Otamixaban for the treatment of patients with non-ST-elevation acute coronary syndromes (SEPIA-ACS1 TIMI 42): a randomised, double-blind, active-controlled, phase 2 trial.
BACKGROUND
Otamixaban is an intravenous direct factor Xa inhibitor. We aimed to assess its efficacy and safety in non-ST-elevation acute coronary syndromes and to identify the optimum dose range for further assessment in a phase 3 study.


METHODS
In this double-blind, phase 2 trial undertaken in 196 sites in 36 countries, 3241 patients with non-ST-elevation acute coronary syndromes were randomly assigned via a central, telephone-based interactive voice response system 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 microg/kg intravenous bolus followed by an infusion of 1.0-2.0 microg/kg/min [n=449]). Both investigators and patients were unaware of treatment allocation. Enrolment into the lowest dose group was stopped early at the recommendation of the Data Monitoring Committee. The primary efficacy endpoint was a composite of death, myocardial infarction, urgent revascularisation, or bailout glycoprotein IIb/IIIa inhibitor use up to 7 days. The primary safety endpoint was TIMI major or minor bleeding not related to coronary-artery bypass grafting. Efficacy analyses were by intention to treat; safety analyses were in treated patients. This study is registered with ClinicalTrials.gov, number NCT00317395.


RESULTS
Rates of the primary efficacy endpoint in the five otamixaban doses were 7.2% (nine of 125) with 0.035 mg/kg/h, 4.6% (31/676) with 0.070 mg/kg/h, 3.8% (25/662) with 0.105 mg/kg/h, 3.6% (24/658) with 0.140 mg/kg/h, and 4.3% (29/671) with 0.175 mg/kg/h (p=0.34 for trend). In the control group, the rate was 6.2% (28/449), yielding relative risks for the five otamixaban doses of 1.16 (95% CI 0.56-2.38), 0.74 (0.45-1.21), 0.61 (0.36-1.02), 0.58 (0.34-1.00), and 0.69 (0.42-1.15), respectively. Rates of the primary safety endpoint in the five otamixaban doses were 1.6% (two of 122), 1.6% (11/669), 3.1% (20/651), 3.4% (22/651), and 5.4% (36/664), respectively (p=0.0001 for trend); the rate in the control group was 2.7% (12/448).


CONCLUSIONS
In patients with non-ST-elevation acute coronary syndromes, otamixaban infusions of 0.100-0.140 mg/kg/h might reduce ischaemic events and have a safety profile similar to unfractionated heparin plus eptifibatide. Further testing in a phase 3 trial is warranted.


BACKGROUND
Sanofi-Aventis.
Sabatine
Marc S
MS
TIMI Study Group, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. msabatine@partners.org
Antman
Elliott M
EM
Widimsky
Petr
P
Ebrahim
Iftikhar O
IO
Kiss
Robert G
RG
Saaiman
André
A
Polasek
Rostislav
R
Contant
Charles F
CF
McCabe
Carolyn H
CH
Braunwald
Eugene
E
D054058:Acute Coronary Syndrome / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D000368:Aged; D015906:Angioplasty, Balloon, Coronary; D000925:Anticoagulants / Q000627:therapeutic use; D017023:Coronary Angiography; D003497:Cyclic N-Oxides / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000077542:Eptifibatide; D005260:Female; D005500:Follow-Up Studies; D006470:Hemorrhage / Q000139:chemically induced; D006493:Heparin / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000627:therapeutic use; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D012449:Safety; D016896:Treatment Outcome
D000925:Anticoagulants; D003497:Cyclic N-Oxides; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D006493:Heparin; D000077542:Eptifibatide; C435830:otamixaban