Angiotensin Receptor Neprilysin Inhibitor: Uses & Side Effects

Sacubitril/valsartan, the first and currently only angiotensin receptor neprilysin inhibitor (ARNI) approved for clinical use, is primarily prescribed to treat heart failure. In its landmark trial, it reduced the combined risk of cardiovascular death or heart failure hospitalization by about 20% compared with a standard older therapy, and it lowered death from any cause by roughly 16%. Those numbers made it a cornerstone of modern heart failure treatment, but the drug also carries a distinct side-effect profile and a few monitoring quirks that anyone taking it should understand.

How It Works

Sacubitril/valsartan is actually two drugs in one pill. The valsartan half blocks receptors for angiotensin II, a hormone that narrows blood vessels, raises blood pressure, and promotes fluid retention. Drugs that block angiotensin II have been around for decades. What makes this combination different is the sacubitril half, which inhibits an enzyme called neprilysin. Neprilysin’s normal job is to break down several hormones in the body, including natriuretic peptides. Those peptides help relax blood vessels, promote the excretion of sodium and water, and reduce scarring in the heart. By preventing neprilysin from breaking them down, sacubitril lets those beneficial hormones stick around longer. The result is a two-pronged approach: block the harmful pathway while boosting the protective one.

The Evidence in Heart Failure with Reduced Pumping Strength

The drug’s reputation rests on PARADIGM-HF, one of the largest heart failure trials ever run. More than 8,400 patients with heart failure and reduced ejection fraction were randomly assigned to receive either sacubitril/valsartan or enalapril, a well-established ACE inhibitor. The trial was stopped early because the benefits of sacubitril/valsartan were already clear: the primary outcome of cardiovascular death or hospitalization for heart failure occurred in about 22% of the sacubitril/valsartan group compared with roughly 27% of the enalapril group, a 20% relative risk reduction. Death from cardiovascular causes specifically dropped by 20%, and hospitalization for heart failure fell by 21%. All-cause mortality was also lower, with about 17% of the sacubitril/valsartan group dying during follow-up versus nearly 20% in the enalapril group.

Those benefits held up across a range of background medications. Whether patients were also taking beta-blockers, mineralocorticoid receptor antagonists, or other standard heart failure drugs, the advantage of sacubitril/valsartan over enalapril remained consistent.

Heart Failure When the Pumping Strength Is Preserved

Not all heart failure involves a weakened pump. In heart failure with preserved ejection fraction, the heart squeezes normally but stiffens, making it hard to fill. The PARAGON-HF trial tested sacubitril/valsartan in this population and fell just short of statistical significance for its primary endpoint overall. That said, pre-specified subgroup analyses hinted at a possible benefit in patients whose ejection fraction sat at the lower end of the “preserved” range and in women.

⁴

This is an area where guideline panels have had to use judgment. Some now include sacubitril/valsartan as a reasonable option for patients in that gray zone between clearly reduced and clearly preserved ejection fraction, but the strength of the recommendation is weaker than for patients with a clearly weakened pump.

Starting in the Hospital After a Flare-Up

Doctors once waited until patients were stable at home before switching to sacubitril/valsartan. The PIONEER-HF trial challenged that approach. Patients hospitalized for acute decompensated heart failure who were hemodynamically stable were started on sacubitril/valsartan while still in the hospital. Compared with enalapril, it produced a substantially greater drop in NT-proBNP, a marker of heart wall stress, as early as the first week. Rates of kidney problems, high potassium, low blood pressure, and angioedema were similar between the two groups in this acute setting.

⁵

An open-label extension of that trial reinforced the finding: patients who switched from enalapril to sacubitril/valsartan after the initial blinded period also did well, and early initiation was tolerated without unexpected safety concerns.

⁶

From a cost standpoint, starting the drug during the hospitalization rather than waiting appears to save money over the long run, largely because it reduces rehospitalizations. One analysis estimated savings of roughly $450 per patient per year compared with continuing enalapril, and about $2,550 per patient over five years.

⁷

Reverse Remodeling and Structural Heart Improvement

One of the more encouraging findings with sacubitril/valsartan goes beyond symptom relief. In patients with a weak pump, the drug appears to partially reverse the structural damage heart failure causes. In one study, patients saw an average five-percentage-point improvement in ejection fraction after about three months, along with measurable reductions in the size and mass of the left ventricle.

⁸

Another study examined whether this remodeling benefit depended on how long someone had been living with heart failure. Patients diagnosed less than a year prior showed the largest ejection fraction gains, around 12 percentage points over 12 months, but even those who had been living with heart failure for more than five years still saw improvements of about 8 to 9 percentage points. That’s reassuring for people who worry they have been sick too long for the drug to make a structural difference.

⁹

Common Side Effects

The side effect that comes up most often in practice is low blood pressure. Blood pressure drops are expected given the drug’s mechanism, and most cases happen within a few hours of the first dose. Some patients experience dizziness, lightheadedness, or fatigue, especially at the start. In rare cases, the hypotension can be more prolonged: one reported case involved a blood pressure drop that began 8 to 18 hours after the first dose and lasted three to six days.

¹⁰

Elevated potassium is another concern, particularly in patients who are also taking mineralocorticoid receptor antagonists like spironolactone. However, PARADIGM-HF data showed that severe hyperkalemia was actually less common with sacubitril/valsartan than with enalapril, at about 2.2 versus 3.1 events per 100 patient-years among patients on a mineralocorticoid receptor antagonist.

¹¹

Angioedema, a swelling of the deeper layers of skin typically around the face and throat, is the most feared adverse reaction because it can obstruct the airway. A meta-analysis pooling over 14,000 patients from randomized trials found that the rate of angioedema was about 0.5% with sacubitril/valsartan compared with 0.3% in control groups. That numerical difference was not statistically significant, but the risk is real enough that the drug carries a clear label warning, and it should never be used alongside or shortly after an ACE inhibitor.

¹²

Uncommon but documented reactions include skin disorders. A case report described a patient who developed psoriasis while on sacubitril/valsartan, saw improvement after the drug was stopped, and then developed the same skin lesions again when it was restarted. Events like this are rare enough that they appear mainly as case reports rather than in trial data.

¹³

The Washout Period When Switching from an ACE Inhibitor

If you are switching from an ACE inhibitor like enalapril, lisinopril, or ramipril, the manufacturer requires a 36-hour gap between your last ACE inhibitor dose and your first sacubitril/valsartan dose. The reason is angioedema risk: both ACE inhibitors and neprilysin inhibitors can increase levels of bradykinin, a substance that promotes swelling. Taking them too close together compounds that risk. A small study of 33 patients found that about two-thirds received the full 36-hour washout when transitioning in the hospital, and there were no angioedema events regardless of whether the washout was complete. That’s a small sample, though, and sticking to the recommended gap remains standard practice.

¹⁴

Patients already on an angiotensin receptor blocker do not need a washout period, because the angioedema mechanism is different.

How It Affects Blood Tests and Monitoring

Here is a detail that catches some patients and even some clinicians off guard. BNP, a blood test widely used to track heart failure severity, rises when you start sacubitril/valsartan. That sounds alarming until you understand why: neprilysin is one of the enzymes that normally clears BNP from the bloodstream. Block neprilysin and BNP levels go up, even though the heart is actually doing better. In the PARADIGM-HF cohort, median BNP rose from about 202 to 235 ng/L after two months on the drug, with roughly one in five patients seeing their BNP double. NT-proBNP, a related marker that is not broken down by neprilysin, continued to fall as expected and remains the reliable test for tracking heart failure status while on this drug.

¹⁵

If your doctor orders a BNP test while you are on sacubitril/valsartan, the number may look worse than your condition actually is. Make sure the care team knows you are taking the drug and that NT-proBNP is the more appropriate marker for monitoring.

Kidney Effects

Kidney function is a constant concern in heart failure patients, because poor cardiac output starves the kidneys of blood flow. A meta-analysis of patients with both heart failure and chronic kidney disease found that sacubitril/valsartan modestly improved estimated kidney filtration rates compared with standard renin-angiotensin system blockers. The improvement was small but statistically significant, and blood pressure and heart failure biomarkers also improved.

¹⁶

That said, kidney function still needs monitoring on this drug. In the PIONEER-HF trial, rates of worsening kidney function were similar between sacubitril/valsartan and enalapril when started in hospitalized patients, so the drug does not appear to be harder on the kidneys than standard therapy. But individual patients, particularly those who are dehydrated or on multiple blood-pressure-lowering drugs, can develop acute kidney injury, and creatinine checks remain part of routine follow-up.

Blood Pressure Lowering Beyond Heart Failure

Sacubitril/valsartan lowers blood pressure more effectively than angiotensin receptor blockers alone. A meta-analysis of hypertension trials found that a 200-mg dose reduced systolic blood pressure by about 4.6 mmHg and diastolic blood pressure by about 2.1 mmHg more than an ARB alone. At the higher 400-mg dose, the additional reductions were about 5.5 mmHg systolic and 2.5 mmHg diastolic.

¹⁷

This added blood-pressure-lowering effect has been confirmed in different populations, including elderly patients with stiff arteries, where sacubitril/valsartan outperformed the ARB olmesartan in reducing both peripheral and central aortic pressures.

¹⁸

Despite this evidence, the drug is not widely prescribed as a first-line blood pressure medication. Cost and the lack of long-term cardiovascular outcome data specifically in people who only have high blood pressure (and not heart failure) have kept it largely reserved for heart failure patients.

The Alzheimer’s Disease Concern

Because neprilysin also breaks down amyloid-beta, the protein that accumulates in the brains of Alzheimer’s patients, there was an early worry that blocking this enzyme could accelerate dementia. On paper, the concern makes sense: less neprilysin activity could mean more amyloid-beta deposits. In practice, clinical evidence to date has not borne this out. A 2024 review that pooled clinical trial data, real-world observational studies, and pharmacovigilance reports found no signal of increased cognitive decline in patients taking sacubitril/valsartan.

¹⁹

The honest caveat is that the monitoring periods in most studies have been relatively short, typically two to four years, and the patients enrolled tend to be in their 60s and already on multiple medications that could independently affect brain health. Some researchers have noted that longer follow-up in larger populations is needed before the concern can be fully dismissed.

²⁰

After a Heart Attack

Researchers tested whether sacubitril/valsartan could improve outcomes in patients who had just suffered a heart attack complicated by reduced heart function or lung congestion. The PARADISE-MI trial compared it head to head with ramipril, a well-established ACE inhibitor used in this setting. Over about 22 months, the primary composite of cardiovascular death, incident heart failure, or other major events occurred in about 12% of the sacubitril/valsartan group versus 13% of the ramipril group. The difference was not statistically significant.

²¹

So while the drug did not show clear superiority in the post-heart-attack setting, it also was not worse. For patients already on sacubitril/valsartan who then have a heart attack, there is no reason based on this trial to stop it. But the evidence does not yet support switching someone from a standard ACE inhibitor to sacubitril/valsartan specifically because of a heart attack.

Use in Children

Pediatric heart failure is rare, and so the evidence base for sacubitril/valsartan in children is thin. A pilot study found that children with heart failure who received the drug generally required lower doses and slower dose increases than adults, partly because younger patients, especially those recovering from congenital heart surgery, were more prone to hypotension.

²²

A single-center study of 29 patients with congenital heart disease reinforced the need for caution: about 41% experienced hypotension requiring dose adjustment or temporary discontinuation, and the drug had to be permanently stopped in about a quarter of patients due to low blood pressure, kidney injury, or worsening heart failure.

²³

Pediatric use remains off-label and largely exploratory, guided by individual clinical judgment rather than the kind of large trial evidence available in adults.

Why Sticking with It Matters

A drug only works if you take it consistently, and real-world data on sacubitril/valsartan adherence are sobering. Among nearly 900 patients prescribed the drug at hospital discharge, only about a third maintained high adherence over the following months. Those who did had markedly better outcomes: at one year, highly adherent patients had a roughly 31% lower risk of rehospitalization and a 47% lower risk of death compared with patients who took the drug inconsistently. Every five-percentage-point increase in adherence was associated with a small but significant additional reduction in both outcomes.

²⁴

The reasons for non-adherence vary, but cost and side effects, particularly dizziness from low blood pressure, are frequently cited. If side effects are making it hard for you to keep taking the medication, working with your prescriber to adjust the dose can sometimes bridge the gap. Abruptly stopping without medical guidance is risky because heart failure can worsen quickly once the drug’s protective effects are removed.