Combining ARNI with Beta-Blockers in Heart Failure with Reduced Ejection Fraction
Yes, an Angiotensin Receptor-Neprilysin Inhibitor (ARNI) can and should be combined with a beta-blocker such as carvedilol in the treatment of Heart Failure with Reduced Ejection Fraction (HFrEF). 1
Evidence for Combination Therapy
- Current guidelines from the American College of Cardiology/American Heart Association/Heart Failure Society of America strongly recommend a four-pillar approach to HFrEF treatment that includes both ARNIs and beta-blockers as foundational therapies 1
- The clinical strategy of inhibition of the renin-angiotensin system with ARNIs in conjunction with evidence-based beta-blockers (such as carvedilol) and other therapies is recommended with the highest level of evidence (Class I) to reduce morbidity and mortality in patients with chronic HFrEF 1
- Beta-blockers (specifically bisoprolol, carvedilol, or sustained-release metoprolol succinate) have a Class I, Level of Evidence A recommendation for patients with HFrEF to reduce mortality and hospitalizations 1
- ARNIs are similarly recommended with Class I, Level of Evidence A for patients with HFrEF and NYHA class II to III symptoms to reduce morbidity and mortality 1
Optimal Sequencing of Medications
- Modern approaches recommend rapid implementation of all four foundational drug classes for HFrEF within 2-4 weeks, rather than the historical sequential approach that could take 6+ months 2
- A proposed accelerated approach includes simultaneous initiation of a beta-blocker and an SGLT2 inhibitor, followed 1-2 weeks later by ARNI initiation, and then a mineralocorticoid receptor antagonist 1-2 weeks after that 2
- This rapid sequencing approach recognizes that each foundational therapy has independent benefits, and low starting doses of all four classes provide substantial therapeutic benefits 2
Special Considerations
- When transitioning from an ACE inhibitor to an ARNI, a 36-hour washout period is required to minimize the risk of angioedema 1
- Patients should be monitored for potential side effects including hypotension, renal insufficiency, and hyperkalemia when on combination therapy 1
- Carvedilol may have more favorable effects on glycemic control than other beta-blockers in patients with both diabetes and HFrEF 1
- ARNIs have been shown to be effective even in patients with advanced chronic kidney disease (CKD) when used with careful monitoring 3
Efficacy of Combination Therapy
- Network meta-analyses have shown that ARNIs have the highest probability of reducing all-cause mortality (OR=0.67) and heart failure hospitalization (OR=0.55) compared to other RAAS blockers 4
- The combination of evidence-based therapies including ARNIs and beta-blockers provides additive benefits in reducing morbidity and mortality in HFrEF patients 1
- The 2022 ACC/AHA/HFSA guidelines emphasize that even if symptoms improve with therapy, long-term treatment with both ARNIs and beta-blockers should be maintained to reduce the risk of disease progression and major cardiovascular events 1
Practical Implementation
- Start with low doses of both medications and titrate gradually to target doses as tolerated 1
- Monitor blood pressure, heart rate, renal function, and electrolytes regularly, especially during initiation and dose adjustments 1
- Abrupt withdrawal of beta-blocker therapy should be avoided as it can lead to clinical deterioration 1
- For patients already on an ACE inhibitor or ARB who are being switched to an ARNI, the beta-blocker therapy should be continued without interruption 1
In conclusion, the combination of an ARNI with a beta-blocker represents the current standard of care for patients with HFrEF according to major cardiovascular guidelines, with both medication classes working through complementary mechanisms to improve outcomes.