What is the difference in treatment between heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF)?

Treatment Differences Between HFpEF and HFrEF

The fundamental difference in treatment is that HFrEF has robust evidence-based guideline-directed medical therapy (GDMT) with proven mortality benefit, while HFpEF treatment focuses primarily on symptom management with diuretics, SGLT2 inhibitors, and comorbidity optimization, with limited mortality-reducing therapies. 1

HFrEF Treatment: Established GDMT with Mortality Benefit

For HFrEF (LVEF ≤40%), the following medications constitute GDMT and provide high economic value with proven mortality reduction: 1

Core Pharmacologic Therapy for HFrEF:

• ACE inhibitors or ARBs (if ACEi not tolerated) - Class I recommendation 1
• ARNi (sacubitril/valsartan) - preferred over ACEi/ARB, provides superior mortality benefit 1
• Beta-blockers - proven mortality reduction 1
• Mineralocorticoid receptor antagonists (MRAs) - for NYHA class II-IV symptoms 1
• SGLT2 inhibitors - reduces cardiovascular death and HF hospitalizations 1

Additional HFrEF-Specific Therapies:

• Hydralazine plus isosorbide dinitrate - specifically for self-identified African American patients with NYHA class III-IV on optimal therapy 1
• Implantable cardioverter-defibrillators (ICDs) - for primary prevention when LVEF ≤35% 1
• Cardiac resynchronization therapy (CRT) - for LVEF ≤35%, sinus rhythm, LBBB with QRS ≥150 ms, NYHA class II-IV 1

HFpEF Treatment: Limited Disease-Modifying Options

For HFpEF (LVEF ≥50%), treatment is fundamentally different with no therapies proven to reduce mortality, focusing instead on symptom management and hospitalization reduction: 1

Evidence-Based HFpEF Pharmacotherapy:

• SGLT2 inhibitors - Class 2a recommendation, reduces HF hospitalizations and cardiovascular death composite endpoint 1, 2
• Diuretics as needed - for congestion management, symptom relief 1
• ARNi (sacubitril/valsartan) - Class 2b recommendation, may reduce hospitalizations particularly in patients with LVEF closer to 50% 1, 2
• MRAs - Class 2b recommendation, greater benefit in patients with LVEF closer to 50% 1
• ARBs - Class 2b recommendation, may decrease hospitalizations particularly with lower-end LVEF in the preserved range 1

Ineffective Therapies in HFpEF:

• Nitrates and phosphodiesterase-5 inhibitors - Class 3 (no benefit) for routine use to increase activity or quality of life 1

Critical Management Distinctions

Diagnostic Approach Differences:

HFpEF diagnosis requires additional evidence beyond symptoms and reduced EF, including: 1

• Elevated natriuretic peptides (BNP >35 pg/mL or NT-proBNP >125 pg/mL ambulatory) 1
• Evidence of increased LV filling pressures (E/e' ≥15, invasive hemodynamics) 1
• Structural heart disease (increased LA volume index, increased LV mass index) 1
• H2FPEF score may aid diagnosis (obesity, AF, age >60, ≥2 antihypertensives, E/e' >9, PA systolic pressure >35 mmHg) 1

Imaging Priorities:

• Both HFrEF and HFpEF: Transthoracic echocardiography is usually appropriate for EF classification 1
• HFrEF-specific: Distinguish ischemic vs non-ischemic etiology with coronary CTA, stress testing, or cardiac MRI to guide revascularization decisions 1
• HFpEF-specific: Exercise stress echocardiography with diastolic parameter assessment if diagnosis uncertain 1

Trajectory and Reclassification Considerations

Patients with HFrEF who improve LVEF to >40% are classified as HFimpEF (heart failure with improved EF) and must continue HFrEF GDMT to prevent relapse, even if asymptomatic - Class I recommendation 1. Withdrawal of therapy frequently results in EF decline 1.

Common Pitfalls to Avoid:

• Do not discontinue HFrEF medications when EF improves above 40% - these patients remain HFimpEF and require continued GDMT 1
• Do not apply HFrEF therapies to HFpEF expecting mortality benefit - only SGLT2 inhibitors have shown composite endpoint reduction 1, 2
• Do not diagnose HFpEF without objective evidence of elevated filling pressures or structural abnormalities beyond symptoms alone 1
• Recognize HFmrEF (LVEF 41-49%) as a distinct intermediate category, often representing dynamic trajectory between HFrEF and HFpEF 1

Pathophysiologic Basis for Treatment Differences

The divergent treatment responses reflect fundamentally different disease mechanisms: 3, 4, 5

• HFrEF: Primarily systolic dysfunction with neurohormonal activation responsive to ACEi/ARB/ARNi, beta-blockade, and MRA antagonism 5
• HFpEF: Diastolic dysfunction driven by systemic inflammation, coronary microvascular endothelial dysfunction, comorbidity burden (obesity, diabetes, hypertension), and myocardial stiffness 3, 4, 5

Risk factor profiles also differ: obesity, smoking, and atrial fibrillation predict HFpEF specifically, while male sex, higher cholesterol, hypertension, coronary disease, LVH, and LBBB predict HFrEF 6, 7