Efficacy and Safety of LCZ696 Compared to Valsartan on Cognitive Function in Patients With Chronic Heart Failure and Preserved Ejection Fraction

This study was a multi-center, randomized, double-blind, parallel group, active comparator trial designed to evaluate the overall effect of LCZ696 compared to valsartan on cognitive function as assessed by the CogState comprehensive cognitive battery in patients with Heart failure and preserved ejection fraction (HFpEF).

The Screening epoch of approximately 3 weeks was used to assess eligibility. Eligible patients then entered the single-blind treatment run-in epoch (Active Run-In Epoch), which was designed to assess patient's tolerability to study drug and to determine patients who were likely to stay on study drug for the duration of the trial. The treatment run-in consisted of valsartan 40 mg bid (if necessary), followed by valsartan 80 mg bid, and then followed by LCZ696 100 mg bid, over 3 to 8 weeks duration. Patients unable to tolerate either valsartan or LCZ696 at the prescribed doses during the treatment run-in were not eligible for randomization and were discontinued from the study.

At randomization (Visit 199/201), eligible patients were randomized 1:1 to receive either LCZ696 200 mg bid or valsartan 160 mg bid (double-blind period).

Patients who terminated the study early were expected, and were encouraged, to attend all the protocol specified study visits, to perform all measurements as stipulated in the visit schedule and to remain in follow up for the duration of the trial.

Eligibility Criteria:
Key Inclusion Criteria:

* Chronic heart failure with current symptoms NYHA class II-IV
* Left ventricular ejection fraction \> 40%
* NT-proBNP \>= 125 pg/mL at screening visit
* Patient with evidence of adequate functioning to complete study assessments

Key Exclusion Criteria:

* Patients with acute decompensated heart failure requiring augmented therapy with diuretics, vasodilators and/or inotropic drugs
* Acute coronary syndrome (including myocardial infarction (MI)), cardiac surgery, other major CV surgery, or urgent percutaneous coronary intervention (PCI), carotid surgery or carotid angioplasty, history of stroke or transient ischemic attack within the 3 months prior to Screening visit or an elective PCI within 30 days prior to Screening visit
* Patients with history of hereditary or idiopathic angioedema or angioedema related to previous ACEi or ARB therapies
* Patients who require treatment with 2 or more of the following: an ACEi, an ARB or a renin inhibitor
* Patients with one of the following:

  1. Patients with serum potassium \>5.2 mmol/L (mEq/L) at Screening visit
  2. Patients with serum potassium \>5.4 mmol/L (mEq/L) at any visit during run-in treatment period or at randomization visit
  3. Systolic blood pressure (SBP) ≥180 mmHg at Screening visit, or
  4. SBP \<110 mmHg at Screening visit, or
  5. SBP \<100 mmHg or symptomatic hypotension as determined by the investigator at Visit 103 or at randomization visit
  6. Body mass index (BMI) \>45 kg/m\^2
* Patients with

  1. known pericardial constriction, genetic hypertrophic cardiomyopathy, infiltrative cardiomyopathy
  2. hemodynamically significant obstructive valvular disease
* Life-threatening or uncontrolled dysrhythmia, including symptomatic or sustained ventricular tachycardia and atrial fibrillation or flutter with a resting ventricular rate \>110 beats per minute
* Inability to perform cognitive battery or other study evaluations based on significant motor (e.g. hemiplegia, muscular-skeletal injury) or sensory (blindness, decreased or uncorrected visual or auditory acuity) skill
* Clinically significant cerebral pathology for example large cerebral aneurysm or space occupying lesion that may impact cognition as assessed by central MRI reader
* Mini mental state examination score less than 24 at screening
* Patients with a clinical diagnosis of Alzheimer's disease or other dementia syndromes or any indication for or current treatment with cholinesterase inhibitors and/or another prescription AD treatment (e.g. memantine).