The HALT-IT Trial Collaborators
Lancet 2020, 395: 1927–36
AIM OF STUDY
To assess the effects of tranexamic acid in patients with gastrointestinal bleeding
DESIGN (& LOCATION)
Randomised, double blinded, placebo-controlled.
Multi-centred – 164 hospitals across Multi-nations (15 countries)
World Bank (income)
- High: UK, Australia, Spain, Ireland, Saudi Arabia, Romania
- Mid-high: Malaysia, Albania, Georgia
- Mid-low: Pakistan, Egypt, Nigeria, Nepal, Papua New Guinea
- Low: Sudan
Approval
- UK NRES Committee East of England (reference number 12/EE/0038); or,
- national / local research ethics committees non-UK participant countries
Data collection – Jul 2013 to Jul 2019
Funding – NIHR
METHODOLOGY
Randomisation
- Numbers generated by Sealed Envelope (London, UK), independent statistician.
Treatment packs created/masked by:
- Sharp Clinical Services UK (Crickhowell, UK), a Good Manufacturing Practice certified service
- Removing manufacturer’s label and replacing it with the clinical trial label and randomisation number
- Coding checked by testing each batch of ampoules with high-performance liquid chromatography
Enrolment
Inclusion:
Adult (age ≥ 16-18)
Significant bleeding as defined by:
- ↓BP, ↑HR, shocked
- transfusion likely
- urgent endoscopy or surgery)
Clinician unsure about TXA
Exclusion: none
Consent
- If capacity was impaired and a personal or professional representative was available, consent was sought from the representative.
- If neither were able to provide consent, it was waived, and the patient was informed about the trial and consented for ongoing data collection as soon as possible afterwards.
Eligible patients:
- randomly assigned as possible
- lowest numbered treatment pack was taken from a box of eight packs.
- treatment was started immediately.
Intervention
- Loading: 1g TXA in 100mL 0.9% NaCl infused over 10 minutes.
- Maintenance: 3g TXA in 1000ml of any isotonic IV solution 125mg/h for 24h
Control –
- placebo (sodium chloride 0·9%)
Outcome data collected at death, discharge from the randomising hospital, or 28 days after randomisation, whichever occurred first.
PRIMARY OUTCOME
Death due to bleeding within 5 days
SECONDARY OUTCOMES
Re-bleeding
Arterial thromboembolism (MI/CVA)
Venous thromboembolism (PE/DVT)
Surgical, endoscopic, or radiological intervention
Transfusion of blood products
Other complications (pneumonia, liver/renal failure, sepsis, seizures)
STATISTICS
Randomisation
- block non stratified
- 12,009 patients. 5994 Intervention (49·9%) and 6015 Placebo (50.1%)
Original sample size
-based on all-cause mortality 1° outcome, assuming baseline 10% mortality.
-powered (90%) to detect ↓25% mortality 10% to 7.5%; estimated sample size 8000
Amended sample size:
-1° outcome changed to death within 5days of randomisation, 9 months before end of trial
-based on TXA T½=2–3h (99% eliminated by 2d of randomisation);
-to avoid dilution of sample from all-cause mortality
-powered (85%) ↓25% death due to bleeding from 4 to 3%; estimated sample size 12000
Modified intention-to-treat used. Excluded those who received neither dose or where outcome data on death were unavailable:
- received neither: dose 52 (TXA 29, Placebo 23) /12,009 [0.43%]
- consent withdrawn and outcome unavailable:
- 17 (TXA 6, Placebo 11) /12,009 [0.14%]
- Consent withdrawn but outcome available:
- 12 (TXA 5, Placebo 7) /12,009 [0.1%]
Statistical analysis plan published by Brenner et al; Trials; (20:467; 2019);
- DOI:10.1186/s13063-019-3561-7
- Exact statistical tests applied – not published.
RESULTS
Death: No difference
TXA: 222/5956 [4%] vs placebo 226/5981 [4%]
(RR 0·99, 95% CI 0·82–1·18)
ATE: No difference
TXA 42/5952 [0.7%] vs placebo 46/5977 [0.8%]
(RR 0·92, 95% CI 0·60 to 1·39)
VTE: higher in TXA group
TXA 48/5952 [0.8%] vs 26/5977 [0.4%]
RR 1·85; 95% CI 1·15 to 2·98).
AUTHORS’ CONCLUSIONS/DISCUSSION
TXA did not reduce death from gastrointestinal bleeding.
- Ruled out large mortality reduction suggested by the Cochrane systematic review (2012)
TXA should not be used outside the context of a randomised trial.
AUTHORS’ STATED LIMITATIONS FROM STUDY
- use of the pre-endoscopy Rockall score might have misclassified baseline risk.
- strict criteria to diagnose thromboembolic event (i.e. positive ultrasound imaging or post mortem) might have led to some under reporting.
- in gastrointestinal bleeding it is difficult to determine the time of bleeding onset, presentation is often delayed. This is unlike in trauma / obstetrics where TXA can be given ≤3h.
- cannot rule out a modest increase or decrease in death due to bleeding with tranexamic acid.
DISCUSSION FROM JOURNAL CLUB MEETING (? Change of practice)
Strengths
- Good overall design and well powered for 1° outcome.
- Multi-centred, multinational.
- Baseline characteristics well matched
- Minimal loss to follow up (<1%) & small number of protocol violations
Weaknesses
- Enrolment by principle of uncertainty. Unclear if this over or under reports the benefits/risks of TXA where if patient outcome is more clearly indicated/contraindicated.
- VTE incidence very small for large sample, data lacking clarity on timing and severity.
- Uncertainty for patients with liver disease with their complex coagulation picture
- No recommendation for or against TXA usage identified by various gastroenterology colleges of UK / USA / Canada / Europe
Does this change practice?
- Raised awareness for caution in GI bleeding cases when uncertain of TXA benefit/risk.
- VTE risk needs to be factored into decision making process, but small incidence numbers suggest risk not as big as previously thought.
- To look into alternative/additional data (ie TEG) to assess VTE risk
Summary by Dr J He. Journal Club Meeting 2 February 2023.
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