Association of Proton Pump Inhibitor Use on Cardiovascular Outcomes with Clopidogrel and Ticagrelor: Insights from PLATO
Background—The clinical significance of the interaction between clopidogrel and proton pump inhibitors (PPI) remains unclear.
Methods and Results—We examined the relationship between PPI use and 1-year cardiovascular (CV) events (CV death, myocardial infarction, or stroke) in acute coronary syndrome (ACS) patients randomized to clopidogrel or ticagrelor in a pre-specified, non-randomized subgroup analysis of the PLATO trial. The primary endpoint rates were higher for individuals on a PPI (n=6539) compared to those not on a PPI (n=12060) at randomization in both the clopidogrel (13.0% vs. 10.9%, adjusted hazard ratio [HR] 1.20, 95% confidence interval [CI] 1.04-1.38) and ticagrelor (11.0% vs. 9.2%, HR 1.24, 95% CI 1.07-1.45) groups. Patients on non-PPI gastrointestinal (GI) drugs had similar primary endpoint rates compared to those on a PPI (PPI vs. non-PPI GI treatment: clopidogrel HR 0.98, 95% CI 0.79-1.23; ticagrelor HR 0.89, 95% CI 0.73-1.10). In contrast, patients on no gastric therapy had a significantly lower primary endpoint rate (PPI vs. no GI treatment: clopidogrel HR 1.29, 95% CI 1.12-1.49; ticagrelor HR 1.30, 95% CI 1.14-1.49).
Conclusions—The use of a PPI was independently associated with a higher rate of CV events in ACS patients receiving clopidogrel. However, a similar association was observed between CV events and PPI use during ticagrelor treatment and with other non-PPI GI treatment. Therefore, in the PLATO trial, the association between PPI use and adverse events may be due to confounding, with PPI use more of a marker for, than a cause of, higher rates of CV events.
Clinical Trial Registration Information—http://www.clinicatrials.gov; NCT00391872
- Received April 15, 2011.
- Accepted January 5, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited