What is the most appropriate medication adjustment for a patient with heart failure with reduced ejection fraction (HFrEF) and impaired renal function, presenting with dyspnea on exertion, edema, and weight gain?

Management of Refractory Fluid Overload in Heart Failure

Adding metolazone 5 mg orally with the next morning's dose of furosemide is the most appropriate medication adjustment for this patient with worsening heart failure symptoms.

Rationale for Sequential Nephron Blockade

The patient presents with clear signs of fluid overload despite being on an optimized heart failure regimen:

• Dyspnea on exertion
• 2+ pitting edema
• 5-pound weight gain in one month

Despite receiving guideline-directed medical therapy including:

• Sacubitril/valsartan at target dose (97/103 mg BID)
• Carvedilol at appropriate dose (25 mg BID)
• Spironolactone 25 mg daily
• Empagliflozin 10 mg daily
• Furosemide 40 mg BID

The patient has developed diuretic resistance to the current loop diuretic regimen, necessitating intensification of diuretic therapy.

Evidence Supporting Metolazone Addition

The ACC/AHA guidelines specifically recommend sequential nephron blockade with metolazone when patients develop resistance to loop diuretics 1. The guidelines state that "diuretic resistance can generally be overcome by the use of 2 or more diuretics in combination (e.g., furosemide and metolazone)" 1.

Sequential nephron blockade works by:

• Loop diuretics inhibit sodium reabsorption at the loop of Henle
• Thiazide-like diuretics (metolazone) block sodium reabsorption at the distal tubule
• This combination prevents compensatory sodium retention that occurs with single-agent therapy

The recommended dose of metolazone for sequential nephron blockade is 2.5-10 mg once daily plus a loop diuretic 1, making the 5 mg dose appropriate.

Considerations for Other Options

1. Changing furosemide to bumetanide: While bumetanide has better bioavailability, simply switching from one loop diuretic to another at equivalent doses (40 mg furosemide ≈ 0.5-1 mg bumetanide) would not address the underlying diuretic resistance 2.

2. Increasing spironolactone: Increasing spironolactone from 25 mg to 50 mg daily could be considered, but:

   • The patient already has mild renal impairment (eGFR 51 mL/min)
   • Potassium is already at the upper limit of normal (4.9 mEq/L)
   • This approach would likely be less effective for acute diuresis than adding metolazone 1

3. Increasing empagliflozin: While SGLT2 inhibitors provide modest diuresis, increasing from 10 mg to 25 mg would not provide the robust diuresis needed for acute volume overload 2.

Important Monitoring and Precautions

When adding metolazone, close monitoring is essential:

• Electrolytes: Metolazone can cause significant hypokalemia and hyponatremia 3
• Renal function: Monitor for worsening renal function, particularly with the patient's baseline creatinine of 1.5 mg/dL 3
• Blood pressure: Watch for hypotension due to enhanced diuresis
• Duration: Use metolazone for a short duration (2-5 days) to avoid excessive electrolyte depletion 4

Administration Recommendations

• Give metolazone 30-60 minutes before furosemide to maximize sequential nephron blockade effect
• Start with a single 5 mg dose and reassess response
• Monitor daily weights, electrolytes, and renal function
• Consider discontinuing metolazone once euvolemia is achieved, continuing with loop diuretic maintenance therapy

Conclusion

For this patient with worsening heart failure symptoms despite optimized medical therapy, adding metolazone 5 mg to the existing furosemide regimen represents the most appropriate next step to overcome diuretic resistance and achieve effective diuresis 1, 2.