Alternatives to Entresto (Sacubitril/Valsartan) If You Can't Fill Your Prescription

Entresto (sacubitril/valsartan) is the preferred ARNI for heart failure with reduced ejection fraction, but if you're unable to fill it — due to availability issues, cost barriers, or side effects — you have options. This guide outlines the main alternatives and what you should discuss with your cardiologist before making any switch.

Important Warning: Never Stop Entresto Without Talking to Your Doctor

Heart failure is a serious and potentially life-threatening condition. Do not stop taking sacubitril/valsartan or switch medications without first speaking to your cardiologist or prescribing physician. Stopping abruptly can lead to worsening heart failure, rebound high blood pressure, and dangerous fluid buildup.

Why Entresto Has No True Equivalent

Entresto is the only FDA-approved angiotensin receptor-neprilysin inhibitor (ARNI) in the United States. Its dual mechanism — sacubitril raises beneficial natriuretic peptides while valsartan blocks angiotensin II — makes it uniquely effective in reducing cardiovascular death and hospitalization for HFrEF. No other single pill replicates both actions simultaneously. That said, other drug classes address overlapping pathways and are critical components of heart failure management.

Alternative 1: ACE Inhibitors (Enalapril, Lisinopril, Ramipril)

ACE inhibitors — such as enalapril (Vasotec), lisinopril (Prinivil, Zestril), and ramipril (Altace) — were the standard of care for HFrEF before Entresto's approval in 2015. The landmark PARADIGM-HF trial showed Entresto was superior to enalapril 10 mg twice daily in reducing cardiovascular mortality and hospitalizations. However, ACE inhibitors remain highly effective, are generic, inexpensive, and widely available.

Critical note: You cannot take an ACE inhibitor at the same time as Entresto. If you're switching back from Entresto to an ACE inhibitor, you must wait at least 36 hours after your last Entresto dose before starting the ACE inhibitor to avoid dangerous angioedema.

Alternative 2: ARBs (Valsartan, Losartan, Candesartan)

Angiotensin receptor blockers (ARBs) — such as valsartan (Diovan), losartan (Cozaar), and candesartan (Atacand) — block the same angiotensin II pathway as the valsartan component in Entresto but lack the neprilysin inhibition from sacubitril. ARBs are an appropriate alternative for patients who cannot tolerate ACE inhibitors (typically due to cough). Note that Entresto already contains valsartan, so switching to an ARB should not occur simultaneously — discuss timing with your doctor.

Alternative 3: SGLT2 Inhibitors (Dapagliflozin, Empagliflozin)

SGLT2 inhibitors — dapagliflozin (Farxiga) and empagliflozin (Jardiance) — have a completely different mechanism from Entresto. They were originally developed for type 2 diabetes but are now FDA-approved and strongly recommended for heart failure regardless of diabetes status. They reduce the risk of cardiovascular death and heart failure hospitalization and work through entirely complementary pathways.

Importantly, SGLT2 inhibitors are often used alongside Entresto — they're part of the same quadruple therapy regimen. If you need to temporarily pause Entresto, your doctor might lean more heavily on your SGLT2 inhibitor during the gap. They are not direct replacements but provide meaningful cardiovascular protection on their own.

Alternative 4: Beta-Blockers (Carvedilol, Metoprolol Succinate)

Beta-blockers — specifically carvedilol (Coreg), metoprolol succinate (Toprol XL), and bisoprolol (Zebeta) — are essential in HFrEF treatment. They slow heart rate, reduce the heart's workload, and have proven mortality benefits. These are used alongside Entresto in quadruple therapy, not as alternatives. However, if you are unable to take an ARNI, your beta-blocker remains a critical pillar of your heart failure regimen.

Alternative 5: Mineralocorticoid Receptor Antagonists (Spironolactone, Eplerenone)

Spironolactone (Aldactone) and eplerenone (Inspra) block aldosterone, a hormone that causes salt and water retention. They reduce hospitalizations and mortality in HFrEF and are part of standard quadruple therapy. Like beta-blockers, these are complementary medications rather than direct substitutes for Entresto.

Comparison at a Glance

Here is a quick summary of Entresto and its alternatives for heart failure:

Entresto (sacubitril/valsartan): ARNI — unique dual mechanism. First-line preferred. Generic now available.

Enalapril / Lisinopril: ACE inhibitors. Strong evidence, very inexpensive, widely available. Cannot use with Entresto.

Losartan / Valsartan: ARBs. Good evidence, especially when ACE inhibitors are not tolerated. Cannot use with Entresto.

Farxiga / Jardiance: SGLT2 inhibitors. Complementary mechanism; can be used with or without Entresto.

Carvedilol / Metoprolol succinate: Beta-blockers. Essential in HFrEF; used alongside, not instead of, Entresto.

Spironolactone / Eplerenone: MRAs. Reduce fluid retention; used alongside other therapies.

First, Try Harder to Find Entresto

Before switching medications, exhaust your options to fill Entresto. Check whether the generic sacubitril/valsartan is available even if the brand is not. Use medfinder to search pharmacies near you. Read our guide on how to find Entresto in stock for a full strategy. Only switch after a genuine search and after consulting your cardiologist.