How should I initiate sacubitril/valsartan (angiotensin‑receptor‑neprilysin inhibitor) in a patient with dilated cardiomyopathy and symptomatic heart failure with reduced ejection fraction (≤40%) who is stabilized on an ACE inhibitor or ARB, and what are the contraindications?

Initiating Sacubitril/Valsartan in Dilated Cardiomyopathy with HFrEF

In patients with dilated cardiomyopathy and symptomatic heart failure with reduced ejection fraction (≤40%) who are stabilized on an ACE inhibitor or ARB, you should replace the ACE inhibitor or ARB with sacubitril/valsartan to reduce cardiovascular death and heart failure hospitalization. 1

Indications for ARNI Therapy

Sacubitril/valsartan is indicated for patients meeting all of the following criteria 1:

• Heart failure with reduced ejection fraction (EF ≤40%)
• NYHA class II-IV symptoms
• Currently tolerating an ACE inhibitor or ARB after at least 3 months of therapy
• Administered in conjunction with guideline-directed medical therapy (beta-blockers, mineralocorticoid receptor antagonists, SGLT2 inhibitors as appropriate)

The PARADIGM-HF trial demonstrated a 20% reduction in the composite endpoint of cardiovascular death or heart failure hospitalization (hazard ratio 0.80; 95% CI 0.73-0.87) with sacubitril/valsartan compared to enalapril, with benefits seen across the entire spectrum of reduced ejection fraction 1, 2.

Absolute Contraindications

Do not initiate sacubitril/valsartan if the patient has: 3

• History of angioedema related to previous ACE inhibitor or ARB therapy
• Hypersensitivity to any component of the medication
• Concomitant use with ACE inhibitors (requires 36-hour washout)
• Concomitant use with aliskiren in patients with diabetes
• Pregnancy (causes fetal toxicity and death)

Switching from ACE Inhibitor to ARNI

Critical washout requirement: You must observe a 36-hour washout period when switching from an ACE inhibitor to sacubitril/valsartan to avoid angioedema 1, 3. This washout is not required when switching from an ARB 1.

Starting Dose Based on Prior Therapy 1

For patients on high-dose ACE inhibitor (e.g., enalapril ≥10 mg twice daily):

• Start sacubitril/valsartan 49/51 mg twice daily

For patients on low- or medium-dose ACE inhibitor (e.g., enalapril <10 mg twice daily):

• Start sacubitril/valsartan 24/26 mg twice daily

For patients on high-dose ARB (e.g., valsartan 160 mg total daily):

• Start sacubitril/valsartan 49/51 mg twice daily
• No washout period required

For patients on low- or medium-dose ARB (e.g., valsartan <160 mg total daily):

• Start sacubitril/valsartan 24/26 mg twice daily
• No washout period required

Dose Titration Strategy

Target maintenance dose: 97/103 mg twice daily 1

• Titrate every 2-4 weeks by doubling the dose if tolerated 1
• A gradual titration approach (over 6 weeks) maximizes attainment of target dose compared to condensed approaches (3 weeks) 1
• At least 50% of target dose (49/51 mg twice daily) should be achieved to provide meaningful clinical benefit 1

Special Populations Requiring Dose Adjustment

Start with 24/26 mg twice daily in: 1, 3

• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Moderate hepatic impairment (Child-Pugh Class B)
• Elderly patients (age ≥75 years)
• Patients naive to ACE inhibitors or ARBs

Severe hepatic impairment (Child-Pugh Class C): Use is not recommended 3.

Monitoring Requirements

Within 1-2 weeks after initiation and with each dose increase, monitor: 1

• Blood pressure (symptomatic hypotension occurs in 14% vs 9.2% with enalapril) 1
• Renal function (serum creatinine, eGFR)
• Serum potassium (hyperkalemia risk, especially with concomitant MRA use)

Ongoing monitoring:

• Continue beta-blocker therapy throughout ARNI initiation—do not discontinue 4
• Consider reducing diuretic doses in non-congested patients due to enhanced natriuresis 5

Common Pitfalls to Avoid

Do not delay ARNI initiation waiting for aldosterone antagonist therapy—lack of MRA treatment should not prevent switching to sacubitril/valsartan 1.

Do not use sacubitril/valsartan concomitantly with ACE inhibitors—this increases angioedema risk significantly 4, 3.

Do not stop beta-blocker therapy when initiating ARNI—these medications have complementary mechanisms and should be used together 4.

Avoid in patients with eGFR <30 mL/min/1.73 m² unless using reduced starting dose with close monitoring 1, 3.

Expected Clinical Benefits

Patients with dilated cardiomyopathy treated with sacubitril/valsartan demonstrate 1, 6, 7:

• Progressive recovery of ejection fraction (median increase from 28.2% to 37.8% at 12 months in PROVE-HF)
• Reduction in cardiac volumes (LV end-diastolic and end-systolic volume indices)
• Improvement in functional status and quality of life
• Reduction in heart failure hospitalizations
• 20% reduction in sudden cardiac death compared to enalapril

The benefits of sacubitril/valsartan are consistent across the entire spectrum of reduced ejection fraction, with no evidence of heterogeneity when LVEF is modeled continuously 2.