Treatment with clopidogrel and proton pump inhibitors in combination: a review of emerging evidence

David A. Johnson, Danial E. Baker

.

DOI: 10.4236/ojim.2011.13011                

Abstract

Proton pump inhibitors often are prescribed in combination with clopidogrel to decrease risk of gastrointestinal bleeding after acute coronary syndrome. Clopidogrel is a prodrug that has to be metabolized in the liver to generate the active metabolite. Both medications are metabolized largely by the CYP2C19 enzyme; therefore, concerns exist that a drug-drug interaction during concomitant treatment with clopidogrel and a proton pump inhibitor may result in reduction of platelet inhibition. We have reviewed observational and randomized control studies that have evaluated the potential influence of proton pump inhibitors on the platelet inhibitory effect of clopidogrel, along with cardiovascular outcomes. We also have summarized regulatory and academic guidelines for treatment of patients in which concomitant therapy with clopidogrel and proton pump inhibitors may be indicated. Confounding issues, including differential effects of individual proton pump inhibitors on the pharmacodynamics of clopidogrel and variation in clopidogrel metabolism mediated by CYP2C19 gene polymorphisms, also are discussed.

Keywords

Proton Pump Inhibitors; Clopidogrel; Dual Antiplatelet Therapy; Drug-Drug Interaction; Gastrointestinal Bleeding; Myocardial Infarction; Percutaneous Coronary Intervention

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Anderson, J.L., Adams, C.D., Antman, E.M., et al. (2011) 2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: A report of the American College Of Cardiology Foundation/American Heart Association task force on practice guidelines. Circulation, 123, e426-e579. doi:10.1161/CIR.0b013e318212bb8b
[2]	Kushner, F.G., Hand, M., Smith, S.C. Jr, et al. (2009) 2009 Focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Journal of American College of Cardiology, 54, 2205
[3]	Tanigawa, T., Watanabe, T., Nadatani, Y., et al. (2011) Gastrointestinal bleeding after percutaneous coronary intervention. Digestion, 83, 153-160. doi:10.1159/000321813
[4]	Schreiner, G.C., Laine, L., Murphy, S.A. and Cannon, C.P. (2007) Evaluation of proton pump inhibitor use in patients with acute coronary syndromes based on risk factors for gastrointestinal bleed. Critical Pathways in Cardiology, 6, 169-172. doi:10.1097/HPC.0b013e318159921e
[5]	Lanas, A., García-Rodríguez, L.A., Arroyo, M.T., et al. (2007) Investigators of the Asociación Espanola de Gastroenterología (AEG), Effect of antisecretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants. American Journal of Gastroenterology, 102, 507-515. doi:10.1111/j.1572-0241.2006.01062.x
[6]	Hsu, P.-I., Lai, K.-H. and Liu, C.-P. (2011) Esomeprazole with clopidogrel reduces peptic ulcer recurrence, compared with clopidogrel alone, in patients with atherosclerosis. Gastroenterology, 140, 791-798. doi:10.1053/j.gastro.2010.11.056
[7]	Luinstra, M., Naunton, M., Peterson, G.M., Bereznicki, L. (2010) PPI use of patients commenced on clopidogrel: a retrospective cross-sectional evaluation. Journal of Clinical Pharmacy and Therapeutics, 35, 213-217. doi:10.1111/j.1365-2710.2009.01089.x
[8]	Plavix (prescribing information) (2011) Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, Bridgewater.
[9]	AcipHex (prescribing information) (2010) Eisai Co., Ltd., Toyko.
[10]	Dexilant (prescribing information) (2011) Takeda Pharmaceuticals North America, Inc., Deerfield.
[11]	Lansoprazole (prescribing information) (2009) Teva Pharmaceuticals USA, Sellersville.
[12]	Nexium (prescribing information) (2010) AstraZeneca Pharmaceuticals LP, Wilmington.
[13]	Protonix (prescribing information) (2011) Wyeth Pharmaceuticals Inc, Philadelphia.
[14]	Li, X.-Q., Andersson, T.B., Ahlstrom, M. and Weidolf, L. (2004) Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome p450 activities. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 32, 821-827. doi:10.1124/dmd.32.8.821
[15]	Siller-Matula, J.M., Spiel, A.O., Lang, I.M., Kreiner, G., Christ, G. and Jilma, B. (2009) Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. American Heart Journal, 157, 148, e1-e5.
[16]	Gremmel, T., Steiner, S., Seidinger, D., Koppensteiner, R., Panzer, S. and Kopp, C.W. (2010) The influence of proton pump inhibitors on the antiplatelet potency of clopidogrel evaluated by 5 different platelet function tests. Journal of Cardiovascular Pharmacology, 56, 532-539. doi:10.1097/FJC.0b013e3181f68209
[17]	Juurlink, D.N., Gomes, T., Ko, D.T., et al. (2009) A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. Canadian Medical Association Journal, 180, 713-718. doi:10.1503/cmaj.082001
[18]	Ho, P.M., Maddox, T.M., Wang, L., et al. (2009) Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. Journal of the American Medical Association, 301, 937-944. doi:10.1001/jama.2009.261
[19]	Rassen, J.A., Choudhry, N.K., Avorn, J. and Schneeweiss, S. (2009) Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation, 120, 2322-2329. doi:10.1161/CIRCULATIONAHA.109.873497
[20]	Evanchan, J., Donnally, M.R., Binkley, P. and Mazzaferri, E. (2010) Recurrence of acute myocardial infarction in patients discharged on clopidogrel and a proton pump inhibitor after stent placement for acute myocardial infarction. Clinical Cardiology, 33, 168-171. doi:10.1002/clc.20721
[21]	Gupta, E., Bansal, D., Sotos, J. and Olden, K. (2010) Risk of adverse clinical outcomes with concomitant use of clopidogrel and proton pump inhibitors following percutaneous coronary intervention. Digestive Diseases and Sciences, 55, 1964-1968. doi:10.1007/s10620-009-0960-8
[22]	Huang, C.C., Chen, Y.C., Leu, H.B., et al. (2010) Risk of adverse outcomes in Taiwan associated with concomitant use of clopidogrel and proton pump inhibitors in patients who received percutaneous coronary intervention. American Journal of Cardiology, 105, 1705-1709. doi:10.1016/j.amjcard.2010.01.348
[23]	Kreutz, R.P., Stanek, E.J., Aubert, R., et al. (2010) Impact of proton pump inhibitors on the effectiveness of clopidogrel after coronary stent placement: The clopidogrel Medco outcomes study. Pharmacotherapy, 30, 787-796. doi:10.1592/phco.30.8.787
[24]	Ray, W.A., Murray, K.T., Griffin, M.R., et al. (2010) Outcomes with concurrent use of clopidogrel and proton-pump inhibitors. Annals of Internal Medicine, 152, 337- 345.
[25]	Stockl, K.M., Le, L., Zakharyan, A., et al. (2010) Risk of rehospitalization for patients using clopidogrel with a proton pump inhibitor. Archives of Internal Medicine, 170, 704-710. doi:10.1001/archinternmed.2010.34
[26]	Van Boxel, O.S., van Oijen, M.G.H., Hagenaars, M.P., Smout, A.J. and Siersema, P.D. (2010) Cardiovascular and gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a large Dutch Cohort Study. The American Journal of Gastroenterology, 105, 2430- 2436. doi:10.1038/ajg.2010.334
[27]	Banjeree, S., Weideman, R.A., Weideman, M.W., et al. (2011) Effect of concomitant use of clopidogrel and proton pump inhibitors after percutaneous coronary intervention. American Journal of Cardiology, 107, 871-878. doi:10.1016/j.amjcard.2010.10.073
[28]	Simon, T., Steg, P.G., Gilard, M., et al. (2011) Clinical events as a function of proton pump inhibitor use, clopidogrel use, and cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction. Circulation, 123, 474-482. doi:10.1161/CIRCULATIONAHA.110.965640
[29]	Gaglia, M.A. Jr, Torguson, R., Hanna, N., et al. (2010) Relation of proton pump inhibitor use after percutaneous coronary intervention with drug-eluting stents to outcomes. American Journal of Cardiology, 105, 833-838. doi:10.1016/j.amjcard.2009.10.063
[30]	Juurlink, D.N., Gomes, T., Mamdani, M.M., Gladstone, D.J. and Kapral, M.K. (2011) The safety of proton pump inhibitors and clopidogrel in patients after stroke. Stroke, 42, 128-132. doi:10.1161/STROKEAHA.110.596643
[31]	Gilard, M., Arnaud, B., Cornily, J.C., et al. (2008) Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. Journal of the American College of Cardiology, 51, 256-260. doi:10.1016/j.jacc.2007.06.064
[32]	Bhatt, D.L., Cryer, B.L., Contant, C.F., et al. (2010) COGENT Investigators, Clopidogrel with or without omeprazole in coronary artery disease. New England Journal of Medicine, 363, 1909-1917. doi:10.1056/NEJMoa1007964
[33]	Pasquali, S.K., Yow, E., Jennings, L.K. and Li, J.S. (2010) Platelet activity associated with concomitant use of clopidogrel and proton pump inhibitors in children with cardiovascular disease. Congenital Heart Disease, 5, 552-555. doi:10.1111/j.1747-0803.2010.00461.x
[34]	O’Donoghue, M.L., Braunwald, E., Antman, E.M., et al. (2009) Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: An analysis of two randomised trials. Lancet, 374, 989-997. doi:10.1016/S0140-6736(09)61525-7
[35]	Small, D.S., Farid, N.A., Payne, C.D., et al. (2008) Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel. Journal of Clinical Pharmacology, 48, 475-484. doi:10.1177/0091270008315310
[36]	Yun, K.H., Rhee, S.J., Park, H.-Y., et al. (2010) Effects of omeprazole on the antiplatelet activity of clopidogrel. International Heart Journal, 51, 13-16.
[37]	Zhang, R., Ran, H.H., Zhu, H.L. and Chen, Q. (2010) Differential effects of esomeprazole on the antiplatelet activity of clopidogrel in healthy individuals and patients after coronary stent implantation. The Journal of International Medical Research, 38, 1617-1625.
[38]	Angiolillo, D.J., Gibson, C.M., Cheng, S., et al. (2011) Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: Randomized, placebo-controlled, crossover comparison studies. Clinical Pharmacology and Therapeutics, 89, 65-74. doi:10.1038/clpt.2010.219
[39]	Sibbing, D., Morath, T., Stegherr, J., et al. (2009) Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thrombosis and Haemostasis, 101, 714-719.
[40]	Neubauer, H., Engelhardt, A., Krüger, J.C., et al. (2010) Pantoprazole does not influence the antiplatelet effect of clopidogrel-a whole blood aggregometry study after coronary stenting. Journal of Cardiovascular Pharmacology, 56, 91-97. doi:10.1097/FJC.0b013e3181e19739
[41]	Cuisset, T., Frere, C., Quilici, J., et al. (2009) Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose: the PACA (Proton Pump Inhibitors and Clopidogrel Association) prospective randomized study. Journal of the American College of Cardiology, 54, 1149-1153. doi:10.1016/j.jacc.2009.05.050
[42]	Siriswangvat, S., Sansanayudh, N., Nathisuwan, S., Panomvana, D. (2010) Comparison between the effect of omeprazole and rabeprazole on the antiplatelet action of clopidogrel. Circulation Journal, 74, 2187-2192. doi:10.1253/circj.CJ-09-0913
[43]	Allen, M.J. and McLean-Veysey, P. (2009) Interaction between clopidogrel and proton pump inhibitors. Canadian Medical Association Journal, 180, 1228-1229. doi:10.1503/cmaj.1090017
[44]	US Food and Drug Administration (2010) FDA drug safety communication: reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug. http://www.fda.gov/Drugs/DruSafety/PostmarketDrugSafetyInformationforPatientsandProvider s/ucm203888.htm
[45]	Holmes, D.R. Jr, Dehmer, G.J., Kaul, S., Leifer, D., O’Gara, P.T. and Stein, C.M. (2010) ACCF/AHA clopidogrel clinical alert: approaches to the FDA “boxed warning”: A report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the American Heart Association endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Journal of the American College of Cardiology, 56, 321-341. doi:10.1016/j.jacc.2010.05.013
[46]	Hulot, J.S., Wuerzner, G., Bachelot-Loza, C., et al. (2010) Effect of an increased clopidogrel maintenance dose or lansoprazole co-administration on the antiplatelet response to clopidogrel in CYP2C19-genotyped healthy subjects. Journal of Thrombosis and Haemostasis, 8, 610-613. doi:10.1111/j.1538-7836.2009.03729.x
[47]	Furuta, T., Iwaki, T. and Umemura, K. (2010) Influences of different proton pump inhibitors on the anti-platelet function of clopidogrel in relation to CYP2C19 genotypes. British Journal of Clinical Pharmacology, 70, 383-392. doi:10.1111/j.1365-2125.2010.03717.x
[48]	European Medicines Agency (2010) Public statement on possible interaction between clopidogrel and proton pump inhibitors. http://www.ema.europa.eu/docs/en_GB/docment_library/Public_statement/2009/11/WC500014 409.pdf
[49]	Society for Cardiovascular Angiography and Interventions (2009) SCAI statement on “a national study of the effect of individual proton pump inhibitors on cardiovascular outcomes in patients treated with clopidogrel following coronary stenting”. http://www.scai.org/SecondsCount/News/Detail.aspx?cid= fd3f649b-ecaf-4401-bd29-ec74009db354
[50]	US Food and Drug Administration (2009) 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). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviers/DrugSafetyInforma tionforHeathcareProfessionals/ucm190787.htm
[51]	European Medicines Agency (2010) Interaction between clopidogrel and proton-pump inhibitors. http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2010/03/WC500076346.pdf
[52]	Abraham, N.S., Hlatky, M.A., Antman, E.M., et al. (2010) ACCF/ACG/AHA, 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. The American Journal of Gastroenterology, 105, 2533-2549. doi:10.1038/ajg.2010.445