PMID- 36063821
OWN - NLM
STAT- MEDLINE
DCOM- 20220928
LR  - 20220930
IS  - 1474-547X (Electronic)
IS  - 0140-6736 (Linking)
VI  - 400
IP  - 10357
DP  - 2022 Sep 24
TI  - Factor XIa inhibition with asundexian after acute non-cardioembolic ischaemic 
      stroke (PACIFIC-Stroke): an international, randomised, double-blind, 
      placebo-controlled, phase 2b trial.
PG  - 997-1007
LID - S0140-6736(22)01588-4 [pii]
LID - 10.1016/S0140-6736(22)01588-4 [doi]
AB  - BACKGROUND: Asundexian (Bayer AG, Leverkusen, Germany), an oral small molecule 
      factor XIa (FXIa) inhibitor, might prevent thrombosis without increasing 
      bleeding. Asundexian's effect for secondary prevention of recurrent stroke is 
      unknown. METHODS: In this randomised, double-blind, placebo-controlled, phase 2b 
      dose-finding trial (PACIFIC-Stroke), patients with acute (within 48 h) 
      non-cardioembolic ischaemic stroke were recruited from 196 hospitals in 23 
      countries. Patients were eligible if they were aged 45 years or older, to be 
      treated with antiplatelet therapy, and able to have a baseline MRI (either before 
      or within 72 h of randomisation). Eligible participants were randomly assigned 
      (1:1:1:1), using an interactive web-based response system and stratified 
      according to anticipated antiplatelet therapy (single vs dual), to once daily 
      oral asundexian (BAY 2433334) 10 mg, 20 mg, or 50 mg, or placebo in addition to 
      usual antiplatelet therapy, and were followed up during treatment for 26-52 
      weeks. Brain MRIs were obtained at study entry and at 26 weeks or as soon as 
      possible after treatment discontinuation. The primary efficacy outcome was the 
      dose-response effect on the composite of incident MRI-detected covert brain 
      infarcts and recurrent symptomatic ischaemic stroke at or before 26 weeks after 
      randomisation. The primary safety outcome was major or clinically relevant 
      non-major bleeding as defined by International Society on Thrombosis and 
      Haemostasis criteria. The efficacy outcome was assessed in all participants 
      assigned to treatment, and the safety outcome was assessed in all participants 
      who received at least one dose of study treatment. This study is registered with 
      ClinicalTrials.gov, NCT04304508, and is now complete. FINDINGS: Between June 15, 
      2020, and July 22, 2021, 1880 patients were screened and 1808 participants were 
      randomly assigned to asundexian 10 mg (n=455), 20 mg (n=450), or 50 mg (n=447), 
      or placebo (n=456). Mean age was 67 years (SD 10) and 615 (34%) participants were 
      women, 1193 (66%) were men, 1505 (83%) were White, and 268 (15%) were Asian. The 
      mean time from index stroke to randomisation was 36 h (SD 10) and median baseline 
      National Institutes of Health Stroke Scale score was 2.0 (IQR 1.0-4.0). 783 (43%) 
      participants received dual antiplatelet treatment for a mean duration of 70.1 
      days (SD 113.4) after randomisation. At 26 weeks, the primary efficacy outcome 
      was observed in 87 (19%) of 456 participants in the placebo group versus 86 (19%) 
      of 455 in the asundexian 10 mg group (crude incidence ratio 0.99 [90% CI 
      0.79-1.24]), 99 (22%) of 450 in the asundexian 20 mg group (1.15 [0.93-1.43]), 
      and 90 (20%) of 447 in the asundexian 50 mg group (1.06 [0.85-1.32]; t statistic 
      -0.68; p=0.80). The primary safety outcome was observed in 11 (2%) of 452 
      participants in the placebo group versus 19 (4%) of 445 in the asundexian 10 mg 
      group, 14 (3%) of 446 in the asundexian 20 mg group, and 19 (4%) of 443 in the 
      asundexian 50 mg group (all asundexian doses pooled vs placebo hazard ratio 1.57 
      [90% CI 0.91-2.71]). INTERPRETATION: In this phase 2b trial, FXIa inhibition with 
      asundexian did not reduce the composite of covert brain infarction or ischaemic 
      stroke and did not increase the composite of major or clinically relevant 
      non-major bleeding compared with placebo in patients with acute, 
      non-cardioembolic ischaemic stroke. FUNDING: Bayer AG.
CI  - Copyright (c) 2022 Elsevier Ltd. All rights reserved.
FAU - Shoamanesh, Ashkan
AU  - Shoamanesh A
AD  - Division of Neurology, McMaster University, Population Health Research Institute, 
      Hamilton, ON, Canada. Electronic address: ashkan.shoamanesh@phri.ca.
FAU - Mundl, Hardi
AU  - Mundl H
AD  - TA Thrombosis and Vascular Medicine, Bayer AG, Wuppertal, Germany.
FAU - Smith, Eric E
AU  - Smith EE
AD  - Department of Clinical Neurosciences, Hotchkiss Brain Institute, Cumming School 
      of Medicine, University of Calgary, Calgary, AB, Canada; Department of Radiology, 
      Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, 
      Calgary, AB, Canada.
FAU - Masjuan, Jaime
AU  - Masjuan J
AD  - Neurology Department, Hospital Universitario Ramon y Cajal, Madrid, Spain; 
      Departamento de Medicina, Facultad de Medicina, Universidad de Alcala, IRYCIS, 
      RICORS-ICTUS, Madrid, Spain.
FAU - Milanov, Ivan
AU  - Milanov I
AD  - Medical University, University Hospital for Neurology and Psychiatry "St Naum", 
      Sofia, Bulgaria.
FAU - Hirano, Teruyuki
AU  - Hirano T
AD  - Department of Stroke and Cerebrovascular Medicine, School of Medicine, Kyorin 
      University, Tokyo, Japan.
FAU - Agafina, Alina
AU  - Agafina A
AD  - Clinical Research Department, City Hospital #40, Saint Petersburg, Russia.
FAU - Campbell, Bruce
AU  - Campbell B
AD  - Department of Medicine and Neurology, Melbourne Brain Centre at the Royal 
      Melbourne Hospital, University of Melbourne, Parkville, VIC, Australia.
FAU - Caso, Valeria
AU  - Caso V
AD  - Stroke Unit, Santa Maria della Misericordia Hospital, University of Perugia, 
      Perugia, Italy.
FAU - Mas, Jean-Louis
AU  - Mas JL
AD  - Department of Neurology, GHU Paris, Hopital Sainte-Anne, Universite Paris-Cite, 
      Inserm U1266, Paris, France.
FAU - Dong, Qiang
AU  - Dong Q
AD  - Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
FAU - Turcani, Peter
AU  - Turcani P
AD  - 1st Department of Neurology, Medical Faculty, Comenius University, Bratislava, 
      Slovakia.
FAU - Christensen, Hanne
AU  - Christensen H
AD  - Department of Neurology, University Hospital of Copenhagen, Bispebjerg, Denmark.
FAU - Ferro, Jose M
AU  - Ferro JM
AD  - Instituto de Medicina Molecular Joao Lobo Antunes, Faculdade de Medicina, 
      Universidade de Lisboa, Lisbon, Portugal.
FAU - Veltkamp, Roland
AU  - Veltkamp R
AD  - Neurology Department, Alfried-Krupp Hospital, Essen, Germany.
FAU - Mikulik, Robert
AU  - Mikulik R
AD  - International Clinical Research Center and Neurology Department, St Anne's 
      University Hospital, Brno, Czech Republic; Medical Faculty, Masaryk University, 
      Brno, Czech Republic.
FAU - De Marchis, Gian Marco
AU  - De Marchis GM
AD  - Department of Neurology and Stroke Center, University Hospital of Basel and 
      University of Basel, Basel, Switzerland.
FAU - Robinson, Thompson
AU  - Robinson T
AD  - College of Life Sciences, University of Leicester, Leicester, UK.
FAU - Lemmens, Robin
AU  - Lemmens R
AD  - Department of Neurosciences, Experimental Neurology, KU Leuven - University of 
      Leuven, Leuven, Belgium; VIB-KU Leuven Center for Brain and Disease Research, 
      Leuven, Belgium; Department of Neurology, University Hospitals Leuven, Leuven, 
      Belgium.
FAU - Stepien, Adam
AU  - Stepien A
AD  - Department of Neurology, Military Institute of Medicine, Warsaw, Poland.
FAU - Greisenegger, Stefan
AU  - Greisenegger S
AD  - Department of Neurology, Medical University of Vienna, Vienna, Austria.
FAU - Roine, Risto
AU  - Roine R
AD  - Division of Clinical Neurosciences, University of Turku, Turku, Finland.
FAU - Csiba, Laszlo
AU  - Csiba L
AD  - DE Clinical Center (DEKK), Health Service Units, Clinics, Department of 
      Neurology, University of Debrecen, Debrecen, Hungary.
FAU - Khatri, Pooja
AU  - Khatri P
AD  - Department of Neurology and Rehabilitation Sciences, University of Cincinnati, 
      Cincinnati, OH, USA.
FAU - Coutinho, Jonathan
AU  - Coutinho J
AD  - Department of Neurology, Amsterdam UMC, University of Amsterdam, Amsterdam, 
      Netherlands.
FAU - Lindgren, Arne G
AU  - Lindgren AG
AD  - Department of Clinical Sciences Lund (Neurology), Lund University, Lund, Sweden; 
      Department of Neurology, Skane University Hospital, Lund, Sweden.
FAU - Demchuk, Andrew M
AU  - Demchuk AM
AD  - Department of Clinical Neurosciences, Hotchkiss Brain Institute, Cumming School 
      of Medicine, University of Calgary, Calgary, AB, Canada; Department of Radiology, 
      Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, 
      Calgary, AB, Canada.
FAU - Colorado, Pablo
AU  - Colorado P
AD  - Bayer US Pharmaceuticals, Whippany, NJ, USA.
FAU - Kirsch, Bodo
AU  - Kirsch B
AD  - Statistics and Data Insights, Bayer AG, Berlin, Germany.
FAU - Neumann, Christoph
AU  - Neumann C
AD  - Bayer AG, Wuppertal, Germany.
FAU - Heenan, Laura
AU  - Heenan L
AD  - Department of Statistics, McMaster University, Population Health Research 
      Institute, Hamilton, ON, Canada.
FAU - Xu, Lizhen
AU  - Xu L
AD  - Department of Statistics, McMaster University, Population Health Research 
      Institute, Hamilton, ON, Canada.
FAU - Connolly, Stuart J
AU  - Connolly SJ
AD  - Department of Medicine, McMaster University, Population Health Research 
      Institute, Hamilton, ON, Canada.
FAU - Hart, Robert G
AU  - Hart RG
AD  - Division of Neurology, McMaster University, Population Health Research Institute, 
      Hamilton, ON, Canada.
CN  - PACIFIC-Stroke Investigators
LA  - eng
SI  - ClinicalTrials.gov/NCT04304508
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20220902
PL  - England
TA  - Lancet
JT  - Lancet (London, England)
JID - 2985213R
RN  - 0 (Anticoagulants)
RN  - 0 (Platelet Aggregation Inhibitors)
RN  - EC 3.4.21.27 (Factor XIa)
SB  - IM
MH  - Aged
MH  - Anticoagulants/therapeutic use
MH  - *Brain Ischemia/drug therapy/prevention & control
MH  - Double-Blind Method
MH  - Factor XIa
MH  - Female
MH  - Hemorrhage/chemically induced/drug therapy
MH  - Humans
MH  - *Ischemic Stroke
MH  - Male
MH  - Platelet Aggregation Inhibitors/therapeutic use
MH  - *Stroke/drug therapy/prevention & control
MH  - *Thrombosis
MH  - Treatment Outcome
COIS- Declaration of interests All coauthors or their institutions received financial 
      support from Bayer for participation in the PACIFIC-Stroke trial except HM, PC, 
      BK, and CN who are employees of Bayer. HM, PC, BK, and CN do not hold any stock 
      or stock options with Bayer.
EDAT- 2022/09/06 06:00
MHDA- 2022/09/28 06:00
CRDT- 2022/09/05 19:02
PHST- 2022/06/29 00:00 [received]
PHST- 2022/08/12 00:00 [revised]
PHST- 2022/08/12 00:00 [accepted]
PHST- 2022/09/06 06:00 [pubmed]
PHST- 2022/09/28 06:00 [medline]
PHST- 2022/09/05 19:02 [entrez]
AID - S0140-6736(22)01588-4 [pii]
AID - 10.1016/S0140-6736(22)01588-4 [doi]
PST - ppublish
SO  - Lancet. 2022 Sep 24;400(10357):997-1007. doi: 10.1016/S0140-6736(22)01588-4. Epub 
      2022 Sep 2.