Effect of the Factor XIa Inhibitor Asundexian According to Baseline Infarct Pattern and on MRI Covert Infarct Outcomes
Eric E. Smith, Ashkan Shoamanesh, Lizhen Xu, Laura Heenan, Feryal Saad, Pablo Colorado, Chih‐Hao Chen, Robin Lemmens, Gian Marco De Marchis, Valeria Caso, Jaime Masjuán, Teruyuki Hirano, Ivan Milanov, Bruce Campbell, Jean‐Louis Mas, Stuart J. Connolly, Hardi Mundl, Robert G. Hart, Peter Bailey, Bruce Campbell, Timothy Kleinig, Dennis Cordato, Philip Choi, Carlos García-Esperón, Andrew Chew, Geoffrey Cloud, Vimal Stanislaus, Maurício Krause, Miriam Priglinger, Rohan Grimley, Darshan Ghia, Ramesh Sahathevan, Henry G. Brown, Chiu‐Yin Kwan, Michael J. Devlin, Stefan Greisenegger, S. Bonelli-Nauer, Jakob Rath, A. Langer, Martha Marko, Jéssica Tonin Ferrari, Alexandra Bernegger, M. Baumgartinger, Matthias Vigl, Stefan Krebs, W. Lang, M. Knoflach, Benjamin Dejakum, Sophia J. Kiechl, Thomas Töll, Lena Domig, Johannes Sebastian Mutzenbach, Bernhard Ganser, Constantin Hecker, Cornelia Rösler, Nele Bubel, Slaven Pikija, Tobias Zellner, Ursula Leitner, Otto Berger, B. Surböck, Sebastian Beirer, Dimitre Staykov, Daniel Schrammel, Altuna Halilović, Michael Frattner, D. Barmherzigen, Christian Lampl, Christopher Hofer, S. Nagl, Christoph Bocksrucker, Robin Lemmens, Jelle Demeestere, P. Desfontaines, C Ciobanu, Adinda De Pauw, Annelies Terwecoren, M.C. Hasenbroekx, Fiona Clement, Nina De Klippel, Peter Soors, Sabine Hermans, Sylvie De Raedt, Fenne Vandervorst, Laura Seynaeve, Niels Fockaert, Sofie de Smet, Matthieu Pierre Rutgers, Nicole Del Gaudio, Perrine Paindeville, Ivan Staikov, A. Simeonova, Irina I. Stoyanova, Maria Cholakova, N. Mihnev, T. Petrova, A. Koralova, D. Dimov, Y. Kuzev, Maya Danovska
Abstract
BACKGROUND: Exploratory analysis of the phase 2 PACIFIC-Stroke (Program of Anticoagulation via Inhibition of FXIa by the Oral Compound BAY 2433334-Non-Cardioembolic Stroke) randomized trial suggested that asundexian, an oral factor XIa inhibitor, prevents recurrent stroke and transient ischemic attacks in patients with atherosclerotic stroke. In this post hoc exploratory analysis, we hypothesized that asundexian would be more effective in patients enrolled with large, multiple, or cortical acute infarcts on magnetic resonance imaging than in patients enrolled with a single small subcortical acute infarct, and asundexian would prevent incident cortical covert infarcts. METHODS: In this placebo-controlled double-blinded randomized controlled trial, patients with mild-to-moderate noncardioembolic ischemic stroke were assigned to asundexian (10, 20, or 50 mg once daily) or placebo, in addition to antiplatelet therapy. Brain magnetic resonance imagings were required within 72 hours of randomization and repeated at 26 weeks or at discontinuation of the study drug. RESULTS: Of 1808 randomized patients, 1780 (98.5%) had interpretable baseline magnetic resonance imagings, of which 1628 (91.5%) had ≥1 diffusion-weighted imaging positive acute infarcts. Magnetic resonance imaging follow-up was obtained in 1439 patients, of whom 1358 had no symptomatic stroke during the trial period. Compared with placebo, asundexian 50 mg daily conferred a trend toward reduced risk of recurrent ischemic stroke or incident covert infarcts (hazard ratio, 0.71 [95% CI, 0.45-1.11]) and recurrent ischemic stroke or transient ischemic attack (secondary outcome; hazard ratio, 0.59 [95% CI, 0.33-1.06]) that was not evident in patients with single small subcortical infarcts (hazard ratios, 1.14 [95% CI, 0.62-2.10] and 0.93 [95% CI, 0.28-3.06]). Incident cortical covert infarcts were reduced in patients taking asundexian 50 mg, but the difference was not statistically significant (crude incidence ratio, 0.56 [95% CI, 0.28-1.12]). CONCLUSIONS: These exploratory, unconfirmed results suggest that asundexian may prevent new embolic infarcts but not small artery occlusion. The hypothesis that subtypes of covert brain infarcts respond differently to anticoagulant prevention should be tested in future trials. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT04304508.