Skip to main content

Advertisement

SpringerLink
Log in

Outcomes of a multi-ethnic Asian population on combined treatment with clopidogrel and omeprazole in 12,440 patients

  • Published:
Journal of Thrombosis and Thrombolysis Aims and scope Submit manuscript

Abstract

Omeprazole is commonly co-prescribed with clopidogrel. Clopidogrel requires bio-activation by cytochrome P450 CYP2C19. Omeprazole may reduce clopidogrel’s antithrombotic efficacy by inhibiting CYP2C19. Studies in Caucasians receiving omeprazole with clopidogrel showed no significant increase in death and myocardial infarction with this drug–drug interaction. There are limited large-scale studies in Asians, who may have a greater prevalence of CYP2C19 loss-of-function polymorphisms. A single centre retrospective cohort study was undertaken based on a review of medication records and prescription data. Patients prescribed clopidogrel from 2009 to 2012 were followed-up with until December 2012 (median:29 months). The primary outcome was all-cause mortality and secondary outcomes were myocardial infarction (MI), cerebrovascular accidents, and subsequent coronary interventions. Of 12,440 patients prescribed clopidogrel, 62%(n = 7714) were on omeprazole (63.8% Chinese, 13.9% Malay, 12.4% Indian, 10.0% others), and 38%(n = 4726) were not on omeprazole or other proton pump inhibitors (62.6% Chinese, 13.5% Malay, 10.7% Indian, 13.2% others). Mortality after co-prescription occurred in 14.3%(n = 1101) of patients, compared to 6.3%(n = 300) of patients prescribed clopidogrel only. Multivariate analysis using propensity score adjusted analysis showed no significant increase in all-cause mortality with co-prescription (adjusted hazards ratio [AHR] 1.13, [95%CI 0.95–1.35]). Patients on co-prescription had a higher risk of subsequent MI (16% vs 3.8%; AHR 2.03 [95%CI 1.70–2.44]), but not of cerebrovascular accidents (5.0% vs 2.0%; AHR 0.98 [95%CI 0.76–1.27]) or coronary interventions (1.7% vs 0.7%; AHR 1.28 [95%CI 0.83–1.96]). The risk of a subsequent MI was higher in the Malay (AHR 2.43 [95%CI 1.68–3.52]) and Chinese (AHR 2.06 [95%CI 1.63–2.60]) population as compared to the Indian (AHR 1.56 [95%CI 1.06–2.31]) population. In conclusion, the use of clopidogrel with omeprazole is associated with an increased risk of MI, but not mortality or stroke, in this multi-ethnic Asian population. These risks appear to vary among different ethnic groups.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, Wang C, Li H, Meng X, Cui L, Jia J, Dong Q, Xu A, Zeng J, Li Y, Wang Z, Xia H, Johnston SC (2013) Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 369:11–19

    Article  CAS  Google Scholar 

  2. CAPRIE Steering Committee (1996) A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet (London, England), 348(9038):1329–1339

  3. Moukarbel GV, Signorovitch JE, Pfeffer MA, McMurray JJ, White HD, Maggioni AP, Velazquez EJ, Califf RM, Scheiman JM, Solomon SD (2009) Gastrointestinal bleeding in high risk survivors of myocardial infarction: the VALIANT Trial. Eur Heart J 30:2226–2232

    Article  Google Scholar 

  4. Yeomans N, Lanas A, Labenz J, van Zanten SV, van Rensburg C, Racz I, Tchernev K, Karamanolis D, Roda E, Hawkey C, Naucler E, Svedberg LE (2008) Efficacy of esomeprazole (20 mg once daily) for reducing the risk of gastroduodenal ulcers associated with continuous use of low-dose aspirin. Am J Gastroenterol 103:2465–2473

    Article  CAS  Google Scholar 

  5. Melloni C, Washam JB, Jones WS, Halim SA, Hasselblad V, Mayer SB, Heidenfelder BL, Dolor RJ (2015) Conflicting results between randomized trials and observational studies on the impact of proton pump inhibitors on cardiovascular events when coadministered with dual antiplatelet therapy: systematic review. Circ Cardiovasc Qual Outcomes 8:47–55

    Article  Google Scholar 

  6. Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, Mansourati J, Mottier D, Abgrall JF, Boschat J (2008) 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 51:256–260

    Article  CAS  Google Scholar 

  7. Savi P, Combalbert J, Gaich C, Rouchon MC, Maffrand JP, Berger Y, Herbert JM (1994) The antiaggregating activity of clopidogrel is due to a metabolic activation by the hepatic cytochrome P450–1A. Thromb Haemost 72:313–317

    Article  CAS  Google Scholar 

  8. Tantry US, Kereiakes DJ, Gurbel PA (2011) Clopidogrel and proton pump inhibitors: influence of pharmacological interactions on clinical outcomes and mechanistic explanations. JACC Cardiovasc Interv 4:365–380

    Article  Google Scholar 

  9. Ibeanu GC, Ghanayem BI, Linko P, Li L, Pederson LG, Goldstein JA (1996) Identification of residues 99, 220, and 221 of human cytochrome P450 2C19 as key determinants of omeprazole activity. J Biol Chem 271:12496–12501

    Article  CAS  Google Scholar 

  10. U.S. Food & Drug Administration (2010) Information on Clopidogrel Bisulfate (marketed as Plavix). http://Wayback.Archive-It.Org/7993/20170111075953/Http:/Www.Fda.Gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/Ucm190836.Htm

  11. Stockl KM, Le L, Zakharyan A, Harada AS, Solow BK, Addiego JE, Ramsey S (2010) Risk of rehospitalization for patients using clopidogrel with a proton pump inhibitor. Arch Intern Med 170:704–710

    Article  CAS  Google Scholar 

  12. Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Rumsfeld JS (2009) Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 301:937–944

    Article  CAS  Google Scholar 

  13. 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 (2010) Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 363:1909–1917

    Article  CAS  Google Scholar 

  14. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Meneveau N, Steg PG, Ferrieres J, Danchin N, Becquemont L (2009) Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 360:363–375

    Article  CAS  Google Scholar 

  15. Shuldiner AR, O’Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA (2009) Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 302:849–857

    Article  CAS  Google Scholar 

  16. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS (2009) Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 360:354–362

    Article  CAS  Google Scholar 

  17. Chan MY, Tan K, Tan HC, Huan PT, Li B, Phua QH, Lee HK, Lee CH, Low A, Becker RC, Ong WC, Richards MA, Salim A, Tai ES, Koay E (2012) CYP2C19 and PON1 polymorphisms regulating clopidogrel bioactivation in Chinese, Malay and Indian subjects. Pharmacogenomics 13:533–542

    Article  CAS  Google Scholar 

  18. Ishizaki T, Sohn DR, Kobayashi K, Chiba K, Lee KH, Shin SG, Andersson T, Regardh CG, Lou YC, Zhang Y et al (1994) Interethnic differences in omeprazole metabolism in the two S-mephenytoin hydroxylation phenotypes studied in Caucasians and Orientals. Ther Drug Monit 16:214–215

    Article  CAS  Google Scholar 

  19. Chan MY, Shah BR, Gao F, Sim LL, Chua T, Tan HC, Yeo TC, Ong HY, Foo D, Goh PP, Surrun SK, Pieper KS, Granger CB, Koh TH, Salim A, Tai ES (2011) Recalibration of the Global Registry of Acute Coronary Events risk score in a multiethnic Asian population. Am Heart J 162:291–299

    Article  Google Scholar 

  20. de Carvalho LP, Gao F, Chen Q, Hartman M, Sim LL, Koh TH, Foo D, Chin CT, Ong HY, Tong KL, Tan HC, Yeo TC, Yew CK, Richards AM, Peterson ED, Chua T, Chan MY (2014) Differences in late cardiovascular mortality following acute myocardial infarction in three major Asian ethnic groups. Eur Heart J Acute Cardiovasc Care 3:354–362

    Article  Google Scholar 

  21. Hughes K, Lun KC, Yeo PP (1990) Cardiovascular diseases in Chinese, Malays, and Indians in Singapore. I. Differences in mortality. J Epidemiol Community Health 44:24–28

    Article  CAS  Google Scholar 

  22. Global Mobility Laboratory (2021) The Care Quest Platform. https://www.globalmobility.net/index.php/carequest/

  23. Austin PC, Stuart EA (2015) Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. Stat Med 34(28):3661–3679

    Article  Google Scholar 

  24. Chi NF, Wen CP, Liu CH, Li JY, Jeng JS, Chen CH, Lien LM, Lin CH, Sun Y, Chang WL, Hu CJ, Hsu Chung Y (2018) Comparison between aspirin and clopidogrel in secondary stroke prevention based on real-world data. J Am Heart Assoc 7:e009856

    Article  Google Scholar 

  25. Worldometer (2017) Asia Population. https://www.worldometers.info/world-population/asia-population/

  26. Shah NH, LePendu P, Bauer-Mehren A, Ghebremariam YT, Iyer SV, Marcus J, Nead KT, Cooke JP, Leeper NJ (2015) Proton pump inhibitor usage and the risk of myocardial infarction in the general population. PLoS ONE 10:e0124653

    Article  Google Scholar 

  27. Luo HR, Poland RE, Lin KM, Wan YJ (2006) Genetic polymorphism of cytochrome P450 2C19 in Mexican Americans: a cross-ethnic comparative study. Clin Pharmacol Ther 80:33–40

    Article  CAS  Google Scholar 

  28. Man M, Farmen M, Dumaual C, Teng CH, Moser B, Irie S, Noh GJ, Njau R, Close S, Wise S, Hockett R (2010) Genetic variation in metabolizing enzyme and transporter genes: comprehensive assessment in 3 major East Asian subpopulations with comparison to Caucasians and Africans. J Clin Pharmacol 50:929–940

    Article  CAS  Google Scholar 

  29. Wedemeyer RS, Blume H (2014) Pharmacokinetic drug interaction profiles of proton pump inhibitors: an update. Drug Saf 37:201–211

    Article  CAS  Google Scholar 

  30. Chan MY (2012) Clopidogrel pharmacogenetics of east, south and other Asian populations. Eur Heart J Suppl 14:A41–A42

    Article  CAS  Google Scholar 

  31. Chan MY TK, Phua QH, Tan HC, Richards AR, Huan PT, Koay E (2011) Differential prevalence and pharmacodynamic impact of cyp2c19 polymorphisms in 3 major Asian ethnicities. In: Presented at the XXIII International Society of Thrombosis and Haemostasis. Abstract number P-TU-092

  32. Goldstein JA, Ishizaki T, Chiba K, de Morais SM, Bell D, Krahn PM, Evans DA (1997) Frequencies of the defective CYP2C19 alleles responsible for the mephenytoin poor metabolizer phenotype in various Oriental, Caucasian, Saudi Arabian and American black populations. Pharmacogenetics 7:59–64

    Article  CAS  Google Scholar 

  33. Kwan J, Htun WW, Huang Y, Ko W, Kwan TW (2011) Effect of proton pump inhibitors on platelet inhibition activity of clopidogrel in Chinese patients with percutaneous coronary intervention. Vasc Health Risk Manag 7:399–404

    Article  CAS  Google Scholar 

  34. Zou D, Goh KL (2017) East Asian perspective on the interaction between proton pump inhibitors and clopidogrel. J Gastroenterol Hepatol 32:1152–1159

    Article  Google Scholar 

  35. Kivisild T, Bamshad MJ, Kaldma K, Metspalu M, Metspalu E, Reidla M, Laos S, Parik J, Watkins WS, Dixon ME (1999) Deep common ancestry of Indian and western-Eurasian mitochondrial DNA lineages. Curr Biol 9:1331–1334

    Article  CAS  Google Scholar 

  36. Southworth MR, Temple R (2010) Interaction of clopidogrel and omeprazole. N Engl J Med 363:1977

    Article  Google Scholar 

  37. European Medicines Agency (2010) Public statement on interaction between clopidogrel and proton-pump inhibitors. https://www.ema.europa.eu/en/news/public-statement-interaction-between-clopidogrel-proton-pump-inhibitors

  38. Clopidogrel and proton pump inhibitors: interaction—updated advice (2010) Gov.UK. https://www.gov.uk/drug-safety-update/clopidogrel-and-proton-pump-inhibitors-interaction-updated-advice

  39. Levine GN, Bates ER, Bittl JA, Brindis RG, Fihn SD, Fleisher LA, Granger CB, Lange RA, Mack MJ, Mauri L, Mehran R, Mukherjee D, Newby LK, O’Gara PT, Sabatine MS, Smith PK, Smith SC Jr, Halperin JL, Al-Khatib SM, Birtcher KK, Bozkurt B, Cigarroa JE, Curtis LH, Gentile F, Gidding S, Hlatky MA, Ikonomidis JS, Joglar JA, Pressler SJ, Wijeysundera DN (2016) 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Thorac Cardiovasc Surg 152:1243–1275

    Article  Google Scholar 

  40. Yan Y, Wang X, Fan JY et al (2016) Impact of concomitant use of proton pump inhibitors and clopidogrel or ticagrelor on clinical outcomes in patients with acute coronary syndrome. J Geriatr Cardiol 13(3):209–217

    PubMed  PubMed Central  Google Scholar 

Download references

Funding

Mark Y. Chan is a recipient of the National Medical Research Council, Singapore Clinician Scientist Award (NMRC/CSA-INV/0006/2016). This work was funded by the National University Heart Centre, Singapore, Singapore Cardiac Databank, National Heart Centre, Singapore and National Registry of Disease Office (Singapore Myocardial Infarct Registry).

Author information

Author notes

  1. Mark D. Muthiah, Huili Zheng and Nicholas W. S. Chew have contributed equally as first authors.

  2. James W. L. Yip and Mark Y. Chan have supervised the work equally at senior authors.

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, National University Hospital, Singapore, Singapore

    Mark D. Muthiah, Lee Guan Lim, Yock-Young Dan & K. Y. Ho

  2. National Registry of Disease Office, Health Promotion Board, Singapore, Singapore

    Huili Zheng & Ling-li Foo

  3. National University Heart Centre, National University of Singapore, Singapore, Singapore

    Nicholas W. S. Chew, Huay-Cheem Tan, Chi-Hang Lee, Adrian F. Low, A. Mark Richards, James W. L. Yip & Mark Y. Chan

  4. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Mark D. Muthiah, Jieling Xiao, Huay-Cheem Tan, Chi-Hang Lee, Adrian F. Low, A. Mark Richards, Yock-Young Dan, K. Y. Ho, James W. L. Yip & Mark Y. Chan

Authors
  1. Mark D. Muthiah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Huili Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicholas W. S. Chew
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jieling Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lee Guan Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Huay-Cheem Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chi-Hang Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Adrian F. Low
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ling-li Foo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A. Mark Richards
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yock-Young Dan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. K. Y. Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. James W. L. Yip
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Mark Y. Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark D. Muthiah.

Ethics declarations

Conflict of interest

Mark Y. Chan receives grants and honoraria from Bayer, Astra-Zeneca and Eli-Lilly. All other authors declare that they have on conflicts of interest related to this work.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards with a waiver of written informed consent granted by the National Healthcare Group Domain Specific Research Board (Domain C).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Muthiah, M.D., Zheng, H., Chew, N.W.S. et al. Outcomes of a multi-ethnic Asian population on combined treatment with clopidogrel and omeprazole in 12,440 patients. J Thromb Thrombolysis 52, 925–933 (2021). https://doi.org/10.1007/s11239-021-02472-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11239-021-02472-w

Keywords

Search

Navigation