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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
Trials. 2019;20(1):467
Abstract
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.
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Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster randomised feasibility trial
Jairath V, Kahan BC, Gray A, Dore CJ, Mora A, James MW, Stanley AJ, Everett SM, Bailey AA, Dallal H, et al
Lancet. 2015;386((9989)):137-44.
Abstract
BACKGROUND Transfusion thresholds for acute upper gastrointestinal bleeding are controversial. So far, only three small, underpowered studies and one single-centre trial have been done. Findings from the single-centre trial showed reduced mortality with restrictive red blood cell (RBC) transfusion. We aimed to assess whether a multicentre, cluster randomised trial is a feasible method to substantiate or refute this finding. METHODS In this pragmatic, open-label, cluster randomised feasibility trial, done in six university hospitals in the UK, we enrolled all patients aged 18 years or older with new presentations of acute upper gastrointestinal bleeding, irrespective of comorbidity, except for exsanguinating haemorrhage. We randomly assigned hospitals (1:1) with a computer-generated randomisation sequence (random permuted block size of 6, without stratification or matching) to either a restrictive (transfusion when haemoglobin concentration fell below 80 g/L) or liberal (transfusion when haemoglobin concentration fell below 100 g/L) RBC transfusion policy. Neither patients nor investigators were masked to treatment allocation. Feasibility outcomes were recruitment rate, protocol adherence, haemoglobin concentration, RBC exposure, selection bias, and information to guide design and economic evaluation of the phase 3 trial. Main exploratory clinical outcomes were further bleeding and mortality at day 28. We did analyses on all enrolled patients for whom an outcome was available. This trial is registered, ISRCTN85757829 and NCT02105532. FINDINGS Between Sept 3, 2012, and March 1, 2013, we enrolled 936 patients across six hospitals (403 patients in three hospitals with a restrictive policy and 533 patients in three hospitals with a liberal policy). Recruitment rate was significantly higher for the liberal than for the restrictive policy (62% vs 55%; p=004). Despite some baseline imbalances, Rockall and Blatchford risk scores were identical between policies. Protocol adherence was 96% (SD 10) in the restrictive policy vs 83% (25) in the liberal policy (difference 14%; 95% CI 7-21; p=0005). Mean last recorded haemoglobin concentration was 116 (SD 24) g/L for patients on the restrictive policy and 118 (20) g/L for those on the liberal policy (difference -20 [95% CI -120 to 70]; p=050). Fewer patients received RBCs on the restrictive policy than on the liberal policy (restrictive policy 133 [33%] vs liberal policy 247 [46%]; difference -12% [95% CI -35 to 11]; p=023), with fewer RBC units transfused (mean 12 [SD 21] vs 19 [28]; difference -07 [-16 to 03]; p=012), although these differences were not significant. We noted no significant difference in clinical outcomes. INTERPRETATION A cluster randomised design led to rapid recruitment, high protocol adherence, separation in degree of anaemia between groups, and non-significant reduction in RBC transfusion in the restrictive policy. A large cluster randomised trial to assess the effectiveness of transfusion strategies for acute upper gastrointestinal bleeding is both feasible and essential before clinical practice guidelines change to recommend restrictive transfusion for all patients with acute upper gastrointestinal bleeding. FUNDING NHS Blood and Transplant Research and Development.Copyright © 2015 Elsevier Ltd. All rights reserved.
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Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (trigger): pragmatic, cluster randomised, feasibility trial
Gray A, Jairath V, Kahan B, Dore C, Palmer K, Travis S, Logan R, Walsh T, Murphy M
Emergency Medicine Journal. 2014;31((9):):780.. Abstract No. 008
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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
Trials. 2014;15((450):)
Abstract
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).
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Update on the transfusion in gastrointestinal bleeding (TRIGGER) trial: statistical analysis plan for a cluster-randomised feasibility trial
Kahan BC, Jairath V, Murphy MF, Dore CJ
Trials [Electronic Resource]. 2013;14:206
Abstract
BACKGROUND Previous research has suggested an association between more liberal red blood cell (RBC) transfusion and greater risk of further bleeding and mortality following acute upper gastrointestinal bleeding (AUGIB). METHODS AND DESIGN The Transfusion in Gastrointestinal Bleeding (TRIGGER) trial is a pragmatic cluster-randomised feasibility trial which aims to evaluate the feasibility of implementing a restrictive vs. liberal RBC transfusion policy for adult patients admitted to hospital with AUGIB in the UK. This trial will help to inform the design and methodology of a phase III trial. The protocol for TRIGGER has been published in Transfusion Medicine Reviews. Recruitment began in September 2012 and was completed in March 2013. This update presents the statistical analysis plan, detailing how analysis of the TRIGGER trial will be performed. It is hoped that prospective publication of the full statistical analysis plan will increase transparency and give readers a clear overview of how TRIGGER will be analysed. TRIAL REGISTRATION ISRCTN85757829.
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Restrictive vs liberal blood transfusion for acute upper gastrointestinal bleeding: rationale and protocol for a cluster randomized feasibility trial
Jairath V, Kahan BC, Gray A, Dore CJ, Mora A, Dyer C, Stokes EA, Llewelyn C, Bailey AA, Dallal H, et al
Transfusion Medicine Reviews. 2013;27((3):):146-53.
Abstract
Acute upper gastrointestinal bleeding (AUGIB) is the commonest reason for hospitalization with hemorrhage in the UK and the leading indication for transfusion of red blood cells (RBCs). Observational studies suggest an association between more liberal RBC transfusion and adverse patient outcomes, and a recent randomised trial reported increased further bleeding and mortality with a liberal transfusion policy. TRIGGER (Transfusion in Gastrointestinal Bleeding) is a pragmatic, cluster randomized trial which aims to evaluate the feasibility and safety of implementing a restrictive versus liberal RBC transfusion policy in adult patients admitted with AUGIB. The trial will take place in 6 UK hospitals, and each centre will be randomly allocated to a transfusion policy. Clinicians throughout each hospital will manage all eligible patients according to the transfusion policy for the 6-month trial recruitment period. In the restrictive centers, patients become eligible for RBC transfusion when their hemoglobin is <8 g/dL. In the liberal centers patients become eligible for transfusion once their hemoglobin is <10 g/dL. All clinicians will have the discretion to transfuse outside of the policy but will be asked to document the reasons for doing so. Feasibility outcome measures include protocol adherence, recruitment rate, and evidence of selection bias. Clinical outcome measures include further bleeding, mortality, thromboembolic events, and infections. Quality of life will be measured using the EuroQol EQ-5D at day 28, and the costs associated with hospitalization for AUGIB in the UK will be estimated. Consent will be sought from participants or their representatives according to patient capacity for use of routine hospital data and day 28 follow up. The study has ethical approval for conduct in England and Scotland. Results will be analysed according to a pre-defined statistical analysis plan and disseminated in peer reviewed publications to relevant stakeholders. The results of this study will inform the feasibility and design of a phase III randomized trial. Copyright 2013 Elsevier Inc. All rights reserved.