Impact of CYP2C19 Metabolizer Status on Patients With ACS Treated With Prasugrel Versus Clopidogrel

doi:10.1016/j.jacc.2015.12.036

Journal of the American College of Cardiology

Volume 67, Issue 8, 1 March 2016, Pages 936-947

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Abstract

Background

Certain alleles of the CYP2C19 gene are associated with higher platelet reactivity and increased ischemic events among patients treated with clopidogrel. However, the relationship of CYP2C19 genotype and outcomes in medically managed patients with acute coronary syndromes (ACS) is not known.

Objectives

This study sought to assess the effect of CYP2C19 genotype on ischemic outcomes in patients with ACS initially managed medically without revascularization who were randomized to either clopidogrel or prasugrel.

Methods

We classified patients as extensive metabolizers (EM) or reduced metabolizers (RM) based on CYP2C19 genotype and evaluated ischemic outcomes and platelet reactivity. Among 9,326 patients enrolled from 2008 to 2011, 5,736 participated in the genetics cohort; of these, 2,236 had platelet function testing data.

Results

There was no association between CYP2C19 metabolizer status (EM vs. RM) and the primary composite endpoint of cardiovascular death, myocardial infarction (MI), or stroke (hazard ratio [HR]: 0.86). EM and RM patients had similar rates of the primary endpoint whether treated with prasugrel (HR: 0.82) or clopidogrel (HR: 0.91; p for interaction = 0.495). After adjusting for clinical and treatment variables, EM patients had a lower risk of MI versus RM patients (HR: 0.80), but risks of other outcomes were similar. RM patients had significantly higher mean P2Y₁₂ reaction units versus EM patients when treated with clopidogrel (39.93), but not with prasugrel (3.87).

Conclusions

CYP2C19 metabolizer status is not associated with the composite outcome of cardiovascular death, MI, or stroke in medically managed ACS patients treated with clopidogrel or prasugrel. Our findings do not support routine CYP2C19 genetic testing in this population. (A Comparison of Prasugrel and Clopidogrel in Acute Coronary Syndrome Subjects [TRILOGY ACS]; NCT00699998)

Key Words

acute coronary syndrome

dual antiplatelet therapy

genetics

platelets

Abbreviations and Acronyms

ACS

acute coronary syndrome

confidence interval

CYP

cytochrome P450

extensive metabolizer(s)

FDA

U.S. Food and Drug Administration

hazard ratio

myocardial infarction

NSTEMI

non–ST-segment elevation myocardial infarction

PCI

percutaneous coronary intervention

PRU

P2Y₁₂ reaction unit

reduced metabolizer(s)

unstable angina

Cited by (0)

: The TRILOGY ACS study was supported by Daiichi-Sankyo Incorporated and Eli Lilly and Company. The study sponsors had no role in the conception and design of this study or in creating the first draft of the manuscript. Employees of Eli Lilly (Drs. Winters, Duvvuru, and Jakubowski) and Cabernet Pharmaceuticals (Dr. Sundseth) participated as authors during subsequent drafts of the manuscript. All data analyses were performed independently by the Duke Clinical Research Institute. Dr. Roe receives research funding from Eli Lilly and Company, Sanofi, Daiichi-Sankyo, Janssen Pharmaceuticals, Ferring Pharmaceuticals, American College of Cardiology, American Heart Association, and the Familial Hypercholesterolemia Foundation; and consulting or honoraria from Pri-Med, AstraZeneca, Boehringer Ingelheim, Merck, Amgen, Myokardia, Eli Lilly, and Elsevier Publishers. Dr. Armstrong has received consulting fees from Eli Lilly and Company, Hoffmann-La Roche, Merck & Co., Axio Research, and Orexigen; grant support from Boehringer Ingelheim, Hoffmann-La Roche, Sanofi, Scios, Ortho Biotech, Johnson & Johnson, Janssen Pharmaceuticals, GlaxoSmithKline, Amylin Pharmaceuticals, and Merck & Co.; and payment for developing educational presentations from AstraZeneca and Eli Lilly and Company. Dr. White has received grant support from Sanofi, Eli Lilly and Company, the National Institutes of Health (NIH), Merck Sharp & Dohme, AstraZeneca, GlaxoSmithKline, Daiichi-Sankyo Pharma Development, George Institute, Omthera Pharmaceuticals, Pfizer New Zealand, Intarcia Therapeutics Inc., Elsai Inc., and DalGen Products and Services; and participates in advisory boards for AstraZeneca. Dr. Prabhakaran has received research grants from Eli Lilly and Company and the Medtronic Foundation; and honoraria from Eli Lilly and Company. Drs. Winters, Duvvuru, and Jakubowski are employees of Eli Lilly and Company. Dr. Sundseth is an employee of Cabernet Pharmaceuticals, Inc. Dr. Gurbel has served as a consultant for Daiichi-Sankyo, Eli Lilly and Company, Bayer, AstraZeneca, Boehringer Ingelheim, Merck & Co., CSL, Janssen, and New Haven Pharmaceuticals; received grants from the NIH, Daiichi-Sankyo, Merck, New Haven Pharmaceuticals, Haemonetics, Sinnowa, Coramed, and Duke Clinical Research Institute; and holds patents in the area of personalized antiplatelet therapy and interventional cardiology. Dr. Bhatt has served on the advisory boards of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, and Regado Biosciences; served on the board of directors of Boston VA Research Institute and Society of Cardiovascular Patient Care; has chaired the American Heart Association Get With The Guidelines Steering Committee; has served on the data monitoring committees of Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, and Population Health Research Institute; has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC. org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including TRILOGY ACS), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Associate Editor; Section Editor, Pharmacology), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), WebMD (CME steering committees), and Clinical Cardiology (Deputy Editor); has received research funding from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi, The Medicines Company; has served as site co-investigator for Biotronik and St. Jude Medical; is a trustee of the American College of Cardiology; and has received unfunded research grants from FlowCo, PLx Pharma, and Takeda. Dr. Ohman has received grant support and travel expenses from Daiichi-Sankyo and Eli Lilly and Company; consulting fees from Abiomed, AstraZeneca, Biotie, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly and Company, Gilead Sciences, Janssen Pharmaceuticals, Liposcience, Merck & Co., Pozen, Hoffmann-La Roche, Sanofi, Stealth Peptides, The Medicines Company, Medscape, and Web MD; grant support from Gilead Sciences; and lecture fees from Gilead Sciences, Boehringer Ingelheim, and The Medicines Company. Dr. Fox has received research grants from Eli Lilly and Company, Bayer, Johnson & Johnson, and AstraZeneca; speakers bureau payments from Bayer, Johnson & Johnson, AstraZeneca, and Sanofi; and consulting/other payments from Bayer, Johnson & Johnson, AstraZeneca, Sanofi/Regeneron, Boehringer Ingelheim, GlaxoSmithKline, and Eli Lilly and Company. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Matthew Price, MD, served as Guest Editor for this paper.

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