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

The impact of early outcome events on the effect of tranexamic acid in post-partum haemorrhage:... 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). Keywords: Postpartum haemorrhage, Tranexamic acid, WOMAN trial, Hysterectomy, Death, Bleeding * Correspondence: amy.brenner@lshtm.ac.uk Clinical Trials Unit, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Brenner et al. BMC Pregnancy and Childbirth (2018) 18:215 Page 2 of 9 Background proposed repeated analyses with varying assumptions Tranexamic acid reduces bleeding by inhibiting the about the timing of an exposure’s effect [7]. We aimed breakdown of fibrin blood clots. When given prior to in- to examine whether early outcome events diluted the ef- cision, tranexamic acid reduces blood loss in elective fect of tranexamic acid on death due to bleeding and surgery by about one third [1]. The CRASH-2 trial hysterectomy due to bleeding by conducting repeated showed that early tranexamic acid administration re- analyses excluding outcomes at increasing intervals from duces death due to bleeding in trauma patients with or randomisation. at risk of significant haemorrhage [2]. The WOMAN trial assessed the effects of tranexamic acid on death, Methods hysterectomy and other outcomes in 20,060 women with The WOMAN trial was a randomised, placebo-controlled post-partum haemorrhage (PPH). There was a signifi- trial of the effect of tranexamic acid on death, hysterec- cant reduction in death due to bleeding with tranexamic tomy and other morbidities in women with PPH. It in- acid (RR = 0·81, 95% CI 0·65–1·00; p = 0·045) [3]. As in cluded 20,060 women aged 16 years and older with a traumatic haemorrhage, the reduction was greatest when clinical diagnosis of PPH recruited from 193 hospitals in treatment was given early (within 3 h of delivery), (RR 21 countries between 2010 and 2016. We randomly allo- 0·69, 95% CI 0·53–0·90; p = 0·007), with no apparent re- cated women to receive 1 g of tranexamic acid or placebo duction after 3 h [3, 4]. There was also a decrease in by slow intravenous injection. If bleeding continued after laparotomy to control bleeding in women who received 30 min or restarted within 24 h of the first dose, we gave a tranexamic acid (RR 0·64, 95% CI 0·49–0·85; p = 0·002). second dose of 1 g of tranexamic acid or placebo. We ob- Based on these results, the World Health Organization tained follow-up data for 99.8% of patients. We have pub- has recommended the early use (within 3 h of birth) of lished full details of the trial rationale, design, methods tranexamic acid for the treatment of PPH [5]. and results elsewhere [3, 6]. In the WOMAN trial, tranexamic acid did not prevent We conducted the trial in accordance with good clin- hysterectomy due to bleeding (RR = 0.95 95%CI 0.78– ical practice guidelines. The relevant ethics committees 1.16, p = 0.611). During the trial, we noticed that clini- and regulatory agencies approved the consent proce- cians sometimes decided to perform a hysterectomy at dures. We obtained informed consent from women if or prior to the time of randomisation and so tranexamic their physical and mental capacity allowed. If a woman acid could not influence the decision. We predicted that could not give consent, we obtained proxy consent from including such hysterectomies as ‘outcome measures’ in a relative or representative. If no proxy was available, the trial would reduce or obscure the effect of tranex- then if local regulation allowed, we deferred or waived amic acid [6]. the consent. In these cases, we told the woman about Inappropriate assumptions about the timing of an ex- the trial as soon as possible and obtained consent for posure’s effect can cause bias towards the null [7]. Even use of the data collected. when outcome events occur after randomisation, some will be imminent or inevitable at the time of randomisa- Analysis tion and so cannot be prevented by the trial treatment. We conducted exploratory analyses of the WOMAN This is a particular problem in trials in life threatening trial dataset using the method proposed by Rothman [7]. emergencies when the trial treatment is usually given Our primary outcome was death due to bleeding and after the established treatments. Although a trial would our secondary outcome was hysterectomy due to bleed- ideally evaluate a treatment as it would be used in clin- ing. We prepared frequency bar charts of the time inter- ical practice, it is difficult to ensure that a treatment of vals between randomisation and death due to bleeding uncertain effectiveness is given urgently, particularly and between randomisation and hysterectomy due to when clinicians know that half of the patients will re- bleeding in the treatment and placebo groups to show ceive a placebo. the time course of bleeding-related outcomes. We then Given the extent of blood loss in PPH, many of the examined the effect of tranexamic acid on these out- women enrolled in the WOMAN trial were probably comes among women treated within 3 h of delivery critically ill at the time of randomisation: 59% of women since tranexamic acid only appears to be effective when had haemodynamic instability. As such, hysterectomy or given within this timeframe [3, 4]. We hypothesised that death may have been imminent or inevitable in some maternal deaths or hysterectomies due to bleeding that women. Such outcomes would likely have occurred soon occurred soon after randomisation were imminent or in- after randomisation. We hypothesised that the inclusion evitable at the time of randomisation. As such, we of imminent or inevitable outcome events in the analysis assessed the impact of early deaths or hysterectomies would dilute the treatment effect towards the null. To due to bleeding on the treatment effect by conducting estimate an undiluted measure of effect, Rothman repeated analyses excluding patients with these Brenner et al. BMC Pregnancy and Childbirth (2018) 18:215 Page 3 of 9 outcomes at increasing intervals from randomisation. hysterectomies due to bleeding (2.8%). Here we present We also excluded patients who died from any cause the results of intention-to-treat analyses. In per-protocol within the relevant exclusion period, as they could not analyses, we excluded 19 women who did not receive contribute to the denominator. We increased the length tranexamic acid (n = 9) or placebo (n = 10). The results of the exclusion period by one hour at a time, up to 10 h of the per-protocol analysis were almost identical (see for deaths due to bleeding but 5 h for hysterectomy due Additional file 1: Tables S1 and S2). The trial arms to bleeding since there were few hysterectomies beyond remained balanced by baseline characteristics (see Add- 5 h. We excluded hysterectomies completed before ran- itional file 1: Tables S3 and S4), and there was no evi- domisation. We conducted intention-to-treat and dence of confounding (see Additional file 1: Tables S5 per-protocol analyses and quantified treatment effects and S6). using risk ratios and 99% confidence intervals. We used Figure 1 shows a frequency bar chart of the interval 99% rather than 95% confidence intervals due to the between randomisation and death due to bleeding for multiple number of between-group comparisons. We the placebo group (n = 173) and tranexamic acid group prepared plots of the cumulative percentage of death (n = 138) over the 24 h after randomisation. The distri- due to bleeding and hysterectomy due to bleeding in bution was positively skewed, with 42% of all deaths order to supplement the period-specific risk ratios, from exsanguination occurring within 3 h of randomisa- which can be susceptible to selection bias [8]. We tion, 58% within 5 h, and 80% within 10 h. Thirty-five assessed the proportional hazards assumption using the (10%) deaths from exsanguination occurred more than Grambsch-Therneau global test. 24 h after randomisation. To assess the risk of selection bias from Table 1 shows risk ratios for death due to bleeding in post-randomisation exclusions we examined the distri- women treated within 3 h of delivery, excluding women bution of baseline characteristics by treatment group. who died at increasing intervals from randomisation. We used stratified analyses to assess potential confound- When all women were included, there was a 31% reduc- ing factors including age, time to treatment, type and tion in the risk of death due to bleeding with tranexamic place of delivery, cause of haemorrhage, use of utero- acid (RR = 0.69, 99% CI 0.48–0.98). Excluding women tonic prophylaxis, estimated blood loss, blood transfu- who died soon after randomisation increased the treat- sion, and second dose of the trial treatment (or placebo). ment effect. The effect was largest after excluding We adjusted for relevant factors using multivariable log women who died within 9 h of randomisation, with a binomial regression and selected a final model using 59% reduction in death due to bleeding (RR = 0.41, 99% likelihood ratio tests. We also conducted sensitivity ana- CI 0.19–0.89). Although there was a decreasing trend in lyses of women treated within an hour of delivery, risk ratios, the 99% confidence intervals were wide and women with uterine atony as the primary cause of overlapping. In sensitivity analyses of women treated haemorrhage, and women who underwent caesarean within an hour of delivery, women with uterine atony section. and women who underwent caesarean section, we ob- served the same decreasing trend in risk ratios (see Add- Results itional file 1: Tables S7-S9). In the WOMAN trial, 20,060 women were randomly Figure 2 shows a plot of the cumulative percentage of assigned to receive tranexamic acid (n = 10,051) or pla- deaths from bleeding by time from randomisation in the cebo (n = 10,009). After excluding 39 women who did tranexamic acid and placebo groups. For the first few not fulfil the eligibility criteria, withdrew consent or hours after randomisation the curves overlap but later were lost to follow up, data on 20,021 women were they separate. The Grambsch-Therneau test for propor- available for analysis. Ten women (< 0.1%) had missing tional hazards gave p = 0.06. data on time of delivery or time of randomisation, so Figure 3 shows a frequency bar chart of the interval time to treatment was calculated in the remaining between randomisation and hysterectomy due to bleed- 20,011 women. Of these, 14,923 women were rando- ing in the placebo group (n = 263) and tranexamic acid mised within 3 h of delivery (7518 tranexamic acid and group (n = 245) for the 24 h after randomisation. Again, 7405 placebo), with a mean time from delivery to ran- the distribution was positively skewed with 38% of hys- domisation of 1 h (interquartile range = 0.4–1.5 h). Data terectomies for bleeding occurring within one hour of on time of haemorrhage death were available for all randomisation and 82% within 3 h. Less than 2% of hys- women. Data on time of hysterectomy for bleeding or terectomies for bleeding (n = 9) occurred more than hysterectomy status were missing for 45 women (0.3%), 24 h after randomisation. leaving 14,878 patients for the hysterectomy analyses. Table 2 shows risk ratios for hysterectomy due to Among women randomised within 3 h of delivery, there bleeding for women treated within 3 h of delivery, ex- were 216 deaths due to bleeding (1.5%) and 383 cluding women who underwent hysterectomy at Brenner et al. BMC Pregnancy and Childbirth (2018) 18:215 Page 4 of 9 Fig. 1 Deaths due to bleeding within 24 h of randomisation by treatment group and hours since randomisation increasing intervals from randomisation. When all Discussion women were included, there was no reduction in the risk In the original WOMAN trial, women who experienced of hysterectomy due to bleeding with tranexamic acid PPH were randomized to receive tranexamic acid vs pla- (RR = 0.95, 99% CI 0.73–1.23). Excluding women who cebo. In the WOMAN trial, we observed a 19% reduc- had a hysterectomy for bleeding soon after randomisa- tion in the risk of death from exsanguination in women tion resulted in a decrease in the risk ratio (RR = 0.79; who received tranexamic acid compared to placebo, with 99% CI 0.33–1.86), however, the 99% confidence inter- a 31% reduction in women treated within 3 h of giving vals overlapped the null at each exclusion interval. birth. In this secondary analysis of WOMAN trial data, Figure 4 shows a plot of the cumulative percentage of after excluding deaths due to bleeding that occurred hysterectomy for bleeding by time from randomisation soon after randomisation, we observed a lower risk of in the tranexamic acid and placebo groups. In the first death from exsanguination in women who received early hours after randomisation the curves were similar but tranexamic acid compared to placebo (RR = 0.41; 99% CI with minimal separation later. The Grambsch-Therneau 0.19–0.89). Some women may have been so critically ill test for proportional hazards gave p = 0.17. at the time of randomisation that death was imminent Table 1 Impact of early deaths due to bleeding on the effect of tranexamic acid Exclusion interval Exclusions N Death due to bleeding (hours from TXA (%) Placebo (%) TXA Placebo TXA Placebo Risk ratio randomisation) (%) (%) (99% CI) None –– 7518 7405 89 (1.2) 127 (1.7) 0.69 (0.48–0.98) 1 14 (0.2) 15 (0.2) 7504 7390 76 (1.0) 114 (1.5) 0.66 (0.45–0.96) 2 30 (0.4) 38 (0.5) 7488 7367 61 (0.8) 92 (1.3) 0.65 (0.43–1.00) 3 42 (0.6) 57 (0.8) 7476 7348 50 (0.7) 75 (1.0) 0.66 (0.41–1.05) 4 53 (0.7) 70 (1.0) 7465 7335 42 (0.6) 64 (0.9) 0.64 (0.39–1.07) 5 62 (0.8) 77 (1.0) 7456 7328 33 (0.4) 59 (0.8) 0.55 (0.31–0.96) 6 66 (0.9) 85 (1.2) 7452 7320 29 (0.4) 53 (0.7) 0.54 (0.30–0.97) 7 73 (1.0) 94 (1.3) 7445 7311 23 (0.3) 44 (0.6) 0.51 (0.26–0.99) 8 80 (1.1) 97 (1.3) 7438 7308 18 (0.2) 41 (0.6) 0.43 (0.21–0.89) 9 83 (1.1) 101 (1.4) 7435 7304 16 (0.2) 38 (0.5) 0.41 (0.19–0.89) 10 84 (1.1) 104 (1.4) 7434 7301 16 (0.2) 37 (0.5) 0.42 (0.20–0.91) % is the proportion of the original trial arm excluded (N = 7518 TXA, N = 7405 placebo). TXA = tranexamic acid. Includes women treated within 3 h of delivery only Brenner et al. BMC Pregnancy and Childbirth (2018) 18:215 Page 5 of 9 Fig. 2 Cumulative percentage of deaths due to bleeding by time from randomisation in the tranexamic acid and placebo group and inevitable regardless of treatment. The findings of on the pharmacokinetics and pharmacodynamics of this secondary analysis extend those of the original tranexamic acid in obstetric bleeding will help to de- WOMAN trial by further highlighting the importance of termine the optimal dosing regimen. tranexamic acid as an early life-saving intervention for Our analysis has important limitations. Although the women who experience PPH. statistical analysis plan, which we prepared before seeing The plasma concentration of tranexamic acid the trial results, anticipated that outcomes determined needed to inhibit fibrinolysis is around 5–15 mg/L prior to randomisation would dilute the treatment effect, and tranexamic acid has a half-life of 2–3h[9–14]. the exploratory analyses presented here were not After an intravenous injection of 1 g of tranexamic pre-specified and comprise multiple between-group acid, the plasma concentration should exceed this comparisons. The possibility of a type 1 error cannot be range for several hours [13, 15]. Because it is elimi- excluded and so our results require cautious interpret- nated by the kidneys, the concentration could remain ation. That said, in keeping with our hypothesis, we ob- elevated for much longer in women with severe served an increase in the treatment effect on death due bleeding and renal impairment [16]. Further research to bleeding with an increasing exclusion interval. This Fig. 3 Hysterectomies due to bleeding within 24 h of randomisation by treatment group and hours since randomisation Brenner et al. BMC Pregnancy and Childbirth (2018) 18:215 Page 6 of 9 Table 2 Impact of early hysterectomies due to bleeding on the effect of tranexamic acid Exclusion Exclusions N Death due to bleeding interval (hours TXA (%) Placebo (%) TXA Placebo TXA (%) Placebo (%) Risk ratio (99% CI) from randomisation) None –– 7494 7384 188 (2.5) 195 (2.6) 0.95 (0.73–1.23) 1 90 (1.2) 93 (1.3) 7404 7291 112 (1.5) 117 (1.6) 0.94 (0.67–1.32) 2 175 (2.3) 167 (2.3) 7319 7217 42 (0.6) 64 (0.9) 0.65 (0.39–1.08) 3 205 (2.7) 214 (2.9) 7289 7170 23 (0.3) 34 (0.5) 0.67 (0.33–1.33) 4 217 (2.9) 236 (3.2) 7277 7148 19 (0.3) 25 (0.4) 0.75 (0.34–1.63) 5 227 (3.0) 246 (3.3) 7267 7138 16 (0.2) 20 (0.3) 0.79 (0.33–1.86) % is the proportion of the original trial arm excluded (N = 7494 TXA, N = 7384 placebo). TXA = tranexamic acid. Includes women treated within 3 h of delivery only finding was consistent in several sensitivity analyses. The on patient characteristics at each time point selection temporal distribution of haemorrhage deaths allowed us bias remains a concern. Figure 2 provides some unbiased to exclude women who died soon after randomisation. evidence of a lack of treatment benefit early on, in line We did not observe a statistically significant decrease in with our hypothesis that early deaths due to bleeding the risk of hysterectomy for bleeding associated with may dilute the treatment effect, but this may be a spuri- tranexamic acid compared with placebo after excluding ous finding. hysterectomies performed early after randomization. Al- The validity of our results also depend on the accuracy though this finding suggests that tranexamic acid may of data on the time of randomisation (treatment) and not decrease the need for hysterectomy as a life-saving the time of death but measurement error is inevitable. surgical intervention for PPH, it is possible that our Although we urged investigators to give the trial treat- sample size was inadequate to show a true treatment ment as soon as possible after randomisation, some out- benefit when excluding early hysterectomies. comes would have occurred before the treatment was Period-specific risk ratios are susceptible to selection completed. Time of death could have been misclassified bias [8]. Because tranexamic acid reduces deaths due to since there is often an interval between death and its bleeding, post-randomisation exclusions based on formal confirmation. time-to-outcome are not independent of treatment. In- Because maternal death can occur soon after major deed, we excluded 20 more deaths from the placebo uncontrolled PPH, interventions to compensate for group than from the treatment group. Although this blood loss (e.g. blood transfusion) and control the bleed- might be expected to obscure rather than inflate the de- ing (e.g. hysterectomy) may occur early after PPH diag- layed effects of treatment, because we do not have data nosis, often prior to administration of the trial Fig. 4 Cumulative percentage of hysterectomies for bleeding by time from randomisation in the tranexamic acid and placebo groups Brenner et al. BMC Pregnancy and Childbirth (2018) 18:215 Page 7 of 9 treatment. We conjecture that this may potentially ex- Funding Funding for the WOMAN trial was provided by London School of Hygiene & plain the lack of any effect of tranexamic acid on Tropical Medicine, Pfizer (provided the trial drug), the UK Department of blood transfusion and hysterectomy in the WOMAN Health (grant number HICF-T2–0510-007), the Wellcome Trust (grant number trial. However, theresults for hysterectomywerein- WT094947), and The Bill & Melinda Gates Foundation (grant number OPP1095618). The funders had no role in study design, data collection, ana- conclusive and we did not have data on time of lysis or interpretation, or the writing of the manuscript. transfusion. Future studies are needed to examine the effect of tranexamic acid on haemorrhage-related Availability of data and materials The datasets generated and/or analysed during the current study are not yet morbidity, and should report the timing of relevant publicly available due to ongoing analyses of this recently completed trial. medical and surgical interventions, such as time to After publication of the planned primary and secondary analyses, the trial first transfusion, uterine balloon tamponade, interven- data will be made available via our data-sharing portal, The Free Bank of In- jury and Emergency Research Data (freeBIRD) website at https://ctu-app.lsht- tional radiology, and surgical intervention (including m.ac.uk/freebird/. hysterectomy and laparotomy). Authors’ contributions IR and HS conceived and designed the WOMAN trial. The WOMAN Trial Conclusions Collaborators were responsible for conducting the study and for data In this secondary analysis of data from the WOMAN collection. RC, BF, IR and HS contributed to the conception of this trial, we observed that tranexamic acid was associated analysis. AB conducted the analysis. AB and IR drafted the manuscript. AB, HS, RC, BF, SA and IR participated in the interpretation of the data with a reduced risk of maternal death from exsanguin- and the revising of the manuscript. ation after excluding early maternal deaths from the ana- lysis. This finding is in line with the main findings from Ethics approval and consent to participate Ethical approval was obtained from the London School of Hygiene and the WOMAN trial. Our results suggest that the inclu- Tropical Medicine Ethics Committee and Berkshire Research Ethics sion of early deaths in the analysis may have diluted the Committee, in addition to the following local and national research ethics treatment effect of tranexamic acid towards the null. committees. Albania: Komiteti Kombetar i Etikes. Early outcome events could represent those that are Bangladesh: Ad-din Women’s Medical College Ethics Committee; Ethical Re- imminent and inevitable. Therefore, the outcomes of view Committee Chittagong Medical College; Ethical Committee of Dhaka some women with life-threatening PPH occurring soon Medical College; Ethics Committee Ibn Sina Medical College Hospital; Raj- shahi Medical College Hospital Ethical Committee. after delivery may not be influenced by exposure to the Burkina Faso: Centre Hospitalier Regional de Dedougou; Centre Hospitalier study drug. These findings also raise the possibility that Universitaire Yalgado Ouedraogo. if we give women tranexamic acid as a first line treat- Cameroon: Comite d’Ethique de l’Hopital de District de Banyo; Comite d’ethique de l’hopital gyneco-obstetrique et pediatrique de Yaounde; ment for PPH rather than a last resort, as now recom- Dschang District Hospital; Hopital Laquintinie de Douala; Kumba District Hos- mended by the World Health Organization [5], its effect pital; Limbe Regional Hospital; Le Comite d’ethique de l’Hopital de District on reducing the risk of death due to bleeding may ex- de Sa’a; St Theresa’s Catholic Hospital Local Ethics Committee; Yaounde Cen- tral Hospital; Comite d’ethique de l’hopital gyneco-obstetrique et pediatrique ceed that observed in the WOMAN trial. However, these de Yaounde. results should be viewed with caution due to the ex- Colombia: Ethical and Biomedical Research Committee, Fundacion Valle del ploratory nature of this analysis. It remains uncertain Lili. Cote d’Ivoire: Direction Departementale d’Abobo-Est. whether tranexamic acid reduces the risk of hysterec- Democratic Republic of Congo: Le Comite d’Ethique du CSR Albert Barthel; tomy for bleeding after excluding early hysterectomies Centre de Sante de Reference Kahembe; Centre Hospitalier Notre Dame post-randomisation. Further studies are needed to exam- d’Afrique; Le Comite d’Ethique Institutionnel, Centre Medical Abedeco; Le Comite d’Ethique du Centre Medical VUHE; Comite d’Ethique de CSR Carmel; ine the effect of tranexamic acid on morbidity in PPH. Comite d’Ethique de GESOM; Comite d’Ethique de Hope Medical Center; Le Comite d’Ethique du Centre de l’Hopital Provincial du Nord Kivu/Goma; Le Comite d’Ethique du Centre de l’Hopital General de Reference Virunga. Additional file Egypt: General Organisation for Teaching Hospitals and Institutes. Ethiopia: Jimma University Ethics Committee; St. Paul’s Hospital Millennium Additional file 1: Supplementary data analyses. This file provides per Medical College Ethics Committee. protocol analyses (Tables S1 and S2); an assessment of potential selection Ghana: School of Medical Sciences Committee on Human Research bias (Tables S3 and S4); an assessment of potential confounding (Tables Publications and Ethics. S5 and S6); a sensitivity analysis of women treated within an hour of Jamaica: UHWI/UWI/FMS Ethics Committee. delivery (Table S7); a sensitivity analysis of women with uterine atony as Kenya: AIC Kijabe Hospital Medical Education and Research; Bungoma the primary cause of haemorrhage (Table S8); a sensitivity analysis of District Hospital; Ministry of Medical Services Coast; Ministry of Health, women who underwent caesarean section (Table S9). (DOCX 39 kb) Garissa; Kenyatta National Hospital/University of Nairobi Ethics and Research Committee; Moi Teaching and Referral Hospital Institutional Research and Ethics Committee; Ministry of Health & Sanitation, Mwingi District Hospital; Abbreviations Ministry of Health, Nakuru; Nairobi Hospital Bioethics and Research PPH: Post-partum haemorrhage; TXA: Tranexamic acid; WOMAN trial: World Committee. Maternal Antifibrinolytic trial Nepal: Biratnagar Aspataal & Research Center Ethics Committee; Institutional Ethical Review Board BPKIHS; Mid Western Regional Hospital Ethics Acknowledgments Committee; Nepal Medical College Institutional Research/Review Committee. The authors want to thank all members of the WOMAN Trial Collaborative Nigeria: Abubakar Tafawa Balewa University Teaching Hospital; Oyo State and all women who participated in the WOMAN trial. Research Ethical Review Committee; Aminu Kano Teaching Hospital; Ahmadu Brenner et al. BMC Pregnancy and Childbirth (2018) 18:215 Page 8 of 9 Bello University Teaching Hospital Faculty of Medicine Ethical Sudan: National Medicines and Poisons Board. Committee; Braithwaite Memorial Specialist Hospital Ethics Committee; Tanzania: Prime Ministers Office, Regional Administration and Local Delta State University Teaching Hospital Research Ethics Committee; Government; Muheza Designated District Hospital; Muhimbili National University Teaching Hospital Ado-Ekiti Ethics and Research Committee; Hospital; Mwananyamala Hospital; Temeke Municipal Council. Federal Capital Territory Health Research Ethics Committee; Federal Med- Uganda: Makerere University; Ugandan National Council of Science and ical Centre Abeokuta Research Ethics Committee; Federal Medical Centre Technology. Azare Health Research Ethics Committee; Federal Medical Centre Bida United Kingdom: Nottingham University Hospitals NHS Trust Research & Ethical Committee; Federal Medical Centre Birnin-Kebbi Research Ethics Development Department; Liverpool Women’s NHS Foundation Trust R&D Committee; Federal Medical Centre Gusau Ethic and Research Commit- Department; Central Manchester University Hospitals NHS Foundation Trust tee; Federal Medical Centre Ido-Ekiti Ethics and Research Committee; R&D; Guys and St Thomas NHS Foundation Trust Research and Federal Medical Centre Katsina Medical Research Ethics Committee; Fed- Development; City Hospitals Sunderland NHS Foundation Trust Research and eral Medical Centre Keffi Health Research Ethics Committee; Federal Development; The Newcastle Upon Tyne NHS Foundation Trust Research Medical Centre Lokoja Ethical Review Committee; Federal Medical Centre and Development. Makurdi Committee on Medical Ethics; Federal Medical Centre Owerri Zambia: Chipata General Hospital; Kabwe General Hospital Ethics Committee; Ethical Committee; Federal Medical Centre Owo Ethical Review Commit- University of Zambia Biomedical Ethics Committee; Livingstone General tee; Federal Medical Centre, Umuahia; Federal Medical Centre, Yenagoa; Hospital; St Paul’s Mission Hospital, Kashikishi; St Francis Hospital Research Federal Teaching Hospital Abakaliki Research Ethics Committee; Irrua Ethics Committee; University of Zambia Biomedical Ethics Committee. Specialist Teaching Hospital Research Ethics Committee; Jos University The relevant ethics committees and regulatory agencies approved the teaching Hospital Institutional Health Research Ethics Committee; Kogi consent procedures at each site. We obtained informed consent from State Specialist Hospital Research and Ethical Committee; Ladoke Akin- women if their physical and mental capacity allowed. For fully competent tola University of Technology Teaching Hospital Ethical Committee; women, an information sheet was provided, the study was discussed and Lagos Island Maternity Hospital Ethical Committee; Lagos State University written consent obtained. If the woman was unable to read or write then Teaching Hospital Health Research and Ethics Committee; Lagos Univer- the information sheet was read to her and she then marked the consent sity Teaching Hospital Research & Ethics Committee; Mother & Child form with either a cross or thumbprint. In this event, a witness not Hospital Akure Research Ethics Committee; National Hospital Abuja Ethics associated with the trial provided a full signature confirming the mark. If a Committee; Nigeria National Health Research Ethics Committee; Nnamdi woman could not give consent, we obtained proxy consent from a relative Azikiwe UTH Ethical Committee; Obafemi Awolowo University Teaching or representative in the same manner. If no proxy was available, then if local Hospital Ethics & Research Committee; Plateau State Specialist Hospital regulation allowed, we deferred or waived the consent. In these cases, we Health Research Ethics Committee; Seventh Day Adventist Hospital In- told the woman about the trial as soon as possible and obtained consent for ternal Review Board and Ethics Committee; University of Ibadan/Univer- use of the data collected. The consent procedures are described in detail in sity College Hospital Ethics Committee; University of Abuja Teaching the trial protocol. Hospital Health Research Ethics Committee; University of Calabar Teach- ing Hospital Ethical Committee; University of Ilorin Teaching Hospital Competing interests Ethical Reveiw Committee; University of Maiduguri Teaching Hospital The authors declare that they have no competing interests. Ethics and research Committee; University of Nigeria Hospital Research Ethics Committee; University of Uyo teaching Hospital Institutional Re- Author details view Committee; Usmanu Danfodiyo University Teaching Hospital Sokoto 1 Clinical Trials Unit, London School of Hygiene and Tropical Medicine, Keppel Ethical Research Committee; Obafemi Awolowo University Teaching Hos- 2 Street, London WC1E 7HT, UK. Holy Family Hospital, Gynaecology & pital Ethics & Research Committee. Obstetrics Unit 1, F-762 Said Pur Road, Satellite Town, Rawalpindi, Pakistan. Pakistan: Ayub Teaching Hospital Ethical Committee; Institutional Ethical 3 Department of Obstetrics & Gynaecology, College of Medicine, University of Review Committee Bolan Medical College; Cantonment General Hospital Ibadan, Queen Elizabeth Road, Ibadan, Nigeria. St George’s University of London, Room 1.126, First Floor, Jenner Wing, Cranmer Terrace, London Rawalpindi Ethics Committee; Institutional Ethics Committee, Combined SW17 0RE, UK. Military Hospital Kharian; Combined Military Hospital Lahore Ethics Committee; Rawalpindi Medical College and Allied Hospitals Research and Received: 3 November 2017 Accepted: 25 May 2018 Ethics Committee; Fatima Bai Hospital Ethical Review Committee; Institutional Review Board Fatima Memorial Hospital; Ethical Committee References Federal Government PolyClinic; Institutional Review Board Services Institute 1. Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on of Medical Sciences; Isra University Hospital Ethical Committee; AIMC/Jinnah surgical bleeding: systematic review and cumulative meta-analysis. Br Med J. Hospital Lahore Ethical Review Board; Ethical Review Committee Kahota 2012;344:e3054. 2. CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats Research Laboratory Hospital Islamabad; Institutional Review Board King T, et al. Effects of tranexamic acid on death, vascular occlusive events, and Edward Medical University; Institutional Research & Ethics Board Lady blood transfusion in trauma patients with significant haemorrhage (CRASH- Reading Hospital; Institutional Review Board King Edward Medical University; 2): a randomised, placebo-controlled trial. Lancet. 2010;376:23–32. Liaquat Ethics Review Committee; Ethics Review Committee Liaquat 3. WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post- University Hospital; Ethics Commitee MCH PIMS; Mian Muhammad Trust partum haemorrhage (WOMAN): an international, randomised, double-blind, Hospital Ethics Committee; Research and Ethic Committee Islamabad placebo-controlled trial. Lancet. 2017;389:2105–16. Medical Complex Nescom; Institutional Ethical Review Committee Nishtar 4. CRASH-2 collaborators, Roberts I, Shakur H, Afolabi A, Brohi K, Coats T, et al. Medical College & Hospital Multan; Islamic International College Trust The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Pakistan Railway Hospital; Ethics Committee Patel Hospital; Ethical Review Lancet. 2011;377:1096–1101.e2. Committee People’s University of Medical and Health Sciences; Rehman 5. World Health Organization. WHO recommendations for the prevention and Medical Institute Peshawar Institutional Review Committee; Ethics Committee treatment of postpartum haemorrhage. WHO 2017. Available from: http:// www.who.int/reproductivehealth/publications/tranexamic-acid-pph- Shalamar Hospital; Ethical Committee Sharif Medical and Dental College; treatment/en/ Accessed 12 Jan 2018. Institutional Review Board and Ethics Committee Shifa International Hospital; 6. Shakur H, Roberts I, Edwards P, Elbourne D, Alfirevic Z, Ronsmans C. The Sir Ganga Ram Hospital Lahore Ethics Committee; Zainab Panjwani Memorial effect of tranexamic acid on the risk of death and hysterectomy in women Hospital Ethics Committee; Ziauddin Medical College. with post-partum haemorrhage: statistical analysis plan for the WOMAN Papua New Guinea: School of Medicine Research and Ethics Committee. trial. Trials BioMed Central. 2016;17:249. Brenner et al. BMC Pregnancy and Childbirth (2018) 18:215 Page 9 of 9 7. Rothman KJ. Induction and latent periods. Am J Epidemiol. 1981;114:253–9. 8. Hernán MA. The hazards of hazard ratios. Epidemiology. 2010;21:13–5. 9. Andersson L, Nilsoon IM, Colleen S, Granstrand B, Melander B. Role of urokinase and tissue activator in sustaining bleeding and the management thereof with EACA and AMCA. Ann N Y Acad Sci. 1968;146:642–58. 10. Yee BE, Wissler RN, Zanghi CN, Feng C, Eaton MP. The effective concentration of tranexamic acid for inhibition of fibrinolysis in neonatal plasma in vitro. Anesth Analg. 2013;117:767–72. 11. Pilbrant A, Schannong M, Vessman J. Pharmacokinetics and bioavailability of tranexamic acid. Eur J Clin Pharmacol. 1981;20:65–72. 12. Fletcher DJ, Blackstock KJ, Epstein K, Brainard BM. Evaluation of tranexamic acid and -aminocaproic acid concentrations required to inhibit fibrinolysis in plasma of dogs and humans. Am J Vet Res. 2014;75:731–8. 13. Fears R, Greenwood H, Hearn J, Howard B, Humphreys S, Morrow G, et al. Inhibition of the fibrinolytic and fibrinogenolytic activity of plasminogen activators in vitro by the antidotes -aminocaproic acid, tranexamic acid and aprotinin. Fibrinolysis. 1992;6:79–86. 14. Godier A, Parmar K, Manandhar K, Hunt BJ. An in vitro study of the effects of t-PA and tranexamic acid on whole blood coagulation and fibrinolysis. J Clin Pathol. 2017;70:154–61. 15. Grassin-Delyle S, Theusinger OM, Albrecht R, Mueller S, Spahn DR, Urien S, et al. Optimisation of the dosage of tranexamic acid in trauma patients with population pharmacokinetic analysis. Anaesthesia. 2018; Available from: http://doi.wiley.com/10.1111/anae.14184. Accessed 10 Apr 2018. 16. Andersson L, Eriksson O, Hedlund PO, Kjellman H, Lindqvist B. Special considerations with regard to the dosage of tranexamic acid in patients with chronic renal diseases. Urol Res. 1978;6:83–8. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Pregnancy and Childbirth Springer Journals

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

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Springer Journals
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Copyright © 2018 by The Author(s).
Subject
Medicine & Public Health; Reproductive Medicine; Maternal and Child Health; Gynecology
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1471-2393
DOI
10.1186/s12884-018-1855-5
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Abstract

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). Keywords: Postpartum haemorrhage, Tranexamic acid, WOMAN trial, Hysterectomy, Death, Bleeding * Correspondence: amy.brenner@lshtm.ac.uk Clinical Trials Unit, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Brenner et al. BMC Pregnancy and Childbirth (2018) 18:215 Page 2 of 9 Background proposed repeated analyses with varying assumptions Tranexamic acid reduces bleeding by inhibiting the about the timing of an exposure’s effect [7]. We aimed breakdown of fibrin blood clots. When given prior to in- to examine whether early outcome events diluted the ef- cision, tranexamic acid reduces blood loss in elective fect of tranexamic acid on death due to bleeding and surgery by about one third [1]. The CRASH-2 trial hysterectomy due to bleeding by conducting repeated showed that early tranexamic acid administration re- analyses excluding outcomes at increasing intervals from duces death due to bleeding in trauma patients with or randomisation. at risk of significant haemorrhage [2]. The WOMAN trial assessed the effects of tranexamic acid on death, Methods hysterectomy and other outcomes in 20,060 women with The WOMAN trial was a randomised, placebo-controlled post-partum haemorrhage (PPH). There was a signifi- trial of the effect of tranexamic acid on death, hysterec- cant reduction in death due to bleeding with tranexamic tomy and other morbidities in women with PPH. It in- acid (RR = 0·81, 95% CI 0·65–1·00; p = 0·045) [3]. As in cluded 20,060 women aged 16 years and older with a traumatic haemorrhage, the reduction was greatest when clinical diagnosis of PPH recruited from 193 hospitals in treatment was given early (within 3 h of delivery), (RR 21 countries between 2010 and 2016. We randomly allo- 0·69, 95% CI 0·53–0·90; p = 0·007), with no apparent re- cated women to receive 1 g of tranexamic acid or placebo duction after 3 h [3, 4]. There was also a decrease in by slow intravenous injection. If bleeding continued after laparotomy to control bleeding in women who received 30 min or restarted within 24 h of the first dose, we gave a tranexamic acid (RR 0·64, 95% CI 0·49–0·85; p = 0·002). second dose of 1 g of tranexamic acid or placebo. We ob- Based on these results, the World Health Organization tained follow-up data for 99.8% of patients. We have pub- has recommended the early use (within 3 h of birth) of lished full details of the trial rationale, design, methods tranexamic acid for the treatment of PPH [5]. and results elsewhere [3, 6]. In the WOMAN trial, tranexamic acid did not prevent We conducted the trial in accordance with good clin- hysterectomy due to bleeding (RR = 0.95 95%CI 0.78– ical practice guidelines. The relevant ethics committees 1.16, p = 0.611). During the trial, we noticed that clini- and regulatory agencies approved the consent proce- cians sometimes decided to perform a hysterectomy at dures. We obtained informed consent from women if or prior to the time of randomisation and so tranexamic their physical and mental capacity allowed. If a woman acid could not influence the decision. We predicted that could not give consent, we obtained proxy consent from including such hysterectomies as ‘outcome measures’ in a relative or representative. If no proxy was available, the trial would reduce or obscure the effect of tranex- then if local regulation allowed, we deferred or waived amic acid [6]. the consent. In these cases, we told the woman about Inappropriate assumptions about the timing of an ex- the trial as soon as possible and obtained consent for posure’s effect can cause bias towards the null [7]. Even use of the data collected. when outcome events occur after randomisation, some will be imminent or inevitable at the time of randomisa- Analysis tion and so cannot be prevented by the trial treatment. We conducted exploratory analyses of the WOMAN This is a particular problem in trials in life threatening trial dataset using the method proposed by Rothman [7]. emergencies when the trial treatment is usually given Our primary outcome was death due to bleeding and after the established treatments. Although a trial would our secondary outcome was hysterectomy due to bleed- ideally evaluate a treatment as it would be used in clin- ing. We prepared frequency bar charts of the time inter- ical practice, it is difficult to ensure that a treatment of vals between randomisation and death due to bleeding uncertain effectiveness is given urgently, particularly and between randomisation and hysterectomy due to when clinicians know that half of the patients will re- bleeding in the treatment and placebo groups to show ceive a placebo. the time course of bleeding-related outcomes. We then Given the extent of blood loss in PPH, many of the examined the effect of tranexamic acid on these out- women enrolled in the WOMAN trial were probably comes among women treated within 3 h of delivery critically ill at the time of randomisation: 59% of women since tranexamic acid only appears to be effective when had haemodynamic instability. As such, hysterectomy or given within this timeframe [3, 4]. We hypothesised that death may have been imminent or inevitable in some maternal deaths or hysterectomies due to bleeding that women. Such outcomes would likely have occurred soon occurred soon after randomisation were imminent or in- after randomisation. We hypothesised that the inclusion evitable at the time of randomisation. As such, we of imminent or inevitable outcome events in the analysis assessed the impact of early deaths or hysterectomies would dilute the treatment effect towards the null. To due to bleeding on the treatment effect by conducting estimate an undiluted measure of effect, Rothman repeated analyses excluding patients with these Brenner et al. BMC Pregnancy and Childbirth (2018) 18:215 Page 3 of 9 outcomes at increasing intervals from randomisation. hysterectomies due to bleeding (2.8%). Here we present We also excluded patients who died from any cause the results of intention-to-treat analyses. In per-protocol within the relevant exclusion period, as they could not analyses, we excluded 19 women who did not receive contribute to the denominator. We increased the length tranexamic acid (n = 9) or placebo (n = 10). The results of the exclusion period by one hour at a time, up to 10 h of the per-protocol analysis were almost identical (see for deaths due to bleeding but 5 h for hysterectomy due Additional file 1: Tables S1 and S2). The trial arms to bleeding since there were few hysterectomies beyond remained balanced by baseline characteristics (see Add- 5 h. We excluded hysterectomies completed before ran- itional file 1: Tables S3 and S4), and there was no evi- domisation. We conducted intention-to-treat and dence of confounding (see Additional file 1: Tables S5 per-protocol analyses and quantified treatment effects and S6). using risk ratios and 99% confidence intervals. We used Figure 1 shows a frequency bar chart of the interval 99% rather than 95% confidence intervals due to the between randomisation and death due to bleeding for multiple number of between-group comparisons. We the placebo group (n = 173) and tranexamic acid group prepared plots of the cumulative percentage of death (n = 138) over the 24 h after randomisation. The distri- due to bleeding and hysterectomy due to bleeding in bution was positively skewed, with 42% of all deaths order to supplement the period-specific risk ratios, from exsanguination occurring within 3 h of randomisa- which can be susceptible to selection bias [8]. We tion, 58% within 5 h, and 80% within 10 h. Thirty-five assessed the proportional hazards assumption using the (10%) deaths from exsanguination occurred more than Grambsch-Therneau global test. 24 h after randomisation. To assess the risk of selection bias from Table 1 shows risk ratios for death due to bleeding in post-randomisation exclusions we examined the distri- women treated within 3 h of delivery, excluding women bution of baseline characteristics by treatment group. who died at increasing intervals from randomisation. We used stratified analyses to assess potential confound- When all women were included, there was a 31% reduc- ing factors including age, time to treatment, type and tion in the risk of death due to bleeding with tranexamic place of delivery, cause of haemorrhage, use of utero- acid (RR = 0.69, 99% CI 0.48–0.98). Excluding women tonic prophylaxis, estimated blood loss, blood transfu- who died soon after randomisation increased the treat- sion, and second dose of the trial treatment (or placebo). ment effect. The effect was largest after excluding We adjusted for relevant factors using multivariable log women who died within 9 h of randomisation, with a binomial regression and selected a final model using 59% reduction in death due to bleeding (RR = 0.41, 99% likelihood ratio tests. We also conducted sensitivity ana- CI 0.19–0.89). Although there was a decreasing trend in lyses of women treated within an hour of delivery, risk ratios, the 99% confidence intervals were wide and women with uterine atony as the primary cause of overlapping. In sensitivity analyses of women treated haemorrhage, and women who underwent caesarean within an hour of delivery, women with uterine atony section. and women who underwent caesarean section, we ob- served the same decreasing trend in risk ratios (see Add- Results itional file 1: Tables S7-S9). In the WOMAN trial, 20,060 women were randomly Figure 2 shows a plot of the cumulative percentage of assigned to receive tranexamic acid (n = 10,051) or pla- deaths from bleeding by time from randomisation in the cebo (n = 10,009). After excluding 39 women who did tranexamic acid and placebo groups. For the first few not fulfil the eligibility criteria, withdrew consent or hours after randomisation the curves overlap but later were lost to follow up, data on 20,021 women were they separate. The Grambsch-Therneau test for propor- available for analysis. Ten women (< 0.1%) had missing tional hazards gave p = 0.06. data on time of delivery or time of randomisation, so Figure 3 shows a frequency bar chart of the interval time to treatment was calculated in the remaining between randomisation and hysterectomy due to bleed- 20,011 women. Of these, 14,923 women were rando- ing in the placebo group (n = 263) and tranexamic acid mised within 3 h of delivery (7518 tranexamic acid and group (n = 245) for the 24 h after randomisation. Again, 7405 placebo), with a mean time from delivery to ran- the distribution was positively skewed with 38% of hys- domisation of 1 h (interquartile range = 0.4–1.5 h). Data terectomies for bleeding occurring within one hour of on time of haemorrhage death were available for all randomisation and 82% within 3 h. Less than 2% of hys- women. Data on time of hysterectomy for bleeding or terectomies for bleeding (n = 9) occurred more than hysterectomy status were missing for 45 women (0.3%), 24 h after randomisation. leaving 14,878 patients for the hysterectomy analyses. Table 2 shows risk ratios for hysterectomy due to Among women randomised within 3 h of delivery, there bleeding for women treated within 3 h of delivery, ex- were 216 deaths due to bleeding (1.5%) and 383 cluding women who underwent hysterectomy at Brenner et al. BMC Pregnancy and Childbirth (2018) 18:215 Page 4 of 9 Fig. 1 Deaths due to bleeding within 24 h of randomisation by treatment group and hours since randomisation increasing intervals from randomisation. When all Discussion women were included, there was no reduction in the risk In the original WOMAN trial, women who experienced of hysterectomy due to bleeding with tranexamic acid PPH were randomized to receive tranexamic acid vs pla- (RR = 0.95, 99% CI 0.73–1.23). Excluding women who cebo. In the WOMAN trial, we observed a 19% reduc- had a hysterectomy for bleeding soon after randomisa- tion in the risk of death from exsanguination in women tion resulted in a decrease in the risk ratio (RR = 0.79; who received tranexamic acid compared to placebo, with 99% CI 0.33–1.86), however, the 99% confidence inter- a 31% reduction in women treated within 3 h of giving vals overlapped the null at each exclusion interval. birth. In this secondary analysis of WOMAN trial data, Figure 4 shows a plot of the cumulative percentage of after excluding deaths due to bleeding that occurred hysterectomy for bleeding by time from randomisation soon after randomisation, we observed a lower risk of in the tranexamic acid and placebo groups. In the first death from exsanguination in women who received early hours after randomisation the curves were similar but tranexamic acid compared to placebo (RR = 0.41; 99% CI with minimal separation later. The Grambsch-Therneau 0.19–0.89). Some women may have been so critically ill test for proportional hazards gave p = 0.17. at the time of randomisation that death was imminent Table 1 Impact of early deaths due to bleeding on the effect of tranexamic acid Exclusion interval Exclusions N Death due to bleeding (hours from TXA (%) Placebo (%) TXA Placebo TXA Placebo Risk ratio randomisation) (%) (%) (99% CI) None –– 7518 7405 89 (1.2) 127 (1.7) 0.69 (0.48–0.98) 1 14 (0.2) 15 (0.2) 7504 7390 76 (1.0) 114 (1.5) 0.66 (0.45–0.96) 2 30 (0.4) 38 (0.5) 7488 7367 61 (0.8) 92 (1.3) 0.65 (0.43–1.00) 3 42 (0.6) 57 (0.8) 7476 7348 50 (0.7) 75 (1.0) 0.66 (0.41–1.05) 4 53 (0.7) 70 (1.0) 7465 7335 42 (0.6) 64 (0.9) 0.64 (0.39–1.07) 5 62 (0.8) 77 (1.0) 7456 7328 33 (0.4) 59 (0.8) 0.55 (0.31–0.96) 6 66 (0.9) 85 (1.2) 7452 7320 29 (0.4) 53 (0.7) 0.54 (0.30–0.97) 7 73 (1.0) 94 (1.3) 7445 7311 23 (0.3) 44 (0.6) 0.51 (0.26–0.99) 8 80 (1.1) 97 (1.3) 7438 7308 18 (0.2) 41 (0.6) 0.43 (0.21–0.89) 9 83 (1.1) 101 (1.4) 7435 7304 16 (0.2) 38 (0.5) 0.41 (0.19–0.89) 10 84 (1.1) 104 (1.4) 7434 7301 16 (0.2) 37 (0.5) 0.42 (0.20–0.91) % is the proportion of the original trial arm excluded (N = 7518 TXA, N = 7405 placebo). TXA = tranexamic acid. Includes women treated within 3 h of delivery only Brenner et al. BMC Pregnancy and Childbirth (2018) 18:215 Page 5 of 9 Fig. 2 Cumulative percentage of deaths due to bleeding by time from randomisation in the tranexamic acid and placebo group and inevitable regardless of treatment. The findings of on the pharmacokinetics and pharmacodynamics of this secondary analysis extend those of the original tranexamic acid in obstetric bleeding will help to de- WOMAN trial by further highlighting the importance of termine the optimal dosing regimen. tranexamic acid as an early life-saving intervention for Our analysis has important limitations. Although the women who experience PPH. statistical analysis plan, which we prepared before seeing The plasma concentration of tranexamic acid the trial results, anticipated that outcomes determined needed to inhibit fibrinolysis is around 5–15 mg/L prior to randomisation would dilute the treatment effect, and tranexamic acid has a half-life of 2–3h[9–14]. the exploratory analyses presented here were not After an intravenous injection of 1 g of tranexamic pre-specified and comprise multiple between-group acid, the plasma concentration should exceed this comparisons. The possibility of a type 1 error cannot be range for several hours [13, 15]. Because it is elimi- excluded and so our results require cautious interpret- nated by the kidneys, the concentration could remain ation. That said, in keeping with our hypothesis, we ob- elevated for much longer in women with severe served an increase in the treatment effect on death due bleeding and renal impairment [16]. Further research to bleeding with an increasing exclusion interval. This Fig. 3 Hysterectomies due to bleeding within 24 h of randomisation by treatment group and hours since randomisation Brenner et al. BMC Pregnancy and Childbirth (2018) 18:215 Page 6 of 9 Table 2 Impact of early hysterectomies due to bleeding on the effect of tranexamic acid Exclusion Exclusions N Death due to bleeding interval (hours TXA (%) Placebo (%) TXA Placebo TXA (%) Placebo (%) Risk ratio (99% CI) from randomisation) None –– 7494 7384 188 (2.5) 195 (2.6) 0.95 (0.73–1.23) 1 90 (1.2) 93 (1.3) 7404 7291 112 (1.5) 117 (1.6) 0.94 (0.67–1.32) 2 175 (2.3) 167 (2.3) 7319 7217 42 (0.6) 64 (0.9) 0.65 (0.39–1.08) 3 205 (2.7) 214 (2.9) 7289 7170 23 (0.3) 34 (0.5) 0.67 (0.33–1.33) 4 217 (2.9) 236 (3.2) 7277 7148 19 (0.3) 25 (0.4) 0.75 (0.34–1.63) 5 227 (3.0) 246 (3.3) 7267 7138 16 (0.2) 20 (0.3) 0.79 (0.33–1.86) % is the proportion of the original trial arm excluded (N = 7494 TXA, N = 7384 placebo). TXA = tranexamic acid. Includes women treated within 3 h of delivery only finding was consistent in several sensitivity analyses. The on patient characteristics at each time point selection temporal distribution of haemorrhage deaths allowed us bias remains a concern. Figure 2 provides some unbiased to exclude women who died soon after randomisation. evidence of a lack of treatment benefit early on, in line We did not observe a statistically significant decrease in with our hypothesis that early deaths due to bleeding the risk of hysterectomy for bleeding associated with may dilute the treatment effect, but this may be a spuri- tranexamic acid compared with placebo after excluding ous finding. hysterectomies performed early after randomization. Al- The validity of our results also depend on the accuracy though this finding suggests that tranexamic acid may of data on the time of randomisation (treatment) and not decrease the need for hysterectomy as a life-saving the time of death but measurement error is inevitable. surgical intervention for PPH, it is possible that our Although we urged investigators to give the trial treat- sample size was inadequate to show a true treatment ment as soon as possible after randomisation, some out- benefit when excluding early hysterectomies. comes would have occurred before the treatment was Period-specific risk ratios are susceptible to selection completed. Time of death could have been misclassified bias [8]. Because tranexamic acid reduces deaths due to since there is often an interval between death and its bleeding, post-randomisation exclusions based on formal confirmation. time-to-outcome are not independent of treatment. In- Because maternal death can occur soon after major deed, we excluded 20 more deaths from the placebo uncontrolled PPH, interventions to compensate for group than from the treatment group. Although this blood loss (e.g. blood transfusion) and control the bleed- might be expected to obscure rather than inflate the de- ing (e.g. hysterectomy) may occur early after PPH diag- layed effects of treatment, because we do not have data nosis, often prior to administration of the trial Fig. 4 Cumulative percentage of hysterectomies for bleeding by time from randomisation in the tranexamic acid and placebo groups Brenner et al. BMC Pregnancy and Childbirth (2018) 18:215 Page 7 of 9 treatment. We conjecture that this may potentially ex- Funding Funding for the WOMAN trial was provided by London School of Hygiene & plain the lack of any effect of tranexamic acid on Tropical Medicine, Pfizer (provided the trial drug), the UK Department of blood transfusion and hysterectomy in the WOMAN Health (grant number HICF-T2–0510-007), the Wellcome Trust (grant number trial. However, theresults for hysterectomywerein- WT094947), and The Bill & Melinda Gates Foundation (grant number OPP1095618). The funders had no role in study design, data collection, ana- conclusive and we did not have data on time of lysis or interpretation, or the writing of the manuscript. transfusion. Future studies are needed to examine the effect of tranexamic acid on haemorrhage-related Availability of data and materials The datasets generated and/or analysed during the current study are not yet morbidity, and should report the timing of relevant publicly available due to ongoing analyses of this recently completed trial. medical and surgical interventions, such as time to After publication of the planned primary and secondary analyses, the trial first transfusion, uterine balloon tamponade, interven- data will be made available via our data-sharing portal, The Free Bank of In- jury and Emergency Research Data (freeBIRD) website at https://ctu-app.lsht- tional radiology, and surgical intervention (including m.ac.uk/freebird/. hysterectomy and laparotomy). Authors’ contributions IR and HS conceived and designed the WOMAN trial. The WOMAN Trial Conclusions Collaborators were responsible for conducting the study and for data In this secondary analysis of data from the WOMAN collection. RC, BF, IR and HS contributed to the conception of this trial, we observed that tranexamic acid was associated analysis. AB conducted the analysis. AB and IR drafted the manuscript. AB, HS, RC, BF, SA and IR participated in the interpretation of the data with a reduced risk of maternal death from exsanguin- and the revising of the manuscript. ation after excluding early maternal deaths from the ana- lysis. This finding is in line with the main findings from Ethics approval and consent to participate Ethical approval was obtained from the London School of Hygiene and the WOMAN trial. Our results suggest that the inclu- Tropical Medicine Ethics Committee and Berkshire Research Ethics sion of early deaths in the analysis may have diluted the Committee, in addition to the following local and national research ethics treatment effect of tranexamic acid towards the null. committees. Albania: Komiteti Kombetar i Etikes. Early outcome events could represent those that are Bangladesh: Ad-din Women’s Medical College Ethics Committee; Ethical Re- imminent and inevitable. Therefore, the outcomes of view Committee Chittagong Medical College; Ethical Committee of Dhaka some women with life-threatening PPH occurring soon Medical College; Ethics Committee Ibn Sina Medical College Hospital; Raj- shahi Medical College Hospital Ethical Committee. after delivery may not be influenced by exposure to the Burkina Faso: Centre Hospitalier Regional de Dedougou; Centre Hospitalier study drug. These findings also raise the possibility that Universitaire Yalgado Ouedraogo. if we give women tranexamic acid as a first line treat- Cameroon: Comite d’Ethique de l’Hopital de District de Banyo; Comite d’ethique de l’hopital gyneco-obstetrique et pediatrique de Yaounde; ment for PPH rather than a last resort, as now recom- Dschang District Hospital; Hopital Laquintinie de Douala; Kumba District Hos- mended by the World Health Organization [5], its effect pital; Limbe Regional Hospital; Le Comite d’ethique de l’Hopital de District on reducing the risk of death due to bleeding may ex- de Sa’a; St Theresa’s Catholic Hospital Local Ethics Committee; Yaounde Cen- tral Hospital; Comite d’ethique de l’hopital gyneco-obstetrique et pediatrique ceed that observed in the WOMAN trial. However, these de Yaounde. results should be viewed with caution due to the ex- Colombia: Ethical and Biomedical Research Committee, Fundacion Valle del ploratory nature of this analysis. It remains uncertain Lili. Cote d’Ivoire: Direction Departementale d’Abobo-Est. whether tranexamic acid reduces the risk of hysterec- Democratic Republic of Congo: Le Comite d’Ethique du CSR Albert Barthel; tomy for bleeding after excluding early hysterectomies Centre de Sante de Reference Kahembe; Centre Hospitalier Notre Dame post-randomisation. Further studies are needed to exam- d’Afrique; Le Comite d’Ethique Institutionnel, Centre Medical Abedeco; Le Comite d’Ethique du Centre Medical VUHE; Comite d’Ethique de CSR Carmel; ine the effect of tranexamic acid on morbidity in PPH. Comite d’Ethique de GESOM; Comite d’Ethique de Hope Medical Center; Le Comite d’Ethique du Centre de l’Hopital Provincial du Nord Kivu/Goma; Le Comite d’Ethique du Centre de l’Hopital General de Reference Virunga. Additional file Egypt: General Organisation for Teaching Hospitals and Institutes. Ethiopia: Jimma University Ethics Committee; St. Paul’s Hospital Millennium Additional file 1: Supplementary data analyses. This file provides per Medical College Ethics Committee. protocol analyses (Tables S1 and S2); an assessment of potential selection Ghana: School of Medical Sciences Committee on Human Research bias (Tables S3 and S4); an assessment of potential confounding (Tables Publications and Ethics. S5 and S6); a sensitivity analysis of women treated within an hour of Jamaica: UHWI/UWI/FMS Ethics Committee. delivery (Table S7); a sensitivity analysis of women with uterine atony as Kenya: AIC Kijabe Hospital Medical Education and Research; Bungoma the primary cause of haemorrhage (Table S8); a sensitivity analysis of District Hospital; Ministry of Medical Services Coast; Ministry of Health, women who underwent caesarean section (Table S9). (DOCX 39 kb) Garissa; Kenyatta National Hospital/University of Nairobi Ethics and Research Committee; Moi Teaching and Referral Hospital Institutional Research and Ethics Committee; Ministry of Health & Sanitation, Mwingi District Hospital; Abbreviations Ministry of Health, Nakuru; Nairobi Hospital Bioethics and Research PPH: Post-partum haemorrhage; TXA: Tranexamic acid; WOMAN trial: World Committee. Maternal Antifibrinolytic trial Nepal: Biratnagar Aspataal & Research Center Ethics Committee; Institutional Ethical Review Board BPKIHS; Mid Western Regional Hospital Ethics Acknowledgments Committee; Nepal Medical College Institutional Research/Review Committee. The authors want to thank all members of the WOMAN Trial Collaborative Nigeria: Abubakar Tafawa Balewa University Teaching Hospital; Oyo State and all women who participated in the WOMAN trial. Research Ethical Review Committee; Aminu Kano Teaching Hospital; Ahmadu Brenner et al. BMC Pregnancy and Childbirth (2018) 18:215 Page 8 of 9 Bello University Teaching Hospital Faculty of Medicine Ethical Sudan: National Medicines and Poisons Board. Committee; Braithwaite Memorial Specialist Hospital Ethics Committee; Tanzania: Prime Ministers Office, Regional Administration and Local Delta State University Teaching Hospital Research Ethics Committee; Government; Muheza Designated District Hospital; Muhimbili National University Teaching Hospital Ado-Ekiti Ethics and Research Committee; Hospital; Mwananyamala Hospital; Temeke Municipal Council. Federal Capital Territory Health Research Ethics Committee; Federal Med- Uganda: Makerere University; Ugandan National Council of Science and ical Centre Abeokuta Research Ethics Committee; Federal Medical Centre Technology. Azare Health Research Ethics Committee; Federal Medical Centre Bida United Kingdom: Nottingham University Hospitals NHS Trust Research & Ethical Committee; Federal Medical Centre Birnin-Kebbi Research Ethics Development Department; Liverpool Women’s NHS Foundation Trust R&D Committee; Federal Medical Centre Gusau Ethic and Research Commit- Department; Central Manchester University Hospitals NHS Foundation Trust tee; Federal Medical Centre Ido-Ekiti Ethics and Research Committee; R&D; Guys and St Thomas NHS Foundation Trust Research and Federal Medical Centre Katsina Medical Research Ethics Committee; Fed- Development; City Hospitals Sunderland NHS Foundation Trust Research and eral Medical Centre Keffi Health Research Ethics Committee; Federal Development; The Newcastle Upon Tyne NHS Foundation Trust Research Medical Centre Lokoja Ethical Review Committee; Federal Medical Centre and Development. Makurdi Committee on Medical Ethics; Federal Medical Centre Owerri Zambia: Chipata General Hospital; Kabwe General Hospital Ethics Committee; Ethical Committee; Federal Medical Centre Owo Ethical Review Commit- University of Zambia Biomedical Ethics Committee; Livingstone General tee; Federal Medical Centre, Umuahia; Federal Medical Centre, Yenagoa; Hospital; St Paul’s Mission Hospital, Kashikishi; St Francis Hospital Research Federal Teaching Hospital Abakaliki Research Ethics Committee; Irrua Ethics Committee; University of Zambia Biomedical Ethics Committee. Specialist Teaching Hospital Research Ethics Committee; Jos University The relevant ethics committees and regulatory agencies approved the teaching Hospital Institutional Health Research Ethics Committee; Kogi consent procedures at each site. We obtained informed consent from State Specialist Hospital Research and Ethical Committee; Ladoke Akin- women if their physical and mental capacity allowed. For fully competent tola University of Technology Teaching Hospital Ethical Committee; women, an information sheet was provided, the study was discussed and Lagos Island Maternity Hospital Ethical Committee; Lagos State University written consent obtained. If the woman was unable to read or write then Teaching Hospital Health Research and Ethics Committee; Lagos Univer- the information sheet was read to her and she then marked the consent sity Teaching Hospital Research & Ethics Committee; Mother & Child form with either a cross or thumbprint. In this event, a witness not Hospital Akure Research Ethics Committee; National Hospital Abuja Ethics associated with the trial provided a full signature confirming the mark. If a Committee; Nigeria National Health Research Ethics Committee; Nnamdi woman could not give consent, we obtained proxy consent from a relative Azikiwe UTH Ethical Committee; Obafemi Awolowo University Teaching or representative in the same manner. If no proxy was available, then if local Hospital Ethics & Research Committee; Plateau State Specialist Hospital regulation allowed, we deferred or waived the consent. In these cases, we Health Research Ethics Committee; Seventh Day Adventist Hospital In- told the woman about the trial as soon as possible and obtained consent for ternal Review Board and Ethics Committee; University of Ibadan/Univer- use of the data collected. The consent procedures are described in detail in sity College Hospital Ethics Committee; University of Abuja Teaching the trial protocol. Hospital Health Research Ethics Committee; University of Calabar Teach- ing Hospital Ethical Committee; University of Ilorin Teaching Hospital Competing interests Ethical Reveiw Committee; University of Maiduguri Teaching Hospital The authors declare that they have no competing interests. Ethics and research Committee; University of Nigeria Hospital Research Ethics Committee; University of Uyo teaching Hospital Institutional Re- Author details view Committee; Usmanu Danfodiyo University Teaching Hospital Sokoto 1 Clinical Trials Unit, London School of Hygiene and Tropical Medicine, Keppel Ethical Research Committee; Obafemi Awolowo University Teaching Hos- 2 Street, London WC1E 7HT, UK. Holy Family Hospital, Gynaecology & pital Ethics & Research Committee. Obstetrics Unit 1, F-762 Said Pur Road, Satellite Town, Rawalpindi, Pakistan. Pakistan: Ayub Teaching Hospital Ethical Committee; Institutional Ethical 3 Department of Obstetrics & Gynaecology, College of Medicine, University of Review Committee Bolan Medical College; Cantonment General Hospital Ibadan, Queen Elizabeth Road, Ibadan, Nigeria. St George’s University of London, Room 1.126, First Floor, Jenner Wing, Cranmer Terrace, London Rawalpindi Ethics Committee; Institutional Ethics Committee, Combined SW17 0RE, UK. Military Hospital Kharian; Combined Military Hospital Lahore Ethics Committee; Rawalpindi Medical College and Allied Hospitals Research and Received: 3 November 2017 Accepted: 25 May 2018 Ethics Committee; Fatima Bai Hospital Ethical Review Committee; Institutional Review Board Fatima Memorial Hospital; Ethical Committee References Federal Government PolyClinic; Institutional Review Board Services Institute 1. Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on of Medical Sciences; Isra University Hospital Ethical Committee; AIMC/Jinnah surgical bleeding: systematic review and cumulative meta-analysis. Br Med J. Hospital Lahore Ethical Review Board; Ethical Review Committee Kahota 2012;344:e3054. 2. CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats Research Laboratory Hospital Islamabad; Institutional Review Board King T, et al. Effects of tranexamic acid on death, vascular occlusive events, and Edward Medical University; Institutional Research & Ethics Board Lady blood transfusion in trauma patients with significant haemorrhage (CRASH- Reading Hospital; Institutional Review Board King Edward Medical University; 2): a randomised, placebo-controlled trial. Lancet. 2010;376:23–32. Liaquat Ethics Review Committee; Ethics Review Committee Liaquat 3. WOMAN Trial Collaborators. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post- University Hospital; Ethics Commitee MCH PIMS; Mian Muhammad Trust partum haemorrhage (WOMAN): an international, randomised, double-blind, Hospital Ethics Committee; Research and Ethic Committee Islamabad placebo-controlled trial. Lancet. 2017;389:2105–16. Medical Complex Nescom; Institutional Ethical Review Committee Nishtar 4. CRASH-2 collaborators, Roberts I, Shakur H, Afolabi A, Brohi K, Coats T, et al. Medical College & Hospital Multan; Islamic International College Trust The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Pakistan Railway Hospital; Ethics Committee Patel Hospital; Ethical Review Lancet. 2011;377:1096–1101.e2. Committee People’s University of Medical and Health Sciences; Rehman 5. World Health Organization. WHO recommendations for the prevention and Medical Institute Peshawar Institutional Review Committee; Ethics Committee treatment of postpartum haemorrhage. WHO 2017. Available from: http:// www.who.int/reproductivehealth/publications/tranexamic-acid-pph- Shalamar Hospital; Ethical Committee Sharif Medical and Dental College; treatment/en/ Accessed 12 Jan 2018. 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Published: Jun 7, 2018

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