Tranexamic acid for intracerebral haemorrhage: (TICH-2) trial. Nikola Sprigg On behalf of the TICH-2 investigators

Transcription

1 Tranexamic acid for intracerebral haemorrhage: (TICH-2) trial Nikola Sprigg On behalf of the TICH-2 investigators

2 Disclosures TICH-2 funded by National Institute of Health Research Health Technology Assessment (NIHR HTA project code 11_129_109), and Swiss Heart Foundation. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

3 TICH-2 would not have been possible TICH-2 participants and families Nottingham Stroke Research Partnership Group Christine Knott and Malcolm Jarvis Prof Philip Bath TICH-2 Deputy CI TICH-2 Trials team in Nottingham Sally Utton, Diane Havard, Hayley Foster, Pauline Hyman- Taylor Sponsor's representative: Angela Shone (University of Nottingham) Protocol development - Alexandra Erven, Gillian Bumphrey, Diane Whitham (Nottingham Clinical Trials Unit) Independent Steering Committee Prof Colin Baigent (Chair, Oxford), Prof Yvo Roos (Amsterdam), Prof Matthew Walters (Glasgow), Christine Knott (Nottingham) Data Monitoring Committee Data Monitoring Committee John Bamford (Chair, Leeds), Martin Bland (York), Graham Venables (Sheffield), Wei Tan Events (outcome, SAE) Adjudicators Timothy England (Derby), Amit Mistri (Nottingham) Neuroimaging Adjudicators Lead Robert Dineen (Nottingham), Alessandro Adami (Italy), Lesley Cala (Australia), Ana Casado (Edinburgh), Rebecca Gallagher (Leicester) TICH-2 Collaborators in UK Ass Prof Tim England, Ass Prof Rob Dineen, Prof David Whynes, Prof Leila Duley, Prof Tom Robinson, Prof Stuart J Pocock, Prof Ian Roberts Prof Christine Roffe, Prof David Werring, Rustam Al-Shahi Salman TICH-2 International Advisory Committee Denmark Prof Christensen, Georgia Prof Beridze, Hungary Prof Bereczki, Italy Prof Ciccone, Malaysia J Thanabalan, Poland Prof Czlonkowska, Republic of Ireland R Collins, Spain Prof Egea-Guerrero, Switzerland Prof Lyrer, Turkey Prof Ozturk The TICH-2 sites THANK YOU TO EVERYONE

4 Intracerebral haemorrhage Significant early mortality and morbidity Haematoma expansion occurs early and is associated with bad outcome Preventing haematoma expansion may improve outcome Spot sign may predict haematoma expansion 1 but not routinely performed Haemostatic approaches: Recombinant Factor VIIa no evidence of benefit on functional outcome despite reduction in haematoma expansion 2 Tranexamic acid - anti-fibrinolytic reduces death due to bleeding in trauma and post partum haemorrhage 3 Intensive BP lowering improved functional outcome despite no significant effect on haematoma expansion [1] Demchuck et al. Lancet Neurol 2012 [2] Al Shahi-Salman et al. Cochrane 2018 [3] Gayet-Ageron et al. Lancet 2018

5 Methods

6 Design: Participants Multi-centre, double-blind, blinded-outcome, placebo-controlled trial Inclusion: Adult no upper age limit Spontaneous intracerebral haemorrhage <8 hours symptom onset Exclusion: Secondary ICH (e.g. anticoagulation, AVM, tumour, trauma, SAH) Contra-indication to tranexamic acid (VTE) Pregnancy (do pregnancy test if unsure) Pre-morbid disability (mrs >4) Glasgow coma scale <5 Life expectancy < 3 months due to other disease (e.g. advanced metastatic cancer) Consent: Written informed consent from each participant if they had capacity If participants could not give consent, a relative or representative gave proxy consent in accordance with ethics approval in each country

7 Study procedures Intervention: Tranexamic acid 1g/10 mins,1g/8 hours iv (Sharp plc) Comparator: Placebo identical regime Primary outcome: Primary outcome: modified Rankin Scale at day 90 (central telephone) Pre-specified secondary outcomes: Radiological Haematoma expansion, change in haematoma volume Haematoma expansion defined >6mls or 33% change Safety Early death, serious adverse events, safety outcomes (DVT, PE, MI, ACS, Seizures) Function Barthel index, cognition, mood, HRQOL all day 90 Treatment allocation was concealed from all staff involved in the trial Adopted in UK by National Institute Health Research Clinical Research Network, and registered as ISRCTN

8 Statistical methods Sample size 2000 participants 1,2 : assuming significance of 5%, power of 90%, ordinal odds ratio of 0 79 Randomisation 1:1 by internet: stratification by country and minimisation on key prognostic factors: age; sex; time since onset; systolic blood pressure; stroke severity (NIHSS); IVH; known history of antiplatelet treatment. Analysis of primary outcome: shift in modified Rankin Scale at day 90 using ordinal logistic regression, with adjustment for stratification and minimisation criteria Analyses followed the intention-to-treat (ITT) principle Pre-specified subgroups: age, time, systolic blood pressure, NIHSS score, presence of IVH, history of antiplatelet treatment, spot sign on CT angiography, ICH location and ethnicity [1] Protocol paper TICH-2 Sprigg et al. IJS 2016; [2] Statistical analysis plan Flaherty et al. Trials 2017

9 Results

10 Recruitment Date trial started 01 MAR 2013 Date recruitment started 14 MAR 2013 Date recruitment closed 30 SEP 2017 Number of patients randomised 2325 Number of centres 124 Number of countries 12 Country Total recruited UK 1910 Georgia 141 Italy 96 Malaysia 46 Switzerland 46 Denmark 39 Republic of Ireland 17 Hungary 9 Turkey 9 Sweden 8 Poland 3 Spain 1

11 Trial flow diagram Enrollment Randomised (n= 2325) Allocated to tranexamic acid (n= 1161) Received allocated intervention (n= 1150) Did not receive allocated intervention: No treatment given (n= 9) Not known if treatment given (n= 2) Allocation Allocated to placebo (n= 1164) Received allocated intervention (n= 1157) Did not receive allocated intervention: No treatment given (n= 6) Not known if treatment given (n= 1) Day 2 assessment completed (n= 1161) Lost to follow-up (n= 0) Died by day 2 (n= 40) Follow-Up, day 2 Day 2 assessment completed (n= 1164) Lost to follow-up (n= 0) Died by day 2 (n= 57) Day 7 assessment completed (n= 1161) Lost to follow-up (n= 0) Died by day 7 (n= 101) Follow-Up, day 7 Day 7 assessment completed (n= 1164) Lost to follow-up (n= 0) Died by day 7 (n= 123) Analysed (n= 1152) Died by day 90 (n= 250) Excluded from analysis: Withdrawn (n= 6) Lost to follow-up (n= 3) Analysis, day 90 Analysed (n= 1155) Died by day 90 (n= 249) Excluded from analysis: Withdrawn (n= 3) Lost to follow-up (n= 6)

12 Baseline characteristics Groups well matched at baseline Mean time to enrollment 3.6 hours Moderate stroke severity Predominance of deep haematoma location CTA angiography performed in only 10% Baseline variable TXA Placebo Participants randomised n=1161 n=1164 Age (years)* 69 1 (13 7) 68 7 (13 9) Sex*, male (%) 642 (55 3%) 659 (56 6%) White (%) 986 (85%) 992 (85 2%) Onset to randomisation (hours)* 3 6 [2 6, 5 1] 3 7 [2 6, 5 0] 3 hours (%) 421 (36 3%) 412 (35 4%) 4.5 hours (%) 779 (67 1%) 796 (68 4%) Previous antiplatelet therapy* 316 (27 2%) 295 (25 3%) Pre-stroke mrs, 0 [0, 1] 0 [0, 1] Glasgow coma scale, 13 (2 2) 14 (2 1) NIHSS score*, 13 (7 5) 13 (7 5) Systolic blood pressure* 172 (27 5) 174 (26 8) Haematoma location Supra-tentorial lobar haematoma (%) 379 (32 6%) 359 (30 8%) Supra-tentorial deep haematoma (%) 675 (58 1%) 696 (59 8%) Infra-tentorial haematoma (%) 73 (6 3%) 76 (6 5%) Haematoma volume (ml), 14 1 [5 9, 32 4] 12 5 [5 1, 31 9] Intraventricular haemorrhage*, yes (%) 382 (32 9%) 363 (31 2%) CT angiography performed,(%) 121 (10 6%) 128 (11 3%) Spot positive (%) 24 (19 8%) 32 (25 0%) Spot negative (%) 97 (80 2%) 96 (75 0%) *minimisation criteria, Mean (SD),Median [IQR]

13 Baseline characteristics Groups well matched at baseline Mean time to enrollment 3.6 hours Moderate stroke severity Predominance of deep haematoma location CTA angiography performed in only 10% Baseline variable TXA Placebo Participants randomised n=1161 n=1164 Age (years)* 69 1 (13 7) 68 7 (13 9) Sex*, male (%) 642 (55 3%) 659 (56 6%) White (%) 986 (85%) 992 (85 2%) Onset to randomisation (hours)* 3 6 [2 6, 5 1] 3 7 [2 6, 5 0] 3 hours (%) 421 (36 3%) 412 (35 4%) 4.5 hours (%) 779 (67 1%) 796 (68 4%) Previous antiplatelet therapy* 316 (27 2%) 295 (25 3%) Pre-stroke mrs, 0 [0, 1] 0 [0, 1] Glasgow coma scale, 13 (2 2) 14 (2 1) NIHSS score*, 13 (7 5) 13 (7 5) Systolic blood pressure* 172 (27 5) 174 (26 8) Haematoma location Supra-tentorial lobar haematoma (%) 379 (32 6%) 359 (30 8%) Supra-tentorial deep haematoma (%) 675 (58 1%) 696 (59 8%) Infra-tentorial haematoma (%) 73 (6 3%) 76 (6 5%) Haematoma volume (ml), 14 1 [5 9, 32 4] 12 5 [5 1, 31 9] Intraventricular haemorrhage*, yes (%) 382 (32 9%) 363 (31 2%) CT angiography performed,(%) 121 (10 6%) 128 (11 3%) Spot positive (%) 24 (19 8%) 32 (25 0%) Spot negative (%) 97 (80 2%) 96 (75 0%) *minimisation criteria, Mean (SD),Median [IQR]

14 Baseline characteristics Groups well matched at baseline Mean time to enrollment 3.6 hours Moderate stroke severity Predominance of deep haematoma location CTA angiography performed in only 10% Baseline variable TXA Placebo Participants randomised n=1161 n=1164 Age (years)* 69 1 (13 7) 68 7 (13 9) Sex*, male (%) 642 (55 3%) 659 (56 6%) White (%) 986 (85%) 992 (85 2%) Onset to randomisation (hours)* 3 6 [2 6, 5 1] 3 7 [2 6, 5 0] 3 hours (%) 421 (36 3%) 412 (35 4%) 4.5 hours (%) 779 (67 1%) 796 (68 4%) Previous antiplatelet therapy* 316 (27 2%) 295 (25 3%) Pre-stroke mrs, 0 [0, 1] 0 [0, 1] Glasgow coma scale, 13 (2 2) 14 (2 1) NIHSS score*, 13 (7 5) 13 (7 5) Systolic blood pressure* 172 (27 5) 174 (26 8) Haematoma location Supra-tentorial lobar haematoma (%) 379 (32 6%) 359 (30 8%) Supra-tentorial deep haematoma (%) 675 (58 1%) 696 (59 8%) Infra-tentorial haematoma (%) 73 (6 3%) 76 (6 5%) Haematoma volume (ml), 14 1 [5 9, 32 4] 12 5 [5 1, 31 9] Intraventricular haemorrhage*, yes (%) 382 (32 9%) 363 (31 2%) CT angiography performed,(%) 121 (10 6%) 128 (11 3%) Spot positive (%) 24 (19 8%) 32 (25 0%) Spot negative (%) 97 (80 2%) 96 (75 0%) *minimisation criteria, Mean (SD),Median [IQR]

15 Baseline characteristics Groups well matched at baseline Mean time to enrollment 3.6 hours Moderate stroke severity Predominance of deep haematoma location CTA angiography performed in only 10% Baseline variable TXA Placebo Participants randomised n=1161 n=1164 Age (years)* 69 1 (13 7) 68 7 (13 9) Sex*, male (%) 642 (55 3%) 659 (56 6%) White (%) 986 (85%) 992 (85 2%) Onset to randomisation (hours)* 3 6 [2 6, 5 1] 3 7 [2 6, 5 0] 3 hours (%) 421 (36 3%) 412 (35 4%) 4.5 hours (%) 779 (67 1%) 796 (68 4%) Previous antiplatelet therapy* 316 (27 2%) 295 (25 3%) Pre-stroke mrs, 0 [0, 1] 0 [0, 1] Glasgow coma scale, 13 (2 2) 14 (2 1) NIHSS score*, 13 (7 5) 13 (7 5) Systolic blood pressure* 172 (27 5) 174 (26 8) Haematoma location Supra-tentorial lobar haematoma (%) 379 (32 6%) 359 (30 8%) Supra-tentorial deep haematoma (%) 675 (58 1%) 696 (59 8%) Infra-tentorial haematoma (%) 73 (6 3%) 76 (6 5%) Haematoma volume (ml), 14 1 [5 9, 32 4] 12 5 [5 1, 31 9] Intraventricular haemorrhage*, yes (%) 382 (32 9%) 363 (31 2%) CT angiography performed,(%) 121 (10 6%) 128 (11 3%) Spot positive (%) 24 (19 8%) 32 (25 0%) Spot negative (%) 97 (80 2%) 96 (75 0%) *minimisation criteria, Mean (SD),Median [IQR]

16 Baseline characteristics Groups well matched at baseline Mean time to enrollment 3.6 hours Moderate stroke severity Predominance of deep haematoma location CTA angiography performed in only 10% Baseline variable TXA Placebo Participants randomised n=1161 n=1164 Age (years)* 69 1 (13 7) 68 7 (13 9) Sex*, male (%) 642 (55 3%) 659 (56 6%) White (%) 986 (85%) 992 (85 2%) Onset to randomisation (hours)* 3 6 [2 6, 5 1] 3 7 [2 6, 5 0] 3 hours (%) 421 (36 3%) 412 (35 4%) 4.5 hours (%) 779 (67 1%) 796 (68 4%) Previous antiplatelet therapy* 316 (27 2%) 295 (25 3%) Pre-stroke mrs, 0 [0, 1] 0 [0, 1] Glasgow coma scale, 13 (2 2) 14 (2 1) NIHSS score*, 13 (7 5) 13 (7 5) Systolic blood pressure* 172 (27 5) 174 (26 8) Haematoma location Supra-tentorial lobar haematoma (%) 379 (32 6%) 359 (30 8%) Supra-tentorial deep haematoma (%) 675 (58 1%) 696 (59 8%) Infra-tentorial haematoma (%) 73 (6 3%) 76 (6 5%) Haematoma volume (ml), 14 1 [5 9, 32 4] 12 5 [5 1, 31 9] Intraventricular haemorrhage*, yes (%) 382 (32 9%) 363 (31 2%) CT angiography performed,(%) 121 (10 6%) 128 (11 3%) Spot positive (%) 24 (19 8%) 32 (25 0%) Spot negative (%) 97 (80 2%) 96 (75 0%) *minimisation criteria, Mean (SD),Median [IQR]

17 Baseline characteristics Groups well matched at baseline Mean time to enrollment 3.6 hours Moderate stroke severity Predominance of deep haematoma location CTA angiography performed in only 10% Baseline variable TXA Placebo Participants randomised n=1161 n=1164 Age (years)* 69 1 (13 7) 68 7 (13 9) Sex*, male (%) 642 (55 3%) 659 (56 6%) White (%) 986 (85%) 992 (85 2%) Onset to randomisation (hours)* 3 6 [2 6, 5 1] 3 7 [2 6, 5 0] 3 hours (%) 421 (36 3%) 412 (35 4%) 4.5 hours (%) 779 (67 1%) 796 (68 4%) Previous antiplatelet therapy* 316 (27 2%) 295 (25 3%) Pre-stroke mrs, 0 [0, 1] 0 [0, 1] Glasgow coma scale, 13 (2 2) 14 (2 1) NIHSS score*, 13 (7 5) 13 (7 5) Systolic blood pressure* 172 (27 5) 174 (26 8) Haematoma location Supra-tentorial lobar haematoma (%) 379 (32 6%) 359 (30 8%) Supra-tentorial deep haematoma (%) 675 (58 1%) 696 (59 8%) Infra-tentorial haematoma (%) 73 (6 3%) 76 (6 5%) Haematoma volume (ml), 14 1 [5 9, 32 4] 12 5 [5 1, 31 9] Intraventricular haemorrhage*, yes (%) 382 (32 9%) 363 (31 2%) CT angiography performed,(%) 121 (10 6%) 128 (11 3%) Spot positive (%) 24 (19 8%) 32 (25 0%) Spot negative (%) 97 (80 2%) 96 (75 0%) *minimisation criteria, Mean (SD),Median [IQR]

18 Adherence to treatment Good adherence to treatment 95% received all allocated treatment 98% received at least some treatment Mean time to treatment 21 minutes TXA Placebo p Number of participants randomised All randomised treatment received as intended, n (%) 1101 (94 8%) 1106 (95 0%) 0 96 Some randomised treatment received, n (%) 49 (4 2%) 51 (4 4%) 0 66 No randomised treatment received, n (%) 9 (0 8%) 6 (0 5%) 0 48 Not known what treatment received, n (%) 2 (0 2%) 1 (0 1%) 0 54 Protocol violation submitted for incorrect drug administration*, n (%) Time until first dose (minutes), median [IQR] {range} 31 (2.7%) 26 (2.2%) [13, 33] {1, 167} 21 [13, 32] {1, 196} 0 49

19 Primary outcome: shift analysis mrs day 90 No significant difference in primary outcome OR 0.88 ( ) p=0.11 No significant difference in binary outcome mrs >3 OR 0.82 ( ) p=0.08

20 Secondary outcomes Significant reduction in haematoma change and haematoma expansion By day 7 fewer patients had died in the TXA group No significant differences in any of the functional outcomes at day 90 Radiological TXA Placebo OR/MD* (95% CI) p * Adjusted for minimisation factors Change in haematoma volume from baseline to 24 hours 3 72 (15 9) 4 90 (16 0) MD: (-2 71, -0 04) Participants with haematoma expansion 265 (25 1%) 304 (28 7%) OR: 0 80 (0 66, 0 98) Day 7 Death by day 7, n (%) 101 (8 7%) 123 (10 6%) OR: 0 73 (0 53, 0 99) NIHSS day (8 3) (8 3) MD: (-0 94, 0 09) 0 10 Day 90 Death by day 90, n (%) 250 (21 5%) 249 (21 4%) HR: 0 92 (0 77, 1 10) 0 37 Discharge Length of stay in hospital (47 1) (48 1) MD: 1 09 (0 97, 1 24) 0 16 Disposition at discharge Home 465 (40 1%) 453 (38 9%) OR: 1 14 (0 93, 1 40) 0 20 Institution 505 (43 5%) 506 (43 5%) OR: 0 99 (0 83, 1 18) 0 90

21 Secondary outcomes Significant reduction in haematoma change and haematoma expansion By day 7 fewer patients had died in the TXA group No significant differences in any of the functional outcomes at day 90 Radiological TXA Placebo OR/MD* (95% CI) p * Adjusted for minimisation factors Change in haematoma volume from baseline to 24 hours 3 72 (15 9) 4 90 (16 0) MD: (-2 71, -0 04) Participants with haematoma expansion 265 (25 1%) 304 (28 7%) OR: 0 80 (0 66, 0 98) Day 7 Death by day 7, n (%) 101 (8 7%) 123 (10 6%) OR: 0 73 (0 53, 0 99) NIHSS day (8 3) (8 3) MD: (-0 94, 0 09) 0 10 Day 90 Death by day 90, n (%) 250 (21 5%) 249 (21 4%) HR: 0 92 (0 77, 1 10) 0 37 Discharge Length of stay in hospital (47 1) (48 1) MD: 1 09 (0 97, 1 24) 0 16 Disposition at discharge Home 465 (40 1%) 453 (38 9%) OR: 1 14 (0 93, 1 40) 0 20 Institution 505 (43 5%) 506 (43 5%) OR: 0 99 (0 83, 1 18) 0 90

22 Secondary outcomes Significant reduction in haematoma change and haematoma expansion By day 7 fewer patients had died in the TXA group No significant differences in any of the functional outcomes at day 90 Radiological TXA Placebo OR/MD* (95% CI) p * Adjusted for minimisation factors Change in haematoma volume from baseline to 24 hours 3 72 (15 9) 4 90 (16 0) MD: (-2 71, -0 04) Participants with haematoma expansion 265 (25 1%) 304 (28 7%) OR: 0 80 (0 66, 0 98) Day 7 Death by day 7, n (%) 101 (8 7%) 123 (10 6%) OR: 0 73 (0 53, 0 99) NIHSS day (8 3) (8 3) MD: (-0 94, 0 09) 0 10 Day 90 Death by day 90, n (%) 250 (21 5%) 249 (21 4%) HR: 0 92 (0 77, 1 10) 0 37 Discharge Length of stay in hospital (47 1) (48 1) MD: 1 09 (0 97, 1 24) 0 16 Disposition at discharge Home 465 (40 1%) 453 (38 9%) OR: 1 14 (0 93, 1 40) 0 20 Institution 505 (43 5%) 506 (43 5%) OR: 0 99 (0 83, 1 18) 0 90

23 Cumulative mortality No significant difference in cumulative mortality Adjusted HR 0.92 ( p=0.37)

24 Sub-groups Pre-specified sub-groups: Participants BP < 170mmHg favoured TXA 0.73 ( ) p= Participants onset < 4.5 hours favoured TXA 0.84 ( ) p=0.28 Exploratory post hoc: Participants haematoma size 30-60mls favoured TXA 0.66 ( ) p=0.84

25 Serious adverse events Participants in the TXA groups had fewer safety outcomes and SAEs There was no increase in venous thromboembolism Commonest SAEs were nervous system disorders and infections Median days to event [IQR] TXA 1161 Placebo 1164 p By day (32 6%) 417 (35 8%) By day (39 3%) 497 (42 7%) By day (44 9%) 556 (47 8%) Safety outcomes Death 1 [0, 15] 250 (21 5%) 249 (21 4%) 0 60 ACS or MI 5 [1, 53] 11 (0 9%) 6 (0 5%) 0 24 Deep vein thrombosis (DVT) 15 [10, 34] 19 (1 6%) 14 (1 2%) 0 41 Pulmonary embolism (PE) 16 [8, 29] 20 (1 7%) 23 (2 0%) 0 58 VTE (combined DVT/PE) 16 [10, 30] 39 (3 4%) 37 (3 2%) 0 98 Seizure / convulsions 1 [0, 3] 77 (6 6%) 85 (7 3%) 0 44 Ischaemic stroke or TIA 9 [2, 52] 16 (1 4%) 11 (0 9%) 0 27 SAEs by subcategory Infections and infestations 2 [1, 3] 98 (8 4%) 116 (10 0%) 0 14 Nervous system disorders 1 [0, 1] 149 (12 8%) 163 (14 0%) 0 33

26 Serious adverse events Participants in the TXA groups had fewer safety outcomes and SAEs There was no increase in venous thromboembolism Commonest SAEs were nervous system disorders and infections Median days to event [IQR] TXA 1161 Placebo 1164 p By day (32 6%) 417 (35 8%) By day (39 3%) 497 (42 7%) By day (44 9%) 556 (47 8%) Safety outcomes Death 1 [0, 15] 250 (21 5%) 249 (21 4%) 0 60 ACS or MI 5 [1, 53] 11 (0 9%) 6 (0 5%) 0 24 Deep vein thrombosis (DVT) 15 [10, 34] 19 (1 6%) 14 (1 2%) 0 41 Pulmonary embolism (PE) 16 [8, 29] 20 (1 7%) 23 (2 0%) 0 58 VTE (combined DVT/PE) 16 [10, 30] 39 (3 4%) 37 (3 2%) 0 98 Seizure / convulsions 1 [0, 3] 77 (6 6%) 85 (7 3%) 0 44 Ischaemic stroke or TIA 9 [2, 52] 16 (1 4%) 11 (0 9%) 0 27 SAEs by subcategory Infections and infestations 2 [1, 3] 98 (8 4%) 116 (10 0%) 0 14 Nervous system disorders 1 [0, 1] 149 (12 8%) 163 (14 0%) 0 33

27 Serious adverse events Participants in the TXA groups had fewer safety outcomes and SAEs There was no increase in venous thromboembolism Commonest SAEs were nervous system disorders and infections Median days to event [IQR] TXA 1161 Placebo 1164 p By day (32 6%) 417 (35 8%) By day (39 3%) 497 (42 7%) By day (44 9%) 556 (47 8%) Safety outcomes Death 1 [0, 15] 250 (21 5%) 249 (21 4%) 0 60 ACS or MI 5 [1, 53] 11 (0 9%) 6 (0 5%) 0 24 Deep vein thrombosis (DVT) 15 [10, 34] 19 (1 6%) 14 (1 2%) 0 41 Pulmonary embolism (PE) 16 [8, 29] 20 (1 7%) 23 (2 0%) 0 58 VTE (combined DVT/PE) 16 [10, 30] 39 (3 4%) 37 (3 2%) 0 98 Seizure / convulsions 1 [0, 3] 77 (6 6%) 85 (7 3%) 0 44 Ischaemic stroke or TIA 9 [2, 52] 16 (1 4%) 11 (0 9%) 0 27 SAEs by subcategory Infections and infestations 2 [1, 3] 98 (8 4%) 116 (10 0%) 0 14 Nervous system disorders 1 [0, 1] 149 (12 8%) 163 (14 0%) 0 33

28 Strengths and weaknesses Strengths: Largest RCT of haemostatic agent in ICH Broad inclusion criteria Good allocation concealment Minimal loss to follow-up (<1%) Weaknesses: Although 12 countries, participants mostly recruited from UK Broad inclusion led to heterogenous population Greater proportion of severe stroke compared to other ICH studies Despite efforts to include patients rapidly mean time to enrolment 3.6 hours with only 30% enrolled < 3 hours Caution needed interpreting the sub-group analysis

29 Discussion No significant effect on primary outcome at 90 days despite early benefits Possible that the anticipated treatment effect OR 0.79 was too large and the trial was unable to detect this Other TXA studies in trauma (CRASH-2) and post partum haemorrhage (WOMAN) much larger to detect modest effect sizes OR 0.81 & OR 0.85 Subsequent meta-analysis in 40,138 participants demonstrated that treatment needed to given < 3 hours to benefit [1] Possible that effect on attenuating haematoma growth (mean 1.5mls) was too modest to translate into improved outcome [1] Lancet Jan 13;391(10116):

30 Conclusion No significant difference in primary outcome mrs at day 90 (shift analysis) Evidence of antifibrinolytic effect reduced haematoma expansion, fewer early deaths No safety concerns in this population which was older with more comorbidities than previous tranexamic acid studies Results of several on-going studies awaited but likely larger randomised trials are needed More research needed to explore which sub-groups of patients may benefit Future work should focus on enrolling and treating patients earlier

31 Thank you

32 Hear more about TICH-2: Nottingham Trials Stand Exhibition Hall ICH and Hyperglycaemia 17 th May Hall H TICH-2 MRI Sub-study methods poster 17 th May TICH-2 MRI Sub -study Results 18 th May Hall C