DAPAgliflozin Versus Thiazide Diuretic in Patients With Heart Failure and Diuretic RESISTance (DAPARESIST)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Dapagliflozin 10 MG Oral Tablet; Drug: Metolazone Tablets

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Su E Yeoh, MBChB; Phone Number: 2418 0141 330 2418; Email: SuErn.Yeoh@glasgow.ac.uk
• Study Contact Backup: Name: Katriona JM Brooksbank, PhD; Phone Number: 2418 0141 330 2418; Email: katriona.brooksbank@glasgow.ac.uk

Study Locations

• United Kingdom
  • Strathclyde
    • Glasgow, Strathclyde, United Kingdom, G4 0SF
      • Glasgow Royal Infirmary
    • Glasgow, Strathclyde, United Kingdom, G51 4TF
      • Queen Elizabeth University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in urinary spot sodium	change in urinary spot urine measured in mmol/L	from randomisation to 48 hours
Change in urinary spot sodium	change in urinary spot urine measured in mmol/L	from randomisation to 72 hours
Change in urinary spot sodium	change in urinary spot urine measured in mmol/L	from randomisation to 96 hours
Change in NT-proBNP	measured in pg/ml	from randomisation to 48 hours
Change in NT-proBNP	measured in pg/ml	from randomisation to 72 hours
Change in NT-proBNP	measured in pg/ml	from randomisation to 96 hours
Change in serum uric acid	measured in umol/L	from randomisation to 48 hours
Change in serum uric acid	measured in umol/L	from randomisation to 72 hours
Change in serum uric acid	measured in umol/L	from randomisation to 96 hours
Total net fluid loss	difference between fluid intake and output measured in ml	from randomisation to 48 hours
Total net fluid loss	difference between fluid intake and output measured in ml	from randomisation to 72 hours
Total net fluid loss	difference between fluid intake and output measured in ml	from randomisation to 96 hours
Change in dyspnoea	Change in dyspnoea (breathlessness) measured using a 7 point Likert scale (1= strong positive to 7 = strong negative) and a 11-point Dyspnoea Numerical Rating scale (0= not breathless at all to 10=breathlessness as bad as you can imagine)	from randomisation to 48 hours
Change in dyspnoea	Change in dyspnoea (breathlessness) measured using a 7 point Likert scale (1= strong positive to 7 = strong negative) and a 11-point Dyspnoea Numerical Rating scale (0= not breathless at all to 10=breathlessness as bad as you can imagine)	from randomisation to 72 hours
Change in dyspnoea	Change in dyspnoea (breathlessness) measured using a 7 point Likert scale (1= strong positive to 7 = strong negative) and a 11-point Dyspnoea Numerical Rating scale (0= not breathless at all to 10=breathlessness as bad as you can imagine)	from randomisation to 96 hours
Patient global assessment	Change in patients perception of their own health measured using a 7 point Likert scale (1= strong positive to 7 = strong negative)	from randomisation to 48 hours
Patient global assessment	Change in patients perception of their own health measured using a 7 point Likert scale (1= strong positive to 7 = strong negative)	from randomisation to 72 hours
Patient global assessment	Change in patients perception of their own health measured using a 7 point Likert scale (1= strong positive to 7 = strong negative)	from randomisation to 96 hours
Time from randomisation to discharge	Time from randomisation to discharge measured in hours	through study completion, an average of 5 days
In-hospital mortality	Number of patients who died in hospital	through study completion, an average of 5 days
Serum uric acid ≥360 μmol/L	measured in umol/L	from randomisation to 48 hours
Serum uric acid ≥360 μmol/L	measured in umol/L	from randomisation to 72 hours
Serum uric acid ≥360 μmol/L	measured in umol/L	from randomisation to 96 hours
change in serum glucose	measured in mmol/L	from randomisation to 72 hours
change in serum glucose	measured in mmol/L	from randomisation to 48 hours
change in serum glucose	measured in mmol/L	from randomisation to 96 hours
Rate of heart failure re-hospitalisation or death	Number of patients who are re-admitted to hospital after initial discharge	through study completion (on average 5 days) and up to 90 days
Change in serum creatinine	measured in umol/L	from randomisation to 48 hours
Change in serum creatinine	measured in umol/L	from randomisation to 72 hours
Change in serum creatinine	measured in umol/L	from randomisation to 96 hours
increase in serum creatinine concentration	measured in umol/L	from randomisation to 48 hours
increase in serum creatinine concentration	measured in umol/L	from randomisation to 72 hours
increase in serum creatinine concentration	measured in umol/L	from randomisation to 96 hours
change in blood urea (nitrogen)	measured in mmol/L	from randomisation to 48 hours
change in blood urea (nitrogen)	measured in mmol/L	from randomisation to 72 hours
change in blood urea (nitrogen)	measured in mmol/L	from randomisation to 96 hours
change in serum potassium	measured in mmol/L	from randomisation to 48 hours
change in serum potassium	measured in mmol/L	from randomisation to 72 hours
change in serum potassium	measured in mmol/L	from randomisation to 96 hours
Serum potassium <3.5 mmol/L and ≥5.5 mmol/L	measured in mmol/L	from randomisation to 48 hours
Serum potassium <3.5 mmol/L and ≥5.5 mmol/L	measured in mmol/L	from randomisation to 72 hours
Serum potassium <3.5 mmol/L and ≥5.5 mmol/L	measured in mmol/L	from randomisation to 96 hours
change in serum sodium	measured in mmol/L	from randomisation to 48 hours
change in serum sodium	measured in mmol/L	from randomisation to 72 hours
change in serum sodium	measured in mmol/L	from randomisation to 96 hours
Serum sodium concentration <125 mmol/L	measured in mmol/L	from randomisation to 48 hours
Serum sodium concentration <125 mmol/L	measured in mmol/L	from randomisation to 72 hours
Serum sodium concentration <125 mmol/L	measured in mmol/L	from randomisation to 96 hours

Collaborators and Investigators

• Sponsor: NHS Greater Glasgow and Clyde
• Collaborators: University of Glasgow
• Investigators: Study Chair: John McMurray, MBChB, University of Glasgow and NHS Greater Glasgow and Clyde

Study record dates

Study Major Dates

• Study Start (Actual): April 27, 2021
• Primary Completion (Actual): October 30, 2022
• Study Completion (Anticipated): April 3, 2023

Study Registration Dates

• First Submitted: April 6, 2021
• First Submitted That Met QC Criteria: April 22, 2021
• First Posted (Actual): April 26, 2021

Study Record Updates

• Last Update Posted (Estimate): April 10, 2023
• Last Update Submitted That Met QC Criteria: April 6, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Natriuretic Agents; Membrane Transport Modulators; Diuretics; Sodium-Glucose Transporter 2 Inhibitors; Sodium Chloride Symporter Inhibitors; Dapagliflozin; Metolazone
• Other Study ID Numbers: GN19CA407

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: To be discussed and agreed at TSC

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No