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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: Sanofi-Aventis.

Repeat surgery for coronary artery bypass grafting: the role of the left thoracotomy approach.

OBJECTIVE: Repeat coronary artery bypass surgery has increased risks compared with the first operation, including low cardiac output and injury to patent grafts. The left thoracotomy approach has been advocated specifically in patients with intact grafts of the left internal mammary artery (LIMA) to the left anterior descending coronary artery (LAD) needing lateral wall grafting. We have evaluated this technique in conjunction with an off-pump procedure in all patients. METHODS: There were 55 patients over an 8-year period, and 6 (10.9%) were female. The mean age was 63.2 years (range, 41-82 years), and the age at the time of the previous operation was 51.7 years (range, 31-69 years). Four patients (7.2%) underwent a third operation. Comorbidities were diabetes mellitus (25 patients, 45.5%), renal impairment (8 patients, 14.5%), calcified ascending aorta (9 patients, 16.4%), carotid disease (4 patients, 7.2%), and peripheral vascular disease (11 patients, 20.0%). Fifteen patients (27.2%) had previous coronary stents. Nine patients (16.4%) had a preoperative intra-aortic balloon pump. Predicted mortality (logistic EuroSCORE) was 14.2%. RESULTS: Forty-three patients (78.1%) had intact LIMA-to-LAD grafts. Twenty-two patients (40.0%) required a major posterolateral thoracotomy, and 33 patients (60.0%) had a minor thoracotomy. Thirteen patients (23.6%) had stents placed as a hybrid procedure during the same admission. Thirteen patients (23.6%) additionally underwent anterior wall grafting (LAD to the first marginal area). The LIMA was used in 7 patients where it had not been used before. There were 91 distal grafts (including 4 sequentials). We performed 54 venous grafts and 26 radial artery grafts. Twenty-one patients (38.1%) had 1 distal graft, 32 patients (58.1%) had 2 grafts, and 2 patients (3.6%) had 3 distal grafts performed (mean, 1.6 grafts/patient). The proximal graft site was the proximal descending aorta in 20.0% of the patients, the distal aorta in 67.5%, and the subclavian artery in 12.5%. In 10 patients (18.2%), the distal branches of the right coronary (posterior descendens or right posterolateral) were grafted. No patient required conversion to cardiopulmonary bypass or sternotomy. No patient needed an intra-aortic balloon pump postoperatively. The mean blood loss (24 hours) was 380 mL (range, 125-1100 mL), the mean ventilation time was 4.8 hours (range, 0-12 hours), the mean intensive care unit stay was 2.7 days (range, 2-8 days), and the mean hospital stay was 6.3 days (range, 5-20 days). There was 1 postoperative death (1.8% mortality). One late death occurred on follow-up. Four patients underwent cardiac catheterization for chest pain, and the grafts were shown to be open. CONCLUSION: The procedure is safe, especially in patients with intact LIMA-to-LAD grafts needing lateral and inferior wall revascularization. Multislice computed tomography scanning allows better preoperative planning, especially regarding the site of implantation of the proximal graft, allowing a less invasive incision. The off-pump technique preserves cardiac and pulmonary function. The in-hospital death rate (1.8%) compares very well with the EuroSCORE-predicted mortality (14.2%).