Clopidogrel and proton pump inhibitors--where do we stand in 2012?

World J Gastroenterol. 2012 May 14;18(18):2161-71. doi: 10.3748/wjg.v18.i18.2161.

Abstract

Clopidogrel in association with aspirine is considered state of the art of medical treatment for acute coronary syndrome by reducing the risk of new ischemic events. Concomitant treatment with proton pump inhibitors in order to prevent gastrointestinal side effects is recommended by clinical guidelines. Clopidogrel needs metabolic activation predominantly by the hepatic cytochrome P450 isoenzyme Cytochrome 2C19 (CYP2C19) and proton pump inhibitors (PPIs) are extensively metabolized by the CYP2C19 isoenzyme as well. Several pharmacodynamic studies investigating a potential clopidogrel-PPI interaction found a significant decrease of the clopidogrel platelet antiaggregation effect for omeprazole, but not for pantoprazole. Initial clinical cohort studies in 2009 reported an increased risk for adverse cardiovascular events, when under clopidogrel and PPI treatment at the same time. These observations led the United States Food and Drug Administration and the European Medecines Agency to discourage the combination of clopidogrel and PPI (especially omeprazole) in the same year. In contrast, more recent retrospective cohort studies including propensity score matching and the only existing randomized trial have not shown any difference concerning adverse cardiovascular events when concomitantly on clopidogrel and PPI or only on clopidogrel. Three meta-analyses report an inverse correlation between clopidogrel-PPI interaction and study quality, with high and moderate quality studies not reporting any association, rising concern about unmeasured confounders biasing the low quality studies. Thus, no definite evidence exists for an effect on mortality. Because PPI induced risk reduction clearly overweighs the possible adverse cardiovascular risk in patients with high risk of gastrointestinal bleeding, combination of clopidogrel with the less CYP2C19 inhibiting pantoprazole should be recommended.

Keywords: Acute coronary syndrome; Antiplatelet therapy; Clopidogrel; Cytochromes; Drug interaction; Gastrointestinal bleeding; Platelet reactivity; Proton pump inhibitors; Thienopyridine.

Publication types

  • Review

MeSH terms

  • Animals
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Aspirin / therapeutic use
  • Biotransformation
  • Cardiovascular Diseases / chemically induced
  • Clopidogrel
  • Cytochrome P-450 CYP2C19
  • Drug Interactions
  • Drug Therapy, Combination
  • Gastrointestinal Hemorrhage / chemically induced
  • Gastrointestinal Hemorrhage / prevention & control*
  • Humans
  • Platelet Aggregation Inhibitors / adverse effects
  • Platelet Aggregation Inhibitors / pharmacokinetics
  • Platelet Aggregation Inhibitors / therapeutic use*
  • Proton Pump Inhibitors / adverse effects
  • Proton Pump Inhibitors / pharmacokinetics
  • Proton Pump Inhibitors / therapeutic use*
  • Risk Assessment
  • Risk Factors
  • Ticlopidine / adverse effects
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / pharmacokinetics
  • Ticlopidine / therapeutic use

Substances

  • Platelet Aggregation Inhibitors
  • Proton Pump Inhibitors
  • Clopidogrel
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C19 protein, human
  • Cytochrome P-450 CYP2C19
  • Ticlopidine
  • Aspirin