Otamixaban Is Promising New Treatment For Patients With Acute Coronary Syndromes (SEPIA-ACS1 TIMI 42 Study)

Main Category: Cardiovascular / Cardiology
Also Included In: Heart Disease
Article Date: 03 Sep 2009 - 17:00 PDT

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An Article published Online First and in an upcoming edition of The Lancet shows that otamixaban is a promising new agent for patients with acute coronary syndromes (heart attacks or sudden worsening of angina). The Article, by Dr Marc S Sabatine, TIMI Study Group, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA, and colleagues, is being presented at the European Society of Cardiology meeting, Barcelona.

'Non-ST-elevation acute coronary syndromes' occur when fatty plaques in coronary arteries rupture, leading to the formation of a small blood clot (a thrombus) within the artery, thereby blocking blood flow to heart muscle. A molecule called Factor Xa is a key component in the pathway leading to thrombus formation, and otamixaban is a drug which inhibits factor Xa. The current conventional treatment for these patients is unfractionated heparin, which has a number of disadvantages, including thinning the blood to an unpredictable degree and therefore requiring frequent monitoring . By contrast, otamixaban is very specific in its inhibition of factor Xa and behaves much more predicatably, removing the need for continuous monitoring. In this study, the authors 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 acute coronary syndromes.

In this randomised, double-blind, phase 2 trial undertaken in 196 sites in 36 countries, 3241 patients with non-ST-elevation acute coronary syndromes were assigned to one of five doses of otamixaban (0•08 mg/kg bolus followed by infusions of 0•035 [n=125], 0•070 [676], 0•105 [662], 0•140 [658], or 0•175 [671] 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 μg/kg intravenous bolus followed by an infusion of 1•0-2•0 μg/kg/min [n=449]. Enrolment 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). The primary efficacy endpoint was a composite of death, heart attack, urgent treatment to increase blood flow in the artery, or bailout glycoprotein IIb/IIIa inhibitor use up to 7 days. The primary safety endpoint was major or minor bleeding not related to coronary-artery bypass grafting.

The researchers 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 authors conclude: "Treatment with otamixaban at doses of 0•105 or 0•140 mg/kg/h was associated with a 40% reduction in death or ischaemic 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 add*: "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."

In an accompanying Comment, Dr John W Eikelboom, McMaster University, Hamilton, ON, Canada, and Dr Jeffrey I Weitz, McMaster University and Henderson Research Centre, Hamilton, ON, Canada, suggest that, with other drugs such as bivalirudin on the market, the need for new intravenous agents such as otamixaban is minimal.

They say: "These findings suggest that, like bivalirudin, otamixaban may be a useful alternative to heparin for patients with acute coronary syndromes 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 3 trials to explore these possibilities, nor is otamixaban under development for other clinical indications."

Link to article

Source
The Lancet

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