Can I start spironolactone, sacubitril/valsartan (Entresto), and empagliflozin in a patient with reduced ejection fraction who has just been stabilized from acute decompensated heart failure after intravenous furosemide?

Initiating Guideline-Directed Medical Therapy After Acute Decompensation

Yes, you can and should initiate spironolactone, sacubitril/valsartan (Entresto), and empagliflozin in a patient with reduced ejection fraction who has been stabilized from acute congestion on IV furosemide, following a specific sequence and safety criteria outlined below. 1

Defining "Stabilized" Before GDMT Initiation

Before starting any of these medications, confirm hemodynamic stability by ensuring:

• No increase in IV diuretics for at least 6 hours 2
• No IV vasodilators or inotropes for at least 24 hours 2
• Adequate systolic blood pressure (typically >100 mmHg) 3
• Stable or improving renal function 4
• Resolution of signs of severe congestion (rales, orthopnea, elevated JVP) 5

Recommended Sequencing and Timing

Step 1: Initiate SGLT2 Inhibitor First (Empagliflozin)

Start empagliflozin 10 mg daily as soon as the patient meets stabilization criteria, even during hospitalization. 1, 2

• SGLT2 inhibitors have the strongest evidence for in-hospital initiation, with concordant treatment effects whether started as inpatients or outpatients 1
• Benefits appear within 12 days of initiation, with a 58% relative risk reduction in early worsening heart failure events 2
• No dose titration is required, and empagliflozin has minimal impact on blood pressure, heart rate, or potassium levels 2
• Can be safely initiated with eGFR as low as 20-30 mL/min/1.73m² 2
• A mild, transient eGFR decline may occur but does not indicate kidney injury and should not prompt discontinuation 2
• Empagliflozin reduces the need for diuretic intensification by 33% and allows diuretic dose reduction in many patients 6

Step 2: Initiate Sacubitril/Valsartan (Entresto)

Start sacubitril/valsartan 24/26 mg or 49/51 mg twice daily once hemodynamically stable, ideally before hospital discharge. 1, 3

• The PIONEER-HF trial demonstrated that in-hospital initiation of sacubitril/valsartan in stabilized patients with acute decompensated heart failure led to a 46.7% reduction in NT-proBNP by weeks 4-8, compared to 25.3% with enalapril 3
• Benefits were evident as early as week 1 after initiation 3
• Rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema did not differ from enalapril 3
• In patients with renal dysfunction (eGFR 30-60 mL/min/1.73m²), sacubitril/valsartan improved eGFR by 4.1 mL/min/1.73m² at 10 weeks 4
• Target dose is 97/103 mg twice daily, achieved by 42-54% of patients by week 10 4

Step 3: Add Spironolactone

Initiate spironolactone 12.5-25 mg daily after confirming adequate renal function and normal potassium levels. 7

• Spironolactone can be started concurrently with or shortly after sacubitril/valsartan, provided potassium is <5.0 mEq/L and eGFR >30 mL/min/1.73m² 7
• Monitor potassium and renal function closely, especially when combining with sacubitril/valsartan 7
• Spironolactone has particular benefit in patients with LVEF in the lower range of HFrEF (closer to 40%) 7

Critical Monitoring Parameters

During and after GDMT initiation, monitor:

• Daily weights and clinical signs of congestion 5
• Serum electrolytes (especially potassium) within 1-2 weeks of starting spironolactone or sacubitril/valsartan 5, 4
• Renal function (BUN, creatinine, eGFR) at 1-2 weeks and then periodically 5, 4
• Blood pressure to detect symptomatic hypotension 3
• Symptoms of volume overload or dehydration 5

Diuretic Management During GDMT Initiation

• Continue loop diuretics (furosemide) at the dose needed to maintain euvolemia 5
• Transition from IV to oral furosemide once stable, typically at a dose 2-2.5 times the total daily IV dose 5
• Empagliflozin may allow reduction in loop diuretic dose over time; in one study, furosemide dose decreased from 16.3 mg/day to 8.5 mg/day after empagliflozin initiation 8
• Avoid excessive diuresis that could precipitate hypotension or worsening renal function 7

Common Pitfalls to Avoid

• Do not delay GDMT initiation until after hospital discharge; deferring results in many eligible patients never receiving these medications within 1 year 1, 2
• Do not discontinue SGLT2 inhibitors for mild eGFR decline, as this is expected and provides long-term kidney protection 2
• Do not withhold sacubitril/valsartan due to concerns about renal dysfunction; it actually improves eGFR in patients with baseline renal impairment 4
• Do not start all three medications simultaneously on the first day; sequence them to allow monitoring of individual drug effects 7
• Do not forget to discontinue ACE inhibitors or ARBs at least 36 hours before starting sacubitril/valsartan to avoid angioedema risk 3

Regulatory and Guideline Support

• US FDA drug labels do not reference location of care, and in-hospital versus outpatient status does not impact eligibility for any standard HFrEF therapy 1
• ACC/AHA guidelines provide a Class I recommendation for in-hospital or pre-discharge initiation of GDMT if not previously established, in the absence of contraindications 1
• There are no examples where chronic therapy improved outcomes among outpatients with HFrEF but was ineffective when initiated among stabilized inpatients 1