Initiation and sequencing of guideline-directed medical therapy for heart failure across the ejection fraction spectrum.

Strong evidence supports the importance of rapid sequence or simultaneous initiation of quadruple guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) for substantially reducing risk of mortality and hospitalization. Barring absolute contraindications for each individual medication, employing the strategy of rapid sequence, simultaneous, and/or in-hospital initiation at the time of HF diagnosis best ensures patients with HFrEF have the opportunity to benefit from proven medications and achieve large absolute risk reductions for adverse clinical outcomes. However, despite guideline recommendations supporting this approach, implementation in clinical practice remains persistently low, with less than one-fifth of eligible patients being prescribed the quadruple GDMT regimen. Additionally, for heart failure with mildly reduced or preserved ejection fraction (HFpEF), sodium-glucose co-transporter 2 inhibitors (SGLT2i) and non-steroidal mineralocorticoid receptor antagonists (MRA) constitute foundational therapy for all eligible patients with significant clinical benefits within just weeks of medication initiation. Nonetheless, the burden of symptoms, functional limitations, and hospitalizations remains substantial for many of these patients, even with SGLT2i and non-steroidal MRA therapy. Additional evidence supports consideration of adjunctive therapies for HF with EF > 40% that can be tailored to the patient phenotype, including glucagon-like peptide-1 receptor agonists (GLP-1 RA) for patients with obesity, as well as angiotensin receptor-neprilysin inhibitors (ARNI) for patients with EF below normal. This article reviews the evidence-based sequencing of GDMT for HF across the spectrum of EF, emphasizing the rationale and benefits of early up-front initiation of quadruple medical therapy for HFrEF, rapid initiation of SGLT2i for HF regardless of EF, and prompt phenotype-specific tailored approach to adjunctive therapies for HF with EF > 40%.