Oral tolvaptan is safe and effective in chronic hyponatremia

Abstract

Vasopressin antagonists increase the serum sodium concentration in patients who have euvolemia and hypervolemia with hyponatremia in the short term (</=30 days), but their safety and efficacy with longer term administration is unknown. SALTWATER was a multicenter, open-label extension of the Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT-1 and SALT-2). In total, 111 patients with hyponatremia received oral tolvaptan for a mean follow-up of 701 days, providing 77,369 patient-days of exposure. All patients had hyponatremia at randomization in SALT-1 and SALT-2, and 85% continued to have hyponatremia at entry in SALTWATER. The most common adverse effects attributed to tolvaptan were pollakiuria, thirst, fatigue, dry mouth, polydipsia, and polyuria. Six drug-related adverse effects led to study discontinuation. The increase in serum sodium exceeded the desired 1 mmol/L per h at initiation in five patients. Hypernatremia (>145 mmol/L) led to discontinuation in one patient. Mean serum sodium increased from 130.8 mmol/L at baseline to >135 mmol/L throughout the observation period (P < 0.001 versus baseline at most points). Responses were comparable between patients with euvolemia and those with heart failure but more modest in patients with cirrhosis. In conclusion, prolonged administration of tolvaptan maintains an increased serum sodium with an acceptable margin of safety.

Figure 1.

SALTWATER flow diagram shows progression of study. ^aReceived at least one dose of tolvaptan; ^breceived at least one dose of tolvaptan and had a serum sodium assessment at baseline and at least one postbaseline time point.

Figure 2.

Serum sodium levels obtained in the course of the SALT-1, SALT-2 and SALTWATER trials. Rate of correction of serum sodium levels and the plateaus reached afterwards were similar in both studies. The left-hand figure includes only patients in the SALT-1 and SALT-2 who continued into SALTWATER. Error bars are ± SE. BSL, baseline; FU, follow-up visit 7 days after early withdrawal or trial completion. ^aP < 0.001, tolvaptan versus placebo; ^bP ≤ 0.0011, tolvaptan and tolvaptan (before placebo) versus baseline; ^cP < 0.001, tolvaptan and tolvaptan (before placebo) versus baseline; ^dP = 0.021, tolvaptan versus baseline and P < 0.001 tolvaptan (before placebo) versus baseline; ^eP < 0.001, tolvaptan (before placebo) versus baseline; ^fP = 0.005, tolvaptan (before placebo) versus baseline; ^gP = 0.016 tolvaptan (before placebo) versus baseline.

Figure 3.

Serum sodium measured according to severity of hyponatremia (left) and underlying cause (right). The correction rate had similar kinetics for all groups, except a steeper initial response for the marked hyponatremia subgroup (left). Comparisons versus baseline were statistically significant (P < 0.05) for patients with mild hyponatremia at all time points but week 214 and the follow-up visit; for patients with marked hyponatremia at all visits but weeks 202 and 214; for patients with CHF at all time points but weeks 190, 202, and 214 and the follow-up visit; for patients with cirrhosis at 8 hours, day 31, weeks 10, 18, and 50, and the follow-up visit; and for patients with SIADH/other at all visits but week 214 and the follow-up visit.

Figure 4.

Percentage of patients who normalized their serum sodium according to severity of hyponatremia (top) and etiology (bottom). Approximately half of patients exhibited normal serum sodium levels by week 4. Correction rates seemed to be generally similar among patients with CHF and SIADH/other but may have been somewhat lower among patients with cirrhosis.