Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular disease

Low-dose aspirin as antiplatelet therapy is still the drug of choice for preventing cardiovascular events, but the protection aspirin gives to people at high risk of cardiovascular events is only relatively modest. This review of 28,165 people in two trials where clopidogrel was given in addition to antiplatelet treatment found that in patients with acute coronary syndromes the benefit - a reduction in cardiovascular events - outweighs the harm of major bleeding. However, clopidogrel plus aspirin has no clear positive risk-benefit profile in people at high risk of cardiovascular events (multiple atherothrombotic risk factors) or in people with established cardiovascular disease (known coronary disease, ischemic cerebrovascular disease or peripheral arterial disease) but not presenting with an acute coronary syndrome, and the combination should not be prescribed routinely to prevent cardiovascular disease.

Authors' conclusions: 

The available evidence demonstrates that the use of clopidogrel plus aspirin is associated with a reduction in the risk of cardiovascular events and an increased risk of bleeding compared with aspirin alone. Only in patients with acute non-ST coronary syndrome benefits outweigh harms.

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Background: 

Aspirin is the prophylactic antiplatelet drug of choice for people with cardiovascular disease. Adding a second antiplatelet drug to aspirin may produce additional benefit for those at high risk and those with established cardiovascular disease.

Objectives: 

To quantify the benefit and harm of adding clopidogrel to standard long-term aspirin therapy for preventing cardiovascular events in people at high risk of cardiovascular disease and those with established cardiovascular disease.

Search strategy: 

The searches have been updated: CENTRAL (Issue 3 2009), MEDLINE (2002 to September 2009) and EMBASE (2002 to September 2009).

Selection criteria: 

All randomized controlled trials comparing long term use of aspirin plus clopidogrel with aspirin plus placebo or aspirin alone in patients with coronary disease, ischemic cerebrovascular disease, peripheral arterial disease, or at high risk of atherothrombotic disease were included.

Data collection and analysis: 

Data on mortality, non-fatal myocardial infarction, non-fatal stroke, unstable angina, heart failure, revascularizations, major and minor bleeding, and all adverse events were collected. The overall treatment effect was estimated by the pooled odds ratio (OR) with 95% confidence interval (CI) using a fixed-effect model (Mantel-Haenszel).

Main results: 

No new studies were identified from the updated searches. A total of two RCTs were found: the CHARISMA and the CURE study. The CURE study enrolled only patients with a recent non-ST segment elevation acute coronary syndrome. The use of clopidogrel plus aspirin, compared with placebo plus aspirin, was associated with a lower risk of cardiovascular events (OR: 0.87, 95% CI 0.81 to 0.94; P<0.01) and a higher risk of major bleeding (OR 1.34, 95% CI 1.14 to 1.57; P<0.01). Overall, we would expect 13 cardiovascular events to be prevented for every 1000 patients treated with the combination, but 6 major bleeds would be caused. In the CURE trial, for every 1000 people treated, 23 events would be avoided and 10 major bleeds would be caused. In the CHARISMA trial, for every 1000 people treated, 5 cardiovascular events would be avoided and 3 major bleeds would be caused.

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