Author + information
- Received July 11, 2016
- Revision received November 11, 2016
- Accepted January 1, 2017
- Published online March 20, 2017.
- Emily S. Lau, MDa,
- Eugene Braunwald, MDb,
- Sabina A. Murphy, MPHb,
- Stephen D. Wiviott, MDb,
- Marc P. Bonaca, MD, MPHb,
- Steen Husted, MDc,†,
- Stefan K. James, MD, PhDd,
- Lars Wallentin, MD, PhDd,
- Peter Clemmensen, MD, PhDe,f,
- Matthew T. Roe, MD, MHSg,
- E. Magnus Ohman, MDg,
- Robert A. Harrington, MDh,
- Jessica L. Mega, MD, MPHi,
- Deepak L. Bhatt, MD, MPHb,
- Marc S. Sabatine, MD, MPHb and
- Michelle L. O’Donoghue, MD, MPHb,∗ ()
- aDepartment of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
- bTIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts
- cDepartment of Cardiology, Århus University Hospital, Århus, Denmark
- dDepartment of Medical Sciences and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden
- eDepartment of General and Interventional Cardiology, University Heart Center Hamburg-Eppendorf, Hamburg, Germany
- fDepartment of Medicine, Nykoebing F Hospital, University of Southern Denmark, Odense, Denmark
- gDivision of Cardiology, Duke Clinical Research Institute, Durham, North Carolina
- hDepartment of Medicine, Stanford University, Stanford, California
- iVerily Life Sciences, Mountain View, California
- ↵∗Address for correspondence:
Dr. Michelle L. O’Donoghue, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, 60 Fenwood Road, 7th Floor, Boston, Massachusetts 02115.
Background Sex-specific differences in response to antiplatelet therapies have been described. Whether women and men derive comparable benefit from intensification of antiplatelet therapy remains uncertain.
Objectives The study investigated the efficacy and safety of the potent P2Y12 inhibitors in patients with coronary artery disease.
Methods A collaborative sex-specific meta-analysis was conducted of phase III or IV randomized trials of potent P2Y12 inhibitors, including prasugrel, ticagrelor, and intravenous cangrelor. Seven trials were included that enrolled a total of 24,494 women and 63,346 men. Major adverse cardiovascular events (MACE) were defined as the primary endpoint for each trial.
Results Potent P2Y12 inhibitors significantly reduced the risk of MACE by 14% in women (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.78 to 0.94) and by 15% in men (HR: 0.85; 95% CI: 0.80 to 0.90; p interaction = 0.93). Treatment reduced the risk of myocardial infarction by 13% in women (HR: 0.87; 95% CI: 0.78 to 0.96) and 16% in men (HR: 0.84; 95% CI: 0.77 to 0.91; p interaction = 0.65), and the risk of stent thrombosis by 51% in women (HR: 0.49; 95% CI: 0.37 to 0.65) and 41% in men (HR: 0.59; 95% CI: 0.42 to 0.84; p interaction = 0.85). Directional consistency was seen for cardiovascular death in women (HR: 0.87; 95% CI: 0.76 to 1.01) and men (HR: 0.85; 95% CI: 0.77 to 0.95; p interaction = 0.86). The potent P2Y12 inhibitors increased major bleeding in women (HR: 1.28; 95% CI: 0.87 to 1.88) and men (HR: 1.52; 95% CI: 1.12 to 2.07; p interaction = 0.62).
Conclusions In randomized trials, the efficacy and safety of the potent P2Y12 inhibitors were comparable between men and women. Given these data, sex should not influence patient selection for the administration of potent P2Y12 inhibitors.
Guideline recommendations now support the use of the potent P2Y12 inhibitors, including prasugrel and ticagrelor, for the management of patients after an acute coronary syndrome (ACS) (1,2). In addition, ticagrelor has demonstrated long-term cardiovascular (CV) efficacy in patients more than 1 year after a myocardial infarction (MI) (3). The intravenous P2Y12 inhibitor cangrelor has been shown to be superior to clopidogrel when administered at the time of urgent or elective percutaneous cardiovascular intervention (PCI) (4).
Because women remain under-represented in CV trials (5), the efficacy and safety of these novel agents in women is less well established (6). These concerns are perhaps more relevant, given that sex-specific differences in the pharmacodynamics and clinical efficacy of other antiplatelet therapies, including aspirin (7), clopidogrel (8), and glycoprotein IIb/IIIa inhibitors (9), have been previously described (10). Moreover, several reports have indicated that women are at increased risk of bleeding after ACS and PCI, as compared with men, yet results have not always been consistent (11–16).
Because individual studies of these antiplatelet agents have been underpowered to examine outcomes within patient subgroups, we conducted a collaborative sex-specific meta-analysis to examine the relative efficacy and safety of the potent P2Y12 inhibitors in women versus men with stable and unstable coronary artery disease (CAD).
A computerized search of published studies was conducted from January 2006 until June 2016 of the MEDLINE, PubMed, ClinicalTrials.gov, and Cochrane databases to identify all phase III or IV randomized clinical trials that were designed primarily to examine the CV efficacy and safety of the potent P2Y12 inhibitors in patients with CAD, including prasugrel, ticagrelor, and cangrelor (Online Appendix) (3,4,17–21). Trials were considered for inclusion regardless of whether there was an active or placebo-treated comparator arm and regardless of treatment duration (Online Figure 1). Trials were excluded from participation if patients in both treatment arms received a more potent P2Y12 inhibitor, if clinical efficacy or safety outcomes were not reported, or if fewer than 100 clinical outcome events were reported (Online Figure 1).
We identified 1,822 potential titles for inclusion in the analysis on the basis of broad search criteria. Twenty-six randomized controlled trials were identified, and a total of 7 trials fulfilled all criteria for inclusion (Table 1, Online Figure 1) (3,4,17–21). The principal investigators of each trial agreed to participate in a collaborative meta-analysis and contributed sex-specific data in tabular format. Of these 7 trials, 6 trials had an active comparator (clopidogrel) and 1 trial (PEGASUS–TIMI 54 [Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis In Myocardial Infarction 54]) was placebo-controlled (Table 1).
Endpoints and data extraction
The primary efficacy outcome of interest was major adverse cardiovascular events (MACE), which was defined as the original primary endpoint for each trial (Table 1). Additional efficacy outcomes of interest included the composite of CV death, MI, or stroke, and the individual elements of CV death, MI, stroke, as well as stent thrombosis (Academic Research Consortium [ARC] definite and ARC definite or probable) (22). The primary safety outcome was pre-specified to be Thrombolysis In Myocardial Infarction (TIMI) major bleeding (non–coronary artery bypass graft surgery [CABG]-related). Additional safety outcomes that were collected included TIMI (non–CABG-related) minor bleeding, TIMI (non-CABG-related) major or minor bleeding, all-cause mortality, and intracranial hemorrhage (ICH).
Stent thrombosis was not a predefined endpoint in the TRILOGY-ACS (A Comparison of Prasugrel and Clopidogrel in Acute Coronary Syndrome Subjects) trial (21) because patients were to be medically managed without PCI. CV death and ICH were not predefined endpoints in the CHAMPION (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) PCI and CHAMPION PLATFORM trials (19,20); therefore, all-cause death was used in relevant endpoints, rather than CV death. Stroke and ARC probable stent thrombosis were not predefined endpoints in the CHAMPION PHOENIX trial due to the short duration of follow-up (4). ICH was captured in the CHAMPION PHOENIX trial, but data were excluded because only 4 events were reported, and therefore sex stratification of data led to cells with zero counts. In TRILOGY-ACS, all available data were included, regardless of patient age, although all patients age ≥75 years received a lower (5 mg/day) dose of prasugrel (21).
Outcomes were collected from the time of randomization to the end of available follow-up. All of the collected data were verified by each of the participating investigators.
Publication bias was evaluated by the Egger test for small-study effects, and by assessing funnel plot asymmetry for each endpoint. A meta-analysis was conducted for each outcome, stratified by patient sex using random effects models, as previously described (23). The appropriateness of pooling data across trials was assessed by the Cochran Q statistic and I2 test for heterogeneity, and differences between men and women were assessed by calculating the Cochran Q statistic. Heterogeneity by patient sex was assessed by calculating the relative risk for the interaction term between treatment arm and sex for each individual trial, combining these point estimates in random effects models, and calculating p values for the combined interaction effect. Event rates for each outcome are presented as frequencies on the basis of pooled data. All statistical analyses were performed using Stata/SE, version 14.1 (StataCorp, College Station, Texas). All tests were 2-sided, with p < 0.05 considered significant.
The features of each trial included in the meta-analysis are displayed in Table 1, including the treatment arms, study populations, primary endpoints, and median duration of follow-up. There was no apparent evidence of publication bias across key efficacy and safety endpoints (Online Figure 2). A total of 87,840 patients were enrolled across these trials, of whom 24,494 (27.9%) were women. Table 2 shows the baseline characteristics for each study. Across all trials, women were significantly more likely to be older and to have comorbidities including diabetes mellitus, hypertension, prior stroke or transient ischemic attack, prior heart failure, and lower estimated glomerular filtration rate. Men were significantly more likely to be white, current smokers, and have a history of prior MI or coronary revascularization.
Efficacy outcomes by patient sex
The use of a potent P2Y12 inhibitor significantly reduced the risk of MACE by 14% in women (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.78 to 0.94; p = 0.002) and by 15% in men (HR: 0.85; 95% CI: 0.80 to 0.90; p < 0.001) without heterogeneity (p interaction [sex] = 0.93) (Figure 1, Central Illustration). Similar results were observed when the composite of CV death, MI, or stroke was examined (HR: 0.89; 95% CI: 0.81 to 0.97; p = 0.01 [women]; HR: 0.85; 95% CI: 0.80 to 0.90; p < 0.001 [men]; p interaction = 0.60) (Table 3, Online Figure 3). In women, the use of a potent P2Y12 inhibitor significantly reduced the risk of MI by 13% (HR: 0.87; 95% CI: 0.78 to 0.96; p = 0.01) (Online Figure 4) with directional consistency for CV death (HR: 0.87; 95% CI: 0.76 to 1.01; p = 0.06) (Online Figure 4) and stroke (HR: 0.92; 95% CI: 0.55 to 1.56; p = 0.76) (Table 3). Similarly, in men, the potent P2Y12 inhibitors significantly reduced the risk of CV death by 15% (HR: 0.85; 95% CI: 0.77 to 0.95; p = 0.002; p interaction = 0.86) (Online Figure 4) and MI by 16% (HR: 0.84; 95% CI: 0.76 to 0.91; p < 0.001; p interaction = 0.65) (Online Figure 5) with a neutral effect on the risk of stroke (HR: 0.99; 95% CI: 0.82 to 1.18; p = 0.87; p interaction = 0.72).
The use of a potent P2Y12 inhibitor significantly reduced the risk of ARC definite stent thrombosis by 51% in women (HR: 0.49; 95% CI: 0.37 to 0.65; p < 0.001) and 41% in men (HR: 0.59; 95% CI: 0.42 to 0.84; p = 0.003; p interaction = 0.85) (Online Figure 6), as well as definite or probable stent thrombosis (HR: 0.59; 95% CI: 0.28 to 1.22; p = 0.16 [women]; HR: 0.61, 95% CI: 0.42 to 0.89; p = 0.009 [men]; p interaction = 0.94) (Table 3).
Safety outcomes by patient sex
In both men and women, the potent P2Y12 inhibitors increased the risk of TIMI (non–CABG-related) major bleeding compared with standard therapy (clopidogrel or placebo) (HR: 1.28; 95% CI: 0.87 to 1.88; p = 0.21 [women]; HR: 1.52; 95% CI: 1.12 to 2.07; p < 0.01 [men]; p interaction = 0.62) (Figure 2, Central Illustration). The potent P2Y12 inhibitors also increased the risk of TIMI (non–CABG-related) major or minor bleeding (HR: 1.54; 95% CI: 1.16 to 2.05; p = 0.003 [women]; HR: 1.45; 95% CI: 1.09 to 1.93; p = 0.01 [men]; p interaction = 0.76) (Table 4, Online Figure 7) in both men and women. Finally, the use of a potent P2Y12 inhibitor significantly increased the risk of ICH in men by 47% (HR: 1.47; 95% CI: 1.02 to 2.11; p = 0.04), but not in women (HR: 0.96; 95% CI: 0.46 to 1.98; p = 0.91); however, the events were few, and the test for heterogeneity by sex was not significant (p interaction = 0.24) (Online Figure 8).
The potent P2Y12 inhibitors reduced all-cause mortality by 11% (HR: 0.89; 95% CI: 0.78 to 1.01; p = 0.07) in women and significantly reduced all-cause death by 11% in men (HR: 0.89; 95% CI: 0.81 to 0.99; p = 0.02; p interaction = 0.99) (Table 4, Online Figure 9).
Sensitivity analyses were conducted excluding the PEGASUS–TIMI 54 trial because it was the only trial that did not have an active comparator arm, and therefore contributed to significant between-trial heterogeneity for the bleeding outcomes, including TIMI (non–CABG-related) major bleeding (p between-trial heterogeneity = 0.01 [men]; = 0.051 [women]). Qualitatively consistent results were observed when the results of PEGASUS–TIMI 54 were excluded, and heterogeneity across trials was no longer significant (p heterogeneity = 0.72 [men], = 0.16 [women]). Sensitivity analyses excluding the PEGASUS–TIMI 54 trial for other efficacy and safety endpoints also demonstrated consistent results (Online Table 1).
Additional sensitivity analyses were conducted excluding the data from the CHAMPION program (Online Table 2), with qualitatively consistent results. Similar results were also observed when the results of both PEGASUS–TIMI 54 and the CHAMPION trials were excluded (Online Table 3).
To further investigate the potential impact of sex on efficacy and safety outcomes in selected patient populations, analyses were further stratified on the basis of age and a prior history of PCI. The efficacy and safety of the potent P2Y12 inhibitors was comparable between men and women, regardless of patient age. Although event rates were higher in individuals over the age of 75 years, the excess in bleeding with more potent P2Y12 inhibitor use was qualitatively comparable to that observed in younger patients. Although CIs were wide, the efficacy of novel P2Y12 inhibitors tended to be attenuated in men over 75 years of age, but was maintained in women, regardless of age (Online Tables 4 and 5). Similarly, the efficacy and safety of potent P2Y12 inhibitors was similar in men versus women, regardless of history of PCI (Online Tables 6 and 7). Inferences could not be made regarding the relative efficacy and safety of potent P2Y12 inhibitors for patients who did or did not have a history of PCI because different trials were represented in each cohort.
The results of this collaborative meta-analysis of randomized trials demonstrate that the efficacy and safety of potent P2Y12 inhibitors, namely prasugrel, ticagrelor, and cangrelor, appear to be comparable in both women and men with CAD. In addition, regardless of patient sex, the use of these potent antiplatelet therapies reduced the risk of both MACE and all-cause mortality in patients with stable and unstable coronary disease, but with increased bleeding. Despite the previous paucity of sex-specific data, recent registry analyses show that patients treated with prasugrel or ticagrelor are more likely to be male (24). Our findings therefore support the concept that patient sex should not be a determining factor when selecting potent P2Y12 receptor antiplatelet therapy in patients with an appropriate indication for use.
In the past, sex-specific differences in response to certain antiplatelet therapies have been described. Sex-specific meta-analyses of aspirin use in primary prevention have suggested efficacy in both women and men, but its benefit appeared to be largely driven by a reduction in stroke in women, as opposed to a reduction in MI in men (7,25). When the efficacy of glycoprotein IIb/IIIa inhibitors was examined across trials, concerns were raised that these potent antiplatelet therapies potentially conferred harm in women; however, the benefit of therapy appeared to be more comparable when restricted to higher-risk women with troponin elevation (9). A meta-analysis examining cardiovascular efficacy of clopidogrel in patient subgroups suggested no significant difference in efficacy between men and women (26). Questions have been raised about appropriate dosing of antiplatelet therapies in women on the basis of body mass and renal function (12,13). Although reports are conflicting (27), some studies have also described a higher frequency of clopidogrel “hyporesponsiveness” in women than in men (28–30). However, it remains incompletely understood whether these observations reflect true differences in pharmacodynamic responses to clopidogrel, or whether these observations are explained by higher baseline pre-treatment platelet reactivity in women (31,32). If such baseline differences in platelet reactivity exist, ongoing research is examining whether this might be explained by fundamental distinctions in platelet biology or a higher prevalence of comorbidities, such as diabetes mellitus, that may potentiate platelet responsiveness (33). However, more frequent hyporesponsiveness to clopidogrel in women could, in theory, enhance the benefit of a more potent antiplatelet therapy, with less interindividual variability.
Despite the advantages for the administration of potent P2Y12 inhibitors in women, there are concerns. In particular, observational studies have described a higher risk of bleeding in women, as compared with men, after ACS and PCI, irrespective of antiplatelet drug use (11–14). As previously noted, lower body weight and creatinine clearance in women may also increase drug exposure, and therefore increase risk of bleeding with some antiplatelet therapies. In the TRITON–TIMI 38 trial (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis In Myocardial Infarction 38), individuals weighing <60 kg or who were older than 75 years appeared to have less apparent treatment benefit with prasugrel compared with other patients, but heterogeneity was not seen by patient sex (34).
In the current meta-analysis of 63,346 men and 24,494 women with CAD, both the efficacy and safety of potent P2Y12 inhibitors appeared to be similar between men and women. In women, the use of these more novel therapies reduced the risk of MACE by 14% and stent thrombosis by 51%, which was comparable to the benefit observed in men. In contrast to a prior report with clopidogrel (8), directional consistency was observed across the individual elements of MACE, including CV death and MI, in both women and men, supporting the concept of similar pathobiological effects regardless of patient sex. The only exception was a suggestion of a more neutral effect toward stroke reduction in men, albeit the difference between men and women was not significant.
As anticipated on the basis of the individual trial results, the potent P2Y12 inhibitors increased the rate of major (non–CABG-related) bleeding to a similar extent in both men and women. Interestingly, potent P2Y12 inhibitors significantly increased the risk of ICH in men (HR: 1.47; 95% CI: 1.02 to 2.11), but not in women (HR: 0.96; 95% CI: 0.46 to 1.98). However, because events were few and the test for heterogeneity between sexes was not significant, these observations can only be described as hypothesis-generating. Nonetheless, these overall findings provide additional reassurance regarding the relative safety of these potent therapies in women (35).
As with any meta-analysis, there exist differences between the study designs and study populations for each trial. In particular, the studies differed in terms of follow-up duration, but the average study duration was longer than 1 year and consistent results were observed across trials. To that end, heterogeneity across trials was only observed for the major bleeding outcome, and the heterogeneity was dissipated when the results of the PEGASUS–TIMI 54 trial were excluded, as it was the only trial with a placebo comparator arm. Moreover, none of the trials were individually powered to look at outcomes by patient sex, and subgroup analyses inherently increase the risk that findings may be explained by chance. Nonetheless, there exist inherent limitations when meta-analyzing results across studies with different study designs and durations of follow-up. Despite an extensive search of published studies and tests for publication bias, we cannot exclude the possibility that eligible studies may have been inadvertently excluded.
This large collaborative meta-analysis across randomized trials of the potent P2Y12 inhibitors has demonstrated consistency in the efficacy and safety of these novel therapies in both women and men. Because women remain undertreated in regard to evidence-based therapies, these findings provide important evidence to support the use of these potent therapies in both women and men with appropriate indications for use.
COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILL: Compared with clopidogrel or placebo, the potent P2Y12 inhibitors prasugrel, ticagrelor, and cangrelor reduced MACE and increased major bleeding in men and women similarly.
TRANSLATIONAL OUTLOOK: Future trials evaluating antithrombotic agents for patients with acute and chronic CAD should collect pharmacokinetic and pharmacodynamic data in both women and men to allow meaningful correlations with clinical outcomes.
For supplemental figures and tables, please see the online version of this paper.
↵† Dr. Husted is deceased.
The TRITON–TIMI 38 trial was funded by grant support through Eli Lilly and Daiichi-Sankyo. The PLATO trial was funded by AstraZeneca. The TRILOGY-ACS trial was funded by grant support through Eli Lilly and Daiichi-Sankyo. The CHAMPION PHOENIX trial was funded by The Medicines Company. The PEGASUS–TIMI 54 trial was funded by AstraZeneca. Dr. Braunwald has received research grant support from Eli Lilly, AstraZeneca, Novartis, Merck, Daiichi-Sankyo, and GlaxoSmithKline; uncompensated consultancies and lectures with Merck and Novartis; and consultancies with The Medicines Company and Theravance. Dr. Wiviott has received research funding from Amgen, Arena, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Eisai, Eli Lilly, Janssen, Merck, and Sanofi; has been a consultant for Arena, Aegerion, Allergan, Angelmed, Aralez, Boehringer Ingelheim, Boston Clinical Research Institute, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Icon Clinical, Janssen, Lexicon, and Xoma. Dr. Bonaca serves as a consultant for AstraZeneca, Merck, Bayer, and Roche Diagnostics. Dr. Husted has received consulting fees, honoraria, or both from AstraZeneca, Bayer, Boehringer Ingelheim, and Pfizer; and grant support from GlaxoSmithKline. Dr. James has received institutional research grants from AstraZeneca and The Medicines Company; and honoraria from AstraZeneca and Janssen/Bayer. Dr. Wallentin has received research grants to his institution from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, GlaxoSmithKline, Merck, Roche, and Schering-Plough; has been a consultant for Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and GlaxoSmithKline; receives lecture fees and travel support from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, and GlaxoSmithKline; and holds patents involving GDF-15. Dr. Clemmensen has received research funding from Abbott, AstraZeneca, Aventis, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Fibrex, Janssen, Merck, Myogen, Medtronic, The Medicines Company, Nycomed, Organon, Pfizer, Pharmacia, Regado, Sanofi, Sarle, and Servier; speaker fees from Abbott, AstraZeneca, Aventis, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Merck, Medtronic, The Medicines Company, Nycomed, Pfizer, Pharmacia, Sanofi, and Servier; and served on advisory boards for AstraZeneca, Aventis, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Evolva, Merck, Medtronic, Mitsubishi Pharma, The Medicines Company, Nycomed, Pfizer, Pharmacia, Sanofi, and Servier. Dr. Roe has received research grants or contracts from AstraZeneca, Eli Lilly & Company, Janssen Pharmaceuticals, Sanofi, Daiichi-Sankyo, Familial Hypercholesterolemia Foundation, Ferring Pharmaceuticals; has lectured for Amgen and Bristol-Myers Squibb; and has served as a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Merck & Co., Daiichi-Sankyo, Elsevier Publishers, PriMed, and MyoKardia. Dr. Ohman has received research grants from Daiichi-Sankyo, Gilead Sciences, and Janssen Pharmaceuticals; and has been a consultant for Abiomed, Abbott Vascular, AstraZeneca, Biotie, Boehringer Ingelheim, Daiichi-Sankyo, Faculty Connection, Merck, St. Jude Medical, Stealth Peptides, The Medicines Company, and Medscape. Dr. Harrington has received research grants from AstraZeneca, Bristol-Myers Squibb, CSL, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Merck, Portola, Sanofi, The Medicines Company, Regado, and Janssen Pharmaceuticals; and has been a consultant/advisor for Amgen, Bristol-Myers Squibb, Gilead, Johnson & Johnson, Merck, MyoKardia, The Medicines Company, and WebMD. Dr. Bhatt has served on the advisory boards of Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; has served on the boards of directors of the Boston VA Research Institute and Society of Cardiovascular Patient Care; has chaired the American Heart Association Quality Oversight Committee; has served on the data monitoring committees of the 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), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor; associate editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (chief medical editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), WebMD (CME steering committees); other: Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (vice-chair), VA CART Research and Publications Committee (chair); has received research funding from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi, and The Medicines Company (including for his role as co-chair of the CHAMPION PHOENIX trial); has received royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); has served as site coinvestigator for Biotronik, Boston Scientific, and St. Jude Medical; has served as trustee for the American College of Cardiology; and has performed unfunded research for FlowCo, PLx Pharma, and Takeda. Dr. Sabatine has received research grants to his institution from Abbott Laboratories, Amgen, AstraZeneca, Critical Diagnostics, Daiichi-Sankyo, Eisai, Gilead, GlaxoSmithKline, Intarcia, Merck, Roche Diagnostics, Sanofi, Takeda, Novartis, Poxel, Janssen Research Development, and MedImmune; and has been a consultant for Alnylam, AstraZeneca, CVS Caremark, Merck, and Ionis. Dr. O’Donoghue has received research grant support from GlaxoSmithKline, Eisai, Merck, Janssen, and AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of the paper to disclose.
Stephen Ellis, MD, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- acute coronary syndrome
- Academic Research Consortium
- coronary artery bypass graft
- coronary artery disease
- confidence interval
- hazard ratio
- intracranial hemorrhage
- major adverse cardiovascular events
- myocardial infarction
- percutaneous coronary intervention
- Thrombolysis In Myocardial Infarction
- Received July 11, 2016.
- Revision received November 11, 2016.
- Accepted January 1, 2017.
- 2017 American College of Cardiology Foundation
- Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology (ESC),
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