A Multicenter, Phase 2, Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Dose-Finding Trial of the Oral Factor XIa Inhibitor Asundexian to Prevent Adverse Cardiovascular Outcomes After Acute Myocardial Infarction

作者：Sunil V. Rao, Bodo Kirsch, Deepak L. Bhatt, Andrzej Budaj, Rosa Coppolecchia, John W. Eikelboom, Stefan James, W. Schuyler Jones, Béla 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, E Hoffer, Christophe Beauloye, Luc Janssens, Pascal Vranckx, Herbert De Raedt, Thomas Vanassche, Matthias Vrolix, Richard Rokyta, Jiří Pařenica, Radek Pelouch, Zuzanna Motovska, David Alan, Jiří Kettner, Rostislav Polášek, Ondřej Čermák, Pavel Sedloň, Jiří Haniš, Martin Novák, Jan Bělohlávek, Thomas Horacek, Stefan Leggewie, Philip Wenzel, Juergen vom Dahl, Burkhard Sievers, Jan Pulz, Sebastian Schellong, Peter Clemmensen, Matthias Muller-Hennessen, Tienush Rassaf, Jozsef Falukozi, Zoltán Ruzsa, János Tomcsányi, Zoltán Csanádi, Béla Herczeg, Zsolt Kőszegi, András Vorobcsuk, Róbert Gábor Kiss, Csaba Baranyai, Csaba András Dézsi, Béla Merkely, Géza Lupkovics, Roberta Rossini, Marino Scherillo, Pier Sergio Saba, Gianluca Campo, Leonardo Calò, Daniele Nassiacos, Giorgio Quadri, Alessandro Sciahbasi, Giancarlo Marenzi, Bernhard Reimers, Gian Piero Perna, Salvatore Saccà, Luciano Fattore, Claudio Brunelli, Andréa 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, Taro Shibasaki, Daisuke Maebuchi, Akihiko Takahashi, Taishi Yonetsu, Tsunekazu Kakuta, Hidetaka Nishina, Rohit M. Oemrawsingh, Reinhart Dorman, Ton Oude Ophius, Paco Prins, N.Y.Y. al Windy, Stijntje Zoet-Nugteren, Rik Hermanides, Martijn van Eck, Roderick W.C. Scherptong, Jan H. Cornel, Peter Damman, Gerhard Jan Willem Bech, R. Torquay, Bas Kietselaer, Paweł Grzelakowski, Dyrbus Krzysztof, Andrzej Budaj, Paweł Miękus, Andrzej Przybylski, Maciej Zarębiński, Paweł Balsam, Joanna Szachniewicz, Marek Gierlotka, Agnieszka Tycińska, Andres Iniguez Romo, Antonio Fernández‐Ortíz, Anna Carrasquer Cucarella, Marcelo Sanmartin Fernandez, Alessandro Sionís, Hector Bueno Zamora, Jose Luis Ferreiro Gutierrez, Luís Almenar, Ignacio Ferreira González, Domingo A. Pascual‐Figal, Manuel Almendro Delia, Miriam Jiménez Fernández, Mika Skeppholm, Crister Zedigh, Oskar Angerås, Jörg Lauermann, David Erlinge, Robin Gustafsson, Thomas Mooe, Alejandro Utreras, Stefan James, Per Grimfjärd, Giovanni Pedrazzini, François Mach, Stéphane Fournier, Laurent Haegeli, Jürg H. Beer, Gregor Leibundgut, Richard Kobza, Christoph Kaiser, Vijay Kunadian, Rasha Al‐Lamee, Diana A. Gorog, Sohail Q. Khan, Jasper Trevelyan, Iqbal Toor, James Smith, Bhaskar Purushottam, Charles B. Treasure, Frank Arena, Amarnath Vedere, David Henderson, Syed Amir Gilani, Alonzo H. Jones, Rodolfo Carrillo-Jimenez, Eve Gillespie, Gregary Marhefka, David Wang, Charles E. Olson, Stephen R. Bloom, Faizan Iftikhar, David Brabham, John B. McGinty, Charles Thompson, James V. Talano, Wilson Ginete, Marcus Williams, Ali Mas’ud, Mehrdad Ariani, Fahed Bitar, Thomas J. Wang, Bradley Samuelson · 发表于：Circulation · 年份：2022 · DOI：10.1161/circulationaha.122.061612 · 被引用次数：156 · 研究领域：Coagulation, Bradykinin, Polyphosphates, and Angioedema、Heart Failure Treatment and Management、Atrial Fibrillation Management and Outcomes

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...