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Alternative routes for tranexamic acid treatment in obstetric bleeding (WOMAN-PharmacoTXA trial): a randomised trial and pharmacological study in caesarean section births
Shakur-Still H, Roberts I, Grassin-Delyle S, Chaudhri R, Geer A, Arribas M, Lamy E, Mansukhani R, Lubeya MK, Javaid K, et al
BJOG : an international journal of obstetrics and gynaecology. 2023
Abstract
OBJECTIVE To examine the safety, efficacy and pharmacology of intravenous (IV), intramuscular (IM) and oral tranexamic acid (TXA) use in pregnant women. DESIGN Randomised, open-label trial. SETTING Hospitals in Pakistan and Zambia. POPULATION Women giving birth by caesarean section. METHODS Women were randomised to receive 1 g IV, 1 g IM, 4 g oral TXA or no TXA. Adverse events in women and neonates were recorded. TXA concentration in whole blood was measured and the concentrations over time were examined with population pharmacokinetics. The relationship between drug exposure and D-dimer was explored. The trial registration is NCT04274335. MAIN OUTCOME MEASURES Concentration of TXA in maternal blood. RESULTS Of the 120 women included in the randomised safety study, there were no serious maternal or neonatal adverse events. TXA concentrations in 755 maternal blood and 87 cord blood samples were described by a two-compartment model with one effect compartment linked by rate transfer constants. Maximum maternal concentrations were 46.9, 21.6 and 18.1 mg/L for IV, IM and oral administration, respectively, and 9.5, 7.9 and 9.1 mg/L in the neonates. The TXA response was modelled as an inhibitory effect on the D-dimer production rate. The half-maximal inhibitory concentration (IC(50) ) was 7.5 mg/L and was achieved after 2.6, 6.4 and 47 minutes with IV, IM and oral administration of TXA, respectively. CONCLUSIONS Both IM and oral TXA are well tolerated. Oral TXA took about 1 hour to reach minimum therapeutic concentrations and would not be suitable for emergency treatment. Intramuscular TXA inhibits fibrinolysis within 10 minutes and may be a suitable alternative to IV.
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The effect of tranexamic acid by baseline risk of death in acute bleeding patients: a meta-analysis of individual patient-level data from 28 333 patients
Ageron FX, Gayet-Ageron A, Ker K, Coats TJ, Shakur-Still H, Roberts I
Br J Anaesth. 2020
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Editor's Choice
Abstract
BACKGROUND Early administration of the antifibrinolytic drug tranexamic acid reduces death from bleeding in trauma and postpartum haemorrhage. We examined how the effectiveness and safety of antifibrinolytic drugs varies by the baseline risk of death as a result of bleeding. METHODS We performed an individual patient-level data meta-analysis of randomised trials including more than 1000 patients that assessed antifibrinolytics in acute severe bleeding. We identified trials performed between January 1, 1946 and July 5, 2018 (PROSPERO, number 42016052155). RESULTS Two randomised trials were selected where 28 333 patients received tranexamic acid treatment within 3 h after the onset of acute bleeding. Baseline characteristics to estimate the risk of death as a result of bleeding were divided into four categories: Low (0-5%), intermediate (6-10%), high (11-20%), and very high (>20%). Most patients had a low baseline risk of death as a result of bleeding (23 008 [81%]). Deaths as a result of bleeding occurred in all baseline risk categories with 240 (1%), 202 (8%), 232 (14%), and 357 (30%) deaths in the low-, intermediate-, high-, and very high-risk categories, respectively. The effectiveness of tranexamic acid did not vary by baseline risk when given within 3 h after bleeding onset (P=0.51 for interaction term). There was no increased risk of vascular occlusive events with tranexamic acid and it did not vary by baseline risk categories (P=0.25). CONCLUSIONS Tranexamic acid appears to be safe and effective regardless of baseline risk. Because many deaths are in patients at low and intermediate risk, tranexamic acid use should not be restricted to the most severely injured or bleeding patients.
PICO Summary
Population
Patients with acute bleeding due to post-partum haemorrhage or trauma (2 studies, n= 28,333).
Intervention
Antifibrinolytic drugs (aprotinin, tranexamic acid, aminocaproic acid, and aminomethylbenzoic acid).
Comparison
Placebo.
Outcome
Baseline characteristics to estimate the risk of death as a result of bleeding were divided into four categories: Low (0–5%), intermediate (6–10%), high (11–20%), and very high (>20%). Most patients had a low baseline risk of death as a result of bleeding (23,008 [81%]). Deaths as a result of bleeding occurred in all baseline risk categories with 240 (1%), 202 (8%), 232 (14%), and 357 (30%) deaths in the low-, intermediate-, high-, and very high-risk categories, respectively. The effectiveness of tranexamic acid did not vary by baseline risk when given within 3 hours after bleeding onset. There was no increased risk of vascular occlusive events with tranexamic acid and it did not vary by baseline risk categories.
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The WOMAN trial: clinical and contextual factors surrounding the deaths of 483 women following post-partum haemorrhage in developing countries
Picetti R, Miller L, Shakur-Still H, Pepple T, Beaumont D, Balogun E, Asonganyi E, Chaudhri R, El-Sheikh M, Vwalika B, et al
BMC Pregnancy Childbirth. 2020;20(1):409
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Editor's Choice
Abstract
BACKGROUND Post-partum haemorrhage (PPH) is a leading cause of maternal death worldwide. The WOMAN trial assessed the effects of tranexamic acid (TXA) on death and surgical morbidity in women with PPH. The trial recorded 483 maternal deaths. We report the circumstances of the women who died. METHODS The WOMAN trial recruited 20,060 women with a clinical diagnosis of PPH after a vaginal birth or caesarean section. We randomly allocated women to receive TXA or placebo. When a woman died, we asked participating clinicians to report the cause of death and to provide a short narrative of the events surrounding the death. We collated and edited for clarity the narrative data. RESULTS Case fatality rates were 3.0% in Africa and 1.7% in Asia. Nearly three quarters of deaths were within 3 h of delivery and 91% of these deaths were from bleeding. Women who delivered outside a participating hospital (12%) were three times more likely to die (OR = 3.12, 95%CI 2.55-3.81) than those who delivered in hospital. Blood was often unavailable due to shortages or because relatives could not afford to buy it. Clinicians highlighted late presentation, maternal anaemia and poor infrastructure as key contributory factors. CONCLUSIONS Although TXA use reduces bleeding deaths by almost one third, mortality rates similar to those in high income countries will not be achieved without tackling late presentation, maternal anaemia, availability of blood for transfusion and poor infrastructure.
PICO Summary
Population
Women with postpartum haemorrhage (PPH) in 193 centres in 21 countries enrolled in the international WOMAN trial (n= 20,060).
Intervention
Intravenous injection of 1 g of tranexamic acid (n= 10,051).
Comparison
Matching placebo (n= 10,009).
Outcome
There were 483 maternal deaths in developing countries. Case fatality rates were 3.0% in Africa and 1.7% in Asia. Nearly three quarters of deaths were within 3 hours of delivery and 91% of these deaths were from bleeding. Women who delivered outside a participating hospital (12%) were three times more likely to die than those who delivered in hospital. Key contributory factors highlighted by clinicians were: late presentation, maternal anaemia and poor infrastructure.
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Secondary analysis of the WOMAN trial to explore the risk of sepsis after invasive treatments for postpartum hemorrhage
Cornelissen L, Woodd S, Shakur-Still H, Fawole B, Noor S, Etuk S, Akintan AL, Chaudhri R, Roberts I
International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2019
Abstract
OBJECTIVE To examine the association between the use of invasive treatments for postpartum hemorrhage and the risk of sepsis and severe sepsis. METHODS Secondary data analysis of the WOMAN randomized controlled trial, including 20 060 women with postpartum hemorrhage in 21 countries. Logistic regression with random effects was used. RESULTS The cumulative incidence was 1.8% for sepsis and 0.5% for severe sepsis. All-cause mortality was 40.4% in women with severe sepsis versus 2.2% for women without. After adjusting for bleeding severity and other confounders, intrauterine tamponade, hysterectomy, and laparotomy increased the risk of sepsis (aOR 1.77 [95% CI 1.21-2.59], P=0.004; aOR 1.97 [95% CI 1.49-2.65], P<0.001; and aOR 6.63 [95% CI 4.29-10.24], P<0.001, respectively) and severe sepsis (aOR 2.60 [95% CI 1.47-4.59], P=0.002; aOR 1.97 [95% CI 0.83-2.46], P=0.033; and aOR 5.35 [95% CI 2.61-10.98], P<0.001, respectively). CONCLUSION In this secondary data analysis, certain invasive treatments for postpartum hemorrhage appear to increase the risk of sepsis. Further research is needed to confirm this finding and investigate the role of prophylactic antibiotics during these procedures. The harms and benefits of such interventions must be carefully weighed, both in treatment guidelines and during individual patient management. This article is protected by copyright. All rights reserved.
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No effect of tranexamic acid on platelet function and thrombin generation (ETAPlaT) in postpartum haemorrhage: a randomised placebo-controlled trial
Dallaku K, Shakur-Still H, Beaumont D, Roberts I, Huque S, Delius M, Holdenrieder S, Gliozheni O, Mansmann U
Wellcome open research. 2019;4:21
Abstract
Background: Postpartum hemorrhage (PPH) is a leading cause of maternal mortality and morbidity. The WOMAN trial showed that tranexamic acid (TXA) reduces death due to bleeding in women with PPH. To determine whether TXA has pro-thrombotic effects in women with PPH, we measured endogenous thrombin potential (ETP), coagulation factors V, VIII, von Willebrand (vW), fibrinogen, D-Dimers and platelet function. Methods: We conducted a sub-study within the WOMAN trial, an international randomized, parallel-group, double blind, placebo-controlled trial. Women with primary PPH were randomly allocated to receive 1 gram of tranexamic acid or matching placebo. Baseline blood samples were collected just prior to the first dose and a follow up sample was collected 30+/-15 minutes afterwards. We compared before and after changes in coagulation parameters between treatment groups using repeated measurement ANOVA. Change in ETP was the primary outcome. We did an intention-to-treat analysis using ANCOVA with adjustment for baseline and the time interval between the blood samples. Findings: A total of 187 patients were randomized to receive TXA (n=93) or matching placebo (n=94). Six patients were excluded due to incomplete data. The reduction in ETP from baseline to follow up was 43.2 nM*min (95%CI, -16.6 to 103.1) in the TXA group and 4.6 nM*min (95%CI, -51.4 to 60.6) in the placebo group. The difference was not statistically significant (95%CI, -42.9 to 120). There were no significant effects of TXA treatment on any other parameters (ADPtest, TRAPtest, coagulation factors activity, fibrinogen levels, D-Dimer level). Conclusion: We found no evidence that tranexamic acid treatment for PPH has substantial pro-coagulant effects. However, larger studies are needed to confirm or refute more modest effects. Trial registration: ISRCTN76912190 (initially registered 10/12/2008, WOMAN-ETAPlat included on 28/10/2013) and NCT00872469 (initially registered 31/03/2009, WOMAN-ETAPlat included on 28/10/2013).
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Effect of tranexamic acid on coagulation and fibrinolysis in women with postpartum haemorrhage (WOMAN-ETAC): a single-centre, randomised, double-blind, placebo-controlled trial
Shakur-Still H, Roberts I, Fawole B, Kuti M, Olayemi OO, Bello A, Huque S, Ogunbode O, Kotila T, Aimakhu C, et al
Wellcome Open Research. 2018;3:100.
Abstract
Background: Postpartum haemorrhage (PPH) is a leading cause of maternal death. The WOMAN trial showed that tranexamic acid (TXA) reduces death due to bleeding in women with PPH. We evaluated the effect of TXA on fibrinolysis and coagulation in a sample of WOMAN trial participants. Methods: Adult women with a clinical diagnosis of PPH were randomised to receive 1 g TXA or matching placebo in the WOMAN trial. Participants in the WOMAN trial at University College Hospital (Ibadan, Nigeria) also had venous blood taken just before administration of the first dose of trial treatment and again 30 (+/-15) min after the first dose (the ETAC study). We aimed to determine the effects of TXA on fibrinolysis (D-dimer and rotational thromboelastometry maximum clot lysis (ML)) and coagulation (international normalized ratio and clot amplitude at 5 min). We compared outcomes in women receiving TXA and placebo using linear regression, adjusting for baseline measurements. Results: Women (n=167) were randomised to receive TXA (n=83) or matching placebo (n=84). Due to missing data, seven women were excluded from analysis. The mean (SD) D-dimer concentration was 7.1 (7.0) mg/l in TXA-treated women and 9.6 (8.6) mg/l in placebo-treated women (p=0.09). After adjusting for baseline, the D-dimer concentration was 2.16 mg/l lower in TXA-treated women (-2.16, 95% CI -4.31 to 0.00, p=0.05). There was no significant difference in ML between TXA- and placebo-treated women (12.3% (18.4) and 10.7% (12.6), respectively; p=0.52) and no significant difference after adjusting for baseline ML (1.02, 95% CI -3.72 to 5.77, p=0.67). There were no significant effects of TXA on any other parameters. Conclusion: TXA treatment was associated with reduced D-dimer levels but had no apparent effects on thromboelastometry parameters or coagulation tests. Registration: ISRCTN76912190 (initially registered 10/12/2008, WOMAN-ETAC included on 22/03/2012) and NCT00872469 (initially registered 31/03/2009, WOMAN-ETAC included on 22/03/2012).