Clinical trial NCT04860011: DAPAgliflozin Versus Thiazide Diuretic in Patients With Heart Failure and Diuretic RESISTance
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Heart Failure
Lead sponsor: NHS Greater Glasgow and Clyde
Sponsor class: OTHER
Collaborators: name: University of Glasgow
First posted: 2021-04-26
Enrollment: 61
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective, randomised, active-comparator, multi-centre, open label study.
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Diuretic effect
timeFrame: from randomisation to 48 hours
measure: Diuretic effect
timeFrame: from randomisation to 72 hours
measure: Diuretic effect
timeFrame: from randomisation to 96 hours
Secondary outcomes:
measure: Change in congestion measured by ultrasound
timeFrame: from randomisation to 48 hours
measure: Change in congestion measured by ultrasound
timeFrame: from randomisation to 72 hours
measure: Change in congestion measured by ultrasound
timeFrame: from randomisation to 96 hours
measure: Loop diuretic efficiency
timeFrame: from randomisation to 48 hours
measure: Loop diuretic efficiency
timeFrame: from randomisation to 72 hours
measure: Loop diuretic efficiency
timeFrame: from randomisation to 96 hours
measure: Change in ADVOR clinical congestion score
timeFrame: from randomisation to 48 hours
measure: Change in ADVOR clinical congestion score
timeFrame: from randomisation to 72 hours
measure: Change in ADVOR clinical congestion score
timeFrame: from randomisation to 96 hours
Other outcomes:
measure: Change in urinary spot sodium
timeFrame: from randomisation to 48 hours
measure: Change in urinary spot sodium
timeFrame: from randomisation to 72 hours
measure: Change in urinary spot sodium
timeFrame: from randomisation to 96 hours
measure: Change in NT-proBNP
timeFrame: from randomisation to 48 hours
measure: Change in NT-proBNP
timeFrame: from randomisation to 72 hours
measure: Change in NT-proBNP
timeFrame: from randomisation to 96 hours
measure: Change in serum uric acid
timeFrame: from randomisation to 48 hours
measure: Change in serum uric acid
timeFrame: from randomisation to 72 hours
measure: Change in serum uric acid
timeFrame: from randomisation to 96 hours
measure: Serum uric acid ≥360 μmol/L
timeFrame: from randomisation to 48 hours
measure: Serum uric acid ≥360 μmol/L
timeFrame: from randomisation to 72 hours
measure: Serum uric acid ≥360 μmol/L
timeFrame: from randomisation to 96 hours
measure: Total net fluid loss
timeFrame: from randomisation to 48 hours
measure: Total net fluid loss
timeFrame: from randomisation to 72 hours
measure: Total net fluid loss
timeFrame: from randomisation to 96 hours
measure: Change in dyspnoea
timeFrame: from randomisation to 48 hours
measure: Change in dyspnoea
timeFrame: from randomisation to 72 hours
measure: Change in dyspnoea
timeFrame: from randomisation to 96 hours
measure: Patient global assessment
timeFrame: from randomisation to 48 hours
measure: Patient global assessment
timeFrame: from randomisation to 72 hours
measure: Patient global assessment
timeFrame: from randomisation to 96 hours
measure: change in serum glucose
timeFrame: from randomisation to 72 hours
measure: change in serum glucose
timeFrame: from randomisation to 48 hours
measure: change in serum glucose
timeFrame: from randomisation to 96 hours
measure: Time from randomisation to discharge
timeFrame: through study completion, an average of 5 days
measure: In-hospital mortality
timeFrame: through study completion, an average of 5 days
measure: Rate of heart failure re-hospitalisation or death
timeFrame: through study completion (on average 5 days) and up to 90 days
measure: Change in serum creatinine
timeFrame: from randomisation to 48 hours
measure: Change in serum creatinine
timeFrame: from randomisation to 72 hours
measure: Change in serum creatinine
timeFrame: from randomisation to 96 hours
measure: increase in serum creatinine concentration
timeFrame: from randomisation to 48 hours
measure: increase in serum creatinine concentration
timeFrame: from randomisation to 72 hours
measure: increase in serum creatinine concentration
timeFrame: from randomisation to 96 hours
measure: change in blood urea (nitrogen)
timeFrame: from randomisation to 48 hours
measure: change in blood urea (nitrogen)
timeFrame: from randomisation to 72 hours
measure: change in blood urea (nitrogen)
timeFrame: from randomisation to 96 hours
measure: change in serum potassium
timeFrame: from randomisation to 48 hours
measure: change in serum potassium
timeFrame: from randomisation to 72 hours
measure: change in serum potassium
timeFrame: from randomisation to 96 hours
measure: Serum potassium <3.5 mmol/L and ≥5.5 mmol/L
timeFrame: from randomisation to 48 hours
measure: Serum potassium <3.5 mmol/L and ≥5.5 mmol/L
timeFrame: from randomisation to 72 hours
measure: Serum potassium <3.5 mmol/L and ≥5.5 mmol/L
timeFrame: from randomisation to 96 hours
measure: change in serum sodium
timeFrame: from randomisation to 48 hours
measure: change in serum sodium
timeFrame: from randomisation to 72 hours
measure: change in serum sodium
timeFrame: from randomisation to 96 hours
measure: Serum sodium concentration <125 mmol/L
timeFrame: from randomisation to 48 hours
measure: Serum sodium concentration <125 mmol/L
timeFrame: from randomisation to 72 hours
measure: Serum sodium concentration <125 mmol/L
timeFrame: from randomisation to 96 hours
Locations:
city: Glasgow
country: United Kingdom
facility: Glasgow Royal Infirmary
state: Strathclyde
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
state: Strathclyde
Study officials:
affiliation: University of Glasgow and NHS Greater Glasgow and Clyde
name: John McMurray, MBChB
role: STUDY_CHAIR
References: