European Heart Journal Supplements (2006) 8 (Supplement G), G15G19 doi:10.

1093/eurheartj/sul049

Update on clopidogrel and dual anti-platelet therapy: neurology

Hans-Christoph Diener
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Department of Neurology, University Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany

KEYWORDS
Stroke; Secondary prevention; Clopidogrel; Acetylsalicylic acid; Combination therapy; Bleeding complications

Patients suffering a transient ischaemic attack (TIA) or ischaemic stroke (IS) have a high recurrence risk. The inhibition of platelet function is effective in the reduction of secondary vascular events in patients with TIA or stroke. This is true for acetylsalicylic acid (ASA), clopidogrel, ticlopidine, and the combination of ASA and slowrelease dipyridamole. This review analyses the results of recent trials like clopidogrel as well as the combination of clopidogrel plus ASA. Clopidogrel is superior to ASA in the prevention of vascular events in patients with IS, myocardial infarction, or peripheral arterial disease. The difference is highest for high-risk patients such as diabetics, patients who underwent coronary bypass surgery, and patients with additional vascular events. A prediction model which allows to identify patients in whom clopidogrel is superior to ASA for the secondary prevention of stroke is presented. In high-risk patients with TIA or stroke, the combination of clopidogrel plus ASA is not superior to clopidogrel monotherapy, but results in a higher rate of bleeding complications. Combination therapy is superior to aspirin monotherapy for the prevention of strokes but not for a combined vascular endpoint.

Introduction
Patients at risk of ischaemic events
Atherosclerosis is a chronic, disseminated process that causes structural changes in the intima and media of large and medium-sized arteries, initially resulting in endothelial abnormalities and eventually producing atherosclerotic plaques. Thrombosis, as the main complication of atherosclerosis, is mainly caused by platelet activation and aggregation arising from disruption of an atherosclerotic plaque. Atherothrombosis leads to local occlusion or distal embolism, the three common clinical manifestations being coronary heart disease [myocardial infarction (MI) and angina pectoris (AP)], peripheral arterial disease (PAD), and cerebrovascular events such as transient ischaemic attacks (TIA) and ischaemic stroke (IS).
Corresponding author. E-mail address: h.diener@uni-essen.de

Stroke
Acute stroke is increasingly recognized as one of the leading factors of morbidity and mortality worldwide. Its economical burden is among the highest of all diseases. Over the past decades, acute stroke has increasingly being recognized as a medical emergency. Acute, post-acute, and rehabilitation care of stroke patients in specialized wards as well as revascularizing therapies have been shown to be effective in acute IS. IS accounts for  85% of all strokes, whereas the remaining 15% are due to cerebral haemorrhage. Large vessel atherothrombosis, cardiac embolism, and small vessel occlusion each account for around 20% of all strokes, whereas the aetiology is undetermined in 15% and the remaining 5% are due to other dened causes.1 Especially, in middle-aged men (4570 years), large vessel disease is a predominant aetiology. Besides a higher risk of recurrent cerebral events, stroke patients are also at high risk of developing cardiac events.2

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Secondary prevention of stroke with anti-platelet drugs

Recurrence risk after TIA or IS ranges from 5 to 20% per year.1,3,4 The risk is highest immediately after the rst event.58 Numerous trials and meta-analyses have left little doubt that anti-platelet therapy effectively reduces stroke risk in patients with prior IS or TIA.912 The latest publication from the Antithrombotic Trialistss Collaboration9 involves the meta-analysis of 287 trials with 135 000 patients in comparisons of antiplatelet therapy vs. controls, and 77 000 in comparisons of different anti-platelet regimens. The main results were summarized as a reduction of serious vascular events [which includes non-fatal MI, non-fatal stroke, or vascular death (VD)] by about 25% (relative percentage). In absolute terms, the events prevented include 3.6% treated for 2 years among those with previous IS or TIA. The absolute benets substantially outweigh the absolute risks of major extracranial bleeding. Nevertheless, controversies exist. Foremost among them is the debate over the optimal anti-platelet regimen. The majority of research in secondary stroke prevention supports the clinical value of acetylsalicylic acid (ASA). Several key questions, however, remain unanswered. Is the routine use of anti-platelet therapy justied for all eligible patients? Should ASA be used alone or in combination with another anti-platelet agent such as clopidogrel with a different mode of action? Will administration of low-dose ASA reduce the incidence of side effects? Are the new anti-platelet drugs like clopidogrel superior to ASA? This article is an updated version of an earlier review13 and summarizes the results of recent clinical trials performed with clopidogrel in the context of evolving strategies for stroke prevention.

18.7). However, the CAPRIE study was not designed to specically address this subgroup of patients. In several post hoc analyses of the CAPRIE trial, the benet of clopidogrel was demonstrated to be amplied among high-risk subgroups, including patients with a history of previous IS or MI,15 patients with diabetes,16 those with prior cardiac surgery,17 and those receiving lipid-lowering therapy.18 In the 4496 patients with a history of previous IS or MI before their qualifying event, clopidogrel produced an RRR of 14.9% vs. ASA for the primary CAPRIE endpoint (P 0.045).15 This risk reduction translates into a number of patients needed to treat (NNT) of 71 per year with clopidogrel instead of ASA to prevent further vascular events. For comparison, the NNT is 200 patients per year for the overall CAPRIE population.
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CARESS trial
The CARESS trial, in which the combined use of clopidogrel and ASA was signicantly more effective than ASA alone in reducing cerebral microemboli measured by transcranial Doppler sonography in patients with recently symptomatic moderate-to-severe carotid stenosis, identied a subgroup of patients in whom combination therapy might be superior to monotherapy with ASA.19 The number of patients, 110, was too small to reach a signicant reduction in clinical endpoints. Numerically, the number of strokes was smaller in the combination group (0 vs. 4). In CARESS, patients received either a loading dose of 300 mg clopidogrel followed by 75 mg for 7 days plus aspirin or aspirin monotherapy.

MATCH trial
The MATCH (Management of ATherothrombosis with Clopidogrel in High-risk patients with recent TIA or IS) trial was a randomized, double-blind, placebo-controlled trial that compared ASA (75 mg/day) vs. placebo in 7599 high-risk patients with recent TIA or IS and at least one additional vascular risk factor in patients receiving clopidogrel 75 mg/day.20,21 Additional vascular risk factors were dened as previous IS, previous MI, angina pectoris, diabetes mellitus, or symptomatic PAD within the previous 3 years. The duration of treatment and follow-up was 18 months. The primary endpoint was a composite of IS, MI, VD, or rehospitalization for acute ischaemia (including rehospitalization for TIA, angina pectoris, or worsening of PAD). Five hundred and ninety-six (15.7%) patients reached the primary endpoint in the group receiving ASA plus clopidogrel compared with 636 (16.7%) patients in the clopidogrel alone group [RRR 6.4%, 95% CI 2 4.6, 16.3; absolute risk reduction 1% (95% CI 2 0.6, 2.7); Figure 1]. Life-threatening bleedings were signicantly higher in the group receiving ASA plus clopidogrel [96 (2.6%) vs. clopidogrel alone 49 (1.3%); (absolute risk increase 1.3%) 95% CI 0.6, 1.9)]. Major bleedings were also increased in the group receiving ASA in addition to clopidogrel but there was no difference in mortality. Adding ASA to clopidogrel in high-risk patients with recent IS or TIA is associated with a

Clinical efcacy
Clopidogrel for the prevention of vascular events in patients with IS, MI, or PAD (CAPRIE)
The CAPRIE study was the largest study to date that has tested clopidogrel in the setting of stroke patients.14 It was a randomized, double-blind study, which compared the effects of 75 mg of clopidogrel with 325 mg of ASA once daily. The aim was to reduce a composite endpoint, which consisted of either IS, MI, or VD. A total of 19 185 patients with a previous MI or IS, or established PAD were randomized. TIA patients were not included into the CAPRIE-trial. After a mean follow-up period of 1.9 years there was a signicant absolute risk reduction of 0.5% and a relative risk reduction (RRR) of 8.7% in favour of clopidogrel. Thus, clopidogrel is slightly more effective than ASA in preventing a composite endpoint of vascular events. It is the agent of choice in patients with contraindications to, or adverse effects on, ASA. For the subgroup of patients in the CAPRIE trial with IS (n 6431) as the qualifying event, the RRR was 7.3% and not statistically signicant (95% CI 2 5.7 to

Update on clopidogrel and dual anti-platelet therapy

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Table 1 Stroke prediction model based on the stroke subgroup in the CAPRIE trial Risk factors , 65 years 6575 years . 75 years Hypertension (Yes) Diabetes (Yes) Previous MI Other cardiovascular disease (except MI and AF) PAD Smoker (Yes) Additional TIA or IS in addition to qualifying event Points 0 1 2 1 1 1 1 1 1 1

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Figure 1 Patients remaining event-free over time for the primary endpoint (MI, IS, CVD, or rehospitalization due to ischaemic event) in the MATCH trial; intention-to treat population.

non-signicant difference in terms of major vascular events. However, the risk of life-threatening and major bleeding is increased by the addition of ASA. Predened subgroup analyses were unable to identify a group of patients were the benet of combination therapy would outweigh the bleeding risk. The benet of the combination therapy was highest in patients randomized early after the qualifying event, whereas the differences in bleeding complications emerged only after 3 months. Theoretically, this would indicate that there is a window of opportunity for short-term use of the combination. This, however has to be investigated in a separate trial (FASTER, see below).

Figure 2 Annual event rate for IS (%) in the MATCH trial gained from the IS population according to the risk score (see Table 1). Please note that the risk scores of 7 and 8 are based on small patient numbers and have wide condence intervals.

Risk model to identify patients at high risk for stroke recurrence

Based on a subgroup analysis of the stroke cohort in the CAPRIE trial15 and the risk factors identied by logistic regression analysis, we developed a predictive model.13 As shown in Table 1, we assigned points to certain baseline variables and risk factors. The maximal possible score is 10. Rates for recurrent strokes were calculated for each risk factor group separately for ASA and clopidogrel. Overall, the patient population can be separated at an annual stroke risk of smaller or grater than 4% into a low- and a high-risk group. As can be seen from Figure 2, in the low-risk group, there is no difference between ASA and clopidogrel. In the high-risk group (36 points), clopidogrel is superior to ASA. The very high-risk group (. 6 points) contains few patients and the results have wide condence intervals. These results clearly favour a strategy in which the stroke recurrence risk guides the decision to use either ASA or clopidogrel for secondary stroke prevention.

CHARISMA study
The CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance) study, which has recruited 15 603 patients investigated the role of clopidogrel in both primary and secondary prevention.22,23 The target study population was one at high risk of atherothrombotic eventssubjects have documented cerebrovascular, cardiovascular, or PAD. However, subjects with vascular risk factors without a documented event were also enrolled (primary prevention). CHARISMA compared the combination of clopidogrel plus ASA with ASA plus placebo. The rate of the primary efcacy endpoint (composite of MI, IS, or death from cardiovascular causes) showed a RRR of 7% in favour of the combination therapy.24 This difference was not signicant. The only secondary endpoint which showed a signicant benet of combination over monotherapy was non-fatal stroke (150/189 strokes). The results for the patients with stroke as a qualifying event are not yet published.

Ongoing trials
The Fast Assessment of Stroke and TIA to prevent Early Recurrence trial (FASTER) will focus on clopidogrel and

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Table 2 Ongoing and planned clinical trials of anti-platelet therapy in stroke prevention [after (Hankey, 2004 #1)] Trial ARCH ACTIVE Patients TIA or IS and aortic arch plaque (14 mm) AF (high-risk) Onset 06 months Interventions Clopidogrel 75 mg ASA 75325 mg vs. warfarin Clopidogrel ASA vs. warfarin Clopidogrel ASA vs. ASA Irbesartan vs. Placebo Primary endpoint IS, MI, VD, or emboli IS, MI, VD ( emboli for the comparisons between Clopidogrel ASA vs. ASA and between Clopidogrel ASA vs. warfarin) Stroke at 90 days, combined outcome of myocardial infarction, stroke, or VD at 90 days, stroke severity First recurrent stroke Sample size 1 500 14 000

FASTER

TIA or minor IS, Treatment within 12 h after symptom onset

012 h

Clopidogrel 300 mg loading dose, 75 mg/day vs. placebo. ASA for all patients. Simvastatin 40 mg vs. placebo Clopidogrel vs. Dipyridamole ASA; Telmisartan vs. Placebo Clopidogrel vs. Placebo ASA for all patients

7 500

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ProFESS

IS

090 days

20 000

SPS3

Small subcortical stroke (MRI) MMSE  22

03 months

Stroke

2 500

ASA in the setting of TIA. In this trial, a loading dose of 300 mg clopidogrel is used. A secondary consideration is whether simvastatin is superior to placebo. The primary endpoint is the 90-day risk of stroke. Inclusion time12 h after a TIAis short. Therefore, FASTER will focus on early secondary prevention (Table 2). The SPS3 (Secondary Prevention of Small Subcortical Strokes) trial investigates not only whether recurrent stroke can be avoided but also whether dementiaa high risk in this populationcan be prevented. Around 2500 patients with small subcortical strokes will be included; those with cardioembolic, cortical or haemorrhagic stroke are excluded. The trial has two treatment arms. In the anti-platelet study, patients will be randomized to ASA and placebo or ASA and clopidogrel. The other treatment arm investigates moderate vs. aggressive blood pressure control. The ongoing PROFESS trial will recruit 20 000 patients with IS and compare 75 mg clopidogrel with the combination of low-dose ASA with slow-release dipyridamole. This trial is supposed to identify subgroups of patients who might benet more from one treatment regimen than the other based on risk factors and concomitant diseases.

combination of clopidogrel plus ASA cannot be recommended in high-risk patients with TIA or IS. In this group, the combination is not superior to clopidogrel or aspirin monotherapy but leads to more bleeding complications. In the future, trials may show that the combination of clopidogrel plus ASA is superior to ASA or clopidogrel alone in the secondary prevention of stroke in high-risk patients, vascular events after TIA, lacunar stroke, and vascular dementia. However, this higher efcacy may come at the price of a higher bleeding rate. The results of ongoing trials, including PROFESS, will help us assess this riskbenet ratio accurately.

Acknowledgements
Financial support for research projects was provided by Astra/ Zeneca, GSK, Bo hringer Ingelheim, Novartis, Janssen-Cilag, sano-aventis. The Department of Neurology at the University, Duisburg-Essen received research grants from the German Research Council (DFG), the German Ministry of Education and Research (BMBF), the European Union, the Bertelsmann Foundation, and the Heinz-Nixdorf Foundation. Conict of interest: H.-C.D. received honoraria for participation in clinical trials, contribution to advisory boards or oral presentations from Abbott, AstraZeneca, Bayer Vital, Bo hringer Ingelheim, D-Pharm, Fresenius, GlaxoSmithKline, Janssen Cilag, MSD, Novartis, Novo-Nordisk, Paion, Parke-Davis, Pzer, sanoaventis, Sankyo, Servier, Solvay, Wyeth, Yamaguchi.

Conclusions
Clopidogrel is effective in the prevention of vascular events in high-risk patients and, as shown in subgroup analyses of CAPRIE, this is especially true for people with PAD or diabetes mellitus. A stroke recurrence prediction model offers guidance on which patients should receive ASA or clopidogrel for secondary stroke prevention. Clopidogrel has fewer gastrointestinal side-effects than ASA. However, it does not demonstrate difference from ASA in patients with IS overall. Presently, the

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