Advances in stroke prevention: plenary symposium at the 11th European Stroke Conference, Geneva, Switzerland, May 29 - June 1, 2002

Advances in Stroke Prevention Plenary Symposium at the 11th European Stroke Conference Geneva, Switzerland, May 29–June 1, 2002 Supported by an Educational Grant from Sanofi-Synthelabo

Editors

Julien Bogousslavsky, Lausanne Marie-Germaine Bousser, Paris

13 figures and 6 tables, 2003

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Vol. 16, Supplement 1, 2003

Contents

1 Introduction Bousser, M.-G. (Paris); Bogousslavsky, J. (Lausanne) 3 Long-Term Outcome after Stroke due to Atrial Fibrillation Mattle, H.P. (Bern) 9 Outcome after Brain Haemorrhage Dennis, M.S. (Edinburgh) 14 Long-Term Outcome after Ischaemic Stroke/Transient Ischaemic Attack Hankey, G.J. (Perth) 20 Evidence with Antiplatelet Therapy and ADP-Receptor Antagonists Easton, J.D. (Providence, R.I.)

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Cerebrovasc Dis 2003;16(suppl 1):1–2 DOI: 10.1159/000069933

Introduction

Stroke is the principal cause of disability, dependency and loss of social competence in the western world. The majority of strokes are of ischaemic origin, and most ischaemic strokes are due to atherothrombosis. Clearly, a thorough knowledge of prognosis and effective secondary prevention strategies are of paramount importance for clinicians who care for stroke patients. At the 11th European Stroke Conference, held in Geneva, Switzerland, between May 29 and June 1, 2002, delegates had the opportunity to attend two important symposia – an Educational Symposium entitled Longterm outcome after different stroke subtypes and a Satellite Symposium entitled Future trends in long-term prevention of ischaemic stroke – the role of atherothrombosis management. This supplement to Cerebrovascular Diseases is based on key presentations made during these sessions. In the first article of this supplement, Dr Heinrich Mattle provides an overview of long-term outcome after stroke due to atrial fibrillation (AF). AF, which is the most common cardiac arrhythmia and whose prevalence increases with age, places the patient at risk for left atrial thrombus formation, distal embolism and associated ischaemic stroke. AF is associated with substantial cardiovascular mortality and morbidity. Indeed, long-term survival data from the Framingham Heart Study indicates that AF is independently associated with an approximate doubling in mortality in both men and women. Moreover, in the European Atrial Fibrillation Trial, the annualized rate of vascular death, nonfatal stroke, nonfatal myocardial infarction or systemic embolism in patients who received placebo was 12%. There is clear evidence that antithrom-

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botic therapy reduces the risk of serious vascular ischaemic events in AF patients. Oral anticoagulation reduces the risk of stroke recurrence by approximately 60% compared with placebo. Acetylsalicylic acid (ASA) is less effective than anticoagulation, reducing the risk of stroke by around 20%. Thus, the use of ASA as first-line antithrombotic therapy in AF patients is limited to those at low risk. An important topic for future investigation is whether dual antiplatelet therapy, for example clopidogrel in addition to ASA, is a suitable alternative to warfarin for the reduction of thromboembolism in high- or intermediate-risk AF patients. This will be the topic of the planned ACTIVE trial. Dr Martin Dennis then describes our current knowledge on outcome after primary intracerebral haemorrhage (PICH). Dr Dennis highlights the methodological difficulties that hamper the study of PICH prognosis, including the small proportion of all strokes that are due to PICH, the need for brain imaging (or autopsy) to arrive at a reliable diagnosis of PICH, differences in definition of PICH according to imaging method and its timing, and the heterogeneity of haemorrhage aetiologies and types. Although individual estimates of 1-month case fatality have wide confidence intervals, pooled data from unselected PICH cohorts provide a more precise estimate of about 42%. After PICH, greater age and stroke severity are both associated with increased case fatality and poorer functional outcomes. Currently, there is no definite evidence to indicate that the risk of recurrent stroke after PICH differs from that after ischaemic stroke of equivalent clinical severity. Generation of more precise data on progno-

sis after PICH will require pooling of data from community-based studies that have used consistent definitions and methodology. It is already well established that bloodpressure lowering dramatically reduces the risk of recurrent intracerebral haemorrhage. In the first of two articles relating to the generalized nature of atherothrombosis and its consequences, Dr Graeme Hankey reviews the evidence from high-quality studies on short- and long-term predictors of post-stroke outcome and studies on prognosis in patients with transient ischaemic attack (TIA) or ischaemic stroke. This article demonstrates that the most consistent predictor of short-term (1-month) mortality is stroke severity, whereas over the longer term (1–5 years), the strongest predictor of death is increasing age, closely followed by cardiac failure. Additional predictive factors for death over this time period include a history of previous symptomatic atherothrombosis and risk factors for atherothrombotic disease. Furthermore, over time, the annual risk of recurrent cerebrovascular events decreases but the risk of cardiovascular events increases, emphasizing that patients with TIA and ischaemic stroke are at risk of recurrent ischaemic events of both the brain and the heart. On the basis of these findings, Dr Hankey concludes that strategies for secondary prevention after TIA or stroke should include removal of symptomatic disease, control of risk factors for atherogenesis, and prevention of atherothrombosis in all vascular beds. Finally, Dr J. Donald Easton provides an overview of current evidence and future prospects for ADP-receptor antagonist therapy for the prevention of vascular ischaemic events in atherothrombotic patients, with a particular focus on patients with symptomatic cerebrovascular disease. As shown in meta-analyses by the Antithrombot-

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Cerebrovasc Dis 2003;16(suppl 1):1–2

ic Trialists’ Collaboration and the Cochrane Stroke Group, the ADP-receptor antagonists clopidogrel and ticlopidine are associated with superior protection against major atherothrombotic events (stroke, MI or vascular death) compared with ASA. The Cochrane Group also confirmed that compared with ticlopidine, clopidogrel offers a more favourable safety/tolerability profile. The CURE trial, which provided ‘proof of principle’ for the use of clopidogrel on top of ASA to provide incremental benefit in high-risk atherothrombtic patients, has stimulated interest in advanced antiplatelet strategies in patients with ischaemic stroke. Since Geneva, this interest has been reinforced by publication of the results of the CREDO trial, which showed that long-term use of clopidogrel on top of ASA provides sustained, incremental benefit in patients who undergo percutaneous coronary intervention. The ongoing MATCH study is comparing clopidogrel on top of ASA versus clopidogrel alone in an international, randomized, double-blind trial in patients with recent TIA or ischaemic stroke who are at high risk of atherothrombotic recurrence. The ongoing CHARISMA trial compares clopidogrel and placebo on top of usual treatment based on low-dose ASA in high-risk atherothrombotic patients. Additional trials of clopidogrel on top of standard therapy including ASA are planned in neurology, including SPS3, in patients with small subcortical strokes, and ATARI, in patients who have recently recovered from a TIA. The articles assembled here represent a current reference source on outcome after stroke and its management. We hope that you find them useful and informative. Marie-Germaine Bousser, MD Julien Bogousslavsky, MD

Introduction

Cerebrovasc Dis 2003;16(suppl 1):3–8 DOI: 10.1159/000069934

Long-Term Outcome after Stroke due to Atrial Fibrillation Heinrich P. Mattle Department of Neurology, Inselspital, University of Bern, Bern, Switzerland

Key Words Atrial fibrillation W Prognosis W Stroke

Abstract Atrial fibrillation (AF) is the most common cardiac arrhythmia. AF is paroxysmal or persistent and becomes permanent when it does not convert to sinus rhythm spontaneously or when attempted cardioversion fails. The prevalence of AF is 0.4% in the general population and increases with age up to 6–8% in octogenarians. In men, the age-adjusted prevalence is generally higher than in women. During AF, synchronous mechanical atrial activity is disturbed, resulting in haemodynamic impairment. This can give rise to thrombus formation and embolism to the systemic circulation. Thrombus associated with AF arises most frequently in the left atrial appendage. Cerebrovascular emboli in AF patients most often manifest as transient ischaemic attacks or ischaemic strokes. The overall rate of ischaemic stroke among patients with nonrheumatic AF averages 5% per year, but the rate increases with age. Patients with AF are at higher risk of cerebrovascular events from all causes. Of all strokes, one in every six occurs in patients with AF. Including transient ischaemic attacks and silent strokes detected radiographically, the overall rate of all cerebro-

vascular events in AF patients rises to more than 7% per year, although approximately one third of these are due to causes that are only secondarily or incidentally associated with AF or related anticoagulant therapy. Antiarrhythmic therapy is useful to improve cardiac rate and function in AF. However, to reduce first or recurrent emboli, antithrombotic therapy is of paramount importance. Results from several randomized clinical trials of antithrombotic therapies have shown that adjusted-dose warfarin reduces first or recurrent stroke by about 60% compared with placebo. When patients with nonvalvular AF are anticoagulated, the odds against ischaemic stroke and intracranial bleeding favour an INR between 2.0 and 3.0. Acetylsalicylic acid is less efficacious than warfarin in AF patients, reducing the risk of stroke by about 20%. Therefore, this antiplatelet agent should be used only for AF patients at low risk. Anticoagulation is the current treatment modality in AF patients at high or intermediate risk, i.e. patients with history of transient ischaemic attack or stroke, those aged 1 65 years, those with a history of hypertension, diabetes, heart failure or structural heart disease, valvular disease or significant systolic dysfunction. The benefit of dual antiplatelet regimens in AF patients is unknown, and combining antiplatelet agents with different mechanisms of action is an important topic for future investigation. Copyright © 2003 S. Karger AG, Basel

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Heinrich Mattle, MD Department of Neurology Inselspital, University of Bern CH–3010 Bern (Switzerland) Tel. +41 31 6329784, Fax +41 31 6320321, E-Mail [email protected]

12 Women Men

Prevalence (%)

10 8 6 4 2 0 <55

55–59 60–64 65–69 70–74 75–79 80–84

85

Age (years)

Fig. 2. Left atrial appendage thrombus in a 73-year-old female

patient with AF [reproduced with kind permission from Prof. Thomas Schaffner, Department of Pathology, University of Bern]. Fig. 1. Prevalence of AF by age and gender [reproduced with kind

permission, 2].

Introduction

Atrial fibrillation (AF) is the most common cardiac arrhythmia. It occurs more often concomitantly with structural heart disease than alone. Approximately 16% of stroke patients have AF, and the disease itself accounts for 10% of all strokes. In the USA, it is estimated that 2.2–2.3 million people have AF [1, 2]. A crude estimate, assuming a 0.95% prevalence of AF in Europe, is that 8.3 million of the 874 million people living in Eastern and Western Europe have AF. The incidence and prevalence of AF rises with age (fig. 1) [2]. Indeed, after the age of 55, the prevalence doubles with each decade. The prevalence of AF is 0.4% in the general population and increases with age up to 6–8% in octogenarians. In men, the age-adjusted prevalence is generally higher than in women. However, because of their greater longevity, there are more women than men with AF. The incidence and prevalence of AF are expected to rise substantially in future decades due to the growing proportion of elderly individuals, which in the USA is expected to increase 2.5-fold over the next 50 years. Data on the typical characteristics of the stroke patient in AF are available from the International Stroke Trial [3]. IST was a large, randomized trial of antithrombotic therapy in over 19,000 patients with acute ischaemic stroke, of which 3,169 had AF. In this study, stroke

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Cerebrovasc Dis 2003;16(suppl 1):3–8

patients who had AF were more likely to be older (odds ratio (OR) = 7.2; 95% CI 6.9–7.6), female (OR = 1.6; 95% CI 1.5–1.7), have depressed consciousness (OR = 2.4; 95% CI 2.2–2.6), and have a larger stroke (total anterior circulation syndrome) (OR = 2.1; 95% CI 2.0–2.3) than those in sinus rhythm [4]. Patients with AF carry a substantial risk of thromboembolism. In AF, the contraction of the left atrium is disturbed, resulting in haemodynamic impairment of both the atrium and the ventricle. This leads to stasis and thrombus formation, especially in the left atrial appendage (fig. 2). The end result is a risk of distal embolization to the systemic circulation, and ultimately a silent cerebral infarction, transient ischaemic attack, or ischaemic stroke.

Prognosis of AF

AF is an independent predictor of first-ever stroke, increasing the risk by up to 5-fold [5]. Based on long-term survival data from the Framingham Heart Study, the mortality of men and women with AF was significantly higher than that of subjects without AF [6]. After 10 years of follow-up, 61.5% of men aged 55–74 years had died compared with 30.0% of men without AF. In women, 57.6% of those with AF had died at 10 years compared with 20.9% of women without AF (fig. 3). Comparable results were observed in subjects aged 75–94 years. Moreover, in a secondary multivariate analysis that was limited to those subjects who were initially free of cardiovascular

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45 40

No AF AF

Incidence (%)

35 30 25 20 15 10 5

Fig. 3. Cumulative mortality during long-term follow-up in subjects

aged 55–74 years with and without AF in the Framingham Heart Study [reproduced with kind permission, 6].

0 Death at 2 weeks

Death at 6 months

Fig. 4. Stroke fatality at 2 weeks and 6 months in AF patients

enrolled in the International Stroke Trial [reproduced with kind permission, 4].

disease and valvular heart disease, AF was independently associated with an approximate doubling in mortality in both men and women (OR for men = 2.4, 95% CI 1.8–3.3; OR for women = 2.2, 95% CI 1.6–3.1) [6]. A number of independent predictors of ischaemic stroke have been identified in patients with AF. The Atrial Fibrillation Investigators group analysed pooled data from the control groups of five randomized primary prevention trials and found the following risk factors on multivariate analysis: previous stroke or transient ischaemic attack, OR = 2.5; hypertension, OR = 1.6; diabetes, OR = 1.7; age, OR = 1.6 per 10 years [7]. Analysis of echocardiograms from three of these trials subsequently found that moderate-to-severe left ventricular dysfunction was also predictive of stroke (OR = 2.5) [8]. Broadly similar findings were reported by Hart et al. [9] based on analysis of data from patients receiving acetylsalicylic acid (ASA) in the SPAF (Stroke Prevention in Atrial Fibrillation) I, II and III trials. Transoesophageal echocardiography has also identified predictors of stroke in AF patients. These include thrombus of the left atrial appendage, spontaneous echo contrast, and aortic arch plaques [10]. In the IST trial, stroke patients with AF were slightly more likely to experience a recurrent ischaemic stroke or an intracranial haemorrhage, and were more than twice as likely to die within 2 weeks as those without AF (fig. 4). A similar effect of AF on mortality was also observed at 6 months. Data on longer-term outcome have been reported in the European Atrial Fibrillation Trial (EAFT) [11] (fig. 5).

Prognosis of Atrial Fibrillation

Fig. 5. Survival analysis for primary outcome event (vascular death, nonfatal stroke, nonfatal myocardial infarction or systemic embolism) in the European Atrial Fibrillation Trial [11]. Anticoagulants reduced the annualized rate of primary outcome events from 17 to 8%. The annual stroke rate (not shown) was reduced from 12 to 4% [reproduced with kind permission, 11].

Overall, the annualized rate of the primary endpoint (vascular death, nonfatal stroke, nonfatal MI or systemic embolism) in the placebo arm of this study was 17%. The annualized rates of all-cause stroke and of death were 12 and 9%, respectively.

Cerebrovasc Dis 2003;16(suppl 1):3–8

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Table 1. Risk categories in patients with AF

Risk category

Risk factors

Annual risk Number needed to treat of stroke

Highest

Previous stroke or transient ischaemic attack

12%

14 (warfarin vs. placebo)

High

Age 1 75 years Hypertension Left ventricular dysfunction Risk factor detected by transoesophageal echocardiograpy Rheumatic or valvular heart disease 1 1 moderate risk factor

F6%

28 (warfarin vs. placebo)

Moderate

Age 65–75 years Diabetes Coronary heart disease No high-risk criteria

F3.5%

48 (warfarin vs. placebo)

Low

Age ! 65 years No high-risk factors

F1%

Prevention of Stroke in AF Patients

Antithrombotic therapy has clearly been shown to reduce the risk of serious vascular ischaemic events in patients with AF [12]. A meta-analysis of six randomized trials that compared dose-adjusted warfarin versus placebo in a total of 2,900 patients found a pooled relative risk reduction of 62% (95% CI 48–72%) for the endpoint of all-cause stroke [13]. In these trials, the absolute risk reduction for primary prevention was 2.7% per year (data from 5 trials) and for secondary prevention it was 8.4% per year (data from a single trial (EAFT)). Major extracranial haemorrhage was increased by warfarin therapy (absolute risk increase 0.3% per year, relative risk = 2.4, 95% CI 1.2–4.6). Six trials have compared the use of ASA versus placebo for stroke prevention in AF patients [13]. The pooled estimate from these studies gave an overall 22% (95% CI 2–38%) reduction in the risk of all-cause stroke. Pooled analysis of data from five trials that compared adjusted-dose warfarin plus ASA versus ASA alone showed that combination therapy was superior to ASA monotherapy, being associated with a 36% (95% CI 14– 52%) relative risk reduction for all-cause stroke. Major extracranial haemorrhage was higher in those who received warfarin relative to those who received ASA (relative risk = 2.0, 95% CI 1.2–3.4) [13]. In EAFT, anticoagulation therapy was more effective than ASA in preventing serious vascular events, reducing the rate of the primary endpoint from 17% per year with

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F500 (ASA vs. placebo) F250 (warfarin vs. ASA)

placebo to 8% per year and the annual rate of all-cause stroke from 12 to 4%. A major limitation of oral anticoagulation is its narrow therapeutic window. In patients with nonrheumatic AF, the risk of stroke has been found to rise steeply at INR values !2.0. Thus, at an INR of 1.7, the adjusted odds ratio for stroke, as compared with the risk at an INR of 2.0, is 2.0 (95% CI 1.6–2.4) [14]. At INR values 14.0, the risk of intracranial haemorrhage rises exponentially [15]. Therefore, in nonrheumatic AF, an INR of 2.0–3.0 gives the optimal risk:benefit ratio for the prevention of stroke [12]. In patients with valvular disease, a higher INR (3.0– 3.5) should be targeted. AF patients can be categorized according to stroke risk, which is influenced by a number of variables and which should be taken into account when initiating antithrombotic therapy (table 1). AF patients who have suffered a previous stroke or transient ischaemic attack have the highest risk of stroke, which is estimated at 12% per year. Patients in the lowest risk category (those aged !65 years with no high-risk factors) have an estimated annual stroke risk of 1%, making them potential candidates for ASA therapy. For warfarin, the number needed to treat (NNT) to prevent one stroke per year ranges from 14 in the highest risk category to 48 in moderate-risk patients. In the lowest risk category, the NNT for ASA versus placebo is about 500 and for warfarin compared with ASA the NNT is about 250.

Mattle

The risk of thromboembolism with atrial flutter is of the same order as the risk with AF. Therefore, anticoagulants should be used with atrial flutter in the same way as with AF. Another issue in AF is rate and rhythm control. Several trials have shown that restoration of sinus rhythm improves cardiac function and exercise tolerance, but does not reduce the risk of vascular death or thromboembolism substantially [16–18]. For younger patients with structurally normal hearts, restoration and maintenance of sinus rhythm is still the goal, but in the great majority of AF patients, rhythm control does not bring any advantage over rate control. In older patients, patients with congestive heart failure and patients with coronary artery disease, rhythm control was even associated with a higher risk of death [17]. In the AFFIRM study, during a mean follow-up of 3.5 years, the overall ischaemic stroke rate was 6.3%. Mortality was 26.3%. The implications from the rate and rhythm control trials are that rate control is the primary approach to the treatment of AF, that rhythm control, if used, can be abandoned early if it is not fully satisfactory, and that continuous anticoagulation is warranted in all patients with AF and risk factors for stroke, even when sinus rhythm appears to be restored and maintained.

Unanswered Questions and Future Prospects

Patients with AF would clearly benefit from antithrombotic therapy that is superior to ASA, equally efficacious as oral anticoagulation, easy to use and has an excellent safety profile. Therefore, the question arises of whether dual antiplatelet regimens would be an alternative or even superior to anticoagulation. There is a strong rationale to evaluate the use of clopidogrel on top of ASA in AF patients, because: (1) the typical patient with AF who requires antithrombotic therapy also has multiple risk factors for arterial vascular disease as well as for left atrial thrombus; (2) based on the results of the CURE [19] and CREDO trials [20], it is justifiable to expect that clopidogrel plus ASA would be superior to ASA in this patient population, and (3) in the only trial (in coronary stenting) that has compared an ADP-receptor antagonist plus thromboxane-inhibiting ASA versus warfarin plus ASA, ticlopidine plus ASA significantly reduced the risk of death or MI by 49% compared with warfarin plus ASA, with a substantially lower risk of serious bleeding [21]. The answer to the question of whether a dual antiplatelet regimen will be superior or comparable to anticoagulation

Prognosis of Atrial Fibrillation

will most likely come from the ACTIVE trial. ACTIVE is planned to compare clopidogrel on top of ASA with warfarin in AF patients. Another unresolved issue is whether warfarin has a favourable benefit:risk ratio in very elderly AF patients (those aged 180 years), bearing in mind the increased risk of haemorrhage in this population. In the absence of reliable data on this topic, a reasonable approach is to treat these very elderly patients in the same way as slightly younger patients. Mechanical devices are under development for endovascular occlusion of the left atrial appendage to prevent thrombus formation and embolization. In a recent pilot study, 15 high-risk AF patients who were poor candidates for warfarin therapy underwent successful implantation of an expandable cage for occlusion of the left atrial appendage [22]. However, further studies are required to demonstrate the long-term efficacy and safety of this approach for the prevention of atrial thrombus formation in patients with AF.

Conclusions

AF is an important risk factor for stroke and other vascular events and is a predictor of increased stroke severity and mortality. Thus, antithrombotic therapy is of paramount importance to prevent first or recurrent embolism in patients with AF. In higher-risk patients, warfarin has a superior benefit:risk ratio compared with ASA. In contrast, in patients with the lowest risk of stroke (F1% per year) there is little, if any, net benefit of warfarin therapy and therefore ASA is the current preferred option. Evaluation of dual antiplatelet therapy, for example clopidogrel on top of ASA, in AF patients may provide evidence of a new alternative to warfarin for the reduction of thromboembolism in high- or intermediate-risk AF patients.

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9 Hart RG, Pearce LA, McBride R, Rothbart RM, Asinger RW on behalf of the Stroke Prevention in Atrial Fibrillation (SPAF) Investigators: Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: Analysis of 2,012 participants in the SPAF I– III clinical trials: Stroke Prevention in Atrial Fibrillation (SPAF) Investigators. Stroke 1999; 30:1223–1229. 10 Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography: Transesophageal echocardiographic correlates of thromboembolism in high-risk patients with nonvalvular atrial fibrillation. Ann Intern Med 1998;128:639–647. 11 EAFT (European Atrial Fibrillation Trial) Study Group: Secondary prevention in nonrheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993;342: 1255–1262. 12 Albers GW, Dalen JE, Laupacis A, Manning WJ, Petersen P, Singer DE: Antithrombotic therapy in atrial fibrillation. Chest 2001;119: 194S–206S. 13 Hart RG, Benavente O, McBride R, Pearce LA: Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: A meta-analysis. Ann Intern Med 1999;131:492–501. 14 Hylek EM, Skates SJ, Sheehan MA, Singer DE: An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996;335:540–546. 15 Hylek EM, Singer DE: Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1993;118:511–520. 16 Hohnloser SH, Kuck KH, Lilienthal J, for the PIAF Investigators: Rhythm or rate control in atrial fibrillation – Pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet 2000;356:1789–1794.

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17 The Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Investigators: A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825–1833. 18 Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma T, Said SA, Darmanata JI, Timmermans AJM, Tijssen JGP, Crijns HJGM, for the Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group: A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834–1840. 19 The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators: Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without STsegment elevation. N Engl J Med 2001;345: 494–502. 20 Steinhubl SR, Berger PB, Mann JT III, Fry ETA, DeLago A, Wilmer C, Topol EJ, for the CREDO Investigators: Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention. A randomized controlled trial. JAMA 2002;288:2411–2420. 21 Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KKL, Giambartolomei A, Diver DJ, Lasorda DM, Williams DO, Pocock SJ, Kuntz RE: A clinical trial comparing three antithrombotic-drug regimens after coronaryartery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998; 339:1665–1671. 22 Sievert H, Lesh MD, Trepels T, Omran H, Bartorelli A, Bella PD, Nakai T, Reisman M, DiMario C, Block P, Kramer P, Fleschenberg D, Krumsdorf U, Scherer D: Percutaneous left atrial appendage transcatheter occlusion to prevent stroke in high-risk patients with atrial fibrillation. Circulation 2002;105:1887–1889.

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Cerebrovasc Dis 2003;16(suppl 1):9–13 DOI: 10.1159/000069935

Outcome after Brain Haemorrhage Martin S. Dennis Department of Clinical Neurosciences, Western General Hospital, Edinburgh, UK

Key Words Intracerebral haemorrhage W Prognosis

Abstract Between 10 and 20% of strokes are due to intracerebral haemorrhage. The 1-month case fatality is about 42% in unselected cohorts. This relatively low incidence (compared with ischaemic stroke) and high early case fatality means that relatively few patients are available for longterm follow-up and therefore the available data on prognosis are imprecise. Moreover, improvements in diagnostic methods, such as the introduction of gradient echo MRI, which is very sensitive to intracerebral haemorrhage, are altering the types of patients being entered into studies of prognosis. Despite these methodological difficulties, it does appear that the overall prognosis with respect to survival and residual disability is similar to that for ischaemic stroke of equivalent clinical severity. Greater age and stroke severity, whether graded by neurological score or extent of haemorrhage on imaging, are both associated with increased case fatality and poorer functional outcomes. There is no definite evidence of differential recovery between ischaemic and haemorrhagic stroke. Epileptic seizures occur more commonly after haemorrhagic stroke (about 8 per 100 patient-years) compared with ischaemic stroke and more commonly in lobar rather than basal ganglia haemorrhage. There is no reliable evidence to indicate that the risk of recurrent stroke after haemorrhage differs from that after isch-

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aemic stroke. However, strokes due to haemorrhage, like those due to infarction, are heterogeneous not only in terms of severity but also in their causes. The causes (e.g. amyloid angiopathy, hypertension, coagulation deficits) are likely to influence the risk of subsequent stroke. Pooling of data from community-based studies of haemorrhagic stroke that have used consistent definitions and methods represents the only feasible way to obtain more precise data on prognosis after intracerebral haemorrhage. Copyright © 2003 S. Karger AG, Basel

Introduction

In general, the term primary intracerebral haemorrhage (PICH) refers to stroke due to intracranial haemorrhage and excludes those that are due to subarachnoid or subdural haemorrhage, traumatic haematoma, that are secondary to arterial or venous infarction, or that are due to bleeding into a tumour. It is unclear whether published studies on this topic have excluded cases of haemorrhage due to vasculitis, underlying arteriovenous malformation, or saccular aneurysm, and if so, how aggressively the patient was investigated to exclude these aetiologies. Therefore, as in lacunar disease, there is a difficulty in defining homogeneous populations of patients with PICH. There are several reasons for studying prognosis in PICH. First, physicians wish to talk to patients and their

Martin Dennis, MD Department of Clinical Neurosciences Bramwell Dott Building, Crewe Road Edinburgh EH4 2XU (UK) Tel. +44 131 5371000, Fax +44 131 3325150, E-Mail [email protected]

Table 1. Overview of community-based studies of 1-month case fatality after PICH [6–17]

Study (first author)

Location

Patient population

Inclusion criteria

Strokes

PICH, n (%)

Anderson [6]

Perth, Australia

138,708

536

37 (6.9)

Counsell [7] Vemmos [8] Kolominsky-Rabas [9] Ellekjær [10]

Oxfordshire, UK Arcadia, Greece Erlangen, Germany Innherred, Norway

Belluno, Italy 211,389 Valle d’Aosta, Italy 114,325 Dijon, France 150,000 Umbria, Italy 49,218 Benghazi, Libya 518,745 Melbourne, Australia F3,500,000 L’Aquila, Italy 297,838

675 555 354 432 first-ever strokes 161 recurrent strokes 474 254 984 375 329 370 819

66 (9.8) 77 (13.9) 48 (13.6) 45 (10.4)

Lauria [11] D’Alessandro [12] Giroud [13] Ricci [14] Ashok [15] Thrift [16] Carolei [17]

Stroke or transient ischaemic attack First-ever stroke First-ever stroke First-ever stroke First-ever and recurrent stroke First-ever stroke First-ever stroke First-ever stroke First-ever stroke First-ever stroke Consecutive cases of PICH First-ever stroke

F105,000 80,774 101,450 69,295

relatives to give them an indication of what may occur in the future, and to be able to balance risks and benefits of interventions in an informed manner. Second, information on the prognosis of groups of patients is useful for the design of randomized clinical trials, to estimate sample size and decide on the optimal inclusion/exclusion criteria. Finally, data on prognosis of patients can be used in the assessment of quality of care, although this requires adequate adjustment of outcomes for case mix [1, 2]. Several methodological problems affect studies of the prognosis of PICH and their results. First, PICH is relatively rare, accounting for only 10–20% of all stroke cases. Therefore, most studies have generally contained too few patients to give precise estimates of prognosis or to reliably identify the factors that predict outcome. Second, PICH is only reliably identified by brain imaging or autopsy, and the definition of PICH is dependent on the imaging method and its timing. Third, PICH patients comprise a heterogeneous group, representing a range of haemorrhage aetiologies and types. Finally, outcome after PICH is influenced in the different studies by the treatment given to patients, and this varies greatly according to geographical location. The ‘ideal’ study [3] of long-term outcome after PICH should provide unbiased and precise estimates of prognosis. The study should identify all first-ever strokes in a large, well-defined population, including all patients that are not referred to hospital. The study should then identify all cases of PICH in the group of first-ever strokes, to produce an unselected, representative group at the begin-

10

Cerebrovasc Dis 2003;16(suppl 1):9–13

93 (19.6) 33 (13.0) 87 (8.8) 37 (9.9) 63 (19.1) 40 (10.8) 122 (14.9)

ning of the study. This requires either CT scanning within 7 days of stroke onset or a gradient echo MRI (or equivalent) if later in all cases and an autopsy in fatal cases where such scanning was not possible [4]. Patients should be identified as soon after the initial stroke as possible, and patients should be followed prospectively, with frequent follow-up until death. Stroke recurrences should be characterized clinically, and should be investigated with early CT or MRI scans to determine if these are haemorrhagic or ischaemic events. Regular measurements should also be made regarding impairment, disability and handicap, and quality of life.

Outcome after PICH

Overview of Current Data Most of the community-based studies to date have included only small populations – typically 50,000– 200,000 – resulting in the analysis of relatively small numbers of first-ever strokes and even smaller numbers of PICH. Most have been in White populations, so relatively little is known about the prognosis of PICH in other ethnic groups. Hospital-based and less rigorous communitybased ones will not identify all stroke patients occurring in a defined population. In these circumstances, certain types of patients will be underrepresented: these include patients with minor strokes, who are less likely to be referred, patients with major strokes, who may die without diagnosis, and others who are not admitted to hospi-

Dennis

Study Perth

n/N 13/37

Oxfordshire

34/66

Arcadia

37/77

Erlangen

20/48

Innherred

17/45

Belluno

32/93

Aosta

15/33

Dijon

47/87

Umbria

14/37

Libya

32/63

Melbourne L’Aquila All

18/40 63/122 331/748 20

30

40

50

60

Case fatality(%)

Fig. 1. One-month case fatality in PICH identified in community-

based studies [6–17]. The squares indicate the point estimate and the horizontal lines indicate the 95% confidence intervals of the estimates. The size of the squares reflects the number of patients with PICH included in the study. The diamond indicates the pooled estimate.

Fig. 2. Long-term survival after PICH or cerebral infarction in the

Oxfordshire Community Stroke Project. Kaplan-Meier plot showing proportion of patients surviving at increasing intervals after a firstever stroke due to PICH or cerebral infarction [reprinted with permission, 19].

Survival Data Twelve community-based studies reporting 1-month case fatality after PICH have been published (table 1) [6–

17]. The majority (9) of these studies included patients with first-ever stroke, while one each studied outcome in patients with stroke or transient ischaemic attack [6], first-ever and recurrent stroke [10] or in consecutive cases of PICH [16]. Study populations ranged in size from F50,000 to 3.5 million patients, and the number of patients with PICH in these cohorts ranged from 33 to 122. Although the estimates of 1-month case fatality from the individual studies have wide confidence intervals, reflecting the small number of PICHs in the individual cohorts, the pooled estimate is more precise, and gives a value of 42% for 1-month case fatality (fig. 1). Several factors have been identified in studies as being associated with a high early case fatality [18]. These are: increasing age; clinical severity of PICH; poor pre-stroke function; volume of PICH; presence of intraventricular blood, and anticoagulant therapy. There is, of course, a degree of interrelation between these factors, since, for example, the volume of PICH and the presence of intraventricular blood are related to the clinical stroke severity. Moreover, studies which have suggested that patients receiving anticoagulants die more frequently may not have adjusted for volume of PICH. Kaplan-Meier analysis of survival in the Oxfordshire Community Stroke Project (OCSP) confirms the high early mortality in PICH patients compared with ischaemic stroke patients over the time period (fig. 2) [19]. Over longer-term (30-day to 5-year) follow-up, the survival curves

Outcome after Brain Haemorrhage

Cerebrovasc Dis 2003;16(suppl 1):9–13

tal. In the available studies, many did not perform a CT scan within 7 days of stroke onset, and none routinely had good access to gradient echo MRI, which is probably the most sensitive and reliable way of identifying previous haemorrhage. This may lead to certain types of haemorrhage being underrepresented in these study cohorts. Misdiagnosis may result from delays. These may be attributable to patient delay in reporting symptoms, delay in referral to hospital, and delay in imaging to arrive at the diagnosis. The latter type of delay may not occur in hospital-based practice, but certainly occurred in the community-based stroke registers, which provide the most unbiased information on prognosis in PICH [5]. Other problems that potentially affect the studies of prognosis of PICH include losses to follow-up in some studies, small numbers of survivors due to high early mortality, lack of uniform adoption of standard definitions, an absence of treatment description or recurrence characterization, and the fact that assessments looking at predictive factors are often not blinded to patient outcome.

11

Fig. 3. Stroke recurrence after PICH in the Oxfordshire Community

Stroke Project [reprinted with permission, 7].

for PICH patients and those with ischaemic stroke appear to converge. However, this is probably due to a survival effect, with long-term survivors of PICH being younger and fitter than the survivors of ischaemic stroke several years after the index event. Functional Outcome Data on 1-year outcomes from the OCSP indicate that around 25% of PICH patients are independent in their activities of daily living, and around 10–15% survive but are dependent. In the same study, patients within the total anterior circulation infarction (TACI) category had a similar case fatality at 1 year, but the majority of survivors were dependent in everyday activities [20]. The most likely explanation for this is that TACI patients form a homogeneous group with clinically severe stroke and high stroke scale scores, whilst PICH patients are more heterogeneous in terms of severity. In a prospective study of 1,000 unselected patients with acute stroke, Jorgensen et al. [21] analysed the outcomes of intracerebral haemorrhage versus infarction, with adjustment for initial stroke severity. In this analysis, the relative frequency of PICH rose exponentially with increasing stroke severity. However, on multivariate analysis, pathological type (i.e., cerebral infarction versus PICH) did not independently predict mortality, neurological outcome, functional outcome, or the time course of recovery. These data suggest that the poorer prognosis in patients with PICH is due to the increase in frequency of intracerebral haemorrhage with increasing stroke severity.

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Cerebrovasc Dis 2003;16(suppl 1):9–13

Recurrence after PICH Very few data are available on the risk of recurrence after a first PICH. In the OCSP, the annual risk of recurrent stroke between 30 days and 5 years of follow-up was 7% (fig. 3) [7]. However, in this study the sample size was small, with only 66 patients with PICH at the start of follow-up, leading to wide 95% confidence intervals. A systematic review of studies reporting recurrent stroke after PICH has recently been reported by Bailey et al. [22]. This overview analysed data from three community-based populations (total sample size = 146 patients) and seven hospital-based cohorts (total sample size = 1,734 patients). From these pooled data, the overall stroke recurrence rate was 4.3% per patient-year, with rates of 6.2% per patient-year in community-based studies and 4.0% per patient-year in hospital-based studies (p = 0.04). These recurrence rates are very similar to those reported for recurrence after ischaemic stroke [23]. In the same overview, over half (59%) of the recurrent strokes were haemorrhagic, 26% were ischaemic, and 15% were of unknown aetiology. This finding may have implications for our approach to secondary prevention and in particular the use of antithrombotic medication. Although the overall risk of recurrence in PICH patients is probably between 4 and 7% per year, it is probable that certain factors will indicate a higher or lower than average risk. It seems likely that the site of the first haemorrhage, which to some extent reflects the underlying cause of the haemorrhagic stroke, will be important. For example, in the review by Bailey et al. [22], recurrence was more likely in those with lobar haemorrhage than in those with a deep hemispheric PICH (4.4 vs. 2.1% per patient-year; p = 0.002). Lobar haemorrhage often results from amyloid angiopathy which seems to carry a higher risk of recurrence. Indeed, many patients may have several haemorrhages within a few days or weeks of each other. Furthermore, it seems likely that patients with abnormal coagulation and those with vascular malformations (e.g. arteriovenous fistula) will have a higher risk of recurrence. In a systematic review by Al Shahi and Warlow [24], patients who had an arteriovenous malformation and who presented with a haemorrhage had an 18% annual risk of recurrent bleed, compared with lower rates amongst patients with other presentations, such as epileptic seizures. Although not yet formally studied, it is likely that patients who present with a first stroke due to an intracerebral haemorrhage but who on gradient echo T2 have many microhaemorrhages will have a higher than average risk of recurrence. The results of the PROGRESS trial showed that lowering blood pressure, even within the

Dennis

‘normal’ range, reduced the risk of recurrent stroke [25]. This was particularly marked in those who entered the study following a haemorrhagic stroke. Thus, blood pressure during follow-up is likely to be a major factor in determining an individual’s risk of recurrence. Risk of Epilepsy Very few data are available on the risk of epileptic seizures after first-ever stroke. In the OCSP, Kaplan-Meier analysis showed that patients with PICH have a higher risk of developing seizures than do ischaemic stroke patients (hazard ratio = 10.2; 95% CI 3.7–27.9) [26]. The risk of epilepsy is higher in the first year after the index event and overall, corresponds to about 8 per 100 patient-years. The risk is probably higher in those with lobar haemorrhage, which more commonly involves the cerebral cortex.

Conclusions

Current data from community-based studies indicate that the 1-month case fatality after PICH is around 40– 45% and that haemorrhage severity is the major predictor of mortality. Functional outcome is similar to that of cerebral infarction and again depends on the initial severity of the stroke. The recurrence rate is perhaps between 4 and 7%, i.e. very similar to that of ischaemic stroke, and probably depends on the cause and also on blood pressure. The seizure rate is estimated at 8%, and is probably dependent on the location of the haemorrhage. Pooling of data from community-based studies of haemorrhagic stroke that have used consistent definitions and methods represents the only feasible way to obtain more precise data on prognosis after PICH.

References 1 Davenport RJ, Dennis MS, Warlow CP: Effect of correcting outcome data for case mix: An example from stroke medicine. BMJ 1996;312: 1503–1505. 2 Weir N, Dennis M: Scottish Stroke Outcomes Group: Towards a national system for monitoring the quality of hospital-based stroke services. Stroke 2001;32:1415–1421. 3 Sudlow CLM, Warlow CP: Comparing stroke incidence worldwide: What makes studies comparable? Stroke 1996;27:550–558. 4 Wardlaw JM, Keir SL, Dennis MS: The impact of delays in computed tomography of the brain on the accuracy of diagnosis and subsequent management in patients with minor stroke. J Neurol Neurosurg Psychiatry 2003;74:77–81. 5 Keir SL, Wardlaw JM, Warlow CP: Stroke epidemiology studies have underestimated the frequency of intracerebral haemorrhage. A systematic review of imaging in epidemiological studies. J Neurol 2002;249:1226–1231. 6 Anderson CS, Jamrozik KD, Burvill PW, Chakera TM, Johnson GA, Stewart-Wynne EG: Determining the incidence of different subtypes of stroke: Results from the Perth Community Stroke Study, 1989–1990. Med J Aust 1993;158:85–89. 7 Counsell C, Boonyakarnkul S, Dennis M, Sandercock P, Bamford J, Burn J, Warlow C: Primary intracerebral haemorrhage in the Oxfordshire Community Stroke Project. 2. Prognosis. Cerebrovasc Dis 1995;5:26–34. 8 Vemmos KN, Bots ML, Tsibouris PK, Zis VP, Grobbee DE, Stranjalis GS, Stamelopoulos S: Stroke incidence and case fatality in southern Greece. The Arcadia Stroke Registry. Stroke 1999;30:363–370. 9 Kolominsky-Rabas PL, Sarti C, Heuschmann PU, Graf C, Siemonsen S, Neundoerfor B, Katalinc A, Lang E, Gassmann KG, von Stockert TR: A prospective community-based study of stroke in Germany – The Erlangen Stroke Pro-

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ject (ESPro). Incidence and case fatality at 1, 3 and 12 months. Stroke 1998;29:2501–2506. Ellekjær H, Holmen J, Indredavik B, Terent A: Epidemiology of stroke in Innherred, Norway, 1994–1996: Incidence and 30-day case-fatality rate. Stroke 1997;28:2180–2184. Lauria G, Gentile M, Fassetta G, Casetta I, Agnoli F, Andreotta G, Barp C, Caneve G, Cavallero A, Cielo R, Mongillo D, Mosca M, Olivieri PG: Incidence and prognosis of stroke in the Belluno Province, Italy. First-year results of a community-based study. Stroke 1995;26: 1787–1793. D’Alessandro G, Di Giovanni M, Roveyaz L, Iannizzi L, Pesenti Compagnoni M, Blanc S, Bottacchi E: Incidence and prognosis of stroke in the Valle d’Aosta, Italy: First-year results of a community-based study. Stroke 1992;23: 1712–1715. Giroud M, Gras P, Chadan N, Beuriat P, Milan C, Arveux P, Duams R: Cerebral haemorrhage in a French prospective population study. J Neurol Neurosurg Psychiatry 1991;54:595– 598. Ricci S, Celani MG, La Rosa F, Vitali R, Duca E, Ferraguzzi R, Paolotti M, Seppoloni D, Caputo N, Chiurulla C, Scaroni R, Signorini E: SEPIVAC: A community-based study of stroke incidence in Umbria, Italy. J Neurol Neurosurg Psychiatry 1991;54:695–698. Ashok PP, Radhakrishnan K, Sridharan R, ElMangoush MA: Incidence and pattern of cerebrovascular disease in Benghazi, Libya. J Neurol Neurosurg Psychiatry 1986;49:519–523. Thrift AG, Dewey HM, Macdonell RAL, McNeil JJ, Donnan GA: Stroke incidence on the East Coast of Australia. The North East Melbourne Stroke Incidence Study (NEMESIS). Stroke 2000;31:2087–2092. Carolei A, Marini C, Di Naploi M, Di Gianfilippo G, Santalucia P, Baldassarre M, De Matteis G, di Orio F: High stroke incidence in the

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prospective community-based L’Aquila registry (1994–1998). First year’s results. Stroke 1997;28:2500–2506. Counsell C, Dennis M: Systematic review of prognostic models in patients with acute stroke. Cerebrovasc Dis 2001;12:159–170. Dennis MS, Burn JPS, Sandercock PAG, Bamford JM, Wade DT, Warlow CP: Long-term survival after first-ever stroke: The Oxfordshire Community Stroke Project. Stroke 1993;24: 796–800. Warlow CP, Dennis MS, Van Gijn J, Hankey G, Bamford J, Wardlaw J: A practical approach to management of stroke patients; in Stroke: A Practical Guide to Management, ed 2. Oxford, Blackwell Scientific, 2000, pp 414–441. Jorgensen HS, Nakayama H, Raaschou HO, Olsen TS: Intracerebral hemorrhage versus infarction: Stroke severity, risk factors and prognosis. Ann Neurol 1995;38:45–50. Bailey RD, Hart RG, Benavente O, Pearce LA: Recurrent brain hemorrhage is more frequent than ischemic stroke after intracranial hemorrhage. Neurology 2001;56:773–777. Burn J, Dennis M, Bamford J, Sandercock P, Wade D, Warlow C: Long-term risk of recurrent stroke after a first-ever stroke. Stroke 1994;25:333–337. Al-Shahi R, Warlow C: A systematic review of the frequency and prognosis of arteriovenous malformations of the brain in adults. Brain 2001;124:1900–1926. PROGRESS Collaborative Group: Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;358:1033–1041. Burn J, Dennis M, Bamford J, Sandercock P, Wade D, Warlow C: Epileptic seizures after a first stroke: The Oxfordshire Community Stroke Project. BMJ 1997;315:1582–1587.

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Cerebrovasc Dis 2003;16(suppl 1):14–19 DOI: 10.1159/000069936

Long-Term Outcome after Ischaemic Stroke/Transient Ischaemic Attack Graeme J. Hankey Stroke Unit, Royal Perth Hospital and Department of Medicine, University of Western Australia, Perth, WA, Australia

Key Words Ischaemic stroke W Prognosis W Transient ischaemic attack

Abstract During the first 30 days after a stroke, the case fatality is about 25% and the major cause of death is the index stroke and its sequelae. The most consistent predictor of 30-day mortality after stroke is stroke severity. Other predictors include increasing age, a history of previous stroke, cardiac failure, and a high blood glucose concentration and white blood cell count. Other less common, but important, causes of early mortality are recurrent ischaemic stroke and a coronary event. The risk of a recurrent cerebrovascular event is highest in the first month (4%) and year (12%) after a stroke and transient ischaemic attack (TIA), probably reflecting the presence of active, unstable atherosclerotic plaque. Thereafter, the risk of a recurrent cerebrovascular event falls to about 5% per year, similar to the risk of a coronary event. During years 1–5 after a TIA and ischaemic stroke, cardiovascular disease increasingly becomes the major cause of death, reflecting the generalized nature of atherothrombosis, the most common cause of the index stroke. The most robust predictor of death within 1–5 years after stroke is increasing age, closely followed by cardiac fail-

ure. Additional baseline predictors of longer-term mortality include a history of previous symptomatic atherothrombosis (TIA, ischaemic stroke, peripheral arterial disease, and early-onset ischaemic heart disease), risk factors for atherothrombosis (smoking), other heart diseases (cardiac failure, atrial fibrillation) and increasing stroke severity. Lacunar syndromes can be predictive of relative longevity. At 5 years after stroke, survival is about 40%, and about half of survivors are disabled and dependent. The most robust predictors of disability at 5 years after stroke are increasing age, stroke severity, and recurrent stroke. The most powerful predictor of early recurrent stroke (within 30 days after stroke) is an atherosclerotic ischaemic stroke caused by large-artery atherosclerosis with 150% stenosis, whereas the strongest predictor of stroke recurrence over 5 years is diabetes. Other predictors of recurrent stroke include increasing age, previous TIA, atrial fibrillation, high alcohol consumption, haemorrhagic index stroke, and hypertension at discharge. The clinical implication of these findings is that strategies for optimizing long-term outcome after TIA and stroke should be directed toward reducing the high risk of recurrent stroke and coronary events by removing/recanalizing the symptomatic atherosclerotic plaque, controlling the underlying causal vascular risk factors, and administering long-term, effective antiplatelet therapy. Copyright © 2003 S. Karger AG, Basel

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Graeme J. Hankey, MD Stroke Unit, Department of Neurology Royal Perth Hospital, Wellington Street Perth, WA 6001 (Australia) Tel. +61 8 9224 2598, Fax +61 8 9224 3323, E-Mail [email protected]

Introduction

The long-term prognosis for survival free of a recurrent stroke and coronary event after a stroke is of importance to patients and their carers, relatives and clinicians. For the clinician, reliable information on long-term prognosis helps to guide patient management. It facilitates: (1) the selection of appropriate and treatments (particularly those that are risky or expensive); (2) provision of reliable information to patients and their relatives; (3) comparisons of patient outcome with the outcome of other patients (by allowing adjustment for case mix); (4) improved design and analysis of clinical trials (e.g. risk stratification and sample size calculation), and (5) improved understanding of the underlying causal disease, which is atherothrombosis in most cases of stroke. The ideal study of the prognosis after transient ischaemic attack (TIA) and stroke is one that is characterized by: (1) complete ascertainment of all cases of first-ever stroke and TIA from large community-based inception cohorts in which the standard diagnostic criteria and details of disease severity, co-morbidity and socio-demographic factors are described at inception; (2) patients are followed up at regular intervals prospectively and completely; (3) valid, reliable and objective and standardized measures of important outcomes which are recorded prospectively and blinded to the study hypotheses, and (4) actuarial methods of survival analyses are used, with adjustment for extraneous prognostic factors [1]. Since 1966, more than 250 published studies have described prognostic models of outcome after stroke, but the majority (around three-quarters) of these are not internally valid, and all but 3% (12% of the remainder) are prone to hospital-referral selection bias [2]. The number of robust studies on long-term outcome after TIA or

stroke is similarly limited. The aim of this article is to review current evidence from the small proportion of high-quality studies on the prognosis of patients with TIA or ischaemic stroke and the predictors of short- and longterm mortality, disability and recurrent stroke.

Long-Term Stroke and Cardiac Risk in Stroke/TIA Patients

Prospective, Community-Based Studies of Prognosis of TIA There have been three prospective, community-based studies of the long-term prognosis after TIA (table 1). These were undertaken in Söderhamn, Sweden [3], Oxfordshire, UK [4] and Perugia, Italy [5] over two successive 3-year periods, 5 years and 9 years, respectively. The average annual risk of stroke was 5.3% (95% CI 3.1– 7.4%) over each of the two 3-year periods in Söderhamn, 6.7% (95% CI 4.7–8.9%) over 5 years in Oxfordshire, and 2.4% (95% CI 0.7–4.7%) over 9 years in Perugia. The risk of stroke was highest within the first month (4.4% (95% CI 1.5–7.3%) in Oxfordshire) and first year (11.6% (95% CI 6.9–16.3%) in Oxfordshire) after TIA and fell thereafter to about 2–3% per year during subsequent years. The average annual risk of death after MI was 2.5% in both Oxfordshire and Perugia (no data were reported for Söderhamn). In contrast to stroke, there was no excess early risk of MI. The average annual risk of death was 4.9% (95% CI 0.1–10.3%) and 7.3% (95% CI 1.1–14.4%) over two 3-year periods in Söderhamn, 7.2% (95% CI 5.2– 9.5%) over 5 years in Oxfordshire, and 7.0% over 9 years in Perugia. The proportion of fatalities due to cardiac causes was similar to the proportion caused by stroke in Oxfordshire (35 vs. 31%) and Perugia (22 vs. 20%).

Table 1. Community-based studies of long-term prognosis after TIA [3–5]

Study

Location

Terént [3]

Söderhamn, Sweden

Dennis et al. [4] Ricci et al. [5]

Oxfordshire, UK Umbria, Italy

a

Time period

1975–1979/ 1983–1987 1981–1986 1986–1989

Patients

Follow-up Annual event rate, % years stroke MI

death

97

3

5.3, 5.3a

–

4.9, 7.3a

184 94

5 9

6.7 (4.7–8.9) 2.4

2.5 (1.2–4.0) 2.5

7.2 (5.2–9.5) 7.0

Data are for two successive 3-year periods.

Outcome after Ischaemic Stroke/TIA

Cerebrovasc Dis 2003;16(suppl 1):14–19

15

Fig. 2. Proportion of patients dying from different causes during dif-

ferent time intervals from the onset of their first-ever stroke in the Perth Community Stroke Study [reproduced with permission, 13].

shire [7], Kaplan-Meier analysis for stroke-free survival reveals a high risk of stroke in the first 1–6 months after stroke (fig. 1), which probably reflects active, unstable atherosclerotic plaque. In contrast, the Kaplan-Meier curve for coronary events exhibits a long-term linear trend after TIA (fig. 1). In prospective hospital-based studies of TIA, the most important cause of death is observed to be cardiac disease (42%), followed by stroke (23%).

Fig. 1. Event rate curves for survival free of stroke (a) and coronary events (b) in hospital-referred TIA patients [reproduced with permission, 7].

Prospective, Hospital-Based Studies of Prognosis of TIA The scant information from community-based studies of TIA prognosis is supplemented by data from four major hospital-based studies recording stroke and cardiac events after TIA (table 2) [6–9]. In these studies, which followed larger cohorts of younger patients compared with the community-based cohorts, the annual rate of stroke was 2.2– 5.0% over 4–5 years, which is similar to the risk of MI (1.1–4.6%) over the same period. In the study in Oxford-

16

Cerebrovasc Dis 2003;16(suppl 1):14–19

Prospective Studies of Stroke There have been 11 community-based studies of the long-term prognosis after all stroke, first-ever stroke, or first-ever ischaemic stroke. Six of these recorded stroke and cardiac events over 5 years (table 3) [10–15]. At 5 years of follow-up, the proportion of deaths due to cardiac causes was equal to, or greater than, the proportion due to stroke (the index event and recurrent stroke). In the Perth Community Stroke Study, the proportion of death due to stroke decreased with the passage of time after the index stroke, and the proportion of deaths due to coronary events and non-vascular events increased over time (fig. 2). The average annual risk of recurrent stroke was about 6% (95% CI 4–8%) over 5 years. The risk of stroke was highest within the first 6 months (9%) and first year (13–14%) after stroke, and fell thereafter to about 4–5% per year during subsequent years.

Hankey

Table 2. Hospital-based studies of long-

term prognosis after TIA [6–9]

Study

Time period

Patients

Mean age Follow-up Annual event rate, % years years stroke MI

Heyman et al. [6] Hankey et al. [7] Carolei et al. [8] Howard et al. [9]

1974–1978 1977–1986 1977–1980 1987–1991

390 469 712 280

61.7 62.1 55.7 64

5 5 4 4

5.0 3.4 2.2 3.0

4.6 3.1 1.1 4.2

Table 3. Overview of community-based studies of stroke, recording stroke and cardiac events over 5 years [10–15]

Study

Location

Stroke type

Time period

Patients

Mortality at Causes of death, % 5 years, % stroke cardiac

Scmidt et al. [10] Burn et al. [11]a Petty et al. [12] Hankey et al. [13] Hartmann et al. [14]a Brønnum-Hansen et al. [15]

Moscow, Russia Oxfordshire, UK Rochester, USA Perth, Australia Northern Manhattan, USA Copenhagen County, Denmark

First stroke First stroke First ischaemic stroke First stroke First ischaemic stroke All stroke

1972–1974 1981–1986 1975–1989 1989–1995 1990–1997 1982–1991

941 675 1,111 370 980 4,162

72 45 53 60 41 60

a

23 36 27 27 15 32

42 34 24 31 29 23

Data are for causes of death in the first 30 days after index event.

Predictive Factors for Stroke Prognosis

Predictors of Mortality Current findings on short- and long-term predictors of death, disability and recurrent stroke are summarized in table 4. Probably the most reliable data on mortality comes from Olmsted County, Minnesota, USA, where 30-day and 5-year follow-up data between 1985 and 1989 have been reported for a cohort of 454 patients with firstever ischaemic stroke [12], and 10-year follow-up data are available for a cohort of 1,111 first-ever ischaemic stroke patients followed between 1975 and 1989 [16]. For death at 30 days after ischaemic stroke, the two major predictors of early mortality were age (relative risk (RR)/10 years = 1.3; 95% CI 1.03–1.7) and severe stroke as measured by the Rankin scale (RR = 11.6; 95% CI 2.8–49). For mortality at 5 years, age and severe stroke continued to predict outcome. In addition, congestive heart failure (RR = 1.7; 95% CI 1.2–2.3) and early-onset ischaemic heart disease (RR = 5.0; 95% CI 1.8–13) also had statistically significant predictive power. Ischaemic stroke caused by large-artery atherosclerosis with 150% stenosis was associated with a lower risk of 5-year mortality (RR = 0.5; 95% CI 0.3–0.8). From the study with 10-

year follow-up data, age at presentation continued to have predictive power for long-term mortality, whereas stroke severity did not. However, atrial fibrillation, congestive heart failure, and early- and late-onset ischaemic heart disease at baseline were significant predictors of 10year mortality. Five-year follow-up data are also available from the Northern Manhattan Stroke Study [17], which analyzed predictors of outcome in 323 ischaemic stroke patients between 1983 and 1988. In this cohort, the predictors of death at 30 days were again stroke severity (as assessed by depressed consciousness, major hemispheric or basilar syndrome, and hyperglycaemia at hospital admission), as well as congestive heart failure. At 5 years of follow-up, stroke severity and congestive heart failure continued to be predictors of mortality, and increasing age also had statistically significant predictive power. Patients who presented with lacunar ischaemic stroke syndromes had significantly lower mortality at 5 years after the index stroke. In the Perth Community Stroke Study, data were available for 1- and 5-year mortality [13, 18]. Predictors of death at 1 year were increasing stroke severity and a history of previous cardiac disease (atrial fibrillation or conges-

Outcome after Ischaemic Stroke/TIA

Cerebrovasc Dis 2003;16(suppl 1):14–19

17

Table 4. Short- and long-term predictors of death, disability and stroke recurrence

Outcome

Predictors short-term

long-term

Death

Severe stroke Impairments (coma, weakness, incontinence) Syndromes (TACS, POCS) Laboratory findings (blood glucose level, white cell count)

Increasing age Cardiac disease Cardiac failure Ischaemic heart disease Atrial fibrillation Syndromes (LACS protective)

Disability

Severe stroke Impairments (coma, weakness, incontinence) Syndromes (TACS, POCS) Laboratory findings (blood glucose level, white cell count) Pre-stroke dependency and not living alone

Increasing age Stroke severity Recurrent stroke

Recurrent stroke

Large-artery atherosclerotic ischaemic stroke

Diabetes mellitus Previous TIA Atrial fibrillation Hypertension at discharge High alcohol consumption Intracerebral haemorrhage Increasing age

LACS = Lacunar syndrome; TACS = total anterior circulation syndrome; POCS = posterior circulation syndrome.

tive heart failure). At 5 years, increasing stroke severity at baseline was again predictive of mortality, together with evidence at baseline of multi-bed vascular disease was also predictive (previous TIA: RR = 1.9 (95% CI 1.3–2.9); peripheral arterial disease: RR = 1.7 (95% CI 1.2–2.5); cardiac failure: RR = 1.6 (95% CI 1.1–2.3)). These data indicate that long-term prevention of coronary events is essential for long-term reduction of mortality in stroke patients. Other community-based prediction models for mortality have been reported for shorter follow-up periods (30 days to 3 years) [19–24]. Predictors of Disability In most models, the major predictor of early (30 days after stroke) dependency is stroke severity. In the Oxfordshire Community Stroke Project [22, 25], which is the only externally validated predictive model, pre-stroke independence, and normal Glasgow Coma Scale verbal score, arm power, and ability to walk were significant predictors of survival free of dependency at 6 months, whereas increasing age and living alone were associated with a poorer outcome for this parameter. In the Perth Community Stroke Study, the major predictor of new disability at 5 years was recurrent stroke (odds ratio = 12.4, 95% CI

18

Cerebrovasc Dis 2003;16(suppl 1):14–19

3.3–63); other independent predictors were increasing age and stroke severity [26]. Predictors of Stroke Recurrence Around 12% of patients have a recurrent stroke within the first year and 30% experience recurrence over 5 years [11, 27]. In Rochester, Minnesota, the major baseline predictor of recurrent stroke at 30 days was atherosclerotic ischaemic stroke with 150% stenosis (RR = 3.3, 95% CI 1.2–9.3), whereas at 5 years, the major predictor was diabetes (RR = 1.9, 95% CI 1.2–2.8) [12]. At 10 years in Rochester, the major predictors were diabetes (RR = 1.7, 95% CI 1.3–2.2) and increasing age (RR/10 years = 1.2, 95% CI 1.1–1.4) [16]. In the Northern Manhattan Stroke Study, baseline predictors of recurrent stroke at 5 years were high alcohol consumption (RR = 2.5, 95% CI 1.4–4.4), hypertension at discharge (RR = 1.6, 95% CI 1.01–2.6), and blood glucose concentration at hospital admission (RR/10 mg/dl increment = 1.4, 95% CI 1.1–1.7) [17]. The Perth Community Stroke Study also found older age, 75–84 years (RR = 2.6, 95% CI 1.1–6.2) and diabetes (RR = 2.1, 95% CI 1.0–4.4) to be major predictors of recurrent stroke at 5 years, as was intracerebral haemor-

Hankey

rhage (RR = 2.1, 95% 1.0–4.4) [27]. Baseline predictors of stroke recurrence at 5 years in the Malmö Stroke Registry were diabetes (RR = 1.6, 95% CI 1.1–2.5), TIA (RR = 1.6, 95% CI 1.1–2.4) and atrial fibrillation (RR = 1.8, 95% CI 1.1–2.9) [23].

Conclusions

Data from prospective, community-based studies indicate that patients with TIA and ischaemic stroke are at risk of a recurrent event affecting the brain and ischaemic events involving the coronary arteries. The risk of a recurrent cerebrovascular event is higher within the first month (and year) after TIA and stroke, but thereafter the risk of a

cardiac event becomes equal, if not greater. Furthermore, non-cerebral cardiovascular disease becomes the major, and ever-increasing, cause of death amongst patients with TIA and ischaemic stroke with the passage of time. The major predictors of long-term mortality and morbidity are ischaemic heart disease and its complications, and causal risk factors for atherothrombosis. Atherothrombosis is a multifocal, systemic disease, which represents the major cause of index and recurrent stroke and the major cause of cardiac events. Strategies for secondary prevention after TIA/stroke should be directed toward removing the symptomatic disease, which is usually atherothrombosis, control of major causal risk factors for atherogenesis, and optimal antiplatelet therapy.

References 1 Sackett DL, Haynes RB, Guyatt GH, Tugwell MD: Clinical Epidemiology. A Basic Science for Clinical Medicine, ed 2. Boston, Little, Brown, 1991, pp 173–185. 2 Counsell C, Dennis M: Systematic review of prognostic models in patients with acute stroke. Cerebrovasc Dis 2001;12:159–170. 3 Terént A: Survival after stroke and transient ischemic attacks during the 1970s and 1980s. Stroke 1989;20:1320–1326. 4 Dennis M, Bamford J, Sandercock P, Warlow C: Prognosis of transient ischemic attacks in the Oxfordshire Community Stroke Project. Stroke 1990;21:848–853. 5 Ricci S, Cantisani AT, Righetti E, Duca E, Spizzichino L: Long-term follow-up of TIAs: The SEPIVAC Study. Neuroepidemiology 1998;17:31–54. 6 Heyman A, Wilkinson WE, Hurwitz BJ, Haynes CS, Utley CM, Rosati RA, Burch JG, Gore TB: Risk of ischemic heart disease in patients with TIA. Neurology 1984;34:626– 630. 7 Hankey GJ, Slattery JM, Warlow CP: The prognosis of hospital-referred transient ischaemic attacks. J Neurol Neurosurg Psychiatry 1991;54:793–802. 8 Carolei A, Candelise L, Fiorelli M, Francucci BM, Motolese M, Fieschi C: Long-term prognosis of transient ischemic attacks and reversible ischemic neurologic deficits: A hospitalbased study. Cerebrovasc Dis 1992;2:266– 272. 9 Howard G, Evans GW, Rouse JR III, Toole JF, Ryu JE, Tegeler C, Frye-Pierson J, Mitchell E, Sanders L: A prospective reevaluation of transient ischemic attacks as a risk factor for death and fatal or nonfatal cardiovascular events. Stroke 1994;25:342–345.

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10 Scmidt EV, Smirnov VE, Ryabova VS: Results of the seven-year prospective study of stroke patients. Stroke 1988;19:942–949. 11 Burn J, Dennis M, Bamford J, Sandercock P, Wade D, Warlow C: Long-term risk of recurrent stroke after a first-ever stroke. The Oxfordshire Community Stroke Project. Stroke 1994; 25:333–337. 12 Petty GW, Brown RD Jr, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO: Ischemic stroke subtypes. A population-based study of functional outcome, survival and recurrence. Stroke 2000;31:1062–1068. 13 Hankey GJ, Jamrozik K, Broadhurst RJ, Forbes S, Burvill PW, Anderson CS, StewartWynne EG: Five-year survival after first-ever stroke and related prognostic factors in the Perth Community Stroke Study. Stroke 2000; 31:2080–2086. 14 Hartmann A, Rundek T, Mast H, Paik MC, Boden-Albala B, Mohr JP, Sacco RL: Mortality and causes of death after first ischemic stroke. Neurology 2001;57:2000–2005. 15 Brønnum-Hansen H, Davidsen M, Thorvaldsen P, for the Danish MONICA Study Group: Long-term survival and causes of death after stroke. Stroke 2001;32:2131–2136. 16 Petty GW, Brown RD Jr, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO: Survival and recurrence after first cerebral infarction: A population-based study in Rochester, Minnesota, 1975 through 1989. Neurology 1998;50:208– 216. 17 Sacco RL, Shi T, Zamanillo MC, Kargman DE: Predictors of mortality and recurrence after hospitalized cerebral infarction in an urban community: The Northern Manhattan Stroke Study. Neurology 1994;44:626–634. 18 Anderson CS, Jamrozik KD, Broadhurst RJ, Stewart-Wynne EG: Predicting survival for 1 year among different subtypes of stroke. Results from the Perth Community Stroke Study. Stroke 1994;25:1935–1944.

19 Czlonkowska A, Ryglewicz D, Lechowicz W: Basic analytical parameters as the predictive factors for 30-day case fatality rate in stroke. Acta Neurol Scand 1997;97:121–124. 20 Carlberg B, Asplund K, Hagg E: The prognostic value of admission blood pressure in patients with acute stroke. Stroke 1993;24:1372–1375. 21 Nakayama H, Jorgensen HS, Raaschou HO, Olsen TS: The influence of age on stroke outcome. The Copenhagen Stroke Study. Stroke 1994;25:808–813. 22 Counsell C, Dennis M, McDowall M, Warlow C: Predicting outcome after acute and subacute stroke. Development and validation of new prognostic models. Stroke 2002;33:1041– 1047. 23 Elneihoum AM, Göransson M, Flake P, Janzon L: Three-year survival and recurrence after stroke in Malmö, Sweden. An analysis of Stroke Registry Data. Stroke 1998;29:2114– 2117. 24 Bonita R, Ford MA, Stewart AW: Predicting survival after stroke: A three-year follow-up. Stroke 1988;19:669–673. 25 The FOOD Trial Collaboration: Performance of a statistical model to predict stroke outcome in the context of a large, simple, randomized, controlled trial of feeding. Stroke 2003;34:127– 133. 26 Hankey GJ, Jamrozik K, Broadhurst RJ, Forbes S, Anderson CS: Long-term disability after first-ever stroke and related prognostic factors in the Perth Community Stroke Study, 1989–1990. Stroke 2002;33:1034–1040. 27 Hankey GJ, Jamrozik K, Broadhurst RJ, Forbes S, Burvill PW, Anderson CS, StewartWynne EG: Long-term risk of first recurrent stroke in the Perth Community Stroke Study. Stroke 1998;29:2491–2500.

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Cerebrovasc Dis 2003;16(suppl 1):20–26 DOI: 10.1159/000069937

Evidence with Antiplatelet Therapy and ADP-Receptor Antagonists J. Donald Easton Department of Neurology, Brown University, Providence, R.I., USA

Key Words Acetylsalicylic acid W Antiplatelet therapy W Clopidogrel W Stroke

Abstract Antiplatelet drugs have been shown to prevent a range of atherothrombotic events, including transient ischaemic attack (TIA) and ischaemic stroke. Clopidogrel and ticlopidine are adenosine diphosphate (ADP)-receptor antagonists that inhibit ADP-induced fibrinogen binding to platelets, a necessary step in the platelet aggregation process. The Antithrombotic Trialists’ Collaboration recently published a major meta-analysis that assessed the effect of antiplatelet therapy in patients with various manifestations of atherosclerosis. In total, this analysis included 135,000 patients in comparisons of antiplatelet agents versus control and 77,000 patients in comparisons of different antiplatelet regimens. This meta-analysis found that overall, antiplatelet therapy reduces the combined odds of stroke, myocardial infarction (MI) or vascular death by 22%, and that antiplatelet agents reduce the odds of a non-fatal stroke by 25% over a wide range of patients with or without a history of cerebrovascular disease. In the CAPRIE trial of clopidogrel versus acetylsalicylic acid (ASA), there was a 10% odds reduction for stroke, MI or vascular death in favour of clopidogrel (p = 0.03). In a meta-analysis performed by the Coch-

rane Stroke Group, ADP-receptor antagonist therapy significantly reduced the odds of a serious vascular event (stroke, MI or vascular death) by 9% (2p = 0.01) and of any stroke by 12%. The safety/tolerability profile of clopidogrel was superior to that of ticlopidine, and at least as good as that of ASA. In CURE, a long-term benefit was observed with the use of clopidogrel on top of standard therapy (including ASA in all patients), with a 20% relative risk reduction for the primary endpoint of cardiovascular death, MI or stroke (p ! 0.001) in patients with unstable angina and non-Q-wave MI. A consistent benefit was seen across all patient subgroups, including patients with a previous history of stroke. More recently, CREDO has demonstrated the incremental benefit of prolonged use of clopidogrel on top of ASA in patients undergoing elective PCI, with a 27% reduction in the combined risk of death, MI or stroke after 12 months of therapy (p = 0.02) and a 25% reduction in stroke over the same time period. The MATCH trial is currently being conducted to test the hypothesis that long-term administration of clopidogrel on top of ASA is superior to clopidogrel alone for the reduction of major ischaemic events in patients with recent TIA or ischaemic stroke who are at high risk of atherothrombotic recurrence. Further trials of clopidogrel on top of standard therapy (including ASA) are planned in neurology; these include SPS3, in patients with small subcortical strokes, and ATARI, in patients who have recently recovered from a TIA. Copyright © 2003 S. Karger AG, Basel

ABC

© 2003 S. Karger AG, Basel 1015–9770/03/0165–0020$19.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/ced

J. Donald Easton, MD Rhode Island Hospital 110 Lockwood Street, Suite 324 Providence, RI 02903 (USA) Tel. +1 401 4448795, Fax +1 401 4448781, E-Mail [email protected]

Introduction

Atherothrombosis is the acute pathophysiological process whereby platelet activation and aggregation occurs at the site of a ruptured or eroded atherosclerotic plaque [1]. The clinical manifestations of atherothrombosis include transient ischaemic attack (TIA), ischaemic stroke, unstable angina, myocardial infarction (MI) and intermittent claudication [2], and patients with symptomatic disease in one vascular bed are liable to have diffuse disease, placing them at risk of subsequent events in additional vascular territories. This is illustrated in the case of stroke patients, in whom the long-term risk of cardiac disease matches or exceeds that of recurrent stroke [3–7]. Antiplatelet therapy has been shown to prevent a broad range of atherothrombotic events, and international guidelines recommend that all patients who have experienced stroke or TIA should receive regular antiplatelet therapy to reduce the risk of recurrent stroke and other vascular ischaemic events [8, 9]. The pivotal role of the platelet in chronic atherogenesis and its acute complications has led to the development and evaluation of a range of antiplatelet agents. Currently available oral antiplatelet agents for stroke prevention include acetylsalicylic acid (ASA), the adenosine diphosphate (ADP)-receptor antagonists clopidogrel and ticlopidine, and dipyridamole (either alone or in combination with low-dose ASA). In contrast to ASA, which inhibits cyclooxygenase activity and ultimately the thromboxane A2 pathway of platelet activation [10], clopidogrel, like ticlopidine, is a specific inhibitor of the P2Y12 ADP receptor on human platelets, resulting in irreversible inhibition of binding of ADP to the platelet membrane [11]. The mechanism of action of dipyridamole is less well defined, and this agent has been reported to exhibit both antiplatelet and vasodilatory effects [12].

Antithrombotic Trialists’ Collaboration Meta-Analysis

The Antithrombotic Trialists’ Collaboration recently published a major updated meta-analysis that assessed the effects of antiplatelet drugs in patients with various manifestations of atherosclerosis, including TIA and ischaemic stroke, as well as many other types of patient who are at risk for atherothrombotic events [13]. The final analysis included 287 randomized studies involving 135,000 patients in comparisons of antiplatelet therapy versus control and 77,000 patients in randomized, head-

Evidence with ADP-Receptor Antagonists

to-head comparisons of different antiplatelet regimens. Data from recent large trials such as CAPRIE [14], ESPS2 [15], CAST [16] and IST [17] were included. The latest findings reinforced the messages of the previous meta-analysis [18]. Moreover, the update incorporated substantial new data on patients with a history of stroke or TIA, those treated early after an acute stroke, and those with stable angina, atrial fibrillation, peripheral arterial disease, or diabetes, extending the range of patient types for whom antiplatelet therapy is of clear benefit. Overall, antiplatelet therapy reduced the overall odds of a serious vascular event (stroke, MI or vascular death) by 22%, with odds reductions of 25% for non-fatal stroke, 34% for non-fatal MI and 15% for vascular mortality [13]. Based on trials comparing ASA versus control, the risk of bleeding appeared to be dose-related, but there was no evidence of heterogeneity with regards to efficacy according to ASA dose ranges. Interestingly, a similar effect was observed in the recent CURE trial, in which all patients received daily ASA, but the precise dose (75–325 mg) was at the discretion of the investigator [19]. Based on data from the CAPRIE trial [14], the metaanalysis found a statistically significant 10% (B4%) odds reduction (10.1 vs. 11.1%) in favour of clopidogrel versus ASA for the composite endpoint of stroke (all-cause), MI or vascular death (p = 0.03). This is consistent with the 12% (B7%) odds reduction (21.1 vs. 23.2%) for the same endpoint obtained from pooled data of four trials of ticlopidine versus ASA in patients with different clinical manifestations of atherothrombosis [13].

Trials of ASA in Stroke Patients

In 1999, Algra and van Gijn [20] published a metaanalysis of 11 placebo-controlled trials of ASA treatment in patients with a previous TIA or ischaemic stroke. Pooled data from over 10,000 patients yielded a relative risk reduction of 13% (95% CI 6–19%) in the combined endpoint of vascular death, MI or stroke. As noted by the authors, these data underscore the need for more efficacious antiplatelet regimens.

Cochrane Meta-Analysis of ADP-Receptor Antagonist Data

A systematic review of all unconfounded, randomized trials that directly compared an ADP-receptor antagonist with ASA was recently reported by the Cochrane Stroke

Cerebrovasc Dis 2003;16(suppl 1):20–26

21

Group [21]. This analysis identified four trials that enrolled a total of 22,566 high-risk patients with a history of vascular disease, including 9,840 patients in whom the qualifying event was symptomatic cerebrovascular disease. Overall, the meta-analysis showed that ADP-receptor antagonist therapy was superior to ASA, reducing the odds of a serious vascular event, i.e. stroke (all-cause), MI or vascular death by 9% (odds ratio (OR) = 0.91, 95% CI 0.84–0.98; 2p = 0.01), corresponding to the prevention of 11 (95% CI 2–19) events per 1,000 patients treated for F2 years. Compared with ASA, ADP-receptor antagonist treatment had a consistent, favourable effect on a range of secondary effectiveness outcomes, with a significant reduction in all-cause stroke (OR = 0.88, 95% CI 0.79– 0.98), and a trend towards a significant reduction in ischaemic stroke/stroke of unknown aetiology (OR = 0.90, 95% CI 0.81–1.01), MI (OR = 0.88, 95% CI 0.76–1.01), vascular death/death of unknown cause (OR = 0.93, 95% CI 0.82–1.06), and all-cause mortality (OR = 0.95, 95% CI 0.85–1.05). Comparison of adverse event data for clopidogrel and ticlopidine revealed the superior safety/tolerability profile of clopidogrel compared with ticlopidine. Whereas clopidogrel was associated with a slight increase in the incidence of skin rash compared with ASA (OR = 1.32, 95% CI 1.17–1.50), the corresponding odds ratio for ticlopidine was 2.23 (OR = 2.23, 95% CI 1.74–2.86). The difference between clopidogrel and ticlopidine was highly significant (2p = 0.0003). Moreover, there was no excess of neutropenia (OR = 0.63, 95% CI 0.29–1.36) or thrombocytopenia (OR = 1.00, 95% CI 0.57–1.74) for clopidogrel compared with ASA [21].

CAPRIE

Evidence for the efficacy of clopidogrel was provided by the CAPRIE trial, which compared clopidogrel with ASA in 19,185 patients with symptomatic atherothrombosis [14]. In CAPRIE, clopidogrel was associated with an 8.7% relative risk reduction (or 10% odds reduction) in the combined risk of ischaemic stroke, MI or vascular death, the primary study endpoint (p = 0.043). Further analyses of the CAPRIE data set have demonstrated the consistent benefit of clopidogrel over ASA for the individual components of the primary endpoint [14, 22, 23] and for a range of composite endpoints related to vascular ischaemia [24–26]. The largest benefit of clopidogrel compared with ASA was seen for fatal or non-fatal MI, with a relative risk reduction of 19.2% (p = 0.008) [22].

22

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Dual Antiplatelet Therapy

Existing Data Mechanistic studies have revealed the involvement of multiple agonists and signalling pathways in the activation of the glycoprotein (GP) IIb/IIIa receptor and subsequent platelet activation [27]. This realization led to the hypothesis that by inhibiting the platelet P2Y12 ADPreceptor antagonist on a background of thromboxane A2 inhibition, a potentiation of platelet inhibition would be obtained. Indeed, a synergistic antithrombotic effect is observed when clopidogrel is used with ASA, and this effect has been demonstrated in a range of animal models [28–30] and in post-MI patients [31]. The recent Antithrombotic Trialists’ Collaboration meta-analysis also contains updated information from randomized comparisons of dual antiplatelet regimens compared with ASA alone. In the latest meta-analysis, which incorporates data from the ESPS2 trial [15], the combination of dipyridamole and ASA was associated with a non-significant 6% (B6%) reduction in the odds of vascular death, MI or stroke compared with ASA alone (fig. 2) [13]. Analysis of each of the components of this endpoint reveals that only non-fatal stroke was numerically lower in patients treated with dipyridamole and ASA, and that this finding was driven by the results of a single, large trial, i.e. ESPS2 [13]. Fifteen trials have compared the combination of short-term intravenous GP IIb/ IIIa antagonist therapy and ASA versus ASA alone. The pooled data generate a 19% (B4%) odds reduction for this combination (p ! 0.0001). One trial has compared the use of ticlopidine on top of ASA versus ASA alone, in coronary stent patients [32]. In this study, the use of an ADPreceptor antagonist on top of ASA was associated with an incremental 20% reduction in vascular death, stroke or MI (p = n.s.). Subsequent to the preparation of the latest Antithrombotic Trialists’ Collaboration analysis, two randomized trials have provided evidence to support the long-term use of clopidogrel on top of ASA in patients with coronary manifestations of atherothrombosis. CURE has demonstrated the benefit of clopidogrel in patients with unstable angina and non-Q-wave MI [33]. In CURE, clopidogrel therapy was associated with a 20% relative risk reduction for the primary endpoint of cardiovascular death, stroke or MI (p ! 0.001) (fig. 1) [33]. Importantly, long-term clopidogrel therapy in CURE (maximum = 12 months) was associated with a sustained benefit over placebo, and the relative benefit of clopidogrel was consistent for each of the components of the primary endpoint, including a 14%

Easton

% odds

Odds ratio

Comparison

reduction

p

Antithrombotic Trialists’ Collaboration

Dipyridamole Ticlopidine IV GP IIb/IIIa inhibitor Subtotal

6 20 19 15

NS NS <0.0001 <0.0001

20*

0.00009

CURE

Clopidogrel 0.0

Fig. 1. Overview of the effects of different

0.5

1.0

Dual antiplatelet regimen better

dual antiplatelet regimens for the prevention of major atherothrombotic events [13, 33]. * Relative risk reduction.

1.5

2.0

ASA alone better

Fig. 2. Kaplan-Meier curves for the compos-

ite endpoint death, MI or stroke after longterm treatment with clopidogrel or placebo in the CREDO trial. * The relative risk reduction for all-cause stroke with long-term clopidogrel was 25.1% [reproduced with kind permission, 35].

Combined endpoint occurrence (%)

15

11.5% 27% RRR*

10

p = 0.02 8.5%

5 Placebo Clopidogrel 0 0

3

6

9

12

Months from randomization

relative risk reduction for all-cause stroke. The benefit of clopidogrel for the primary endpoint was observed across a range of prespecified subgroups. These included higherrisk patients such as those with diabetes, those with previous MI, and those with elevated cardiac enzymes or markers at baseline. Of particular interest to the neurologist are the observations that in the 506 CURE patients who had a prior history of stroke, the overall incidence of the primary study endpoint was higher than in those with no such history (n = 12,056 patients), while the benefit of clopidogrel was consistent between the two patient populations. This finding parallels a recent analysis by Budaj et al. [34], in which CURE patients were categorized into

low-, intermediate- and high-risk strata on the basis of TIMI risk scores. The results of this study demonstrate a consistent benefit of clopidogrel across the TIMI risk categories, with the highest absolute benefit in the stratum with the highest risk. Very recently, the CREDO (Clopidogrel for Reduction of Events During Observation) trial has confirmed the significant and sustained benefit of long-term clopidogrel therapy on top of standard therapy including ASA in patients undergoing elective PCI. In CREDO, 2,116 patients referred for PCI or who were deemed at high likelihood of PCI were randomized to receive a preprocedural clopidogrel loading dose or placebo. After PCI, all pa-

Evidence with ADP-Receptor Antagonists

Cerebrovasc Dis 2003;16(suppl 1):20–26

23

ASA Clopidogrel

Fig. 3. Elevated event rates and amplified

benefit of clopidogrel over ASA in CAPRIE patients with a history of diabetes at study entry. Data are shown for the composite of vascular death, MI, stroke, or rehospitalization for ischaemia or bleeding. Numbers within the arrows indicate the number of events prevented per 1,000 patient-years for this endpoint [reproduced with kind permission, 40].

Annual event rate (%)

25

38 21

20 9

15 10

15.6% 11.8%

5 0

Non diabetic

Future Prospects for Clopidogrel in Neurology Although CURE has demonstrated the benefit of clopidogrel on top of standard therapy (including ASA) in patients with unstable angina/non-Q-wave MI [33], this regimen has not been proven in patients with recent manifestations of cerebrovascular atherothrombosis. This is being addressed in the ongoing MATCH (Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischaemic Attack or Ischaemic Stroke) study [37]. MATCH is comparing the efficacy and

Cerebrovasc Dis 2003;16(suppl 1):20–26

17.7%

12.7%

tients received clopidogrel 75 mg/day for 28 days. Between 29 days and 1 year, patients in the loading-dose group received clopidogrel 75 mg/day, and those in the control group received placebo. All patients received ASA for the duration of the study. Long-term data showed that continuation of clopidogrel for 12 months rather than 1 month after PCI was associated with a 26.9% relative risk reduction for the composite of death, MI or stroke at 1 year (p = 0.023) (fig. 2) [35]. As was observed in the CURE study, long-term clopidogrel therapy in CREDO reduced the incidence of each component of the primary endpoint, including a 25.1% reduction for all-cause stroke. Moreover, administration of a clopidogrel loading dose 66 h before PCI was associated with a 38.6% reduction in the composite of death, MI, or urgent target vessel revascularization at 28 days (p = 0.05). These data reinforce the benefit of early and sustained clopidogrel administration that was observed in the PCI-CURE substudy of CURE patients who underwent PCI after randomization [36].

24

17.7%

21.5%

All diabetic patients

Treated with insulin

safety of long-term clopidogrel on top of ASA versus clopidogrel alone in an international, randomized, doubleblind trial in patients with recent TIA or ischaemic stroke who have additional factors that are associated with an increased risk of atherothrombotic recurrence, i.e. previous ischaemic stroke, previous MI, prior history of angina [38], symptomatic peripheral disease [39], or history of diabetes (fig. 3) [40]. Patients are randomized to receive ASA 75 mg/day or matching placebo, and all patients receive clopidogrel 75 mg/day as part of standard therapy. Patients receive study medication and are followed for 18 months after randomization. The primary endpoint for efficacy is a composite of ischaemic stroke, MI, vascular death or rehospitalization for acute ischaemia during the treatment period. Patient enrolment into MATCH was completed in April 2002, with a total of 7,601 patients recruited in 28 countries. Initial data from this important trial are anticipated in 2004. Additional trials of clopidogrel in neurology are planned. ATARI will use a factorial design to compare the use of clopidogrel, low-molecular-weight heparin, both, or neither on a background of ASA therapy in patients who have suffered a TIA in the previous 12 h. The primary endpoint in ATARI will be a composite of vascular death, stroke or MI. The Secondary Prevention of Small Subcortical Strokes (SPS3) trial will evaluate the efficacy of clopidogrel in patients with small subcortical strokes (lacunar infarcts). Although this stroke subtype accounts for around 25% of all cerebral infarcts, the effects of antiplatelet therapy and blood pressure lowering have not specifically been studied in this clinical setting. SPS3 will

Easton

therefore compare the use of clopidogrel on top of ASA versus ASA alone and usual blood pressure treatment versus intensive blood pressure reduction in the prevention of subsequent stroke and vascular events in patients with subcortical strokes. A further major study is CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilization, Management and Avoidance), a double-blind, randomized, placebo-controlled trial that will evaluate the long-term efficacy and safety of clopidogrel in a broad spectrum of patients at high risk of atherothrombosis. CHARISMA will compare clopidogrel versus placebo on top of standard therapy (including low-dose ASA) in over 15,000 high-risk patients (qualifying with a combination of atherothrombotic risk factors and/or documented cerebrovascular disease and/or documented coronary disease and/or symptomatic PAD) [40].

Conclusions

The ADP-receptor antagonists clopidogrel and ticlopidine are associated with superior protection against major atherothrombotic events (stroke, MI or vascular death) compared with ASA. However, compared with ticlopidine, clopidogrel offers a more favourable safety/ tolerability profile. The landmark CURE trial represents ‘proof of principle’ for the use of clopidogrel on top of ASA to provide incremental benefit in high-risk atherothrombotic patients. Based on a consideration of the modes of action of clopidogrel and ASA, and the pathophysiology of atherothrombosis, there is a sound basis to hypothesize that the dual antiplatelet approach will be of value in patients with cerebrovascular manifestations of the disease. This is the subject of the ongoing MATCH trial, and the planned SPS3 and ATARI studies. These important new trials form part of an extensive programme whose aim is to enable a more extensive assessment of the efficacy and safety of clopidogrel on top of ASA in a range of clinical settings.

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