Response to: The BRAIN TRIAL: a randomized, placebo controlled trial of a Bradykinin B2 receptor antagonist (Anatibant) in patients with traumatic brain injury - authors' reply

A response to the letter regarding The BRAIN TRIAL: a randomized, placebo controlled trial of a Bradykinin B2 receptor antagonist (Anatibant) in patients with traumatic brain injury, by Mr Vincent Simmon President and CEO of Xytis Inc

Effects of tranexamic acid treatment in severely and non-severely injured trauma patients.

Urgent treatment with tranexamic acid (TXA) reduces bleeding deaths but there is disagreement about which patients should be treated. We examine the effects of TXA treatment in severely and non-severely injured trauma patients. We did an individual patient data meta-analysis of randomized trials with over 1000 trauma patients that assessed the effects of TXA on survival. We defined the severity of injury according to characteristics at first assessment: systolic blood pressure of less than 90 mm Hg and a heart rate greater than 120 beats per minute or Glasgow Coma Scale score of less than nine or any GCS with one or more fixed dilated pupils. The primary measure was survival on the day of the injury. We examined the effect of TXA on survival in severely and non-severely injured patients and how these effects vary with the time from injury to treatment. We obtained data for 32,944 patients from two randomized trials. Tranexamic acid significantly increased survival on the day of the injury (OR = 1.22, 95% CI 1.11-1.34; p < .01). The effect of tranexamic acid on survival in non-severely injured patients (OR = 1.25, 1.03-1.50) was similar to that in severely injured patients (OR = 1.22, 1.09-1.37) with no significant heterogeneity (p = .87). In severely and non-severely injured pateints, treatment within the first hour after injury was the most effective. Early tranexamic acid treatment improves survival in both severely and non-severely injured trauma patients. Its use should not be restricted to the severely injured

The impact of early outcome events on the effect of tranexamic acid in post-partum haemorrhage: an exploratory subgroup analysis of the WOMAN trial.

BACKGROUND: In severe post-partum haemorrhage, death can occur within hours of bleeding onset so interventions to control the bleeding must be given immediately. In clinical trials of treatments for life-threatening bleeding, established treatments are given priority and the trial treatment is usually given last. However, enrolling patients in whom severe maternal morbidity or death is imminent or inevitable at the time of randomisation may dilute the effects of a trial treatment. METHODS: We conducted an exploratory analysis of data from the WOMAN trial, an international, randomised placebo-controlled trial of the effects of tranexamic acid on death and surgical intervention in 20,060 women with post-partum haemorrhage. We assessed the impact of early maternal death or hysterectomy due to exsanguination on the effect of tranexamic acid on each of these respective outcomes. We conducted repeated analyses excluding patients with these outcomes at increasing intervals from the time of randomisation. We quantified treatment effects using risk ratios (RR) and 99% confidence intervals (CI) and prepared cumulative failure plots. RESULTS: Among 14,923 women randomised within 3 h of delivery (7518 tranexamic acid and 7405 placebo), there were 216 bleeding deaths (1.5%) and 383 hysterectomies due to bleeding (2.8%). After excluding deaths from exsanguination at increasing time intervals following randomization, there was a significant reduction in the risk of death due to bleeding with tranexamic acid (RR = 0.41; 99% CI 0.19-0.89). However, after excluding hysterectomies at increasing time intervals post-randomization, there was no reduction in the risk of hysterectomy due to bleeding with tranexamic acid (RR = 0.79; 99% CI 0.33-1.86). CONCLUSIONS: Findings from this analysis provide further evidence that tranexamic acid reduces the risk of death from exsanguination in women who experience postpartum haemorrhage. It is uncertain whether tranexamic acid reduces the risk of hysterectomy for bleeding after excluding early hysterectomies. TRIAL REGISTRATION: ISRCTN trial registration number ISRCTN76912190, 8 Dec 2008; ClinicalTrials.gov number NCT00872469, 30 March 2009; PACTR number PACTR201007000192283, 9 Feb 2010; EudraCT number 2008-008441-38, 8 Dec 2010 (retrospectively registered)

CRASH2 in Germany [ISRCTN86750102]

ABSTRACT: In June 2005, the Study Centre of the German Surgical Society (SDGC) in Heidelberg, Germany, agreed to participate in the investigator initiated trial CRASH2. Regulatory and administrative affairs within Germany were assigned to the Coordination Centre for Clinical Trials (KKS) at the University of Heidelberg, Germany. For more than nine months the KKS and the SDGC have been trying to procure a separate insurance for CRASH2 in Germany. Unfortunately, these attempts have not been successful, yet. One major reason is the way in which German authorities and authorities of some other countries have interpreted the EU Directive (Directive 2001/20/EC) with regards to the need for "adequate" indemnity for clinical trials. The indemnity insurance for CRASH2 procured by the LSHTM for all participating hospitals throughout the world (except for the USA) did not comply with the limits required by the federal German drug law (AMG)

Ductile bulk metallic glass by controlling structural heterogeneities

A prerequisite to utilize the full potential of structural heterogeneities for improving the room-temperature plastic deformation of bulk metallic glasses (BMGs) is to understand their interaction with the mechanism of shear band formation and propagation. This task requires the ability to artificially create heterogeneous microstructures with controlled morphology and orientation. Here, we analyze the effect of the designed heterogeneities generated by imprinting on the tensile mechanical behavior of the Zr52.5Ti5Cu18Ni14.5Al10 BMG by using experimental and computational methods. The imprinted material is elastically heterogeneous and displays anisotropic mechanical properties: strength and ductility increase with increasing the loading angle between imprints and tensile direction. This behavior occurs through shear band branching and their progressive rotation. Molecular dynamics and finite element simulations indicate that shear band branching and rotation originates at the interface between the heterogeneities, where the characteristic atomistic mechanism responsible for shear banding in a homogeneous glass is perturbed

Use of tranexamic acid in major trauma: a sex-disaggragated analysis of the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2 and CRASH-3) trials and UK trauma registry (Trauma and Audit Research Network) data.

Women are less likely than men to receive some emergency treatments. This study examines whether the effect of tranexamic acid (TXA) on mortality in trauma patients varies by sex and whether the receipt of TXA by trauma patients varies by sex. First, we conducted a sex-disaggregated analysis of data from the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH)-2 and CRASH-3 trials. We used interaction tests to determine whether the treatment effect varied by sex. Second, we examined data from the Trauma and Audit Research Network (TARN) to explore sex differences in the receipt of TXA. We used logistic regression models to estimate the odds ratio for receipt of TXA in females compared with males. Results are reported as n (%), risk ratios (RR), and odds ratios (OR) with 95% confidence intervals. Overall, 20 211 polytrauma patients (CRASH-2) and 12 737 patients with traumatic brain injuries (CRASH-3) were included in our analysis. TXA reduced the risk of death in females (RR=0.69 [0.52-0.91]) and in males (RR=0.80 [0.71-0.90]) with no significant heterogeneity by sex (P=0.34). We examined TARN data for 216 364 patients aged ≥16 yr with an Injury Severity Score ≥9 with 98 879 (46%) females and 117 485 (54%) males. TXA was received by 7198 (7.3% [7.1-7.4%]) of the females and 19 697 (16.8% [16.6-17.0%]) of the males (OR=0.39 [0.38-0.40]). The sex difference in the receipt of TXA increased with increasing age. Administration of TXA to patients with bleeding trauma reduces mortality to a similar extent in women and men, but women are substantially less likely to be treated with TXA

What concentration of tranexamic acid is needed to inhibit fibrinolysis? A systematic review of pharmacodynamics studies

Intravenous tranexamic acid (TXA) reduces death because of bleeding in patients with trauma and postpartum haemorrhage. However, in some settings intravenous injection is not feasible. To find different routes of administration, we first need to determine the minimal concentration of TXA in the blood that is required to inhibit fibrinolysis. We conducted a systematic review of in-vitro and in-vivo pharmacodynamics studies. We searched MEDLINE, EMBASE, OviSP, and ISI Web of Science from database inception to November 2017 for all in-vitro (including simulated clotting models) or in-vivo studies reporting the relationship between the TXA concentration in blood or plasma and any reliable measure of fibrinolysis. We found 21 studies of which 20 were in vitro and one was in vivo. Most in-vitro studies stimulated fibrinolysis with tissue plasminogen activator and measured fibrinolysis using viscoelastic, optical density, or immunological assays. TXA concentrations between 10 and 15 mg/l resulted in substantial inhibition of fibrinolysis, although concentrations between 5 and 10 mg/l were partly inhibitory. TXA concentrations of 10–15 mg/l may be suitable targets for pharmacokinetic studies, although TXA concentrations above 5 mg/l may also be effective

Pharmacokinetics of intramuscular tranexamic acid in bleeding trauma patients: a clinical trial.

BACKGROUND: Intravenous tranexamic acid (TXA) reduces bleeding deaths after injury and childbirth. It is most effective when given early. In many countries, pre-hospital care is provided by people who cannot give i.v. injections. We examined the pharmacokinetics of intramuscular TXA in bleeding trauma patients. METHODS: We conducted an open-label pharmacokinetic study in two UK hospitals. Thirty bleeding trauma patients received a loading dose of TXA 1 g i.v., as per guidelines. The second TXA dose was given as two 5 ml (0·5 g each) i.m. injections. We collected blood at intervals and monitored injection sites. We measured TXA concentrations using liquid chromatography coupled to mass spectrometry. We assessed the concentration time course using non-linear mixed-effect models with age, sex, ethnicity, body weight, type of injury, signs of shock, and glomerular filtration rate as possible covariates. RESULTS: Intramuscular TXA was well tolerated with only mild injection site reactions. A two-compartment open model with first-order absorption and elimination best described the data. For a 70-kg patient, aged 44 yr without signs of shock, the population estimates were 1.94 h-1 for i.m. absorption constant, 0.77 for i.m. bioavailability, 7.1 L h-1 for elimination clearance, 11.7 L h-1 for inter-compartmental clearance, 16.1 L volume of central compartment, and 9.4 L volume of the peripheral compartment. The time to reach therapeutic concentrations (5 or 10 mg L-1) after a single intramuscular TXA 1 g injection are 4 or 11 min, with the time above these concentrations being 10 or 5.6 h, respectively. CONCLUSIONS: In bleeding trauma patients, intramuscular TXA is well tolerated and rapidly absorbed. CLINICAL TRIAL REGISTRATION: 2019-000898-23 (EudraCT); NCT03875937 (ClinicalTrials.gov)