Atopaxar treatment in patients with coronary artery disease increased overall bleeding by CURE criteria compared to placebo (3.9% vs 0.6%; RR 6.82, P=0.03), with no difference in major bleeding.
RCT (n=720)
Double-blind
randomized
Does atopaxar increase bleeding or reduce ischemic events in patients with coronary artery disease?
In patients with CAD, the PAR-1 antagonist atopaxar achieved high platelet inhibition but increased minor bleeding and caused transient transaminitis and QTc prolongation, without a statistically significant reduction in ischemic events.
Effect estimate: RR 6.82
Absolute Event Rate: 3.9% vs 0.6%
p-value: p=0.03
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.
Wiviott et al. (2011) conducted an RCT in Coronary Artery Disease (n=720). Atopaxar vs. Placebo was evaluated on Bleeding according to CURE criteria (RR 6.82, p=0.03). Atopaxar treatment in patients with coronary artery disease increased overall bleeding by CURE criteria compared to placebo (3.9% vs 0.6%; RR 6.82, P=0.03), with no difference in major bleeding.