• Thrombotic Disorders Clinical Trials

In stable patients with a history of atherosclerosis, the investigational protease–activated receptor (PAR)–1 antagonist vorapaxar was effective at reducing further atherothrombotic events. David A. Morrow, MD, MPH, Brigham & Women's Hospital, Boston, Massachusetts, USA, presented data from the Thrombin Receptor Antagonist in Secondary Prevention–TIMI 50 Trial [TRA 2P; NCT00526474] which showed that vorapaxar significantly reduced the risk of deaths from cardiovascular disease (CVD), myocardial infarction (MI), or stroke compared with placebo.

This was a worldwide, placebo–controlled, randomized, double–blind study that enrolled 26,449 patients (median age 61 years) with a history of spontaneous MI, ischemic stroke, or peripheral arterial disease (PAD). Subjects were treated with 2.5 mg/day vorapaxar or placebo, in addition to standard care including aspirin and/or thienopyridine. Overall, patients were followed for a median of 30 months. However, after a median follow–up of 24 months, treatment was discontinued in patients with a history of stroke due to a higher risk of intracranial hemorrhage (ICH) in that population. The primary efficacy endpoint was a composite of CV death, MI, or stroke. The secondary composite endpoint also included urgent coronary revascularization. The primary safety endpoint was GUSTO moderate or severe bleeding. The primary analysis was conducted on all data from all randomized patients. Additional analyses were conducted on patients without prior stroke and those who qualified with MI (67% of subjects).

In the overall population, the primary endpoint occurred in 9.3% of subjects who were randomized to vorapaxar compared with 10.5% of those who were randomized to placebo (HR, 0.87; 95% CI, 0.80 to 0.94; p<0.001). Subjects who qualified with an MI had a significant benefit from treatment with vorapaxar (HR, 0.80; 95% CI, 0.72 to 0.89), as did all patients (MI and PAD cohorts) without a history of stroke (8.3% vs 9.6%; HR, 0.84; 95% CI, 0.76 to 0.93; both p<0.001).

Voraxapar also significantly reduced the composite secondary endpoint (HR, 0.88; 95% CI, 0.82 to 0.95; p=0.001) and the composite of CV death or MI (HR, 0.86; 95% CI, 0.78 to 0.94; p=0.002). Both GUSTO moderate or severe and clinically significant TIMI bleeding were increased with vorapaxar (HR, 1.66; 95% CI, 1.43 to 1.93; and HR, 1.46; 95% CI, 1.36 to 1.57, respectively), as was ICH (HR, 1.94; 95% CI, 1.39 to 2.70; all p<0.001). There was no difference in fatal bleeding.

The investigators concluded that PAR–1 is a valuable novel target and that adding vorapaxar to standard therapy could be an effective treatment for long–term secondary prevention of atherothrombotic events in stable patients with a history of previous MI. However, the benefits for treating patients with PAD remain uncertain, and the risk of ICH in patients with prior stroke is unacceptable with this agent. Careful patient selection is recommended when using vorapaxar [Morrow DA et al. N Engl J Med 2012].

• © 2012 MD Conference Express®