American College of Cardiology Scientific Session: Antiplatelet Therapy
As the lead investigator of the Thrombin iteceptor Antagonist in Percutaneous Coronary intervention (TRA-PCI) trial, Dr. Moliterno also took up the recurring theme that for patients undergoing PCI, new agents intended to further reduce clinical events without adding a tendency to cause bleeding have been elusive so far.
His study evaluated a novel thrombin receptor antagonist (TRA, SCH 530348, Schering-Plough), derived from the bark of the Australian rhododendron plant. He pointed out that MIs or other adverse ischemic events occur in 4% to 8% of patients undergoing PCI, even with the optimal use of antiplatelet, anticoagulant, and antithrombotic agents.
Among patients undergoing non-urgent PCI or coronary angiography (with the intent to undergo PCI), the oral, selective TRA was given in a double-blind fashion as a pre-PCI loading dose (10 mg, 20 mg, 40 mg, or placebo) and as a post-loading PCI dose as daily maintenance therapy for 60 days (0.5 mg, 1 mg, 2.5 mg, or placebo).
All of the patients (422 receiving TRA, 151 receiving placebo) were given aspirin. Those undergoing PCI received canadian clopidogrel and an antithrombin agent (heparin, bivalirudin [Angiomax], or a GPIIb/IIIa inhibitor).
The primary endpoint was safety (TIMI [Thrombosis in Myocardial infarction] major bleeding plus minor bleeding). The secondary endpoint was efficacy (death or major adverse cardiac events).
The endpoint of TIMI major or minor bleeding was reported in 3.3% of placebo patients and in 2.8% of patients receiving TRA (P = 0.77). TIMI major bleeding was similar for TRA 40 mg (0.6%) and for placebo (3.3%); however, overall major and minor bleeding was slightly higher with the highest TRA dose: 4% for TRA vs. 3.3% for placebo (P = 0.73).
The incidence of death or major adverse cardiac events was 8.6% with placebo, 5.9% with all doses of the study drug, and 4.6% with TRA 40 mg (a 46% reduction; P = 0.15).
At 60 days, the rates of death or MI were 7.3% with placebo and 4% with TRA 40 mg (P = 0.20). The rate of MI was reduced by 52% with TRA 40 mg (for 7.3% of patients receiving placebo and for 3.5% of patients receiving TRA 40 mg).
Even though these efficacy endpoints demonstrated favorable trends for TRA, Dr. Moliterno cautioned that the TRA-PCI trial was not adequately powered to evaluate efficacy. He concluded that a large-scale phase 3 trial was warranted.