Use of clopidogrel and proton pump inhibitors after a serious acute coronary event: Risk of coronary events and peptic ulcer bleeding

Summary

Some pharmacokinetic studies have reported that proton pump inhibitors (PPIs) reduce the activity of clopidogrel, but the results of studies assessing clinical outcomes in patients receiving both drugs are inconsistent. We have therefore carried out a population-based cohort study with nested case–control analysis, in order to evaluate changes in the risk of cardiovascular and peptic ulcer bleeding (PUB) events associated with PPI use in patients receiving clopidogrel. A total of 42,542 patients aged 50–84 years in 2000–2007 who survived an acute coronary event were identified in two UK-based primary care databases (The Health Improvement Network and the General Practice Research Database). Individuals were followed up to identify incident cases of non-fatal myocardial infarction/coronary death (n = 2,546) and PUB (n = 194). Controls were frequency matched to cases by age, sex and calendar year. Compared with PPI non-use, current continuous PPI use was not associated with a significant change in risk of non-fatal myocardial infarction/coronary death among current continuous users of clopidogrel monotherapy (relative risk [RR], 1.06; 95% confidence interval [95% CI], 0.47 to 2.36) or dual antiplatelet therapy (DAT; RR, 0.80; 95% CI, 0.47 to 1.37) who initiated their antiplatelet therapy shortly after their coronary event. Among patients prescribed DAT at the start date, the RR of PUB events associated with current PPI use initiated at the start date was 0.66 (95% CI, 0.27 to 1.60).

Keywords

Clopidogrel - proton pump inhibitors - drug interactions

• References

• 1 Becker RC, Meade TW, Berger PB. et al. The primary and secondary prevention of coronary artery disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th ed). Chest 2008; 133 (Suppl. 06) 776S-814S.
• 2 Patrono C, Andreotti F, Arnesen H. et al. Antiplatelet agents for the treatment and prevention of atherothrombosis. Eur Heart J 2011; 32: 2922-2932.
• 3 European Medicines Agency. Public statement on possible interaction between clopidogrel and proton pump inhibitors. Available at: http://www.emea.europa.eu/docs/en_GB/document_library/Public_statement/2009/11/WC500014409.pdf . Accessed March 11, 2013.
• 4 Food and Drug Administration. Early communication about an ongoing safety review of clopidogrel bisulfate (marketed as Plavix). Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm079520.htm . Accessed March 11, 2013
• 5 European Medicines Agency. Interaction between clopidogrel and proton-pump inhibitors. Available at: http://www.emea.europa.eu/docs/en_GB/document_library/Public_statement/2010/03/WC500076346.pdf . Accessed March 11, 2013.
• 6 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/ucm190787.htm . Accessed March 11, 2013.
• 7 Lima JP, Brophy JM. The potential interaction between clopidogrel and proton pump inhibitors: a systematic review. BMC Med 2010; 8: 81
• 8 Blume H, Donath F, Warnke A. et al. Pharmacokinetic drug interaction profiles of proton pump inhibitors. Drug Saf 2006; 29: 769-784.
• 9 Kwok CS, Loke YK. Meta-analysis: effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel. Aliment Pharmacol Ther 2010; 31: 810-823.
• 10 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 2011; 271: 257-263.
• 11 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.
• 12 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; 123: 474-482.
• 13 Tsai YW, Wen YW, Huang WF. et al. Cardiovascular and gastrointestinal events of three antiplatelet therapies: clopidogrel, clopidogrel plus proton-pump inhibitors, and aspirin plus proton-pump inhibitors in patients with previous gastrointestinal bleeding. J Gastroenterol 2011; 46: 39-45.
• 14 van Boxel OS, van Oijen MG, Hagenaars MP. et al. 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.
• 15 Schmidt M, Johansen MB, Robertson DJ. et al. Concomitant use of clopidogrel and proton pump inhibitors is not associated with major adverse cardiovascular events following coronary stent implantation. Aliment Pharmacol Ther 2012; 35: 165-174.
• 16 Douglas IJ, Evans SJ, Hingorani AD. et al. Clopidogrel and interaction with proton pump inhibitors: comparison between cohort and within person study designs. Br Med J 2012; 345: e4388
• 17 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.
• 18 Lewis JD, Schinnar R, Bilker WB. et al. Validation studies of the health improvement network (THIN) database for pharmacoepidemiology research. Pharmacoepidemiol Drug Saf 2007; 16: 393-401.
• 19 Herrett E, Thomas SL, Schoonen WM. et al. Validation and validity of diagnoses in the General Practice Research Database: a systematic review. Br J Clin Pharmacol 2010; 69: 4-14.
• 20 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.
• 21 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.
• 22 Blackburn DF, Lamb DA, McLeod MM. et al. Increased use of acid-suppressing drugs before the occurrence of ischemic events: a potential source of confounding in recent observational studies. Pharmacotherapy 2010; 30: 985-993.
• 23 Goodman SG, Clare R, Pieper KS. et al. Association of proton pump inhibitor use on cardiovascular outcomes with clopidogrel and ticagrelor: insights from the platelet inhibition and patient outcomes trial. Circulation 2012; 125: 978-986.
• 24 Scott SA, Sangkuhl K, Gardner EE. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther 2011; 90: 328-332.
• 25 Sorich MJ, Polasek TM, Wiese MD. Systematic review and meta-analysis of the association between cytochrome P450 2C19 genotype and bleeding. Thromb Haemost 2012; 108: 199-200.
• 26 Lanas A, García Rodríguez LA, Arroyo MT. et al. Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations. Gut 2006; 55: 1731-1738.
• 27 Ibáñez L, Vidal X, Vendrell L. et al. Upper gastrointestinal bleeding associated with antiplatelet drugs. Aliment Pharmacol Ther 2006; 23: 235-242.
• 28 Hallas J, Dall M, Andries A. et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case–control study. Br Med J 2006; 333: 726
• 29 García Rodríguez LA, Lin KJ, Hernández-Díaz S. et al. Risk of upper gastrointestinal bleeding with low-dose acetylsalicylic acid alone and in combination with clopidogrel and other medications. Circulation 2011; 123: 1108-1115.
• 30 Kwok CS, Nijjar RS, Loke YK. Effects of proton pump inhibitors on adverse gastrointestinal events in patients receiving clopidogrel: systematic review and meta-analysis. Drug Saf 2011; 34: 47-57.
• 31 García Rodriguez LA, Cea-Soriano L, Martin-Merino E. et al. Discontinuation of low dose aspirin and risk of myocardial infarction: case–control study in UK primary care. Br Med J 2011; 343: d4094
• 32 García Rodríguez LA, Cea Soriano L, Hill C. et al. Increased risk of stroke after discontinuation of acetylsalicylic acid: a UK primary care study. Neurology 2011; 76: 740-746.
• 33 Taneja AK, Collinson J, Flather MD. et al. Mortality following non-ST elevation acute coronary syndrome: 4 years follow-up of the PRAIS UK Registry (Prospective Registry of Acute Ischaemic Syndromes in the UK). Eur Heart J 2004; 25: 2013-2018.
• 34 Holmes Jr. DR, Kim LJ, Brooks MM. et al. The effect of coronary artery bypass grafting on specific causes of long-term mortality in the Bypass Angioplasty Revascularization Investigation. J Thorac Cardiovasc Surg 2007; 134: 38-46.
• 35 Yusuf S, Hawken S, Ounpuu S. et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case–control study. Lancet 2004; 364: 937-952.
• 36 Donaldson GC, Hurst JR, Smith CJ. et al. Increased risk of myocardial infarction and stroke following exacerbation of COPD. Chest 2010; 137: 1091-1097.
• 37 García Rodríguez LA, Tacconelli S, Patrignani P. Role of dose potency in the prediction of risk of myocardial infarction associated with nonsteroidal anti-inflammatory drugs in the general population. J Am Coll Cardiol 2008; 52: 1628-1636.
• 38 Abraham NS, Hlatky MA, Antman EM. 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. Circulation 2010; 122: 2619-2633.