Is sacubitril/valsartan (Entresto) indicated for a patient with rheumatic heart disease and severe mitral regurgitation?

Entresto in Rheumatic Heart Disease with Severe Mitral Regurgitation

Entresto (sacubitril/valsartan) is NOT indicated for rheumatic heart disease (RHD) with severe mitral regurgitation (MR), as the evidence base and FDA approval specifically address secondary (functional) MR in heart failure, not primary valvular disease like RHD.

Key Distinction: Primary vs Secondary MR

The critical issue here is understanding that rheumatic MR is primary (organic) valvular disease, where the valve leaflets themselves are structurally damaged. This is fundamentally different from secondary (functional) MR where the valve is structurally normal but fails to close properly due to left ventricular dysfunction and remodeling.

Evidence Base Applies Only to Secondary MR

All available evidence for Entresto in MR specifically addresses secondary/functional MR in the context of heart failure with reduced ejection fraction (HFrEF):

• The 2022 AHA/ACC/HFSA Heart Failure Guidelines 1 discuss Entresto's role in reducing effective regurgitant area and volume in secondary MR, noting it works through promoting left ventricular reverse remodeling in HFrEF patients
• The 2021 ACC/AHA Valvular Disease Guidelines 2 recommend GDMT including ACE inhibitors, ARBs, and/or sacubitril/valsartan specifically for patients with severe AR (aortic regurgitation) who have symptoms and/or LV systolic dysfunction - notably, this recommendation addresses symptomatic patients with prohibitive surgical risk, not as primary therapy
• The FDA label 3 explicitly states Entresto is indicated for heart failure with reduced ejection fraction, with pivotal trials (PARADIGM-HF, PARAGON-HF) enrolling patients with LVEF ≤40% and systolic dysfunction

Research Evidence Confirms Mechanism

Multiple studies demonstrate Entresto's benefit in functional MR through LV reverse remodeling:

• A 2019 RCT 4 showed sacubitril/valsartan reduced effective regurgitant orifice area more than valsartan alone in functional MR secondary to LV dysfunction (mean difference -0.04 cm², P=0.032)
• A 2026 study 5 demonstrated 34.6% reduction in EROA after 1 year, with improvement strongly correlated with LV remodeling parameters (r=0.774 for LVESVI, P<0.001)
• A 2025 observational study 6 found reduced all-cause mortality in HFrEF patients with significant MR treated with Entresto, but this was in the context of heart failure, not primary valvular disease

The mechanism is clear: Entresto improves functional MR by reversing LV dilatation and dysfunction, not by treating diseased valve leaflets.

Clinical Algorithm for Your Patient

Step 1: Confirm the Diagnosis

• RHD with severe MR = primary valvular disease with thickened, retracted, calcified leaflets
• This is NOT the population studied in any Entresto trial

Step 2: Assess for Coexisting Heart Failure

IF your RHD patient has developed secondary HFrEF (LVEF ≤40%) with symptoms:

• Entresto IS indicated for the heart failure component 1, 3
• Start at 24/26 mg or 49/51 mg twice daily, titrate to target 97/103 mg twice daily
• Monitor for hypotension (18% incidence), hyperkalemia (12%), and renal dysfunction 3

IF your patient has isolated severe RHD-MR without HFrEF:

• Entresto is NOT indicated
• Focus on surgical intervention per 2021 Valvular Guidelines 2: symptomatic severe primary MR requires valve surgery (Class 1 recommendation)
• Medical therapy should address rate/rhythm control if atrial fibrillation present, diuretics for volume management

Step 3: Definitive Treatment

For RHD with severe MR, the evidence-based approach is surgical or transcatheter valve intervention 2, not pharmacologic therapy with Entresto. The 2022 HF Guidelines 1 explicitly state that cardiologists should guide "timely assessment, optimization of medical therapies, and consideration of surgical or transcatheter interventions" for severe valvular disease.

Critical Pitfalls to Avoid

1. Do not extrapolate functional MR data to primary MR: The pathophysiology is completely different. Entresto cannot reverse structural leaflet damage from rheumatic disease
2. Do not delay surgical evaluation: If your patient has severe symptomatic RHD-MR, they need valve surgery assessment, not a trial of Entresto
3. Monitor blood pressure carefully if used for HF: The FDA label 3 warns that 18% of patients experience hypotension; RHD patients may have additional hemodynamic compromise from severe MR

When Entresto MAY Be Appropriate

The ONLY scenario where Entresto is appropriate in your RHD patient is if they have developed secondary HFrEF (LVEF ≤40%) as a consequence of chronic severe MR 1, 2. In this case:

• Entresto treats the heart failure, not the valve disease
• It should be part of GDMT alongside beta-blockers, mineralocorticoid antagonists, and SGLT2 inhibitors 1
• Surgical valve intervention remains the definitive treatment and should not be delayed 2

Bottom line: Entresto has no role in treating primary rheumatic MR itself. Use it only if concurrent HFrEF is present, and always pursue definitive valve intervention.