Author + information
- Received February 1, 2016
- Revision received July 18, 2016
- Accepted July 28, 2016
- Published online October 24, 2016.
- S1936879816312183-d06c9e6ded92a6a781fdba9f70722405Marc P. Bonaca, MD, MPHa,∗ (, )
- S1936879816312183-0ca618eabadb3c7a6f56fcbb0b4f3ec0Mark A. Creager, MDb,
- S1936879816312183-a7e356f6e1082b9bf07831c6520d8c03Jeffrey Olin, MDc,
- S1936879816312183-7959458b57d17673b87b3546be523c79Benjamin M. Scirica, MDa,
- S1936879816312183-721b9365431c7f9f87eb2be1b1176d84Ian C. Gilchrist Jr., BSa,
- S1936879816312183-89a85d9cc043aa247a8eb5525b131afdSabina A. Murphy, MPHa,
- S1936879816312183-f02b0fa9d7ae22b000082bb005e1b780Erica L. Goodrich, MSa,
- S1936879816312183-c4834eb10938fc641ca921cf1df6d8afEugene Braunwald, MDa and
- S1936879816312183-58cce7a23dd45737f1c15addf3649cb7David A. Morrow, MD, MPHa
- aTIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- bDartmouth-Hitchcock Heart and Vascular Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
- cWiener Cardiovascular Institute and Marie-Jose and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai School of Medicine, New York, New York
- ↵∗Reprint requests and correspondence:
Dr. Marc P. Bonaca, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.
Objectives The aim of this study was to determine whether the reduction in peripheral revascularization with vorapaxar in patients with peripheral artery disease (PAD) is directionally consistent across indications, including acute limb ischemia, progressively disabling symptoms, or both.
Background The protease-activated receptor–1 antagonist vorapaxar reduces peripheral revascularization in patients with PAD.
Methods The TRA 2°P–TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50) trial randomized 26,449 patients with histories of myocardial infarction, stroke, or symptomatic PAD to vorapaxar or placebo on a background of standard therapy. A total of 5,845 patients had a known history of PAD at randomization. Peripheral revascularization procedures reported by the site were a pre-specified outcome. We explored whether the benefit of vorapaxar was consistent across indication and type of procedure.
Results Of the 5,845 patients with known PAD, a total of 934 (16%) underwent at least 1 peripheral revascularization over 2.5 years (median). More than one-half (55%) were for worsening claudication, followed by critical limb ischemia (24%), acute limb ischemia (16%), and asymptomatic severe stenosis (4%). Vorapaxar significantly reduced peripheral revascularization (19.3% for placebo, 15.4% for vorapaxar; hazard ratio: 0.82; 95% confidence interval: 0.72 to 0.93; p = 0.003), with a consistent pattern of efficacy across indication.
Conclusions Vorapaxar reduces peripheral revascularization in patients with PAD. This benefit of vorapaxar is directionally consistent across type of procedure and indication. (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)
Patients with peripheral artery disease (PAD) are at heightened risk for major atherothrombotic events, including myocardial infarction and stroke (1). Their primary vascular morbidity, however, is limb symptoms and tissue loss related to progressive atherosclerosis and thrombosis (2–5). The clinical manifestations of PAD range from asymptomatic disease to intermittent claudication, and to critical limb ischemia at the end stages of disease (6).
Progressive disease prompting intervention is common in symptomatic patients, occurring in approximately 1 in 4 patients over a 4-year period (7). Although these procedures provide symptom relief and help prevent tissue loss in severe disease, the durability of peripheral revascularization is variable (4,5). Restenosis and loss of graft patency may require some patients to undergo recurrent interventions (5). Currently there are no medical therapies that have been shown prospectively to reduce peripheral revascularization procedures in patients with symptomatic PAD (5).
Protease-activated receptor (PAR)-1 is expressed on platelets, vascular endothelium, smooth muscle, and inflammatory cells (8–10). Thrombin is the primary agonist for PAR-1, leading to platelet activation as well as mitogenic and proinflammatory effects on other tissues (10). In the TRA 2°P–TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50) trial, the PAR-1 antagonist vorapaxar reduced major adverse cardiovascular events, acute limb ischemia (ALI), and peripheral revascularization across a variety of indications (11). We investigated the indications for and the types of peripheral revascularization procedures that occurred in TRA 2°P–TIMI 50. We hypothesized that if PAR-1 antagonism has both antiplatelet and direct vascular effects, there may be a consistent pattern of reduction across indications, including both thrombotic causes and disease progression.
Study population and procedures
TRA 2°P–TIMI 50 randomized 26,449 subjects with stable atherosclerotic vascular disease, including coronary artery disease (recent myocardial infarction), cerebrovascular disease (recent stroke), and symptomatic PAD. The details of the trial design have been reported previously (11,12). To qualify for inclusion on the basis of PAD, patients had to have histories of intermittent claudication in conjunction with an ankle-brachial index <0.85 or previous revascularization for limb ischemia (13). Qualifying and follow-up ankle-brachial index assessments were performed by trained personnel at the study site using standardized procedures (12). Randomization was stratified according to the qualifying diagnosis (12). The primary population for the present analysis was the population of patients who had a known history of PAD at randomization, regardless of how they qualified for the trial. Additional analyses were performed in patients with prior PAD among those without stroke or transient ischemic attack (TIA), the population in which vorapaxar is approved for clinical use (14).
Patients were ineligible if they had planned revascularization that had not yet been performed, had a history of a bleeding diathesis, were receiving vitamin K antagonist therapy, or had active hepatobiliary disease (12). The trial was approved by the responsible institutional review or ethics committee for each participating institution. All patients gave written informed consent.
Eligible patients were randomized in a 1:1 fashion to receive vorapaxar sulfate 2.5 mg/day or matching placebo and stratified by both qualifying disease state and intention to prescribe a thienopyridine. All concomitant medical therapy, including use of other antiplatelet agents or anticoagulant agents during the trial, was managed by the local treating physician.
The primary efficacy and safety endpoints of TRA 2°P–TIMI 50 have been described previously (12). Pre-specified limb efficacy endpoints included ALI, peripheral revascularization (urgent and elective), amputation for vascular causes, and urgent hospitalization for vascular cause of an ischemic nature. Peripheral revascularization was defined as any peripheral procedure performed to treat limb ischemia or prevent major limb ischemic events and included endovascular or surgical revascularization as well as amputation. All peripheral revascularization and amputation events were site reported on a detailed electronic case report form page indicating the reasons for and types of interventions.
The primary analysis was performed on an intention-to-treat basis with all randomized patients with known histories of PAD at randomization. Additional analyses were performed, which included patients with PAD but no stroke or TIA as approved for use in the United States (14). Baseline characteristics for patients with and without peripheral revascularization during the trial were compared using the chi-square test for categorical variables and the Wilcoxon rank sum test for continuous ones. The efficacy analyses were performed using a Cox proportional hazards model, with the investigational treatment allocation and planned use of a thienopyridine as covariates. Cumulative event rates at 3 years were calculated using the Kaplan-Meier method. Safety analyses were performed among patients who received 1 or more doses of study drug and included events through 60 days after premature cessation of study therapy or 30 days after a final visit at the conclusion of the trial. An exploratory analysis was performed for safety and efficacy endpoints that occurred in the 3 days after peripheral revascularization. Analyses were performed using Stata version 14.1 (StataCorp LP, College Station, Texas).
A total of 26,449 patients were randomized in the TRA 2°P–TIMI 50 trial, of whom 5,845 had known histories of PAD prior to randomization. Baseline characteristics are shown in Table 1. A total of 1,518 peripheral revascularization procedures occurred in 934 subjects (16%) over a median of 2.5 years of follow-up. At 3 years, the rate of peripheral revascularization in patients randomized to placebo was 19.3% (6.4% annualized). Patients who underwent peripheral revascularization were older and more likely to have risk factors, including current smoking, diabetes mellitus, and hyperlipidemia. In addition, patients who underwent a peripheral revascularization were more likely to have claudication, abnormal ankle-brachial index, and prior peripheral revascularization (Table 1).
Indications for and types for peripheral revascularization
More than one-half of peripheral revascularizations were performed for worsening claudication (n = 838 [55%]). The remainder were performed for critical limb ischemia (n = 370 [24%]) and ALI (n = 242 [16%]). Revascularization for severe stenosis identified during monitoring for previous graft or stent placement occurred in 68 patients (4%) (Figure 1A). Endovascular revascularization was performed in 1,051 patients (70%), surgical revascularization was performed in 377 (25%), and amputation for vascular causes occurred in 73 (5%) (Figure 1B). The type of intervention was missing for 17 patients (1.1%).
Vorapaxar and peripheral revascularization
Overall, vorapaxar significantly reduced the risk for peripheral revascularization by 18% at 3 years (19.3% for placebo, 15.4% for vorapaxar; hazard ratio [HR], 0.82; 95% confidence interval [CI]: 0.72 to 0.93; p = 0.003) (Figure 2A). Examining all peripheral revascularizations (including repeat procedures), there was a consistent significant reduction with vorapaxar (n = 671 for vorapaxar vs. n = 847 for placebo; HR: 0.80; 95% CI: 0.69 to 0.92; p = 0.002).
When examining first peripheral revascularization within the composite, the pattern of benefit of vorapaxar compared with placebo was consistent across indications, including revascularization for ALI (2.7% vs. 2.0%; HR: 0.74; 95% CI: 0.52 to 1.05; p = 0.096), revascularization for claudication (11.6% vs. 9.4% for vorapaxar; HR: 0.85; 95% CI: 0.72 to 1.00; p = 0.055), revascularization for critical limb ischemia (4.0% vs. 3.4%; HR: 0.85; 95% CI: 0.65 to 1.12; p = 0.26), and revascularization for asymptomatic severe stenosis (0.9% vs. 0.6%; HR: 0.66; 95% CI: 0.36 to 1.21; p = 0.18) (Table 2). Results were similar when including repeat procedures (Table 2).
Similarly, there was directional consistency in the effect of vorapaxar across types of peripheral revascularization, including endovascular (HR: 0.89; 95% CI: 0.77 to 1.03; p = 0.13) (Figure 2B), surgical revascularization (HR: 0.59; 95% CI: 0.48 to 0.74; p < 0.001) (Figure 2C), and amputation (HR: 0.90; 95% CI: 0.57 to 1.43; p = 0.66) (Figure 2D); however, magnitude of reduction was greatest for surgical revascularization (41%). The majority of amputations were above or below the knee, followed by transmetatarsal amputation (Table 3).
Efficacy stratified by history of peripheral revascularization at randomization
To evaluate whether efficacy was consistent for patients with no histories of peripheral revascularization as well as for those with histories of peripheral revascularization, the cohort was divided into subgroups of those with no prior peripheral intervention (abnormal ABI and claudication alone, n = 2,940), those with prior revascularization (any history of endovascular or surgical revascularization but not amputation, n = 2,674), and those with prior amputation for ischemia (n = 231). Rates of peripheral revascularization at 3 years in patients randomized to placebo were lower in those with no histories of prior intervention (12.7%) relative to those with histories of peripheral revascularization (25.3%) or amputation (29.2%) (Figure 3). There was no heterogeneity in the benefit of vorapaxar for reducing peripheral revascularization on the basis of history (p for interaction = 0.327) (Figure 3) including first ever peripheral revascularization (HR: 0.79; 95% CI: 0.63 to 0.99; p = 0.039) and repeat intervention (HR: 0.86; 95% CI: 0.73 to 1.01; p = 0.062).
Peripheral revascularization with vorapaxar and timing of benefit
The magnitude of reduction in peripheral revascularization for ALI appeared similar both early (from day 0 through 450 days from randomization; HR: 0.75; 95% CI: 0.50 to 1.11) and late (from day 451 through the end of follow-up; HR: 0.64; 95% CI: 0.38 to 1.07). Peripheral revascularization for claudication, however, appeared to show a different pattern in that it was not as apparent early (from day 0 through 450 days; HR: 1.01; 95% CI: 0.83 to 1.23) and appeared late (from day 451 through the end of follow-up; HR: 0.73; 95% CI: 0.58 to 0.93) (Online Figure 1).
Outcomes with vorapaxar in patients with PAD with no stroke or TIA
Vorapaxar has been approved by the U.S. Food and Drug Administration for use in patients with PAD and no histories of stroke or TIA (14). When evaluating the efficacy of vorapaxar for peripheral revascularization in this population (history of PAD with no history of stroke or TIA, n = 4,677), results were consistent with those cited previously, with vorapaxar significantly reducing peripheral revascularization with directional consistency among indications (Table 4). Vorapaxar increased GUSTO (Global Use of Strategies to Open Occluded Arteries) moderate or severe bleeding compared with placebo (Table 4). There were numerically more GUSTO severe bleeding events with vorapaxar relative to placebo (Table 4), but the difference was not statistically significant. There were no significant differences in the numbers of fatal bleeding events, intracranial hemorrhages, and all-cause deaths with vorapaxar compared with placebo in this population.
Bleeding complications in patients undergoing peripheral revascularization on vorapaxar
First major adverse limb events occurred during follow-up in 934 subjects, with 790 (85%) on study treatment (prior to the last dose of study drug) at the time of the procedure. In addition, 505 procedures (54%) were performed on thienopyridine therapy and 805 (86%) on aspirin. Numbers of bleeding and major adverse cardiovascular events occurring in the 3 days after intervention are reported in Online Table 1. Overall GUSTO severe bleeding events were infrequent after both endovascular revascularization (1 with vorapaxar vs. 0 with placebo) and surgical intervention (2 with vorapaxar vs. 3 with placebo).
Patients with symptomatic PAD receiving intensive evidence-based therapies undergo peripheral revascularization frequently, with approximately 1 in 5 (19.3%) undergoing procedures at 3 years. Peripheral revascularization is significantly reduced with the PAR-1 antagonist vorapaxar. This effect appears consistent across indications for peripheral revascularization and types, although surgical revascularization showed the greatest magnitude of reduction (41%).
Peripheral revascularization procedures are performed frequently in patients with symptomatic PAD and are increasing in frequency, with 853,000 occurring in 2013 in the United States, an increase of 66% from 2005 (15). Currently there are no medical therapies available that have been shown prospectively to prevent peripheral revascularization (5,16–19).
Effect of vorapaxar on peripheral revascularization
We have reported previously that vorapaxar reduced peripheral revascularization in patients randomized with symptomatic PAD (13). The present study adds to this observation by demonstrating that the pattern of efficacy was consistent across the spectrum of indications and types of procedures, ranging from acute thrombotic events such as ALI to progressive atherosclerotic vascular disease including worsening claudication and critical limb ischemia. The effects of vorapaxar in reducing peripheral revascularization suggest that the benefits of PAR-1 inhibition as long-term therapy in patients with PAD could extend beyond a purely antithrombotic effects. Although the effect for the prevention of thrombotic outcomes such as stent thrombosis and ALI emerges early after initiation of therapy, the effects for prevention of intervention for claudication appeared to emerge later. Although these observations are hypothesis generating only, they raise the possibility of benefits in attenuating progressive atherosclerosis. These findings require confirmation in additional studies.
First, peripheral revascularization, although pre-specified as an outcome, was site reported and not adjudicated. It is possible that formal adjudication would add further specificity to this endpoint, and such improvement in specificity would be anticipated to increase rather than attenuate any treatment effect. In addition, there is broad variability in the application of revascularization procedures, particularly for progressive disease such as worsening claudication. In the present study, it is unknown whether patients had sufficient utilization of noninvasive treatments such as supervised exercise, and it is possible that broader use of such therapies might reduce the absolute event rates observed. Variation in practice pattern would not, however, bias the effect of vorapaxar versus placebo, as treatment was randomized and therefore unknown to the physicians and patients making the decision to proceed with intervention. Finally, analyses evaluating the benefit of vorapaxar in reducing peripheral revascularization over time, including the choice of stratifying at 450 days, were not pre-specified and are exploratory.
Patients with symptomatic PAD undergo peripheral revascularization frequently and most often to treat progressive disease that has led to worsening symptoms. The PAR-1 antagonist vorapaxar reduces peripheral revascularization with a consistent pattern across indications and types of procedures. These data support PAR-1 as a therapeutic target for the reduction of limb morbidity in patients with PAD.
WHAT IS KNOWN? Patients with PAD experience significant morbidity related to limb disease. This includes acute thrombotic events (e.g., ALI) as well as disabling symptoms or tissue loss due to progressive disease. Limb disease may lead to intervention. Vorapaxar, a PAR-1 antagonist, reduced limb interventions with a consistent pattern of efficacy across indication.
WHAT IS NEW? Prior studies have shown that vorapaxar reduces ALI, presumably through antithrombotic mechanisms. This study evaluated more broadly events leading to peripheral revascularization, including both acute thrombotic indications and progressive disease. Vorapaxar reduced the incidence of peripheral revascularization with a consistent pattern across indications. In addition, this study presents these observations in the context of the overall efficacy and safety of vorapaxar in patients with PAD without stroke or TIA.
WHAT IS NEXT? Additional studies with vorapaxar and other antithrombotic therapies in patients with PAD are needed to better characterize potential limb benefits in the context of overall efficacy and safety.
For a supplemental figure and table, please see the online version of this article.
The TRA 2°P–TIMI 50 trial was supported by a grant from Merck to Brigham and Women's Hospital. Dr. Bonaca was supported by a Research Career Development Award (K12 HL083786) from the National Heart, Lung, and Blood Institute. The TIMI Study Group has received significant research grant support from Accumetrics, Amgen, AstraZeneca, Beckman Coulter, Bristol-Myers Squibb, CV Therapeutics, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Integrated Therapeutics, Merck, 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 Merck, AstraZeneca, and Bayer. Dr. Olin is on the medical advisory board and Steering Committee TRA-2P for Merck and is also on the medical advisory board and the International Steering Committee EUCLID Trial for AstraZeneca. Dr. Scirica received research grants from Merck, AstraZeneca, Daiichi-Sankyo, Gilead, Eisai, Poxel, Biogen Idec, Boehringer Ingelheim, Dr. Reddy's Laboratory, Forest Pharmaceuticals, GlaxoSmithKline, Lexicon, and St. Jude Medical; and received consulting fees from AstraZeneca and Merck. Ms. Murphy has received consulting fees from Eli Lilly and Amarin Pharmaceuticals and has received speaking fees from Merck. Dr. Braunwald received research grant support from Merck. Dr. Morrow has received consulting fees from Beckman-Coulter, Boehringer Ingelheim, Critical Diagnostics, Genentech, Gilead, Instrumentation Laboratory, Merck, Roche Diagnostics, AstraZeneca, GlaxoSmithKline, Novartis, and Servier; and has also received research grant support from Merck, Amgen, AstraZeneca, Daiichi-Sankyo, Eisai, GlaxoSmithKline, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- acute limb ischemia
- confidence interval
- hazard ratio
- peripheral artery disease
- protease-activated receptor
- transient ischemic attack
- Received February 1, 2016.
- Revision received July 18, 2016.
- Accepted July 28, 2016.
- American College of Cardiology Foundation
- European Stroke Organisation,
- Tendera M.,
- Aboyans V.,
- et al.
- Hirsch A.T.,
- Haskal Z.J.,
- Hertzer N.R.,
- et al.
- Mahoney E.M.,
- Wang K.,
- Keo H.H.,
- et al.
- Rooke T.W.,
- Hirsch A.T.,
- Misra S.,
- et al.
- Kumbhani D.J.,
- Steg P.G.,
- Cannon C.P.,
- et al.
- Morrow D.A.,
- Scirica B.M.,
- Fox K.A.,
- et al.
- Bonaca M.P.,
- Scirica B.M.,
- Creager M.A.,
- et al.
- Magnani G.,
- Bonaca M.P.,
- Braunwald E.,
- et al.
- ↵Creswell J, Abelson R. Medicare payments surge for stents to unblock blood vessels in limbs. The New Your Times. January 29, 2015. Available at: http://www.nytimes.com/2015/01/30/business/medicare-payments-surge-for-stents-to-unblock-blood-vessels-in-limbs.html?_r=0. Accessed August 19, 2016.
- Robertson L.,
- Ghouri M.A.,
- Kovacs F.
- Cacoub P.P.,
- Bhatt D.L.,
- Steg P.G.,
- Topol E.J.,
- Creager M.A.,
- for the CHARISMA Investigators