AntiCoagulation via Inhibition of FXIa by the Oral Compound BAY 2433334 – Non-cardioembolic Stroke - PACIFIC-STROKE

Sep 08, 2022
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Kim A. Eagle, MD, MACC
Trial Sponsor:
Bayer AG
Date Presented:
08/28/2022
Original Posted Date:
09/08/2022
References

Contribution To Literature:

The PACIFIC-Stroke trial showed that asundexian did not reduce the composite of covert brain infarction or ischemic stroke compared with placebo among patients with acute non-cardioembolic ischemic stroke.

Description:

The goal of the trial was to assess the safety and efficacy of 3 doses of asundexian compared with placebo in patients with non-cardioembolic ischemic stroke ≤48 hours from symptom onset.

Study Design

This was a phase II trial. Patients were randomized in a double-blind 1:1:1:1 fashion to either asundexian 50 mg daily (n = 447), asundexian 20 mg daily (n = 450), asundexian 10 mg daily (n = 455), or matching placebo (n = 456).

  • Total number of enrollees: 1,808
  • Duration of follow-up: 6 months

Inclusion criteria:

  • Age ≥45 years
  • Non-cardioembolic ischemic stroke with persistent signs and symptoms of stroke lasting for ≥24 hours or acute brain infarction documented by computed tomography (CT) or magnetic resonance imaging (MRI), and intention to be treated with antiplatelet therapy during the study conduct
  • Imaging of brain (CT or MRI) ruling out hemorrhagic stroke or another pathology that could explain symptoms (e.g., brain tumor, abscess, vascular malformation)
  • Randomization within 48 hours after the onset of symptoms of the index event

Exclusion criteria:

  • Prior ischemic stroke within last 30 days of index event
  • History of atrial fibrillation (AF) or suspicion of cardioembolic source of stroke
  • Dysphagia with inability to safely swallow study medication
  • Contraindication to perform brain MRI
  • Active bleeding; known bleeding disorder

Principal Findings:

The primary efficacy outcome, ischemic stroke or covert stroke at 6 months for asundexian 50 mg daily vs. asundexian 20 mg daily vs. asundexian 10 mg daily vs. placebo, was: 20.1% vs. 22.0% vs. 18.9% vs. 19.1% (all asundexian vs. placebo, p = 0.80).

Primary safety outcome, major or clinically relevant nonmajor bleeding, was: 4.3% vs. 3.1% vs. 4.3% vs. 2.4% (all asundexian vs. placebo, p > 0.05).

Secondary outcomes (for asundexian 50 mg daily vs. asundexian 20 mg daily vs. asundexian 10 mg daily vs. placebo):

  • Recurrent ischemic stroke or transient ischemic attack (TIA): 5.4% vs. 6.2% vs. 7.7% vs. 8.3% (p > 0.05); hazard ratio for asundexian 50 mg vs. placebo: 0.64, 95% confidence interval 0.41-0.98
  • Hemorrhagic transformation of stroke: 0% vs. 0.4% vs. 1.1% vs. 1.4% (p > 0.05)

Interpretation:

The results of this phase II trial indicate that asundexian did not reduce the composite of covert brain infarction or ischemic stroke compared with placebo in patients with acute non-cardioembolic ischemic stroke. No increase in bleeding was noted. On subgroup analysis, there appeared to be a benefit with asundexian 50 mg vs. placebo for recurrent symptomatic ischemic strokes and TIAs, particularly among patients with atherosclerosis. This finding is hypothesis generating. Asundexian will be tested in a phase III trial among patients with ischemic stroke.

Asundexian is a novel oral factor XIa inhibitor that is being evaluated across a variety of indications including acute coronary syndrome, stroke, and AF.

References:

Presented by Dr. Ashkan Shoamanesh at the European Society of Cardiology Congress (ESC 2022), Barcelona, Spain, August 28, 2022.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Arrhythmias and Clinical EP, Dyslipidemia, Noninvasive Imaging, Prevention, Anticoagulation Management and ACS, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Novel Agents, Computed Tomography, Magnetic Resonance Imaging, Nuclear Imaging

Keywords: Acute Coronary Syndrome, Anticoagulants, Atrial Fibrillation, Atherosclerosis, Brain Infarction, Embolic Stroke, ESC22, ESC Congress, Factor XIa, Hemorrhage, Hemorrhagic Stroke, Ischemic Attack, Transient, Ischemic Stroke, Magnetic Resonance Imaging, Platelet Aggregation Inhibitors, Secondary Prevention, Stroke, Tomography, X-Ray Computed, Vascular Diseases


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