What are the treatment options for Heart Failure with Reduced Ejection Fraction (HFrEF)?

Treatment Options for Heart Failure with Reduced Ejection Fraction (HFrEF)

The cornerstone of HFrEF management is quadruple therapy with SGLT2 inhibitors, beta-blockers, renin-angiotensin system inhibitors (preferably ARNi), and mineralocorticoid receptor antagonists, which significantly reduce mortality and hospitalizations. 1, 2

Foundation Medications for HFrEF

First-Line Quadruple Therapy

1. SGLT2 Inhibitors

   • Dapagliflozin 10mg daily or Empagliflozin 10mg daily
   • Reduces HF hospitalizations and cardiovascular mortality
   • NNT to prevent one death over 36 months: 22

2. Beta-Blockers

   • Options: Bisoprolol (1.25mg → 10mg daily), Carvedilol (3.125mg → 25-50mg BID), Metoprolol succinate (12.5-25mg → 200mg daily)
   • Start at low doses and titrate gradually
   • NNT to prevent one death over 36 months: 9

3. Renin-Angiotensin System Inhibitors

   • Preferred: Angiotensin Receptor-Neprilysin Inhibitor (ARNi)
     • Sacubitril/Valsartan (49/51mg → 97/103mg BID)
     • More effective than ACEi alone in reducing morbidity and mortality
   • Alternatives if ARNi not tolerated:
     • ACEi: Lisinopril (2.5-5mg → 20-40mg daily), Enalapril (2.5mg → 10-20mg BID), Ramipril (1.25-2.5mg → 10mg daily)
     • ARB: Candesartan (4-8mg → 32mg daily)
   • NNT to prevent one death over 36 months: 26

4. Mineralocorticoid Receptor Antagonists (MRAs)

   • Spironolactone (12.5-25mg → 25-50mg daily) or Eplerenone (25mg → 50mg daily)
   • For patients with LVEF ≤35% and NYHA class II-IV symptoms
   • Monitor renal function and potassium levels
   • NNT to prevent one death over 36 months: 6

Timing of Initiation

• All four medication classes should be introduced over a 4-6 week period, followed by dose up-titration over 8 weeks 3
• Begin with low doses and titrate to target doses or maximum tolerated doses

Additional Pharmacological Options

1. Diuretics

   • Essential for symptomatic relief of congestion
   • Not proven to reduce mortality but improve symptoms and quality of life

2. Hydralazine/Nitrates

   • Particularly beneficial in African American patients
   • NNT to prevent one death over 36 months: 7

3. Ivabradine

   • Consider for patients in sinus rhythm with heart rate ≥70 bpm despite maximally tolerated beta-blocker dose

4. Vericiguat

   • Novel oral guanylate cyclase stimulator
   • May provide additional benefit when added to standard therapy

Device Therapy Options

1. Implantable Cardioverter-Defibrillator (ICD)

   • Recommended for primary prevention in patients with NYHA class II-III symptoms on optimal medical therapy and EF ≤35% 2

2. Cardiac Resynchronization Therapy (CRT)

   • Recommended for patients with LVEF ≤35%, QRS ≥150ms, and left bundle branch block morphology 2
   • Improves cardiac function and reduces mortality

3. Transcatheter Mitral Valve Repair

   • For selected patients with functional mitral regurgitation 1

Special Considerations

HFmrEF (LVEF 41-49%)

• SGLT2 inhibitors are beneficial in decreasing HF hospitalizations and cardiovascular mortality (Class 2a, Level B-R) 1
• Evidence-based beta-blockers, ARNi, ACEi/ARB, and MRAs may be considered, particularly for patients with LVEF on the lower end of this spectrum (Class 2b, Level B-NR) 1

Common Pitfalls and Caveats

1. Suboptimal Dosing

   • Despite compelling evidence, guideline-directed medical therapy is vastly underutilized in real-world practice 4
   • Target doses or maximum tolerated doses should be the goal

2. Medication Monitoring

   • Monitor renal function and potassium with MRAs and ACEi/ARB/ARNi
   • Watch for hypotension, especially when initiating multiple agents

3. Patient Education

   • Emphasize importance of medication adherence
   • Self-monitoring of weight (sudden gain >2kg in 3 days requires attention)
   • Salt restriction and fluid management

4. Recovered EF

   • Patients with recovered EF still have risk of re-deterioration of systolic function 5
   • Continue guideline-directed medical therapy even after EF improvement

Implementation Strategy

1. Start all four foundation medications within 4-6 weeks
2. Begin with low doses and titrate gradually over 8 weeks
3. Monitor for side effects (hypotension, hyperkalemia, renal dysfunction)
4. Evaluate for device therapy once on optimal medical therapy
5. Consider advanced therapies for refractory cases (mechanical circulatory support, transplantation)

The evidence strongly supports early initiation of all four foundation medication classes to maximize mortality and morbidity benefits in HFrEF patients, with careful monitoring and dose optimization over time.