Sacubitril/Valsartan Versus Valsartan in Heart Failure With Improved Ejection Fraction (PROSPER-HF)

Prospective Comparison of Sacubitril/Valsartan Versus Valsartan on the Outcome of Heart Failure With Improved Ejection Fraction: a Pilot Study

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.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure, Systolic
• Intervention / Treatment: Drug: Sacubitril-Valsartan; Drug: Valsartan

Detailed Description

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.

• Study Type: Observational
• Enrollment (Anticipated): 100

Contacts and Locations

• Study Contact: Name: Jinoh Choi, MD, PhD; Phone Number: 82234103417; Email: choijean5@gmail.com
• Study Contact Backup: Name: Yoonjee Park, MD; Phone Number: 821026729748; Email: yoonjeedrpark@gmail.com

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 06351
    • Recruiting
    • Samsung Medical Center
    • Contact: Jinoh Choi, MD, PhD; Phone Number: 82234103417; Email: choijean5@gmail.com
    • Contact: Yoonjee Park, MD; Phone Number: 821026729748; Email: yoonjeedrpark@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

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.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Sacubitril/valsartan; Patients undergoing continued treatment with sacubitril/valsartan after improvement of LVEF >40% with > 3 months of sacubitril/valsartan treatment. Dose and titration schedule will be individualized by discretion of the attending physician.	Drug: Sacubitril-Valsartan; Participants will receive individualized dosage and titration as part of routine medical care, and a the effect will be studied for at least 12 months. The investigator does not assign specific interventions to the study participants.; Other Names: Entresto
Valsartan; Patients undergoing continued treatment with valsartan after improvement of LVEF >40% with > 3 months of sacubitril/valsartan treatment. Dose and titration schedule will be individualized by discretion of the attending physician.	Drug: Valsartan; Participants will receive individualized dosage and titration as part of routine medical care, and a the effect will be studied for at least 12 months. The investigator does not assign specific interventions to the study participants.; Other Names: Diovan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in NT-proBNP concentration	pg/ml	Baseline, 6 months, 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heart failure relapse	One or more of the following: LVEF <40 percent by cardiac imaging including but not refined to: echocardiography, cardiac magnetic resonance imaging; symptomatic congestive heart failure: symptoms and signs of heart failure such as dyspnea, edema, abdominal fullness, and fatigue	6 months and 12 months
Hospitalization for heart failure (HHF)	Hospitalization for acute decompensated heart failure	6 months and 12 months
Death caused by heart failure	Heart failure being either the immediate or contributing cause of death.	6 months and 12 months
Mortality	All-cause mortality	6 months and 12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
left ventricular (LV) ejection fraction (LVEF, percent)	measurement based on echocardiography with the following priority; Modified Simpson's method; Visual estimation by a qualified echocardiography specialist; M-mode	6 months (optional, personalized) and 12 months
LV end-systolic dimension (LVESD, mm)	measurement based on echocardiography with the following priority; M-mode from parasternal long-axis view; 2-d caliper from parasternal long-axis view; M-mode from parasternal short-axis view; 2-d caliper from parasternal short-axis view; 2-d caliper from any other view	6 months (optional, personalized) and 12 months
LV end-diastolic dimension (LVEDD, mm)	measurement based on echocardiography with the following priority; M-mode from parasternal long-axis view; 2-d caliper from parasternal long-axis view; M-mode from parasternal short-axis view; 2-d caliper from parasternal short-axis view; 2-d caliper from any other view	6 months (optional, personalized) and 12 months
LV mass index (LVMI; g/m^2)	Calculated by the following measurements based on echocardiography. Equation: LVMI = LV mass / BSA; {(0.8 * [1.04 * ((LVEDD + IVSd + PWd)^3 - LVEDD^3)]) + 0.6} / BSA IVSd: Interventricular septum dimension (mm)* PWd: LV Posterior wall dimension (mm)* BSA: body surface area (kg/m^2) calculated from weight (kg) and height (m) at the timing of echocardiography (BSA = weight/ (height)^2 * LVEDD, IVSd, PWd are measured with the following priority; M-mode from parasternal long-axis view; 2-d caliper from parasternal long-axis view; M-mode from parasternal short-axis view; 2-d caliper from parasternal short-axis view; 2-d caliper from any other view	6 months (optional, personalized) and 12 months
Left atrial volume index (LAVI, ml/m^2)	LAVI = LA volume (ml) /BSA (m^2); LA volume is measured by the biplane area-length method in the apical 4-chamber and apical 2-chamber view as described in:(Eur J Echocardiogr. 2008 May;9(3):351-5. doi: 10.1016/j.euje.2007.05.004. Epub 2007 Jul 23.) LA volume = (0.85 × A1 × A2)/(L1 -L2 /2).; BSA: body surface area (kg/m^2) calculated from weight (kg) and height (m) at the timing of echocardiography (BSA = weight/ (height)^2	6 months (optional, personalized) and 12 months
E/E' ratio	measurements based on echocardiography E: by pulsed wave Doppler of mitral inflow velocity E': by tissue Doppler of early diastolic mitral annulus velocity	6 months (optional, personalized) and 12 months
Right ventricular systolic pressure (RVSP, mmHg)	Right ventricular systolic pressure (RVSP) estimated by Tricuspid valve Regurgitation jet maximum velocity (TR Vmax) base on continuous wave Doppler echocardiographic measurements. Modified Bernoulli equation: RVSP = 4V^2 + RA pressure(*) * RA pressure (mmHg) is estimated by the following: RAP=5 when inferior vena cava (IVC) diameter =< 2.1cm and abscent plethora; RAP=10 when IVC =< 2.1cm and present plethora; RAP=10 when IVC > 2.1cm and abscent plethora; RAP=15 when IVC > 2.1cm and present plethora.	6 months (optional, personalized) and 12 months
LV 4-dimensional strain (percent)	Using a Vivid E9, E90, E95 ultrasound system (GE Healthcare, Chicago, IL, USA) with a 2.5-3.6 MHz 4-dimensional Volume transducer, a 4D full-volume scan is obtained from the apical position during an end-expiratory apnea. From a twelve-slice display mode, the examiner ensures that the whole LV structure be included in the 4D full-volume image. The frame rate was required to be over 40 percent of the heart rate (HR). The global strain values, including LV GLS, GRS, GCS, and GAS, were automatically calculated by the software. Specific techniques are described in (Eur J Echocardiogr. 2011 Jan;12(1):26-32. doi: 10.1093/ejechocard/jeq095. Epub 2010 Aug 24.) * GLS = global longitudinal strain; GRS = global radial strain; GCS = global circumferential strain; GAS = global area strain;	6 months (optional, personalized) and 12 months
Change in hemoglobin (g/dL)	Changes in laboratory values between time periods	Baseline, 6 months and 12 months
Change in albumin (g/dL)	Changes in laboratory values between time periods	Baseline, 6 months and 12 months
Change in total bilirubin (mg/dL)	Changes in laboratory values between time periods	Baseline, 6 months and 12 months
Change in fasting blood glucose (mg/dL)	Changes in laboratory values between time periods	Baseline, 6 months and 12 months
Change in blood urea nitrogen (mg/dL)	Changes in laboratory values between time periods	Baseline, 6 months and 12 months
Change in creatinine (mg/dL)	Changes in laboratory values between time periods	Baseline, 6 months and 12 months
Change in estimated GFR (ml/min/1.73m^2)	Changes in laboratory values between time periods Calculated by CKD-EPI equation CKD-EPI eGFR(mL/min/1.73m^2) = A × (Scr/B)^C × 0.993^(age) , where A, B, and C are the following: Female Scr ≤0.7; A = 144, B = 0.7, C = -0.329 Scr ≤0.9; A = 141, B = 0.9, C = -0.411 Male Scr >0.7; A = 144, B = 0.7, C = -1.209 Scr >0.9; A = 141, B = 0.9, C = -1.209	Baseline, 6 months and 12 months
Change in sodium (mmol/L)	Changes in laboratory values between time periods	Baseline, 6 months and 12 months
Change in potassium (mmol/L)	Changes in laboratory values between time periods	Baseline, 6 months and 12 months
Change in hemoglobin A1c (percent)	Changes in laboratory values between time periods	Baseline, 6 months and 12 months
Reason for discontinuation of study drug	Choose one answer from the following: cardiogenic shock: persistent hypotension (SBP<90mmHg or MAP drop 30mmHg) with cardiac index < 1.8L/min/m2 without support (< 2.2 with support); noncardiogenic shock: persistent hypotension and inadequate tissue perfusion(*) excluding cardiac origin; drug intolerance - 'orthostatic hypotension' or 'others'; renal dysfunction (**); switch to other RAS blocker - specify reason in free text; decision for other advanced cardiac treatment: left ventricular assist device, heart transplantation.; others (free text) [*] Shock as defined in (N Engl J Med 2013; 369:1726-1734). [**] Renal dysfunction defined as: Acute kidney injury (AKI) by KDIGO (Kidney Int Suppl. 2012;2(Suppl 1):8.); Progression of CKD defined as: sustained reduction in eGFR by 15 mL/min/1.73 m2 (or CKD stage change), or to <10 mL/min/1.73 m2 (or initiation of dialysis).	6 months and 12 months

Collaborators and Investigators

• Sponsor: Samsung Medical Center

Publications and helpful links

General Publications

• Halliday BP, Wassall R, Lota AS, Khalique Z, Gregson J, Newsome S, Jackson R, Rahneva T, Wage R, Smith G, Venneri L, Tayal U, Auger D, Midwinter W, Whiffin N, Rajani R, Dungu JN, Pantazis A, Cook SA, Ware JS, Baksi AJ, Pennell DJ, Rosen SD, Cowie MR, Cleland JGF, Prasad SK. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial. Lancet. 2019 Jan 5;393(10166):61-73. doi: 10.1016/S0140-6736(18)32484-X. Epub 2018 Nov 11.
• Januzzi JL Jr, Prescott MF, Butler J, Felker GM, Maisel AS, McCague K, Camacho A, Pina IL, Rocha RA, Shah AM, Williamson KM, Solomon SD; PROVE-HF Investigators. Association of Change in N-Terminal Pro-B-Type Natriuretic Peptide Following Initiation of Sacubitril-Valsartan Treatment With Cardiac Structure and Function in Patients With Heart Failure With Reduced Ejection Fraction. JAMA. 2019 Sep 17;322(11):1085-1095. doi: 10.1001/jama.2019.12821.
• Wilcox JE, Fang JC, Margulies KB, Mann DL. Heart Failure With Recovered Left Ventricular Ejection Fraction: JACC Scientific Expert Panel. J Am Coll Cardiol. 2020 Aug 11;76(6):719-734. doi: 10.1016/j.jacc.2020.05.075.

Study record dates

Study Major Dates

• Study Start (Actual): March 16, 2021
• Primary Completion (Anticipated): February 1, 2024
• Study Completion (Anticipated): February 1, 2025

Study Registration Dates

• First Submitted: February 25, 2021
• First Submitted That Met QC Criteria: March 16, 2021
• First Posted (Actual): March 17, 2021

Study Record Updates

• Last Update Posted (Actual): August 18, 2021
• Last Update Submitted That Met QC Criteria: August 17, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Valsartan; Sacubitril/valsartan; Heart Failure with reduced Ejection Fraction; Heart Failure with improved Ejection Fraction
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Heart Failure, Systolic; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Valsartan; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: 2020-08-082

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: The access criteria has not been discussed yet.

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No