TICH-2

Clinical Context

Hematoma expansion occurs in a significant proportion of patients with acute intracerebral hemorrhage (ICH) and is a strong predictor of poor outcome. Tranexamic acid (TXA) is an antifibrinolytic agent that inhibits the breakdown of fibrin clots. By stabilizing the initially formed hematoma, TXA has been hypothesized to reduce hematoma expansion and thereby improve clinical outcomes after ICH. Previous studies of TXA in trauma (e.g., CRASH-2) and postpartum hemorrhage had shown benefits in reducing bleeding and mortality, prompting investigation in ICH. Smaller, earlier studies in ICH had suggested potential benefits on hematoma growth.

The TICH-2 (Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage) trial was a large, pragmatic, international phase 3 trial designed to definitively assess whether TXA, administered within 8 hours of ICH onset, could improve functional outcomes.

Patient Population

TICH-2 enrolled 2325 adult patients (≥18 years) from 124 hospitals in 12 countries. Eligible patients had:

• Spontaneous intracerebral hemorrhage confirmed by CT or MRI.
• Ability to receive the study drug (TXA or placebo) within 8 hours of symptom onset.
• No upper or lower limits for Glasgow Coma Scale (GCS) score or initial hematoma volume were imposed, reflecting the trial’s pragmatic design.

Key exclusion criteria included ICH known to be due to an underlying structural lesion (e.g., aneurysm, AVM, tumor) or trauma, pre-stroke modified Rankin Scale (mRS) score >4 (indicating severe pre-existing disability), known contraindications to tranexamic acid (such as a history of deep vein thrombosis, pulmonary embolism, severe renal impairment, or seizures), or if neurosurgical evacuation of the hematoma was planned within 24 hours.

The median age of participants was approximately 69 years. About 57% were male. The median GCS at randomization was 14. The median time from symptom onset to randomization was 3.6 hours.

Study Design

TICH-2 was an international, multicenter, prospective, randomized, double-blind, placebo-controlled, phase 3 superiority trial.

Protocol Details

Eligible patients were randomized 1:1 to receive either:

• Intervention Group (Tranexamic Acid): An intravenous loading dose of tranexamic acid 1 g administered over 10 minutes, followed immediately by a second intravenous infusion of tranexamic acid 1 g administered over the next 8 hours.
• Control Group (Placebo): Matching placebo (0.9% sodium chloride) administered intravenously with the same appearance, volume, and infusion rates as the tranexamic acid.

Both groups received standard medical care for ICH according to local and international guidelines.

Outcome Assessment

The primary outcome was assessed at 90 days. Assessment of the modified Rankin Scale (mRS) was performed by trained personnel, typically via face-to-face interview or telephone, blinded to treatment allocation. Hematoma volume was assessed by CT scans at baseline and approximately 24 hours.

Power Analysis & Statistical Approach

The primary outcome was functional status at 90 days, analyzed as an ordinal shift in the mRS scores using logistic regression, adjusted for key baseline prognostic factors. The trial was powered to detect a common odds ratio of 0.79 (equivalent to about a 5-7% absolute difference in favorable outcome) with 90% power at a 5% significance level.

Risk of Bias Analysis

(Content for this section needs to be added. Considerations: Double-blind, placebo-controlled design is a major strength; pragmatic inclusion criteria; international multicenter involvement.)

Results

A total of 2325 patients were randomized: 1161 to tranexamic acid and 1164 to placebo. Baseline characteristics were well-balanced between the groups. Over 95% of patients received the allocated treatment.

Primary Outcome: Functional Status (mRS distribution) at 90 Days

The analysis of the ordinal distribution of mRS scores at 90 days showed no statistically significant difference between the tranexamic acid group and the placebo group.

• The adjusted common odds ratio (acOR) for a better outcome (lower mRS score) with tranexamic acid was 0.88 (95% CI, 0.76–1.03; p=0.11).

Secondary Outcomes

• Hematoma Expansion at 24 hours (defined as >6 mL or >33% increase):
  • Tranexamic acid group: 25%
  • Placebo group: 29%
    (Adjusted OR 0.80, 95% CI 0.66–0.98; p=0.0300). TXA was associated with a small but statistically significant reduction in hematoma expansion.
• Mortality at 7 days:
  • Tranexamic acid group: 9%
  • Placebo group: 11%
    (Adjusted OR 0.73, 95% CI 0.53–0.99; p=0.0406). TXA was associated with a reduction in early mortality.
• Mortality at 90 days:
  • Tranexamic acid group: 21.1%
  • Placebo group: 22.7%
    (Adjusted OR 0.88, 95% CI 0.72–1.08; p=0.22). No significant difference in overall 90-day mortality.
• Favorable Functional Outcome (mRS 0–3) at 90 days:
  • Tranexamic acid group: 53.0%
  • Placebo group: 53.5%
    (Adjusted OR 0.94, 95% CI 0.79–1.12; p=0.50). No significant difference.

Safety Outcomes

• Thromboembolic Events (venous or arterial): Occurred in similar proportions in both groups (TXA: 11%; Placebo: 10%).
• Seizures: Occurred in similar proportions (TXA: 7%; Placebo: 6%).
• Overall rates of serious adverse events were comparable.

Final Thoughts & Critical Appraisal

The TICH-2 trial was a large, well-executed study that addressed an important clinical question regarding the use of tranexamic acid in acute ICH. Despite showing some positive effects on surrogate markers (reduced hematoma expansion) and early mortality, TXA did not translate these into a significant improvement in overall functional outcome at 90 days.

Key takeaways:

• No Improvement in 90-Day Functional Outcome: The primary finding is that TXA, when administered within 8 hours of ICH onset, did not lead to a statistically significant improvement in the distribution of mRS scores at 90 days.
• Reduction in Hematoma Expansion and Early Death: TXA was associated with a modest reduction in hematoma expansion at 24 hours and a reduction in death within 7 days. These findings are consistent with its known antifibrinolytic mechanism.
• Lack of Translation to Long-Term Benefit: The failure of these early positive effects to translate into better 90-day functional status is a crucial point. It suggests that either the effect on hematoma growth was too small to impact long-term recovery, other mechanisms of secondary brain injury are more dominant, or the 8-hour window might still be too late for a substantial functional impact in many patients.
• Safety Profile: TXA appeared to be safe in this population, with no significant increase in thromboembolic events or seizures compared to placebo, which was an important finding given theoretical concerns.
• Implications for Practice: The results of TICH-2, combined with the more recent INTREPID trial (which tested TXA in an even earlier window and also found no functional benefit), generally do not support the routine use of tranexamic acid for patients with acute intracerebral hemorrhage with the aim of improving 90-day functional outcome.

TICH-2 was a pivotal trial that, while not demonstrating the hoped-for functional benefit, provided valuable information on the effects and safety of TXA in ICH. It has significantly influenced guidelines and clinical practice regarding the use of antifibrinolytics in this condition.

How do we reconcile the results with other studies?

(Content for this section needs to be added, comparing TICH-2 with INTREPID, CRASH trials (trauma/TBI), WOMAN trial (postpartum hemorrhage), and discussing the differences in pathophysiology or treatment windows that might explain varying efficacy of TXA across different bleeding conditions.)

Found an error or want to suggest an improvement? Edit this page on GitHub.