Correspondence

Tolvaptan for Hyponatremia

N Engl J Med 2007; 356:961-963March 1, 2007

Article

To the Editor:

Schrier and colleagues (Nov. 16 issue)1 report the overall efficacy and safety of tolvaptan in raising and maintaining serum sodium concentrations in patients with hyponatremia due to various causes. However, they do not report whether the primary end points were achieved in each of the subgroups (patients with the syndrome of inappropriate antidiuretic hormone secretion [SIADH], those with liver cirrhosis, and those with chronic heart failure), although a previous preliminary report suggests that this treatment results in differences in the resolution of hyponatremia among these groups.2 Furthermore, little mention is made about whether the treatment groups were similar with respect to water intake or the use of angiotensin-converting–enzyme inhibitors, angiotensin-receptor blockers, and diuretics — all factors affecting fluid balance. Nor is there any discussion of the characteristics of the patients who withdrew from the Study of Ascending Levels of Tolvaptan (SALT) 1 and 2 studies (30% and 26% of patients, respectively) or of the reasons for their withdrawal. This lack of reported information makes it difficult for the reader to understand the clinical setting in which maximum use is likely to be achieved for this new agent. We certainly need more long-term efficacy and safety data3 before vasopressin blockers are considered to be standard therapy for hyponatremia of all causes.

Wolfgang J. Weise, M.D.
Jeffrey M. Rimmer, M.D.
Virginia L. Hood, M.B., B.S., M.P.H.
University of Vermont, Burlington, VT 05401
jrimmer@uvm.edu

3 References

1. 1

   Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V₂-receptor antagonist, for hyponatremia. N Engl J Med 2006;355:2099-2112
   Full Text | Web of Science | Medline

2. 2

   Greenberg A, Verbalis JG. Vasopressin receptor antagonists. Kidney Int 2006;69:2124-2130
   CrossRef | Web of Science | Medline

3. 3

   Gheorghiade M, Orlandi C, Burnett JC, et al. Rationale and design of the multicenter, randomized, double-blind, placebo-controlled study to evaluate the Efficacy of Vasopressin antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST). J Card Fail 2005;11:260-269
   CrossRef | Web of Science | Medline

To the Editor:

We think that the article by Schrier et al. lacks important information needed for critical interpretation of the results. First, how was hypovolemic, normovolemic, or hypervolemic hyponatremia determined? In an earlier study, Chung et al. reported that clinical assessment correctly identified only 47% of patients with hypovolemia and 48% of patients with normovolemic hyponatremia.1 Second, how was SIADH diagnosed? SIADH is not always treated as a diagnosis of exclusion, and ample literature suggests its overdiagnosis.2 Third, did any patients have signs of the osmotic demyelination syndrome? The introduction of “vaptans,” such as tolvaptan, might increase the incidence of the osmotic demyelination syndrome, which can occur with a correction of 11 mmol per liter per day.2 Finally, more information is needed about how the control group was treated for hyponatremia. It would be important to know whether vasopressin-receptor antagonists are superior to traditional therapeutic options. Answers to these questions are important for a critical evaluation of the clinical applicability of these new drugs.

Ewout J. Hoorn, M.D.
Robert Zietse, M.D.
Erasmus Medical Center, 3015 GD Rotterdam, the Netherlands
ejhoorn@gmail.com

2 References

1. 1

   Chung HM, Kluge R, Schrier RW, Anderson RJ. Clinical assessment of extracellular fluid volume in hyponatremia. Am J Med 1987;83:905-908
   CrossRef | Web of Science | Medline

2. 2

   Hoorn EJ, Halperin ML, Zietse R. Diagnostic approach to a patient with hyponatraemia: traditional versus physiology-based options. QJM 2005;98:529-540
   CrossRef | Medline

To the Editor:

Although the prospect of providing a cure for the most common electrolyte abnormality in hospital medicine is exciting, the enthusiasm generated by the SALT trials would be best tempered with a few notes of caution.

First, the stringent inclusion criteria in the trials meant that the very patients who are among those most likely to benefit from this therapy were excluded. Hemodynamic, renal, and adrenal dysfunction and a Child–Pugh score of more than 10 are highly prevalent among patients with advanced liver disease, which is commonly accompanied by hyponatremia.1-3 Such patients were excluded, and the results of the trial may not be generalizable to the majority of patients with cirrhosis and hyponatremia.

Second, although the efficacy of tolvaptan in correcting hyponatremia is not in question, the same cannot be said about its capacity to improve the prognosis for patients with this condition. Indeed, like preceding trials,4 SALT failed to show a survival benefit with V₂-receptor antagonists.

Given these limitations, one can only conclude that the wholesale treatment of hyponatremia with tolvaptan in everyday clinical practice cannot currently be recommended.

Muhammad F. Dawwas, M.R.C.P.
Cambridge University Hospitals NHS Trust, Cambridge CB2 2QQ, United Kingdom
drdawwas@gmail.com

4 References

1. 1

   Arroyo V, Colmenero J. Ascites and hepatorenal syndrome in cirrhosis: pathophysiological basis of therapy and current management. J Hepatol 2003;38:Suppl 1:S69-S89
   CrossRef | Web of Science | Medline

2. 2

   Tsai MH, Peng YS, Chen YC, et al. Adrenal insufficiency in patients with cirrhosis, severe sepsis and septic shock. Hepatology 2006;43:673-681
   CrossRef | Web of Science | Medline

3. 3

   Angeli P, Wong F, Watson H, Gines P. Hyponatremia in cirrhosis: results of a patient population survey. Hepatology 2006;44:1535-1542
   CrossRef | Web of Science | Medline

4. 4

   Palm C, Pistrosch F, Herbrig K, Gross P. Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia. Am J Med 2006;119:Suppl 1:S87-S92
   CrossRef | Web of Science | Medline

To the Editor:

Schrier et al. report promising results of their study of the efficacy of tolvaptan in patients with euvolemic or hypervolemic hyponatremia. The study was planned so that tolvaptan was added to standard medical treatment “without . . . a change in the patient's medication regimen, such as use of diuretics.” However, more than half of the group had received the diagnosis of either chronic heart failure or cirrhosis. The management of these conditions differs from that of SIADH, and usually involves the administration of various types and doses of diuretics. It is surprising that the authors did not analyze their data separately for patients who received diuretics. The addition of this information would probably be helpful for the future clinical use of tolvaptan.

Cigdem Ozkan, M.D.
Alper Kirkpantur, M.D.
Mustafa Arici, M.D.
Hacettepe University, 06100 Ankara, Turkey
marici@hacettepe.edu.tr

Author/Editor Response

The SALT program studied vasopressin-dependent forms of hyponatremia. Tolvaptan, through vasopressin V₂-receptor antagonism, considerably improved each major cause of hyponatremia (SIADH, chronic heart failure, and cirrhosis). The baseline distribution of concomitant medications was similar among the placebo and tolvaptan subgroups for each condition, and the efficacy of tolvaptan was unaffected by the use of diuretics. My reply is addressed to all the correspondents together, since the issues they raise are similar. Although the SALT studies were not designed to assess the effects of tolvaptan on morbidity, they showed improved patient-reported outcomes. The recently completed EVEREST trial, with more than 4000 patients with chronic heart failure, will soon report the effect of tolvaptan on morbidity, mortality, and the improvement of fluid-overload symptoms.1

In our study, fluid status was assessed according to clinical signs such as those described by Chung et al.2 Patients with chronic heart failure or cirrhosis are known to have increased levels of total body sodium and were typically classified as hypervolemic. The group categorized as having “SIADH/other” did not have evidence of increased total body sodium and were predominantly classified as euvolemic. When clinically indicated, saline infusion was used to exclude hypovolemia.

Fluid restriction was an available option for all patients and was recommended for those with moderately severe hyponatremia. However, loosening the fluid restriction during the initial titration was permitted to avoid episodes of a too-rapid increase in sodium concentration. Only four patients had an increase in the serum sodium concentration of more than 12 mmol per liter in the first 24 hours, and only four had measurements of serum sodium that were more than 146 mmol per liter at any time during the study. To date, there have been no reports of the osmotic demyelination syndrome in any of the patients who received tolvaptan (more than 1750 patient-years of exposure in patients with hyponatremia or congestive heart failure).

The rates of serious adverse events (29% overall) and death (6% overall) during an observation period of 37 days were similar in the two groups; these findings attest to this study population's comparability to the population with hyponatremia in general. More than 30% of patients with cirrhosis had a Child–Pugh class C score, with many scores greater than 10 allowed by the medical monitor. Even with this relatively ill group of patients, only 12% in each group withdrew from the study because of adverse events.

As with any new class of agents, the clinical use of vasopressin V₂-receptor antagonists will be guided by experience built on carefully planned and conducted controlled clinical trials.

Robert W. Schrier, M.D.
University of Colorado, Denver, CO 80262
robert.schrier@uchsc.edu

for the SALT Investigators

2 References

1. 1

   Gheorghiade M, Orlandi C, Burnett JC, et al. Rationale and design of the multicenter, randomized, double-blind, placebo-controlled study to evaluate the Efficacy of Vasopressin antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST). J Card Fail 2005;11:260-269
   CrossRef | Web of Science | Medline

2. 2

   Chung HM, Kluge R, Schrier RW, Anderson RJ. Clinical assessment of extracellular fluid volume in hyponatremia. Am J Med 1987;83:905-908
   CrossRef | Web of Science | Medline

Citing Articles (4)

Citing Articles

1. 1

   Richard C Josiassen, Jessica Curtis, Dawn M Filmyer, Brett Audino, Nina Skuban, Rita A Shaughnessy. (2010) Tolvaptan: a new tool for the effective treatment of hyponatremia in psychotic disorders. Expert Opinion on Pharmacotherapy 11:4, 637-648
   CrossRef

2. 2

   R. Zietse, N. van der Lubbe, E. J. Hoorn. (2009) Current and future treatment options in SIADH. NDT Plus 2:Supplement 3, iii12-iii19
   CrossRef

3. 3

   E. J. Hoorn, N. van der Lubbe, R. Zietse. (2009) SIADH and hyponatraemia: why does it matter?. NDT Plus 2:Supplement 3, iii5-iii11
   CrossRef

4. 4

   Richard C. Josiassen, Morris Goldman, Meera Jessani, Rita A. Shaughnessy, Ala Albazzaz, Jennifer Lee, John Ouyang, Cesare Orlandi, Frank Czerwiec. (2008) Double-Blind, Placebo-Controlled, Multicenter Trial of a Vasopressin V2-Receptor Antagonist in Patients with Schizophrenia and Hyponatremia. Biological Psychiatry 64:12, 1097-1100
   CrossRef