NCT05129722

Polydiuretic Therapy for HFpEF, a Randomised Controlled Trial

Polydiuretic Therapy for Heart Failure With Preserved Ejection Fraction: A Pilot Trial

• Status: Terminated
• Phase: Phase 4
• Study type: Interventional
• Enrollment: 3 (actual)
• Sponsor: The George Institute · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

Heart Failure (HF) in Australia affects 1-2% of the population. Heart failure with preserved ejection fraction (HFpEF) refers to a syndrome of clinical heart failure without impairment of systolic cardiac function. HFpEF has few therapeutic agents that are proven to improve outcomes and it was only recently, the published EMPEROR-Preserved trial demonstrated that empagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i) reduced composite outcome of heart failure hospitalisation and cardiovascular death by 21% among patients with HFpEF.\[1\] HFpEF therapies have traditionally aimed at providing symptomatic relief and treating coexisting illnesses. This multi-centre randomised clinical trial aims to establish the feasibility of a fixed low dose combination polypill consisting of bumetanide 0.5 mg, eplerenone 25 mg, and empagliflozin 10 mg in patients with HFpEF compared against empagliflozin 10 mg monotherapy in patients with HFpEF. Fixed dose combination low dose diuretics of this nature have not been rigorously studied in patients with HFpEF, and this study aims to help improve the treatment paradigm for this patient population.

Detailed description

Heart failure with preserved ejection fraction (HFpEF) refers to a complex syndrome of clinical heart failure without impairment of systolic cardiac function. HFpEF accounts for more than half of patients with heart failure, and this prevalence continues to increase in population studies. Unlike Heart failure with reduced ejection fraction (HFrEF), there are few therapeutic agents that are proven to improve outcomes such as heart failure hospitalisation in this group. The recently published EMPEROR Preserved trial demonstrated that empagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), reduced the composite outcome of heart failure hospitalisation and cardiovascular death by 21% (95% CI: 10% to 31%) among patients with HFpEF. This was the first study to meet this clinical endpoint in HFpEF patients. In addition to reducing hospitalisation and CV death, additional therapies in HFpEF are aimed at providing symptomatic relief, through intravascular volume management with diuretics, and treating coexisting illnesses. However, patients may experience diuretic resistance that leads to lower efficacy of diuresis despite increasing doses; this, in turn, can lead to progression of renal dysfunction and other side effects. Researchers and clinicians must develop strategies to help improve efficacy of diuresis and avoid diuretic resistance, which may be possible through the use of multiple diuretics at lower doses and including newer agents such as sodium-glucose cotransporter 2 (SGLT2) inhibitors. This multi-centre, double-blinded, randomised (1:1), proof-of-concept, pilot trial aims to establish the feasibility of a fixed low dose combination polypill consisting of bumetanide 0.5 mg, eplerenone 25 mg, and empagliflozin 10 mg in patients with HFpEF compared against empagliflozin 10 mg monotherapy in patients with HFpEF. There will be 15 patients per arm (n=30 across two sites). The study will recruit patients from the community including cardiology clinics, primary care providers and will be undertaken in the Royal Prince Alfred (RPA) Cardiology Clinic and St Vincent's Hospital, Sydney, Australia Cardiology Clinic. The primary implementation hypothesis for this study is that it is feasible to recruit 30 participants to this trial over 6 months and to complete 4 weeks of follow up, with adherence to the protocol and study related procedures (screening, randomisation, study drug allocation, follow-up procedures, and retention) in \>/=80% of participants. There are several secondary hypotheses including that the proposed polydiuretic, as compared to SGLT2i, empagliflozin monotherapy on top of usual care will: increase medication compliance, improve rates of optimal medical therapy, reduce N-terminal pro hormone BNP, improve New York Heart Association (NYHA) Class, reduce fluid overload, improve blood pressure, and body weight at 4 weeks alongside exploratory outcomes of change in their KCCQ. Additionally, the safety hypotheses include that patients will have no increase in Adverse events, Serious Adverse Events, or Adverse events of special interest. Fixed dose combination low dose diuretics of this nature have not been rigorously studied in patients with HFpEF, and this study aims to help improve the treatment paradigm for this patient population. This combination of agents draws upon the existing nature of evidence based therapies used in HFpEF that target the kidney.

Conditions

• Heart Failure With Preserved Ejection Fraction

Interventions

Type	Name	Description
DRUG	Low dose combination polydiuretic therapy	Low dose combination polydiuretic therapy treatment consists of: Loop diuretic bumetanide 0.5 mg Mineralocorticoid receptor antagonist eplerenone 25 mg Sodium-glucose co-transporter 2 inhibitor (SGLT2i): empagliflozin 10mg
DRUG	Comparator monotherapy empagliflozin	Sodium-glucose co-transporter 2 inhibitor (SGLT2i): empagliflozin 10mg

Timeline

• Start date: 2022-10-01
• Primary completion: 2024-05-01
• Completion: 2024-05-01
• First posted: 2021-11-22
• Last updated: 2024-11-21

Locations

2 sites across 1 country: Australia