Aspirin has been traditionally used in prevention of ischemic events and dual antiplatelet is a norm now in acute coronary syndrome or in patients undergoing percutaneous intervention. In contrast, among patients with stable atherosclerosis, a reduced rate of thrombotic events with antiplatelet therapy in addition to aspirin therapy has not been established.

TRA 2P: TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events Trial)was a phase III randomized, double-blinded, placebo controlled, multinational study that followed patients in 32 countries for more than two years {1}. This was one of the largest trials of the TIMI group so far; involving 26,449 patients evaluated the use of a newer anti platelet agent Vorapaxar vs. placebo for secondary prevention of atherothrombotic ischaemic events over the standard therapy. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of protease activated receptor (PAR-1).

In the trial the patients with a history of MI (n=17779) or ischaemic stroke (n=4883) or peripheral vascular disease (n=3787) were randomised to either receive vorapaxar 2.5 mg or matching placebo in addition to standard treatment and were followed up for 30 months.  Vorapaxar and placebo were administered orally in a blinded fashion once daily until the end of follow-up. Patients were ineligible if they were planning to undergo a revascularization procedure, had a history of bleeding diathesis, had recent active abnormal bleeding, were receiving on-going treatment with warfarin, or had active hepato-biliary disease.

The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction or stroke. The major secondary end point was a composite of cardiovascular death, myocardial infarction, stroke or recurrent ischemia leading to urgent coronary revascularization. Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) moderate or severe bleeding was defined as the safety end point of primary interest.

 The stroke group was discontinued from the study due to increased risk of intracranial bleeding seen in this subgroup.  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). The primary end point was significantly reduced in the post-MI patients and there was a small trend toward benefit in the PAD patients and a neutral effect in patients with a previous cerebrovascular event. 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 haemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). Rates of TIMI clinically significant bleeding and rates of TIMI major bleeding not related to coronary-artery bypass grafting were also both significantly increased in the vorapaxar group as compared with the placebo group (P<0.001). The rate of death from any cause did not differ significantly between the vorapaxar group and the placebo group (5.0% and 5.3%, respectively; hazard ratio, 0.95; 95% CI, 0.85 to 1.07; P=0.41

In terms of absolute risk reduction there was less than 1% net clinical benefit with vorapaxar but it came at an expense of high bleeding risk. The results of this study establish that interruption of the platelet-directed cellular actions of thrombin, suggested in preclinical studies to be pivotal to thrombosis, translates into a clinical effect on major thrombotic events. Antagonism of PAR-1 was complementary to inhibition of the thromboxane A2 and P2Y12-receptor pathways with aspirin and thienopyridines, with respect to the protective effect against recurrent thrombosis. Although it is a novel pathway its use may still not become possible in all comers.