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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.
The aims and methods of the WOMAN 13 and the ETAC 14 trials are described in detail elsewhere. Briefly, adult women with clinically diagnosed primary PPH after vaginal or caesarean delivery were eligible Ref 7 & 13 for inclusion. After the appropriate consent procedure was completed, each woman was randomly allocated to receive 1 g TXA or matching placebo by intravenous injection. If bleeding continued after 30 min, or if bleeding stopped and restarted within 24 h, a second dose of 1 g of TXA or placebo was given. We collected patient entry and outcome data as per the WOMAN trial protocol 13. WOMAN trial participants at University College Hospital, Ibadan, Nigeria were also considered for inclusion in the ETAC trial. In addition to the WOMAN trial procedures, women had 15 ml venous blood taken after randomisation and before administration of the first dose of trial treatment. A second venous blood sample of about 15 ml was taken 30 (±15) min after the first dose and before a second dose was given. We divided each venous blood sample into three vacutainer tubes. We collected one 5 ml sample in a tube containing potassium EDTA for full blood count analysis and two 4.5 ml samples in tubes containing 0.5 ml sodium citrate (0.109 mol/l) for coagulation and rotational thromboelastometry (ROTEM). We used a five-parameter particle counter Sysmex KN analyser (Sysmex Corporation, Kobe, Japan) for the full blood count analysis. After centrifuging the blood at 3000 g for 20 min, we extracted the plasma without disturbing the buffy coat layer, and measured prothrombin time (PT), activated partial thromboplastin time (APTT), Clauss fibrinogen and D-dimers using a HumaClot Junior automated coagulation analyser. We measured ROTEM parameters at 37°C using two of the four channels (EXTEM, APTEM) of the ROTEM coagulation analyser (TEM®, Munich, Germany)). The ROTEM was allowed to run for 60 min. The following ROTEM variables were examined from the EXTEM and APTEM traces: clotting Time), clot amplitude at 5 and 10 min (CA-t), maximum clot firmness (MCF), maximum clot lysis (ML) and lysis index (LI). We stored the ROTEM reagents at 2–8°C with temperature monitoring and we used in-date reagents. The clinical staff had no access to the results of ROTEM analysis carried out for the ETAC trial. In addition, we collected the following information: time of blood samples, time the trial treatment was administered, time laboratory analysis started and ended, any treatment given that may affect coagulation, adverse events, and technical problems with analysis. We published a statistical analysis plan before the allocation was unblinded 14. We assumed that D-dimer mean and standard deviation in the control group would be 9,000 ng/ml and 7,200 ng/ml, respectively. Taking into account that we would adjust for baseline measurement and assuming a correlation between baseline and follow-up of 0.4, we estimated that a study with about 180 patients would have 90% power (two-sided alpha=5%) to detect a reduction of 30% in the mean D-dimer value in the tranexamic group. We conducted a per-protocol analysis that included all participants who satisfied the eligibility criteria, received the allocated treatment, had follow up samples and at least one measurement of the primary outcome. We did not exclude outliers or impute missing data as it would be inappropriate in a study aimed at understanding the biological effects of TXA. We assessed the effect of TXA on fibrinolysis by assessing D-dimer and ML as our co-primary outcome. For each co-primary outcome, we compared the follow up results of each treatment group (t-test). Our secondary outcomes included INR, PT, APTT, fibrinogen, haemoglobin and the following ROTEM EXTEM parameters: clotting time (CT), clot amplitude at 5 (A5) and 10 min (A10), LI at 30 and 60 min and MCF. We compared the mean follow-up result in women receiving TXA and those receiving placebo using the t-test. We also compared follow-up results of each treatment group using linear regression, adjusting for the corresponding baseline measurement. The effect of TXA on our co-primary outcomes, D-dimer and maximum lysis, were explored stratified by time since delivery, type of delivery, cause of postpartum haemorrhage and maternal anaemia. A t-test was conducted to compare means between treatment arms, and the likelihood ratio test was used to test for interaction between subgroups. We defined hyperfibrinolysis as ML>15% on ROTEM EXTEM and coagulopathy as an INR >1.2 and A5 ≤40 mm. We used logistic regression to assess multivariate odds ratios between baseline variables and hyperfibrinolysis and coagulopathy. Stata 15 was used for all statistical analyses 15. To set the results of the ETAC study in context of an almost identical haematological sub-study conducted within the WOMAN trial but in a different location (Albania) and provide a more robust estimate of the effect of TXA on D-dimer, we conducted a meta-analysis of the two studies. 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. We log-transformed individual patient data for D-dimer, and calculated the arithmetic mean (SD) of the log-transformed values for each study. A meta- analysis of the arithmetic means of transformed data gives a mean difference, which after back-transforming, corresponds to a meta-analysis of the ratio of geometric means in the original scale. Statistical heterogeneity was examined by visual inspection of forest plots, the I 2 statistic and χ 2 test. This analysis was not included in the statistical analysis plan for the ETAC trial. The trial was conducted in accordance with the ICH-GCP 17. Approvals were obtained from the Ethics Committees of London school of Hygiene and Tropical Medicine (Reference A275 5536) and the University of Ibadan & University College Hospital Ethics Committee (Reference UI/EC/09/0131). Regulatory approval was obtained from the Nigerian National Agency for Food and Drug Administration and Control. The consent procedures are described in detail in the WOMAN Trial protocol 13. In summary, consent was obtained from women if their physical and mental capacity allowed. If a woman was unable to give consent, proxy consent was obtained from a relative or representative. If a proxy was unavailable, then consent was deferred or waived. When consent was deferred or given by a proxy, the woman was informed about the trial as soon as possible, and consent obtained for on-going data collection, if needed.
