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.
Journal
Lancet (London, England)
ISSN: 1474-547X
Titre abrégé: Lancet
Pays: England
ID NLM: 2985213R
Informations de publication
Date de publication:
09 04 2022
09 04 2022
Historique:
received:
14
02
2022
revised:
24
02
2022
accepted:
25
02
2022
pubmed:
7
4
2022
medline:
13
4
2022
entrez:
6
4
2022
Statut:
ppublish
Résumé
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. 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 CHA 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 CHA 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. Bayer.
Sections du résumé
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 CHA
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 CHA
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.
FUNDING
Bayer.
Identifiants
pubmed: 35385695
pii: S0140-6736(22)00456-1
doi: 10.1016/S0140-6736(22)00456-1
pii:
doi:
Substances chimiques
Anticoagulants
0
Factor Xa Inhibitors
0
Pyrazoles
0
Pyridones
0
apixaban
3Z9Y7UWC1J
Banques de données
ClinicalTrials.gov
['NCT04218266']
Types de publication
Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
1383-1390Investigateurs
Johann Auer
(J)
Martin Hubauer
(M)
Sead Pandzic
(S)
Eva Preishuber
(E)
Carina Primus-Grabscheit
(C)
Dietmar Reitgruber
(D)
Florian Schmalzer
(F)
Christopher Adlbrecht
(C)
Andreas Schober
(A)
Johannes Hajos
(J)
Christoph Keil
(C)
Alexandra Schratter
(A)
Matthias Frick
(M)
Magdalena Anna Benda
(MA)
Maximilian Mächler
(M)
Beatrix Mutschlechner
(B)
Christoph Saely
(C)
Lukas Sprenger
(L)
Michael Lichtenauer
(M)
Miriam Eber
(M)
Uta Hoppe
(U)
Tobias Kolbitsch
(T)
Peter Michael Jirak
(PM)
Moritz Mirna
(M)
Robert Schönbauer
(R)
Jutta Bergler-Klein
(J)
Christian Hengstenberg
(C)
Stefan Stojkovic
(S)
Daniel Scherr
(D)
Martin Manninger-Wünscher
(M)
Ursula Rohrer
(U)
Markus Stühlinger
(M)
Wilfried Schgoer
(W)
Jana Schwarzl
(J)
Helmut Pürerfellner
(H)
Michael Derndorfer
(M)
Christian Ebner
(C)
Veronika Eder
(V)
Georgios Kollias
(G)
Thomas Sturmberger
(T)
Stefan Sieghartsleitner
(S)
Johan Vijgen
(J)
Peter Koopman
(P)
Karl Dujardin
(K)
Wim Anné
(W)
Michel De Ceuninck
(M)
Rene Tavernier
(R)
Mattias Duytschaever
(M)
Sébastien Knecht
(S)
Luc Missault
(L)
Yves Vandekerckhove
(Y)
Tom Rossenbacker
(T)
Bavo Ector
(B)
Filip Charlier
(F)
Philippe Debruyne
(P)
Willem Dewilde
(W)
Luc Janssens
(L)
John Roosen
(J)
Bart Vankelecom
(B)
Hein Heidbuchel
(H)
Michiel Delesie
(M)
Gert Vervoort
(G)
Hans Rombouts
(H)
Thomas Vanassche
(T)
Matthias Engelen
(M)
Peter Verhamme
(P)
Rik Willems
(R)
Christian Constance
(C)
Nicolas Pranno
(N)
Jafna Cox
(J)
Iqbal Bata
(I)
Laurent Macle
(L)
Martin Aguilar
(M)
Julia Cadrin Tourigny
(JC)
Marc Dubuc
(M)
Katia Dyrda
(K)
Peter Guerra
(P)
Paul Khairy
(P)
Blandine Mondésert
(B)
Léna Rivard
(L)
Denis Roy
(D)
Rafik Tadros
(R)
Mario Talajic
(M)
Bernard Thibault
(B)
Isabelle Nault
(I)
Louis Blier
(L)
Jean Champagne
(J)
Franck Molin
(F)
Gilles O'Hara
(G)
François Philippon
(F)
Benoit Plourde
(B)
Jean-François Sarrazin
(JF)
Christian Steinberg
(C)
Zdenek Coufal
(Z)
David Balazsik
(D)
Michal Mikulica
(M)
Jakub Zapeca
(J)
Ondrej Cermak
(O)
Tomas Drasnar
(T)
Matej Falc
(M)
Josef Hornof
(J)
Blazej Racz
(B)
Danica Weissova
(D)
Hana Linkova
(H)
Eva Paskova
(E)
Robert Petr
(R)
Andrea Sirakova
(A)
Jiri Kettner
(J)
Ales Benak
(A)
Martin Holek
(M)
Ivo Podpera
(I)
Monika Podperova
(M)
Vlastimil Vancura
(V)
Tomas Jandik
(T)
Jiri Smid
(J)
Vratislav Dedek
(V)
Jan Banik
(J)
Vaclav Durdil
(V)
Tomas Hnat
(T)
Nicolas Lellouche
(N)
Ségolène Rouffiac
(S)
Guillaume Taldir
(G)
Valentin Bridonneau
(V)
Philippe Couffon
(P)
Magalie Daudin
(M)
Cécile Hamon
(C)
Jonathan Lacaze
(J)
Anne Quentin
(A)
Christophe Thebault
(C)
Emmanuel Boiffard
(E)
Olivier Billon
(O)
Fabien Miette
(F)
Hervé Pouliquen
(H)
Guillaume Turlotte
(G)
Hervé Gorka
(H)
Franck Albert
(F)
Sandrine Bayle
(S)
Reda Bensaid
(R)
Madalina Dasoveanu
(M)
Thibaud Demichili
(T)
Teodora Dutoiu
(T)
Cliff Khalil
(C)
Caterina Loghin
(C)
Grégoire Range
(G)
Laurent Roussel
(L)
Pierre Socié
(P)
Christophe Thuaire
(C)
Fabrice Extramiana
(F)
Vincent Algalarrondo
(V)
Haten Boughanmi
(H)
Noreddine El Mansour
(N)
Usman Mohammad
(U)
Romain Sellier
(R)
Meyer Elbaz
(M)
Clémence Laperche
(C)
Philippe Maury
(P)
Robert Kiss
(R)
Tunde Borsanyi
(T)
Zoltan Gingl
(Z)
Balaza Polgar
(B)
Bela Benczur
(B)
Alexandra Bodor
(A)
Tamas Hepp
(T)
Eva Malati
(E)
Laszlo Nagy
(L)
Norbert Erdei
(N)
Jozsef Kapus
(J)
Katalin Kapus
(K)
Brigitta Toth
(B)
Andras Matoltsy
(A)
Tunde Kiss
(T)
Bela Merkely
(B)
Szilvia Herczeg
(S)
Orsolya Kiss
(O)
Zoltan Sallo
(Z)
Kalman Toth
(K)
Tamas Habon
(T)
Miklos Rabai
(M)
Kinga Totsimon
(K)
Zsolt Zilahi
(Z)
Gabriella Bencze
(G)
Janos Santa
(J)
Daniel Aradi
(D)
Barbara Kelemen
(B)
Leonardo Bolognese
(L)
Martina Nesti
(M)
Pasquale Giovanni Notarstefano
(PG)
Simona D'Orazio
(S)
Franco Cosmi
(F)
Cecilia Becattini
(C)
Giancarlo Agnelli
(G)
Belinda Broccatelli
(B)
Maria Giulia Mosconi
(MG)
Maurizio Paciaroni
(M)
Chiara Urbini
(C)
Vito Maurizio Parato
(VM)
Camilla Notaristefani
(C)
Michele Scarano
(M)
Pietro Ameri
(P)
Giorgio Ghigliotti
(G)
Giulia Guglielmi
(G)
Roberta Lotti
(R)
Andrea Carlo Merlo
(AC)
Maria Lorenza Muiesan
(ML)
Andrea Abondio
(A)
Caterina Berasi
(C)
Elena Mattiuzzo
(E)
Claudio Mutti
(C)
Massimo Salvetti
(M)
Pasquale Pignatelli
(P)
Danilo Menichelli
(D)
Daniele Pastori
(D)
Eiji Tamiya
(E)
Takahiro Matsumoto
(T)
Tomosato Takabe
(T)
Shoichi Yamamoto
(S)
Haruyo Yamashita
(H)
Shinichi Higashiue
(S)
Onichi Furuya
(O)
Norihiko Hiramatsu
(N)
Kensuke Kasuga
(K)
Saburo Kojima
(S)
Masatoshi Komooka
(M)
Satoshi Kuroyanagi
(S)
Makoto Matsuura
(M)
Tetsushi Takemoto
(T)
Shuji Yamamoto
(S)
Katusmi Saito
(K)
Takuro Abe
(T)
Issei Ishida
(I)
Yuji Iwanami
(Y)
Shohei Kataoka
(S)
Tetsu Moriyama
(T)
Akira Murohashi
(A)
Akihito Sasaki
(A)
Yuichiro Nakamura
(Y)
Tetsuya Ueno
(T)
Akira Shimane
(A)
Tomoyo Hamana
(T)
Hirotoshi Ichibori
(H)
Tomohiro Inoue
(T)
Mitsuaki Itoh
(M)
Seigo Iwane
(S)
Hiroya Kawai
(H)
Tatsuya Kokawa
(T)
Akiko Masumoto
(A)
Koki Matsuo
(K)
Taishi Miyata
(T)
Shinsuke Nakano
(S)
Shogo Oishi
(S)
Tetsuari Onishi
(T)
Takahiro Sawada
(T)
Takayuki Saito
(T)
Mitsuhiko Shoda
(M)
Nobuyuki Takahashi
(N)
Tomofumi Takaya
(T)
Yasuyo Taniguchi
(Y)
Shota Tsukamoto
(S)
Yasue Tsukishiro
(Y)
Yoshiro Tsukiyama
(Y)
Hiroshi Tsunamoto
(H)
Kenzo Uzu
(K)
Hiroyuki Yamamoto
(H)
Tetsuya Yamamoto
(T)
Kiminobu Yokoi
(K)
Chiaki Yoshida
(C)
Nobuhiro Watanabe
(N)
Tetsuo Betsuyaku
(T)
Kumiko Adachi
(K)
Kouichi Awane
(K)
Daisuke Goto
(D)
Mamoru Sakakibara
(M)
Masashi Watanabe
(M)
Hideki Ueno
(H)
Yoshitaka Hiroe
(Y)
Koshi Matsuo
(K)
Kenji Ayata
(K)
Ko Fukuda
(K)
Yoshiki Hata
(Y)
Katsushi Hashimoto
(K)
Hiroaki Matsumi
(H)
Akira Nikaido
(A)
Shuichi Okamoto
(S)
Iveta Sime
(I)
Valters Stirna
(V)
Ilze Reinholde
(I)
Silvija Hansone
(S)
Anita Kozlovska
(A)
Janina Romanova
(J)
Dace Klincare
(D)
Natalja Pontaga
(N)
Igors Dirmans
(I)
Artis Kalnins
(A)
Dana Upite
(D)
Arcils Gersamija
(A)
Arturs Teleznikovs
(A)
Nadezda Rozkova
(N)
Jelena Safro
(J)
Ignasi Anguera Camós
(I)
Paolo Domenico Dallaglio
(P)
Rafael Salguero Bodes
(R)
Fernando Arnbas
(F)
Luis Borrego
(L)
Alvaro Marco
(A)
Javier Ramos Jimenez
(JR)
Juan José Gómez-Doblas
(JJ)
Alejandro Pérez Cabeza
(A)
Ignacio Ferreira Gonzålez
(I)
Javier Limeres Freire
(J)
Merce Lopez Grau
(M)
Xavier Viñolas Prat
(X)
Zoraida Moreno Weidmann
(Z)
Jose Maria Guerra Ramos
(JM)
Maria Concepcion Alonso Martin
(MC)
Bieito Campos Garcia
(B)
Javier Mauricio Mogro Carranza
(JM)
Francisco Javier Mendez Zurita
(FJ)
Enrique Rodriguez Font
(E)
Carlos Eduardo Gonzales Matos
(CE)
Víctor García Hernando
(V)
Carl-Johan Lindholm
(CJ)
Jörgen Thulin
(J)
Håkan Wallén
(H)
Kristina Hagwall
(K)
Ken Eliasson
(K)
Martin Lundvall
(M)
Jens Olsson
(J)
Björn Kjellman
(B)
Markus Lind
(M)
Lars Johansson
(L)
Niclas Svedberg
(N)
Stefan Berglund
(S)
Julia Söderberg
(J)
Christer Zedigh
(C)
Thomas Mooe
(T)
Mattias Axelsson
(M)
Emil Binsell
(E)
Daniel Huber
(D)
Christian Müller
(C)
Isabelle Danier
(I)
Michael Kühne
(M)
Bernhard Okamura
(B)
Hadrien Schoepfer
(H)
Cornelia Simmen
(C)
Tobias Reichlin
(T)
Laurève Chollet
(L)
Anna Lam
(A)
Severin Wittmer
(S)
Hans Rickli
(H)
Christian Gall
(C)
Greta Hametner
(G)
Stephanie Intorp
(S)
Daniel Luescher
(D)
Laurent Haegeli
(L)
Jan Christopher Berg
(JC)
Ramin Ebrahimi
(R)
Angelo Auricchio
(A)
Carmela Crljenica
(C)
Tizziano Moccetti
(T)
Cristina Monti
(C)
Elena Pasotti
(E)
Iveta Petrova
(I)
Mariagrazia Rossi
(M)
François Mach
(F)
Mehdi Namdar
(M)
Joris de Groot
(J)
Virginnio Proost
(V)
Joline Neefs
(J)
Dominik Linz
(D)
Twan van Stipdonk
(T)
Dennis den Uijl
(D)
Marco Alings
(M)
Jeroen Schaap
(J)
Dolf Segers
(D)
Noemi Wouters
(N)
Louis Bartels
(L)
Robert Tieleman
(R)
Ron Pisters
(R)
Tim de Vries
(T)
Jaap Selig
(J)
Aaf Kuijper
(A)
Pieter Bot
(P)
Mitran Keijzers
(M)
Gerardus Verdel
(G)
Raymond Tukkie
(R)
Ewout van den Bos
(E)
Floris Kauer
(F)
Rohit Oemrawsingh
(R)
Jeroen Stevenhagen
(J)
Jan van Es
(J)
Gregory Lip
(G)
Dhiraj Gupta
(D)
Agnieszka Kotalczyk
(A)
Anthony Gunstone
(A)
Richard David Brixey
(RD)
Diana Gorog
(D)
Danial Dinarvand
(D)
Ying Gue
(Y)
Rahim Kanji
(R)
Vassilios Memtsas
(V)
Roxy Senior
(R)
Gabriel Bioh
(G)
Yuk-Ki Wong
(YK)
Nick Child
(N)
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2022 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests JPP is supported by R01AG074185 from the National Institute on Aging. He also receives grants for clinical research from Abbott, the American Heart Association, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, iRhythm, and Philips, and serves as a consultant to Abbott, AbbVie, Ablacon, Altathera, Biotronik, Boston Scientific, Bristol Myers Squibb, LivaNova, Medtronic, Milestone, ElectroPhysiology Frontiers, Pfizer, Sanofi, Philips, and Up-to-Date. VC has research grants from Boehringer Ingelheim and is an advisory board member or consultant to Bayer, Boehringer Ingelheim, and Bristol Myers Squibb/Pfizer. SJC has received consulting honoraria and is involved in research grants related to atrial fibrillation, anticoagulation, bleeding, or stroke prevention with the following: Abbott, AstraZeneca, Alexion, Atricure, Bayer, Boston Scientific, Bristol Myers Squibb, Daiichi Sankyo, Javelin, and Pfizer. MRP has research grants from Bayer, Janssen, Novartis, Heartflow, the National Heart, Lung, and Blood Institute, the Moore Foundation, and Idorsia, and serves as an advisory board member or consultant to Bayer, Janssen, Novartis, and Medscape. All other authors declare no competing interests.