ORLANDO, Fla.--Despite promising data in its Phase 2 trial, the thrombin receptor antagonist vorapaxar added to standard therapy failed to significantly improve outcomes for patients with acute coronary syndromes (ACS) and increased the risk of major bleeding, including intracranial hemorrhage. The results of the TRA-CER trial, which had been halted Jan. 8 on recommendation of the trial’s data safety and monitoring board, were unveiled Nov. 13 at the 2011 American Heart Association’s conference.
The study was simultaneously published online in the New England Journal of Medicine.
Based on the bleeding risk, “this is not a viable strategy as it was used in this trial,” said Robert A. Harrington, MD, chair of the TRA-CER steering committee and director of the Duke Clinical Research Institute in Durham, N.C., in a press conference following the study presentation. In a follow-up discussion, Keith A.A. Fox, MBChB of the Edinburgh Centre for Cardiovascular Science in Edinburgh, Scotland, also concluded that risk outweighed benefit but added that there still is opportunity for anti-thrombotic therapies to reduce ischemic complications in these patients.
“TRA-CER was designed as a large trial to test the hypothesis that the addition of vorapaxar to stent therapy would reduce the risk of ischemic events in a group of patients with non-ST- elevation acute syndromes,” Harrington explained. To do so, they enrolled 12,944 ACS patients without ST-segment elevation who within 24 hours of presenting at a hospital had acute symptoms of coronary ischemia, and either increased biomarkers or echocardiographic changes and one high-risk feature.
The study’s primary efficacy endpoint was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. The secondary endpoint was a composite of cardiovascular-related death, MI, or stroke. The safety endpoint was a composite of moderate or severe bleeding (as classified under the Global Use of Strategies to Open Occluded Coronary Arteries [GUSTO]) and clinically significant bleeding (classified under Thrombolysis in Myocardial Infarction [TIMI]).
Patients were randomized to a vorapaxar group (with a loading dose of 40 mg and a maintenance dose of 2.5 mg daily, plus standard therapy) or a control group. Follow-up was scheduled at one, four, eight and 12 months and then every six months. Based on the Jan. 8 safety review, the trial was stopped.
Harrington said the study showed no significantly statistical difference in the primary and secondary endpoints and there was no difference is selected efficacy outcomes.
“There was an increased risk in bleeding over that of the placebo,” he noted, with a rate of moderate or severe bleeding of 7.2 percent in the vorapaxar group compared with 5.2 percent in the control group. The rate of clinically significant TIMI bleeding was higher in the voraoaxar group as well, at 20.2 percent versus 14.6 percent.
“Whether PAR-1 [protease-activated receptor-1] blockade improves outcomes with different medication strategies or in other patient populations with coronary artery disease awaits further study.”
Fox described TRA-CER as a “carefully conducted study” and noted that there is potential need for new antithrombotic treatments for ACS patients. “After 15 days, patients have ongoing event rates, despite secondary prevention,” he said. “In fact, over 80 percent of CV deaths are post-discharge.”
Reviewing TRA-CER results, Fox emphasized that the study was sufficiently powered for the bleeding analyses. “The potential remains to reduce thrombotic events after ACS, but I would argue that unfortunately, TRA-CER missed the sweet spot between efficacy and safety.”
In the press conference, Harrington explained that a second vorapaxar vs. placebo trial, TRA-2P TIMI 50, is in progress based on a different patient population that will continue to closeout in 2012. The same data safety and monitoring board that oversaw TRA-CER is handling this trial, and consequently the study team cannot review the board’s TRA-CER minutes. He added that the study group hoped that findings in the ongoing trial “provide insight and context to understand the TRA-CER results.”