Is Entresto (sacubitril/valsartan) 49/51 better than Valsartan (valsartan) 160 mg twice daily (Bid) for treating heart failure with reduced ejection fraction or hypertension?

Entresto 49/51 mg Twice Daily is Superior to Valsartan 160 mg Twice Daily for Heart Failure with Reduced Ejection Fraction

For patients with heart failure with reduced ejection fraction (HFrEF), Entresto (sacubitril/valsartan) 49/51 mg twice daily is definitively better than valsartan 160 mg twice daily, as it significantly reduces cardiovascular death and heart failure hospitalizations compared to ARB monotherapy. 1, 2

Evidence Base for Superiority

The landmark PARADIGM-HF trial directly demonstrated that sacubitril/valsartan reduced the composite primary endpoint of cardiovascular death or first hospitalization for worsening heart failure by 20% compared to enalapril (an ACE inhibitor comparable to ARB therapy). 2 This represents a Class I recommendation from the European Society of Cardiology for replacing ACE inhibitors or ARBs with sacubitril/valsartan in symptomatic HFrEF patients. 1

Key Clinical Benefits Over Valsartan Alone:

• Mortality reduction: Sacubitril/valsartan reduces death from any cause more effectively than ACE inhibitors/ARBs alone 2
• Hospitalization reduction: Significantly fewer heart failure hospitalizations and urgent visits occur with sacubitril/valsartan 1, 2
• Cardiac remodeling: Substantial improvements in left ventricular ejection fraction occur regardless of heart failure duration, with absolute LVEF improvements ranging from 6.9% to 12.2% 3
• Biomarker improvements: Significant decreases in NT-proBNP, high-sensitivity cardiac troponin T, and soluble ST2 occur with sacubitril/valsartan 3
• Quality of life: Meaningful improvements in Kansas City Cardiomyopathy Questionnaire scores and 6-minute walk distance 3, 4

Treatment Algorithm Position

The European Society of Cardiology recommends a stepwise approach for HFrEF: 1

1. First-line: ACE inhibitor (or ARB) + beta-blocker
2. Second-line: Add mineralocorticoid receptor antagonist if symptomatic
3. Third-line: Replace ACE inhibitor/ARB with sacubitril/valsartan if patient remains symptomatic despite optimal therapy 5, 1

Critical point: You don't need to wait for patients to "fail" optimal medical therapy. All HFrEF patients on ARBs are candidates for switching to sacubitril/valsartan, even with mild symptoms (NYHA Class II). 1

Practical Implementation When Switching from Valsartan

No Washout Period Required

Unlike switching from ACE inhibitors (which requires 36 hours washout), you can switch directly from valsartan to sacubitril/valsartan without any washout period. 1, 6

Dosing Strategy

• Standard starting dose: 49/51 mg twice daily (the dose in your question) 6
• Target dose: Titrate to 97/103 mg twice daily over 2-4 weeks as tolerated 1, 6
• Lower starting dose (24/26 mg twice daily) only for: 6
  • Severe renal impairment (eGFR <30 mL/min/1.73 m²)
  • Moderate hepatic impairment (Child-Pugh B)
  • Elderly patients ≥75 years
  • Systolic BP ≤100 mm Hg

Managing Common Barriers

Asymptomatic hypotension is not a reason to avoid switching—sacubitril/valsartan provides mortality benefit even with lower blood pressure. 1 If symptomatic hypotension occurs:

• Reduce diuretic dose first (due to enhanced natriuresis with sacubitril/valsartan) 1
• Temporarily reduce sacubitril/valsartan dose, then re-titrate 1
• 40% of patients requiring temporary dose reduction can be restored to target doses 1

Mild creatinine elevation (<0.5 mg/dL increase) is acceptable and doesn't require dose adjustment. 1

Safety Considerations

Sacubitril/valsartan was generally well tolerated in clinical trials with no increase in life-threatening adverse events compared to ACE inhibitors. 2 Key safety points:

• Symptomatic hypotension is more common than with enalapril but manageable 2
• Angioedema incidence remains low 2
• Contraindications: History of angioedema with ACE inhibitors/ARBs, pregnancy, concomitant ACE inhibitor use 1, 6

Clinical Context: When Valsartan Alone Might Be Used

The only scenario where valsartan 160 mg twice daily would be preferred is if the patient has absolute contraindications to sacubitril/valsartan (history of angioedema, pregnancy) or cannot afford the medication despite assistance programs. 1 Otherwise, the evidence overwhelmingly supports sacubitril/valsartan as superior therapy.

Bottom line: For HFrEF, Entresto 49/51 mg twice daily should replace valsartan 160 mg twice daily in virtually all eligible patients, as it provides superior outcomes in mortality, hospitalizations, cardiac remodeling, and quality of life. 1, 2, 3