Clopidogrel and Proton Pump Inhibitors: Influence of Pharmacological Interactions on Clinical Outcomes and Mechanistic Explanations


The following are 10 points to remember about this state-of-the-art paper:

1. Dual antiplatelet therapy with aspirin and clopidogrel is associated with a significant reduction in vascular ischemic events; however, gastrointestinal bleeding (GIB) events are a major concern in high-risk and older patients.

2. Prior observations provide a rationale for concomitant administration of proton pump inhibitors (PPIs) in patients treated with either aspirin alone or dual antiplatelet therapy, particularly those at greatest risk for GIB complications.

3. Whether or not the pharmacological interaction between clopidogrel and PPI, which results in diminished antiplatelet effect, adversely influences clinical efficacy is highly controversial and the subject of debate.

4. Most absorbed clopidogrel (85%) is hydrolyzed by hepatic carboxylesterase to an inactive carboxylic acid metabolite, SR26334, and the remaining 15% is converted to an active thiol metabolite by hepatic cytochromes (CYP) in a two-step process.

5. All PPIs, except for rabeprazole, are extensively metabolized by and competitively inhibit CYP2C19 and CYP3A4.

6. Although several observational studies have suggested that this interaction may attenuate clopidogrel’s therapeutic efficacy and may be associated with increased adverse clinical outcomes, interpretation of these post hoc, nonrandomized analyses is confounded by covariate imbalance and statistical bias.

7. The concern regarding concomitant PPI-thienopyridine administration persists and has been heightened by a Food and Drug Administration communication, but this concern has not been substantiated to date by adequately powered, large-scale randomized trials with clinical endpoints.

8. No difference in cardiovascular outcomes was observed between clopidogrel alone versus clopidogrel plus omeprazole in a single, prematurely terminated randomized clinical trial (COGENT).

9. Based on the lack of definitive data regarding a clinically relevant interaction between these drugs, it is not appropriate at this time to recommend termination of PPI coadministration (including omeprazole) in clopidogrel-treated patients, or to suggest alternative therapeutic strategies.

10. Administration of PPIs (with or without concomitant clopidogrel treatment) should be guided at this time by the individual patient’s risk for GIB.

Clinical Topics: Novel Agents

Keywords: United States Food and Drug Administration, Carboxylesterase, Cytochromes, Pyridines, Omeprazole, Gastrointestinal Hemorrhage, Proton Pump Inhibitors, United States

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