These patients experienced fewer deaths from cardiovascular causes, nonfatal MIs, and strokes than did patients receiving placebo plus aspirin (75 to 325 mg/d).724 Similar results were found in the CREDO (Clopidogrel for Reduction of Events During Observation) study. Combined therapy for an average of 1 year signifi- cantly reduced the risk of death, MI, or stroke.725 In contra- distinction to these positive results among high-risk patients, a comparison of aspirin alone versus aspirin combined with clopidogrel in 15 603 patients with multiple cardiovascular risk factors (most of whom were without a prior cardiovas- cular event) in the CHARISMA (Clopidogrel for High Atherothrombotic Risk Ischemic Stabilization, Management, and Avoidance) trial demonstrated no differences in the rates of MI, stroke, or death.393 A post hoc analysis of this study suggested that a subgroup of patients with documented prior MI, ischemic stroke, or symptomatic PAD might have had Fihn et al Stable Ischemic Heart Disease: Full Text e403 better outcomes from dual antiplatelet therapy (DAPT) with clopidogrel plus aspirin.719 In a meta-analysis of 5 RCTs comparing clopidogrel plus aspirin to aspirin alone in patients with IHD, the incidence of all-cause mortality, MI, and stroke was found to be reduced in the clopidogrel-plus-aspirin group, whereas the risk of major bleeding increased signifi- cantly.726 Overall, it appears that the addition of clopidogrel to aspirin could be beneficial in certain high-risk groups of patients with SIHD, but data on specific subgroups are lacking,727 and further research will be required to identify the ideal target population. The effectiveness of clopidogrel depends on generation of the active metabolite in 2 steps that are catalyzed by enzymes of the cytochrome P450 system, principally CYP2C19. 