Work

Design, Rationale, and Methods of the INITIATE-HFrEF Trial

Year: 2026

Type: article

Abstract: BACKGROUND: Angiotensin receptor-neprilysin inhibitors (ARNi) and sodium glucose co-transporter 2 inhibitors (SGLT2i) are backbone guideline-directed medical therapies for patients with heart failure with reduced ejection fraction (HFrEF). Expert documents suggest that ARNi and SGLT2i should both be started rapidly. However, to date, no studies have assessed the efficacy and safety of these therapies when started simultaneously or sequentially. OBJECTIVES: The purpose of this study was to evaluate the efficacy and safety of simultaneous vs sequential initiation of ARNi and SGLT2i in HFrEF. METHODS: Randomized noninferiority trial comparing 2 treatment strategies: 1) simultaneous ARNi/SGLT2i initiation (up to 5 days apart); vs 2) sequential initiation of one agent followed by the other (4-12 weeks later). The primary endpoint is a composite of hypotension, hyperkalemia, hypokalemia, estimated glomerular filtration rate drop ≥50% from baseline, emergency visit for HF, HF hospitalization, or cardiovascular death. The prespecified noninferiority margin for the absolute between-group difference is 20% with a two-sided 95% CI. Follow-up time was approximately 24 weeks. RESULTS: , and serum potassium was 4.3 ± 0.5 mmol/L. Most patients in the sequential group (n = 27) were started on SGLT2i and 6 were started on ARNi. CONCLUSIONS: Initiation of ARNi and SGLT2i in Patients With HFrEF is a randomized trial to test whether a simultaneous initiation of ARNi and SGLT2i is noninferior to a sequential initiation of one agent followed by the other 4 to 12 weeks apart.

Source: JACC Advances

DOI: 10.1016/j.jacadv.2026.102589