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Oral anticoagulant rivaroxaban meets secondary, not primary, efficacy endpoint in dose-finding study, will advance to Phase III trial

Thursday, November 13 2008 | Comments

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What's This? By Selma Kaszczuk

Rivaroxaban, an oral direct factor Xa inhibitor, did not meet the primary efficacy endpoint of the ATLAS ACS-TIMI 46 trial, but results related to secondary efficacy endpoints of this Phase II dose-escalation investigation were significant and a Phase III trial is expected to begin next month, according to lead investigator Dr. C. Michael Gibson, chief of clinical research at Beth Israel Deaconess Medical Center in Boston.

The study, which was designed primarily to assess safety and secondarily certain efficacy endpoints, included 3,491 patients with a recent acute coronary syndrome (ACS) event who were being treated with either aspirin (n=761) or aspirin plus clopidogrel (n=2,730). None of the subjects had received treatment with warfarin. These patients were randomized to receive placebo or 1 of 4 doses of rivaroxaban (5 mg, 10 mg, 15 mg, and 20 mg) administered either once daily or split into 2 daily doses for 6 months. Treatment was initiated 1 to 7 days after the patient's index event.

Clinically significant bleeding was looked at as a part of the safety evaluation. Major bleeding was defined as intracranial bleeding or clinically overt bleeding associated with a decrease in hemoglobin >=5 g/dL or an absolute drop in hematocrit >=15%. Minor bleeding was defined as clinically overt bleeding associated with a decrease in hemoglobin >=3 g/dL but <5 g/dL. Dr. Gibson noted that other bleeding requiring medical attention but not meeting the major or minor bleeding criteria, such as nosebleed, also was considered clinically significant bleeding.

At 6 months, a dose-response effect was evident for clinically significant bleeding. Compared with the placebo group, which had a bleeding rate of 3.3%, the 20 mg rivaroxaban group had a clinically significant bleeding rate of 15.3% (hazard ratio [HR], 5.1; 95% CI, 3.4-7.4; P<.001) whereas the 5 mg rivaroxaban group had a rate of 6.1% (HR, 2.2; 95% CI, 1.25-3.91; P<.01).

Another safety parameter evaluated was abnormalities in liver function tests, and Dr. Gibson noted that the results revealed no differences in liver toxicities between placebo and all rivaroxaban groups.

The primary efficacy endpoint was a composite of death, myocardial infarction (MI), stroke, and severe recurrent ischemia requiring revascularization. While there was a trend toward significance favoring a reduced risk with rivaroxaban versus placebo after 6 months (HR, 0.79; P=.10), there was not a statistically significant difference between the rivaroxaban and placebo groups in the proportion of patients experiencing this endpoint (5.6% vs 7.0%, respectively). However, risk for the secondary efficacy endpoint, which was a composite of death, MI, and stroke, was reduced significantly by 31% among rivaroxaban-treated patients (3.9%) as compared with placebo-treated patients (5.5%; HR, 0.69; 95% CI, 0.50-0.96; P=.028).

Based on these safety and efficacy data, the Phase III investigation will evaluate the efficacy of twice daily dosing of 2.5 mg and 5.0 mg of rivaroxaban in up to 16,000 patients with ACS.

"It's a very delicate balance in terms of safety and efficacy," Dr. Gibson remarked.

The study was sponsored by Bayer HealthCare and Johnson & Johnson Pharmaceutical Research & Development LLC. (Abstract Oral Session 1309.)

This information concerns a use that has not been approved by the Food and Drug Administration.

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