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Polydiuretic Therapy for HFpEF, a Randomised Controlled Trial
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.
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.
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
Inclusion criteria
Exclusion criteria
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
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
| DRUG: Low dose combination polydiuretic therapy
|
ACTIVE_COMPARATOR: Comparator group receiving monotherapy empagliflozin
| DRUG: Comparator monotherapy empagliflozin
|
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 |
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