A Randomized, Double-blind Controlled Study Comparing LCZ696 to Medical Therapy for Comorbidities in HFpEF Patients
Condition: Heart Failure With Preserved Ejection Fraction
MeSH terms: Heart Failure
Intervention: sacubitril/valsartan; Enalapril; Valsartan; Placebo to match sacubitril/valsartan; Placebo to match enalapril; Placebo to match valsartan
Intervention description: Sacubitril/valsartan is available as 24 mg/26 mg, 49 mg/51 mg, 97 mg/103 mg, respectively in tablet form to be taken orally; Enalapril is available as 2.5 mg, 5 mg, and 10 mg tablet form to be taken orally; Valsartan is available as 40 mg, 80 mg, 160 mg tablet form to be taken orally; Placebo to match LCZ696 50 mg, 100 mg, 200 mg tablet form to be taken orally; Placebo to match enalapril 2.5 mg, 5 mg, 10 mg tablet form to be taken orally; Placebo to match valsartan 40 mg, 80 mg, 160 mg tablet form to be taken orally
Intervention MeSH terms: Valsartan; Enalapril; Enalaprilat; Sacubitril and valsartan sodium hydrate drug combination
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 2572.0
Sex: All
Minimum age: 45 Years
Healthy volunteers: No
Keywords: Cardiovascular Diseases; Heart Failure; Heart failure with Preserved Ejection Fraction; NT-proBNP; 6 MWT; KCCQ; SF-36; NYHA Class; LCZ696; Enalapril; Valsartan; Angiotensin-Converting Enzyme Inhibitors (ACEi); Angiotensin II Type 1 Receptor Blockers (ARB); Renin Angiotensin System Inhibitors (RASi)

Summary:

      The purpose of this study is to demonstrate the superiority of LCZ696 over individualized
      medical therapy for comorbidities in reducing N-terminal pro-brain natriuretic peptide
      (NT-proBNP) and improving exercise capacity and HF symptoms in patients with heart failure
      with preserved ejection fraction (HFpEF).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Left ventricular ejection fraction (LVEF) >40% by echo within 6 months prior to study
             entry or during the screening epoch

          -  Symptom(s) of heart failure (HF) requiring treatment with diuretics (including loop,
             or thiazide diuretics, or mineralocorticoid antagonist [MRAs]) for at least 30 days
             prior to study entry

          -  NYHA class II-IV

          -  Structural heart disease (left atrial enlargement or left ventricular hypertrophy)
             documented by echocardiogram.

          -  NT-proBNP > 220 pg/mL for patients with no atrial fibrillation/atrial flutter (AF) or
             >600 pg/mL for patients with AF

          -  KCCQ clinical summary score < 75

          -  Patients on ACEi or ARB therapy must have a history of HTN

        Exclusion Criteria:

          -  Any prior measurement of LVEF ≤ 40%, under stable conditions

          -  Acute coronary syndrome (including MI), cardiac surgery, other major CV surgery within
             3 months , or urgent percutaneous coronary intervention (PCI) within 3 months or an
             elective PCI within 30 days prior to study entry

          -  Any clinical event within the 6 months prior to Visit 1 that could have reduced the
             LVEF (eg MI, coronary artery bypass graft [CABG]), unless an echo measurement was
             performed after the event confirming the LVEF to be >40%

          -  Current (within 30 days from Visit 1) acute decompensated HF requiring therapy.

          -  Current (within 30 days from Visit 1) use of renin inhibitor(s), dual RAS blockade or
             LCZ696

          -  History of hypersensitivity to LCZ696 or its components

          -  Patients with a known history of angioedema

          -  Walk distance primarily limited by non-cardiac comorbid conditions at study entry

          -  Alternative reason for shortness of breath such as: significant pulmonary disease or
             severe COPD, hemoglobin (Hgb) <10 g/dL males and < 9.5 g/dL females, or body mass
             index (BMI) > 40 kg/m^2.

          -  Systolic blood pressure (SBP) ≥ 180 mmHg at study entry, or SBP >150 mmHg and <180
             mmHg at study entry unless the patient is receiving 3 or more antihypertensive drugs,
             or SBP < 110 mmHg at study entry.

          -  Patients with HbA1c > 7.5% not treated for diabetes

          -  Patients with prior major organ transplant or intent to transplant (ie on transplant
             list)

          -  eGFR < 30 ml/min/1.73 m^2 as measured by MDRD at screening

          -  Serum potassium > 5.2 mmol /L (or equivalent plasma potassium value) at study entry

          -  History or presence of any other disease with a life expectancy of < 3 years

          -  Pregnant or nursing women or women of child-bearing potential unless they are using
             highly effective methods of contraception

        Other protocol-defined inclusion/exclusion criteria may apply.