Can Angiotensin Receptor Neprilysin Inhibitors (ARNI) be combined with beta blockers for heart failure?

From the Guidelines

Yes, ARNIs can be combined with beta blockers for heart failure treatment, and this combination is actually recommended as part of standard therapy for many patients with heart failure with reduced ejection fraction (HFrEF). The most recent and highest quality study, published in the European Journal of Heart Failure in 2020 1, supports the use of neprilysin inhibitors, such as sacubitril/valsartan, in combination with beta-adrenergic blockers, like carvedilol, metoprolol succinate, and bisoprolol, as essential treatments for patients with chronic heart failure and a reduced ejection fraction.

When initiating this combination, patients should be on stable doses of beta blockers before adding the ARNI. The typical starting dose of sacubitril/valsartan is 24/26 mg twice daily, which can be titrated up to 97/103 mg twice daily as tolerated. Patients should be monitored for hypotension, as both medications can lower blood pressure. This combination works well because the medications have complementary mechanisms: beta blockers reduce heart rate and cardiac workload, while ARNIs both block harmful neurohormonal activation and enhance beneficial peptides that improve cardiac function, reduce fluid retention, and decrease strain on the heart.

Key points to consider when using this combination include:

• The importance of titrating the dose of sacubitril/valsartan to minimize the risk of hypotension and renal insufficiency
• The need to monitor patients for signs of angioedema, a rare but potentially life-threatening side effect of ARNIs
• The benefits of using this combination to reduce morbidity and mortality in patients with HFrEF, as demonstrated in large randomized controlled trials 1
• The recommendation to use this combination as part of a comprehensive treatment plan that includes other evidence-based therapies, such as mineralocorticoid receptor antagonists and sodium-glucose co-transporter 2 inhibitors, as needed.

Overall, the combination of ARNIs and beta blockers is a powerful tool in the management of heart failure with reduced ejection fraction, and its use is supported by strong evidence from recent and high-quality studies 1.

From the FDA Drug Label

CONCOMITANT USE WITH ACE INHIBITORS. (4,7.1)

DRUG INTERACTIONS • Avoid concomitant use with aliskiren in patients with estimated glomerular filtration rate (eGFR) less than 60. (7.1) • Potassium-sparing diuretics: May lead to increased serum potassium. (7. 2) • Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): May lead to increased risk of renal impairment. (7.3) • Lithium: Increased risk of lithium toxicity. (7.4)

The FDA drug label does not answer the question about combining arni's with beta blockers for heart failure, as it only discusses concomitant use with ACE inhibitors, aliskiren, potassium-sparing diuretics, NSAIDs, and lithium 2.

From the Research

Combination of ARNI and Beta Blockers for Heart Failure

• The use of angiotensin receptor-neprilysin inhibitors (ARNI) in combination with beta blockers for heart failure with reduced ejection fraction (HFrEF) has been supported by several studies 3, 4, 5, 6.
• According to the study by 6, patients with HFrEF should be treated with a β-blocker and one of an angiotensin receptor-neprilysin inhibitor, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker as foundational therapy.
• The study by 3 suggests that combining a neprilysin inhibitor with an angiotensin II type 1 receptor blocker, such as ARNI, avoids the risk of angioedema and is associated with greater reductions in mortality and morbidity compared to enalapril.
• The real-world experience from Taiwan, as reported by 5, shows that ARNI is safe and effective in patients with HFrEF, with improvements in left ventricular ejection fraction and reductions in B-type natriuretic peptide and uric acid levels.
• However, the study by 7 notes that the current evidence for beta blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in heart failure with preserved ejection fraction (HFpEF) is limited and does not support their use in the absence of an alternative indication.

Safety and Efficacy of ARNI and Beta Blockers

• The study by 4 provides compelling evidence that sacubitril-valsartan, an ARNI, is superior to an angiotensin-converting enzyme inhibitor in reducing mortality and heart failure hospitalization and improving quality of life in patients with stage C HFrEF.
• The real-world experience from Taiwan, as reported by 5, shows that ARNI is safe and effective in patients with HFrEF, with a low rate of all-cause death, cardiovascular death, and heart failure readmission.
• However, the study by 7 notes that beta blockers may reduce the risk of cardiovascular mortality in HFpEF, but further trials are needed to confirm this finding.

Clinical Implications

• The use of ARNI in combination with beta blockers is a recommended treatment strategy for patients with HFrEF, as supported by several studies 3, 4, 5, 6.
• Clinicians should consider the use of ARNI and beta blockers as foundational therapy for patients with HFrEF, unless there are specific contraindications.
• Further research is needed to determine the efficacy and safety of ARNI and beta blockers in patients with HFpEF.