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December 12, 2012

Lixivaptan for Hyponatremia—The Numbers Game

JAMA. 2012;308(22):2345-2346. doi:10.1001/jama.2012.54515

On September 13, 2012, the Cardiovascular and Renal Drugs Advisory Committee of the US Food and Drug Administration (FDA) reviewed lixivaptan, a new vasopressin receptor antagonist.1 These agents correct hyponatremia by producing a selective water diuresis without affecting sodium and potassium excretion; the resultant urinary free water loss raises serum sodium levels. Hyponatremia, diagnosed as a laboratory serum sodium of less than 138 mEq/L, is seen in nearly 38% of hospitalized patients and creates a potentially large population eligible for therapy.2 Historically, severe reductions in serum sodium levels have been accepted as a surrogate end point by the FDA, leading to approval in the United States of both tolvaptan and conivaptan. The label for these approved drugs specifies an indication for the treatment of severe hyponatremia— a serum sodium level of 125 mEq/L—or less marked hyponatremia that is symptomatic and resistant to correction with fluid restriction in patients with syndrome of inappropriate secretion of antidiuretic hormone (SIADH), acute decompensated heart failure, or cirrhosis. However, the validity and clinical utility of serum sodium levels as a surrogate marker for clinical benefit remain uncertain.

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