Sunil V. Rao, Bodo Kirsch, Deepak L. Bhatt, Andrzej Budaj, Rosa Coppolecchia, John Eikelboom, Stefan K. James, W. Schuyler Jones, Bela Merkely, Lars Keller, Renicus S. Hermanides, Gianluca Campo, José Luis Ferreiro, Taro Shibasaki, Hardi Mundl, John H. Alexander, Christian Hengstenberg, Clemens Steinwender, Hannes Alber, Regina Steringer-Mascherbauer, Andreas Schober, Johann Auer, Franz Xaver Roithinger, Dirk von Lewinski, Deddo Moertl, Kurt Huber, Patrick Coussement, Etienne Hoffer, Christophe Beauloye, Luc Janssens, Pascal Vranckx, Herbert De Raedt, Thomas Vanassche, Matthias Vrolix, Richard Rokyta, Jiri Parenica, Radek Pelouch, Zuzanna Motovska, David Alan, Jiri Kettner, Rostislav Polasek, Ondrej Cermak, Pavel Sedlon, Jiri Hanis, Martin Novak, Jan Belohlavek, Thomas Horacek, Stefan Leggewie, Philip Wenzel, Juergen vom Dahl, Burkhard Sievers, Jan Pulz, Sebastian Schellong, Peter Clemmensen, Matthias Muller-Hennessen, Tienush Rassaf, Jozsef Falukozi, Zoltan Ruzsa, Janos Tomcsanyi, Zoltan Csanadi, Bela Herczeg, Zsolt Koszegi, Andras Vorobcsuk, Robert Kiss, Csaba Baranyai, Csaba Dezsi, Geza Lupkovics, Roberta Rossini, Marino Scherillo, Pier Sergio Saba, Gianluca Calogero Campo, Leonardo Calo, Daniele Nassiacos, Giorgio Quadri, Alessandro Sciahbasi, Gian Carlo Silvio Marenzi, Bernhard Reimers, Gian Piero Perna, Salvatore Sacca, Luciano Fattore, Claudio Brunelli, Andrea Picchi, Takehiko Kuramochi, Kazuhisa Kondo, Takahiko Aoyama, Takashi Kudoh, Tadashi Yamamoto, Tomofumi Takaya, Yasushi Mukai, Kazuki Fukui, Nobuyuki Morioka, Kenji Ando, Atsushi Yamamuro, Yasuhiro Morita, Yasuaki Koga, Tetsuya Watanabe, Tomohiro Sakamoto, Daisuke Maebuchi, Akihiko Takahashi, Taishi Yonetsu, Tsunekazu Kakuta, Hidetaka Nishina, Rohit Oemrawsingh, Reinhart Dorman, Ton Oude Ophius, Paco Prins, N.Y.Y. al Windy, S.K. Zoet-Nugteren, Rik Hermanides, Martijn van Eck, Roderick Scherptong, J.H. Cornel, Peter Damman, Gerhard Bech, R. Torquay, Bas Kietselaer, Pawel Grzelakowski, Dyrbus Krzysztof, Pawel Miekus, Andrzej Przybylski, Maciej Zarebinski, Pawel Balsam, Joanna Szachniewicz, Marek Gierlotka, Agnieszka Tycinska, Andres Iniguez Romo, Antonio Fernandez Ortiz, Anna Carrasquer Cucarella, Marcelo Sanmartin Fernandez, Alessandro Sionis, Hector Bueno Zamora, Jose Luis Ferreiro Gutierrez, Luis Almenar, Ignacio Ferreira Gonzalez, Domingo A. Pascual Figal, Manuel Almendro Delia, Miriam Jimenez Fernandez, Mika Skeppholm, Crister Zedigh, Oskar Angeras, Jorg Lauermann, David Erlinge, Robin Gustafsson, Thomas Mooe, Alejandro Utreras, Stefan James, Per Grimfjard, Giovanni Pedrazzini, Francois Mach, Stephane Fournier, Laurent Haegeli, Jurg H. Beer, Gregor Leibundgut, Richard Kobza, Christoph Kaiser, Vijay Kunadian, Rasha Al-Lamee, Diana Gorog, Sohail Khan, Jasper Trevelyan, Iqbal Toor, James Smith, Bhaskar Purushottam, Charles Treasure, Frank Arena, Amarnath Vedere, David Henderson, Syed Gilani, Alonzo Jones, Rodolfo Carrillo-Jimenez, Eve Gillespie, Gregary Marhefka, David Wang, Charles Olson, Stephen Bloom, Faizan Iftikhar, David Brabham, John McGinty, Charles Thompson, James Talano, Wilson Ginete, Marcus Williams, Ali Masud, Mehrdad Ariani, Fahed Bitar, Thomas Wang, and Bradley Samuelson
Background: Oral activated factor XI (FXIa) inhibitors may modulate coagulation to prevent thromboembolic events without substantially increasing bleeding. We explored the pharmacodynamics, safety, and efficacy of the oral FXIa inhibitor asundexian for secondary prevention after acute myocardial infarction (MI). Methods: We randomized 1601 patients with recent acute MI to oral asundexian 10, 20, or 50 mg or placebo once daily for 6 to 12 months in a double-blind, placebo-controlled, phase 2, dose-ranging trial. Patients were randomized within 5 days of their qualifying MI and received dual antiplatelet therapy with aspirin plus a P2Y12 inhibitor. The effect of asundexian on FXIa inhibition was assessed at 4 weeks. The prespecified main safety outcome was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding comparing all pooled asundexian doses with placebo. The prespecified efficacy outcome was a composite of cardiovascular death, MI, stroke, or stent thrombosis comparing pooled asundexian 20 and 50 mg doses with placebo. Results: The median age was 68 years, 23% of participants were women, 51% had ST-segment–elevation MI, 80% were treated with aspirin plus ticagrelor or prasugrel, and 99% underwent percutaneous coronary intervention before randomization. Asundexian caused dose-related inhibition of FXIa activity, with 50 mg resulting in >90% inhibition. Over a median follow-up of 368 days, the main safety outcome occurred in 30 (7.6%), 32 (8.1%), 42 (10.5%), and 36 (9.0%) patients receiving asundexian 10 mg, 20 mg, or 50 mg, or placebo, respectively (pooled asundexian versus placebo: hazard ratio, 0.98 [90% CI, 0.71–1.35]). The efficacy outcome occurred in 27 (6.8%), 24 (6.0%), 22 (5.5%), and 22 (5.5%) patients assigned asundexian 10 mg, 20 mg, or 50 mg, or placebo, respectively (pooled asundexian 20 and 50 mg versus placebo: hazard ratio, 1.05 [90% CI, 0.69–1.61]). Conclusions: In patients with recent acute MI, 3 doses of asundexian, when added to aspirin plus a P2Y12 inhibitor, resulted in dose-dependent, near-complete inhibition of FXIa activity without a significant increase in bleeding and a low rate of ischemic events. These data support the investigation of asundexian at a dose of 50 mg daily in an adequately powered clinical trial of patients who experienced acute MI. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04304534; URL: https://www.clinicaltrialsregister.eu/ctr-search/search ; Unique identifier: 2019-003244-79.