What is the maximum dose of sacubitril (Angiotensin Receptor Neprilysin Inhibitor) valsartan?

Maximum Dose of Sacubitril/Valsartan

The maximum dose of sacubitril/valsartan is 97/103 mg twice daily (total daily dose of 194/206 mg). 1

Target Dosing Strategy

• The target maintenance dose is sacubitril 97 mg/valsartan 103 mg twice daily, which represents the evidence-based dose proven to reduce mortality and morbidity in heart failure with reduced ejection fraction (HFrEF). 1

• This maximum dose should be achieved through systematic up-titration, typically doubling the dose every 2-4 weeks as tolerated, starting from either 24/26 mg or 49/51 mg twice daily depending on patient factors. 1

Dose Titration Schedule

Standard titration pathway:

• Start at 49/51 mg twice daily for most patients already on ACE inhibitors or ARBs 1
• Up-titrate to 97/103 mg twice daily after 2-4 weeks if tolerated 1

Modified starting dose for specific populations:

• Patients with severe renal impairment (eGFR <30 mL/min/1.73 m²): start at 24/26 mg twice daily, then double every 2-4 weeks to target 97/103 mg twice daily 1, 2
• Patients with moderate hepatic impairment (Child-Pugh B): start at 24/26 mg twice daily, then double every 2-4 weeks to target 97/103 mg twice daily 1, 2
• Patients with systolic blood pressure 100-110 mmHg: consider gradual 6-week up-titration rather than rapid 3-week titration to improve tolerability (approximately 80% achieve target dose with gradual approach). 3

Clinical Performance Benchmarks

• At least 50% of the target dose (49/51 mg twice daily) is considered the minimum acceptable maintenance dose for quality metrics in HFrEF management. 1

• In real-world Canadian practice, 64.6% of patients achieved the maximum dose of 97/103 mg twice daily at 6 months, with 62.3% maintaining this dose at 12 months. 4

Direct-to-Maximum Dose Approach

• For patients already on target-dose ACE inhibitors or ARBs (equivalent to enalapril 10 mg twice daily), direct switching to maximum-dose sacubitril/valsartan 97/103 mg twice daily is safe and well-tolerated, with only 14% discontinuation and 6% requiring dose reduction at 12 months. 5

• This approach eliminates unnecessary titration steps but requires close monitoring for hypotension (26% developed symptomatic hypotension in one study). 5

Critical Monitoring Parameters

Within 1-2 weeks after initiation or dose increase, assess:

• Blood pressure (watch for systolic BP <90 mmHg or symptomatic hypotension) 1, 3
• Serum creatinine and eGFR (monitor for acute kidney injury) 1, 2
• Serum potassium (monitor for hyperkalemia) 1, 2

Contraindications to Maximum Dosing

Absolute contraindications:

• Severe hepatic impairment (Child-Pugh C) - no dose is safe 1, 2
• History of angioedema with ACE inhibitors or ARBs 1, 2
• Concomitant use within 36 hours of ACE inhibitor (must have washout period) 2

Relative contraindications requiring dose reduction:

• Persistent symptomatic hypotension despite volume optimization 1, 3
• Progressive renal dysfunction (rising creatinine >30% from baseline) 1, 2
• Hyperkalemia >5.5 mEq/L despite management 1

Common Pitfalls to Avoid

• Do not delay up-titration unnecessarily - the mortality benefit is dose-dependent, and patients should reach maximum tolerated dose within 3-6 weeks unless contraindicated. 1

• Do not assume low systolic blood pressure (100-110 mmHg) is an absolute barrier - over 70% of these patients can achieve target dose with gradual titration. 3

• Do not switch patients from valsartan monotherapy to sacubitril/valsartan in heart failure without compelling reason - the combination has proven mortality benefit at the target dose of 97/103 mg twice daily. 6, 7