Can a patient with heart failure with reduced ejection fraction take Entresto (sacubitril/valsartan) and spironolactone together?

Can a Patient Take Entresto and Spironolactone Together?

Yes, patients with heart failure with reduced ejection fraction should take Entresto (sacubitril/valsartan) and spironolactone together as part of standard guideline-directed medical therapy, as both medications are foundational components of the modern quadruple therapy approach that provides approximately 73% mortality reduction over 2 years. 1

Why This Combination is Recommended

The combination of Entresto and spironolactone is explicitly endorsed by current guidelines as complementary therapy for HFrEF. 1 Both medications work through different mechanisms:

• Entresto (ARNI) provides at least 20% mortality reduction superior to ACE inhibitors, reducing cardiovascular death and heart failure hospitalization 1
• Mineralocorticoid receptor antagonists (MRAs) like spironolactone provide at least 20% mortality reduction and reduce sudden cardiac death 1

Importantly, Entresto actually reduces the risk of hyperkalemia when combined with MRAs compared to ACE inhibitors plus MRAs, making this combination safer than traditional RAAS inhibitor approaches. 1

The Modern Quadruple Therapy Framework

Current guidelines recommend starting four foundational medication classes simultaneously as soon as possible after HFrEF diagnosis: 1

1. SGLT2 inhibitor (dapagliflozin or empagliflozin)
2. Mineralocorticoid receptor antagonist (spironolactone or eplerenone)
3. Beta-blocker (carvedilol, metoprolol succinate, or bisoprolol)
4. ARNI (Entresto) or ACE inhibitor/ARB if ARNI not tolerated

Spironolactone is recommended for all symptomatic patients with HFrEF and LVEF ≤35% to reduce mortality and HF hospitalization. 1

Safety Profile of the Combination

Hyperkalemia Risk is Lower Than Expected

The combination of Entresto plus MRA carries lower hyperkalemia risk than ACE inhibitor plus MRA. 1 A recent 2025 study specifically examining hospitalized patients receiving both sacubitril-valsartan and spironolactone found: 2

• Overall adverse drug reactions occurred in 20% of patients receiving both medications
• Hyperkalemia occurred in 10% of patients receiving the combination 2
• The study concluded that adding spironolactone to sacubitril-valsartan following stabilization of acute decompensated heart failure did not lead to a significantly greater incidence of overall adverse drug reactions 2

Renal Function Considerations

Changes in kidney function during GDMT optimization must be interpreted in the context of decongestion—worsening kidney function with successful decongestion is associated with lower mortality than failure to decongest with stable kidney function. 1

Spironolactone can be used if eGFR >30 ml/min/1.73 m². 1 For patients with more advanced chronic kidney disease (CKD stage IV), the combination creates extreme hyperkalemia risk and should be avoided unless under nephrology co-management with very close monitoring. 3

Practical Implementation Strategy

Initiation Approach

Start SGLT2 inhibitor and MRA (spironolactone) first since they have minimal blood pressure effects, making them ideal first agents. 1 This sequencing allows for safer subsequent addition of Entresto, which can cause hypotension.

Dosing for Spironolactone

• Starting dose: 12.5-25 mg daily 3
• Target dose: 25-50 mg daily 4, 3

Dosing for Entresto

• Starting dose: 49/51 mg twice daily (or 24/26 mg twice daily for severe renal impairment) 5
• Target dose: 97/103 mg twice daily 5
• Titration: Double dose every 2-4 weeks as tolerated 5

Monitoring Requirements

Close monitoring of potassium and renal function is essential when using this combination: 4

• Check potassium and creatinine at 1-2 weeks after initiation and with each dose increase 1
• For patients on spironolactone, check electrolytes every 5-7 days after initiation until stable 3
• Baseline requirements before starting spironolactone: Potassium <5.0 mEq/L and eGFR >30 mL/min/1.73 m² 4, 1

Modest increases in creatinine (up to 30% above baseline) are acceptable and should not prompt discontinuation. 1

Managing Hyperkalemia if it Develops

If hyperkalemia develops, consider potassium binders like patiromer rather than discontinuing life-saving medications. 1 Discontinuation of RAAS inhibitors after hyperkalemia was associated with two to fourfold higher risk of subsequent adverse events. 1

Critical Contraindications to Avoid

Never combine Entresto with ACE inhibitors—ensure a mandatory 36-hour washout period if transitioning from an ACE inhibitor. 6, 5 This is to avoid angioedema risk. 5

Avoid triple combination of ACE inhibitor + ARB + MRA due to hyperkalemia and renal dysfunction risk. 1 However, the combination of Entresto (which is an ARNI, not an ACE inhibitor) + spironolactone is safe and recommended. 1

Common Pitfalls to Avoid

• Do not withhold spironolactone due to fear of hyperkalemia when used appropriately with Entresto—this combination is safer than older RAAS inhibitor approaches 1
• Do not discontinue medications for asymptomatic laboratory changes—use potassium binders and continue monitoring 1
• Do not delay initiation of all four medication classes—simultaneous initiation is recommended 1
• Do not accept suboptimal doses without attempting titration—aggressive uptitration to target doses improves outcomes 1

Special Populations

Advanced Chronic Kidney Disease (CKD Stage IV)

The combination of Entresto and spironolactone in CKD stage IV creates extreme hyperkalemia risk. 3 In this setting:

• Avoid spironolactone unless under nephrology co-management with very close monitoring (potassium checks every 3-5 days) 3
• Consider alternative diuretic strategies such as maximizing loop diuretics or adding metolazone 3

Diabetes and CKD

Spironolactone reduces mortality in patients with heart failure with reduced ejection fraction, but causes hyperkalemia particularly with reduced kidney function (eGFR <45 ml/min/1.73 m²). 4