Tranexamic acid for acute gastrointestinal bleeding (the HALT-IT trial): statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial

IntroductionThe management of acute upper gastrointestinal bleeding (UGIB) is challenging in patients with cirrhosis, as it is responsible for severe complications and high mortality rates. Tranexamic acid (TXA) may help control the bleeding by counterbalancing cirrhosis-related hyperfibrinolysis. Still, there is a lack of unbiased data to conclude on its efficacy. The aim of this study is to evaluate the efficacy of TXA in the early treatment of acute UGIB in patients with cirrhosis.Methods and analysisThis study is a multicentre, randomised, double-blind, placebo-controlled trial, for adult patients with cirrhosis presenting with an acute UGIB and allocated to one of two arms: TXA or placebo (saline). Physicians from emergency mobile services, emergency departments (EDs) or intensive care units (ICUs) can include patients. Besides study intervention, standard care for UGIB will be performed as recommended. Intervention will consist an intravenous infusion of 10 mL of TXA (1 g) or saline, immediately followed by three identical intravenous infusions over 8 hours each (total dose of 4 g of TXA or 40 mL of placebo over 24 hours). Main analyses will be conducted in intention to treat on every patient included, then in modified intention to treat on patients with underlying lesion of portal hypertension visualised by endoscopy. The main objective is to show efficacy of TXA until day 5 on a composite criterion (bleeding control, rebleeding episodes and mortality). Secondary objectives aim at showing the efficacy of TXA on each individual component of the main outcome measure and others at 6 weeks and later (transjugular intrahepatic portosystemic shunt procedure, cirrhosis-specific complications, length of stay in ICU and in hospital, safety and tolerance of TXA, liver transplantation). Included patients will be followed up to 1 year after inclusion.500 patients will be necessary to show a reduction in the prevalence of the primary outcome from 30% to 18% with a bilateral alpha risk of 5% and a power of 80%.Ethics and disseminationEthical approval has been obtained from the Comité de Protection des Personnes Ile-de-France 1 (CPP-IDF1). Results will be disseminated via publications in peer-review medical journals and scientific forums.Protocol versionThis protocol is based on the latest version, as established on 11 October 2017 and validated by the IRB CPP Ile-de-France 1.Trial registration numberNCT03023189.

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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

10.21203/rs.2.276/v1 ◽

2019 ◽

Author(s):

Amy Charlotte Brenner ◽

Adefemi Afolabi ◽

Syed Masroor Ahmad ◽

Monica Arribas ◽

Rizwana Chaudhri ◽

...

Keyword(s):

Statistical Analysis ◽

Blood Transfusion ◽

Tranexamic Acid ◽

Primary Outcome ◽

Controlled Trial ◽

Gi Bleeding ◽

Double Blind ◽

Double Blind Placebo ◽

Upper Gi ◽

Lower Gi Bleeding

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 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 8,000) with acute upper or lower GI bleeding. Eligible patients are randomly allocated to receive tranexamic acid (1g loading dose followed by 3g maintenance dose over 24 hours) or matching placebo. The main analysis will compare those randomised to tranexamic acid with those randomised to placebo on an intention-to-treat basis, presenting the results as effect estimates (relative and absolute 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 prepared and submitted for publication before the treatment allocation was un-blinded. Trial Registration: Current Controlled Trials ISRCTN11225767 (3/07/2012); Clinicaltrials.gov NCT01658124 (26/07/2012). Keywords: Gastrointestinal haemorrhage, tranexamic acid, clinical trial, statistical analysis.

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Comparison of the efficacy of intravenous tranexamic acid with and without topical administration versus placebo in urgent endoscopy rate for acute gastrointestinal bleeding: A double-blind randomized controlled trial

United European Gastroenterology Journal ◽

10.1177/2050640617714940 ◽

2017 ◽

Vol 6 (1) ◽

pp. 46-54 ◽

Cited By ~ 8

Author(s):

Nader Tavakoli ◽

Marjan Mokhtare ◽

Shahram Agah ◽

Ali Azizi ◽

Mohsen Masoodi ◽

...

Keyword(s):

Blood Transfusion ◽

Gastrointestinal Bleeding ◽

Tranexamic Acid ◽

Surgical Intervention ◽

Controlled Trial ◽

Topical Administration ◽

Double Blind ◽

Treatment Groups ◽

Acute Gastrointestinal Bleeding ◽

Elective Procedure

Background Tranexamic acid (TXA), a synthetic antifibrinolytic drug, is effective as a treatment for serious hemorrhage, including bleeding arising from major trauma and post-operative interventions. Significant acute gastrointestinal bleeding may have a poor outcome despite routine medical and endoscopic treatments. The aim of this study was to assess whether early intravenous and/or intravenous plus topical administration of TXA reduces the need for urgent endoscopy for acute gastrointestinal bleeding. Method This double-blind randomized clinical trial included 410 patients with proven acute gastrointestinal bleeding. All patients received conventional therapy. The subjects were randomized to three groups: (A) 138 patients received intravenous TXA (1 g q6h); (B) 133 patients received topical TXA (1 g single dose by nasogastric tube) plus systemic TXA; and (C) 139 patients received a placebo (sodium chloride 0.9%) for 24 hours. Subgroup statistical analyses were conducted for urgent endoscopy, mortality, re-bleeding, blood transfusion, endoscopic and/or surgical intervention rates, and health status. Results The time to endoscopy was significantly shorter in group C (15.58 ± 7.994, p < 0.001). A need for urgent endoscopy was seen in 14.49%, 10.52%, and 30.21% of patients in groups A, B, and C, respectively ( p < 0.001). No significant statistical differences were seen between treatment groups regarding mortality, re-bleeding, blood transfusion, and endoscopic and/or surgical intervention rates. No thromboembolic event was documented during the 1-week follow up. Conclusions Our results showed that the antifibrinolytic properties of TXA can aid in changing an urgent endoscopy to an elective procedure, with better outcomes for both physicians and patients.

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