Digestive Diseases and Sciences

, Volume 57, Issue 5, pp 1304–1313

Lack of Significant Interactions Between Clopidogrel and Proton Pump Inhibitor Therapy: Meta-Analysis of Existing Literature

  • Lauren B. Gerson
  • Donal McMahon
  • Ingram Olkin
  • Christopher Stave
  • Stanley G. Rockson
Original Article

Abstract

Background

Published data regarding the effect of concomitant clopidogrel and proton pump inhibitor (PPI) therapy on cardiovascular outcomes have been conflicting.

Aim

To perform an updated meta-analysis in order to determine changes in risk differences (RD) between primary and secondary outcome analyses.

Methods

Primary analysis was based on definite vascular outcomes, including all cause mortality, cardiac death, myocardial infarction, and/or stroke. Secondary analysis also incorporated probable cardiac events, which included re-hospitalization for cardiac symptoms or revascularization procedures. RD were combined using a random-effects model.

Results

We reviewed 1,204 publications of which 26 studies (16 published articles, 10 abstracts) met inclusion criteria. The meta-analysis of outcomes from the two randomized controlled trials did not show an increased risk (RD 0.0, 95% CI −0.01, 0.01) for adverse outcomes. The meta-analysis of primary outcomes showed a RD of 0.02 (95% CI 0.01, 0.03) for all studies. The meta-analysis for secondary outcomes yielded a RD of 0.02 (95% CI 0.01–0.04) based on 19 published papers and abstracts. When primary and secondary outcomes were combined, the meta-analysis for published papers yielded an overall RD of 0.05 (95% CI 0.03–0.06).

Conclusions

In patients using concomitant clopidogrel and PPI therapy, the risk of adverse cardiac outcomes was 0% based on data from well-controlled randomized trials. Data from retrospective studies and the addition of probable vascular events significantly increased the RD estimates, likely due to lack of adjustment for potential confounders.

Keywords

Proton pump inhibitor Clopidogrel Meta-analysis 

References

  1. 1.
  2. 2.
  3. 3.
    Sibbing D, Morath T, Stegherr J, et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost. 2009;101:714–719.PubMedGoogle Scholar
  4. 4.
    Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009;301:937–944.PubMedCrossRefGoogle Scholar
  5. 5.
    Aubert RE, Epstein RS, Teagarden JR, et al. Proton pump inhibitors effect on clopidogrel effectiveness: the clopidogrel medco outcomes study. Circulation. 2008;118:S815.Google Scholar
  6. 6.
    Dunn SP, Macaulay TE, Brennan DM, et al. Baseline proton pump inhibitor use is associated with increased cardiovascular events with and without the use of clopidogrel in the CREDO trial. Circulation. 2008;118:S815.Google Scholar
  7. 7.
    O’Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet. 2009;374:989–997.PubMedCrossRefGoogle Scholar
  8. 8.
    Kwok CS, Loke YK. Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel. Aliment Pharmacol Ther. 2010;31:810–823.PubMedGoogle Scholar
  9. 9.
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188.PubMedCrossRefGoogle Scholar
  10. 10.
    Pezalla E, Day D, Pulliadath I. Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors. J Am Coll Cardiol. 2008;52:1038–1039.PubMedCrossRefGoogle Scholar
  11. 11.
    Zairis MN, Patsourakos NG, Makrygiannis SS, et al. The impact of oral proton pump inhibitors on the effectiveness of combined aspirin and clopidogrel drug therapy during the first year after elective coronary stenting. Eur Heart J. 2008;29:134.Google Scholar
  12. 12.
    Tsiaousis GZ, Zairis MN, Patsourakos NG, et al. Oral proton pump inhibitors and their impact on the effectiveness of dual anti-platelet therapy during the first year after elective coronary stenting. J Am Coll Cardiol. 2009;53:A335.Google Scholar
  13. 13.
    Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. Can Med Assoc J. 2009;180:713–718.CrossRefGoogle Scholar
  14. 14.
    Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010;363:1909–1917.Google Scholar
  15. 15.
    Hsu PI, Lai KH. Esomeprazole prevents recurrent peptic ulcers in clopidogrel users with ulcer history. Gastroenterology. 2010;138:S20.CrossRefGoogle Scholar
  16. 16.
    Banerjee S, Weideman RA, Weideman MW, et al. Effect of concomitant use of clopidogrel and proton pump inhibitors after percutaneous coronary intervention. Am J Cardiol. 2011;107:871–878.Google Scholar
  17. 17.
    Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009;360:363–375.PubMedCrossRefGoogle Scholar
  18. 18.
    Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360:354–362.PubMedCrossRefGoogle Scholar
  19. 19.
    Rassen JA, Choudhry NK, Avorn J, Schneeweiss S. Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation. 2009;120:2322–2329.PubMedCrossRefGoogle Scholar
  20. 20.
    van Boxel OS, van Oijen MG, Hagenaars MP, Smout AJ, Siersema PD. Cardiovascular and gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a large dutch cohort study. Am J Gastroenterol. 2010;105:2430–2436.Google Scholar
  21. 21.
    Kreutz RP, Stanek EJ, Aubert R, et al. Impact of proton pump inhibitors on the effectiveness of clopidogrel after coronary stent placement: the clopidogrel medco outcomes study. Pharmacotherapy. 2010;30:787–796.PubMedCrossRefGoogle Scholar
  22. 22.
    Wu CY, Chan FK, Wu MS, et al. Histamine2-receptor antagonists are an alternative to proton pump inhibitor in patients receiving clopidogrel. Gastroenterology. 2010;139:1165–1171.PubMedCrossRefGoogle Scholar
  23. 23.
    Sarafoff N, Sibbing D, Sonntag U, et al. Risk of drug-eluting stent thrombosis in patients receiving proton pump inhibitors. Thromb Haemost. 2010;104:626–632.PubMedCrossRefGoogle Scholar
  24. 24.
    Stockl KM, Le L, Zakharyan A, et al. Risk of rehospitalization for patients using clopidogrel with a proton pump inhibitor. Arch Intern Med. 2010;170:704–710.PubMedCrossRefGoogle Scholar
  25. 25.
    Tentzeris I, Jarai R, Farhan S, Brozovic I, Smetana P, Geppert A, et al. Impact of concomitant treatment with proton pump inhibitors and clopidogrel on clinical outcome in patients after coronary stent implantation. Thromb Haemost. 2010;104:1211–1218.Google Scholar
  26. 26.
    Torguson R, Chou C, Kaneshige K, et al. Does proton pump inhibitor use following percutaneous coronary intervention with drug-eluting stents impact clinical outcome? Circulation. 2009;120:S968.Google Scholar
  27. 27.
    Zairis MN, Tsiaousis GZ, Patsourakos NG, Georgilas AT, Kontos CF, Adamopoulou EN, et al. The impact of treatment with omeprazole on the effectiveness of clopidogrel drug therapy during the first year after successful coronary stenting. Can J Cardiol. 2010;26:54–57.Google Scholar
  28. 28.
    Gupta E, Bansal D, Sotos J, Olden K. Risk of adverse clinical outcomes with concomitant use of clopidogrel and proton pump inhibitors following percutaneous coronary intervention. Dig Dis Sci. 2010;55:1964–1968.PubMedCrossRefGoogle Scholar
  29. 29.
    Charlot M, Ahlehoff O, Norgaard ML, et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: a nationwide cohort study. Ann Intern Med. 2010;153:378–386.PubMedGoogle Scholar
  30. 30.
    Ray WA, Murray KT, Griffin MR, et al. Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study. Ann Intern Med. 2010;152:337–345.PubMedGoogle Scholar
  31. 31.
    Evanchan J, Donnally MR, Binkley P, Mazzaferri E. Recurrence of acute myocardial infarction in patients discharged on clopidogrel and a proton pump inhibitor after stent placement for acute myocardial infarction. Clin Cardiol. 2010;33:168–171.PubMedCrossRefGoogle Scholar
  32. 32.
    Harjai K, Orshaw P, Boura J, Rogers G. Six-month outcomes with or without proton-pump inhibitors after successful PCI: insights from the Guthrie PCI registry. J Am Coll Cardiol. 2010;55:A179.Google Scholar
  33. 33.
    Ching G, Li DD, McKay R, Mather J, Lundbye J. Proton pump inhibitors increase major adverse cardiac events among post percutaneous coronary intervention patients on clopidogrel. Circulation. 2009;120:S936–S937.Google Scholar
  34. 34.
    Ramirez JF, Selzer F, Chakaprani R, et al. Proton pump inhibitor and clopidogrel combination is not associated with adverse clinical outcomes after PCI: the NHLBI dynamic registry. J Am Coll Cardiol. 2009;53:A27.Google Scholar
  35. 35.
    Banerjee S, Varghese C, Weideman RA, Weideman MW, Little BB. Proton pump inhibitors increase the risk of major adverse cardiovascular events in post-PCI patients who are on clopidogrel. Eur Heart J. 2009;30:P653.Google Scholar
  36. 36.
    Kim MS, Jung SY, Kim YJ, Choi NK, Park BJ. Association of proton pump inhibitors with clopidogrel effectiveness in elderly stroke patients. Pharmacoepidemiol Drug Saf. 2009;18:S7–S8.CrossRefGoogle Scholar
  37. 37.
    Sweeny JM, Kini A, Muntner P, Jakkula M, Farkouh M, Sharma S. Mortality associated with proton pump inhibitors following percutaneous coronary interventions with drug eluting stents. Circulation. 2009;120:S936.Google Scholar
  38. 38.
    Wang SS-W, Tsai S–S, Hsu P-C, Yang C-Y, Wu D-C. Concomitant use of clopidogrel and proton pump inhibitors or cimetidine after acute myocardial infarction would increase the risk of re-infarction. Am J Gastroenterol. 2009;104:3116–3117.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Lauren B. Gerson
    • 1
    • 2
  • Donal McMahon
    • 3
  • Ingram Olkin
    • 3
  • Christopher Stave
    • 1
  • Stanley G. Rockson
    • 1
    • 4
  1. 1.Department of MedicineStanford UniversityStanfordUSA
  2. 2.Division of Gastroenterology and HepatologyStanford UniversityRedwood CityUSA
  3. 3.Department of StatisticsStanford UniversityStanfordUSA
  4. 4.Department of CardiologyStanford UniversityStanfordUSA

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