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.

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.

Drugs

Indications