The Medical Letter on Drugs and Therapeutics
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1515
Drug Interaction: Clopidogrel and PPIs
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 Select a term to see related articles  Aciphex   Clopidogrel   Dexilant   Dexlansoprazole   Drug Safety   Esomeprazole   Lansoprazole   Losec   Nexium   Olex   Omep   Omeprazole   Pantoloc   pantoprazole Protonix   Pariet   Plavix   Prevacid   Prilosec   Proton pump inhibitors   Rabeprazole   Zegerid 

The antiplatelet drug clopidogrel (Plavix, and others) reduces major cardiovascular events, but can cause bleeding. Proton pump inhibitors (PPIs) are often used with clopidogrel to prevent gastrointestinal bleeding, however, some evidence suggests that PPIs may interfere with the activation of clopidogrel and diminish its antiplatelet effect.1 FDA-approved labeling recommends avoiding concurrent use of the PPIs omeprazole and esomeprazole with clopidogrel.

POSSIBLE MECHANISM — Clopidogrel is a prodrug; the CYP2C19 isozyme appears to be mainly responsible for its bioactivation.2 Concurrent use of clopidogrel and drugs that inhibit CYP2C19 could inhibit conversion of clopidogrel to its active form. Among the PPIs, omeprazole and esomeprazole appear to be the strongest inhibitors of CYP2C19 and pantoprazole appears to be the weakest.3,4

CLINICAL STUDIES — Some pharmacodynamic and pharmacokinetic studies have reported reductions in platelet inhibition and the AUC of the clopidogrel active metabolite in patients taking clopidogrel with omeprazole or esomeprazole. Similar effects were not reported with pantoprazole, lansoprazole, or dexlansoprazole.5-8

Whether concurrent use of clopidogrel and PPIs results in clinically significant adverse cardiovascular outcomes is not clear. The results of several (mostly observational) studies have been inconsistent.9,10 In a case-control study in patients ≥66 years old who were started on clopidogrel after an acute MI, concurrent use of a PPI (other than pantoprazole) was associated with an increased risk of recurrent MI within 90 days.11 In a retrospective cohort study in 8205 patients with acute coronary syndrome (ACS), use of a PPI with clopidogrel after hospital discharge was associated with a higher risk of death or rehospitalization due to ACS.12

In a retrospective cohort study of patients who were prescribed clopidogrel after hospitalization for acute MI, coronary artery revascularization, or unstable angina, concurrent use of a PPI was not associated with a statistically significant increased risk of serious cardiovascular disease.13

In a randomized, placebo-controlled trial (COGENT), use of omeprazole in patients taking clopidogrel and aspirin decreased the incidence of GI bleeding without increasing the risk of a cardiovascular event.14 The FDA concluded, however, that because of study design limitations and a low number of reported cardiovascular events, the results do not prove that concurrent use of clopidogrel and omeprazole is safe.15 In addition, the fixed-dose combination of omeprazole and clopidogrel used in the trial was specifically developed to delay absorption of omeprazole in order to minimize an interaction.16

Some studies have suggested that PPI use is a confounder associated with, rather than the cause of, adverse cardiovascular outcomes in patients taking clopidogrel.17,18

CONCLUSION — Concurrent use of clopidogrel and a proton pump inhibitor (PPI) may result in decreased levels of the clopidogrel active metabolite, and possibly its antiplatelet activity, but whether it results in clinically significant adverse cardiovascular outcomes is not clear. Since omeprazole and esomeprazole appear to be most likely to affect the antiplatelet activity of clopidogrel and the FDA specifically warns against their concomitant use, it would be reasonable to use another PPI such as pantoprazole in patients taking clopidogrel.

  1. NS Abraham et al. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. J Am Coll Cardiol 2010; 56:2051.
  2. JL Mega et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360:354.
  3. T Zvyaga et al. Evaluation of six proton pump inhibitors as inhibitors of various human cytochromes P450: focus on cytochrome P450 2C19. Drug Metab Dispos 2012; 40:1698.
  4. RS Wedemeyer and H Blume. Pharmacokinetic drug interaction profiles of proton pump inhibitors: an update. Drug Saf 2014; 37:201.
  5. AL Frelinger 3rd et al. A randomized, 2-period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers. J Am Coll Cardiol 2012; 59:1304.
  6. JM Siller-Matula et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J 2009;157:148.e1.
  7. DJ Angiolillo et al. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies. Clin Pharmacol Ther 2011; 89:65.
  8. N Simon et al. Omeprazole, pantoprazole, and CYP2C19 effects on clopidogrel pharmacokinetic-pharmacodynamic relationships in stable coronary artery disease patients. Eur J Clin Pharmacol 2015; 71:1059.
  9. SA Scott et al. Antiplatelet drug interactions with proton pump inhibitors. Expert Opin Drug Metab Toxicol 2014; 10:175.
  10. SD Bouziana and K Tziomalos. Clinical relevance of clopidogrel-proton pump inhibitors interaction. World J Gastrointest Pharmacol Ther 2015; 6:17.
  11. DN Juurlink et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009; 180:713.
  12. PM Ho et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009; 301:937.
  13. WA Ray et al. Outcomes with concurrent use of clopidogrel and proton pump inhibitors: a cohort study. Ann Intern Med 2010; 152:337.
  14. DL Bhatt et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010; 363:1909.
  15. MR Southworth and R Temple. Interaction of clopidogrel and omeprazole. N Engl J Med 2010; 363:1977.
  16. DN Juurlink. Comment on: Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2011; 364:681.
  17. SP Dunn et al. Impact of proton pump inhibitor therapy on the efficacy of clopidogrel in the CAPRIE and CREDO trials. J Am Heart Assoc 2013; 2:e004564.
  18. SG Goodman et al. Association of proton pump inhibitor use on cardiovascular outcomes with clopidogrel and ticagrelor. Circulation 2012; 125:978.
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