Can spironolactone and Entresto (sacubitril/valsartan) be used together in patients with heart failure, particularly those with resistant hypertension or heart failure with reduced ejection fraction?

Can Spironolactone and Entresto Be Used Together?

Yes, spironolactone and Entresto (sacubitril/valsartan) should be used together as part of standard guideline-directed medical therapy for heart failure with reduced ejection fraction, providing approximately 73% mortality reduction over 2 years when combined. 1

Guideline-Endorsed Combination Therapy

The combination of Entresto and spironolactone is explicitly endorsed by current guidelines as complementary therapy for HFrEF. 1 This represents modern quadruple therapy, where four foundational medication classes should be started simultaneously as soon as possible after HFrEF diagnosis: SGLT2 inhibitor, mineralocorticoid receptor antagonist (spironolactone), beta-blocker, and ARNI (Entresto). 1

The 2022 AHA/ACC/HFSA guidelines recommend both medications together for patients with symptomatic HF and LVEF ≤40%. 2 Entresto provides at least 20% mortality reduction superior to ACE inhibitors, while spironolactone provides at least 20% mortality reduction and reduces sudden cardiac death. 1

Safety Profile: Lower Hyperkalemia Risk Than Expected

Critically, the combination of Entresto plus spironolactone carries lower hyperkalemia risk than ACE inhibitor plus spironolactone. 1 This is a key advantage that makes this combination safer than older regimens. Recent research confirms that sacubitril/valsartan does not show an increased risk of hyperkalemia or worsening renal function compared to valsartan alone. 3

The FDA label for sacubitril/valsartan notes that potassium-sparing diuretics may lead to increased serum potassium, but this is manageable with appropriate monitoring. 4

Patient Selection Criteria

Before initiating this combination, verify: 1, 5

• Potassium <5.0 mEq/L
• eGFR >30 mL/min/1.73 m²
• Serum creatinine <2.5 mg/dL

For patients with 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. 1

Practical Implementation Strategy

Start SGLT2 inhibitor and spironolactone first since they have minimal blood pressure effects, making them ideal first agents. 1 Then add Entresto and beta-blockers.

Spironolactone Dosing:

• Start: 12.5-25 mg daily 1, 5
• Target: 25-50 mg daily 1, 5
• Titrate after 4-8 weeks if tolerated 5

Entresto Dosing:

• Start: 49 mg/51 mg twice daily 4
• Target: 97 mg/103 mg twice daily 4
• Adjust every 2-4 weeks to target maintenance dose 4

Mandatory Monitoring Protocol

Check potassium and creatinine within 3 days of initiation, at 1 week, monthly for 3 months, then every 3 months thereafter. 1, 5 This aggressive monitoring schedule prevents life-threatening hyperkalemia.

Hyperkalemia Management Algorithm:

• K+ 5.0-5.5 mEq/L: Continue current dose with close monitoring 5
• K+ >5.5 mEq/L: Halve the spironolactone dose and recheck within 3 days 5
• K+ >6.0 mEq/L: Stop spironolactone immediately 5

If hyperkalemia develops, consider potassium binders like patiromer rather than discontinuing life-saving medications, as 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, to avoid angioedema risk. 1, 4 The FDA label explicitly contraindicates concomitant use with ACE inhibitors. 4

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

Do not combine spironolactone with other potassium-sparing diuretics (amiloride, triamterene). 5, 6

Application Beyond HFrEF

For heart failure with mildly reduced ejection fraction (HFmrEF, LVEF 41-49%), both medications receive Class 2b recommendations, particularly for patients with LVEF at the lower end of this spectrum. 2 Post hoc analysis of TOPCAT showed spironolactone reduced cardiovascular mortality in patients with LVEF 44-49%. 2

For resistant hypertension with left ventricular hypertrophy, spironolactone 25 mg daily provides superior LVH regression and significant additional blood pressure reduction when added to multidrug regimens. 6

Common Pitfalls

Gynecomastia occurs in approximately 10% of men on spironolactone; consider switching to eplerenone if this occurs. 5 Hypotension risk is higher with Entresto compared to valsartan alone, but this does not increase hyperkalemia or renal dysfunction risk. 3, 7