Sacubitril/Valsartan (Entresto) for Heart Failure with Reduced Ejection Fraction and Hypertension
For an adult with chronic heart failure (EF ≤40%, NYHA II-IV) and coexisting hypertension, sacubitril/valsartan is the preferred first-line therapy over ACE inhibitors, providing superior mortality reduction of at least 20% while simultaneously controlling blood pressure. 1
Indications and Patient Selection
Sacubitril/valsartan is FDA-approved for all patients with NYHA class II-IV heart failure and reduced ejection fraction (EF ≤40%), regardless of blood pressure status. 2, 3 The presence of hypertension is not a contraindication—in fact, it makes the patient an ideal candidate since the drug provides dual benefit: heart failure management and blood pressure control. 1
Eligibility Criteria Before Initiation
- Systolic blood pressure must be ≥100 mm Hg (though lower values are not an absolute contraindication if the patient is hemodynamically stable). 1
- Estimated glomerular filtration rate must be >30 mL/min/1.73 m² for standard dosing. 2, 1
- Serum potassium must be <5.2 mmol/L before starting therapy. 2
- Patient must be symptomatic (NYHA class II-IV), as asymptomatic patients were not studied in pivotal trials. 2
Transitioning from ACE Inhibitors or ARBs
Mandatory Washout Period
If the patient is currently on an ACE inhibitor, you must discontinue it immediately and observe a strict 36-hour washout period before administering the first dose of sacubitril/valsartan to avoid life-threatening angioedema. 1, 3 This is an FDA black-box requirement and cannot be shortened. 3
If switching from an ARB, no washout period is required—you can start sacubitril/valsartan the next day. 1
Initial Dosing Strategy
For patients previously on high-dose ACE inhibitors (equivalent to enalapril ≥10 mg daily), start sacubitril/valsartan at 49/51 mg twice daily. 1, 3
For patients on low-to-medium dose ACE inhibitors (equivalent to enalapril <10 mg daily) or ARBs, start at 24/26 mg twice daily. 1, 3
For special populations—severe renal impairment (eGFR <30 mL/min/1.73 m²), moderate hepatic impairment (Child-Pugh B), age ≥75 years, or systolic BP 100-110 mm Hg—start at the lower dose of 24/26 mg twice daily. 1, 3
Titration Protocol
Double the dose every 2-4 weeks as tolerated, aiming for the target dose of 97/103 mg twice daily, which provides the maximal mortality benefit demonstrated in the PARADIGM-HF trial. 1, 4 This target dose is non-negotiable for optimal outcomes—accepting lower doses forfeits proven survival benefit. 1
| Week | Dose (twice daily) | Criteria to Advance |
|---|---|---|
| 0 | 24/26 mg or 49/51 mg | Based on prior therapy |
| 2-4 | 49/51 mg | SBP >80 mmHg, no symptomatic hypotension |
| 4-8 | 97/103 mg (target) | Same tolerability criteria |
Managing Blood Pressure During Optimization
Hypertensive Patients (SBP >140 mm Hg)
Sacubitril/valsartan will effectively lower blood pressure while treating heart failure—this is a therapeutic advantage, not a concern. 1 Aggressive up-titration to target dose is both safe and indicated. 1
Patients with Borderline Blood Pressure (SBP 100-120 mm Hg)
Do not delay or avoid up-titration due to asymptomatic low blood pressure with adequate perfusion. 1 The drug maintains efficacy and safety even in patients with baseline SBP <110 mm Hg. 1
If symptomatic hypotension occurs:
- First, reduce loop diuretic dose in non-congested patients—sacubitril/valsartan enhances natriuresis, often allowing diuretic reduction. 1
- If hypotension persists, temporarily reduce sacubitril/valsartan dose, then re-titrate once symptoms resolve. 1
- Never permanently discontinue for asymptomatic hypotension—40% of patients who required temporary dose reduction were successfully restored to target doses. 1
Comprehensive Heart Failure Management
Sacubitril/valsartan should be part of quadruple therapy, which includes:
- SGLT2 inhibitor (dapagliflozin 10 mg or empagliflozin 10 mg once daily) 1, 5
- Mineralocorticoid receptor antagonist (spironolactone 25-50 mg or eplerenone 25-50 mg daily) 1, 5
- Evidence-based beta-blocker (carvedilol, metoprolol succinate, or bisoprolol) 1, 5
- Sacubitril/valsartan (replacing ACE inhibitor/ARB) 1, 5
This combination reduces all-cause mortality by 61% (HR 0.39,95% CI 0.32-0.49) and adds approximately 5.3 life-years per patient. 5
Monitoring Requirements
Monitor blood pressure, renal function (serum creatinine and eGFR), and serum potassium at baseline and regularly during titration, particularly when combined with mineralocorticoid receptor antagonists. 1, 6
- Check labs 1-2 weeks after each dose increment. 5
- Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation. 5
- If potassium rises >5.0 mEq/L, consider potassium binders (e.g., patiromer) rather than stopping life-saving therapy. 5
Common Pitfalls to Avoid
- Never combine sacubitril/valsartan with an ACE inhibitor—this is absolutely contraindicated due to angioedema risk. 1, 3
- Never accept suboptimal doses (e.g., staying at 49/51 mg) without attempting forced titration to 97/103 mg twice daily. 1
- Never discontinue therapy for asymptomatic hypotension with adequate perfusion—benefits are maintained even with SBP <110 mm Hg. 1
- Never delay initiation of SGLT2 inhibitors or mineralocorticoid receptor antagonists while debating sacubitril/valsartan—start all four classes as soon as possible. 5
Drug Interactions
Sacubitril inhibits hepatic transporters (OATP1B1, OATP1B3, OAT1, OAT3), which may increase statin levels. 6 Consider lower doses of atorvastatin, rosuvastatin, or simvastatin when used with sacubitril/valsartan. 1
Evidence Base
The PARADIGM-HF trial demonstrated that sacubitril/valsartan reduced cardiovascular death or heart failure hospitalization by 20% compared to enalapril in 8,442 patients with chronic HFrEF (70.1% NYHA class II, 23.9% class III, 0.7% class IV). 2, 4, 7 This led to FDA approval in 2015 and Class I, Level B recommendations from ACC/AHA/HFSA guidelines. 2, 7