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Clinical outcomes associated with proton pump inhibitor use among clopidogrel-treated patients within CYP2C19 genotype groups following acute myocardial infarction

The Pharmacogenomics Journal volume 15, pages 20–25 (2015)Cite this article

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Abstract

We examined clinical outcomes with proton pump inhibitors (PPI) use within CYP2C19 genotype groups during clopidogrel treatment following acute myocardial infarction (AMI). 2062 patients were genotyped for CYP2C19*2 and *17 variants in TRIUMPH. 12 month clinical outcomes were analyzed among patients discharged on clopidogrel within CYP2C19*2 carrier, CYP2C19*17 carrier, and CYP2C19*1 homozygote genotype groups. PPI use was not associated with a difference in mortality. Among clopidogrel-treated Caucasians following AMI, PPI use was associated with a significantly higher rate of cardiac rehospitalization (HR 1.62, 95% CI 1.19–2.19; P=0.002) compared with no PPI use. PPI users who were carriers of the CYP2C19*17 variant experienced significantly higher rates of cardiac rehospitalization (HR 2.05, 95% CI 1.26–3.33; P=0.003), carriers of the CYP2C19*2 variant had a trend toward increased 1-year cardiac rehospitalization (HR 1.69, 95% CI 0.95–2.99; P=0.07), while no significant differences were observed among CYP2C19*1 homozygotes. These results indicate that the risks associated with PPI use among clopidogrel-treated Caucasian post-MI patients are impacted by CYP2C19 genotype, and suggest knowledge of genotype may be useful for personalizing PPI use among patients following AMI to reduce rehospitalization.

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References

  1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB et al. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation 2013; 127: e6–e245.

    PubMed  Google Scholar 

  2. Bhatt DL . Role of antiplatelet therapy across the spectrum of patients with coronary artery disease. Am J Cardiol 2009; 103: 11A–19A.

    Article  CAS  PubMed  Google Scholar 

  3. Depta JP, Bhatt DL . Aspirin and platelet adenosine diphosphate receptor antagonists in acute coronary syndromes and percutaneous coronary intervention: role in therapy and strategies to overcome resistance. Am J Cardiovasc Drugs 2008; 8: 91–112.

    Article  CAS  PubMed  Google Scholar 

  4. Somma KA, Bhatt DL, Fonarow GC, Cannon CP, Cox M, Laskey W et al. Guideline adherence after ST-segment elevation versus non-ST segment elevation myocardial infarction. Am J Cardiovasc Drugs 2012; 5: 654–661.

    Google Scholar 

  5. Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ, Becker R et al. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol 2010; 56: 919–933.

    Article  CAS  PubMed  Google Scholar 

  6. Depta JP, Bhatt DL . Antiplatelet therapy and proton pump inhibition: cause for concern? Curr Opin Cardiol 2012; 27: 642–650.

    Article  PubMed  Google Scholar 

  7. Depta JP, Bhatt DL . Omeprazole and clopidogrel: Should clinicians be worried? Cleve Clin J Med 2010; 77: 113–116.

    Article  PubMed  Google Scholar 

  8. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360: 354–362.

    Article  CAS  PubMed  Google Scholar 

  9. Shi S, Klotz U . Proton pump inhibitors: an update of their clinical use and pharmacokinetics. Eur J Clin Pharmacol 2008; 64: 935–951.

    Article  CAS  PubMed  Google Scholar 

  10. Frelinger AL 3rd, Lee RD, Mulford DJ, Wu J, Nudurupati S, Nigam A et al. A randomized, 2-period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers. J Am Coll Cardiol 2012; 59: 1304–1311.

    Article  CAS  PubMed  Google Scholar 

  11. O’Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y 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; 374: 989–997.

    Article  PubMed  Google Scholar 

  12. O’Donoghue ML . CYP2C19 genotype and proton pump inhibitors in clopidogrel-treated patients: does it take two to tango? Circulation 2011; 123: 468–470.

    Article  PubMed  Google Scholar 

  13. Arnold SV, Chan PS, Jones PG, Decker C, Buchanan DM, Krumholz HM et al. Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients’ Health Status (TRIUMPH): design and rationale of a prospective multicenter registry. Circ Cardiovasc Qual Outcomes 2011; 4: 467–476.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Cresci S, Wu J, Province MA, Spertus JA, Steffes M, McGill JB et al. Peroxisome proliferator-activated receptor pathway gene polymorphism associated with extent of coronary artery disease in patients with type 2 diabetes in the bypass angioplasty revascularization investigation 2 diabetes trial. Circulation 2011; 124: 1426–1434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lanfear DE, Jones PG, Cresci S, Tang F, Rathore SS, Spertus JA . Factors influencing patient willingness to participate in genetic research after a myocardial infarction. Genome medicine 2011; 3: 39.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L et al. A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 2006; 79: 103–113.

    Article  CAS  PubMed  Google Scholar 

  17. Wang H, An N, Wang H, Gao Y, Liu D, Bian T et al. Evaluation of the effects of 20 nonsynonymous single nucleotide polymorphisms of CYP2C19 on S-mephenytoin 4′-hydroxylation and omeprazole 5'-hydroxylation. Drug Metab Dispos 2011; 39: 830–837.

    Article  CAS  PubMed  Google Scholar 

  18. Yan AT, Yan RT, Tan M, Eagle KA, Granger CB, Dabbous OH et al. In-hospital revascularization and one-year outcome of acute coronary syndrome patients stratified by the GRACE risk score. Am J Cardiol 2005; 96: 913–916.

    Article  PubMed  Google Scholar 

  19. Tang EW, Wong CK, Herbison P . Global Registry of Acute Coronary Events (GRACE) hospital discharge risk score accurately predicts long-term mortality post acute coronary syndrome. Am Heart J 2007; 153: 29–35.

    Article  PubMed  Google Scholar 

  20. Ohbuchi M, Noguchi K, Kawamura A, Usui T . Different effects of proton pump inhibitors and famotidine on the clopidogrel metabolic activation by recombinant CYP2B6, CYP2C19 and CYP3A4. Xenobiotica 2012; 42: 633–640.

    Article  CAS  PubMed  Google Scholar 

  21. Zvyaga T, Chang SY, Chen C, Yang Z, Vuppugalla R, Hurley J et al. Evaluation of six proton pump inhibitors as inhibitors of various human cytochromes P450: focus on cytochrome P450 2C19. Drug Metab Dispos 2012; 40: 1698–1711.

    Article  CAS  PubMed  Google Scholar 

  22. Fernando H, Bassler N, Habersberger J, Sheffield LJ, Sharma R, Dart AM et al. Randomized double-blind placebo-controlled crossover study to determine the effects of esomeprazole on inhibition of platelet function by clopidogrel. J Thromb Haemost 2011; 9: 1582–1589.

    Article  CAS  PubMed  Google Scholar 

  23. Furuta T, Iwaki T, Umemura K . Influences of different proton pump inhibitors on the anti-platelet function of clopidogrel in relation to CYP2C19 genotypes. Br J Clin Pharmacol 2010; 70: 383–392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hulot JS, Wuerzner G, Bachelot-Loza C, Azizi M, Blanchard A, Peyrard S et al. Effect of an increased clopidogrel maintenance dose or lansoprazole co-administration on the antiplatelet response to clopidogrel in CYP2C19-genotyped healthy subjects. J Thromb Haemost 2010; 8: 610–613.

    Article  CAS  PubMed  Google Scholar 

  25. Liu Q, Dang DS, Chen YF, Yan M, Shi GB, Zhao QC . The influence of omeprazole on platelet inhibition of clopidogrel in various CYP2C19 mutant alleles. Genet Test Mol Biomarkers 2012; 16: 1293–1297.

    Article  CAS  PubMed  Google Scholar 

  26. 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 Myocardial Infarction (FAST-MI) registry. Circulation 2011; 123: 474–482.

    Article  CAS  PubMed  Google Scholar 

  27. Harmsze AM, van Werkum JW, Souverein PC, Breet NJ, Bouman HJ, Hackeng CM et al. Combined influence of proton-pump inhibitors, calcium-channel blockers and CYP2C19*2 on on-treatment platelet reactivity and on the occurrence of atherothrombotic events after percutaneous coronary intervention. J Thromb Haemost 2011; 9: 1892–1901.

    Article  CAS  PubMed  Google Scholar 

  28. Gladding P, Webster M, Zeng I, Farrell H, Stewart J, Ruygrok P et al. The pharmacogenetics and pharmacodynamics of clopidogrel response: an analysis from the PRINC (Plavix Response in Coronary Intervention) trial. JACC Cardiovasc Interv 2008; 1: 620–627.

    Article  PubMed  Google Scholar 

  29. Frere C, Cuisset T, Morange PE, Quilici J, Camoin-Jau L, Saut N et al. Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. Am J Cardiol 2008; 101: 1088–1093.

    Article  CAS  PubMed  Google Scholar 

  30. Brandt JT, Close SL, Iturria SJ, Payne CD, Farid NA, Ernest CS 2nd et al. Common polymorphisms of CYP2C19 and CYP2C9 affect the pharmacokinetic and pharmacodynamic response to clopidogrel but not prasugrel. J Thromb Haemost 2007; 5: 2429–2436.

    Article  CAS  PubMed  Google Scholar 

  31. Frere C, Cuisset T, Gaborit B, Alessi MC, Hulot JS . The CYP2C19*17 allele is associated with better platelet response to clopidogrel in patients admitted for non-ST acute coronary syndrome. J Thromb Haemost 2009; 7: 1409–1411.

    Article  CAS  PubMed  Google Scholar 

  32. Muhlestein JB, Horne BD, Bair TL, Li Q, Madsen TE, Pearson RR et al. Usefulness of in-hospital prescription of statin agents after angiographic diagnosis of coronary artery disease in improving continued compliance and reduced mortality. Am J Cardiol 2001; 87: 257–261.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work and S. Cresci’s effort are supported in part by the National Institutes of Health (Cresci R01 NR013396). TRIUMPH was sponsored by the National Institutes of Health: Washington University School of Medicine SCCOR Grant P50 HL077113.

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Authors and Affiliations

  1. Department of Medicine, Washington University School of Medicine, St Louis, MO, USA

    J P Depta, R G Bach & S Cresci

  2. Department of Genetics, Washington University School of Medicine, St Louis, MO, USA

    P A Lenzini & S Cresci

  3. Heart and Vascular Institute, Henry Ford Hospital, Detroit, MI, USA

    D E Lanfear

  4. Duke Clinical Research Institute, Duke, Durham, NC, USA

    T Y Wang

  5. Saint Luke’s Mid America Heart Institute and the University of Missouri-Kansas City, Kansas City, MO, USA

    J A Spertus

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  1. J P Depta
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Correspondence to S Cresci.

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Competing interests

TY Wang has received research grants from Lilly USA (significant), Daiichi Sankyo (significant) and Gilead Science (significant), and is a consultant to Astra Zeneca (modest), American College of Cardiology Foundation (significant). JA Spertus has received research grants from Eli Lilly, EveHeart, Genentech and Gilead, and is a consultant to St Jude Medical (modest), United Healthcare (modest), Amgen (modest), Gilead (modest), Genentech (modest), Janssen (modest) and Novartis (modest). Copyrights/Patents apply to Seattle Angina Questionnaire, Kansas City Cardiomyopathy Questionnaire and Peripheral Artery Questionnaire. US Patents: 7,643,969; 7,853,456; 12/965,656; and 13/615,401. RG Bach has received research grants from AstraZeneca, Eli Lilly, Bristol-Myers Squibb and Merck/Schering-Plough, and is a consultant (CEC activity only) to Roche (significant), Pfizer (modest). The remaining authors declare no conflict of interest.

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Depta, J., Lenzini, P., Lanfear, D. et al. Clinical outcomes associated with proton pump inhibitor use among clopidogrel-treated patients within CYP2C19 genotype groups following acute myocardial infarction. Pharmacogenomics J 15, 20–25 (2015). https://doi.org/10.1038/tpj.2014.28

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  • DOI: https://doi.org/10.1038/tpj.2014.28

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