The Medical Letter on Drugs and Therapeutics
Drug Interaction: Clopidogrel and PPIs
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The antiplatelet drug clopidogrel (Plavix, and others) reduces major cardiovascular events, but can cause bleeding. Proton pump inhibitors (PPIs) are often used with clopidogrel to prevent gastrointestinal bleeding, however, some evidence suggests that PPIs may interfere with the activation of clopidogrel and diminish its antiplatelet effect.1 FDA-approved labeling recommends avoiding concurrent use of the PPIs omeprazole and esomeprazole with clopidogrel.

POSSIBLE MECHANISM — Clopidogrel is a prodrug; the CYP2C19 isozyme appears to be mainly responsible for its bioactivation.2 Concurrent use of clopidogrel and drugs that inhibit CYP2C19 could inhibit conversion of clopidogrel to its active form. Among the PPIs, omeprazole and esomeprazole appear to be the strongest inhibitors of CYP2C19 and pantoprazole appears to be the weakest.3,4

CLINICAL STUDIES — Some pharmacodynamic and pharmacokinetic studies have reported reductions in platelet inhibition and the AUC of the clopidogrel active metabolite in patients taking clopidogrel with omeprazole or esomeprazole. Similar effects were not reported with pantoprazole, lansoprazole, or dexlansoprazole.5-8

Whether concurrent use of clopidogrel and PPIs results in clinically significant adverse cardiovascular outcomes is not clear. The results of several (mostly observational) studies have been inconsistent.9,10 In a case-control study in patients ≥66 years old who were started on clopidogrel after an acute MI, concurrent use of a PPI (other than pantoprazole) was associated with an increased risk of recurrent MI within 90 days.11 In a retrospective cohort study in 8205 patients with acute coronary syndrome (ACS), use of a PPI with clopidogrel after hospital discharge was associated with a higher risk of death or rehospitalization due to ACS.12

In a retrospective cohort study of patients who were prescribed clopidogrel after hospitalization for acute MI, coronary artery revascularization, or unstable angina, concurrent use of a PPI was not associated with a statistically significant increased risk of serious cardiovascular disease.13

In a randomized, placebo-controlled trial (COGENT), use of omeprazole in patients taking clopidogrel and aspirin decreased the incidence of GI bleeding without increasing the risk of a cardiovascular event.14 The FDA concluded, however, that because of study design limitations and a low number of reported cardiovascular events, the results do not prove that concurrent use of clopidogrel and omeprazole is safe.15 In addition, the fixed-dose combination of omeprazole and clopidogrel used in the trial was specifically developed to delay absorption of omeprazole in order to minimize an interaction.16

Some studies have suggested that PPI use is a confounder associated with, rather than the cause of, adverse cardiovascular outcomes in patients taking clopidogrel.17,18

CONCLUSION — Concurrent use of clopidogrel and a proton pump inhibitor (PPI) may result in decreased levels of the clopidogrel active metabolite, and possibly its antiplatelet activity, but whether it results in clinically significant adverse cardiovascular outcomes is not clear. Since omeprazole and esomeprazole appear to be most likely to affect the antiplatelet activity of clopidogrel and the FDA specifically warns against their concomitant use, it would be reasonable to use another PPI such as pantoprazole in patients taking clopidogrel.

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