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. Issue 16 (27th August 2022)

• Record Type: Journal Article
• Authors: Rao, Sunil V.; Kirsch, Bodo; Bhatt, Deepak L.; Budaj, Andrzej; Coppolecchia, Rosa; Eikelboom, John; James, Stefan K.; Jones, W. Schuyler; Merkely, Bela; Keller, Lars; Hermanides, Renicus S.; Campo, Gianluca; Ferreiro, José Luis; Shibasaki, Taro; Mundl, Hardi; Alexander, John H.
• Other Names: Hengstenberg Christian author non-byline.; Steinwender Clemens author non-byline.; Alber Hannes author non-byline.; Steringer-Mascherbauer Regina author non-byline.; Schober Andreas author non-byline.; Auer Johann author non-byline.; Roithinger Franz Xaver author non-byline.; von Lewinski Dirk author non-byline.; Moertl Deddo author non-byline.; Huber Kurt author non-byline.; Coussement Patrick author non-byline.; Hoffer Etienne author non-byline.; Beauloye Christophe author non-byline.; Janssens Luc author non-byline.; Vranckx Pascal author non-byline.; De Raedt Herbert author non-byline.; Vanassche Thomas author non-byline.; Vrolix Matthias author non-byline.; Rokyta Richard author non-byline.; Parenica Jiri author non-byline.; Pelouch Radek author non-byline.; Motovska Zuzanna author non-byline.; Alan David author non-byline.; Kettner Jiri author non-byline.; Polasek Rostislav author non-byline.; Cermak Ondrej author non-byline.; Sedlon Pavel author non-byline.; Hanis Jiri author non-byline.; Novak Martin author non-byline.; Belohlavek Jan author non-byline.; Horacek Thomas author non-byline.; Leggewie Stefan author non-byline.; Wenzel Philip author non-byline.; vom Dahl Juergen author non-byline.; Sievers Burkhard author non-byline.; Pulz Jan author non-byline.; Schellong Sebastian author non-byline.; Clemmensen Peter author non-byline.; Muller-Hennessen Matthias author non-byline.; Rassaf Tienush author non-byline.; Falukozi Jozsef author non-byline.; Ruzsa Zoltan author non-byline.; Tomcsanyi Janos author non-byline.; Csanadi Zoltan author non-byline.; Herczeg Bela author non-byline.; Koszegi Zsolt author non-byline.; Vorobcsuk Andras author non-byline.; Kiss Robert author non-byline.; Baranyai Csaba author non-byline.; Dezsi Csaba author non-byline.; Merkely Bela author non-byline.; Lupkovics Geza author non-byline.; Rossini Roberta author non-byline.; Scherillo Marino author non-byline.; Sergio Saba Pier author non-byline.; Calogero Campo Gianluca author non-byline.; Calo Leonardo author non-byline.; Nassiacos Daniele author non-byline.; Quadri Giorgio author non-byline.; Sciahbasi Alessandro author non-byline.; Silvio Marenzi Gian Carlo author non-byline.; Reimers Bernhard author non-byline.; Perna Gian Piero author non-byline.; Sacca Salvatore author non-byline.; Fattore Luciano author non-byline.; Brunelli Claudio author non-byline.; Picchi Andrea author non-byline.; Kuramochi Takehiko author non-byline.; Kondo Kazuhisa author non-byline.; Aoyama Takahiko author non-byline.; Kudoh Takashi author non-byline.; Yamamoto Tadashi author non-byline.; Takaya Tomofumi author non-byline.; Mukai Yasushi author non-byline.; Fukui Kazuki author non-byline.; Morioka Nobuyuki author non-byline.; Ando Kenji author non-byline.; Yamamuro Atsushi author non-byline.; Morita Yasuhiro author non-byline.; Koga Yasuaki author non-byline.; Watanabe Tetsuya author non-byline.; Sakamoto Tomohiro author non-byline.; Shibasaki Taro author non-byline.; Maebuchi Daisuke author non-byline.; Takahashi Akihiko author non-byline.; Yonetsu Taishi author non-byline.; Kakuta Tsunekazu author non-byline.; Nishina Hidetaka author non-byline.; Oemrawsingh Rohit author non-byline.; Dorman Reinhart author non-byline.; Oude Ophius Ton author non-byline.; Prins Paco author non-byline.; al Windy N.Y.Y. author non-byline.; Zoet-Nugteren S.K. author non-byline.; Hermanides Rik author non-byline.; van Eck Martijn author non-byline.; Scherptong Roderick author non-byline.; Cornel J.H. author non-byline.; Damman Peter author non-byline.; Bech Gerhard author non-byline.; Torquay R. author non-byline.; Kietselaer Bas author non-byline.; Grzelakowski Pawel author non-byline.; Krzysztof Dyrbus author non-byline.; Budaj Andrzej author non-byline.; Miekus Pawel author non-byline.; Przybylski Andrzej author non-byline.; Zarebinski Maciej author non-byline.; Balsam Pawel author non-byline.; Szachniewicz Joanna author non-byline.; Gierlotka Marek author non-byline.; Tycinska Agnieszka author non-byline.; Iniguez Romo Andres author non-byline.; Fernandez Ortiz Antonio author non-byline.; Carrasquer Cucarella Anna author non-byline.; Sanmartin Fernandez Marcelo author non-byline.; Sionis Alessandro author non-byline.; Bueno Zamora Hector author non-byline.; Ferreiro Gutierrez Jose Luis author non-byline.; Almenar Luis author non-byline.; Ferreira Gonzalez Ignacio author non-byline.; Pascual Figal Domingo A. author non-byline.; Almendro Delia Manuel author non-byline.; Jimenez Fernandez Miriam author non-byline.; Skeppholm Mika author non-byline.; Zedigh Crister author non-byline.; Angeras Oskar author non-byline.; Lauermann Jorg author non-byline.; Erlinge David author non-byline.; Gustafsson Robin author non-byline.; Mooe Thomas author non-byline.; Utreras Alejandro author non-byline.; James Stefan author non-byline.; Grimfjard Per author non-byline.; Pedrazzini Giovanni author non-byline.; Mach Francois author non-byline.; Fournier Stephane author non-byline.; Haegeli Laurent author non-byline.; Beer Jurg H. author non-byline.; Leibundgut Gregor author non-byline.; Kobza Richard author non-byline.; Kaiser Christoph author non-byline.; Kunadian Vijay author non-byline.; Al-Lamee Rasha author non-byline.; Gorog Diana author non-byline.; Khan Sohail author non-byline.; Trevelyan Jasper author non-byline.; Toor Iqbal author non-byline.; Smith James author non-byline.; Purushottam Bhaskar author non-byline.; Treasure Charles author non-byline.; Arena Frank author non-byline.; Vedere Amarnath author non-byline.; Henderson David author non-byline.; Gilani Syed author non-byline.; Jones Alonzo author non-byline.; Carrillo-Jimenez Rodolfo author non-byline.; Gillespie Eve author non-byline.; Marhefka Gregary author non-byline.; Wang David author non-byline.; Olson Charles author non-byline.; Bloom Stephen author non-byline.; Iftikhar Faizan author non-byline.; Brabham David author non-byline.; McGinty John author non-byline.; Thompson Charles author non-byline.; Talano James author non-byline.; Ginete Wilson author non-byline.; Williams Marcus author non-byline.; Masud Ali author non-byline.; Ariani Mehrdad author non-byline.; Bitar Fahed author non-byline.; Wang Thomas author non-byline.; Samuelson Bradley author non-byline.;
• Is Part Of: Circulation. Volume 146:Issue 16(2022)
• Page Start: 1196
• Page End: 1206
• Publication Date: 2022-08-27
• Subjects: anticoagulants -- factor XIa -- myocardial infarction; Blood -- Circulation -- Periodicals; Cardiovascular system -- Periodicals; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; 616.1
• DOI: 10.1161/CIRCULATIONAHA.122.061612
• Languages: English
• ISSNs: 0009-7322

Abstract

Abstract : 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.