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. Vari- ants of the CYP2C19 gene have been identified that are associated with impaired antiplatelet effects, as measured by ex vivo platelet aggregation assays, and with higher cardio- vascular event rates after ACS and percutaneous revascular- ization procedures.728 731 Poor metabolizers of clopidogrel can be identified by clinically available tests, but optimal dosing strategies for these individuals have not been estab- lished in clinical outcome trials.732,733 Other drugs that are metabolized by CYP2C19 could competitively inhibit the enzyme and impair metabolism of clopidogrel. Several stud- ies have demonstrated a pharmacodynamic interaction be- tween proton pump inhibitors and clopidogrel.734,735 Obser- vational studies have suggested that use of a proton pump inhibitor in combination with clopidogrel is associated with an approximately 25% increased RR of adverse cardiovascu- lar events,736,737 although post hoc analyses of several clinical trials and a recent observational study have failed to demon- strate a clinically significant interaction.738,739 Pantoprazole is less likely than other proton pump inhibitors to inhibit CYP2C19 and does not impair the pharmacodynamic re- sponse to clopidogrel740 742; alternatively, treatment with an H2 antagonist or antacid could be sufficient in some patients. The combination of clopidogrel with a statin can be pre- scribed safely on the basis of a secondary analysis of the CHARISMA trial in 10 078 patients with cardiovascular disease or multiple high-risk coronary risk factors.743 There was no difference in the composite endpoint of MI, stroke, or cardiovascular death between the agents, independent of the metabolism pathway of the statin. 