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.
Details
Serval ID
serval:BIB_1D724CA694A5
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
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.
Journal
Circulation
Working group(s)
PACIFIC AMI Investigators
Contributor(s)
Hengstenberg C., Steinwender C., Alber H., Steringer-Mascherbauer R., Schober A., Auer J., Roithinger F.X., von Lewinski D., Moertl D., Huber K., Coussement P., Hoffer E., Beauloye C., Janssens L., Vranckx P., De Raedt H., Vanassche T., Vrolix M., Rokyta R., Parenica J., Pelouch R., Motovska Z., Alan D., Kettner J., Polasek R., Cermak O., Sedlon P., Hanis J., Novak M., Belohlavek J., Horacek T., Leggewie S., Wenzel P., Vom Dahl J., Sievers B., Pulz J., Schellong S., Clemmensen P., Muller-Hennessen M., Rassaf T., Falukozi J., Ruzsa Z., Tomcsanyi J., Csanadi Z., Herczeg B., Koszegi Z., Vorobcsuk A., Kiss R., Baranyai C., Dezsi C., Merkely B., Lupkovics G., Rossini R., Scherillo M., Sergio Saba P., Calogero Campo G., Calo L., Nassiacos D., Quadri G., Sciahbasi A., Silvio Marenzi G.C., Reimers B., Perna G.P., Sacca S., Fattore L., Brunelli C., Picchi A., Kuramochi T., Kondo K., Aoyama T., Kudoh T., Yamamoto T., Takaya T., Mukai Y., Fukui K., Morioka N., Ando K., Yamamuro A., Morita Y., Koga Y., Watanabe T., Sakamoto T., Shibasaki T., Maebuchi D., Takahashi A., Yonetsu T., Kakuta T., Nishina H., Oemrawsingh R., Dorman R., Oude Ophius T., Prins P., Al Windy NYY, Zoet-Nugteren S.K., Hermanides R., van Eck M., Scherptong R., Cornel J.H., Damman P., Bech G., Torquay R., Kietselaer B., Grzelakowski P., Krzysztof D., Budaj A., Miekus P., Przybylski A., Zarebinski M., Balsam P., Szachniewicz J., Gierlotka M., Tycinska A., Iniguez Romo A., Fernandez Ortiz A., Carrasquer Cucarella A., Sanmartin Fernandez M., Sionis A., Bueno Zamora H., Ferreiro Gutierrez J.L., Almenar L., Ferreira Gonzalez I., Pascual Figal D.A., Almendro Delia M., Jimenez Fernandez M., Skeppholm M., Zedigh C., Angeras O., Lauermann J., Erlinge D., Gustafsson R., Mooe T., Utreras A., James S., Grimfjard P., Pedrazzini G., Mach F., Fournier S., Haegeli L., Beer J.H., Leibundgut G., Kobza R., Kaiser C., Kunadian V., Al-Lamee R., Gorog D., Khan S., Trevelyan J., Toor I., Smith J., Purushottam B., Treasure C., Arena F., Vedere A., Henderson D., Gilani S., Jones A., Carrillo-Jimenez R., Gillespie E., Marhefka G., Wang D., Olson C., Bloom S., Iftikhar F., Brabham D., McGinty J., Thompson C., Talano J., Ginete W., Williams M., Masud A., Ariani M., Bitar F., Wang T., Samuelson B.
ISSN
1524-4539 (Electronic)
ISSN-L
0009-7322
Publication state
Published
Issued date
18/10/2022
Peer-reviewed
Oui
Volume
146
Number
16
Pages
1196-1206
Language
english
Notes
Publication types: Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial
Publication Status: ppublish
Publication Status: ppublish
Abstract
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).
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.
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]).
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.
URL: https://www.
gov; Unique identifier: NCT04304534; URL: https://www.clinicaltrialsregister.eu/ctr-search/search; Unique identifier: 2019-003244-79.
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.
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]).
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.
URL: https://www.
gov; Unique identifier: NCT04304534; URL: https://www.clinicaltrialsregister.eu/ctr-search/search; Unique identifier: 2019-003244-79.
Keywords
Acute Coronary Syndrome/therapy, Aged, Anticoagulants/therapeutic use, Aspirin/therapeutic use, Double-Blind Method, Factor XIa, Female, Hemorrhage/chemically induced, Humans, Male, Myocardial Infarction/etiology, Percutaneous Coronary Intervention/adverse effects, Platelet Aggregation Inhibitors/therapeutic use, Prasugrel Hydrochloride, Ticagrelor, Treatment Outcome, anticoagulants, factor XIa, myocardial infarction
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Web of science
Create date
08/11/2022 10:37
Last modification date
09/11/2022 6:41
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