CYP2C19 Genotype and Proton Pump Inhibitors in Clopidogrel-Treated Patients
2011; Lippincott Williams & Wilkins; Volume: 123; Issue: 5 Linguagem: Inglês
10.1161/circulationaha.110.006866
ISSN1524-4539
Autores Tópico(s)Synthesis of β-Lactam Compounds
ResumoHomeCirculationVol. 123, No. 5CYP2C19 Genotype and Proton Pump Inhibitors in Clopidogrel-Treated Patients Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCYP2C19 Genotype and Proton Pump Inhibitors in Clopidogrel-Treated PatientsDoes It Take Two to Tango? Michelle L. O'Donoghue, MD, MPH Michelle L. O'DonoghueMichelle L. O'Donoghue From the TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA. Originally published24 Jan 2011https://doi.org/10.1161/CIRCULATIONAHA.110.006866Circulation. 2011;123:468–470Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2011: Previous Version 1 The debate continues regarding the existence of an adverse interaction between proton pump inhibitors (PPIs) and clopidogrel. Concerns for a drug-drug interaction first emerged when experimental pharmacodynamic data indicated that omeprazole might diminish the in vitro antiplatelet effects of clopidogrel.1,2 These concerns were escalated when retrospective data from 2 large observational studies demonstrated that use of a PPI was associated with an increased risk of cardiovascular events for patients treated with clopidogrel.3,4 In response to these findings, the US Food and Drug Administration updated the drug's label to warn that the effectiveness of clopidogrel is reduced when administered in combination with omeprazole.5 However, these findings have since been disputed by a growing number of analyses from clinical trial populations that have failed to show an increased risk of adverse outcomes when PPIs are administered in combination with clopidogrel.6–8 Furthermore, the results of the only randomized clinical trial to address this issue demonstrated similar cardiovascular risk regardless of whether subjects were assigned to clopidogrel alone or in combination with omeprazole.9Article see p 474In light of the accumulating evidence that suggests that PPIs can be administered safely in combination with clopidogrel, one may wonder why this continues to be a topic of heated debate. There are several valid reasons that support these theoretical concerns. Clopidogrel is a prodrug that requires hepatic biotransformation that involves 2 CYP2C19-dependent steps to form its active metabolite.10 In turn, PPIs variably inhibit CYP2C19 enzyme activity.11 As well, genetic polymorphisms that naturally confer reduced CYP2C19 enzyme activity are associated with an increased risk of cardiovascular events in clopidogrel-treated patients,12 thereby supporting the concept that the isoenzyme is an integral step in the metabolism of clopidogrel. Finally, studies have consistently demonstrated that some PPIs, in particular omeprazole, diminish the pharmacodynamic effects of clopidogrel.1,2,13 However, the evidence to suggest that changes in this surrogate end point carry clinical consequences remains conflicting.In the current issue of Circulation, Simon and colleagues14 looked for evidence of a clinical interaction between PPIs and clopidogrel in 2744 subjects in the French Acute non–ST- or ST-elevation Myocardial Infarction (FAST-MI) Registry, a French registry of subjects after hospitalization for a myocardial infarction. After multivariable analysis, use of a PPI was not associated with an increased risk of cardiovascular events before hospital discharge (adjusted hazard ratio 0.90, 95% confidence interval 0.60 to 1.35) or at 1 year (adjusted hazard ratio 0.98, 95% confidence interval 0.90 to 1.08) in clopidogrel-treated patients. These findings were consistent when repeated in a propensity-matched cohort analysis. Of those subjects prescribed a PPI, more than two-thirds were taking omeprazole, which is believed to be one of the stronger inhibitors of the CYP2C19 enzyme. When individual types of PPIs were examined, the risk of 1-year cardiovascular outcomes was similar for subjects taking omeprazole compared with those not taking a PPI (1-year outcomes: adjusted hazard ratio 0.82, 95% confidence interval 0.54 to 1.24) on a background of clopidogrel.14These new data support a growing number of recent publications that suggest that PPIs and clopidogrel can be coadministered without a clear increase in cardiovascular risk.2,6–8 Although omeprazole appears to attenuate some of the antiplatelet effects of clopidogrel, there is insufficient evidence to suggest that this in vitro finding translates into a higher risk of cardiovascular events. A diminished pharmacodynamic response to clopidogrel has been observed when coadministered with lipophilic statins and calcium channel blockers.15–17 However, concerns about a clinical drug-drug interaction with statins largely have been dismissed because subsequent outcome studies failed to demonstrate increased cardiovascular risk.18,19 These findings highlight the fact that observational analyses are subject to confounding and also raise concern about the use of in vitro platelet reactivity as a surrogate end point.To that end, there is still much we need to learn to better understand the relationship between in vitro platelet reactivity and adverse clinical outcomes. It is plausible that the pharmacodynamic interaction between clopidogrel, PPIs, calcium channel blockers, or lipophilic statins is too weak to translate into cardiovascular harm. Another consideration is that the shape of the relationship between platelet reactivity and clinical outcomes is not linear; rather, there might exist a threshold effect such that platelet reactivity must be raised above a certain threshold before a patient is placed at increased risk. In support of this hypothesis, it has been reported that ischemic events appear to be most clustered above a particular cut point in the upper tertile or quartile of on-treatment platelet reactivity.20Perhaps the most intriguing question to be addressed in the present analysis is whether the pharmacodynamic interaction between PPIs and clopidogrel might be clinically relevant only to those individuals who carry a loss-of-function CYP2C19 allele. To date, it remains unknown whether CYP2C19 genotype and PPI use might have an additive effect toward diminishing the antiplatelet effects of clopidogrel. In the present analysis, a DNA sample was available in 1579 subjects (67%), and 446 (28%) of those subjects carried at least 1 loss-of-function CYP2C19 allele. In propensity-matched cohorts, PPI use was not associated with an increased risk of either in-hospital (odds ratio 0.29, 95% confidence interval 0.06 to 1.44) or 1-year cardiovascular events (odds ratio 0.68, 95% confidence interval 0.26 to 1.79) in carriers of a single loss-of-function CYP2C19 allele, although the confidence intervals were relatively wide.14 These new data support our previously published findings from the TRITON-TIMI 38 study (TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel-Thrombolysis In Myocardial Infarction 38), which similarly demonstrated that PPI use was not associated with an increased risk of adverse outcomes in either wild-type carriers or carriers of a loss-of-function CYP2C19 allele.7Although the present study was underpowered to examine whether a drug-drug interaction might exist in carriers of 2 loss-of-function CYP2C19 alleles, such an interaction is unlikely to be clinically meaningful. Because the most common loss-of-function alleles (*2 and *3) code for an inactive form of the CYP2C19 isoenzyme, carriers of 2 loss-of-function alleles would be expected to have little or no CYP2C19 enzyme activity at baseline. As such, it is unlikely that PPI use could lead to further inhibition of the CYP2C19 enzyme to an extent that would be clinically meaningful.A possible limitation to the present analysis is whether the FAST-MI registry is an appropriate study population in whom to examine outcomes for carriers of a single loss-of-function CYP2C19 allele. Although several studies have shown that carriers of a single loss-of-function CYP2C19 allele are at increased risk of adverse outcomes on clopidogrel,12 these findings were not replicated in the present study population. Rather, in FAST-MI, carriers of a single loss-of-function allele had a trend toward a lower risk of cardiovascular events than wild-type carriers, whereas those who carried 2 copies of a loss-of-function allele had excess risk.21 These findings are perhaps explained by a lower incidence of percutaneous coronary intervention in the study population, because the relative benefit of clopidogrel appears to be greater in patients in whom a coronary stent has been implanted.22 Unfortunately, pharmacodynamic data are not available to help us better understand whether carriers of a single loss-of-function allele had higher or lower on-treatment platelet reactivity than wild-type carriers.Additional limitations to the present study merit consideration. In particular, in the present study, use of a PPI was only captured during the index hospitalization. Because patients may have started or stopped a PPI during the year after hospital discharge, the results could be biased toward the null. Finally, as with all observational studies, there exists the risk of residual confounding, because it is nearly impossible to identify all variables that may influence the decision to treat a patient with a PPI.Nevertheless, the present findings provide further supportive evidence to indicate that PPIs can be used safely in patients taking clopidogrel. Although omeprazole might attenuate some of the in vitro antiplatelet effects of clopidogrel, convincing evidence is currently lacking to indicate that this combination places patients at increased risk of harm. Furthermore, PPIs have been shown to decrease the risk of gastrointestinal complications, including bleeding, for patients taking dual-antiplatelet therapy,9 and in turn, gastrointestinal bleeding is associated with an increased risk of cardiovascular events.23 Until the relationship between platelet function assays and clinical outcomes is better delineated, the weight of the evidence suggests that clopidogrel can be administered safely in combination with a PPI for patients at risk of gastrointestinal complications.2DisclosuresDr O'Donoghue reports receiving grant funding from GlaxoSmithKline and Eisai, and has received honoraria for educational seminars supported by Eli Lilly and Daiichi Sankyo.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Michelle L. O'Donoghue, MD, MPH, TIMI Study Group, Brigham and Women's Hospital, 350 Longwood Ave, 1st Floor, Boston, MA 02115. E-mail [email protected]orgReferences1. 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; 51:256–260.CrossrefMedlineGoogle Scholar2. Abraham NS, Hlatky MA, Antman EM, Bhatt DL, Bjorkman DJ, Clark CB, Furberg CD, Johnson DA, Kahi CJ, Laine L, Mahaffey KW, Quigley EM, Scheiman J, Sperling LS, Tomaselli GF. 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.MedlineGoogle Scholar3. Juurlink DN, Gomes T, Ko DT, Szmitko PE, Austin PC, Tu JV, Henry DA, Kopp A, Mamdani MM. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009; 180:713–718.CrossrefMedlineGoogle Scholar4. Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Rumsfeld JS. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009; 301:937–944.CrossrefMedlineGoogle Scholar5. 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). November17, 2009. Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm190787.htm. Accessed December 1, 2010.Google Scholar6. Dunn SP, Macaulay TE, Brennan DM, Campbell CL, Charnigo RJ, Smyth SS, Berger PB, Steinhubl SR, Topol EJ. Baseline proton pump inhibitor use is associated with increased cardiovascular events with and without the use of clopidogrel in the CREDO trial. Circulation. 2008; 118:S-815. Abstract 3999.LinkGoogle Scholar7. O'Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, 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; 374:989–997.CrossrefMedlineGoogle Scholar8. Goodman SG, Clare R, Pieper KS, James SK, Nicolau JC, Storey RF, Cantor WJ, Angiolillo DJ, Husted S, Cannon CP, Steg PG, Mahaffey KH, Kilhamn J, Harrington RA, Wallentin L. Proton pump inhibitor use is likely a marker for, rather than a cause of, a higher risk of cardiovascular events: insights from PLATO. Circulation. 2010; 122:A12092. Abstract.LinkGoogle Scholar9. 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. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010; 363:1909–1917.CrossrefMedlineGoogle Scholar10. Kazui M, Nishiya Y, Ishizuka T, Hagihara K, Farid NA, Okazaki O, Ikeda T, Kurihara A. 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; 38:92–99.CrossrefMedlineGoogle Scholar11. Ishizaki T, Horai Y. Review article: cytochrome P450 and the metabolism of proton pump inhibitors: emphasis on rabeprazole. Aliment Pharmacol Ther. 1999; 13(suppl 3):27–36.CrossrefMedlineGoogle Scholar12. Mega JL, Simon T, Collet JP, Anderson JL, Antman EM, Bliden K, Cannon CP, Danchin N, Giusti B, Gurbel P, Horne BD, Hulot JS, Kastrati A, Montalescot G, Neumann FJ, Shen L, Sibbing D, Steg PG, Trenk D, Wiviott SD, Sabatine MS. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010; 304:1821–1830.CrossrefMedlineGoogle Scholar13. Angiolillo DJ, Gibson CM, Cheng S, Ollier C, Nicolas O, Bergougnan L, Perrin L, Lacreta FP, Hurbin F, Dubar M. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies. Clin Pharmacol Ther. 2011; 89:65–74.CrossrefMedlineGoogle Scholar14. Simon T, Steg PG, Gilard M, Blanchard D, Bonello L, Hanssen M, Lardoux H, Coste P, Lefevre T, Drouet E, Mulak G, Bataille V, Ferrieres J, Verstuyft C, Danchin N. 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.LinkGoogle Scholar15. Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS, Tait AR, Carville DG, Guyer KE, Bates ER. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation. 2003; 107:32–37.LinkGoogle Scholar16. Siller-Matula JM, Lang I, Christ G, Jilma B. Calcium-channel blockers reduce the antiplatelet effect of clopidogrel. J Am Coll Cardiol. 2008; 52:1557–1563.CrossrefMedlineGoogle Scholar17. Gremmel T, Steiner S, Seidinger D, Koppensteiner R, Panzer S, Kopp CW. Calcium-channel blockers decrease clopidogrel-mediated platelet inhibition. Heart. 2010; 96:186–189.CrossrefMedlineGoogle Scholar18. Saw J, Steinhubl SR, Berger PB, Kereiakes DJ, Serebruany VL, Brennan D, Topol EJ. Lack of adverse clopidogrel-atorvastatin clinical interaction from secondary analysis of a randomized, placebo-controlled clopidogrel trial. Circulation. 2003; 108:921–924.LinkGoogle Scholar19. Saw J, Brennan DM, Steinhubl SR, Bhatt DL, Mak KH, Fox K, Topol EJ. Lack of evidence of a clopidogrel-statin interaction in the CHARISMA trial. J Am Coll Cardiol. 2007; 50:291–295.CrossrefMedlineGoogle Scholar20. Bonello L, Tantry US, Marcucci R, Blindt R, Angiolillo DJ, Becker R, Bhatt DL, Cattaneo M, Collet JP, Cuisset T, Gachet C, Montalescot G, Jennings LK, Kereiakes D, Sibbing D, Trenk D, Van Werkum JW, Paganelli F, Price MJ, Waksman R, Gurbel PA. Consensus and future directions on the definition of high on-treatment platelet reactivity to adenosine diphosphate. J Am Coll Cardiol. 2010; 56:919–933.CrossrefMedlineGoogle Scholar21. Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Meneveau N, Steg PG, Ferrieres J, Danchin N, Becquemont L. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009; 360:363–375.CrossrefMedlineGoogle Scholar22. Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK, Giambartolomei A, Diver DJ, Lasorda DM, Williams DO, Pocock SJ, Kuntz RE; Stent Anticoagulation Restenosis Study Investigators. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. N Engl J Med. 1998; 339:1665–1671.CrossrefMedlineGoogle Scholar23. Nikolsky E, Stone GW, Kirtane AJ, Dangas GD, Lansky AJ, McLaurin B, Lincoff AM, Feit F, Moses JW, Fahy M, Manoukian SV, White HD, Ohman EM, Bertrand ME, Cox DA, Mehran R. Gastrointestinal bleeding in patients with acute coronary syndromes: incidence, predictors, and clinical implications: analysis from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. J Am Coll Cardiol. 2009; 54:1293–1302.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Ford N (2016) The Metabolism of Clopidogrel: CYP2C19 Is a Minor Pathway, The Journal of Clinical Pharmacology, 10.1002/jcph.769, 56:12, (1474-1483), Online publication date: 1-Dec-2016. Depta J, Lenzini P, Lanfear D, Wang T, Spertus J, Bach R and Cresci S (2014) Clinical outcomes associated with proton pump inhibitor use among clopidogrel-treated patients within CYP2C19 genotype groups following acute myocardial infarction, The Pharmacogenomics Journal, 10.1038/tpj.2014.28, 15:1, (20-25), Online publication date: 1-Feb-2015. Scott S, Owusu Obeng A and Hulot J (2013) Antiplatelet drug interactions with proton pump inhibitors, Expert Opinion on Drug Metabolism & Toxicology, 10.1517/17425255.2014.856883, 10:2, (175-189), Online publication date: 1-Feb-2014. Karathanos A and Geisler T (2013) Monitoring Aspirin and Clopidogrel Response: Testing Controversies and Recommendations, Molecular Diagnosis & Therapy, 10.1007/s40291-013-0022-y, 17:3, (123-137), Online publication date: 1-Jun-2013. Ojeifo O, Wiviott S, Antman E, Murphy S, Udell J, Bates E, Mega J, Sabatine M and O'Donoghue M (2013) Concomitant Administration of Clopidogrel With Statins or Calcium-Channel Blockers, JACC: Cardiovascular Interventions, 10.1016/j.jcin.2013.06.014, 6:12, (1275-1281), Online publication date: 1-Dec-2013. Gersh B (2012) 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, Yearbook of Cardiology, 10.1016/j.ycar.2012.01.077, 2012, (261-262), Online publication date: 1-Jan-2012. Depta J and Bhatt D (2012) Antiplatelet therapy and proton pump inhibition, Current Opinion in Cardiology, 10.1097/HCO.0b013e32835830b6, 27:6, (642-650), Online publication date: 1-Nov-2012. February 8, 2011Vol 123, Issue 5 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.110.006866PMID: 21262991 Originally publishedJanuary 24, 2011 KeywordsCYP2C19, humanEditorialsproton pump inhibitorsclopidogrelPDF download Advertisement SubjectsMyocardial InfarctionSecondary PreventionThrombosis
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