What is the latest update on the management of Heart Failure with Reduced Ejection Fraction (HFREF)?

Latest Management of Heart Failure with Reduced Ejection Fraction (HFrEF)

The current standard of care for HFrEF now includes four foundational medication classes that should be initiated in nearly all patients: an ARNI (sacubitril/valsartan), a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor. 1, 2

The Four Pillars of GDMT for HFrEF

1. ARNI (Angiotensin Receptor-Neprilysin Inhibitor)

Sacubitril/valsartan is now recommended as first-line therapy over ACE inhibitors or ARBs for all symptomatic HFrEF patients (Class I recommendation). 1

• Start at 24/26 mg or 49/51 mg twice daily, titrate to target dose of 97/103 mg twice daily 1, 3
• Can be initiated de novo without prior ACE inhibitor/ARB exposure in appropriate patients 1
• Demonstrated 20% reduction in cardiovascular death or heart failure hospitalization compared to enalapril in the PARADIGM-HF trial 3
• Must wait 36 hours after stopping ACE inhibitor before starting ARNI to avoid angioedema risk 1
• If ARNI is not tolerated or accessible, use ACE inhibitors (enalapril 2.5 mg twice daily, target 10-20 mg twice daily) or ARBs (candesartan 4-8 mg daily, target 32 mg daily) as alternatives 1, 4, 5

2. Beta-Blockers

One of three evidence-based beta-blockers (bisoprolol, carvedilol, or metoprolol succinate) must be used in all stable HFrEF patients unless contraindicated (Class I recommendation). 1

• Bisoprolol: start 1.25 mg once daily, target 10 mg once daily 1
• Carvedilol: start 3.125 mg twice daily, target 25 mg twice daily (<85 kg) or 50 mg twice daily (≥85 kg) 1
• Metoprolol succinate: start 12.5-25 mg daily, target 200 mg daily 1
• These agents improve ejection fraction and reduce mortality 1, 6

3. Mineralocorticoid Receptor Antagonists (MRAs)

Add spironolactone or eplerenone when LVEF remains ≤35% or symptoms persist despite ARNI and beta-blocker therapy (Class I recommendation). 1, 7

• Spironolactone: start 12.5-25 mg daily, target 25-50 mg daily 1
• Eplerenone: start 25 mg daily, target 50 mg daily 1
• Do not use if serum creatinine >2.5 mg/dL (men) or >2.0 mg/dL (women), or serum potassium >5.0 mEq/L 1
• Monitor potassium and renal function within 1-2 weeks after initiation 4

4. SGLT2 Inhibitors

Dapagliflozin or empagliflozin should be added to all HFrEF patients regardless of diabetes status (Class 2a recommendation). 1, 2

• Dapagliflozin: 10 mg once daily (both starting and target dose) 1
• Empagliflozin: 10 mg once daily (both starting and target dose) 1
• Reduces cardiovascular death and heart failure hospitalization in patients with and without type 2 diabetes 1
• This represents the most significant recent addition to HFrEF therapy since 2017 1, 2

Sequencing and Titration Strategy

Start GDMT immediately upon diagnosis—delayed initiation is associated with never achieving optimal therapy. 1

Practical Initiation Approach:

• Begin with ARNI (or ACE inhibitor if ARNI not available) plus beta-blocker simultaneously 1
• Add SGLT2 inhibitor early, as it can be started at target dose without titration 1
• Add MRA once LVEF ≤35% or symptoms persist (NYHA II-IV) 1
• Titrate medications every 2-4 weeks, doubling doses at each step until target doses achieved 4
• Aim for target doses used in clinical trials, not just "tolerated" doses, as benefits are often dose-dependent 8, 2

Additional Therapies for Specific Indications

Diuretics for Volume Management

Loop diuretics are essential for symptom control in patients with current or prior fluid retention, but do not improve survival. 1

• Furosemide: start 20-40 mg once or twice daily, maximum 600 mg daily 1
• Torsemide: start 10-20 mg once daily, maximum 200 mg daily (longer duration of action preferred) 1
• Congestion drives symptoms and hospitalizations—diligent volume management is critical 1

Ivabradine

Add ivabradine if heart rate remains ≥70 bpm despite maximally tolerated beta-blocker in patients with sinus rhythm and LVEF ≤35% (Class 2a recommendation). 1

• Start 2.5-5 mg twice daily, titrate to achieve heart rate 50-60 bpm, maximum 7.5 mg twice daily 1

Hydralazine/Isosorbide Dinitrate

Add fixed-dose combination hydralazine/isosorbide dinitrate for self-identified Black patients with NYHA III-IV symptoms despite optimal GDMT (Class I recommendation). 1

• Start 20 mg/37.5 mg (1 tablet) three times daily, target 2 tablets three times daily 1
• Also consider in patients who cannot tolerate ARNI, ACE inhibitors, or ARBs 1

Digoxin

Digoxin may be considered for symptom reduction in patients with persistent symptoms despite optimal GDMT, but does not reduce mortality. 1

• Primary role now is rate control for atrial fibrillation in patients with low blood pressure 1

Critical Monitoring Parameters

Check blood pressure, serum creatinine/eGFR, and serum potassium within 1-2 weeks after initiating or increasing doses of ARNI, ACE inhibitors, ARBs, or MRAs. 4

Managing Common Adverse Effects:

Worsening renal function or hyperkalemia:

• Use less than target doses of ARNI/ACE inhibitor/ARB and discontinue MRA if eGFR <30 mL/min or potassium >5.0 mEq/L 1
• Low-dose ACE inhibitor still provides survival benefit and may be preferred with marginal blood pressure 1

Symptomatic hypotension:

• First exclude over-diuresis, non-CV medications causing hypotension, and autonomic dysfunction 1
• Reduce doses of GDMT only after addressing other causes 1
• Consider advanced HF specialist referral for persistent hypotension 1

What NOT to Do

Never combine ARB + ACE inhibitor + MRA (triple combination)—this is potentially harmful and increases risk of hypotension, renal dysfunction, and life-threatening hyperkalemia (Class III: Harm). 4

Do not routinely combine ARB + ACE inhibitor, as this showed increased HF hospitalizations without mortality benefit. 4

Avoid routine use of nitrates or phosphodiesterase-5 inhibitors in HFpEF (Class 3: No Benefit). 1

Device Therapy Considerations

Delay primary prevention ICD and cardiac resynchronization therapy (CRT) decisions until after 3-6 months of optimal GDMT, then reassess EF and device indications. 1, 9

• CRT is Class I indication for symptomatic patients with LVEF ≤35%, QRS ≥150 ms with LBBB morphology 9

Special Populations and Comorbidities

Diabetes mellitus: SGLT2 inhibitors provide dual benefit for both diabetes control and HF outcomes 1, 2

Atrial fibrillation: Treat appropriately with rate/rhythm control; early pulmonary vein ablation may reduce mortality in selected patients 7

Iron deficiency: Check iron status and supplement when ferritin <100 ng/mL or ferritin 100-299 ng/mL with transferrin saturation <20% 7

Improved LVEF Management

Patients with previous HFrEF who now have LVEF >40% should continue their HFrEF treatment—do not discontinue GDMT based on improved EF alone. 1