• Myocardial Infarction Clinical Trials

The results of the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA•CER trial), reported by Kenneth W. Mahaffey, MD, Duke Clinical Research Institute, Durham, North Carolina, USA, showed that vorapaxar does not significantly improve outcomes in high-risk patients with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS) and significantly increases the risk of major bleeding, including intracranial hemorrhage (ICH).

The TRA•CER trial [NCT00527943] evaluated the efficacy and safety of vorapaxar, a first-in-class, orally active, potent, and selective platelet protease-activated receptor-1 (PAR-1) antagonist, compared with placebo in high-risk patients with NSTE-ACS who were treated with the current standard of care. TRA•CER was a prospective, randomized, double-blind, placebo-controlled trial that enrolled 12,944 ACS patients from 37 countries. Eligible patients had ischemic symptoms within 24 hours of hospital presentation, either elevated troponin or CK-MB or ST-segment changes on ECG, and at least 1 additional high-risk criterion: age ≥55 years, prior myocardial infarction (MI) or revascularization procedure (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG]), diabetes mellitus (DM), or peripheral arterial disease. Vorapaxar or placebo was given as a loading dose (40 mg) at least 1 hour prior to revascularization, followed by a maintenance dose (2.5 mg daily). The primary efficacy endpoint was the composite of cardiovascular (CV) death, MI, stroke, hospitalization for ischemia, or urgent revascularization. The secondary efficacy endpoint was the composite of CV death, MI, or stroke. Safety-related endpoints included the composite of moderate and severe GUSTO bleeding and clinically significant TIMI bleeding.

The mean age of participants was 64 years, 28% was female, 31.4% had DM, 29% prior had MI, and 94% had elevated cardiac biomarkers at baseline. The majority of participants were from western Europe. Concomitant antiplatelet therapy consisted of aspirin (∼97% of patients) and thienopyridine (∼87%). The majority of patients (88%) underwent angiography, with 58% having subsequent PCI and 10% CABG.

Follow-up in the trial was terminated early (median follow-up of 502 days) after a review by the data safety monitoring board. Treatment with vorapaxar did not significantly reduce the primary endpoint compared with placebo (18.5% vs 19.9%; HR, 0.92; 95% CI, 0.85 to 1.01; p=0.07). Although the primary endpoint was neutral, there was a reduction in the secondary endpoint, a composite of death from CV causes, MI, or stroke with vorapaxar compared with placebo (14.7% vs 16.4%; HR, 0.89; 95% CI, 0.81 to 0.98; p=0.02), which was primarily driven by a reduction in spontaneous MI (11.1% vorapaxar vs 12.5% placebo; HR, 0.88; 95% CI, 0.79 to 0.98; p=0.02). The individual rates of CV death, stroke, and hospitalization for ischemia, urgent revascularization, stent thrombosis, and all-cause mortality were not significantly different between the two groups.

Treatment with vorapaxar was associated with increased bleeding compared with placebo, including the primary safety endpoint of GUSTO moderate/severe bleeding (7.2% vs 5.2%; HR, 1.35; 95% CI, 1.16 to 1.58; p<0.001) as well as ICH (1.1% vs 0.2%; HR, 3.39; 95% CI, 1.78 to 6.45; p<0.001). The excess bleeding with vorapaxar occurred early and continued to accrue over time. Clinically significant TIMI, severe GUSTO, and major TIMI bleeding were also significantly (p<0.001) higher for the patients who were randomized to vorapaxar. Fatal bleeds were low and not different between the two groups. Rates of nonhemorrhagic adverse events were similar in the two groups. There was an interaction between GUSTO moderate or severe bleeding with vorapaxar and thienopyridine therapy at randomization (p=0.04), with no significant hazard with vorapaxar for patients who were not taking thienopyridines (HR, 0.95; 95% CI, 0.65 to 1.40) but a significant hazard for those who were taking thienopyridines (HR, 1.45; 95% CI, 1.23 to 1.71). In addition, patients with lower body weight had higher rates of bleeding (p-interaction=0.03).

Overall, these results show that vorapaxar, as administered in this trial (40-mg loading dose and 2.5 mg daily), was not associated with a reduction in ischemic events and was associated with increased bleeding, with significant interactions for concomitant thienopyridine therapy and low body weight. Whether PAR-1 blockade improves outcomes with different medication strategies or in other patient populations with coronary artery disease requires further study.

• © 2011 MD Conference Express®