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Article Efficacy and Tolerance of Urea Compared with Vaptans for Long-Term Treatment of Patients with SIADH Alain Soupart,*† Michel Coffernils,* Bruno Couturier,† Fabrice Gankam-Kengne,† and Guy Decaux† Summary Background and objectives Vaptans (vasopressin V2-receptor antagonists) are a new approach for the treatment of hyponatremia. However, their indications remain to be determined, and their benefit compared with that of the usual treatments for the syndrome of inappropriate antidiuretic hormone secretion (SIADH) have not been *Department of fi Internal Medicine, evaluated. This prospective, long-term study compared the ef cacy, tolerability, and safety of two oral vaptans Jolimont/Tubize with those of oral urea in patients with SIADH. Hospital, Tubize, Brabant, Belgium; and † Design, setting, participants, & measurements Patients with chronic SIADH of various origins were treated first Research Unit for the Study of Hydromineral with vaptans for 1 year. After an 8-day holiday period, they received oral urea for an additional 1-year follow-up. Metabolism, Serum sodium was measured every 2 months, and drug doses were adjusted accordingly. Department of General Internal Results Thirteen participants were initially included in the study (serum sodium, 12563 mEq/L); 12 completed Medicine, Erasmus the 2-year treatment period. Treatment with vaptans (satavaptan, 5–50 mg/d, n=10; tolvaptan, 30–60 mg/day, University Hospital, Brussels, Belgium n=2) increased natremia (serum sodium, 13563 mEq/L) during the 1-year vaptan period without escape. Hyponatremia recurred in the 12 participants when vaptans were stopped (holiday period). Urea improved the Correspondence: natremia with the same efficacy (serum sodium, 13562 mEq/L) as vaptans during the 1-year urea treatment Dr. Alain Soupart, period. One participant treated with tolvaptan withdrew from the study early because of excessive thirst. Department of Another patient receiving urea developed hypernatremia without complications. General Internal Medicine, Erasmus fi University Hospital, Conclusions Urea has ef cacy similar to that of vaptans for treatment of chronic SIADH. Tolerance is generally Route de Lennik, 808, good for both agents. 1070 Brussels, Clin J Am Soc Nephrol 7: 742–747, 2012. doi: 10.2215/CJN.06990711 Belgium. Email: alainsoupart@skynet. be Introduction patients with SIADH, including satavaptan (selective The syndrome of inappropriate antidiuretic hormone V2), tolvaptan (V2), lixivaptan (V2), and conivaptan secretion (SIADH) results from nonosmotic release of (V1/V2) (14). Two of these are currently available vasopressin from the pituitary gland or from ectopic on the market: In the United States, conivaptan is secretion. Antidiuretic hormone secretion induces an approved for intravenous use in euvolemic and hy- excess of total body water due to a decrease in elec- pervolemic hyponatremia (15,16), and oral tolvaptan trolyte free water excretion with relatively normal total- is approved for euvolemic and hypervolemic hypo- body sodium, resulting in euvolemic hyponatremia (1). natremia (17,18). Tolvaptan is approved in the Euro- The resulting hyponatremia can be transitory or be- pean Union only for SIADH. come chronic depending on the initial cause of the However, none of the published studies compared the SIADH. Many conditions can be associated with therapeutic effect of the V2 antagonists with effects of SIADH, but approximately one third of cases are of un- any alternative available methods of correction in pa- known origin (idiopathic), especially in the elderly (2,3). tients with SIADH on a long-term basis. We studied a Usual therapeutic options in hyponatremic patients series of patients with chronic SIADH of various origins fi with SIADH consist of fluid restriction, usually to less by successively comparing the long-term (1-year) ef - than 800–1200 ml/d (an intake difficult to maintain, cacy and tolerability of two different vaptans (satavaptan particularly in patients with reset osmostat) (4,5); and tolvaptan) with those of oral urea (1 year). fi demeclocycline, which works in only 60%–70% of pa- Participants were rst treated with different vaptans; tients and can cause nephrotoxicity (5); furosemide with when these drugs were no longer available, hyponatremia oral salt supplementation (6,7); and oral urea, an agent was then corrected with urea. long used to treat hyponatremia of various origins (8–13). The recent development of oral nonpeptide vaso- Materials and Methods pressin V2-receptor antagonists (vaptans) offers a Patients new therapeutic approach that targets the mechanism Between June 2007 and December 2009, 13 patients of the disorder. Several vaptans have been studied in from our hospitals were included in different studies 742 Copyright © 2012 by the American Society of Nephrology www.cjasn.org Vol 7 May, 2012 Clin J Am Soc Nephrol 7: 742–747, May, 2012 Treatment of SIADH by Vaptans or Urea, Soupart et al. 743 to evaluate the efficacy and tolerability of vaptans in chronic In the second part of the protocol (additional 12 months), hyponatremia related to SIADH. Results of these studies all participants who met the inclusion criteria were then have been published for satavaptan (2) and tolvaptan (17,18). treated with oral urea at adjusted dosages of 15–30 g/d after After 12 months, the vaptans were no longer provided by meal (in one or two doses). Urea powder (medicinal urea, the companies. We then decided to treat hyponatremia with Certa, Braine-L’Alleud, Belgium) was mixed with orange urea in those participants. juice or syrup. The target serum sodium level was similar All the participants met the classic criteria for SIADH to that used with vaptan treatment (serum sodium level (hypo-osmolality, inappropriately concentrated urine with . 135 mEq/L). fl urine osmolality 100 mOsm/kg H2O hypertonic to se- During the entire study, a total uid intake limited to rum and urine sodium concentration . 30 mEq/L with nor- 1500–2000 ml/d was recommended to all participants but mal salt and water intake) (1). All patients had normal renal, was not measured. The efficacy and safety of both treat- adrenal, and thyroid function. Inclusion criteria were age ments were assessed during the 24-month follow-up. older than 18 years, chronic (.72-hour) hyponatremia (se- Blood samples for serum sodium, serum urea, and serum rum sodium .115–132 mEq/L) due to SIADH (idiopathic or creatinine measurements were collected every 2 months related to various secondary causes). Exclusion criteria were during the entire study period. transient SIADH (e.g., due to pneumonia), cardiac failure, Safety was assessed at all visits for the 2-year study symptomatic liver disease or serum aminotransferase or as- duration for each participant by recording adverse events, partate aminotransferase levels greater than twice the upper vital signs, and physical examination findings based on limit of normal, uncontrolled diabetes (blood glucose symptoms and diagnosis. level . 200 mg/dl), and symptomatic gastric ulcer (for urea). Written informed consent was obtained for each patient, Statistical Analyses and the study protocol was approved by the local ethics Data are provided as the mean 6 SD. All statistical tests committee. were two sided at a 5% significance level. Data were com- pared between treatment groups using ANOVA for con- tinuous data and Tukey-Kramer multiple-comparison tests Protocol (Statsdirect Software; Statsdirect Ltd.). Table 1 lists the characteristics and treatments for the study patients. In the first part of the study (12 months), all the participants were treated with open-label vaptans Results (V2 selective receptor antagonists). Twelve participants (six women and six men), with a Ten participants received oral satavaptan (Sanofi- mean age of 73617 years (range, 28–89 years), completed Synthélabo)atanadjusteddosageof5–25 mg/d; three others the 2-year follow-up study. SIADH was considered idio- received oral tolvaptan(Samsca,Otsuka),30–60 mg/d. pathic in nine patients and was associated with central ner- The drug was administered in the morning under fasting vous system disorders in the other three patients (Table 1). conditions for each vaptan. The dose was adjusted to At baseline, all patients presented moderate hyponatremia obtain a serum sodium level between 135 and 145 mEq/L. (mean serum sodium level, 12563 mEq/L [range, 120–131 After the first 12-month period of treatment, vaptans were mEq/L]). The mean serum urea level was 2667 mg/dl discontinued. An 8-day holiday period followed to ensure the (range, 18–41 mg/dl), and the mean serum uric acid level recurrence of hyponatremia (serum sodium , 132 mEq/L) in was 3.361.2 mg/dl (range, 1.2–5.3 mg/dl). Mean urinary 6 – all participants. Patients in whom hyponatremia did not re- osmolality was 487 162 mOsm/kg H2O (range, 264 800 cur were withdrawn from the study. mOsm/kg H2O). Table 1. Clinical characteristics and treatment in patients with syndrome of inappropriate antidiuretic hormone secretion Patient No. Sex Age (yr) Origin of SIADH Vaptan Dose (mg) Urea Dose (g) 1 F 86 Idiopathic Satavaptan, 25 30 2 M 88 Idiopathic Satavaptan, 12.5 30 3 F 89 Idiopathic Satavaptan, 5 15 4 M 70 Idiopathic Satavaptan, 5 15 5 M 76 Idiopathic Satavaptan, 25 30 6 M 84 Idiopathic Satavaptan, 12.5 30 7 M 56 Idiopathic Satavaptan, 10 30 8 F 85 Idiopathic Satavaptan, 5 15 9 F 70 CNS hemorrhage Satavaptan, 25 15 10 F 70 Neurolupus Tolvaptan, 60 30 11 M 59 Idiopathic Satavaptan, 50 15–30 12 F 28 Olfactive neuroblastoma Tolvaptan, 30 30 13 M 70 Idiopathic Tolvaptan, 30 NA SIADH, syndrome of inappropriate antidiuretic hormone secretion; F, female; M, male; CNS, central nervous system; NA, not applicable. 744 Clinical Journal of the American Society of Nephrology Vaptan Course (12 Months) additional months. Evolution of the serum sodium level The evolution of serum sodium levels throughout the during urea treatment is shown in Figure 1 and Table 2. firstyearoftreatmentwithvaptansisshowninTable2 The serum sodium level increased significantly in the 12 and Figure 1.
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  • Lixivaptan: a Vasopressin Receptor Antagonist for the Treatment of Hyponatremia

    Lixivaptan: a Vasopressin Receptor Antagonist for the Treatment of Hyponatremia

    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector commentary promotes angiogenesis in normocholes- 9. Vasquez-Vivar J, Kalyanaraman B, Martasek P zed their serum sodium levels as com- terolemic animals. Nat Med 2000; 6: et al. Superoxide generation by endothelial 4,5 1004–1010. nitric oxide synthase: the influence of pared with placebo. Data also demon- 8. Guzik TJ, Mussa S, Gastaldi D et al. cofactors. Proc Natl Acad Sci USA 1998; 95: strate the long-term safety and efficacy Mechanisms of increased vascular superoxide 9220–9225. (out to approximately 2 years) of production in human diabetes mellitus: role 10. Tsutsui M, Milstien S, Katusic ZS. Effect of 6 of NAD(P)H oxidase and endothelial nitric tetrahydrobiopterin on endothelial function tolvaptan. The ability to specifically oxide synthase. Circulation 2002; 105: in canine middle cerebral arteries. Circ Res target arginine vasopressin provided a 1656–1662. 1996; 79: 336–342. physiologically based therapy for hypo- natremia that was safe and reliable. In two articles in this issue of Kidney see original articles on page 1215 and 1223 International, Abraham and colleagues report on the effects of a new oral, Lixivaptan: a vasopressin receptor non-peptide vasopressin V2 receptor, lixivaptan, in the treatment of both in- antagonist for the treatment of and outpatients with euvolemic hypo- natremia.7,8 The studies, LIBRA and hyponatremia HARMONY, differ in that the former trial required initial titration of Mitchell H. Rosner1 lixivaptan in the inpatient setting, whereas, in the latter trial, lixivaptan was Hyponatremia, the most common electrolyte disorder encountered in initiated in the outpatient setting (Table 2 clinical practice, is associated with significant morbidity and mortality.