Effect of the clopidogrel-proton pump inhibitor drug interaction on adverse cardiovascular events in patients with acute coronary syndrome

Pharmacotherapy. 2012 Sep;32(9):809-18. doi: 10.1002/j.1875-9114.2012.01112.x. Epub 2012 Jun 28.


Study objective: To examine the effect of the drug interaction between clopidogrel and proton pump inhibitors (PPIs) on the risk of an adverse cardiovascular event.

Design: Population-based, retrospective cohort study.

Data source: IMS LifeLink Health Plan administrative claims database.

Patients: A total of 10,101 patients aged 18 years or older with a diagnosis of acute coronary syndrome (ACS) made during a hospitalization or emergency department visit between 2001 and 2008 and who had their first clopidogrel prescription within 90 days after their ACS diagnosis were included in the study. Patients were stratified according to concurrent use (clopidogrel plus PPI group) or no use (clopidogrel alone group) of the following PPIs: esomeprazole, lansoprazole, omeprazole, pantoprazole, or rabeprazole.

Measurements and main results: Data were collected on baseline patient demographic and clinical characteristics. Patients were followed from their first clopidogrel prescription until they experienced an adverse cardiovascular event, defined as inpatient hospitalization or emergency department visits for myocardial infarction, percutaneous coronary intervention, or intermediate coronary syndrome; were disenrolled; discontinued clopidogrel; or reached the end of the study period. Using a propensity scoring method, the clopidogrel plus PPI group was matched in a 1:1 ratio with the clopidogrel alone group. Exposure to overlapping clopidogrel-PPI prescriptions was modeled as a time-dependent covariate. The Cox hazards regression model was used to estimate the risk of an adverse cardiovascular event in the clopidogrel plus PPI group versus the clopidogrel alone group. Propensity score matching resulted in 2674 patient pairs. In the propensity score-matched sample, the mean age was 61.30 years, with a mean follow-up of 268 days, and 70.04% were male. Concurrent use of clopidogrel with a PPI was associated with a significantly increased risk of a cardiovascular adverse event (hazard ratio 1.438, 95% confidence interval 1.237-1.671) compared with clopidogrel alone.

Conclusion: Concurrent use of clopidogrel plus a PPI was associated with a significant increase in risk of an adverse cardiovascular event in patients with ACS. Large randomized studies are needed to confirm this finding. Until then, clinicians should prescribe the concurrent use of these two drugs cautiously.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Coronary Syndrome / drug therapy
  • Acute Coronary Syndrome / physiopathology
  • Aged
  • Cardiovascular Diseases / epidemiology*
  • Cardiovascular Diseases / etiology
  • Cardiovascular Diseases / physiopathology
  • Clopidogrel
  • Cohort Studies
  • Drug Interactions
  • Female
  • Follow-Up Studies
  • Hospitalization
  • Humans
  • Male
  • Middle Aged
  • Platelet Aggregation Inhibitors / adverse effects*
  • Platelet Aggregation Inhibitors / therapeutic use
  • Proportional Hazards Models
  • Proton Pump Inhibitors / adverse effects*
  • Proton Pump Inhibitors / therapeutic use
  • Regression Analysis
  • Retrospective Studies
  • Ticlopidine / adverse effects
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / therapeutic use
  • Time Factors


  • Platelet Aggregation Inhibitors
  • Proton Pump Inhibitors
  • Clopidogrel
  • Ticlopidine