What are the primary pharmacological drug classes for symptomatic patients with heart failure and a reduced ejection fraction (EF) of 35-40%?

Primary Pharmacological Drug Classes for Heart Failure with Reduced Ejection Fraction (EF 35-40%)

Beta-blockers and angiotensin-converting enzyme inhibitors (ACEIs) are the two primary pharmacological drug classes that should be considered for all symptomatic patients with an EF of 35-40% because of their proven reduction in morbidity and mortality. 1

Evidence-Based Rationale

The 2022 AHA/ACC/HFSA Guideline for Management of Heart Failure recommends a foundation of neurohormonal blockade therapy for patients with heart failure with reduced ejection fraction (HFrEF), which includes:

1. Beta-blockers:

   • Examples: bisoprolol, carvedilol, metoprolol succinate
   • Initial doses: bisoprolol 1.25 mg once daily, carvedilol 3.125 mg twice daily, metoprolol succinate 12.5-25 mg once daily
   • Target doses: bisoprolol 10 mg once daily, carvedilol 25-50 mg twice daily, metoprolol succinate 200 mg once daily 2

2. ACE inhibitors:

   • Examples: lisinopril, enalapril, ramipril
   • Initial doses: lisinopril 2.5-5 mg once daily, enalapril 2.5 mg twice daily, ramipril 1.25-2.5 mg once daily
   • Target doses: lisinopril 20-40 mg once daily, enalapril 10-20 mg twice daily, ramipril 10 mg once daily 2

Expanded Treatment Algorithm

First-Line Therapy (Class I Recommendations)

1. Start with beta-blockers and ACEIs concurrently

   • Begin at low doses and titrate gradually to target doses or maximum tolerated doses 1
   • For patients who cannot tolerate ACEIs due to cough or angioedema, ARBs (angiotensin receptor blockers) are an appropriate alternative 3

2. Add mineralocorticoid receptor antagonists (MRAs)

   • For patients with LVEF ≤35% and NYHA class II-IV symptoms
   • Examples: spironolactone (12.5-25 mg daily) or eplerenone (25 mg daily)
   • Monitor renal function and potassium levels carefully 1

Additional Therapy Based on Clinical Status

1. Diuretics

   • For symptomatic relief of congestion
   • Not proven to reduce mortality but essential for symptom management 1

2. Consider ARNI (Angiotensin Receptor-Neprilysin Inhibitor)

   • Sacubitril/valsartan can replace ACEI/ARB in patients who remain symptomatic despite optimal therapy 2

3. SGLT2 inhibitors

   • Dapagliflozin or empagliflozin can be added regardless of diabetes status 2, 4

Device Therapy Considerations

For patients with EF 35-40%, consider:

• ICD (Implantable Cardioverter-Defibrillator) for primary prevention in patients with NYHA class II-III symptoms on optimal medical therapy 1, 3
• CRT (Cardiac Resynchronization Therapy) for patients with LVEF ≤35%, QRS ≥150 ms, and left bundle branch block morphology 1

Clinical Impact and Outcomes

• Beta-blockers have a Number Needed to Treat (NNT) of 9 to prevent one death over 36 months 2
• ACE inhibitors/ARBs have an NNT of 26 2
• Comprehensive disease-modifying therapy (including beta-blockers, ACEIs/ARBs, MRAs, and SGLT2 inhibitors) can provide substantial survival benefits compared to conventional therapy 5

Common Pitfalls and Caveats

1. Underdosing: Many patients are maintained on suboptimal doses of beta-blockers and ACEIs. Always aim for target doses shown to be effective in clinical trials.

2. Inappropriate discontinuation: Temporary hypotension or mild worsening of renal function should not lead to permanent discontinuation of these life-saving medications.

3. Monitoring requirements: Regular monitoring of renal function, potassium, and blood pressure is essential, especially when initiating or titrating medications.

4. Drug interactions: Be cautious with concomitant use of NSAIDs, which can worsen heart failure and reduce the efficacy of ACEIs and diuretics 3.

5. Combination therapy: The combination of ACEIs and ARBs is not recommended as it may increase adverse effects without additional benefit 6.

By implementing this evidence-based approach to pharmacological management of heart failure with reduced ejection fraction, clinicians can significantly improve morbidity and mortality outcomes for their patients.