Tranexamic acid for acute gastrointestinal bleeding (the HALT-IT trial): statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial
Brenner A, Afolabi A, Ahmad SM, Arribas M, Chaudhri R, Coats T, Cuzick J, Gilmore I, Hawkey C, Jairath V, et al
BACKGROUND Acute gastrointestinal (GI) bleeding is an important cause of mortality worldwide. Bleeding can occur from the upper or lower GI tract, with upper GI bleeding accounting for most cases. The main causes include peptic ulcer/erosive mucosal disease, oesophageal varices and malignancy. The case fatality rate is around 10% for upper GI bleeding and 3% for lower GI bleeding. Rebleeding affects 5-40% of patients and is associated with a four-fold increased risk of death. Tranexamic acid (TXA) decreases bleeding and the need for blood transfusion in surgery and reduces death due to bleeding in patients with trauma and postpartum haemorrhage. It reduces bleeding by inhibiting the breakdown of fibrin clots by plasmin. Due to the methodological weaknesses and small size of the existing trials, the effectiveness and safety of TXA in GI bleeding is uncertain. The Haemorrhage ALleviation with Tranexamic acid - Intestinal system (HALT-IT) trial aims to provide reliable evidence about the effects of TXA in acute upper and lower GI bleeding. METHODS The HALT-IT trial is an international, randomised, double-blind, placebo-controlled trial of tranexamic acid in 12,000 adults (increased from 8000) with acute upper or lower GI bleeding. Eligible patients are randomly allocated to receive TXA (1-g loading dose followed by 3-g maintenance dose over 24 h) or matching placebo. The main analysis will compare those randomised to TXA with those randomised to placebo on an intention-to-treat basis, presenting the results as effect estimates (relative risks) and confidence intervals. The primary outcome is death due to bleeding within 5 days of randomisation and secondary outcomes are: rebleeding; all-cause and cause-specific mortality; thromboembolic events; complications; endoscopic, radiological and surgical interventions; blood transfusion requirements; disability (defined by a measure of patient's self-care capacity); and number of days spent in intensive care or high-dependency units. Subgroup analyses for the primary outcome will consider time to treatment, location of bleeding, cause of bleed and clinical Rockall score. DISCUSSION We present the statistical analysis of the HALT-IT trial. This plan was published before the treatment allocation was unblinded. TRIAL REGISTRATION Current Controlled Trials, ID: ISRCTN11225767. Registered on 3 July 2012; Clinicaltrials.gov, ID: NCT01658124. Registered on 26 July 2012.
HALT-IT - tranexamic acid for the treatment of gastrointestinal bleeding: study protocol for a randomised controlled trial
Roberts I, Coats T, Edwards P, Gilmore I, Jairath V, Ker K, Manno D, Shakur H, Stanworth S, Veitch A
BACKGROUND Gastrointestinal bleeding is a common emergency that causes substantial mortality worldwide. Acute upper and lower gastrointestinal bleeding accounts for about 75,000 hospital admissions each year in the UK and causes the death of about 10% of these patients.Tranexamic acid has been shown to reduce the need for blood transfusion in surgical patients and to reduce mortality in bleeding trauma patients, with no apparent increase in thromboembolic events.A systematic review of clinical trials of upper gastrointestinal bleeding shows a reduction in the risk of death with tranexamic acid but the quality of the trials was poor and the estimates are imprecise. The trials were also too small to assess the effect of tranexamic acid on thromboembolic events. METHODS HALT-IT is a pragmatic, randomised, double-blind, placebo-controlled trial which will determine the effect of tranexamic acid on mortality, morbidity (re-bleeding, non-fatal vascular events), blood transfusion, surgical intervention, and health status in patients with acute gastrointestinal bleeding. Eight thousand adult patients who fulfil the eligibility criteria will be randomised to receive tranexamic acid or placebo.Adults with significant acute upper or lower gastrointestinal bleeding can be included if the responsible doctor is substantially uncertain as to whether or not to use tranexamic acid in that particular patient.Trial treatment consists of a loading dose of tranexamic acid (1 g by intravenous injection) or placebo (sodium chloride 0.9%) given as soon as possible after randomisation, followed by an intravenous infusion of 3 g tranexamic acid or placebo (sodium chloride 0.9%) over 24 hours.The main analyses will compare those allocated tranexamic acid with those allocated placebo, on an intention-to-treat basis. Results will be presented as effect estimates with a measure of precision (95% confidence intervals). Subgroup analyses for the primary outcome will be based on time to treatment, source of bleeding (upper versus lower), suspected variceal bleeding and severity of bleeding. A study with 8,000 patients will have over 90% power to detect a 25% reduction in mortality from 10% to 7.5%. TRIAL REGISTRATION Current Controlled Trials ISRCTN11225767 (registration date: 3 July 2012); Clinicaltrials.gov NCT01658124 (registration date: 26 July 2012).