How does Entresto (sacubitril/valsartan) compare to losartan (angiotensin‑II receptor blocker) for treating heart failure with reduced ejection fraction?

Entresto vs Losartan for Heart Failure with Reduced Ejection Fraction

For patients with symptomatic HFrEF already tolerating an ACE inhibitor or ARB (including losartan), Entresto (sacubitril/valsartan) is superior and should replace the ARB to reduce cardiovascular death and heart failure hospitalizations.

Primary Recommendation

The 2022 AHA/ACC/HFSA guidelines explicitly state that sacubitril/valsartan is recommended as a replacement for an ACE inhibitor or ARB to further reduce the risk of HF hospitalization and death in ambulatory patients with HFrEF who remain symptomatic despite optimal treatment 1, 2, 3, 4. This represents a Class I, Level B recommendation in the 2016 ESC guidelines 1.

The landmark PARADIGM-HF trial demonstrated that sacubitril/valsartan reduced the composite endpoint of cardiovascular death or HF hospitalization by 20% (hazard ratio 0.80; 95% CI 0.73-0.87; p<0.001) compared to enalapril, with all-cause mortality reduced by 16% (hazard ratio 0.84; 95% CI 0.76-0.93; p<0.001) 5, 6. This benefit was consistent regardless of baseline blood pressure or hypertension history 5.

Clinical Algorithm for Switching from Losartan to Entresto

Step 1: Confirm Patient Eligibility

• LVEF ≤40% (some guidelines use ≤35%)
• NYHA Class II-III symptoms despite optimal medical therapy
• Already tolerating an ARB (losartan) or ACE inhibitor at adequate doses
• Elevated natriuretic peptides (BNP ≥150 pg/mL or NT-proBNP ≥600 pg/mL)

Step 2: Screen for Contraindications

• History of angioedema with ACE inhibitors or ARBs (absolute contraindication)
• Systolic blood pressure <100 mmHg (relative contraindication)
• Severe renal impairment (eGFR <30 mL/min/1.73m²)
• Serum potassium >5.4 mEq/L
• Pregnancy or planned pregnancy (absolute contraindication)

Step 3: Washout Period

Wait 36 hours after the last dose of losartan before initiating Entresto to minimize angioedema risk 6, 3, 7. This is critical—concomitant use of ACE inhibitors with neprilysin inhibitors caused unacceptable angioedema rates in the omapatrilat trials 3.

Step 4: Initiation and Titration

• Start with 24 mg/26 mg (sacubitril/valsartan) twice daily if systolic BP 100-110 mmHg or concerns about tolerability
• Start with 49 mg/51 mg twice daily for most patients
• Target dose: 97 mg/103 mg twice daily (equivalent to valsartan 160 mg twice daily) 7
• Titrate every 2-4 weeks as tolerated, monitoring blood pressure, renal function, and potassium

Step 5: Monitoring

• Blood pressure at each visit (watch for symptomatic hypotension)
• Renal function and potassium at 1-2 weeks, then periodically
• NT-proBNP levels decrease significantly with Entresto (24% reduction at 16 weeks vs 6% with valsartan) 7

Important Caveats and Pitfalls

The Dose Equivalency Issue

A critical 2024 meta-analysis found that Entresto is NOT superior to equivalent doses of ACE inhibitors/ARBs—the PARADIGM-HF benefit was achieved because enalapril 10 mg twice daily is a sub-equivalent dose compared to the target valsartan 160 mg twice daily component in Entresto 8. When compared to truly equivalent doses, there was no statistical difference in total mortality, cardiovascular mortality, or worsening heart failure 8.

However, this does not negate the guideline recommendation because:

1. The neprilysin inhibition component (sacubitril) provides additional natriuretic peptide enhancement beyond RAAS blockade alone
2. Real-world studies confirm mortality and hospitalization benefits 9, 10
3. Guidelines are based on the actual trial evidence (PARADIGM-HF), which used these specific doses

Race-Based Considerations

Real-world data from a large U.S. cohort showed that the benefit of Entresto over ACE/ARB was observed in white patients (HR 0.83) but NOT in Black patients (HR 1.00; interaction p=0.032) 10. This warrants careful consideration and closer monitoring in Black patients, though it should not preclude a trial of therapy.

Advanced Heart Failure (NYHA Class IV)

The LIFE trial attempted to study Entresto in advanced HF but was stopped early due to COVID-19 11. Patients with NYHA Class IV symptoms or 6-minute walk distance <100 meters were excluded from PARADIGM-HF, so evidence is limited in this population 1.

Cost-Effectiveness

Multiple analyses confirm Entresto provides high value (cost per QALY <$60,000) compared to ACE inhibitors, though this assumes treatment effectiveness extends beyond the 27-month PARADIGM-HF study period 3. If benefit were limited to 27 months, it would be intermediate value 3.

What About HFpEF and HFmrEF?

For HFmrEF (LVEF 41-49%): Entresto receives a Class 2a recommendation (can be beneficial) 2, 4. The PARAGON-HF subgroup with LVEF 45-57% showed benefit (rate ratio 0.78; 95% CI 0.64-0.95) 12, 4.

For HFpEF (LVEF ≥50%): Entresto receives a Class 2b recommendation (may be considered) 2, 4. PARAGON-HF narrowly missed its primary endpoint (p=0.06), though it improved KCCQ scores and NYHA class 12, 13. Real-world data shows no significant difference between Entresto and ARBs for HFpEF 14.

Bottom Line

Switch from losartan to Entresto in symptomatic HFrEF patients who tolerate the ARB, following the 36-hour washout protocol and targeting the 97/103 mg twice-daily dose. The mortality and hospitalization benefits are guideline-supported and clinically meaningful 1, 2, 6, 3, 4. Monitor closely for hypotension, renal dysfunction, and hyperkalemia 5, 7. Consider patient-specific factors including race, blood pressure tolerance, and cost when individualizing the approach 10.