Is metolazone (Metolazone) recommended in combination with furosemide (Furosemide) for diuresis in patients with hypoosmolar hyponatremia and heart failure?

From the Guidelines

Metolazone is not recommended as a first-line treatment alongside furosemide for diuresis in hypoosmolar hyponatremia with heart failure. The primary approach in managing hypoosmolar hyponatremia with heart failure should focus on fluid restriction and the cautious use of loop diuretics like furosemide alone 1. Adding metolazone, a thiazide-like diuretic, could potentially worsen hyponatremia since thiazide diuretics impair the kidney's diluting capacity and can further lower serum sodium levels.

Key Considerations

• When diuresis is needed in heart failure with hyponatremia, furosemide should be used cautiously, starting at lower doses (20-40 mg IV or oral) and titrating based on response while closely monitoring electrolytes 1.
• The combination of loop and thiazide diuretics (like metolazone) is more appropriate for resistant fluid overload in heart failure patients with normal sodium levels or hypernatremia, where the powerful sequential nephron blockade can overcome diuretic resistance 1.
• In hyponatremic heart failure patients, other approaches like vasopressin receptor antagonists (tolvaptan) might be considered if fluid restriction and careful loop diuretic use are insufficient, as these medications can increase free water excretion without significantly affecting sodium balance.

Management Strategies

• Fluid restriction (typically to 1-1.5 L/day) is a cornerstone in the management of hypoosmolar hyponatremia with heart failure.
• Careful monitoring of electrolytes and renal function is essential when using diuretics in this patient population.
• The use of metolazone alongside furosemide should be reserved for cases of diuretic resistance or significant fluid overload that is not responsive to loop diuretics alone, and even then, with careful consideration of the potential effects on serum sodium levels 1.

From the FDA Drug Label

Metolazone tablets, USP, and furosemide administered concurrently have produced marked diuresis in some patients where edema or ascites was refractory to treatment with maximum recommended doses of these or other diuretics administered alone. The use of metolazone along with furosemide for diuresis in hypoosmolar hyponatremia with heart failure is not explicitly recommended in the provided drug labels. However, it is mentioned that metolazone and furosemide can produce marked diuresis when administered concurrently in patients with refractory edema or ascites.

• The combination of metolazone and furosemide may be considered in patients with heart failure and hypoosmolar hyponatremia who are refractory to treatment with maximum recommended doses of diuretics alone.
• Caution should be exercised when using this combination, as it may cause unusually large or prolonged losses of fluid and electrolytes 2.
• Patients should be closely monitored for signs of fluid and electrolyte imbalance, and dosage adjustments may be necessary to minimize the risk of adverse effects 2.

From the Research

Diuresis in Hypoosmolar Hyponatremia with Heart Failure

• The use of metolazone along with furosemide for diuresis in hypoosmolar hyponatremia with heart failure has been studied in several research papers 3, 4, 5, 6.
• A study published in the Journal of the American Heart Association in 2018 found that metolazone was strongly associated with hyponatremia, hypokalemia, and worsening renal function, and increased mortality after multivariate and propensity adjustment 3.
• Another study published in the Israel journal of medical sciences in 1986 found that the combination of furosemide and metolazone induced greater natriuresis, urinary output, and weight loss than did furosemide or metolazone alone, without profound diuresis, severe hyponatremia, or deterioration of renal function 4.
• A retrospective study published in the Journal of cardiovascular pharmacology and therapeutics in 2013 found that the combination of furosemide and metolazone was associated with greater increases in urine output, but also with a higher incidence of hyponatremia and electrolyte abnormalities 5.
• A cohort study published in Critical care research and practice in 2021 found that adding metolazone to furosemide was not independently associated with death or re-hospitalization in patients with severe acute decompensated heart failure 6.
• A review article published in The American journal of cardiology in 2005 discussed the current treatments and novel pharmacologic treatments for hyponatremia in congestive heart failure, including the use of loop diuretics, fluid restriction, and arginine vasopressin receptor antagonists 7.

Key Findings

• The combination of furosemide and metolazone may be effective for diuresis in hypoosmolar hyponatremia with heart failure, but may also be associated with increased risk of hyponatremia, hypokalemia, and worsening renal function 3, 4, 5.
• The use of metolazone along with furosemide may not be associated with increased mortality or re-hospitalization in patients with severe acute decompensated heart failure 6.
• Other treatment options, such as arginine vasopressin receptor antagonists, may be effective for hyponatremia in congestive heart failure, but require further study 7.