Author + information
- Received April 8, 2014
- Revision received August 6, 2014
- Accepted September 5, 2014
- Published online December 9, 2014.
- Marc P. Bonaca, MD, MPH∗ (, )
- Benjamin M. Scirica, MD, MPH,
- Eugene Braunwald, MD,
- Stephen D. Wiviott, MD,
- Michelle L. O'Donoghue, MD, MPH,
- Sabina A. Murphy, MPH and
- David A. Morrow, MD, MPH
- TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
- ↵∗Reprint requests and correspondence:
Dr. Marc P. Bonaca, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.
Background Vorapaxar, a novel thrombin receptor antagonist, reduces cardiovascular death and recurrent thrombotic events when added to standard antiplatelet therapy in patients with stable atherosclerotic vascular disease.
Objectives The goal of this study was to test the hypothesis that treatment with vorapaxar reduces the rate of coronary stent thrombosis (ST) in stable patients with a history of coronary stenting.
Methods TRA 2°P-TIMI 50 (Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis In Myocardial Infarction 50) was a multinational, randomized, double-blind, placebo-controlled trial of vorapaxar in stable patients with prior myocardial infarction, peripheral arterial disease, or stroke. We evaluated the rates of definite ST as adjudicated by a central events committee using Academic Research Consortium (ARC) criteria.
Results A total of 26,449 patients were randomized, with 14,042 (53%) having a history of a coronary stent implantation before randomization, and an additional 449 patients receiving a coronary stent during the trial (total 14,491). During follow-up (median 2.5 years), there were 152 definite ST events, with the majority (92%) occurring late or very late. Vorapaxar reduced ARC definite ST (1.1% vs. 1.4%, hazard ratio [HR]: 0.71, 95% confidence interval [CI]: 0.51 to 0.98; p = 0.037). The reduction was consistent, regardless of time from percutaneous coronary intervention, history of diabetes, use of drug-eluting stents, and use of dual antiplatelet therapy (DAPT) at randomization. Vorapaxar increased GUSTO moderate/severe bleeding (HR: 1.57, 95% CI: 1.26 to 1.94; p < 0.001).
Conclusions The rate of ARC definite ST in stable patients, the majority of whom were receiving DAPT, was approximately 1.4% at 3 years. In stable patients with coronary stenting receiving standard antiplatelet therapy, vorapaxar administered for long-term secondary prevention significantly reduced ARC definite ST, including very late ST. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Patients With Atherosclerosis [TRA 2°P-TIMI 50] [P04737]; NCT00526474)
Stents are routinely used in coronary interventions to reduce the risk of complications such as acute dissection and recoil, as well as late coronary restenosis. Stent thrombosis (ST) is an uncommon, but serious, complication of coronary stenting, and may occur at various times after implantation. ST may be classified on the basis of timing as acute (<24 h), subacute (24 h to 30 days), late (30 days to 1 year), and very late (>1 year) (1–3). Late and very late ST occur at a lower rate than acute and subacute ST, but remain a life-threatening complication (4,5).
Dual antiplatelet therapy with aspirin and an adenosine diphosphate (ADP) receptor blocker reduces ST compared with aspirin monotherapy. Newer generations of more potent ADP receptor blockers (e.g., prasugrel, ticagrelor) further reduce this risk relative to clopidogrel within the first year after an acute coronary syndrome (ACS) (6,7). It is unknown whether intensive antiplatelet therapy in patients with stable coronary artery disease and prior coronary stenting reduces later events, particularly very late ST. It is also not known whether antiplatelet agents targeting novel receptors and pathways are effective at modifying the risk of stent-related events.
The TRA 2°P-TIMI 50 trial (Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis In Myocardial Infarction 50) studied vorapaxar, a novel antiplatelet agent acting through inhibition of the platelet protease-activated receptor (PAR)-1, for long-term secondary prevention when added to standard antiplatelet therapy, including aspirin (98%) and a thienopyridine (78%), in patients with stable atherosclerosis, including prior myocardial infarction (MI), prior stroke, and peripheral arterial disease (PAD) (8,9). We tested the hypothesis that PAR-1 inhibition with vorapaxar would reduce the risk of ST in stable patients in whom a coronary stent was implanted, and evaluated whether any effect observed was modified by background antiplatelet therapy or timing from stent implantation.
Study population and procedures
TRA 2°P-TIMI 50 was a multinational, randomized, double-blind, placebo-controlled trial among 26,449 subjects with stable atherosclerotic vascular disease manifested by prior MI, PAD, or ischemic stroke (8). The trial design details were previously reported (8,9). Participants in whom a coronary stent was implanted before randomization or who received a coronary stent during follow-up are the basis for the present, pre-specified analysis. For patients receiving a first coronary stent during follow-up, observation was started at the time of stent placement. Additional analyses of safety and efficacy using this pre-specified population with coronary stents, but excluding patients with history of stroke or transient ischemic attack (TIA), are presented in the Results section, consistent with the population approved for the use of vorapaxar by the U.S. Food and Drug Administration (FDA) (10).
Patients with MI qualified for the trial on the basis of a history of spontaneous MI occurring 2 weeks to 12 months before randomization (8). In order to qualify for inclusion on the basis of PAD, patients were required to have a history of intermittent claudication in conjunction with an ankle-brachial index <0.85 or previous revascularization for limb ischemia. Patients with qualifying stroke were required to have a history of symptomatic ischemic stroke occurring 2 weeks to 12 months before randomization. Patients were ineligible if they had a planned revascularization that had not yet been performed, had a history of a bleeding diathesis, a history of intracranial hemorrhage, or were receiving vitamin K antagonist therapy.
Details of prior coronary stenting were collected for all patients at baseline, and information for new coronary stents were collected during follow-up. The institutional review board or ethics committee for each participating institution approved the trial. All patients gave written informed consent.
Randomization was stratified both by qualifying disease state and by the pre-randomization assessment of whether use of a thienopyridine was planned (8). Eligible patients were randomized in a 1:1 fashion to receive vorapaxar 2.5 mg daily or matching placebo.
The primary efficacy and safety definitions, as well as the results of the TRA 2°P-TIMI 50 trial were previously described (9). All potential ST events during the trial were collected through investigator report and prospective review of all cases of death, MI, urgent coronary revascularization, and unstable angina for possible unreported ST. Source documents, including hospitalization records and angiogram reports, were collected for all potential ST events and assembled into endpoint packets for review and formal adjudication by the clinical events committee (8).
To qualify as definite thrombosis in accordance with the Academic Research Consortium (ARC) (1), there needed to be an angiographic report documenting Thrombolysis In Myocardial Infarction (TIMI) flow grade 0 with occlusion originating in the stent or in the segment 5 mm proximal or distal to the stented region in the presence of a thrombus, or TIMI flow grade 1, 2, or 3 and the presence of thrombus originating in the stent or in the segment 5 mm proximal or distal to the stented region and at least 1 of the following criteria: new onset of ischemic symptoms at rest (typical pain >20 min); new ischemic electrocardiographic changes suggestive of acute ischemia; typical rise and fall in cardiac biomarkers (1,9). Any unexplained death within 30 days of coronary stenting, or MI at any time occurring in the territory of an implanted stent without angiographic confirmation, or other obvious cause qualified as probable ST, and any unexplained death more than 30 days after coronary stenting qualified as possible ST, in accordance with the ARC criteria (9). Incidental angiographic documentation of silent stent occlusion in the absence of clinical signs or symptoms was not considered a confirmed ST (9).
Baseline characteristics were compared using the chi-square test for categorical variables and the Wilcoxon rank sum test for continuous ones. Efficacy analyses were performed using a Cox proportional hazards model, with the investigational treatment allocation and planned use of a thienopyridine as covariates. In addition, subgroups of interest were analyzed using the Cox model and including the subgroup, randomized treatment, and relevant interaction terms. Cumulative event rates at 3 years were calculated with the Kaplan-Meier method. Efficacy data were analyzed on an intention-to-treat basis. Analyses were performed using Stata version 12.1 (Stata Corp., College Station, Texas).
A total of 14,491 patients had at least 1 coronary stent. Of these patients, 14,042 (97%) had a coronary stent before randomization, and 449 (3%) received a first coronary stent during follow-up. Just under one-half of patients (47%) had drug-eluting stents (DES). The median duration of follow-up was 2.5 years. The median time from most recent coronary stent implantation to randomization was 3 months. Baseline characteristics were balanced between treatment groups and are shown in Table 1. The majority of patients (93%) with coronary stents qualified for the trial with a recent MI, 22% were diabetic, 98% received aspirin, and 83% received dual antiplatelet therapy (DAPT) with aspirin and a thienopyridine, predominantly clopidogrel. Use of other background cardiovascular therapies was frequent, including statins (95%) and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (79%).
During follow-up there were 152 occurrences of ARC definite ST. The majority (92%) of events in this stable secondary prevention population occurred late or very late (>1 year) after stent implantation (Figure 1⇓, Online Figure 1). Definite ST events occurring more than 1 year from stent implantation (65%) were distributed evenly over the follow-up period (Figure 1). The rate of ARC definite ST in the placebo group was 1.4% at 3 years (0.47% annualized). There were 169 patients with definite/probable ST (placebo event rate 0.50% annualized), and 310 patients with definite/probable/possible ST (placebo event rate of 0.90% annualized).
Compared with the 14,339 patients with coronary stents who did not develop definite ST, subjects who experienced a definite ST event (ARC definite) were younger, had a greater prevalence of dyslipidemia and current tobacco use, and more frequently had DES (61% vs. 46%; p < 0.001) (Online Table 1). There was no significant regional heterogeneity in the occurrence of definite ST (p = 0.07).
Effect of PAR-1 inhibition with vorapaxar on ST
Vorapaxar significantly reduced ARC definite ST compared with placebo by 29% (1.1% vs. 1.4%, hazard ratio [HR]: 0.71, 95% confidence interval [CI]: 0.51 to 0.98; p = 0.037) (Table 2, Figure 2). This reduction was directionally consistent in all subgroups, including prior ST-segment elevation MI, whether or not the patient had a DES, and smoking status (Figure 3). Patients with diabetes had a numerically greater reduction in definite ST with vorapaxar (0.60% vs. 1.57%, HR: 0.38, 95% CI: 0.17 to 0.85; p = 0.019) compared with nondiabetic patients (1.21% vs. 1.37%, HR: 0.81, 95% CI: 0.57 to 1.16; p = 0.25); however, there was no definite statistical heterogeneity (p for interaction = 0.092) (Figure 3). The reduction in definite ST was consistent when limiting the population to stented patients who qualified for the trial with MI or PAD and had no history of stroke or TIA (1.0% vs. 1.4%, HR: 0.70, 95% CI: 0.50 to 0.98; p = 0.039) (Table 2, Online Table 2, Figure 3). In addition, findings were numerically consistent, but no longer statistically significant, when using broader, less specific definitions of ST, including definite/probable ST (HR: 0.74, 95% CI: 0.55 to 1.01; p = 0.058) and definite/probable/possible ST (HR: 0.84, 95% CI: 0.67 to 1.05; p = 0.12) (Table 2).
Timing of ST
The reduction in definite ST with vorapaxar was consistent at all previously defined times, including events occurring within the first month, from 30 days to 1 year, and after 1 year (Figure 4). Very late ST was significantly reduced with vorapaxar (HR: 0.65, 95% CI: 0.43 to 0.97; p = 0.037).
Outcomes after ST
Definite ST required documentation of ST, thereby excluding patients who died before angiography; however, 11% (16 of 152) died after a definite ST event, with the majority (11 of 16) dying within 4 days. Mortality after definite/probable ST was 14% (23 of 169), with the majority (13 of 23) occurring at the time of the event.
Influence of background antiplatelet therapy
The majority of patients were on background aspirin (98%) and, when stratified by aspirin dose (low dose ≤150 mg, high dose >150 mg), there was no heterogeneity in the reduction in definite ST with vorapaxar (high dose HR: 0.62, 95% CI: 0.34 to 1.13; low dose HR: 0.78, 95% CI: 0.53 to 1.15; p for interaction = 0.52) compared with placebo.
The majority (83%) of patients were on DAPT with aspirin and a thienopyridine (∼98% clopidogrel) at baseline. The reduction in definite ST was similar in those planned for thienopyridine therapy (HR: 0.72, 95% CI: 0.51 to 1.02) and those not planned for thienopyridine therapy (HR: 0.67, 95% CI: 0.29 to 1.54) (p for interaction = 0.88) (Figure 5).
To determine whether the reduction in definite ST with vorapaxar was consistent in patients treated with long-term thienopyridine therapy, a sensitivity analysis was performed, evaluating the effect of vorapaxar in the subgroup of patients treated with thienopyridine, both at baseline and at 18 months or the end of follow-up (long-term thienopyridine: n = 6,779, 59% of those on DAPT at baseline). The reduction in definite ST with vorapaxar was consistent in patients on long-term thienopyridine therapy (HR: 0.72, 95% CI: 0.51 to 1.04), without heterogeneity from the effect of vorapaxar in patients who were on a thienopyridine at randomization, but stopped before 18 months (short-term thienopyridine 41%, HR: 0.87, 95% CI: 0.33 to 2.25; p for interaction = 0.73).
Efficacy and bleeding in patients with coronary stents
Consistent with the primary findings in the overall trial, in the population with coronary stents, vorapaxar reduced the primary endpoint of cardiovascular death, MI, or stroke (HR: 0.83, 95% CI: 0.74 to 0.93; p = 0.001) (Table 2) with benefit driven primarily by reductions in MI (HR: 0.82, 95% CI: 0.72 to 0.94; p = 0.003) (Table 2) and ischemic stroke (HR: 0.68, 95% CI: 0.49 to 0.94; p = 0.02) (Table 2). GUSTO (Global Utilization Of Streptokinase and Tpa for Occluded arteries) moderate or severe bleeding was increased (HR: 1.57, 95% CI: 1.26 to 1.94) (Table 2). In this population with coronary stents, severe bleeding events, including intracranial hemorrhage (placebo rate 0.4% at 3 years, or 0.13% per year) and fatal bleeding (0.1% at 3 years or 0.03% per year) (Table 2), were infrequent. In this cohort, rates of intracranial hemorrhage and fatal bleeding were not statistically increased with vorapaxar (Table 2). When examined among patients in the FDA-approval population (MI or PAD and no history of stroke or TIA) who had coronary stents, findings with vorapaxar were similar, with a reduction in definite ST (HR: 0.70, 95% CI: 0.50 to 0.98; p = 0.039, number needed to treat [NNT] = 277) and cardiovascular death/MI/stroke (HR: 0.79, 95% CI: 0.70 to 0.89; p < 0.001, NNT = 56), but an increase in GUSTO moderate or severe bleeding (HR: 1.50, 95% CI: 1.20 to 1.89; p < 0.001, number needed to harm [NNH] = 112) (Table 2).
In stable patients with established atherosclerosis and a history of coronary stenting, adding vorapaxar to standard background antiplatelet therapy for long-term secondary prevention of atherothrombotic events reduced definite ST (Central Illustration). This reduction was consistent, regardless of the dose of aspirin used or the use of a thienopyridine. Notably, vorapaxar reduced the incidence of very late ST (occurring more than a year after implantation) with consistent benefit at all time points from stent implantation. Together, these findings identify PAR-1 as a therapeutic target for reducing the risk of definite ST in long-term secondary prevention (Central Illustration). As anticipated, this potent antiplatelet drug increased bleeding. However, there was no increase in fatal or intracranial bleeding with vorapaxar in this population with coronary stents.
Antiplatelet therapy and very late ST
The incidence of very late ST is not well established, with few robustly sized studies of patients with stable coronary artery disease and coronary stents receiving modern therapy. In a recent publication, the annualized rate of definite ST after ACS was 1.93% in patients with ACS within a year (7). A recently published meta-analysis, including patients receiving percutaneous coronary intervention for any indication (stable coronary artery disease and ACS), reported a composite 1.5% incidence of definite ST at 22 months (0.81% annualized) (11).
In this population of stable patients with prior MI, 98% on aspirin and 83% on DAPT, we observed an annual rate of definite ST of 0.47%. Of note, although the majority of patients had a history of MI in the last year, ST events continued to occur at a linear rate even a year after stent implantation, without any sign of decreasing frequency with time. Because of this constant risk, the stable nature of our cohort, and the 3 years of follow-up (placebo group in Figure 2), the majority of events (65%) accrued more than a year after stent implantation.
Although the absolute rate of definite ST is low relative to de novo MI, as we previously reported in the cohort who qualified with MI (2.7% per year), it is similar to that of ischemic stroke in the same population (1.5% at 3 years, 0.47% per year) (12). Similar to ischemic stroke, ST remains a feared ischemic outcome because of high rates of associated mortality. In a recent analysis from the PLATO (Study of Platelet Inhibition and Patient Outcomes) trial, ST was associated with increased rates of all-cause mortality, with a similar pattern observed in the current cohort (7). This concern has been the impetus for a series of trials investigating whether prolonged DAPT with aspirin and a thienopyridine can modify the risk of late ischemic events (13).
Completed trials of prolonged DAPT beyond a year from stenting have not shown reduction of ischemic events or ST; however, these trials may have been underpowered for rare events (14,15). PAR-1 is expressed on a variety of cell types, including vascular smooth muscle and endothelium, and inhibition of PAR-1 in animals was shown to have antimitogenic effects in balloon-injured vessels. Vorapaxar was shown to reduce peripheral revascularization in a manner that suggests mechanisms beyond that of platelet inhibition alone (16). Whether the benefit of vorapaxar in reduction of definite ST is solely mediated by PAR-1 antagonism on platelets is uncertain and warrants further study.
Although this analysis was focused on the question of whether PAR-1 inhibition reduces coronary ST in stable patients with a history of stenting, data are presented regarding the broad efficacy and safety of vorapaxar in patients with coronary stents and no history or stroke or TIA (FDA-approval population). On the basis of the overall reduction in major adverse cardiovascular events (cardiovascular death, MI, or stroke), the NNT is 56 in the stented population. Because ST is infrequent in stable patients, the NNT for vorapaxar for this endpoint is 227. GUSTO moderate or severe bleeding was increased with an NNH of 112. There were numeric but not statistically significant increases in GUSTO severe bleeding (NNH = 939), intracranial hemorrhage (NNH = 1,334), and fatal bleeding (NNH = 1,691). It is not possible to comment on the magnitude of benefit of other antithrombotics (e.g., prasugrel or ticagrelor) in this population, as they have not yet been studied in this stable setting. Ongoing trials will provide such data in the future.
First, the adjudication of ST in this study was performed using detailed medical records, including angiographic reports, rather than central review of the angiograms. Although use of central “core lab” angiographic review increases detection of ST, the process used in this study is consistent with that used in several recent analyses of ST (6,7,17). The impact would only be expected to diminish our power to detect a difference between therapies, and any loss of specificity would be expected to bias our analyses toward the null result. Secondly, because of this trial’s timing, contemporary antiplatelet therapy after stenting was predominantly with clopidogrel. Although we have shown that PAR-1 antagonism with vorapaxar adds to ADP receptor pathway inhibition, we do not have data to address this question in the setting of more potent inhibition with prasugrel or ticagrelor. In addition, although specific DES types are not available, the types represented may include those used during and prior to 2007, when the trial completed recruitment. Therefore, findings, particularly regarding absolute rates of ST, should not be extrapolated to later-generation stent types. Thirdly, despite this study’s large sample size, given the low overall incidence of late and very late ST, our statistical power to identify heterogeneity in some subgroup analyses is low. Fourthly, the effect of vorapaxar on broader, less specific ST endpoints was numerically consistent with that observed for definite ST, but no longer statistically significant. Definite ST is the most specific of the ARC endpoints, and is therefore most likely to represent the true effect of therapy on ST. Broader definitions, such as probable ST and possible ST, include events such as unexplained death, which may or may not be related to ST, and thus, although they increase the total number of events, they decrease the specificity of the endpoint for true ST. Lastly, although the findings may appear to contrast with those from the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial, in which ST was not significantly reduced, updated analyses from this trial using angiographic adjudication have shown a consistent reduction with vorapaxar, further supporting the findings of this analysis (18).
Any clinical use of vorapaxar would have to weigh the observed reduction in ST and other thrombotic events (9) against the risk of bleeding. Nevertheless, our findings provide important evidence for PAR-1 antagonism as a viable target for reducing late and very late ST, and indicate that a reduction in definite ST is an antithrombotic benefit of vorapaxar to be considered in weighing its potential benefits versus risks for the individual patient.
In stable patients with established atherosclerosis and a history of coronary stenting, long-term therapy with vorapaxar reduced the risk of definite ST. The benefit was consistent over time, including a reduction in very late events, occurring more than a year after stent implantation, and was not modified by background use of DAPT with aspirin and a thienopyridine.
COMPETENCY IN MEDICAL KNOWLEDGE: In stable patients with coronary stents, the PAR-1 receptor antagonist vorapaxar reduced the risk of stent thrombosis by approximately 30% compared with placebo when added to aspirin or dual anti-platelet therapy with aspirin and a thienopyridine.
TRANSLATIONAL OUTLOOK: Further studies are needed to more accurately identify patients most likely to benefit from long-term therapy with vorapaxar and determine whether efficacy would be diminished or safety enhanced if aspirin were withdrawn from the combination regimen.
This study was supported by a grant from Merck & Co. The TIMI Study Group has received significant research grant support from Accumetrics, Amgen, AstraZeneca, Beckman Coulter, Bristol-Myers Squibb, CV Therapeutics, Daiichi-Sankyo Co. Ltd., Eli Lilly and Company, GlaxoSmithKline, Integrated Therapeutics, Merck & Co., Nanosphere, Novartis Pharmaceuticals, Nuvelo, Ortho-Clinical Diagnostics, Pfizer, Roche Diagnostics, Sanofi, Sanofi-Synthelabo, Siemens Medical Solutions, and Singulex. Dr. Bonaca has received consulting fees from Roche Diagnostics, Merck & Co., AstraZeneca, and Bayer. Dr. Scirica has received research grants via the TIMI Study and Brigham and Women's Hospital from AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Johnson & Johnson, Bayer Healthcare, Gilead, Eisai, and Merck & Co.; and consulting fees from AstraZeneca, GE Healthcare, Gilead, Lexicon, Arena, Eisai, St. Jude's Medical, Forest Pharmaceuticals, Bristol-Myers Squibb, Boston Clinical Research Institute, Covance, University of Calgary, and Elsevier Practice Update Cardiology. Dr. Braunwald has received research grants (institutional) from Daiichi-Sankyo, Duke University, AstraZeneca, Merck & Co., and GlaxoSmithKline; has received fees for lectures from Daiichi-Sankyo, Menarini International, and Medscape; has received fees as a consultant for The Medicines Company and Sanofi; and has been an unpaid consultant and has given unpaid lectures for Merck & Co. Dr. Wiviott has received research grants from Merck & Co., AstraZeneca, and Eisai; and has been a consultant for Eli Lilly and Company, AstraZeneca, Johnson & Johnson, St. Jude Medical, ICON, and Bristol-Myers Squibb. Dr. O'Donoghue has received research grants from GlaxoSmithKline, AstraZeneca, and Eisai; and has been a consultant with Aegerion. Dr. Morrow has received research grant support from Abbott, Amgen, AstraZeneca, Beckman Coulter, BG Medicine, BRAHMS, Bristol-Myers Squibb, Critical Diagnostics, CV Therapeutics, Daiichi-Sankyo Co. Ltd., Eli Lilly and Company, GlaxoSmithKline, Johnson & Johnson, Merck and Co., Novartis Pharmaceuticals, Roche Diagnostics, Sanofi, and Singulex; and has received consulting fees from Abbott Laboratories, BG Medicine, Daiichi-Sankyo, Eli Lilly and Company, Gilead, Instrumentation Laboratory, Johnson & Johnson, Konica Minolta, Merck & Co., Novartis, Roche Diagnostics, and Servier. Ms. Murphy has reported that she has no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute coronary syndrome(s)
- adenosine diphosphate
- Academic Research Consortium
- confidence interval
- dual antiplatelet therapy
- drug-eluting stent(s)
- U.S. Food and Drug Administration
- hazard ratio
- myocardial infarction
- number needed to harm
- number needed to treat
- peripheral artery disease
- protease-activated receptor
- stent thrombosis
- transient ischemic attack
- Received April 8, 2014.
- Revision received August 6, 2014.
- Accepted September 5, 2014.
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