What are the recommended angiotensin system inhibitors (Angiotensin Receptor Neprilysin Inhibitors (ARNI)), such as sacubitril/valsartan (Entresto), and mineralocorticoid receptor antagonists (MRA), like spironolactone or eplerenone, for patients with heart failure with reduced ejection fraction?

Angiotensin System Inhibitors and Mineralocorticoid Receptor Antagonists for Heart Failure with Reduced Ejection Fraction

The recommended angiotensin system inhibitors for heart failure with reduced ejection fraction (HFrEF) include ACE inhibitors, ARBs, and preferably ARNI (sacubitril/valsartan), while the recommended mineralocorticoid receptor antagonists (MRAs) are spironolactone and eplerenone. 1

Angiotensin System Inhibitors

ACE Inhibitors

• Captopril (starting: 6.25 mg TID; target: 50 mg TID) 1
• Enalapril (starting: 2.5 mg BID; target: 10-20 mg BID) 1
• Lisinopril (starting: 2.5-5.0 mg daily; target: 20-35 mg daily) 1
• Ramipril (starting: 2.5 mg daily; target: 10 mg daily) 1
• Trandolapril (starting: 0.5 mg daily; target: 4 mg daily) 1

Angiotensin Receptor Blockers (ARBs)

• Candesartan (starting: 4-8 mg daily; target: 32 mg daily) 1
• Valsartan (starting: 40 mg BID; target: 160 mg BID) 1
• Losartan (starting: 50 mg daily; target: 150 mg daily) 1

Angiotensin Receptor Neprilysin Inhibitor (ARNI)

• Sacubitril/valsartan (Entresto) (starting: 49/51 mg BID; target: 97/103 mg BID) 1, 2
  • Preferred over ACE inhibitors/ARBs for patients with HFrEF who remain symptomatic despite optimal treatment 1, 2
  • Reduces cardiovascular mortality by 20% compared to enalapril 1
  • FDA approved for NYHA class II-IV patients with reduced ejection fraction 1, 3
  • Requires 36-hour washout period when switching from ACE inhibitors 2, 3

Mineralocorticoid Receptor Antagonists (MRAs)

• Spironolactone (starting: 12.5-25 mg daily; target: 50 mg daily) 1
• Eplerenone (starting: 25 mg daily; target: 50 mg daily) 1

Treatment Algorithm for HFrEF

1. First-line therapy: ACE inhibitor/ARB + beta-blocker 2, 4
2. Second-line therapy: Add MRA (spironolactone or eplerenone) if patient remains symptomatic 2, 4
3. Third-line therapy: Replace ACE inhibitor/ARB with sacubitril/valsartan (ARNI) if patient remains symptomatic despite optimal therapy 2, 4
4. Additional therapy: Consider SGLT2 inhibitor (dapagliflozin or empagliflozin) 4

Clinical Benefits

• ACE inhibitors reduce morbidity and mortality in patients with mild, moderate, or severe HF symptoms 1
• ARBs are alternatives for ACE inhibitor-intolerant patients 1
• ARNI (sacubitril/valsartan) provides superior reduction in cardiovascular death and HF hospitalization compared to ACE inhibitors 1, 5
• MRAs reduce mortality and hospitalization in symptomatic HFrEF patients 1, 4

Important Considerations and Precautions

• Monitor for hypotension, especially when initiating or titrating sacubitril/valsartan 2
• Check renal function and electrolytes regularly, particularly when using MRAs 2, 4
• Sacubitril/valsartan is contraindicated with concomitant ACE inhibitor use 3
• For patients with moderate hepatic impairment, start sacubitril/valsartan at the lowest dose (24/26 mg BID) 2
• Diuretic doses may need reduction when initiating sacubitril/valsartan due to enhanced natriuresis 2

Common Pitfalls to Avoid

• Failure to titrate medications to target doses 2, 4
• Inappropriate discontinuation of medications due to asymptomatic hypotension or mild laboratory changes 2
• Underutilization of guideline-directed medical therapy 4
• Treating heart failure less aggressively than other life-threatening conditions 2

By following this evidence-based approach to angiotensin system inhibitors and MRAs in HFrEF, clinicians can significantly reduce mortality and hospitalization rates while improving quality of life for patients with heart failure.