Sodium-Glucose Cotransporter-2 Inhibitor for Acute Cardiorenal Syndrome: A Feasibility Study

Study Overview
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Brief Summary
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The overall objective of this study is to determine whether the addition of SGLT2 inhibitors to usual care during acute heart failure shortens the time to symptomatic improvement and kidney function recovery. The study aims to assess feasibility, acceptability, and impact on decongestion and early biomarkers of kidney injury.

Detailed Description
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Acute heart failure is associated with a significant risk of acute kidney injury and treatment interruptions as a result. It is present in up to a third of patients at the time of hospitalization. As adequate kidney function is necessary for self-decongestion, kidney injury makes the treatment of acute heart failure particularly challenging. SGLT2i are drugs consistently shown to reduce hospitalizations in heart failure as well as progression of chronic kidney disease but are frequently discontinued during acute kidney injury and rarely resumed. Although they have been included in the armamentarium of heart failure care as guideline directed medical therapy, a major limitation to their uptake has been a concern about the efficacy and safety in patients with kidney dysfunction. This study aims to enroll patients with acute congestive cardiorenal syndrome in a randomized clinical trial of SGLT2i versus usual care to compare markers of decongestion and biomarkers of kidney injury and health to inform a larger randomized clinical trial. The overall aim is to assess if SGLT2i improve diuretic efficiency thereby reducing hospital length of stay. Additionally this study will could prevent premature discontinuation of such drugs during kidney dysfunction in this setting thereby improving uptake in the community, and ultimately reducing hospitalizations due to heart failure. To that end, this study aims to promote increased use of SGLT2i by demonstrating their safety and possible benefit in patients who develop kidney injury during acute heart failure to avoid interruptions in this setting. The primary objective of this is study is to test the feasibility and acceptability of SGLT2i in adults hospitalized with acute heart failure in a randomized clinical trial. The secondary objectives of this study are: To compare changes in biomarkers of kidney injury, repair and tubular function in order to test whether the SGLT2 inhibitor (dapagliflozin) improves response to standard treatment To compare markers of decongestion (weight, urine volume, symptom score, diuretic de-escalation) to test whether the addition of SGLT2i to standard of care improves heart failure symptoms faster. To compare possible adverse events such as: sodium or potassium derangements, metabolic acidosis, urinary tract infections (UTI) or genital mycotic infections in those exposed to the SGLT2i dapagliflozin vs usual care. To compare hospital length of stay, mortality, progression to a higher stage of AKI, and persistent AKI at discharge

Official Title
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Sodium-Glucose Cotransporter-2 Inhibitor for Acute Cardiorenal Syndrome: A Feasibility Study

Conditions
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Cardiorenal Syndrome

Intervention / Treatment
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* Drug: Dapagliflozin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated informed consent form Stated willingness to comply with all study procedures and availability for the duration of the study Male or female, aged ≥ 18 and ≤ 85 years-old Diagnosed with heart failure of either preserved or reduced left ventricular function NT-proBNP > 300 pg/mL Ability to take an oral medication Willing to adhere to the SGLT2i + usual care regimen Exclusion Criteria: Current use of SGLT2 inhibitor or use in the past 72 hours Pregnancy or lactation (a pregnancy test will be performed prior to enrollment in women of child-bearing age) Known allergic reactions to components of an SGLT2 inhibitor Treatment with another investigational drug for heart failure different from or in addition to usual care within the 72 hours preceding AKI Any individual who meets any of the following criteria will be excluded from participation in this study: Documented history of ileal conduit (neobladder) No means of collecting urine such as patients with documented incontinence without indwelling or external urinary catheter Advanced kidney disease at baseline defined as baseline eGFR < 25 ml/min/1.73m2 Unexplained hypoglycemia in the past 30 days from enrollment History of Fournier's gangrene (pelvic necrotizing fasciitis) History of recurrent urinary tract infection (UTI): defined as documented UTI at least 2x in the past 6 months or 3 x in the past 12 months End-stage kidney disease with dialysis requirement Oliguria: defined as less than 30 ml urine output per hour for more than two consecutive hours or less than 500 ml over the preceding 24 hours Severe acute kidney injury with indications for dialysis Current dialysis receipt for acute kidney injury Comfort measures only Solid organ transplant on immunosuppression

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SGLT2i administration<br>A 10 mg oral dose of dapagliflozin will be administered daily for three days. | Drug: Dapagliflozin<br>* Receipt of 10mg oral dose of dapagliflozin once daily for three days<br>|
| No Intervention: Usual Care<br>Subjects continue with usual care. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of eligible versus consented patients | Number of patients deemed eligible after assessment of inclusion and exclusion criteria and number of patients who consent, which serves as a measure of feasibility of enrolling patients with acute cardiorenal syndrome in a randomized clinical trial of SGLT2i. | From study initiation to study close (about 2 years) | 
| Percentage of enrolled patients with completed sample collections | Percentage of enrolled patients who have provided at least two days of urine samples and percentage of enrolled patients who have provided at least two days of blood samples, which serves as a measure of feasibility of enrolling and retaining patients with acute cardiorenal syndrome in a randomized clinical trial of SGLT2i. | From study initiation to study close (about 2 years) | 
| Enrollment rate | Total enrollment into the study over study duration, to serve as a measure of feasibility. | From study initiation to study close (about 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Slope of creatinine | Comparison between study arms of the slope of the serum biomarker creatinine over five days, as a measure of kidney function | 5 days following randomization | 
| Slope of cystatin-C | Comparison between study arms of the slope of the serum biomarker cystatin-C over five days, as a measure of kidney function | 5 days following randomization | 
| Slope of NT-proBNP | Comparison between study arms of the slope of the serum biomarker NT-proBNP over five days, as a measure of decongestion. | 5 days following randomization | 
| Slope of kidney tubular injury and repair biomarkers | Comparison between study arms of the slopes of the following urinary biomarkers of renal tubular kidney injury, inflammation and repair over five days: molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), monocyte chemoattractant protein-1 (MCP-1), uromodulin (UMOD), chitinase-3-like protein (YKL-40). | 5 days following randomization | 
| Slope of urine volume | Comparison between study arms of 24 hour urine volume collection as a measure of decongestion | 72 hours from randomization | 
| Weight | Weight of subjects at 72 hours post-randomization as a measure of decongestion. | 72 hours from randomization | 
| Breathlessness score | Based on the 3 item symptom scale questionnaire given to subjects. Breathlessness scores range from 1-5, with higher scores indicating higher breathlessness. This score serves as a measure of decongestion. | 72 hours from randomization | 
| Loop diuretic dose de-escalation | Time from randomization to de-escalation of loop diuretic, serving as a measure of decongestion. | From randomization up to 72 hours from randomization | 
| Mortality | Time to in-hospital death | Assessed from randomization to time of death up to 14 days post-randomization or discharge | 
| Dialysis | Time to in-hospital dialysis | Assessed from point of randomization to the date of first documented dialysis order during index hospitalization, up to 14 days post-randomization or discharge | 
| Rate of rehospitalization with heart failure | Number of patients rehospitalized for heat failure after index hospitalization, wtihin 90 days of discharge | 90 days post-index discharge | 
| Time-to-prescription of an SGLT2i | Time to prescription of any SGLT2 by patient's primary provider, up to 90 days post-randomization | 90 days post-randomization |