Dapagliflozin in PRESERVED Ejection Fraction Heart Failure

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

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03030235

Acronym

PRESERVED-HF

Enrollment

324

Registered

2017-01-24

Start date

2017-03-01

Completion date

2021-08-13

Last updated

2022-10-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Chronic Heart Failure With Preserved Systolic Function

Keywords

heart failure, dapagliflozin, SGLT-2 inhibitors

Brief summary

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.

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.

Interventions

DRUGDapagliflozin 10Mg Oral Tablet

Dapagliflozin 10Mg Oral Tablet

DRUGDapagliflozin matching placebo

Dapagliflozin matching placebo

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

19 Years to 119 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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)	Baseline to Week 12	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.

Secondary

Measure	Time frame	Description
Effect of Dapagliflozin, as Compared With Placebo, on N-terminal Pro B-type Natriuretic Peptide (NTproBNP)	Baseline to Week 12	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.
Effect of Dapagliflozin, as Compared With Placebo, on Brain Natriuretic Peptide (BNP)	Baseline to Week 12	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.
Effect of Dapagliflozin, as Compared With Placebo, on 6 Minute Walk Test Distance	Baseline to Week 12	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.
Effect of Dapagliflozin, as Compared With Placebo, on Hemoglobin A1c	Baseline to Week 12	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.
Effect of Dapagliflozin, as Compared With Placebo, on Heart Failure Related Health Status Using the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OS)	Baseline to Week 12	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.
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)	Baseline to Week 12	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.
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)	Baseline to Week 12	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.
Effect of Dapagliflozin, as Compared With Placebo, on Weight	Baseline to Week 12	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.
Effect of Dapagliflozin, as Compared With Placebo, on Systolic Blood Pressure	Baseline to Week 12	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.
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)	Baseline to Week 12	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.

Countries

United States

Participant flow

Participants by arm

Arm	Count
Dapagliflozin Dapagliflozin 10 mg oral tablet, once daily, for 12 weeks Dapagliflozin 10Mg Oral Tablet: Dapagliflozin 10Mg Oral Tablet	162
Placebo Dapagliflozin matching placebo oral tablet, once daily, for 12 weeks Dapagliflozin matching placebo: Dapagliflozin matching placebo	162
Total	324

Baseline characteristics

Characteristic	Total	Placebo	Dapagliflozin
6 minute walk test	244 meters	244 meters	244 meters
Age, Continuous	70 years	71 years	69 years
Angiotensin converting enzyme inhibitor (ACEI) / Angiotensin II receptor blocker (ARB)	196 Participants	98 Participants	98 Participants
Angiotensin receptor-neprilysin inhibitor (ARNI)	5 Participants	3 Participants	2 Participants
Anticoagulant Agents	155 Participants	84 Participants	71 Participants
Atrial Fibrillation	171 Participants	89 Participants	82 Participants
Beta-blockers	235 Participants	116 Participants	119 Participants
Body Mass Index (BMI)	34.7 kg/m^2	34.6 kg/m^2	35.1 kg/m^2
Brain Natriuretic Peptide (BNP) - overall	142 pg/mL	151 pg/mL	137 pg/mL
Brain Natriuretic Peptide (BNP) - participants with atrial fibrillation	154 pg/mL	151 pg/mL	169 pg/mL
Brain Natriuretic Peptide (BNP) - participants with no atrial fibrillation	128 pg/mL	161 pg/mL	107 pg/mL
Duration of Heart Failure	3.0 years	3.2 years	3.0 years
Ejection Fraction	60 percent	60 percent	60 percent
Estimated glomerular filtration rate (eGFR)	55 mL/minute	54 mL/minute	56 mL/minute
Heart Rate	68 beats per minute	68 beats per minute	70 beats per minute
Hemoglobin	12.6 g/dL	12.6 g/dL	12.7 g/dL
Hemoglobin A1c	6.1 percent of glycosylated hemoglobin	6.2 percent of glycosylated hemoglobin	6.0 percent of glycosylated hemoglobin
Hydralazine	43 Participants	18 Participants	25 Participants
Internal Cardiac Defibrillator (ICD)	16 Participants	9 Participants	7 Participants
Ischemic Heart Disease	63 Participants	31 Participants	32 Participants
Kansas City Cardiomyopathy Questionnaire - Clinical Summary Score (KCCQ-CS)	62.6 units on a scale STANDARD_DEVIATION 20	61.8 units on a scale STANDARD_DEVIATION 20.3	63.4 units on a scale STANDARD_DEVIATION 19.7
Kansas City Cardiomyopathy Questionnaire - Overall Summary Score (KCCQ-OS)	62.7 units on a scale STANDARD_DEVIATION 20.4	62.3 units on a scale STANDARD_DEVIATION 20.6	63.2 units on a scale STANDARD_DEVIATION 20.4
Lipid-Lowering Agents	259 Participants	127 Participants	132 Participants
Long-Acting Nitrates	61 Participants	27 Participants	34 Participants
Loop Diuretics	286 Participants	135 Participants	151 Participants
Mineralocorticoid receptor agonist (MRA)	118 Participants	68 Participants	50 Participants
New York Heart Association (NYHA) Class II	186 Participants	90 Participants	96 Participants
New York Heart Association (NYHA) Class III/IV	137 Participants	72 Participants	65 Participants
N-terminal pro B-type natriuretic peptide (NT-proBNP) - overall	671 pg/mL	710 pg/mL	641 pg/mL
N-terminal pro B-type natriuretic peptide (NT-proBNP) - participants with atrial fibrillation	816 pg/mL	816 pg/mL	830 pg/mL
N-terminal pro B-type natriuretic peptide (NT-proBNP) - participants with no atrial fibrillation	459 pg/mL	485 pg/mL	438 pg/mL
Previous Hospitalization for Heart Failure	181 Participants	83 Participants	98 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Asian	3 Participants	0 Participants	3 Participants
Race (NIH/OMB) Black or African American	97 Participants	47 Participants	50 Participants
Race (NIH/OMB) More than one race	2 Participants	2 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants	1 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	5 Participants	4 Participants	1 Participants
Race (NIH/OMB) White	215 Participants	107 Participants	108 Participants
Region of Enrollment United States	324 participants	162 participants	162 participants
Sex: Female, Male Female	184 Participants	92 Participants	92 Participants
Sex: Female, Male Male	140 Participants	70 Participants	70 Participants
Systolic Blood Pressure	133 mm Hg	132 mm Hg	134 mm Hg
Type 2 Diabetes	181 Participants	91 Participants	90 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	1 / 162	2 / 162
other Total, other adverse events	13 / 162	16 / 162
serious Total, serious adverse events	31 / 162	22 / 162

Outcome results

Primary

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.