DICTATE-AHF: Efficacy and Safety of Dapagliflozin in Acute Heart Failure

Sponsor
Vanderbilt University Medical Center (Other)
Overall Status
Recruiting
CT.gov ID
NCT04298229
Collaborator
AstraZeneca (Industry)
240
6
2
34
40
1.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
  • Drug: Dapagliflozin 10 MG
  • Other: Protocolized Diuretic Therapy
Phase 3

Detailed Description

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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
240 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention 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.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 (Outcomes Assessor)
Masking Description:
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 inhospital 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
Primary Purpose:
Treatment
Official Title:
A Randomized, Open-label Study of Dapagliflozin in Patients With or Without Type 2 Diabetes Admitted With Acute Heart Failure
Actual Study Start Date :
Apr 1, 2020
Anticipated Primary Completion Date :
Dec 31, 2022
Anticipated Study Completion Date :
Jan 31, 2023

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: 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.

Other: Protocolized Diuretic Therapy
Structured usual care arm with protocolized diuretic therapy based on urine output.

Experimental: 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.

Drug: Dapagliflozin 10 MG
SGLT2 inhibitors being investigated for its diuretic and natriuretic effects on top of protocolized diuretic therapy.
Other Names:
  • sodium-glucose cotransporter-2(SGLT2) inhibitors
  • Other: Protocolized Diuretic Therapy
    Structured usual care arm with protocolized diuretic therapy based on urine output.

    Outcome Measures

    Primary Outcome Measures

    1. Cumulative change in weight (kilograms) [Baseline to Day 5 or discharge if earlier]

      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

    Secondary Outcome Measures

    1. Incidence of worsening heart failure [Baseline to hospital discharge, an average of 5 days]

      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

    2. Hospital readmission [Day 30]

      Hospital readmission within 30 days of discharge for heart failure or diabetic reasons as adjudicated by the Clinical Event Adjudication Committee

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    • 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

    • Diffuse anasarca with 4+ edema and projected hypervolemia exceeding 40-pounds

    • Severe hepatic impairment (Child-Pugh class C)

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Mississippi Medical Center Jackson Mississippi United States 39216
    2 University of North Carolina Chapel Hill North Carolina United States 27514
    3 INTEGRIS Oklahoma City Oklahoma United States 73112
    4 TriStar Centennial Medical Center Nashville Tennessee United States 37203
    5 Saint Thomas West Hospital Nashville Tennessee United States 37205
    6 Vanderbilt University Medical Center Nashville Tennessee United States 37232

    Sponsors and Collaborators

    • Vanderbilt University Medical Center
    • AstraZeneca

    Investigators

    • Principal Investigator: JoAnn Lindenfeld, MD, Vanderbilt University Medical Center

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Zachary L. Cox, Co-Principal Investigator, Vanderbilt University Medical Center
    ClinicalTrials.gov Identifier:
    NCT04298229
    Other Study ID Numbers:
    • 200017
    First Posted:
    Mar 6, 2020
    Last Update Posted:
    Feb 17, 2022
    Last Verified:
    Feb 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    Yes
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Feb 17, 2022