Tranexamic acid in patients with intracerebral haemorrhage (STOP-AUST): a multicentre, randomised, placebo-controlled, phase 2 trial.

Aged Aged, 80 and over Antifibrinolytic Agents / administration & dosage Cerebral Hemorrhage / diagnostic imaging Double-Blind Method Female Humans Male Middle Aged Outcome Assessment, Health Care Prospective Studies Tranexamic Acid / administration & dosage

Journal

The Lancet. Neurology
ISSN: 1474-4465
Titre abrégé: Lancet Neurol
Pays: England
ID NLM: 101139309

Informations de publication

Date de publication:
12 2020
Historique:
received: 18 08 2020
revised: 08 09 2020
accepted: 22 09 2020
pubmed: 1 11 2020
medline: 15 12 2020
entrez: 31 10 2020
Statut: ppublish

Résumé

Despite intracerebral haemorrhage causing 5% of deaths worldwide, few evidence-based therapeutic strategies other than stroke unit care exist. Tranexamic acid decreases haemorrhage in conditions such as acute trauma and menorrhoea. We aimed to assess whether tranexamic acid reduces intracerebral haemorrhage growth in patients with acute intracerebral haemorrhage. We did a prospective, double-blind, randomised, placebo-controlled, investigator-led, phase 2 trial at 13 stroke centres in Australia, Finland, and Taiwan. Patients were eligible if they were aged 18 years or older, had an acute intracerebral haemorrhage fulfilling clinical criteria (eg, Glasgow Coma Scale score of >7, intracerebral haemorrhage volume <70 mL, no identified or suspected secondary cause of intracerebral haemorrhage, no thrombotic events within the previous 12 months, no planned surgery in the next 24 h, and no use of anticoagulation), had contrast extravasation on CT angiography (the so-called spot sign), and were treatable within 4·5 h of symptom onset and within 1 h of CT angiography. Patients were randomly assigned (1:1) to receive either 1 g of intravenous tranexamic acid over 10 min followed by 1 g over 8 h or matching placebo, started within 4·5 h of symptom onset. Randomisation was done using a centralised web-based procedure with randomly permuted blocks of varying size. All patients, investigators, and staff involved in patient management were masked to treatment. The primary outcome was intracerebral haemorrhage growth (>33% relative or >6 mL absolute) at 24 h. The primary and safety analyses were done in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT01702636). Between March 1, 2013, and Aug 13, 2019, we enrolled and randomly assigned 100 participants to the tranexamic acid group (n=50) or the placebo group (n=50). Median age was 71 years (IQR 57-79) and median intracerebral haemorrhage volume was 14·6 mL (7·9-32·7) at baseline. The primary outcome was not different between the two groups: 26 (52%) patients in the placebo group and 22 (44%) in the tranexamic acid group had intracerebral haemorrhage growth (odds ratio [OR] 0·72 [95% CI 0·32-1·59], p=0·41). There was no evidence of a difference in the proportions of patients who died or had thromboembolic complications between the groups: eight (16%) in the placebo group vs 13 (26%) in the tranexamic acid group died and two (4%) vs one (2%) had thromboembolic complications. None of the deaths was considered related to study medication. Our study does not provide evidence that tranexamic acid prevents intracerebral haemorrhage growth, although the treatment was safe with no increase in thromboembolic complications. Larger trials of tranexamic acid, with simpler recruitment methods and an earlier treatment window, are justified. National Health and Medical Research Council, Royal Melbourne Hospital Foundation.

Sections du résumé

BACKGROUND
Despite intracerebral haemorrhage causing 5% of deaths worldwide, few evidence-based therapeutic strategies other than stroke unit care exist. Tranexamic acid decreases haemorrhage in conditions such as acute trauma and menorrhoea. We aimed to assess whether tranexamic acid reduces intracerebral haemorrhage growth in patients with acute intracerebral haemorrhage.
METHODS
We did a prospective, double-blind, randomised, placebo-controlled, investigator-led, phase 2 trial at 13 stroke centres in Australia, Finland, and Taiwan. Patients were eligible if they were aged 18 years or older, had an acute intracerebral haemorrhage fulfilling clinical criteria (eg, Glasgow Coma Scale score of >7, intracerebral haemorrhage volume <70 mL, no identified or suspected secondary cause of intracerebral haemorrhage, no thrombotic events within the previous 12 months, no planned surgery in the next 24 h, and no use of anticoagulation), had contrast extravasation on CT angiography (the so-called spot sign), and were treatable within 4·5 h of symptom onset and within 1 h of CT angiography. Patients were randomly assigned (1:1) to receive either 1 g of intravenous tranexamic acid over 10 min followed by 1 g over 8 h or matching placebo, started within 4·5 h of symptom onset. Randomisation was done using a centralised web-based procedure with randomly permuted blocks of varying size. All patients, investigators, and staff involved in patient management were masked to treatment. The primary outcome was intracerebral haemorrhage growth (>33% relative or >6 mL absolute) at 24 h. The primary and safety analyses were done in the intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT01702636).
FINDINGS
Between March 1, 2013, and Aug 13, 2019, we enrolled and randomly assigned 100 participants to the tranexamic acid group (n=50) or the placebo group (n=50). Median age was 71 years (IQR 57-79) and median intracerebral haemorrhage volume was 14·6 mL (7·9-32·7) at baseline. The primary outcome was not different between the two groups: 26 (52%) patients in the placebo group and 22 (44%) in the tranexamic acid group had intracerebral haemorrhage growth (odds ratio [OR] 0·72 [95% CI 0·32-1·59], p=0·41). There was no evidence of a difference in the proportions of patients who died or had thromboembolic complications between the groups: eight (16%) in the placebo group vs 13 (26%) in the tranexamic acid group died and two (4%) vs one (2%) had thromboembolic complications. None of the deaths was considered related to study medication.
INTERPRETATION
Our study does not provide evidence that tranexamic acid prevents intracerebral haemorrhage growth, although the treatment was safe with no increase in thromboembolic complications. Larger trials of tranexamic acid, with simpler recruitment methods and an earlier treatment window, are justified.
FUNDING
National Health and Medical Research Council, Royal Melbourne Hospital Foundation.

Identifiants

DOI: 10.1016/S1474-4422(20)30369-0 PMID: 33128912
pubmed: 33128912
pii: S1474-4422(20)30369-0
doi: 10.1016/S1474-4422(20)30369-0
pii:
doi:

Substances chimiques

Antifibrinolytic Agents 0
Tranexamic Acid 6T84R30KC1

Banques de données

ClinicalTrials.gov
['NCT01702636']

Types de publication

Journal Article Multicenter Study Randomized Controlled Trial Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

980-987

Subventions

Organisme : CIHR
ID : 362185
Pays : Canada

Commentaires et corrections

Type : CommentIn
Type : CommentIn

Informations de copyright

Copyright © 2020 Elsevier Ltd. All rights reserved.

Auteurs

Atte Meretoja (A)

The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia; Departments of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia; Department of Neurology, Helsinki University Hospital, Helsinki, Finland. Electronic address: atte.meretoja@hus.fi.

Nawaf Yassi (N)

The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia; Departments of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia; Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.

Teddy Y Wu (TY)

Departments of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia; New Zealand Brain Research Institute, Christchurch, New Zealand.

Leonid Churilov (L)

Departments of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia; Department of Mathematics and Statistics, University of Melbourne, Melbourne, VIC, Australia.

Gerli Sibolt (G)

Department of Neurology, Helsinki University Hospital, Helsinki, Finland.

Jiann-Shing Jeng (JS)

Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.

Timothy Kleinig (T)

Department of Neurology, Royal Adelaide Hospital, Adelaide, SA, Australia.

Neil J Spratt (NJ)

Department of Neurology, John Hunter Hospital, University of Newcastle, Newcastle, NSW, Australia.

Vincent Thijs (V)

The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia; Department of Neurology, Austin Hospital, Heidelberg, VIC, Australia.

Tissa Wijeratne (T)

Department of Neurology, Western Hospital, Melbourne, VIC, Australia.

Der-Yang Cho (DY)

Department of Neurosurgery, China Medical University Hospital, Taichung, Taiwan.

Darshan Shah (D)

Department of Neurology, Princess Alexandra Hospital, Woolloongabba, QLD, Australia.

Geoffrey C Cloud (GC)

Department of Neurology, Alfred Hospital, Monash University, Melbourne, VIC, Australia; Department of Clinical Neuroscience, Central Clinical School, Monash University, Melbourne, VIC, Australia.

Thanh Phan (T)

Department of Neurology, Monash Medical Centre, Monash University, Melbourne, VIC, Australia; School of Clinical Sciences, Monash University, Melbourne, VIC, Australia.

Christopher Bladin (C)

The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia; Department of Neurosciences, Eastern Health Medical School, Monash University, Melbourne, VIC, Australia; Ambulance Victoria, Melbourne, VIC, Australia.

Andrew Moey (A)

Department of Neurology, Lyell McEwin Hospital, Adelaide, SA, Australia.

Richard I Aviv (RI)

Department of Radiology, Neuroradiology Section, The Ottawa Hospital and University of Ottawa, Ottawa, ON, Canada.

Christen D Barras (CD)

Department of Radiology, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia; South Australian Health and Medical Research Institute, The University of Adelaide, Adelaide, SA, Australia.

Gagan Sharma (G)

Department of Radiology, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia.

Chung Y Hsu (CY)

Department of Neurology, China Medical University Hospital, Taichung, Taiwan.

Henry Ma (H)

Department of Neurology, Monash Medical Centre, Monash University, Melbourne, VIC, Australia; School of Clinical Sciences, Monash University, Melbourne, VIC, Australia.

Bruce C V Campbell (BCV)

The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia; Departments of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia.

Peter Mitchell (P)

Department of Radiology, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia.

Bernard Yan (B)

Departments of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia.

Mark W Parsons (MW)

Departments of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia.

Marjaana Tiainen (M)

Department of Neurology, Helsinki University Hospital, Helsinki, Finland.

Sami Curtze (S)

Department of Neurology, Helsinki University Hospital, Helsinki, Finland.

Daniel Strbian (D)

Department of Neurology, Helsinki University Hospital, Helsinki, Finland.

Sung-Chun Tang (SC)

Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.

Jackson Harvey (J)

Department of Neurology, Royal Adelaide Hospital, Adelaide, SA, Australia.

Christopher Levi (C)

Department of Neurology, John Hunter Hospital, University of Newcastle, Newcastle, NSW, Australia; Sydney Partnership for Health, Education, Research and Enterprise (SPHERE), Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.

Geoffrey A Donnan (GA)

The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia; Departments of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia.

Stephen M Davis (SM)

Departments of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia.

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Tranexamic acid in patients with intracerebral...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Sujet âgé de 80 ans ou plus › Tranexamic acid in patients with intracerebral...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Agents hématologiques › Coagulants › Hémostatiques › Antifibrinolytiques › Tranexamic acid in patients with intracerebral...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Hémorragie › Hémorragies intracrâniennes › Hémorragie cérébrale › Tranexamic acid in patients with intracerebral...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Méthodologie en recherche épidémiologique › Méthode en double aveugle › Tranexamic acid in patients with intracerebral...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Tranexamic acid in patients with intracerebral...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Tranexamic acid in patients with intracerebral...
questionsmedicales.fr › Qualité, accès, évaluation des soins de santé › Qualité des soins de santé › Mécanismes d'évaluation des soins de santé › Évaluation des résultats et des processus en soins de santé › Évaluation de résultat (soins) › Tranexamic acid in patients with intracerebral...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Études prospectives › Tranexamic acid in patients with intracerebral...
questionsmedicales.fr › Composés chimiques organiques › Acides carboxyliques › Acides carbocycliques › Acide tranéxamique › Tranexamic acid in patients with intracerebral...