Development and validation of a prognostic model to predict death in patients with traumatic bleeding, and evaluation of the effect of tranexamic acid on mortality according to baseline risk: a secondary analysis of a randomised controlled trial.

BACKGROUND: Severe bleeding accounts for about one-third of in-hospital trauma deaths. Patients with a high baseline risk of death have the most to gain from the use of life-saving treatments. An accurate and user-friendly prognostic model to predict mortality in bleeding trauma patients could assist doctors and paramedics in pre-hospital triage and could shorten the time to diagnostic and life-saving procedures such as surgery and tranexamic acid (TXA). OBJECTIVES: The aim of the study was to develop and validate a prognostic model for early mortality in patients with traumatic bleeding and to examine whether or not the effect of TXA on the risk of death and thrombotic events in bleeding adult trauma patients varies according to baseline risk. DESIGN: Multivariable logistic regression and risk-stratified analysis of a large international cohort of trauma patients. SETTING: Two hundred and seventy-four hospitals in 40 high-, medium- and low-income countries. PARTICIPANTS: We derived prognostic models in a large placebo-controlled trial of the effects of early administration of a short course of TXA [Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2) trial]. The trial included 20,127 trauma patients with, or at risk of, significant bleeding, within 8 hours of injury. We externally validated the model on 14,220 selected trauma patients from the Trauma Audit and Research Network (TARN), which included mainly patients from the UK. We examined the effect of TXA on all-cause mortality, death due to bleeding and thrombotic events (fatal and non-fatal myocardial infarction, stroke, deep-vein thrombosis and pulmonary embolism) within risk strata in the CRASH-2 trial data set and we estimated the proportion of premature deaths averted by applying the odds ratio (OR) from the CRASH-2 trial to each of the risk strata in TARN. INTERVENTIONS: For the stratified analysis according baseline risk we considered the intervention TXA (1 g over 10 minutes followed by 1 g over 8 hours) or matching placebo. MAIN OUTCOME MEASURES: For the prognostic models we included predictors for death in hospital within 4 weeks of injury. For the stratified analysis we reported ORs for all causes of death, death due to bleeding, and fatal and non-fatal thrombotic events associated with the use of TXA according to baseline risk. RESULTS: A total of 3076 (15%) patients died in the CRASH-2 trial and 1705 (12%) in the TARN data set. Glasgow Coma Scale score, age and systolic blood pressure were the strongest predictors of mortality. Discrimination and calibration were satisfactory, with C-statistics > 0.80 in both CRASH-2 trial and TARN data sets. A simple chart was constructed to readily provide the probability of death at the point of care, while a web-based calculator is available for a more detailed risk assessment. TXA reduced all-cause mortality and death due to bleeding in each stratum of baseline risk. There was no evidence of heterogeneity in the effect of TXA on all-cause mortality (p-value for interaction = 0.96) or death due to bleeding (p= 0.98). There was a significant reduction in the odds of fatal and non-fatal thrombotic events with TXA (OR = 0.69, 95% confidence interval 0.53 to 0.89; p= 0.005). There was no evidence of heterogeneity in the effect of TXA on the risk of thrombotic events (p= 0.74). CONCLUSIONS: This prognostic model can be used to obtain valid predictions of mortality in patients with traumatic bleeding. TXA can be administered safely to a wide spectrum of bleeding trauma patients and should not be restricted to the most severely injured. Future research should evaluate whether or not the use of this prognostic model in clinical practice has an impact on the management and outcomes of trauma patients.

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.

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.

Antifibrinolytic drugs for acute traumatic injury.

BACKGROUND: Uncontrolled bleeding is an important cause of death in trauma victims. Antifibrinolytic treatment has been shown to reduce blood loss following surgery and may also be effective in reducing blood loss following trauma. OBJECTIVES: To quantify the effect of antifibrinolytic drugs in reducing blood loss, transfusion requirement and mortality after acute traumatic injury. SEARCH STRATEGY: We searched the Cochrane Injuries Group's Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, EMBASE, Science Citation Index, National Research Register, Zetoc, SIGLE, Global Health, LILACS, and Current Controlled Trials. SELECTION CRITERIA: We included all randomised controlled trials of antifibrinolytic agents (aprotinin, tranexamic acid [TXA] and epsilon-aminocaproic acid) following acute traumatic injury. DATA COLLECTION AND ANALYSIS: The titles and abstracts identified in the electronic searches were screened by two independent reviewers to identify studies that had the potential to meet the inclusion criteria. The full reports of all such studies were obtained. From the results of the screened electronic searches, bibliographic searches, and contacts with experts, two reviewers independently selected trials meeting the inclusion criteria, with any disagreements resolved by consensus. MAIN RESULTS: Two studies met the inclusion criteria. The study by Auer (1979), with 20 randomised patients, provided no useable outcome data. The study by McMichan (1982), with 77 randomised patients, was reported in four separate reports. Outcome data were reported for death, the proportion undergoing surgical intervention and the volume of blood transfused. Because of the small number of randomised participants, the estimates for each of these outcomes were highly imprecise. Data on the proportion undergoing re-operation and the proportion receiving blood transfusion were not reported. REVIEWERS' CONCLUSIONS: There is insufficient evidence from randomised controlled trials of antifibrinolytic agents in trauma to either support or refute a clinically important treatment effect. Further randomised controlled trials of antifibrinolytic agents in trauma are required.