What are the primary pharmacological drug classes for symptomatic patients with a Left Ventricular Ejection Fraction (LVEF) of 35-40%?

Primary Pharmacological Drug Classes for Symptomatic HF with EF 35-40%

According to the 2022 AHA/ACC/HFSA Guideline for Management of Heart Failure, the two primary pharmacological drug classes that should be considered for all symptomatic patients with an EF of 35-40% because of reduction in morbidity and mortality are ACE inhibitors/ARBs (or preferably ARNI) and beta-blockers. 1, 2

Core Medication Classes for HFrEF (EF 35-40%)

The 2022 AHA/ACC/HFSA guideline recommends four core medication classes for patients with HFrEF (which includes patients with EF 35-40%):

1. ACE inhibitors/ARBs or preferably ARNI (Angiotensin Receptor-Neprilysin Inhibitor)

   • Sacubitril/valsartan (ARNI) is now preferred over ACE inhibitors or ARBs as first-line therapy 2
   • ACE inhibitors like enalapril reduce mortality and hospitalization in HFrEF patients 3
   • ARBs are recommended for patients intolerant to ACE inhibitors 1

2. Beta-blockers

   • Specifically carvedilol, metoprolol succinate, or bisoprolol 2
   • Recommended for all patients with current or prior symptoms of HFrEF to reduce morbidity and mortality 1

3. Mineralocorticoid Receptor Antagonists (MRAs)

   • Spironolactone or eplerenone
   • Recommended for patients who remain symptomatic despite treatment with an ACE inhibitor/ARB and a beta-blocker 1

4. SGLT2 inhibitors

   • Dapagliflozin or empagliflozin
   • Recommended regardless of diabetic status 2

Evidence for Mortality and Morbidity Reduction

The strongest evidence for mortality and morbidity reduction in HFrEF patients with EF 35-40% comes from:

• ACE inhibitors/ARBs: In the SOLVD-Treatment trial, enalapril was associated with an 11% reduction in all-cause mortality and a 30% reduction in hospitalization for heart failure in patients with EF ≤35% 3

• Beta-blockers: Evidence-based beta-blockers have demonstrated mortality reduction in patients with reduced LVEF, particularly after myocardial infarction 4

• Combination therapy: The combination of ACE inhibitors and beta-blockers provides additional benefit compared to either medication alone, with hazard ratios of 0.80 for ACE inhibitors, 0.76 for beta-blockers, and 0.68 for the combination 4

Implementation Considerations

• Start all four core medication classes simultaneously rather than sequentially 2
• Begin with lower doses and titrate to target doses as tolerated:
  • Sacubitril/valsartan: Start 24/26mg BID, target 97/103mg BID
  • Enalapril: Start 2.5mg BID, target 10-20mg BID
  • Carvedilol: Start 3.125mg BID, target 25mg BID (<85 kg) or 50mg BID (≥85 kg)
  • Metoprolol succinate: Start 12.5-25mg daily, target 200mg daily
  • Bisoprolol: Start 1.25mg daily, target 10mg daily 2

Common Pitfalls and Caveats

1. Risk-treatment mismatch: Higher-risk patients often receive lower rates of evidence-based therapies despite potentially greater benefit 5

2. Contraindications to consider:

   • ACE inhibitors/ARBs: Renal impairment, hyperkalemia
   • Beta-blockers: Severe bradycardia, hypotension, decompensated HF
   • MRAs: Severe renal dysfunction (creatinine >2.5 mg/dL in men, >2.0 mg/dL in women), hyperkalemia (K+ >5.0 mEq/L) 1

3. Monitoring requirements:

   • Regular assessment of renal function and electrolytes, especially after initiation and dose adjustments
   • Blood pressure monitoring for hypotension, particularly with ARNI therapy 2

4. Medication adherence: Less than 1% of patients receive all life-prolonging treatments at trial-proven doses; target achieving ≥80% of target doses for optimal outcomes 2

By implementing these evidence-based therapies, clinicians can significantly reduce mortality and morbidity in patients with symptomatic heart failure and EF 35-40%.