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Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, Orlandi C, and SALT Investigators. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med. 2006;355:2099-2112. (Reprinted with permission.)

Abstract

  1. Top of page
  2. Abstract
  3. Comment
  4. REFERENCES

BACKGROUND: Hyponatremia (serum sodium concentration, <135 mmol per liter) is a predictor of death among patients with chronic heart failure and cirrhosis. At present, therapy for acute and chronic hyponatremia is often ineffective and poorly tolerated. We investigated whether tolvaptan, an orally active vasopressin V(2)-receptor antagonist that promotes aquaresis—excretion of electrolyte-free water—might be of benefit in hyponatremia. METHODS: In two multicenter, randomized, double-blind, placebo-controlled trials, the efficacy of tolvaptan was evaluated in patients with euvolemic or hypervolemic hyponatremia. Patients were randomly assigned to oral placebo (223 patients) or oral tolvaptan (225) at a dose of 15 mg daily. The dose of tolvaptan was increased to 30 mg daily and then to 60 mg daily, if necessary, on the basis of serum sodium concentrations. The two primary end points for all patients were the change in the average daily area under the curve for the serum sodium concentration from baseline to day 4 and the change from baseline to day 30. RESULTS: Serum sodium concentrations increased more in the tolvaptan group than in the placebo group during the first 4 days (P<0.001) and after the full 30 days of therapy (P<0.001). The condition of patients with mild or marked hyponatremia improved (P<0.001 for all comparisons). During the week after discontinuation of tolvaptan on day 30, hyponatremia recurred. Side effects associated with tolvaptan included increased thirst, dry mouth, and increased urination. A planned analysis that combined the two trials showed significant improvement from baseline to day 30 in the tolvaptan group according to scores on the Mental Component of the Medical Outcomes Study 12-item Short-Form General Health Survey. CONCLUSIONS: In patients with euvolemic or hypervolemic hyponatremia, tolvaptan, an oral vasopressin V2-receptor antagonist, was effective in increasing serum sodium concentrations at day 4 and day 30. (ClinicalTrials.gov numbers, NCT00072683 [ClinicalTrials.gov] [SALT-1] and NCT00201994 [ClinicalTrials.gov] [SALT-2].).

Comment

  1. Top of page
  2. Abstract
  3. Comment
  4. REFERENCES

Hyponatremia is the most frequent metabolic disorder encountered in hospitalized patients. In chronic liver disease, hyponatremia (serum sodium <135 mmol/l) is seen in 49% of hospitalized patients with cirrhosis and is associated with an increased rate of encephalopathy, development of spontaneous bacterial peritonitis, onset of the hepatorenal syndrome, as well as worsening of ascites.1 Hyponatremia in cirrhosis adds predictive value to the MELD score and is thus a significant predictor of decreased patient survival and the need for liver transplant.2 The pathogenesis of cirrhosis-associated hyponatremia is secondary to increase renal water retention due to a reduced aquaresis (solute-free water clearance) although it should be recognized that not all patients with decompensated cirrhosis have abnormal free water clearance. Thus, these patients have increased total body water as well as increased total body sodium despite the hyponatremia; this condition is called dilutional hyponatremia.3

Vasopressin release in cirrhosis is the most important factor mediating a reduction in aquaresis via V2 receptors on the collecting ducts of the renal nephron.4 Vasopressin binding to V2 receptors results in insertion of aquaporin-2 water channels into the collecting ducts. The net result is retention of free water. Treatment of significant hyponatremia in cirrhosis has always been difficult. Traditional approaches include cessation of diuretics in combination with water restriction.5 However, such approaches rarely work for any length of time. Additional approaches include the use of hypertonic saline if the serum sodium is extremely low and potentially life threatening.5 It should also be noted that too rapid an increase in serum sodium in these situations is potentially hazardous, because of the complication central pontine myelinolysis.

Because there is a lack of specific and efficient treatment of hyponatremia, oral V2 receptor vasopressin antagonists (vaptans) have been developed to induce an aquaresis.4 A recent report by Schrier et al. describes 2 identically designed clinical trials (SALT 1 and SALT 2) in which a vasopressin V2 receptor antagonist, tolvaptan, was used to treat hyponatremia in a randomized, double-blinded, placebo-controlled study of 448 patients.6 The trials were performed predominantly on outpatients with serum sodium levels <130 mmol/l on enrollment. Fluid restriction was not mandatory, and patients were allowed to continue concurrent diuretic use. Patients with cirrhosis who had a Child-Pugh score >10 were excluded. Cirrhosis was the cause of the hyponatremia in 27% of the patients, and the primary outcome measure was an improvement in serum sodium compared to baseline at day 4 and 30 of treatment. If both studies are combined, 63 patients with cirrhosis received tolvaptan whereas 57 received the placebo. Serum sodium was significantly increased in both studies at 4 and 30 days with tolvaptan treatment compared to placebo. At 30 days, serum sodium level increased from 131.3 mmol/l to 135.8 mmol/l. Normal mean serum sodium was achieved by day 11 in both studies with tolvaptan treatment but not in the placebo arm of each study. These changes were observed in patients with mild (130-143 mmol/l) as well as marked (>130 mmol/l) hyponatremia. Aquaresis was assessed at day 1 and there was a significantly greater net fluid loss with tolvaptan treatment compared to placebo (1273 ml/day versus 393 ml/day). Adverse events for the treatment and placebo groups were similar, with the most common tolvaptan-associated side effect being thirst and dry mouth. The number of deaths in each group did not differ significantly, and hypernatremia (serum sodium level >145 mmol/l) or a serum sodium increase > 0.5 mmol/hour was seen in only 4 of 223 tolvaptan-treated patients. Therefore, selective vasopressin V2 receptor antagonism, at least in the short term, appears to be effective in the treatment of hyponatremia associated with cirrhosis.

The treatment of ascites with vaptans has now also been reported, with Satavaptan and RWJ-351647 being used effectively along with concurrent diuretic use even in the absence of hyponatremia.7, 8 Further, Satavaptan has been shown to decrease the rate of ascites recurrence after large-volume paracetenesis.9 Although there is significant optimism regarding the use of vaptans to treat cirrhosis-associated hyponatremia and/or ascites, there is currently no long-term efficacy and safety data or a demonstrated survival benefit associated with these new agents. These questions will need to be answered before the vaptans can be said to have fulfilled their promise as novel agents effective at treating hyponatremia and/or ascites in patients with cirrhosis.

REFERENCES

  1. Top of page
  2. Abstract
  3. Comment
  4. REFERENCES
  • 1
    Angeli P, Wong F, Watson H, Gines P. Hyponatremia in cirrhosis: Results of a patient population survey. HEPATOLOGY 2006; 44: 15351542.
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  • 6
    Schrier RW, Gross P, Gheorghiade M, Berl T, Verbalis JG, Czerwiec FS, et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006; 355: 20992112.
  • 7
    Thuluvath PJ, Maheshwari A, Wong F, Yoo HW, Schrier RW, Parikh C, et al. Oral V2 receptor antagonist (RWJ-351647) in patients with cirrhosis and ascites: a randomized, double-blind, placebo-controlled, single ascending dose study. Aliment Pharmacol Ther 2006; 24: 973982.
  • 8
    Gines P, Wong F, Watson H, Ruiz del Arbol LR, Bilic A, Dobru D. Effects of a selective vasopressin V2 receptor antagonist, satavaptan (SR121463B) in patients with cirrhosis and ascites without hyponatremia. HEPATOLOGY 2006; 44: A691.
  • 9
    Wong F, Gines P, Watson H, Kujundzic M, Angeli P, Horsmans Y. Effects of a selective vasopressin V2 receptor antagonist, satavaptan (SR121463B) on recurrence of ascites after large volume paacentesis. HEPATOLOGY 2006; 44: A180.