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Risk of major adverse cardiovascular events for concomitant use of clopidogrel and proton pump inhibitors in patients inheriting CYP2C19 loss-of-function alleles: meta-analysis

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Abstract

Background Efficacy of clopidogrel may be diminished due to either co-administration of proton pump inhibitors or carrying CYP2C19 loss-of-function alleles. However, patients may be at greater risk of major adverse cardiovascular events if taking clopidogrel together with proton pump inhibitors and also inherited the CYP2C19 loss-of-function alleles which may cause further reduction of clopidogrel efficacy. This is due to the cumulative effects of drug-drug interactions and drug-gene interactions collectively referred to as multifactorial drug-gene interactions. Aim of the review The aim of this analysis was to estimate aggregated risk of major adverse cardiovascular events for either coronary heart disease or stroke patients with multifactorial drug-gene interactions versus clopidogrel alone with or without drug-gene interactions. Methods Literatures were searched using different resources based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analysis was performed using RevMan software following either fixed/random effects model based on the levels of heterogeneity. A p value < 0.05 (2-sided) was considered statistically significant. Results In total, five studies consisting 8,802 patients of coronary artery diseases or stroke were included in this meta-analysis in which 3,767 were prescribed clopidogrel alone, 1,931 were concomitantly taking clopidogrel and PPIs, 2,146 were carrying CYP2C19 loss-of-function alleles and 958 were taking both clopidogrel and proton pump inhibitors while also carrying CYP2C19 loss-of-function alleles. It was found that patients with multifactorial drug-gene interactions were associated with significantly increased risk of major adverse cardiovascular events compared to those taking clopidogrel alone without CYP2C19 loss-of-function alleles (12% vs. 5.8%; RR 1.73; 95% CI 1.12–2.67; p = 0.01). Patients with multifactorial drug-gene interactions were also associated with significantly increased risk of major adverse cardiovascular events compared to drug-gene interactions (RR 1.63; 95% CI 1.31–2.03; p < 0.0001). Patients taking clopidogrel with proton pump inhibitors were also associated with 35% significantly increased risk of major adverse cardiovascular events compared to those taking only clopidogrel (RR 1.35; 95% CI 1.11–1.65; p = 0.003). Conclusion Patients inheriting CYP2C19 loss-of-function alleles have significantly increased risk of major adverse cardiovascular events when taking clopidogrel and proton pump inhibitors concurrently.

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References

  1. Zhang Q, Wang C, Zheng M, Li Y, Li J, Zhang L, et al. Aspirin plus clopidogrel as secondary prevention after stroke or transient ischemic attack: a systematic review and meta-analysis. Cerebrovasc Dis. 2015;3:13–22.

    Article  Google Scholar 

  2. Scott SA, Sangkuhl K, Stein CM, Hulot JS, Mega JL, Roden DM, et al. Clinical pharmacogenetics implementation consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013;94:317–23.

    Article  CAS  Google Scholar 

  3. Damman P, Woudstra P, Kuijt WJ, De Winter RJ, James SK. P2Y12 platelet inhibition in clinical practice. J Thromb Thrombolysis. 2012;4:143–53.

    Article  Google Scholar 

  4. Gong IY, Crown N, Suen CM, Schwarz UI, Dresser GK, Knauer MJ, et al. Clarifying the importance of CYP2C19 and PON1 in the mechanism of clopidogrel bioactivation and in vivo antiplatelet response. Eur Heart J. 2012;33:2856–64.

    Article  CAS  Google Scholar 

  5. Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, et al. Identification of the human cytochrome P450 enzymes involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. Drug Metab Dispos. 2010;38:92–9.

    Article  CAS  Google Scholar 

  6. Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ, Clark CB, 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. Circulation. 2010;122:2619–33.

    Article  Google Scholar 

  7. Labos C, Dasgupta K, Nedjar H, Turecki G, Rahme E. Risk of bleeding associated with combined use of selective serotonin reuptake inhibitors and antiplatelet therapy following acute myocardial infarction. CMAJ. 2011;183:1835–43.

    Article  Google Scholar 

  8. Lauren BG, Ingram O, Stanley GR, Christopher S, Stanley GR, Donal MM. Lack of significant interactions between clopidogrel and proton pump inhibitor therapy: meta-analysis of existing literature. Dig Dis Sci. 2012;2:115.

    Google Scholar 

  9. 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. 2019;5:965–74.

    Google Scholar 

  10. Burkard T, Kaiser CA, Brunner-La Rocca H, Osswald S, Pfisterer ME, Jeger RV. 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;271:257–63.

    Article  CAS  Google Scholar 

  11. Zou JJ, Chen SL, Tan J, Lin G, Zhao YY, Xu HM, et al. Increased risk for developing major adverse cardiovascular events in stented Chinese patients treated with dual antiplatelet therapy after concomitant use of the proton pump inhibitor. PLoS ONE. 2014;9:1033.

    Google Scholar 

  12. Serbin MA, Guzauskas GF, Veenstra DL. Clopidogrel-proton pump inhibitor drug-drug interaction and risk of adverse clinical outcomes among PCI-treated ACS patients: a meta-analysis. J Manag Care Spec Pharm. 2016;1:939–47.

    Google Scholar 

  13. Hu W, Tong J, Kuang X, Chen W, Liu Z. Influence of proton pump inhibitors on clinical outcomes in coronary heart disease patients receiving aspirin and clopidogrel. Med (United States). 2018;97.

  14. EMA. Public statement on possible interaction between clopidogrel and proton pump inhibitors. Eur Med Agency [Internet]. 2009;EMEA/32895:328956. http://www.emea.europa.eu/docs/en_GB/document_library/Public_statement/2009/11/WC500014409.pdf

  15. Johnson DA, Chilton R, Liker HR. Proton-pump inhibitors in patients requiring antiplatelet therapy: new FDA labeling. Postgrad Med. 2014;126:239–45.

    Article  Google Scholar 

  16. Tsantes AE, Ikonomidis I, Papadakis I, Bonovas S, Gialeraki A, Kottaridi C, et al. Impact of the proton pump inhibitors and CYP2C19*2 polymorphism on platelet response to clopidogrel as assessed by four platelet function assays. Thromb Res. 2013;132:109.

    Article  Google Scholar 

  17. Biswas M. Global distribution of CYP2C19 risk phenotypes affecting safety and effectiveness of medications. Pharmacogenomics J. 2020;3:74.

    Google Scholar 

  18. Cavallari LH, Jeong H, Bress A. Role of cytochrome P450 genotype in the steps toward personalized drug therapy. Pharmgenomics Pers Med. 2011;2:123–36.

    Google Scholar 

  19. Jeong YH, Tantry US, Kim IS, Koh JS, Kwon TJ, Park Y, et al. Effect of CYP2C19 *2 and *23 loss-of-function alleles on platelet reactivity and adverse clinical events in East Asian acute myocardial infarction survivors treated with clopidogrel and aspirin. Circ Cardiovasc Interv. 2011;4:585–94.

    Article  Google Scholar 

  20. Xi Z, Fang F, Wang J, AlHelal J, Zhou Y, Liu W. CYP2C19 genotype and adverse cardiovascular outcomes after stent implantation in clopidogrel-treated Asian populations: a systematic review and meta-analysis. Platelets. 2019;30:229–40.

    Article  CAS  Google Scholar 

  21. Cavallari LH, Lee CR, Beitelshees AL, Cooper-DeHoff RM, Duarte JD, Voora D, et al. Multisite investigation of outcomes with implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention. JACC Cardiovasc Interv. 2018;11:181–91.

    Article  Google Scholar 

  22. Zabalza M, Subirana I, Sala J, Lluis-Ganella C, Lucas G, Tomás M, et al. Meta-analyses of the association between cytochrome CYP2C19 loss- and gain-of-function polymorphisms and cardiovascular outcomes in patients with coronary artery disease treated with clopidogrel. Heart. 2012;5:100–8.

    Article  Google Scholar 

  23. Zou JJ, Xie HG, Chen SL, Tan J, Lin L, Zhao YY, et al. Influence of CYP2C19 loss-of-function variants on the antiplatelet effects and cardiovascular events in clopidogrel-treated Chinese patients undergoing percutaneous coronary intervention. Eur J Clin Pharmacol. 2013;69:771–7.

    Article  Google Scholar 

  24. Biswas M, Dias TH, Daneshi N, Milward Liz KK. Pharmacogenomics of cardiovascular drugs. Aust Pharm. 2017;36:50–3.

    Google Scholar 

  25. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ WV. Cochrane Handbook for Systematic Reviews of Interventions version 6.0 (updated July 2019). Cochrane, 2019. Handbook. 2019.

  26. Eriksen MB, Frandsen TF. The impact of patient, intervention, comparison, outcome (Pico) as a search strategy tool on literature search quality: a systematic review. J Med Libr Assoc. 2018;106:420–31.

    Article  Google Scholar 

  27. Ouzzani M, Hammady H, Fedorowicz Z, Elmagarmid A. Rayyan-a web and mobile app for systematic reviews. Syst Rev. 2016;5:110.

    Article  Google Scholar 

  28. Wells G, Shea B, O’Connell D, Peterson J. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses [Internet]. Ottawa, Ottawa Hosp. Res. Inst. 2000. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp

  29. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin Trials. 1996;17:1–12.

    Article  CAS  Google Scholar 

  30. Hokimoto S, Mizobe M, Akasaka T, Arima Y, Kaikita K, Nakagawa K, et al. Impact of CYP2C19 polymorphism and proton pump inhibitors on platelet reactivity to clopidogrel and clinical outcomes following stent implantation. Thromb Res. 2014;133:599–605.

    Article  CAS  Google Scholar 

  31. Yi X, Han Z, Zhou Q, Cheng W, Lin J, Wang C. Concomitant use of proton-pump inhibitors and clopidogrel increases the risk of adverse outcomes in patients with Ischemic stroke carrying reduced-function CYP2C19*2. Clin Appl Thromb. 2018;24:55–62.

    Article  CAS  Google Scholar 

  32. Simon T, Steg PG, Gilard M, Blanchard D, Bonello L, Hanssen 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 myocard. Circulation. 2011;123:474–82.

    Article  CAS  Google Scholar 

  33. Goodman SG, Clare R, Pieper KS, Nicolau JC, Storey RF, Cantor WJ, 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;125:978–86.

    Article  CAS  Google Scholar 

  34. Depta JP, Lenzini PA, Lanfear DE, Wang TY, Spertus JA, Bach RG, et al. Clinical outcomes associated with proton pump inhibitor use among clopidogrel-treated patients within CYP2C19 genotype groups following acute myocardial infarction. Pharmacogenomics J. 2015;15:20–5.

    Article  CAS  Google Scholar 

  35. Niu Q, Wang Z, Zhang Y, Wang J, Zhang P, Wang C, et al. Combination use of clopidogrel and proton pump inhibitors increases major adverse cardiovascular events in patients with coronary artery disease: a meta-analysis. J Cardiovasc Pharmacol Ther. 2017;22:142–52.

    Article  CAS  Google Scholar 

  36. Sorich MJ, Rowland A, McKinnon RA, Wiese MD. CYP2C19 genotype has a greater effect on adverse cardiovascular outcomes following percutaneous coronary intervention and in Asian populations treated with clopidogrel: a meta-analysis. Circ Cardiovasc Genet. 2014;7:895–902.

    Article  CAS  Google Scholar 

  37. Pan Y, Chen W, Xu Y, Yi X, Han Y, Yang Q, et al. Genetic polymorphisms and clopidogrel efficacy for acute ischemic stroke or transient ischemic attack. Circulation. 2017;8:21–33.

    Article  Google Scholar 

  38. Wang Y, Zhao X, Lin J, Li H, Johnston SC, Lin Y, et al. Association between CYP2C19 loss-of-function allele status and efficacy of clopidogrel for risk reduction among patients with minor stroke or transient ischemic attack. JAMA J Am Med Assoc. 2016;316:70–8.

    Article  CAS  Google Scholar 

  39. Kagami T, Yamade M, Suzuki T, Uotani T, Hamaya Y, Iwaizumi M, et al. Comparative Study of Effects of Vonoprazan and Esomeprazole on Antiplatelet Function of Clopidogrel or Prasugrel in Relation to CYP2C19 Genotype. Clin Pharmacol Ther. 2018;103:906–13.

    Article  CAS  Google Scholar 

  40. Eftekhari P, Dias TH, Biswas M, Fossuou-Tagne J, Milward L. Update on genetic testing services in pharmacy practice. Aus Pharmacist. 2019;38(1):60–6.

    Google Scholar 

  41. Ned RM. Genetic Testing for CYP450 Polymorphisms to Predict Response to Clopidogrel: current evidence and test availability. PLoS Curr. 2010;2:1180.

    Article  Google Scholar 

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Acknowledgements

Greatly acknowledging Professor Dr. Mamunur Rashid, Department of Pharmacy, University of Rajshahi, Bangladesh for his generous professional support to lead author.

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Authors and Affiliations

  1. Department of Pharmacy, University of Rajshahi, Rajshahi, 6205, Bangladesh

    Mohitosh Biswas & Shawonur Rahaman

  2. Department of Medicine, Faridpur Medical College Hospital, Faridpur, Bangladesh

    Tapash Kumar Biswas

  3. School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia

    Baharudin Ibrahim

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Biswas, M., Rahaman, S., Biswas, T.K. et al. Risk of major adverse cardiovascular events for concomitant use of clopidogrel and proton pump inhibitors in patients inheriting CYP2C19 loss-of-function alleles: meta-analysis. Int J Clin Pharm 43, 1360–1369 (2021). https://doi.org/10.1007/s11096-021-01261-y

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