Original Investigation
New Ischemic Stroke and Outcomes With Vorapaxar Versus Placebo: Results From the TRA 2°P-TIMI 50 Trial

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Abstract

Background

Vorapaxar, a novel antiplatelet therapy, reduces thrombotic events in patients with a history of myocardial infarction (MI) or peripheral artery disease (PAD); however, because of an increased risk of intracranial hemorrhage, it is contraindicated in patients with a history of stroke.

Objectives

The aim of this study was to investigate the incidence of new ischemic stroke and subsequent death or intracerebral hemorrhage in patients with MI or PAD and no cerebrovascular disease (CVD) treated with vorapaxar.

Methods

The 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 randomized, double-blind, placebo-controlled trial of vorapaxar 2.5 mg daily in 26,449 patients with atherosclerosis, stratified by qualifying disease (MI, PAD, or CVD). A total of 20,170 patients with MI/PAD, but no CVD, were enrolled.

Results

In patients with MI/PAD and no prior stroke or transient ischemic attack, vorapaxar reduced first ischemic stroke (hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.43 to 0.75; p < 0.001). The risk of hemorrhagic conversion after stroke (HR: 1.19, 95% CI: 0.49 to 2.91; p = 0.70) or death (HR: 1.09, 95% CI: 0.57 to 2.07; p = 0.79) during follow-up was not significantly increased with vorapaxar in patients who had a new ischemic stroke (n = 204). Although hemorrhagic stroke was increased (HR: 2.79, 95% CI: 1.00 to 7.73; p = 0.049), overall stroke was significantly reduced (HR: 0.67, 95% CI: 0.52 to 0.87; p = 0.002).

Conclusions

Vorapaxar reduces ischemic stroke in patients with MI or PAD and no known CVD. There does not appear to be a significant increase in the risk of hemorrhagic conversion or death in patients who experienced a first ischemic stroke on vorapaxar. Although primary hemorrhagic stroke is increased, vorapaxar reduces the total incidence of stroke. (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]; NCT00526474)

Key Words

antiplatelet therapy
intracranial hemorrhage
PAR-1
platelet aggregation inhibitors
secondary prevention
thrombin receptor

Abbreviations and Acronyms

CI
confidence interval
CVD
cerebrovascular disease
DAPT
dual antiplatelet therapy
HR
hazard ratio
MI
myocardial infarction
MRS
modified Rankin Scale
PAD
peripheral artery disease
TIA
transient ischemic attack

Cited by (0)

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 was supported by a Research Career Development Award (K12 HL083786) from the National Heart, Lung, and Blood Institute; and 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, Arena, St. Jude Medical, Icon Medical Imaging, and Bristol-Myers Squibb. Dr. Goto has received honoraria from Eisai, Sanofi, Otsuka, Bayer, Novartis, AstraZeneca, Asteras, Pfizer, Medtronics-Japan, Tanabe-Mitsubishi, Takeda, Daiichi-Sankyo, Mochida, and MSD; and has received research grants from Sanofi, Boehringer Ingelheim, Otsuka, and Daiichi-Sankyo. 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 & 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. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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