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

Heart Failure Clinical Trial

— DAPARESIST  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04860011
• Other study ID #: GN19CA407
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: April 27, 2021
• Est. completion date: April 3, 2023

Study information

• Verified date: April 2023
• Source: NHS Greater Glasgow and Clyde
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 61
• Est. completion date: April 3, 2023
• Est. primary completion date: October 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Heart Failure

Intervention

Drug:
• Dapagliflozin 10 MG Oral Tablet
Dapagliflozin 10mg once daily
• Metolazone Tablets
Metolazone 5MG or 10MG once daily

Locations

Country	Name	City	State
United Kingdom	Glasgow Royal Infirmary	Glasgow	Strathclyde
United Kingdom	Queen Elizabeth University Hospital	Glasgow	Strathclyde

Sponsors (2)

Lead Sponsor	Collaborator
NHS Greater Glasgow and Clyde	University of Glasgow

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in urinary spot sodium	change in urinary spot urine measured in mmol/L	from randomisation to 48 hours
Other	Change in urinary spot sodium	change in urinary spot urine measured in mmol/L	from randomisation to 72 hours
Other	Change in urinary spot sodium	change in urinary spot urine measured in mmol/L	from randomisation to 96 hours
Other	Change in NT-proBNP	measured in pg/ml	from randomisation to 48 hours
Other	Change in NT-proBNP	measured in pg/ml	from randomisation to 72 hours
Other	Change in NT-proBNP	measured in pg/ml	from randomisation to 96 hours
Other	Change in serum uric acid	measured in umol/L	from randomisation to 48 hours
Other	Change in serum uric acid	measured in umol/L	from randomisation to 72 hours
Other	Change in serum uric acid	measured in umol/L	from randomisation to 96 hours
Other	Serum uric acid =360 µmol/L	measured in umol/L	from randomisation to 48 hours
Other	Serum uric acid =360 µmol/L	measured in umol/L	from randomisation to 72 hours
Other	Serum uric acid =360 µmol/L	measured in umol/L	from randomisation to 96 hours
Other	Total net fluid loss	difference between fluid intake and output measured in ml	from randomisation to 48 hours
Other	Total net fluid loss	difference between fluid intake and output measured in ml	from randomisation to 72 hours
Other	Total net fluid loss	difference between fluid intake and output measured in ml	from randomisation to 96 hours
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	change in serum glucose	measured in mmol/L	from randomisation to 72 hours
Other	change in serum glucose	measured in mmol/L	from randomisation to 48 hours
Other	change in serum glucose	measured in mmol/L	from randomisation to 96 hours
Other	Time from randomisation to discharge	Time from randomisation to discharge measured in hours	through study completion, an average of 5 days
Other	In-hospital mortality	Number of patients who died in hospital	through study completion, an average of 5 days
Other	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
Other	Change in serum creatinine	measured in umol/L	from randomisation to 48 hours
Other	Change in serum creatinine	measured in umol/L	from randomisation to 72 hours
Other	Change in serum creatinine	measured in umol/L	from randomisation to 96 hours
Other	increase in serum creatinine concentration	measured in umol/L	from randomisation to 48 hours
Other	increase in serum creatinine concentration	measured in umol/L	from randomisation to 72 hours
Other	increase in serum creatinine concentration	measured in umol/L	from randomisation to 96 hours
Other	change in blood urea (nitrogen)	measured in mmol/L	from randomisation to 48 hours
Other	change in blood urea (nitrogen)	measured in mmol/L	from randomisation to 72 hours
Other	change in blood urea (nitrogen)	measured in mmol/L	from randomisation to 96 hours
Other	change in serum potassium	measured in mmol/L	from randomisation to 48 hours
Other	change in serum potassium	measured in mmol/L	from randomisation to 72 hours
Other	change in serum potassium	measured in mmol/L	from randomisation to 96 hours
Other	Serum potassium <3.5 mmol/L and =5.5 mmol/L	measured in mmol/L	from randomisation to 48 hours
Other	Serum potassium <3.5 mmol/L and =5.5 mmol/L	measured in mmol/L	from randomisation to 72 hours
Other	Serum potassium <3.5 mmol/L and =5.5 mmol/L	measured in mmol/L	from randomisation to 96 hours
Other	change in serum sodium	measured in mmol/L	from randomisation to 48 hours
Other	change in serum sodium	measured in mmol/L	from randomisation to 72 hours
Other	change in serum sodium	measured in mmol/L	from randomisation to 96 hours
Other	Serum sodium concentration <125 mmol/L	measured in mmol/L	from randomisation to 48 hours
Other	Serum sodium concentration <125 mmol/L	measured in mmol/L	from randomisation to 72 hours
Other	Serum sodium concentration <125 mmol/L	measured in mmol/L	from randomisation to 96 hours
Primary	Diuretic effect	Diuretic effect, as assessed by mean change in weight	from randomisation to 48 hours
Primary	Diuretic effect	Diuretic effect, as assessed by mean change in weight	from randomisation to 72 hours
Primary	Diuretic effect	Diuretic effect, as assessed by mean change in weight	from randomisation to 96 hours
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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