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 Masjuan; Teruyuki Hirano; Ivan Milanov; Bruce C V Campbell; Jean-Louis Mas; Stuart J Connolly; Hardi Mundl; Robert G Hart; PACIFIC-Stroke Steering Committee and Investigators

doi:10.1161/STROKEAHA.123.043198

Effect of the Factor XIa Inhibitor Asundexian According to Baseline Infarct Pattern and on MRI Covert Infarct Outcomes

Stroke. 2024 Feb;55(2):392-402. doi: 10.1161/STROKEAHA.123.043198. Epub 2024 Jan 4.

Authors

Eric E Smith¹, Ashkan Shoamanesh², Lizhen Xu², Laura Heenan³, Feryal Saad¹, Pablo Colorado⁴, Chih-Hao Chen⁵, Robin Lemmens^{6

7}, Gian Marco De Marchis^{8

9}, Valeria Caso¹⁰, Jaime Masjuan^{11

12}, Teruyuki Hirano^{2

13}, Ivan Milanov¹⁴, Bruce C V Campbell¹⁵, Jean-Louis Mas¹⁶, Stuart J Connolly², Hardi Mundl¹⁷, Robert G Hart²; PACIFIC-Stroke Steering Committee and Investigators

Collaborators

PACIFIC-Stroke Steering Committee and Investigators:
P Bailey, B C V Campbell, T Kleinig, D Cordato, P Choi, C Garcia-Esperon, A Chew, G Cloud, V Stanislaus, M Krause, M Priglinger, R Grimley, D Ghia, R Sahathevan, H Brown, C Kwan, M Devlin, S Greisenegger, S Bonelli-Nauer, J Rath, A Langer, M Marko, J Ferrari, A Bernegger, M Baumgartinger, M Vigl, S Krebs, W Lang, M Knoflach, B Dejakum, S Kiechl, T Töll, L Domig, J S Mutzenbach, B Ganser, C Hecker, C Rösler, N Bubel, S Pikija, T Zellner, U Leitner, O Berger, B Surböck, S Beirer, D Staykov, D Schrammel, A Halilovic, M Frattner, D Barmherzigen, C Lampl, C Höfer, S Nagl, C Bocksrucker, R Lemmens, J Demeestere, P Desfontaines, C Ciobanu, A De Pauw, A Terwecoren, M C Hasenbroekx, F Clement, N De Klippel, P Soors, S Hermans, S De Raedt, F Vandervorst, L Seynaeve, N Fockaert, S Smet, M Rutgers, N Del Gaudio, P Paindeville, I Staikov, A Simeonova, I Stoyanova, M Cholakova, N Mihnev, T Petrova, A Koralova, D Dimov, Y Kuzev, M Danovska, D Marinova, D Marinova-Trifonova, E Ovcharova, I Mladenovski, M Yanakieva, P Stoev, M Dimitrova, S Todorova-Georgieva, L Haralanov, B Milkov, D Solakov, N Petkova, V Ignatova-Valkova, V Karabinov, V Marinova, Y Miteva, V Andonova, D Kasabova, E Kostadinova, Y Shopova-Vrabcheva, D Gatev, D Semova, E Halil, A Kaprelyan, B Ivanov, G Panov, M Grudkova, N Syuleyman, R Kalpachki, F Alexiev, I Ivanova, K Kancheva, T Sakelarova, D Maslarov, D Drenska, V Georgiev, K Petrova, N Petrova, I Ivanova, I Milanov, N Semerdjieva, P Zhelyazkov, S Spasova-Markova, X Dong, D Wang, S Wang, W Huang, H Zhao, C Wang, L Jie, Y Xinyang, Z Ping, Q Dong, Y Wang, Y Fuling, W Yue, R Liu, Y Yang, I Stetkarova, P Mikulenka, P Vasko, T Peisker, M Bar, M Roubec, R Mikulik, M Cabukova, J Vinklarek, M Kovar, M Pansky, P Mencl, O Skoda, M Carek, M Pernicka, M Skodova, P Geier, J Cepkova, J Drlik, T Prax, R Herzig, D Krajickova, E Vitkova, S Haluskova, D Vaclavik, J Martinkova, K Blejcharova, M Tkacova, O Pavlik, M Nevšímalová, J Rosol, M Nevsimalova, R Hruby, H Iversen, A V Andersen, D Rahimi, H Christensen, J Grundtvig, N Hjort, G Andersen, B Sandal, M Stilund, B Modrau, A Strade, M Porobic, S D Andersen, C Kruuse, J Ölmestig, M Kolmos, A Parvez, T Christensen, J Stokholm, H B Jensen, J Putaala, D Strbian, G Sibolt, M Tiainen, N Martinez-Majander, S Curtze, S Raty, Y Kraemer, R Roine, J Aivo, J Ruuskanen, P Ylikotila, S Roine, M Hallikainen, P Jakala, S Kurl, V Julkunen, I Sibon, S Olindo, S Richard, V Larrue, C Gollion, H Catala, H Henon, D S Lucie, D Nelly, J L Mas, D Calvet, A Malbranque, B Mazé, C Barbieux-Ghitu, G H Pitie Salpetriere, C Rosso, Y Samson, S Vannier, T Moulin, L Bonnet, P Reiner, F Buffon, C Denier, K Amri, N Legris, O Chassin, N Selli, S Mariana, J Berrouschot, A Stoll, D Klunk, J Keilitz, M Neustadt, S Zerrenner, R Veltkamp, K Hajjar, A Heeger, E Winezki, L Apel, M Pompsch, P Mueller, P Rappard, R Auer, P A Ringleb, A Berberich, M Heyse, S Mundiyanapurath, T Reiff, S Poli, A Gomez-Exposito, A Mengel, J Tünnerhoff, K Adeyemi, K Poli, V Kusch, J Pelz, D Michalski, K Wartenberg, K Althaus, F Tavares, S Mueller, H Soda, A Rascher, E Hiermann, R Weinhardt, K Weissenborn, A Leotescu, G Grosse, H Worthmann, J Ernst, M Gabriel, R Schuppner, J H Schäfer, D Charisse, K Gruber, N Kurka, S C Reitz, W Pfeilschifter, J I Lee, M Gliem, M Moll, T Steiner, L Segura, N Szegedi, D Barandi, L Uhrinakova, M Czencz, M Pasztor, N Gyuker, N E Bartha, Z May, Z Simony, G Szasz, I Kakuk, N Pető, G F Panczel, A Olah, O Racz, T Balla, B Horvath, K Tuba, V Czinderi, P Klivenyi, A Annus, P Hertelendy, L Szapary, E Bosnyak, P Kalmar, Z Karadi, L Cziba, L Olah, A Berki, L Hudak, M Kozák, S Babel, L Nemeth, B Molnár, Z Simon, L Roveri, F Cerri, G Giacalone, A Zini, G Mauro, G M Asioli, S Forlivesi, G Arnone, V Caso, A Fiaccadori, E Maria Fontana Francesca, G Allegra, M G Mosconi, M Longoni, R Terlizzi, M Paolucci, R Tassi, B Franci, B Lucani, C Domenichelli, D Paoletti, M Acampa, M L Zedde, F R Pezzella, M Mangiardi, P Galizia, S Anticoli, S Scalise, S Lattanzi, D Norata, M Cannuccia, A Cavallini, F Federica, M F Denaro, P Tosi, K Sonoda, M Kawajiri, Y Kusano, K Haraguchi, H Kawano, T Terasaki, C Kaneko, S Murase, M Kumagai, N Murai, Y Miyazaki, T Mori, T Hatano, M Kawanishi, J Ochiai, S Ishihara, T Uehara, M Yasaka, H Nakagawa, M Makino, T Yonehara, Y Fukushima, N Hirotsune, N Sakai, M Yamasaki, J Coutinho, A Wouters, H den Hertog, R Zwartbol, D Beumer, J Kerklaan, P Hilkens, T Schreuder, D Propper, A Slowik, E Wlodarczyk, P Wrona, R Pulyk, A Lasek-Bal, K Kosarz-Lanczek, P Puz, M Bilik, A Magielska, A Zamiela-Żółciak, L Ochocinska, S Bahdasaryan, A Stępień, A Dębiec, K Joanna, M Pawel, S Jacek, P Daniel, S Marta, K Rejdak, J Wojczal, P Luchowski, W Fryze, A Wisniewska, M Krzyzanowska, P Skowron, A Wolosz, A Galan, K Grzymala, M Krajewska, R Nowak, M Kłos, V Cruz, P Castro, J Ferro, P Canhão, R Gouveia, N Inácio, M Rodrigues, A Rachão, C Ionel, L Pereira, M Viana-Baptista, C Machado, C Fernandes, J Sargento, N Inácio, L Timchenko, J Mironova, O Zhadan, A Torgashova, O Bazhenova, M Barashenkova, M Kireeva, N Romadina, I Stepanova, L Lenskaya, L Lukinykh, T Vorontsova, A Agafina, A Fedorova, A Yashina, A Alasheev, A Smolkin, E Prazdnichkova, O Lutskovich, Y Gonysheva, E Mordvintseva, A Nechaev, E Martynova, N Fedoraeva, T Vishnyakova, D Popov, A Merzliakova, K Margarita, L Rechkalova, A Ilyina, N Kurenkova, O Barbarash, E Bazdyrev, T Zvereva, A Hromova, A Morkvenas, E Postnikova, G Kovalenko, I Taran, L Pavlov, M Ott, N Chernitsova, N Vodopyanova, E Drozdova, E Korebo, M Lobanova, N Lazareva, N Snegova, O Nikolaeva, Y Kolesnikov, Y Kosheleva, G Krastev, K Tomasova, M Danis, M Mako, Z Jankovicova, Z Stevkova, M Kovacik, T Kubikova, A Jarosova, V Serdahely, I Cilingova, I Pribulova, J Sedlak, K Slebodova, M Paldaufova, R Risnovsky, B Berndtova, I Urbanova, R Junas, S Karapetian, L Gurcik, A Vantrobova, F Verbovsky, K Vanacka, M Ferenc, P Galik, S Bucakova, M Ferencova, P Kubalova, Z Boksanska, E Zacharova, E Mahundi, H Judita, M Bachnak, P Turcani, A Kvasnicova Kamenska, M Jurik, V Vestenicka, M Kycina, E Sagatova, M Dvorak, A Hlubekova, C Kucera, L Gernath, M Ferenc, P Frimmelova, J Slebodnikova, N Aksteinerova, V Horny, Z Gregova, T Segura, C Romero, O Ayo, J Masjuan Vallejo, A Cruz, A De Felipe, M C Matute, S Garcia, J Tembl Ferrairo, I Vielba, L Morales Caba, C Molina, Á Garcia-Tornel García-Camba, M Requena Ruiz, R Noelia, M Rodriguez-Yañez, E Rodriguez Castro, I Lopez, M Santamaria, S Arias, F Purroy García, D Vázquez Justes, G Mauri Capdevila, M Vicente Pascual, J Martí Fabregas, P Camps Renom, A Rodríguez Campello, E Giralt, J Krupinski, J Molina, S Trillo Senin C Ramos Martin, E De La Fuente Sanz, F Moniche, M R Manuel, B Pardo, I Martínez, M Hernández Pérez, J F Arenillas Lara, M De Lera, J A Egido, C Gomez Escalonilla, M Guillan, J Martinez, A Lindgren, G Andsberg, L Wictor, M Leonidou, M Stenman, N Dalberg, A C Laska, A Grünfeldt, A Lundström, E Nadzjafov, E Rooth, I Dalenbring, P Sandén, E Johansson, G Thomas, G M De Marchis, A V Zietz, S Rudin, T D Dittrich, K Lilian, G Kägi, J Vehoff, M Arnold, A Scutelnic, L Clénin, M Beyeler, M Madlaine, B Maamari, B Siepen, J Vynckier, A Tarnutzer, D Bertschi, M Luciani, C Cereda, F Maulucci, G Bianco, S Shairin, H A Pihan, S Salmen, T Quinn, C McAlpine, F Wright, D Kalladka, E Taylor, J Sohaa, Z Brown, J Dawson, A Cameron, S Muir, S Dima, U Khan, L Zhang, E Warburton, K Chatterjee, A Nallasivan, D Curran, S Haider, U Ghani, A Kenton, B Dallol, M Mirza, B Menezes, R Davies, T G Robinson, L Manning, L Sztriha, T Phinney, P Sethi, I Altafullah, A Sharaf, M Ostrander, S Renati, W S Burgin, K Olds, P Delio, A Malek, J Dissin, P Khatri, M Flaherty, S Demel, S Dofitas

Affiliations

¹ Department of Clinical Neurosciences, University of Calgary, AB, Canada (E.E.S., S.F.).
² Department of Medicine (Neurology), Population Health Research Institute, McMaster University, Hamilton, ON, Canada (A.S., X.L., T.H., S.J.C., R.G.H.).
³ Department of Statistics, Population Health Research Institute, Hamilton, ON, Canada (L.H.).
⁴ Bayer US LLC Pharmaceuticals, Hanover, NJ (P.C.).
⁵ Department of Neurology, National Taiwan University Hospital, Taipei (C.-H.C.).
⁶ Department of Neurosciences, Experimental Neurology, KU Leuven-University of Leuven, Belgium (R.L.).
⁷ Department of Neurology, University Hospitals Leuven, Belgium (R.L.).
⁸ Department of Neurology and Stroke Center, University Hospital Basel and University of Basel, Switzerland (G.M.D.M.).
⁹ Neurology Clinic and Stroke Center, Kantonsspital St. Gallen, Switzerland (G.M.D.M.).
¹⁰ Department of Vascular and Emergency, Stroke Unit, Santa Maria de Misericordia Hospital, University of Perugia, Italy (V.C.).
¹¹ Stroke Unit, Department of Neurology, Instituto Ramón y Cajal de Investigación Sanitaria, Hospital Universitario Ramón y Cajal, Madrid, Spain (J.M.).
¹² Department of Medicine, Universidad de Alcalá, Madrid, Spain (J.M.).
¹³ Department of Stroke and Cerebrovascular Medicine, School of Medicine, Kyorin University, Tokyo, Japan (T.H.).
¹⁴ Department of Neurology, Medical University, University Hospital for Neurology and Psychiatry Sveti Naum, Sofia, Bulgaria (I.M.).
¹⁵ Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia (B.C.V.C.).
¹⁶ Department of Neurology, Groupe Hospitalo-Universitaire Paris, Hôpital Sainte-Anne, Université Paris-Cité, Inserm U1266, France (J.-L.M.).
¹⁷ Bayer AG, Wuppertal, Germany (H.M.).

PMID: 38174569
DOI: 10.1161/STROKEAHA.123.043198

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.

Keywords: anticoagulants; atherosclerosis; cerebral infarction; humans; ischemic stroke.

Publication types

Randomized Controlled Trial

MeSH terms

Anticoagulants / pharmacology
Cerebral Infarction / diagnostic imaging
Cerebral Infarction / drug therapy
Factor XIa
Humans
Ischemic Attack, Transient* / drug therapy
Ischemic Stroke* / drug therapy
Magnetic Resonance Imaging

Substances

Anticoagulants
Factor XIa

Associated data

ClinicalTrials.gov/NCT04304508