Author + information
- Received July 30, 2015
- Revision received December 2, 2015
- Accepted December 3, 2015
- Published online March 1, 2016.
- Jacob A. Doll, MDa,
- Megan L. Neely, PhDb,
- Matthew T. Roe, MD, MHSa,b,
- Paul W. Armstrong, MDc,
- Harvey D. White, MB, ChB, DScd,
- Dorairaj Prabhakaran, MD, DM, MSce,
- Kenneth J. Winters, MDf,
- Suman Duvvuru, PhDf,
- Scott S. Sundseth, PhDg,
- Joseph A. Jakubowski, PhDf,
- Paul A. Gurbel, MDh,
- Deepak L. Bhatt, MD, MPHi,
- E. Magnus Ohman, MDa,b,
- Keith A.A. Fox, MB, ChBj,∗ (, )
- TRILOGY ACS Investigators
- aDivision of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
- bDuke Clinical Research Institute, Durham, North Carolina
- cCanadian VIGOUR Centre, Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
- dGreen Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand
- eCentre for Chronic Disease Control and Public Health Foundation of India, New Delhi, India
- fEli Lilly and Company, Indianapolis, Indiana
- gCabernet Pharmaceuticals, Chapel Hill, North Carolina
- hInova Center for Thrombosis Research and Drug Development, Inova Heart and Vascular Institute, Falls Church, Virginia
- iBrigham and Women’s Hospital Heart & Vascular Center and Harvard Medical School, Boston, Massachusetts
- jBritish Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland, United Kingdom
- ↵∗Reprint requests and correspondence:
Prof. Keith A.A. Fox, British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, Scotland, United Kingdom.
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)
Dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor is a cornerstone of treatment for acute coronary syndromes (ACS). Clopidogrel and prasugrel are P2Y12 receptor inhibitor prodrugs that require conversion to active metabolites via the cytochrome P450 (CYP) system. Certain alleles of CYP2C19 are associated with reduced enzymatic function and reduced conversion of clopidogrel to the active metabolite. Patients carrying these reduced-function alleles (reduced metabolizers [RM]) exhibit higher platelet reactivity when treated with clopidogrel, compared with patients without reduced-function alleles (extensive metabolizers [EM]) (1,2). Clopidogrel-treated RM patients also appear to have greater risk of ischemic events after percutaneous coronary intervention (PCI) (3–6).
However, the relationship between metabolizer status and ischemic outcomes is less clear among other patient populations, including those managed medically for ACS. A systematic review and meta-analysis that examined data from 32 studies comprising an aggregate of 42,016 patients found no association between genotype and cardiovascular events after consideration of small-study bias (7). If an association does exist, it may be greater among patients treated with PCI, potentially due to an increased risk of stent thrombosis (6,8,9).
By contrast, CYP2C19 genotype does not appear to be associated with platelet reactivity or clinical outcomes for patients treated with prasugrel (10), likely because conversion to the active metabolite is more efficient and less dependent on CYP family genetic variation (11). Therefore, identification of reduced-function CYP2C19 alleles could guide selection or dose of P2Y12 receptor inhibitor therapy after ACS, affording the potential to reduce recurrent cardiovascular events. In 2010, the U.S. Food and Drug Administration (FDA) added a “boxed warning” to the prescribing information for clopidogrel that indicates a role for genetic testing for patients taking clopidogrel, with consideration of “other antiplatelet medications or alternative dosing strategies” for poor metabolizers (12). Despite this, the effect of CYP2C19 polymorphisms on clinical outcomes remains unclear, especially among ACS patients who are managed medically without revascularization.
We therefore performed a large genetic substudy within the TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) trial, a randomized, event-driven trial comparing prasugrel to clopidogrel among patients with unstable angina (UA) or non–ST-segment elevation myocardial infarction (NSTEMI) who were initially medically managed without revascularization. There was no significant difference in clinical outcomes between treatment groups in the overall study (13), although prasugrel therapy was associated with lower platelet reactivity compared with clopidogrel (14). In the present study, we sought to determine whether CYP2C19 metabolizer status was associated with clinical outcomes and platelet reactivity among patients treated with prasugrel or clopidogrel.
The detailed design and results of the TRILOGY ACS study have been reported (13,15). Briefly, 9,326 patients with UA or NSTEMI were enrolled from 966 sites in 52 countries from 2008 to 2011. Patients were eligible if they were selected for a treatment strategy of medical management without revascularization. Patients were randomly assigned to treatment with clopidogrel or prasugrel in a double-blind, double-dummy fashion. The daily prasugrel maintenance dose was 10 mg/day for patients <75 years of age and with weight ≥60 kg. A 5 mg/day maintenance dose was used for patients aged ≥75 years and/or weighing <60 kg. The clopidogrel maintenance dose was 75 mg/day. Patients randomized within 72 h of first medical contact without prior clopidogrel use received a loading dose of prasugrel (30 mg) or clopidogrel (300 mg). Patients randomized after 72 h were required to be treated with clopidogrel before receiving the maintenance dose of study drug.
All sites were encouraged to participate in the genetics cohort if permitted by national and local regulations and approved by the applicable institutional review boards. Sites from 46 of the 52 countries participating in the TRILOGY ACS study contributed to the genetics substudy. Patient provision of blood samples for genetic analysis at these sites was voluntary and subject to informed consent separate from that of the overall TRILOGY study. Sites from Brazil, Egypt, Thailand, Tunisia, Greece, and Costa Rica did not enroll any patients in the genetics cohort.
Deoxyribonucleic acid was extracted from peripheral blood using standard methods. Genotyping was performed using the Drug Metabolizing Enzyme and Transporter Gene (DMET) Plus assay system (Affymetrix, Santa Clara, California) at Covance Genomic Laboratories (Seattle, Washington). Genotyping success rate was 99.3%. Variants of the CYP2C19 gene were classified by predicted metabolic phenotype according to published data-based predictions (16–18). The EM phenotype was defined as the combination of alleles *1/*1, *1/*17, or *17/*17. The RM phenotype was defined as *1/*2–*8 or *2–*8/*2–*8. A genotype of *2–*8/*17 is of uncertain metabolic function, and patients with this genotype were not included in the analysis (Table 1).
Sites from 25 of the 52 participating countries were selected for inclusion in an embedded platelet function substudy and requested to enroll patients for both genetic and platelet function testing, as previously reported (13). Countries were selected to provide balance across geographic regions, but no specific criteria were used. Blood samples were collected at baseline, at 2 h, and at 1, 3, 6, 12, 18, 24, and 30 months for patients taking the blinded study drug at each time point. Samples were analyzed with an encrypted VerifyNow device (Accumetrics, San Diego, California), and results were expressed as P2Y12 reaction units (PRUs) (19). We excluded the baseline and 2-h samples from analysis because most patients were treated with clopidogrel before initiation of the study drug, which would affect the PRU values from these samples. PRU values were also excluded if the device-reported percent inhibition exceeded 100% and if the assay was performed <10 min or >4 h after sample collection via venipuncture (14). Patients with both genetic and platelet function data were included in the genetics-pharmacodynamic cohort.
The primary efficacy endpoint for the overall TRILOGY ACS trial was the composite of cardiovascular death, recurrent myocardial infarction (MI), or stroke at 30 months. Secondary efficacy endpoints included all-cause death and the individual components of the composite endpoint. Among patients with platelet function data, a secondary endpoint was the PRU value, assessed both longitudinally and at 1 month.
Baseline demographic, clinical, and treatment characteristics were compared between EM and RM patients among both the genetics and the genetics-pharmacodynamic cohorts. Continuous variables were presented as median (interquartile range) and compared using the analysis of variance F test when assumption of normality was satisfied; otherwise, the Kruskal-Wallis test was used. Categorical variables were presented as counts (proportions) and compared using the chi-square test when appropriate; otherwise, an exact test was used. To describe the relationship between CYP2C19 metabolic phenotype and ischemic outcomes, event counts and Kaplan-Meier rates at 30 months were calculated. Kaplan-Meier curves were then created for each clinical outcome and stratified by CYP2C19 phenotype and by treatment with clopidogrel versus prasugrel.
The relationship between CYP2C19 phenotype and clinical outcomes was assessed by fitting a Cox proportional hazards model for time to first event. To determine whether this relationship differed between treatment arms, an interaction term between CYP2C19 phenotype and treatment assignment was tested. Variables included in the adjusted model were age, weight, sex, NSTEMI presentation, Killip class I at presentation, time from presentation to randomization, family history of coronary artery disease, hypertension, hyperlipidemia, diabetes, current or recent smoker, previous MI, previous coronary artery bypass graft, previous peripheral arterial disease, previous atrial fibrillation, previous heart failure, systolic blood pressure at baseline, heart rate at baseline, angiography at randomization, hemoglobin, creatinine, beta-blocker at baseline, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker at baseline, statin at baseline, proton-pump inhibitor at baseline, use of angiography, time from randomization to study drug initiation, study region (7 regions), study treatment (prasugrel vs. clopidogrel), and time of initial clopidogrel treatment (home use, during first 72 h of hospitalization, or none).
The relationship between CYP2C19 phenotype and platelet reactivity was assessed with measurement of PRU values at 1 month and longitudinally in order to determine whether there is an early difference in platelet reactivity and whether any difference is maintained over long-term follow-up. First, we assessed patterns of missingness in PRU data to determine the potential for bias. Heat-map–style plots of observed missingness were created for the overall cohort and by CYP2C19 phenotype. Missingness patterns were similar across the 2 treatment groups, and missing values were most likely explained by occurrence of a terminal event or by discontinuation of the study drug, neither of which were expected to produce an unrepresentative sample at each time point analyzed in the repeated measures analysis.
Next, the association of CYP2C19 phenotype with longitudinal PRU value was assessed by fitting a mixed-effects linear model with longitudinal PRU values as the response and the CYP2C19 phenotype as the covariate. A random intercept model with compound symmetric covariance matrix was fit in this analysis because PRU trajectories remained relatively flat across the follow-up period starting at 1 month. This model handles missingness using maximum likelihood estimation, using the assumption that missingness is not informative. The association of CYP2C19 phenotype with 1-month PRU values was assessed with a linear model.
Finally, both longitudinal and 1-month PRU models were adjusted by prior clopidogrel exposure (no clopidogrel before randomization vs. started in-hospital before randomization vs. home clopidogrel use) and age strata (<75 years vs. ≥75 years). To determine whether these relationships differ between the P2Y12 receptor inhibitor treatment arms, an interaction term between CYP2C19 phenotype and treatment assignment was tested in both models.
All statistical tests were performed at a significance level of 0.05. Analyses were performed at the Duke Clinical Research Institute, Durham, North Carolina, using SAS version 9.3 (Cary, North Carolina) and R version 2.14.1 (R Foundation for Statistical Computing, Vienna, Austria).
The TRILOGY ACS trial enrolled 9,326 study participants, of whom 5,736 (62%) participated in the genetic cohort (Figure 1). On the basis of CYP2C19 genetic polymorphisms, 3,870 (67.5%) of these were classified as EM, 1,420 (24.7%) were RM, and 446 (7.8%) were unknown. These functional variants were similarly distributed among the prasugrel and clopidogrel arms (Table 1). Within the genetics cohort, 2,236 (39%) patients had at least 1 valid PRU measurement and were included in the genetics-pharmacodynamic cohort; these patients had similar baseline and treatment characteristics to the overall trial population (Online Table 1). There were modest differences between EM and RM patients, with the latter having lower body weight and lower rates of prior heart failure. RM patients were more likely to be enrolled at sites in East Asia or the Indian subcontinent and less likely to be enrolled in Europe (Table 2).
Overall, 468 patients died; of these, 373 died of cardiovascular causes. A total of 453 patients experienced recurrent MI, and 87 experienced a stroke. EM patients had numerically lower rates of the primary composite endpoint at 30 months (18.1% vs. 20.0%; p = 0.07) (Figure 2) and the secondary endpoints of cardiovascular death (9.4% vs. 11.1%; p = 0.12) and MI (10.5% vs. 11.9%; p = 0.11). After adjusting for clinical and treatment covariates, the risk of MI was lower for EM patients (hazard ratio [HR]: 0.80; 95% confidence interval [CI]: 0.65 to 1.00). There was no significant difference in other clinical endpoints after adjustment, including the primary endpoint (HR: 0.85; 95% CI: 0.72 to 1.01) (Table 3). Among a subset of patients with angiographically demonstrated coronary artery disease or prior MI, there was no significant relationship between CYP2C19 phenotype and outcomes (Online Table 2). Also, no significant differences were noted when examining ischemic outcomes of the metabolizer phenotype subgroups: ultra-metabolizers, extensive metabolizers, intermediate metabolizers, and poor metabolizers (Online Table 3). Pairwise comparisons of ultra-metabolizers with the other phenotypic subgroups did not demonstrate significant differences. Finally, we tested whether the hazard ratio for the RM versus EM phenotype was different for early (0 to 30 days) versus late period and observed no significant findings.
When stratified by P2Y12 receptor inhibitor treatment, EM patients had similar rates of the composite endpoint compared with RM patients, whether randomized to treatment with prasugrel (HR: 0.82; 95% CI: 0.65 to 1.03) or clopidogrel (HR: 0.91; 95% CI: 0.73 to 1.14). Secondary outcomes of all-cause death, cardiovascular death, MI, and stroke were also similar for EM and RM. These differences remained nonsignificant after adjustment (Figure 3).
Among patients with PRU measurements (genetics-pharmacodynamic cohort), longitudinal PRU values differed by CYP2C19 functional variant status in the clopidogrel arm but not in the prasugrel arm. Among patients treated with clopidogrel, mean PRU at 30 days was 230.9 for RM patients and 182.4 for EM patients. Longitudinal mean PRU values were significantly higher among RM patients (HR: 39.93; 95% CI: 30.00 to 49.87) compared with EM patients. However, among patients treated with prasugrel, 30-day mean PRU values were similar for EM (108.8) and RM patients (111.1) and longitudinal platelet reactivity did not differ (HR: 3.87; 95% CI: −6.57 to 14.31) (Figure 4). These findings were maintained when comparing only 30-day PRU values and after adjusting for age strata and time of initiation of P2Y12 inhibitor (Table 4).
In this genetic substudy of 5,736 patients from a randomized, controlled trial of prasugrel versus clopidogrel for the treatment of UA/NSTEMI among medically managed ACS patients, there was no significant association between CYP2C19 metabolizer status and the composite primary endpoint of cardiovascular death, MI, or stroke (Central Illustration). Outcomes were similar for EM and RM patients whether treated with prasugrel or clopidogrel. For patients treated with clopidogrel, platelet reactivity was higher among RM patients compared with EM patients, although this was not reflected in a difference in ischemic events.
These findings are in contrast to some studies of CYP2C19 functional variants and outcomes. A substudy of TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction) including 1,477 patients with ACS and planned PCI who were treated with clopidogrel showed that patients with at least 1 reduced-function allele had higher on-treatment platelet reactivity and increased risk of the composite endpoint of cardiovascular death, MI, or stroke (HR: 1.53; 95% CI: 1.07 to 2.19) (4). A genetic cohort of the PLATO (Study of Platelet Inhibition and Patient Outcomes) trial comparing clopidogrel to ticagrelor, an alternative P2Y12 receptor inhibitor that does not require metabolic activation, found higher event rates at 30 days among the clopidogrel treatment arm for patients with versus without a reduced-function allele. However, these differences were not significant at 1 year and the magnitude of difference was less than in the TRITON-TIMI 38 substudy (20). The PLATO study allowed enrollment of ACS patients with planned medical therapy, as opposed to TRITON-TIMI 38 in which all participants had planned PCI. Among clopidogrel-treated patients in these 3 large randomized trials, a diminishing association of genotype with outcomes corresponded with a decrease in the percentage of patients with initial invasive treatment (4,20). The contrasting results of these studies could be explained by the amplification of platelet activity in ACS patients undergoing PCI and the impact of P2Y12-mediated platelet reactivity in determining the risk of stent thrombosis and subsequent ischemic events (21). In fact, among patients treated with clopidogrel, stent thrombosis was significantly more likely in the TRITON-TIMI 38 trial for carriers of a reduced-function allele (2.6% vs. 0.8%; p = 0.02), and the PLATO trial showed a similar trend among clopidogrel- and PCI-treated patients (2.3% vs. 1.5%). Hence, the differences in CYP2C19 metabolizer status may be more important for patients treated with PCI.
Our study did confirm prior observations of the relationship of CYP2C19 metabolizer status with platelet reactivity. Among prasugrel-treated patients, there was no difference in platelet reactivity between EM and RM patients, consistent with previous clinical and pharmacokinetic/pharmacodynamic studies (17,22). Clopidogrel-treated patients did demonstrate higher on-treatment platelet reactivity when carrying a reduced-function allele. However, this did not correspond with an increased event rate. The mean adjusted difference in PRU values (39.2 longitudinal and 48.4 at 1 month) may not have been sufficient to result in differential clinical outcomes. Alternatively, on-treatment PRU values may not be strongly related to outcomes among patients who undergo a medical management strategy for ACS. The findings in this study are in concert with results of the full TRILOGY platelet function substudy (14), which found lower platelet reactivity with prasugrel treatment compared with clopidogrel, but no significant association between platelet reactivity and ischemic outcomes. Differences in platelet reactivity, whether resultant from genetic variation or treatment effects, do not appear to impact ischemic outcomes in this medically managed population.
The potentially causal link between CYP2C19 phenotype, platelet reactivity, and ischemic outcomes has promoted interest in the use of genetic testing for “personalized” selection of P2Y12 inhibitor agent and dose (23). Among patients with stable coronary disease, tripling the maintenance clopidogrel dose (225 mg/day) for patients with 1 reduced-function CYP2C19 allele achieved similar reductions in platelet reactivity as the standard dose among patients without a reduced-function allele (24). Multiple ongoing clinical trials are testing a strategy of selective use of prasugrel or ticagrelor for patients with the RM phenotype presenting with MI or undergoing PCI (NCT01823185, NCT01641510, NCT02048228, NCT01452139, NCT01742117, and NCT01390974).
However, our findings do not support the use of CYP2C19 genetic testing for selection of P2Y12 receptor inhibitor therapy after ACS for patients without planned PCI. After statistical adjustment, we found a decreased risk of MI among EM patients of borderline significance, whereas risk for other endpoints did not differ. This indicates that CYP2C19 genetic data provided minimal additional prognostic information beyond the common clinical variables used for adjustment in our study.
It is possible that the study was underpowered to detect an association between CYP2C19 status and outcomes. Our data showed a trend toward lower risk of events for EM patients. This reached borderline statistical significance for the MI outcome after adjustment. However, the large sample size argues against a substantial effect of CYP2C19 on outcomes. Additionally, the nonsignificant trend was less pronounced among clopidogrel-treated patients, the proposed target of CYP2C19-guided therapy. We also did not include all genetic polymorphisms that could influence platelet reactivity and clinical events during treatment with clopidogrel or prasugrel. Other CYP or non-CYP gene variants may contribute to response to P2Y12 inhibitor therapy. PRU values collected during the index hospitalization (at baseline and 2 h) were not analyzed due to frequent early use of nonrandomized clopidogrel in this trial, so we cannot assess the association of CY2C19 genotype with early platelet inhibition. Our cohort was predominantly from Europe and North America, and had a high burden of comorbidities, and our results may not be generalizable to other populations. This analysis was performed in a subset of the full trial population because not all patients provided consent for genetic testing and not all sites were able to perform genetic or PRU testing. This could introduce selection bias, and in fact, Central/Eastern Europe was overrepresented in the genetics cohort. However, extensive statistical adjustment, including for site region, did not alter the overall findings. Our study included few patients with 2 reduced-function alleles (poor metabolizers), the group of patients referred to in the FDA “boxed warning” for clopidogrel. Thus, we cannot specifically exclude an association of CYP2C19 metabolizer status and outcomes among this group. Finally, the TRILOGY study enrolled only patients with planned noninvasive management, and one-quarter of patients in our study did not have elevated cardiac biomarkers. As such, our findings cannot be generalized to the broader MI population.
Among UA/NSTEMI patients treated with clopidogrel or prasugrel with planned noninvasive treatment strategy, CYP2C19 functional variants were not associated with the composite outcome of cardiovascular death, MI, or stroke. These findings suggest that CYP2C19 genetic testing does not inform decision making regarding the use of either clopidogrel or prasugrel among medically managed UA/NSTEMI patients. Future studies could explore alternative genetic and nongenetic predictors of response to P2Y12 receptor inhibitor therapy in this population.
COMPETENCY IN MEDICAL KNOWLEDGE: Certain alleles of the CYP2C19 gene are associated with reduced conversion of clopidogrel to its active metabolite, leading to higher on-treatment platelet reactivity for some patients. However, among medically treated patients with non–ST-segment elevation ACS, CYP2C19 status is not associated with the composite of cardiovascular death, MI, or stroke, whether treated with clopidogrel or prasugrel.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: Because CYP2C19 variants are not associated with clinical outcomes in patients with ACS managed without revascularization, genetic testing may not help guide antiplatelet therapy for this patient population.
TRANSLATIONAL OUTLOOK: Future studies should explore alternative genetic and nongenetic predictors of response to P2Y12 inhibitor therapy.
The authors thank the following: Karen Pieper, MS, for expert coordination and management of the statistical analytic team; Jonathan McCall, MS, for expert editorial assistance, and Kerry Stenke for expert graphics assistance. Ms. Pieper, Mr. McCall, and Ms. Stenke are employees of the Duke Clinical Research Institute, Durham, North Carolina; none received any compensation for their work on this manuscript other than their usual salaries.
For supplemental tables, please see the online version of this article.
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.
- Abbreviations and Acronyms
- acute coronary syndrome
- confidence interval
- cytochrome P450
- extensive metabolizer(s)
- U.S. Food and Drug Administration
- hazard ratio
- myocardial infarction
- non–ST-segment elevation myocardial infarction
- percutaneous coronary intervention
- P2Y12 reaction unit
- reduced metabolizer(s)
- unstable angina
- Received July 30, 2015.
- Revision received December 2, 2015.
- Accepted December 3, 2015.
- American College of Cardiology Foundation
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