Halting the Canadian STRIDER randomised controlled trial of sildenafil for severe, early-onset fetal growth restriction: ethical, methodological, and pragmatic considerations
Peter von Dadelszen, François Audibert, Emmanuel Bujold, Jeffrey N Bone, Ash Sandhu, Jing Li, Chirag Kariya, Youkee Chung, Tang Lee, Kelvin Au, M Amanda Skoll, Marianne Vidler, Laura A Magee, Bruno Piedboeuf, Philip N Baker, Sayrin Lalji, Kenneth I Lim, Peter von Dadelszen, François Audibert, Emmanuel Bujold, Jeffrey N Bone, Ash Sandhu, Jing Li, Chirag Kariya, Youkee Chung, Tang Lee, Kelvin Au, M Amanda Skoll, Marianne Vidler, Laura A Magee, Bruno Piedboeuf, Philip N Baker, Sayrin Lalji, Kenneth I Lim
Abstract
Objectives: To determine the efficacy and safety of sildenafil citrate to improve outcomes in pregnancies complicated by early-onset, dismal prognosis, fetal growth restriction (FGR). Eligibility: women ≥ 18 years, singleton, 18 + 0-27 + 6 weeks' gestation, estimated fetal weight < 700 g, low PLFG, and ≥ 1 of (i) abdominal circumference < 10th percentile for gestational age (GA); or (ii) reduced growth velocity and either abnormal uterine artery Doppler or prior early-onset FGR with adverse outcome. Ineligibility criteria included: planned termination or reversed umbilical artery end-diastolic flow. Eligibility confirmed by placental growth factor (PLGF) < 5 th percentile for GA measured post randomization. Women randomly received (1:1) either sildenafil 25 mg three times daily or matched placebo until either delivery or 31 + 6 weeks.
Primary outcome: delivery GA. The trial stopped early when Dutch STRIDER signalled potential harm; despite distinct eligibility criteria and IRB and DSMB support to continue, because of futility. NCT02442492 [registered 13/05/2015].
Results: Between May 2017 and June 2018, 21 (90 planned) women were randomised [10 sildenafil; 11 placebo (1 withdrawal)]. Baseline characteristics, PLGF levels, maternal and perinatal outcomes, and adverse events did not differ. Delivery GA: 26 + 6 weeks (sildenafil) vs 29 + 2 weeks (placebo); p = 0.200. Data will contribute to an individual participant data meta-analysis.
Keywords: Early trial halting; Fetal growth restriction; Randomised controlled trial; Sildenafil.
Conflict of interest statement
PvD has received support from Alere International.
© 2022. The Author(s).
Figures
References
- von Dadelszen P, Magee LA, Lee SK, Stewart SD, Simone C, Koren G, et al. Activated protein C in normal human pregnancy and pregnancies complicated by severe preeclampsia: a therapeutic opportunity? Crit Care Med. 2002;30(8):1883–1892. doi: 10.1097/00003246-200208000-00035.
- Lees CC, Stampalija T, Baschat A, da Silva CF, Ferrazzi E, Figueras F, et al. ISUOG practice guidelines: diagnosis and management of small-for-gestational-age fetus and fetal growth restriction. Ultrasound Obstet Gynecol. 2020;56(2):298–312. doi: 10.1002/uog.22134.
- Benton SJ, McCowan LM, Heazell AE, Grynspan D, Hutcheon JA, Senger C, et al. Placental growth factor as a marker of fetal growth restriction caused by placental dysfunction. Placenta. 2016;42:1–8. doi: 10.1016/j.placenta.2016.03.010.
- Wareing M, Myers JE, O'Hara M, Baker PN. Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth restriction. J Clin Endocrinol Metab. 2005;90(5):2550–2555. doi: 10.1210/jc.2004-1831.
- von Dadelszen P, Dwinnell S, Magee LA, Carleton BC, Gruslin A, Lee B, et al. Sildenafil citrate therapy for severe early-onset intrauterine growth restriction. BJOG. 2011;118(5):624–628. doi: 10.1111/j.1471-0528.2010.02879.x.
- Samangaya RA, Mires G, Shennan A, Skillern L, Howe D, McLeod A, et al. A randomised, double-blinded, placebo-controlled study of the phosphodiesterase type 5 inhibitor sildenafil for the treatment of preeclampsia. Hypertens Pregnancy. 2009;28(4):369–382. doi: 10.3109/10641950802601278.
- Pels A, Kenny LC, Alfirevic Z, Baker PN, von Dadelszen P, Gluud C, et al. STRIDER (Sildenafil TheRapy in dismal prognosis early onset fetal growth restriction): an international consortium of randomised placebo-controlled trials. BMC Pregnancy Childbirth. 2017;17(1):440. doi: 10.1186/s12884-017-1594-z.
- Saffer C, Olson G, Boggess KA, Beyerlein R, Eubank C, Sibai BM, et al. Determination of placental growth factor (PlGF) levels in healthy pregnant women without signs or symptoms of preeclampsia. Pregnancy Hypertens. 2013;3(2):124–132. doi: 10.1016/j.preghy.2013.01.004.
- Lausman A, Kingdom J, Maternal Fetal Medicine Committee Intrauterine growth restriction screening diagnosis and management. J Obstet Gynaecol Can. 2013;35(741):8.
- Ganzevoort W, Alfirevic Z, von Dadelszen P, Kenny L, Papageorghiou A, van Wassenaer-Leemhuis A, et al. STRIDER: sildenafil therapy in dismal prognosis early-onset intrauterine growth restriction–a protocol for a systematic review with individual participant data and aggregate data meta-analysis and trial sequential analysis. Syst Rev. 2014;3:23. doi: 10.1186/2046-4053-3-23.
- Pels A, Derks J, Elvan-Taspinar A, van Drongelen J, de Boer M, Duvekot H, et al. Maternal sildenafil vs placebo in pregnant women with severe early-onset fetal growth restriction: a randomized clinical trial. JAMA Netw Open. 2020;3(6):e205323. doi: 10.1001/jamanetworkopen.2020.5323.
- Sharp A, Cornforth C, Jackson R, Harrold J, Turner MA, Kenny LC, et al. Maternal sildenafil for severe fetal growth restriction (STRIDER): a multicentre, randomised, placebo-controlled, double-blind trial. Lancet Child Adolesc Health. 2018;2(2):93–102. doi: 10.1016/S2352-4642(17)30173-6.
- Groom KM, McCowan LM, Mackay LK, Lee AC, Gardener G, Unterscheider J, et al. STRIDER NZAus: a multicentre randomised controlled trial of sildenafil therapy in early-onset fetal growth restriction. BJOG. 2019;126(8):997–1006.
- GroomGanzevoortAlfirevicLimPapageorghiouConsortium KMWZKATS. Clinicians should stop prescribing sildenafil for fetal growth restriction (FGR) comment from the STRIDER consortium. Ultrasound Obstet Gynecol. 2018;52(3):295–6. doi: 10.1002/uog.19186.
Source: PubMed