Drug Interaction Between Clopidogrel and Proton Pump Inhibitors

Abstract

Dual antiplatelet therapy with clopidogrel and aspirin has been shown to reduce recurrent cardiac events in patients with acute coronary syndromes or those who have undergone coronary artery stent placement. Clopidogrel, a thienopyridine, is a prodrug that is transformed in vivo to an active metabolite by the cytochrome P450 enzyme system. Due to the increased risk of bleeding in patients on dual antiplatelet therapy, concomitant gastrointestinal ulcer prophylaxis with a proton pump inhibitor (PPI) is frequently prescribed. Data from recent studies show that PPIs, which are extensively metabolized by the cytochrome system, may decrease the antiplatelet activity of clopidogrel. This article reviews the metabolism of various PPIs and existing data regarding the drug-drug interaction between PPIs and clopidogrel.

Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta‐analysis

“…The lack of such a correlation between pharmacodynamic data and clinical outcome might be explained by various factors: (i) the hepatic cytochrome P450 2C19 (CYP2C19) is not the only active isoenzyme responsible for the conversion of thienopyridine pro‐drugs into active metabolites [59] and exhibits large genotypic differences in its expression levels [60]; (ii) PPIs are competitive inhibitors of active metabolite formation of clopidogrel and differ largely in their pharmacokinetics: omeprazole exhibits the highest potential for drug–drug interactions among PPIs, and pantoprazole the lowest [61]; (iii) if CYP2C19 is blocked, other isoenzymes such as CYP2B6 and CYP3A4 might take over the metabolic conversion [60]; (iv) the different ex vivo assay systems used at present miss acuity and comparability; (v) within these test systems the correct cut offs for the detection of a clinically important inhibition of action of thienopyridines have not been defined so far; and (vi) given the heterogeneity of the included studies the presumed contradiction may be explained by the presence of confounders and bias in the study.…”

One-year safety of ibuprofen/famotidine fixed combination versus ibuprofen alone: pooled analyses of two 24-week randomized, double-blind trials and a follow-on extension

“…Given recent data that raise questions regarding the risk of drug interactions between PPIs and clopidogrel [23][24][25][26] , some clinicians have advocated the use of H2RAs in patients who require chronic use of both NSAIDs and clopidogrel 24,25 . Ibuprofen and famotidine do not appear to have either overlapping or synergistic toxicities, and there are neither data nor theoretical concerns suggesting that co-administration of these drugs would result in increased toxicity compared with administration of either drug alone 14,27 .…”

Relationship between cardiovascular outcomes and proton pump inhibitor use in patients receiving dual antiplatelet therapy after acute coronary syndrome

“…A recent meta‐analysis found that exposure to PPI for patients receiving antiplatelet therapy was associated with a significant reduction in adverse GI events . However, there is some evidence of a potential drug interaction between clopidogrel and PPIs …”