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drug interaction(s) of clopidogrel with proton pump inhibitors

Drug interactions: - proton pump inhibitors may diminish the risk of upper GI bleeding in patients on clopidogrel [16,17] - proton pump inhibitors may diminish antiplatelet effect of clopidogrel [7,8] by inhibiting CYP2C19*, thus inhibiting activation of clopidogrel: - rank order of interaction: - omeprazole > rabeprazole, pantoprazole, lansoprazole; - prasugrel may have less interaction with PPIs [6] - increase risk of adverse outcomes with concurrent use of clopidogrel & proton pump inhibitors following acute coronary syndrome, PCI & coronary stenting (relative to clopidodrel alone) - if an interaction exists, it is unlikely to raise cardiovascular risks by >20% [9] - combination doubles risk of rehospitalization for myocardial infarction or coronary stent placement (after hospitalization for either) [11] - omeprazole does not increase in risk of cardiovascular events in patients taking both aspirin & clopidogrel [12] - risk of adverse cardiovascular events increased with proton pump inhibitor alone; additionally, proton pump inhibitor appears to diminish effectiveness of clopidogrel [13] - interaction of clopidogrel with proton pump inhibitors "clinically unimportant" [19] - proton pump inhibitors do not increase risk for adverse cardiovascular events among patients taking clopidogrel [20,22] * CYP2C19*2 & CYP2C19*3 alleles have no functional metabolism of clopidogrel - these two alleles account for most of the reduced function alleles in patients of Caucasian (85%) & Asian (99%) descent classified as poor metabolizers - see clopidogrel Pharmacokinetics: Management: - proton pump inhibitors are recommended for patients on antiplatelet agents who are at high risk of GI bleed [14,15] - consider use histaminergic blocker [3] a) ranitidine b) famotidine c) cimetidine interacts with clopidogrel by inhibiting CYP2C19 [15]

Properties

DRUGS: clopidogrel proton pump inhibitor

References

  1. Prescriber's Letter 15(11): 2008 Do Proton Pump Inhibitors Decrease Clopidogrel (Plavix) Activity? Detail-Document#: 241114 (subscription needed) http://www.prescribersletter.com
  2. Ho PM et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009 Mar 4; 301:937. PMID: 19258584
  3. Society for Cardiovascular Angiography and Interventions (SCAI) 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: The Clopidogrel Medco Outcomes Study' http://www.scai.org/drlt1.aspx?PAGE_ID=5870
  4. Gilard M et al, Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: The randomized, double- blind OCLA (Omeprazole, CLopidogrel, Aspirin) study. J Am Coll Cardiol 2008, 51:256 PMID: 18206732 - Gurbel PA et al, Omeprazole: A possible new candidate influencing antiplatelet effect of clopidogrel. J Am Coll Cardiol 2008, 51:261 PMID: 18206733
  5. Prescriber's Letter 16(7): 2009 Proton Pump Inhibitor and Plavix Interaction: An Update Detail-Document#: 250706 (subscription needed) http://www.prescribersletter.com
  6. O'Donoghue ML 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 Sep 19; 374:989. PMID: 19726078
  7. Prescriber's Letter 16(11): 2009 Proton Pump Inhibitor and Plavix Interaction: An Update Detail-Document#: 251107 (subscription needed) http://www.prescribersletter.com
  8. FDA MedWatch, Posted 11/17/2009 Clopidogrel (marketed as Plavix) and Omeprazole (marketed as Prilosec) - Drug Interaction http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm190848.htm
  9. Rassen JA et al. Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation 2009 Dec 8; 120:2322. PMID: 19933932 - Juurlink DN. Proton pump inhibitors and clopidogrel: Putting the interaction in perspective. Circulation 2009 Dec 8; 120:2310. PMID: 19933929
  10. Ray WA et al. Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: A cohort study. Ann Intern Med 2010 Mar 16; 152:337 PMID: 20231564
  11. Stockl KM et al, Risk of Rehospitalization for Patients Using Clopidogrel With a Proton Pump Inhibitor Arch Intern Med. 2010;170(8):704-710. PMID: 20421557 http://archinte.ama-assn.org/cgi/content/short/170/8/704
  12. Bhatt DL et al, Clopidogrel with or without Omeprazole in Coronary Artery Disease N Engl J Med October 6, 2010 PMID: 20925534 http://www.nejm.org/doi/full/10.1056/NEJMoa1007964
  13. Charlot M et al. Proton-pump inhibitors are associated with increased cardiovascular risk independent of clopidogrel use: A nationwide cohort study. Ann Intern Med 2010 Sep 21; 153:378. PMID: 20855802 http://www.annals.org/content/153/6/378.abstract - de Aquino Lima JP and Brophy JM. Conflicting evidence: What's a clinician to do? Ann Intern Med 2010 Sep 21; 153:413. PMID: 20855806 http://www.annals.org/content/153/6/413.extract
  14. Abraham NS et al for the American College of Cardiology Foundation Task Force on Expert Consensus Documents, EXPERT CONSENSUS DOCUMENT 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 J Am Coll Cardiol 2010 Dec 7; 56:2051. PMID: 21126648 http://content.onlinejacc.org/cgi/content/full/j.jacc.2010.09.010
  15. Prescriber's Letter 18(1): 2011 Proton Pump Inhibitor and Plavix Interaction: An Update Detail-Document#: 270110 (subscription needed) http://www.prescribersletter.com
  16. Prescriber's Letter 15(21): 2008 Reducing the Risk for GI Bleeding with Antiplatelet Drugs Detail-Document#: 241205 (subscription needed) http://www.prescribersletter.com
  17. Hsu P-I et al. Esomeprazole with clopidogrel reduces peptic ulcer recurrence, compared with clopidogrel alone, in patients with atherosclerosis. Gastroenterology 2011 Mar; 140:791. PMID: 21144850
  18. Prescriber's Letter 19(1): 2012 Proton Pump Inhibitor and Plavix Interaction: An Update Detail-Document#: 280108 (subscription needed) http://www.prescribersletter.com
  19. Douglas IJ et al Clopidogrel and interaction with proton pump inhibitors: comparison between cohort and within person study designs. BMJ 2012;345:e4388 PMID: 22782731 http://www.bmj.com/content/345/bmj.e4388 - Targownik LE Prescribing proton pump inhibitors with clopidogrel BMJ 2012;345:e4558 PMID: 22782732 http://www.bmj.com/content/345/bmj.e4558
  20. Katz PO, Gerson LB, Vela MF. Guidelines for the Diagnosis and Management of Gastroeophageal Reflux Disease. Am J Gastroenterol. 2012 108:308-328 PMID: 23419381 http://gi.org/wp-content/uploads/2013/03/ACG_Guideline_GERD_March_2013.pdf
  21. Mistry SD, Trivedi HR, Parmar DM, Dalvi PS, Jiyo C. Impact of proton pump inhibitors on efficacy of clopidogrel: Review of evidence. Indian J Pharmacol. 2011 Apr;43(2):183-6. PMID: 21572655
  22. Cardoso RN et al. Incidence of cardiovascular events and gastrointestinal bleeding in patients receiving clopidogrel with and without proton pump inhibitors: An updated meta-analysis. Open Heart 2015; 2:e000248 PMID: 26196021 http://openheart.bmj.com/content/2/1/e000248
  23. Burkard T, Kaiser CA, Brunner-La Rocca H et al Combined clopidogrel and proton pump inhibitor therapy is associated with higher cardiovascular event rates after percutaneous coronary intervention: a report from the BASKET trial. J Intern Med. 2012 Mar;271(3):257-63. PMID: 21726302 Free Article
  24. Gerson LB. Proton pump inhibitors and potential interactions with clopidogrel: an update. Curr Gastroenterol Rep. 2013 Jun;15(6):329. Review. PMID: 23695547 - Gerson LB, McMahon D, Olkin I, Stave C, Rockson SG. Lack of significant interactions between clopidogrel and proton pump inhibitor therapy: meta-analysis of existing literature. Dig Dis Sci. 2012 May;57(5):1304-13. PMID: 22198703
  25. Simon T, Steg PG, Gilard M et al 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: results from the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) registry. Circulation. 2011 Feb 8;123(5):474-82. PMID: 21262992 Free Article