Clinical Trials Update from the Annual Scientific Session of the American College of Cardiology 2006

Abstract

The results of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial showed that the addition of clopidogrel to standard, low-dose aspirin did not significantly reduce the combined rate of death, heart attack, or stroke when compared with aspirin alone in a broad population of secondary prevention and high-risk primary prevention patients.1 However, the CHARISMA data also suggested that combination therapy may be useful in patients with established cardiovascular disease, with no apparent benefit in those with multiple risk factors alone. The CHARISMA study design and baseline characteristics are described in detail elsewhere in this supplement.2 Briefly, the study enrolled 15,603 patients at risk for atherothrombotic events caused by documented cardiovascular disease (including documented coronary artery disease, cerebrovascular disease, or peripheral arterial disease) or multiple risk factors alone. Patients were randomly assigned to clopidogrel 75 mg/day or placebo, in addition to low-dose aspirin (75‐162 mg/day), and were observed for a median of 28 months. The primary efficacy end point was a composite of myocardial infarction (MI), stroke, or death from cardiovascular causes, with the secondary end point additionally including hospitalization for ischemia. In the overall population of patients, there was no statistically significant difference in the rate of the primary efficacy end point in the clopidogrel group (6.8%) compared with the placebo group (7.3%; relative risk, 0.93; 95% confidence interval [CI], 0.83‐1.05; p 0.22). For the secondary end point, clopidogrel reduced the combined risk from 17.9% in the placebo group to 16.7% in the clopidogrel group (relative risk, 0.92; 95% CI, 0.86‐0.995; p 0.04). There was no significant difference in the rate of severe bleeding between the clopidogrel and placebo groups (1.7% vs 1.3%; relative risk, 1.25; 95% CI, 0.97‐1.61%; p 0.09). Moderate bleeding, however, was increased from 1.3% in the placebo group to 2.1% in the clopidogrel group (relative risk, 1.62; 95% CI, 1.27‐2.10; p 0.001). In a subgroup analysis of asymptomatic patients (N 3,284) with multiple risk factors alone (meant to represent a high-risk primary prevention population), the primary end point rate was 6.6% with clopidogrel and 5.5% with placebo (relative risk, 1.2; 95% CI, 0.91‐1.59; p 0.20; Figure 1). In the 12,153 symptomatic patients (meant to represent a stable secondary prevention population), there was a suggestion of a benefit; the primary end point rate was 6.9% with clopidogrel plus aspirin and 7.9% with placebo plus aspirin (relative risk, 0.88; 95% CI, 0.77‐0.998; p 0.046). The investigators concluded that dual antiplatelet therapy with clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the primary end point in the broad population tested. Some benefit was noted in a subgroup of patients with prior evidence of cardiovascular disease. Further analysis of different patient groups should help provide insights into the outcomes with single antiplatelet therapy versus dual antiplatelet therapy.