Elsevier

The Lancet

Volume 348, Issue 9038, 16 November 1996, Pages 1329-1339
The Lancet

Articles
A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE)

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Summary

Background

Many clinical trials have evaluated the benefit of long-term use of antiplatelet drugs in reducing the risk of clinical thrombotic events. Aspirin and ticlopidine have been shown to be effective, but both have potentially serious adverse effects. Clopidogrel, a new thienopyridine derivative similar to ticlopidine, is an inhibitor of platelet aggregation induced by adenosine diphosphate.

Methods

CAPRIE was a randomised, blinded, international trial designed to assess the relative efficacy of clopidogrel (75 mg once daily) and aspirin (325 mg once daily) in reducing the risk of a composite outcome cluster of ischaemic stroke, myocardial infarction, or vascular death; their relative safety was also assessed. The population studied comprised subgroups of patients with atherosclerotic vascular disease manifested as either recent ischaemic stroke, recent myocardial infarction, or symptomatic peripheral arterial disease. Patients were followed for 1 to 3 years.

Findings

19 185 patients, with more than 6300 in each of the clinical subgroups, were recruited over 3 years, with a mean follow-up of 1 91 years. There were 1960 first events included in the outcome cluster on which an intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5 32% risk of ischaemic stroke, myocardial infarction, or vascular death compared with 5 83% with aspirin. These rates reflect a statisticaly significant (p=0 043) relative-risk reduction of 8 7% in favour of clopidogrel (95% CI 03–165). Corresponding on-treatment analysis yielded a relative-risk reduction of 9–4%. There were no major differences in terms of safety. Reported adverse experiences in the clopidogrel and aspirin groups judged to be severe included rash (0–26% i/s0–10%), diarrhoea (0–23% vs 0 11%), upper gastrointestinal discomfort (0–97% vs 1 22%), intracranial haemorrhage (0–33% vs 0–47%), and gastrointestinal haemorrhage (0–52% vs 0–72%), respectively. There were ten (0–10%) patients in the clopidogrel group with significant reductions in neutrophils (<1·2 × 109/L) and 16 (0·17%) in the aspirin group.

Interpretation

Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction, or vascular death. The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin.

Introduction

There have been several randomised trials of antiplatelet drugs in patients with disorders in which platelet activation is involved.1 Their purpose was to determine the extent of reduction in various subsequent risks; in particular, risks of ischaemic stroke, myocardial infarction, and death from vascular disease (vascular death). Patients at increased risk of such outcomes included those with atherothrombotic disease such as transient ischaemic attacks or mild stroke, moderate or severe stroke, unstable angina, acute and remote myocardial infarction, and atherosclerotic peripheral arterial disease.2, 3

Interpretation of these studies has been inconsistent. Many investigators and practitioners apply the results from a particular subgroup of patients, such as those with transient ischaemic attacks or mild stroke, only to patients with that disorder and not to patients with different atherothrombotic manifestations, although it is both clinically and biologically plausible to assume that similar treatment benefits would extend to them. There is evidence from the Antiplatelet Trialists' Collaboration to support a widespread effect.2, 3 A meta-analysis of 142 trials, including more than 73 000 high-risk patients in various disease categories, shows clearly that antiplatelet drugs reduce the incidence of a composite outcome of ischaemic stroke, myocardial infarction, and vascular death, the relative-odds reduction being 27%, which is consistent over a wide range of clinical manifestations as well as across subgroups of patients at varying risks within specific clinical subgroups.

Both aspirin3, 4 and ticlopidine3, 5 have been shown to be of benefit in placebo-controlled studies. Relative-risk reductions for the composite outcomes of stroke, myocardial infarction, or vascular death were 25% with aspirin and 33% with ticlopidine. In three studies in which aspirin was compared with ticlopidine, the odds reduction, while not statistically significant, favoured ticlopidine by 10%.3 However, both drugs have potentially serious adverse effects: gastrointestinal discomfort and bleeding with aspirin;4 and bone-marrow depression, rash, and diarrhoea with ticlopidine.6

Clopidogrel (Plavix) is a new thienopyridine derivative, chemically related to ticlopidine (figure 1). Its activity in animal models of thrombosis is greater than that of ticlopidine.7 Clopidogrel prevents arterial as well as venous thrombosis and reduces atherogenesis in several animal species.7, 8 Clopidogrel blocks activation of platelets by adenosine diphosphate (ADP) by selectively and irreversibly inhibiting the binding of this agonist to its receptor on platelets, thereby affecting ADP-dependent activation of the GpIIb-IIIa complex, the major receptor for fibrinogen present on the platelet surface.9, 10 In platelet-aggregation studies, clopidogrel, 75 mg once daily, produces inhibition of ADP-induced platelet aggregation equivalent to that of ticlopidine, 250 mg twice daily.

CAPRIE was a randomised clinical trial to assess the potential benefit of clopidogrel, compared with aspirin, in reducing the risk of ischaemic stroke, myocardial infarction, or vascular death in patients with recent ischaemic stroke, recent myocardial infarction, or peripheral arterial disease.

Section snippets

Protocol

Patient eligibility Clinical evaluation had to establish the diagnosis of ischaemic stroke, myocardial infarction, or symptomatic atherosclerotic peripheral arterial disease. Inclusion and exclusion criteria are shown in Table 1, Table 2. Eligible patients who gave informed consent were entered into the study. Use of anticoagulants or antiplatelet drugs was discontinued before randomisation and thrombolytic treatment should not have been received within the previous 48 h. The study protocol was

Participants and follow-up

19 185 patients from 384 clinical centres were randomised between March, 1992, and February, 1995. Patient follow-up was completed by February, 1996, resulting in 36 731 patient-years at risk. Mean duration of follow-up was 1–91 years.

During the study, 42 patients (0–22%) were lost to follow-up, 22 in the clopidogrel group and 20 in the aspirin group (figure 2); the resulting loss in total patient-years at risk was 49 (0–13%). These 42 patients were included in the analyses with their follow-up

Discussion

CAPRIE is the first study of an antiplatelet drug to include patients from the clinical subgroups of ischaemic cerebrovascular, cardiac, and peripheral arterial disease under a common protocol. We reasoned from available evidence that in a study on prevention, separations within and amongst clinical subgroups are not necessary because the underlying condition is atherothrombosis which can become clinically manifest in different ways. This approach can be justified by the common aetiology

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