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TICH-2

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

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Year of Publication: 2018

Authors: Nikola Sprigg, Katie Flaherty, Jason P Appleton, ..., Philip M Bath

Journal: The Lancet

Citation: Lancet 2018; 391:2107-15

Link: http://dx.doi.org/10.1016/S0140-6736(18)31033-X

PDF: https://www.thelancet.com/action/showPdf...%2818%2931033-X

Clinical Question

Does intravenous tranexamic acid reduce haematoma expansion and improve functional outcome in adults with stroke due to intracerebral haemorrhage when administered within 8 hours of symptom onset?

Bottom Line

Tranexamic acid did not significantly improve functional status at 90 days in patients with acute intracerebral haemorrhage, despite reducing early deaths and haematoma expansion. While safe and inexpensive, larger trials are needed to confirm a clinically significant effect and identify benefiting subgroups.

        Major Points
        TICH-2 is the largest randomized trial of tranexamic acid (TXA) for acute spontaneous intracerebral hemorrhage — 2,325 patients across 124 centers in 12 countries.
Primary outcome (ordinal mRS shift at 90 days) was NOT significantly improved with TXA (aOR 0.88, 95% CI 0.76–1.03, p=0.11), making this a formally negative trial.
However, TXA significantly reduced hematoma expansion at 24h (25% vs 29%, aOR 0.80, p=0.03) and early deaths by day 7 (9% vs 11%, aOR 0.73, p=0.04).
The disconnect between reduced expansion/early death and unchanged 90-day mRS suggests hematoma expansion is necessary but not sufficient for poor outcome — other mechanisms (perihematomal edema, IVH, medical complications) also drive disability.
TXA was remarkably safe — no increase in venous thromboembolic events (3% vs 3%) or arterial occlusive events, and actually FEWER serious adverse events at all time points.
Informed by CRASH-2 (trauma) and WOMAN (postpartum hemorrhage), TICH-2 used the same dosing regimen: 1g IV bolus + 1g over 8h infusion.
The only significant subgroup interaction was baseline SBP ≤170 mmHg (interaction p=0.019), suggesting TXA may be most effective when hypertensive hematoma expansion is less of a competing mechanism.
Enrolled within 8h of onset — broader than many ICH trials. A planned individual patient data meta-analysis (STOP-AUST + TICH-2 + others) aims to identify time-dependent benefit.
TICH-2 results contributed to AHA/ASA 2022 ICH guidelines giving TXA a Class IIb recommendation — 'may be reasonable within 3 hours of onset.'
The FASTEST trial (ultra-early TXA <2h) was subsequently designed to test the hypothesis that earlier treatment is key, but was stopped early for futility.

      

Design

Study Type: International, randomised, placebo-controlled, double-blind, parallel group, phase 3 superiority trial

Randomization: 1

Blinding: Concealed from patients, outcome assessors, and all other health-care workers involved in the trial. Central independent expert assessors for CT scans and serious adverse events were masked to treatment assignment.

Enrollment Period: March 1, 2013, and Sept 30, 2017

Follow-up Duration: 90 days (primary outcome)

Centers: 124

Countries: Denmark, Georgia, Hungary, Ireland, Italy, Malaysia, Poland, Spain, Sweden, Switzerland, Turkey, UK

Sample Size: 2325

Analysis: Intention-to-treat; ordinal logistic regression for primary outcome adjusted for stratification and minimisation criteria; sensitivity analyses for primary outcome; multiple linear regression for continuous secondary outcomes; binary logistic regression for binary secondary outcomes; Cox proportional hazards regression for time-to-event data. No adjustment for multiplicity.

Inclusion Criteria

Adults (≥18 years) with acute spontaneous (non-traumatic) intracerebral hemorrhage confirmed on CT.
Symptom onset (or last seen well) within 8 hours of randomization.
No pre-specified NIHSS or GCS minimum (broad severity range allowed).
Clinical diagnosis of stroke with ICH — no minimum hematoma volume required.

Exclusion Criteria

ICH secondary to anticoagulation (warfarin, DOACs) — these patients have a different pathophysiology requiring reversal agents.
ICH secondary to thrombolysis (sICH after tPA/TNK).
ICH due to trauma (traumatic contusions, epidural/subdural hematomas).
Known underlying structural cause: AVM, aneurysm, tumor, cavernoma.
Tranexamic acid contraindicated (known allergy, active thromboembolic disease, seizure history attributed to TXA).
Prestroke dependency (mRS >4) — to ensure meaningful functional outcome assessment.
GCS <5 — moribund patients unlikely to benefit from intervention.
Life expectancy <3 months from comorbid illness.
Pregnancy or breastfeeding.
Participation in another interventional clinical trial.

Baseline Characteristics

Characteristic	Control	Active
Age, years	68.7 (13.9) [20-101]	69.1 (13.7) [20-97]
Age >70	580 (50%)	584 (50%)
Sex, male	659 (57%)	642 (55%)
Ethnic origin - White	992 (85%)	986 (85%)
Ethnic origin - Other	172 (15%)	174 (15%)
Onset to randomisation, h	3.7 (2.6-5.0) [0.8-8.0]	3.6 (2.6-5.1) [1.0-20.8]
Onset to randomisation ≤3h	412 (35%)	421 (36%)
Onset to randomisation ≤4.5h	796 (68%)	779 (67%)
History - Previous antiplatelet therapy	295 (25%)	316 (27%)
History - Statin use prior to admission	303 (26%)	319 (28%)
History - Previous stroke or transient ischaemic attack	156 (14%)	173 (15%)
History - Ischaemic heart disease	92 (8%)	110 (10%)
Prestroke mRS	0 (0-1) [0-4]	0 (0-1) [0-4]
Glasgow Coma Scale	14 (2.1) [5.0-15.0]	13 (2.2) [5.0-15.0]
NIHSS score	13 (7-5) [0.0-42.0]	13 (7.5) [0.0-41.0]
Systolic blood pressure, mm Hg	174 (26.8) [99.0-265]	172 (27.5) [98.0-265]
Diastolic blood pressure, mm Hg	94 (17.8) [35.5-162]	93 (18.4) [46.0-179]
Haematoma location - Supratentorial lobar	359 (31%)	379 (33%)
Haematoma location - Supratentorial deep	696 (60%)	675 (58%)
Haematoma location - Infratentorial	76 (7%)	73 (6%)
Haematoma location - Combination	33 (3%)	34 (3%)
Intracerebral haematoma volume (mL)	12.5 (5.1-31.9) [0.0-163]	14.1 (5.9-32.4) [0.0-207]
Intraventricular haemorrhage	363 (31%)	382 (33%)
CT angiography done	128 (11%)	121 (11%)
Spot positive	32 (25%)	24 (20%)
Spot negative	96 (75%)	97 (80%)

Arms

Field	Tranexamic acid	Control
Intervention	1 g intravenous tranexamic acid bolus infused over 10 min, followed by an 8 h infusion of 1 g tranexamic acid.	Matching placebo (normal saline 0.9%), administered with an identical regimen.
Duration	8 hours	8 hours

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Functional status at day 90, measured by shift in the modified Rankin Scale (mRS), using ordinal logistic regression.	Primary			0.88	0.11
Haematoma expansion (absolute increase >6 mL or relative growth >33%) at 24 hours	Secondary	304 (29%) of 1058 participants	265 (25%) of 1054 participants	0.8	0.0300
Change in haematoma volume from baseline to 24 hours (mL)	Secondary	4.90 (16.0)	3.72 (15.9)	-1.37	0.0432
Death by day 7	Secondary	123 (11%) of 1164 participants	101 (9%) of 1161 participants	0.73	0.0406
NIHSS day 7 (mean difference)	Secondary	10.29 (8.3)	10.13 (8.3)	-0.43	0.10
Death by day 90	Secondary	249 (21%) of 1155 participants	250 (22%) of 1152 participants	0.92	0.37
mRS >3 at day 90 (dead or dependent)	Secondary	826 (72%)	814 (71%)	0.82	0.08
Length of stay in hospital, days	Secondary	63.73 (48.1)	63.12 (47.1)	1.09	0.16
Disposition at discharge - Home	Secondary	453 (39%)	465 (40%)	1.14	0.20
Disposition at discharge - Institution	Secondary	506 (43%)	505 (43%)	0.99	0.90
Disposition at discharge - Died by discharge	Secondary	205 (18%)	190 (16%)	0.83	0.15
Serious adverse events by day 2	Adverse	417 (36%) patients	379 (33%) patients		0.0272
Serious adverse events by day 7	Adverse	497 (43%) patients	456 (39%) patients		0.0200
Serious adverse events by day 90	Adverse	556 (48%) patients	521 (45%) patients		0.0393
Venous thromboembolic events	Adverse	37 (3%)	39 (3%)		0.98
Arterial occlusions (myocardial infarction, acute coronary syndrome, or peripheral arterial occlusion)	Adverse
Seizure	Adverse	85 (7%)	77 (7%)
Nervous system disorders (most common serious adverse event)	Adverse	163 (14%)	149 (13%)
Infections (second most common serious adverse event)	Adverse	116 (10%)	98 (8%)

Criticisms

Formally negative trial — the primary outcome (ordinal mRS shift at 90 days) did not reach significance (p=0.11). The biologically plausible positive signals (reduced expansion, fewer early deaths) may reflect chance or underpowering.
Wide inclusion criteria (any spontaneous ICH within 8h, no minimum volume) created a heterogeneous population — many patients with small hematomas that wouldn't expand regardless, diluting treatment effect.
Median time to randomization was 3.6-3.7h — most patients treated >3h post-onset. TXA may be most effective ultra-early when active bleeding is ongoing. FASTEST trial addressed this but stopped for futility.
No screening logs collected — unable to assess selection bias or determine how enrolled patients differed from those screened but excluded.
The disconnect between reduced day-7 mortality and unchanged day-90 mortality raises concerns about delayed deaths (infections, withdrawal of care) not being prevented by TXA.
Effect size smaller than expected (aOR 0.88 vs anticipated 0.79) — trial may have been underpowered for the true effect size. Original sample size calculation assumed a larger treatment effect.
Only 11% of patients had CTA performed — the spot sign (a marker of active extravasation) could identify the ideal TXA target population, but this subgroup was drastically underpowered.
No direct comparison with other hemostatic strategies (e.g., platelet transfusion for antiplatelet-associated ICH, rFVIIa). TICH-2 only tested TXA vs placebo.
The 8-hour time window may have been too broad — biological plausibility for antifibrinolytic benefit is strongest within the first 1-3 hours when hematoma expansion is most active.

Subgroup Analysis

Array

Funding

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

Based on: TICH-2 (The Lancet, 2018)