Tolvaptan is an oral, selective vasopressin V2
-receptor antagonist that blocks the effects of AVP, thus increasing free water excretion (aquaresis) and serum sodium concentration. Unlike diuretics, tolvaptan does not significantly affect urinary sodium or potassium excretion. It is currently indicated in the United States for treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium < 125 mEq/L) or less-marked hyponatremia that is symptomatic and resistant to correction by fluid restriction, including treatment of patients with cirrhosis, heart failure, or SIADH [11
In an initial study, tolvaptan was shown to be more effective than fluid restriction in increasing serum sodium in 28 patients with euvolemic or hypervolemic hyponatremia (serum sodium < 135 mEq/L; tolvaptan, n
= 17; fluid restriction, n
= 11) [47
]. Changes in serum sodium concentrations were +1.6 versus −0.8 mEq/L (P
= 0.016) for tolvaptan versus fluid restriction, respectively, at 1 h after the first dose, +5.2 versus +0.7 mEq/L after 5 days (P
= 0.019), and +5.7 versus +1.0 at the last visit (maximum, 27 days of treatment; P
= 0.0065). In a study in 18 Japanese patients with intractable ascites or lower limb edema, in which hyponatremia (<120 mEq/L) was an exclusion criterion, tolvaptan doses of 15, 30, and 60 mg/day for 3 days dose-dependently decreased body weight and abdominal circumference and improved ascites and edema [48
]. Mean changes in body weight after 3 days were −1.6, −2.6, and −3.4 kg for tolvaptan 15, 30, and 60 mg/day, respectively, and changes in abdominal circumference ranged from −2.8 to −6.0 cm. Urine osmolality was markedly decreased and remained decreased until the end of the study.
Tolvaptan was found to reverse euvolemic and hypervolemic hyponatremia (serum sodium < 135 mEq/L) in the Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT)-1 and SALT-2 trials. In these two randomized, double-blind, placebo-controlled, phase 3 trials of similar design [12
], a total of 448 patients were randomized to tolvaptan (n
= 225; 15 mg once daily on day 1, increased at 1-day intervals to 30 and 60 mg/day if necessary during the first 4 days) or placebo (n
= 223) in addition to standard therapy for 30 days. In total, 120 patients (27 %) had cirrhosis, 138 (31 %) had heart failure, and 190 (42 %) had SIADH or other causes of hyponatremia. Fluid restriction was avoided during the first 24 h of treatment to prevent overly rapid correction of serum sodium; 87 % of patients had no fluid restriction during this period [11
]. Thereafter, fluid was restricted as clinically indicated (intake ≤ 1.5 L daily). Tolvaptan treatment resulted in a significantly greater increase in serum sodium at both time points (day 4 and 30) in both studies (P
< 0.0001 for all comparisons). Pooled results for all patients showed changes in average daily serum sodium AUC of 4.0 for tolvaptan versus 0.4 mEq/L for placebo at day 4 and 6.2 versus 1.8 mEq/L at day 30 (both P
< 0.0001) [11
]. Overall, 14 % of tolvaptan versus 25 % of placebo patients (P
< 0.01) required fluid restriction. A significantly greater increase in serum sodium was observed with tolvaptan treatment as early as 8 h after the first dose. Significant reductions in serum sodium at days 4 and 30 were also reported for patient subgroups with baseline sodium < 130 mEq/L and <125 mEq/L (both P
< 0.0001). During a 7-day follow-up after stopping study treatment, serum sodium concentrations in the tolvaptan group decreased to levels similar to those in the placebo group.
The SALT trials included 63 tolvaptan-treated patients and 57 placebo patients with cirrhosis [49
]. The mean age for these patients (52 and 55 years, respectively) was younger than that for patients with heart failure or SIADH/other conditions (67 and 63, respectively) (data on file, Otsuka America Pharmaceutical, Inc., Rockville, MD). At baseline, 44 % had mild hyponatremia (serum sodium 130–134 mEq/L), 56 % had marked hyponatremia (serum sodium < 130 mEq/L), 85 % had cirrhosis due to alcohol and/or hepatitis B/C, and 80 % were Child-Pugh class B/C. Changes in average daily serum sodium AUC for the SALT patients with cirrhosis were 3.5 mEq/L for tolvaptan versus 0.3 mEq/L for placebo at day 4 and 4.2 mEq/L versus 1.2 mEq/L at day 30 (both P
< 0.0001). Patients receiving tolvaptan had significantly greater increases in serum sodium (P
< 0.05) as early as 8 h after the first dose and at days 2, 3, 4, 11, 18, and 25 (Fig. ). The proportion of patients with normalized serum sodium was significantly greater with tolvaptan at day 4 (41 vs. 11 %, P
= 0.0002) and numerically greater at day 30 (33 vs. 19 %, P
= 0.08). Mean mental component summary scores of the Medical Outcomes Study 12-item Short Form General Health Survey (SF-12) improved from baseline to day 30 in the tolvaptan group but not the placebo group (4.68 vs. 0.08, P
= 0.02). Before the study began, 98 % of the tolvaptan group were taking diuretics (with the majority on a moderate dose: spironolactone < 200 mg/day or furosemide < 80 mg/day); only 6 % discontinued diuretic use during the trials. Diuretic use did not appear to have an impact on treatment with tolvaptan [49
]; however, the data from this limited analysis need to be confirmed in larger clinical trials.
Fig. 5 Observed serum sodium concentration throughout the study treatment period (days 1–30) and 7 days after stopping (day 37) in patients receiving tolvaptan or placebo. Error bars are ±SE (standard error of the mean). *P < 0.001, (more ...)
In the open-label SALTWATER study, 111 patients (94 with serum sodium < 135 mEq/L) who had previously received tolvaptan or placebo in the SALT trials were treated with tolvaptan after having returned to standard care for at least 7 days. Average serum sodium levels in these patients increased to approximately the same levels as those observed with tolvaptan treatment in the SALT trials and were maintained for at least 1 year [11
Adverse events in the SALT trials were generally similar in the tolvaptan and placebo groups [12
]. The most common adverse events in tolvaptan patients were thirst (14 % with tolvaptan vs. 5 % with placebo) and dry mouth (13 vs. 4 %, respectively). Desirable rates of sodium correction (>0.5 mEq/L/h) were exceeded in 1.8 % of 223 tolvaptan patients during the 24 h after the first dose. The range of desirable increase was exceeded (>146 mEq/L) in 4 (1.8 %) of the tolvaptan patients.
In the analysis of cirrhotic patients in the SALT trials, gastrointestinal bleeding was reported in six out of 63 (10 %) tolvaptan-treated patients and one out of 57 (2 %) placebo-treated patients (P
= 0.11) [49
]. Among the tolvaptan recipients, five had evidence of upper gastrointestinal hemorrhage and concomitant esophageal varices and one had a self-limited episode of bright red blood per rectum that was attributed to hemorrhoids. The placebo patient had a gingival hemorrhage and concomitant esophageal varices that were not considered to be the cause of bleeding. The investigators suggested that these events were likely related to portal hypertension and esophageal varices, but that this could not be established based on the event descriptions, and noted that thus far there are no known mechanisms by which tolvaptan would increase the risk for variceal bleeding. The overall safety of tolvaptan in patients with cirrhosis remains to be confirmed in larger, prospective, placebo-controlled trials. Tolvaptan should be used in cirrhotic patients only when the need to treat outweighs the risk of gastrointestinal bleeding.