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 multicentre, randomised, open-label pilot trial with blinded end-point assessment (PROBE design) evaluating the safety and feasibility of a delayed-initiation strategy of ARNI and SGLT2i, compared with immediate initiation, in patients with heart failure whose underlying cause has been completely corrected by surgical or procedural intervention. A total of 80 patients (40 per arm) will be enrolled at four centres in South Korea. 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 to 12 months. The between-group difference (delayed minus immediate) will be reported as a point estimate with a two-sided 95% confidence interval and evaluated against a pre-specified decision criterion (lower confidence limit above -5 percentage points). As a pilot trial, DELAY-HF is not powered for a confirmatory non-inferiority test; it aims to estimate the standard deviation of the primary outcome, recruitment and dropout rates, the rescue-therapy rate and safety data needed to design a subsequent confirmatory trial. Key secondary outcomes include cardiovascular and all-cause mortality, heart failure hospitalisation, additional echocardiographic indices, NT-proBNP, KCCQ-12 score, 6-minute walk distance, feasibility metrics, and a cost-effectiveness analysis. By comparing these two strategies, this pilot trial will provide preliminary estimates of the incremental contribution of ARNI and SGLT2i-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 inform the design of a subsequent confirmatory trial addressing whether these agents are truly necessary in this population.

Timeline

Start

2026-05-20

Primary completion

2028-05-20

Completion

2028-12-20

Publications

• Results 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.

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