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

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 (participant and trial staff), 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 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 un-blinded.

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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/v3 ◽

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 ◽

Upper Gi Bleeding ◽

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 (participant and trial staff), 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 published before the treatment allocation was un-blinded.

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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/v2 ◽

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 ◽

Upper Gi Bleeding ◽

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 (participant and trial staff), 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 published before the treatment allocation was un-blinded.

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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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Tranexamic acid for acute intracerebral haemorrhage growth based on imaging assessment (TRAIGE): a multicentre, randomised, placebo-controlled trial

Stroke and Vascular Neurology ◽

10.1136/svn-2021-000942 ◽

2021 ◽

pp. svn-2021-000942

Author(s):

Jingyi Liu ◽

Ximing Nie ◽

Hongqiu Gu ◽

Qi Zhou ◽

Haixin Sun ◽

...

Keyword(s):

Placebo Group ◽

Tranexamic Acid ◽

Intracerebral Haemorrhage ◽

Intracranial Haemorrhage ◽

Primary Outcome ◽

Controlled Trial ◽

Intracerebral Haematoma ◽

Spot Sign ◽

Double Blind ◽

Risk Of Death

BackgroundStudies show tranexamic acid can reduce the risk of death and early neurological deterioration after intracranial haemorrhage. We aimed to assess whether tranexamic acid reduces haematoma expansion and improves outcome in intracerebral haemorrhage patients susceptible to haemorrhage expansion.MethodsWe did a prospective, double-blind, randomised, placebo-controlled trial at 10 stroke centres in China. Acute supratentorial intracerebral haemorrhage patients were eligible if they had indication of haemorrhage expansion on admission imaging (eg, spot sign, black hole sign or blend sign), and were treatable within 8 hours of symptom onset. Patients were randomly assigned (1:1) to receive either tranexamic acid or a matching placebo. The primary outcome was intracerebral haematoma growth (>33% relative or >6 mL absolute) at 24 hours. Clinical outcomes were assessed at 90 days.ResultsOf the 171 included patients, 124 (72.5%) were male, and the mean age was 55.9±11.6 years. 89 patients received tranexamic acid and 82 received placebo. The primary outcome did not differ significantly between the groups: 36 (40.4%) patients in the tranexamic acid group and 34 (41.5%) patients in the placebo group had intracranial haemorrhage growth (OR 0.96, 95% CI 0.52 to 1.77, p=0.89). The proportion of death was lower in the tranexamic acid treatment group than placebo group (8.1% vs 10.0%), but there were no significant differences in secondary outcomes including absolute intracranial haemorrhage growth, death and dependency.ConclusionsAmong patients susceptible to haemorrhage expansion treated within 8 hours of stroke onset, tranexamic acid did not significantly prevent intracerebral haemorrhage growth. Larger studies are needed to assess safety and efficacy of tranexamic acid in intracerebral haemorrhage patients.

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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

Trials ◽

10.1186/s13063-019-3561-7 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 5

Author(s):

Amy Brenner ◽

◽

Adefemi Afolabi ◽

Syed Masroor Ahmad ◽

Monica Arribas ◽

...

Keyword(s):

Statistical Analysis ◽

Gastrointestinal Bleeding ◽

Tranexamic Acid ◽

Controlled Trial ◽

Statistical Analysis Plan ◽

Double Blind ◽

Double Blind Placebo ◽

Acute Gastrointestinal Bleeding

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Prevention of recurrent idiopathic gastroduodenal ulcer bleeding: a double-blind, randomised trial

Gut ◽

10.1136/gutjnl-2019-318715 ◽

2019 ◽

Vol 69 (4) ◽

pp. 652-657 ◽

Cited By ~ 1

Author(s):

Grace L H Wong ◽

Louis H S Lau ◽

Jessica Y L Ching ◽

Yee-Kit Tse ◽

Rachel H Y Ling ◽

...

Keyword(s):

Duodenal Ulcer ◽

Randomised Trial ◽

Ulcer Bleeding ◽

Recurrent Ulcer ◽

Gi Bleeding ◽

Double Blind ◽

Upper Gi Bleeding ◽

Upper Gi ◽

History Of ◽

Bleeding Ulcers

ObjectivePatients with a history of Helicobacter pylori-negative idiopathic bleeding ulcers have a considerable risk of recurrent ulcer complications. We hypothesised that a proton pump inhibitor (lansoprazole) is superior to a histamine 2 receptor antagonist (famotidine) for the prevention of recurrent ulcer bleeding in such patients.DesignIn this industry-independent, double-blind, randomised trial, we recruited patients with a history of idiopathic bleeding ulcers. After ulcer healing, we randomly assigned (1:1) patients to receive oral lansoprazole 30 mg or famotidine 40 mg daily for 24 months. The primary endpoint was recurrent upper GI bleeding within 24 months, analysed in the intention-to-treat population as determined by an independent adjudication committee.ResultsBetween 2010 and 2018, we enrolled 228 patients (114 patients in each study group). Recurrent upper GI bleeding occurred in one patient receiving lansoprazole (duodenal ulcer) and three receiving famotidine (two gastric ulcers and one duodenal ulcer). The cumulative incidence of recurrent upper GI bleeding in 24 months was 0.88% (95% CI 0.08% to 4.37%) in the lansoprazole arm and 2.63% (95% CI 0.71% to 6.91%) in the famotidine arm (p=0.313; crude HR 0.33, 95% CI 0.03 to 3.16, p=0.336). None of the patients who rebled used aspirin, non-steroidal anti-inflammatory drugs or other antithrombotic drugs.ConclusionThis 2-year, double-blind randomised trial showed that among patients with a history of H. pylori-negative idiopathic ulcer bleeding, recurrent bleeding rates were comparable between users of lansoprazole and famotidine, although a small difference in efficacy cannot be excluded.Trial registration numberNCT01180179; Results.

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