The effect of tranexamic acid on the risk of death and hysterectomy in women with post-partum haemorrhage: statistical analysis plan for the WOMAN trial

Haleema Shakur, Ian Roberts, Philip Edwards, Diana Elbourne, Zarko Alfirevic, Carine Ronsmans, Haleema Shakur, Ian Roberts, Philip Edwards, Diana Elbourne, Zarko Alfirevic, Carine Ronsmans

Abstract

Background: Severe haemorrhage is a leading cause of maternal death worldwide. Most haemorrhage deaths occur soon after childbirth. Severe post-partum bleeding is sometimes managed by the surgical removal of the uterus (hysterectomy). Death and hysterectomy are important health consequences of post-partum haemorrhage, and clinical trials of interventions aimed at preventing these outcomes are needed.

Methods: The World Maternal Antifibrinolytic trial aims to determine the effect of tranexamic acid on death, hysterectomy and other health outcomes in women with post-partum haemorrhage. It is an international, multicentre, randomised trial. Approximately 20,000 women with post-partum haemorrhage will be randomly allocated to receive an intravenous injection of either tranexamic acid or matching placebo in addition to usual care. The primary outcome measure is a composite of death in hospital or hysterectomy within 42 days of delivery. The cause of death will be described. Secondary outcomes include death, death due to bleeding, hysterectomy, thromboembolic events, blood transfusion, surgical and radiological interventions, complications, adverse events and quality of life. The health status and occurrence of thromboembolic events in breastfed babies will also be reported. We will conduct subgroup analyses for the primary outcome by time to treatment, type of delivery and cause of haemorrhage. We will conduct an analysis of treatment effect adjusted for baseline risk.

Discussion: The World Maternal Antifibrinolytic trial should provide reliable evidence for the efficacy of tranexamic acid in the prevention of death, hysterectomy and other outcomes that are important to patients. We present a protocol update and the statistical analysis plan for the trial.

Trial registration: Current Controlled Trials ISRCTN76912190 (Registration date 08 December 2008), Clinicaltrials.gov NCT00872469 (Registration date 30 March 2009) and Pan African Clinical Trials Registry: PACTR201007000192283 (Registration date 02 September 2010).

Keywords: Clinical trial; Post-partum haemorrhage; Statistical analysis plan; Tranexamic acid.

Figures

Fig. 1
Fig. 1
Trial profile. †No follow-up relates to those patients where there is no information on the primary endpoint
Fig. 2
Fig. 2
Distribution of cause of death by days since randomisation. Notes: Bars will be stacked to show number of deaths due to bleeding, pulmonary embolism, or other causes.

References

    1. WHO. UNICEF. UNFPA. The World Bank . Trends in maternal mortality: 1990 to 2010. WHO, UNICEF, UNFPA, and The World Bank estimates. Geneva: World Health Organization; 2012.
    1. Say L, Chou D, Gemmill A, Tunçalp O, Moller A, Daniels J, et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health. 2014;2:e323–33. doi: 10.1016/S2214-109X(14)70227-X.
    1. Smith J, Mousa H. Peripartum hysterectomy for primary post-partum haemorrhage: incidence and maternal morbidity. J Obstet Gynaecol. 2007;27:44–7. doi: 10.1080/01443610601016925.
    1. Ker K, Prieto-Merino D, Roberts I. Systematic review, meta-analysis and meta-regression of the effect of tranexamic acid on surgical blood loss. Br J Surg. 2013;100(10):1271–9. doi: 10.1002/bjs.9193.
    1. CRASH-2 trial collaborators. Shakur H, Roberts I, Bautista R, Caballero J, Coats T, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010;376:23–32. doi: 10.1016/S0140-6736(10)60835-5.
    1. CRASH-2 collaborators. Roberts I, Shakur H, Afolabi A, Brohi K, Coats T, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011;377:1096–101. doi: 10.1016/S0140-6736(11)60278-X.
    1. Ducloy-Bouthors AS, Jude B, Duhamel A, Broisin F, Huissoud C, Keita-Meyer H, et al. High-dose tranexamic acid reduces blood loss in postpartum haemorrhage. Crit Care. 2011;15(2):R117s. doi: 10.1186/cc10143.
    1. Sentilhes L, Lasocki S, Ducloy-Bouthors AS, Deruelle P, Dreyfus M, et al. Tranexamic acid for the prevention and treatment of postpartum haemorrhage. Br J Anaesth. 2015;114(4):576–87. doi: 10.1093/bja/aeu448.
    1. Shakur H, Elbourne D, Gülmezoglu M, Alfirevic Z, Ronsmans C, Allen E, et al. The WOMAN trial (world maternal antifibrinolytic trial): tranexamic acid for the treatment of post-partum haemorrhage: an international randomized, double blind placebo controlled trial. Trials. 2010;11:40. doi: 10.1186/1745-6215-11-40.
    1. Schulz K, Altman D, Moher D. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMC Med. 2010;8:18. doi: 10.1186/1741-7015-8-18.
    1. Ferreira-Gonzalez I, Permanyer-Miralda G, Busse JW, et al. Methodologic discussions for using and interpreting composite endpoints are limited, but still identify major concerns. J Clin Epidemiol. 2007;60(7):651–7. doi: 10.1016/j.jclinepi.2006.10.020.
    1. Freemantle N, Calvert M, Wood J, Eastaugh J, Griffin C. Composite outcomes in randomized trials: greater precision but with greater uncertainty? JAMA. 2003;289(19):2554–9. doi: 10.1001/jama.289.19.2554.
    1. Tomlinson G, Detsky A. Composite end points in randomized trials: there is no free lunch. JAMA. 2010;303:267–8. doi: 10.1001/jama.2009.2017.
    1. Sawamura A, Hayakawa M, Gando S, Kubota N, Sugano M, Wada T, et al. Disseminated intravascular coagulation with a fibrinolytic phenotype at an early phase of trauma predicts mortality. Thromb Res. 2009;1214:608–13. doi: 10.1016/j.thromres.2009.06.034.
    1. Lowenstein CJ, Morrell CN, Yamakuchi M. Regulation of Weibel-Palade body exocytosis. Trends Cardiovasc Med. 2005;15:302–8. doi: 10.1016/j.tcm.2005.09.005.
    1. Gando S, Otomo Y. Local hemostasis, immunothrombosis, and systemic disseminated intravascular coagulation in trauma and traumatic shock. Crit Care. 2015;19(1):72. doi: 10.1186/s13054-015-0735-x.
    1. Kruithof E, Tran-Thang C, Gudinchet A, Hauert J, Nicoloso G, Genton C, et al. Fibrinolysis in pregnancy: a study of plasminogen activator inhibitors. Blood. 1987;69:460–6.
    1. Kramer MS, Berg C, Abenhaim H, Dahhou M, Rouleau J, Mehrabadi A, et al. Incidence, risk factors, and temporal trends in severe post-partum hemorrhage. Am J Obstet Gynecol. 2013;209:449.e1–7. doi: 10.1016/j.ajog.2013.07.007.
    1. World Health Organization . WHO guidelines for the management of post-partum haemorrhage and retained placenta. Geneva: World Health Organization; 2009.
    1. Tepper NK, Boulet SL, Whiteman MK, Monsour M, Marchbanks PA, Hooper WC, et al. Post-partum venous thromboembolism: incidence and risk factors. Obstet Gynecol. 2014;123(5):987–96. doi: 10.1097/AOG.0000000000000230.
    1. Pomp ER, Lenselink AM, Rosendaal FR, Doggen CJ. Pregnancy, the post-partum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost. 2008;6:632–7. doi: 10.1111/j.1538-7836.2008.02921.x.
    1. Waterstone M, Wolfe C, Hooper R, Bewley S. Postnatal morbidity after childbirth and severe obstetric morbidity. BJOG-Int J Obstet Gy. 2003;110:128–33. doi: 10.1046/j.1471-0528.2003.02151.x.
    1. EuroQol Group EuroQol – a new facility for the measurement of health-related quality of life. Health Pol. 1990;16:199–208. doi: 10.1016/0168-8510(90)90421-9.
    1. Murkin JM, Falter F, Granton J, Young B, Burt C, Chu M. High-dose tranexamic acid is associated with nonischemic clinical seizures in cardiac surgical patients. Anesth Analg. 2010;110:350–3. doi: 10.1213/ANE.0b013e3181c92b23.
    1. Furtmüller R, Schlag MG, Berger M, Hopf R, Huck S, Sieghart W, et al. Tranexamic acid, a widely used antifibrinolytic agent, causes convulsions by a gamma-aminobutyric acid (A) receptor antagonistic effect. J Pharmacol Exp Ther. 2002;301:168–73. doi: 10.1124/jpet.301.1.168.
    1. ICH . International Conference on Harmonisation (ICH) harmonised tripartite guideline: guideline for good clinical practice (GCP) Geneva: ICH; 1996.
    1. MedDRA® the Medical Dictionary for Regulatory Activities terminology is the international medical terminology developed under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Accessed 11 May 2016.
    1. Summary of Product Characteristics for Tranexamic Acid 100 mg/ml Solution for Injection. (Accessed 15 Sept 2015).
    1. Pocock SJ, Assmann SE, Enos LE, Kasten LE. Subgroup analysis, covariate adjustment and baseline comparisons in clinical trial reporting: current practice and problems. Stat Med. 2002;21(19):2917–30. doi: 10.1002/sim.1296.
    1. Kahan B, Jairath V, Doré C, Morris T. The risks and rewards of covariate adjustment in randomized trials: an assessment of 12 outcomes from 8 studies. Trials. 2014;15:139. doi: 10.1186/1745-6215-15-139.
    1. White IR, Thompson SG. Adjusting for partially missing baseline measurements in randomized trials. Stat Med. 2005;24(7):993–1007. doi: 10.1002/sim.1981.
    1. Sackett DL, Deeks JJ, Altman D. Down with odds ratios! Evid-Based Med. 1996;1:164–7.
    1. Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Br J Radiol. 1971;44(526):793–7. doi: 10.1259/0007-1285-44-526-793.
    1. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br J Cancer. 1977;35(1):1–39. doi: 10.1038/bjc.1977.1.

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