REgression in Left ventrIcular hypErtrophy and Fibrosis in Aortic Stenosis – a randomised controlled trial (RELIEF-AS)

Research question: In patients with severe aortic stenosis (AS) undergoing aortic valve replacement (AVR), does adjuvant pharmacotherapy result in greater reductions in left ventricular hypertrophy, improved myocardial health and Quality of Life than AVR alone? Background: AS is the most common valvular heart disease in the UK, affecting 3% of those over 75 and causing substantial morbidity and mortality. More than 15,000 people in the UK per year (>300,000 world-wide) require surgical or transcatheter AVR. But AVR only partially reverses the myocardial damage caused by AS, so that patients are left with high rates of heart failure (HF), in particular HF with preserved ejection fraction and excess mortality in the years following valve intervention. Recent large-scale randomized trials have shown that sodium–glucose co-transporter 2 (SGLT2) inhibitors and mineralo-corticoid receptor antagonists (MRAs) reduce the risk of HF and cardiovascular death in HF by ~20%. But these trials excluded patients with AS undergoing AVR. We designed the RELIEF-AS trial to investigate the efficacy of SGLT2-inhibitors and MRAs in AS, and to address a major gap in evidence for treatment of AS patients after AVR. Aims and objectives: To establish whether the SGLT2-inhibitor dapagliflozin and the MRA spironolactone result in better left ventricular mass regression, myocardial health and patient-reported outcomes in severe AS without established HF than standard-of-care therapy (AVR) alone. Methods: In this phase 2 multicentre, 2x2 factorial, prospective randomized open label blinded end-point (PROBE) clinical trial, we will randomise 445 patients with severe AS without established HF undergoing AVR to either standard care or administration of two standard HF therapies (dapagliflozin and spironolactone) to enhance and to accelerate myocardial recovery and quality of life post-AVR. Both drugs regress left ventricular mass, are widely used, simple to administer, well-tolerated, safe and economical. Patients will undergo a baseline cardiac MRI scan prior to AVR and at 12 months post AVR. We hypothesise that they result in greater indexed left ventricular mass regression (primary endpoint), improved quality of life (secondary) and myocardial fibrosis regression (mechanistic) at 12 months post AVR. Timelines for delivery: 4 years. Population: Patients with severe native AS awaiting AVR without prior history of heart failure. Intervention: Dapagliflozin (10mg OD orally), spironolactone (25mg OD orally) or their combination for 12 months after AVR and randomisation (1:1:1:1). Comparator: Standard of care. Outcome (primary): Change in indexed left ventricular mass at 1 year post-AVR from baseline. Anticipated impact and dissemination: Our goal is to prevent HF, and decrease the high mortality and morbidity due to untreated myocardial damage in AS. If this efficacy trial demonstrates that SGLT2 inhibitors or MRAs positively impact myocardial health, we will seek funding a clinical effectiveness trial. HF therapy in valvular heart disease is under-researched, with emphasis traditionally focused on the valve rather than myocardial health. Our trial will provide efficacy and mechanistic insights for both drugs in patients with AS, paving the way for other treatments. Results will be disseminated through peer-reviewed publications, patient-friendly summaries, and via national networks. This trial was developed with our patient partners involved at all stages.