美国杜克大学医学院Jonathan P Piccini团队比较了口服因子XIa抑制剂Asundexian与阿哌沙班治疗心房颤动患者的安全性。这一研究成果发表在2022年4月3日出版的《柳叶刀》杂志上。

直接口服抗凝剂用于预防房颤患者的卒中受到出血问题的限制。Asundexian是一种新型口服小分子激活凝血因子XIa（FXIa）抑制剂，可减少血栓形成，对止血效果极小。该研究旨在确定asundexian的最佳剂量，并与阿哌沙班治疗房颤患者的出血发生率进行比较。

在这项随机、双盲、2期剂量发现研究中，研究组比较了45岁及以上、患有房颤、CHA₂DS₂-VASc评分至少为2分（男性）或至少为3分（女性）、且出血风险增加的患者，每日一次口服asundexian 20mg或50mg，与每日两次阿哌沙班5mg的疗效。该研究在14个国家（12个欧洲国家、加拿大和日本）的93个机构中进行。

将参与者按1:1:1随机分配，根据患者在研究开始前是否服用了直接作用的口服抗凝剂进行随机分层。双盲采用双模拟设计，参与者同时接受指定治疗和类似于非指定治疗的安慰剂。主要终点是根据国际血栓形成和止血学会的标准，在所有至少服用一剂研究药物的患者中，评估严重或临床相关的非严重出血的综合结局。

2020年1月30日至2021年6月21日，研究组共招募了862名患者。755名患者被随机分配接受治疗。由于两名患者（asundexian 20mg组）从未服用过任何研究药物，753名患者被纳入最终分析（asundexian 20mg组249名，asundexian 50mg组254名，阿哌沙班组250名）。

参与者的平均年龄为73.7岁，309名（41%）为女性，216名（29%）为慢性肾病，CHA₂DS₂-VASc平均评分为3.9分。Asundexian 20mg组在谷浓度下对FXIa活性的抑制率为81%，在峰浓度下对FXIa活性的抑制率为90%；asundexian 50mg组在谷浓度下的抑制率为92%，在峰浓度下的抑制率为94%。

与阿哌沙班组相比，asundexian 20mg组（三个事件）的主要终点发病率比率为0.50，asundexian 50mg组（一个事件）为0.16，asundexian合并组（四个事件）为0.33。三个治疗组的不良事件发生率相似：asundexian 20mg组中有118例（47%），asundexian 50mg组有120例（47%），阿哌沙班组有122例（49%）。

研究结果表明，与标准剂量的阿哌沙班相比，每日一次服用20 mg和50 mg的FXIa抑制剂asundexian可显著降低心房颤动患者的出血率，且几乎完全抑制体内FXIa。

附：英文原文

Title: Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): a multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 study

Author: Jonathan P Piccini, Valeria Caso, Stuart J Connolly, Keith A A Fox, Jonas Oldgren, W Schuyler Jones, Diana A Gorog, Václav Durdil, Thomas Viethen, Christoph Neumann, Hardi Mundl, Manesh R Patel, Johann Auer, Martin Hubauer, Sead Pandzic, Eva Preishuber, Carina Primus-Grabscheit, Dietmar Reitgruber, Florian Schmalzer, Christopher Adlbrecht, Andreas Schober, Johannes Hajos, Christoph Keil, Alexandra Schratter, Matthias Frick, Magdalena Anna Benda, Maximilian Mchler, Beatrix Mutschlechner, Christoph Saely, Lukas Sprenger, Michael Lichtenauer, Miriam Eber, Uta Hoppe, Tobias Kolbitsch, Peter Michael Jirak, Moritz Mirna, Robert Schnbauer, Jutta Bergler-Klein, Christian Hengstenberg, Stefan Stojkovic, Daniel Scherr, Martin Manninger-Wünscher, Ursula Rohrer, Markus Stühlinger, Wilfried Schgoer, Jana Schwarzl, Helmut Pürerfellner, Michael Derndorfer, Christian Ebner, Veronika Eder, Georgios Kollias, Thomas Sturmberger, Stefan Sieghartsleitner, Johan Vijgen, Peter Koopman, Karl Dujardin, Wim Anné, Michel De Ceuninck, Rene Tavernier, Mattias Duytschaever, Sébastien Knecht, Luc Missault, Yves Vandekerckhove, Tom Rossenbacker, Bavo Ector, Filip Charlier, Philippe Debruyne, Willem Dewilde, Luc Janssens, John Roosen, Bart Vankelecom, Hein Heidbuchel, Michiel Delesie, Gert Vervoort, Hans Rombouts, Thomas Vanassche, Matthias Engelen, Peter Verhamme, Rik Willems, Christian Constance, Nicolas Pranno, Jafna Cox, Iqbal Bata, Laurent Macle, Martin Aguilar, Julia Cadrin Tourigny, Marc Dubuc, Katia Dyrda, Peter Guerra, Paul Khairy, Blandine Mondésert, Léna Rivard, Denis Roy, Rafik Tadros, Mario Talajic, Bernard Thibault, Isabelle Nault, Louis Blier, Jean Champagne, Franck Molin, Gilles OHara, Franois Philippon, Benoit Plourde, Jean-Franois Sarrazin, Christian Steinberg, Zdenek Coufal, David Balazsik, Michal Mikulica, Jakub Zapeca, Ondrej Cermak, Tomas Drasnar, Matej Falc, Josef Hornof, Blazej Racz, Danica Weissova, Hana Linkova, Eva Paskova, Robert Petr, Andrea Sirakova, Jiri Kettner, Ales Benak, Martin Holek, Ivo Podpera, Monika Podperova, Vlastimil Vancura, Tomas Jandik, Jiri Smid, Vratislav Dedek, Jan Banik, Vaclav Durdil, Tomas Hnat, Nicolas Lellouche

Issue&Volume: 2022-04-03

Abstract:

Background

Direct-acting oral anticoagulant use for stroke prevention in atrial fibrillation is limited by bleeding concerns. Asundexian, a novel, oral small molecule activated coagulation factor XIa (FXIa) inhibitor, might reduce thrombosis with minimal effect on haemostasis. We aimed to determine the optimal dose of asundexian and to compare the incidence of bleeding with that of apixaban in patients with atrial fibrillation.

Methods

In this randomised, double-blind, phase 2 dose-finding study, we compared asundexian 20 mg or 50 mg once daily with apixaban 5 mg twice daily in patients aged 45 years or older with atrial fibrillation, a CHA2DS2-VASc score of at least 2 if male or at least 3 if female, and increased bleeding risk. The study was conducted at 93 sites in 14 countries, including 12 European countries, Canada, and Japan. Participants were randomly assigned (1:1:1) to a treatment group using an interactive web response system, with randomisation stratified by whether patients were receiving a direct-acting oral anticoagulant before the study start. Masking was achieved using a double-dummy design, with participants receiving both the assigned treatment and a placebo that resembled the non-assigned treatment. The primary endpoint was the composite of major or clinically relevant non-major bleeding according to International Society on Thrombosis and Haemostasis criteria, assessed in all patients who took at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT04218266, and EudraCT, 2019-002365-35.

Findings

Between Jan 30, 2020, and June 21, 2021, 862 patients were enrolled. 755 patients were randomly assigned to treatment. Two patients (assigned to asundexian 20 mg) never took any study medication, resulting in 753 patients being included in the analysis (249 received asundexian 20 mg, 254 received asundexian 50 g, and 250 received apixaban). The mean age of participants was 73·7 years (SD 8·3), 309 (41%) were women, 216 (29%) had chronic kidney disease, and mean CHA2DS2-VASc score was 3·9 (1·3). Asundexian 20 mg resulted in 81% inhibition of FXIa activity at trough concentrations and 90% inhibition at peak concentrations; asundexian 50 mg resulted in 92% inhibition at trough concentrations and 94% inhibition at peak concentrations. Ratios of incidence proportions for the primary endpoint were 0·50 (90% CI 0·14–1·68) for asundexian 20 mg (three events), 0·16 (0·01–0·99) for asundexian 50 mg (one event), and 0·33 (0·09–0·97) for pooled asundexian (four events) versus apixaban (six events). The rate of any adverse event occurring was similar in the three treatment groups: 118 (47%) with asundexian 20 mg, 120 (47%) with asundexian 50 mg, and 122 (49%) with apixaban.

Interpretation

The FXIa inhibitor asundexian at doses of 20 mg and 50 mg once daily resulted in lower rates of bleeding compared with standard dosing of apixaban, with near-complete in-vivo FXIa inhibition, in patients with atrial fibrillation.

DOI: 10.1016/S0140-6736(22)00456-1

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00456-1/fulltext