What is the maximum dose of sacubitril (Angiotensin Receptor-Neprilysin Inhibitor) valsartan for a patient with heart failure with reduced ejection fraction and no significant kidney dysfunction?

Maximum Dose of Sacubitril/Valsartan

The maximum dose of sacubitril/valsartan is 97/103 mg twice daily (total daily dose of 194 mg sacubitril and 206 mg valsartan), which represents the target dose that provides maximum mortality benefit in patients with heart failure with reduced ejection fraction and no significant kidney dysfunction. 1, 2

Target Dosing Strategy

• The target maintenance dose of 97/103 mg twice daily should be achieved through systematic uptitration, doubling the dose every 2-4 weeks as tolerated from the starting dose. 1, 2
• This maximum dose was established in the PARADIGM-HF trial and demonstrated the greatest reduction in cardiovascular death and heart failure hospitalization compared to ACE inhibitors. 3, 2
• Approximately 50% of patients achieve this target dose within 10 weeks when initiated in-hospital or shortly after discharge. 2, 4

Starting Dose Considerations

The initial dose depends on prior therapy exposure:

• Patients previously on high-dose ACE inhibitors or ARBs: Start at 49/51 mg twice daily. 1, 2
• Most other patients: Start at 49/51 mg twice daily. 1
• High-risk patients (severe renal impairment with eGFR <30 mL/min/1.73 m², moderate hepatic impairment, age ≥75 years, or low/medium-dose prior ACE inhibitor/ARB exposure): Start at 24/26 mg twice daily. 1, 2, 4

Critical Transition Requirements

• When switching from an ACE inhibitor, a mandatory 36-hour washout period is required to avoid the risk of angioedema. 1, 2, 4
• No washout period is needed when switching from an ARB to sacubitril/valsartan. 2, 3

Managing Barriers to Achieving Maximum Dose

Hypotension Management

• Asymptomatic hypotension is NOT a reason to avoid uptitration to the maximum dose, as the drug maintains efficacy and safety even with systolic BP <110 mmHg. 2, 4, 3
• For symptomatic hypotension: First reduce loop diuretic doses in non-congested patients, ensure adequate hydration, and provide patient education about postural changes. 2, 4, 5
• If symptomatic hypotension persists, temporarily reduce sacubitril/valsartan dose, then re-titrate upward rather than permanently accepting a lower dose. 2, 4

Renal Function Considerations

• For patients with eGFR ≥30 mL/min/1.73 m² and no significant kidney dysfunction, the maximum dose of 97/103 mg twice daily remains appropriate. 1, 5
• Mild creatinine elevation (<0.5 mg/dL increase) is acceptable and does not require dose adjustment. 3
• Sacubitril/valsartan may actually improve renal function over time, with studies showing eGFR improvements even in patients with baseline renal dysfunction. 6

Common Pitfalls to Avoid

• Do not fail to uptitrate due to asymptomatic hypotension or mild laboratory changes, as these do not predict adverse outcomes and the mortality benefit is dose-dependent. 2, 4
• Do not make permanent dose reductions when temporary reductions with subsequent re-titration would be more appropriate. 2, 4
• Do not believe that medium-range doses provide most of the benefits—the target dose of 97/103 mg twice daily provides maximum mortality benefit. 2
• Approximately 40% of patients who require temporary dose reduction can subsequently be restored to target doses with careful management. 3

Special Population Considerations

• The maximum dose of 97/103 mg twice daily remains indicated even in NYHA class IV patients, though data in this population are more limited. 2
• Benefits occur within weeks of initiation and are maintained across vulnerable populations including elderly patients, those with recent heart failure hospitalization, and those with signs of congestion. 2, 3