What are the treatment recommendations for patients with Cardiovascular (CV) disease and Heart Failure with mid-range ejection fraction (HFmrEF)?

Treatment Recommendations for Cardiovascular Disease and HFmrEF

For patients with cardiovascular disease and heart failure with mid-range ejection fraction (HFmrEF, LVEF 40-49%), SGLT2 inhibitors (dapagliflozin or empagliflozin) are the strongest evidence-based therapy to reduce HF hospitalization and cardiovascular death, with weaker but reasonable evidence supporting the use of beta-blockers, ACE inhibitors/ARBs/ARNi, and mineralocorticoid receptor antagonists. 1

Primary Pharmacological Therapy

First-Line Therapy

• SGLT2 inhibitors (dapagliflozin or empagliflozin) are recommended (Class I) for patients with HFmrEF to reduce the risk of HF hospitalization or cardiovascular death 1
• This represents the strongest evidence-based recommendation specifically for the HFmrEF population 1

Additional Neurohormonal Therapies (Class IIa-IIb)

The following therapies can be beneficial, particularly for patients with LVEF on the lower end of the 40-49% spectrum 1:

• Beta-blockers (bisoprolol, carvedilol, or sustained-release metoprolol succinate) may be considered to reduce HF hospitalization and cardiovascular mortality 1
• ACE inhibitors or ARBs may be considered, with ARNi (sacubitril/valsartan) as an alternative 1
• Mineralocorticoid receptor antagonists (MRAs) may be considered for symptom reduction and outcomes improvement 1

Important caveat: These neurohormonal therapies carry weaker recommendations (Class IIb) in HFmrEF compared to their Class I recommendations in HFrEF, reflecting less robust evidence in this specific population 1

Symptomatic Management

• Diuretics are recommended for patients with signs and/or symptoms of congestion to alleviate symptoms, improve exercise capacity, and reduce HF hospitalizations 1

Management of Concurrent Coronary Artery Disease

Revascularization Considerations

For HFmrEF patients (LVEF >35%) with suspected chronic coronary syndromes 1:

• With low or moderate pre-test likelihood (>5%-50%) of obstructive CAD: Coronary CT angiography or functional imaging is recommended 1
• With very high pre-test likelihood (>85%) of obstructive CAD: Invasive coronary angiography (with FFR, iFR, or QFR when needed) is recommended 1
• For symptomatic angina despite medical therapy: Coronary revascularization (CABG or PCI) is reasonable to improve symptoms 1

Multidisciplinary Management

• Enrollment in a multidisciplinary HF management program is recommended to reduce HF hospitalization risk and improve survival 1

Device Therapy Considerations

Critical distinction: Device therapy recommendations in HFmrEF differ substantially from HFrEF because the LVEF threshold for most device indications is ≤35% 1:

• ICD therapy is NOT indicated for primary prevention in HFmrEF patients unless LVEF drops to ≤35% despite ≥3 months of optimized therapy 1
• CRT is NOT indicated unless LVEF is ≤35% with appropriate QRS criteria 1
• Exception: ICD is recommended for secondary prevention in patients who have recovered from ventricular arrhythmia causing hemodynamic instability, regardless of LVEF 1

Comorbidity Management

Hypertension Control

• Blood pressure control according to published guidelines is essential, with systolic BP goal <130 mm Hg when using guideline-directed medical therapy 1
• Prioritize medications that also treat HF (ACE inhibitors, ARBs, beta-blockers, MRAs) 1

Atrial Fibrillation Management

• AF management according to published guidelines is reasonable to improve symptomatic HF 1
• Rate control or rhythm control strategies should allow for optimization of HF therapies 1

Diabetes Management

• SGLT2 inhibitors serve dual purpose in diabetic patients with HFmrEF, addressing both glycemic control and HF outcomes 1
• Avoid thiazolidinediones (pioglitazone, rosiglitazone) due to increased HF risk 1

Evidence Strength and Clinical Context

Key clinical pearls:

• The HFmrEF population represents a heterogeneous group, with clinical profiles and outcomes intermediate between HFrEF and HFpEF 2, 3
• Observational data suggests patients with HFmrEF who receive neurohormonal therapies (beta-blockers, RAS inhibitors) have improved mortality outcomes 4, 3
• Many HFmrEF patients have history of recovered systolic function from prior HFrEF, and continuation of HFrEF therapies is reasonable in this context 1, 3
• The evidence base for HFmrEF-specific therapies is evolving, with most recommendations extrapolated from HFrEF trials or derived from post-hoc analyses 2, 3

Practical Implementation Algorithm

1. Initiate SGLT2 inhibitor (dapagliflozin 10 mg daily or empagliflozin 10 mg daily) as first-line therapy 1
2. Add diuretics as needed for congestion management 1
3. Consider adding neurohormonal therapies sequentially, particularly if LVEF is 40-44% or if patient has history of lower EF 1, 3:
   • Beta-blocker (evidence-based agent)
   • ACE inhibitor/ARB or ARNi
   • MRA (if eGFR >30 mL/min/1.73m² and K+ <5.0 mEq/L)
4. Evaluate for coronary revascularization if angina or ischemia present despite medical therapy 1
5. Monitor LVEF serially, as progression to HFrEF (LVEF ≤40%) would strengthen indications for all neurohormonal therapies and potentially device therapy 1