Is an Angiotensin-Receptor Neprilysin Inhibitor (ARNI) or Angiotensin-Converting Enzyme (ACE) inhibitor/Angiotensin Receptor Blocker (ARB) more effective in treating Heart Failure with Reduced Ejection Fraction (HFrEF) or Heart Failure with Mildly Reduced Ejection Fraction (HFmrEF)?

ARNI Offers Superior Outcomes Compared to ACE Inhibitors/ARBs in HFrEF and HFmrEF

For patients with HFrEF (LVEF ≤40%), sacubitril-valsartan (ARNI) is superior to ACE inhibitors or ARBs and should replace them in all patients who tolerate these medications, as it reduces cardiovascular death and heart failure hospitalization by 20% compared to enalapril. 1

Evidence for HFrEF (LVEF ≤40%)

Primary Recommendation

• The 2022 ACC/AHA/HFSA guidelines give a Class I recommendation for replacing ACE inhibitors or ARBs with ARNI in patients with chronic symptomatic HFrEF (NYHA Class II-III) who tolerate these medications. 1
• The landmark PARADIGM-HF trial demonstrated that sacubitril-valsartan reduced the composite endpoint of cardiovascular death or HF hospitalization by 20% relative to enalapril, with benefits observed equally for both death and hospitalization. 1
• This mortality and morbidity benefit was consistent across all prespecified subgroups. 1

Practical Implementation in HFrEF

• ARNI can be initiated de novo (without prior ACE inhibitor/ARB use) in hospitalized patients with acute HFrEF before discharge, simplifying management rather than requiring sequential uptitration of ACE inhibitors first. 1
• The PIONEER-HF trial showed that ARNI reduced NT-proBNP levels in hospitalized patients with acute decompensated HF without increased adverse events (worsening renal function, hyperkalemia, symptomatic hypotension, angioedema) compared to enalapril. 1
• The TRANSITION trial confirmed that early initiation (before or after discharge) had similar safety outcomes, supporting simplified early initiation. 1

When ACE Inhibitors/ARBs Remain Appropriate

• ACE inhibitors remain strongly advised for patients in whom ARNI is inappropriate due to cost, intolerance, or contraindications. 1
• ARBs are recommended (Class I) for patients intolerant to ACE inhibitors due to cough or angioedema, though they should be used with caution as some patients develop angioedema with ARBs as well. 1
• Both ACE inhibitors and ARBs reduce morbidity and mortality in HFrEF through large randomized controlled trials, making them acceptable alternatives when ARNI cannot be used. 1

Evidence for HFmrEF (LVEF 41-49%)

Moderate Evidence Supporting ARNI

• For HFmrEF, ARNI receives a Class 2b recommendation (may be considered), which is weaker than the Class I recommendation for HFrEF. 1
• Post-hoc analysis of PARAGON-HF showed that in patients with LVEF 45-57% (lower range of the trial), sacubitril-valsartan demonstrated benefit versus valsartan alone (rate ratio 0.78,95% CI 0.64-0.95). 1
• The EMPEROR-Preserved trial subgroup with LVEF 41-49% showed empagliflozin (an SGLT2 inhibitor, not ARNI) reduced cardiovascular death or HF hospitalization, suggesting this population responds to guideline-directed medical therapy. 1

Treatment Algorithm for HFmrEF

• SGLT2 inhibitors (empagliflozin or dapagliflozin) receive the strongest recommendation (Class 2a) for HFmrEF, reducing HF hospitalization by 21-29%. 1, 2
• ACE inhibitors, ARBs, and ARNI all receive Class 2b recommendations for HFmrEF based on post-hoc analyses and subset data from HFrEF trials. 1
• Evidence-based beta-blockers and mineralocorticoid receptor antagonists also receive Class 2b recommendations for this population. 1

Key Distinction Between HFrEF and HFmrEF

• The evidence base for ARNI superiority is robust and definitive in HFrEF (Class I, Level B-R evidence), whereas in HFmrEF it relies on post-hoc analyses and receives only a Class 2b recommendation. 1
• Patients with HFmrEF should have repeat LVEF evaluation to determine disease trajectory, as those on the lower end of the spectrum (closer to 40%) may respond similarly to HFrEF patients. 1

Safety Considerations

Common Adverse Effects

• ARNI is more frequently associated with symptomatic hypotension compared to ACE inhibitors, requiring careful blood pressure monitoring. 1
• Angioedema incidence is comparable between ARNI and enalapril, though still rare. 1
• A 36-hour washout period is required when switching from ACE inhibitors to ARNI to minimize angioedema risk. 1

Monitoring Parameters

• Give ARNI with caution in patients with low systemic blood pressure, renal insufficiency, or elevated serum potassium (>5.0 mEq/L). 1
• Start at low doses and titrate upward to target doses shown to reduce cardiovascular events in clinical trials (target dose: sacubitril 97 mg/valsartan 103 mg twice daily). 1

Cost-Effectiveness

• While ACE inhibitors and ARBs are available as low-cost generics and provide high value across multiple cost-effectiveness analyses, ARNI's superior efficacy justifies its use despite higher cost in patients who can access it. 1
• Generic ACE inhibitor therapy remains high-value for patients unable to afford or access ARNI. 1