At the recent ESVS meeting in Prague, Czech Republic, Marc Cairols, Barcelona, Spain, presented an update from the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilisation, Management and Avoidance) trial. The CHARISMA trial was design to investigate whether clopidogrel could be applied to broad population of high-risk patients receiving low-dose aspirin therapy. Such a population includes patients with previous cardiovascular, neurovascular or peripheral arterial manifestations of atherothrombosis and patients with combinations of recognised risk factors for atherosclerosis.
The trial assessed the efficacy of clopidogrel 75mg once-daily by comparison with a placebo, in preventing cardiovascular morbidity/mortality. The study compared the efficacy of the two regimens in preventing the occurrence of major cardiovascular complications (stroke, heart attack, cardiovascular death) in high-risk patients who are otherwise receiving low-dose aspirin therapy (75-162mg daily).
A total of 15,306 patients were enrolled in the trial, all over 45 years of age and at high risk of atherothrombotic events, were randomised into two equal groups to receive either low-dose aspirin (75-162mg/day) plus clopidogrel (75mg/day) or low-dose aspirin plus placebo. The primary efficacy endpoint was myocardial infarction, stroke or cardiovascular death, and the primary safety endpoint was severe bleeding (GUSTO definition).
At 30 months, 7.3% of patients in the aspirin plus placebo group and in 6.8% of those in the clopidogrel plus aspirin group had reached the primary endpoint (RRR 7.1%, p=0.22). In the clopidogrel plus aspirin group there was a trend towards severe bleeding (1.7% vs. 1.3%, p=0.09), while moderate bleeding was significantly higher (2.1% vs. 1.3%, p<0.001). Cardiovascular mortality was non-significantly higher in the clopidogrel plus aspirin group (3.1% vs. 2.9%, p=0.68). Among patients with qualifying CAD, CVD or PAD at entry (n=12,153), the primary endpoint occurred significantly less frequently in the clopidogrel plus aspirin group (p=0.046). However, in those patients without events but with multiple risk factors, the trend favoured aspirin plus placebo (p=0.20). Severe bleeding was more commonly seen in those on placebo in the multiple risk factor group (p=0.07), but was similar for both treatments among those with documented cardiovascular disease (1.6% clopidogrel plus aspirin vs. 1.4% placebo, p=0.39). Cairols said that the CHARISMA trial had helped to expanding the understanding about which patients benefit from dual anti-platelet therapy. In patients with multiple risk factors only, without established CV disease, dual anti-platelet therapy was not beneficial. However, in patients with established CV disease, long-term clopidogrel use plus ASA resulted in a significant 12.5% RRR in CV death/MI/stroke with no significant increase in severe bleeding compared to ASA alone. Cairols said that the clinical implications of CHARISMA and prior studies demonstrated that in an acute setting, there was a benefit of dual anti-platelet therapy for one-year post acute coronary syndrome or percutaneous coronary intervention. For stable patients, the results suggested differential long-term effects of dual anti-platelet therapy by patient type. As a result, dual anti-platelet therapy is not recommended for primary prevention, although it is beneficial for secondary prevention (CAD, CVD or PAD) with ten events (CV death/MI/stroke) prevented for every 1,000 patients treated. Although there were two severe GUSTO bleeds for every 1,000 patients treated.