Is sacubitril/valsartan (ARNI) or hydralazine better for heart failure?

From the Guidelines

ARNIs (Angiotensin Receptor-Neprilysin Inhibitors) are generally considered superior to hydralazine for heart failure management, as they have demonstrated greater benefits in reducing hospitalizations and mortality in patients with heart failure with reduced ejection fraction (HFrEF) compared to hydralazine, as shown in the 2022 AHA/ACC/HFSA guideline for the management of heart failure 1. The most common ARNI, sacubitril/valsartan (Entresto), is typically started at 24/26 mg twice daily and titrated to a target dose of 97/103 mg twice daily as tolerated. Hydralazine, often used in combination with isosorbide dinitrate (especially in African American patients), is generally considered a second-line therapy when patients cannot tolerate ACE inhibitors, ARBs, or ARNIs due to kidney dysfunction or angioedema. Some key points to consider when choosing between ARNIs and hydralazine include:

• ARNIs work by simultaneously blocking the harmful effects of angiotensin II while enhancing beneficial natriuretic peptide systems, providing dual action that improves cardiac function, reduces fluid retention, and decreases cardiac remodeling.
• Individual patient factors, including blood pressure, kidney function, and medication tolerance, should guide therapy selection.
• Some patients may benefit from hydralazine-based regimens, particularly African American patients who show enhanced response to this combination, as noted in the 2022 AHA/ACC/HFSA guideline for the management of heart failure 1 and the 2020 European Journal of Heart Failure article on guideline-directed medical therapy for heart failure 1.
• The 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure also recommends the use of ARNIs in patients with chronic symptomatic HFrEF who tolerate an ACE inhibitor or ARB, to further reduce morbidity and mortality 1.
• The 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure recommend sacubitril/valsartan as a replacement for an ACE-I to further reduce the risk of HF hospitalization and death in ambulatory patients with HFrEF who remain symptomatic despite optimal treatment with an ACE-I, a beta-blocker, and an MRA 1.
• The 2022 AHA/ACC/HFSA guideline for the management of heart failure notes that hydralazine and isosorbide dinitrate can prolong survival, but the combination may be inferior to ACE inhibitors with respect to mortality, and its use is based on an analysis of a relatively small number of events in a select population 1.

From the Research

Comparison of ARNI and Hydralazine for Heart Failure

• ARNI (Angiotensin Receptor-Neprilysin Inhibitor) has been shown to be effective in reducing mortality and hospitalization in patients with heart failure with reduced ejection fraction (HFrEF) 2, 3, 4.
• Hydralazine, on the other hand, is a vasodilator that is often used in combination with nitrates for the treatment of heart failure, particularly in patients who are intolerant to ACE inhibitors or ARBs 5, 6.
• A study comparing the effects of ARNI and ACE inhibitors on mortality and hospitalization in patients with HFrEF found that ARNI was superior in reducing these outcomes 2.
• Another study found that early initiation of ARNI therapy in patients with acute heart failure syndrome (AHFS) and reduced LVEF significantly decreased NT-proBNP levels, reduced hospital stay, and improved in-hospital mortality compared to standard care 4.
• However, there is limited direct comparison between ARNI and hydralazine in the treatment of heart failure, and more studies are needed to determine the relative efficacy and safety of these two treatments.

Mechanism of Action

• ARNI works by inhibiting the angiotensin II receptor and neprilysin, which leads to increased levels of natriuretic peptides and decreased levels of angiotensin II, resulting in improved cardiac function and reduced mortality 2, 3.
• Hydralazine, on the other hand, works by directly relaxing vascular smooth muscle, leading to decreased peripheral resistance and improved cardiac output 5, 6.

Clinical Implications

• The use of ARNI has been recommended as a first-line treatment for patients with HFrEF, particularly those who are intolerant to ACE inhibitors or ARBs 2, 6.
• Hydralazine may be considered as an alternative treatment for patients who are intolerant to ACE inhibitors or ARBs, or in combination with nitrates for the treatment of heart failure 5, 6.
• Further studies are needed to determine the optimal treatment strategy for patients with heart failure and to compare the efficacy and safety of ARNI and hydralazine in different patient populations 4.