Is combining carvedilol (beta-blocker) and losartan (angiotensin II receptor antagonist) with angiotensin receptor-neprilysin inhibitor (ARNI) better than switching to ARNI in patients with Heart Failure with Reduced Ejection Fraction (HFrEF)?

Optimal Management of HFrEF: ARNI vs. ARB and Beta-Blocker Combinations

In patients with Heart Failure with Reduced Ejection Fraction (HFrEF), switching from losartan (ARB) to an ARNI (sacubitril/valsartan) while continuing carvedilol is recommended over combining losartan with an ARNI, as this replacement strategy significantly reduces morbidity and mortality. 1

Evidence-Based Recommendations for HFrEF Management

ARNI Therapy

• For patients with NYHA class II-III HFrEF who tolerate an ACE inhibitor or ARB, replacement with an ARNI is strongly recommended to further reduce morbidity and mortality (Class 1, Level B-R) 1
• ARNIs should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor (Class 3: Harm, Level B-R) 1
• Sacubitril/valsartan (ARNI) significantly reduced the composite endpoint of cardiovascular death or HF hospitalization by 20% compared to enalapril in the PARADIGM-HF trial 1

Beta-Blocker Therapy

• Carvedilol is a preferred beta-blocker in patients with HFrEF and should be continued as part of guideline-directed medical therapy 1
• Target doses of beta-blockers should be achieved whenever possible, with carvedilol target dose being 25 mg twice daily for patients <85 kg and 50 mg twice daily for patients >85 kg 1
• Carvedilol may have more favorable effects on glycemic control than metoprolol succinate or bisoprolol in patients with HFrEF and diabetes 1

Important Clinical Considerations

Why ARNI Should Replace ARB (Not Be Combined)

• ARNIs and ARBs work through overlapping mechanisms targeting the renin-angiotensin system, making their combination redundant and potentially harmful 1
• The 2022 AHA/ACC/HFSA guidelines specifically recommend replacement of ACEi or ARB with ARNI, not addition 1
• Sacubitril/valsartan already contains valsartan (an ARB) plus sacubitril (neprilysin inhibitor), making additional ARB therapy (losartan) unnecessary and potentially increasing risk of hypotension 1

Optimal Medication Sequence

• For patients already on ARB therapy (losartan) and beta-blocker (carvedilol), the recommended approach is:
  1. Switch from losartan to sacubitril/valsartan (ARNI) while continuing carvedilol 1
  2. Consider adding a mineralocorticoid receptor antagonist (MRA) if not already prescribed 1, 2
  3. Consider adding SGLT2 inhibitor as part of comprehensive therapy 2, 3

Practical Implementation

• When switching from losartan to sacubitril/valsartan, no washout period is required (unlike when switching from ACEi) 1
• Start with appropriate dose of sacubitril/valsartan based on prior ARB dose:
  • If patient is taking equivalent of >160 mg daily of valsartan: start with 49/51 mg twice daily 1
  • If patient is taking lower doses: start with 24/26 mg twice daily 1
• Monitor blood pressure, electrolytes, and renal function after initiation and during titration 1

Benefits of Comprehensive HFrEF Therapy

• Comprehensive disease-modifying pharmacological therapy (ARNI, beta-blocker, MRA, and SGLT2 inhibitor) compared to conventional therapy (ACEi/ARB and beta-blocker) provides substantial survival benefits 2
• The estimated hazard ratio for cardiovascular death or hospital admission for heart failure with comprehensive therapy is 0.38 (95% CI 0.30-0.47) 2
• Recent network meta-analyses show that ARNI+BB+MRA and SGLT2i+ACEI+BB+MRA are among the most effective combinations for reducing mortality and hospitalization in HFrEF 3, 4

Common Pitfalls to Avoid

• Combining an ARNI with an ARB (losartan) is not recommended and may increase risk of hypotension and other adverse effects 1
• Underdosing of beta-blockers is common in clinical practice - aim for target doses whenever possible 1
• Failure to transition eligible patients from ACEi/ARB to ARNI represents a missed opportunity to reduce mortality and hospitalizations 5
• Patients seen in specialized heart failure clinics are more likely to receive appropriate GDMT, suggesting potential benefit of specialist referral for newly diagnosed HFrEF 5

By following these evidence-based recommendations, you can optimize outcomes for patients with HFrEF through appropriate medication selection and sequencing.