Consensus recommendations from cardiology and gastroenterology societies endorse the use of proton-pump inhibitors (PPIs) in patients who receive antiplatelet therapy and are at high risk for gastrointestinal bleeding (Am J Gastroenterol 2008; 103:2890). However, data from recent observational studies have suggested that PPI use might attenuate the antiplatelet effect of the thienopyridine clopidogrel in patients who receive it after an acute coronary syndrome (ACS) event. Moreover, one study identified a significantly higher composite rate of all-cause mortality and rehospitalization for ACS in patients who took both a PPI and clopidogrel than in those who took clopidogrel alone (JW Gastroenterol Mar 6 2009). To assess the effects of PPI use on both platelet function and cardiovascular endpoints, researchers retrospectively analyzed data from two industry-funded, randomized trials involving ACS patients treated with clopidogrel or another thienopyridine, prasugrel.
In the first trial, involving 201 patients scheduled to undergo percutaneous coronary intervention (PCI), 26% were taking a PPI at randomization. In the clopidogrel group, significantly more PPI users than nonusers experienced inadequate inhibition of platelet aggregation during the first day after clopidogrel administration, with a nonsignificant trend in that direction after 15 days of clopidogrel maintenance therapy. In the prasugrel group, the difference was significant after 15 days but was not consistent across time points during the first day after clopidogrel administration.
In the second trial, involving 13,608 participants who underwent PCI, 33% were taking a PPI at randomization. In both the clopidogrel and prasugrel groups, incidence of the primary endpoint of cardiovascular death, myocardial infarction, or stroke at 30 days did not differ significantly between PPI users and nonusers.
Comment: Platelet-function tests and data from observational studies might be factual, but they are not always accurate for extrapolation, as evident from recommendations by national societies and government agencies that PPIs and clopidogrel should not be coprescribed. The present findings, along with results from a recent prospective trial comparing omeprazole plus clopidogrel versus clopidogrel alone, show that concomitant PPI and thienopyridine use is not associated with adverse cardiovascular outcomes. Platelet assays and observational data are no substitutes for randomized controlled data. Gastroenterologists should be proactive in making sure that patients with an appropriate indication for PPI cotherapy neither stop nor avoid starting this therapy because of any misunderstanding of the PPI–clopidogrel interaction.
— David A. Johnson, MD
Published in Journal Watch Gastroenterology October 16, 2009
O'Donoghue ML et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: An analysis of two randomised trials. Lancet 2009 Sep 19; 374:989.
