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The Lancet

Volume 364, Issue 9431, 24–30 July 2004, Pages 331-337
The Lancet

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Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial

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Summary

Background

Clopidogrel was superior to aspirin in patients with previous manifestations of atherothrombotic disease in the CAPRIE study and its benefit was amplified in some high-risk subgroups of patients. We aimed to assess whether addition of aspirin to clopidogrel could have a greater benefit than clopidogrel alone in prevention of vascular events with potentially higher bleeding risk.

Methods

We did a randomised, double-blind, placebo-controlled trial to compare aspirin (75 mg/day) with placebo in 7599 high-risk patients with recent ischaemic stroke or transient ischaemic attack and at least one additional vascular risk factor who were already receiving clopidogrel 75 mg/day. Duration of treatment and follow-up was 18 months. The primary endpoint was a composite of ischaemic stroke, myocardial infarction, vascular death, or rehospitalisation for acute ischaemia (including rehospitalisation for transient ischaemic attack, angina pectoris, or worsening of peripheral arterial disease). Analysis was by intention to treat, using logrank test and a Cox's proportional-hazards model.

Findings

596 (15.7%) patients reached the primary endpoint in the group receiving aspirin and clopidogrel compared with 636 (16·7%) in the clopidogrel alone group (relative risk reduction 6.4%, [95% CI −4·6 to 16·3]; absolute risk reduction 1% [−0·6 to 2·7]). Life-threatening bleedings were higher in the group receiving aspirin and clopidogrel versus clopidogrel alone (96 [2·6%] vs 49 [1·3%]; absolute risk increase 1·3% [95% CI 0·6 to 1·9]). Major bleedings were also increased in the group receiving aspirin and clopidogrel but no difference was recorded in mortality.

Interpretation

Adding aspirin to clopidogrel in high-risk patients with recent ischaemic stroke or transient ischaemic attack is associated with a non-significant difference in reducing major vascular events. However, the risk of life-threatening or major bleeding is increased by the addition of aspirin.

Introduction

Antiplatelet therapy is a proven component of secondary prevention in patients with transient ischaemic attack or ischaemic stroke.1 In the CAPRIE trial,2 clopidogrel was superior to aspirin in the overall population of patients with recent ischaemic stroke, recent myocardial infarction, or symptomatic peripheral arterial disease, reducing the relative risk for the primary endpoint (ischaemic stroke, myocardial infarction, or vascular death) by 8·7% versus aspirin (p=0·043). For the subgroup of patients with ischaemic stroke as the qualifying event the relative risk reduction was 7·3% and not significant. However, the CAPRIE study was not designed to specifically address this subgroup of patients. In post-hoc analyses, the benefit of clopidogrel was shown to be amplified in high-risk subgroups, including patients with a history of previous ischaemic stroke or myocardial infarction,3 those with diabetes,4 those with previous cardiac surgery,5 and those receiving lipid-lowering therapy.6 In patients with a history of previous ischaemic stroke or myocardial infarction before their qualifying event, clopidogrel produced a relative risk reduction of 14·9% versus aspirin for the primary CAPRIE endpoint.

Findings of randomised controlled trials in patients with coronary manifestations of atherothrombosis (CURE, CREDO)7, 8 have shown the sustained benefit of clopidogrel on top of standard treatment including aspirin. These therapeutic benefits were all obtained with an acceptable increase in the risk of major bleeding complications.7, 8 These trials provided the rationale to undertake MATCH (Management of ATherothrombosis with Clopidogrel in High-risk patients), to find out whether aspirin added to clopidogrel would further reduce the risk of recurrent ischaemic vascular events in high-risk patients after transient ischaemic attack or ischaemic stroke. The potential bleeding risk after addition of aspirin to clopidogrel in some stroke populations, such as in small-vessel disease (patients with lacunar stroke), could not be estimated from previous cardiology trials. Here, we report the main findings from the MATCH trial.

Section snippets

Patients

Between December, 2000, and April, 2002, we enrolled individuals at 507 centres (stroke units and neurology departments) in 28 countries. Patients were eligible for inclusion in the study if they had had an ischaemic stroke or transient ischaemic attack in the previous 3 months and had one or more of five additional risk factors—previous ischaemic stroke, previous myocardial infarction, angina pectoris, diabetes mellitus, or symptomatic peripheral arterial disease—within the previous 3 years.

Results

A total of 7599 patients were randomised: 3802 were allocated placebo and clopidogrel and 3797 aspirin and clopidogrel (figure 1). At 18 months of follow-up, data were available for 7276 patients (96%), including those who died during the study and those alive at the end of the 18-month period of follow-up: 3621 in the aspirin and clopidogrel group and 3655 in the placebo and clopidogrel group. In 13 patients, vital status was not obtained.

Table 1 shows baseline demographics and medical

Discussion

In most patients, a consistent reduction of primary and secondary vascular events was recorded with aspirin added to clopidogrel, although the differences were not significant. The relative risk reduction in favour of aspirin in the intention-to-treat population of 6·4% is in the range that was reported in the CAPRIE trial (8·7%).2 Addition of aspirin to clopidogrel in the MATCH trial resulted in a significantly higher bleeding rate that offset any beneficial effect. No significant increase in

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