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

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.

Eligibility

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.

Conditions4

Interventions3

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