Reviewer: Dr Hüseyin Durak

Name of the Study: PACIFIC-AMI (A Multicenter, Phase 2, Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Dose-Finding Trial of the Oral Factor XIa Inhibitor Asundexian to Prevent Adverse Cardiovascular Outcomes Following Acute Myocardial Infarction)

Published Congress: ESC 2022

Link : https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.061612

Background:

Following an acute myocardial infarction (MI), patients are hypercoagulable state and at risk for recurrent atherothrombotic events. Guidelines recommend dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor for 12 months following an acute MI. Despite the use of dual antiplatelet therapy, patients remain at risk for recurrent MI, stroke, and death. The plasma serine protease zymogen factor XI (FXI) plays a key role in amplification of thrombin generation following plaque rupture but is thought to be less important in hemostasis. This conclusion is supported by the results of experimental and animal studies as well as experience in patients with congenital factor XI deficiency who appear to be protected against ischemic events but have little increased risk of bleeding. Based on this, it was predicted that the use of the FXIa inhibitor Asundexian in patients following an acute MI would reduce the risk of recurrent MI, stroke and death with little increased risk of bleeding.

Objective:

The objective of the present study is to explore the pharmacodynamics, safety, and efficacy of the oral FXIa inhibitor asundexian for secondary prevention after acute MI.

Methods:

A total 1601 patients were randomized with recent acute MI to oral asundexian 10, 20, or 50 mg or placebo once daily for 6–12 months in a double-blind, placebo-controlled, phase 2, dose-ranging trial. Patients were randomized within 5 days of their qualifying MI and received dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor. The prespecified main safety outcome was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding comparing all pooled asundexian doses with placebo. The prespecified efficacy outcome was a composite of cardiovascular death, MI, stroke, or stent thrombosis comparing pooled asundexian 20 and 50 mg doses with placebo.

Results:

The median age was 68 years, 23% were women, 51% had ST-elevation MI, 80% were treated with aspirin plus ticagrelor or prasugrel, and 99% underwent percutaneous coronary intervention before randomization. Asundexian caused dose-related inhibition of FXIa activity with 50 mg resulting in >90% inhibition. Over a median follow-up of 368 days, the main safety outcome occurred in 30 (7.6%), 32 (8.1%), 42 (10.5%), and 36 (9.0%) patients receiving asundexian 10, 20, 50 mg, and placebo (pooled asundexian vs. placebo: HR 0.98, 90% CI 0.71–1.35). The efficacy outcome occurred in 27 (6.8%), 24 (6.0%), 22 (5.5%), and 22 (5.5%) patients assigned asundexian 10, 20, 50 mg, and placebo (pooled asundexian 20 and 50 mg vs. placebo: HR 1.05, 90% CI 0.69–1.61).

Conclusion:

In patients with recent acute MI, 3 doses of asundexian, when added to aspirin plus a P2Y12 inhibitor, resulted in dose-dependent, near-complete inhibition of FXIa activity without a significant increase in bleeding and a low rate of ischemic events. These data support the investigation of asundexian at a dose of 50 mg daily in an adequately powered clinical trial of patients following acute MI.

Interpretations:

PACIFIC-AMI trial expanded the evidence that use of asundexian in patients with recent AMI has the potential to reduce the incidence of ischemic events without increasing risk of bleeding.