STEPwise De-escalation and Optimizing Withdrawal of ARNI and SGLT2i in Normalized Heart Failure

NCT07631156 | Not Yet Recruiting Phase 4 DMC

• 2 other identifiers: IRB number: 2026-04-022-003RS-2026-25475665
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 5

Brief Summary

This is a multicenter, randomized, open-label pilot study to evaluate whether stepwise withdrawal of two heart failure medications-angiotensin receptor-neprilysin inhibitor (ARNI) and sodium-glucose cotransporter-2 inhibitor (SGLT2i)-is safe in patients with Heart Failure with improved Ejection Fraction (HFimpEF) whose underlying structural cause (valvular heart disease or ischemic cardiomyopathy) has been completely corrected by surgery or intervention. Eighty adult patients (40 per arm) whose left ventricular ejection fraction (LVEF) has recovered to 50% or higher and whose NT-proBNP is below 250 ng/L will be randomized 1:1 to either (1) stepwise withdrawal of ARNI followed by SGLT2i over one month under close echocardiographic monitoring, or (2) continuation of their current guideline-directed medical therapy. The primary outcome is the change in LVEF at 12 months, with non-inferiority of the withdrawal strategy declared if the LVEF decline is within 5 percentage points of the continuation arm. Secondary outcomes include cardiovascular death, heart failure hospitalization, NT-proBNP, quality of life (KCCQ-12), 6-minute walk distance, and adverse events. Results from this pilot will inform the design and sample size of a subsequent definitive non-inferiority trial and may provide initial evidence to guide deprescribing decisions in clinical practice.

Conditions

Heart Failure; Ventricular Dysfunction, Left; Heart Failure With Reduced Ejection Fraction

Keywords

HFimpEF; ARNI; Sacubitril/Valsartan; SGLT2 Inhibitor; Guideline-Directed Medical Therapy; Reverse Remodeling; Valvular Heart Disease; Ischemic Cardiomyopathy

Outcome Measures

Primary Outcomes (1)

• Change in Left Ventricular Ejection Fraction (LVEF) at 12 Months

  Absolute change (percentage points) in LVEF from baseline to 12 months, measured by transthoracic echocardiography. Non-inferiority of stepwise withdrawal versus continuation is declared if the lower bound of the one-sided 95% confidence interval for the between-group difference exceeds -5 percentage points in the per-protocol population.

  Baseline to 12 months

Secondary Outcomes (7)

• Composite of Cardiovascular Death or Heart Failure Hospitalization

  Up to 12 months

• Change in NT-proBNP

  Baseline to 12 months

• Change in NYHA Functional Class

  Baseline to 12 months

• Change in Quality of Life (KCCQ-12 Total Score)

  Baseline, 3 months, 6 months, 12 months

• Change in 6-Minute Walk Distance

  Baseline, 6 months, 12 months

Study Arms (2)

Stepwise Withdrawal

EXPERIMENTAL

Stepwise discontinuation of ARNI followed by SGLT2i. ARNI is withdrawn first; if no echocardiographic deterioration (LVEF drop \<10 percentage points) and NT-proBNP remains ≤250 ng/L after 1 month, SGLT2i is then withdrawn. MRA and beta-blockers, if previously prescribed, are continued. Intensive echocardiographic monitoring is performed at 1 and 3 months.

Drug: Stepwise Withdrawal of ARNI and SGLT2i

Continuation

ACTIVE COMPARATOR

Continuation of all current heart-failure medications including ARNI and SGLT2i per guideline-directed medical therapy, with standard follow-up.

Drug: Continued Guideline-Directed Medical Therapy

Interventions

Stepwise Withdrawal of ARNI and SGLT2i DRUG

Sequential discontinuation of angiotensin receptor-neprilysin inhibitor (ARNI; e.g., sacubitril/valsartan) and sodium-glucose cotransporter-2 inhibitor (SGLT2i; e.g., dapagliflozin or empagliflozin). ARNI is discontinued first; after a 1-month observation with echocardiographic and biomarker assessment, SGLT2i is discontinued if no signs of deterioration are observed. Concomitant MRA and beta-blocker therapy is continued.

Stepwise Withdrawal

Continued Guideline-Directed Medical Therapy DRUG

Continuation of currently prescribed ARNI and SGLT2i, together with any concomitant MRA and beta-blocker, at the doses being received at enrollment, per current guideline-directed medical therapy.

Continuation

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults aged 19 years or older
• Prior left ventricular ejection fraction (LVEF) ≤40% before surgery or intervention, with recovery to ≥50% (normalized range) at the time of enrollment
• N-terminal pro-B-type natriuretic peptide (NT-proBNP) \<250 ng/L
• Complete correction of a reversible underlying cause of heart failure: surgical or transcatheter correction of valvular heart disease (mitral regurgitation, aortic stenosis, aortic regurgitation), or percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) for ischemic cardiomyopathy
• Currently receiving both ARNI and SGLT2i for at least 3 months at enrollment (MRA and/or beta-blocker may also be used)
• Clinically stable outpatient with no heart failure-related hospitalization within the prior 6 months
• Able to provide written informed consent

You may not qualify if:

• Heart failure due to irreversible etiology (e.g., idiopathic dilated cardiomyopathy, toxic cardiomyopathy, genetic cardiomyopathy)
• For valvular disease: moderate or greater paravalvular leak, or residual moderate or greater mitral or aortic regurgitation
• For ischemic disease: incomplete revascularization or graft occlusion on post-operative coronary CT
• Chronic kidney disease stage 4 or higher (eGFR \<30 mL/min/1.73 m²)
• Symptomatic hypotension (systolic blood pressure \<90 mmHg) or symptomatic bradycardia (heart rate \<50 beats/min)
• Pregnant, suspected pregnancy, or breastfeeding
• Terminal malignancy or end-stage organ failure with life expectancy \<12 months
• Participation in another clinical trial within 3 months prior to screening
• Any condition that, in the investigator's judgment, makes the participant unsuitable for the study

Sponsors & Collaborators

• Ajou University Hospital, Suwon, South Korea: collaborator
• Korea University Anam Hospital: collaborator
• Pusan National University Yangsan Hospital: collaborator
• Kyungsub Song: lead
• Seoul National University Bundang Hospital: collaborator

Study Sites (5)

Keimyung University Dongsan Hospital

Daegu, Daegu, 42601, South Korea

Location

Seoul National University Bundang Hospital

Seongnam-si, Gyeonggi-do, 13620, South Korea

Location

Ajou University Hospital

Suwon, Gyeonggi-do, 16499, South Korea

Location

Pusan National University Yangsan Hospital

Yangsan, Gyeongsangnam-do, 50612, South Korea

Location

Korea University Anam Hospital

Seoul, Seoul, 02841, South Korea

Location

MeSH Terms

Conditions

Heart Failure; Ventricular Dysfunction, Left; Heart Valve Diseases

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Ventricular Dysfunction

Study Officials

• Hyung Gon Je, Professor

  Seoul National University Bundang Hospital

  PRINCIPAL INVESTIGATOR

• Su Jin Park, Professor

  Ajou University School of Medicine

  PRINCIPAL INVESTIGATOR

• Jun Ho Lee, Professor

  Korea University Anam Hospital

  PRINCIPAL INVESTIGATOR

• Younju Rhee, Professor

  Pusan National University Yangsan Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kyungsub Song, Professor

CONTACT

82)1065564907; chest.songks@gmail.com

In Cheol Kim, Professor

CONTACT

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: ssistant Professor, Department of Cardiovascular and Thoracic Surgery, Keimyung University Dongsan Hospital

Model Details: Eligible participants are randomized 1:1 to either stepwise withdrawal of ARNI followed by SGLT2i or continuation of current guideline-directed medical therapy. Randomization is centralized via a web-based system (Sealed Envelope) and stratified by baseline NT-proBNP (≤50, 51-125, 126-250 ng/L). The trial is open-label; outcome assessors interpreting echocardiograms are blinded to allocation where feasible.

Study Record Dates

• First Submitted: June 1, 2026
• First Posted: June 5, 2026
• Study Start (Estimated): June 30, 2026
• Primary Completion (Estimated): June 30, 2029
• Study Completion (Estimated): December 30, 2029
• Last Updated: June 5, 2026

Record last verified: 2026-06

Locations

KR (5)