In the intent-to-treat analysis, 596 (15.7%) patients achieved the primary endpoint in the group receiving aspirin plus clopidogrel compared with 636 (16.7%) in the clopidogrel plus placebo group (relative risk reduction 6.4%, [95% CI, -4.6 to 16.3]; absolute risk reduction 1% [-0.6 to 2.7]). Life-threatening bleeding (defined as any fatal bleeding event, a drop in hemoglobin of ≥50her clopidogrel 75 mg plus aspirin 75 mg once daily or clopidogrel 75 mg plus placebo once daily. Eligible patients had experienced a TIA or ischemic stroke within the last three months and had evidence of at least one additional risk factor within the last three years (prior ischemic stroke, MI, stable or unstable angina pectoris, diabetes, or symptomatic PAD). The primary endpoint was the composite of ischemic stroke, MI, vascular death, and rehospitalization for an acute ischemic event. The duration of treatment and follow-up was 18 months for each patient (Diener, 2004a; Diener, 2004b).
In the intent-to-treat analysis, 596 (15.7%) patients achieved the primary endpoint in the group receiving aspirin plus clopidogrel compared with 636 (16.7%) in the clopidogrel plus placebo group (relative risk reduction 6.4%, [95% CI, -4.6 to 16.3]; absolute risk reduction 1% [-0.6 to 2.7]). Life-threatening bleeding (defined as any fatal bleeding event, a drop in hemoglobin of ≥50 g/L, significant hypotension with need for inotropes [hemorrhagic shock], symptomatic intracranial hemorrhage, or transfusion of at least four units of red blood cells or equivalent amount of whole blood) was higher in the group receiving aspirin plus clopidogrel versus the group receiving clopidogrel plus placebo (96 [2.6%] versus 49 [1.3%]; absolute risk increase 1.3% [95% CI, 0.6-1.9]). Major bleeding (defined as significantly disabling [with persistent sequelae], intraocular bleeding leading to significant loss of vision, or transfusion of at least three units of red blood cells or equivalent amount of whole blood) was also increased in the group receiving aspirin and clopidogrel versus clopidogrel alone, but no difference was recorded in mortality (Table 3).
Adding aspirin to clopidogrel resulted in significantly more bleeding complications (almost double) than in the placebo and clopidogrel arm. Thng (defined as any fatal bleeding event, a drop in hemoglobin of ≥50 g/L, significant hypotension with need for inotropes [hemorrhagic shock], symptomatic intracranial hemorrhage, or transfusion of at least four units of red blood cells or equivalent amount of whole blood) was higher in the group receiving aspirin plus clopidogrel versus the group receiving clopidogrel plus placebo (96 [2.6%] versus 49 [1.3%]; absolute risk increase 1.3% [95% CI, 0.6-1.9]). Major bleeding (defined as significantly disabling [with persistent sequelae], intraocular bleeding leading to significant loss of vision, or transfusion of at least three units of red blood cells or equivalent amount of whole blood) was also increased in the group receiving aspirin and clopidogrel versus clopidogrel alone, but no difference was recorded in mortality (Table 3).
Adding aspirin to clopidogrel resulted in significantly more bleeding complications (almost double) than in the placebo and clopidogrel arm. The MATCH trial demonstrated that monotherapy with clopidogrel is as effective as combination therapy with clopidogrel plus aspirin in specific high-risk cerebrovascular patients, and that the risk of life-threatening or major bleeding was clinically and statistically significantly increased by the addition of aspirin to clopidogrel.
The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study was designed to evaluate the efficacy and safety of clopidogrel plus aspirin versus placebo plus aspirin in patients with established CAD, PAD, or cerebrovascular disease, or in patients with multiple risk factors for atherothrombosis who have not yet sustained an ischemic event (ie, primary stroke prevention)(Bhatt, 2006a). This randomized, international, multicenter, double-blinded, placebo-controlled study enrolled a total of 15,603 patients worldwide. The rate of the primary efficacy endpoint (a composite of MI, stroke, or death from cardiovascular causes) was 6.8% with clopidogrel plus aspirin and 7.3% with placebo plus aspirin (relative risk, 0.93; 95% CI, 0.83-1.05; P=0.22). Overall, the combination of clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the rate of the primary endpoint; however, statistically significant decreases were shown for individual secondary endpoints, including hospitalizations for ischemic events and nonfatal stroke.
In a pre-specified subgroup analysis, the rate of the primary endpoint among asymptomatic patients with multiple risk factors was 6.6% with clopidogrel plus aspirin and 5.5% with placebo plus aspirin (relative risk, 1.2; 95% CI, 0.91-1.59; P=0.20) and the rate of death from cardiovascular causes also was higher with combination treatment with clopidogrel plus aspirin (3.9% versus 2.2%, P=0.01). In the subgroup with clinically evident atherothrombosis (ie, symptomatic), the 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 rate of the primary safety endpoint (severe bleeding according to the Global Utilization of Strategies To Open Occluded Arteries [GUSTO] definition) was 1.7% in the clopidogrel plus aspirin group and 1.3% in the placebo plus aspirin group (relative risk, 1.25; 95% CI, 0.97-1.61; P=0.09).The rate of moderate bleeding was 2.1% in the clopidogrel plus aspirin group, as compared with 1.3% in the placebo plus aspirin group (relative risk, 1.62; 95% CI, 1.27-2.10; P<0.001). The rate of intracranial hemorrhage was similar in the two treatment groups. Hence, in CHARISMA, the rate of severe bleeding was not significantly greater with clopidogrel than with placebo, but clopidogrel was associated with a significant increase in the rate of moderate bleeding.
Overall, CHARISMA suggested some benefit may be observed with combination clopidogrel and aspirin treatment in patients with symptomatic atherothrombosis, but that the risks of bleeding may outweigh these benefits especially in patients with multiple risk factors.
Conversely, the combination of clopidogrel plus aspirin has been demonstrated to be superior to treatment with aspirin alone for patients with acute coronary syndromes and after coronary stenting (Ault,1999; Mehta, 2003; Steinbuhl, 2003; Mehta, 2001; Steinhubl, 2002; Peters, 2003). Whether dual antiplatelet therapy is superior to aspirin monotherapy for high-risk secondary prevention (ie, after TIA/stroke) requires further investigation.
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