Aspirin Versus Metformin in Pregnancies at High Risk of Preterm Preeclampsia: a 3-arm Randomized Controlled Trial

Summary

This is a prospective, multicenter, randomized controlled, double-blind trial of three treatment arms: (1) aspirin 75 mg/day vs. (2) aspirin 150 mg/day vs. (3) aspirin 75 mg/day with metformin 1.5 g/day from the first trimester to compare the incidence of preterm preeclampsia with delivery at \<37 week's gestation between the treatment arms, in order to determine the optimal therapeutic intervention for the prevention of preterm preeclampsia among Chinese women at high-risk of preeclampsia.

Timeline

Start

2023-07-03

Primary completion

2025-01-01

Completion

2025-11-30

Publications

• Background Women's Heart Health Group of Chinese Society of Cardiology of Chinese Medical Association; Hypertension Group of Chinese Society of Cardiology of Chinese Medical Association. [Expert consensus on blood pressure management in hypertensive disorders of pregnancy (2019)]. Zhonghua Xin Xue Guan Bing Za Zhi. 2020 Mar 24;48(3):195-204. doi: 10.3760/cma.j.cn112148-20191024-00652. Chinese.
• Background Witlin AG, Saade GR, Mattar F, Sibai BM. Predictors of neonatal outcome in women with severe preeclampsia or eclampsia between 24 and 33 weeks' gestation. Am J Obstet Gynecol. 2000 Mar;182(3):607-11. doi: 10.1067/mob.2000.104224.
• Background Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of mothers and fathers after pre-eclampsia: population based cohort study. BMJ. 2001 Nov 24;323(7323):1213-7. doi: 10.1136/bmj.323.7323.1213.
• Background von Dadelszen P, Magee LA, Roberts JM. Subclassification of preeclampsia. Hypertens Pregnancy. 2003;22(2):143-8. doi: 10.1081/PRG-120021060.
• Background Chaemsaithong P, Pooh RK, Zheng M, Ma R, Chaiyasit N, Tokunaka M, Shaw SW, Seshadri S, Choolani M, Wataganara T, Yeo GSH, Wright A, Leung WC, Sekizawa A, Hu Y, Naruse K, Saito S, Sahota D, Leung TY, Poon LC. Prospective evaluation of screening performance of first-trimester prediction models for preterm preeclampsia in an Asian population. Am J Obstet Gynecol. 2019 Dec;221(6):650.e1-650.e16. doi: 10.1016/j.ajog.2019.09.041. Epub 2019 Oct 4.
• Background Akolekar R, Syngelaki A, Sarquis R, Zvanca M, Nicolaides KH. Prediction of early, intermediate and late pre-eclampsia from maternal factors, biophysical and biochemical markers at 11-13 weeks. Prenat Diagn. 2011 Jan;31(1):66-74. doi: 10.1002/pd.2660.
• Background Askie LM, Duley L, Henderson-Smart DJ, Stewart LA; PARIS Collaborative Group. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007 May 26;369(9575):1791-1798. doi: 10.1016/S0140-6736(07)60712-0.
• Background Rolnik DL, Wright D, Poon LC, O'Gorman N, Syngelaki A, de Paco Matallana C, Akolekar R, Cicero S, Janga D, Singh M, Molina FS, Persico N, Jani JC, Plasencia W, Papaioannou G, Tenenbaum-Gavish K, Meiri H, Gizurarson S, Maclagan K, Nicolaides KH. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. N Engl J Med. 2017 Aug 17;377(7):613-622. doi: 10.1056/NEJMoa1704559. Epub 2017 Jun 28.
• Background Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, Forest JC, Giguere Y. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol. 2010 Aug;116(2 Pt 1):402-414. doi: 10.1097/AOG.0b013e3181e9322a.
• Background Roberge S, Villa P, Nicolaides K, Giguere Y, Vainio M, Bakthi A, Ebrashy A, Bujold E. Early administration of low-dose aspirin for the prevention of preterm and term preeclampsia: a systematic review and meta-analysis. Fetal Diagn Ther. 2012;31(3):141-6. doi: 10.1159/000336662. Epub 2012 Mar 21.
• Background Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N, Bujold E. The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. Am J Obstet Gynecol. 2017 Feb;216(2):110-120.e6. doi: 10.1016/j.ajog.2016.09.076. Epub 2016 Sep 15.
• Background Caron N, Rivard GE, Michon N, Morin F, Pilon D, Moutquin JM, Rey E. Low-dose ASA response using the PFA-100 in women with high-risk pregnancy. J Obstet Gynaecol Can. 2009 Nov;31(11):1022-1027. doi: 10.1016/S1701-2163(16)34346-8.
• Background Rey E, Rivard GE. Is testing for aspirin response worthwhile in high-risk pregnancy? Eur J Obstet Gynecol Reprod Biol. 2011 Jul;157(1):38-42. doi: 10.1016/j.ejogrb.2011.02.026. Epub 2011 Mar 25.
• Background Hypertensive Disorders in Pregnancy Subgroup, Chinese Society of Obstetrics and Gynecology, Chinese Medical Association. [Diagnosis and treatment of hypertension and pre-eclampsia in pregnancy: a clinical practice guideline in China（2020）]. Zhonghua Fu Chan Ke Za Zhi. 2020 Apr 25;55(4):227-238. doi: 10.3760/cma.j.cn112141-20200114-00039. Chinese.
• Background Brownfoot FC, Hastie R, Hannan NJ, Cannon P, Tuohey L, Parry LJ, Senadheera S, Illanes SE, Kaitu'u-Lino TJ, Tong S. Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction. Am J Obstet Gynecol. 2016 Mar;214(3):356.e1-356.e15. doi: 10.1016/j.ajog.2015.12.019. Epub 2015 Dec 22.
• Background Syngelaki A, Nicolaides KH, Balani J, Hyer S, Akolekar R, Kotecha R, Pastides A, Shehata H. Metformin versus Placebo in Obese Pregnant Women without Diabetes Mellitus. N Engl J Med. 2016 Feb 4;374(5):434-43. doi: 10.1056/NEJMoa1509819.
• Background Chiswick C, Reynolds RM, Denison F, Drake AJ, Forbes S, Newby DE, Walker BR, Quenby S, Wray S, Weeks A, Lashen H, Rodriguez A, Murray G, Whyte S, Norman JE. Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2015 Oct;3(10):778-86. doi: 10.1016/S2213-8587(15)00219-3. Epub 2015 Jul 9.
• Background ACOG Practice Bulletin No. 202: Gestational Hypertension and Preeclampsia. Obstet Gynecol. 2019 Jan;133(1):1. doi: 10.1097/AOG.0000000000003018.
• Background Poon LC, Volpe N, Muto B, Syngelaki A, Nicolaides KH. Birthweight with gestation and maternal characteristics in live births and stillbirths. Fetal Diagn Ther. 2012;32(3):156-65. doi: 10.1159/000338655. Epub 2012 Jul 26.
• Background Wright D, Poon LC, Rolnik DL, Syngelaki A, Delgado JL, Vojtassakova D, de Alvarado M, Kapeti E, Rehal A, Pazos A, Carbone IF, Dutemeyer V, Plasencia W, Papantoniou N, Nicolaides KH. Aspirin for Evidence-Based Preeclampsia Prevention trial: influence of compliance on beneficial effect of aspirin in prevention of preterm preeclampsia. Am J Obstet Gynecol. 2017 Dec;217(6):685.e1-685.e5. doi: 10.1016/j.ajog.2017.08.110. Epub 2017 Sep 6.
• Liu J, Shen L, Nguyen-Hoang L, Zhou Q, Wang CC, Lu X, Sahota D, Chong KC, Ying H, Gu W, Zhou R, Yang H, Jiang Y, Chen D, Li X, Poon L. Aspirin versus metformin in pregnancies at high risk of preterm pre-eclampsia in China (AVERT): protocol for a multicentre, double-blind, 3-arm randomised controlled trial. BMJ Open. 2024 Apr 17;14(4):e074493. doi: 10.1136/bmjopen-2023-074493.

Drugs

Indications