Sacubitril/Valsartan Is Superior to Lisinopril in Heart Failure with Reduced Ejection Fraction
Sacubitril/valsartan is preferred over lisinopril in heart failure with reduced ejection fraction (HFrEF) because it significantly reduces cardiovascular death and heart failure hospitalizations compared to ACE inhibitors like lisinopril. 1
Mechanism and Clinical Evidence
Sacubitril/valsartan (Entresto) is an angiotensin receptor-neprilysin inhibitor (ARNI) that combines:
- Sacubitril: inhibits neprilysin, increasing beneficial natriuretic peptides
- Valsartan: blocks angiotensin II receptors
The landmark PARADIGM-HF trial demonstrated that sacubitril/valsartan was superior to enalapril (an ACE inhibitor similar to lisinopril) with:
- 20% reduction in cardiovascular death
- 21% reduction in heart failure hospitalizations
- 16% reduction in all-cause mortality 1
This evidence was so compelling that current guidelines recommend sacubitril/valsartan as a replacement for ACE inhibitors in patients with HFrEF to reduce the risk of heart failure hospitalization and cardiovascular death. 1
Guideline Recommendations
The 2024 European Society of Cardiology guidelines explicitly state:
- "Sacubitril/valsartan is recommended as a replacement for an ACE-I or ARB in CCS patients with HFrEF to reduce the risk of HF hospitalization and of cardiovascular and all-cause death." (Class I, Level B recommendation) 1
Similarly, American College of Cardiology guidelines recommend:
- Transitioning patients with NYHA class II-III HFrEF who can tolerate an ACE inhibitor or ARB to an ARNI to further reduce morbidity and mortality 1
Additional Benefits Beyond ACE Inhibitors
Sacubitril/valsartan offers several advantages over lisinopril:
Improved cardiac remodeling: Increases left ventricular ejection fraction and reverses ventricular remodeling more effectively 1, 2
Reduced arrhythmia risk: May have antiarrhythmic properties that reduce ventricular arrhythmias and sudden cardiac death risk 3
Better symptom improvement: Provides greater improvement in NYHA functional class and quality of life measures 4
Benefits across ejection fraction spectrum: Shows benefits that may extend to patients with mildly reduced ejection fraction, not just those with severely reduced EF 5
Safety Considerations
When switching from lisinopril to sacubitril/valsartan:
- A 36-hour washout period is required between stopping the ACE inhibitor and starting sacubitril/valsartan to reduce angioedema risk 6
- Monitor for hypotension, as this is more common with sacubitril/valsartan (15.9% vs 5.7% with conventional therapy) 7
- Watch for hyperkalemia and renal function changes, though these risks are similar to ACE inhibitors 4
Implementation Algorithm
Patient Selection:
- HFrEF patients (LVEF ≤40%)
- NYHA class II-IV symptoms
- Currently on stable doses of ACE inhibitor/ARB
Switching Process:
- Stop ACE inhibitor (lisinopril)
- Wait 36 hours (mandatory washout period)
- Start sacubitril/valsartan at 49/51 mg twice daily
- Titrate to target dose of 97/103 mg twice daily over 2-4 weeks as tolerated 6
Monitoring:
- Blood pressure, renal function, and electrolytes at 1-2 weeks after each dose increment
- Follow-up at 3 months and every 6 months thereafter 8
Special Considerations
- Contraindications: History of angioedema, pregnancy, severe hepatic impairment, concomitant ACE inhibitor use 6
- Dose adjustments: Start at lower doses (24/26 mg twice daily) in patients with severe renal impairment or moderate hepatic impairment 6
- Women may benefit more: Some evidence suggests women may derive benefit at higher ejection fractions compared to men 5
Conclusion
The evidence strongly supports using sacubitril/valsartan instead of lisinopril in HFrEF patients due to its superior effects on mortality, hospitalization rates, and cardiac function. The transition should be managed carefully with appropriate monitoring, but the clinical benefits make this switch worthwhile for eligible patients.