What is the recommended treatment for heart failure with preserved ejection fraction?

Treatment for Heart Failure with Preserved Ejection Fraction (HFpEF)

SGLT2 inhibitors (dapagliflozin or empagliflozin) are the cornerstone disease-modifying therapy for HFpEF and should be initiated in all patients without contraindications, as they provide the most robust and consistent reduction in heart failure hospitalizations and cardiovascular death across the entire HFpEF spectrum. 1

Core Pharmacologic Strategy

First-Line Disease-Modifying Therapy

SGLT2 Inhibitors are the primary evidence-based treatment:

• Empagliflozin reduced the composite of HF hospitalization and cardiovascular death by 21% (HR 0.79,95% CI 0.69-0.90) in EMPEROR-PRESERVED 1
• Dapagliflozin reduced worsening HF and cardiovascular death by 18% (HR 0.82,95% CI 0.73-0.92) in DELIVER 1
• Both agents reduced HF hospitalizations by approximately 23-29% 1
• Benefit is consistent across the entire LVEF spectrum (≥40%), including patients with LVEF ≥60% 2

Additional Disease-Modifying Agents

Mineralocorticoid Receptor Antagonists (MRAs):

• Spironolactone reduced HF hospitalizations (HR 0.83,95% CI 0.69-0.99) in TOPCAT, particularly in North American patients 1
• Finerenone (non-steroidal MRA) reduced cardiovascular death and total HF events (RR 0.83,95% CI 0.74-0.94) in FINEARTS-HF 3
• Monitor potassium and renal function closely at initiation and follow-up 1

Angiotensin Receptor-Neprilysin Inhibitors (ARNIs):

• Sacubitril/valsartan showed borderline benefit in PARAGON-HF (rate ratio 0.87,95% CI 0.75-1.01) 1
• Greater benefit observed in patients with LVEF closer to 50% (LVEF 45-57%: rate ratio 0.78,95% CI 0.64-0.95) 1
• Women derived more benefit (rate ratio 0.73,95% CI 0.59-0.90) 1
• Consider particularly for patients with LVEF 50-59% 2

Combination Therapy:

• The triple combination of ARNI + MRA + SGLT2i provides the greatest reduction in cardiovascular death and HF hospitalization (HR 0.56,95% CI 0.43-0.71) 2
• This benefit is most pronounced in HFmrEF (LVEF 41-49%) and robust in LVEF 50-59%, with marginal benefit in LVEF ≥60% 2

Symptomatic Management

Loop Diuretics:

• Use judiciously as needed to reduce congestion and improve symptoms 1
• Titrate to achieve euvolemia without excessive volume depletion 1

Beta-Blockers:

• Reserve for specific indications: prior myocardial infarction (up to 3 years post-MI), angina, or atrial fibrillation 1
• Monitor exercise tolerance due to potential chronotropic incompetence 1
• Not recommended as routine HFpEF therapy without these specific indications 1

Phenotype-Directed Therapies

For HFpEF with Obesity:

• GLP-1 receptor agonists (semaglutide, tirzepatide) reduce HF hospitalizations and improve quality of life in obese HFpEF patients 4, 5
• Consider as adjunctive therapy in patients with BMI ≥30 kg/m² or obesity-related HFpEF phenotype 5, 6

For HFpEF with Diabetes:

• SGLT2 inhibitors provide dual benefit for glycemic control and HF outcomes 1
• 45-49% of patients in major HFpEF trials had type 2 diabetes 1

For HFpEF with Chronic Kidney Disease:

• SGLT2 inhibitors and finerenone offer both cardiovascular and renal benefits 7
• Careful monitoring of potassium and renal function essential with MRAs 7

Comorbidity Management

Aggressive treatment of contributing conditions is essential: 1

• Hypertension: Target blood pressure control
• Atrial fibrillation: Rate/rhythm control and anticoagulation
• Coronary artery disease: Optimize anti-ischemic therapy
• Obstructive sleep apnea: Screen and treat
• Anemia and iron deficiency: Investigate and correct

Non-Pharmacologic Interventions

• Structured exercise programs improve functional capacity and quality of life 6
• Weight loss in obese patients reduces HF burden 1, 6
• Wireless pulmonary artery pressure monitoring may guide hemodynamic-directed therapy 1, 6

Common Pitfalls to Avoid

Do not use therapies proven ineffective in HFpEF: 1

• ACE inhibitors (perindopril), ARBs alone (irbesartan, candesartan showed minimal benefit)
• Nitrates (NEAT-HFpEF negative)
• Digoxin, ivabradine, sildenafil, serelaxin

Avoid excessive diuresis: Can worsen symptoms and reduce cardiac output in patients dependent on preload 1

Monitor for hyperkalemia: Particularly when combining ARNI + MRA, or in patients with CKD 1, 3

Do not withhold SGLT2 inhibitors in non-diabetic patients: Benefit is independent of diabetes status 1, 2