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Background: Atopaxar (E5555) is a reversible protease-activated receptor-1 thrombin receptor antagonist that interferes with platelet signaling. The primary objective of the Lessons From Antagonizing the Cellular Effects of Thrombin-Acute Coronary Syndromes (LANCELOT—ACS) trial was to evaluate the safety and tolerability of atopaxar in patients with ACS., Methods and Results: Six hundred and three subjects were randomized within 72 hours of non-ST-elevation ACS to 1 of 3 doses of atopaxar (400-mg loading dose followed by 50, 100, or 200 mg daily) or matching placebo. The incidence of Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) major or minor bleeding did not differ significantly between the combined atopaxar and placebo groups (3.08% versus 2.17%, respectively; P=0.63), and there was no dose-related trend (P=0.80). The incidence of CURE major bleeding was numerically higher in the atopaxar group compared with the placebo group (1.8% versus 0%; P=0.12). The incidence of cardiovascular death, myocardial infarction, stroke, or recurrent ischemia was similar between the atopaxar and placebo arms (8.03% versus 7.75%; P=0.93). The incidence of CV death, MI, or stroke was 5.63% in the placebo group and 3.25% in the combined atopaxar group (P=0.20). Dose-dependent trends for efficacy were not seen. Atopaxar significantly reduced ischemia on continuous ECG monitoring (Holter) at 48 hours compared with placebo (relative risk, 0.67; P=0.02). Transient dose-dependent transaminase elevation and relative QTc prolongation were observed with the highest doses of atopaxar., Conclusion: In patients after ACS, atopaxar significantly reduced early ischemia on Holter monitoring without a significant increase in major or minor bleeding. Larger trials are required to fully establish the efficacy and safety of atopaxar., Clinical Trial Registration: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00548587.

Background: Thrombin is a key mediator of platelet activation. Atopaxar is a reversible protease-activated receptor-1 antagonist that interferes with thrombin-mediated platelet effects. The phase II Lessons From Antagonizing the Cellular Effect of Thrombin-Coronary Artery Disease (LANCELOT-CAD) trial examined the safety and tolerability of prolonged therapy with atopaxar in subjects with CAD., Methods and Results: Subjects with a qualifying history were randomized in a double-blind fashion to 3 dosing regimens of atopaxar (50, 100, or 200 mg daily) or matching placebo for 24 weeks and followed up for an additional 4 weeks. The key safety end points were bleeding according to the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) and Thrombolysis in Myocardial Infarction (TIMI) classifications. Secondary objectives included platelet aggregation and major adverse cardiac events. Seven hundred and twenty subjects were randomized. Overall bleeding rates tended to be higher with atopaxar compared with placebo by CURE criteria (placebo, 0.6%; atopaxar, 3.9%; relative risk, 6.82, P=0.03; 50 mg, 3.9%; 100 mg, 1.7%; 200 mg, 5.9%; P for trend=0.01) and TIMI criteria (placebo, 6.8%; atopaxar, 10.3%; relative risk, 1.52, P=0.17; 50 mg, 9.9%; 100 mg, 8.1%; 200 mg, 12.9%; P for trend=0.07). There was no difference in major bleeding. Major adverse cardiac events were numerically lower in the atopaxar subjects. All atopaxar regimens achieved high levels of platelet inhibition. A transient elevation in liver transaminases and dose-dependent QTc prolongation without apparent complications were observed in higher-dose atopaxar treatment groups., Conclusions: In this dose-ranging study of patients with CAD, treatment with atopaxar resulted in platelet inhibition, more minor bleeding, and numerically but not statistically fewer ischemic events. Larger-scale trials are needed to determine whether these patterns translate into clinically meaningful effects., Clinical Trial Registration: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00312052.

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.