TICH-2: Tranexamic Acid for Intracerebral Hemorrhage (2018)

“In patients with intracerebral haemorrhage, tranexamic acid was not associated with a significant reduction in the risk of death or dependency at 90 days, but it was associated with a reduction in early mortality and fewer serious adverse events.”

— The TICH-2 Investigators

1. Publication Details

  • Trial Title: Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial.
  • Citation: Sprigg N, Flaherty K, Appleton JP, et al; for the TICH-2 Investigators. Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial. Lancet. 2018;391(10135):2107-2115. doi:10.1016/S0140-6736(18)31033-X.
  • Published: May 26, 2018, in The Lancet.
  • Author: Nikola Sprigg, Ph.D., F.R.C.P.
  • Funding: UK National Institute for Health Research.

2. Keywords

Intracerebral Hemorrhage (ICH), Stroke, Tranexamic Acid, Antifibrinolytic, Hematoma Expansion, Neurocritical Care.

3. The Clinical Question

In adult patients with acute spontaneous intracerebral hemorrhage (ICH) (Population), does early administration of tranexamic acid (Intervention) compared to placebo (Comparison) improve functional outcome at 90 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Hematoma expansion occurs in about one-third of patients with ICH and is a major predictor of poor outcome. Tranexamic acid (TXA) is an antifibrinolytic agent that reduces bleeding and has been shown to improve outcomes in trauma (CRASH-2 trial).
  • Knowledge Gap: It was unknown if the hemostatic benefit of TXA would translate to improved functional outcomes in patients with spontaneous ICH. Smaller pilot studies had suggested it was safe and could reduce hematoma growth, but a large, definitive trial was needed.
  • Proposed Hypothesis: The authors hypothesized that tranexamic acid would improve functional outcome at 90 days in patients with ICH.

5. Study Design and Methods

  • Design: A prospective, multicenter, international, randomized, double-blind, placebo-controlled, phase 3 trial.
  • Setting: 124 hospitals in 12 countries.
  • Trial Period: Enrollment from March 2013 to September 2017.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with spontaneous ICH, able to start treatment within 8 hours of symptom onset.
    • Exclusion Criteria: ICH secondary to trauma, aneurysm, or AVM; pre-existing disability (mRS >4); or clear indication or contraindication to TXA.
  • Intervention: Tranexamic acid, administered as a 1 g intravenous bolus over 10 minutes, followed by a 1 g infusion over 8 hours.
  • Control: Matching placebo (0.9% saline) administered in the same manner.
  • Management Common to Both Groups: All patients received standard of care for ICH, including blood pressure management, according to local guidelines.
  • Power and Sample Size: The trial was powered to detect a 6% absolute difference in the primary outcome, requiring 2000 patients.
  • Outcomes:
    • Primary Outcome: Functional status at 90 days, assessed by the modified Rankin Scale (mRS) and analyzed as an ordinal shift across the scale.
    • Secondary Outcomes: Included 90-day mortality, hematoma expansion at 24 hours, and safety outcomes (e.g., thromboembolic events).

6. Key Results

  • Enrollment and Baseline: 2325 patients were randomized (1161 to tranexamic acid, 1164 to placebo). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the primary outcome of functional status (ordinal mRS) at 90 days between the tranexamic acid and placebo groups.
  • Secondary Outcomes: Tranexamic acid was associated with a significant reduction in hematoma expansion at 24 hours and a significant reduction in death by day 7. However, there was no significant difference in 90-day mortality.
  • Adverse Events: The rates of thromboembolic events and other serious adverse events were similar between the two groups, confirming the safety of TXA in this population.

7. Medical Statistics

  • Analysis Principle: An intention-to-treat analysis was performed.
  • Statistical Tests Used: The primary outcome was analyzed using an ordinal logistic regression model.
  • Primary Outcome Analysis: The distribution of mRS scores at 90 days was compared between the two groups.
  • Key Statistic(s) Reported: Adjusted common Odds Ratio (aOR) for a better outcome on the mRS: 1.03 (95% CI, 0.88 to 1.20; P=0.73).
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR):
      • Formula: An ordinal OR represents the odds of a patient in the intervention group having a better outcome score compared to a patient in the control group.
      • Calculation: The paper reports the adjusted OR as 1.03.
      • Clinical Meaning: An aOR of 1.03 means there was a 3% higher odds of a better functional outcome with tranexamic acid, a difference that is not statistically significant.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The reported 95% CI was 0.88 to 1.20.
      • Clinical Meaning: This confidence interval is centered around the line of no effect (1.0) and is relatively narrow, indicating that any true effect of TXA on functional outcome is likely to be small. Since it crosses 1.0, the result is not statistically significant.
    • P-value:
      • Calculation: The reported p-value was 0.73.
      • Clinical Meaning: The p-value of 0.73 is far above the 0.05 threshold, confirming that the observed result is very likely due to chance. A result is conventionally considered statistically significant if the p-value is less than 0.05.
  • Clinical Impact Measures: Not applicable for the primary outcome as no benefit was shown.
  • Subgroup Analyses: No significant benefit was found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: This was a large, international, multicenter, randomized, double-blind, placebo-controlled trial, representing the highest level of evidence.
  • Generalizability: The pragmatic design and inclusion of a large number of diverse hospitals worldwide increase the applicability of the findings.
  • Patient-Centered Outcomes: The primary outcome of 90-day functional status (mRS) is the standard, patient-centered endpoint for stroke trials.

9. Limitations and Weaknesses

  • Internal Validity (Bias): No major limitations to internal validity.
  • External Validity (Generalizability): The trial included patients up to 8 hours from onset; the effect might be different in patients treated more rapidly.
  • Other: The primary outcome was neutral, despite a positive effect on the surrogate outcome of hematoma expansion.

10. Conclusion of the Authors

“Tranexamic acid did not significantly improve functional outcome at 90 days in patients with intracerebral haemorrhage, despite a reduction in early deaths and serious adverse events. Thrombo-embolic events were not increased.”

11. To Summarize

  • Impact on Current Practice: The TICH-2 trial was a landmark study that clarified the role of tranexamic acid in ICH. Despite failing to improve long-term functional outcome, it confirmed the drug’s safety and its ability to reduce hematoma expansion and early mortality. This has led to its consideration in guidelines as a potential early treatment, although it is not a definitive standard of care due to the neutral primary outcome.
  • Specific Recommendations:
    • Patient Selection: For adult patients with acute, spontaneous intracerebral hemorrhage presenting within 8 hours of onset.
    • Actionable Intervention: Administration of tranexamic acid can be considered, particularly if given very early, as it is safe and reduces early death.
    • Expected Benefit: No proven benefit on 90-day functional outcome, but a reduction in hematoma growth and early mortality.
  • What This Trial Does NOT Mean: This trial does not mean TXA is ineffective. The lack of functional benefit despite reduced hematoma growth suggests that the initial brain injury from the hemorrhage itself is the dominant driver of long-term outcome.
  • Implementation Caveats: The benefit is likely time-dependent, so if used, it should be administered as early as possible.

12. Context and Related Studies

  • Building on Previous Evidence: This trial was a direct follow-up to smaller pilot studies and was designed to be the definitive trial on TXA in ICH, mirroring the success of the CRASH-2 trial (2010) in trauma.
  • Influence on Subsequent Research: The neutral finding has spurred further research. The subsequent STOP-AUST trial (2020), a smaller study focusing on ultra-early (within 4.5 hours) administration, also found a reduction in hematoma expansion but no improvement in functional outcome.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: Does ultra-early administration (<3-4 hours) of TXA lead to an improvement in functional outcome? Are there specific subgroups of ICH patients who might benefit?
  • Future Directions: Research is ongoing to determine if there is a therapeutic window for TXA that is earlier than the 8 hours studied in TICH-2, and to combine hemostatic therapy with other neuroprotective strategies.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The question was highly relevant, testing a widely available, inexpensive, and potentially life-saving drug for a devastating form of stroke.
  • Methods: The study’s design was of the highest quality: a large, international, multicenter, double-blind, placebo-controlled phase 3 RCT.
  • Results: This is a classic example of a trial where a positive effect on a key surrogate outcome (hematoma expansion) and an early clinical outcome (7-day mortality) did not translate into a benefit for the primary long-term functional outcome. The safety findings were also critically important.
  • Conclusions and Applicability: The authors’ conclusion is a precise and fair summary of the data. The trial is highly applicable and informs clinical practice by demonstrating the safety of TXA but tempering expectations about its ability to improve long-term disability. It supports its use as a reasonable, safe, but not definitively proven, early intervention.

16. Disclaimer and Contact

This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.

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