Pregnancy AntihyperteNsive Drugs: which Agent is best? (giant PANDA study)

Research question: In women with pregnancy hypertension (P), what is the effect of a treatment initiation strategy with nifedipine (I) versus labetalol (C) on severe maternal hypertension (O) and a composite of perinatal loss or neonatal unit admissions (O)? Design: Prospective, late phase, pragmatic, parallel group, open-label, multicentre, two-arm randomised controlled trial of treatment initiation with nifedipine or labetalol in women with pregnancy hypertension. Setting: 40-50 UK consultant-led maternity units. Population: Pregnant women with hypertension. Inclusion criteria: Pregnancy (=34+0 weeks’ gestation); pregnancy hypertension (chronic or gestational hypertension or pre-eclampsia); decision made to initiate or continue use of antihypertensive; aged =18 years; written informed consent. Exclusion criterion: Contraindication to either agent; already taking both agents and not able (or willing) to be switched onto single agent. Health technologies: Treatment initiation with any preparation of modified release nifedipine, a calcium channel blocker, (intervention arm) vs. labetalol, a mixed alpha/ beta blocker, (active control arm) by random allocation (1:1). All other aspects of antenatal and delivery care will follow the usual care pathways underpinned by NICE 2019 guidelines for pregnancy hypertension. Co-primary outcomes: Maternal: Severe hypertension (proportion of healthcare professional measured systolic blood pressure readings (=160mmHg) up to delivery). Perinatal: Perinatal death (stillbirth after 20 weeks’ gestation or neonatal death up to 7 days) or neonatal unit admission up to hospital discharge. Secondary maternal and perinatal outcomes include clinical and patient-reported outcomes in addition to health care resource use. Sample size: 2,300 pregnant women with hypertension. Assuming 90% power, 2.5% one-sided significance for non-inferiority, a control group event rate for the co-primary outcome of neonatal unit admission of 25%, 5% loss to follow up, a total of approximately 2,300 women would be required to detect a clinically meaningful non-inferiority margin of 6%. For the maternal co-primary outcome, a sample size of 2,190 will allow the detection of a 2.3% superiority difference between the mean proportions of clinic and hospital systolic blood measurements =160mmHg. This is equivalent to an effect size of 0.14 of a standard deviation, based on a two-sample t-test (5% two-sided alpha, 90% power) e.g. from around a mean of 9.6% to 11.9%. Economic evaluation: A cost-effectiveness analysis using a decision analytical model with a lifetime horizon and an NHS perspective, and a cost-consequence analysis up to hospital discharge. Difference between pathways: Standard care pathways advise antihypertensive treatment; both nifedipine and labetalol are currently used in practice. In the trial, choice of antihypertensive treatment will be randomly allocated, but other care will follow usual antenatal care pathways. Timetable: Months 1-8: set-up; Months 9-17: internal pilot; Months 18-33: recruitment; Months 34-41: follow-up; Months 42-48: analysis and write-up. Expertise in team: The multidisciplinary team draws on UK-wide clinical academic expertise across the health professional spectrum with extensive trials experience in pregnancy hypertension, a PPI co-applicant (experience of pregnancy hypertension) and an experienced Clinical Trials Unit. Dissemination and impact: Academic outputs (presentations, papers) and active engagement with public and patient dissemination routes. For impact, the trial is intended to provide definitive evidence to inform guidelines and linked shared decision-making tools for early uptake into clinical practice.