Exploratory Analysis of PACIFIC-Stroke Trial Suggests Asundexian May Prevent Recurrent Ischemic Stroke Without Increased Bleeding

August 28, 2022—The European Society of Cardiology (ESC) announced that inhibition of factor XIa with the anticoagulant asundexian (Bayer) reduced recurrent ischemic stroke and transient ischemic attack (TIA) without increasing bleeding in an exploratory analysis of the PACIFIC-Stroke trial. However, the trial failed to reach its primary endpoint.

The late-breaking research was presented in a Hot Line session at the 2022 ESC Congress held August 26-29 in Barcelona, Spain.

The phase 2 PACIFIC-Stroke trial investigated the efficacy, safety, and optimal dosage of asundexian for secondary stroke prevention after an acute noncardioembolic ischemic stroke.

In the ESC press release, study investigator Ashkan Shoamanesh, MD, of the Population Health Research Institute in Hamilton, Canada, commented, “This was the first completed randomized trial comparing factor XIa inhibition versus placebo, both on top of antiplatelet therapy, for secondary prevention of noncardioembolic ischemic stroke. The results of PACIFIC-Stroke indicate that the potential of asundexian to prevent stroke in selected patients should be investigated further.”

Dr. Shoamanesh further stated, “More effective preventive strategies are needed for secondary stroke prevention. Dual-pathway inhibition combining an anticoagulant with an antiplatelet agent is hypothetically appealing, but there have been concerns that currently available oral anticoagulants may raise the likelihood of bleeding. There is emerging evidence that factor XIa inhibitors such as asundexian may prevent thrombosis without increasing bleeding.”

According to the ESC press release, the PACIFIC-Stroke trial was conducted at 196 sites in 23 countries. A total of 1,808 patients were randomized within 48 hours (mean interval, 36 hours) of noncardioembolic ischemic stroke to once daily 10, 20, or 50 mg asundexian or placebo on top of usual antiplatelet therapy. The average age was 67 years, and 34% were women.

Patients underwent brain MRI at study entry and after 6 months, with images independently analyzed by two radiologists blinded to treatment allocation. Patients were followed for 6 to 12 months.

The primary efficacy outcome was the dose-response effect on the composite of incident MRI-detected covert brain infarcts or recurrent symptomatic ischemic stroke at 6 months. The primary safety outcome was major or clinically relevant nonmajor bleeding at 12 months. Secondary exploratory outcomes included ischemic stroke and the composite of ischemic stroke and TIA.

As summarized by ESC, the investigators reported the following:

• There were 362 primary efficacy outcomes at 6 months: 87 (19.1%) in the placebo group, 86 (18.9%) in the asundexian 10 mg group, 99 (22%) in the 20 mg group, and 90 (20.1%) in the 50 mg group. There was no dose-dependent reduction of the primary efficacy outcome with asundexian (t statistic: −0.68; P = .8) at 6 months.
• During the total follow-up (median, 10.6 months), 125 recurrent symptomatic ischemic strokes or TIA occurred: 38 (8.3%) in the placebo group, 35 (7.7%) in the asundexian 10 mg group, 28 (6.2%) in the 20 mg group, and 24 (5.4%) in the 50 mg group.
• In a secondary exploratory analysis, recurrent ischemic stroke or TIA was reduced among patients assigned to asundexian 50 mg compared with placebo (hazard ratio [HR], 0.64; 90% CI, 0.41-0.98), with the largest reduction among those patients with extracranial or intracranial atherosclerotic plaque (HR, 0.39; 90% CI, 0.18-0.85).
• The primary safety outcome was not significantly increased at 12 months with asundexian, occurring in 2.4% of patients assigned to placebo and 3.9% of those assigned to asundexian (HR, 1.57; 90% CI, 0.91-2.71).

Dr. Shoamanesh concluded in the ESC press release, “The promising results from this phase 2 trial require validation in an adequately powered phase 3 randomized trial before being applied to clinical care for secondary stroke prevention. These findings may form the foundation for a phase 3 study investigating asundexian in addition to antiplatelet therapy in patients with noncardioembolic ischemic stroke.”

On August 28, Bayer announced the start of the phase 3 OCEANIC clinical development program to investigate the efficacy and safety of asundexian in patients with atrial fibrillation and in patients with noncardioembolic ischemic stroke or high-risk TIA.