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 (original) (raw)
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The Journal of Emergency Medicine, 2020
Background Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0•9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0•9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124.
Health technology assessment, 2021
BACKGROUND Tranexamic acid reduces blood loss in surgery and the risk of death in trauma patients. Meta-analyses of small trials suggest that tranexamic acid decreases the number of deaths from gastrointestinal bleeding, but these meta-analyses are prone to selection bias. OBJECTIVE The trial provides reliable evidence of the effect of tranexamic acid on mortality, rebleeding and complications in significant acute gastrointestinal bleeding. DESIGN A multicentre, randomised, placebo-controlled trial and economic analysis. Patients were assigned by selecting one treatment pack from a box of eight, which were identical apart from the pack number. Patients, caregivers and outcome assessors were masked to allocation. The main analyses were by intention to treat. SETTING The setting was 164 hospitals in 15 countries, co-ordinated from the London School of Hygiene & Tropical Medicine. PARTICIPANTS Adults with significant upper or lower gastrointestinal bleeding (n = 12,009) were eligible i...
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:...
Gastrointestinal Endoscopy, 2019
Background and Aims: TC-325 (Hemospray, Cook Medical, Winston-Salem, NC) is an inorganic hemostatic powder recently approved by the U.S. Food and Drug Administration. This study aimed to examine the effectiveness, safety, and predictors of TC-325 failure in a large real-life cohort. Methods: This was a retrospective study conducted at 21 Spanish centers. All patients treated with TC-325 until September 2018 were included. The primary outcome was treatment failure, defined as failed intraprocedural hemostasis or recurrent bleeding within the first 30 postprocedural days. Secondary outcomes included safety and survival. Risk and predictors of failure were assessed via competing-risk models. Results: The cohort comprised 261 patients, of whom 219 (83.9%) presented with upper gastrointestinal bleeding (GIB). The most common causes were peptic ulcer (28%), malignancy (18.4%), and therapeutic endoscopy-related GIB (17.6%). TC-325 was used as rescue therapy in 191 (73.2%) patients. The rate of intraprocedural hemostasis was 93.5% (95% confidence interval [CI], 90%-96%). Risks of TC-325 failure at postprocedural days 3, 7, and 30 were 21.1%, 24.6%, and 27.4%, respectively. On multivariate analysis, spurting bleeding (P Z .004), use of vasoactive drugs (P Z .02), and hypotension (P Z .008) were independent predictors of failure. Overall 30-day survival was 81.9% (95% CI, 76%-86%) and intraprocedural hemostasis was associated with a better prognosis (adjusted hazard ratio, 0.29; P Z .006). Two severe adverse events were noted. Conclusion: TC-325 was safe and effective for intraprocedural hemostasis in more than 90% of patients, regardless of the cause or site of bleeding and its use as rescue therapy. In this high-risk cohort treated with TC-325, the 30-day failure rate exceeded 25% and was highest with spurting bleeding or hemodynamic instability.
Outcome measures in clinical trials of treatments for acute severe haemorrhage
Trials
Background: Acute severe haemorrhage is a common complication of injury, childbirth, surgery, gastrointestinal pathologies and other medical conditions. Bleeding is a major cause of death, but patients also die from non-bleeding causes, the frequency of which varies by the site of haemorrhage and between populations. Because patients can bleed to death within hours, established interventions inevitably take priority over randomisation into a trial. These circumstances raise challenges in selecting appropriate outcome measures for clinical trials of haemostatic interventions. Main body: We use data from three large randomised controlled trials in acute severe haemorrhage (CRASH-2, WOMAN and HALT-IT) to explore the strengths and limitations of outcome measures commonly used in trials of haemostatic treatments, including all-cause and cause-specific mortality, blood transfusion and surgical interventions. Many deaths following acute severe haemorrhage are due to patient comorbidities or complications rather than bleeding. If nonbleeding deaths are unaffected by a haemostatic intervention, even large trials will have low power to detect an effect on all-cause mortality. Due to the dilution from deaths unaffected or reduced by the trial treatment, all-cause mortality can also obscure important harmful effects. Additionally, because the relative contributions of different causes of death vary within and between patient populations, all-cause mortality is not generalisable. Different causes of death occur at different time intervals from bleeding onset, with bleeding deaths generally occurring early. Time-specific mortality can therefore be used as a proxy for cause in un-blinded trials where bias is a concern or in situations where cause of death cannot be assessed. Urgent treatment is critical, and so post-randomisation blood transfusion and surgery are often planned before or at the time of randomisation and therefore cannot be influenced by the trial treatment. Conclusions: All-cause mortality has low power, lacks generalisability and can obscure harmful effects. Cause-specific mortality, such as death due to bleeding or thrombosis, avoids these drawbacks. In certain scenarios, time-specific mortality can be used as a proxy for cause-specific mortality. Blood transfusion and surgical procedures have limited utility as outcome measures in trials of haemostatic treatments.