Angiotensin Receptor-Neprilysin Inhibitor (ARNI): A Breakthrough in Heart Failure Treatment

Q: What is the main benefit of taking an ARNI?

The main benefit of an ARNI is that it helps heart failure patients live longer and reduces the likelihood of being hospitalized for heart-related issues. It also improves the heart's pumping efficiency over time.

Q: How does ARNI differ from an ACE inhibitor?

Unlike an ACE inhibitor, an ARNI uses a dual-action approach. It combines an ARB to lower blood pressure with a neprilysin inhibitor that helps the body remove excess sodium and widen blood vessels more effectively.

Q: Why is there a 36-hour wait when switching from an ACE inhibitor?

The 36-hour wait, known as a washout period, is necessary to prevent angioedema. This is a potentially dangerous swelling under the skin that can occur if both medications are present in the body at the same time.

Q: What are the most common side effects of ARNI?

The most common side effects include low blood pressure (hypotension), which can cause dizziness, high potassium levels (hyperkalemia), and potential changes in kidney function.

Q: Can I take ARNI if I am pregnant?

No, ARNI medications should not be taken during pregnancy or while nursing, as they can cause harm to the developing fetus or infant.

Q: How is the dosage of ARNI determined?

Dosage usually starts low (49/51 mg twice daily) and is increased after two to four weeks to a target dose of 97/103 mg. Providers may use even lower doses for those with kidney issues.

Q: Does ARNI treat all types of heart failure?

ARNI is primarily used for heart failure with reduced ejection fraction (HFrEF) but can also be beneficial for some patients with preserved ejection fraction (HFpEF) whose hearts are stiff.

Q: What monitoring is required while taking an ARNI?

Patients need regular blood tests to check potassium levels and kidney function, as well as frequent blood pressure checks, especially during the first few weeks of therapy.

Q: Can ARNI help with a chronic cough caused by other heart meds?

Yes, many patients switch to an ARNI because it does not typically cause the chronic, dry cough often associated with ACE inhibitors.

Q: How long does it take for ARNI side effects to go away?

Most side effects associated with starting ARNI therapy go away within about 14 days. If they persist, a healthcare provider may adjust the dosage.

Dr. Baraa Alnahhal

Oct 8

7 min read

Updated: 3 days ago

Medically reviewed by Dr. Baraa Alnahhal, MD · Last reviewed: October 2026

Quick Answer

An angiotensin receptor-neprilysin inhibitor (ARNI) is a combination medication of sacubitril and valsartan used to treat heart failure by lowering blood pressure and easing the heart's workload. It helps the body remove excess sodium, widens blood vessels and increases urine production [1]. It is mainly used for a reduced ejection fraction of 40% or less, improving survival and reducing hospitalizations [1] [2].

What the research says

ARNI beat the older standard drug, enalapril, in people with reduced ejection fraction. In the PARADIGM-HF trial of 8,442 patients with an ejection fraction of 40% or less, the combined outcome of cardiovascular death or hospitalization for heart failure occurred in 21.8% of patients taking sacubitril/valsartan (studied as LCZ696) versus 26.5% of patients taking enalapril (hazard ratio 0.80; 95% CI 0.73 to 0.87; P<0.001). The trial was stopped early because of overwhelming benefit. Low blood pressure and non-serious angioedema were more common with the ARNI, while kidney impairment, high potassium, and cough were less common (PubMed: McMurray et al., N Engl J Med, 2014) [2].
The benefit is less clear when the ejection fraction is preserved. In the PARAGON-HF trial, 4,822 patients with an ejection fraction of 45% or higher took either sacubitril/valsartan or valsartan. The difference in total hospitalizations for heart failure and cardiovascular death was not statistically significant (rate ratio 0.87; 95% CI 0.75 to 1.01; P=0.06), although possible benefit was suggested in patients with a lower ejection fraction and in women (PubMed: Solomon et al., N Engl J Med, 2019) [3].

What is angiotensin receptor-neprilysin inhibitor (ARNI) therapy?

Angiotensin receptor-neprilysin inhibitors, commonly referred to as ARNI medications, represent a significant advancement in the pharmacological management of heart failure. This treatment class functions by combining two distinct drugs into a single therapeutic agent to target multiple pathways involved in cardiac dysfunction. Currently, the combination of sacubitril and valsartan is the only FDA-approved ARNI available for clinical use [1].

The primary objective of ARNI therapy is to improve the heart's ability to pump oxygen-rich blood to the rest of the body, particularly in patients with a reduced ejection fraction. Ejection fraction measures how much blood the left ventricle pumps out with each contraction; a normal range is typically between 55% and 65%, while ARNI is often prescribed when this value drops to 40% or lower [1].

ARNI mechanism of action: sacubitril inhibits neprilysin, which promotes vasodilation and sodium excretion, while valsartan blocks angiotensin II to prevent blood vessel constriction, together improving heart function – rinnit.com

How do angiotensin receptor-neprilysin inhibitors (ARNI) work?

The effectiveness of an ARNI drug stems from the synergistic relationship between its two components. Each part of the medication addresses a different aspect of the cardiovascular system to lower blood pressure and reduce strain on the heart muscle.

Component	Drug Type	Primary Function
Valsartan	Angiotensin II Receptor Blocker (ARB)	Prevents blood vessels from constricting to lower blood pressure [1].
Sacubitril	Neprilysin Inhibitor	Allows the body to excrete sodium, dilate vessels, and increase urine [1].

By inhibiting the enzyme neprilysin, sacubitril allows beneficial peptides to remain active in the body longer. These peptides assist in removing salt from the bloodstream and widening blood vessels. Simultaneously, valsartan blocks the action of angiotensin II, a hormone that causes blood vessels to narrow. Together, these actions make it significantly easier for the heart to circulate blood.

When are angiotensin receptor-neprilysin inhibitors (ARNI) used?

ARNI medications are primarily used to treat chronic heart failure in adults. Clinical guidelines specifically recommend ARNI for patients in Stage C of heart failure, which is characterized by structural heart disease and active symptoms.

Reduced Ejection Fraction (HFrEF): Prescribed for patients with an ejection fraction of 40% or less [1] to improve pumping function.
Preserved Ejection Fraction (HFpEF): May also benefit patients with an ejection fraction of 50% or higher where the heart is stiff and cannot hold enough blood.
Transitioning Treatments: Patients currently taking ACE inhibitors or ARBs may be switched to ARNI to achieve better clinical outcomes or to eliminate side effects like chronic coughing [1].

ARNI treatment pathway: a 36-hour washout after stopping an ACE inhibitor, a starting dose of 49/51 mg twice daily, then titration to the target dose of 97/103 mg twice daily – rinnit.com

How are angiotensin receptor-neprilysin inhibitors (ARNI) dosed and taken?

Standard ARNI therapy involves a gradual increase in dosage to ensure patient safety and tolerance. Most healthcare providers follow a specific titration schedule to reach the target therapeutic level.

Starting Phase: Patients typically begin with a dose of 49/51 mg of sacubitril/valsartan taken twice daily [1].
Titration Phase: After two to four weeks, the dose is usually increased to the target level of 97/103 mg twice daily [1].
Adjustments: A lower starting dose of 24/26 mg may be used for patients with kidney dysfunction, low blood pressure, or those previously on low-dose ACE inhibitors.

Critical Safety Note: When switching from an ACE inhibitor to an ARNI, a 36-hour washout period is mandatory [1]. Starting ARNI too soon after stopping an ACE inhibitor significantly increases the risk of angioedema, a severe swelling under the skin.

What are the benefits and clinical outlook of ARNI therapy?

Clinical studies have demonstrated that ARNI therapy offers superior protection compared to traditional heart failure medications. Research indicates that patients taking an ARNI experience a 20% reduction in the risk of cardiovascular death or hospitalization related to heart failure [1] [2].

Furthermore, ARNI use has been linked to structural improvements in the heart. One study showed that after one year of treatment, patients saw their left ventricle's ejection fraction increase from an average of 28.2% to 37.8% [1]. For older patients, this therapy can add between 1.6 and 2.1 years of life without major heart-related hospital events [1].

Safety and monitoring for ARNI therapy: check potassium levels with blood tests, monitor kidney function, and track blood pressure at home and in clinic – rinnit.com

What are the potential risks and side effects of ARNI medications?

ARNI medications are highly effective but can cause side effects such as low blood pressure, high potassium, kidney changes and rare angioedema [1], which require medical monitoring. During the first few weeks of treatment, healthcare providers typically perform blood tests to check potassium levels [1] and ensure the kidneys are functioning correctly.

Common side effects and risks include:

Hypotension: Low blood pressure [1] [2], which may cause dizziness or fainting.
Hyperkalemia: High levels of potassium in the blood [1].
Kidney Dysfunction: Potential changes in how well the kidneys filter waste [1].
Angioedema: Rare but serious facial swelling, which is more common in Black patients [1].

Conclusion

Angiotensin receptor-neprilysin inhibitors represent a cornerstone of modern heart failure management. By combining the benefits of blood vessel dilation and sodium excretion, ARNI therapy helps patients live longer [2] and maintain a higher quality of life. While it requires careful initiation, particularly the 36-hour washout period when switching from ACE inhibitors [1], the long-term benefits in reducing hospitalizations and improving cardiac function make it a vital option for many living with heart failure.

Frequently Asked Questions

1. What is the main benefit of taking an ARNI?

The main benefit of an ARNI is that it helps heart failure patients live longer and reduces the likelihood of being hospitalized for heart-related issues. It also improves the heart's pumping efficiency over time.

2. How does ARNI differ from an ACE inhibitor?

Unlike an ACE inhibitor, an ARNI uses a dual-action approach. It combines an ARB to lower blood pressure with a neprilysin inhibitor that helps the body remove excess sodium and widen blood vessels more effectively.

3. Why is there a 36-hour wait when switching from an ACE inhibitor?