Should all patients at high risk of atherothrombotic events receive dual antiplatelet therapy?

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Abstract

BACKGROUND

Antithrombotic treatment with aspirin for patients with unstable angina or myocardial infarction who are at high risk of ischemic events can be augmented by adding clopidogrel. It is not known whether dual aspirin and clopidogrel therapy can reduce the vascular event rate in patients at high risk of atherothrombotic events.

OBJECTIVE

To compare the effect of combined clopidogrel and aspirin therapy with that of aspirin alone on the atherothrombotic event rate.

DESIGN

The double-blind Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study prospectively enrolled patients at least 45 years old, who had diagnosed coronary artery disease, cerebrovascular disease or symptomatic peripheral arterial disease, or numerous atherothrombotic risk factors.

INTERVENTION

All eligible patients were randomly assigned 75 mg clopidogrel and 75-162 mg aspirin daily, or placebo and 75-162 mg aspirin daily, and they also received standard background therapy. During follow-up visits at 1, 3 and 6 months, and every 6 months thereafter, medication compliance and all interventions and events were recorded

OUTCOME MEASURES

The primary efficacy endpoint was the first occurrence of stroke, myocardial infarction or cardiovascular-related death. The main safety endpoint was the incidence of major bleeding.

RESULTS

In total, 7,802 patients received combined therapy, and 7,801 received placebo and aspirin therapy. After a median of 28 months' follow-up, there was no significant difference in the number of cardiovascular-related deaths, strokes or myocardial infarctions between the two groups (534 [6.8%] in the aspirin-clopidogrel group versus 573 [7.3%] in the aspirin-placebo group; relative risk 0.93, 95% CI 0.83-1.05; P=0.22). The incidence of the secondary efficacy endpoint-the primary endpoint plus revascularization and hospitalization for unstable angina or transient ischemic attack-was lower in the dual antiplatelet therapy group than in the aspirinonly group (1,301 events [16.7%] versus 1,395 events [17.9%]; relative risk 0.92, 95% CI 0.86-0.995; P=0.04); however, the major bleeding event rate was slightly higher in the clopidogrel-aspirin group (130 events [1.7%] versus 104 events [1.3%]; relative risk 1.25, 95% CI 0.97-1.61; P=0.09). There was an increase in adverse events (6.6% versus 5.5%; relative risk 1.2, 95% CI 0.91-1.59; P=0.20) and cardiovascular-related mortality (5.4% versus 3.8%; P=0.04) in patients with multiple atherothrombotic risk factors (asymptomatic patients) with dual antiplatelet therapy compared with aspirin therapy. Notably there was a marginal benefit with added clopidogrel in patients with documented coronary, cerebrovascular or peripheral vascular disease (symptomatic patients).

CONCLUSION

The authors do not support the use of combined clopidogrel and aspirin therapy in patients at risk of atherothrombotic events; although symptomatic patients could benefit, dual antiplatelet therapy could harm asymptomatic patients.

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