HALT-IT: Tranexamic Acid in Gastrointestinal Bleeding (2020)

“We found no evidence that tranexamic acid reduces death from gastrointestinal bleeding. Our results show an increased risk of venous thromboembolism and seizures, and do not support the use of tranexamic acid in patients with acute gastrointestinal bleeding.”

  • The HALT-IT Trial Collaborators

1. Publication Details

  • Trial Title: Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial
  • Citation: HALT-IT Trial Collaborators. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet. 2020;395(10241):1927-1936. DOI: 10.1016/S0140-6736(20)30848-5
  • Published: June 20, 2020, in The Lancet
  • Author: The HALT-IT Trial Collaborators
  • Funding: UK National Institute for Health Research Health Technology Assessment programme.

2. Keywords

  • Gastrointestinal Bleeding, Tranexamic Acid (TXA), Antifibrinolytic, Hemorrhage, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with significant acute gastrointestinal (GI) bleeding (Population), does treatment with tranexamic acid (TXA) (Intervention) compared to placebo (Comparison) reduce death due to bleeding within 5 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Tranexamic acid, an antifibrinolytic agent, had been proven to be a life-saving intervention in trauma (CRASH-2 trial) and postpartum hemorrhage (WOMAN trial) by reducing bleeding-related deaths.
  • Knowledge Gap: Despite its proven benefit in other major bleeding states, the role of TXA in acute GI bleeding was unknown. It was a critical and unanswered question whether the benefits would translate to this very common and life-threatening condition.
  • Proposed Hypothesis: The authors hypothesized that tranexamic acid would be superior to placebo in reducing death due to bleeding in patients with acute GI hemorrhage.

5. Study Design and Methods

  • Design: A very large, international, multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: 164 hospitals in 15 countries.
  • Trial Period: Enrollment ran from July 2013 to September 2019.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) with significant acute GI bleeding (defined as a risk of death, hypotension, tachycardia, or requiring transfusion).
    • Exclusion Criteria: Included patients for whom the clinician was certain that tranexamic acid was either indicated or contraindicated.
  • Intervention: Patients received a loading dose of tranexamic acid (1g over 10 minutes) followed by an infusion of 3g over 24 hours.
  • Control: Patients received a matching intravenous placebo (0.9% saline).
  • Management Common to Both Groups: All other aspects of care for GI bleeding, including endoscopic therapy, were at the discretion of the treating clinicians.
  • Power and Sample Size: The authors calculated that a sample size of 12,000 patients would provide 90% power to detect a 2.5% absolute risk reduction in the primary outcome. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: Death due to bleeding within 5 days of randomization.
    • Secondary Outcomes: Included all-cause mortality, need for surgery or angiography, blood product transfusion, and the incidence of vascular occlusive events (e.g., myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism).

6. Key Results

  • Enrollment and Baseline: 12,009 patients were randomized (5994 to TXA and 6015 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. Death due to bleeding occurred in 222 of 5994 patients (3.7%) in the TXA group, compared with 223 of 6015 patients (3.7%) in the placebo group (p=0.99).
  • Secondary Outcomes: There was no significant difference in all-cause mortality or the need for transfusion.
  • Adverse Events: The incidence of venous thromboembolic events (deep vein thrombosis and pulmonary embolism) was significantly higher in the tranexamic acid group (0.8% vs. 0.4%; p=0.025).

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death due to bleeding between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for death due to bleeding: 1.00 (95% CI, 0.82 to 1.22; P-value: 0.99).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the result as 1.00.
      • Clinical Meaning: An RR of 1.00 indicates absolutely no difference in the risk of death due to bleeding between the two groups.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.82 to 1.22.
      • Clinical Meaning: Since this range crosses the line of no effect (1.0), it confirms that the result is not statistically significant. Clinically, this means the true effect could range from an 18% benefit to a 22% harm.
    • P-value: The p-value of 0.99 is much higher than the 0.05 threshold, indicating the result is not statistically significant and providing strong evidence of no effect (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures (for the outcome of venous thromboembolism):
    • Absolute Risk Increase (ARI):
      • Formula: ARI = (Risk in Intervention Group) – (Risk in Control Group)
      • Calculation: ARI = 0.8% – 0.4% = 0.4%.
      • Clinical Meaning: For every 1000 patients treated with TXA for GI bleeding, about 4 additional venous thromboembolic events occurred.
    • Number Needed to Harm (NNH):
      • Formula: NNH = 1 / ARI
      • Calculation: NNH = 1 / 0.004 = 250.
      • Clinical Meaning: You would need to treat 250 patients with TXA to cause one additional venous thromboembolic event.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The very large, multicenter, randomized, double-blind, placebo-controlled design is the gold standard and provided a massive amount of high-quality data.
  • Generalizability: The pragmatic design with broad inclusion criteria and enrollment across 15 diverse countries makes the findings highly generalizable to a wide range of patients with GI bleeding.
  • Statistical Power: The enormous sample size provided definitive power to confidently rule out even a small but clinically important mortality benefit.
  • Patient-Centered Outcomes: The primary outcome of death due to bleeding is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a very low risk of bias.
  • External Validity (Generalizability): The findings are highly generalizable to a broad population of patients with significant acute GI bleeding.
  • Other: The study did not find a benefit, but it did find a signal of harm (increased VTE), which is a critical finding.

10. Conclusion of the Authors

  • The authors concluded that tranexamic acid does not reduce death from gastrointestinal bleeding and that the risk of venous thromboembolism is increased.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial. It provided definitive evidence that a therapy proven to be life-saving in other bleeding conditions is not effective and may be harmful in acute GI bleeding. It led to the immediate de-adoption of this practice.
  • Specific Recommendations:
    • Patient Selection: For adult patients with significant acute gastrointestinal bleeding.
    • Actionable Intervention: Do not administer tranexamic acid.
  • What This Trial Does NOT Mean: This trial does NOT mean that TXA is not a useful drug. Its findings are specific to the pathophysiology of GI bleeding and do not negate its proven benefit in trauma or postpartum hemorrhage.
  • Implementation Caveats: The key takeaway is that evidence for an intervention in one clinical condition cannot be automatically extrapolated to another, even if they seem similar.

12. Context and Related Studies

  • Building on Previous Evidence: The HALT-IT trial (2020) was designed to see if the dramatic life-saving benefits of TXA seen in the CRASH-2 (2010) and WOMAN (2017) trials would apply to GI bleeding.
  • Influence on Subsequent Research: The definitive neutral-to-harmful result of this trial has largely settled the question of TXA’s role in GI bleeding and has been highly influential in shaping clinical practice guidelines.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question with a clear neutral result.
  • Future Directions: The results of this trial have shifted the focus of research in GI bleeding to other areas, such as optimizing endoscopic techniques and managing anticoagulation.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, testing a simple, inexpensive, and potentially life-saving intervention for a very common and deadly condition.
  • Methods: The very large, multicenter, double-blind RCT design was of the highest quality and was essential for providing a definitive answer. The pragmatic design ensured high external validity.
  • Results: The study reported a clear neutral finding for its primary outcome. The finding of a statistically significant increase in harm (venous thromboembolism) was a critical safety signal.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The trial is a landmark in evidence-based medicine, serving as a powerful example of how a therapy that is life-saving in one context can be ineffective and even harmful in another. Its findings are broadly applicable and provide a strong recommendation against the use of TXA in GI bleeding.

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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