PDF: TICH-2
(2018)Objective
Evaluate whether IV tranexamic acid reduces hematoma expansion and improves functional outcomes in patients with spontaneous ICH when administered within 8 hours of onset.
Study Summary
• In patients with spontaneous ICH treated within 8 hours, tranexamic acid did not significantly improve 90-day functional outcomes compared to placebo. However, it reduced early deaths, hematoma expansion, and serious adverse events without increasing thromboembolic complications.
Intervention
Multicenter, international, double-blind, placebo-controlled phase 3 trial. N=2325 adults with spontaneous ICH randomized 1:1 to receive: • Tranexamic acid: 1 g IV bolus + 1 g IV infusion over 8 hrs • Placebo: matching saline regimen Primary outcome: mRS at 90 days (ordinal analysis). Secondary outcomes included hematoma expansion, early mortality, adverse events, and quality of life measures.
Study Design
Arms: Array
Outcome
• Primary outcome (mRS shift at day 90): aOR 0.88 (95% CI 0.76–1.03); p=0.11
• Hematoma expansion: 25% (TXA) vs. 29% (placebo); OR 0.80 (95% CI 0.66–0.98); p=0.03
• Death by day 7: 9% (TXA) vs. 11% (placebo); OR 0.73 (95% CI 0.53–0.99); p=0.04
• Death by day 90: 22% (TXA) vs. 21% (placebo); HR 0.92 (95% CI 0.77–1.10); p=0.37
• Serious adverse events by day 90: 45% (TXA) vs. 48% (placebo); p=0.039
• No increase in thromboembolic events
• Subgroup with SBP ≤170 mmHg showed a trend toward benefit (interaction p=0.0188)
• Hematoma expansion: 25% (TXA) vs. 29% (placebo); OR 0.80 (95% CI 0.66–0.98); p=0.03
• Death by day 7: 9% (TXA) vs. 11% (placebo); OR 0.73 (95% CI 0.53–0.99); p=0.04
• Death by day 90: 22% (TXA) vs. 21% (placebo); HR 0.92 (95% CI 0.77–1.10); p=0.37
• Serious adverse events by day 90: 45% (TXA) vs. 48% (placebo); p=0.039
• No increase in thromboembolic events
• Subgroup with SBP ≤170 mmHg showed a trend toward benefit (interaction p=0.0188)
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.
Study Design
- Study Type
- International, randomised, placebo-controlled, double-blind, parallel group, phase 3 superiority trial
- Randomization
- Yes
- 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.
- Sample Size
- 2325
- Follow-up
- 90 days (primary outcome)
- Centers
- 124
- Countries
- Denmark, Georgia, Hungary, Ireland, Italy, Malaysia, Poland, Spain, Sweden, Switzerland, Turkey, UK
Primary Outcome
Definition: Functional status at day 90, measured by shift in the modified Rankin Scale (mRS), using ordinal logistic regression.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | 0.88 (0.76-1.03) | 0.11 |
Limitations & 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.
Citation
Lancet 2018; 391:2107-15