Vorapaxar in the secondary prevention of atherothrombotic events.

Thrombolysis in Myocardial Infarction (TIMI) Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
New England Journal of Medicine (Impact Factor: 55.87). 03/2012; 366(15):1404-13. DOI: 10.1056/NEJMoa1200933
Source: PubMed


Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1.
We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage.
At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001).
Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 number, NCT00526474.).

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Available from: Keith A A Fox, Dec 14, 2013
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    • "To date many PAR1 antagonists have been synthesized and characterized [7]–[10] and the high affinity non-peptide PAR1 antagonist, Vorapaxar, completed phase III clinical trials. The Vorapaxar TRA-CER trial was terminated due to an association of treatment with an increased risk of bleeding including intracranial hemorrhage however, the TRA-2P-TIMI 50 trial, excluding patients presenting with previous stroke, was completed and showed that PAR1 antagonism is effective in reducing cardiovascular death and ischemic events [11]–[13]. PAR4 as the low affinity thrombin receptor is consequently engaged by high concentrations of thrombin and thus subject to differential temporal engagement by thrombin. Our lab and others have documented signaling differences between PAR1 and PAR4 indicating that although activated by the same endogenous agonist and purportedly couple to the same G-proteins, platelet thrombin receptor signaling is fundamentally distinct [14]–[19]. "
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