Concomitant use of proton pump inhibitors and clopidogrel in patients with coronary, cerebrovascular, or peripheral artery disease in the factores de Riesgo y ENfermedad Arterial (FRENA) registry

J Cardiovasc Pharmacol. 2011 Jan;57(1):13-9. doi: 10.1097/FJC.0b013e3181fc65e5.


Background: Among patients receiving clopidogrel for coronary artery disease, concomitant therapy with proton pump inhibitors (PPIs) has been associated with an increased risk for recurrent coronary events.

Patients and methods: Factores de Riesgo y ENfermedad Arterial (FRENA) is an ongoing, multicenter, observational registry of consecutive outpatients with coronary artery disease, cerebrovascular disease, or peripheral artery disease. We retrospectively examined the influence of concomitant use of PPIs on outcome in patients receiving clopidogrel.

Results: As of March 2009, 1222 patients were using clopidogrel: 595 had coronary artery disease, 329 cerebrovascular disease, and 298 had peripheral artery disease. Of these, 519 (42%) were concomitantly using PPIs. Over a mean follow-up of 15 months, 131 patients (11%) had 139 subsequent ischemic events: myocardial infarction 44, ischemic stroke 40, and critical limb ischemia 55. Seventeen of them (13%) died within 15 days of the subsequent event. PPI users had a higher incidence of myocardial infarction (rate ratio, 2.5; 95% confidence interval [CI], 1.3-4.8), ischemic stroke (rate ratio, 1.9; 95% CI, 1.03-3.7), and a nonsignificantly higher rate of critical limb ischemia (rate ratio, 1.6; 95% CI, 0.95-2.8) than nonusers. On multivariate analysis, concomitant use of clopidogrel and PPIs was independently associated with an increased risk for subsequent ischemic events both in the whole series of patients (hazard ratio, 1.8; 95% CI, 1.1-2.7) and in those with cerebrovascular disease or peripheral artery disease (hazard ratio, 1.5; 95% CI, 1.01-2.4).

Conclusions: In patients with established arterial disease, concomitant use of PPIs and clopidogrel was associated with a nearly doubling of the incidence of subsequent myocardial infarction or ischemic stroke. This higher incidence persisted after multivariate adjustment.

Publication types

  • Comparative Study
  • Multicenter Study

MeSH terms

  • Aged
  • Cerebrovascular Disorders / chemically induced
  • Clopidogrel
  • Contraindications
  • Coronary Artery Disease / chemically induced
  • Coronary Artery Disease / drug therapy*
  • Drug Interactions
  • Female
  • Humans
  • Male
  • Middle Aged
  • Myocardial Infarction / chemically induced
  • Myocardial Infarction / therapy
  • Peripheral Arterial Disease / drug therapy*
  • Platelet Aggregation Inhibitors / therapeutic use
  • Proton Pump Inhibitors / adverse effects*
  • Proton Pump Inhibitors / therapeutic use
  • Registries*
  • Retrospective Studies
  • Stroke / chemically induced
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / therapeutic use


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