Effects of Proton Pump Inhibitors on Adverse Gastrointestinal Events in Patients Receiving Clopidogrel

Abstract

There has been recent concern regarding a possible adverse interaction between clopidogrel and proton pump inhibitors (PPIs), coupled with uncertainty as to whether PPIs genuinely help in reducing gastrointestinal (GI) harm. To perform a meta-analysis of GI outcomes in patients taking clopidogrel, with and without concomitant PPI. We searched MEDLINE, EMBASE and the Cochrane Controlled Trials Register from inception to March 2010, and checked conference abstracts for randomized and non-randomized studies that reported on adverse GI events (haemorrhage, ulcer, perforation or obstruction) with PPI exposure in patients taking clopidogrel. Relevant studies were subcategorized according to the degree of aspirin (acetylsalicylic acid) co-administration and nature of GI events, where available. We performed random effects meta-analysis for risk of adverse GI events with PPI exposure in clopidogrel-treated patients, and assessed heterogeneity using the I2 statistic. Our review evaluated 71,277 participants in nine retrospective studies and one randomized trial. Exposure to PPI for patients receiving dual antiplatelet therapy (aspirin and clopidogrel in seven studies) was associated with a significant reduction in adverse GI events, odds ratio (OR) 0.38 (95% CI 0.21, 0.68; p=0.001; I2=17%). There was significant heterogeneity in the analysis of patients receiving clopidogrel monotherapy (two studies), and no definite benefit was found. Restricting the analysis to studies specifically reporting upper GI bleeds with any clopidogrel exposure yielded an OR of 0.31 (95% CI 0.19, 0.51; p<0.001; I2=27%) with associated PPI exposure. Use of PPIs is associated with a reduction in adverse GI events (particularly haemorrhages) in patients who are receiving dual antiplatelet therapy. Clinicians should carefully weigh up the evidence for potential GI benefits against the uncertainties surrounding any possible adverse cardiovascular impact of concomitant clopidogrel PPI therapy.