How is ejection fraction (EF) classified in heart failure and what guideline‑directed medical therapy (GDMT) is recommended for heart failure with reduced EF (HFrEF, EF < 40%), heart failure with mildly reduced EF (HFmrEF, EF 40‑49%), and heart failure with preserved EF (HFpEF, EF ≥ 50%)?

Ejection Fraction Classification in Heart Failure

EF-Based Classification

Heart failure is classified into three distinct categories based on left ventricular ejection fraction (LVEF): HFrEF with EF ≤40%, HFmrEF with EF 41-49%, and HFpEF with EF ≥50%. 1

• HFrEF (Heart Failure with Reduced Ejection Fraction): LVEF ≤40% 2, 3, 1
• HFmrEF (Heart Failure with Mildly Reduced Ejection Fraction): LVEF 41-49% 2, 3, 1
• HFpEF (Heart Failure with Preserved Ejection Fraction): LVEF ≥50% 2, 3, 1
• HFimpEF (Heart Failure with Improved Ejection Fraction): Previously ≤40% with subsequent improvement to >40% 2, 1

Diagnostic Requirements Beyond EF

For HFmrEF and HFpEF Diagnosis

Establishing a diagnosis of HFmrEF or HFpEF requires more than just measuring EF—you must document objective evidence of elevated left ventricular filling pressures or structural cardiac abnormalities. 1

• Elevated natriuretic peptides: BNP >35 pg/mL (ambulatory) or >100 pg/mL (hospitalized); NT-proBNP >125 pg/mL (ambulatory) or >300 pg/mL (hospitalized) 4, 1
• Echocardiographic evidence: E/e' ratio ≥15, diastolic dysfunction parameters, increased left atrial volume index (LAVI), or increased left ventricular mass index (LVMI) 2, 4, 1
• Direct evidence of congestion: Pulmonary or systemic congestion on imaging or physical examination 4

Critical Diagnostic Pitfall

Do not diagnose HFpEF based solely on preserved EF and dyspnea—systematically exclude pulmonary disease, obesity-related dyspnea, anemia, renal dysfunction, and other non-cardiac causes first. 4

Guideline-Directed Medical Therapy by EF Category

HFrEF (EF ≤40%): Robust Evidence-Based Therapy

HFrEF has the strongest evidence base with multiple proven mortality-reducing therapies. 2

• Foundational therapy includes: ACE inhibitors/ARBs (or ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors 2
• Device therapy: ICD for primary prevention when LVEF ≤35% despite ≥3 months of optimal medical therapy; CRT for LVEF ≤35% with QRS ≥150ms and LBBB 3
• These medications have demonstrated mortality reduction in randomized controlled trials exclusively in the HFrEF population 2

HFmrEF (EF 41-49%): Emerging Evidence

HFmrEF patients should be treated similarly to HFrEF patients, as they share more clinical characteristics with HFrEF than HFpEF, particularly regarding coronary artery disease prevalence and response to neurohormonal blockade. 5

• Beta-blockers, ACE inhibitors/ARBs, and MRAs are recommended based on extrapolation from HFrEF trials and observational data showing benefit 6, 5
• SGLT2 inhibitors show benefit across the EF spectrum including HFmrEF 6
• NT-proBNP-guided therapy improves outcomes in HFmrEF similar to HFrEF, but not in HFpEF 5
• Clinical characteristics: Higher prevalence of coronary artery disease compared to HFpEF, intermediate comorbidity burden, and better 1-year survival (20%) compared to HFrEF (28%) 7, 5

HFpEF (EF ≥50%): Limited Proven Therapies

HFpEF management focuses on SGLT2 inhibitors as first-line therapy, diuretics for congestion, and aggressive treatment of comorbidities—traditional HFrEF medications have not demonstrated mortality benefit in this population. 4

• SGLT2 inhibitors (dapagliflozin or empagliflozin): First-line therapy with ~20% reduction in HF hospitalization or cardiovascular death 4
• Loop diuretics: Essential for managing congestion; titrate based on symptoms 4
• Mineralocorticoid receptor antagonists (spironolactone): May benefit selected patients, particularly women and those with lower-range EF (50-55%) 4
• ARNI (sacubitril/valsartan): Consider in symptomatic patients despite first-line therapy, particularly women 4
• Avoid: NSAIDs that worsen congestion; use beta-blockers only for specific indications (prior MI, angina, atrial fibrillation rate control) 4

Important Clinical Considerations

Natriuretic Peptide Interpretation

Natriuretic peptide levels are typically lower in HFpEF compared to HFrEF for equivalent filling pressures, and obesity—common in HFpEF—further suppresses these biomarkers. 4

Sex-Specific Risk Factors

In women with HFpEF, a history of pre-eclampsia significantly increases risk and should be elicited during history-taking. 4

Echocardiographic Assessment

E/e' ratio is the best-established echocardiographic parameter for HFpEF diagnosis, but shows only modest correlation (r=0.56) with invasively measured filling pressures—use multiple parameters in an integrated assessment rather than relying on E/e' alone. 2

Functional Classification

Use the NYHA functional classification (Class I-IV based on symptom severity with activity) alongside EF categories to guide treatment intensity and prognosis. 1