Dapagliflozin in PRESERVED Ejection Fraction Heart Failure (PRESERVED-HF)

Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With PRESERVED Ejection Fraction Heart Failure

The primary purpose of this study is to evaluate the impact of dapagliflozin, as compared with placebo, on heart failure, disease specific biomarkers, symptoms, health status and quality of life in patients with chronic heart failure with preserved systolic function.

Study Overview

• Status: Completed
• Conditions: Chronic Heart Failure With Preserved Systolic Function
• Intervention / Treatment: Drug: Dapagliflozin 10Mg Oral Tablet; Drug: Dapagliflozin matching placebo

Detailed Description

A 12-week randomized, double-blind, placebo-controlled trial to evaluate the effects of once-daily dapagliflozin 10 mg on heart failure disease-specific biomarkers (NTproBNP and BNP), symptoms, health status, and quality of life in patients with chronic heart failure with preserved systolic function. An imaging substudy will also be conducted to explore the effects of dapagliflozin vs. placebo on various echocardiographic parameters.

• Study Type: Interventional
• Enrollment (Actual): 324
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Fairhope, Alabama, United States, 36532
      • Heart Group of the Eastern Shore
  • California
    • Los Angeles, California, United States, 90032
      • University of Southern California
  • Florida
    • Jacksonville, Florida, United States, 32256
      • First Coast Cardiovascular Institute
    • Port Charlotte, Florida, United States, 33952
      • Charlotte Heart Group Research Center
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Emory University
  • Illinois
    • Evanston, Illinois, United States, 60208
      • Northwestern University
    • Evanston, Illinois, United States, 60201
      • NorthShore University HealthSystem Research Insititute
    • Hazel Crest, Illinois, United States, 60429
      • Chicago Medical Research
    • Peoria, Illinois, United States, 61606
      • OSF HealthCare Cardiovascular Institute
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • St. Vincent Cardiovascular Research Institute
  • Kansas
    • Topeka, Kansas, United States, 66606
      • Cotton O'Neil Clinical Research Center
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Mid America Heart Institute
    • Saint Louis, Missouri, United States, 63110
      • Washington University
  • New York
    • New York, New York, United States, 10032
      • Columbia University
    • New York, New York, United States, 11576
      • St. Francis Hospital
  • North Carolina
    • New Bern, North Carolina, United States, 28562
      • Eastern Nephrology Associates
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny Health Network Research Institute
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75204
      • Baylor Scott and White Research Institute
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah
  • Virginia
    • Norfolk, Virginia, United States, 23501
      • Eastern Virginia Medical School

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years to 117 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Symptoms of dyspnea (NYHA class II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea
2. Ejection fraction (EF) ≥ 45% as determined on imaging study within 24 months of enrolment with no change in clinical status suggesting potential for deterioration in systolic function
3. Elevated NT-proBNP (≥ 225 pg/ml) or BNP (≥ 75 pg/ml). For patients with permanent atrial fibrillation inclusion thresholds will be BNP ≥ 100 pg/mL or NTproBNP ≥ 375 pg/mL
4. Stable medical therapy for heart failure for 15 days as defined by: i. No addition or removal of ACE, angiotensin receptor blockers (ARBs), valsartan/sacubitril, beta-blockers, calcium channel blockers (CCBs) or aldosterone antagonists; ii.No substantial change in dosage (100% or greater increase or decrease from baseline dose) of ACE, ARBs, beta-blockers, CCBs or aldosterone antagonists
5. On a diuretic ≥15 days prior to screening visit and a stable diuretic therapy for 7 days
6. At least one of the following: i. Hospitalization for decompensated HF in the last 12 months; ii. Acute treatment for HF with intravenous loop diuretic or hemofiltration in the last 12 months; iii. Mean pulmonary capillary wedge pressure ≥15 mmHg or LV end diastolic pressure (LVEDP) ≥15 mmHg documented during catheterization at rest, or pulmonary capillary wedge pressure or LVEDP ≥25 mmHg documented during catheterization with exercise; iv. Structural heart disease evidenced by at least one of the following echo findings (any local measurement made within the 24 months prior to screening visit): a) left atrial (LA) enlargement defined by at least one of the following: LA width ≥3.8cm or LA length ≥5.0 cm or LA area ≥20 cm2 or LA volume ≥55 mL or LA volume index ≥29 mL/m2 b) or left ventricular hypertrophy (LVH) defined by septal thickness or posterior wall thickness ≥1.1 cm.

Exclusion Criteria:

1. Decompensated heart failure (hospitalization for heart failure within 7 days prior to screening)
2. History of type 1 diabetes
3. History of diabetic ketoacidosis
4. Estimated glomerular filtration rate (eGFR) < 20 at the screening visit by modified MDRD equation GFR (mL/min/1.73 m2 ) = 175 x (Scr) -1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if African American)
5. Admission for an acute coronary syndrome (ST-elevation MI, non-ST-elevation MI, or unstable angina), percutaneous coronary intervention, or cardiac surgery within 30 days prior to the screening visit.
6. Admission for cardiac resynchronization therapy (CRT) within 90 days prior to the screening visit.
7. Planned cardiovascular revascularization (percutaneous intervention or surgical) or major cardiac surgery (coronary artery bypass grafting, valve replacement, ventricular assist device, cardiac transplantation, or any other surgery requiring thoracotomy, or transcatheter aortic valve replacement) or CRT within the 90 days after the screening visit.
8. Participation in any interventional clinical trial (with an investigational drug or device) that is not an observational registry within 15 days of the screening visit.
9. History of hypersensitivity to dapagliflozin
10. For women of child-bearing potential: Current or planned pregnancy or currently lactating.
11. Life expectancy <1 year at the screening visit
12. Patients who are volume depleted based upon physical examination at the time of the screening or randomization visit
13. BNP <75 pg/mL and NTproBNP<225 pg/mL at the screening visit. For patients with permanent atrial fibrillation exclusion thresholds will be BNP<100 pg/mL and NTproBNP<375pg/mL.
14. Patients currently being treated with any SGLT-2 inhibitor (dapagliflozin, canagliflozin, empagliflozin, ertugliflozin) or having received treatment with any SGLT-2 inhibitor within the 12 weeks prior to the screening visit.
15. Average supine systolic BP <100 mmHg at the screening or randomization visit
16. Current history of bladder cancer
17. Donation of blood or bone marrow 12 weeks prior to the screening visit and no planned donations during the study period
18. Heart failure due to restrictive/infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, severe stenotic valve disease, and HOCM (hypertrophic obstructive cardiomyopathy).
19. Heart failure due to severe aortic or mitral regurgitation
20. Severe COPD thought to be a primary contributor to dyspnea
21. Isolated right heart failure due to pulmonary disease
22. Active and significant ischemia thought to be a primary contributor to dyspnea
23. Documentation of previous EF < 45%, under stable conditions, within the past 36 months
24. Complex congenital heart disease
25. Uncontrolled hypertension, defined as systolic blood pressure ≥200 mmHg during the screening visit (average value of three blood pressure measurements obtained in supine position)
26. Any other condition that in the judgment of the investigator would jeopardize the patient's participation in the study or that may interfere with the interpretation of study data or if the patient is considered unlikely to comply with study procedures, restrictions and requirements
27. Bariatric surgery within the past 6 months or planned bariatric surgery within the study time course.
28. CardioMems device implantation within previous 4 weeks or planned CardioMems implantation during study period
29. For echo substudy only: patients with ventricular paced rhythm or left bundle branch block on the most recent clinically available 12-lead electrocardiogram.
30. For echo substudy only: permanent atrial fibrillation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Dapagliflozin; Dapagliflozin 10 mg oral tablet, once daily, for 12 weeks	Drug: Dapagliflozin 10Mg Oral Tablet; Dapagliflozin 10Mg Oral Tablet; Other Names: Farxiga
Placebo Comparator: Placebo; Dapagliflozin matching placebo oral tablet, once daily, for 12 weeks	Drug: Dapagliflozin matching placebo; Dapagliflozin matching placebo; Other Names: Placebo Oral Tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of Dapagliflozin, as Compared With Placebo, on Heart Failure Related Health Status Using the Kansas City Cardiomyopathy Questionnaire Clinical Summary Summary Score (KCCQ-CS)	Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CS) at Week 12. The KCCQ is a disease-specific health status instrument composed of 23 items that quantifies the domains of physical limitations, symptoms, self-efficacy, social limitation and quality of life from heart failure. Scores range from 0-100, in which higher scores reflect better health status. For the KCCQ-CS, a small but clinically meaningful change is considered to be ≥ 5 points. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.	Baseline to Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of Dapagliflozin, as Compared With Placebo, on Heart Failure Related Health Status Using the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OS)	Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OS) at Week 12. The KCCQ is a disease-specific health status instrument composed of 23 items that quantifies the domains of physical limitations, symptoms, self-efficacy, social limitation and quality of life from heart failure. Scores range from 0-100, in which higher scores reflect better health status. For the KCCQ-OS, a small but clinically meaningful change is considered to be ≥ 5 points. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.	Baseline to Week 12
Effect of Dapagliflozin, as Compared With Placebo, on N-terminal Pro B-type Natriuretic Peptide (NTproBNP)	NTproBNP at Week 12. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.	Baseline to Week 12
Effect of Dapagliflozin, as Compared With Placebo, on Brain Natriuretic Peptide (BNP)	BNP at Week 12. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.	Baseline to Week 12
Effect of Dapagliflozin, as Compared With Placebo, on 6 Minute Walk Test Distance	6 minute walk test distance at 12 weeks. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.	Baseline to Week 12
Effect of Dapagliflozin, as Compared With Placebo, on Hemoglobin A1c	Hemoglobin A1c at Week 12. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.	Baseline to Week 12
Effect of Dapagliflozin, as Compared With Placebo, on the Proportion of Patients With a ≥ 5 Point Increase in KCCQ Clinical Summary Score (KCCQ-CS) and KCCQ Overall Summary Score (KCCQ-OS)	Proportion of patients with a ≥ 5 point increase in KCCQ-CS and KCCQ-OS at Week 12. The KCCQ is a disease-specific health status instrument composed of 23 items that quantifies the domains of physical limitations, symptoms, self-efficacy, social limitation and quality of life from heart failure. Scores range from 0-100, in which higher scores reflect better health status. For KCCQ-CS and KCCQ-OS, a small but clinically meaningful change is considered to be ≥ 5 points. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.	Baseline to Week 12
Effect of Dapagliflozin, as Compared With Placebo, on the Proportion of Patients With a ≥ 20% Decrease in N-terminal Pro B-type Natriuretic Peptide (NTproBNP)	Proportion of patients with a ≥ 20% decrease in NTproBNP at Week 12. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.	Baseline to Week 12
Effect of Dapagliflozin, as Compared With Placebo, on Proportion of Patients With ≥ 5 Point Increase in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CS) and ≥ 20% Decrease in N-terminal Pro B-type Natriuretic Peptide(NTproBNP)	Proportion of patients with a ≥ 5 point increase in KCCQ-CS and a ≥ 20% decrease in NTproBNP at Week 12. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.	Baseline to Week 12
Effect of Dapagliflozin, as Compared With Placebo, on Weight	Weight at Week 12. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.	Baseline to Week 12
Effect of Dapagliflozin, as Compared With Placebo, on Systolic Blood Pressure	Systolic blood pressure at Week 12. Values have been adjusted for the corresponding baseline value, history of type 2 diabetes, sex, atrial fibrillation, baseline estimated glomerular filtration rate and left ventricular ejection fraction.	Baseline to Week 12

Collaborators and Investigators

• Sponsor: Saint Luke's Health System
• Investigators: Study Chair: Mikhail Kosiborod, MD, Saint Luke's Mid America Heart Institute

Publications and helpful links

General Publications

• Nassif ME, Kosiborod M. Effects of sodium glucose cotransporter type 2 inhibitors on heart failure. Diabetes Obes Metab. 2019 Apr;21 Suppl 2:19-23. doi: 10.1111/dom.13678.
• Nassif ME, Windsor SL, Borlaug BA, Kitzman DW, Shah SJ, Tang F, Khariton Y, Malik AO, Khumri T, Umpierrez G, Lamba S, Sharma K, Khan SS, Chandra L, Gordon RA, Ryan JJ, Chaudhry SP, Joseph SM, Chow CH, Kanwar MK, Pursley M, Siraj ES, Lewis GD, Clemson BS, Fong M, Kosiborod MN. The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial. Nat Med. 2021 Nov;27(11):1954-1960. doi: 10.1038/s41591-021-01536-x. Epub 2021 Oct 28.

Helpful Links

• Dapagliflozin information

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2017
• Primary Completion (Actual): August 13, 2021
• Study Completion (Actual): August 13, 2021

Study Registration Dates

• First Submitted: January 20, 2017
• First Submitted That Met QC Criteria: January 20, 2017
• First Posted (Estimate): January 24, 2017

Study Record Updates

• Last Update Posted (Actual): October 19, 2022
• Last Update Submitted That Met QC Criteria: September 26, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: heart failure; dapagliflozin; SGLT-2 inhibitors
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: D1690C00053

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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.: No