What is the best next step for a patient with ischemic cardiomyopathy, ejection fraction (EF) of 30%, on Lisinopril (Angiotensin-Converting Enzyme inhibitor), Metoprolol (beta-blocker), and Statins, who still has symptoms of New York Heart Association (NYHA) class II heart failure?

Management of Ischemic Cardiomyopathy with Persistent NYHA Class II Symptoms

Recommendation

The appropriate action is to stop Lisinopril and start Entresto (sacubitril/valsartan) for this patient with ischemic cardiomyopathy, EF of 30%, and persistent NYHA class II symptoms despite current therapy with Lisinopril, Metoprolol, and statins. 1

Rationale for Switching to Entresto

Entresto (sacubitril/valsartan) is indicated for patients with:

• Heart failure with reduced ejection fraction (HFrEF) with EF ≤40%
• NYHA class II-IV symptoms
• Currently on ACE inhibitor or ARB therapy 1

This patient meets all criteria:

• Has HFrEF with EF of 30%
• Has persistent NYHA class II symptoms despite current therapy
• Is currently on an ACE inhibitor (Lisinopril)

Evidence Supporting This Decision

1. Clinical Outcomes: The PARADIGM-HF trial demonstrated that sacubitril/valsartan reduced the risk of cardiovascular death or heart failure hospitalization by 20% compared to enalapril in patients with HFrEF 1. The number needed to treat to prevent one primary endpoint over 27 months was only 21.

2. Cardiac Remodeling Benefits: Sacubitril/valsartan has been shown to improve:

   • Left ventricular ejection fraction (median increase from 28.2% to 37.8% after 12 months)
   • Decreased left ventricular end-diastolic and end-systolic volumes
   • Improved diastolic function parameters 1, 2

3. Symptom Improvement: Real-world data shows that patients initiated on sacubitril/valsartan experienced significant reductions in:

   • Fatigue (51.8% to 39.5%, p=0.027)
   • Shortness of breath (66.7% to 51.8%, p=0.008) 3
   • Hospitalization rates (27.5% to 17.0%, p=0.009) 3

Implementation Process

1. Discontinuation of Lisinopril:

   • A 36-hour washout period is required when switching from an ACE inhibitor to sacubitril/valsartan to avoid angioedema 1
   • Stop Lisinopril and wait 36 hours before starting Entresto

2. Initiation of Entresto:

   • Start with the lowest dose (24/26 mg twice daily) for patients previously on low-dose ACE inhibitors
   • For patients on higher doses of ACE inhibitors, consider starting with 49/51 mg twice daily 1
   • Titrate up every 2-4 weeks as tolerated toward target dose of 97/103 mg twice daily

3. Monitoring:

   • Check blood pressure, renal function, and potassium levels within 1-2 weeks after initiation
   • Monitor for symptomatic hypotension, which occurs more frequently with sacubitril/valsartan (14.0% vs. 9.2% with ACE inhibitors) 1

Important Considerations and Precautions

• Maintain Other Guideline-Directed Medical Therapy:

  • Continue beta-blocker (Metoprolol) and statin therapy
  • Consider adding a mineralocorticoid receptor antagonist (MRA) if not already prescribed, as triple therapy with ARNI, beta-blocker, and MRA provides optimal outcomes 1

• Contraindications to Entresto:

  • History of angioedema related to previous ACE inhibitor or ARB therapy
  • Concomitant use with ACE inhibitors (hence the washout period)
  • Severe hepatic impairment
  • Pregnancy

• Potential Side Effects:

  • Hypotension (most common)
  • Hyperkalemia
  • Cough
  • Dizziness
  • Renal dysfunction

Why Not the Other Options?

1. Adding Entresto to current therapy (Option A): Contraindicated due to the risk of serious angioedema when combining an ACE inhibitor with sacubitril/valsartan 1

2. Adding Hydralazine/Isosorbide Dinitrate (Option B): While this combination has benefits in heart failure, current guidelines recommend it primarily for:

   • African American patients with NYHA class III-IV symptoms
   • Patients who cannot tolerate ACE inhibitors, ARBs, or ARNIs
   • As an add-on therapy after optimization of other guideline-directed medical therapies 1

For this patient who is eligible for ARNI therapy and has persistent symptoms on an ACE inhibitor, switching to sacubitril/valsartan represents the most evidence-based approach to improve symptoms, cardiac function, and clinical outcomes.