A Randomized, Double-blind Controlled Study Comparing LCZ696 to Medical Therapy for Comorbidities in HFpEF Patients

This study was a 24-week, randomized, double-blind, multi-center, parallel group, active controlled study to evaluate sacubitril/valsartan compared to individualized medical therapy on NT proBNP, exercise capacity, symptoms and QoL in patients with heart failure and preserved left ventricular ejection (HFpEF) fraction (LVEF > 40%). Patients were initially stratified into one of three strata according to prior treatment for comorbidities: Angiotensin converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB) or no prior renin angiotensin system inhibitors (RASi). Patients in each stratum were randomized in a 1:1 ratio and received either sacubitril/valsartan or comparator (i.e.

enalapril for patients in ACEi strata, valsartan for patients in the ARB strata and placebo for patients in the No RASi strata). There was no designated proportion of patients planned in each stratum; the strata were populated based upon the patient's prior treatment regimen. The study consisted of a screening epoch of up to 2 weeks and a randomized treatment epoch of 24 weeks, which included a 1 to 4 week study drug up-titration epoch followed by a 20 to 23 week maintenance epoch. Uptitration to target doses was recommended to occur within the first four weeks of the study, and was performed by Investigator's discretion based on the patient's clinical status.

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.