DAPAgliflozin Versus Thiazide Diuretic in Patients With Heart Failure and Diuretic RESISTance

Study Overview
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Brief Summary
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To assess the effect of dapagliflozin compared with metolazone, added to furosemide, on diuresis and decongestion in hospitalised heart failure patients with diuretic resistance, and renal impairment. The primary analysis will be in patients with HFrEF but patients with HFpEF will also be recruited in an ancillary study and included in supplementary analyses.

Detailed Description
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The investigators aim to assess whether SGLT2i (in addition to IV loop diuretic) results in greater diuresis and decongestion compared to the standard practice of treatment with the thiazide-like diuretic metolazone (in addition to IV loop diuretic) in patients hospitalised for heart failure, with both renal impairment and diuretic resistance. Dapagliflozin has received National Institute for Health and Care Excellence (NICE) approval as an add-on option to optimised standard care in patients with HFrEF. The investigators primary focus is patients with HFrEF as it is in ambulatory patients with this phenotype that SGLT2 inhibition has already been shown to reduce morbidity and mortality (DAPA-HF).However, the investigators will also enrol patients with HFpEF in an ancillary study as they present the same management challenges as patients with HFrEF and the study hypothesis and aims are as clinically relevant in HFpEF as in HFrEF. HFpEF patients in the ancillary study will undergo the same protocol as the main study. One recent trial demonstrating benefit of a SGLT1/2 inhibitor, the Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF), included patients with both HFrEF and HFpEF hospitalised with worsening heart failure (NCT03521934). This trial demonstrated similar efficacy of sotagliflozin on cardiovascular death and worsening heart failure in patients with a LVEF <50% and ≥50%.There are other large trials currently underway specifically with SGLT2i in ambulatory patients with HFpEF underway. These trials are either fully recruited, or close to full enrolment. Both already have extensive follow-up of several thousand patients and are due to complete follow up in the next 1-2 years (EMPEROR-Preserved and DELIVER). Therefore, the findings will be contemporaneous and complementary to the results of those trials.

Official Title
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Sodium Glucose Cotransporter-2 Inhibitor DAPAgliflozin Versus Thiazide Diuretic in Patients With Heart Failure and Diuretic RESISTance: a Multi-centre, Open-label, Randomised Controlled Clinical Trial

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Dapagliflozin 10 MG Oral Tablet
* Drug: Metolazone Tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Male or female ≥18 years of age Informed consent Primary reason for admission to hospital is worsening HF meeting the European Society of Cardiology (ESC) definition.14 Diuretic Resistance as defined as: Lack of weight loss or absence of a negative fluid balance (as defined above) over the preceding 24 hours despite treatment with high dose IV loop diuretic (equivalent of ≥160mg IV furosemide in 24 hours) Plasma BNP ≥ 100 pg/mL or plasma NT-proBNP ≥ 400 pg/mL in current hospital admission eGFR <60 ml/min/1.73m2 required within 24 hours before randomisation Ongoing clinical evidence of congestion: pitting peripheral oedema and/or ascites and/or elevated jugular venous pressure, and/or radiographic or ultrasonic evidence of pulmonary congestion Expected hospital length of stay >3 days Exclusion Criteria: Inability to give informed consent e.g. due to significant cognitive impairment Intravascular volume depletion based on investigator's clinical assessment eGFR <20 mL/min/1.73 m2 Alternative explanation for worsening renal function such as obstructive nephropathy, contrast induced nephropathy, or acute tubular necrosis Enrollment in another randomised clinical trial involving medical or device-based interventions (co-enrolment in observational studies is permitted) Women of child-bearing potential History of allergy to SGLT2i or thiazide or thiazide-like diuretics or any of the excipients Hypertrophic obstructive cardiomyopathy (HOCM) or significant valvular disease in whom surgical or percutaneous repair or replacement may be considered. SGLT2i, thiazide or thiazide-like diuretics administration in the previous 48 hours prior to randomisation Active genital tract infections Anyone who, in the investigators' opinion, is not suitable to participate in the trial for other reasons

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, randomised, active-comparator, multi-centre, open label study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SGLT2i<br>Sodium-glucose Co-transporter-2 inhibitors | Drug: Dapagliflozin 10 MG Oral Tablet<br>* Dapagliflozin 10mg once daily<br>* Other names: dapagliflozin;|
| Experimental: Thiazide<br>Thiazide or thiazide like diuretic | Drug: Metolazone Tablets<br>* Metolazone 5MG or 10MG once daily<br>* Other names: metolazone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diuretic effect | Diuretic effect, as assessed by mean change in weight | from randomisation to 48 hours | 
| Diuretic effect | Diuretic effect, as assessed by mean change in weight | from randomisation to 72 hours | 
| Diuretic effect | Diuretic effect, as assessed by mean change in weight | from randomisation to 96 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in congestion measured by ultrasound | Change in congestion, assessed using lung ultrasound as a measure of the sum of B-lines across 8 zones | from randomisation to 48 hours | 
| Change in congestion measured by ultrasound | Change in congestion, assessed using lung ultrasound as a measure of the sum of B-lines across 8 zones | from randomisation to 72 hours | 
| Change in congestion measured by ultrasound | Change in congestion, assessed using lung ultrasound as a measure of the sum of B-lines across 8 zones | from randomisation to 96 hours | 
| Loop diuretic efficiency | Loop diuretic efficiency will be defined as weight loss in kilograms divided by furosemide equivalents in milligrams. | from randomisation to 48 hours | 
| Loop diuretic efficiency | Loop diuretic efficiency will be defined as weight loss in kilograms divided by furosemide equivalents in milligrams. | from randomisation to 72 hours | 
| Loop diuretic efficiency | Loop diuretic efficiency will be defined as weight loss in kilograms divided by furosemide equivalents in milligrams. | from randomisation to 96 hours | 
| Change in ADVOR clinical congestion score | Change in ADVOR clinical congestion score will be measured on a scale of 0 to 10 with 0 being the least congested | from randomisation to 48 hours | 
| Change in ADVOR clinical congestion score | Change in ADVOR clinical congestion score will be measured on a scale of 0 to 10 with 0 being the least congested | from randomisation to 72 hours | 
| Change in ADVOR clinical congestion score | Change in ADVOR clinical congestion score will be measured on a scale of 0 to 10 with 0 being the least congested | from randomisation to 96 hours |