Should Omeprazole or Clopidogrel Be Substituted When Given Concomitantly?

Jenny A. Van Amburgh, PharmD, CDE

March 01, 2010

Question

Is the proton-pump inhibitor drug interaction with clopidogrel a class effect? Should clopidogrel be substituted with prasugrel?

Response from Jenny A. Van Amburgh, PharmD, CDE
Associate Clinical Professor, School of Pharmacy, Northeastern University, Boston, Massachusetts; Director of the Clinical Pharmacy Team and Residency Director, Harbor Health Services, Inc., Boston, Massachusetts

The question "How should we manage drug interactions between clopidogrel and proton-pump inhibitors?" generated much interest and many follow-up questions from readers. Here, Dr. Van Amburgh responds to readers' questions about alternative therapy.

Evidence on concurrent use of clopidogrel (Plavix®) and proton-pump inhibitors (PPIs), particularly omeprazole, inarguably demonstrates the existence of a drug-drug interaction. The clinical implication of this interaction, however, is less certain. The proposed implication is increased risk for recurring thrombotic events, including myocardial infarction and stroke, due to a diminished antiplatelet effect of clopidogrel. The basis for this concept comes from a number of studies, the limitations of which have been spotlighted in recent months' reviews and editorials.[1-4] As such, clinicians wonder whether PPIs other than omeprazole and antiplatelet agents other than clopidogrel should be used when the combination is required.

Is This a Class Effect of PPIs?

PPIs are prescribed in many patients on clopidogrel following acute coronary syndrome with or without percutaneous coronary intervention in accordance with consensus guidelines to reduce the risk for gastrointestinal bleeding associated with antiplatelet therapy.[5]

The first study to demonstrate diminished clopidogrel effects in association with concomitant PPIs was an ex vivo study by Gilard and colleagues[6] in 2006. Platelet reactivity was measured in 105 patients on clopidogrel and aspirin with or without omeprazole. One of the finding, a 25% higher platelet reactivity in PPI-treated patients compared with patients without PPI therapy (P = .007), provided the impetus for subsequent studies on the interaction between PPIs and clopidogrel.

The widely accepted explanation for the interaction is competitive inhibition of cytochrome 450 (CYP) 2C19, the isoenzyme responsible for the conversion of clopidogrel to its therapeutically active form.[4] All PPIs are metabolized by CYP2C19 to varying degrees. In a comparative in vitro study using human liver preparations, omeprazole, esomeprazole, and lansoprazole showed the greatest degree of CYP2C19 inhibition, followed by pantoprazole and rabeprazole.[7] Thus, the supposition is that PPIs with lesser CYP2C19 involvement, namely pantoprazole and rabeprazole, provide a safer alternative for patients on clopidogrel who require gastroprotection.

Studies have analyzed individual PPIs to elucidate this theory.[8-11] However, the matter remains unclear. Several studies provide evidence to support the use of pantoprazole over other PPIs based on decreased risk for readmission for myocardial infarction,[8] or decreased platelet reactivity or aggregation.[9,10] A large retrospective analysis,[11] however, reported an increased risk for major cardiovascular adverse events for each PPI, including pantoprazole, in patients receiving clopidogrel for prevention of coronary artery stent restenosis.

Many clinicians consider using pantoprazole over other PPIs due to the lack of convincing evidence on either side; histaminergic (H2) blockers are also considered by some.

Should Clopidogrel Be Substituted With Prasugrel?

Clopidogrel, a second-generation thienopyridine, is the mainstay for secondary prevention of acute coronary syndromes. Because the active moiety is formed by CYP isoenzymes, genetic polymorphisms conferring reduced enzymatic activity in some patients may also suppress the full therapeutic effects of clopidogrel. The genetic polymorphisms are known to vary by ethnicity, with over 55% of East Asians, 40% of blacks, and 30% of whites carrying variants that could result in significantly diminished pharmacokinetic and pharmacodynamic responses to clopidogrel.[12] Discussions on management of drug-drug interactions in clinical practice have logically called for an evaluation of alternative antiplatelet agents in place of clopidogrel, namely prasugrel (Effient®).

Prasugrel, a third-generation thienopyridine, requires bioactivation by hepatic enzymes, albeit to a lesser degree by CYP 2C19 than clopidogrel.[12] A trial comparing prasugrel with clopidogrel revealed a 19% relative risk reduction with prasugrel in the primary efficacy composite endpoint of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. However, an increased risk for bleeding was observed in prasugrel-treated patients compared with clopidogrel-treated patients.[13] Data are needed to delineate which patients may benefit from prasugrel over the current standard of clopidogrel.

Recommendations

The latest Food and Drug Administration alert[14] heightened public awareness of the interaction and advised practitioners of the following:

  • Avoid using omeprazole and clopidogrel together in the absence of a compelling indication;

  • Avoid coadministration of other drugs with clopidogrel that are competitive inhibitors of CYP2C19; and

  • Separating doses of these agents has not been shown to circumvent the problem as was previously suggested.

No advice was offered on the use of other PPIs or prasugrel. Guidelines for the use of PPIs with clopidogrel have not changed, only to emphasize judicious assessment of an individual patient's need for concurrent PPI therapy.

Results from COGENT,[15] a randomized controlled trial comparing the combination of clopidogrel and omeprazole with clopidogrel and placebo, and post-hoc analyses from the PRINCIPLE-TIMI 44 and TRITON-TIMI 38 trials[3] are providing evidence that no association exists between the pharmacodynamic interaction with clopidogrel and PPIs and cardiovascular outcomes.

Clinicians should be on alert for more outcomes data as it unfolds. Attempts to circumvent the interaction should not compromise the cardioprotective and gastroprotective effects of antiplatelet and PPI therapy in patients who require both.

The author wishes to acknowledge the assistance of Nga T. Pham, PharmD, Pharmacy Practice Resident, Northeastern University School of Pharmacy and Harbor Health Services, and Jason W. Lancaster, PharmD, Assistant Clinical Professor, Northeastern University School of Pharmacy.

Do you have other questions or comments on this topic? Discuss them here.

References

  1. Sibbing D, Kastrati A. Risk of combining PPIs with thienopyridines: fact or fiction? (letter) Lancet. 2009;374:952-954.

  2. Howard PA, Vacek JL. Potential interaction between clopidogrel and proton pump inhibitors. Am J Cardiovasc Drugs. 2009;9:353-359. Abstract

  3. Last EJ, Sheehan AH. Review of recent evidence: potential interaction between clopidogrel and proton pump inhibitors. Am J Health-Syst Pharm. 2009;66:2117-2122.

  4. Juurlink DN. Proton pump inhibitors and clopidogrel: putting the interaction in perspective. Circulation. 2009;120:2310-2312. Abstract

  5. Bhatt DL, Scheiman J., Abraham NS, et al, for the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. 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 Clinical Expert Consensus Documents. Circulation. 2008;118:1894-1909. Abstract

  6. Gilard M, Arnaud B, Le Gal G, Abgrall JF, Boschat J. Influence of omeprazole on the antiplatelet action of clopidogrel associated to aspirin. (letter) J Thromb Haemost. 2006;4:2508-2509.

  7. Li XQ, Andersson TB, Ahlstrom M, Weidolf L. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos. 2004;32:821-827. Abstract

  8. Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009;180:713-718. Abstract

  9. Siller-Matula JM, Spiel AO, Lang IM, Kreiner JG, Christ G, Jilma B. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J. 2009;157:148.e1-148.e5.

  10. Sibbing D, Morath T, Stegherr J, et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thomb Haemost. 2009;101:607-609.

  11. Aubert RE, Epstein RS, Teagarden JR, et al. Abstract 3998: proton pump inhibitors effect on clopidogrel effectiveness: The Clopidogrel Medco Outcomes Study. Circulation. 2008;118:S815.

  12. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation. 2009;119:2553-2560. Abstract

  13. Montalescot G, Wiviott SD, Braunwald E, et al, for the TRITON-TIMI investigators. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet. 2009;373:723-731. Abstract

  14. US Food and Drug Administration. Information for healthcare professionals: update to the labeling of clopidogrel bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC). Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ DrugSafetyInformationforHeathcareProfessionals/ucm190784.htm Accessed December 1, 2009.

  15. Bhatt DL. COGENT: a prospective, randomized, placebo-controlled trial of omeprazole in patients receiving aspirin and clopidogrel. Program and abstracts of the Transcatheter Cardiovascular Therapeutics (TCT) 21st Annual Scientific Symposium; September 21-25, 2009; San Francisco, California.