The CRASH-2 trial: a randomised controlled trial and economic evaluation of the effects of tranexamic acid on death, vascular occlusive events and transfusion requirement in bleeding trauma patients.
TL;DR: The CRASH-2 trial aimed to determine the effect of the early administration of tranexamic acid on death and transfusion requirement in bleeding trauma patients and the cost-effectiveness of the short course of TXA on death, vascular occlusive events and the receipt of blood transfusion in trauma patients.
Abstract: BACKGROUND Among trauma patients who survive to reach hospital, exsanguination is a common cause of death. A widely practicable treatment that reduces blood loss after trauma could prevent thousands of premature deaths each year. The CRASH-2 trial aimed to determine the effect of the early administration of tranexamic acid on death and transfusion requirement in bleeding trauma patients. In addition, the effort of tranexamic acid on the risk of vascular occlusive events was assessed.
OBJECTIVE Tranexamic acid (TXA) reduces bleeding in patients undergoing elective surgery. We assessed the effects and cost-effectiveness of the early administration of a short course of TXA on death, vascular occlusive events and the receipt of blood transfusion in trauma patients.
DESIGN Randomised placebo-controlled trial and economic evaluation. Randomisation was balanced by centre, with an allocation sequence based on a block size of eight, generated with a computer random number generator. Both participants and study staff (site investigators and trial co-ordinating centre staff) were masked to treatment allocation. All analyses were by intention to treat. A Markov model was used to assess cost-effectiveness. The health outcome was the number of life-years (LYs) gained. Cost data were obtained from hospitals, the World Health Organization database and UK reference costs. Cost-effectiveness was measured in international dollars ($) per LY. Deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results to model assumptions.
SETTING Two hundred and seventy-four hospitals in 40 countries.
PARTICIPANTS Adult trauma patients (n = 20,211) with, or at risk of, significant bleeding who were within 8 hours of injury.
INTERVENTIONS Tranexamic acid (loading dose 1 g over 10 minutes then infusion of 1 g over 8 hours) or matching placebo.
MAIN OUTCOME MEASURES The primary outcome was death in hospital within 4 weeks of injury, and was described with the following categories: bleeding, vascular occlusion (myocardial infarction, stroke and pulmonary embolism), multiorgan failure, head injury and other.
RESULTS Patients were allocated to TXA (n = 10,096) and to placebo (n = 10,115), of whom 10,060 and 10,067 patients, respectively, were analysed. All-cause mortality at 28 days was significantly reduced by TXA [1463 patients (14.5%) in the TXA group vs 1613 patients (16.0%) in the placebo group; relative risk (RR) 0.91; 95% confidence interval (CI) 0.85 to 0.97; p = 0.0035]. The risk of death due to bleeding was significantly reduced [489 patients (4.9%) died in the TXA group vs 574 patients (5.7%) in the placebo group; RR 0.85; 95% CI 0.76 to 0.96; p = 0.0077]. We recorded strong evidence that the effect of TXA on death due to bleeding varied according to the time from injury to treatment (test for interaction p < 0.0001). Early treatment (≤ 1 hour from injury) significantly reduced the risk of death due to bleeding [198 out of 3747 patients (5.3%) died in the TXA group vs 286 out of 3704 patients (7.7%) in the placebo group; RR 0.68; 95% CI 0.57 to 0.82; p < 0.0001]. Treatment given between 1 and 3 hours also reduced the risk of death due to bleeding [147 out of 3037 patients (4.8%) died in the TXA group vs 184 out of 2996 patients (6.1%) in the placebo group; RR 0.79; 95% CI 0.64 to 0.97; p = 0.03]. Treatment given after 3 hours seemed to increase the risk of death due to bleeding [144 out of 3272 patients (4.4%) died in the TXA group vs 103 out of 3362 patients (3.1%) in the placebo group; RR 1.44; 95% CI1.12 to 1.84; p = 0.004]. We recorded no evidence that the effect of TXA on death due to bleeding varied by systolic blood pressure, Glasgow Coma Scale score or type of injury. Administering TXA to bleeding trauma patients within 3 hours of injury saved an estimated 755 LYs per 1000 trauma patients in the UK. The cost of giving TXA to 1000 patients was estimated at $30,830. The incremental cost of giving TXA compared with not giving TXA was $48,002. The incremental cost per LY gained of administering TXA was $64.
CONCLUSIONS Early administration of TXA safely reduced the risk of death in bleeding trauma patients and is highly cost-effective. Treatment beyond 3 hours of injury is unlikely to be effective. Future work [the Clinical Randomisation of an Antifibrinolytic in Significant Head injury-3 (CRASH-3) trial] will evaluate the effectiveness and safety of TXA in the treatments of isolated traumatic brain injury (http://crash3.lshtm.ac.uk/).
TRIAL REGISTRATION Current Controlled Trials ISRCTN86750102, ClinicalTrials.gov NCT00375258 and South African Clinical Trial Register DOH-27-0607-1919.
FUNDING The project was funded by the Bupa Foundation, the J P Moulton Charitable Foundation and the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 10. See HTA programme website for further project information.
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TL;DR: The guideline now recommends that patients be transferred directly to an appropriate trauma treatment centre and encourages use of a restricted volume replacement strategy during initial resuscitation, and may also serve as a basis for local implementation.
Abstract: Severe trauma continues to represent a global public health issue and mortality and morbidity in trauma patients remains substantial. A number of initiatives have aimed to provide guidance on the management of trauma patients. This document focuses on the management of major bleeding and coagulopathy following trauma and encourages adaptation of the guiding principles to each local situation and implementation within each institution. The pan-European, multidisciplinary Task Force for Advanced Bleeding Care in Trauma was founded in 2004 and included representatives of six relevant European professional societies. The group used a structured, evidence-based consensus approach to address scientific queries that served as the basis for each recommendation and supporting rationale. Expert opinion and current clinical practice were also considered, particularly in areas in which randomised clinical trials have not or cannot be performed. Existing recommendations were reconsidered and revised based on new scientific evidence and observed shifts in clinical practice; new recommendations were formulated to reflect current clinical concerns and areas in which new research data have been generated. This guideline represents the fourth edition of a document first published in 2007 and updated in 2010 and 2013. The guideline now recommends that patients be transferred directly to an appropriate trauma treatment centre and encourages use of a restricted volume replacement strategy during initial resuscitation. Best-practice use of blood products during further resuscitation continues to evolve and should be guided by a goal-directed strategy. The identification and management of patients pre-treated with anticoagulant agents continues to pose a real challenge, despite accumulating experience and awareness. The present guideline should be viewed as an educational aid to improve and standardise the care of the bleeding trauma patients across Europe and beyond. This document may also serve as a basis for local implementation. Furthermore, local quality and safety management systems need to be established to specifically assess key measures of bleeding control and outcome. A multidisciplinary approach and adherence to evidence-based guidance are key to improving patient outcomes. The implementation of locally adapted treatment algorithms should strive to achieve measureable improvements in patient outcome.
1,247 citations
Cites background from "The CRASH-2 trial: a randomised con..."
...21 22 The cost-effectiveness of TXA in trauma has been calculated in three countries [417, 418]: 23 Tanzania as an example of a low-income country, India as a middle-income country and the 24...
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TL;DR: The biological mechanisms and clinical implications of the cascade of events caused by large-scale trauma that leads to multiorgan failure and death, despite the stemming of blood loss are examined.
540 citations
TL;DR: Paradigms in clinical trials suggest a much broader indication for antifibrinolytics than previously thought, and suggest the need for additional drugs to treat trauma is much greater than currently thought.
413 citations
TL;DR: There is considerable variation in the consent, recruitment and retention rates in publicly funded RCTs and investigators should bear this in mind at the planning stage of their study and not be overly optimistic about their recruitment projections.
Abstract: Background Substantial amounts of public funds are invested in health research worldwide. Publicly funded randomised controlled trials (RCTs) often recruit participants at a slower than anticipated rate. Many trials fail to reach their planned sample size within the envisaged trial timescale and trial funding envelope. Objectives To review the consent, recruitment and retention rates for single and multicentre randomised control trials funded and published by the UK9s National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme. Data sources and study selection HTA reports of individually randomised single or multicentre RCTs published from the start of 2004 to the end of April 2016 were reviewed. Data extraction Information was extracted, relating to the trial characteristics, sample size, recruitment and retention by two independent reviewers. Main outcome measures Target sample size and whether it was achieved; recruitment rates (number of participants recruited per centre per month) and retention rates (randomised participants retained and assessed with valid primary outcome data). Results This review identified 151 individually RCTs from 787 NIHR HTA reports. The final recruitment target sample size was achieved in 56% (85/151) of the RCTs and more than 80% of the final target sample size was achieved for 79% of the RCTs (119/151). The median recruitment rate (participants per centre per month) was found to be 0.92 (IQR 0.43–2.79) and the median retention rate (proportion of participants with valid primary outcome data at follow-up) was estimated at 89% (IQR 79–97%). Conclusions There is considerable variation in the consent, recruitment and retention rates in publicly funded RCTs. Investigators should bear this in mind at the planning stage of their study and not be overly optimistic about their recruitment projections.
272 citations
Additional excerpts
...601–800 12 (8) >800 39 (26) Final recruitment target achieved Yes 85 (56) No, but with 80% of target 119 (79) No, <80% of target 32 (21) Timing of primary outcome follow-up (months postrandomisation) <1 month 27 (18) 9 (10) 6 0–48 1–6 months 54 (36) 6–18 months 36 (24) >18 months 21 (14) Missing 13 (9) Timing of final follow-up (months postrandomisation)...
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Dalhousie University1, McMaster University2, University of Rochester Medical Center3, University of Washington4, McGill University5, University of Florida6, University of Pennsylvania7, Beaumont Hospital8, Wayne State University9, University of Helsinki10, University of Pittsburgh11, University of Modena and Reggio Emilia12, Pontifical Catholic University of Chile13, University of Los Andes14, University of Minnesota15
TL;DR: These evidence-based guidelines from the American Society of Hematology intend to support decision making about preventing VTE in patients undergoing surgery by making conditional recommendations for mechanical prophylaxis over no proPHylaxis and against inferior vena cava filters.
271 citations
Cites methods from "The CRASH-2 trial: a randomised con..."
...The small amount of direct evidence, with a lack of information on undesirable outcomes, together with the very low certainty on the treatment effect, led the panel to consider the indirect data from hip fracture repair studies for treatment RR estimates(255-266) and applying baseline VTE and bleeding risks from studies on trauma patients.(391,392)...
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References
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TL;DR: The appropriate use and reporting of the multiple imputation approach to dealing with missing data is described by Jonathan Sterne and colleagues.
Abstract: Most studies have some missing data. Jonathan Sterne and colleagues describe the appropriate use and reporting of the multiple imputation approach to dealing with them
5,293 citations
01 Jan 2014
TL;DR: The 2014 edition of the PSSRU Unit-Costs series as mentioned in this paper is the latest volume in a well-established series bringing together information from a variety of sources to estimate national unit costs for a wide range of health and social care services.
Abstract: This is the latest updated volume in a well-established series bringing together information from a variety of sources to estimate national unit costs for a wide range of health and social care services. This report consists of tables for more than 130 types of service which, as well as providing the most detailed and comprehensive information possible, also quotes sources and assumptions so users can adapt the information for their own purposes. This year we have included a guest editorial on ‘Big Data’: increasing productivity while reducing costs in health and social care and three short articles on The cost of integrated care; Shared lives – improving understanding of the costs of family-based support and the costs of providing a group intervention to people with dementia and their family carers:SHIELD: RYCT & CSP intervention costs (Remembering Yesterday Caring Today and Carer Support Programme). There are also several new schema providing the costs of: advocacy for people with learning disabilities; a hospice rapid response service; the early years classroom management programme; residential parenting assessments; independent review officers; time banks; dentists and care home costs for people with dementia. The 2014 edition is also available in full, free of charge, at the PSSRU website www.pssru.ac.uk/unit-costs/2014/ as an Acrobat file.
1,875 citations
Book•
15 Oct 2003
TL;DR: An Introduction to Survival Analysis Using Stata, Third Edition provides the foundation to understand various approaches for analyzing time-to-event data and gain intuition about how various survival analysis estimators work and what information they exploit.
Abstract: An Introduction to Survival Analysis Using Stata, Third Edition provides the foundation to understand various approaches for analyzing time-to-event data. It is not only a tutorial for learning survival analysis but also a valuable reference for using Stata to analyze survival data. Although the book assumes knowledge of statistical principles, simple probability, and basic Stata, it takes a practical, rather than mathematical, approach to the subject. This updated third edition highlights new features of Stata 11, including competing-risks analysis and the treatment of missing values via multiple imputation. Other additions include new diagnostic measures after Cox regression, Statas new treatment of categorical variables and interactions, and a new syntax for obtaining prediction and diagnostics after Cox regression. After reading this book, you will understand the formulas and gain intuition about how various survival analysis estimators work and what information they exploit. You will also acquire deeper, more comprehensive knowledge of the syntax, features, and underpinnings of Statas survival analysis routines.
1,834 citations
TL;DR: There was an improved access to the medical system, greater proportion of late deaths due to brain injury and lack of the classic trimodal distribution, in the Denver City and County trauma system during 1992.
Abstract: OBJECTIVE: Recognizing the impact of the 1977 San Francisco study of trauma deaths in trauma care, our purpose was to reassess those findings in a contemporary trauma system. DESIGN: Cross-sectional. MATERIAL AND METHODS: All trauma deaths occurring in Denver City and County during 1992 were reviewed; data were obtained by cross-referencing four databases: paramedic trip reports, trauma registries, coroner autopsy reports and police reports. MEASUREMENTS AND MAIN RESULTS: There were 289 postinjury fatalities; mean age was 36.8 +/- 1.2 years and mean Injury Severity Score (ISS) was 35.7 +/- 1.2. Predominant injury mechanisms were gunshot wounds in 121 (42%), motorvehicle accidents in 75 (38%) and falls in 23 (8%) cases. Seven (2%) individuals sustained lethal burns. Ninety eight (34%) deaths occurred in the pre-hospital setting. The remaining 191 (66%) patients were transported to the hospital. Of these, 154 (81%) died in the first 48 hours (acute), 11 (6%) within three to seven days (early) and 26 (14%) after seven days (late). Central nervous system injuries were the most frequent cause of death (42%), followed by exsanguination (39%) and organ failure (7%). While acute and early deaths were mostly due to the first two causes, organ failure was the most common cause of late death (61%). CONCLUSIONS: In comparison with the previous report, we observed similar injury mechanisms, demographics and causes of death. However, in our experience, there was an improved access to the medical system, greater proportion of late deaths due to brain injury and lack of the classic trimodal distribution.
1,701 citations
TL;DR: Clinical trials need a predefined statistical analysis plan for uses of baseline data, especially covariate-adjusted analyses and subgroup analyses, and investigators and journals need to adopt improved standards of statistical reporting, and exercise caution when drawing conclusions from subgroup findings.
1,055 citations