What is Sacubitril?
Sacubitril is a neprilysin inhibitor that is combined with valsartan (an angiotensin receptor blocker) in a single medication called sacubitril/valsartan, which is the first-in-class angiotensin receptor-neprilysin inhibitor (ARNI) used primarily to reduce cardiovascular death and heart failure hospitalization in patients with heart failure and reduced ejection fraction. 1, 2
Mechanism of Action
Sacubitril functions as a prodrug that is rapidly converted to its active metabolite, sacubitrilat, which inhibits the enzyme neprilysin 3. By blocking neprilysin, sacubitril prevents the breakdown of beneficial natriuretic peptides, bradykinin, and other vasoactive substances, leading to enhanced natriuresis, vasodilation, and reduced cardiac remodeling 2. The combination with valsartan simultaneously blocks the harmful effects of angiotensin II, providing dual neurohormonal modulation 1, 3.
Primary Clinical Indication
The American Heart Association and American College of Cardiology recommend sacubitril/valsartan as a replacement for ACE inhibitors or ARBs in patients with symptomatic heart failure with reduced ejection fraction (HFrEF) who remain symptomatic despite optimal medical therapy with an ACE inhibitor, beta-blocker, and mineralocorticoid receptor antagonist. 1, 4
Evidence for HFrEF
- Sacubitril/valsartan reduces cardiovascular death by 20% compared to the gold-standard ACE inhibitor enalapril 1, 4
- It significantly decreases heart failure hospitalizations (rate ratio 0.85) 5, 1
- Benefits occur within weeks of initiation and are maintained regardless of baseline blood pressure, even with systolic BP <110 mmHg 1
Treatment Algorithm Placement
The European Society of Cardiology recommends the following stepwise approach for HFrEF 1:
- First-line therapy: ACE inhibitor + beta-blocker 1
- Second-line therapy: Add mineralocorticoid receptor antagonist (MRA) if patient remains symptomatic 1
- Third-line therapy: Replace ACE inhibitor/ARB with sacubitril/valsartan if patient remains symptomatic 1
- Additional therapy: Add SGLT2 inhibitor (dapagliflozin or empagliflozin) to reduce hospitalization and death risk 1
Recent guidelines now support direct initiation of sacubitril/valsartan without prior ACE inhibitor or ARB exposure as a safe and effective strategy, eliminating the need for pretreatment. 1, 4
Dosing and Administration
Initial Dosing
The American College of Cardiology recommends the following starting doses 1:
- 49/51 mg twice daily for patients previously on high-dose ACE inhibitors 1
- 24/26 mg twice daily for patients on low/medium-dose ACE inhibitors or ARBs 1
- 24/26 mg twice daily for treatment-naïve patients (de novo) 1
- 24/26 mg twice daily for patients with severe renal impairment (eGFR <30 mL/min/1.73 m²), moderate hepatic impairment (Child-Pugh B), or age ≥75 years 1
Titration Schedule
Double the dose every 2-4 weeks as tolerated to reach the target dose of 97/103 mg twice daily, which provides maximum mortality benefit. 1
Critical Washout Period
When transitioning from an ACE inhibitor to sacubitril/valsartan, a mandatory 36-hour washout period must be observed to avoid life-threatening angioedema. 1 No washout period is required when switching from an ARB 1.
Evidence in Heart Failure with Preserved Ejection Fraction (HFpEF)
In the PARAGON-HF trial involving 4,822 patients with HFpEF (LVEF ≥45%), sacubitril/valsartan compared to valsartan did not achieve a significant reduction in the primary composite endpoint of cardiovascular death or total heart failure hospitalizations (rate ratio 0.87; 95% CI 0.75-1.01; P=0.06) 5, 6. However, exploratory subgroup analyses suggested potential benefit in patients with LVEF 45-57% (rate ratio 0.78) and in women (rate ratio 0.73) 5, 6.
The American College of Cardiology gives sacubitril/valsartan a Class 2b recommendation for heart failure with mildly reduced ejection fraction (HFmrEF, LVEF 41-49%), indicating it may be considered in this population. 1
Managing Common Adverse Effects
Hypotension
Hypotension is the most common side effect, occurring in 16% of patients (asymptomatic) and 11% (symptomatic) 4. Critically, asymptomatic hypotension should not prevent initiation or uptitration, as efficacy and safety are maintained regardless of baseline blood pressure. 1, 4
- Reduce diuretic doses in non-congested patients first
- Temporarily reduce sacubitril/valsartan dose rather than discontinuing (40% of patients requiring temporary dose reduction can be restored to target doses)
- Continue monitoring, as benefits persist even with lower blood pressure
Other Adverse Effects
- Hyperkalemia: Lower incidence compared to ACE inhibitors 5
- Angioedema: Higher incidence than valsartan alone; contraindicated in patients with history of ACE inhibitor-related angioedema 5, 1
- Renal function decline: Favorable compared to valsartan (composite outcome of renal decline favored sacubitril/valsartan) 5
- Hyponatremia: Rare but reported cases exist 7
Important Drug Interactions
Sacubitril/valsartan may increase levels of statins that are substrates of OATP1B1, OATP1B3, OAT1, and OAT3 transporters. 1 The American Heart Association recommends considering lower doses of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin when used in combination with sacubitril/valsartan 1. Notably, atorvastatin maximum plasma concentration increases 2-fold and AUC increases 1.3-fold, while simvastatin pharmacokinetics remain unaffected 3.
Pharmacokinetics
Sacubitril is rapidly absorbed and converted to sacubitrilat, with peak plasma concentrations reached at 0.5 hours for sacubitril, 1.5-2.0 hours for sacubitrilat, and 2.0-3.0 hours for valsartan 3. Steady-state is achieved within 3 days with twice-daily dosing 3. Sacubitril is eliminated predominantly as sacubitrilat through the kidneys, while valsartan is eliminated mainly by the biliary route 3.
In patients with severe renal impairment and end-stage renal disease, sacubitrilat AUC increases 2.9-fold and 3.3-fold respectively, necessitating dose adjustment to 24/26 mg twice daily. 1, 3
Special Populations and Considerations
Hospitalized Patients
Sacubitril/valsartan can be initiated in hospitalized patients after hemodynamic stabilization, defined as resolution of acute pulmonary congestion 1. Approximately 25% of patients may develop hypotension when treated in the hospital setting, requiring close monitoring 4.
Elderly Patients
Age does not affect the pharmacokinetics of sacubitril/valsartan, and benefits occur regardless of age 1, 3. However, patients ≥75 years should start with the lowest dose (24/26 mg twice daily) 1.
Contraindications
Absolute contraindications include 1, 4:
- History of angioedema related to previous ACE inhibitor or ARB therapy
- Concomitant use with ACE inhibitors (requires 36-hour washout)
- Pregnancy or lactation
- Severe hepatic impairment
Common Pitfalls to Avoid
The European Society of Cardiology warns against 1:
- Failing to titrate to target doses due to asymptomatic hypotension or mild laboratory changes
- Making permanent dose reductions when temporary reductions with subsequent re-titration would be more appropriate
- Believing that medium-range doses provide most of the benefits of target doses (they do not)
- Treating heart failure less aggressively than other life-threatening conditions despite similar mortality risks