STEPwise De-escalation and Optimizing Withdrawal of ARNI and SGLT2i in Normalized Heart Failure (STEP-DOWN HF)

STEPwise De-escalation and Optimizing Withdrawal of ARNI and SGLT2i in Normalized Heart Failure (STEP-DOWN HF Trial)

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Heart Failure; Ventricular Dysfunction, Left; Heart Failure With Reduced Ejection Fraction
• Intervention / Treatment: Drug: Stepwise Withdrawal of ARNI and SGLT2i; Drug: Continued Guideline-Directed Medical Therapy

Detailed Description

Background The 4-pillar guideline-directed medical therapy (GDMT) for heart failure-comprising ARNI, SGLT2i, mineralocorticoid receptor antagonists (MRA), and beta-blockers-is the established standard of care for patients with reduced ejection fraction. However, evidence guiding medication withdrawal in patients whose ejection fraction has normalized after correction of a reversible structural cause (HFimpEF) is lacking. The TRED-HF trial demonstrated that withdrawing GDMT in patients with idiopathic or familial dilated cardiomyopathy led to relapse in approximately 40% within six months. In contrast, WITHDRAW-AF, which enrolled patients whose tachycardia-induced cardiomyopathy resolved after successful catheter ablation, observed only 8.3% relapse, and CATHEDRAL-HF, which retained beta-blockers while withdrawing other agents, reported approximately 10% relapse. These findings suggest that selective, stepwise withdrawal in patients with fully corrected underlying disease may be safer than indiscriminate discontinuation.

Rationale for a Pilot Trial This pilot study addresses three objectives prior to a definitive non-inferiority trial: (1) primary safety assessment of a stepwise withdrawal protocol after structural correction; (2) feasibility of multicenter enrollment and follow-up; and (3) estimation of event rates and variance of the primary outcome to inform sample-size calculation for the subsequent confirmatory trial.

Study Design Multicenter, randomized, open-label, parallel-group pilot trial. Eighty patients will be randomized 1:1 to stepwise withdrawal or continuation, stratified by baseline NT-proBNP (≤50, 51-125, 126-250 ng/L) using a web-based central randomization system (Sealed Envelope). Five centers in the Republic of Korea will participate.

Intervention Stepwise Withdrawal Arm: ARNI is discontinued first. After one month of clinical and echocardiographic assessment, SGLT2i is discontinued only if there is no echocardiographic deterioration (LVEF drop <10 percentage points) and NT-proBNP remains ≤250 ng/L. MRA and beta-blockers, if present, are continued.

Continuation Arm: All current heart-failure medications, including ARNI and SGLT2i, are maintained per standard practice.

Safety Monitoring Two key safeguards are implemented: (1) a strictly sequential, stepwise withdrawal that prevents abrupt neurohormonal activation; and (2) mandatory transthoracic echocardiography at 1 and 3 months post-withdrawal to detect early subclinical deterioration before symptomatic relapse. This intensive echocardiographic surveillance distinguishes the protocol from prior trials, which relied primarily on serum biomarkers. Patients meeting predefined deterioration criteria (LVEF decline ≥10 percentage points from baseline, LVEF <40%, heart failure hospitalization, or emergency-department visit) are immediately reinstated on full GDMT and recorded as protocol withdrawal events. An independent Data and Safety Monitoring Board reviews safety data periodically.

Endpoints Primary Endpoint: Change in LVEF from baseline to 12 months. Non-inferiority 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, with ITT analysis as a supportive analysis.

Secondary Endpoints: Composite of cardiovascular death and heart failure hospitalization at 12 months; absolute LVEF change; NT-proBNP change at 3 and 12 months; NYHA functional class change; KCCQ-12 quality-of-life score; 6-minute walk distance; incidence and severity of adverse events; and rate and timing of medication reinstatement.

Eligibility Adults (≥19 years) with a prior LVEF ≤40% that has recovered to ≥50% following complete surgical or interventional correction of valvular heart disease (mitral regurgitation, aortic stenosis, aortic regurgitation) or ischemic cardiomyopathy (PCI or CABG); NT-proBNP <250 ng/L at enrollment; receiving both ARNI and SGLT2i for at least three months; and no heart-failure hospitalization within the prior six months. Major exclusions include irreversible cardiomyopathy, incomplete revascularization, residual moderate or greater valvular regurgitation, eGFR <30 mL/min/1.73 m², symptomatic hypotension or bradycardia, pregnancy, and limited life expectancy.

Follow-up Scheduled visits at 1, 3, 6, 9, and 12 months. Assessments include vital signs, NT-proBNP, renal function, electrolytes, echocardiography (baseline, 1, 3, 6, 12 months), ECG, KCCQ-12, 6-minute walk test, and adverse event capture.

Statistical Analysis The pilot sample size of 40 per arm (total 80) is based on precision estimates for the primary outcome: assuming a 10% event rate, this yields approximately ±9.3% precision per arm and ±6.6% overall (Wilson method), which is adequate for variance estimation. A 15% drop-out rate is anticipated. All analyses will be conducted with SPSS and R.

Expected Contribution By generating the first prospective evidence on stepwise ARNI/SGLT2i withdrawal in patients with structurally corrected HFimpEF, this pilot trial aims to lay the methodological foundation for a definitive non-inferiority trial and ultimately to inform evidence-based deprescribing guidelines for this growing patient population.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Kyungsub Song, Professor; Phone Number: 82)1065564907; Email: chest.songks@gmail.com
• Study Contact Backup: Name: In Cheol Kim, Professor

Study Locations

• South Korea
  • Daegu
    • Daegu, Daegu, South Korea, 42601
      • Keimyung University Dongsan Hospital
  • Gyeonggi-do
    • Seongnam-si, Gyeonggi-do, South Korea, 13620
      • Seoul National University Bundang Hospital
    • Suwon, Gyeonggi-do, South Korea, 16499
      • Ajou University Hospital
  • Gyeongsangnam-do
    • Yangsan, Gyeongsangnam-do, South Korea, 50612
      • Pusan National University Yangsan Hospital
      • Contact: Younju Rhee, Professor; Phone Number: 82)55-360-1000; Email: rheeyounju@gmail.com
  • Seoul
    • Seoul, Seoul, South Korea, 02841
      • Korea University Anam Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Stepwise Withdrawal; 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; 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.
Active Comparator: Continuation; 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; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of Cardiovascular Death or Heart Failure Hospitalization	Cumulative incidence of the composite endpoint of cardiovascular death or hospitalization for heart failure during the 12-month follow-up period.	Up to 12 months
Change in NT-proBNP	Change from baseline in serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration at 3 and 12 months.	Baseline to 12 months
Change in NYHA Functional Class	Change from baseline in New York Heart Association (NYHA) functional classification at 12 months.	Baseline to 12 months
Change in Quality of Life (KCCQ-12 Total Score)	Change from baseline in the Kansas City Cardiomyopathy Questionnaire-12 (KCCQ-12) total score. Scores range from 0 to 100, with higher scores indicating better health status.	Baseline, 3 months, 6 months, 12 months
Change in 6-Minute Walk Distance	Change from baseline in the distance walked (in meters) during a standardized 6-minute walk test.	Baseline, 6 months, 12 months
Incidence and Severity of Adverse Events	Frequency and severity of treatment-emergent adverse events and serious adverse events, including events specifically related to medication withdrawal (e.g., heart failure decompensation, hypotension, electrolyte abnormalities).	Up to 12 months
Rate and Timing of Medication Reinstatement	Proportion of participants in the stepwise withdrawal arm requiring reinstatement of ARNI and/or SGLT2i due to clinical deterioration or protocol-defined criteria, and time from withdrawal to reinstatement.	Up to 12 months

Collaborators and Investigators

• Sponsor: Kyungsub Song
• Collaborators: Korea University Anam Hospital; Seoul National University Bundang Hospital; Pusan National University Yangsan Hospital; Ajou University Hospital, Suwon, South Korea
• Investigators: Principal Investigator: 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

Study record dates

Study Major Dates

• Study Start (Estimated): June 30, 2026
• Primary Completion (Estimated): June 30, 2029
• Study Completion (Estimated): December 30, 2029

Study Registration Dates

• First Submitted: June 1, 2026
• First Submitted That Met QC Criteria: June 1, 2026
• First Posted (Actual): June 5, 2026

Study Record Updates

• Last Update Posted (Actual): June 5, 2026
• Last Update Submitted That Met QC Criteria: June 1, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Valvular Heart Disease; Ischemic Cardiomyopathy; ARNI; Sacubitril/Valsartan; SGLT2 Inhibitor; Guideline-Directed Medical Therapy; Reverse Remodeling; HFimpEF
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Ventricular Dysfunction; Heart Failure; Ventricular Dysfunction, Left; Heart Valve Diseases
• Other Study ID Numbers: IRB number: 2026-04-022-003; RS-2026-25475665 (Other Grant/Funding Number: National Research Foundation of Korea)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: A decision regarding sharing of individual participant data (IPD) has not yet been made. The sponsor and steering committee will determine the IPD-sharing plan prior to the primary completion date, taking into account the requirements of journals selected for primary results publication, applicable Korean data-protection regulations (Personal Information Protection Act, Bioethics and Safety Act), and any conditions specified by the Institutional Review Board. If sharing is approved, de-identified IPD, the study protocol, statistical analysis plan, and informed consent form will be made available to qualified investigators upon reasonable request to the principal investigator.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No