Circulation: Novel anticoagulants prevent recurrent ischemic stroke (PACIFIC-Stroke study)

Atrial fibrillation is the most common sustained cardiac arrhythmia, affecting more than 33 million people worldwide and is associated with increased rates of death, stroke, and other thromboembolic events

Asundexian (BAY 2433334) is a direct and potent inhibitor of activated coagulation factor XI (FXIa) once daily with a mean terminal half-life of 15.

August 28, 2022 The PACIFIC-Stroke trial failed to meet its primary endpoint, but inhibition of factor XIa Asundexian reduced recurrent ischemic stroke and transient ischemic attack (TIA) in an exploratory analysis Does not increase bleeding

PACIFIC-AF is a multicenter, randomized, double-blind, double-blind Phase 2 clinical study comparing two doses of Asundexian with a standard dose of apixaban

Subjects were assigned 1:1:1 by central randomization to either the two doses of Asundexian or the standard dose of apixaban

Subjects were randomly assigned to: Asundexian 20 mg orally once daily; Asundexian 50 mg orally once daily; or to the standard dose of apixaban (ie, 5 mg orally twice daily), if patients met At least two of the following, i.

The primary endpoint of the study was a composite of major bleeding or clinically relevant nonmajor bleeding, according to the International Society on Thrombosis and Haemostasis (ISTH) criteria

"This is the first randomized trial to be completed comparing factor XIa inhibition with placebo, both on top of antiplatelet therapy, for noncardiac disease," said study author Ashkan Shoamanesh, PhD, of the Hamilton Institute for Population Health in Canada.

Patients with ischemic stroke are at increased risk of recurrent stroke, and long-term antiplatelet therapy is recommended to reduce recurrence

A total of 862 patients were screened, 107 of whom did not meet the inclusion criteria, and 755 were randomly assigned, but two did not receive any study drug

Baseline characteristics of patients according to treatment assignment are detailed in Table 1

The primary efficacy outcome was the dose-response effect of the composite at 6 months on MRI-detected occult cerebral infarction or recurrent symptomatic ischemic stroke

There were 362 primary efficacy outcomes at 6 months, 87 (19.

During the entire follow-up period (median 10.

The primary safety outcome did not increase significantly at 12 months, with 2.

In patients with recent acute myocardial infarction, the addition of asundexian to aspirin and a P2Y12 inhibitor resulted in a dose-dependent, almost complete inhibition of FXIa activity without a significant increase in bleeding and ischemic events

"The promising results of this phase 2 trial need to be validated in a sufficiently robust phase 3 randomized trial before it can be applied in clinical care for secondary stroke prevention," said Dr.
Shoamanesh
.
A phase 3 study investigating asundexian in addition to antiplatelet therapy in hemorrhagic stroke patients lays the groundwork
.
"

References:

SV, Kirsch B, Bhatt DL, Budaj A, Coppolecchia R, Eikelboom J, James SK, Jones WS, Merkely B, Keller L, Hermanides RS, Campo G, Ferreiro JL, Shibasaki T, Mundl H, Alexander JH.
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.
Circulation.
2022 Aug 27.
doi: 10.
1161/CIRCULATIONAHA .
122.
061612