In an asymptomatic patient with heart failure with reduced ejection fraction who is already on a stable ACE inhibitor, should he be switched to an angiotensin receptor‑neprilysin inhibitor (sacubitril/valsartan)?

Should an Asymptomatic HFrEF Patient on ACE Inhibitor Be Switched to ARNI?

No, an asymptomatic patient with heart failure and reduced ejection fraction on a stable ACE inhibitor should not be switched to sacubitril/valsartan, as current FDA approval and guideline recommendations specifically target symptomatic patients (NYHA class II-IV), and the pivotal PARADIGM-HF trial that established ARNI superiority enrolled predominantly symptomatic patients. 1, 2

Guideline-Based Indications for ARNI

The FDA approved sacubitril/valsartan specifically for patients with chronic heart failure NYHA functional class II to IV with reduced ejection fraction, not for asymptomatic patients. 1, 2 The ACC/AHA/HFSA guidelines similarly recommend sacubitril/valsartan with a Class I indication only for patients with NYHA FC II to III HFrEF who remain symptomatic despite optimal medical therapy. 1

The drug label explicitly states the indication is "to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure" with benefits most clearly evident in patients with LVEF below normal—the term "chronic heart failure" in this context refers to symptomatic disease. 2

Evidence Base Limitations

The PARADIGM-HF trial, which forms the entire evidence base for sacubitril/valsartan approval, enrolled predominantly symptomatic patients: 70.1% were NYHA class II, 23.9% were class III, and only 0.7% were class IV. 1 Critically, asymptomatic patients (NYHA class I) were not studied. 1

A systematic review and meta-analysis of 48 trials with 19,086 participants confirmed that sacubitril/valsartan showed evidence of benefit in HFrEF participants, with a 14% reduction in all-cause mortality (RR 0.86; 95% CI 0.79-0.94) and 11% reduction in serious adverse events (RR 0.89; 95% CI 0.86-0.93). 3 However, these trials enrolled symptomatic patients, not asymptomatic individuals.

Clinical Algorithm for Asymptomatic HFrEF Patients

Step 1: Confirm Symptom Status

• Carefully assess for subtle symptoms that patients may not report spontaneously—many patients with "asymptomatic" HFrEF actually have mild exertional dyspnea or fatigue they've attributed to aging or deconditioning. 4
• Use objective measures: 6-minute walk test, cardiopulmonary exercise testing, or NT-proBNP levels to detect subclinical disease activity. 4

Step 2: Optimize Current ACE Inhibitor Therapy

• Ensure the patient is on target dose ACE inhibitor (equivalent to enalapril 10 mg twice daily), as PARADIGM-HF required this as an entry criterion. 1
• Verify the patient is also on evidence-based beta-blocker (carvedilol, metoprolol succinate, or bisoprolol) at target dose. 4

Step 3: Add Complementary GDMT Components

• Immediately initiate SGLT2 inhibitor (dapagliflozin or empagliflozin), which provides substantial mortality benefit regardless of symptom status and has minimal blood pressure effects. 4
• Add mineralocorticoid receptor antagonist (spironolactone or eplerenone) if LVEF ≤35%, which provides at least 20% mortality reduction. 4
• These medications are appropriate for asymptomatic patients and complete the modern quadruple therapy approach. 4

Step 4: Monitor for Symptom Development

• Schedule regular follow-up every 3-6 months to reassess symptom status. 4
• If symptoms develop (even mild NYHA class II), then switch from ACE inhibitor to sacubitril/valsartan becomes strongly indicated. 1, 4

Safety Considerations for Switching

If a switch to ARNI is contemplated despite asymptomatic status, critical safety requirements include:

• 36-hour washout period from ACE inhibitor before initiating sacubitril/valsartan to avoid angioedema risk. 2
• Baseline systolic blood pressure >100 mmHg (PARADIGM-HF excluded patients with SBP ≤100 mmHg). 1
• eGFR >30 mL/min/1.73 m² (PARADIGM-HF excluded patients with eGFR ≤30). 1
• Serum potassium <5.2 mmol/L. 1

For patients already on target-dose ACE inhibitors, one study showed that switching directly to maximum-dose sacubitril/valsartan (200 mg twice daily) was safe and generally well tolerated, with only 14% discontinuation at 12 months. 5 However, this study enrolled symptomatic patients, not asymptomatic individuals. 5

Common Pitfalls to Avoid

• Do not switch asymptomatic patients based solely on reduced ejection fraction—symptom status is the key determinant for ARNI indication. 1, 2
• Do not delay SGLT2 inhibitor and MRA initiation while debating ARNI switch—these provide proven mortality benefit in all HFrEF patients regardless of symptom status. 4
• Do not assume "asymptomatic" without thorough evaluation—many patients minimize or fail to report symptoms. 4
• Do not switch if the patient is not on target-dose ACE inhibitor—optimize current therapy first. 1

When ARNI Switch Becomes Appropriate

The switch from ACE inhibitor to sacubitril/valsartan becomes strongly indicated when:

• Any symptoms develop (NYHA class II or higher), even if mild. 1, 4
• Patient is already on target doses of ACE inhibitor, beta-blocker, and MRA. 1
• The goal is to achieve the 20% cardiovascular mortality reduction demonstrated in PARADIGM-HF. 1, 3

Real-world data from the Veterans Affairs system showed that only 4.2% of eligible HFrEF patients were switched to sacubitril/valsartan within the first 2 years of FDA approval, and those who were switched had lower all-cause hospitalizations at 4 months (11.2% vs 14.0%; RR 0.80). 6 However, these were symptomatic patients meeting guideline criteria. 6