Tranexamic acid for the prevention of postpartum bleeding: Protocol for a systematic review and individual patient data meta-analysis

The Anti-fibrinolytics Trialists Collaborators – Obstetric Trial; Ker, Katharine; Shakur-Still, haleema; Sentilhes, Loïc; Pacheco, Luis; Saade, George; Deneux-Tharaux, Catherine; Brenner, Amy; Mansukhani, Raoul; Ageron, Francois; Prowse, Danielle; Chaudhri, Rizwana; Olayemi, Oladapo; Roberts, ian;

Alternative routes for tranexamic acid treatment in obstetric bleeding (WOMAN-PharmacoTXA trial): a randomised trial and pharmacological study in caesarean section births

Haleema Shakur-Still, Ian Roberts, Stanislas Grassin-Delyle, Rizwana Chaudhri, Amber Geer, Monica Arribas, Elodie Lamy, Raoul Mansukhani, Mwansa Ketty Lubeya, Kiran Javaid, Aasia Kayani, Naila Israr, Syeda Batool Mazhar, Saïk Urien, Naïm Bouazza, Frantz Foissac, Danielle Prowse, Laura Carrington, Collette Barrow, Julio Gil Onandia, Eni Balogun

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 (IC50) 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.

Effect of tranexamic acid on coagulation and fibrinolysis in women with postpartum haemorrhage (WOMAN-ETAC): a single-centre, randomised, double-blind, placebo-controlled trial

Haleema Shakur-Still and Ian Roberts and Bukola Fawole and Modupe Kuti and Oladapo O Olayemi and Adenike Bello and Sumaya Huque and Olayinka Ogunbode and Taiwo Kotila and Chris Aimakhu and Olujide A Okunade and Tolulase Olutogun and Cecilia O Adetayo and Kastriot Dallaku and Ulrich Mansmann and Beverley J Hunt and Tracey Pepple and Eni Balogun

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.

Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial

WOMAN trial collaborators

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 (IC50) 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.
Background: Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage.

Methods: In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15000 to 20000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283.
 
Findings: Between March, 2010, and April, 2016, 20060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group.
 
Interpretation: Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset.
 

Tranexamic acid for the prevention of postpartum bleeding in women with anaemia: study protocol for an international, randomised, double-blind, placebo-controlled trial

Katharine Ker, Ian Roberts, Rizwana Chaudhri, Bukola Fawole, Danielle Beaumont, Eni Balogun, Danielle Prowse, Tracey Pepple, Kiran Javaid, Aasia Kayani, Sabaratnam Arulkumaran, Imelda Bates & Haleema Shakur-Still on behalf of the WOMAN-2 trial collaborators

Maternal anaemia and the risk of postpartum haemorrhage: a cohort analysis of data from the WOMAN-2 trial

The WOMAN-2 trial collaborators

Does tranexamic acid prevent postpartum haemorrhage? A systematic review of randomised controlled trials

K Ker, H Shakur, I Roberts

Effect of treatment delay on the effectiveness and safety of antifibrinolytics in acute severe haemorrhage: a meta-analysis of individual patient-level data from 40138 bleeding patients

Angèle Gayet-Ageron, David Prieto-Merino, Katharine Ker, Haleema Shakur, François-Xavier Ageron, Ian Roberts, for the Antifibrinolytic
Trials Collaboration

Postpartum haemorrhage in anaemic women: assessing outcome measures for clinical trials

Amy Brenner, Ian Roberts, Eni Balogun, Folasade Adenike Bello, Rizwana Chaudhri, Charlotte Fleming, Kiran Javaid, Aasia Kayani, Mwansa Ketty Lubeya, Raoul Mansukhani, Oladapo Olayemi, Danielle Prowse, Bellington Vwalika & Haleema Shakur-Still

Anti-fibrinolytic agents in post partum haemorrhage: a systematic review

Pili Ferrer, Ian Roberts, Emma Sydenham, Karen Blackhall and Haleema Shakur

The WOMAN trial: clinical and contextual factors surrounding the deaths of 483 women following post-partum haemorrhage in developing countries

Roberto Picetti, Lori Miller , Haleema Shakur-Still , Tracey Pepple , Danielle Beaumont , Eni Balogun, Etienne Asonganyi , Rizwana Chaudhri , Mohamed El-Sheikh , Bellington Vwalika, Sabaratnam Arulkumaran, Ian Roberts and on behalf of the WOMAN trial collaborators

Risk factors for blood transfusion in traumatic and postpartum hemorrhage patients: Analysis of the CRASH-2 and WOMAN trials

David A. KolinID, Haleema Shakur-Still , Adenike Bello, Rizwana Chaudhri , Imelda Bates, Ian Roberts

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

Amy Brenner1* , Haleema Shakur-Still1 , Rizwana Chaudhri2 , Bukola Fawole3 , Sabaratnam Arulkumaran4 , Ian Roberts1 and on behalf of the WOMAN Trial Collaborators

Finding Better Ways to Prevent Postpartum Hemorrhage

Shakur-Still, Haleema; Roberts, Ian;