Dapagliflozin in PRESERVED Ejection Fraction Heart Failure
Condition: Chronic Heart Failure With Preserved Systolic Function
MeSH terms: Heart Failure
Intervention: Dapagliflozin 10Mg Oral Tablet; Dapagliflozin matching placebo
Intervention description: Dapagliflozin 10Mg Oral Tablet; Dapagliflozin matching placebo
Intervention MeSH terms: Dapagliflozin
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 324.0
Sex: All
Minimum age: 19 Years
Maximum age: 119 Years
Healthy volunteers: No
Keywords: heart failure; dapagliflozin; SGLT-2 inhibitors

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.
    

Eligibility criteria:

        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