Once-Daily Dosing of Sacubitril/Valsartan is NOT Supported
Sacubitril/valsartan must be administered twice daily—once-daily dosing has no evidence base and should not be used in clinical practice. All clinical trials demonstrating mortality benefit, all guideline recommendations, and FDA approval are based exclusively on twice-daily administration 1, 2, 3.
Why Twice-Daily Dosing is Mandatory
The pharmacokinetic profile and clinical efficacy of sacubitril/valsartan are predicated on twice-daily administration. The PARADIGM-HF trial and all subsequent studies used BID dosing, achieving a 20% reduction in cardiovascular death or heart failure hospitalization compared to ACE inhibitors 1. No studies have evaluated once-daily dosing, and extrapolating from twice-daily data would be inappropriate and potentially harmful 2.
Standard Dosing Regimen
Initial dose: Start at 49/51 mg twice daily for patients previously on high-dose ACE inhibitors, or 24/26 mg twice daily for those on low/medium-dose ACE inhibitors/ARBs or treatment-naïve patients 1, 3
Target dose: Titrate every 2-4 weeks to reach 97/103 mg twice daily, which provides maximum mortality benefit 1, 3
Special populations: Patients with severe renal impairment (eGFR <30 mL/min/1.73 m²), moderate hepatic impairment, or age ≥75 years should start at 24/26 mg twice daily 1, 3
Practical Considerations for Adherence
If adherence to twice-daily dosing is a concern, address the barrier directly rather than compromising the dosing schedule. Real-world data show that only 17% of patients achieve target doses within 4-6 months, often due to inadequate titration rather than true intolerance 4, 5.
Strategies to Optimize Adherence
Patient education: Emphasize that twice-daily dosing is essential for the medication to work—this is not negotiable 2
Simplify regimen: Coordinate timing with other twice-daily medications (e.g., beta-blockers) to minimize pill burden 1
Use pill organizers: Provide tools to help patients remember both doses 6
Monitor closely: Follow up at 1-2 weeks after initiation or dose changes to reinforce adherence and manage side effects 1, 3
Why Once-Daily Dosing Would Fail
The dual mechanism of neprilysin inhibition and angiotensin receptor blockade requires sustained drug levels throughout the 24-hour period. Sacubitril/valsartan tablets must be swallowed whole and cannot be split, crushed, or modified 2. The absorption occurs primarily in the stomach and proximal small bowel, and the pharmacokinetics are designed for twice-daily administration 2.
Common Pitfalls to Avoid
Do not reduce to once-daily dosing even if patients struggle with adherence—instead, work on adherence strategies or consider whether the patient is truly a candidate for this therapy 1, 6
Do not split tablets to create different doses—use commercially available lower-strength tablets if dose reduction is needed 2
Do not confuse with SGLT2 inhibitors, which offer simple once-daily dosing without titration and should be part of the HFrEF regimen alongside sacubitril/valsartan 7, 1
Alternative Approaches if Adherence is Problematic
If a patient cannot reliably take twice-daily medications, consider whether sacubitril/valsartan is the right choice at this time. The alternative is to optimize other guideline-directed medical therapies that may have simpler dosing schedules 7:
SGLT2 inhibitors (dapagliflozin or empagliflozin): Once-daily dosing, no titration required, complementary mortality benefit 7, 1
Continue ACE inhibitor or ARB: If twice-daily dosing is insurmountable, maintaining once-daily ACE inhibitor/ARB therapy is preferable to incorrectly dosed sacubitril/valsartan 1
Address adherence barriers: Work with social services, pharmacy support, or home health to enable proper twice-daily dosing before initiating sacubitril/valsartan 6
Monitoring Requirements with Twice-Daily Dosing
Blood pressure, renal function, and potassium should be monitored at baseline and 1-2 weeks after each dose change 1, 3
Asymptomatic hypotension should not prevent titration—benefits are maintained even with systolic BP <110 mmHg 1
Mild creatinine elevation (<0.5 mg/dL increase) is acceptable and does not require dose adjustment 1