What is the guideline-directed medical therapy (GDMT) for a patient with heart failure with mid-range ejection fraction (HFmrEF) of 40%?

GDMT for HFmrEF with EF 40%

For a patient with heart failure and ejection fraction of 40% (HFmrEF), initiate SGLT2 inhibitors immediately (Class 2a recommendation), and strongly consider the full quadruple therapy regimen used for HFrEF—including ARNI/ACEi/ARB, evidence-based beta-blockers, and mineralocorticoid receptor antagonists—particularly since an EF of 40% sits at the lower end of the HFmrEF spectrum where these therapies demonstrate similar efficacy to HFrEF. 1

Primary Recommendation: SGLT2 Inhibitors (Class 2a)

• Start empagliflozin or dapagliflozin immediately as this is the only Class 2a (strongest) recommendation specifically for HFmrEF, demonstrating reduction in heart failure hospitalizations and cardiovascular mortality in the EMPEROR-Preserved trial. 1
• SGLT2 inhibitors showed consistent benefit across the LVEF spectrum of 41-49% without significant interaction by ejection fraction subgroups. 1
• These agents require no dose titration, have minimal blood pressure impact, and provide benefits within weeks of initiation. 2, 3

Secondary Recommendations: Consider Full HFrEF GDMT (Class 2b)

Since your patient's EF of 40% sits at the absolute lower boundary of HFmrEF, the evidence strongly supports treating similarly to HFrEF:

Evidence-Based Beta-Blockers (Class 2b)

• Use only carvedilol, metoprolol succinate, or bisoprolol—no substitutions. 1, 2
• The BBmeta-HF meta-analysis showed beta-blockers reduced all-cause and cardiovascular mortality in 575 patients with LVEF 40-49% in sinus rhythm. 1
• Start at low doses and uptitrate every 1-2 weeks to target doses. 3

ARNI/ACEi/ARB (Class 2b)

• Prefer ARNI (sacubitril-valsartan) if tolerated, based on PARAGON-HF subgroup analysis showing benefit in patients with LVEF 45-57% (rate ratio 0.78,95% CI 0.64-0.95). 1
• If switching from ACEi to ARNI, observe strict 36-hour washout period to avoid angioedema. 2, 3
• Post-hoc analysis of CHARM trials showed candesartan reduced cardiovascular death and HF hospitalization in 1322 patients with LVEF 41-49%. 1

Mineralocorticoid Receptor Antagonists (Class 2b)

• Use spironolactone (12.5-25 mg daily) or eplerenone (25 mg daily). 1, 2
• TOPCAT post-hoc analysis in 520 patients with LVEF 44-49% showed spironolactone reduced the composite endpoint of cardiovascular death, HF hospitalization, or resuscitated sudden death. 1
• Prioritize spironolactone if poorly controlled hypertension is present, given its blood pressure management benefits. 1
• Monitor potassium and creatinine closely during uptitration. 3

Implementation Strategy

Simultaneous Initiation Approach

• Start all four medication classes simultaneously at low doses rather than sequential initiation, following the same protocol as HFrEF. 2, 3, 4
• Uptitrate every 1-2 weeks until target doses are achieved. 3, 4
• Check blood pressure, renal function, and electrolytes 1-2 weeks after each dose increment. 3, 4

Managing Common Barriers

• Do not withhold therapy for asymptomatic low blood pressure—patients with adequate perfusion tolerate systolic BP 80-100 mmHg. 2, 3
• If blood pressure is limiting, prioritize in this order: SGLT2 inhibitors and MRAs first (minimal BP impact), then beta-blockers, then ARNI/ACEi/ARB. 2, 3
• Accept modest creatinine increases up to 30% above baseline—do not discontinue ARNI/ACEi/ARB for this alone. 3, 4

Critical Monitoring

• Repeat LVEF evaluation to determine disease trajectory—patients with HFmrEF may improve to HFpEF or decline to HFrEF. 1
• If EF improves above 40%, continue all HFrEF medications as discontinuation may lead to clinical deterioration. 1, 2
• More frequent monitoring is needed in elderly patients and those with chronic kidney disease. 2

Evidence Strength Considerations

The Class 2b recommendations for beta-blockers, ARNI/ACEi/ARB, and MRAs are based entirely on post-hoc and subset analyses—no prospective RCTs exist specifically for HFmrEF. 1 However, the data consistently show that patients with LVEF on the lower end of the 41-49% spectrum (like your patient at 40%) respond similarly to HFrEF patients. 1, 5 Research demonstrates that each mg equivalent of bisoprolol (HR 0.95% CI 0.91-1.00) and ramipril (HR 0.95% CI 0.90-1.00) was associated with incremental mortality reductions in HFmrEF. 5