Conflicting Results Between Randomized Trials and Observational Studies on the Impact of Proton Pump Inhibitors on Cardiovascular Events When Coadministered With Dual Antiplatelet Therapy: Systematic Review | Ten Points to Remember

Melloni C, Washam JB, Jones WS, et al.
Circ Cardiovasc Qual Outcomes 2015;8:47-55.

The following are 10 points to remember about the impact of proton pump inhibitors (PPIs) on cardiovascular events when coadministered with dual antiplatelet therapy:

  1. PPIs are often prescribed together with antiplatelet therapy to prevent gastrointestinal complications, such as ulceration and bleeding.
  2. A significant decrease in the effect of clopidogrel on platelet aggregation when coadministered with PPI omeprazole has been reported in several pharmacodynamic studies.
  3. Clopidogrel, a potent antiplatelet used in the treatment of patients with coronary artery disease, is a prodrug that requires metabolic transformation in the liver by cytochrome P-450 isoenzyme (CYP2C19) to acquire its antiaggregation properties.
  4. PPIs are also metabolized by CYP enzymes, leading to a potential competitive inhibition of CYP2C19 and reduced activation of clopidogrel when used together.
  5. The clinical effect of the pharmacodynamic interaction between PPIs and clopidogrel remains unclear because results from observational studies have been discordant.
  6. The Food and Drug Administration and European Medicines Evaluation Agency discourage the combination of clopidogrel and omeprazole.
  7. Omeprazole was the only PPI studied in randomized controlled trials. Results from randomized controlled trials did not show increased risk of ischemic events when omeprazole was coadministered with clopidogrel.
  8. A systematic assessment of the data obtained from observational studies suggested increased risk of cardiovascular outcomes when PPIs (as a class) were coadministered with clopidogrel. However, questions remain on the causality of this association, and even models and propensity scores adopted in observational data may have not fully addressed biases in patient selection.
  9. Overall, the systematic review of available evidence suggests the need of future randomized studies combining the assessment of pharmacodynamic parameters and their association with clinical outcomes.
  10. Prospective trials directly comparing pharmacodynamic parameters and clinical events of different PPIs in patients with unstable angina/non–ST-segment elevation myocardial infarction treated with dual antiplatelet therapy are warranted.

Clinical Topics: Acute Coronary Syndromes, Novel Agents

Keywords: Angina, Unstable, Coronary Artery Disease, Acute Coronary Syndrome, Omeprazole, Proton Pump Inhibitors, Cytochrome P-450 Enzyme System, Platelet Aggregation, Propensity Score, Prospective Studies, United States Food and Drug Administration

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