Delayed Initiation of ARNI and SGLT2i in Heart Failure With Corrected Aetiology (DELAY-HF), Pilot Study

NCT07572032 | Not Yet Recruiting Phase 4 DMC

• 2 other identifiers: 2026-04-005-001 April 21, 2026RS-2026-25475665
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 4

Brief Summary

In patients with heart failure due to a reversible underlying cause-such as valvular heart disease or coronary artery disease-surgical or procedural correction of the underlying lesion (valve repair/replacement, TAVI, PCI, or CABG) frequently leads to spontaneous recovery of cardiac function, even without neurohormonal modulators. In this clinical setting, a substantial proportion of patients may not require the full set of guideline-directed medical therapies routinely prescribed for chronic HFrEF. The purpose of this study is to determine whether ARNI (angiotensin receptor-neprilysin inhibitor) and SGLT2 inhibitors are truly necessary in patients whose left ventricular function recovers spontaneously after treatment of a correctable cause of heart failure. The DELAY-HF trial (DELayed initiation of ARNI and SGLT2i in heart failure with corrected aetiologY) is a multi-center, randomized controlled non-inferiority trial evaluating whether a delayed-initiation strategy of ARNI and SGLT2i is non-inferior to immediate initiation in patients with heart failure whose underlying cause has been completely corrected by surgical or procedural intervention. Adults with a preoperative left ventricular ejection fraction (LVEF) ≤40% who have undergone successful correction of a reversible cause of heart failure-either revascularization (PCI or CABG) for ischemic cardiomyopathy or valvular surgery (including TAVI) for left-sided valvular heart disease causing volume overload-will be randomized 1:1 to (1) delayed initiation, in which ARNI/SGLT2i are withheld for 6 months and started only in patients whose LVEF remains ≤40% at the 6-month assessment, versus (2) immediate guideline-directed medical therapy (GDMT) including ARNI/SGLT2i started shortly after the corrective procedure. All patients are followed for 12 months. The primary outcome is the absolute change in LVEF from baseline at 12 months. Key secondary outcomes include cardiovascular mortality, heart failure hospitalization, additional echocardiographic indices, NT-proBNP, KCCQ quality-of-life score, 6-minute walk distance, and a cost-effectiveness analysis. By comparing these two strategies, this trial will clarify the incremental contribution of ARNI and SGLT2i-both to further LVEF recovery and to clinical outcomes-in patients who have already demonstrated spontaneous improvement in cardiac function after correction of the underlying cause, and will thereby help define whether these agents are truly necessary in this population.

Conditions

Heart Failure Due to Coronary Artery Disease; Valvular Cardiomyopathy; Heart Failure

Keywords

Heart failure; Recovered ejection fraction; ARNI (Angiotensin receptor-neprilysin inhibitor); SGLT2 inhibitor; Valvular heart disease; Ischemic cardiomyopathy

Outcome Measures

Primary Outcomes (1)

• Change in left ventricular ejection fraction (LVEF) at 12 months

  Absolute change in left ventricular ejection fraction (LVEF), expressed in percentage points, from baseline (at randomization) to the 12-month follow-up assessment. LVEF will be measured by transthoracic echocardiography using the biplane Simpson's method according to current ASE/EACVI guidelines, and analyzed by readers blinded to treatment assignment. The primary hypothesis is non-inferiority of the delayed-initiation strategy compared with the immediate-initiation strategy. Non-inferiority will be declared if the lower bound of the two-sided 95% confidence interval for the between-group difference in LVEF change (delayed minus immediate) lies above -5 percentage points; that is, the LVEF improvement in the delayed-initiation arm is no more than 5 percentage points worse than in the immediate-initiation arm.

  Baseline (at randomization) and 12 months after randomization

Secondary Outcomes (10)

• Cardiovascular mortality

  From randomization through 12 months

• Heart failure hospitalization

  From randomization through 12 months

• Change in echocardiographic remodeling parameters at 12 months

  Baseline and 12 months after randomization

• Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score

  Baseline and 12 months after randomization

• Change in 6-minute walk distance (6MWD)

  Baseline and 12 months after randomization

Study Arms (2)

Delayed initiation of ARNI and SGLT2i

EXPERIMENTAL

After surgical or procedural correction of the underlying cause of heart failure (valvular surgery/TAVI or PCI/CABG), ARNI and SGLT2 inhibitors are withheld and patients are observed for 6 months on background therapy excluding ARNI/SGLT2i. At the 6-month assessment, ARNI and SGLT2i are initiated only in patients whose LVEF remains ≤40%. Patients with LVEF \>40% continue without ARNI/SGLT2i under observation. If symptomatic heart failure worsening or a ≥10 percentage-point decrease in LVEF occurs during the observation period, full guideline-directed medical therapy including ARNI and SGLT2i is started immediately as rescue therapy. All participants are followed for 12 months from randomization.

Drug: Sacubitril / Valsartan; Drug: SGLT-2 inhibitor

Immediate initiation of ARNI and SGLT2i (standard GDMT)

ACTIVE COMPARATOR

After surgical or procedural correction of the underlying cause of heart failure (valvular surgery/TAVI or PCI/CABG), full guideline-directed medical therapy including ARNI and SGLT2 inhibitors is initiated and titrated to the maximally tolerated doses according to current heart failure guidelines, and continued throughout the follow-up period. All participants are followed for 12 months from randomization.

Drug: Sacubitril / Valsartan; Drug: SGLT2 Inhibition

Interventions

SGLT-2 inhibitor DRUG

In the delayed-initiation arm, the SGLT2 inhibitor (dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily) is withheld during the first 6 months and initiated at the 6-month assessment only in patients whose LVEF remains ≤40%; patients whose LVEF has recovered to \>40% continue without SGLT2i under observation. If heart failure worsens during the observation period, the SGLT2 inhibitor is started immediately as rescue therapy. Patients receiving SGLT2i prior to enrollment undergo a 1-week washout before randomization.

Delayed initiation of ARNI and SGLT2i

Sacubitril / Valsartan DRUG

In the delayed-initiation arm, sacubitril/valsartan is withheld for 6 months after the corrective procedure; valsartan is used for blood pressure control and background heart failure therapy. At the 6-month assessment, sacubitril/valsartan is initiated only in patients with LVEF ≤40%. Patients with LVEF \>40% continue their existing regimen without ARNI. If heart failure worsens during observation (symptomatic deterioration or a ≥10 percentage-point drop in LVEF), sacubitril/valsartan is started immediately as rescue therapy. Patients on ARNI prior to enrollment undergo a 1-week washout before randomization.

Delayed initiation of ARNI and SGLT2i

SGLT2 Inhibition DRUG

An SGLT2 inhibitor (dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily, at the discretion of the treating physician) is used as one of the foundational therapies of guideline-directed medical therapy for heart failure. In the immediate-initiation arm, the SGLT2 inhibitor is started after correction of the underlying cause of heart failure and continued throughout the 12-month follow-up.

Immediate initiation of ARNI and SGLT2i (standard GDMT)

Eligibility Criteria

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

You may qualify if:

• Age ≥ 18 years.
• Preoperative left ventricular ejection fraction (LVEF) ≤ 40% on echocardiography.
• Successful surgical or procedural correction of a correctable underlying cause of heart failure: Valvular heart disease: mitral valve surgery, aortic valve surgery, transcatheter aortic valve implantation (TAVI), or tricuspid valve surgery, OR Ischemic cardiomyopathy: complete revascularization by coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI).
• Enrollment between 3 months before and 10 days after the corrective procedure.
• Hemodynamically stable post-operative state with NYHA class I, defined at the time of randomization as: Systolic blood pressure ≥ 100 mmHg sustained for at least 6 hours; No up-titration of intravenous diuretics within the preceding 6 hours; No use of intravenous vasodilators within the preceding 6 hours; No use of intravenous inotropes within the preceding 24 hours; Heart rate 50-110 bpm and no clinical signs of volume overload.
• Patients receiving ARNI or SGLT2 inhibitors prior to enrollment must complete a 1-week washout period before randomization.
• Provision of written informed consent.

You may not qualify if:

• Prior history of sustained ventricular tachycardia or ventricular fibrillation.
• Greater-than-moderate paravalvular leak or residual mitral regurgitation after aortic or mitral valve surgery.
• Incomplete revascularization in patients with coronary artery disease (residual significant disease in any major coronary territory: LAD, LCX, or RCA).
• Graft occlusion documented on coronary CT angiography after CABG. Planned pregnancy during the study period.
• Uncontrolled hypertension on medical therapy (systolic blood pressure \> 160 mmHg).
• Estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73 m².
• Inability to tolerate ARNI, defined as inability to take sacubitril/valsartan 25 mg twice daily (e.g., due to symptomatic hypotension, history of angioedema, or bilateral renal artery stenosis).
• Inability to tolerate SGLT2 inhibitors (e.g., type 1 diabetes mellitus or history of recurrent diabetic ketoacidosis).
• Any other condition that, in the opinion of the investigator, would interfere with study participation or follow-up.

Sponsors & Collaborators

• Kyungsub Song: lead
• Seoul National University Bundang Hospital: collaborator
• Korea University Anam Hospital: collaborator
• Ajou University Medical Center: collaborator

Study Sites (4)

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

Korea University Anam Hospital

Seoul, Seoul, 02841, South Korea

Location

Related Publications (1)

• 1. Wilcox JE et al. Heart Failure With Recovered LVEF: JACC Scientific Expert Panel. JACC 2020;76(6):719-34. 2. Kodur N, Tang WHW. Management of HFimpEF: Current Evidence and Controversies. JACC Heart Fail 2025;13(4):537-53. 3. Velazquez EJ et al. Coronary-Artery Bypass Surgery in Patients with Ischemic Cardiomyopathy (STICH). N Engl J Med 2011;364:1607-16. 4. Myocardial Revascularization in Patients With Ischemic Cardiomyopathy. J Am Heart Assoc 2022. 5. Recovery of LV Function After Surgery for Aortic and Mitral Regurgitation With HF. J Cardiovasc Dev Dis 2024. 6. Halliday BP et al. Withdrawal of pharmacological treatment for HF in patients with recovered DCM (TRED-HF). Lancet 2019;393:61-73. 7. Cheng RK et al. Long-term follow-up of TRED-HF. Eur J Heart Fail 2025;27:113-21. 8. Heidenreich PA et al. 2022 AHA/ACC/HFSA Guideline for Management of Heart Failure. Circulation 2022;145:e895-e1032. 9. Bocchi EA et al. Carvedilol as Single Therapy for HFimpEF (CATHEDRAL-HF). JACC Heart Fail 2025;13(7):882-91. 10. Hawkins NM et al. Withdrawal of HF therapy after AF rhythm control with EF normalization (WITHDRAW-AF). Eur Heart J 2026;47(2):250-60. 11. ReReRe study: Withdrawal of GDMT in patients with recovered LV and reversible etiology in valvular regurgitation. Eur Heart J 2025;46(Suppl 1):ehaf784.1245. 12. Sauer AJ et al. How to Initiate and Uptitrate GDMT in Heart Failure. JACC Heart Fail 2023;11(1):21-30. 13. Early Initiation of GDMT for Heart Failure After Cardiac Surgery. Ann Thorac Surg 2024;118(4):887-94. 14. Whitehead AL et al. Estimating the sample size for a pilot randomised trial. Pilot Feasibility Stud 2016;2:17.

  RESULT

MeSH Terms

Conditions

Heart Failure; Heart Valve Diseases

Interventions

sacubitril and valsartan sodium hydrate drug combination; Sodium-Glucose Transporter 2 Inhibitors

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Hypoglycemic Agents; Physiological Effects of Drugs

Study Officials

• Kyungsub Song, MD

  Keimyung University Dongsan Medical Center

  STUDY DIRECTOR

Central Study Contacts

Kyungsub Song, MD

CONTACT

82)053-258-7307; chest.songks@gmail.com

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: Assistant Professor, Department of Cardiovascular and Thoracic Surgery, Keimyung University Dongsan Hospital

Model Details: Arm 1 - Delayed-initiation group (Experimental): After correction of the underlying cause, ARNI and SGLT2i are withheld and patients are observed for 6 months on background therapy (excluding ARNI/SGLT2i). At the 6-month assessment, ARNI and SGLT2i are initiated only in patients whose LVEF remains ≤40%. Patients whose LVEF has recovered to \>40% continue without ARNI/SGLT2i and remain under observation. If symptomatic heart failure worsening or a ≥10 percentage-point drop in LVEF occurs during the observation period, full GDMT including ARNI/SGLT2i is started immediately as rescue therapy. Arm 2 - Immediate-initiation group (Active Comparator): After correction of the underlying cause, full guideline-directed medical therapy including ARNI and SGLT2i is initiated and titrated according to current heart failure guidelines, and continued throughout follow-up.

Study Record Dates

• First Submitted: April 30, 2026
• First Posted: May 7, 2026
• Study Start (Estimated): May 20, 2026
• Primary Completion (Estimated): May 20, 2028
• Study Completion (Estimated): December 20, 2028
• Last Updated: May 7, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Beginning 6 months after publication of the primary study results, and ending 5 years after publication.
• Access Criteria: Access will be granted to qualified investigators whose proposed use of the data has been reviewed and approved by an independent committee designated by the principal investigator. Requests must include: (1) a detailed research proposal with specific aims, methodology, and analysis plan; (2) the name and affiliation of the requesting investigator; and (3) a signed data access and confidentiality agreement. Requests should be submitted in writing to the principal investigator at the coordinating center (Keimyung University Dongsan Hospital). Approved investigators will receive deidentified data via a secure data transfer platform. The principal investigator and the steering committee retain the right to decline requests that conflict with patient privacy protections, applicable regulations, or the original informed consent provided by participants.

Locations

KR (4)