Boston, Massachusetts (PressExposure) September 15, 2009 -- Results from a phase II trial of an investigational intravenous drug designed to block the formation of blood clots, shows potential to reduce the risk of death, a second heart attack, or other coronary complications compared with the current standard of care in patients with acute coronary syndromes (heart attacks or unstable angina). The findings will be presented at the European Society of Cardiology meeting in Barcelona, Sunday, August 30, 2009 and appear simultaneously on line in the journal the Lancet.
Otamixaban inhibits the activity of Factor Xa, a key enzyme involved in the process of blood coagulation. It has already shown promising results when tested in low-risk patients undergoing elective angioplasty. In this trial, otamixaban was studied in high-risk patients with acute coronary syndromes undergoing urgent coronary angiography. Otamixaban was compared with heparin, a very commonly used blood thinner, and eptifibatide, an intravenous GP IIb/IIIa platelet inhibitor, the combination of which represents current standard of care for acute coronary syndromes. Heparin, however, has many limitations, including thinning the blood to an unpredictable degree and therefore requires frequent monitoring. "There is intense interest in finding a more effective, reliable, and safe replacement for heparin," said study's lead author, Marc S. Sabatine, MD, MPH, an Investigator in the TIMI Study Group and a cardiologist at Brigham and Women's Hospital, who presented the findings at the European Society of Cardiology meeting in Barcelona.
Sabatine, along with Professor Eugene Braunwald, Chairman of the TIMI Study Group, and colleagues studied the use of otamixaban in 3241 patients from 36 countries around the world who presented with an acute coronary syndrome. Study medications were started within 24 hours of presentation. Patients received state-of-the-art care with 98 percent getting aspirin, 98 percent getting clopidogrel, and 99 percent undergoing early coronary angiography. Otamixaban or heparin was given for approximately 5 hours (typically until the end of the angioplasty).
The study (called SEPIA-ACS1 TIMI 42) was designed to identify the optimal dose of otamixaban. Patients were randomized to one of 5 doses of otamixaban (an initial loading dose of 0.080 mg/kg followed by an infusion of 0.035, 0.070, 0.105, 0.140, or 0.175 mg/kg/hr) or to heparin plus the intravenous platelet inhibitor eptifibatide. The researchers tracked study participants for the incidence of death, a second heart attack, additional coronary complications, and bleeding through 7 days as well as over the following 6 months. The lowest dose group of otamixaban was stopped early at the recommendation of the Data Safety Monitoring Committee due to inadequate anticoagulation; the remaining dose groups enrolled in the study to scheduled completion.
At the end of the study, Dr. Sabatine and colleagues found that in all of the otamixaban dosage groups, except the lowest one, the rate of death, second heart attack, or additional coronary complications tended to be lower with otamixaban than with heparin plus eptifibatide. Specifically, patients receiving an intermediate dose of otamixaban (0.105 or 0.140 mg/kg/hr) had a 40 percent lower rate of death, second heart attack, or additional coronary complications than those treated with the current standard of care - heparin plus eptifibatide. Moreover, these patients had a 46 percent reduction in death or a second heart attack. These benefits persisted through 180 days. There was a significant increase in bleeding across the 5 otamixaban dosage groups, but the rate in intermediate doses of otamixaban (0.105 or 0.140 mg/kg/hr) was similar to the rate in patients treated with heparin plus eptifibatide.
"The data show that intermediate doses of otamixaban may offer a substantial reduction in major coronary complications in patients presenting with an acute coronary syndrome, with bleeding rates comparable to current therapy," says Sabatine. "These findings will need to be tested in a large phase III trial to establish the definitive role of otamixaban in the treatment of acute coronary syndromes."
Otamixaban is under development at Sanofi-Aventis, and sponsored the study. Dr. Sabatine has received research support, honoraria for educational presentations, and consulting fees from Sanofi-Aventis.