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.

1. Scientific Background and Rationale Contemporary heart failure (HF) guidelines recommend the early and simultaneous initiation of the four foundational pillars of guideline-directed medical therapy (GDMT)-ARNI (or ACEi/ARB), beta-blocker, mineralocorticoid receptor antagonist, and SGLT2 inhibitor-in patients with a reduced left ventricular ejection fraction (LVEF). The pivotal trials supporting these recommendations, however, were conducted predominantly in patients with chronic HFrEF in whom the underlying aetiology was either non-correctable or had not been definitively addressed.

   A clinically distinct population is encountered when the underlying cause of heart failure is fully reversible: patients with ischaemic cardiomyopathy who undergo complete revascularization, and patients with left-sided valvular disease causing chronic pressure or volume overload (severe aortic stenosis, aortic regurgitation, primary mitral regurgitation) who undergo valvular surgery or transcatheter intervention. In these patients, removal of the haemodynamic insult itself drives a substantial portion of subsequent LVEF recovery, independent of neurohormonal blockade. Consequently, universal and immediate initiation of ARNI and SGLT2i in this population may expose patients who would have recovered spontaneously to drug-related adverse effects (symptomatic hypotension, hyperkalaemia, renal dysfunction, genitourinary infection, ketoacidosis), to the burden of polypharmacy, and to avoidable cost, with uncertain incremental benefit on cardiac function or clinical outcome.

   The optimal timing of ARNI and SGLT2i initiation in patients whose underlying cause of HF has been definitively corrected has not been prospectively examined.

2. Study Hypothesis The central hypothesis of DELAY-HF is that, in patients in whom the underlying cause of heart failure has been surgically or procedurally corrected, the LVEF recovery attributable to treatment of the underlying cause is substantially greater than the incremental recovery attributable to ARNI and SGLT2i. A strategy of delayed initiation-in which ARNI and SGLT2i are withheld for 6 months and started only in patients without sufficient LVEF recovery-will therefore be non-inferior to immediate initiation with respect to the change in LVEF at 12 months.

3. Pre-specified Analyses

Four pre-specified analyses are planned to fully characterise the contribution of ARNI/SGLT2i in this population:

1. Effect of early ARNI/SGLT2i on LVEF recovery. Patients in the delayed-initiation arm who never received ARNI/SGLT2i during the 12-month follow-up (those without recovery at 6 months who were ultimately not started, plus those who recovered spontaneously) will be compared with the immediate-initiation arm to estimate the contribution of early ARNI/SGLT2i to LVEF recovery beyond the recovery driven by treatment of the underlying cause.
2. Safety of delayed initiation. Within the delayed-initiation arm, patients who received delayed ARNI/SGLT2i and recovered will be compared with those who received delayed therapy without recovery, to evaluate whether postponing therapy by 6 months in non-recovering patients is associated with an attenuation of subsequent LVEF response.
3. Twelve-month head-to-head comparison. The proportion of patients achieving LVEF recovery and the magnitude of LVEF improvement at the 12-month assessment will be compared directly between the delayed-initiation and immediate-initiation arms.
4. Spontaneous versus pharmacologic recovery. Among patients in the delayed-initiation arm whose LVEF recovered spontaneously after correction of the underlying cause (without medication), the magnitude of LVEF recovery will be compared with that achieved in patients in the immediate-initiation arm whose recovery occurred while on ARNI/SGLT2i.

4. Exploratory Analyses A pre-specified exploratory aim of the trial is to estimate the proportion of patients in the delayed-initiation arm in whom ARNI and SGLT2i can ultimately be deemed unnecessary-that is, those whose cardiac function has recovered sufficiently at 6 months that initiation is not warranted under the trial protocol. A formal cost-effectiveness analysis (incremental cost-effectiveness ratio) will compare the two strategies from the healthcare-system perspective.

5. Expected Implications If the delayed-initiation strategy is shown to be non-inferior, the findings will support a more individualized prescribing approach in patients with a corrected cause of heart failure-reserving ARNI and SGLT2i for those who fail to recover spontaneously-and will reduce unnecessary drug exposure, adverse-effect burden, and cost in a population that is currently treated uniformly under generalized HFrEF guidelines.

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Deidentified individual participant data (IPD) underlying the published results, including baseline demographic and clinical characteristics, echocardiographic parameters (LVEF, LV volumes, diastolic indices), laboratory values (NT-proBNP, eGFR, electrolytes), KCCQ-12 scores, 6-minute walk distance, randomization assignment, study drug exposure, and adjudicated clinical events (cardiovascular and all-cause mortality, heart failure hospitalization, MACE), will be made available. The full study protocol, statistical analysis plan, and informed consent form will also be shared. Only deidentified data without any direct or indirect identifiers will be released, in accordance with the Personal Information Protection Act of the Republic of Korea and the Bioethics and Safety Act.

Beginning 6 months after publication of the primary study results, and ending 5 years after publication.

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.