What are the differences in treatment approaches for Heart Failure with reduced Ejection Fraction (HFrEF) versus Heart Failure with mid-range Ejection Fraction (HFmEF)?

From the Guidelines

Treatment approaches for Heart Failure with reduced Ejection Fraction (HFrEF) and Heart Failure with mid-range Ejection Fraction (HFmEF) differ, with HFrEF requiring a more aggressive pharmacological approach, including the "quadruple therapy" of ACE inhibitors/ARNIs, beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors, as recommended by the 2022 AHA/ACC/HFSA guideline 1. For HFrEF (EF ≤40%), the cornerstone therapy includes ACE inhibitors/ARNIs, beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors, which have demonstrated mortality benefits by addressing neurohormonal activation and reducing cardiac remodeling.

• Key medications for HFrEF include:
  • ACE inhibitors/ARNIs (like enalapril 2.5-20mg BID or sacubitril/valsartan 24/26-97/103mg BID)
  • Beta-blockers (carvedilol 3.125-25mg BID, metoprolol succinate 12.5-200mg daily)
  • Mineralocorticoid receptor antagonists (spironolactone 12.5-50mg daily)
  • SGLT2 inhibitors (empagliflozin 10mg daily or dapagliflozin 10mg daily) For HFmEF (EF 41-49%), treatment has historically been less defined, with guidelines only recently evolving. Current evidence suggests that HFmEF patients may benefit from similar therapies as HFrEF, particularly SGLT2 inhibitors and mineralocorticoid receptor antagonists, as supported by the 2024 ESC guidelines for the management of elevated blood pressure and hypertension 1.
• Key considerations for HFmEF include:
  • SGLT2 inhibitors and mineralocorticoid receptor antagonists may be beneficial
  • Beta-blockers and ACE inhibitors/ARBs are also commonly used, though with less robust mortality evidence than in HFrEF Both groups require diuretics for symptom management, but these don't offer mortality benefits. Treatment should be initiated at low doses and titrated gradually while monitoring renal function, blood pressure, and electrolytes. Non-pharmacological approaches including sodium restriction, fluid management, and cardiac rehabilitation are important for both groups.

From the Research

Treatment Approaches for HFrEF and HFmEF

The treatment approaches for Heart Failure with reduced Ejection Fraction (HFrEF) and Heart Failure with mid-range Ejection Fraction (HFmEF) have some similarities, but also some differences.

• The use of β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists, and sacubitril/valsartan is reasonable in patients with HFmEF, similar to HFrEF patients 2.
• In HFrEF, the European Society of Cardiology (ESC), Canadian Cardiovascular Society, and the American College of Cardiology Heart Failure (HF) guidelines recommend the use of Angiotensin Converting Enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARBs) and Beta Blockers (BB) 3.
• Newer medications such as sacubitril/valsartan and dapagliflozin have shown benefits in mortality and can be used in HFrEF patients 3.
• Patients with HFmrEF are treated more like HFrEF patients, potentially because of a history of systolic dysfunction that has partially recovered 2.
• The treatment of HFmEF is still evolving, and more research is needed to determine the best treatment approaches for this group of patients 4.

Differences in Treatment Approaches

• The main difference in treatment approaches between HFrEF and HFmEF is the lack of clear guidelines for HFmEF, and the treatment is often based on the individual patient's characteristics and comorbidities 2, 4.
• HFrEF patients have more established treatment guidelines, and the use of ACE inhibitors, ARBs, and beta blockers is more widespread 3, 5.
• The use of sacubitril/valsartan and dapagliflozin in HFmEF patients is not as well established as in HFrEF patients, and more research is needed to determine their effectiveness in this group 3.

Clinical Implications

• The treatment of HFmEF patients should be individualized, taking into account their unique characteristics and comorbidities 2, 4.
• HFrEF patients should be treated according to established guidelines, with the use of ACE inhibitors, ARBs, and beta blockers as first-line therapy 3, 5.
• The use of newer medications such as sacubitril/valsartan and dapagliflozin should be considered in both HFrEF and HFmEF patients, but more research is needed to determine their effectiveness in HFmEF patients 3.