Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study

Ann Intern Med. 2010 Sep 21;153(6):378-86. doi: 10.7326/0003-4819-153-6-201009210-00005.


Background: Controversy remains on whether the dual use of clopidogrel and proton-pump inhibitors (PPIs) affects clinical efficacy of clopidogrel.

Objective: To examine the risk for adverse cardiovascular outcomes related to concomitant use of PPIs and clopidogrel compared with that of PPIs alone in adults hospitalized for myocardial infarction.

Design: A nationwide cohort study based on linked administrative registry data.

Setting: All hospitals in Denmark.

Patients: All patients discharged after first-time myocardial infarction from 2000 to 2006.

Measurements: The primary outcome was a composite of rehospitalization for myocardial infarction or stroke or cardiovascular death. Patients were examined at several assembly time points, including 7, 14, 21, and 30 days after myocardial infarction. Follow-up was 1 year.

Results: Of 56 406 included patients, 9137 (16.2%) were re-hospitalized for myocardial infarction or stroke or experienced cardiovascular death. Of the 24 702 patients (43.8%) who received clopidogrel, 6753 (27.3%) received concomitant PPIs. The hazard ratio for cardiovascular death or rehospitalization for myocardial infarction or stroke for concomitant use of a PPI and clopidogrel among the cohort assembled at day 30 after discharge was 1.29 (95% CI, 1.17 to 1.42). The corresponding ratio for use of a PPI in patients who did not receive clopidogrel was 1.29 (CI, 1.21 to 1.37). No statistically significant interaction occurred between a PPI and clopidogrel (P = 0.72).

Limitations: Unmeasured and residual confounding, time-varying measurement errors of exposure, and biases from survival effects were possible.

Conclusion: Proton-pump inhibitors seem to be associated with increased risk for adverse cardiovascular outcomes after discharge, regardless of clopidogrel use for myocardial infarction. Dual PPI and clopidogrel use was not associated with any additional risk for adverse cardiovascular events over that observed for patients prescribed a PPI alone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cardiovascular Diseases / epidemiology*
  • Cardiovascular Diseases / mortality
  • Clopidogrel
  • Cohort Studies
  • Drug Interactions
  • Drug Therapy, Combination
  • Humans
  • Myocardial Infarction / drug therapy*
  • Platelet Aggregation Inhibitors / adverse effects*
  • Proportional Hazards Models
  • Proton Pump Inhibitors / adverse effects*
  • Recurrence
  • Regression Analysis
  • Risk Factors
  • Ticlopidine / adverse effects
  • Ticlopidine / analogs & derivatives*
  • Time Factors


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