ORLANDO – Adding the investigational agent vorapaxar to dual-antiplatelet therapy did not impact the primary end point and significantly increased bleeding among high-risk patients with non–ST elevation acute coronary syndrome in the prospective phase III TRACER trial.
Use of the oral protease-activated receptor-1 (PAR-1) antagonist was associated with a significant, 35% increased risk of moderate to severe bleeding based on GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) criteria, compared with placebo (7.2% vs. 5.2%; hazard ratio, 1.35), as well as a 43% increase in the risk of clinically significant TIMI (Thrombolysis in Myocardial Infarction) bleeding (20.2% vs. 14.6%; HR, 1.43), also a significant difference.
Dr. Keith A. Fox
Fatal bleeding was not significantly increased, but intracranial hemorrhage was 3.4-fold higher with vorapaxar, senior author Dr. Kenneth Mahaffey said at the annual scientific sessions of the American Heart Association.
Excess moderate and severe bleeding based on GUSTO criteria and intracranial hemorrhage with vorapaxar occurred early and continued to accrue over time in the phase III TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial.
Notably, patients were on vorapaxar for much longer than in previous dual-antiplatelet trials, at a median of 379 days, he said.
Invited discussant Dr. Keith A. Fox, professor of cardiology at the University of Edinburgh, said there is an absolute excess at 2 years of about two moderate or severe bleeds, almost five clinically significant TIMI bleeds, and almost one additional intracranial hemorrhage per 100 patients treated, without an impact on the primary end point.
"The potential I think still remains to reduce thrombotic events after [acute coronary syndrome], but I would argue that TRACER has missed the ‘sweet spot’ between efficacy and safety," he said.
TRACER was halted early this year after meeting the prerequisite number of events. It enrolled 12,944 patients with non–ST elevation ACS within 24 hours of presentation who had elevated troponin levels, elevated creatine kinase MB levels, or new ST-segment changes, and at least one other high-risk feature such as diabetes, previous MI, or coronary artery bypass graft surgery.
Patients were randomized to placebo or vorapaxar at a loading dose of 40 mg and maintained at 2.5 mg daily.
Clopidogrel was given to 92% of patients during the index hospitalization; 88% of patients underwent cardiac stenting, and 10% underwent coronary artery bypass grafting. About 87% of patients in each arm were on a thienopyridine, and 40% were taking at least 100 mg/day of aspirin.
At 2 years, the composite primary end point of cardiovascular death, MI, stroke, hospitalization for recurrent ischemia, or urgent revascularization was reported in 18.5% of patients on vorapaxar and 19.9% on placebo, a nonsignificant difference (P = .072; hazard ratio, 0.92), said Dr. Mahaffey, codirector of cardiovascular research at Duke Clinical Research Institute in Durham, N.C.
There was a nominal yet significant relative risk reduction of 11% in the secondary end point of reduced cardiovascular death, MI, or stroke with vorapaxar at 14.7%, compared with 16.4% with placebo, that was primarily driven by a decrease in spontaneous MI.
Interestingly, the subgroup of patients not on a thienopyridine at baseline had a trend toward improved efficacy with vorapaxar and less risk of GUSTO moderate to severe bleeding than those receiving a thienopyridine, he noted.
Session comoderator Dr. Jeffrey Weitz, holder of the Canada Research Chair in Thrombosis and professor of medicine at McMaster University in Hamilton, Ont., said the subgroup analysis suggests that clinicians are "reaching a ceiling" in terms of what they can do with triple therapy and should instead be looking at this class of drugs to substitute one antiplatelet or anticoagulant therapy for another.
Dr. Mahaffey responded that "we are on the precipice of a paradigm shift in how we think about antiplatelets and antithrombins" and that the challenge is to find "what drug, what dosages, and now for how long."
Additional insights are expected to come from ongoing analyses and from the companion phase III TRA-2P TIMI-50 (Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events) trial, Dr. Mahaffey said. TRA-2P TIMI-50 is evaluating vorapaxar in addition to standard of care as chronic therapy in patients with a history of coronary artery disease and peripheral artery disease, with results expected in 2012.
The full results of TRACER were simultaneously published in the New England Journal of Medicine (2011 Nov. 13 [doi:10.1056/NEJMoa1109719}).
Merck funded the trial. Dr. Mahaffey is a consultant to and has received grants from Merck and numerous other drug companies. At press time, disclosures were not available for Dr. Cox and Dr. Weitz.