Overall, the safety of clopidogrel is comparable to that of aspirin, with only minor differences.533 As with ticlopidine, diarrhea and rash are more frequent than with aspirin, but aside from diarrhea, gastrointestinal symptoms and hemorrhages are less frequent. Neutropenia did not occur more frequently among patients assigned to clopidogrel than among those given aspirin or placebo in published trials,443,533 but a few cases of thrombotic thrombocytopenic purpura have been described.540 Recently, evidence has emerged that proton pump inhibitors (PPIs), such as esomeprazole, may reduce the effectiveness of clopidogrel.541 However, a large population study from Denmark suggested that PPIs themselves may increase the risk of cardiovascular events, so that when they are used with clopidogrel, the PPI may be the culprit.542 When antacid therapy is required in a patient taking clopidogrel, an H2 blocker should be considered, and if a PPI is used, pantoprazole may be preferable to omeprazole because of reduced effects at the CYP2C19 P-450 cytochrome site.543 In addition to PPI effects on the CYP2C19 system, functional genetic variants in CYP genes can affect the effectiveness of platelet inhibition in patients taking clopidogrel. Carriers of at least 1 CYP2C19 reduced-function allele had a relative reduction of 32% in plasma exposure to the active metabolite of clopidogrel compared with noncarriers