Researchers reported on a study of a new oral anti-clotting agent - rivaroxaban - designed to identify doses that would be safe to test in subsequent Phase III efficacy and safety trials. The results of ATLAS ACS-TIMI 46 were presented as a late-breaking clinical trial at the American Heart Association's Scientific Sessions 2008.
"The goal of any early study is to find the right dose and the right way to give the drug, and we met that objective," said C. Michael Gibson, M.S., M.D., principal investigator, chief of clinical research at the Beth Israel Deaconess Medical Center and director of the Thrombolysis in Myocardial Infarction (TIMI) data coordinating center at Brigham and Women's Hospital, Boston, Mass. "We studied four different doses and both once-a-day and twice-a-day dosing schedules for this Factor Xa, (pronounced ten-A) inhibitor."
The Phase II, randomized, placebo-controlled study on 3,491 patients treated at 297 medical centers in 27 countries originally had safety as the primary endpoint, but its design also included efficacy endpoints, he said. 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.
Earlier studies had shown the experimental drug rivaroxaban effective at keeping blood clots from forming in the veins during and after major orthopedic surgery. ATLAS ACS-TIMI 46 is the first test of the drug in the arteries - which face higher pressures than the venous circulation - and the first study of the drug in acute coronary syndrome, defined as a heart attack or unstable angina, said Gibson.
The drug was added to the regimen of patients who were already taking either aspirin or aspirin plus a thienopyridine. 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 increasing doses of rivaroxaban. Bleeding ranged from 6.1 percent of patients receiving 5 milligrams (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, he 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 (p=0.10) for rivaroxaban patients compared to placebo patients for the primary efficacy composite endpoint of all-cause death, heart attack, stroke and severe recurrent chest pain (ischemia) requiring revascularization with bypass surgery or angioplasty. It did report a significant risk reduction for treated vs. placebo patients for the secondary efficacy composite endpoint of death, heart attack or stroke and that finding did reach statistical significance (p=0.028), he said.
The study followed patients being treated for ACS who were first divided into two strata depending on what usual care they received at their home medical center, he explained. Patients receiving aspirin entered Stratum I (706 patients) while those receiving aspirin plus a thienopyridine entered Stratum II (2,731 patients). All patients then had either placebo or one of four total daily doses of the Factor Xa inhibitor on a once- or twice-a-day schedule added to their regimen.
Aspirin and thienopyridines are anti-clotting agents that interfere with platelet aggregation, which is the clumping together of these blood cells. Factor Xa inhibitors interfere with formation of the fine threads of thrombin that bind the platelets together into a blood clot, he said.
Warfarin, the most commonly used anticoagulant, or anti-clotting medication, works on several aspects of the clotting process, including Factor X. Compared to rivaroxaban, warfarin seems to be slower to reach therapeutically effective levels in the body and it requires repeated blood testing of patients who take it, beginning with tests to ensure that the therapy has achieved the goal of reduced clotting speed, Gibson said. This is important because if their blood clots too quickly, it could lead to a stroke or heart attack; if it clots too slowly that could lead to bleeding, he explained.
The ATLAS ACS-TIMI 46 Trial is more than twice the size of the second-largest study. That study, APPRAISE, found a non-significant trend toward benefits and a clear dose-response with more bleeding events at higher doses, he said.
A 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 months is expected to begin in December 2008.
Co-authors include Jessica L. Mega, M.D.; Christopher J. Hammett M.D.; Vasil Hricak M.D.; Pascual Bordes M.D.; Adam Witkowski M.D.; Valentin Markov M.D.; Paul Burton M.D.; and Eugene Braunwald M.D. who chaired the study. Individual author disclosures can be found on the abstract.
The study was sponsored by Bayer AG, Leverkusen, Germany and Johnson & Johnson Pharmaceutical Research & Development, Raritan, N.J.