What are the proven helpful drugs in Heart Failure with Reduced Ejection Fraction (HFrEF)?

Proven Helpful Drugs in Heart Failure with Reduced Ejection Fraction (HFrEF)

The four cornerstone medication classes that have proven mortality and morbidity benefits in HFrEF are SGLT2 inhibitors, mineralocorticoid receptor antagonists (MRAs), beta-blockers, and renin-angiotensin system inhibitors (ACE inhibitors/ARBs/ARNIs). 1

Core Medication Classes

1. Renin-Angiotensin System Inhibitors

• ACE Inhibitors (Level of Evidence: A)

  • Examples: Enalapril (2.5mg BID → 10-20mg BID), Lisinopril (2.5-5mg daily → 20-35mg daily), Ramipril (2.5mg daily → 10mg daily) 2
  • Reduce morbidity and mortality in all stages of HFrEF 2

• Angiotensin Receptor Blockers (Level of Evidence: A)

  • Examples: Valsartan (40mg BID → 160mg BID), Candesartan (4-8mg daily → 32mg daily), Losartan (50mg daily → 150mg daily) 2
  • Alternative for patients intolerant to ACE inhibitors due to cough or angioedema 3

• Angiotensin Receptor-Neprilysin Inhibitor (ARNI) (Level of Evidence: B-R)

  • Sacubitril/valsartan (24/26mg BID → 97/103mg BID) 2, 4
  • Preferred over ACE inhibitors/ARBs as it further reduces cardiovascular death and HF hospitalization by 20% 2, 4
  • Mechanism: Inhibits neprilysin (increasing beneficial natriuretic peptides) while blocking angiotensin II effects 4

2. Beta-Blockers (Level of Evidence: A)

• Evidence-based options:
  • Carvedilol (3.125mg BID → 25mg BID for <85kg or 50mg BID for ≥85kg)
  • Metoprolol succinate (12.5-25mg daily → 200mg daily)
  • Bisoprolol (1.25mg daily → 10mg daily)
  • Nebivolol (1.25mg daily → 10mg daily) 2, 1
• Reduce mortality and morbidity even in patients with stable HF 1

3. Mineralocorticoid Receptor Antagonists (MRAs) (Level of Evidence: A)

• Options:
  • Spironolactone (12.5-25mg daily → 25-50mg daily)
  • Eplerenone (25mg daily → 50mg daily) 2, 1
• Reduce mortality and hospitalization in selected patients with NYHA class II-IV HF 3
• Monitor renal function and potassium levels carefully (serum creatinine ≤2.5mg/dl in men, ≤2.0mg/dl in women; potassium <5.0mEq/L) 3

4. SGLT2 Inhibitors (High Level of Evidence)

• Options:
  • Dapagliflozin (10mg daily)
  • Empagliflozin (10mg daily) 1
• Improve outcomes regardless of diabetic status 5
• Associated with improved health-related quality of life (HRQoL) 2

Additional Beneficial Therapies

1. Ivabradine

• Mechanism: If channel inhibitor that reduces heart rate in sinus rhythm 6
• Indicated for patients with resting heart rate ≥70 bpm despite maximally tolerated beta-blocker dose 5
• Improves health-related quality of life 2

2. Hydralazine-Isosorbide Dinitrate Combination

• Particularly beneficial in African American patients with NYHA class II-IV HF 3
• Improves health-related quality of life 2

3. Diuretics

• Loop diuretics (furosemide, bumetanide, torasemide) are first-line for volume overload 2, 3
• Aim to achieve and maintain euvolemia with lowest effective dose 2
• May be combined with thiazides for resistant edema 2

Implementation Strategy

Medication Initiation and Titration

1. Start with medications having minimal BP-lowering effects:

   • SGLT2 inhibitors and MRAs 1

2. Add and titrate beta-blockers:

   • Start at very low doses
   • Titrate gradually every 2 weeks 1

3. Add and titrate ACEi/ARB/ARNI:

   • Start at low doses
   • Titrate gradually every 2 weeks 1

4. Titrate one medication at a time:

   • Aim for target doses or maximally tolerated doses
   • Target at least 50% of target dose for each medication class 1

Common Pitfalls to Avoid

1. Undertreatment: Many patients receive suboptimal doses; strive for target doses or document specific reasons for not achieving them 1

2. Inappropriate discontinuation: Consider dose reduction rather than discontinuation when side effects occur 1

3. Clinical inertia: Don't delay uptitration due to apparent clinical stability; outcomes improve with higher doses even in stable patients 1

4. Neglecting follow-up: Schedule follow-up within 7-14 days after hospital discharge to assess response and adjust medications 1

5. Inadequate monitoring: Regularly assess vital signs, volume status, renal function, and electrolytes at each visit 1

By implementing this comprehensive approach to pharmacotherapy in HFrEF, clinicians can significantly reduce mortality, decrease hospitalizations, and improve quality of life for patients with this challenging condition.