Effects of tranexamic acid on platelet function and thrombin generation (ETAPlaT): WOMAN trial sub-study

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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).

Section: Discussionsupporting

confidence: 78%

“…Data from the ETAC trial and ETAPlaT (a single centre sub-study of the WOMAN trial) were pooled. Eligibility criteria for both trials were the same and blood samples were collected for D-dimer in the same way in both trials 16 . We computed the pooled ratio of D-dimers in women receiving TXA compared to women receiving placebo.…”

Section: Methodsmentioning

confidence: 99%

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-Still¹,

Roberts²,

Fawole³

et al. 2018

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“…The main criterion for eligibility was the uncertainty of clinician to use or not use TXA in a particular woman diagnosed with PPH. The study was carried out according to the guidelines of good clinical practice 12 and adhered to the regulatory requirements for Albania.…”

Section: Methods and Study Designmentioning

confidence: 99%

No effect of tranexamic acid on platelet function and thrombin generation (ETAPlaT) in postpartum haemorrhage: a randomised placebo-controlled trial

Dallaku¹,

Shakur-Still²,

Roberts³

et al. 2019

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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) andNCT00872469(initially registered 31/03/2009, WOMAN-ETAPlat included on 28/10/2013).

“…This SAP is a technical extension of the WOMAN ETAPlaT study protocol (Version 1.1, dated August 29, 2014), which is published elsewhere ( Dallaku et al ., 2016 ). The SAP follows the principles of the International Conference on Harmonization (ICH) guidelines E3, E6 and E9 ( ICH, 2016 ).…”

Section: Abbreviationsmentioning

confidence: 99%

“…Blood samples will be collected at the baseline and at 30 ±15 minutes after the first dose of study treatment is given. Analysis will be performed on processed, separated platelet poor plasma, and preserved in deep freeze, as described in the ETAPlaT protocol ( Dallaku et al ., 2016 ).…”

Section: Study Objectives and Endpoints Of Woman-etaplatmentioning

confidence: 99%

Statistical analysis plan for the WOMAN-ETAPlaT study: Effect of tranexamic acid on platelet function and thrombin generation

Dallaku¹,

Shakur²,

Edwards³

et al. 2017

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Abstract. Postpartum haemorrhage (PPH) is a potentially life-threatening Background complication for women, and the leading cause of maternal mortality. Tranexamic acid (TXA) is an antifibrinolytic used worldwide to treat uterine haemorrhage and to reduce blood loss in general surgery. TXA may have effects on thrombin generation, platelet function and coagulation factors as a result of its inhibition on the plasmin.. WOMAN ETAPlaT is a sub-study of the World Maternal Methods Antifibrinolitic trial (WOMAN trial). All adult women clinically diagnosed with PPH after a vaginal delivery or caesarean section, are eligible for inclusion in the study. Blood samples will be collected at the baseline and 30 minutes after the first dose of study treatment is given. Platelet function will be evaluated in whole blood immediately after sampling with Multiplate® tests (ADPtest and TRAPtest). Thrombin generation, fibrinogen, D-dimer, and coagulation factors vW, V and VIII will be analysed using platelet poor plasma.Recruitment to WOMAN ETAPlaT started on 04 November 2013 and Results. closed on 13 January 2015, during this time 188 patients were recruited. The final participant follow-up was completed on 04 March 2015. This article introduces the statistical analysis plan for the study, without reference to unblinded data.The data from this study will provide evidence for the effect of Conclusion. TXA on thrombin generation, platelet function and coagulation factors in women with PPH. Amendments from Version 1The differences of the second version of "Statistical analysis plan for the WOMAN-ETAPlaT study: Effect of tranexamic acid on platelet function and thrombin generation" has been based on the comments from referees:1. Removed the exploratory subgroup analysis section, because the total sample size was small and the subgroup analyses run the risk of false positive. Also, it was removed a section with evidence about effect of TXA on thrombin generation, because some evidence it was provided at the protocol paper of ETAPlaT sub-study.2. We added a flowchart according to CONSORT to report the participant progress in the ETAPlaT sub-study (Figure 1), allocation of patients in TXA or placebo group, lost of follow up and exclusion from analysis. Two sections were added, one section for safety report for all patients randomized in the substudy, about adverse events and serious adverse events. Another section added was about adherence, to report measures of compliance by trial arm. See referee reports REVISED PrefaceThe purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study findings by pre-specifying the statistical approaches to the analysis of the study data prior to hard locking the database and unblinding of the WOMAN ETAPlaT trial data. To prevent outcome bias and selective reporting, a detailed SAP is presented in order to avoid post hoc decisions that may influence the interpretation of the results and the statistical analyses of the final data.This SAP is a technical extension of the WOMAN ...