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Polydiuretic Therapy for HFpEF, a Randomised Controlled Trial

PHASE4RECRUITING

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.

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

Have provided written informed consent

Adults ≥ 18 years old

Established diagnosis of NYHA Class II - IV heart failure with preserved ejection fraction, which has been present for at least 2 months

Left ventricular ejection fraction ≥50% on echocardiography within the last 12 months prior to study enrolment, and no previous echocardiogram with EF < 40% NB: Patients in which additional pharmacological or device therapy is contemplated, or should be considered, must not be enrolled until therapy has been optimised and is stable for ≥ 1 month.

NT-proBNP >300 pg/ml (or if hospitalised for heart failure within the previous 12 months, NT-proBNP ≥400 pg/ml) at enrolment. If concomitant atrial fibrillation at Visit 1, NT-proBNP must be ≥900 pg/ml (irrespective of history of heart failure hospitalisation)

Exclusion criteria

Known contraindication to bumetanide, eplerenone, or empagliflozin.

Concurrently prescribed prohibited medications which are mineralocorticoid receptor antagonists (Spironolactone and Eplerenone) and SGLT2i agents.

Symptomatic hypotension or systolic BP <95 mmHg at 2 out of 3 measurements at Visit 0

Current acute decompensated HF or hospitalisation due to decompensated HF <4 weeks prior to enrolment.

Myocardial infarction, unstable angina, stroke, or transient ischaemic attack (TIA) within 12 weeks prior to enrolment.

HF due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic (obstructive) cardiomyopathy or uncorrected primary valvular disease or reduced EF < 50%

Symptomatic bradycardia or second or third-degree heart block without a pacemaker.

Evidence of secondary cause of hypertension e.g., renal artery stenosis; significant renal impairment (eGFR <50 ml/min/1.73 m2), raised serum potassium (above lab normal limit of 5.0 mEq/L).

Previous history of ketoacidosis

Women who are pregnant, breast feeding or of childbearing potential and are not using and do not plan to continue using medically acceptable form of contraception throughout the study (pharmacological or barrier methods).

Concomitant illness, physical impairment or mental condition which in the opinion of the study team / primary care physician could interfere with the conduct of the study including outcome assessment.

Participation in a concurrent interventional medical investigation or pharmacologic clinical trial. Participants in observational, natural history or epidemiological studies not involving an intervention are eligible.

Participant's responsible primary care or other responsible physician believes it is not appropriate for participant to participate in the study.

Inability or unwillingness to provide written informed consent.

Involvement in the planning and/or conduct of the study.

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Eligibility

Age eligible for study : 18 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2022-10-01

Primary completion: 2023-12-31

Study completion finish: 2024-06-01

Study type

TREATMENT

Phase

PHASE4

Trial ID

NCT05129722

Intervention or treatment

DRUG: Low dose combination polydiuretic therapy

DRUG: Comparator monotherapy empagliflozin

Conditions

• Heart Failure With Preserved Ejection Fraction

Image related to Heart Failure With Preserved Ejection Fraction

Condition: Heart Failure With Preserved Ejection Fraction
DRUG: Low dose combination polydiuretic therapy and other drugs
Camperdown, New South Wales, Australia and more
Sponsor: The George Institute

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Find a site

Closest Location:

Royal Prince Alfred Hospital

Research sites nearby

Select from list below to view details:

Royal Prince Alfred Hospital
Camperdown, New South Wales, Australia
St Vincent's Hospital Sydney
Darlinghurst, New South Wales, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Patients receiving low dose combination polydiuretic therapy This patient group will receive a low dose combination polydiuretic therapy treatment consisting of: bumetanide 0.5 mg (loop diuretic), eplerenone 25 mg (mineralocorticoid receptor antagonist) and empagliflozin 10mg (sodium-glucose co-transporter 2 inhibitor) daily on top of their background therapy.	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
ACTIVE_COMPARATOR: Comparator group receiving monotherapy empagliflozin This comparator patient group will receive empagliflozin 10mg (sodium-glucose co-transporter 2 inhibitor) daily on top of their background therapy.	DRUG: Comparator monotherapy empagliflozin Sodium-glucose co-transporter 2 inhibitor (SGLT2i): empagliflozin 10mg

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
Feasibility of recruitment and compliance with study protocol (30 participants and 80% participant completion of study protocol)	Recruitment of 30 participants, with completion of study related procedures (screening, randomisation, study drug allocation, follow-up procedures, and retention over 4 weeks) in ≥ 80% of participants.	6 months

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
NT-proBNP	Change in NT-proBNP (ng/L) from baseline to 4 weeks	4 weeks
NYHA Class	Change in NYHA Class (I-IV) from baseline to 4 weeks	4 weeks
6-minute Walk Test (6MWT) distance	Change in 6MWT distance (metres) from baseline to 4 weeks	4 weeks
Systolic and Diastolic Blood Pressure	Change in systolic and diastolic blood pressure (mmHg) from baseline to 4 weeks	4 weeks
Body Weight	Change in body weight from baseline to 4 weeks (Kg)	4 weeks
Haemoglobin A1c	Change in haemoglobin A1c (mmol//mol and %) from baseline to 4 weeks	4 weeks
Haemoglobin and haematocrit	Change in haemoglobin (g/L) and haematocrit from baseline to 4 weeks	4 weeks
Renal Function	Change in renal function measured by creatinine(umol/L) and estimated glomerular filtration rate (ml/min/1.73m2) from baseline to 4 weeks	4 weeks
Potassium	Change in blood potassium concentration (mmol/L) from baseline to 4 weeks	4 weeks
Total Diuretic Dose	Change in total diuretic dose from baseline to 4 weeks	4 weeks
Pill Burden	Number of pills taken during 4-week trial period	4 weeks

Frequently Asked Questions

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References

Clinical Trials Gov: Polydiuretic Therapy for HFpEF, a Randomised Controlled Trial