Prognosis of concomitant users of clopidogrel and proton-pump inhibitors in a high-risk population for upper gastrointestinal bleeding

BMC Clinical Pharmacology

Yunxia Lu²  Jesper Lagergren¹  Rickard Ljung³  Qing Wang⁴ 

[1] Division of Cancer Studies, King’s College London, London, United Kingdom;Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom;Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden;Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden

关键词: Cardiovascular disease;    Gastrointestinal bleeding;    Proton-pump inhibitors;    Clopidogrel;   

Others  :  860339
DOI  :  10.1186/2050-6511-15-22

 received in 2013-08-02, accepted in 2014-03-25,  发布年份 2014

【 摘 要 】

Background

It is unclear whether concomitant use of clopidogrel and proton-pump inhibitors (PPIs) increases the risk of recurrence of cardiovascular disease or death in patients at high risk of upper gastrointestinal (GI) bleeding.

Methods

Based on the Swedish Patient Register, a cohort of cardiovascular disease (including acute myocardial infarction, stroke and angina, from 2006 to 2008) was selected from a population with any diagnosis of upper GI bleeding. Data on drug prescription was retrieved from the Prescribed Drug Register. Patients entered into the cohort after their first discharge for cardiovascular disease and were followed up to death, recurrence of cardiovascular disease, or 90 days. A Cox regression model was conducted and hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated to evaluate the risks among users of different drug prescriptions.

Results

Patients who were current users of only PPIs (HR 2.02, 95% CI 1.19-3.44), only clopidogrel (HR 1.14, 95% CI 0.53-2.45) and nonusers of both (HR 2.36, 95% CI 1.39-4.00) were at a higher risk of death compared with patients with a concomitant use. Results were similar among 1779 patients who had any history of upper GI bleeding (HR 2.05, 95% CI 1.18-3.54; HR 1.25, 95% CI 0.57-2.72; HR 2.30, 95% CI 1.33-3.98, respectively).

Conclusion

Among patients at high risk of upper GI bleeding, those with a concomitant use of PPIs and clopidogrel were at a decreased risk of mortality, and possibly also a decreased risk of recurrence of cardiovascular disease.

【 授权许可】

   
2014 Wang et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Terpening C: Clopidogrel: a pharmacogenomic perspective on its use in coronary artery disease. Clin Med Insights Cardiol 2010, 4:117-128. PubMed PMID: 21151850. Pubmed Central PMCID: 2998935. Epub 2010/12/15. eng
• [2]Tran H, Anand SS: Oral antiplatelet therapy in cerebrovascular disease, coronary artery disease, and peripheral arterial disease. JAMA 2004, 292(15):1867-1874. PubMed PMID: 15494585. Epub 2004/10/21. eng
• [3]Rogowski W, Burch J, Palmer S, Craigs C, Golder S, Woolacott N: The effect of different treatment durations of clopidogrel in patients with non-ST-segment elevation acute coronary syndromes: a systematic review and value of information analysis. Health Technol Assess 2009, 13(31):1-77. iii-iv, ix-xi, PubMed PMID: 19573471. Epub 2009/07/04. eng
• [4]Jackowski L, Stocks N, Rowett D: Reducing the risk of adverse thrombotic events - The role of aspirin and clopidogrel. Aust Fam Physician 2008, 37(9):721-723. 5–6. PubMed PMID: 18797530. Epub 2008/09/18. eng
• [5]Boparai V, Rajagopalan J, Triadafilopoulos G: Guide to the use of proton pump inhibitors in adult patients. Drugs 2008, 68(7):925-947. PubMed PMID: 18457460. Epub 2008/05/07. eng
• [6]Madanick RD: Proton pump inhibitor side effects and drug interactions: much ado about nothing? Cleve Clin J Med 2011, 78(1):39-49. PubMed PMID: 21199906. Epub 2011/01/05. eng
• [7]Furuta T: Risk and benefit of proton pump inhibitor for patients undergoing anti-platelet therapy including clopidogrel. Intern Med 2009, 48(21):1847-1848. PubMed PMID: 19881232. Epub 2009/11/03. eng
• [8]Moayyedi P, Sadowski DC: Proton pump inhibitors and clopidogrel - hazardous drug interaction or hazardous interpretation of data? Can J Gastroenterol 2009, 23(4):251-252. PubMed PMID: 19373416. Pubmed Central PMCID: 2711671. Epub 2009/04/18. eng
• [9]Barrison AF, Jarboe LA, Weinberg BM, Nimmagadda K, Sullivan LM, Wolfe MM: Patterns of proton pump inhibitor use in clinical practice. Am J Med Genet 2001, 111(6):469-473. PubMed PMID: 11690573
• [10]Huang CC, Chen YC, Leu HB, Chen TJ, Lin SJ, Chan WL, Chen JW: Risk of adverse outcomes in Taiwan associated with concomitant use of clopidogrel and proton pump inhibitors in patients who received percutaneous coronary intervention. Am J Cardiol 2010, 105(12):1705-1709. PubMed PMID: 20538118. Epub 2010/06/12. eng
• [11]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 2009, 55(7):1964-1968. PubMed PMID: 19731021. Epub 2009/09/05. eng
• [12]Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Peterson ED, Rumsfeld JS: Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009, 301(9):937-944. PubMed PMID: 19258584. Epub 2009/03/05. eng
• [13]Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp A, Mamdami MM: A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 2009, 180(7):713-718. PubMed PMID: 19176635. Pubmed Central PMCID: 2659819. Epub 2009/01/30. eng
• [14]Stockl KM, Le L, Zakharyan A, Harada AS, Solow BK, Addiego JE, Ramsey S: Risk of rehospitalization for patients using clopidogrel with a proton pump inhibitor. Arch Intern Med 2010, 170(8):704-710. PubMed PMID: 20421557. Epub 2010/04/28. eng
• [15]Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, Mansourati J, Mottier D, Abgrall JF, Boschat J: 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(3):256-260. PubMed PMID: 18206732. Epub 2008/01/22. eng
• [16]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(12):1038-1039. author reply 9. PubMed PMID: 18786491. Epub 2008/09/13. eng
• [17]Bhatt DL, Cryer BL, Contant CF, Cohen M, Lanas A, Schnitzer TJ, Shook TL, Lapuerta P, Goldsmith MA, Laine L, Scirica BM, Murphy SA, Cannon CP, COGENT Investigators: Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010, 363(20):1909-1917. PubMed PMID: 20925534. Epub 2010/10/12. Eng
• [18]O'Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y, Rozenman Y, Michelson AD, Hautvast RW, Ver Lee PN, Close SL, Shen L, Mega JL, Sabatine MS, Wiviott SD: 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(9694):PubMed PMID: 19726078-PubMed PMID: 19726997. PubMed PMID: 19726078
• [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(23):2322-2329. PubMed PMID: 19933932. Pubmed Central PMCID: 2818789. Epub 2009/11/26. eng
• [20]Ray WA, Murray KT, Griffin MR, Chung CP, Smalley WE, Hall K, Hall K, Daugherty JR, Kaltenbach LA, Stein CM: Outcomes with concurrent use of clopidogrel and proton-pump inhibitors: a cohort study. Ann Intern Med 2010, 152(6):337-345. PubMed PMID: 20231564. Pubmed Central PMCID: 3176584
• [21]Administration. UFaD: 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). U.S. Department of Health and Human Services; 11/17/2009. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm190787.htm webcite
• [22]Juhasz M, Herszenyi L, Tulassay Z: Current standings of the proton pump inhibitor and clopidogrel co-therapy: review on an evolving field with the eyes of the gastroenterologist. Digestion 2010, 81(1):10-15. PubMed PMID: 20029203. Epub 2009/12/24. eng
• [23]Tsai YW, Wen YW, Huang WF, Chen PF, Kuo KN, Hsiao FY: 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(1):39-45. PubMed PMID: 20811753
• [24]Hsu PI, Lai KH, Liu CP: Esomeprazole with clopidogrel reduces peptic ulcer recurrence, compared with clopidogrel alone, in patients with atherosclerosis. Gastroenterology 2011, 140(3):791-798. PubMed PMID: 21144850
• [25]Gaglia MA Jr, Torguson R, Hanna N, Gonzalez MA, Collins SD, Syed AI, Syed AI, Ben-Dor I, Maluenda G, Delhaye C, Wakabayashi K, Xue Z, Suddath WO, Kent KM, Satler LF, Pichard AD, Waksman R: Relation of proton pump inhibitor use after percutaneous coronary intervention with drug-eluting stents to outcomes. Am J Cardiol 2010, 105(6):833-888. PubMed PMID: 20211327
• [26]Hsiao FY, Mullins CD, Wen YW, Huang WF, Chen PF, Tsai YW: Relationship between cardiovascular outcomes and proton pump inhibitor use in patients receiving dual antiplatelet therapy after acute coronary syndrome. Pharmacoepidemiol Drug Saf 2011, 20(10):1043-1049. PubMed PMID: 21823195
• [27]Ahsberg K, Hoglund P, Stael von Holstein C: Mortality from peptic ulcer bleeding: the impact of comorbidity and the use of drugs that promote bleeding. Aliment Pharmacol Therapeut Symp 2010, 32(6):801-810. PubMed PMID: 20653635
• [28]Jepsen P, Vilstrup H, Lash TL: Development and Validation of a Comorbidity Scoring System for Patients With Cirrhosis. Gastroenterology 2014, 146(1):147-156. quiz e15-6. doi: 10.1053/j.gastro.2013.09.019. Epub 2013 Sep 18. PubMed PMID: 24055278
• [29]Bratanic A, Puljiz Z, Ljubicicz N, Caric T, Jelicic I, Puljiz M, Puljiz M, Perko Z: Predictive factors of rebleeding and mortality following endoscopic hemostasis in bleeding peptic ulcers. Hepatogastroenterology 2013, 60(121):112-117. PubMed PMID: 22709912
• [30]Lau JY, Barkun A, Fan DM, Kuipers EJ, Yang YS, Chan FK: Challenges in the management of acute peptic ulcer bleeding. Lancet 2013, 381(9882):2033-2043. PubMed PMID: 23746903
• [31]Kwok CS, Jeevanantham V, Dawn B, Loke YK: No consistent evidence of differential cardiovascular risk amongst proton-pump inhibitors when used with clopidogrel: meta-analysis. Int J Cardiol 2013, 167(3):965-974. PubMed PMID: 22464478
• [32]Focks JJ, Brouwer MA, van Oijen MG, Lanas A, Bhatt DL, Verheugt FW: Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome- a systematic review. Heart 2013, 99(8):520-527. PubMed PMID: 22851683
• [33]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 2010, 34(1):47-57. PubMed PMID: 21047145. Epub 2010/11/05. eng
• [34]Hulot JS, Collet JP, Silvain J, Pena A, Bellemain-Appaix A, Barthelemy O, Cayla G, Beygui F, Montalescot G: Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol 2010, 56(2):134-143. PubMed PMID: 20620727
• [35]Kwok CS, Loke YK: Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel. Aliment Pharmacol Therapeut Symp 2010, 31(8):810-823. PubMed PMID: 20102352
• [36]Siller-Matula JM, Jilma B, Schror K, Christ G, Huber K: Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel: a systematic review and meta-analysis. J Thromb Haemostasis 2010, 8(12):2624-2641. PubMed PMID: 20831618
• [37]Siller-Matula JM, Spiel AO, Lang IM, Kreiner G, Christ G, Christ G, Jilma B: Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel. Am Heart J 2009, 157(1):148 e1-5. PubMed PMID: 19081411. Epub 2008/12/17. eng
• [38]Bhurke SM, Martin BC, Li C, Franks AM, Bursac Z, Said Q: Effect of the clopidogrel-proton pump inhibitor drug interaction on adverse cardiovascular events in patients with acute coronary syndrome. Pharmacotherapy 2012, 32(9):809-818. PubMed PMID: 22744772. Pubmed Central PMCID: 3531962
• [39]Leontiadis GI, Howden CW: PPI co-therapy did not adversely affect outcomes in clopidogrel users. Aliment Pharmacol Therapeut Symp 2012, 35(2):313-314. PubMed PMID: 22172084
• [40]Schmidt M, Johansen MB, Robertson DJ, Maeng M, Kaltoft A, Jensen LO, Tilsted HH, Bøtker HE, Sørensen HT, Baron JA: Concomitant use of clopidogrel and proton pump inhibitors is not associated with major adverse cardiovascular events following coronary stent implantation. Alimentary pharmacology & therapeutics 2012, 35(1):165-174. PubMed PMID: 22050009
• [41]Valkhoff VE, t Jong GW, Van Soest EM, Kuipers EJ, Sturkenboom MC: Risk of recurrent myocardial infarction with the concomitant use of clopidogrel and proton pump inhibitors. Aliment Pharmacol Therapeut Symp 2011, 33(1):77-88. PubMed PMID: 21083580