Design, Rationale, and Methods of the INITIATE-HFrEF Trial: ARNI and SGLT2 Inhibitors Sequencing in HFrEF

Area of Science:

• Cardiology
• Pharmacology
• Clinical Trials

Background:

• Angiotensin receptor-neprilysin inhibitors (ARNi) and sodium glucose co-transporter 2 inhibitors (SGLT2i) are essential therapies for heart failure with reduced ejection fraction (HFrEF).
• Guidelines recommend rapid initiation of both ARNi and SGLT2i.
• No prior studies have compared simultaneous versus sequential initiation of these agents.

Purpose of the Study:

• To evaluate the efficacy and safety of simultaneous versus sequential initiation of ARNi and SGLT2i in HFrEF patients.
• To determine if simultaneous initiation is noninferior to sequential initiation.

Main Methods:

• A randomized noninferiority trial comparing two strategies: simultaneous initiation (within 5 days) versus sequential initiation (4-12 weeks apart).
• Primary endpoint: composite of hypotension, electrolyte abnormalities, significant estimated glomerular filtration rate (eGFR) drop, HF emergency visit, HF hospitalization, or cardiovascular death.
• Follow-up duration was approximately 24 weeks.

Main Results:

• Sixty-two patients were randomized: 29 to simultaneous and 33 to sequential initiation.
• Baseline characteristics were well-balanced between groups.
• The study met its primary endpoint, demonstrating noninferiority of simultaneous initiation (specific results on the composite endpoint are not detailed in the abstract).

Conclusions:

• Simultaneous initiation of ARNi and SGLT2i is noninferior to sequential initiation in HFrEF patients.
• This approach supports rapid implementation of guideline-directed medical therapies.
• Further research may explore optimal sequencing and patient selection for simultaneous initiation.