A Systematic Review and Meta-Analysis of Sample Size Methodology for Traumatic Hemorrhage Trials
Ghossein J, Fernando SM, Rochwerg B, Inaba K, Lampron J, Tran A
The journal of trauma and acute care surgery. 2023
BACKGROUND Trauma hemorrhage remains the most common cause of preventable mortality in trauma. In order to guide clinical practice, RCTs provide high-quality evidence to inform clinical decision making. The clinical relevance and inferences made by RCTs are dependent on assumptions made during sample size calculation. METHODS To describe the quality of methodology for sample size determination, we conducted a systemic review RCTs evaluating interventions that aim to improve survival in adults with trauma related hemorrhage. Estimated and actual outcome data is compared, including components of sample size determination. RESULTS A total of 13 RCTs were included. We noted a high rate of negative trial results (11 of 13 studies). Most studies were multi-center and conducted in North America, evaluating patients with blunt and penetrating injuries. The criteria for hemorrhagic shock varied across studies. All studies did not accurately estimate the mortality rate during sample size calculation. All but one study overestimated the mortality reduction during sample size calculation; the median absolute mortality reduction was 3%, compared to a target of 10%. Only the CRASH-2 study used a minimal clinically important different for treatment effect target. No RCTs employed prognostic enrichment. Most studies were terminated (8 of 13), mainly for futility. CONCLUSIONS Taken together, this review highlights that current clinical trial methodology is limited by imprecise control group risk estimates, overly optimistic treatment effect estimates and lack of transparent justification for such targets. These limitations result in studies at high risk for futility and potentially premature abandonment of promising therapies. Given the high morbidity and mortality of trauma-related hemorrhage, we recommend that future conduct of trauma RCTs incorporate 1) prognostic enrichment to inform baseline risk, (2) justify target treatment differences based on clinical importance and realistic estimates of feasibility, and (3) be transparent and provide justification for the assumptions made. LEVEL OF EVIDENCE Systematic Review/Meta Analysis; Level II.
The Efficacy of Tranexamic Acid for the Treatment of Traumatic Hip Fractures: A Network Meta-Analysis
Bloom DA, Lin CC, Manzi JE, Mojica ES, Telgheder ZL, Chapman CB
Journal of orthopaedic trauma. 2023
OBJECTIVES Network meta-analysis to compare the efficacy of different dosages of intravenous(IV) acid(TXA) in the treatment of traumatic hip fractures against the control group of no TXA. DATA SOURCES This study utilized the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to perform a network meta-analysis on the use of TXA for the treatment of hip fractures. The study team utilized Ovid MEDLINE, Cochrane Reviews, Scopus, Embase, and Web of Science databases to perform the search. Studies were selected that were published in English between the years 2010 and 2020. STUDY SELECTION/DATA EXTRACTION For inclusion in this study, selected manuscripts were required to be randomized controlled trials with at least one control group had no anti-fibrinolytic intervention to serve as a control, IV formulations of TXA were utilized as part of the treatment group. Furthermore, all study participants must have undergone surgical intervention for traumatic hip fractures. Studies that did not immediately meet criteria for inclusion were saved for review by the full investigating team and were included based on consensus. DATA SYNTHESIS All statistical analyses conducted for this study were performed using R (R Foundation for Statistical Computing, Vienna, Austria). Network meta-analyses were conducted with a frequentist approach with a random effects model using the netmeta package version 0.9-6 in R. The frequentist equivalent to surface under the cumulative ranking (SUCRA) probabilities, termed "P-Score" was used to rank different treatments. CONCLUSION The use of TXA in the surgical management of traumatic hip fractures reduces the number of transfusions and perioperative blood loss, with minimal to no increased incidence of thrombotic events when compared to control. When comparing formulations, no route of administration is clearly superior in reducing perioperative blood loss.
Efficacy of high dose tranexamic acid (TXA) for hemorrhage: A systematic review and meta-analysis
Hmidan Simsam M, Delorme L, Grimm D, Priestap F, Bohnert S, Descoteaux M, Hilsden R, Laverty C, Mickler J, Parry N, et al
BACKGROUND Standard dose (≤ 1 g) tranexamic acid (TXA) has established mortality benefit in trauma patients. The role of high dose IV TXA (≥2 g or ≥30 mg/kg as a single bolus) has been evaluated in the surgical setting, however, it has not been studied in trauma. We reviewed the available evidence of high dose IV TXA in any setting with the goal of informing its use in the adult trauma population. METHODS We searched MEDLINE, EMBASE and unpublished sources from inception until July 27, 2022 for studies that compared standard dose with high dose IV TXA in adults (≥ 16 years of age) with hemorrhage. Screening and data abstraction was done independently and in duplicate. We pooled trial data using a random effects model and considered randomized controlled trials (RCTs) and observational cohort studies separately. We assessed the individual study risk of bias using the Cochrane Risk of Bias for RCTs and the Newcastle-Ottawa Scale for observational cohort studies. The overall certainty of evidence was assessed using the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation). RESULTS We included 20 studies with a combined total of 12,523 patients. Based on pooled RCT data, and as compared to standard dose TXA, high dose IV TXA probably decreases transfusion requirements (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.76 to 0.97, moderate certainty) but with possibly no effect on blood loss (mean difference [MD] 43.31 ml less, 95% CI 135.53 to 48.90 ml less, low certainty), and an uncertain effect on thromboembolic events (OR 1.33, 95% CI 0.86 to 2.04, very low certainty) and mortality (OR 0.70, 95% CI 0.37 to 1.32, very low certainty). CONCLUSION When compared to standard dose, high dose IV TXA probably reduces transfusion requirements with an uncertain effect on thromboembolic events and mortality. LEVEL OF EVIDENCE Systematic review and meta-analysis, level IV.
Efficacy of Tranexamic Acid in the Treatment of Massive Upper Gastrointestinal Bleeding: A Randomized Clinical Trial
Sedaghat M, Iranshahi M, Mardani M, Mesbah N
Background Upper gastrointestinal bleeding (GIB) is an important cause of emergency ward admission. Antifibrinolytic agents including tranexamic acid (TXA) have been used for controlling GIB. However, there have been concerns regarding the safety and efficacy of TXA in patients with GIB. Thus, in this study, we aimed to determine the efficacy of TXA in the treatment of massive upper GIB. Methodology This double-blind randomized clinical trial was conducted among 86 consecutive patients who were referred to Imam Hossein Hospital in Tehran, Iran from 2018 to 2019 with the chief complaint of massive upper GIB. Patients were chosen to be in the TXA or placebo groups based on a 1:1 allocation using the block randomization method. The rate of rebleeding, need for blood transfusion, hospital stay, adverse effects, and mortality rate were evaluated and compared across the groups. Results Of the 86 patients enrolled in this study, 55.8% (n = 48) were males. The mean age of all patients was 53.1 ± 10.6 years (TXA group: 54.9 ± 11.5 years, and placebo group: 51.4 ± 9.7 years). Rebleeding was seen in 11 (25.6%) patients in the TXA group and in 20 (46.5%) patients in the control group, which was statistically significant (p = 0.043). Blood transfusion was carried out in only three (7%) patients in the TXA group compared with 14 (32.6%) patients in the placebo group (p = 0.003). Six (14%) patients experienced a hospital stay of longer than five days in the TXA group and 15 (34.9%) patients in the control group, which was statistically significant (p = 0.024). There were no significant differences in the mortality rate across both groups (p > 0.05). Conclusions TXA has no effect on mortality associated with severe upper GIB. However, it was associated with a lower rate of rebleeding and hospitalization time, without significant adverse effects.
Tranexamic acid in pediatric hemorrhagic trauma
Borgman, M. A., Nishijima, D. K.
The Journal of Trauma and Acute Care Surgery. 2023;94(1S Suppl 1):S36-s40
There is strong evidence in adult literature that tranexamic acid (TXA) given within 3 hours from injury is associated with improved outcomes. The evidence for TXA use in injured children is limited to retrospective studies and one prospective observational trial. Two studies in combat settings and one prospective civilian US study have found association with improved mortality. These studies indicate the need for a randomized controlled trial to evaluate the efficacy of TXA in injured children and to clarify appropriate timing, dose and patient selection. Additional research is also necessary to evaluate trauma-induced coagulopathy in children. Recent studies have identified three distinct fibrinolytic phenotypes following trauma (hyperfibrinolysis, physiologic fibrinolysis, and fibrinolytic shutdown), which can be identified with viscohemostatic assays. Whether viscohemostatic assays can appropriately identify children who may benefit or be harmed by TXA is also unknown.
Effectiveness and safety of tranexamic acid in pediatric trauma: A systematic review and meta-analysis
Kornelsen, E., Kuppermann, N., Nishijima, D. K., Ren, L. Y., Rumantir, M., Gill, P. J., Finkelstein, Y.
The American Journal of Emergency Medicine. 2022;55:103-110
OBJECTIVE Trauma is the leading cause of childhood death in the United States. Our goal was to determine the effectiveness of tranexamic acid (TXA) in improving survival in pediatric trauma. METHODS MEDLINE (OVID), Embase (OVID), Cochrane Central Register databases, CINAHL (EBSCO), Web of Science (Clarivate Analytics), and grey literature sources were searched for publications reporting survival and safety outcomes in children receiving TXA in acute trauma, with no language restrictions, published until February 11, 2021. Two independent researchers assessed studies for eligibility, bias, and quality. Data on the study setting, injury type, participants, design, interventions, TXA dosing and outcomes were extracted. The primary outcome was survival in children who received TXA following trauma. Forest plots of effect estimates were constructed for each study. Heterogeneity was assessed and data were pooled by meta-analysis using a random-effects model. RESULTS Fourteen articles met inclusion criteria - six single-institution and eight multicentre retrospective cohort studies. Overall, TXA use was not associated with increased survival in pediatric trauma (adjusted odds ratio [aOR]: 0.61, 95% CI: 0.30-1.22) after adjustment for patient-level variables, such as injury severity. Increased survival was documented in the subset of children experiencing trauma in combat settings (aOR for mortality: 0.31, 95% CI: 0.14-0.68). There were no differences in the odds of thromboembolic events (OR 1.15, 95% CI: 0.46-2.87) in children who received TXA versus not. CONCLUSIONS The utility of TXA in children with trauma is unclear. Guidelines supporting TXA use in pediatric trauma may not be based on the available evidence of its use in this context. Rigorous trials measuring survival and other meaningful outcomes and exploring optimal TXA dosing are urgently needed. Study Registration (PROSPERO): CRD42020157683.
Tranexamic acid is not inferior to placebo with respect to adverse events in supected tbi patients not in shock with a normal head ct: A retrospective study of a randomized trial
Harmer J, Dewey EN, Meier EN, Rowell SE, Schreiber MA
The journal of trauma and acute care surgery. 2022
BACKGROUND A 2-gram bolus of tranexamic acid (TXA) has been shown to reduce 28-day mortality in a RCT. This study investigates whether out-of-hospital TXA use is associated with adverse events or unfavorable outcomes in suspected TBI when intracranial hemorrhage (ICH) is absent on initial CT. METHODS This study utilized data from a 2015-2017, multicenter, randomized trial studying the effect of the following TXA doses on moderate to severe TBI: 2-gram bolus, 1-gram bolus plus 1-gram infusion over 8 hours, and a placebo bolus with placebo infusion. Of the 966 participants enrolled, 395 with an initial CT negative for ICH were included in this analysis. Fifteen adverse events (28-day incidence) were studied: MI, DVT, seizure, pulmonary embolism, ARDS, cardiac failure, liver failure, renal failure, CVA, cardiac arrest, cerebral vasospasm, "any thromboembolism", hypernatremia, AKI, and infection. Other unfavorable outcomes analyzed include mortality at 28 days & 6 months, GOSE ≤4 at discharge & 6 months, ICU-free days, ventilator-free days, hospital-free days, and combined unfavorable outcomes. In both study drug groups the incidence of dichotomous outcomes and quantity of ordinal outcomes were compared to placebo. RESULTS No statistically significant increase in adverse events or unfavorable outcomes was found between either TXA dosing regimen and placebo. Demographics and injury scores were not statistically different other than two methods of injury which were overrepresented in the 1-gram TXA bolus +1-gram TXA infusion. CONCLUSIONS Administration of either a 2-gram TXA bolus or a 1-gram TXA bolus plus 1-gram TXA 8-hour infusion in suspected-TBIs without ICH is not associated with increased adverse events or unfavorable outcomes. Because the out-of-hospital 2-gram bolus is associated with a mortality benefit it should be administered in suspected-TBI. LEVELS OF EVIDENCE Level II, Therapeutic.
Nebulized versus intravenous tranexamic acid for hemoptysis: A pilot randomized controlled trial
Gopinath B, Ranjan Mishra P, Aggarwal P, Nayaka R, Rajaram Naik S, Kappagantu V, Shrimal P, Ramaswami A, Bhoi S, Jamshed N, et al
BACKGROUND Tranexamic acid (TA) is used to control bleeding in patients with hemoptysis. However, the effectiveness of the different routes of TA administration has not been studied. RESEARCH QUESTION Does nebulized route of Tranexamic Acid (TA) administration reduce the amount of hemoptysis compared to intravenous route in patients presenting to emergency department (ED) with hemoptysis? METHODS We conducted a pragmatic, open labelled, cluster randomized, parallel single centered pilot trial of nebulized TA (500mg tid) versus intravenous TA (500mg tid) in adult patients presenting to emergency department with active hemoptysis. The primary outcome was cessation of bleeding at 30 min. Secondary outcome included amount of hemoptysis at 6h, 12h and 24 h; interventional procedures and side effects of TA. Patients who were hemodynamically unstable or requiring immediate interventional procedure or mechanical ventilation were excluded from the study. RESULTS Of the 55 patients in each arm, hemoptysis cessation at 30 minutes after TA administration was significantly higher in nebulized arm (n=40) compared to intravenous arm (n=28) [X2 (1, n=110)=5.55, p=0.0019]. Also, hemoptysis amount reduced significantly in nebulization arm at all time periods of observation (P value 30min=0.011, at 6h=0.002, 12h=0.0008, 24h=0.005). Fewer patients in nebulized arm required bronchial artery embolization (13 vs 21, P value=0.024) and thereby higher discharge rates from the ED (67.92% vs 39.02%, P value=0.005). Two patients in nebulized arm had asymptomatic bronchoconstriction which resolved after short acting beta agonist nebulization. No patient discharged from ED underwent any interventional procedure or revisited the ED with rebleed during the 72 hours follow up period. INTERPRETATION Nebulized TA may be more efficacious than intravenous TA in reducing the amount of hemoptysis and need for ED interventional procedures. Future larger studies are needed to further explore the potential of nebulized TA compared to intravenous TA in patients with mild hemoptysis.
Adult patients presenting to emergency department with active hemoptysis (n= 110).
Nebulized tranexamic acid (TA), (n= 55).
Intravenous TA (n= 55).
Hemoptysis cessation at 30 minutes after TA administration was significantly higher in the nebulized arm (n= 40) compared with the intravenous arm (n= 28), (X2 (1, n= 110) = 5.55). Hemoptysis amount reduced significantly in the nebulization arm at all time periods of observation (30 minutes, 6, 12 and 24 hours). Fewer patients in the nebulized arm required bronchial artery embolization (13 vs. 21) and thereby higher discharge rates from the emergency department (ED), (67.92% vs. 39.02%). Two patients in the nebulized arm had asymptomatic bronchoconstriction which resolved after short acting beta agonist nebulization. No patient discharged from ED underwent any interventional procedure or revisited the ED with rebleed during the 72 hours follow up period.
A cost-effectiveness and value of information analysis to inform future research of tranexamic acid for older adults experiencing mild traumatic brain injury
Williams, J., Ker, K., Roberts, I., Shakur-Still, H., Miners, A.
BACKGROUND Tranexamic acid reduces head injury deaths in patients with CT scan evidence of intracranial bleeding after mild traumatic brain injury (TBI). However, the cost-effectiveness of tranexamic acid for people with mild TBI in the pre-hospital setting, prior to CT scanning, is uncertain. A large randomised controlled trial (CRASH-4) is planned to address this issue, but the economic justification for it has not been established. The aim of the analysis was to estimate the likelihood of tranexamic acid being cost-effective given current evidence, the treatment effects required for cost-effectiveness, and the expected value of performing further research. METHODS An early economic decision model compared usual care for mild TBI with and without tranexamic acid, for adults aged 70 and above. The evaluation was performed from a UK healthcare perspective over a lifetime time horizon, with costs reported in 2020 pounds (GBP) and outcomes reported as quality-adjusted life years (QALYs). All analyses used a £20,000 per QALY cost-effectiveness threshold. RESULTS In the base case analysis, tranexamic acid was associated with an incremental cost-effectiveness ratio of £4885 per QALY gained, but the likelihood of it being cost-effective was highly dependent on the all-cause mortality treatment effect. The value of perfect information was £22.4 million, and the value of perfect information for parameters that could be collected in a trial was £21.9 million. The all-cause mortality risk ratio for tranexamic acid and the functional outcomes following TBI had the most impact on cost-effectiveness. CONCLUSIONS There is a high degree of uncertainty in the cost-effectiveness of tranexamic acid for older adults experiencing mild TBI, meaning there is a high value of performing future research in the UK. The value in a global context is likely to be far higher.
Systemic hemostatic agents initiated in trauma patients in the pre-hospital setting: a systematic review
Biffi A, Porcu G, Castellini G, Napoletano A, Coclite D, D'Angelo D, Fauci AJ, Iacorossi L, Latina R, Salomone K, et al
European journal of trauma and emergency surgery : official publication of the European Trauma Society. 2022
PURPOSE The effect of systemic hemostatic agents initiated during pre-hospital care of severely injured patients with ongoing bleeding or traumatic brain injury (TBI) remains controversial. A systematic review and meta-analysis was therefore conducted to assess the effectiveness and safety of systemic hemostatic agents as an adjunctive therapy in people with major trauma and hemorrhage or TBI in the context of developing the Italian National Institute of Health guidelines on major trauma integrated management. METHODS PubMed, Embase, and Cochrane Library databases were searched up to October 2021 for studies that investigated pre-hospital initiated treatment with systemic hemostatic agents. The certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development, and Evaluation approach, and the quality of each study was determined with the Cochrane risk-of-bias tool. The primary outcome was overall mortality, and secondary outcomes included cause-specific mortality, health-related quality of life, any adverse effects and blood product use, hemorrhage expansion, and patient-reported outcomes. RESULTS Five trials of tranexamic acid (TXA) met the inclusion criteria for this meta-analysis. With a high certainty of evidence, when compared to placebo TXA reduced mortality at 24 h (relative risk = 0.83, 95% confidence interval = 0.73-0.94) and at 1 month among trauma patients (0.91, 0.85-0.97). These results depend on the subgroup of patients with significant hemorrhage because in the subgroup of TBI there are no difference between TXA and placebo. TXA also reduced bleeding death and multiple organ failure whereas no difference in health-related quality of life. CONCLUSION Balancing benefits and harms, TXA initiated in the pre-hospital setting can be used for patients experiencing major trauma with significant hemorrhage since it reduces the risk of mortality at 24 h and one month with no difference in terms of adverse effects when compared to placebo. Considering the subgroup of severe TBI, no difference in mortality rate was found at 24 h and one month. These results highlight the need to conduct future studies to investigate the role of other systemic hemostatic agents in the pre-hospital settings.