Otamixaban, an intravenous anticoagulant, compared well with standard anticoagulant therapy in treating high-risk, non-ST-segment elevation acute coronary syndromes in a phase II study.
Otamixaban was associated with a 40% decrease in the composite outcome of all-cause mortality, myocardial infarction, severe recurrent ischemia requiring urgent revascularization, and “bailout” use of a glycoprotein IIb/IIIa inhibitor for recurrent ischemia or a thrombotic complication during percutaneous coronary intervention. There was no accompanying increase in bleeding events with the drug up to 7 days, study investigators reported.
Moreover, otamixaban has an almost immediate onset of action plus a 30-minute half-life. This allows rapid on-off anticoagulation, “a desirable feature in the setting of invasive management of an acute coronary syndrome,” wrote Dr. Marc S. Sabatine of Brigham and Women's Hospital, Boston, and his associates in this trial by the TIMI (Thrombolysis in Myocardial Infarction) Study Group.
Dr. Sabatine presented the results simultaneously with the publication at the annual congress of the European Society of Cardiology in Barcelona.
Otamixaban is a direct, selective inhibitor of factor Xa, “a key component of the prothrombinase complex that drives… the coagulation cascade” in acute coronary syndrome (ACS). Unlike unfractionated heparin, which has been the cornerstone of anticoagulant therapy for acute ACS, otamixaban doesn't cause thrombocytopenia and has predictable pharmacodynamic activity, so it doesn't require anticoagulation monitoring.
In a preliminary, dose-ranging study of 3,241 patients with acute ACS treated at 196 medical centers in 36 countries, study participants were randomly assigned to receive one of five doses of intravenous otamixaban or standard (control) anticoagulation therapy with unfractionated heparin plus eptifibatide. The study was funded by Sanofi-Aventis, the maker of otamixaban.
The two low doses of otamixaban appeared to provide inadequate anticoagulation, as patients who received these doses were at twice the risk as were those who received standard therapy for requiring a bailout glycoprotein IIb/IIIa inhibitor or for developing a thrombotic complication during PCI.
Conversely, the highest dose of otamixaban caused significantly more major or minor bleeding complications than did standard therapy.
The two intermediate doses of otamixaban, however, were associated with a 40% reduction in death, recurrent MI, or additional ischemic complications, compared with standard anticoagulation therapy. At these doses (0.105 and 0.140 mg/kg per hour), bleeding complications were similar between the drug and standard anticoagulation therapy (Lancet 2009 Aug. 30 [doi:10.1016/S0140-6736(09)61454-9
Otamixaban offers another advantage over heparin plus eptifibatide: With less than 25% excretion through the kidneys, it requires no dose adjustments in patients who have renal impairment, the investigators wrote.
In an editorial comment accompanying this report, Dr. John W. Eikelboom and Dr. Jeffrey I. Weitz of Hamilton (Ont.) General Hospital wrote, “These findings suggest that, like bivalirudin, otamixaban might be a useful alternative to heparin for patients who are undergoing PCI.
“However, do we need another parenteral agent for this indication?” they asked (Lancet 2009 Aug. 30 [doi:10.1016/S0140-6736(09)61529-4
“Without safety or convenience advantages, otamixaban would need to show 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,” Dr. Eikelboom and Dr. Weitz noted.
“Most of the attention in acute coronary syndromes has moved away from parenteral anticoagulants, such as otamixaban, and is focused on new oral agents,” they added.
Dr. Sabatine reports receiving honoraria and consulting fees from Sanofi-Aventis and Bristol-Myers Squibb Co. The TIMI study group receives research grant support from Sanofi-Aventis, Johnson & Johnson, Bayer Healthcare AG, and Daiichi Sankyo. Dr. Eikelboom has received honoraria, research support, or both from companies that are developing or marketing drugs mentioned in his editorial comment, including Bayer, Bristol-Myers Squibb, Eli Lilly & Co., GlaxoSmithKline, Regado Biosciences Inc., and Sanofi-Aventis.
Dr. Weitz also has received honoraria from companies that are developing or marketing drugs mentioned in his editorial comment, including Bristol-Myers Squibb, Sanofi-Aventis, and the Medicines Company.
Otamixaban has a quick onset of action plus a 30-minute half-life, allowing for rapid on-off anticoagulation.
Source Dr. Sabatine