Statins in General Practice: Pocketbook

Statins in General Practice

Statins in General Practice Second Edition

Allan Gaw, MD, PhD Director, Clinical Trials Unit Glasgow Royal Infirmary Glasgow G4 OSF UK

© 2001, 2003 Martin Dunitz, an imprint of the Taylor & Francis Group First published in the United Kingdom in 2001 by Martin Dunitz, an imprint of the Taylor & Francis Group, 11 New Fetter Lane, London EC4P 4EE Tel.: +44 (0) 20 7583 9855 Fax.: +44 (0) 20 7842 2298 E-mail: [email protected] Website: http://www.dunitz.co.uk This edition published in the Taylor & Francis e-Library, 2005. “To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to www.eBookstore.tandf.co.uk.” Second edition 2003 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. A CIP record for this book is available from the British Library. ISBN 0-203-42793-9 Master e-book ISBN

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Contents

Preface

vi

1.

Why do we use statins?

1

2.

How do we assess dyslipidaemia?

12

3.

What are the statins and how do they work?

16

4.

What evidence do we have that statins work?

32

5.

Who should receive statin therapy?

42

6.

What about statin use in the elderly?

47

7.

What does the future hold?

53

Glossary of terms

60

Further reading

68

Index

71

Allan Gaw, MD, PhD Dr Gaw is currently the Director of the Clinical Trials Unit at Glasgow Royal Infirmary and is responsible for the conduct of major clinical trials in the lipid and hypertension fields. He has been researching the pharmacology and clinical effectiveness of statins for more than a decade, and has lectured widely to general practitioners and practice nurses on the use of statins in primary care. He is the author of over 100 original papers and reviews and has written several books, including Clinical Biochemistry: An Illustrated Colour Text (Harcourt Brace, 2003), Coronary Risk Factors: Measurement and Management (Martin Dunitz, 1999). He is also co-editor of Coronary Heart Disease Prevention: A Handbook for the Healthcare Team (Churchill Livingstone, 1997), Statins: The HMG CoA Reductase Inhibitors in Perspective (Martin Dunitz, 2000), and the Lipid and Atherosclerosis Annuals 2001 and 2003 (Martin Dunitz 2001, 2003). Disclaimer Although every attempt has been made to provide accurate and up-to-date prescribing information, this is an evolving field and the prescriber should always check the most recent data sheet for the latest details of each drug mentioned.

Preface

The success of the first edition of this book and the many comments I have received are not only very gratifying but also serve as a reminder of just how important this field of clinical practice and prescribing has become. No member of the primary care team can afford to be indifferent to the tremendous developments that have taken place in the areas of coronary heart disease and vascular disease prevention. Central to this has been the introduction and widespread adoption of statin therapy. But, what more could be said on this subject that was not already included in the first edition of this book? To answer this we only have to look at the wealth of literature published on statins in the last two years. We have major new clinical trials, including PROSPER and the Heart Protection Study, that have effectively doubled our statin trial experience and extended it to specific patient groups not previously studied; we have longer term follow-up of statin-treated patients; we have new evidence about the differential safety of the statins, that culminated in the withdrawal of cerivastatin; and we have the further development and introduction of major new practice guidelines. Again, as with the first edition, I remind readers that this book is not intended to be the definitive work on the pharmacology of the statins, but rather aims to be a very practical and user-friendly introduction to these drugs. The primary care team need to know about a great many medical subject areas and statins, how they work and how they should be used is undoubtedly one of those areas. This short book contains everything the general practitioner or practice nurse needs to know to use statins effectively and safely. A selected list of further reading is provided for those wishing to go deeper into this subject, and an expanded glossary is included to serve as a ready reference. Finally, I would like to thank my publishers for giving me the opportunity to update and revise this work and to my commissioning editor at Martin Dunitz, Pete Stevenson, whose gentle encouragement appears to make all things possible and all deadlines attainable. Allan Gaw Glasgow 2003

vii

Preface to the First Edition After a long period of doubt and confusion the use statins in clinical practice has now become an established part of modern medical care. The statins were introduced in the late 1980s and early 1990s as a new group of cholesterollowering drugs in an attempt to offer patients with hypercholesterolaemia a safe and effective means of reducing their plasma cholesterol. This they achieved and clinicians began to use them in place of alternative therapies such as sequestrant resins and fibrates even before the publication of the large intervention studies. But, it was with the startling results of studies such as 4S, WOSCOPS, CARE and LIPID, that the statins came to be thought of in a different light. From simple, but highly effective, cholesterol-lowering drugs the statins are now regarded as drugs that have an important effect in reducing not only blood lipid levels but also, more importantly, an individual’s risk of vascular disease. My aim in this book is to place the use of statins in primary care in a clinical context and to explain how these remarkable drugs work. As a necessary prerequisite we will remind ourselves of the link between blood lipids and atherosclerotic disease and the nature of the disease we are trying to prevent. The pharmacology of the statins will be discussed and their comparative mechanisms explored, but practical considerations will be at the forefront throughout. Day-today problems such as deciding who should receive statin therapy will be examined in depth. Finally, we shall look into the future to see how we may use statins in the years ahead. This book is intended not as a definitive work on the pharmacology of the statins—that can be found elsewhere. Rather, this small volume is intended to be of practical use to the members of the primary care team who on a daily basis are faced with prescribing and management decisions. Every piece of writing takes time—time that could have been spent on other things and with other people. I would therefore like to acknowledge the people who were short-changed by this project— my wife Moira and our children, Stephen and Alexandra. Without their forgiveness this work could not have been finished. Allan Gaw Glasgow 2001

1 Why do we use statins?

Over the past three decades, enormous resources have been put into the study of human lipid and lipoprotein metabolism. Similarly, great efforts have been made to develop and test drugs that alter the lipid profile. The reason for these endeavours is simple. We now know that a raised blood cholesterol concentration causes atherosclerosis. This disease process in turn causes coronary, cerebral and peripheral vascular disease, and, by lowering the blood cholesterol level, we can prevent a significant proportion of these diseases. This book focuses specifically on the statins, a group of drugs that indisputably have had the most important impact in this field. It is important, however, to remember that when we prescribe statins we do so in an attempt to reduce the risk of vascular disease in our patients and not simply to lower cholesterol. Cholesterol lowering has been the focus of much of our attention over the years but cholesterol lowering per se is not the primary goal— it is to prevent vascular events, such as heart attacks and strokes, in our at-risk patients. Because of this, it is a necessary prerequisite to understand the nature of the disease that we are targetting before we go on to consider the statins themselves. Risk factors for CHD There are now a large number of characteristics or traits that have been identified as risk factors for coronary heart disease (CHD). A small number of these function as independent risk factors, i.e. they exert their influence independently of the presence of any other risk factor. There are many other risk factors that are secondary, i.e. they have a positive correlation with CHD but require the presence of other risk factors for this to be manifest. It is useful to consider risk factors in the clinical setting as those that can be modified, either by lifestyle changes or therapeutic intervention, and those that cannot. A list of the major risk factors is shown in Table 1.1.

2 WHY DO WE USE STATINS?

Table 1.1 Risk factors for CHD. Modifiable

Non-modifiable

Smoking Raised LDL-cholesterol Low HDL-cholesterol Raised triglyceride Raised blood pressure Diabetes mellitus Obesity Diet Thrombogenic factors Lack of exercise Excessive alcohol consumption

Age Male sex Family Personal history of CHD

It is important to realize that risk factors do not generally occur in isolation but tend to cluster in an individual. This is significant because when risk factors coexist they interact and their combined effect is much greater than would be expected from the sum of their individual effects. The concept of multiple CHD risk factors is of great practical importance because it means that the patient at greatest risk is not necessarily the individual with a single serious risk factor such as severe hypercholesterolaemia. Instead, the individual with a poor profile of risk factors, such as the male smoker with moderate hypertension and moderately elevated lipids, is at relatively greater risk. This is illustrated in Figure 1.1. While this book focuses on hyperlipidaemia as a risk factor for vascular disease, it is important to recognize that other risk factors are equally important. In clinical terms, any attempt to modify a patient’s vascular disease risk profile must attend to all the major correctable risk factors, especially dyslipidaemia, smoking and hypertension. Dyslipidaemia Cholesterol and low-density lipoproteins (LDL) The identification of cholesterol as a possible risk factor for CHD was first made after the recognition that in countries with high mean blood cholesterol levels the mortality from CHD was also high. Figure 1.2 shows the results from one such study, which illustrates the relationship between mean total cholesterol and the number of CHD deaths. The country with the highest cholesterol levels in this study, Finland, also experienced the highest CHD mortality. The position of Japan on this graph is significant as it experiences a relatively low CHD mortality. This is in keeping with the generally low cholesterol levels

STATINS IN GENERAL PRACTICE 3

Figure 1.1 Multiples of risk associated with smoking, hypertension and hypercholesterolaemia, and with combinations of these common risk factors. (Adapted from Poulter et al, 1993.)

of the Japanese, but occurs in spite of high population rates of smoking and hypertension, two other important risk factors for CHD. This relationship was studied further in the Ni-Hon-San study, which looked at CHD rates and risk factors in Japanese men in three societies. The results of this study are summarized in Table 1.2. It is clear from this that serum cholesterol level is one of the most important factors in predicting CHD risk in the population. Table 1.2 Ni-Hon-San study: CHD rates and risk factors in Japanese men in three societies.

Acute MI rate/1000 Hypertensive heart disease/1000 Non-smokers (%) Serum total cholesterol (mmol/l)

Japan

Hawaii

California

7.3 9.3 26.0 4.7

13.2 1.4 57.0 5.6

31.4 4.6 64.0 5.9

Cholesterol is directly involved in atherogenesis and it has been shown that the severity of atherosclerosis is directly proportional to the concentration of cholesterol in the blood. It is clear that diet is important in determining plasma cholesterol levels, as studies such as the Seven Countries Study have shown that

4 WHY DO WE USE STATINS?

Figure 1.2 International relationship between CHD mortality and total serum cholesterol. (Adapted from Simons, 1986.)

CHD is inversely related to the ratio of polyunsaturated to saturated fats in the diet. The above studies have identified the association between CHD and cholesterol, but in order to quantify the risk it was necessary to design prospective cohort studies. The results of three such studies are illustrated in Figure 1.3. In these studies the relationship between CHD risk and cholesterol level is positive and curvilinear. This was reinforced by the much larger Multiple Risk Factor Intervention Trial (MRFIT) study, which was able to show that the relationship between cholesterol and CHD was not one of threshold, i.e. there is a graded and continuous risk, and there is probably no cholesterol level which can be considered completely safe in terms of cardiovascular risk. There has been some concern over the risks of low cholesterol as MRFIT demonstrated a J-shaped relationship between total cholesterol and total mortality. These relationships are compared in Figure 1.4. This increase in total mortality occurring at cholesterol levels below 4 mmol/l has been duplicated in

STATINS IN GENERAL PRACTICE 5

Figure 1.3 Relation between plasma cholesterol level and relative risk of CHD in three prospective studies. (Adapted from Grundy, 1986.)

other studies and it has been suggested that low cholesterol levels may cause cancer. However, international comparative data do not support this hypothesis. For example, in Japan, where 90% of men have cholesterol levels below 4.4, the overall risk of cancer is no greater than that experienced by American or Northern European men. A more likely explanation is that a low plasma cholesterol level is an effect of cancer rather than a cause. Indeed, in population screening the finding of particularly low cholesterol levels should be followed up to exclude underlying malignancy. Our discussion so far has centred on total cholesterol as a risk factor, but since 60–70% of plasma cholesterol is transported in the form of LDL, the effects of total cholesterol reflect the effects of LDL-cholesterol. High-density lipoprotein (HDL) cholesterol There is considerable evidence to support an inverse relationship between plasma HDL and CHD risk. This inverse relationship exists for both men and women,

6 WHY DO WE USE STATINS?

Figure 1.4 CHD and total mortality according to serum total cholesterol. (Adapted from Martin et al, 1986.)

and is equally strong in patients with established heart disease as well as those who are asymptomatic. Premenopausal women have levels of HDL-cholesterol which are usually 0.2–0.3 mmol/l higher than those of men. After the menopause this difference diminishes with increasing age but it may partly explain the relative protection of women from CHD. Plasma HDL is lowered by: ■ Smoking ■ Obesity ■ Physical inactivity Modification of these lifestyle factors reverses this HDL-lowering effect. In addition, drug treatment may be used to raise HDL-cholesterol levels. Fibrates are often thought of as the lipid-regulating agents of choice to affect HDL levels but, as we shall see below, statins also have HDL-raising properties, which undoubtedly contribute to their overall beneficial effect on cardiovascular risk.

STATINS IN GENERAL PRACTICE 7

Diets containing high polyunsaturated fat levels have been shown to decrease LDL-cholesterol while simultaneously lowering HDL-cholesterol, but it is possible to lower LDL-cholesterol while maintaining HDL levels by reducing saturated fat and replacing it with moderate amounts of monounsaturated and polyunsaturated fats. The importance of HDL as a risk factor is related to LDL levels, and the ratio of total cholesterol to HDL-cholesterol is a better predictor of CHD risk than either of the variables alone. A ratio of five or less appears to be desirable and is of particular importance when considering treatment options for patients whose cholesterol levels are in the 5–6.5 mmol/1 range. Atherosclerosis Atherosclerosis is a pathological process, which may be defined as a focal, inflammatory fibro-proliferative response to multiple forms of endothelial injury. The response-to-injury hypothesis for the development of atherosclerosis was formally proposed more than 20 years ago and has been refined and developed since, but not superseded. The first lesions that may be recognized as truly atherosclerotic are called fatty streaks (Figure 1.5a). These are small lesions that, on gross inspection, are hardly raised, and are caused by localized collections of lipid-filled macrophages (foam cells) within the intima, just below the endothelium. The fatty streak lesion may be the precursor of larger atherosclerotic plaques but may also be an entirely reversible phenomenon. We know this because of post-mortem studies in infants from societies around the world where atherosclerosis is a relatively rare cause of death. These infants, although unlikely to have died from CHD if they had lived to maturity, had many fatty streaks in their arteries. Progression of a fatty streak to a larger, more complex lesion is believed to occur through two key processes. First, the foam cells begin to die and break down in the centre of the fatty streak. Release of their cytoplasmic contents leads to the presence of extracellular lipids and the secretion of growth factors as part of the inflammatory response. Vascular smooth muscle cell migration and proliferation is the second process involved in the progression of the fatty streak (Figure 1.5b). Smooth muscle cells push into the lipid-rich plaque where they divide and begin to synthesize a connective tissue matrix. The increase in cell numbers and the laying down of collagenous matrix both serve to increase the bulk of the plaque, which may now protrude into the artery lumen; this is referred to as a raised fibrolipid or advanced plaque. Such plaques are difficult to age but necropsy studies suggest that they take approximately 10–15 years to develop. It is also believed that new fatty streaks are continually forming throughout adult life.

8 WHY DO WE USE STATINS?

Figure 1.5 Pathogenesis of atherosclerosis. (a) As a result of endothelial injury, monocytes/macrophages adhere to the endothelial surface and begin to invade the subendothelial space. By ingesting lipoproteins these cells become lipid-filled foam cells and as they accumulate at the lesion site they bulge under the endothelial surface, creating the physical appearance of the fatty streak. (b) As the lesion increases in size, smooth muscle cells proliferate and migrate into the subendothelial space and platelet mural thrombi may form on the surface. Progression of these processes by continual release of regulatory molecules that stimulate and recruit other cells to the site, and the laying down of fibrous tissue, leads to the development of an advanced plaque. Note that this entire process is by no means a one-way system and reversal of each of the steps is now thought to be clinically possible. (c) The plaque has a large defect in the fibrous cap, through which a dumb-bell-shaped thrombus has formed, part being in the plaque and part partially occluding the lumen of the artery. This effect has greatly increased the size of the plaque suddenly and may result in symptoms for the first time.

Plaque rupture and thrombosis The atheroslerotic plaque poses a threat to the integrity of the coronary blood

STATINS IN GENERAL PRACTICE 9

flow by its size, but more importantly by its tendency to fissure and rupture. The final pathway to a major clinical event, such as an acute myocardial infarction (MI), is not clear but rupture or fissuring of a plaque haemorrhage into the plaque or thrombosis on its surface are all mechanisms that are likely to be involved (Figure 1.5c). In patients with unstable angina and acute MI it has been shown that thrombus formation is an important and dynamic process. Post-mortem studies have shown that coronary thrombi are nearly all related to the fissuring of the atheromatous plaque. The factors that determine whether thrombus does occur within the lumen are partially local, including the size and geometry of the intimal tear, whether lipid is extruded into the lumen itself, the degree of stenosis and the blood flow rate at the site. Systemic factors such as the thrombotic or thrombolytic potential at the time will also play a part.

Regression of the atherosclerotic plaque The concept of therapeutic intervention producing reversal or regression of atherosclerotic lesions originates more than 50 years ago, when post-mortem examinations on individuals who had suffered great weight losses prior to their death revealed that the extent of plaque development in the aorta and coronary arteries was much less than expected. That regression is possible clinically has since been proven in randomized, controlled clinical studies using lipid-lowering therapy. In the Familial Atherosclerosis Treatment Study, middle-aged men who had moderately elevated LDL, a family history of CHD and angiographic evidence of CHD had reduced frequency of progression of coronary lesions, increased frequency of regression and reduced incidence of CHD events if prescribed lipid-lowering therapy. Clinical manifestations of atherosclerosis Atherosclerosis may occur in many different arteries. The most common clinical manifestations are seen when the coronary arteries are involved and this will be discussed further below. However, atherosclerosis can also affect the peripheral arteries, resulting in leg muscle ischaemia, termed intermittent claudication. The aorta is also frequently affected and although there is seldom complete occlusion of blood flow through this, the largest of our arteries, there can be serious clinical consequences. The atherosclerotic lesions weaken the aortic wall and can contribute to the development of aneurysms, particularly in the abdominal aorta. Rupture of an aortic aneurysm will result in sudden death. When the cerebral arteries are affected by atherosclerosis the patient may suffer a spectrum of effects ranging from mild neurological disturbances, such as reversible memory loss, through transient ischaemic attacks to a fatal stroke.

10 WHY DO WE USE STATINS?

Clinical picture of CHD There are a number of clinical presentations of CHD. The most common of these are: ■ Sudden death ■ MI, which may be recognized or silent ■ Angina pectoris, which may be stable or unstable Acute MI develops when myocardial ischaemia occurs for sufficient time to cause necrosis of a localized area of the myocardium. The crushing, central chest pain of MI is similar to that of angina pectoris, but results from irreversible myocardial ischaemia. The pain does not subside with rest or nitrate therapy and may last for several hours. The intensity of pain gives no indication as to the severity of the infarction. Indeed, particularly in the elderly, MI may be ‘silent’ and present, without pain but with some other feature such as acute left ventricular failure. Up to 50% of all deaths from MI occur within 2 hours of onset, mainly as a result of dysrhythmia. The majority of these deaths occur outside hospital. In addition, for many individuals the first and only presentation of CHD will be a fatal MI. While the advocacy of secondary prevention of CHD is sound, we must not forget that for many of our patients secondary prevention is not an option and their only hope is that of primary prevention. This important point will be further discussed in Chapter 5. Diagnosis of CHD As always in clinical medicine, a good history is the most important aid in the diagnosis of CHD but there are many other techniques available for its full evaluation. These include simple non-invasive tests such as the resting or excercise electrocardiogram (ECG), and progress to invasive evaluations such as angiography and radionucleide imaging. The diagnosis of acute MI is based on the combination of clinical symptoms and signs, with serial ECG changes and serum markers of myocardial damage such as the enzymes AST and CK and/or the muscle protein, troponin T. Typical ECG and enzyme changes are illustrated in Figures 1.6 and 1.7.

STATINS IN GENERAL PRACTICE 11

Figure 1.6 ECC changes following an MI. Left panel: normal ECG. Right panel: 2 hours after onset of chest pain. Note elevated ST segment. (Reproduced with permission from Clinical Biochemistry: An Illustrated Colour Text, 3rd edn, Gaw et al, 2003.)

Figure 1.7 Serum enzyme changes following an uncomplicated Ml. (Reproduced with permission from Clinical Biochemistry: An Illustrated Colour Text 3rd edn, Gaw et al, 2003.)

2 How do we assess dyslipidaemia?

Lipid profiles The most common aberrant lipid profile linked with atherogenesis and an increased risk of vascular disease is an elevated plasma LDL-cholesterol level, but increasingly it is being recognized that individuals with a low plasma HDLcholesterol level and hypertriglyceridaemia are also at increased risk. The units for measured cholesterol and triglyceride levels are either mg/dl or mmol/l. The conversion factors for these are shown below. Cholesterol mg/dl=mmol/l×38.67 Triglyceride mg/dl=mmol/l×88.57 Blood for lipid analysis may be collected into plain containers, which will give the serum level, or into containers with the anticoagulant ethylenediaminetetraacetic acid (EDTA), which allows plasma levels to be measured. Tubes containing heparin should not be used for lipid measurements. Some laboratories, including our own, prefer to measure plasma levels, the advantage being that the EDTA enhances lipoprotein stability during storage. Samples may be kept for up to 4 days prior to analysis, provided they are refrigerated at 4°C, but it is always best to check the requirements of your local laboratory. A range of different analyses may be performed on the blood sample by the biochemistry laboratory, increasing in complexity from a simple total cholesterol measurement to a full lipoprotein analysis and perhaps even DNA analysis. Most commonly, total cholesterol and triglyceride levels will be measured and, in addition, an HDL-cholesterol level may be provided. As well as these measured values, the LDL-cholesterol level may be calculated, using the Friedewald formula, provided the three aforementioned parameters are known. The accuracy with which the LDL-cholesterol is estimated using this formula is relatively poor due to the summation of different analytical errors, but it does provide some useful information. It is important to note, however, that the Friedewald formula should not be used if the plasma triglyceride level is above 4.0 mmol/l.

STATINS IN GENERAL PRACTICE 13

The most comprehensive (and expensive) analysis is known as a beta quantification, which provides measurements for total cholesterol, triglyceride, very-low-density lipoprotein (VLDL)-cholesterol, LDL-cholesterol and HDLcholesterol. In most circumstances this full lipoprotein profile is not necessary and patients can be adequately managed knowing total cholesterol, triglyceride and HDL-cholesterol levels, with or without a calculated LDL one. Timing of samples: when to measure If a total cholesterol measurement is all that is required then fasting is not necessary. For plasma triglyceride or lipoprotein cholesterol levels to be measured accurately the patient should have been instructed to fast. It is very important to give explicit instructions regarding fasting to ensure that the patient neither eats nor drinks anything, except water, for 12–14 hours prior to the blood sampling. As with all blood chemistries, there are a number of factors that affect the results of plasma lipid levels reported from the biochemistry laboratory. ■ Biological variation, which might give different results from one day to the next; ■ Analytical imprecision, which may produce slightly different values even if the same blood sample is measured in the same laboratory but on different days. Because of these sources of variation, it is important to obtain more than one sample for lipid analysis before any action is taken, especially the initiation of long-term drug therapy. International guidelines often recommend that at least three measurements should be carried out on three separate samples before management decisions are made. Interpretation of results There is probably no level of cholesterol below which an individual is completely safe from the development of vascular disease. However, it is still useful to have an idea of the statistically normal range of lipid measurements that occur in the population, as the people who exist at the upper limit of these distributions are prime candidates for risk-factor modification. The results obtained by the Lipid Research Council in their prevalence study to ascertain the distribution of various lipid and lipoprotein levels are shown in Table 2.1. The influence of age is clearly demonstrated.

14 HOW DO WE ASSESS DYSLIPIDAEMIA?

Clinical Disorders of lipid metabolism Disorders of lipoprotein metabolism are among the commonest metabolic diseases seen in clinical practice. In addition to their important role in the development of CHD, some lipid disorders have other consequences, most notably acute pancreatitis, failure to thrive in infants, neurological disorders and the development of cataracts. Table 2.1 Plasma lipid levels in US white males (mmol/l). Total cholesterol Age (years)

Mean level (mmol/l)

5th-95th percentiles (mmol/l)

0–19 20–24 25–29 30–34 35–39 40–44 45–69 70+ Triglyceride Age (years) 0–9 10–14 15–19 20–24 25–29 30–34 35–39 40–54 55–64 65+

4.0 4.3 4.7 4.9 5.2 5.3 5.6 5.3

3.0–5.2 3.2–5.4 3.5–6.3 3.6–6.6 3.7–7.0 3.9–7.0 4.0–7.1 3.9–7.0

Mean level (mmol/l) 0.6 0.7 0.9 1.1 1.3 1.5 1.7 1.7 1.6 1.5

5th-95th percentiles (mmol/l) 0.3–1.1 0.3–1.4 0.4–1.6 0.5–2.3 0.5–2.8 0.5–3.0 0.6–3.6 0.6–3.6 0.6–3.3 0.6–3.0

There is currently no satisfactory comprehensive classification of dyslipidaemia. The simplest means of dividing them is into primary and secondary disorders. Classification of dyslipidaemia The Fredrickson or World Health Organization classification is the most widely accepted. This classification relies on the findings of analysis of the patient’s

STATINS IN GENERAL PRACTICE 15

plasma rather than genetics. It is therefore a phenotypic rather than genotypic classification, which has a number of consequences. Patients with the same underlying genetic defect may fall into different groups, or may change grouping as their disease progresses or is treated. However, the major advantage of using this classification is that it is very widely known and gives some guidance to management. It is also important to realize that the six different classes of hyperlipoproteinaemia defined in the Fredrickson classification are not equally common in the population. Types I and V are rare, while types IIa, IIb and IV are very common. Type III hyperlipoproteinaemia, also known as familial dyslipoproteinaemia, is intermediate in frequency, occurring in about 1/5000 of the population. Genetic classifications have been attempted but are becoming increasingly complex as different mutations are discovered. Some of the recognized genetic causes of hyperlipidaemia are shown in Table 2.2. Until the advent of gene therapy and/or specific substitution therapy, genetic classifications, while biologically interesting, are unlikely to prove very useful in clinical practice. Table 2.2 Some examples of specific genetic causes of hyperlipidaemia. Disease

Genetic defect

Fredrickson

Risk

Familial hypercholesteroaemia (FH) Familial hypercholesteroaemia Familial combined hyperlipidaemia (FCH) Lipoprotein lipase deficiency

Reduced numbers of functional LDL receptors Possibly single gene defect Possibly single gene defect

IIa or IIb

Increased risk of CHD

IV or V

? Invreased risk of CHD ? Increased risk of CHD

Reduced levels of functonal lipoprotein lipase

IIa, IIb, IV or V

I

Increased riskof pancreatitis

3 What are the statins and how do they work?

Discovery The statins are a group of drugs that owes its exsitence to the considerable efforts of Japanese and American biochemists working in the 1970s. Akira Endo and his colleagues in Japan first isolated the antibiotic mevastatin from the mould Penicillium citrinum in 1973, and they demonstrated that this novel compound lowered serum cholesterol levels in dogs by inhibiting the rate-limiting enzyme in cholesterol biosynthesis: hepatic 3-hydroxy-3-methyl glutaryl coenzyme A (HMG CoA) reductase. At the time no one fully appreciated the impact that this discovery would have on vascular disease prevention worldwide, and it was only after the publication of the first large statin intervention trials in the 1990s that clinicians throughout the world truly understood what a breakthrough this was. In considering the statins we must first answer the most commonly asked question relating to these drugs—are they all the same? The answer is perhaps predictable given our now extensive knowledge of this field of pharmacology— yes and no. Yes, statins are all the same, for by definition they are all drugs that affect the lipid profile by inhibiting the key enzyme that controls the cell’s ability to make cholesterol—HMG CoA reductase. All new compounds that share this pharmacological trait, irrespective of their chemical structure, are likely to be suffixed ‘-statin’. However, in many other pharmacological respects the statins differ significantly from each other. Before exploring further the differences between the statins it is important to understand how, as enzyme inhibitors, they control the lipid profile. Mechanism of action When the enzyme HMG CoA reductase is inhibited and intracellular cholesterol levels fall then the hepatocyte upregulates the cellsurface LDL receptors to

STATINS IN GENERAL PRACTICE 17

Figure 3.1 Upregulation of the cell-surface LDL receptors in response to inhibition of HMG CoA reductase by statin therapy.

import more cholesterol from the plasma (Figure 3.1). In this the statins are similar to the bile acid sequestrant resins, as these drugs also ultimately result in upregulation of the cell-surface LDL receptors. Considering the similar mechanisms of action of the statins and the resins it might be expected that their effects would be additive and, indeed, this is the case. LDL-cholesterol reductions of 60% have been observed when the drugs have been used in combination. Despite its name, the LDL receptor is also involved in clearing other more triglyceride-rich lipoproteins from the plasma and, as such, when statins upregulate the receptor there is also a fall in circulating triglyceride as well as LDL-cholesterol. This effect on plasma triglyceride is common to all statins, but the magnitude of the fall is proportional to the starting triglyceride level, i.e. those with hypertriglyceridaemia may experience 25% reductions in triglyceride and cholesterol levels, while normotriglyceridaemic subjects may only experience 5–10% reductions in their triglyceride level but greater reductions in their cholesterol. Plasma levels of HDL-cholesterol are also significantly increased by statin therapy (e.g. 5–10%), although the precise mechanisms are unclear. Certainly,

18 WHAT ARE THE STATINS AND HOW DO THEY WORK?

Figure 3.2 Comparative chemical structures of the statins.

most manoeuvres that lower plasma triglyceride also raise HDL-cholesterol, as the two are very closely linked metabolically. Comparative pharmacokinetics Comparison of the structures of the statins as shown in Figure 3.2 reveal a number of important differences, which translate into pharmacokinetic differences (see Table 3.1). Most notable is the fact that pravastatin and rosuvastatin are the only water-soluble statins, while atorvastatin and rosuvastatin have by far the longest plasma half-lives (approximately 14 and 19 hours respectively, compared to 2–3 hours for the other statins). Mechanisms beyond cholesterol lowering Laboratory and clinical evidence is certainly accumulating to the effect that individual statins may possess benefits beyond their cholesterol-lowering capability, particularly with regard to: ■ ■ ■ ■ ■

Plaque stabilization Endothelial function Cellular immunity Anti-inflammation Lipoprotein oxidation

Table 3.1 Comparative pharmacokinetics of the statins.

STATINS IN GENERAL PRACTICE 19

■ Rheology and blood coagulation ■ Glucose intolerance

20 WHAT ARE THE STATINS AND HOW DO THEY WORK?

Each of these potential benefits is evaluated and summarized below. Statins and plaque stabilization Before the statins were introduced, clinical trial experience with earlier lipidlowering drugs had suggested that an inevitable delay of 2 years or more was to be expected prior to the onset of benefit from cholesterol reduction. Most pathologists linked this to regression of the atherosclerotic lesion, which they imagined led to its shrinkage and, in consequence, an improvement in downstream tissue perfusion. Large, pre-occlusive lesions were therefore considered to be the primary target for intervention strategies, consistent with the abundant experimental evidence that links the total vascular atherosclerosis burden to ultimate risk of cardiovascular death. However, despite the welcome provision of symptomatic relief, surgical intervention, in contrast to medical management of risk factors, does not significantly extend life or reduce coronary mortality overall. This suggests that the large lesion is not necessarily the culprit leading to potentially fatal events. In this regard, recent post-mortem studies have redirected our attention to what seems to be a continuing and, in general, asymptomatic process of lesion rupture and healing, seen equally commonly in non-occlusive as in occlusive plaques (Figure 3.3). Repetition of this cycle is frequently accompanied by intramural thrombosis, leading to substantial and sudden lesion growth. Table 3.2 Characteristic features of the vulnerable atherosclerotic plaque. Thin, fragmented fibrous cap Underdeveloped connective tissue skeleton Lipid enrichment Inflammatory cell infiltration Evidence of proteolytic enzyme release Apoptosis

Occasionally, thrombus may propagate into the vessel lumen, producing a catastrophic occlusive MI. So, plaque vulnerability to rupture is probably of greater clinical relevance than plaque size. Not surprisingly, therefore, those factors that govern the vulnerability of the plaque itself are under intensive investigation. Table 3.2 describes what are thought to be the key players in this process. Pathological studies of patients who have died suddenly of CHD are consistent with the view that the typical causal lesion is a previously unrecognized minimally occlusive plaque, whose thin or fragmented fibrous cap, poorly supported by an internal connective tissue skeleton, has ruptured, exposing the blood to the underlying, highly thrombogenic lipid-rich core

STATINS IN GENERAL PRACTICE 21

Figure 3.3 Proportion of large, medium and small atherosclerotic plaques leading to MI. (Adapted from Falk et al, 1995.)

infiltrated with inflammatory cells. Cytokines released by the latter have already attracted vascular smooth muscle cells from the media into the subintimal space. Both cell types trigger further matrix degeneration within the lesion by releasing metalloproteinases. Statin therapy inhibits many of the above processes, helping to reduce the likelihood of plaque rupture or limiting thrombus formation should rupture occur. Comparative investigations suggest that the lipid-soluble statins are capable of modulating smooth muscle cell growth independently of their cholesterollowering capability (Figure 3.4). Interestingly, the water-soluble statin pravastatin has no appreciable effect on vascular smooth muscle cells at normal pharmacological doses, which is possibly explained on the basis of tissue penetration. The statins may also exert a direct suppressant effect on platelet activation, thereby limiting platelet thrombus formation (Figure 3.5). In addition, their LDLlowering actions result in a reduction in the number of inflammatory cells within the plaque and a change in plaque composition, leading to the development of a stiffer, more stable lesion. Statins and endothelial function Until relatively recently the endothelium was thought of as merely a watertight, but metabolically inactive, pavement of cells lining our blood vessels. This perception was challenged by the discovery that the vascular endothelium, in

22 WHAT ARE THE STATINS AND HOW DO THEY WORK?

Figure 3.4 Differential effects of HMG CoA reductase inhibitors on vascular smooth muscle cells. †Drug concentration required to inhibit 25% of human vascular smooth muscle cell proliferation. Samples were obtained from the left internal mammary artery of CABG patients. Proliferation was analysed by measuring mitochondrial dehydrogenase activity. (Adapted from Soma et al, 1995.)

response to increasing flow-mediated shear stress, elaborates a chemical signal which promotes relaxation of the underlying arterial smooth muscle cells and, in consequence, coordinates vasomotor changes throughout the vascular bed. The signal is now known to be nitric oxide. As our knowledge of this agent grows, it is becoming clear that endotheliumdependent relaxation is depressed in atherosclerotic coronary arteries. Even in apparently healthy vessels, high LDL concentrations directly inhibit the relaxation process so that vasodilatation in response to acetylcholine is impaired in hypercholesterolaemia, well in advance of the structural, histologic or clinical appearance of disease. Interestingly, it appears that oxidized LDL rather than the native circulating lipoprotein is the main culprit in this process. Hypercholesterolaemic patients seem to be unable to release nitric oxide in adequate amounts to induce vasodilatation. Early in 1989, studies showed that the vasospasm detected in hypercholesterolaemic rabbits could be reversed or attenuated by statin therapy. These findings were soon confirmed in hypercholesterolaemic patients. Treatment with a variety of lipid-lowering drugs, or with therapy designed to limit lipoprotein oxidation, restored the physiological coronary vasodilator response to acetylcholine in proportion to the cholesterol reduction.

STATINS IN GENERAL PRACTICE 23

Figure 3.5 Platelet deposition and the effects of pravastatin therapy. Bar graphs showing platelet deposition at the high shear rate of 2546/s (top) and at the low shear rate of 754/s (bottom) in normocholesterolaemic (Normochol) and hypercholesterolaemic patients at baseline (Basal) and after treatment with pravastatin (after Prava). (Adapted from Lacoste et al, 1995.)

Statins and cellular immunity In a prospective randomized trial of pravastatin therapy administered to heart transplant recipients the question of whether transplant vasculopathy, associated with raised plasma lipid levels, could be avoided was assessed. Serendipitously, the investigators noted that pravastatin therapy not only lowered plasma lipid levels, but also reduced episodes of acute rejection and, in consequence, prolonged graft survival (Figure 3.6). This line of investigation was pursued with

24 WHAT ARE THE STATINS AND HOW DO THEY WORK?

Figure 3.6 Cardiac transplant rejection and the effects of pravastatin therapy. Panel A: Mean (+/− SE) cholesterol levels during the first year after cardiac transplantation in the study patients (pravastatin group n=47, control group n=50). Panel B: Survival during the first year after cardiac transplantation in the study patients (pravastatin group n=47, control group n=50). (Adapted from Kobashigawa et al, 1995.)

a second study, which demonstrated prolongation of kidney graft survival following pravastatin treatment as well. Several possible explanations for these intriguing findings have been proposed, including reduction in natural killer cell cytotoxicity, enhancement of immunosuppression due to synergism between pravastatin and cyclosporin, and simple reduction of plasma lipid levels. In partial dismissal of the latter, it has

STATINS IN GENERAL PRACTICE 25

been pointed out that the immunosuppressive action is apparently independent of the degree of cholesterol reduction achieved. A similar effect has been demonstrated with simvastatin, but whether this effect is applicable to the whole class of HMG CoA reductase inhibitors remains to be determined. Large-scale prospective clinical studies are urgently needed in this potentially very important new therapeutic use of statins. Statins and inflammation One of the most exciting developments in the last few years has been the appreciation that inflammatory processes play a key role in the development of the atherosclerotic plaque and that the statins may have a significant impact on these processes, and therefore also on the progression and destabilization of such plaques. The association between plasma levels of inflammatory markers such as C-reactive protein (CRP) and increased cardiovascular risk has been clearly demonstrated (Figure 3.7). It should be noted that this association has only been shown when high-sensitivity CRP assays are used and so the abbreviation hsCRP is used to denote this. Routine CRP measurements, such as those performed to monitor infections, are not sensitive enough to define cardiovascular risk. More recently, a subgroup of the Cholesterol and Recurrent Events (CARE) study cohort has been examined, and hs-CRP levels were measured at baseline and after 5 years. Among these MI survivors on standard therapy plus placebo, hs-CRP levels tended to increase over 5 years of follow-up. In contrast, randomization to pravastatin therapy resulted in significant reductions in this inflammatory marker (−39%, p=0.002) that were not related to the magnitude of lipid alterations observed. These data provide important new evidence for the non-lipid-lowering effects of pravastatin and may further explain the clinical benefits seen with this drug in the large-scale intervention West of Scotland Coronary Prevention Study (WOSCOPS), the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) study and CARE study. Statins and lipoprotein oxidation Individuals may have raised concentrations of LDL-cholesterol in their plasma because they fail to clear this lipoprotein fraction adequately from their bloodstream. The circulating half-life of these particles is therefore increased and, in consequence, they are susceptible to greater levels of oxidation. Oxidation of LDL is a prerequisite to its uptake by macrophages, a key event in early atherogenesis. In addition, oxidized LDL possesses additional atherogenic properties, which include cytotoxicity and stimulation of thrombotic and inflammatory events. As described above, the statins achieve their LDL-cholesterol-lowering effect by activating the LDL receptor on the cell surface. This results in accelerated uptake of the lipoprotein by the liver and a decrease in its transit time through the

26 WHAT ARE THE STATINS AND HOW DO THEY WORK?

Figure 3.7 Relative risk (RR) of MI stratified by quartile of baseline plasma hs-CRP. (Adapted from Ridker et al, 1997.)

plasma. With statin therapy the potential for lipoprotein oxidation in the circulation should consequently be reduced. In addition to their effects on LDL metabolism, statins produce changes in the composition of the circulating lipoprotein by decreasing the cholesterol:protein ratio in the particle, in line with the concept that stimulation of hepatic LDLreceptor activity results in preferential removal of cholesterol-enriched particles. Such changes again could alter the susceptibility of the lipoprotein to oxidation (Figure 3.8). The concept that the accelerated catabolism induced by statin therapy should reduce the age of the circulating LDL population, alter its composition and increase its resistance to oxidative modification has been tested directly in vivo. As expected, all clinically available statins were found to reduce the susceptibility of the lipoprotein to oxidation. This decrease in lipoprotein oxidizability might be an important class-related ancillary mechanism by which statin therapy helps prevent atherosclerosis progression in humans.

Statins, rheology and blood coagulation In addition to their ability to lower plasma lipid levels, some statins also appear capable of improving platelet function and reducing blood viscosity. As illustrated in Figure 3.5, pravastatin was shown to have significant effects on platelet thrombus formation.

STATINS IN GENERAL PRACTICE 27

Figure 3.8 Susceptibility of LDL to in vitro oxidation and statin therapy. LDL was isolated from hypercholesterolaemic patients treated for up to 18 weeks with increasing doses of either simvastatin or pravastatin (10, 20 and 40 mg daily for 6 weeks each, respectively) *P<0.05, **P<0.01, ***P<0.001, for significance between pre- and posttreatment values. (Adapted from Kleinveld et al, 1993.)

Similarly, statin-induced cholesterol reduction also seems to promote a fall in blood viscosity, with resulting improvements in tissue perfusion. In WOSCOPS, treatment with pravastatin lowered plasma and whole-blood viscosity (Figure 3.9). This finding was not driven by a change in plasma fibrinogen but rather by decrements in circulating LDL and VLDL. While the magnitude of the viscosity change may appear small in numerical terms, it corresponds to the mean difference between men who suffered an MI and those who did not, and may account for about 25% of the risk reduction achieved with pravastatin in WOSCOPS. Statins and diabetes In a recent analysis of WOSCOPS, interesting new findings have emerged, which would suggest that pravastatin therapy in that cohort had a significant impact on the participants’ risk of developing Type 2 diabetes throughout the 5year study period, using a modified American Diabetes Association definition of diabetes. A total of 5940 of the 6595 randomized subjects were included in the analysis and 139 subjects became diabetic during the study. The baseline predictors of this transition to diabetes from normality were studied. Body mass index (BMI), plasma triglyceride concentration, white cell count, systolic blood

28 WHAT ARE THE STATINS AND HOW DO THEY WORK?

pressure, total and HDL-cholesterol, glucose and randomized treatment assignment to pravastatin were significant predictors. In a multivariate model, only BMI, plasma triglyceride concentration and pravastatin therapy were predictive. The investigators concluded that assignment to pravastatin therapy resulted in a significant reduction (30%) in the hazard of developing Type 2 diabetes (Figure 3.10). Pravastatin therapy, by lowering plasma triglyceride levels, may favourably influence the development of diabetes, but other explanations such as the anti-inflammatory properties of this drug in combination with its beneficial effects on endothelial function may prove to be important. Clinical use The statins are indicated in the treatment of dyslipidaemia and, following the publication of the large-scale statin intervention trials outlined below, they also now have additional indications in the primary and secondary prevention of CHD. The major contraindication to the use of statin therapy is active liver disease, although its use should also be avoided in pregnancy and lactation, and in women whose contraceptive methods are unreliable. Similarly, care should be taken in patients with renal impairment. None of the statins are licensed for use in children in the UK, but in October 2002 pravastatin was granted a paediatric license in the US for use in children aged 8 and over with familial hypercholesterolaemia (FH). Side effects, if they occur, are usually mild: gastrointestinal upsets, headache, fatigue and skin rashes. There are, however, two important, uncommon side effects that clinicians need to be aware of when prescribing statins. One is an effect on liver enzymes, which is usually unnoticed by the patient but may necessitate alanine aminotransferase (ALT) monitoring and if levels climb to more than three times the upper limit of the laboratory reference range even withdrawal of the drug. The second uncommon side effect is that statins can occasionally affect muscle function, causing pain or weakness, and leakage of the muscle enzyme, creatine kinase (CK or CPK) into the blood stream. This is a marker of muscle damage and if raised by more than 10 times the upper limit of the laboratory reference range then the drug should be discontinued. A practical point to note, however, is that in patients of African descent the serum CK levels are normally higher than in Caucasian subjects, so the usual laboratory reference ranges may not be applicable. In its most extreme form this statin-induced myopathy may lead to rhabdomyolysis. This was recently highlighted by the withdrawal from clinical practice of cerivastatin in August 2001. This was the result of a significant increase in the number of cases of fatal rhabdomyolysis in patients receiving this statin. A number of these cases were the result of co-prescription of cerivastatin and gemfibrozil—a combination that is well known to increase the risk of myopathy. Other cases could not be attributed to combination therapy, but some were linked to the use of a newly introduced higher dose of cerivastatin.

STATINS IN GENERAL PRACTICE 29

Figure 3.9 Fibrinogen and plasma viscosity and the effects of pravastatin therapy. Fibrinogen (top) and plasma viscosity (bottom) changes in the first year of WOSCOPS. (Adapted from Rumley et al, 1997.)

This serves as a reminder that at high doses, and in certain combinations, statins can lead to severe and even life-threatening complications, such as rhabdomylosis, although this has only very rarely been observed with other approved statins. A review of statin safety was recently undertaken by the Committee on Safety of Medicines in the UK and they stated that, ‘Due to pharmacokinetic and lipohilicity differences, the potential for inducing muscle disorders varies with individual drugs’. This committee went on to conclude ‘The rare risk of myopathy must be considered in the context of the

30 WHAT ARE THE STATINS AND HOW DO THEY WORK?

Figure 3.10 Development of diabetes in the placebo group and the pravastatin-treated group in WOSCOPS. (Adapted from Freeman et al, 2001.)

overwhelmingly beneficial effects of the statins in the prevention of coronary artery disease. These benefits clearly outweigh the potential risks’. This green light to the clinical use of statins puts any safety concerns we might have had after the withdrawal of cerivastatin into context. Statins are available as capsules or tablets to be taken once daily. Many statin manufacturers recommend dosing at night. The rationale for this being that cholesterol synthesis exhibits a diurnal rhythm, the maximum rate occurring at night. Since the drugs inhibit cholesterol synthesis by inhibiting the rate-limiting enzyme, maximum effect should be seen if it is given at the time of peak enzyme activity. In practice, however, if a patient can be encouraged to take their statin therapy at the same time each day on a regular basis this is more important than adhering strictly to night-time dosing. Indeed, the most recently introduced statin — rosuvastatin—is recommended for dosing at any time of day. Drug-drug interactions Since the statins are predominantly metabolized by the cytochrome P450 system in the liver there exists the possibility of drug-drug interaction at this level, because a large number of other commonly prescribed drugs are also metabolized by this system. Exceptions to this are the water-soluble statins pravastatin and, perhaps to a lesser extent, rosuvastatin. Because of these drugs’ water solubilities they are not metabolized to any significant extent by the liver,

STATINS IN GENERAL PRACTICE 31

and therefore drug-drug interactions should be significantly lower with them than with other statins. This may be of particular importance when patients receiving multiple other drugs are considered for statin therapy. One such group would be the elderly. In the recent Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), whose participants were aged 75 years on average, there was, as expected, a large amount of concomitant medication. Despite this, pravastatin 40 mg daily was not associated with any increase in side effects. (A more detailed discussion of the use of statins in the elderly is given in Chapter 6.)

4 What evidence do we have that statins work?

We are fortunate as clinicians when it comes to statins, for over the last decade an unmatched portfolio of clinical trial results has been assembled which forms the foundation of our evidence-based practice. The largest placebo-controlled statin studies to date are summarized in Table 4.1 and these trials will be further reviewed, and summarized below. Scandinavian Simvastatin Survival Study: 4S This secondary prevention study, published in 1994 by the Scandinavian Survival Study Group, was a double-blind, randomized, placebo-controlled trial looking at the effects of lowering cholesterol in men and women between the ages of 35 and 70 who had a history of angina or MI. The subjects recruited (4444) had cholesterol levels of between 5.5 and 8.0 mmol/l and triglyceride levels less than or equal to 2.5 mmol/l. Half of the subjects were given simvastatin 20–40 mg daily, while the other half were given a placebo and both groups were regularly reviewed over a 5-year period. Results The mean changes in lipid levels observed in the simvastatin group were as follows: ■ ■ ■ ■

Total cholesterol fell by 25% LDL-cholesterol fell by 35% Triglyceride fell by 10% HDL-cholesterol increased by 8%

STATINS IN GENERAL PRACTICE 33

Table 4.1 CHD prevention with statins. Clinical trial

Drug used

Number of subjects (% male)

Relative reduction in fatal of non-fatal MI (%)

West of Scotland Coronary Prevention Study (WOSCOPS) Cholesterol and Recurrent Events (CARE) Study Scandinavian Simvastatin Survival Study (4S) Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Air Force/Texas Coronary Prevention Study(AF/TEXCAPS) Heart Protection Study (HPS) Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) *Expanded endpoint of cardiac death

Pravastatin

6595 (100)

31

Pravastatin

4159 (86)

24

Simvastatin 4444 (81)

34

Pravastatin

9014 (82)

23

Lovastatin

6605 (85)

36*

Simvastatin 20,536 (75)

27

Privastatin

19

5805 (48)

combined unstable angina, fatal and non-fatal MI and sudden

The primary endpoint was total mortality. Figure 4.1 demonstrates that the mortality rates of the simvastatin and placebo groups began to diverge at around 18 months into the study and continued this trend throughout the period of the trial. From these results it was calculated that there was a 30% reduction in total mortality for the patients on simvastatin. The secondary endpoint was major coronary events and here also there was an impressive risk reduction (34%) for the simvastatintreated group. The 4S study looked at two important subgroups, namely women and those over 60 years of age. The results show that simvastatin reduced the risk of major coronary events in women to a similar extent as that seen in men and that survival rates for those over 60 years of age were significantly improved. The study also demonstrated one important negative result: there was no increase in non-CHD mortality, such as death due to violence or cancer, observed in the simvastatin group. This puts to rest suggestions made by previous studies that lowering cholesterol may lead to increased mortality from other causes.

34 WHAT EVIDENCE DO WE HAVE THAT STATINS WORK?

Figure 4.1 Survival curves for total mortality in 4S. (Adapted from Scandinavian Simvastatin Survival Study Group, 1994.)

The frequency of adverse events was similar for both the simvastatin and placebo groups. Rhabdomyolysis occurred in one patient on simvastatin but recovery followed on cessation of treatment. Overall, the benefits of prescribing simvastatin to a group of 100 middle-aged, CHD patients for 6 years were summarized as follows: ■ Four of the expected nine deaths would be avoided ■ Seven of the 21 expected MI would be prevented ■ Six out of 19 revascularization procedures would be unnecessary West of Scotland Coronary Prevention Study: WOSCOPS This study, published in 1995 by Shepherd and his colleagues, was of a similar design to 4S, in that it was randomized, placebo-controlled and double blind, but it differed in that it was concerned with primary prevention and only men were included. A total of 6595 men, between the ages of 45 and 64 years, who had no history of MI were recruited. Subjects with stable angina, however, were eligible, provided they had not been hospitalized over the previous 12 months. LDL-cholesterol levels of the participants were within the 4.5–6.0 mmol/l range.

STATINS IN GENERAL PRACTICE 35

Figure 4.2 Event curve for fatal or non-fatal MI in WOSCOPS. (Adapted from Shepherd et al, 1995.)

Recruits were given either placebo or pravastatin 40 mg daily to be taken in the evening. The subjects were followed up over a 5-year period and those on pravastatin showed significant improvement in their lipid profile: ■ ■ ■ ■

Total cholesterol fell by 20% LDL-cholesterol fell by 26% Triglyceride fell by 12% HDL-cholesterol increased by 5%

The primary endpoint for WOSCOPS was fatal or non-fatal MI, and Kaplan Meier analysis, as shown in Figure 4.2, demonstrates that this was reduced by 31%. Deaths from any cause were also reduced in the pravastatin group by 22% and, as with 4S, there was no excess of non-cardiac deaths. The subgroup analysis of WOSCOPS also revealed some interesting findings. In particular, it was apparent that the benefits of pravastatin therapy were not affected by age. Those aged 55 and older obtained the same benefit as younger subjects. Similarly, smoking habits did not counter the beneficial effect of the drug. It was also noted that a significant benefit was seen in the subgroup without multiple risk factors and in those without pre-existing vascular disease.

36 WHAT EVIDENCE DO WE HAVE THAT STATINS WORK?

Extrapolation of the WOSCOPS data reveals that treatment with pravastatin over 5 years of 1000 middle-aged men with hypercholesterolaemia, but with no evidence of a previous MI, will avoid: ■ ■ ■ ■ ■

14 coronary angiograms Eight revascularization procedures 20 non-fatal MI Seven cardiovascular deaths Two deaths from other causes Cholesterol and Recurrent Events: CARE

The CARE study was performed in multiple centres throughout the USA and Canada and was published in 1996. The objective of this Table 4.2 Characteristics of the study subjects in Care baseline

Mean age (years) Total cholesterol (mg/dl) LDL-cholesterol (mg/dl) HDL-cholesterol (mg/dl) Triglyceride (mg/dl) % Female % Hypertensive % Diabetic % Current smokers

Placebo (n=2078)

Pravastatin (n=2081)

59 209 139 39 155 14 43 15 21

59 209 139 39 156 14 42 14 21

secondary prevention trial was to evaluate the effects of pravastatin therapy on rates of non-fatal MI and CHD death in post-MI patients without elevated total plasma cholesterol concentrations, who continued to receive standard post-MI treatments [aspirin, beta-blockers, percutaneous transluminal coronary angioplasty (PTCA)/coronary artery bypass graft (CABG)]. This was a double-blind, placebo-controlled, randomized trial of 4159 subjects between the ages of 21 and 75 who were 3–20 months post-MI. The subjects in the study were randomized to receive either pravastatin 40 mg daily or placebo and followed up for an average of 5 years. The primary combined endpoint was recurrent non-fatal MI or CHD death. Other endpoints of the study included coronary death, non-fatal MI, total mortality, the need for revascularization and stroke. The baseline characteristics of the study subjects are shown in Table 4.2. In the CARE study pravastatin therapy resulted in:

STATINS IN GENERAL PRACTICE 37

■ ■ ■ ■ ■

32% reduction in LDL-cholesterol (p<0.001) 24% reduction in fatal or non-fatal MI (p=0.003) 31% reduction in stroke (p=0.03) 26% reduction in CABG (p=0.005) 22% reduction in PTCA (p =0.01)

In summary, if 1000 post-MI patients with total cholesterol levels below 6.2 mmol/l (240 mg/dl) were treated for 5 years then 150 cardiovascular events would be prevented and 51 patients would be spared from having at least one such event. For patients over 60 years of age the corresponding figures would be 207 cardiovascular events and 71 patients. If the 1000 patients were all female the figures would be 228 cardiovascular events and 97 patients. Air Force/Texas Coronary Atherosclerosis Prevention Study: AF/TexCAPS This study randomized 6605 subjects (15% women) to either placebo or lovastatin, titrated up to 40 mg daily in order to achieve a target LDL-cholesterol goal of below 2.84 mmol/l (110 mg/dl). These individuals had no clinical evidence of atherosclerotic cardiovascular disease and the interesting feature of this study was that their baseline total plasma cholesterol level was, on average, 5.71 mmol/l (220 mg/dl), with an LDL-cholesterol level of 3.88 mmol/l (150 mg/ dl). Five years of therapy changed the lipid profiles as shown below: ■ ■ ■ ■

Total cholesterol LDL-cholesterol Triglyceride HDL-cholesterol

−18% −25% −15% +6%

Although these lipid changes did not result in significant reductions in CHD or total mortality they did result in the following significant changes: ■ Combined unstable angina, fatal and non-fatal MI or sudden −37% cardiac death ■ Revascularizations −33%

Long-term Intervention with Pravastatin in Ischaemic Disease: LIPID This study revealed equally interesting data. Here, 9014 subjects (17% female) drawn from 87 centres in Australia and New Zealand, with an average total cholesterol level of 5.65 mmol/l (218 mg/dl), were randomized to pravastatin 40

38 WHAT EVIDENCE DO WE HAVE THAT STATINS WORK?

mg daily or placebo and followed for an average of 6 years. Pravastatin therapy produced the following lipid changes: ■ ■ ■ ■

Total cholesterol LDL-cholesterol Triglyceride HDL-cholesterol

−18% −25% −11% +5%

and the following highly significant reductions in risk of mortality and morbidity: ■ ■ ■ ■

All cause mortality CHD deaths Fatal CHD and non-fatal MI Total strokes

−22% −24% −24% −19%

One unique aspect of the LIPID study arose from the decision to recruit substantial numbers of patients with unstable angina. These individuals benefited in terms of event avoidance as much as recruits with a history of MI. In conclusion, the principal investigator of the study summarized the clinical importance of the LIPID study by stating that the results suggested that ‘… virtually all patients presenting with myocardial infarction or unstable angina should now be considered for drug therapy’.

Atorvastatin Versus Revascularization Treatment: AVERT The AVERT study examined the effect of aggressive lipid-lowering therapy compared with angioplasty in stable angina pectoris patients. Three hundred and forty-one patients with stable CHD, relatively normal left ventricular function, asymptomatic or mild to moderate angina, and a serum LDL-cholesterol level of 115 mg/dl (3.0 mmol/l) or above, referred for PTCA, were recruited. The patients were randomly assigned to either atorvastatin 80 mg daily or to undergo PTCA followed by usual care, possibly including lipid-lowering or statin therapies. The follow-up period was 18 months. Of the atorvastatin-treated subjects, 13% suffered an ischaemic event compared to 21% in the angioplasty/usual care group (p=0.048). Furthermore, atorvastatin-treated patients had a significantly longer time to the first event compared to the control group (p=0.03). The authors concluded that in these relatively low-risk patients with stable coronary disease, aggressive lipid lowering with atorvastatin therapy was at least as effective as angioplasty and usual care in reducing the incidence of ischaemic events.

STATINS IN GENERAL PRACTICE 39

Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering: MIRACL The background to this study is based on the fact that all previous large-scale statin studies have systematically excluded acute patients from recruitment: in the 4S study entry was more than 6 months post-event, in the CARE study entry was 3–20 months post-event and in the LIPID study entry was 3 months to 3 years post-event. In the crucial period between the acute event and 3 months later many patients die or suffer second or subsequent events. While statin therapy has been proven to be of clinical benefit in stable patients more than 3 months after an event, no large study has examined the effects of statin therapy in this early high mortality/morbidity period. The MIRACL study recruited 3086 patients within 24–96 hours of an acute coronary syndrome. They were randomized to either atorvastatin 80 mg daily or placebo for 16 weeks, both with dietary education and counselling. Patients treated with atorvastatin experienced a significant reduction (16%, p=0.048) in the risk of the primary combined endpoint of death, non-fatal MI, cardiac arrest with resuscitation or recurrent symptomatic myocardial ischaemia requiring emergency hospitalization. The reduction in this combined endpoint was primarily due to a favourable effect of atorvastatin on recurrent symptomatic myocardial ischaemia, which was reduced by 26% (p=0.02). In addition, the incidence of stroke was significantly reduced in the atorvastatin-treated group compared to the placebo group. Atorvastatin therapy reduced the average LDLcholesterol level from 123 mg/dl (3.2 mmol/l), at baseline, to 72 mg/dl (1.9 mmol/ l). Pravastatin Pooling Project: PPP The PPP was a prospectively planned project designed to evaluate the consistency of the treatment effect of pravastatin at 40 mg daily on the clinical outcomes of coronary and all-cause mortality in three large, randomized, placebo-controlled studies—WOSCOPS, CARE and LIPID. These studies provided a combined patient population of approximately 20,000, followed for 5 years or more and yielding approximately 100,000 patient-years experience. Endpoint definitions were reviewed and prospectively defined based on individual study definitions as established in the respective protocols. In addition to the evaluation of fatal and non-fatal cardiovascular events, a combined analysis of non-cardiovascular outcomes was pre-specified. This included evaluation of the impact of cholesterol reduction on accidental death, violence, depression, suicides or cancers. PPP evaluated the effectiveness of treatment in special populations such as the elderly, women and diabetics, and in populations with a wide range of age and lipid values. The results of the PPP subgroup analyses are shown in Figure 4.3. These data clearly demonstrate the significant clinical benefits achieved in a broad spectrum

40 WHAT EVIDENCE DO WE HAVE THAT STATINS WORK?

Figure 4.3 The results of major subgroup analyses from PPP. *CHD death and non-fatal MI, PTCA and CABG, 19,768 patients with 3717 patients with events. (Data from Sacks et al, 2000).

of patients using pravastatin. In a further recent analysis of the mortality data from the PPP, highly significant reductions in total mortality (−20%, p<0.0001) and CHD mortality (−24%, p<0.001) were confirmed. Equally important, the PPP investigators confirmed that pravastatin was not associated with any increase in non-cardiovascular mortality. Heart Protection Study: HPS The HPS is a large trial designed to examine the effects of simvastatin and antioxidant vitamins on cardiovascular morbidity and mortality. Over 20,000 subjects were recruited into the HPS across a wide age range but all with a total cholesterol level above 3.5 mmol/l. In addition, all subjects were either secondary prevention candidates with a history of CHD, stroke or other vascular disease, or were at high risk because of a history of hypertension or diabetes. The study was designed in a 2×2 factorial format, comparing simvastatin 40 mg daily with antioxidants and placebo, singly or in combination. The mean follow-up period was 5.5 years, and the study included large cohorts of women, diabetic patients and subjects over 70 years of age. Based on an intention-to-treat analysis, the main findings of the HPS were: total mortality fell by 13%, cardiovascular death fell by 17%, fatal and non-fatal stroke fell by 25%, and all major vascular events fell by 24%. The corresponding

STATINS IN GENERAL PRACTICE 41

figures from the intention-to-treat analysis in PPP are 20, 24, 20 and 17%. Importantly, the rates of non-vascular deaths in the HPS were no different in the simvastatin-treated group and the placebo group. Importantly, the antioxidant vitamin arm of the HPS showed no benefit at all in the prevention of vascular events or all-cause mortality. However, HPS did demonstrate the benefits of statin therapy across a wide range of subjects, with both low and high cholesterol values. Diabetic patients without previous CHD benefited from therapy, and primary and secondary stroke prevention with statin therapy was confirmed.

5 Who should receive statin therapy?

Evidence base Both primary prevention and secondary prevention of CHD using statins are now based on a strong foundation of clinical trial evidence. Interestingly, the evidence gathered from the major statin trials reveals an apparently startling similarity in the clinical effectiveness of the three natural statins tested to date (simvastatin, pravastatin and lovastatin). Relative risk reductions of 25–30% in cardiovascular endpoints are seen across the trials, with virtually all patients, irrespective of baseline risk or cholesterol levels, benefiting from treatment. However, these figures do not reveal the wide variations in absolute risk reductions seen in different patient groups (Figure 5.1). While nearly all patients studied benefit from statin therapy, the absolute risk reductions achieved will vary considerably depending on baseline global risk. This has important implications for the number needed to treat (NNT) to prevent one event. This concept is an important one, which allows us to put risk reductions achieved with statins into a meaningful clinical context. For example, the NNT has been calculated to be 86 in the case of the low-risk population studied in AF/ TexCAPS, and to be approximately 43, 17 and 12 in WOSCOPS, CARE and 4S, respectively. Clearly, the higher the risk the smaller the number of patients needed to be treated to prevent one major event. In order to make the most cost-effective use of statin therapy it is therefore important to assess the global risk of vascular disease in patients before deciding whether or not to treat. However, even if this approach is adopted, the question of what threshold risk level at which to treat remains. In many respects this question is not a medical one but a socio-economic one, in that the answer is determined by financial and health service considerations. If the risk level for intervention with statins is set low then a large number of patients would be eligible for treatment, while a higher risk threshold would significantly reduce the number treated and the associated cost of therapy

STATINS IN GENERAL PRACTICE 43

Figure 5.1 Absolute versus relative risk (RR) reductions in the major statin trials. Hazards are calculated on the most comprehensive endpoint per person-year and vary slightly between trials.

Figure 5.2 Proportions of the population that would be treated using different risk thresholds.

(Figure 5.2). Consequently, the threshold risk level that can be tolerated will vary from country to country and between different health care systems. Arguments for a threshold annual risk of 3% in primary prevention have been proposed as a

44 WHO SHOULD RECEIVE STATIN THERAPY?

workable compromise between desirability and affordability, and this level is advocated by the authors of the Sheffield tables. The present author would argue that the risk level chosen should at least encompass all patients who have suffered a vascular event, as the evidence for cost-effective protection with statins in these individuals is overwhelming. This approach of secondary prevention is often viewed as distinct from the prevention or delay of first vascular events. So-called primary prevention is viewed by many as a more controversial option, as it deals with patients at apparently much lower risk than those who have already demonstrated their high-risk status by suffering an event. Furthermore, many view primary prevention as not being cost-effective. This is, to some extent, erroneous. First, a recent international costeffectiveness analysis of WOSCOPS (a primary prevention study) has revealed that statin use is both clinically effective and cost-effective across a range of health care systems, and the authors concluded that this primary prevention approach should fit within the bounds set by already accepted therapies in most countries. Second, as can be seen in Figure 5.3, the risk spectrum does not neatly separate primary and secondary prevention. Indeed, some individuals who have not yet suffered an event, such as the highest risk participants in WOSCOPS, actually have a higher global risk score than some of the post-MI patients in the CARE study. Clearly, it is inappropriate to advocate secondary prevention and simultaneously question the validity of higher risk primary prevention if one believes in treating all patients at high risk. It is essential to appreciate that all patients who may be considered for primary prevention are not equal, at least in terms of their baseline cardiovascular risk. Clinicians entrusted with the management of vascular risk must cater for a wide range of clinical need. For example, within their care there will be healthy young women whose risk of a major cardiovascular event over the next decade may be vanishingly small. However, there will also be smoking, hypertensive, Type 2 diabetics whose risk of an event will often be close to that of an MI survivor. It would be inappropriate to assign automatically a low risk to patients simply because they have not yet suffered an event. This approach is ratified by the latest National Cholesterol Education Program (NCEP) guidelines from the US, which have introduced the concept of CHD risk equivalence. Patients who have diabetes or even the metabolic syndrome are viewed as being at particularly high risk, and diabetic patients, according to the NCEP ATP III guidelines, should be managed as if they were candidates for secondary rather than primary prevention, even if they have no history of overt cardiovascular disease. Thus, the threshold risk level used should not only encompass all subjects who have suffered an event but also those at highest risk of a first event. Any such level is, by necessity, arbitrary, but a figure of 2% per annum is both reasonable and one that was advocated by the original Joint European Guidelines. This argument does, however, beg the question of how should global vascular risk be assessed.

STATINS IN GENERAL PRACTICE 45

Figure 5.3 CHD risk spectrum. The overlap between primary and secondary prevention is shown.

Risk assessment Statins, it may be argued, should be prescribed not on the basis of cholesterol levels alone but rather using global risk scores that include lipid levels but do not depend on them. Others would support this argument against a lipocentric approach and, indeed, many guidelines outside the US have taken this global risk approach. There are a number of charts, calculators and computer programs available to assist the clinician. None of these devices is definitive, as none of them are able to incorporate all known CHD risk factors. For example, family history is often omitted from risk assessment tools, despite the fact that this is regarded as one of the most important predictors of future vascular disease. However, all these tools serve to reduce the focus on single risk factors in an attempt to assess the

46 WHO SHOULD RECEIVE STATIN THERAPY?

integrated or global risk. These relatively simple devices allow the clinician to combine a number of major discrete and continuous risk factors into a single risk score in the form of a percentage chance of suffering a major vascular or coronary event over the next 5–10 years, and then to base the treatment decision upon this number. The choice of risk assessment tool has been the subject of some debate and a number of studies have compared different approaches. The revised Sheffield tables have recently been introduced as have updated New Zealand tables. The new Sheffield tables incorporate a total cholesterol:HDL-cholesterol ratio rather than total cholesterol alone in order to improve the accuracy of risk estimation. This has been one of the major criticisms of the former Sheffield tables, which some have regarded as significantly underestimating the risk in women. The New Zealand tables have proven popular since their introduction and a recent survey of the clinical usefulness of different risk assessment tools found that among doctors and nurses these tables were the most favoured, while the Sheffield tables were the least favoured. Whatever tool is used, it should be based on data derived from large prospective studies such as Framingham or the Prospective Cardiovascular Minister (PROCAM). The Framingham Heart Study risk equations have been shown to be valid in UK populations and these may be preferred. Also, with advancing technology it makes sense to adopt computerized or even interactive versions of these in order to maximize their utility. The most useful risk assessment devices are therefore likely to be computer-based, Framinghamderived, non-tabular systems, such as that accompanying the Joint British Guidelines. The practicalities of putting any risk assessment or treatment strategy into practice must also be considered alongside the scientific evidence that underpins it. Even with close clinical follow-up or detailed physician education it may be very difficult to achieve the implementation of any new set of guidelines. Even accurate risk assessment, however, does not resolve all the challenges to the practicing clinician in this field. Usually, risk assessment is performed at baseline before intervention, either by lifestyle approaches or by drug therapy. However, if risk assessment is repeated at a later date and, as a result of lifestyle changes, the risk estimate has fallen below the threshold for intervention, should drug therapy be ruled out? Similarly, many physicians are perplexed by which risk factors they should tackle first in the high-risk patient. Many patients will present with obesity, hypertension and hyperlipidaemia. This is a difficult situation but the clinician should adopt an evidence-based approach and, in so doing, should intervene early, as appropriate, with statin therapy. .

6 What about statin use in the elderly?

The results of PROSPER have added enormously to our understanding of the use of statins in the elderly. Before describing the results of that study in detail it is useful to look at what evidence was available to support the use of statin therapy in the elderly pre-PROSPER. Although, prior to PROSPER no published statin trial had been directed exclusively at elderly subjects, there were elderly cohorts within several studies. In 4S, a subgroup analysis was performed on those subjects aged 65 or over and it was clear that this group, although relatively small in number in the study, enjoyed a similar event reduction to their younger counterparts. In the second major secondary prevention trial with a statin—the CARE study—a similar analysis was performed and again the same result was found: older subjects appeared to benefit from statin therapy in much the same way as younger subjects in the trial. CARE involved almost 1300 elderly patients (between the ages of 65 and 75) with a previous history of MI. These were patients whose plasma total cholesterol before entering the study was below 6.2 mmol/1, and whose LDL-cholesterol levels were in the range of 3.0–4.5 mmol/1. In the CARE study, the relative risk of a major coronary event was reduced by 32% in those receiving pravastatin (40 mg daily) compared to placebo (p<0.001) over the 5 years of the study. It was clear from the results of the CARE study that in older patients with established CHD, even those with average cholesterol levels, secondary prevention with pravastatin dramatically reduced the risk of subsequent coronary events and strokes. The CARE investigators noted, however, that despite their high risk, such older patients are much less likely to receive medication that might protect them from cardiovascular events than their younger counterparts. In Figure 6.1 the cardiovascular event reduction in age-specific subgroups from the LIPID study are shown. Perhaps, best of all, this demonstrates the difficulty in relying on subgroup analyses and the reasons behind the ongoing controversy over the use of lipid-lowering drugs in the elderly. In the LIPID study, which was a large trial performed in Australia and New Zealand, involving more than 9000 subjects, the benefit of prescribing pravastatin to highrisk individuals was tested. Overall, the group showed highly significant

48 WHAT ABOUT STATIN USE IN THE ELDERLY?

Figure 6.1 Relative risk reductions in coronary events: a subset analysis of the LIPID study. *CHD death and non-fatal MI. NS, Not significant. (Adapted from the Lipid Study Group, 1998.)

reductions in total and CHD mortality. In common with the 4S and CARE investigators, the LIPID investigators also examined the impact of age on event reduction. Younger and middle-aged groups appeared to do well, as did those up to the age of 69 years, but in the 70 years and older group there was no significant change in the risk of cardiovascular events. Does this mean that the over 70s do not benefit or is this simply a function of the relatively small numbers of subjects in this age group recruited into the LIPID study, which after all was not primarily a study of the elderly? Almost certainly, it is the latter, but nevertheless these data have been used to support discussion of a veto on the use of statins in this age group. Thus far, we have looked exclusively at the evidence for using statins in the elderly to prevent CHD. However, we should not forget that one of the principal manifestations of atherosclerotic disease in the elderly is cerebrovascular disease. Stroke rates are mercifully low in younger populations but increase exponentially with age, with the highest rates in the over 70s. Is there any evidence that stroke rates can be affected by lipid-lowering therapy? Again, we must rely on subgroup analyses from the major statin trials, as there have been no dedicated stroke prevention studies performed to date.

STATINS IN GENERAL PRACTICE 49

The first concrete evidence that manipulation of the lipid profile using a statin would reduce the risk of stroke came from a post hoc analysis of 4S. In this study hypercholesterolaemic subjects with clinical coronary disease were randomized to simvastatin 20–40 mg daily or placebo and followed for approximately 5 years. The 4S investigators conducted a post hoc analysis of their data to answer the following question: does simvastatin reduce cerebrovascular risk in patients with established coronary disease and raised total cholesterol levels? They observed a 28% reduction in the relative risk of total cerebrovascular events (stroke plus TIA) (p=0.03). Definitive evidence that stroke rates could be reduced in high-risk subjects came from two further major statin trials—the CARE and LIPID studies. Importantly, in both of these studies stroke was a pre-specified endpoint. In the CARE trial over 4000 survivors of MI with average total cholesterol levels were examined. Using a fixed dose of pravastatin (40 mg daily) there were significant reductions in the relative risk of cardiovascular events and a 32% reduction in risk of stroke (p=0.03). The LIPID study used the same dose of pravastatin as did the CARE study and again demonstrated significant risk reduction for stroke, which was also a prespecified endpoint. In subjects who either had suffered an MI or who had unstable angina there was a 19% reduction in the relative risk of stroke (p<0.05). These clinical trials offer compelling evidence that statin therapy will reduce the risk of stroke as well as coronary disease in high-risk patients. But does this apply equally to the elderly? Because the majority of patients in 4S and the CARE and LIPID studies were middle-aged, some clinicians have been unconvinced about the use of statins to prevent the clinical consequences of cerebrovascular disease in the elderly. What is required is trial evidence for the prevention of both coronary and cerebrovascular disease in large, elderly cohorts. Two studies have now addressed this deficiency in our evidence portfolio. The HPS has recently provided data on the impact of simvastatin in a large patient group that includes over 5000 patients aged 70 or older. In this group, statin therapy had significant benefit over a 5.5-year period on both coronary and cerebrovascular events. Shortly after the publication of the HPS came the first dedicated study of the elderly using statin therapy—PROSPER. Prospective Study of Pravastatin in the Elderly at Risk: PROSPER PROSPER is a double-blind, randomized, placebo-controlled multicentre study that was completed in 2002, and was designed to examine the hypothesis that pravastatin would reduce cardiovascular and cerebrovascular events in elderly subjects with either existing vascular disease or a high risk of developing the condition. Recruited from primary care 5804 elderly men and women, 70–82 years of age, with total plasma cholesterol levels of 4.0–9.0 mmol/1 and triglyceride

50 WHAT ABOUT STATIN USE IN THE ELDERLY?

levels below 6 mmol/1. This study is the first in which the proportion of female participants exceeds that of males (52% versus 48%, respectively). Participants were randomized to pravastatin 40 mg daily or placebo and were followed up for approximately 3 years. This makes PROSPER the shortest of the major placebo-controlled statin trials. The primary endpoint was a combination of CHD death (definite plus suspect), non-fatal MI (definite plus suspect) and fatal plus non-fatal stroke. Secondary analyses examined the primary end-point in each of the following subgroups: men, women and subjects with and without preexisting vascular disease. Coronary and cerebrovascular events were also looked at separately. It is important to note that no distinction was drawn between primary and secondary prevention in this study, and that the lipid inclusion range was very wide. The impact of pravastatin 40 mg daily on the plasma lipid profile was as expected: there were highly significant reductions in total (−23%) and LDLcholesterol (−34%), and triglyceride (−13%), and a significant increase in HDLcholesterol (+5%). These effects were sustained throughout the study and were not associated with any increase in hepatic or muscle side effects. In fact, despite the high concomitant medication rates in this population there were no cases of rhabdomyolysis. The impact of pravastatin on the major clinical endpoints in PROSPER are shown in Figures 6.2 and 6.3. In PROSPER there was a significant (15%) reduction in the combined primary endpoint of the study. When the coronary components of this endpoint were looked at separately a 19% reduction in coronary events and a 24% reduction in coronary deaths was observed. In this cohort, whose average age was 75, pravastatin can therefore prevent approximately one in five of all heart attacks and a quarter of all heart attack deaths. The impact of pravastatin on stroke rates in the study was looked at separately, but over the relatively short duration of the study no significant difference was noted. Interestingly, other statin trials, such as 4S, and the CARE and LIPID studies that have reported stroke reductions, have only done so over a 5–6 year period. PROSPER provides clear evidence that, as in middle age, statin therapy in the elderly reduces the risk of coronary disease, even in as short a period as 3 years. This supports the view that the elderly should be treated with a statin to reduce their cardiovascular risk, especially if they are at increased risk. Thus, this study adds to the consensus that statin treatment, at any age, is best targeted at those at greatest risk. With the collective evidence from the first statin trials and more recently the large elderly cohort in HPS coupled with the results of PROSPER, we should now have the confidence to use statins in elderly patients in the same way that for many years they have been used in middle-aged patients, i.e. age should no longer be a barrier to statin treatment.

STATINS IN GENERAL PRACTICE 51

Figure 6.2 Effects of pravastatin on combined primary endpoint (CHD death and nonfatal MI, and fatal and non-fatal stroke) in PROSPER (RRR, relative risk reduction).

52 WHAT ABOUT STATIN USE IN THE ELDERLY?

Figure 6.3 Effects of pravastatin on combined CHD death and non-fatal MI (a), and on the CHD death alone (b) in PROSPER (RRR, relative risk reduction).

7 What does the future hold?

The growth of statin usage is almost exponential at present. In addition, new statins are scheduled for launch in the near future. Statins are being proposed for other therapeutic targets such as stroke and diabetes, but there remain many unanswered questions about the appropriate use of statins, even in patients at risk of CHD. This section will take a forward look at these issues. Unanswered questions Despite the enormous amount of statin clinical trial data that has been assembled over the last decade there remain a number of clinically important questions to which we are only just beginning to formulate answers. A number of these questions are being addressed in a series of large clinical trials that are currently under way. At present there are probably more than 30 major statin trials active, but it would not be possible to cover all of these here. Instead, examples of these trials will be discussed in the context of the outstanding questions that they are attempting to answer. Should statins be used in diabetes? Type 2 diabetic patients are a very high-risk group of patients with respect to vascular disease. Subgroup analysis from studies such as 4S and the CARE study have suggested that statin therapy would be even more effective in this group than in non-diabetic subjects. However, to date, no large-scale intervention trials have been conducted specifically to address this question. This will change soon when the results of a series of statin and diabetes studies are published. An example of such a study is the Collaborative Atorvastatin and Diabetes Study (CARDS). This study of atorvastatin 10 mg daily versus placebo is being conducted in 2750 Type 2 diabetics with no history of CHD but with one other CHD risk factor. The primary endpoint will be major cardiovascular events such as fatal and non-fatal MI, but will also include diabetic sequelae such as proteinuria and retinopathy.

54 WHAT DOES THE FUTURE HOLD?

Should statins be used to prevent stroke? Again, subgroup analyses from the large intervention trials with statins have provided some good evidence that simvastatin and pravastatin significantly reduce the rate of stroke in patients with pre-existing coronary disease. But what of stroke prevention in patients with no history of vascular disease or in those who have already suffered one or more cerebrovascular events? Some useful information has been provided by HPS and PROSPER but further dedicated stroke trials are warranted. One such study is the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study. Which statin is best? Given that there are now six commercially available statins worldwide, with four of these currently marketed in the UK, this is an obvious and important clinical question. The statins are clearly not identical structurally or pharmacologically but the most important facet of their mechanism of action is their ability to prevent vascular events. Whether all statins are equal in this respect can only be tested in true head-to-head trials. A number of these are now underway. One of the largest, the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial, was announced at the end of 1999 and will be the first head-tohead trial to compare pravastatin and atorvastatin using a clinical event endpoint. This clinical trial is also designed to study the effects of anti-infective therapy (gatifloxacin) on cardiovascular event reduction with regard to the role of Chlamydia pneumoniae. In addition, PROVE-IT will measure inflammatory markers of coronary heart disease, including hs-CRP. PROVE-IT is a double-blind, randomized controlled trial that will enroll approximately 4000 patients from 500 US and international sites, all of whom have experienced an acute coronary syndrome within the previous 10 days. Patients will receive either 40 mg daily of pravastatin or 80 mg daily of atorvastatin shortly following their event and will be followed for a period of at least 1.5 years. The primary endpoint of the trial will be a composite of major cardiovascular events. To study the role of infection in CHD, one half of the patients in the trial will also receive the antibiotic gatifloxacin in addition to either statin. The other half of the patient population will receive an antibiotic placebo (a 2×2 factorial randomization). Which dose is best? There is a simple answer to this question: the dose that was tried and tested in the major clinical trial. The practice of evidence-based medicine calls not only for the adoption of those drugs used in randomized, controlled trials but also for the prescription of those drug doses used in the trials. All major pravastatin trials

STATINS IN GENERAL PRACTICE 55

have used a single dose of 40 mg daily, without titration. Similarly, the lion’s share of major simvastatin trial participants were treated with 40 mg daily. Thus, it can be argued that all patients receiving pravastatin or simvastatin should be prescribed 40 mg daily. Clearly, the simple answer, although correct, is not necessarily what some clinicians wish to hear, for they are seeking justification to use the lowest and often the least expensive statin doses that can be effective. In a climate where cost-containment is advocated this approach is understandable but, unfortunately, we do not have extensive dose-ranging data on the clinical effectiveness of the statins at present. As such, the present author would argue that we should fall back on what we know for certain. This means taking the trial evidence and using the drugs and doses found to be effective in terms of reducing clinical endpoints and extending life. We will have more information on this important point in the future when studies such as the Treat to New Target (TNT) study and the Study of the Effectiveness of Additional Reductions of Cholesterol and Homocysteine (SEARCH) report their findings. The TNT study aims to compare the clinical outcomes in two groups of patients receiving either low dose (10 mg daily) or high dose (80 mg daily) atorvastatin, while SEARCH is comparing simvastatin 20 versus 80 mg daily. What about alternatives to statins? The clinical benefits of statins are so impressive that some enthusiasts have been emboldened to write that they ‘are to atherosclerosis what penicillin was to infectious disease’. Taking that analogy one step further might lead us to wonder whether statins represent the pinnacles of our needs as far as lipid-lowering is concerned. If antibiotics have taught us anything, it must surely be that nature is not as easily tamed as we might imagine. Cholesterol-lowering with statin therapy might not be the whole answer to atherosclerosis and vascular disease prevention, for it may be argued that if it were, coronary events would have been eliminated in the published trials rather than ‘merely’ reduced by 30%. Clinical trials are, of course, not the whole story and do not systematically test the multiple risk-factor modification approach that should be adopted in daily clinical practice. However, there is another more cogent reason why we should gain comfort from continuing lipid-lowering drug development. The primary mechanism of action of statins is to promote the clearance of LDL-cholesterol from the circulation. But the majority of dyslipidaemic patients admitted to the coronary care unit usually exhibit raised plasma cholesterol and triglyceride levels rather than hypercholesterolaemia alone. While the statins were specifically designed to deal with the latter problem, their ability to lower plasma triglyceride levels is usually more limited.

56 WHAT DOES THE FUTURE HOLD?

Thus, the pharmaceutical industry has embarked on a search for new drugs to target triglyceride-rich lipoprotein production and some of these drugs are currently in early trials. One other approach to lipid-lowering that may complement statin therapy is the development of drugs to block cholesterol absorption from the gut, while yet another is to seek new drugs that will act primarily on raising HDL-cholesterol. One such inhibitor of cholesterol absorption is the new drug ezetimibe. This drug appears to be a useful adjunct to statin therapy in patients whose cholesterol goals cannot be achieved by monotherapy. There is certainly no shortage of activity in this rapidly evolving field and we can expect several novel lipid-lowering drugs in the next few years. How can patient compliance be improved? As with any chronic medication for an asymptomatic condition, statin therapy is unfortunately associated with relatively poor patient compliance. Indeed, some investigators report a 50% dropout rate from therapy after only 12 months. Impressive as the clinical trial results with statin therapy may be, we will never translate these findings into clinical reality if we cannot achieve better compliance amongst our patients. In order to assist us in this goal it is worthwhile examining the background to our patients’ and our own perceptions of CHD risk. These have recently been evaluated in a series of surveys. Patients perceive a greater risk of CHD from smoking and parental death from a coronary event than from cholesterol and blood pressure. In a primary care survey of middle-aged men and women, more patients were optimistic (37%) than pessimistic (21%) about their risk of developing CHD. Over-optimistic perceptions of risk and indifferent attitudes to change may explain why health promotion campaigns have had only a modest effect in changing attitudes about prevention of CHD. Even post-MI patients, who may be expected to be highly focused, have been reported to be more concerned about the risks of non-cardiovascular diseases. The recent pan-European Leader Panel (HELP) study was designed to provide more information about awareness and attitudes towards reducing CHD. The investigators interviewed over 10,000 patients across Europe and found that individuals had a reasonable knowledge of the risks involved in triggering an acute coronary event, yet many displayed an indifference in reducing this risk, even those who had suffered a previous MI. Both the general public and high-risk groups identified cancer and heart disease as the two major causes of death. Surprisingly, 72% of the general public claimed to have had their cholesterol level checked, compared with only 51% of the high-risk group. However, more patients in both of these groups said they had received information about cholesterol reduction from friends and magazines rather than from their doctor. Despite this, both groups rated the cardiologist,

STATINS IN GENERAL PRACTICE 57

primary care physician and hospital as the three most credible sources of information. Although post-MI patients said that they were not overly worried about experiencing another heart attack, 80% reported making spontaneous changes to their lifestyle after the heart attack. More post-MI patients received information from the medical profession than from television, magazines and newspapers, compared with the general public (Table 7.1). However, only 23% of the postMI group had been warned that their cholesterol level was too high and of these patients only 21% could recall their cholesterol level, while 16% of the post-MI patients reported being advised to lower Table 7.1 Proportion of the general public and post-MI patients who obtain their heart health information from health care professionals and from various media sources. (Adapted from Shepherd et al, 1997.) Source

Number of patients (%)

General public

Post-MI patiets

Television Newspapers Magazines Doctor Cardiologist Consultant Family Friends Don’t know Other

20 18 14 16 2 2 6 5 6 11

5 4 2 30 28 13 2 1 3 12

their blood pressure. Of the post-MI group, 53% claimed to have followed all of their primary care physician’s advice, while 27% reported having followed most of it. All groups also returned a very high level of satisfaction with the advice given by the primary care physician. The HELP study concluded that although patients had access to many sources of heart health information, which in the case of the medical profession were perceived as highly credible, this had only a limited impact on their adherence to preventive treatments and advice. This study also highlights the fact that once information is provided, little is done to ensure that it is implemented. It seems that where lifestyle changes fail to be carried through, the use of statin therapy is less than adequate. In post-MI patients, in particular, the medical profession believes that only certain messages such as diet, exercise, smoking, regular screening and stress management are getting through to patients, whereas messages of cholesterol-lowering, therapy compliance, weight reduction and family screening are not (Table 7.2).

58 WHAT DOES THE FUTURE HOLD?

What are the barriers to prescribing statins? We now know what we should be doing but often it does not happen. Why should this be so? Many barriers have been identified which obstruct the implementation of evidence-based therapy in the secondary prevention of CHD. This treatment gap may result from one or more weaknesses in the chain of responsibilities to Table 7.2 Physicians’ perceptions about which messages regarding CHD prevention are succeeding and those which are failing to get through to post-MI patients. (Adapted from Shepherd et al, 1997.) Succeeding

Failing

Diet and health Exercise Smoking Regular screening Stress management

Cholesterol-lowering Therapy compliance Weight redaction Family screening

provide risk-reduction care. These include the formulation and implementation of a risk-reduction plan by the hospital, the effectiveness with which the plan is communicated to primary care follow-up, the formulation of a new plan or implementation of the hospital recommended plan, and finally patient compliance with the treatment plan. The primary care team are in a favourable position to take on the task of secondary CHD prevention because they have an ongoing relationship with the patient, which offers them the chance to monitor the patient’s progress, motivate the patient to make lifestyle changes and ensure long-term compliance with drug therapy. The lack of clear, national or local guidelines for secondary prevention is reported to be a shared barrier for both cardiologists and primary care physicians in taking any preventive action. However, in England at least, this may now be dealt with in the form of the National Service Framework for Coronary Heart Disease. Here, despite its many critics, is a reasonable attempt at formulating a national and consistent strategy. Embedded in this strategy is a firm and unequivocal endorsement of statin use both in primary and secondary prevention. Statin prescribing tomorrow Despite all the difficulties, the appropriate prescription of statin therapy is growing rapidly, stimulated no doubt by the publication of new and authoritative evidence-based guidelines. The one remaining barrier to full implementation is financial. Many economists, health professionals and governments remain

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concerned over the impact that this will have on health care budgets. Consequently, old, unproven, albeit cheaper, therapeutic approaches remain in place, despite evidence of the clear benefits of statin therapy. This is poor medicine and of questionable benefit to society. However, the weight of clinical trial evidence is now so strong that it is impossible to ignore and new strategy documents produced by traditionally conservative bodies now firmly endorse the appropriate use of statins in both primary and secondary prevention. These cost-containment arguments will, however, dissolve in the future as the loss of statin patent protection, which will occur over the next few years, will lead to the introduction of lower-priced statin generics. Indeed, in the foreseeable future, and subject to the longer-term proven safety of these drugs, statins may receive widespread over-the-counter status, thereby transferring the cost consideration of their use from health authorities to the individual. Perhaps then, evidence-based medicine will truly be adopted.

Glossary of terms

4S,

AF/TexCAPS, Apolipoproteins,

Apo A-I,

Apo E,

Arcus, Arteriosclerosis,

ASCOT, Atheroma, Atherosclerosis,

Atorvastatin,

AVERT, Beta-quantification,

Scandinavian Simvastatin Survival Study. AF/ TexCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study. Air Force/Texes Coronary Atherosclerosis Prevention Study. these are special proteins that are present in lipoproteins. They are named by letters and numbers and each has a specific structural or metabolic function. apolipoprotein A-I is the major apolipoprotein in HDL. Apo B, apolipoprotein B is the major apolipoprotein of VLDL, IDL and LDL, and acts as a ligand for the LDL receptor. Apo C-II, apolipoprotein C-II is the cofactor necessary for the action of lipoprotein lipase. apolipoprotein E is present in VLDL, HDL and chylomicron remnants, and acts as a ligand for the LDL receptor. see Corneal arcus. means hardening of the arteries. This term is often used interchangeably with atherosclerosis but it is a much less specific term describing a broad range of vascular pathology. Anglo-Scandinavian Cardiac Outcomes Trial. see Atherosclerosis. a chronic disease process characterized by a focal, inflammatory fibro-proliferative response to multiple forms of endothelial injury. This results in the buildup of fibrofatty deposits called plaques within the artery wall. an HMG CoA reducatse inhibitor that has a prolonged half-life. This statin was used in the AVERT, ASCOT and MIRACL trials. Atorvastatin Versus Revascularization Treatment study. detailed form of lipid profiling that provides the following measurements: total cholesterol, total

GLOSSARY OF TERMS 61

triglyceride, LDL-cholesterol, VLDL-cholesterol and HDL-cholesterol. Rarely required for routine patient management. Bezafibrate, a fibric acid derivative used in the management of patients with dyslipidaemia, principally those with hypertriglyceridaemia and low HDL. Bile acid sequestrant resin,class of lipid-lowering drugs. These compounds are not absorbed from the gut but bind bile acids and prevent their reabsorption from the terminal ileum. The liver has then to increase its synthesis of bile acids, which it does by using the circulating cholesterol as a building block. These drugs therefore result in lowering of plasma cholesterol and, more specifically, the LDL-cholesterol. BMI, see Body mass index. Body mass index, calculated by dividing the body weight in kilograms by the height squared in metres. CABG, coronary artery bypass graft. CAD, see Coronary artery disease. CARDS, Collaborative Atorvastatin and Diabetes Study. CARE Study, Cholesterol and Recurrent Events study. Cerivastatin, an HMG CoA reductase inhibitor prescribed in microgram rather than milligram doses. This statin was withdrawn in August 2001 because of safety concerns. CETP, see Cholesteryl ester transfer protein. CHD, see Coronary heart disease. Cholesterol, a white waxy substance insoluble in water. Cholesterol is composed of 27 carbon atoms in the form of four interconnecting rings with a tail. It is found only in animal cells; plants cannot manufacture cholesterol. Cholesteryl ester, form of cholesterol in which a fatty acid is attached to its third carbon atom through an ester bond. This is the storage form of cholesterol which is found inside cells and in the core of lipoproteins. Cholesteryl ester transfer an enzyme involved in the exchange of cholesteryl protein, esters and triglyceride between lipoproteins. Cholestyramine, a bile acid sequestrant resin sometimes used in the treatment of hypercholesterolaemia. Chylomicron, the largest of the lipoproteins, this particle is made in the gut where it is used to carry dietary fats to the rest of the body. It is normally absent from the bloodstream after an overnight fast.

62 GLOSSARY OF TERMS

Ciprofibrate,

a fibric acid derivative used in the management of patients with dyslipidaemia, principally those with hypertriglyceridaemia and low HDL. Colestipol, a bile acid sequestrant resin sometimes used in the treatment of hypercholesterolaemia. Corneal arcus, deposit of cholesterol in the clear outer covering (cornea) of the eye. Corneal arcus before the age of about 55 is usually indicative of an underlying lipid disorder. However, when present in the elderly (arcus senilis) it does not have the same significance. Coronary arteries, the arteries that supply blood, and therefore oxygen and nutrients, to the heart muscle. There are three major coronary arteries: the right coronary artery, the left anterior descending coronary artery and the left circumflex coronary artery. Coronary artery disease, see Coronary heart disease. Coronary heart disease, this is the commonest cause of serious illness and death in the industrialized world. It results from blockages of the coronary arteries and leads to the development of angina if the blockages are incomplete or an MI if the coronary arteries become completely occluded. CRP, C-reactive protein. Dyslipidaemia, any disorder characterized by an aberrant lipid profile, often used when a general term is required to cover increased lipid levels, abnormal patterns and decreased lipid levels. ECG, electrocardiogram. Endothelium, the layer of cells that line the interior surface of any blood vessel. Ezetimibe, a novel inhibitor of cholesterol absorption that blocks intestinal absorption of both dietary and biliary cholesterol without affecting the absorption of fatsoluble vitamins or triglyceride. Familial combined an inherited disorder causing premature coronary hyperlipidaemia (FCH), heart disease in which affected individuals have either a raised blood cholesterol level alone, a raised blood triglyceride level alone or both. Familial an inherited disorder causing premature coronary hypercholesterolaemia heart disease in which affected individuals have high (FH), levels of total cholesterol and, specifically, LDLcholesterol. FH is due to an inherited defect in the LDL receptor that prevents removal of LDL particles from the blood-stream at a normal rate. Subjects with

GLOSSARY OF TERMS 63

a single faulty copy of the LDL receptor gene are called FH heterozygotes and those with two faulty copies are called FH homozygotes. Fasting sample, a blood sample collected after a 12–14 hour fast (i.e. no foods or calorie-containing fluids consumed). This is done to obtain a lipid profile uncontaminated by dietary lipids. Fatty acid, a member of the lipid family, this type of molecule consists of a chain of carbon atoms whose length and degree of saturation vary. Saturated fatty acids are those where all the positions in the carbon chain are occupied or saturated with hydrogen atoms, i.e. no double bonds. A monounsaturated fatty acid is one where a single position in the carbon chain is unsaturated, i.e. two adjacent carbon atoms are missing one hydrogen atom and are joined by a double bond. Fatty streak, the earliest visible stage of the atherosclerotic process. These are slightly raised yellow streaks visible on the interior of the artery and are due to the accumulation of lipid-filled macrophages within the artery wall. FCH, see Familial combined hyperlipidaemia. Fenofibrate, a fibric acid derivative used in the management of patients with dyslipidaemia, principally those with hyper-triglyceridaemia and low HDL. FH, see Familial hypercholesterolaemia. Fibrate, a drug derived from fibric acid used to lower blood lipid levels (see Bezafibrate, Ciprofibrate, Fenofibrate, Gemfibrozil). Fluvastatin, the first synthetic HMG CoA reductase inhibitor. Fredrickson’s the WHO classification of lipid disorders which is classification, based on a phenotypic analysis of the plasma appearance and the lipid levels. This system divides lipid disorders into six classes: types I, IIa, IIb, III, IV and V hyper-lipoproteinaemia. Gemfibrozil, a fibric acid derivative used in the management of patients with dyslipidaemia, principally those with hyper-triglyceridaemia and low HDL. HDL, see High density lipoprotein. Heterozygote, an individual with two different copies of a gene, usually one normal and one faulty. High-density lipoprotein a lipoprotein that carries about 20–25% of the blood (HDL), cholesterol. About 50% of HDL is protein, the major

64 GLOSSARY OF TERMS

HMG CoA reductase inhibitor,

HPS, hs-CRP, Hypercholesterolaemia, Hyperlipidaemia,

Hypertriglyceridaemia, IDL, Intermediate density lipoprotein (IDL),

Ischaemia,

Joint European Guidelines,

LDL,

constituent being Apo A-I. HDL removes cholesterol from the surface of cells, esterifies it and then transfers the cholesteryl ester to other lipoproteins for delivery to the liver for processing. HDL is sometimes referred to as ‘good’ cholesterol because high levels of HDL are associated with a lower risk of coronary heart disease and low levels with a higher risk. a class of drugs, also known as statins, that block the manufacture of cholesterol by cells by inhibiting the action of an enzyme called HMG CoA reductase. These drugs reduce the amount of cholesterol inside cells, leading to an increase in the number of LDL receptors on the cell surface and an increased removal of LDL from the blood (see Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Pravastatin, Rosuvastatin and Simvastatin). Homozygote, an individual with two identical copies of a gene, usually both faulty. Heart Protection Study. high-sensitivity CRP. a high level of total cholesterol in the blood. a high level of lipids (cholesterol, triglyceride or both) in the blood. May be corrected by diet, drugs or surgical means. a high level of total triglyceride in the blood. see Intermediate density lipoprotein. a transient intermediate generated from VLDL en route to LDL as a by-product of the breakdown of triglyceride in VLDL and VLDL remnants. IDL is relatively enriched in cholesterol. Some IDL is removed from the bloodstream by the LDL receptor and the remainder is converted to LDL by further delipidation. lack of oxygen to cells, leading to injury and, if severe enough, to permanent damage or scarring of the tissue. recommendations of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension. This is an important consensus statement by three large European organizations, including detailed guidelines for the screening and treatment of individuals at risk of coronary disease. see Low-density lipoprotein.

GLOSSARY OF TERMS 65

LDL receptor,

Lipid, Lipid clinic, Lipid profile,

LIPID study, Lipoprotein,

Lipoprotein lipase, Lovastatin, Low-density lipoprotein (LDL), Macrophage,

MIRACL, Monounsaturated fats,

MRFIT, Myocardial infarction (MI),

NCEP,

a cell-surface receptor present on many cell types that is involved in the trapping and internalization of lipoprotein particles, mainly LDL and IDL. This receptor was discovered by Joseph Goldstein and Michael Brown, who won the Nobel Prize in 1985 for their work. Defects in the LDL receptor result in the condition Familial Hypercholesterolaemia. any substance that is insoluble in water but soluble in apolar solvents, such as ether or chloroform. usually hospital based, this is a clinic that specializes in the diagnosis and management of dyslipidaemias. a blood test in which the blood levels of cholesterol, triglyceride and some combination of HDL-, VLDLand LDL-cholesterol are measured. Long-term Intervention with Pravastatin in Ischaemic Disease study. a complex of proteins called apolipoproteins and lipids, such as cholesterol, cholesteryl esters, triglyceride and phospholipids. Lipoproteins are responsible for transporting lipids between various organs of the body. an enzyme responsible for the breakdown of triglyceride in either chylomicrons or VLDL. the first HMG CoA reductase inhibitor to reach clinical practice. is the major carrier of cholesterol in blood. A high level of LDL promotes the development of atherosclerosis and, in turn, coronary heart disease. a scavenger cell that is involved in many of the protective inflammatory responses in the body and which has a key role in the development of the atherosclerotic plaque. Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering study. clear oily substances that are liquid at room temperature. Monounsaturated fats (e.g. olive oil) are rich in monounsaturated fatty acids. Multiple Risk Factor Intervention Trial. when the muscle of the heart (myocardium) is deprived of oxygen, the muscle cells die (infarction). This process is often called a heart attack. If the patient survives, the infarcted area will heal but will remain scarred. National Cholesterol Education Program.

66 GLOSSARY OF TERMS

NTT, Phospholipids,

Plaque, Polyunsaturated fats,

Post-prandial lipaemia, PPP, Pravastatin, Primary prevention,

PROCAM, PROSPER, PROVE-IT, PTCA, Regression, Resin, Rhabdomyolysis,

Risk factor,

Rosuvastatin, Saturated fats,

number needed to treat. a class of lipids usually containing a glycerol backbone, two fatty acids and a third polar component in which a chemical compound is attached to the glycerol through its phosphorus component. Phospholipids act as detergent molecules. see Atherosclerosis. clear oily substances that are liquid at room temperature. Polyunsaturated fats (e.g. safflower and sunflower oils) are rich in polyunsaturated fatty acids. the increase in blood lipid levels seen after a meal. Pravastatin Pooling Project. an HMG CoA reductase inhibitor used in WOSCOPS, the CARE and LIPID studies, the PPP and PROSPER. as applied to coronary prevention, this term is used to describe the strategy of preventing coronary events from occurring in normal, healthy individuals. Prospective Cardiovascular Minister Study. Prospective Study of Pravastatin in the Elderly at Risk. Pravastatin or Atorvastatin Evaluation and Infection Therapy study. percutaneous transluminal coronary angioplasty. the process whereby atheromatous plaques shrink in size as a result of aggressive lipid-lowering therapy. see Bile acid sequestrant resin, Cholestyramine, and Colestipol. destruction of the skeletal muscle which leads to kidney failure. This is a rare but potentially serious side effect of statin therapy. as applied to atherosclerosis, a condition or state that predisposes to the development and progression of atherosclerosis. The major risk factors are: age, male sex, smoking, dyslipidaemia, hypertension, diabetes, obesity, and a family history of premature coronary heart disease. The evidence for these risk factors comes primarily from the large and still on-going epidemiological survey of cardiovascular disease, the Framingham Study, and from MRFIT. an HMG CoA reductase inhibitor that is being studied in the Galaxy Programme of clinical trials. white, oily substances that are solid at room temperature. Chemically, these fats are esters of glycerol and saturated fatty acids. Saturated fats are

GLOSSARY OF TERMS 67

SEARCH, Secondary prevention,

Simvastatin,

SPARCL, Statin,

TIA, TNT, Triglyceride,

Very-low-density lipoprotein (VLDL),

VLDL, WOSCOPS, Xanthelasma,

Xanthoma,

the main constituent of the visible fat around meat, and of butter, cheese, whole milk and ice-cream. Saturated fats are also plentiful in coconut oil, palm kernel oil and palm oil, three vegetable oils widely used in commercially processed foods. Study of the Effectiveness of Additional Reductions of Cholesterol and Homocysteine. as applied to coronary prevention, this term is used to describe the strategy of preventing further coronary events in patients who have already been diagnosed as having vascular disease. an HMG CoA reductase inhibitor that was used in 4S, the first secondary prevention trial to show that lipidlowering can save lives. Stroke Prevention by Aggresive Reduction in Cholesterol Levels study. see HMG CoA reductase inhibitor, Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Pravastatin, Rosuvastatin and Simvastatin. transient ischaemic attack—a mini-stroke that completely resolves within 24 hours. Treat to New Target study. also called triacylglycerol, a member of the lipid family in which three fatty acids are attached to a glycerol backbone through ester bonds. is the major carrier of triglyceride in the bloodstream of the fasting subject. VLDL is assembled in the liver and contains about 65% of its weight as triglyceride. It also contains Apo B, Apo E and Apo C. As the triglyceride in VLDL is broken down by the action of lipoprotein lipase, VLDL remnants and then IDL are produced. Some of these particles are taken up by the liver via its cell surface receptors, but the rest are converted into LDL. see Very-low-density lipoprotein. West of Scotland Coronary Prevention Study. yellowish, flat deposits of lipid on the eyelids or under the eyes often indicating the presence of a dyslipidaemia. a deposit of lipid in the skin or tendons. Xanthomas occur in people with several different kinds of blood lipid disorders. Achilles’ and elbow tendon xanthomas are particularly common in people with FH.

Further reading

Brown MS, Goldstein JL (1987) The LDL receptor. In: Gallo LL, ed, Cardiovascular Disease (Plenum Press, New York) 87–91. Campbell NC, Thain J, Deans HG et al (1998) Secondary prevention in coronary heart disease: baseline survey of provision in general practice, BMJ 326:1430–4. Caro J, Klittich W, McGuire A et al (1999) International economic analysis of primary prevention of cardiovascular disease with pravastatin in WOSCOPS, Eur Heart J 20: 263–8. Crisby M, Nordin-Fredriksson G, Shah PK et al (2001) Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization, Circulation 103:926–33. Downs JR, Clearfield M, Weis S et al (1998) Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TEXCAPS Research Group, JAMA 279:1615–22. Durrington PN, Prais H, Bhatnagar D et al (1999) Indications for cholesterol-lowering medication: comparison of risk-assessment methods, Lancet 353:278–81. EURO ASPIRE Study Group (1997) A European Society of Cardiology survey on secondary prevention of coronary heart disease: principal results, Eur Heart J 18: 1569–82. Falk E, Shah PK, Fuster V (1995) Coronary plaque disruption. Circulation 92:657–71. Freeman DJ, Norrie J, Sattar N et al (2001) Pravastatin and the development of diabetes mellitus. Circulation 103:357–62. Freeman DJ, Norrie J, Caslake MJ et al (2002) C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study, Diabetes 51:1596–600. Gaw A, Murphy M, Cowan RA et al (2003) Clinical Biochemistry: An Illustrated Colour Text, 3rd edn, (Harcourt Brace, Edinburgh). Gaw A, Packard CJ, Shepherd J (eds) (2003) Statins. The HMG CoA Reductase Inhibitors in Perspective. 2nd edn (Martin Dunitz, London). Grover SA, Lowensteyn I, Esrey KL et al (1995) Do doctors accurately assess coronary risk in their patients? Preliminary results of the coronary health assessment study. BMJ 310:975–8. Grundy SM (1986) Cholesterol and heart disease: a new era. JAMA 256:2849–58. Grundy SM (1999) Primary prevention of coronary heart disease. Integrating risk assessment with intervention. Circulation 100: 8–98. Heart Protection Study Collaborative Group (2002) MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet 360:7–22.

FURTHER READING 69

Hingorami AD, Vallance P (1999) A simple computer program for guiding management of cardiovascular risk factors and prescribing. BMJ 318:101–5. Hulscher MEJL, van Drenth BB, Mokkink HGA et al (1997) Effects of outreach visits by trained nurses on cardiovascular risk-factor recording in general practice: a controlled trial. Eur J Gen Pract 3:90–5. Isles CG, Ritchie LD, Murchie P, Norrie J (2000) Risk assessment in primary prevention of coronary heart disease: randomised comparison of three scoring methods. BMJ 320:690–1. Jackson R (2000) Updated New Zealand cardiovascular disease risk-benefit prediction guide. BMJ 320:709–10. Kannel WB, Castelli W, Gordon T et al (1971) Serum cholesterol lipoproteins and risk of coronary heart disease: the Framingham Study, Ann Int Med 74:1–12. Keys A (1980) Seven Countries: A Multivariate Analysis of Death and Coronary Heart Disease (Harvard University Press, Cambridge, MA). Kleinveld HA, Demacker PNM, de Haan AFJ, Stalenhoef AFH (1993) Decreased in vitro oxidisability of LDL in hypercholesterolemic patients treated with HMG CoA reductase inhibitors. Eur J Clin Invest 23:289–95. Kobashigawa J, Katznelson S, Laks H et al (1995) Effect of pravastatin on outcomes after cardiac transplantation, N Engl J Med 333:621–7. Lacoste L, Lam JYT, Hung J et al (1995) Hyperlipidemia and coronary disease: correction of the increased thrombogenic potential with cholesterol reduction, Circulation 92: 3172–7. LIPID Study Group (1998) Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of cholesterol levels, N Engl J Med 339:1349–57. Marmot MG, Syme SL, Kagan A et al (1975) Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: prevalence of coronary and hypertensive heart disease and associated risk factors, Am J Epidemiol 102:514–25. Marteau TM, Kinmonth AL, Pyke S, Thompson SG (1995) Readiness for lifestyle advice: self-assessments of coronary risk prior to screening in the British Family Heart Study. Family Heart Study Group, Br J Gen Pract 45:3905–8. Martin MJ, Hulley SB, Browner WS et al (1986) Serum cholesterol, blood pressure and mortality: implications from a cohort of 361,662 men, Lancet 2:933–6. National Service Framework for Coronary Heart Disease. London: Deparment of Health, 2000. NCEP (2001) Executive summary of the third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III), JAMA 285:2486–97. Pickin DM, McCabe CJ, Ramsey LE et al (1999) Cost effectiveness of HMG-CoA reductase inhibitor (statin) treatment related to the risk of coronary heart disease and cost of drug treatment, Heart 82:325–32. Poulter N, Sever P, Thom S (1993) Cardiovascular disease: practical issues for prevention. (Caroline Black, St. Albans). Pyörälä K, De Backer G, Graham I et al (1994) Prevention of coronary heart disease in clinical practice. Recommendations of the Task Force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension, Eur Heart J 15:13–31.

70 FURTHER READING

Ramachandran S, French JM, Vanderpump MPJ et al (2000) Using the Framingham model to predict heart disease in the United Kingdom: retrospective study, BMJ 320: 676–7. Ributs WC (1996) The underused miracle: the statin drugs are to atherosclerosis what penicillin was to infectious disease, Am J Cardiol 78:377–8. Ridker PM, Cushman M, Stampfer MJ et al (1997) Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men, N Eng J Med 336:973–9. Rumley A, Lowe GDO, Norrie J (1997) Blood rheology and outcome in the West of Scotland Coronary Prevention Study, Br J Haematol 97:78(Abstr). Sacks FM, Pfeffer MA, Moye LA et al (1996) The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels, N Eng J Med 335:1001–9. Sacks FM, Tonkin AM, Shepherd J et al (2000) Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project, Circulation 102:1893–900. Scandinavian Simvastatin Survival Study Group (1994) Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S), Lancet 344:1383–9. Shepherd J, Blauw GJ, Murphy MB et al (2002) Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial, Lancet 360:1623–30. Shepherd J, Alcade V, Befort P-A for the HELP Study Group (1997) International comparison of awareness and attitudes towards coronary risk factor reduction: the HELP Study. J Cardiovasc Risk 4:373–84. Shepherd J, Cobbe SM, Ford I et al (1995) Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia, N Eng J Med 333:1301–7. Simes J, Furberg CD, Braunwald E et al (2002) Effects of pravastatin on mortality in patients with and without coronary disease across a broad range of cholesterol levels, Eur Heart J 23:207–15. Simons LA (1986) Interrelations of lipids and lipoproteins with coronary artery disease mortality in 19 countries, Am J Cardiol 57(14):G5–10. Soma MR, Parolini C, Donetti E et al (1995) Inhibition of isoprenoid biosynthesis and arterial smooth muscle cell proliferation, J Cardiovasc Pharm 25(Suppl. 4):S20–4. Standing medical advisory committee on the use of statins. London: NHS Executive, Department of Health. Wallis EJ, Ramsay LE, Haq IU et al (2000) Coronary and cardiovascular risk estimation for primary prevention: validation of a new Sheffield table in the 1995 Scottish health survey population, BMJ 320:671–6. West of Scotland Coronary Prevention Study Group (1998) Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 97:1440–5. Wood DA, De Backer G, Faergeman O et al (1998) Prevention of coronary heart disease in clinical practice. Recommendations of the second joint task force of the European Society of Cardiology, European Atherosclerosis Society and European Society of Hypertension, Eur Heart J 19: 1434–503.

Index

Numbers in italics indicate tables and figures. 4S (Scandinavian Simvastatin Survival Study) 39–42, 40, 41, 51, 59 absolute risk reductions 51–2, 51 AF/TEXCAPS (Air Force/Texas Coronary Atherosclerosis Prevention Study) 40, 45 antioxidants 49, 50 apolipoproteins 75 arteriosclerosis 75 atherosclerosis clinical manifestations 11 defined 8, 75 pathogenesis 8–10, 9, 26–7 plaque regression 11 plaque rupture 10, 26, 27 risk factors 83 thrombus formation 9, 10–11, 26 atorvastatin AVERT study 47 CARDS 65–6 chemical structure 23 effect on vascular smooth muscle 27 MIRACL study 47–8 pharmacokinetics 24 PROVE-IT study 66–7 TNT study 67–8 AVERT (Atorvastatin Versus Revascularization Treatment) study 47

CARDS (Collaborative Atorvastatin and Diabetes Study) 65–6 CARE (Cholesterol and Recurrent Events) study 31, 40, 43–5, 44, 57–8, 59 cellular immunity, effects of statins 29–31, 30 cerivastatin effect on vascular smooth muscle 27 withdrawal from clinical practice 37 CHD see coronary heart disease (CHD) chemical structures of statins 23 cholesterol 76–7 and CHD risk 3–6, 4, 5, 6, 7 low levels and cancer 5–6 measurement 15–17 cholesteryl ester 77 cholesteryl ester transfer protein 77 cholestyramine 77 chylomicrons 77 ciprofibrate 77 clinical trials of statins current/future 65–8 in the elderly 57–63, 58, 61, 62 largest summarized 40 see also specific trials clinical use of statins 36–8 colestipol 77 contraindications for therapy 36 corneal arcus 77 coronary heart disease (CHD) 77 clinical presentations 12 diagnosis 12–13, 13 dyslipidaemia and 3–8, 4, 5, 6, 7 prevention messages 70–1, 71

beta quantification 16 bezafibrate 76 bile acid sequestrant resins 22, 76 blood viscosity, effects of statins 34, 35 cancer and low cholesterol levels 5–6

71

72 INDEX

risk see risk of CHD role of infection, PROVE-IT study 66, 67 cost considerations 52–3, 72–3 C-reactive protein (CRP) 31–2, 32 creatine kinase 37 diabetes risk of CHD 54 statins and development of 34–5, 36 statin trials 65–6 discovery of statins 21 dosage 67–8 drug interactions 38 dyslipidaemia 78 and CHD risk 3–8, 4, 5, 6, 7 classification 17–19, 19 lipid profiles 15–17 elderly patients 4S 57, 59 CARE study 57–8, 59 Heart Protection Study 60 LIPID study 58–9, 58 PROSPER 40, 60–3, 61, 62 stroke prevention 59–60, 61, 63 endothelial function 29 ezetimbibe 69, 78 Familial Atherosclerosis Treatment Study 11 familial combined hyperlipidaemia (FCH) 19, 78 familial hypercholesterolaemia (FH) 19, 78 familial hypertriglyceridaemia 19 fatty acids 78 fatty streaks 8, 9, 10, 79 fenofibrate 79 financial considerations 52–3, 72–3 fluvastatin chemical structure 23 effect on vascular smooth muscle 27 pharmacokinetics 24 Fredrickson’s classification of dyslipidaemia 17–19, 19, 79 gatifloxacin 66, 67

gemfibrozil 79 genetic causes of hyperlipidaemia 19 HDL (high-density lipoproteins) and CHD risk 6–8 effect of statins 23 measurement 15–17 heart health information sources 70–1, 70, 71 HELP study 69–71 HMG CoA reductase, inhibition by statins 21 HPS (Heart Protection Study) 40, 49–50, 60 hypertension and CHD risk 3, 3 IDLs (intermediate density lipoproteins) 80 inflammation, effects of statins 31–2 intermittent claudication 11 Japanese, CHD in 4–5, 5 Joint European Guidelines 80–1 LDLs (low-density lipoproteins) and CHD risk 3–6, 4, 5, 6, 7 measurement 15–17 statins and oxidation of 32–3, 33 LDL receptors 81 effects of statins 22–3, 22 LIPID (Long-term Intervention with Pravastatin in Ischaemic Disease) study 40, 46, 58–9, 58, 59–60 lipid profiles distribution 18 interpretation of results 17 laboratory analyses 15–16 specimen collection 15 timing of measurements 16–17 lipoprotein lipase deficiency 19 lipoprotein oxidation, effects of statins 32– 3, 33 lipoproteins 81 lovastatin AF/TEXCAPS study 40, 45 chemical structure 23 effect on vascular smooth muscle 27 pharmacokinetics 24

INDEX 73

mechanisms of action of statins anti-inflammation 31–2 blood viscosity reduction 34, 35 cellular immunity changes 29–31, 30 cholesterol lowering 22–3, 22 endothelial function enhancement 29 on glucose intolerance 34–5, 36 on lipoprotein oxidation 32–3 plaque stabilization 25–9, 26, 27, 28 mevastatin 21 MIRACL (Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering) study 47–8 muscle side effects 37 myocardial infarction (MI) 12–13, 13, 82 National Cholesterol Education Program (NCEP) guidelines (US) 54 National Service Framework for Coronary Heart Disease 72 New Zealand tables 56 Ni-Hon-San study 4–5, 5 nitric oxide 29 novel lipid-lowering drugs 68–9 number needed to treat (NNT) 52 oxidation of LDL, effects of statins 32–3, 33 patient compliance 69 pharmacokinetics of statins 23–5, 23, 24 phospholipids 82 plaques (atheromas) formation 8–10, 9 regression 11 rupture 10, 26, 27 size and MI 25, 26, 26 stabilization by statins 27–9, 28 thrombus formation 9, 10–11, 26 platelets, effects of statins 28, 28 PPP (Pravastatin Pooling Project) 48–9, 49 pravastatin blood viscosity reduction 34, 35 CARE study 31, 40, 43–5, 44, 57–8, 59 chemical structure 23 and development of diabetes 34–5, 36 effect on hs-CRP levels 31

effect on vascular smooth muscle 27–8, 27 and graft survival 29–31, 30 LIPID study 40, 46, 58–9, 58, 59–60 pharmacokinetics 24 PPP 48–9, 49 PROSPER 40, 60–3, 61, 62 PROVE-IT study 66–7 stroke prevention 59–60, 61, 63 WOSCOPS 34–5, 35, 36, 40, 42–3, 43 primary prevention 53–5, 54, 82 PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) 40, 60– 3, 61, 62 PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) study 66–7 relative risk reductions 51, 51 rhabdomyolysis 37, 83 risk of CHD assessment 55–6 dyslipidaemia and 3–8, 4, 5, 6, 7 in Japanese men 4–5, 5 patients’ perceptions 69 reductions achieved with statins 51–2, 51 risk factors 1–3, 2, 3 spectrum 54 thresholds for treatment 52–5, 52 rosuvastatin chemical structure 23 pharmacokinetics 24 safety review 37 saturated fats 83 Scandinavian Simvastatin Survival Study (4S) 39–42, 40, 41, 57, 59 SEARCH (Study of the Effectiveness of Additional Reductions of Cholesterol and Homocysteine) 67–8 secondary prevention of CHD barriers to 71–2 defined 83 risk spectrum 54 Sheffield tables 55–6 side effects of statins 36–7

74 INDEX

simvastatin 4S 39–12, 40 , 41, 57, 59 chemical structure 23 effect on vascular smooth muscle 27 Heart Protection Study 40, 49–50, 60 pharmacokinetics 24 SEARCH 67–8 stroke prevention 59, 60 smoking and CHD risk 3, 3 SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) study 66 specimen collection for lipid analysis 15 stroke prevention 59–60, 61, 63, 66 thrombosis 9, 10–11, 26 TNT (Treat to New Target) study 67–8 triglycerides 84 effect of statins 23 measurement 15–17 VLDL (very-low-density lipoprotein) 84 WHO classification of dyslipidaemia 17– 19, 19, 79 WOSCOPS (West of Scotland Coronary Prevention Study) 34–5, 35, 36, 40, 42– 3, 43 xanthomata 84