Efficacy and Safety of Vorapaxar as Approved for Clinical Use in the United States

• Published in: Journal of the American Heart Association Vol. 4; no. 3; p. e001505
• Main Authors: Magnani, Giulia, Bonaca, Marc P., Braunwald, Eugene, Dalby, Anthony J., Fox, Keith A. A., Murphy, Sabina A., Nicolau, José Carlos, Oude Ophuis, Ton, Scirica, Benjamin M., Spinar, Jindrich, Theroux, Pierre, Morrow, David A.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 19.03.2015
• Subjects: Aged; Double-Blind Method; Drug Approval; Female; Hemorrhage - chemically induced; Humans; Ischemic Attack, Transient - mortality; Ischemic Attack, Transient - prevention & control; Kaplan-Meier Estimate; Lactones - adverse effects; Lactones - therapeutic use; Male; Middle Aged; Myocardial Infarction - diagnosis; Myocardial Infarction - drug therapy; Myocardial Infarction - metabolism; Myocardial Infarction - mortality; Original Research; Peripheral Arterial Disease - diagnosis; Peripheral Arterial Disease - drug therapy; Peripheral Arterial Disease - metabolism; Peripheral Arterial Disease - mortality; Platelet Aggregation Inhibitors - adverse effects; Platelet Aggregation Inhibitors - therapeutic use; Pyridines - adverse effects; Pyridines - therapeutic use; Receptor, PAR-1 - antagonists & inhibitors; Receptor, PAR-1 - metabolism; Recurrence; Risk Factors; Secondary Prevention - methods; Stroke - mortality; Stroke - prevention & control; Time Factors; Treatment Outcome; United States - epidemiology; United States Food and Drug Administration; United States; atherosclerosis; vorapaxar; peripheral arterial disease; secondary prevention; antiplatelet therapy; myocardial infarction
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.114.001505

Vorapaxar is a protease-activated receptor-1 antagonist approved by the U.S. Food and Drug Administration (FDA) for the reduction of thrombotic cardiovascular (CV) events in patients with a history of myocardial infarction (MI) and peripheral artery disease (PAD), without a previous stroke or transient ischemic attack (TIA). We examined the efficacy and safety of vorapaxar in the intended use population, considering 20,170 patients randomized in the multinational, double-blinded, placebo-controlled TRA 2°P-TIMI 50 trial. Of these, 16,897 qualified with a history of MI in the prior 2 weeks to 1 year and 3273 with PAD. At baseline 97% of the patients were treated with aspirin, 71% with a thienopyridine, and 93% a statin. At 3 years, the endpoint of CV death, MI, or stroke was significantly reduced with vorapaxar compared with placebo (7.9% versus 9.5%, HR, 0.80; 95% CI 0.73 to 0.89; P<0.001). Vorapaxar also significantly reduced the composite of CV death, MI, stroke, and urgent coronary revascularization (10.1% versus 11.8%, HR, 0.83; 95% CI 0.76 to 0.90; P<0.001), as well as the rate of CV death or MI (P<0.001). The safety endpoint of GUSTO moderate or severe bleeding, was increased in the vorapaxar group (3.7 versus 2.4, HR, 1.55; 95% CI 1.30 to 1.86, P<0.001). Intracranial bleeding (ICH) was 0.6% versus 0.4%, P=0.10 with vorapaxar versus placebo, with fatal bleeding 0.2% versus 0.2%; P=0.70. In patients with prior MI or PAD who have not had a previous stroke or TIA, vorapaxar added to standard therapy is effective for long-term secondary prevention of thrombotic CV events, while increasing moderate or severe bleeding. URL: clinicaltrials.gov Unique Identifier: NCT00526474.