Dapagliflozin at Discharge on Hospital Heart Failure Readmission

Study Overview
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Brief Summary
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This study will be the first trial to evaluate the safety and efficacy of dapagliflozin treatment in preventing readmissions/ER visits/urgent clinic visits, and death in patients with and without T2D after admission for heart failure. Treatment with SGLT2-i has been shown to reduce both heart failure hospitalizations and mortality in patients with established heart disease. However, the time of initiation of SGLT2-i therapy has not been evaluated in patients with HF. In addition, the impact of treatment on HF symptoms quality of life, resource utilization, and cost-effectiveness of dapagliflozin versus placebo will be evaluated. The results of this study have great potential to impact and facilitate care and to change current clinical guidelines in the management of patients with heart failure.

Detailed Description
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The prevalence of both heart failure and type 2 diabetes (T2D) or prediabetes are reaching epidemic proportions globally and in the United States. More than 40% of patients with established heart failure (HF) have diabetes. This study will be the first trial to evaluate the safety and efficacy of dapagliflozin treatment in preventing hospital re-admissions/ER visits/urgent clinic visits, and death in patients with and without T2D after admission for heart failure. Treatment with SGLT2-i has been shown to reduce both heart failure hospitalizations and mortality in patients with established heart disease. However, the time of initiation of SGLT2-i therapy has not been evaluated in patients with HF. In addition, the impact of treatment on HF symptoms quality of life, resource utilization, and cost-effectiveness of dapagliflozin versus placebo will be evaluated. The results of this study have great potential to impact and facilitate care and to change current clinical guidelines in the management of patients with heart failure. Patients with and without diabetes who have acute decompensated heart failure (ADHF) will be randomized to receive either dapagliflozin (10 mg once daily) or placebo at hospital discharge for 26 weeks.

Official Title
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Effect of Dapagliflozin at Discharge on Hospital Re-Admissions in Patients With Acutely Decompensated Heart Failure: A Randomized Controlled Study

Conditions
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Heart Failure, Diabetes

Intervention / Treatment
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* Drug: Dapagliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females between the ages of 18 and 90 years, with ADHF, and New York Heart Association (NYHA) class II, III, or IV symptoms discharged after hospital admission with a clinical diagnosis ADHF Elevated natriuretic peptide tests measure levels of BNP (NT-pro-BNP) ≥300 pg/ml or B-type natriuretic peptide (BNP) ≥100 pg/ml on admission Interpretable echocardiogram during hospital admission (or within 12 months prior to index hospitalization) Blood glucose level <400 mg/dL without evidence of diabetic ketoacidosis (serum bicarbonate <18 milliequivalent (mEq)/L or positive serum or urinary ketones), in patients with T2D Exclusion Criteria: Age < 18 or > 90 years Subjects with a history of type 1 diabetes Treatment with thiazolidinediones (TZDs) or SGLT2-i during the past 3 months of admission Recurrent episodes of severe hypoglycemia or hypoglycemic unawareness History of recurrent HF admissions considered to be due to non-compliance (evaluated by the research staff for participation) Patients with clinically significant hepatic disease (cirrhosis, jaundice, end-stage liver disease, portal hypertension) and elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 3 times upper limit of normal Patients with impaired renal function (GFR < 25 ml/min) Mental condition rendering the subject unable to understand the nature, scope, and possible consequences of the study Patients on ventricular assist devices (VADs) History of heart transplant or listed for heart transplant History of cardiac surgery (within 90 days prior to enrollment) or planned cardiac interventions within the following 6 months, including percutaneous coronary intervention (PCI), ablation, cardiac resynchronization therapy (CRT) implantable cardioverter-defibrillator (ICD) HF due to restrictive/infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, severe stenotic valvular diseases, hypertrophic cardiomyopathy, or congenital heart disease History of SGLT2-i allergy Systolic blood pressure < 100 mmHg Uncontrolled hypertension, defined as a systolic blood pressure > 200 mmHg at randomization Female subjects who are pregnant or breast-feeding at time of enrollment into the study Females of childbearing potential who are not using adequate contraceptive methods In hospice or expected life expectancy less than 6 months Patients with diabetic foot infection, osteomyelitis and history of amputation of lower extremities within 6 months of admission Patients anticipated to undergo major surgical procedures during the following 6 months Patients with active hematuria, urinary tract infection (UTI), or history of frequent UTIs or genital mycotic infections Uncontrolled atrial fibrillation or atrial flutter with a resting heart rate >110bpm documented by ECG at randomization Any condition that in the opinion of the investigator would contraindicate the assessment of distance walked in 6 minutes (6MWD) Chronic pulmonary disease, i.e. with known forced expiratory volume in the first second (FEV1) <50% requiring home oxygen, or oral steroid therapy or current hospitalization for severe chronic obstructive pulmonary disease (COPD) thought to be a primary contributor to dyspnea, or significant chronic pulmonary disease in the Investigator's opinion, or primary pulmonary arterial hypertension Patients with active history of bladder cancer Patients with previous history of diabetic ketoacidosis, per American Diabetes Association (ADA) criteria

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin<br>Patients admitted with exacerbation of chronic heart failure by clinical and radiologic features randomized to receive 10 mg of dapagliflozin, once daily for 26 weeks. | Drug: Dapagliflozin<br>* Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Participants will receive 10 mg/day of dapagliflozin, beginning at hospital discharge, for 26 weeks.<br>* Other names: FARXIGA;|
| Placebo Comparator: Placebo<br>Patients admitted with exacerbation of chronic heart failure by clinical and radiologic features randomized to receive a placebo to match 10 mg of dapagliflozin, once daily for 26 weeks. | Drug: Placebo<br>* Participants will receive a placebo to match 10 mg/day of dapagliflozin, beginning at hospital discharge, for 26 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Hospital Admissions, Emergency Department Visits, Urgent Clinic Visits for Heart Failure (HF) and Death After Admission With Acute Decompensated Heart Failure (ADHF) | The number of participants meeting criteria for a composite of hospital admissions, emergency department visits, urgent clinic visits for Heart Failure (HF) and death after admission with acute decompensated heart failure (ADHF) will be determined. | Up to 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Score | The Kansas City Cardiomyopathy Questionnaire is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. In the KCCQ, an overall summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. | Baseline, Week 12, Week 26 | 
| Chronic Heart Failure Questionnaire - Self-Administered Standardized Format (CHQ-SAS) Score | Chronic Heart Failure Questionnaire - Self-Administered Standardized Format (CHQ-SAS) assesses patients' perception of their heart failure and measures the impact of heart failure symptoms. The CHQ-SAS contains 16 standardized questions that assess dyspnea during daily activities, fatigue and emotional function. Items are rated on a 7-point Likert scale ranging from 1 to 7. The total score is the mean of the item scores and higher scores indicate better quality of life. | Baseline, Week 12, Week 26 | 
| N-terminal (NT)-Pro Hormone BNP (NT-proBNP) Levels | The heart failure, disease-specific biomarker N-terminal (NT)-pro hormone BNP (NT-proBNP) is a non-active prohormone. Levels increase when heart failure develops or gets worse and levels goes down when heart failure is stable. | Baseline, Week 12, Week 26 | 
| 6-Minute Walk Distance (6MWD) | The 6-Minute Walk Distance (6MWD) test measures the distance, in meters, that a patient can quickly walk on a flat, hard surface in a period of 6 minutes | Baseline, Week 12, Week 26 | 
| Hemoglobin A1C (HbA1c) Level | HbA1c will be quantified by blood test, in participants with type 2 diabetes (T2D) or prediabetes. Higher percentages of glycated hemoglobin on red blood cells (RBCs) indicate higher blood glucose levels in the previous three months. A normal HbA1c level is below 5.7 percent. | Baseline, Week 12, Week 26 | 
| Weight | Weight is measured in kilograms | Baseline,Week 12, Week 26 | 
| Systolic Blood Pressure | Systolic blood pressure is measured in millimeters of mercury (mmHg). A normal systolic blood pressure level is less than 120 mmHg. | Baseline, Week 12, Week 26 | 
| Left Atrial Volume Index (LAVI) | Left atrial volume index assesses diastolic function and is a predictor of mortality. LAVI can identify abnormal atrial dilation and is calculated as the left atrium volume (mL) divided by body surface area (m^2). The normal range is between 16 and 35 mL/m^2. Increased LAVI is a predictor of mortality following acute myocardial infarction. | Baseline, Week 12, Week 26 | 
| Serum Magnesium | Normal levels of serum magnesium are between 1.7 and 2.3 milligrams per deciliter (mg/dL). | Baseline, Week 12, Week 26 | 
| Number of Participants Dying From Cardiovascular Reasons | The number of participants dying due to cardiovascular reasons was documented. | Up to Week 26 | 
| Number of Participants With Non-fatal Myocardial Infarction (MI) | The number of participants with non-fatal myocardial infarction (MI) was documented. | Up to Week 26 | 
| Number of Participants With Stroke | The number of participants experiencing a stroke was documented. | Up to Week 26 | 
| Number of Participants With Acute Kidney Injury | The number of participants experiencing acute kidney injury was documented. | Up to Week 26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hospitalization, mortality, time of initiation of therapy, quality of life, cost-effectiveness, dapagliflozin, clinical trial, diabetes