What is the recommended agent for treating symptomatic heart failure across the spectrum of ejection fraction in the United States?

D. Empagliflozin is the correct answer—it is the only agent among these options approved for symptomatic heart failure across the entire spectrum of ejection fraction in the United States.

Why Empagliflozin is the Answer

Empagliflozin (an SGLT2 inhibitor) has FDA approval for heart failure treatment regardless of ejection fraction, making it unique among the listed options. 1 The 2022 AHA/ACC/HFSA guidelines specifically state that SGLT2 inhibitors can be beneficial in decreasing HF hospitalizations and cardiovascular mortality in patients with HFmrEF (LVEF 41-49%), and the EMPEROR-Preserved trial demonstrated benefit in patients with LVEF >40%. 1

• SGLT2 inhibitors have Class I, Level of Evidence: A guideline recommendations and demonstrated substantial relative and absolute risk reductions across multiple endpoints in heart failure patients. 1
• The evidence shows benefit across the full spectrum: HFrEF, HFmrEF, and HFpEF populations. 1

Why the Other Options Are Incorrect

B. Valsartan-Sacubitril (Sacubitril/Valsartan)

Sacubitril/valsartan is NOT approved across the spectrum of ejection fraction. While it has broader approval than initially, its indication remains focused on reduced and mildly reduced ejection fraction:

• The FDA approved sacubitril/valsartan in 2015 specifically for HFrEF (LVEF ≤40%) based on the PARADIGM-HF trial. 1
• Following PARAGON-HF, the indication was revised to state: "Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal." 2
• The FDA explicitly clarified that the product label does not refer to HFpEF. 2
• The drug label from PARAGON-HF shows it was tested in patients with LVEF ≥45%, but failed to meet the pre-defined threshold for statistical significance in this population. 3

C. Spironolactone

Spironolactone is approved only for HFrEF, not across the spectrum:

• Mineralocorticoid receptor antagonists like spironolactone are recommended for symptomatic patients with LVEF ≤35% to reduce mortality and hospitalization. 4
• The 2022 guidelines give it only a Class 2b recommendation for HFmrEF (may be considered), not a strong indication. 1
• There is no approval or strong evidence for use in HFpEF. 1

A. Nebivolol

Nebivolol is a beta-blocker without specific approval for heart failure across the ejection fraction spectrum:

• Evidence-based beta-blockers for HFrEF include carvedilol, metoprolol succinate, and bisoprolol—not nebivolol as a primary agent. 4
• Beta-blockers have a Class 2b recommendation for HFmrEF (may be considered, particularly at lower LVEF ranges). 1
• Beta-blockers are not recommended as foundational therapy in HFpEF. 1

Clinical Context: The Evolving Landscape

The question specifically asks about approval "to this date" in the United States, which is critical:

• SGLT2 inhibitors represent the newest class with the broadest approval across ejection fraction categories. 1
• The EMPEROR-Preserved trial showed a 21% reduction in the primary composite endpoint (time to HF hospitalization or cardiovascular death) in patients with LVEF >40%, driven by a 29% reduction in HF hospitalization. 1
• The benefit was similar regardless of diabetes status, making it applicable to the broad heart failure population. 1

Common Pitfall to Avoid

Do not confuse "guideline-recommended" with "FDA-approved across the spectrum." Sacubitril/valsartan has strong guideline support for HFrEF and is increasingly used in HFmrEF, but its FDA approval explicitly states benefits are "most clearly evident in patients with LVEF below normal"—not across the full spectrum including preserved EF. 2 Only SGLT2 inhibitors like empagliflozin have demonstrated benefit and gained approval across HFrEF, HFmrEF, and HFpEF populations. 1