Efficacy and Safety of Dapagliflozin in Acute Heart Failure
NCT ID: NCT04298229
Last Updated: 2024-03-15
Study Results
Results available
Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.
View full resultsBasic Information
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Recruitment Status
COMPLETED
Clinical Phase
PHASE3
Total Enrollment
240 participants
Study Classification
INTERVENTIONAL
Study Start Date
2020-04-01
Study Completion Date
2023-05-17
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.
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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.
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.
Conditions
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Heart Failure
Diabetes Mellitus, Type 2
Study Design
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Allocation Method
RANDOMIZED
Intervention Model
PARALLEL
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.
Primary Study Purpose
TREATMENT
Blinding Strategy
SINGLE
Outcome Assessors
The Clinical Event Adjudication Committee will consist of 3 independent clinicians, which will consist of at least one endocrinologist and at least one heart failure specialist. The members of this committee will be independent of the study implementation teams and will be blinded to study arm assignment. This committee will review abstracted clinical data to determine when primary endpoints and major events have occurred. The CEAC will review data for the following study outcomes:
* Potential in-hospital worsening heart failure events
* 30-day readmission events for heart failure or diabetes-related care
* Prolonged hospitalization as a result of the following safety outcomes: hypotension requiring medical intervention or hypoglycemia requiring medical intervention
* Inpatient mortality events
* Potential ketoacidosis events
* Potential in-hospital worsening heart failure events
* 30-day readmission events for heart failure or diabetes-related care
* Prolonged hospitalization as a result of the following safety outcomes: hypotension requiring medical intervention or hypoglycemia requiring medical intervention
* Inpatient mortality events
* Potential ketoacidosis events
Study Groups
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Protocolized diuretic therapy
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.
Group Type
ACTIVE_COMPARATOR
Protocolized Diuretic Therapy
Intervention Type
OTHER
Structured usual care arm with protocolized diuretic therapy based on urine output.
Protocolized diuretic therapy plus SGLT2 inhibitor therapy
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.
Group Type
EXPERIMENTAL
Dapagliflozin 10 MG
Intervention Type
DRUG
SGLT2 inhibitors being investigated for its diuretic and natriuretic effects on top of protocolized diuretic therapy.
Protocolized Diuretic Therapy
Intervention Type
OTHER
Structured usual care arm with protocolized diuretic therapy based on urine output.
Interventions
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Dapagliflozin 10 MG
SGLT2 inhibitors being investigated for its diuretic and natriuretic effects on top of protocolized diuretic therapy.
Intervention Type
DRUG
Protocolized Diuretic Therapy
Structured usual care arm with protocolized diuretic therapy based on urine output.
Intervention Type
OTHER
Other Intervention Names
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sodium-glucose cotransporter-2(SGLT2) inhibitors
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
* 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
* 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
Minimum Eligible Age
18 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
No
Sponsors
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AstraZeneca
INDUSTRY
Sponsor Role
collaborator
Vanderbilt University Medical Center
OTHER
Sponsor Role
lead
Responsible Party
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Zachary L. Cox
Co-Principal Investigator
Responsibility Role
PRINCIPAL_INVESTIGATOR
Principal Investigators
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JoAnn Lindenfeld, MD
Role: PRINCIPAL_INVESTIGATOR
Vanderbilt University Medical Center
Locations
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University of Mississippi Medical Center
Jackson, Mississippi, United States
Site Status
University of North Carolina
Chapel Hill, North Carolina, United States
Site Status
INTEGRIS
Oklahoma City, Oklahoma, United States
Site Status
TriStar Centennial Medical Center
Nashville, Tennessee, United States
Site Status
Saint Thomas West Hospital
Nashville, Tennessee, United States
Site Status
Vanderbilt University Medical Center
Nashville, Tennessee, United States
Site Status
Countries
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United States
References
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BACKGROUND
Cox ZL, Collins SP, Hernandez GA, McRae AT 3rd, Davidson BT, Adams K, Aaron M, Cunningham L, Jenkins CA, Lindsell CJ, Harrell FE Jr, Kampe C, Miller KF, Stubblefield WB, Lindenfeld J. Efficacy and Safety of Dapagliflozin in Patients With Acute Heart Failure. J Am Coll Cardiol. 2024 Apr 9;83(14):1295-1306. doi: 10.1016/j.jacc.2024.02.009.
Reference Type
DERIVED
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Other Identifiers
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200017
Identifier Type: -
Identifier Source: org_study_id
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