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

From the Guidelines

For most patients with heart failure with reduced ejection fraction (HFrEF), ARNIs are generally considered superior to hydralazine due to their ability to reduce mortality and hospitalizations more effectively than standard ACE inhibitor therapy, as demonstrated in the PARADIGM-HF trial 1. The main ARNI currently available is sacubitril/valsartan (Entresto), which has been shown to reduce the composite endpoint of cardiovascular death or heart failure hospitalization by 20% relative to enalapril 1. Some key points to consider when choosing between ARNIs and hydralazine include:

• ARNIs work by simultaneously blocking the harmful effects of the renin-angiotensin system while enhancing beneficial natriuretic peptide effects, providing dual action against the neurohormonal imbalances in heart failure 1.
• Side effects of ARNIs include hypotension, hyperkalemia, and angioedema, while hydralazine may cause headaches, tachycardia, and lupus-like syndrome with long-term use 1.
• Hydralazine, often used in combination with isosorbide dinitrate (especially in African American patients or those who cannot tolerate ACE inhibitors/ARBs), is considered a second-line therapy 1.
• The choice between these medications should be individualized based on patient characteristics, comorbidities, and tolerance, with consideration of the most recent guidelines and evidence, such as the 2022 AHA/ACC/HFSA guideline for the management of heart failure 1. Typical dosing of sacubitril/valsartan starts at 24/26 mg twice daily and can be titrated up to 97/103 mg twice daily as tolerated 1. It is also important to note that the use of ARNIs has been supported by additional clinical trial evidence, meta-analyses, and observational clinical effectiveness studies, which further support the use of valsartan/sacubitril in replacement of ACE inhibitor or ARB therapy to reduce mortality and morbidity 1. In contrast, hydralazine and isosorbide dinitrate are recommended to reduce the risk of HF hospitalization and death in symptomatic patients with LVEF <45% combined with a dilated LV in NYHA Class III–IV despite treatment with an ACE-I, a beta-blocker and an MRA, but this is based on older guidelines and evidence 1. Overall, the most recent and highest quality evidence supports the use of ARNIs over hydralazine for most patients with HFrEF, due to their superior efficacy in reducing mortality and hospitalizations 1.

From the FDA Drug Label

The FDA drug label does not answer the question.

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.
• Studies have demonstrated that sacubitril-valsartan, an ARNI, is superior to ACE inhibitors in improving outcomes for patients with HFrEF 2, 5.
• 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.
• There is limited direct comparison between ARNI and hydralazine in the provided studies, but ARNI has been shown to be more effective in reducing mortality and hospitalization in patients with HFrEF 2, 3, 4.
• The use of ARNI has been recommended in recent guidelines for the treatment of heart failure with reduced ejection fraction, and it is considered a valuable treatment option for patients with HFrEF 2, 4, 6.

Mechanism of Action

• ARNI works by inhibiting the neprilysin enzyme, which breaks down natriuretic peptides, and blocking the angiotensin receptor, which reduces the effects of angiotensin II on the heart and blood vessels 2, 5.
• Hydralazine, as a vasodilator, works by relaxing the smooth muscle in blood vessels, reducing peripheral resistance, and increasing cardiac output.
• The mechanism of action of ARNI is more targeted towards the neurohormonal pathways involved in heart failure, whereas hydralazine has a more general vasodilatory effect.

Clinical Evidence

• The clinical evidence supporting the use of ARNI in heart failure is strong, with multiple large-scale randomized controlled trials demonstrating its efficacy in reducing mortality and hospitalization 2, 3, 4.
• The evidence for hydralazine is less robust, and it is often used as an alternative or adjunctive therapy in patients who are intolerant to other treatments.