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

ConditionsHeart Failure With Reduced Ejection FractionHeart FailureVentricular Dysfunction, Left
Trial statusRecruiting
Trial phasePhase 4
Trial typeInterventional
Biological sexAll
Age19+
SponsorKyungsub Song

About this 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 ≤ 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.

Eligibility criteria

This trial does not accept healthy volunteers

Qualifiers

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

Disqualifiers

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)

Trial design

Design model

Parallel

Treatments tested in this trial

  • 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.

  • 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.

Treatment groups

80 Participants
are divided into 2 treatment groups
Group A: Stepwise WithdrawalExperimental treatment 1 intervention
Group B: ContinuationActive comparator 1 intervention

Trial outcomes

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.

Time frame
Baseline to 12 months

Secondary outcomes

1

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.

Time frame
Up to 12 months
2

Change in NT-proBNP

Change from baseline in serum N-terminal pro-B-type natriuretic peptide (NT-proBNP, ng/L) concentration at 3 and 12 months.

Time frame
Baseline to 12 months
3

Change in NYHA Functional Class

Change from baseline in New York Heart Association (NYHA) functional classification at 12 months.

Time frame
Baseline to 12 months
4

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.

Time frame
Baseline, 3 months, 6 months, 12 months

Other outcomes

Sponsors and contacts

Click on the lead sponsor to view all of their trials.

Kyungsub Song

Lead sponsor

Keimyung University Dongsan Medical Center

Sponsor institution

Seoul National University Bundang Hospital

Collaborator

Ajou University School of Medicine

Collaborator

Korea University Anam Hospital

Collaborator

Pusan National University Yangsan Hospital

Collaborator

Source ClinicalTrials.gov
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