What is the recommended treatment with Angiotensin Receptor Neprilysin Inhibitors (ARNI) drugs for patients with heart failure with reduced ejection fraction?

Angiotensin Receptor Neprilysin Inhibitor (ARNI) Treatment for Heart Failure with Reduced Ejection Fraction

Sacubitril/valsartan is recommended as a first-line therapy to replace ACE inhibitors or ARBs in patients with heart failure with reduced ejection fraction (HFrEF) to reduce the risk of cardiovascular death and hospitalization. 1, 2

Indications for ARNI Therapy

• ARNI (sacubitril/valsartan) is indicated to reduce the risk of cardiovascular death and hospitalization in adult patients with chronic heart failure, with benefits most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal 2
• Specifically recommended for patients with HFrEF (LVEF ≤40%) with NYHA class II-IV symptoms 1
• Can be used as replacement therapy for symptomatic HFrEF with NYHA class II or III who tolerate an ACEI or ARB 1
• Should be administered in conjunction with evidence-based beta-blockers and aldosterone antagonists in selected patients 1

Efficacy and Benefits

• Sacubitril/valsartan reduced the composite endpoint of cardiovascular death or HF hospitalization by 20% compared to enalapril in the PARADIGM-HF trial 1
• Benefits were seen to a similar extent for both death and HF hospitalization and were consistent across subgroups 1
• ARNI therapy is associated with improvement in diastolic function, left ventricular function, quality of life, and reduced burden of ventricular arrhythmias 1, 3
• In the PROVE-HF study, 12 months of therapy with sacubitril/valsartan resulted in significant improvements in cardiac structure and function, including increased LVEF from 28.2% to 37.8% 1
• Real-world evidence shows sacubitril/valsartan is associated with symptom improvements (reduced fatigue and shortness of breath) and reduction in hospitalizations within 4 months of treatment 4

Dosing Recommendations

• The recommended starting dose for adults is 49/51 mg orally twice daily 2
• Target maintenance dose is 97/103 mg orally twice daily 2
• Adjust adult doses every 2 to 4 weeks to the target maintenance dose, as tolerated by the patient 2
• Consider a lower starting dose (24/26 mg twice daily) for:
  • Patients not currently taking an ACE inhibitor or ARB 2
  • Patients previously taking low doses of these agents 2
  • Patients with severe renal impairment or moderate hepatic impairment 2
  • Patients with low blood pressure (SBP <100 mmHg) 1

Important Considerations and Precautions

• A 36-hour washout period is required when switching from an ACE inhibitor to sacubitril/valsartan to avoid angioedema 1, 2
• No washout period is required when switching from an ARB to sacubitril/valsartan 1
• Sacubitril/valsartan is contraindicated in patients with:
  • History of angioedema related to previous ACE inhibitor or ARB therapy 2
  • Concomitant use with ACE inhibitors 2
  • Concomitant use with aliskiren in patients with diabetes 2
• Monitor for hypotension, which is more common with sacubitril/valsartan than with ACE inhibitors (14.0% vs. 9.2%) 1, 5
• Monitor renal function and potassium levels, especially in susceptible patients 2

Approach to Treatment in Special Populations

• For patients with low blood pressure (SBP <100 mmHg):

  • Start with SGLT2 inhibitors and mineralocorticoid receptor antagonists (MRAs) first, as they have the least effect on BP 1
  • Consider a very low dose of sacubitril/valsartan (25 mg twice daily) and gradually up-titrate if possible 1
  • If sacubitril/valsartan is not tolerated, consider a low-dose ACE inhibitor or ARB 1

• For patients with coronary artery disease and HFrEF:

  • Sacubitril/valsartan is recommended to reduce the risk of HF hospitalization and cardiovascular death 1
  • Should be used as part of comprehensive therapy including beta-blockers, MRAs, and SGLT2 inhibitors 1

Implementation in Clinical Practice

• Most patients in real-world practice initiate sacubitril/valsartan at the lowest dose of 24/26 mg twice daily 4
• Only about 17% of patients achieve the target dose of 97/103 mg twice daily after 4 months of treatment in real-world settings 4
• Discontinuation rates are low (5.5% within first 6 weeks) suggesting good tolerability 4
• A gradual titration approach may maximize attainment of the target dose in patients previously receiving low doses of an ACEI/ARB 1

Common Pitfalls and Caveats

• Failure to observe the mandatory 36-hour washout period when switching from ACE inhibitors to sacubitril/valsartan increases risk of angioedema 1, 2
• Adding an ACE inhibitor to patients already treated with an ARNI is contraindicated due to increased risk of angioedema and other complications 1
• Adding an ARB to ARNI therapy is not clinically advocated as an ARB is already a component of the ARNI regimen 1
• The addition of an ARB to the combination of an ACE inhibitor and an MRA is not recommended due to increased risk of renal dysfunction and hyperkalemia 1
• Sacubitril/valsartan should be discontinued when pregnancy is detected due to fetal toxicity risks 2