restenosis (MB: 28.3%, SB: 37.7%) and TLR rate (21%) at six-month follow-up. However, this stent has been removed from the market and is not under investigation anymore since the company has been acquired by Boston Scientific, which slightly modified the stent creating the PetalTM stent system. StentysTM (Stentys S.A.S., Clichy, France) The StentysTM bifurcated bare-metal or drug-eluting stent (22–24) (Fig. 8) is the first of the next-generation bifurcation stents. The current drug-eluting version of StentysTM is coated on R the abluminal side with Paclitaxel (0.8 ␮g/mm2 of stent) incorporated in ProTeqtor
[a durable polymer matrix of polysulfone (PESU) and soluble polyvinylpyrrolidone (PVP) as the excipient] that permits controlled drug elution (22,24). The StentysTM is a provisional, self-expanding nitinol stent made of Z-shaped struts linked by small interconnections that can be disconnected in prespecified points every 1.5 mm all around the circumference and the length of the stent except for the most proximal and distal 2.5 mm segments (22,24). The unique feature of this stent is the ability to disconnect these stent struts with an angioplasty balloon. Thus an opening for the SB can be created anywhere in the stent after it is implanted in the vessel while the disconnected struts scaffold the SB ostium. In comparison to the implantation of some of the other bifurcation stents such as the PetalTM and the AntaresTM , the procedural success is not dependant on accurate positioning of the stent, and there is significant placement tolerance with the StentysTM . However, it would appear from the design that the disconnected struts only partially scaffold the ostium. The implantation procedure is performed in three steps: (i) StentysTM is implanted in the MB with an approximate positioning, like a standard stent; (ii) optimal location for the SB opening is chosen by inserting a balloon through the stent mesh; (iii) the balloon inflation disconnects the mesh and creates the opening. Maximum ostial coverage is best achieved with bifurcating angulations of 30 degrees to 70 degrees by opening of the cell closest to the carina. It is hoped that the self-expanding property of the stent will allow in-situ modeling of the stent

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Anatomical reconstruction of the bifurcation shape Positioning tolerance (disconnectable struts on full length)

Excellent ostium coverage with SB stent Excellent SB access

Distal MB stented

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(B) Figure 8 (A) The design features of the StentysTM and inset demonstrating electron microscopy of a cleanly disconnected strut. (B) The deployment sequence of the StentysTM : StentysTM is implanted in the MB over a single wire, like a standard stent, without specific positioning related to the SB; if access or treatment of the SB is required, a guidewire and a balloon are advanced through the stent mesh; a low-pressure balloon inflation disconnects the connectors and creates the opening—the self-expanding property allows in situ modeling of the stent. Baseline angiography (C, right anterior oblique cranial view; D, left anterior oblique cranial view) of the left coronary artery showing a moderate-to-severe stenosis in the mid-left anterior descending artery just after the origin of the first diagonal branch (in the white circles). Positioning of the StentysTM coronary bifurcation system at the level of the lesion in the mid-left anterior descending artery, over the ostium of the first diagonal branch (E). (F) The single wire 5F delivery system: the stent is delivered in the MB by means of a covering sheath that is retracted at the moment of deployment; the delivery system has a marker on the end of the sheath and on the stent stopper to facilitate easy deployment. Passage of a second coronary wire into the diagonal branch through the Stentys struts in the cell closest to the carina (G). StentBoost Subtract imaging of the Stentys system after deployment in the left anterior descending artery, before balloon angioplasty of the ostium of the side branch, showing good conformability of the stent to the anatomy of the bifurcation (H). StentBoost Subtract after balloon angioplasty of the ostium of the diagonal branch, showing a gap in the angiographic ‘‘profile’’ of the Stentys system (white arrow ), which indicates an effective disconnection of the struts at the level of the bifurcation (I). Final angiographic results (J and K), with “step-up” and “step-down” phenomena at the proximal and distal edge of the stent, respectively, because of the self-expanding property of the stent itself. Source: Adapted from Ref. 38. (Continued on pages 227 and 228 )

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to fit the patient’s unique arterial anatomy and that the superelastic properties of nitinol as well as the fact that the disconnections are created in prespecified points would prevent permanent strut deformation. However, it is not known if the StentysTM is more prone to stent fracture due to its disconnectable strut design. A multicenter FIM study has been completed to evaluate the safety and efficacy of the Stentys in de novo bifurcation lesions. The StentysTM OPEN I study (Stentys Coronary Bifurcation Stent System fOr the PErcutaNeous treatment of de novo lesions in native bifurcated coronary arteries), enrolled a total of 40 patients between September 2007 and September 2008 in nine European clinical sites. The primary endpoint was the procedural success that was defined as technical and angiographic success in the absence of a major adverse cardiac event (MACE) at hospital discharge (23,24). Procedural success was achieved in 39 of 40 cases and the only case of device failure was due to inability to track the stent in one patient with an extremely tortuous

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vessel. In total 6 (15%) paclitaxel-eluting and 33 (85%) BMS StentysTM stents were successfully implanted, and simple disconnection of the stent mesh overlying the SB ostium was achieved in 37 (94.9%) of 39 cases. In two cases, disconnection was not attempted, as the StentysTM had been malpositioned to distal to the bifurcation, and thus the nondisconnectable proximal end of the stent was covering the SB ostium (23,24). The MACE at 30 days was 5% as a result of one non–Q-wave MI following the procedure and one ischemia-driven revascularization six days after the procedure. At six months, the MACE had increased 25% (10 of 40), and this was predominantly accounted for by a further eight clinically driven TLR. The late lumen loss in the 30 bare-metal StentysTM was 0.85 ± 0.63 mm, which is similar to a conventional BMS. An IVUS substudy confirmed excellent stent apposition at six months, with an increase in mean minimum stent cross-sectional area from 7.93 ± 1.33 mm2 to 11.55 ± 2.12 mm2 at six months, suggesting a type of “chronic gain” in keeping with the self-expanding properties of this nitinol stent (23,24). PetalTM (Boston Scientific) SB occlusion caused by vessel deformation and plaque shift remains a concern with current approaches to bifurcation PCI. The PetalTM stent (Fig. 9), with a side aperture located mid-stent and deployable struts (a “sleeve”), may be an attractive solution to prevent SB occlusion after MB stenting. A guidewire is placed in the MB and another in the SB. The dual side-exchange (double balloon) delivery system has a main lumen that guides the catheter to the primary lesion over the MB guidewire. The secondary lumen (side sheath) facilitates proper albeit passive rotational alignment of the aperture to the SB ostium as it tracks over the SB guidewire. The SDS has four marker bands (two smaller markers on SB balloon and two larger markers on MB balloon) to ensure correct alignment. In addition to a conventional cylindrical-shaped balloon, there is a secondary elliptical balloon adjacent to the main balloon and connected to the same inflation lumen so that a single inflation device is needed. The PetalTM stent is crimped over both balloons such that the elliptical balloon is under the side aperture and petal elements. Upon inflation, the main balloon deploys the stent into the MB, whereas the elliptical balloon deploys the petal elements into the SB ostium. The purpose of the “petal” aperture is to retain access to the SB during and after deployment and to scaffold the SB ostium with outwardly deploying strut elements that extend up to 2 mm into the branch during deployment. This unique feature has potential for delivery of antiproliferative drug to the most common site of bifurcation restenosis. The projecting petal elements facilitate the placement of a stent in the SB without gaps in scaffolding or drug application, and so may reduce restenosis. The first-generation of this stent, called AST PetalTM , developed by Advanced Stent Technologies was a 316 L stainless steel slotted tube design. In a FIM study, the AST PetalTM was successfully implanted in 12 of 13 patients with the one failure due to inability to advance the device after vessel dissection from predilatation (25). Of note, in another four patients, device delivery was temporarily impeded by wire wrap (three cases) and incomplete device rotation (one case). In nine patients, an additional stent was required in the bifurcation and the TLR rate was 15% (2 of 13) at six months. The PetalTM stent was acquired by Boston Scientific in 2004 and modified into the Taxus PetalTM stent. This second-generation PetalTM stent is a platinum chromium alloy stent, which is coated with Paclitaxel on a Translute polymer [poly(styrene-bisobutylene-b-styrene)], which is the same polymer currently utilized by the TaxusTM stent. The platinum chromium is superior to its stainless steel predecessor in that the new alloy allows even thinner stent struts with increased flexibility and radiopacity. The Taxus PetalTM stent is currently under investigation in a FIM trial to assess this device’s acute performance and safety (death, myocardial infarction, target vessel revascularization) at 30 days and 6 months, as well as continued annual follow-up for 5 years. The main inclusion criteria are de novo bifurcation lesions with a bifurcation angle between 30 degrees and 90 degrees and disease length limited to 20 mm MB and 14 mm SB. The Taxus PetalTM was successfully delivered in 25 of the 28 patients in the FIM trial, but the implant success per device was 73.5% (25 of 34), as it was not possible to deliver nine stents (26). Main reasons for device failure were wire wrap and wire bias, which made it challenging to achieve rotational alignment with the PetalTM stent in some cases. The primary endpoint (30-day death, MI, TVR) occurred

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Side branch lumen (SBL) SBL Marker bands

Side (petal) balloon Petal

Main branch marker bands

Main branch stent

Main branch balloon

(A)

(B) Figure 9 (A) A graphical representation of the Taxus PetalTM delivery catheter and balloon. Markers on the catheter are used to aid stent placement. The PetalTM is mounted on a dual lumen, double balloon stent delivery system with an elliptical SB balloon that deploys the SB struts when both balloons are inflated by a single indeflator. (B) The PetalTM stent; the stent name alludes to the “petal” elements that are expanded into the SB ostium (inset demonstrates petal elements before deployment). Baseline angiography (C) showing a bifurcation lesion at the crux of the right coronary artery. (D) Advancement of the Taxus Petal stent over the MB guidewire, with the SB wire protruding from the tip of the SB component to avoid wire wrap (twisting). Placement of the SB wire without “wrap,” and the PetalTM was then advanced to the bifurcation with separation of the markers (E). (F) Separation of the proximal and distal catheter markers confirm rotational alignment of the stent within the bifurcation (separation denoted by arrows). Balloon inflation to 12 atm deploying the stent (arrow denotes elliptical petal balloon inflation), followed by kissing balloon postdilatation with noncompliant balloons (G). Final angiography (H) confirms an excellent result that was maintained at six months (I). Final angiographic assessment of the Taxus Petal stent (J) (arrow indicates the level of IVUS image), IVUS image from the MB at the level of the bifurcation, demonstrating the SB ostium within the petal elements (K). Six-month follow-up angiography (L) demonstrates a minor neointimal response within the proximal end of the stent and widely patent SB ostium. (M) Six-month IVUS assessment from the MB at the level of the bifurcation. Source: Adapted from Ref. 39. (Continued on pages 231 and 232 )

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in one patient (3.7%) due to a non–Q-wave MI. At six months after implantation, two further events had occurred: one target vessel and one target lesion revascularization but no additional MI or deaths. Angiographic outcomes at six months demonstrated a restenosis rate of 5% in the proximal MB, 10% in distal MB, and 10% in the SB. The late lumen loss was 0.42 ± 0.58 mm in the MB and 0.18 ± 0.40 mm in the SB. Antares SASTM (Trireme Medical Inc) The Antares Stent SystemTM with automatic SB support deployment (Fig. 10) consists of a single balloon expandable 316 L stainless steel stent. It has an ostial preservation (OP) structure in the center of the stent provided with radiopaque tantalum markers for positioning and orienting at the bifurcation site. The original AntaresTM system had four radiopaque tantalum markers, but the current generation system has only two markers. Stent deployment is achieved using a single rapid-exchange balloon catheter and a preloaded SB stabilizing wire encased in a peel away lumen to minimize wire crossing. As the stent approaches the targeted bifurcation, the catheter is torqued to align the stent central opening with the SB ostium. The SB wire is advanced into the ostium, thus assisting with accurate placement and facilitating access after MB stent deployment. Upon expansion of the main stent body, the OP structure is automatically deployed with elements protruding approximately 2 mm into the SB to scaffold the ostium. The AntaresTM is very similar to the PetalTM stent but has the advantage of tracking over a single wire, and unlike the PetalTM that uses a balloon to expand the SB elements, they expand automatically with this stent. Furthermore, in comparison to the Petal that relies on passive rotation (selfpositioning) for placement, the AntaresTM SDS is torqueable, thus allowing active alignment and rotation of the device that facilitates accurate positioning of the OP structure, particularly in challenging lesions. There is also a DES version currently under development.

Ostial preservation structure Side branch wire lumen

• Provides excellent ostial coverage • Asymmetric “wings” allow treatment of all SB angles • Radiopaque markers facilitate precise SB stent placement if needed

•Allows placement of wire to maintain SB access at all times • Peel away prevents wire wrap

Torqueable shaft

Single balloon

• Allows proper alignment of OPS to SB

Low profile tip

• Allows low crossing profile

Small crossing profile (A)

Figure 10 A graphical representation of the design features of the AntaresTM delivery system and stent (A). A Medina 1.1.0 bifurcation lesion at the crux of the right coronary artery that underwent provisional stenting with the AntaresTM (B). Both branches of the bifurcation were wired; the posterior descending artery was predilated (C), which resulted in plaque shift toward the ostium of the posterolateral branch (D), and thus the SB was also dilated (E). (F) The AntaresTM is advanced on the MB wire to the bifurcation, and using the hub, the delivery system is actively rotated until correctly positioned. Accurate positioning is confirmed when both the MB and SB wires are visible parallel to each other and only a single ostial (central) radiopaque marker is visible. The SB access wire is then advanced into the SB. Inflation of the balloon at nominal pressure to deploy the MB stent also results in automatic expansion of the SB elements. (G), followed by postdilatation of the AntaresTM stent (H). Final angiographic result (I). Source: Photos courtesy of Dr. Riccardo Costa. (Continued on pages 234 and 235 )

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(G)

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Figure 10 (Continued )

The 30-day results of the first 11 patients/lesions treated with the AntaresTM stent were presented at the 2008 SCAI-ACCi2 summit (27). Device success in this small cohort was 100% and there were no adverse events in-hospital or at 30-day follow-up. Subsequently, results from the TOP (TMI Ostial Preservation) multicenter single arm FIM study have become available (28). The TOP Study will enroll up to 100 patients with de novo bifurcation lesions to undergo AntaresTM implantation on the MB, and if SB stenting is required the protocol mandates Taxus LiberteTM implantation. Preliminary results on the first 39 patients showed an excellent device success with 100% deliverability of the AntaresTM . At 30 days, the MACE rate was 5.9% (2/34) due to a periprocedural non–Q-wave MI in one patient and another patient suffering from a subacute stent thrombosis, which resulted in a MI and TLR (28). SideguardTM (Cappella Inc) The Cappella SideguardTM coronary side branch stent (Fig. 11) is a self-expanding trumpetshaped nitinol stent with a three-segment design (cup, transition zone, anchor) that is deployed

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using a special balloon release sheath system. It is currently a bare-metal stent, but there may be a next-generation drug-eluting version with a biodegradable polymer. The Sideguard’sTM trumpet-shaped design helps the stent conform to the anatomy of the ostium allowing for complete stent-to-wall apposition, optimizing scaffolding and potential drug delivery. Its short length, self-expandable nitinol system, and low-profile (3.1 Fr) delivery system allow greater navigability even in very tortuous anatomy. Radiopaque markers located at the distal and proximal ends of the SideguardTM delivery system facilitate positioning of the stent at the SB ostium. SideguardTM will be indicated for bifurcation angles from 45 degrees to 135 degrees before wiring. The stent is deployed using a nominal pressure balloon, which helps tear a protective sheath that keeps the SideguardTM in place until deployment. Once released, the SideguardTM self-expands into place. The delivery system and the guidewire are then removed from the SB. A conventional stent is then placed in the MB, the SB is reaccessed with a guidewire and the procedure is completed with a standard final kissing inflation. The six-month results of the first 20 patients enrolled in the SideguardTM FIM trial (SG-1) were presented at TCT 2007. Technical success was achieved in 16 (80%) patients. At six months, the TLR rate was 12.5% (2/16) and there were no cases of stent thrombosis (29)

Spacer

Cup

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Cup • Flared end with three markers, conforms to ostium of side branch • Excellent ostial coverage and protection • Lowest radial force (easy to cross)

Anchor

Gimbal • Cylindrical portion with higher radial force (550 mm Hg) to dilate ostial lesions • Provides expanding force to open the side branch • Transition zone between cup and anchor

Anchor • Cylindrical portion with lower radial force (225 mm Hg); two markers • “Spacer” improves anchoring, keeping stent from migrating • Enhances crossing flexibility

A Figure 11 (A) The design characteristics of the self-expanding SideguardTM coronary side branch stent. The delivery system has the lowest profile of any of the self-expanding stents and unlike other self-expanding stents has a unique balloon actuated splittable sheath that allows for accurate placement (B). Baseline angiography showing a true bifurcation lesion of the left anterior descending artery and large second diagonal branch (C and D). Both branches of the bifurcation were wired and predilated (E and F). The SideguardTM stent was then advanced into the SB (G) and a semicompliant balloon into the MB to the level of the bifurcation. The SideguardTM is then positioned (H) with the proximal ostial marker on the ostium border line (OBL). The SideguardTM catheter is then inflated to split the sheath and deploy the stent (I). After waiting a few seconds for the SideguardTM to fully expand, the delivery system and guidewire are removed from the SB (J). The MB balloon is then inflated to ensure that are no struts into the MB lumen (K). (L) The angiographic result after SideguardTM implantation. A drug-eluting stent is then implanted on the MB across the ostium of the SB (M); the SB is recrossed with a guidewire; and final kissing inflation is performed (N). (O) The final result graphically and angiographically. (Continued on pages 237–240 )

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(O) Figure 11 (Continued )

A second multicenter nonrandomized trial has been completed with the next-generation SideguardTM device (SG-2). The new SideguardTM device has undergone minor changes to the SDS and a major change to the stent design. The stent has a mixed open and closed cell design with a new mid-distal open cell that acts as a built-in anchoring system preventing the SideguardTM from migrating following deployment. The technical success overall in the 93 patients enrolled in the SideguardTM FIM trials is 86%; however with design changes mentioned above, the device success increased to 97%. Interim results from the combined SG-1 and SG-2 FIM trials showed a MACE rate of 4.8% at 30 days and 10.8% at six months. An interesting IVUS substudy performed on 11 patients suggests further stent expansion at the carina preserving ostial lumen dimensions (30). The SB stent area (at the carina) increased from 3.9 ± 1.2 to 4.6 ± 1.1 mm2 (p = 0.04), resulting in no change in lumen area (3.9 ± 1.3 vs. 4.0 ± 1.3 mm2 , p = 0.77) despite an intimal hyperplasia area of 0.6 ± 0.7 mm2 . This data suggest that chronic stent expansion due to the self-expanding nitinol properties of the SideguardTM may be sufficient to compensate for the late loss that occurs with this bare-metal stent. TrytonTM (Tryton Medical) The TrytonTM SB stent (Fig. 12) is a slotted tube, cobalt chromium balloon expandable stent designed to be implanted in the SB of a bifurcation. The stent consists of three zones: a distal SB zone (that treats the disease in the SB); a transition zone (positioned at the SB ostium); and an MB zone. The central transition zone has a specific geometry, which contains three panels, each of which can be deformed in an independent fashion. The proximal MB zone is composed of three fronds that are connected proximally to the transitional panel and terminate in a circumferential band and the distal zone has the design characteristics of a standard slotted tube workhorse stent. Treatment of a bifurcation with the TrytonTM stent generally commits the operator to implant two stents in the bifurcation, and the technique is identical in approach

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when performing the Culotte technique. The TrytonTM stent is deployed across the SB ostium first. The initial FIM experience has shown that predilatation of the TrytonTM is essential to allow a MB stent to be advanced through the TrytonTM struts (31,32). A standard MB stent is then tracked through the proximal MB zone of the TrytonTM into the distal MB and deployed. The MB stent struts then have to be recrossed in order to perform a final kissing inflation.

(A)

(B) Figure 12 (A) The design features and characteristics of the TrytonTM SB stent. Baseline angiography demonstrating a complex true bifurcation lesion of the left anterior descending artery and large first diagonal branch (B). Both branches of the bifurcation were wired and predilated (C and D). (E) The result after predilatation. The TrytonTM stent was then positioned on the diagonal branch (F) utilizing the two central markers, which should straddle the ostium of the SB (preferably 3/4 of this central transition zone should be in the SB and 1/4 in the MB). The TrytonTM was then deployed at nominal pressure and the SDS removed. The left anterior descending artery was then easily rewired and the proximal MB zone of the TrytonTM postdilated. A drug-eluting stent was then advanced into the MB and deployed across the bifurcation (G and H). The SB was then rewired and final kissing inflation performed. (I) The final angiographic result. IVUS performed at the carina confirmed good stent expansion and ostial coverage (J). Source: Photos courtesy of Dr. Antonio Bartorelli. (Continued on pages 242–244)

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(J) Figure 12 (Continued )

The Tryton I FIM trial assessed the safety and performance of the TrytonTM SB stent in conjunction with a standard DES in 30 patients (31,32). The TrytonTM was successfully implanted in all but 1 patient (96.7% angiographic success), and at 6-month follow-up, 3 (9.9%) patients had experienced a MACE. There were two re-interventions at the bifurcation (TLR = 6.6%), only one of which was in the TrytonTM stent whereas the other was in the MB stent. Angiographic follow-up was performed in 78% of patients and demonstrated a late loss of 0.17 ± 0.35 mm and in-segment restenosis in one patient (4.3%) in the MB proximal to the stent. There are also four other ongoing trials with TrytonTM : (a) Tryton II or IUVANT (Intravascular Ultrasound Evaluation of Tryton Stent) study, a single-center IVUS study in 30 patients; (b) Tryton III, a single-center OCT study in 15 patients; (c) Tryton IV, a multicenter left main coronary artery feasibility study in 30 patients; and (d) E-Tryton 150 Registry, a multicenter registry to assess the TrytonTM in real-world patients. BiguardTM (Lepu Medical Ltd.) The BiguardTM is also a SB specific stent (Fig. 13) designed specifically for coverage of ostial SB disease while allowing the exchange of devices in the MB (33). The Biguard is a stainless-steel sirolimus-eluting stent that has only three stent struts in the proximal segment that are 3 mm in length and separated by 120 degrees. Thus the space between these three struts is large enough to allow the advancement of guidewires, balloons, or stents. The stent has three markers: two at the proximal and distal points, and another one at the intersection site providing SB positioning. The stent is placed from the MB to SB with the middle marker positioned at the carina. The BiguardTM was thus designed to treat isolated ostial SB lesions (Medina 0.0.1) and to facilitate the culotte technique when stenting of both branches is required, similar to the TrytonTM . Axxess PlusTM (Devax Inc) The Axxess PlusTM stent (Fig. 14) was the first of these dedicated bifurcation stents designed to elute an antirestenotic drug. It delivers Biolimus-A9, a sirolimus derivative, via a bio-erodable polylactic acid (PLA) polymer carrier. The AxxessTM is a self-expanding, nickel-titanium (Nitinol) alloy, conically shaped stent that is placed at the level of the carina. It has a rapidexchange delivery system with hydrophilic coating with controlled deployment upon withdrawal of a cover sheath using the actuator. However, the AxxessTM stent may be limited by the

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Figure 13 Lateral view of the Biguard stent demonstrating that there are only three strut strings (3 mm in length) separated by every 120 degrees at its proximal segment. The middle marker (arrow ) is aligned with the ostium of the SB during positioning of the stent. Source: Adapted from Ref. 33.

fact that it needs to be precisely nested at the carina to be effective and in majority cases will need another stent to fully treat the bifurcation. Grube et al. have published the results of the prospective multicenter single-arm Axxess Plus trial that enrolled 139 patients (34). The AxxessTM stent was successfully implanted in the MB in 93.5% of cases with 80% of the patients receiving an additional stent to the MB or SB and 42% of patients requiring three stents to completely treat the bifurcation. Six of the 9 device failures were due to improper alignment when the stent was placed distal or proximal to the intended location. At six-month follow-up, the in-stent late loss was 0.09 ± 0.56 mm, in-stent restenosis within the Axxess stent was 4.8% and the overall TLR rate was 7.5%. The AxxessTM

AXXESS PLUS CONCEPT

Axxess

stent is implanted first.

A successful implant will span the ostia of both branching vessels, indicated by the presence of one marker in each branch vessel. Stents for the branch vessels are selected to match the length and diameter of the disease. The Axxess distal markers provide a reference point to guide the placement of distal stents.

(A) Figure 14 Panel (A) shows a picture of an expanded AxxessTM stent and demonstrates the Axxess concept of bifurcation stenting where three stents will be required to fully treat a severely diseased true bifurcation. (B and C) A significant true bifurcation lesion (Medina type 1.1.1) involving the proximal left anterior descending artery and a large first diagonal branch. Final angiographic result, in the left anterior oblique caudal (D) and in the right anterior oblique cranial (E) views, after deployment of the AxxessTM stent in the proximal part of the bifurcation and two Cypher sirolimus-eluting stents (Cordis Corp, Johnson & Johnson, Warren, NJ), with the V-stenting technique, in the two branches of the bifurcation. The three distal markers of the AxxessTM stent are clearly deep in the two branches of the bifurcation. “StentBoost Subtract” enhanced sequence view of the stented bifurcation in the right anterior oblique cranial views (F). Source: Adapted from Ref. 40. (Continued on page 246 )

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(B)

(C)

(D)

(E)

(F) Figure 14 (Continued )

stent and Axxess technique of bifurcation stenting then underwent evaluation in the large multicenter single-arm DIVERGE (Drug-Eluting Stent Intervention for Treating Side Branches Effectively) Study that enrolled 302 patients with de novo coronary bifurcations (35). The AxxessTM stent was deployed at the level of the carina followed by additional sirolimus-eluting stents in the distal MB and/or SB. The primary endpoint was the nine-month rate of MACE,

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a composite of death, MI, and TLR. Primary device success was obtained in 297 (98.3%) of 302 patients and placement of the AxxessTM was scored as optimal by the angiographic core laboratory in 93% of cases. In keeping with the Axxess concept, 88% of patients required an additional stent to the AxxessTM : 67% in both branches, 17.7% in the distal MB, and 4% only in the SB. The cumulative nine-month MACE rate was 7.7%, including 0.7% death, 4.3% MI, and 4.3% TLR. Subacute and late stent thrombosis occurred in 0.7% and 0.3% of patients. In-bifurcation restenosis occurred in 9 (6.4%) of the 140 patients who underwent angiographic follow-up. These low rates of restenosis are certainly promising for this new bifurcation-specific technology. DevaxTM have also developed a larger version of this self-expanding conical stent, the Axxess-LMTM stent that was designed to cover the left main coronary artery and ostium of the bifurcation. In the multicenter AXXENT (AXXESS Stent in Left Main Coronary Artery Bifurcation Lesions) Trial, the safety and efficacy of the Axxess-LMTM stent in the left main coronary artery was evaluated in 33 patients using a three stent technique of implanting the Axxess-LMTM in the distal left main and two Cypher stents in the left anterior descending and circumflex arteries (36,37). At six-month follow-up, there was minimal late loss (0.01 ± 0.34 mm) and no restenosis in the AxxessTM stent, whereas the restenosis rate was 6.9% for the left anterior descending artery and 16.1% for the circumflex artery. The overall TLR rate was 9.1% and there were no cases of stent thrombosis in this small pilot study. An IVUS study on 26 patients of the AXXENT trial demonstrated that AxxessTM stent in the LMCA showed enlargement during the six-month follow-up, with a 12.4% increase in stent volume at follow-up compared with postprocedure (p = 0.04) (36). Thus, once again confirming that chronic passive expansion occurs with these self-expanding stents. The AxxessTM also resulted in significant neointimal suppression with a percent neointimal volume obstruction of 3.0 ± 4.1%. It would also appear that relatively inadequate stent expansion and greater neointimal formation may have contributed to the luminal narrowing and higher restenosis rates at the left circumflex ostium. REGULATORY CHALLENGES FACING DEDICATED BIFURCATION STENT SYSTEMS A number of these devices are CE marked and commercially available in Europe, including at the time of writing this chapter: AxxessTM , Twin-RailTM , Nile CroCoTM , SideguardTM , TrytonTM , StentysTM , and AntaresTM . However, none of these devices are FDA approved for use in the United States. The FDA requirement for approval of any of these devices will most likely be an adequately powered noninferiority trial compared to provisional SB stenting with superiority of the dedicated device for procedural data. As for the dedicated stents that mandate stenting of both branches, a superiority trial for angiographic outcomes will be essential. CONCLUSION Dedicated bifurcation stent systems are an exciting technology, as they are an attempt to find specific technological solutions to a specific subset of coronary lesions. These devices have undergone a rapid evolution from the pioneering dedicated stents that were bulky and impractical. The newer devices are rapidly changing with second- and third-generation devices entering the market and more clinical data becoming available. The new devices have a lower profile but adequate lesion preparation remains vital to ensure their implantation success. There are still a number of devices that require two wires to be delivered, and wire wrap and bias remain important reasons for failure. Also there are some devices that have a poor placement tolerance, or where accurate placement is vital to the success of the device. Many devices rely on passive rotation for their accurate placement questioning their utility in highly complex lesions. Drugeluting versions have been an essential advancement for the future of many of these devices whose first-generation bare-metal versions were hampered by high degrees of restenosis. Given the innate variability of bifurcation anatomy, no single device will be utilizable in all lesions, and a “family” of dedicated bifurcation stents may be required to optimally treat highly variable bifurcation lesions. There is clearly a learning curve with all of these devices, and the interventionalist will have to gain experience by performing a number of implants that are proctored before optimal results and device success are achieved. However, these innovative devices also carry many possible advantages including “decomplexifying” bifurcation PCI by facilitating both the provisional and double-stenting approaches. The promise of dedicated bifurcation devices is procedures that are less complex, with shorter procedural

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times, less contrast usage, a lower risk of SB closure, and possibly improved angiographic and clinical outcomes. However, before dedicated stents become approved, they will have to show significant advantages over current techniques either with regard to procedural variables or clinical outcomes-–this will require adequately powered randomized controlled trials. ACKNOWLEDGMENTS The authors would like to acknowledge the following persons for their invaluable assistance in providing up-to-date clinical information, images, and/or clinical cases of these new dedicated bifurcation stents: Dr. P. Agostoni (The Netherlands), Dr. J. Ormiston (New Zealand), Dr. R. Costa, and Dr. A. Abizaid (Brazil), Dr. R. Albiero (Italy), Dr. A. Bartorelli (Italy), M. Secerov (Minvasys Inc), G. Ong (Trireme Medical Inc), O. Delporte (Tryton Inc), M. Paguin and M. Gilmore (Cappella Inc), E. Ravanelli (Invatec), and P. Geudens (Stentys). REFERENCES 1. Colombo A, Bramucci E, Sacca S, et al. Randomized study of the crush technique versus provisional side-branch stenting in true coronary bifurcations: the CACTUS (Coronary Bifurcations: Application of the Crushing Technique Using Sirolimus-Eluting Stents) Study. Circulation 2009; 119:71–78. 2. Colombo A, Moses JW, Morice MC, et al. Randomized study to evaluate sirolimus-eluting stents implanted at coronary bifurcation lesions. Circulation 2004; 109:1244–1249. 3. Ferenc M, Gick M, Kienzle RP, et al. Randomized trial on routine vs. provisional T-stenting in the treatment of de novo coronary bifurcation lesions. Eur Heart J 2008; 29:2859–2867. 4. Pan M, de Lezo JS, Medina A, et al. Rapamycin-eluting stents for the treatment of bifurcated coronary lesions: a randomized comparison of a simple versus complex strategy. Am Heart J 2004; 148:857–864. 5. Steigen TK, Maeng M, Wiseth R, et al. Randomized study on simple versus complex stenting of coronary artery bifurcation lesions: the Nordic bifurcation study. Circulation 2006; 114:1955–1961. 6. Latib A, Colombo A. Bifurcation disease: what do we know, what should we do? JACC Cardiovasc Interv 2008; 1:218–226. 7. Latib A, Colombo A, Sangiorgi GM. Bifurcation stenting: current strategies and new devices. Heart 2009; 95:495–504. 8. Ormiston JA. Advanced 3D Bench Imaging to Evaluate Treatment Approaches for Bifurcation Lesions: Focus on Dedicated Bifurcation Stents. Presented at Transcatheter Cardiovascular Therapeutics (TCT); Washington, DC; October 2008. http://www.tctmd.com/show.aspx?id = 71156. Accessed August 28, 2009. 9. Leon M. Perspectives on dedicated bifurcation stent designs: needs assessment, classification of subcategories, and lessons learned from 3D bench imaging. Paper presented at: Third Annual Left Main and Bifurcation Summit; June 5, 2009; New York. http://www.tctmd.com/show.aspx?id = 78864. Accessed August 27, 2009. 10. Meredith I. The Medtronic Y-Stent: design specifications and clinical trial results. Paper presented at: Transcatheter Cardiovascular Therapeutics (TCT); September 21, 2009; San Francisco. http://www.tctmd.com/txshow.aspx?tid = 134&id = 83214&trid = 2. Accessed October 2, 2009. 11. Solar RJ. The Y Med sideKicKTM Stent Delivery System for the treatment of coronary bifurcation and ostial lesions. Paper presented at: Cardiovascular Revascularization Therapies (CRT); March 8, 2007; Washington, DC. http://www.crtonline.org/flash.aspx?PAGE ID = 4328. Accessed December 3, 2007. 12. Lefevre T, Ormiston J, Guagliumi G, et al. The Frontier stent registry: safety and feasibility of a novel dedicated stent for the treatment of bifurcation coronary artery lesions. J Am Coll Cardiol 2005; 46:592–598. 13. Rizik DG. Abbott Pathfinder Stent: Transition to an everolimus-eluting platform and clinical plans. Paper presented at: Transcatheter Cardiovascular Therapeutics (TCT); October 13, 2008; Washington, DC. Available at: http://www.tctmd.com/show.aspx?id = 71156. Accessed August 28, 2009. 14. Lefevre T; on behalf of the Desire Investigators. Invatec Twin Rail Bifurcation Stent. Paper presented at: Transcatheter Cardiovascular Therapeutics (TCT); 2005; Washington, DC. http://www.tctmd.com/ Show.aspx?id = 68990. Accessed July 22, 2008. 15. Albiero R. Invatec Twin-Rail Stent: Design Features and Clinical Updates. Paper presented at: Transcatheter Cardiovascular Therapeutics (TCT); October 13, 2008; Washington, DC. http://www.tctmd .com/show.aspx?id = 71160. Accessed August 28, 2009. 16. Hoffman S. Der Twin Rail Stent in der Behandlung der Bifurkationsstenose: Ein neuer Ausweg aus der Misere? Paper presented at: 72nd Annual Meeting of the German Cardiac Society in Mannheim; April 20–22, 2006. Clin Res Cardiol 2006; 95:(suppl 5).

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17. Cervinka P, Bystron M, Spacek R, et al. Treatment of bifurcation lesions using dedicated bifurcation stents versus classic bare-metal stents. Randomized, controlled trial with 12-month angiographic follow up. J Invasive Cardiol 2008; 20:516–520. 18. Lefevre T, Pavlides G; on behalf of the Nile Registry investigators. Main Results of the Nile Registry. http://www.bifurc.net/files/medtool/webmedtool/icpstool01/stud0112/html/Nile/frame.htm. Accessed December 2, 2007. R 19. Blanco BGD, Brenot P, Royer T, et al. Clinical and Procedural Evaluation of the Nile Croco
Dedicated Stent for Bifurcation—six-month clinical follow-up results of the nile croco registry. Interv Cardiol 2008; 3:46–50. http://www.touchcardiology.com/files/article pdfs/dorado.pdf. Accessed September 4, 2009. 20. Van Geuns R. The Minvasys Nile Paclitaxel-Eluting Sidebranch Access Stent: Results from the BiPAX Study. Paper presented at: Third Annual Left Main and Bifurcation Summit; June 5, 2009; New York. http://www.tctmd.com/show.aspx?id = 78876. Accessed August 27, 2009. 21. Ikeno F, Kim YH, Luna J, et al. Acute and long-term outcomes of the novel side access (SLK-View) stent for bifurcation coronary lesions: a multicenter nonrandomized feasibility study. Catheter Cardiovasc Interv 2006; 67:198–206. 22. Laborde JC, Borenstein N, Behr L, et al. Stentys coronary bifurcation stent. Eurointervention 2007; 3:162–165. 23. Verheye S. First-In-Man study of the Stentys Coronary Bifurcation Stent fOr the Percutaneous treatmEnt of de-novo lesions in Native bifurcated coronary arteries: OPEN I Trial. Paper presented at: Third Annual Left Main and Bifurcation Summit; June 5, 2009; New York. http://www.tctmd.com/ show.aspx?id = 78876. Accessed August 27, 2009. 24. Verheye S, Grube E, Ramcharitar S, et al. First-in-man (FIM) study of the Stentys bifurcation stent— 30 days results. EuroIntervention 2009; 4:566–571. 25. Ormiston JA, Webster M, El-Jack S, et al. The AST petal dedicated bifurcation stent: first-in-human experience. Catheter Cardiovasc Interv 2007; 70:335–340. 26. Grube E. The BSC TAXUS Petal Sidebranch Access Stent: Results from the First Human Use Study. Paper presented at: the Third Annual Left Main and Bifurcation Summit; June 5, 2009; New York. http://www.tctmd.com/show.aspx?id = 78872. Accessed August 27, 2009. 27. Costa RA, Abizaid A, Abizaid A, et al. Preliminary Results of the Novel TMI (TriReme Medical Inc.) Antares Side Branch Adaptive System (Antares SASTM Stent) for the Treatment of De Novo Coronary Bifurcation Lesions—SCAI-ACCi2 Interventional E-Abstract 2900–123. J Am Coll Cardiol 2008; 51:B51. 28. Di Mario C. The Trireme Sidebranch Access Study: Results from the TOP FIM Study. Paper presented at: Third Annual Left Main and Bifurcation Summit; June 5, 2009; New York. http://www.tctmd.com/ show.aspx?id = 78870. Accessed August 27, 2009. 29. Grube E, Wijns W, Schofer J, et al. FIM Results of Cappella SideguardTM for Treatment of Coronary Bifurcations. Paper presented at: Transcatheter Cardiovascular Therapeutics (TCT); October 21, 2007; Washington, DC. R 30. Grube E. The Cappella Sideguard
Coronary Sidebranch Stent. Paper presented at: Third Annual Left Main and Bifurcation Summit; June 5, 2009; New York. http://www.tctmd.com/show.aspx?id = 78866. Accessed August 27, 2009. 31. Kaplan AV, Ramcharitar S, Louvard Y, et al. Tryton I, first-in-man (FIM) study: acute and 30 day outcome. A preliminary report. Eurointervention 2007; 3:54–59. ¨ 32. Onuma Y, Mulle R, Ramcharitar S, et al. Tryton I, first-in-man (FIM) study: six month clinical outcome and angiographic outcome, analysis with new quantitative coronary angiography dedicated for bifurcation lesions. Eurointervention 2008; 3:546–552. 33. Chen SL, Lv SZ, Kwan TW. Novel side branch ostial stent. J Interv Cardiol 2009; 22:145–149. 34. Grube E, Buellesfeld L, Neumann FJ, et al. Six-month clinical and angiographic results of a dedicated drug-eluting stent for the treatment of coronary bifurcation narrowings. Am J Cardiol 2007; 99:1691– 1697. 35. Verheye S, Agostoni P, Dubois CL, et al. 9-month clinical, angiographic, and intravascular ultrasound results of a prospective evaluation of the Axxess self-expanding biolimus A9-eluting stent in coronary bifurcation lesions: the DIVERGE (Drug-Eluting Stent Intervention for Treating Side Branches Effectively) study. J Am Coll Cardiol 2009; 53:1031–1039. 36. Hasegawa T, Ako J, Koo BK, et al. Analysis of left main coronary artery bifurcation lesions treated with biolimus-eluting DEVAX AXXESS plus nitinol self-expanding stent: intravascular ultrasound results of the AXXENT trial. Catheter Cardiovasc Interv 2009; 73:34–41. 37. Verheye S. The Devax Biolimus-Eluting AXXESS Plus Stents: Design Variations and Clinical Results from AXXESS PLUS, DIVERGE and AXXENT Clinical Trials. Paper presented at: Transcatheter Cardiovascular Therapeutics (TCT); October 2008; Washington, DC. http://www.tctmd.com/show.aspx?id = 71178. Accessed August 28, 2009.

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38. Agostoni P, Verheye S. Novel self-expanding stent system for enhanced provisional bifurcation stenting: Examination by StentBoost and intravascular ultrasound. Catheter Cardiovasc Interv 2009; 73:481– 487. 39. Johnson TW, Kay IP, Ormiston JA. A novel paclitaxel-eluting dedicated bifurcation stent: a case report from the first human use Taxus Petal trial. Catheter Cardiovasc Interv 2009; 73:637–640. 40. Agostoni P, Verheye S. Bifurcation stenting with a dedicated biolimus-eluting stent: X-ray visual enhancement of the final angiographic result with “stentboost subtract.” Catheter Cardiovasc Interv 2007; 70:233–236.

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3-D model of classical crush stenting, 199 of crush stenting, 199 of LCX, 201 of left main coronary bifurcation, 194 6-Fr guiding catheter, 139, 163, 168, 170–171, 181 7-Fr guiding catheter, 139, 163, 167 8-Fr guiding catheter, 105, 156–157, 163, 181 Abbott PathfinderTM , 218–219 Abbott Vascular Devices, 110, 181, 214 Achievable optimal result (AOR), 188–189 American College of Cardiology/American Heart Association (ACC/AHA/SCAI) guidelines, 117, 118, 149 AMIGO (Atherectomy before Multi-Link Improves Lumen Gain and Clinical Outcomes) trial, 183–184 Angiographic Versus IVUS Optimization (AVIO), 188 Antares SASTM , 233–235 Antiplatelet therapy, 145 Antithrombotic therapy, 180–181 Aspirin, 145, 180 AST PetalTM , 229 AST SLK-ViewTM , 224–225 Atherosclerotic plaque, 52, 56, 57, 59 AXXENT trial, 247 Axxess PlusTM , 212, 244–247 Balloon jailing, 180 Bare metal stents (BMS), 134, 140, 119, 193 Bench testing of coronary bifurcation stenting techniques clinical practice, 207–209 importance of, 193 methods, 193–195 observations gained from, 195–208 Bifurcation angle, 26–28, 167, 196, 208 BiguardTM , 212, 244 BiPAX trial, 224 Cardiac motion, on coronary artery bifurcation lesions, 19 Carina shift, 22 CASS (Coronary Artery Surgery Study), 117 Charge Coupled Device (CCD) camera, 195 Classical T-stenting technique, 87–88

Clopidogrel, 145, 180–181 Coronary artery bifurcation interventions, 1 evidence-base, review of informed decision, making, 3–7, 8, 9 provisional stenting (PS) vs. elective double stenting (EDS), 2–3 retrospective studies, 2 RCTs, generalizability of, 7, 9 Coronary artery bifurcation lesions, 14 cardiac motion on, 19 classification of, 19 SB compromise, frequency and severity of, 22–28 definition, 14–16 ex vivo characterization of, 16–18 imaging intravascular ultrasound (IVUS), 38–39, 40, 41, 42, 43 multislice computed tomography (MSCT), 44 quantitative coronary angiography (QCA), 29–38, 39 virtual histology (VH) and optical coherence tomography (OCT), 40–41, 43, 44 intersection between anatomy and physiology, 18–19, 20 left main coronary artery bifurcation, 44–45 Coronary artery bypass graft (CABG) surgery, 116, 117, 118, 121, 125, 126, 130, 131 vs. DES, 120–121 durability of, 126 vs. medical therapy, evidence for, 117 vs. PCI, 118, 121–122, 123, 124, 128 Coronary bifurcation stenting techniques, bench testing of, 193 clinical practice, 207–209 importance of, 193 methods, 193–195 observations gained from, 195 crush stenting, 197–201 culotte stenting, 202, 203 double stenting techniques, 196–197 modified T-stenting, 201–202 “MV to SB” stenting technique, 206–207, 208 provisional stenting technique, 195–196 simultaneous kissing stenting (SKS), 202–204 T-stenting and protrusion (TAP), 204–205 V-stenting technique, 204 Cross-sectional area (CSA), 188

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Crush stent technique, 91–98, 163, 188, 197–201 7- or 8-Fr guiding catheter, 163 double kiss step crush technique, 97–98 minicrush stent technique, 91–94 step crush techniques, 94–97, 163–164, 167 Culotte technique, 98–99, 109, 167, 202, 203 6-Fr guiding catheter, 168, 170–171 specific issues, 169–170 Cutting balloon, 58, 183, 184–185 Cypher stent, 168 Debulking coronary atherectomy (DCA), 140 Debulking, role of, 140, 182–185 Dedicated bifurcation stent systems, 211 categories, 212 characteristics, 211–212 description and development, 214, 215–217 Antares SASTM , 233–235 AST SLK-ViewTM , 224–225 Axxess PlusTM , 244–247 BiguardTM , 244 Invatec Twin-RailTM , 219–221 medtronic bifurcation Y-stentTM , 214, 218 Multilink FrontierTM , 214, 218–219 Nile CroCoTM , 222–224 PathfinderTM , 214, 218–219 PetalTM , 229–233 SideguardTM , 235–240 StentysTM , 225–229 TrytonTM , 240–244 Y-med SidekickTM , 214, 218 need for, 211 regulatory challenges, 247 technical challenges, 212–213 Delirium, 125 Delta PaxTM , 222, 224 DESIRE trial, 219 DevaxTM , 247 “Digital caliper” tool, 26 Directional atherectomy, 58, 183–185 DIVERGE (Drug-Eluting Stent Intervention for Treating Side Branches Effectively) Study, 246 Double balloon SDS, 212, 222 Double kiss step crush technique, 97–98 Double stenting techniques, 196–197 Drug-eluting stents (DES), 59, 83, 106, 119, 120, 134, 140, 193 vs. BMS, 119–120 vs. CABG, 120–121 Elective double stenting (EDS) for left main coronary artery (LMCA) bifurcation lesions, 149, 150, 155 angle of branch, 152–154 antithrombotic therapy, 180–181 branch size, 152 concomitant distal disease in the side branch, 154–155 crush technique, 163–167

culotte technique, 167–170 distribution of disease, 150–152 final kissing inflation (FKI), 175, 177–179 guide selection, 181 hemodynamic support, 181 lesion preparation, 182–185, 186–187 modified T-techniques, 175 patient preparation, 180–181 patient selection for, 150–155 side branch (LCX) lesion, 154, 155 side branch (SB), access to, 179–180 stent choice, 185 stent deployment optimization, 185, 188–189 T-techniques, 170–175 technical planning, 181–189 V-stent and simultaneous kissing stent (SKS) techniques, 156–163 for non–left main coronary artery bifurcation lesions, 83, 85 bifurcation lesion anatomy, 83–85 classical T-stenting technique, 87–88 crush stent technique, 91–98 culotte stent technique, 98–99 guide catheter selection, 105 jailed wire technique, 109 lesion preparation, 105–106, 107, 108 MB stent struts, 109–110 modified T-stent technique, 88–90 optimal EDS technique, 113–114 patient preparation, 103, 105 patient selection, 83 stent deployment optimization, 110–113 stent implantation, 106, 109 T And Protrusion (TAP), 90–91 V-stent and kissing stent techniques, 100–103, 104, 105 wire introduction, 105 vs. provisional stenting (PS), 2–3 Elective stenting (ES) vs. provisional stenting (PS), 9 Evidence-based medicine, 3 Ex vivo characterization, of coronary artery bifurcation lesions, 16–18 FAME, 67, 68, 71 FFR-guided provisional stenting, 69–70 Final kissing balloon inflation (FKI), 56, 59, 60–61, 110, 140–143, 176, 177–179 Finet laws, 20 First-In-Man (FIM) studies, 212, 214, 228, 229 Fractional flow reserve (FFR), 67–68, 73, 74, 75, 143–144 FrontierTM , 213 Gage-X metrology software, 16 Glycoprotein IIb/IIIa inhibitor, 145, 181 Impella 2.5 system, 181 Internal mammary artery (IMA) graft, 118 Intra-aortic balloon pump (IABP), 139, 181

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Intravascular ultrasound (IVUS), 19, 20, 38–39, 40, 41, 42, 43, 53, 68, 109, 111–113, 137, 142–143, 185, 188–189 Invatec Twin-RailTM , 219–221 Inverted culotte techniques, 61–62 ISAR-LEFT MAIN, 185 Jailed wire technique, 59, 109, 144 Jailed SBs, 69, 70 Kissing balloon inflation (KBI), 56, 193, 196 Kissing stent techniques, 100–103, 105 Left anterior descending artery (LAD), 71, 72, 73, 74 Left circumflex artery (LCX), 73, 134, 135, 140, 142, 144, 149, 150, 151, 152 Left main coronary artery (LMCA) bifurcation lesions, 44–45, 149 elective double stenting for patient preparation, 180–181 patient selection for, 150–155 technical planning, 181–189 techniques, 155–180 provisional stenting for, 134 anatomic considerations, 134–138 antiplatelet therapy, 145 patient preparation, 139–140 technique execution, 140–144 tips and tricks in, 144–145 Left ventricular ejection fraction (LVEF), 121 Main branch stent, 59 Major adverse cardiac and cerebrovascular events (MACCE), 121, 124 Major adverse cardiac event (MACE), 28, 228, 229 Major adverse events (MAE), 121 MB balloon, 222, 224 Medina classification, 4, 5, 20, 21, 25, 48, 51 of bifurcation lesions, 84 Medtronic bifurcation Y-stentTM , 214, 218 Microfocus X-ray computed tomography (MFCT), 198 3-D model, 199, 201 after culottes tenting, 203 vs. IVUS, 193, 194 of SB stents, 207 after simultaneous kissing stenting, 203, 204 of T-stenting and protrusion (TAP), 204 after V-stenting, 204 Minicrush stent technique, 91–94 Modified balloon crush techniques, 163. See also Step crush techniques Modified T-stent technique, 88–90, 175, 201–202 Multilink FrontierTM , 214, 218–219 Multislice computed tomography (MSCT), 44 Murray’s law, 18, 19, 49 “MV to SB” stenting technique, 206–207, 208 NileTM , 213 Nile CroCoTM , 222–224 Nile DeltaTM , 222, 224 Nile PaxTM , 224

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Non–left main coronary artery bifurcation lesions elective double stenting (EDS) for, 83 bifurcation lesion anatomy, 83–85 optimal EDS technique, 113–114 patient selection, 83 technique description, 85, 103, 104, 105 technique execution, 103, 105–113 provisional stenting technique for, 48 anatomical characteristics of, 48–53, 54 side branch stenting strategy, 53–64 Nonthreatened SB morphologies, 10 Nordic bifurcation study, 61, 67, 71 Nordic Stent Technique Study, 113, 169 One-step kissing postdilation, 167 Optical coherence tomography (OCT), 40–41, 43, 44 Ostial SB lesion, treating, 68 FFR-guided provisional stenting, 69–70 limitations, 70–71 Paclitaxel-eluting stent (PES), 140, 185 PathfinderTM , 214, 218–219 Percutaneous coronary intervention (PCI), 22, 134, 149 vs. CABG, 121–122, 123, 124, 128 for ULMCAD, 118 PERFECT (PrE Rapamycin-eluting stent FlExi-CuT), 184 PetalTM , 229–233 Plaque shift, 22 Point of bifurcation (POB), 26 Polymer matrix of polysulfone (PESU), 225 Polyvinyl acetate (PVA) tubes, 193–194 Polyvinylpyrrolidone (PVP), 228 R ProTeqtor
, 225 Provisional stenting (PS) technique, 53 in coronary bifurcation lesions, 67 case examples, 71–81 FFR-guided provisional stenting, 69–71 fractional flow reserve (FFR), 67–68 ostial SB lesion, treating, 68–71 SB ostial lesions, 68 vs. elective double stenting (EDS), 2–3 guidewire recrossing into SB, 195 kissing balloon inflation (KBI), 196 for left main coronary artery bifurcation lesions, 134 antiplatelet therapy, 145 concomitant disease, in the distal circumflex artery, 137, 138 distal LMCA bifurcation, 137, 138 guide selection, 140 lesion preparation, 140, 141 main branch stenting, 140 patient preparation, 139–140 plaque distribution and side branch lesion severity, 134 SB (LCX artery), size of, 134–137 SB management, 140–142 stent deployment optimization, 142–144 tips and tricks in, 144–145

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Provisional stenting (PS) technique (Continued) for non–left main coronary bifurcation lesions, 48 anatomical characteristics of, 48–54 angle between the branches, 48 final kissing inflation (FKI), 60–61 lesion length, 48–49, 52 main branch, stenting, 59 observed/expected diameter, 49, 52 plaque distribution, 52–53, 54 predilation, 56–58 SB rewiring, 60 side branch stenting strategy, 53, 61–64 wiring both branches, 55 Provisional T-stenting, 142 Proximal Angle A, 152, 154 Proximal cross vs. distal cross, 58, 60 Pseudo-bifurcations, 60 Pseudostenosis, 154

T-stenting and protrusion (TAP), 61, 90–91, 204–205, 175 T-stenting technique, 175 classical T-stenting technique, 87–88 modified T-stent technique, 88–90 T And Protrusion (TAP), 90–91 T-techniques, 61, 170–175 Target lesion revascularization (TLR), 221 Target vessel failure (TVF), 121 Taxus PetalTM , 229, 233 Threatened SB morphologies, 9, 10 TOP (TMI Ostial Preservation), 235 Transcatheter Cardiovascular Therapeutics (TCT), 219 True bifurcations lesions, 20, 54, 60, 83, 84, 245 TrytonTM , 212, 240–244 Twin-Pass catheter, 159 Twin-RailTM , 213 Two-step kissing inflation, 167

Quantitative coronary angiography (QCA), 19, 26, 29–38, 39

ULTIMA (Unprotected Left Main Trunk Intervention Multicenter Assessment), 118 Unequivocal evidence, 116 Unprotected left main coronary artery disease (ULMCAD), 116 CABG surgery vs. medical therapy, evidence for, 117 vs. PCI, 118 clinical practice guidelines and clinical judgment, 116–117 evidence beyond current guidelines, 118 BMS vs. DES, 119–120 DES vs. CABG, 120–121 PCI vs. CABG, 121–122, 123, 124, 128 good-risk surgical patients with, 126–131 revascularization of patients, 122 neglected surgical endpoints, 125–126

Randomized controlled trials (RCTs), 48, 83, 116, 117, 211 generalizability of, 7, 9 Retrospective studies, 2 Reverse crush technique, 142 Rotational atherectomy, 58, 182, 183 SB lesion severity and length, 25–26 SB occlusion (SBO), 7, 8, 9 SB ostial lesions, 68 SB size and myocardial territory, 22, 24–25 Side branch rewiring, 60 SideguardTM , 212, 235–240 SidekickTM , 213 Simple T technique, 61 Simultaneous kissing stent (SKS) techniques, 156–163, 196, 197, 202–204 Sirolimus-eluting stent (SES), 140, 185 Sleeve technique, 98 Smartscope MVP100, 16 “Standard of care,” 116, 125, 130 Stent delivery systems (SDS), 212, 229 StentysTM , 213, 225–229 Step crush techniques, 94–97, 163–164, 167 SYNTAX score, 121, 122, 124

V-stent techniques, 100–103, 104, 105, 156–163, 204 Virtual histology (VH), 40–41, 43, 44 Wall Shear Stress (WSS), 52 Wire bias, 212 Wire twisting, 212 Wire wrap, 212 Y-med SidekickTM , 214, 218 Zeta stent, 173

About the book There is much discussion in the field of interventional cardiovascular therapy as to what is the best approach to treating coronary bifurcation lesions. Many advocate for provisional stenting, stenting of the main vessel with subsequent stenting of the side branch as needed, while some advocate for elective double stenting of both branches. This book is the first of its kind to take a unique approach to this issue by considering the management of bifurcation lesions in the context of the individual patient’s bifurcation anatomy. A highly-illustrated, evidence-based and practical guide, this text offers a patient-centered outlook on the technical decision making in the treatment of coronary bifurcation lesions.

Moussa Colombo

Tips and Tricks in Interventional Therapy of Coronary Bifurcation Lesions

Key features include: • An overview of the gap between evidence-based medicine and patient-centered decision making in the field of interventional treatment of coronary bifurcations

• Practical tips and tricks that will help to optimize results and manage complications • Concluding chapters that consider the role of in vitro bifurcation modeling and the state of dedicated bifurcation stent systems

About the editors ISSAM D. MOUSSA, M.D., is Associate Professor of Medicine at the Weill Medical College of Cornell University and is the Director of Endovascular Services at the New York Presbyterian Hospital-Weill Cornell Medical Center’s Division of Cardiology. He received his medical degree from the Damascus University School of Medicine, Damascus, Syria. Dr. Moussa is a highly experienced specialist in complex cardiovascular interventions and has published extensively in the field with a special focus on treatment of coronary bifurcations. He is a fellow of multiple medical organizations including the Society for Cardiovascular Angiography and Interventions, the American College of Cardiology and the American Heart Association. He sits on the editorial board of several peer reviewed medical journals and he is a section editor of the journal of Catheterization and Cardiovascular Interventions. ANTONIO COLOMBO, M.D., is a Visiting Professor of Medicine at Columbia University Hospital in New York. He is Director of the Cardiac Catheterization Laboratory, Columbus Hospital Milan, Italy and the Cardiac Catheterization Lab and Vascular Interventions, San Raffaele Scientific Institution, Milan, Italy. Since receiving his M.D. from the University of Milan School of Medicine, Dr. Colombo has gone on to become a foremost expert in the field of Interventional Cardiology. He pioneered the concept of adequate stent deployment during coronary interventions, and he defined the role of intravascular ultrasound in this setting. He also played a pivotal role in development of the field of coronary bifurcation interventions. An active member of many international medical societies, Dr. Colombo is a fellow of the American College of Cardiology and the European Society of Cardiology. He sits on the editorial board of multiple major journals including Circulation and the Journal of American College of Cardiology.

Tips and Tricks in Interventional Therapy of

• Guidance on tailoring technical approaches to patients with left main and non-left main bifurcation lesions

Coronary Bifurcation Lesions

• An overview of the fundamentals of coronary bifurcation anatomy and its importance in making treatment decisions

Tips and Tricks in Interventional Therapy of

Coronary Bifurcation Lesions

Edited by Telephone House, 69-77 Paul Street, London EC2A 4LQ, UK 52 Vanderbilt Avenue, New York, NY 10017, USA

www.informahealthcare.com

Issam D. Moussa Antonio Colombo