ACC: Novel Anticoagulant May Sidestep Bleeding Risk

NEW ORLEANS, March 25 -- An investigational oral thrombin receptor antagonist led to a trend toward reduced fatal and non-fatal cardiac events, with a low bleeding risk, in a phase II trial of patients with percutaneous coronary interventions, mostly stenting.

In the early results on the efficacy of SCH 530348, the first oral thrombin receptor antagonist, there was a slight but not statistically significant increase in major and minor bleeding events -- 4% versus 3.3% for placebo -- with a 40-mg dose. In further trials, 40 mg is the investigational dose that is expected to be pursued.

So reported David J. Moliterno, M.D., of the University of Kentucky in Lexington at the American College of Cardiology meeting here. He said the bleeding increase was mostly driven by minor bleeding events.

SCH 530348 was tested at three different doses, and by combining results form all three arms, the drug met its primary endpoint of reducing major and minor bleeding events (2.8% versus 3.3% in placebo), he said. But the difference did not reach statistical significance

The agent yielded a nonsignificant 32% reduction in death and major adverse cardiac events, with a 41% reduction in myocardial infarction, Dr. Moliterno said.

"Oftentimes when investigating drugs in a phase II study, we will continue to increase the dose until we get a pretty good signal that bleeding is occurring," Dr. Moliterno said.

"So, we were really surprised at the extent in the reduction in ischemic events," he continued, "appreciating that none of this reached statistical significance."

This has always been the sought after paradigm in anticoagulation, commented Steven Nissen, M.D., of the Cleveland Clinic and president of the ACC.

"What everybody is looking for is the sweet spot where you have enough anticoagulation to prevent events but not so much that you increase bleeding," Dr. Nissen said, though he cautioned that the early results could not demonstrate the goal has been reached.

The double-blind, dose-ranging study included 1,030 patients planned for non-urgent percutaneous coronary interventions. The study compared SCH 530348 against placebo in addition to standard background therapy that typically included aspirin, clopidogrel (Plavix) and heparin or direct thrombin inhibitor therapy.

Patients were randomized to a 10-, 20- or 40-mg loading dose of SCH 530348 prior to percutaneous coronary interventions and then daily maintenance for 60 days at a dose of 0.5, 1.0 or 2.5 mg. The overwhelming majority of patients underwent stenting as percutaneous coronary interventions.

Most patients were men (70% study drug versus 80% placebo) with an average age 62 to 64. About a third of had diabetes, 35% to 37% had a prior myocardial infarction, and nearly half had a prior revascularization in both groups.

Almost every patient received aspirin and clopidogrel during the preliminary study. For antithrombin therapy, 40% to 43% received heparin and 46% to 50% received bivalrudin (Angiomax).

Among participants who underwent percutaneous coronary interventions as planned, there were no significant differences reported between groups or between dose arms. The safety findings were:

• For combined TIMI major and minor bleeding, 4.0% for 40 mg, 2.5% for 20 mg, 1.6% for 10 mg, 2.8% overall and 3.3% for placebo,
• For TIMI major bleeding, 0.6% for 40 mg, 0.0% for 20 mg, 1.6% for 10 mg, 0.7% overall, and 1.3% for placebo, and
• For stringently monitored non-TIMI bleeding, 43% for 40 mg and 20 mg, 36% for 10 mg, 41% overall, and 32% for placebo.

For the primary efficacy endpoint of combined death and major adverse cardiac events, there was a nonsignificant 32% overall reduction with the investigational agent compared with placebo. The rates at 60 days among PCI patients were:

• 4.6% for the 40 mg dose (a 46% reduction compared with placebo),
• 5.0% for the 20 mg dose,
• 8.5% for the 10 mg dose,
• 5.9% overall, and
• 8.6% for placebo.

The efficacy differences appeared to be driven by myocardial infarction (5.7% for the investigational agent overall versus 8.6% for placebo). Again, the agent showed a nonsignificant but numerically impressive 41% overall reduction in myocardial infarction, which was even greater at 52% for the highest dose.

None of the differences between dose arms in safety or efficacy were significant.

The researchers also reported 80% or greater inhibition of platelet aggregation within one to two hours in 68% to 96% of patients who received the 40-mg loading dose. The 1-mg and 2.5-mg maintenance doses kept platelet aggregation at or below 80% for all patients at both 30 days and 60 days.

Dr. Moliterno speculated that since the agent specifically blocks a single thrombin pathway, it would serve as an add-on rather than replacement to other drugs. Therefore, cost may be an issue.

It's feasible to give patients a combination of three drugs after PCI, Dr. Nissen said, but cost-effectiveness may outweigh such a strategy for patients who are not at high risk.

Nevertheless, he concluded that the findings justify further study.