A high-dose 24-hour tranexamic acid infusion for the treatment of significant gastrointestinal bleeding: HALT-IT RCT.

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 if the responsible clinician was substantially uncertain about whether or not to use tranexamic acid. The clinical diagnosis of significant bleeding implied a risk of bleeding to death, including hypotension, tachycardia or signs of shock, or urgent transfusion, endoscopy or surgery. INTERVENTION: Tranexamic acid (a 1-g loading dose over 10 minutes, then a 3-g maintenance dose over 24 hours) or matching placebo. MAIN OUTCOME MEASURES: The primary outcome was death due to bleeding within 5 days of randomisation. Secondary outcomes were all-cause and cause-specific mortality; rebleeding; need for endoscopy, surgery or radiological intervention; blood product transfusion; complications; disability; and days spent in intensive care or a high-dependency unit. RESULTS: A total of 12,009 patients were allocated to receive tranexamic acid (n = 5994, 49.9%) or the matching placebo (n = 6015, 50.1%), of whom 11,952 (99.5%) received the first dose. Death due to bleeding within 5 days of randomisation occurred in 222 (3.7%) patients in the tranexamic acid group and in 226 (3.8%) patients in the placebo group (risk ratio 0.99, 95% confidence interval 0.82 to 1.18). Thromboembolic events occurred in 86 (1.4%) patients in the tranexamic acid group and 72 (1.2%) patients in the placebo group (risk ratio 1.20, 95% confidence interval 0.88 to 1.64). The risk of arterial thromboembolic events (myocardial infarction or stroke) was similar in both groups (0.7% in the tranexamic acid group vs. 0.8% in the placebo group; risk ratio 0.92, 95% confidence interval 0.60 to 1.39), but the risk of venous thromboembolic events (deep-vein thrombosis or pulmonary embolism) was higher in tranexamic acid-treated patients than in placebo-treated patients (0.8% vs. 0.4%; risk ratio 1.85, 95% confidence interval 1.15 to 2.98). Seizures occurred in 38 patients who received tranexamic acid and in 22 patients who received placebo (0.6% vs. 0.4%, respectively; risk ratio 1.73, 95% confidence interval 1.03 to 2.93). In the base-case economic analysis, tranexamic acid was not cost-effective and resulted in slightly poorer health outcomes than no tranexamic acid. CONCLUSIONS: Tranexamic acid did not reduce death from gastrointestinal bleeding and, although inexpensive, it is not cost-effective in adults with acute gastrointestinal bleeding. FUTURE WORK: These results caution against a uniform approach to the management of patients with major haemorrhage and highlight the need for randomised trials targeted at specific pathophysiological processes. LIMITATIONS: Although this is one of the largest randomised trials in gastrointestinal bleeding, we cannot rule out a modest increase or decrease in death due to bleeding with tranexamic acid. TRIAL REGISTRATION: Current Controlled Trials ISRCTN11225767, ClinicalTrials.gov NCT01658124 and EudraCT 2012-003192-19. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 58. See the NIHR Journals Library website for further project information.

Acute gastrointestinal bleeding (bleeding from the gut) is a common emergency and an important cause of death and illness worldwide. In the UK, more than 65,000 people each year are admitted to hospital because of acute gastrointestinal bleeding; approximately 10% of them die within 30 days. Gastrointestinal bleeding is also common in low- and middle-income countries. The care of patients with gastrointestinal bleeding has improved in recent decades, but death rates remain high. Gastrointestinal bleeding is often caused by stomach ulcers, but also by liver damage owing to alcohol or hepatitis C infection. An effective and affordable treatment for gastrointestinal bleeding could save many lives and may reduce the need for blood transfusions, which is important because blood is a scarce resource in some health-care settings. Tranexamic acid, also known as TXA, is a cheap drug that reduces bleeding in other conditions. It helps blood to clot, thereby decreasing bleeding. A trial in bleeding accident victims found that tranexamic acid reduced the chances of bleeding to death, without any increase in side effects. We wanted to find out if tranexamic acid safely improves outcomes in patients with gastrointestinal bleeding, particularly to prevent deaths. To investigate this, the HALT-IT (Haemorrhage ALleviation with Tranexamic acid ­ Intestinal system) trial studied 12,009 patients with significant gastrointestinal bleeding in 164 hospitals across 15 countries. Half of the patients received tranexamic acid and the other half received a dummy drug, called a placebo. The treatments were assigned randomly and given in addition to all other treatments needed. Neither the patient nor the doctor knew which treatment a patient received. The trial showed that tranexamic acid did not reduce deaths from gastrointestinal bleeding. Instead, tranexamic acid was linked to an increased risk of complications, including unwanted blood clots (such as deep-vein thrombosis) and seizures. The economic analysis indicated that giving tranexamic acid to patients with gastrointestinal bleeding does not represent value for money for the NHS.

Barriers and facilitators to implementing trauma registries in low- and middle-income countries: Qualitative experiences from Tanzania.

BACKGROUND: The burden of trauma in low and middle-income countries (LMICs) is disproportionately high: LMICs account for nearly 90% of the global trauma deaths. Lack of trauma data has been identified as one of the major challenges in addressing the quality of trauma care and informing injury-preventing strategies in LMICs. This study aimed to explore the barriers and facilitators of current trauma documentation practices towards the development of a national trauma registry (TR). METHODS: An exploratory qualitative study was conducted at five regional hospitals between August 2018 and December 2018. Five focus group discussions (FGDs) were conducted with 49 participants from five regional hospitals. Participants included specialists, medical doctors, assistant medical officers, clinical officers, nurses, health clerks and information communication and technology officers. Participants came from the emergency units, surgical and orthopaedic inpatient units, and they had permanent placement to work in these units as non-rotating staff. We analysed the gathered information using a hybrid thematic analysis. RESULTS: Inconsistent documentation and archiving system, the disparity in knowledge and experience of trauma documentation, attitudes towards documentation and limitations of human and infrastructural resources in facilities we found as major barriers to the implementation of trauma registry. Health facilities commitment to standardising care, Ministry of Health and medicolegal data reporting requirements, and insurance reimbursements criteria of documentation were found as major facilitators to implementing trauma registry. CONCLUSIONS: Implementation of a trauma registry in regional hospitals is impacted by multiple barriers related to providers, the volume of documentation, resource availability for care, and facility care flow processes. However, financial, legal and administrative data reporting requirements exist as important facilitators in implementing the trauma registry at these hospitals. Capitalizing in the identified facilitators and investing to address the revealed barriers through contextualized interventions in Tanzania and other LMICs is recommended by this study.

Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis.

BACKGROUND: After a single-center trial and observational studies suggesting that early, goal-directed therapy (EGDT) reduced mortality from septic shock, three multicenter trials (ProCESS, ARISE, and ProMISe) showed no benefit. This meta-analysis of individual patient data from the three recent trials was designed prospectively to improve statistical power and explore heterogeneity of treatment effect of EGDT. METHODS: We harmonized entry criteria, intervention protocols, outcomes, resource-use measures, and data collection across the trials and specified all analyses before unblinding. After completion of the trials, we pooled data, excluding the protocol-based standard-therapy group from the ProCESS trial, and resolved residual differences. The primary outcome was 90-day mortality. Secondary outcomes included 1-year survival, organ support, and hospitalization costs. We tested for treatment-by-subgroup interactions for 16 patient characteristics and 6 care-delivery characteristics. RESULTS: We studied 3723 patients at 138 hospitals in seven countries. Mortality at 90 days was similar for EGDT (462 of 1852 patients [24.9%]) and usual care (475 of 1871 patients [25.4%]); the adjusted odds ratio was 0.97 (95% confidence interval, 0.82 to 1.14; P=0.68). EGDT was associated with greater mean (±SD) use of intensive care (5.3±7.1 vs. 4.9±7.0 days, P=0.04) and cardiovascular support (1.9±3.7 vs. 1.6±2.9 days, P=0.01) than was usual care; other outcomes did not differ significantly, although average costs were higher with EGDT. Subgroup analyses showed no benefit from EGDT for patients with worse shock (higher serum lactate level, combined hypotension and hyperlactatemia, or higher predicted risk of death) or for hospitals with a lower propensity to use vasopressors or fluids during usual resuscitation. CONCLUSIONS: In this meta-analysis of individual patient data, EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics. (Funded by the National Institute of General Medical Sciences and others; PRISM ClinicalTrials.gov number, NCT02030158 .).

Protocolised Management In Sepsis (ProMISe): a multicentre randomised controlled trial of the clinical effectiveness and cost-effectiveness of early, goal-directed, protocolised resuscitation for emerging septic shock.

BACKGROUND: Early goal-directed therapy (EGDT) is recommended in international guidance for the resuscitation of patients presenting with early septic shock. However, adoption has been limited and uncertainty remains over its clinical effectiveness and cost-effectiveness. OBJECTIVES: The primary objective was to estimate the effect of EGDT compared with usual resuscitation on mortality at 90 days following randomisation and on incremental cost-effectiveness at 1 year. The secondary objectives were to compare EGDT with usual resuscitation for requirement for, and duration of, critical care unit organ support; length of stay in the emergency department (ED), critical care unit and acute hospital; health-related quality of life, resource use and costs at 90 days and at 1 year; all-cause mortality at 28 days, at acute hospital discharge and at 1 year; and estimated lifetime incremental cost-effectiveness. DESIGN: A pragmatic, open, multicentre, parallel-group randomised controlled trial with an integrated economic evaluation. SETTING: Fifty-six NHS hospitals in England. PARTICIPANTS: A total of 1260 patients who presented at EDs with septic shock. INTERVENTIONS: EGDT (n = 630) or usual resuscitation (n = 630). Patients were randomly allocated 1 : 1. MAIN OUTCOME MEASURES: All-cause mortality at 90 days after randomisation and incremental net benefit (at £20,000 per quality-adjusted life-year) at 1 year. RESULTS: Following withdrawals, data on 1243 (EGDT, n = 623; usual resuscitation, n = 620) patients were included in the analysis. By 90 days, 184 (29.5%) in the EGDT and 181 (29.2%) patients in the usual-resuscitation group had died [p = 0.90; absolute risk reduction -0.3%, 95% confidence interval (CI) -5.4 to 4.7; relative risk 1.01, 95% CI 0.85 to 1.20]. Treatment intensity was greater for the EGDT group, indicated by the increased use of intravenous fluids, vasoactive drugs and red blood cell transfusions. Increased treatment intensity was reflected by significantly higher Sequential Organ Failure Assessment scores and more advanced cardiovascular support days in critical care for the EGDT group. At 1 year, the incremental net benefit for EGDT versus usual resuscitation was negative at -£725 (95% CI -£3000 to £1550). The probability that EGDT was more cost-effective than usual resuscitation was below 30%. There were no significant differences in any other secondary outcomes, including health-related quality of life, or adverse events. LIMITATIONS: Recruitment was lower at weekends and out of hours. The intervention could not be blinded. CONCLUSIONS: There was no significant difference in all-cause mortality at 90 days for EGDT compared with usual resuscitation among adults identified with early septic shock presenting to EDs in England. On average, costs were higher in the EGDT group than in the usual-resuscitation group while quality-adjusted life-years were similar in both groups; the probability that it is cost-effective is < 30%. FUTURE WORK: The ProMISe (Protocolised Management In Sepsis) trial completes the planned trio of evaluations of EGDT across the USA, Australasia and England; all have indicated that EGDT is not superior to usual resuscitation. Recognising that each of the three individual, large trials has limited power for evaluating potentially important subgroups, the harmonised approach adopted provides the opportunity to conduct an individual patient data meta-analysis, enhancing both knowledge and generalisability. TRIAL REGISTRATION: Current Controlled Trials ISRCTN36307479. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 97. See the NIHR Journals Library website for further project information.

Trial of early, goal-directed resuscitation for septic shock.

BACKGROUND: Early, goal-directed therapy (EGDT) is recommended in international guidelines for the resuscitation of patients presenting with early septic shock. However, adoption has been limited, and uncertainty about its effectiveness remains. METHODS: We conducted a pragmatic randomized trial with an integrated cost-effectiveness analysis in 56 hospitals in England. Patients were randomly assigned to receive either EGDT (a 6-hour resuscitation protocol) or usual care. The primary clinical outcome was all-cause mortality at 90 days. RESULTS: We enrolled 1260 patients, with 630 assigned to EGDT and 630 to usual care. By 90 days, 184 of 623 patients (29.5%) in the EGDT group and 181 of 620 patients (29.2%) in the usual-care group had died (relative risk in the EGDT group, 1.01; 95% confidence interval [CI], 0.85 to 1.20; P=0.90), for an absolute risk reduction in the EGDT group of -0.3 percentage points (95% CI, -5.4 to 4.7). Increased treatment intensity in the EGDT group was indicated by increased use of intravenous fluids, vasoactive drugs, and red-cell transfusions and reflected by significantly worse organ-failure scores, more days receiving advanced cardiovascular support, and longer stays in the intensive care unit. There were no significant differences in any other secondary outcomes, including health-related quality of life, or in rates of serious adverse events. On average, EGDT increased costs, and the probability that it was cost-effective was below 20%. CONCLUSIONS: In patients with septic shock who were identified early and received intravenous antibiotics and adequate fluid resuscitation, hemodynamic management according to a strict EGDT protocol did not lead to an improvement in outcome. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment Programme; ProMISe Current Controlled Trials number, ISRCTN36307479.).

The STOP the Bleeding Campaign.

According to the World Health Organization, traumatic injuries worldwide are responsible for over 5 million deaths annually. Post-traumatic bleeding caused by traumatic injury-associated coagulopathy is the leading cause of potentially preventable death among trauma patients. Despite these facts, awareness of this problem is insufficient and treatment options are often unclear. The STOP the Bleeding Campaign therefore aims to increase awareness of the phenomenon of post-traumatic coagulopathy and its appropriate management by publishing European guidelines for the management of the bleeding trauma patient, by promoting and monitoring the implementation of these guidelines and by preparing promotional and educational material, organising activities and developing health quality management tools. The campaign aims to reduce the number of patients who die within 24 hours after arrival in the hospital due to exsanguination by a minimum of 20% within the next 5 years.

Intravenous or nebulised magnesium sulphate versus standard therapy for severe acute asthma (3Mg trial): a double-blind, randomised controlled trial.

BACKGROUND: Previous studies suggested intravenous or nebulised magnesium sulphate (MgSO(4)) might improve respiratory function in patients with acute asthma. We aimed to determine whether intravenous or nebulised MgSO(4) improve symptoms of breathlessness and reduce the need for hospital admission in adults with severe acute asthma. METHODS: In our double-blind, placebo-controlled trial, we enrolled adults (aged ≥16 years) with severe acute asthma at emergency departments of 34 hospitals in the UK. We excluded patients with life-threatening features or contraindication to study drugs. We used a central randomisation system to allocate participants to intravenous MgSO(4) (2 g in 20 min) or nebulised MgSO(4) (three 500 mg doses in 1 h) alongside standard therapy including salbutamol, or placebo control plus standard therapy alone. We assessed two primary outcome measures in all eligible participants who started treatment, according to assigned treatment group: the proportion of patients admitted to hospital within 7 days and breathlessness measured on a 100 mm visual analogue scale (VAS) in the 2 h after initiation of treatment. We adjusted for multiple testing using Simes's method. The trial stopped before recruitment was completed because funding expired. This study is registered, number ISRCTN04417063. FINDINGS: Between July 30, 2008, and June 30, 2012, we recruited 1109 (92%) of 1200 patients proposed by the power calculation. 261 (79%) of 332 patients allocated nebulised MgSO(4) were admitted to hospital before 7 days, as were 285 (72%) of 394 patients allocated intravenous MgSO(4) and 281 (78%) of 358 controls. Breathlessness was assessed in 296 (89%) patients allocated nebulised MgSO(4), 357 (91%) patients allocated intravenous MgSO(4), and 323 (90%) controls. Rates of hospital admission did not differ between patients treated with either form of MgSO(4) compared with controls or between those treated with nebulised MgSO(4) and intravenous MgSO(4). Change in VAS breathlessness did not differ between active treatments and control, but change in VAS was greater for patients in the intravenous MgSO(4) group than it was in the nebulised MgSO(4) group (5·1 mm, 0·8 to 9·4; p=0·019). Intravenous or nebulised MgSO(4) did not significantly decrease rates of hospital admission and breathlessness compared with placebo: intravenous MgSO(4) was associated with an odds ratio of 0·73 (95% CI 0·51 to 1·04; p=0·083) for hospital admission and a change in VAS breathlessness of 2·6 mm (-1·6 to 6·8; p=0·231) compared with placebo; nebulised MgSO(4) was associated with an odds ratio of 0·96 (0·65 to 1·40; p=0·819) for hospital admission and a change in VAS breathlessness of -2·6 mm (-7·0 to 1·8; p=0·253) compared with placebo. INTERPRETATION: Our findings suggest nebulised MgSO(4) has no role in the management of severe acute asthma in adults and at best suggest only a limited role for intravenous MgSO(4) in this setting. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

Confident interpretation of Bayesian decision tree ensembles for clinical applications.

Bayesian averaging (BA) over ensembles of decision models allows evaluation of the uncertainty of decisions that is of crucial importance for safety-critical applications such as medical diagnostics. The interpretability of the ensemble can also give useful information for experts responsible for making reliable decisions. For this reason, decision trees (DTs) are attractive decision models for experts. However, BA over such models makes an ensemble of DTs uninterpretable. In this paper, we present a new approach to probabilistic interpretation of Bayesian DT ensembles. This approach is based on the quantitative evaluation of uncertainty of the DTs, and allows experts to find a DT that provides a high predictive accuracy and confident outcomes. To make the BA over DTs feasible in our experiments, we use a Markov Chain Monte Carlo technique with a reversible jump extension. The results obtained from clinical data show that in terms of predictive accuracy, the proposed method outperforms the maximum a posteriori (MAP) method that has been suggested for interpretation of DT ensembles.