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6th September 2022
Asundexian is a promising and novel anticoagulant and which reduced a composite of cardiovascular death, myocardial infarction, stroke, or stent thrombosis in post-myocardial infarction patients. This was the main finding of a study by researchers from Duke University School of Medicine, Durham, US, according to a press release and which was presented at the European Society of Cardiology conference, Barcelona.
Activated coagulation factor XI (FXIa) contributes to the development and propagation of thrombosis but has only a minor role in haemostasis and therefore represents an attractive antithrombotic target. Asundexian is potent oral FXIa inhibitor with antithrombotic efficacy in arterial and venous thrombosis models in both prevention and intervention settings and which does not increase bleeding. Although direct acting oral anticoagulants have an important role in stroke prevention among patients with atrial fibrillation, there are concerns over the risk of bleeding and in a randomised, double-blind phase 2 trial, asundexian was shown to result in lower rates of bleeding compared with standard dosing of apixaban, with near-complete in-vivo FXIa inhibition, in patients with atrial fibrillation.
For the present study, the US team sought to understand whether asundexian might potentially reduce ischaemic events, but without significantly increasing bleeding, for patients following a myocardial infarction and in other clinical settings where vascular thrombosis or thromboembolism play a role. Their phase 2 PACIFIC-AMI trial assessed the pharmacodynamics, efficacy and safety of three doses of asundexian (10 mg daily, 20 mg daily, and 50 mg daily) compared with placebo in patients treated with dual anti-platelet therapy (aspirin and a P2Y12 inhibitor) following an acute myocardial infarction.
For the study, 1,601 patients aged 45 years and older, were randomly allocated to asundexian 10 mg, 20 mg, 50 mg or placebo, within five days of the myocardial infarction. The median age of participants was 68 years (23% women) with 51% who had had an ST-segment elevation myocardial infarction (STEMI) and 49% a non-STEMI. Virtually all patients (99%) underwent percutaneous coronary intervention as treatment for their myocardial infarction and patients were treated with prasugrel or ticagrelor (80%) and clopidogrel (20%) as their P2Y12 inhibitor. Individuals were treated for between six and 12 months and the median follow up, starting from the first dose, was 368 days. The primary endpoint of the trial was the cardiovascular composite described above and the main safety outcome was a composite of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding.
Asundexian clinical efficacy
Asundexian produced a dose related reduction in factor XIa inhibition, with the 50 mg dose resulting in more than 90% inhibition of factor XIa. The primary endpoint occurred in 6.8%, 6.0% and 5.5% of patients in the 10 mg, 20 mg, and 50 mg asundexian groups, respectively and in 5.5% of placebo group patients.
The main safety outcome occurred in 7.6%, 8.1% and 10.5% patients in the three asundexian groups and in 9% of the placebo group, hence there was no significant observed increase in bleeding with asundexian at any dose or in comparison to placebo.
The lead author, Professor John Alexander concluded that ‘the trial suggests that asundexian, at a dose of 50 mg daily, will inhibit factor XIa and potentially without a large increase in bleeding. Plans are underway for larger phase 3 clinical trials to test asundexian in patients with acute myocardial infarction and other conditions where vascular thrombosis or thromboembolism play a role.’