Should Entresto (sacubitril/valsartan) be dosed twice daily, and are there situations where it can be dosed once daily?

Dosing of Entresto (Sacubitril/Valsartan) in Heart Failure Patients

Entresto (sacubitril/valsartan) should be dosed twice daily in all patients, with no situations where once-daily dosing is recommended. 1

Standard Dosing Regimen

• Entresto is specifically designed and FDA-approved for twice-daily administration, with target doses of 97/103 mg twice daily for adults with heart failure with reduced ejection fraction (HFrEF) 1
• The recommended starting dose for adults is 49/51 mg twice daily, with dose doubling after 2-4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated 1
• Clinical trials demonstrating mortality benefit used twice-daily dosing exclusively, with no evidence supporting once-daily administration 2

Dose Adjustments for Special Populations

• For patients with severe renal impairment (eGFR <30 mL/min/1.73m²), start at half the usual recommended dose (24/26 mg twice daily), but maintain the twice-daily frequency 1
• No dose adjustment is needed for mild or moderate renal impairment, but the twice-daily schedule must be maintained 1
• For pediatric patients (≥1 year), dosing remains twice daily with weight-based adjustments, but the frequency is never changed to once daily 1

Titration Considerations

• Titration should occur every 2-4 weeks in adults, with the goal of achieving target doses shown to be efficacious in reducing cardiovascular mortality and HF hospitalizations 2
• In clinical practice, only about 27% of patients achieve the target dose of 200 mg twice daily within 6 months, often due to slower uptitration than in clinical trials 3
• Common barriers to achieving target doses include symptomatic hypotension, worsening renal function, and patient non-compliance 3

Clinical Evidence Supporting Twice-Daily Dosing

• The landmark PARADIGM-HF trial, which demonstrated superiority of sacubitril/valsartan over enalapril in reducing cardiovascular death and HF hospitalizations, exclusively used twice-daily dosing 4
• The pharmacokinetics and mechanism of action of sacubitril/valsartan necessitate twice-daily dosing to maintain consistent therapeutic drug levels 4, 5
• Guidelines from the American College of Cardiology/American Heart Association specifically list sacubitril/valsartan as requiring twice-daily administration in their tables of recommended medications for HFrEF 2

Common Pitfalls in Entresto Dosing

• Failure to uptitrate to target doses: Many clinicians maintain patients on starting doses indefinitely, which may not provide the full mortality benefit seen in clinical trials 2
• Inappropriate once-daily dosing: There is no evidence supporting once-daily dosing of Entresto, and this practice may lead to suboptimal outcomes 1
• Permanent dose reductions: In clinical practice, temporary dose reductions often become permanent, whereas in clinical trials, efforts were made to restore patients to target doses whenever possible 2

Conclusion

Entresto (sacubitril/valsartan) must be administered twice daily in all patients. The FDA-approved labeling, clinical trial evidence, and cardiology guidelines all consistently recommend twice-daily dosing with no provisions for once-daily administration under any circumstances. While dose adjustments may be necessary based on tolerability or renal function, the twice-daily frequency should always be maintained.