Efficacy and Safety of Dapagliflozin in Acute Heart Failure

Study Overview
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Brief Summary
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This is a randomized trial of the addition of dapagliflozin to patients with or without type 2 diabetes hospitalized with acute decompensated heart failure (ADHF). Participants will be recruited following an initial standard evaluation in the ED and randomized within 24 hours of presentation for ADHF in a 1:1 fashion to protocolized diuretic therapy or dapagliflozin + protocolized diuretic therapy.

Detailed Description
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Patients with acute decompensated HF (ADHF) are generally admitted due to symptoms of congestion and 90% are treated with a loop diuretic. However at least one-third of these patients are inadequately decongested due primarily to diuretic resistance and/ or cardiorenal syndrome. The inability to achieve decongestion is associated with a worse prognosis and a higher rate of re-hospitalization for ADHF. More than 40% of all patients admitted with ADHF have diabetes and that percentage is growing both in Heart Failure with Reduced Ejection Fraction (HFrEF) and Preserved Ejection Fraction (HFpEF). The admission blood glucose is elevated in approximately one-half of ADHF hospitalizations. We recently demonstrated the admission blood glucose was within 50mg/dl of the chronic average blood glucose in 66% of patients with diabetes admitted with ADHF. The median (IQR) admission blood glucose change from the chronic blood glucose was only -7 (-29, 26) mg/dl. Thus, the acute glucose in patients with T2DM presenting with acute heart failure is most often related to poor chronic glucose control suggesting that these patients would benefit from attempts to initiate therapies to improve chronic glucose control while in the hospital. No new therapies have been introduced in the United States for ADHF in several decades. Natriuretic peptides such as nesiritide and ularitide have failed to improve outcomes in either the chronic or acute heart failure patients. Diuretic resistance and hyperglycemia are common problems in ADHF admissions and represent a therapeutic opportunity for new therapies. The sodium-glucose cotransporter-2(SGLT2) inhibitors, now approved for the anti-hyperglycemic therapies also have an osmotic diuretic and natriuretic effect. In the chronic setting SGLT2 inhibitors reduce weight with modest decrements in systolic and diastolic blood pressure with a marked drop in albuminuria and a small drop in estimated GFR (-5 mL min-1.1.73 m-2) which returns to baseline over time. In patients with diabetes the SGLT2 transporter likely accounts for as much as 14% of total sodium chloride absorption. In the acute setting following a single dose, SGLT2 inhibitors did not increase urine volume. However, the acute diuretic effects have not been studied in a population with heart failure with or without concomitant hyperglycemia who are undergoing diuresis. To our knowledge, no current trials are investigating the effects of SGLT2 inhibition in ADHF. The current studies planned in HF are investigating the acute effects of SGLT2 on stable HF (NCT03027960), the chronic effects of SGLT2 inhibition in compensated, chronic HF (NCT03619213, NCT02653482, NCT03030235, NCT03057977), changes in pulmonary pressure hemodynamics in patients monitored by CardioMEMs devices (NCT03030222), and effects on cardiopulmonary exercise fitness in chronic HF (NCT02862067). Congestion remains the major cause of hospital readmission for heart failure and an inpatient plan of care that allowed more effective decongestion would be rapidly and widely adopted by the medical community. Therefore, we propose to test the decongesting effects of the SGLT2 inhibitor dapagliflozin in patients with or without Type II diabetes admitted with an acute decompensation of chronic heart failure.

Official Title
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A Randomized, Open-label Study of Dapagliflozin in Patients With or Without Type 2 Diabetes Admitted With Acute Heart Failure

Conditions
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Heart Failure, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: Dapagliflozin 10 MG
* Other: Protocolized Diuretic Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of 18 years or older Randomized within 24 of presentation during a hospital admission for hypervolemic decompensated heart failure defined as: pulmonary artery catheterization with a pulmonary capillary wedge pressure greater than 19mmHg plus a systemic physical exam finding of hypervolemia (peripheral edema, ascites, or pulmonary edema on auscultation) in the absence of pulmonary artery catheterization data 2 of the following signs or symptoms: peripheral edema, ascites, jugular venous pressure > 10mmHg, orthopnea, paroxysmal nocturnal dyspnea, 5-pound weight gain, or signs of congestion on chest x-ray or lung ultrasound Planned use of IV loop diuretic therapy during current hospitalization eGFR of 25 ml/min/1.73m2 by the MDRD equation or greater Exclusion Criteria: Type 1 diabetes Serum glucose < 80mg/dl at enrollment Systolic blood pressure < 90mmHg at enrollment Requirement of intravenous inotropic therapy or anticipated need during the study History of hypersensitivity to any SGLT2 inhibitors Women who are pregnant or breastfeeding Severe anemia (Hemoglobin < 7.5g/dl) Severe uncorrected aortic or mitral stenosis Inability to perform standing weights or measure urine output accurately History of diabetic ketoacidosis Scheduled combination nephron blockade with loop and thiazide therapy as an outpatient for more than 7 days prior to admission (excluding HCTZ < 50mg for blood pressure) Diffuse anasarca with 4+ edema and projected hypervolemia exceeding 40-pounds Severe hepatic impairment (Child-Pugh class C) Clinical picture consistent with acute myocardial infarction including troponin rise and fall or ischemic changes on electrocardiogram Site investigator determines the subject is not a good candidate to participate in the study at this tine

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: Participants will be recruited following an initial standard evaluation in the ED and randomized within 24 hours of presentation for ADHF in a 1:1 fashion to protocolized diuretic therapy or dapagliflozin + protocolized diuretic therapy.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Protocolized diuretic therapy<br>The patients with diabetes will receive standard of care point of care blood glucose monitoring 4 times daily (before meals and at bedtime) and sliding scale insulin. The initial loop diuretic regimen after enrollment: Loop diuretic naïve: If the patient does not take a scheduled loop diuretic as an outpatient, the initial IV loop diuretic dose will be 40mg of furosemide equivalents every 12 hours. Chronic, oral loop diuretic therapy: If the patient takes a scheduled loop diuretic regimen as an outpatient prior to hospital admission, the initial IV loop diuretic daily dose will be 2 times the total daily home regimen dose. Diuretic therapy will be titrated to goal urine output using a standardized diuretic protocol. | Other: Protocolized Diuretic Therapy<br>* Structured usual care arm with protocolized diuretic therapy based on urine output.<br>|
| Experimental: Protocolized diuretic therapy plus SGLT2 inhibitor therapy<br>The patients with diabetes will receive standard of care point of care blood glucose monitoring 4 times daily (before meals and at bedtime) and sliding scale insulin. The initial loop diuretic regimen after enrollment: Loop diuretic naïve: If the patient does not take a scheduled loop diuretic as an outpatient, the initial IV loop diuretic dose will be 40mg of furosemide equivalents every 12 hours. Chronic, oral loop diuretic therapy: If the patient takes a scheduled loop diuretic regimen as an outpatient prior to hospital admission, the initial IV loop diuretic daily dose will be 2 times the total daily home regimen dose. Diuretic therapy will be titrated to goal urine output using a standardized diuretic protocol. The patient will receive SGLT2 inhibitor therapy with dapagliflozin 10 mg orally once daily until 5 days or hospital discharge. | Drug: Dapagliflozin 10 MG<br>* SGLT2 inhibitors being investigated for its diuretic and natriuretic effects on top of protocolized diuretic therapy.<br>* Other names: sodium-glucose cotransporter-2(SGLT2) inhibitors;Other: Protocolized Diuretic Therapy<br>* Structured usual care arm with protocolized diuretic therapy based on urine output.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative change in weight (kilograms) | cumulative change in weight (kilograms) per 40mg of IV furosemide equivalents from enrollment to day 5 or discharge (if earlier) between protocolized diuretic therapy and dapagliflozin plus protocolized diuretic therapy guided by urine output | Baseline to Day 5 or discharge if earlier | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of worsening heart failure | Incidence of worsening heart failure during hospitalization requiring IV inotropic therapy with dobutamine, milrinone, or dopamine or admission to an intensive care unit as adjudicated by the Clinical Event Adjudication Committee | Baseline to hospital discharge, an average of 5 days | 
| Hospital readmission | Hospital readmission within 30 days of discharge for heart failure or diabetic reasons as adjudicated by the Clinical Event Adjudication Committee | Day 30 |