Heart failure (HF) is a chronic disease with weakened heart muscles or abnormal pressure within the heart chambers result in breathlessness, leg edema, or fatigue. A subclass of HF shows reduced heart muscle contractility, which is represented by the left ventricular ejection fraction (LVEF). Valsartan is an angiotensin II receptor blocker, a major drug class for heart failure. Sacubitril/valsartan is a combination of 2 drugs, classified as a new class of drug called angiotensin receptor neprilysin inhibitor (ARNI). Although these medications are both first-line treatment in HF with reduced LVEF, recent guidelines encourage the use of sacubitril/valsartan in patients with ongoing symptoms. After successful treatment, some patients experience recovery of LVEF. In these patients, otherwise called heart failure with improved ejection fraction (HFiEF), it is not clear whether continued treatment with sacubitril/valsartan or valsartan is beneficial in terms of relapse of heart failure or worsening of LVEF. Therefore, the investigators aim to determine whether the treatment with sacubitril/valsartan versus valsartan differs in clinical outcomes after 1 year in HFiEF patients by observing the change in blood test markers of heart failure (N-terminal prohormone of brain natriuretic peptide; NT-proBNP) and aggravation of HF defined as reduced LVEF, congestive symptoms, hospitalization or death from HF.

1. Background and study purpose Heart failure (HF) is caused by structural or functional abnormality of the myocardium or elevated intracardiac pressures, resulting in symptoms and signs of low cardiac output or congestion, such as dyspnea, peripheral edema, elevated jugular venous pressures, pulmonary congestion, and fatigue. HF with reduced left ventricular ejection fraction (HFrEF) is defined as an LVEF <40% by the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines. Recent guidelines recommend the use of angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blocker (ARB)/angiotensin receptor neprilysin inhibitor (ARNI), beta blockers (BB), aldosterone antagonists (AA), and sodium-glucose co-transporter-2 inhibitors (SGLT2i) in HFrEF patients. ACEI/ARB/ARNI, collectively known as renin-angiotensin-system (RAS) blockers, are considered the most important drug class in the treatment for HFrEF and recently, ARNI is increasingly preferred as the first-choice drug. Unlike for initial treatment of HFrEF, continued treatment for patients who experience recovery of LVEF is not as well established. In these patients, called heart failure with improved ejection fraction (HFiEF), it is not clear whether continued treatment with sacubitril/valsartan or valsartan is beneficial in terms of relapse of heart failure or worsening of LVEF. Therefore, the investigators aim to determine whether the treatment with sacubitril/valsartan versus valsartan differs in clinical outcomes after 1 year in HFiEF patients by observing the change in serum N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and clinical relapse of HF.

2. Registry factors

1. Source data verification will be done by comparing the data to electronic medical records and paper and electronic case report forms.
2. Data dictionary with detailed description of each variables are given.
3. Sample size assessment was calculated by comparing mean NT-proBNP levels at baseline and after 12 months in the two groups by two-sample t-test (two-sided, effect size=0.6, type I error=0.05, type II error=0.8, allocation ratio=1). With a drop-out rate of 10%, 50 patients in each group are needed. As the change of NT-proBNP in HFiEF with sacubitril/valsartan or valsartan has rarely been reported, estimation from the TRED-HF study (Lancet. 2019 Jan 5; 393(10166):61) was used as reference for effect size. This reference was a small study of 25 patients in each group. Therefore, the effect size used for calculation was modified to 0.6 rather than 0.8 by intuition of the investigators.
4. Plan for missing data: To avoid unavailable data, clinical visits will be monitored and calls will be made for missed appointments. Uninterpretable or out-of-range results will be discussed by participating investigators through regular meetings.
5. Statistical analysis Based on intention-to-treat analysis, the primary outcome (NT-proBNP changes) will be log-transformed and compared by paired t-tests. Baseline characteristics will be presented according to initial drug assignment and compared with the Mann-Whitney test for continuous variables or Fisher's exact test for categorical variables. Data are presented as median and IQR or as n (%). Occurrence of the secondary endpoint will be graphically displayed per group with Kaplan-Meier survival plots and compared with the log-rank test. Cox proportional hazards models will be used to investigate predictors of worsening NT-proBNP levels or occurrence of clinical adverse events in patients of each group. A p value less than 0.05 will be considered significant.

Inclusion Criteria: (AND)

• Patient with a history of HF with reduced EF (HFrEF; LVEF <40 percent) and received treatment with sacubitril/valsartan for at least 3 months, after which showing improvement of LVEF to >40 percent and symptoms of NYHA functional class I or II
• serum NT-proBNP levels < 400 pg/dL for sinus rhythm and < 600pg/dL for atrial fibrillation
• Patients on stable doses of diuretics for 1 week

Exclusion Criteria: (OR)

• History of hospitalization for heart failure within 30 days before enrollment
• History of acute coronary syndrome (acute myocardial infarction or unstable angina), percutaneous coronary artery intervention or cardiac surgery within 30 days before enrollment
• History of cardiac resynchronization therapy within 90 days before screening
• Planned percutaneous or surgical coronary artery revascularization, or major cardiac surgery (coronary artery bypass, valvuloplasty, mechanical cardiac support or heart transplantation) within 90 days after enrollment
• Contraindicated or has history of hypersensitivity to RAS blockers including ACEI or ARB
• Use of inotropes
• Survival estimate < 3months
• Otherwise deemed as inappropriate by the attending physician

1. Consecutive participant sampling was done for all eligible patients.
2. Patients visiting a specialized heart failure clinic at one of the top tertiary level hospitals in Seoul, Korea. Patients have a nationwide distribution geographically, and show a wide range of clinical presentations.

The access criteria has not been discussed yet.