ESC: Sanofi's otamixaban performs well for ACS patientsis it necessary?
The study, simultaneously published in the Lancet, was presented by lead author Marc S. Sabatine, MD, of the TIMI Study Group at Brigham and Women's Hospital and Harvard Medical School in Boston.
The current conventional treatment for STEMI patients is unfractionated heparin, which has a number of disadvantages, including thinning the blood to an unpredictable degree and therefore requiring frequent monitoring, according to the authors. “By contrast, otamixaban is very specific in its inhibition of factor Xa and behaves much more predictably, removing the need for continuous monitoring,” Sabatine and colleagues wrote.
In this study, they compared a range of otamixaban doses with unfractionated heparin and eptifibatide, an intravenous glycoprotein IIb/IIIa platelet inhibitor, the combination of which represents current standard of care for ACS.
In this randomized, double-blind, phase 2 trial undertaken in 196 sites in 36 countries, the researchers assigned 3,241 patients with non-ST-elevation acute coronary syndromes to one of five doses of otamixaban (0.08 mg/kg bolus followed by infusions of 0.035 [125 patients], 0.07 [676 patients], 0.105 [662 patients], 0.14 [658 patients] or 0.175 [671 patients] mg/kg/h) or to a control of unfractionated heparin (60 IU/kg intravenous bolus followed by an infusion of 12 IU/kg/h) plus eptifibatide (180 ug/kg intravenous bolus followed by an infusion of 1-2 ug/kg/min [449 patients].
Enrollment into the lowest dose group was stopped early at the recommendation of the Data Monitoring Committee, due to higher numbers of patients going on to have full heart attacks and/or dying), according to Sabatine and colleagues.
The primary efficacy endpoint was a composite of death, MI, urgent treatment to increase blood flow in the artery, or bailout glycoprotein IIb/IIIa inhibitor use up to seven days, the authors wrote. The primary safety endpoint was major or minor bleeding not related to CABG.
The researchers found that, in all of the otamixaban dosage groups, except the lowest one, the rate of death, second MI or additional coronary complications tended to be lower with otamixaban than with heparin plus eptifibatide.
Specifically, they reported that patients receiving an intermediate dose of otamixaban (0.105 or 0.14 mg/kg/hr) had a 40 percent lower rate of death, second MI 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 MI. The benefits persisted through 180 days.
However, Sabatine and colleagues reported that there was a significant increase in bleeding across the five otamixaban dosage groups, but the rate in intermediate doses of otamixaban (0.105 or 0.14 mg/kg/hr) was similar to the rate in patients treated with heparin plus eptifibatide.
The authors concluded that treatment with “otamixaban at doses of 0.105 or 0.14 mg/kg/h was associated with a 40 percent reduction in death or ischemic complications compared with unfractionated heparin plus eptifibatide…Our study offers additional preliminary evidence for the efficacy and safety of direct factor Xa inhibition with otamixaban in patients with coronary disease.”
They added that their findings will need to be “tested in a large phase III trial to establish the definitive role of otamixaban in the treatment of ACS.”
In an accompanying commentary, John W. Eikelboom, MD, McMaster University in Hamilton, Ontario, and Jeffrey I Weitz, MD, McMaster University and Henderson Research Centre in Hamilton, Ontario, wrote that with other drugs such as bivalirudin [Angiomax from The Medicines Company] on the market, the need for new intravenous agents such as otamixaban is minimal.
Eikelboom and Weitz wrote that the findings suggest that, “like bivalirudin, otamixaban may be a useful alternative to heparin for patients with ACS who are undergoing PCI. However, do we need another parenteral agent for this indication? Without safety or convenience advantages, otamixaban would need to demonstrate efficacy that is superior not only to heparin, but also to bivalirudin, before it would be adopted for clinical use. To our knowledge, there are no ongoing phase III trials to explore these possibilities, nor is otamixaban under development for other clinical indications.”