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

Amy Brenner, Haleema Shakur-Still, Rizwana Chaudhri, Bukola Fawole, Sabaratnam Arulkumaran, Ian Roberts, WOMAN Trial Collaborators, Amy Brenner, Haleema Shakur-Still, Rizwana Chaudhri, Bukola Fawole, Sabaratnam Arulkumaran, Ian Roberts, WOMAN Trial Collaborators

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: Bleeding; Death; Hysterectomy; Postpartum haemorrhage; Tranexamic acid; WOMAN trial.

Conflict of interest statement

Ethics approval and consent to participate

Ethical approval was obtained from the London School of Hygiene and Tropical Medicine Ethics Committee and Berkshire Research Ethics Committee, in addition to the following local and national research ethics committees.

Albania: Komiteti Kombetar i Etikes.

Bangladesh: Ad-din Women’s Medical College Ethics Committee; Ethical Review Committee Chittagong Medical College; Ethical Committee of Dhaka Medical College; Ethics Committee Ibn Sina Medical College Hospital; Rajshahi Medical College Hospital Ethical Committee.

Burkina Faso: Centre Hospitalier Regional de Dedougou; Centre Hospitalier Universitaire Yalgado Ouedraogo.

Cameroon: Comite d’Ethique de l’Hopital de District de Banyo; Comite d’ethique de l’hopital gyneco-obstetrique et pediatrique de Yaounde; Dschang District Hospital; Hopital Laquintinie de Douala; Kumba District Hospital; Limbe Regional Hospital; Le Comite d’ethique de l’Hopital de District de Sa’a; St Theresa’s Catholic Hospital Local Ethics Committee; Yaounde Central Hospital; Comite d’ethique de l’hopital gyneco-obstetrique et pediatrique de Yaounde.

Colombia: Ethical and Biomedical Research Committee, Fundacion Valle del Lili.

Cote d’Ivoire: Direction Departementale d’Abobo-Est.

Democratic Republic of Congo: Le Comite d’Ethique du CSR Albert Barthel; Centre de Sante de Reference Kahembe; Centre Hospitalier Notre Dame d’Afrique; Le Comite d’Ethique Institutionnel, Centre Medical Abedeco; Le Comite d’Ethique du Centre Medical VUHE; Comite d’Ethique de CSR Carmel; 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.

Egypt: General Organisation for Teaching Hospitals and Institutes.

Ethiopia: Jimma University Ethics Committee; St. Paul’s Hospital Millennium Medical College Ethics Committee.

Ghana: School of Medical Sciences Committee on Human Research Publications and Ethics.

Jamaica: UHWI/UWI/FMS Ethics Committee.

Kenya: AIC Kijabe Hospital Medical Education and Research; Bungoma District Hospital; Ministry of Medical Services Coast; Ministry of Health, 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; Ministry of Health, Nakuru; Nairobi Hospital Bioethics and Research Committee.

Nepal: Biratnagar Aspataal & Research Center Ethics Committee; Institutional Ethical Review Board BPKIHS; Mid Western Regional Hospital Ethics Committee; Nepal Medical College Institutional Research/Review Committee.

Nigeria: Abubakar Tafawa Balewa University Teaching Hospital; Oyo State Research Ethical Review Committee; Aminu Kano Teaching Hospital; Ahmadu Bello University Teaching Hospital Faculty of Medicine Ethical Committee; Braithwaite Memorial Specialist Hospital Ethics Committee; Delta State University Teaching Hospital Research Ethics Committee; University Teaching Hospital Ado-Ekiti Ethics and Research Committee; Federal Capital Territory Health Research Ethics Committee; Federal Medical Centre Abeokuta Research Ethics Committee; Federal Medical Centre Azare Health Research Ethics Committee; Federal Medical Centre Bida Ethical Committee; Federal Medical Centre Birnin-Kebbi Research Ethics Committee; Federal Medical Centre Gusau Ethic and Research Committee; Federal Medical Centre Ido-Ekiti Ethics and Research Committee; Federal Medical Centre Katsina Medical Research Ethics Committee; Federal Medical Centre Keffi Health Research Ethics Committee; Federal Medical Centre Lokoja Ethical Review Committee; Federal Medical Centre Makurdi Committee on Medical Ethics; Federal Medical Centre Owerri Ethical Committee; Federal Medical Centre Owo Ethical Review Committee; Federal Medical Centre, Umuahia; Federal Medical Centre, Yenagoa; Federal Teaching Hospital Abakaliki Research Ethics Committee; Irrua Specialist Teaching Hospital Research Ethics Committee; Jos University teaching Hospital Institutional Health Research Ethics Committee; Kogi State Specialist Hospital Research and Ethical Committee; Ladoke Akintola University of Technology Teaching Hospital Ethical Committee; Lagos Island Maternity Hospital Ethical Committee; Lagos State University Teaching Hospital Health Research and Ethics Committee; Lagos University Teaching Hospital Research & Ethics Committee; Mother & Child Hospital Akure Research Ethics Committee; National Hospital Abuja Ethics Committee; Nigeria National Health Research Ethics Committee; Nnamdi Azikiwe UTH Ethical Committee; Obafemi Awolowo University Teaching Hospital Ethics & Research Committee; Plateau State Specialist Hospital Health Research Ethics Committee; Seventh Day Adventist Hospital Internal Review Board and Ethics Committee; University of Ibadan/University College Hospital Ethics Committee; University of Abuja Teaching Hospital Health Research Ethics Committee; University of Calabar Teaching Hospital Ethical Committee; University of Ilorin Teaching Hospital Ethical Reveiw Committee; University of Maiduguri Teaching Hospital Ethics and research Committee; University of Nigeria Hospital Research Ethics Committee; University of Uyo teaching Hospital Institutional Review Committee; Usmanu Danfodiyo University Teaching Hospital Sokoto Ethical Research Committee; Obafemi Awolowo University Teaching Hospital Ethics & Research Committee.

Pakistan: Ayub Teaching Hospital Ethical Committee; Institutional Ethical Review Committee Bolan Medical College; Cantonment General Hospital Rawalpindi Ethics Committee; Institutional Ethics Committee, Combined Military Hospital Kharian; Combined Military Hospital Lahore Ethics Committee; Rawalpindi Medical College and Allied Hospitals Research and Ethics Committee; Fatima Bai Hospital Ethical Review Committee; Institutional Review Board Fatima Memorial Hospital; Ethical Committee Federal Government PolyClinic; Institutional Review Board Services Institute of Medical Sciences; Isra University Hospital Ethical Committee; AIMC/Jinnah Hospital Lahore Ethical Review Board; Ethical Review Committee Kahota Research Laboratory Hospital Islamabad; Institutional Review Board King Edward Medical University; Institutional Research & Ethics Board Lady Reading Hospital; Institutional Review Board King Edward Medical University; Liaquat Ethics Review Committee; Ethics Review Committee Liaquat University Hospital; Ethics Commitee MCH PIMS; Mian Muhammad Trust Hospital Ethics Committee; Research and Ethic Committee Islamabad Medical Complex Nescom; Institutional Ethical Review Committee Nishtar Medical College & Hospital Multan; Islamic International College Trust Pakistan Railway Hospital; Ethics Committee Patel Hospital; Ethical Review Committee People’s University of Medical and Health Sciences; Rehman Medical Institute Peshawar Institutional Review Committee; Ethics Committee Shalamar Hospital; Ethical Committee Sharif Medical and Dental College; Institutional Review Board and Ethics Committee Shifa International Hospital; Sir Ganga Ram Hospital Lahore Ethics Committee; Zainab Panjwani Memorial Hospital Ethics Committee; Ziauddin Medical College.

Papua New Guinea: School of Medicine Research and Ethics Committee.

Sudan: National Medicines and Poisons Board.

Tanzania: Prime Ministers Office, Regional Administration and Local Government; Muheza Designated District Hospital; Muhimbili National Hospital; Mwananyamala Hospital; Temeke Municipal Council.

Uganda: Makerere University; Ugandan National Council of Science and Technology.

United Kingdom: Nottingham University Hospitals NHS Trust Research & Development Department; Liverpool Women’s NHS Foundation Trust R&D Department; Central Manchester University Hospitals NHS Foundation Trust R&D; Guys and St Thomas NHS Foundation Trust Research and Development; City Hospitals Sunderland NHS Foundation Trust Research and Development; The Newcastle Upon Tyne NHS Foundation Trust Research and Development.

Zambia: Chipata General Hospital; Kabwe General Hospital Ethics Committee; University of Zambia Biomedical Ethics Committee; Livingstone General Hospital; St Paul’s Mission Hospital, Kashikishi; St Francis Hospital Research Ethics Committee; University of Zambia Biomedical Ethics Committee.

The relevant ethics committees and regulatory agencies approved the consent procedures at each site. We obtained informed consent from women if their physical and mental capacity allowed. For fully competent women, an information sheet was provided, the study was discussed and written consent obtained. If the woman was unable to read or write then the information sheet was read to her and she then marked the consent form with either a cross or thumbprint. In this event, a witness not associated with the trial provided a full signature confirming the mark. If a woman could not give consent, we obtained proxy consent from a relative or representative in the same manner. If no proxy was available, then if local regulation allowed, we deferred or waived the consent. In these cases, we told the woman about the trial as soon as possible and obtained consent for use of the data collected. The consent procedures are described in detail in the trial protocol.

Competing interests

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Deaths due to bleeding within 24 h of randomisation by treatment group and hours since randomisation
Fig. 2
Fig. 2
Cumulative percentage of deaths due to bleeding by time from randomisation in the tranexamic acid and placebo group
Fig. 3
Fig. 3
Hysterectomies due to bleeding within 24 h of randomisation by treatment group and hours since randomisation
Fig. 4
Fig. 4
Cumulative percentage of hysterectomies for bleeding by time from randomisation in the tranexamic acid and placebo groups

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