Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial

Nikola Sprigg; Katie Flaherty; Jason P Appleton; Rustam Al-Shahi Salman; Daniel Bereczki; Maia Beridze; Hanne Christensen; Alfonso Ciccone; Ronan Collins; Anna Czlonkowska; Robert A Dineen; Lelia Duley; Juan Jose Egea-Guerrero; Timothy J England; Kailash Krishnan; Ann Charlotte Laska; Zhe Kang Law; Serefnur Ozturk; Stuart J Pocock; Ian Roberts; Thompson G Robinson; Christine Roffe; David Seiffge; Polly Scutt; Jegan Thanabalan; David Werring; David Whynes; Philip M Bath; TICH-2 Investigators

doi:10.1016/S0140-6736(18)31033-X

Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial

Nikola Sprigg, Katie Flaherty, Jason P Appleton, Rustam Al-Shahi Salman, Daniel Bereczki, Maia Beridze, Hanne Christensen, Alfonso Ciccone, Ronan Collins, Anna Czlonkowska, Robert A Dineen, Lelia Duley, Juan Jose Egea-Guerrero, Timothy J England, Kailash Krishnan, Ann Charlotte Laska, Zhe Kang Law, Serefnur Ozturk, Stuart J Pocock, Ian RobertsThompson G Robinson, Christine Roffe, David Seiffge, Polly Scutt, Jegan Thanabalan, David Werring, David Whynes, Philip M Bath, TICH-2 Investigators

Department of Clinical Medicine

126 Citations (Scopus)

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Abstract

BACKGROUND: Tranexamic acid can prevent death due to bleeding after trauma and post-partum haemorrhage. We aimed to assess whether tranexamic acid reduces haematoma expansion and improves outcome in adults with stroke due to intracerebral haemorrhage.

METHODS: We did an international, randomised placebo-controlled trial in adults with intracerebral haemorrhage from acute stroke units at 124 hospital sites in 12 countries. Participants were randomly assigned (1:1) to receive 1 g intravenous tranexamic acid bolus followed by an 8 h infusion of 1 g tranexamic acid or a matching placebo, within 8 h of symptom onset. Randomisation was done centrally in real time via a secure website, with stratification by country and minimisation on key prognostic factors. Treatment allocation was concealed from patients, outcome assessors, and all other health-care workers involved in the trial. The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale, using ordinal logistic regression with adjustment for stratification and minimisation criteria. All analyses were done on an intention-to-treat basis. This trial is registered with the ISRCTN registry, number ISRCTN93732214.

FINDINGS: We recruited 2325 participants between March 1, 2013, and Sept 30, 2017. 1161 patients received tranexamic acid and 1164 received placebo; the treatment groups were well balanced at baseline. The primary outcome was assessed for 2307 (99%) participants. The primary outcome, functional status at day 90, did not differ significantly between the groups (adjusted odds ratio [aOR] 0·88, 95% CI 0·76-1·03, p=0·11). Although there were fewer deaths by day 7 in the tranexamic acid group (101 [9%] deaths in the tranexamic acid group vs 123 [11%] deaths in the placebo group; aOR 0·73, 0·53-0·99, p=0·0406), there was no difference in case fatality at 90 days (250 [22%] vs 249 [21%]; adjusted hazard ratio 0·92, 95% CI 0·77-1·10, p=0·37). Fewer patients had serious adverse events after tranexamic acid than after placebo by days 2 (379 [33%] patients vs 417 [36%] patients), 7 (456 [39%] vs 497 [43%]), and 90 (521 [45%] vs 556 [48%]).

INTERPRETATION: Functional status 90 days after intracerebral haemorrhage did not differ significantly between patients who received tranexamic acid and those who received placebo, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect.

FUNDING: National Institute of Health Research Health Technology Assessment Programme and Swiss Heart Foundation.

Original language	English
Journal	Lancet Oncology
Volume	391
Issue number	10135
Pages (from-to)	2107-2115
Number of pages	9
ISSN	1470-2045
DOIs	https://doi.org/10.1016/S0140-6736(18)31033-X
Publication status	Published - 26 May 2018

Keywords

Acute Disease
Adult
Aged
Aged, 80 and over
Antifibrinolytic Agents/therapeutic use
Cerebral Hemorrhage/complications
Double-Blind Method
Female
Humans
Male
Middle Aged
Stroke/etiology
Tranexamic Acid/therapeutic use
Treatment Outcome
Young Adult

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Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trialFinal published version, 0.99 MBLicence: CC BY

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Sprigg, N., Flaherty, K., Appleton, J. P., Al-Shahi Salman, R., Bereczki, D., Beridze, M., Christensen, H., Ciccone, A., Collins, R., Czlonkowska, A., Dineen, R. A., Duley, L., Egea-Guerrero, J. J., England, T. J., Krishnan, K., Laska, A. C., Law, Z. K., Ozturk, S., Pocock, S. J., ... TICH-2 Investigators (2018). Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial. Lancet Oncology, 391(10135), 2107-2115. https://doi.org/10.1016/S0140-6736(18)31033-X

Sprigg, N, Flaherty, K, Appleton, JP, Al-Shahi Salman, R, Bereczki, D, Beridze, M, Christensen, H, Ciccone, A, Collins, R, Czlonkowska, A, Dineen, RA, Duley, L, Egea-Guerrero, JJ, England, TJ, Krishnan, K, Laska, AC, Law, ZK, Ozturk, S, Pocock, SJ, Roberts, I, Robinson, TG, Roffe, C, Seiffge, D, Scutt, P, Thanabalan, J, Werring, D, Whynes, D, Bath, PM & TICH-2 Investigators 2018, 'Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial', Lancet Oncology, vol. 391, no. 10135, pp. 2107-2115. https://doi.org/10.1016/S0140-6736(18)31033-X

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abstract = "BACKGROUND: Tranexamic acid can prevent death due to bleeding after trauma and post-partum haemorrhage. We aimed to assess whether tranexamic acid reduces haematoma expansion and improves outcome in adults with stroke due to intracerebral haemorrhage.METHODS: We did an international, randomised placebo-controlled trial in adults with intracerebral haemorrhage from acute stroke units at 124 hospital sites in 12 countries. Participants were randomly assigned (1:1) to receive 1 g intravenous tranexamic acid bolus followed by an 8 h infusion of 1 g tranexamic acid or a matching placebo, within 8 h of symptom onset. Randomisation was done centrally in real time via a secure website, with stratification by country and minimisation on key prognostic factors. Treatment allocation was concealed from patients, outcome assessors, and all other health-care workers involved in the trial. The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale, using ordinal logistic regression with adjustment for stratification and minimisation criteria. All analyses were done on an intention-to-treat basis. This trial is registered with the ISRCTN registry, number ISRCTN93732214.FINDINGS: We recruited 2325 participants between March 1, 2013, and Sept 30, 2017. 1161 patients received tranexamic acid and 1164 received placebo; the treatment groups were well balanced at baseline. The primary outcome was assessed for 2307 (99%) participants. The primary outcome, functional status at day 90, did not differ significantly between the groups (adjusted odds ratio [aOR] 0·88, 95% CI 0·76-1·03, p=0·11). Although there were fewer deaths by day 7 in the tranexamic acid group (101 [9%] deaths in the tranexamic acid group vs 123 [11%] deaths in the placebo group; aOR 0·73, 0·53-0·99, p=0·0406), there was no difference in case fatality at 90 days (250 [22%] vs 249 [21%]; adjusted hazard ratio 0·92, 95% CI 0·77-1·10, p=0·37). Fewer patients had serious adverse events after tranexamic acid than after placebo by days 2 (379 [33%] patients vs 417 [36%] patients), 7 (456 [39%] vs 497 [43%]), and 90 (521 [45%] vs 556 [48%]).INTERPRETATION: Functional status 90 days after intracerebral haemorrhage did not differ significantly between patients who received tranexamic acid and those who received placebo, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect.FUNDING: National Institute of Health Research Health Technology Assessment Programme and Swiss Heart Foundation.",

keywords = "Acute Disease, Adult, Aged, Aged, 80 and over, Antifibrinolytic Agents/therapeutic use, Cerebral Hemorrhage/complications, Double-Blind Method, Female, Humans, Male, Middle Aged, Stroke/etiology, Tranexamic Acid/therapeutic use, Treatment Outcome, Young Adult",

author = "Nikola Sprigg and Katie Flaherty and Appleton, {Jason P} and {Al-Shahi Salman}, Rustam and Daniel Bereczki and Maia Beridze and Hanne Christensen and Alfonso Ciccone and Ronan Collins and Anna Czlonkowska and Dineen, {Robert A} and Lelia Duley and Egea-Guerrero, {Juan Jose} and England, {Timothy J} and Kailash Krishnan and Laska, {Ann Charlotte} and Law, {Zhe Kang} and Serefnur Ozturk and Pocock, {Stuart J} and Ian Roberts and Robinson, {Thompson G} and Christine Roffe and David Seiffge and Polly Scutt and Jegan Thanabalan and David Werring and David Whynes and Bath, {Philip M} and {TICH-2 Investigators}",

year = "2018",

month = may,

day = "26",

doi = "10.1016/S0140-6736(18)31033-X",

language = "English",

volume = "391",

pages = "2107--2115",

journal = "The Lancet Oncology",

issn = "1470-2045",

publisher = "TheLancet Publishing Group",

number = "10135",

}

TY - JOUR

T1 - Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2)

T2 - an international randomised, placebo-controlled, phase 3 superiority trial

AU - Sprigg, Nikola

AU - Flaherty, Katie

AU - Appleton, Jason P

AU - Al-Shahi Salman, Rustam

AU - Bereczki, Daniel

AU - Beridze, Maia

AU - Christensen, Hanne

AU - Ciccone, Alfonso

AU - Collins, Ronan

AU - Czlonkowska, Anna

AU - Dineen, Robert A

AU - Duley, Lelia

AU - Egea-Guerrero, Juan Jose

AU - England, Timothy J

AU - Krishnan, Kailash

AU - Laska, Ann Charlotte

AU - Law, Zhe Kang

AU - Ozturk, Serefnur

AU - Pocock, Stuart J

AU - Roberts, Ian

AU - Robinson, Thompson G

AU - Roffe, Christine

AU - Seiffge, David

AU - Scutt, Polly

AU - Thanabalan, Jegan

AU - Werring, David

AU - Whynes, David

AU - Bath, Philip M

AU - TICH-2 Investigators

PY - 2018/5/26

Y1 - 2018/5/26

N2 - BACKGROUND: Tranexamic acid can prevent death due to bleeding after trauma and post-partum haemorrhage. We aimed to assess whether tranexamic acid reduces haematoma expansion and improves outcome in adults with stroke due to intracerebral haemorrhage.METHODS: We did an international, randomised placebo-controlled trial in adults with intracerebral haemorrhage from acute stroke units at 124 hospital sites in 12 countries. Participants were randomly assigned (1:1) to receive 1 g intravenous tranexamic acid bolus followed by an 8 h infusion of 1 g tranexamic acid or a matching placebo, within 8 h of symptom onset. Randomisation was done centrally in real time via a secure website, with stratification by country and minimisation on key prognostic factors. Treatment allocation was concealed from patients, outcome assessors, and all other health-care workers involved in the trial. The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale, using ordinal logistic regression with adjustment for stratification and minimisation criteria. All analyses were done on an intention-to-treat basis. This trial is registered with the ISRCTN registry, number ISRCTN93732214.FINDINGS: We recruited 2325 participants between March 1, 2013, and Sept 30, 2017. 1161 patients received tranexamic acid and 1164 received placebo; the treatment groups were well balanced at baseline. The primary outcome was assessed for 2307 (99%) participants. The primary outcome, functional status at day 90, did not differ significantly between the groups (adjusted odds ratio [aOR] 0·88, 95% CI 0·76-1·03, p=0·11). Although there were fewer deaths by day 7 in the tranexamic acid group (101 [9%] deaths in the tranexamic acid group vs 123 [11%] deaths in the placebo group; aOR 0·73, 0·53-0·99, p=0·0406), there was no difference in case fatality at 90 days (250 [22%] vs 249 [21%]; adjusted hazard ratio 0·92, 95% CI 0·77-1·10, p=0·37). Fewer patients had serious adverse events after tranexamic acid than after placebo by days 2 (379 [33%] patients vs 417 [36%] patients), 7 (456 [39%] vs 497 [43%]), and 90 (521 [45%] vs 556 [48%]).INTERPRETATION: Functional status 90 days after intracerebral haemorrhage did not differ significantly between patients who received tranexamic acid and those who received placebo, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect.FUNDING: National Institute of Health Research Health Technology Assessment Programme and Swiss Heart Foundation.

AB - BACKGROUND: Tranexamic acid can prevent death due to bleeding after trauma and post-partum haemorrhage. We aimed to assess whether tranexamic acid reduces haematoma expansion and improves outcome in adults with stroke due to intracerebral haemorrhage.METHODS: We did an international, randomised placebo-controlled trial in adults with intracerebral haemorrhage from acute stroke units at 124 hospital sites in 12 countries. Participants were randomly assigned (1:1) to receive 1 g intravenous tranexamic acid bolus followed by an 8 h infusion of 1 g tranexamic acid or a matching placebo, within 8 h of symptom onset. Randomisation was done centrally in real time via a secure website, with stratification by country and minimisation on key prognostic factors. Treatment allocation was concealed from patients, outcome assessors, and all other health-care workers involved in the trial. The primary outcome was functional status at day 90, measured by shift in the modified Rankin Scale, using ordinal logistic regression with adjustment for stratification and minimisation criteria. All analyses were done on an intention-to-treat basis. This trial is registered with the ISRCTN registry, number ISRCTN93732214.FINDINGS: We recruited 2325 participants between March 1, 2013, and Sept 30, 2017. 1161 patients received tranexamic acid and 1164 received placebo; the treatment groups were well balanced at baseline. The primary outcome was assessed for 2307 (99%) participants. The primary outcome, functional status at day 90, did not differ significantly between the groups (adjusted odds ratio [aOR] 0·88, 95% CI 0·76-1·03, p=0·11). Although there were fewer deaths by day 7 in the tranexamic acid group (101 [9%] deaths in the tranexamic acid group vs 123 [11%] deaths in the placebo group; aOR 0·73, 0·53-0·99, p=0·0406), there was no difference in case fatality at 90 days (250 [22%] vs 249 [21%]; adjusted hazard ratio 0·92, 95% CI 0·77-1·10, p=0·37). Fewer patients had serious adverse events after tranexamic acid than after placebo by days 2 (379 [33%] patients vs 417 [36%] patients), 7 (456 [39%] vs 497 [43%]), and 90 (521 [45%] vs 556 [48%]).INTERPRETATION: Functional status 90 days after intracerebral haemorrhage did not differ significantly between patients who received tranexamic acid and those who received placebo, despite a reduction in early deaths and serious adverse events. Larger randomised trials are needed to confirm or refute a clinically significant treatment effect.FUNDING: National Institute of Health Research Health Technology Assessment Programme and Swiss Heart Foundation.

KW - Acute Disease

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antifibrinolytic Agents/therapeutic use

KW - Cerebral Hemorrhage/complications

KW - Double-Blind Method

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Stroke/etiology

KW - Tranexamic Acid/therapeutic use

KW - Treatment Outcome

KW - Young Adult

U2 - 10.1016/S0140-6736(18)31033-X

DO - 10.1016/S0140-6736(18)31033-X

M3 - Journal article

C2 - 29778325

SN - 1470-2045

VL - 391

SP - 2107

EP - 2115

JO - The Lancet Oncology

JF - The Lancet Oncology

IS - 10135

ER -

Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial

Abstract

Keywords

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