FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 360:363-375 January 22, 2009 Number 4 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Supplementary Material Editorial by Freedman, J. E. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background Pharmacogenetic determinants of the response of patients to clopidogrel contribute to variability in the biologic antiplatelet activity of the drug. The effect of these determinants on clinical outcomes after an acute myocardial infarction is unknown.

Methods We consecutively enrolled 2208 patients presenting with an acute myocardial infarction in a nationwide French registry and receiving clopidogrel therapy. We then assessed the relation of allelic variants of genes modulating clopidogrel absorption (ABCB1), metabolic activation (CYP3A5 and CYP2C19), and biologic activity (P2RY12 and ITGB3) to the risk of death from any cause, nonfatal stroke, or myocardial infarction during 1 year of follow-up.

Results Death occurred in 225 patients, and nonfatal myocardial infarction or stroke in 94 patients, during the follow-up period. None of the selected single-nucleotide polymorphisms (SNPs) in CYP3A5, P2RY12, or ITGB3 were associated with a risk of an adverse outcome. Patients with two variant alleles of ABCB1 (TT at nucleotide 3435) had a higher rate of cardiovascular events at 1 year than those with the ABCB1 wild-type genotype (CC at nucleotide 3435) (15.5% vs. 10.7%; adjusted hazard ratio, 1.72; 95% confidence interval [CI], 1.20 to 2.47). Patients carrying any two CYP2C19 loss-of-function alleles (*2, *3, *4, or *5), had a higher event rate than patients with none (21.5% vs. 13.3%; adjusted hazard ratio, 1.98; 95% CI, 1.10 to 3.58). Among the 1535 patients who underwent percutaneous coronary intervention during hospitalization, the rate of cardiovascular events among patients with two CYP2C19 loss-of-function alleles was 3.58 times the rate among those with none (95% CI, 1.71 to 7.51).

Conclusions Among patients with an acute myocardial infarction who were receiving clopidogrel, those carrying CYP2C19 loss-of-function alleles had a higher rate of subsequent cardiovascular events than those who were not. This effect was particularly marked among the patients undergoing percutaneous coronary intervention. (ClinicalTrials.gov number, NCT00673036 [ClinicalTrials.gov] .)

Source Information

From Assistance Publique–Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine, and Université Pierre et Marie Curie (UPMC) Paris 06 (T.S., L.Q., E.D.); AP-HP, Hôpital Bicètre, Université Paris Sud 11 (C.V., L.B.); INSERM, Unite 720 (M.M.-K.); AP-HP, Hôpital Bichat; INSERM, Unite 698; and Université Paris 07 (P.G.S.); and AP-HP, Hôpital Européen Georges Pompidou, Université Rene Descartes Paris 05 (N.D.) — all in Paris; Centre Hospitalier Universitaire Besançon, Besançon (N.M.); and INSERM, Unite 558, Toulouse (J.F.) — all in France.

Drs. Danchin and Becquemont contributed equally to this article.

This article (10.1056/NEJMoa0808227) was published at NEJM.org on December 22, 2008.

Address reprint requests to Dr. Simon at the Department of Pharmacology, UPMC, 27 Rue Chaligny, 75012 Paris, France, or at tabassome.simon{at}sat.aphp.fr.

Full Text of this Article

Related Letters:

Cytochrome P-450 Polymorphisms and Response to Clopidogrel
Taubert D., Bouman H. J., van Werkum J. W., Miao J., Liu R., Li Z., Mega J. L., Wiviott S. D., Sabatine M. S.
Extract | Full Text | PDF  
N Engl J Med 2009; 360:2249-2251, May 21, 2009. Correspondence

This article has been cited by other articles:

• Last, E. J., Sheehan, A. H. (2009). Review of recent evidence: Potential interaction between clopidogrel and proton pump inhibitors. Am J Health Syst Pharm 66: 2117-2122 [Abstract] [Full Text]  
• Kushner, F. G., Hand, M., Smith, S. C. Jr, King, S. B. III, Anderson, J. L., Antman, E. M., Bailey, S. R., Bates, E. R., Blankenship, J. C., Casey, D. E. Jr, Green, L. A., Hochman, J. S., Jacobs, A. K., Krumholz, H. M., Morrison, D. A., Ornato, J. P., Pearle, D. L., Peterson, E. D., Sloan, M. A., Whitlow, P. L., Williams, D. O. (2009). 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (Updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (Updating the 2005 Guideline and 2007 Focused Update): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 54: 2205-2241 [Full Text]  
• Montalescot, G., Hulot, J.-S., Collet, J.-P. (2009). Stent thrombosis: who's guilty?. Eur Heart J 30: 2685-2688 [Full Text]  
• Gladding, P., White, H., Voss, J., Ormiston, J., Stewart, J., Ruygrok, P., Bvaldivia, B., Baak, R., White, C., Webster, M. (2009). Pharmacogenetic Testing for Clopidogrel Using the Rapid INFINITI Analyzer: A Dose-Escalation Study. J Am Coll Cardiol Intv 2: 1095-1101 [Abstract] [Full Text]  
• Meschia, J. F. (2009). Pharmacogenetics and Stroke. Stroke 40: 3641-3645 [Abstract] [Full Text]  
• Giugliano, R. P., Braunwald, E. (2009). The Year in Non-ST-Segment Elevation Acute Coronary Syndrome.. J Am Coll Cardiol 54: 1544-1555 [Full Text]  
• Rudez, G., Bouman, H. J., van Werkum, J. W., Leebeek, F. W.G., Kruit, A., Ruven, H. J.T., ten Berg, J. M., de Maat, M. P.M., Hackeng, C. M. (2009). Common Variation in the Platelet Receptor P2RY12 Gene Is Associated With Residual On-Clopidogrel Platelet Reactivity in Patients Undergoing Elective Percutaneous Coronary Interventions. Circ Cardiovasc Genet 2: 515-521 [Abstract] [Full Text]  
• Cuisset, T., Frere, C., Quilici, J., Poyet, R., Gaborit, B., Bali, L., Brissy, O., Morange, P.-E., Alessi, M.-C., Bonnet, J.-L. (2009). Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose the PACA (Proton Pump Inhibitors And Clopidogrel Association) prospective randomized study.. J Am Coll Cardiol 54: 1149-1153 [Abstract] [Full Text]  
• Marin, F., Gonzalez-Conejero, R., Capranzano, P., Bass, T. A., Roldan, V., Angiolillo, D. J. (2009). Pharmacogenetics in cardiovascular antithrombotic therapy.. J Am Coll Cardiol 54: 1041-1057 [Abstract] [Full Text]  
• Giannakopoulos, B., Krilis, S. A. (2009). How I treat the antiphospholipid syndrome. Blood 114: 2020-2030 [Abstract] [Full Text]  
• Shuldiner, A. R., O'Connell, J. R., Bliden, K. P., Gandhi, A., Ryan, K., Horenstein, R. B., Damcott, C. M., Pakyz, R., Tantry, U. S., Gibson, Q., Pollin, T. I., Post, W., Parsa, A., Mitchell, B. D., Faraday, N., Herzog, W., Gurbel, P. A. (2009). Association of Cytochrome P450 2C19 Genotype With the Antiplatelet Effect and Clinical Efficacy of Clopidogrel Therapy. JAMA 302: 849-857 [Abstract] [Full Text]  
• Bhatt, D. L. (2009). Tailoring Antiplatelet Therapy Based on Pharmacogenomics: How Well Do the Data Fit?. JAMA 302: 896-897 [Full Text]  
• Wallentin, L. (2009). P2Y12 inhibitors: differences in properties and mechanisms of action and potential consequences for clinical use. Eur Heart J 30: 1964-1977 [Abstract] [Full Text]  
• Verstuyft, C., Simon, T., Kim, R. B. (2009). Personalized medicine and antiplatelet therapy: ready for prime time?. Eur Heart J 30: 1943-1963 [Full Text]  
• Kumar, A., Roberts, D. H. (2009). Test Before You Stop. Arch Surg 144: 787-787 [Full Text]  
• Holmes, D. R. Jr, Kereiakes, D. J., Kleiman, N. S., Moliterno, D. J., Patti, G., Grines, C. L. (2009). Combining Antiplatelet and Anticoagulant Therapies.. J Am Coll Cardiol 54: 95-109 [Abstract] [Full Text]  
• Varenhorst, C., James, S., Erlinge, D., Brandt, J. T., Braun, O. O., Man, M., Siegbahn, A., Walker, J., Wallentin, L., Winters, K. J., Close, S. L. (2009). Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease. Eur Heart J 30: 1744-1752 [Abstract] [Full Text]  
• Van de Werf, F. (2009). New antithrombotic agents: are they needed and what can they offer to patients with a non-ST-elevation acute coronary syndrome?. Eur Heart J 30: 1695-1702 [Abstract] [Full Text]  
• Norgard, N. B, Mathews, K. D, Wall, G. C (2009). Drug-Drug Interaction Between Clopidogrel and the Proton Pump Inhibitors. The Annals of Pharmacotherapy 43: 1266-1274 [Abstract] [Full Text]  
• Friesen, M. H. (2009). Interaction between clopidogrel and proton pump inhibitors. CMAJ 180: 1228-1228 [Full Text]  
• Juurlink, D. N., Tu, J. V., Mamdani, M. M. (2009). Interaction between clopidogrel and proton pump inhibitors. CMAJ 180: 1229-1229 [Full Text]  
• Pena, A., Collet, J.-P., Hulot, J.-S., Silvain, J., Barthelemy, O., Beygui, F., Funck-Brentano, C., Montalescot, G. (2009). Can We Override Clopidogrel Resistance?. Circulation 119: 2854-2857 [Full Text]  
• Prasad, A., Holmes, D. R (2009). Update on dual antiplatelet therapy for percutaneous coronary intervention. Heart 95: 861-865 [Full Text]  
• Taubert, D., Bouman, H. J., van Werkum, J. W., Miao, J., Liu, R., Li, Z., Mega, J. L., Wiviott, S. D., Sabatine, M. S. (2009). Cytochrome P-450 Polymorphisms and Response to Clopidogrel. NEJM 360: 2249-2251 [Full Text]  
• Price, M. J. (2009). Bedside Evaluation of Thienopyridine Antiplatelet Therapy. Circulation 119: 2625-2632 [Full Text]  
• Mega, J. L., Close, S. L., Wiviott, S. D., Shen, L., Hockett, R. D., Brandt, J. T., Walker, J. R., Antman, E. M., Macias, W. L., Braunwald, E., Sabatine, M. S. (2009). Cytochrome P450 Genetic Polymorphisms and the Response to Prasugrel: Relationship to Pharmacokinetic, Pharmacodynamic, and Clinical Outcomes. Circulation 119: 2553-2560 [Abstract] [Full Text]  
• Roden, D. M., Stein, C. M. (2009). Clopidogrel and the Concept of High-Risk Pharmacokinetics. Circulation 119: 2127-2130 [Full Text]  
• Desai, N. R., Mega, J. L., Jiang, S., Cannon, C. P., Sabatine, M. S. (2009). Interaction between cigarette smoking and clinical benefit of clopidogrel.. J Am Coll Cardiol 53: 1273-1278 [Abstract] [Full Text]  
• Lau, W. C., Gurbel, P. A. (2009). The drug-drug interaction between proton pump inhibitors and clopidogrel. CMAJ 180: 699-700 [Full Text]  
• Juurlink, D. N., Gomes, T., Ko, D. T., Szmitko, P. E., Austin, P. C., Tu, J. V., Henry, D. A., Kopp, A., Mamdani, M. M. (2009). A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ 180: 713-718 [Abstract] [Full Text]  
• Ho, P. M., Maddox, T. M., Wang, L., Fihn, S. D., Jesse, R. L., Peterson, E. D., Rumsfeld, J. S. (2009). Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome. JAMA 301: 937-944 [Abstract] [Full Text]  
• (2009). Pharmacogenetics of Clopidogrel. JWatch Oncology and Hematology 2009: 2-2 [Full Text]  
• Freedman, J. E., Hylek, E. M. (2009). Clopidogrel, Genetics, and Drug Responsiveness. NEJM 360: 411-413 [Full Text]  
• (2009). Does Genotype Affect a Patient's Response to Clopidogrel?. Journal Watch Cardiology 2009: 1-1 [Full Text]