New anticoagulant moves to phase III trial despite bleeding caveats

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NEW ORLEANS—A new anti-clotting agent—rivaroxaban—that could potentially keep blood clots from forming, will move into a pivotal Phase III trial for the secondary prevention of acute coronary syndrome (ACS) later this year, according to the ATLAS ACS-TIMI 46 late-breaking clinical trial presented Monday at the American Heart Association (AHA) Scientific Sessions.

C. Michael Gibson, MD, director of the TIMI Data Coordinating Center at Brigham and Women’s Hospital in Boston, presented the Phase II clinical data from the ATLAS ACS TIMI 46 trial, designed to explore the safety and efficacy of rivaroxaban at escalating total daily doses, ranging from 5 mg up to 20 mg.

“This was a robust study that achieved its main objective of establishing the preferred dosing scenario for further evaluating rivaroxaban in a large Phase III clinical trial of ACS patients,” Gibson said. “The additional benefit of rivaroxaban over placebo in this study, given on a background of standard antiplatelet therapy, highlights the unmet medical need of this patient population.”

In the stufy, rivaroxaban (Xarelto from Bayer Healthcare and Johnson & Johnson) was administered at once-daily and twice-daily intervals, assessing eight different dosing regimens. They enrolled nearly 3,491 patients treated at 297 medical centers in 27 countries, and all patients received standard antiplatelet therapy of low-dose aspirin and, at the physician’s discretion, a thienopyridine, such as clopidogrel. Patients were then randomized to additionally receive either rivaroxaban or a placebo for six months.

The primary efficacy endpoint was a composite of death, heart attack, stroke and severe ischemia revascularization. The secondary endpoint was a composite of death, heart attack or stroke.

Regarding the safety endpoint, a composite of TIMI major bleeding, TIMI minor bleeding and any bleeding requiring medical attention, the researchers found that bleeding incidents increased with higher doses of rivaroxaban. Bleeding ranged from 6.1 percent of patients receiving 5 mg of the drug each day to 15.3 percent of those receiving 20 mg daily, compared to a 3.3 percent rate of bleeding incidents in patients receiving placebo, Gibson said. Overall, 82 percent of all bleeding incidents fell in the mildest, non-TIMI tier of severity, he added.

The study reported no significant risk reduction for rivaroxaban patients compared to placebo patients for the primary efficacy composite endpoint of death, heart attack, stroke and ischemia requiring revascularization with bypass surgery or angioplasty. He reported a significant risk reduction for treated versus placebo patients for the secondary efficacy composite endpoint of death, heart attack or stroke and that finding was not statistically significance (p=0.028), he said.

ATLAS ACS-TIMI 46 is the first test of the drug—which is approved for use in the European Union for the prevention of venous thromboembolism (VTE) in adult patients—in the arteries and the first study of the drug in ACS.

The Phase III trial—expected to enroll 16,000 patients randomized to twice a day doses of 2.5 mg or 5 mg of rivaroxaban for six month—is expected to begin in December.