Can a 75-year-old woman with heart failure with preserved ejection fraction, stage 3 chronic kidney disease, who is taking furosemide 60 mg daily and midodrine 5 mg three times daily, start sacubitril‑valsartan (Entresto)?

Can Entresto Be Started in This Patient?

Yes, Entresto (sacubitril/valsartan) can be initiated in this 75-year-old woman with HFpEF and stage 3 CKD, but requires careful dose adjustment, close monitoring, and consideration of her midodrine use for potential hypotension.

Key Considerations for Initiation

HFpEF Indication

• Entresto is recommended for HFpEF patients with NYHA class II-III symptoms to reduce morbidity and mortality 1.
• The PARAGON-HF trial demonstrated particular benefit in patients with LVEF below 57% and showed renal protective effects in HFpEF patients 2, 3.
• Frail elderly patients (like this 75-year-old) may derive even greater benefit from sacubitril/valsartan, with the most frail showing enhanced treatment effects 4.

Renal Function Considerations

• Stage 3 CKD is NOT a contraindication to Entresto initiation 5.
• No dose adjustment is required for mild to moderate renal impairment (eGFR 30-90 mL/min/1.73 m²) 5.
• Sacubitril/valsartan actually reduced renal events and slowed eGFR decline compared to valsartan alone in HFpEF patients, with benefits consistent regardless of baseline eGFR 2.
• Even if eGFR subsequently declines below 30 mL/min/1.73 m², continuation of therapy remains beneficial and safe 6.

Critical Drug Interaction: Midodrine

• The concurrent use of midodrine 5 mg TID presents a significant concern for managing blood pressure effects 7.
• Midodrine is a vasopressor used to treat orthostatic hypotension, while Entresto lowers blood pressure 5.
• This combination creates competing hemodynamic effects that require careful titration and monitoring 7.

Recommended Initiation Strategy

Pre-Initiation Assessment

• Assess volume status carefully before starting Entresto 7.
• Check if furosemide 60 mg daily is maintaining euvolemia or if the patient has signs of congestion (elevated JVP, peripheral edema, pulmonary congestion) 8.
• Measure baseline blood pressure in sitting and standing positions given midodrine use 7.
• Obtain baseline potassium, creatinine, and eGFR 9, 5.

Dosing Protocol

• Start with the lowest dose: Entresto 24/26 mg twice daily 5.
• This conservative approach is appropriate given her age, stage 3 CKD, and concurrent midodrine use 7.
• The standard starting dose for patients with moderate hepatic impairment or severe renal impairment is also 24/26 mg twice daily 5.

Diuretic Management

• Consider reducing furosemide dose if no signs of congestion are present 7.
• Excessive diuretic use can lead to volume contraction, increasing hypotension risk with Entresto 8.
• If congestion is present, maintain current furosemide dose initially 8.
• Diuretics should be adjusted based on daily weights and volume status, not discontinued entirely 8.

Midodrine Adjustment Strategy

• Evaluate the necessity of midodrine before starting Entresto 7.
• If midodrine is treating symptomatic orthostatic hypotension, consider reducing the dose or frequency rather than abrupt discontinuation 7.
• Monitor for symptomatic hypotension (dizziness, lightheadedness, syncope) after Entresto initiation 5.
• Educate the patient that transient dizziness upon standing may occur but often improves with continued therapy 7.

Monitoring Protocol

Initial Monitoring (First 1-2 Weeks)

• Check renal function and potassium within 1-2 weeks of initiation 1, 9, 5.
• Monitor blood pressure closely, especially orthostatic measurements given midodrine use 7.
• Assess for symptoms of hypotension (dizziness, fatigue, syncope) 5.
• Watch for signs of hyperkalemia (potassium >5.5 mmol/L requires dose reduction; >6.0 mmol/L requires discontinuation) 5.

Ongoing Monitoring

• Recheck renal function and electrolytes at 1,2,3,6,9, and 12 months, then every 4 months if stable 9.
• Accept modest increases in creatinine (up to 50% or 266 μmol/L from baseline) as expected pharmacologic effects 9.
• Monitor for angioedema, particularly in the first weeks of therapy 5.

Dose Titration

• Uptitrate to target dose of 97/103 mg twice daily as tolerated, typically after 2-4 weeks at each dose level 1, 5.
• Titration should be guided by blood pressure tolerance, renal function stability, and absence of hyperkalemia 1, 9.
• Temporary eGFR declines (>15%) during uptitration are common, usually recover, and should not prompt discontinuation 10.

Absolute Contraindications to Avoid

• Do NOT use if history of angioedema with ACE inhibitors or ARBs 5.
• Do NOT use concomitantly with ACE inhibitors or within 36 hours of last ACE inhibitor dose 5.
• Do NOT use if pregnant or planning pregnancy 5.
• Severe hepatic impairment (Child-Pugh C) is a relative contraindication 5.

Common Pitfalls to Avoid

• Do not discontinue Entresto for modest eGFR declines during initiation or uptitration 6, 10.
• Do not withhold therapy due to asymptomatic hypotension if blood pressure remains adequate for perfusion 7.
• Do not use excessive diuretic doses that cause volume depletion, as this increases hypotension and renal dysfunction risk 8.
• Do not delay initiation due to advanced age or frailty, as these patients may benefit most 4.

Expected Benefits in This Patient

• Reduction in heart failure hospitalizations and cardiovascular death 1, 2.
• Slowing of eGFR decline and reduction in renal events compared to ARB alone 2.
• Decreased NT-proBNP levels and improved cardiac remodeling 1, 5.
• Potential greater benefit given her age and likely frailty status 4.