Factor XI inhibition in patients with acute coronary syndrome

Abstract

A hypercoagulable condition is typical of patients with acute coronary syndrome and is a determining factor in the genesis of recurrent ischaemic events. Modern pharmacological therapies consisting of antiplatelets and anticoagulants derive their rationale for use on the pathophysiological mechanisms most commonly associated with myocardial infarction (MI); they have contributed to reducing the ischaemic risk of these patients, but left ample room for improvement. In particular, trials that have studied the association of an anticoagulant with antiplatelet drugs have provided promising results in terms of efficacy, but highlighted a significant bleeding risk. Evidence derived from experimental animal and epidemiological studies has shown how factor XI (FXI) deficiency is associated with a reduction in thrombotic events but with modest bleeding. These data added to the role that FXI plays in the coagulation cascade constituted an incipit for the pharmacological attempt to decouple thrombosis from haemostasis by means of the inhibition of this factor. The theoretical assumption that FXI inhibitor drugs may be able to reduce the ischaemic risk without significantly increasing the haemorrhagic risk makes these compounds a potential therapeutic aid for patients in secondary prevention after acute MI. To date, on these patients, we only have data from a Phase 2 trial, PACIFIC-AMI (Study to Gather Information About the Proper Dosing and Safety of the Oral FXIa Inhibitor BAY 2 433 334 in Patients Following an Acute Heart Attack). In this study, the primary endpoint—represented by the Bleeding Academic Research Consortium (BARC) composite of Type 2, 3, or 5 bleeding—showed no significant differences between the various doses of asundexian tested (10, 20, and 50 mg quoque die), and between these and placebo (asundexian all doses vs. placebo: hazard ratio, 0.98; 90% confidence interval, 0.71–1.35). The data on efficacy, however, showed neutral results, but it should be noted that the study did not have the adequate statistical power to evaluate this outcome. Valuable information could, therefore, derive in the future from the ongoing Phase 3 trial with milvexian, LIBREXIA-ACS (A Study of Milvexian in Participants After a Recent Acute Coronary Syndrome) and from any future studies that could be started by testing different molecules.