Omeprazole, but not pantoprazole, reduces the antiplatelet effect of clopidogrel: a randomized clinical crossover trial in patients after myocardial infarction evaluating the clopidogrel-PPIs drug interaction

Background Proton pump inhibitors (PPIs) are usually prescribed to patients undergoing dual antiplatelet therapy to decrease the risk of gastrointestinal bleeding. Recent studies have raised concerns that PPIs could reduce clopidogrel's efficacy by competitive inhibition of cytochrome P450 2C19 isoenzyme. All PPIs are metabolized by cytochrome P450 2C19, although to varying degrees, and according to in-vitro studies, pantoprazole is the weakest inhibitor of this isoenzyme. We hypothesized that this drug interaction might not be a class effect. Methods One month after an acute myocardial infarction 34 consecutive patients undergoing dual antiplatelet therapy were prospectively analyzed. Platelet function was measured (VerifyNow system), in each patient, in three consecutive clinical scenarios: (i) first, after a 1-month washout period, without any PPI, (ii) after a 4-week period taking omeprazole 40 mg, and (iii) after another 1-month washout period, followed by 4-weeks taking pantoprazole 40 mg. In this crossover trial, patients were first randomized to receive either omeprazole or pantoprazole. Results We observed a significant reduction in clopidogrel's effect when patients were initiated with omeprazole; the mean P2Y12 reaction units (PRU) increased from 202 +/- 52 to 235 +/- 58 with omeprazole (P < 0.001). With pantoprazole, clopidogrel efficacy was preserved (PRU 215 +/- 54, P = 0.16). Without any PPI, 26% of patients were 'nonresponders' to clopidogrel (PRU >240) but when patients started omeprazole, this proportion increased to 45 versus 23% with pantoprazole. Conclusion In this randomized crossover study analyzing patients after acute myocardial infarction, omeprazole coadministration showed a significant pharmacodynamic interaction with clopidogrel, whereas pantoprazole did not. These data suggest that the clopidogrel-PPIs drug interaction may not be a class effect. Eur J Gastroenterol Hepatol 23: 396-404 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.