Pharmacodynamic impacts of proton pump inhibitors on the efficacy of clopidogrel in vivo--a systematic review

Clin Cardiol. 2013 Apr;36(4):184-9. doi: 10.1002/clc.22094. Epub 2013 Feb 28.


Background: There is considerable debate about whether concomitant use of proton pump inhibitors (PPIs) should be recommended for patients who are prescribed clopidogrel after acute coronary syndrome. Most pharmacokinetic and pharmacodynamic studies in vivo were conducted using small sample sizes and were single centered, resulting in conflicting data.

Hypothesis: PPIs may attenuate the antiplatelet effect of clopidogrel in vivo and lead to an increased risk of cardiovascular events.

Methods: PubMed, the Cochrane Library, Embase, Web of Science, and China Biology Medicine Disc were searched. Randomized controlled trials that compared pharmacodynamic impacts of a PPI on the efficacy of clopidogrel in vivo were included. Two independent reviewers evaluated study quality and extracted data for meta-analysis.

Results: We identified 8 eligible studies. Compared to clopidogrel treatment alone, patients who received both a PPI and clopidogrel had less of a decrease in the platelet reactivity index (weighted mean difference [WMD]: 8.18; 95% confidence interval [CI]: 6.81-9.56; P<0.00001), less adenosine 5'-diphosphate-induced platelet aggregation inhibition (WMD: 7.28; 95% CI: 2.44-12.11; P=0.003), higher P2Y12 reaction units (WMD: 40.58; 95% CI: 19.31-61.86; P=0.0002), and higher risks of clopidogrel resistance (odds ratio [OR]: 2.49; 95% CI: 1.49-4.14; P=0.0005). There were no significant differences, however, for the incidences of major adverse cardiovascular events between the 2 groups (OR: 1.07; 95% CI: 0.44-2.59; P=0.88), and treatment with a PPI and clopidogrel significantly reduced the risk of adverse gastrointestinal events (OR: 0.16; 95% CI: 0.04-0.62; P=0.008).

Conclusions: Concomitant use of a PPI with clopidogrel attenuated the antiplatelet effect of clopidogrel, but may be clinically unimportant because there were no clinical differences in the risk for major adverse cardiovascular events.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Adenosine Diphosphate / pharmacology
  • Blood Platelets / drug effects
  • Cardiovascular Diseases
  • Clopidogrel
  • Drug Interactions
  • Drug Resistance
  • Gastrointestinal Diseases
  • Humans
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / pharmacology*
  • Proton Pump Inhibitors / pharmacology*
  • Receptors, Purinergic P2Y12 / blood
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / pharmacology


  • Platelet Aggregation Inhibitors
  • Proton Pump Inhibitors
  • Receptors, Purinergic P2Y12
  • Adenosine Diphosphate
  • Clopidogrel
  • Ticlopidine