Cardiovascular and gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a large Dutch cohort study

Am J Gastroenterol. 2010 Nov;105(11):2430-6; quiz 2437. doi: 10.1038/ajg.2010.334. Epub 2010 Aug 24.


Objectives: Recent studies have raised concerns on the clinical effectiveness of clopidogrel when taken in combination with proton pump inhibitors (PPIs), demonstrating an increase in the occurrence of cardiovascular events. In this study, the association between the co-administration of a PPI and clopidogrel and the occurrence of cardiovascular and gastrointestinal (GI) events in a large cohort in the Netherlands was investigated.

Methods: A retrospective study was conducted using data from 4 million individuals. New clopidogrel users were identified between January 2006 and December 2007 and followed over time. The Kaplan-Meier method and Cox proportional hazard regression [corrected]analysis were used to calculate the risk of cardiovascular and GI outcomes in clopidogrel patients with or without PPI use.

Results: A total of 18,139 new clopidogrel users were identified; 5,734 subjects (32%) used PPIs concurrently. Patients on PPIs were significantly older, used more co-medications and suffered from more comorbidities. Use of clopidogrel and PPIs was associated with an increased risk of myocardial infarction (hazard ratio (HR) 1.93, 95% confidence interval (CI) 1.40-2.65), unstable angina pectoris (HR 1.79, 95% CI 1.60-2.03), and the composite endpoint (HR 1.75, 95% CI 1.58-1.94) compared with clopidogrel users without PPIs. PPI users also had an increased risk of GI events compared with non-PPI users (HR 4.76, 95% CI 1.18-19.17).

Conclusions: New clopidogrel users on PPIs are at an increased risk of cardiovascular and GI complications compared with those who are not using a PPI. The inferior cardiovascular profile of clopidogrel users on PPIs and the occurrence of channeling bias may be important factors underlying this observation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Cardiovascular Diseases / chemically induced*
  • Clopidogrel
  • Databases, Factual
  • Drug Interactions
  • Drug Therapy, Combination
  • Female
  • Gastrointestinal Diseases / chemically induced*
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Netherlands
  • Platelet Aggregation Inhibitors / adverse effects
  • Platelet Aggregation Inhibitors / therapeutic use
  • Proportional Hazards Models
  • Proton Pump Inhibitors / adverse effects*
  • Proton Pump Inhibitors / therapeutic use
  • Retrospective Studies
  • Ticlopidine / adverse effects
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / therapeutic use
  • Treatment Outcome


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