Yes, Digoxin (Lanoxin) Can Be Appropriately Combined with Sacubitril/Valsartan (Entresto) in Patients with Reduced Ejection Fraction
Digoxin and Entresto are not contraindicated for concurrent use and can be prescribed together in patients with heart failure with reduced ejection fraction (HFrEF), though digoxin is no longer considered essential foundational therapy in the modern treatment paradigm. 1
Current Role of Digoxin in HFrEF Management
Digoxin's Position in Modern Guidelines
Digoxin is classified as a Class II recommendation (reasonable to consider but not essential) because it primarily reduces hospitalizations rather than mortality, with any survival benefit being modest or negligible in the broad HFrEF population 1
The 2022 ACC/AHA/HFSA guidelines list digoxin as an adjunctive therapy to be individualized according to a monogram targeting serum concentrations of 0.5–<0.9 ng/mL, not as part of the four foundational medication classes 1
The four essential medication classes for HFrEF are: (1) ARNI (sacubitril/valsartan) or ACE inhibitor/ARB, (2) evidence-based beta-blockers, (3) mineralocorticoid receptor antagonists, and (4) SGLT2 inhibitors—digoxin is not among these 1, 2, 3
When Digoxin May Be Considered
Digoxin retains a Class I indication for rate control in patients with HFrEF and atrial fibrillation with rapid ventricular rates 1
For patients in sinus rhythm with persistent symptoms despite optimal quadruple therapy (ARNI, beta-blocker, MRA, SGLT2 inhibitor), digoxin may be added to reduce heart failure hospitalizations 1
The 1995 ACC/AHA guidelines gave digoxin a Class II recommendation "for all patients with heart failure due to left ventricular systolic dysfunction," but this predates the modern evidence base for ARNI, MRA, and SGLT2 inhibitor therapy 1
Safety of Combining Digoxin with Entresto
No Direct Drug Interaction
There is no pharmacokinetic or pharmacodynamic contraindication to combining digoxin with sacubitril/valsartan 4
The FDA label for Entresto does not list digoxin as a contraindicated or cautionary co-medication 4
Clinical trials of sacubitril/valsartan (PARADIGM-HF) included patients receiving digoxin as background therapy without safety concerns 5, 6
Monitoring Considerations When Using Both
Monitor serum digoxin levels to maintain therapeutic concentrations of 0.5–<0.9 ng/mL, as higher levels are associated with increased mortality 1
Monitor renal function and electrolytes closely, particularly potassium, because both Entresto (via the valsartan component) and digoxin toxicity are influenced by renal function and hypokalemia potentiates digoxin toxicity 2, 3, 7
Watch for symptomatic bradycardia, especially if the patient is also on a beta-blocker, as the combination of digoxin plus beta-blocker can cause excessive heart rate slowing 1
Practical Algorithm for Decision-Making
Step 1: Optimize Foundational Quadruple Therapy First
- Before adding digoxin, ensure the patient is on target or maximally tolerated doses of:
- Sacubitril/valsartan 97/103 mg twice daily 1, 2
- Evidence-based beta-blocker (carvedilol, metoprolol succinate, or bisoprolol) at target dose 1, 3
- Mineralocorticoid receptor antagonist (spironolactone 25–50 mg daily or eplerenone 50 mg daily) 1, 3
- SGLT2 inhibitor (dapagliflozin 10 mg daily or empagliflozin 10 mg daily) 1, 3
Step 2: Assess Specific Indications for Digoxin
If the patient has atrial fibrillation with inadequate rate control despite beta-blocker therapy, add digoxin 0.125–0.25 mg daily (adjusted for renal function) 1
If the patient remains symptomatic (NYHA class II–IV) despite optimal quadruple therapy and is in sinus rhythm, consider adding digoxin to reduce heart failure hospitalizations 1
If the patient is asymptomatic or mildly symptomatic on current therapy, digoxin is not indicated and should not be added 1
Step 3: Initiate and Monitor Digoxin Appropriately
Start digoxin at 0.125 mg daily (or 0.0625 mg daily if eGFR <30 mL/min/1.73 m² or age >70 years with low body weight) 1
Check serum digoxin level 7–14 days after initiation, targeting 0.5–<0.9 ng/mL 1
Monitor serum potassium and renal function every 1–2 weeks initially, then every 3 months once stable 2, 3
Educate the patient about digoxin toxicity symptoms (nausea, visual changes, confusion, arrhythmias) 1
Common Pitfalls to Avoid
Do not add digoxin before optimizing the four foundational medication classes, as digoxin provides far less mortality benefit than ARNI, beta-blockers, MRAs, or SGLT2 inhibitors 1, 3
Do not use digoxin as a substitute for any of the four foundational therapies—it is adjunctive only 1
Do not target higher digoxin levels (>1.0 ng/mL), as this increases mortality risk without additional benefit 1
Do not assume digoxin is contraindicated with Entresto—there is no pharmacologic basis for this concern 4
Do not delay Entresto initiation or uptitration due to concurrent digoxin use—the two medications can be safely combined 2, 7, 8