New anticoagulant is promising in treatment of ACS

November 11, 2008

An investigational oral anticoagulant-the factor Xa inhibitor rivaroxaban-performed well enough in a Phase II study in patients with acute coronary syndromes (ACS) to support a pivotal Phase III trial in patients with ACS, reports C. Michael Gibson, MD.

An investigational oral anticoagulant-the factor Xa inhibitor rivaroxaban-performed well enough in a Phase II study in patients with acute coronary syndromes (ACS) to support a pivotal Phase III trial in patients with ACS, reports C. Michael Gibson, MD.

The study, known as ATLAS ACS TIMI 46, enrolled 3,491 stable patients with recent ACS who were on aspirin and, if deemed necessary by their treating physician, clopidogrel.

They were randomized to placebo or one of four doses of rivaroxaban (taken either once or twice daily) for 6 months, and were followed for an additional month after discontinuing the therapy.

The primary goal of the trial was to evaluate safety (clinically significant bleeding) and dose response; a primary efficacy endpoint that included a composite of death, myocardial infarction (MI), stroke, and severe ischemia requiring revascularization was also assessed.

As expected, rivaroxaban increased the rate of clinically significant bleeding in a dose-dependent manner. The rates of bleeding were 3.3 percent with placebo, 6.1 percent with 5 mg of rivaroxaban, 10.9 percent with 10 mg of rivaroxaban, 12.7 percent with 15 mg of rivaroxaban, and 15.3 percent with 20 mg of rivaroxaban. Overall, 82 percent of the clinically significant bleeding events were not defined as TIMI major or TIMI minor bleeds.

Although rivaroxaban was associated with a 21 percent relative risk reduction in the primary endpoint, this reduction did not achieve statistical significance (p = 0.1). The study was not sufficiently powered to detect a significant effect on the primary endpoint, notes Dr. Gibson, chief of clinical research, Beth Israel Deaconess Medical Center, Boston. A 31 percent relative risk reduction with rivaroxaban on a secondary endpoint of death, MI, or stroke did achieve significance (p = 0.028).

Based on the study, “we have decided to go forward to Phase III with the two lower doses-2.5 and 5 mg twice daily,” he says. These two lower doses reduced the risk of death, MI, and stroke by 46 percent compared to placebo (p = 0.08) and were associated with a major bleeding rate of 1.2 percent.

Notably, there was no drug-induced liver injury in the study. The development of an oral direct thrombin inhibitor, ximelagatran, had been terminated due to liver toxicity.

A Phase III trial with rivaroxaban in 16,000 patients will begin in December.