Nikola Sprigg1,2, Katie Flaherty1, Jason P Appleton1, Rustam Al-Shahi Salman3, Daniel Bereczki4, Maia Beridze5, Alfonso Ciccone6, Ronan Collins7, Robert A Dineen8,9, Lelia Duley10, Juan José Egea-Guerrero11, Timothy J England12, Michal Karlinski13, Kailash Krishnan1,2, Ann Charlotte Laska14, Zhe Kang Law1,2,15, Christian Ovesen16, Serefnur Ozturk17, Stuart J Pocock18, Ian Roberts19, Thompson G Robinson20, Christine Roffe21, Nils Peters22, Polly Scutt1, Jegan Thanabalan23, David Werring24,25, David Whynes26, Lisa Woodhouse1, Philip M Bath1,2. 1. Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK. 2. Stroke, Nottingham University Hospitals NHS Trust, Nottingham, UK. 3. Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK. 4. Department of Neurology, Semmelweis University, Budapest, Hungary. 5. The First University Clinic of Tbilisi State Medical University, Tbilisi, Georgia. 6. Neurology Unit, Azienda Socio Sanitaria Territoriale di Mantova, Mantua, Italy. 7. Stroke Service, Adelaide and Meath Hospital, Tallaght, Ireland. 8. Radiological Sciences, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK. 9. NIHR Nottingham Biomedical Research Centre, Nottingham, UK. 10. Nottingham Clinical Trials Unit, University of Nottingham, Nottingham, UK. 11. UGC de Medicina Intensiva, Hospital Universitario Virgen del Rocío, IBiS/CSIC/Universidad de Sevilla, Seville, Spain. 12. Vascular Medicine, Division of Medical Sciences & GEM, University of Nottingham, Derby, UK. 13. Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland. 14. Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden. 15. Department of Medicine, National University of Malaysia, Kuala Lumpur, Malaysia. 16. Bispebjerg and Frederiksberg Hospital, University of Copenhagen, Department of Neurology, Copenhagen, Denmark. 17. Department of Neurology, Selcuk University Medical Faculty, Konya, Turkey. 18. Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK. 19. Clinical Trials Unit, London School of Hygiene & Tropical Medicine, London, UK. 20. Department of Cardiovascular Sciences and NIHR Leicester Biomedical Research Centre, University of Leicester, Leicester, UK. 21. Stroke Research, Faculty of Medicine and Health Sciences, Keele University, Keele, UK. 22. Department of Neurology and Stroke Center, University Hospital Basel, Basel, Switzerland. 23. Division of Neurosurgery, Department of Surgery, National University of Malaysia, Kuala Lumpur, Malaysia. 24. Stroke Research Centre, University College London Queen Square Institute of Neurology, Faculty of Brain Sciences of University College London, University College London, London, UK. 25. National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK. 26. School of Economics, University of Nottingham, Nottingham, UK.
Abstract
BACKGROUND:Tranexamic acid reduces death due to bleeding after trauma and postpartum haemorrhage. OBJECTIVE: The aim of the study was to assess if tranexamic acid is safe, reduces haematoma expansion and improves outcomes in adults with spontaneous intracerebral haemorrhage (ICH). DESIGN: The TICH-2 (Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage) study was a pragmatic, Phase III, prospective, double-blind, randomised placebo-controlled trial. SETTING: Acute stroke services at 124 hospitals in 12 countries (Denmark, Georgia, Hungary, Ireland, Italy, Malaysia, Poland, Spain, Sweden, Switzerland, Turkey and the UK). PARTICIPANTS: Adult patients (aged ≥ 18 years) with ICH within 8 hours of onset. EXCLUSION CRITERIA: Exclusion criteria were ICH secondary to anticoagulation, thrombolysis, trauma or a known underlying structural abnormality; patients for whom tranexamic acid was thought to be contraindicated; prestroke dependence (i.e. patients with a modified Rankin Scale [mRS] score > 4); life expectancy < 3 months; and a Glasgow Coma Scale score of < 5. INTERVENTIONS: Participants, allocated by randomisation, received 1 g of an intravenous tranexamic acid bolus followed by an 8-hour 1-g infusion or matching placebo (i.e. 0.9% saline). MAIN OUTCOME MEASURE: The primary outcome was functional status (death or dependency) at day 90, which was measured by the shift in the mRS score, using ordinal logistic regression, with adjustment for stratification and minimisation criteria. RESULTS: A total of 2325 participants (tranexamic acid, n = 1161; placebo, n = 1164) were recruited from 124 hospitals in 12 countries between 2013 and 2017. Treatment groups were well balanced at baseline. The primary outcome was determined for 2307 participants (tranexamic acid, n = 1152; placebo, n = 1155). There was no statistically significant difference between the treatment groups for the primary outcome of functional status at day 90 [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.76 to 1.03; p = 0.11]. Although there were fewer deaths by day 7 in the tranexamic acid group (aOR 0.73, 95% CI 0.53 to 0.99; p = 0.041), there was no difference in case fatality at 90 days (adjusted hazard ratio 0.92, 95% CI 0.77 to 1.10; p = 0.37). Fewer patients experienced serious adverse events (SAEs) after treatment with tranexamic acid than with placebo by days 2 (p = 0.027), 7 (p = 0.020) and 90 (p = 0.039). There was no increase in thromboembolic events or seizures. LIMITATIONS: Despite attempts to enrol patients rapidly, the majority of participants were enrolled and treated > 4.5 hours after stroke onset. Pragmatic inclusion criteria led to a heterogeneous population of participants, some of whom had very large strokes. Although 12 countries enrolled participants, the majority (82.1%) were from the UK. CONCLUSIONS:Tranexamic acid did not affect a patient's functional status at 90 days after ICH, despite there being significant modest reductions in early death (by 7 days), haematoma expansion and SAEs, which is consistent with an antifibrinolytic effect. Tranexamic acid was safe, with no increase in thromboembolic events. FUTURE WORK: Future work should focus on enrolling and treating patients early after stroke and identify which participants are most likely to benefit from haemostatic therapy. Large randomised trials are needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN93732214. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 35. See the NIHR Journals Library website for further project information. The project was also funded by the Pragmatic Trials, UK, funding call and the Swiss Heart Foundation in Switzerland.
RCT Entities:
BACKGROUND:Tranexamic acid reduces death due to bleeding after trauma and postpartum haemorrhage. OBJECTIVE: The aim of the study was to assess if tranexamic acid is safe, reduces haematoma expansion and improves outcomes in adults with spontaneous intracerebral haemorrhage (ICH). DESIGN: The TICH-2 (Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage) study was a pragmatic, Phase III, prospective, double-blind, randomised placebo-controlled trial. SETTING: Acute stroke services at 124 hospitals in 12 countries (Denmark, Georgia, Hungary, Ireland, Italy, Malaysia, Poland, Spain, Sweden, Switzerland, Turkey and the UK). PARTICIPANTS: Adult patients (aged ≥ 18 years) with ICH within 8 hours of onset. EXCLUSION CRITERIA: Exclusion criteria were ICH secondary to anticoagulation, thrombolysis, trauma or a known underlying structural abnormality; patients for whom tranexamic acid was thought to be contraindicated; prestroke dependence (i.e. patients with a modified Rankin Scale [mRS] score > 4); life expectancy < 3 months; and a Glasgow Coma Scale score of < 5. INTERVENTIONS:Participants, allocated by randomisation, received 1 g of an intravenous tranexamic acid bolus followed by an 8-hour 1-g infusion or matching placebo (i.e. 0.9% saline). MAIN OUTCOME MEASURE: The primary outcome was functional status (death or dependency) at day 90, which was measured by the shift in the mRS score, using ordinal logistic regression, with adjustment for stratification and minimisation criteria. RESULTS: A total of 2325 participants (tranexamic acid, n = 1161; placebo, n = 1164) were recruited from 124 hospitals in 12 countries between 2013 and 2017. Treatment groups were well balanced at baseline. The primary outcome was determined for 2307 participants (tranexamic acid, n = 1152; placebo, n = 1155). There was no statistically significant difference between the treatment groups for the primary outcome of functional status at day 90 [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.76 to 1.03; p = 0.11]. Although there were fewer deaths by day 7 in the tranexamic acid group (aOR 0.73, 95% CI 0.53 to 0.99; p = 0.041), there was no difference in case fatality at 90 days (adjusted hazard ratio 0.92, 95% CI 0.77 to 1.10; p = 0.37). Fewer patients experienced serious adverse events (SAEs) after treatment with tranexamic acid than with placebo by days 2 (p = 0.027), 7 (p = 0.020) and 90 (p = 0.039). There was no increase in thromboembolic events or seizures. LIMITATIONS: Despite attempts to enrol patients rapidly, the majority of participants were enrolled and treated > 4.5 hours after stroke onset. Pragmatic inclusion criteria led to a heterogeneous population of participants, some of whom had very large strokes. Although 12 countries enrolled participants, the majority (82.1%) were from the UK. CONCLUSIONS:Tranexamic acid did not affect a patient's functional status at 90 days after ICH, despite there being significant modest reductions in early death (by 7 days), haematoma expansion and SAEs, which is consistent with an antifibrinolytic effect. Tranexamic acid was safe, with no increase in thromboembolic events. FUTURE WORK: Future work should focus on enrolling and treating patients early after stroke and identify which participants are most likely to benefit from haemostatic therapy. Large randomised trials are needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN93732214. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 35. See the NIHR Journals Library website for further project information. The project was also funded by the Pragmatic Trials, UK, funding call and the Swiss Heart Foundation in Switzerland.
Authors: Zhe Kang Law; Jason P Appleton; Polly Scutt; Ian Roberts; Rustam Al-Shahi Salman; Timothy J England; David J Werring; Thompson Robinson; Kailash Krishnan; Robert A Dineen; Ann Charlotte Laska; Philippe A Lyrer; Juan Jose Egea-Guerrero; Michal Karlinski; Hanne Christensen; Christine Roffe; Daniel Bereczki; Serefnur Ozturk; Jegan Thanabalan; Ronan Collins; Maia Beridze; Alfonso Ciccone; Lelia Duley; Angela Shone; Philip M Bath; Nikola Sprigg Journal: Stroke Date: 2021-12-01 Impact factor: 7.914
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