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

The HALT­IT trial was an international, multicentric, randomized, double-blind placebo­ controlled trial. It was carried out in 164 hospitals across 15 countries (UK, Pakistan, Nigeria, Egypt, Malaysia, Georgia, Romania, Nepal, Sudan, Saudi Arabia, Spain, Ireland, Albania, Papua New Guinea, and Australia). Conducted between July 4, 2013, and June 21, 2019.

Inclusion

Included patients were >16 years and older or aged 18 years or older (depending on the definition of adult in their respective country)

If the responsible clinician was “substantially uncertain” whether to use tranexamic acid,and there was clinically significant bleeding: bleeding that carried the risk of bleeding to death included patients with hypotension, tachycardia, or signs of shock, or in need of transfusion or urgent intervention such as endoscopy or surgery. Patients were randomly assigned to get tranexamic acid or placebo as soon as possible and treatment was started immediately.

Patients well-matched at baseline

Intervention

Tranexamic acid Group

Loading dose: 1 g tranexamic acid in 100 mL normal saline and intravenously over 10 min, followed 3 g at 125 mg/h for 24 h.

Control Group

Similar volume of placebo.

Data Collection – 

Outcome data were collected at death, discharge from the randomising hospital, or 28 days after randomisation.

Sample Size 

The sample size calculation was initially based on 28-day all­cause mortality. However,during the course of the study, the investigators observed that over half of all deaths were not due to rebleed. Besides, the short half-life (2h) tranexamic acid was not likely to reduce deaths from rebleeding after several weeks.  Hence, the primary outcome was changed to death due to bleeding within 5 days of randomisation. Based on the amended primary outcome, assuming a risk of death due to bleeding of 4%, a study with 12000 patients has about 85% power (two­sided α of 5%) to detect a clinically important 25% relative reduction in death due to bleeding from 4% to 3%.

Results- 

Patients were well-matched at baseline regarding (age, time from onset to randomization, location of bleeding, variceal bleed, signs of shock, hemodynamic parameters, co-morbidities, Rockall score)

Rockall Score

There were 1112/12009 (5994+6015) deaths . The median time to death was 55 h after randomisation [IQR 18·2–161·8 (6.75 days)].

Primary outcome: The primary outcome was “death due to bleeding” within 5 days of randomisation (Cause of death was assigned by local principal investigators who provided a narrative of events leading to death. These were reviewed by the chief investigator who was masked to treatment allocation and queried if more information was needed to confirm whether death was due to bleeding or another cause).

Secondary outcomes:

Death due to bleeding within 24 h 

Death due to bleeding within 28 days of randomisation

Mortality at 28 days

Rebleeding within 24 h

Rebleedng within 5 days

Rebleeding within 28 days of randomisation, surgery or radiological intervention.

The use of tranexamic acid did not affect the risk of death due to bleeding within 5 days regardless of the following parameters:

Cause-specific mortality at 28 d did not differ

The proportion of patients who had surgery, radiological intervention, and blood product transfusion:  similar between groups.

Thromboembolic events (deep vein thrombosis, pulmonary embolism, stroke, and myocardial infarction),

Seizures

Other complications (including another significant cardiac event, sepsis, pneumonia, respiratory failure, renal failure, liver failure

Strengths – 

• Large, multicentre pragmatic RCT
• Good internal and external validity
• Answered the relevant questions
• Significant epidemiological data on Acute GI bleed – incidence, treatment received etc.
• The minimal loss to follow up

Limitations – 

• Primary outcome revised from all-cause mortality to death due to bleeding within 5 days
• “Clinically significant” bleeding was based on subjective parameters
• Death due to bleeding was a subjective assessment
• Patients with both upper and lower GI bleeding were included. UGI bleed constituted the majority of the patients
• No detailed data regarding the cause of the bleed
• Clinician had to be “substantially uncertain” regarding the benefit of tranexamic acid
• Details of DVT screening are not provided

Summary – 

Landmark trial

No place for tranexamic acid in the treatment of acute GI bleed until we see another trial with opposite results