Effects of Tolvaptan, an Oral Vasopressin V 2 Receptor Antagonist, in Hyponatremia

Abstract

Commentary on Schrier RW, Gross P, Gheorghiade M, et al: Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 355:2099-2112, 2006.Hyponatremia is the most common electrolyte disorder encountered in hospitalized patients and is associated with considerable morbidity and mortality.1Upadhyay A. Jaber B.L. Madias N.E. Incidence and prevalence of hyponatremia.Am J Med. 2006; 119: S30-S35Abstract Full Text Full Text PDF PubMed Scopus (513) Google Scholar, 2Renneboog B. Musch W. Vandemergel X. Manto M.U. Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits.Am J Med. 2006; 119: 71.e1-71.e8Abstract Full Text Full Text PDF PubMed Scopus (637) Google Scholar, 3Adrogué H.J. Madias N.E. Hyponatremia.N Engl J Med. 2000; 342: 1581-1589Crossref PubMed Scopus (1323) Google Scholar Dilutional hyponatremia, by far the most frequent form of the disorder, is generated by water retention, most commonly resulting from a water-excreting defect of the kidneys coupled with water intake in amounts exceeding renal excretory capacity plus insensible losses.3Adrogué H.J. Madias N.E. Hyponatremia.N Engl J Med. 2000; 342: 1581-1589Crossref PubMed Scopus (1323) Google Scholar Excluding acute and chronic renal failure, the water-excreting defect of dilutional hyponatremia largely reflects elevated levels of arginine vasopressin. Currently, the cornerstone of treatment of the commonest causes of chronic hyponatremia of euvolemic (ie, syndrome of inappropriate antidiuretic hormone secretion [SIADH]) or hypervolemic (ie, chronic heart failure or cirrhosis) nature, when oligosymptomatic or asymptomatic, is water restriction.3Adrogué H.J. Madias N.E. Hyponatremia.N Engl J Med. 2000; 342: 1581-1589Crossref PubMed Scopus (1323) Google Scholar However, this often-harsh treatment is poorly tolerated and therefore ineffective. At best, it compensates for, rather than addresses, the underlying pathophysiology. In the November 16, 2006 issue of the New England Journal of Medicine, Schrier et al4Schrier R.W. Gross P. Gheorghiade M. et al.Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia.N Engl J Med. 2006; 355: 2099-2112Crossref PubMed Scopus (965) Google Scholar showed that tolvaptan, an oral vasopressin V2 receptor antagonist, was effective in raising serum sodium concentration in patients with euvolemic or hypervolemic hyponatremia.What Did This Important Study Show?The Study of Ascending Levels of Hyponatremia 1 and 2 (SALT-1 and SALT-2),4Schrier R.W. Gross P. Gheorghiade M. et al.Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia.N Engl J Med. 2006; 355: 2099-2112Crossref PubMed Scopus (965) Google Scholar 2 identically designed, multicenter, randomized, double-blind, placebo-controlled trials (1 carried out in the United States and the other at international sites), assigned patients with hyponatremia (serum sodium concentration less than 135 mEq/L [mmol/L]) due to SIADH, chronic heart failure, or cirrhosis to oral placebo (n = 223) or oral tolvaptan (n = 225) at a dose of 15 mg daily for up to 30 days. Study drug could be increased up to 60 mg daily during the first 4 days of therapy to achieve slow correction of serum sodium concentration to 135 mEq/L (mmol/L) or more. The study protocol did not require fluid restriction (although such was recommended in those with moderately severe hyponatremia) or change in medication regimen, including diuretics. Patients were hospitalized for the first day of study, and the majority were discharged by day 4. The 2 primary end points of the study were the change in the average daily area under the curve for the serum sodium concentration from baseline to day 4 and from baseline to day 30. For both primary endpoints, the increase in serum sodium concentration was greater in the tolvaptan group than in the placebo group (P < 0.001 for both). Absolute increases in serum sodium concentration were higher in the tolvaptan group than in the placebo group within 8 hours from drug administration and at all subsequent visits (P < 0.001 for all comparisons). Both on day 4 and day 30, more tolvaptan-treated patients had normal serum sodium concentration than patients assigned to placebo, and “marked” hyponatremia (serum sodium concentration less than 130 mEq/L [mmol/L]) was present in fewer tolvaptan recipients (P < 0.001 for all comparisons). For example, on day 30, 58% of the tolvaptan group in SALT-2 had normal serum sodium concentration compared with 25% in the placebo group (P < 0.001). However, efficacy results were not reported separately for each of the 3 causal groups of hyponatremia. A prespecified combined analysis of both trials showed improvement in the mental component scores of the SF-12 Health Survey on day 30 in the tolvaptan group (P < 0.02) but no difference in the physical component scores between groups. Hyponatremia recurred during the week after tolvaptan discontinuation. The difference between urine output and fluid intake, measured only during the first day of the study, was greater in the tolvaptan group than in the placebo group (P < 0.001). In 1.8% of the tolvaptan-treated patients, the correction of serum sodium concentration during the first 24 hours of study exceeded the predefined limit of 12 mEq/L (mmol/L), whereas 1.8% of tolvaptan recipients exceeded the predefined serum sodium concentration cutoff of 146 mEq/L (mmol/L) at some point during the entire study. Thirst and dry mouth were the most common adverse effects associated with tolvaptan treatment. Potentially study-related serious adverse effects developed in 8 patients assigned to tolvaptan (including dehydration with hypotension or dizziness, syncope, and acute renal failure) and in 10 patients assigned to placebo (including worsened cardiac failure, hepatic encephalopathy, acute renal failure, and acute dyspnea with edema). Fourteen tolvaptan-treated patients and 13 placebo-treated patients died.How Does This Study Compare With Prior Studies?Conivaptan, a mixed vasopressin V1α and V2 receptor antagonist, is currently approved by the US Food and Drug Administration for intravenous treatment of euvolemic or hypervolemic hyponatremia in hospitalized patients for up to 4 days. In a double-blind, placebo controlled, randomized trial in euvolemic patients maintained on a fluid restriction of 2 liters or less per day, 28.6% of placebo-treated patients and 66.7% of conivaptan-treated patients (20 mg loading dose and 40 mg/day as a continuous infusion over 4 days) achieved at least a 6 mEq/L (mmol/L) increase in serum sodium concentration or normalization of serum sodium concentration to at least 135 mEq/L (mmol/L) on day 4 of treatment.5Astellas Pharma US, Inc: Vaprisol (conivaptan hydrochloride injection) product monograph. Deerfield, IL, 2006Google Scholar Similar results have been reported with lixivaptan, another oral vasopressin V2 receptor antagonist under development, in short-term trials in patients with euvolemic or hypervolemic hyponatremia.6Greenberg A. Verbalis J.G. Vasopressin receptor antagonists.Kidney Int. 2006; 69: 2124-2130Crossref PubMed Scopus (161) Google Scholar, 7Palm C. Pistrosch F. Herbrig K. Gross P. Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia.Am J Med. 2006; 119: S87-S92Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 8Gerbes A.L. Gülberg V. Ginès P. et al.Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: A randomized double-blind multicenter trial.Gastroenterology. 2003; 124: 933-939Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar Yet another oral vasopressin V2 receptor antagonist under development, satavaptan, showed a 79% (25 mg/day) and 83% (50 mg/day) efficacy rate (serum sodium concentration increased by 5 mEq/L [mmol/L] or more or normalized) in SIADH patients treated during a double-blind, in-hospital period of up to 5 days compared with 13% of placebo-treated patients.9Soupart A. Gross P. Legros J.-J. et al.Successful long-term treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion with satavaptan (SR121463B), an orally active nonpeptide vasopressin V2-receptor antagonist.Clin J Am Soc Nephrol. 2006; 1: 1154-1160Crossref PubMed Scopus (119) Google Scholar Of the 26 satavaptan-treated patients, several exceeded the predetermined rates of correction, reaching increases of serum sodium concentration of 14 to 16 mEq/L (mmol/L) during the first 24 hours (3 patients) and 19 mEq/L (mmol/L) during the first 48 hours of the study (1 patient). Nine patients exceeded the more conservative rate of correction of 8 mEq/L (mmol/L) during the first 24 hours of treatment. Hypernatremia (serum sodium concentration of greater than 145 mEq/L [mmol/L]) developed in 2 patients during the double-blind period and in 5 patients during a subsequent, open-label, 23-day dosage-adjustment period, reaching values up to 161 mEq/L (mmol/L). In an open-label, long-term extension of this trial, 10 patients have maintained normal levels of serum sodium concentration (136-145 mEq/L [mmol/L]) for 12 months on adjustable doses of satavaptan (12.5-50 mg/day) and fluid restriction of l.5 liters or less, without major side effects.9Soupart A. Gross P. Legros J.-J. et al.Successful long-term treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion with satavaptan (SR121463B), an orally active nonpeptide vasopressin V2-receptor antagonist.Clin J Am Soc Nephrol. 2006; 1: 1154-1160Crossref PubMed Scopus (119) Google ScholarSeveral studies have documented increased electrolyte-free water clearance and decreased urinary osmolality, as expected from the aquaretic effect of vasopressin V2 receptor antagonism.5Astellas Pharma US, Inc: Vaprisol (conivaptan hydrochloride injection) product monograph. Deerfield, IL, 2006Google Scholar, 6Greenberg A. Verbalis J.G. Vasopressin receptor antagonists.Kidney Int. 2006; 69: 2124-2130Crossref PubMed Scopus (161) Google Scholar, 7Palm C. Pistrosch F. Herbrig K. Gross P. Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia.Am J Med. 2006; 119: S87-S92Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 8Gerbes A.L. Gülberg V. Ginès P. et al.Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: A randomized double-blind multicenter trial.Gastroenterology. 2003; 124: 933-939Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar, 9Soupart A. Gross P. Legros J.-J. et al.Successful long-term treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion with satavaptan (SR121463B), an orally active nonpeptide vasopressin V2-receptor antagonist.Clin J Am Soc Nephrol. 2006; 1: 1154-1160Crossref PubMed Scopus (119) Google Scholar In addition to the relatively frequent occurrence of increased thirst and dry mouth, orthostatic hypotension has been observed in some patients.What Should Clinicians and Researchers Do?Encouraging results to date suggest that aquaresis via nonpeptide vasopressin V2 receptor antagonists will emerge as the mainstay of treatment of euvolemic and hypervolemic hyponatremia. Conivaptan, the currently available mixed vasopressin V1α and V2 receptor antagonist, is an effective and well tolerated agent for the short-term management of moderately symptomatic or asymptomatic hyponatremia in hospitalized patients. Because of its effect on the vasopressin V1α receptor (which mediates vasoconstriction), special caution should be exercised in treating patients with low normal blood pressure, especially those with congestive heart failure or cirrhosis. Administration through large veins and change of the infusion site every 24 hours are recommended to minimize the risk of vascular irritation. When oral vasopressin V2 receptor antagonists become clinically available, practitioners would also be able to utilize aquaresis for the long-term management of hyponatremia and its consequences. Symptomatic relief from fluid overload would also be realized by hypervolemic patients (eg, decrease in dyspnea, edema, and tense ascites).6Greenberg A. Verbalis J.G. Vasopressin receptor antagonists.Kidney Int. 2006; 69: 2124-2130Crossref PubMed Scopus (161) Google Scholar, 7Palm C. Pistrosch F. Herbrig K. Gross P. Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia.Am J Med. 2006; 119: S87-S92Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 10Gheorghiade M. Konstam M.A. Burnett Jr, J.C. et al.Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: The EVEREST clinical status trials.JAMA. 2007; 297: 1332-1343Crossref PubMed Scopus (694) Google Scholar Vasopressin V2 receptor antagonists augment vasopressin levels and stimulate thirst. Therefore, their use would not eliminate the need for fluid restriction but rather lessen substantially its stringency.Additional investigative work is required in several areas. The efficacy (on hyponatremia and other clinical outcomes) and safety of vasopressin V2 receptor antagonists must be defined separately for SIADH, congestive heart failure, and cirrhosis. The potential consequences of the chronic activation of the unblocked vasopressin V1α receptor on the blood vessels (pressor effect) and the heart (mitogenic effect), especially in view of the variably heightened levels of arginine vasopressin resulting from vasopressin V2 receptor antagonism, require careful study. We need to understand better why hyponatremia fails to respond to these agents in a substantial minority of patients. Most of these cases likely reflect increased water intake in response to intense thirst. Nonetheless, hemodynamically induced decreased delivery of filtrate to the distal nephron, gain-of-function mutations in the vasopressin V2 receptor or other components of vasopressin’s intracellular signaling cascade including the aquaporin-2 water channel (nephrogenic syndrome of inappropriate antidiuresis),11Feldman B.J. Rosenthal S.M. Vargas G.A. et al.Nephrogenic syndrome of inappropriate antidiuresis.N Engl J Med. 2005; 352: 1884-1890Crossref PubMed Scopus (266) Google Scholar, 12Decaux G. Vandergheynst F. Bouko Y. Parma J. Vassart G. Vilain C. Nephrogenic syndrome of inappropriate antidiuresis in adults: High phenotypic variability in men and women from a large pedigree.J Am Soc Nephrol. 2007; 18: 606-612Crossref PubMed Scopus (111) Google Scholar or other antidiuretic principles might be at play. The range of correction rates of serum sodium concentration achieved by these agents requires careful definition given that a minority of patients has experienced faster-than-desirable rates and even frank hypernatremia. Although no clinical case of osmotic demyelination has been reported to date, there are firm reasons to expect that this dreaded complication is a potential adverse effect of these agents.3Adrogué H.J. Madias N.E. Hyponatremia.N Engl J Med. 2000; 342: 1581-1589Crossref PubMed Scopus (1323) Google Scholar, 13Soupart A. Silver S. Schroeder B. Sterns R. Decaux G. Comparison of mortality and brain composition in hyponatremic rats treated with vasopressin V1-V2 receptor antagonists or water diuresis.J Am Soc Nephol. 2003; 14 (abstr): A747Google Scholar Close monitoring of serum sodium concentration would be required in all patients during the early stages of treatment, and less intensive but regular oversight in the long term. Patients who cannot respond reliably to thirst (eg, frail or mentally compromised patients) would require particularly close follow up. All patients should also monitor their body weight closely. Defining the potential role of vasopressin V2 receptor antagonists in managing severely symptomatic hyponatremia and better understanding of their utility when co-administered with diuretics are additional areas of research. Because all current aquaretics are both substrates and inhibitors of the cytochrome P450 3A4 (family 3, subfamily A, polypeptide 4) system, the impact on efficacy and safety of their interaction with other drugs involved in this pathway needs careful definition. Commentary on Schrier RW, Gross P, Gheorghiade M, et al: Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 355:2099-2112, 2006. Commentary on Schrier RW, Gross P, Gheorghiade M, et al: Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 355:2099-2112, 2006. Commentary on Schrier RW, Gross P, Gheorghiade M, et al: Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 355:2099-2112, 2006. Hyponatremia is the most common electrolyte disorder encountered in hospitalized patients and is associated with considerable morbidity and mortality.1Upadhyay A. Jaber B.L. Madias N.E. Incidence and prevalence of hyponatremia.Am J Med. 2006; 119: S30-S35Abstract Full Text Full Text PDF PubMed Scopus (513) Google Scholar, 2Renneboog B. Musch W. Vandemergel X. Manto M.U. Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits.Am J Med. 2006; 119: 71.e1-71.e8Abstract Full Text Full Text PDF PubMed Scopus (637) Google Scholar, 3Adrogué H.J. Madias N.E. Hyponatremia.N Engl J Med. 2000; 342: 1581-1589Crossref PubMed Scopus (1323) Google Scholar Dilutional hyponatremia, by far the most frequent form of the disorder, is generated by water retention, most commonly resulting from a water-excreting defect of the kidneys coupled with water intake in amounts exceeding renal excretory capacity plus insensible losses.3Adrogué H.J. Madias N.E. Hyponatremia.N Engl J Med. 2000; 342: 1581-1589Crossref PubMed Scopus (1323) Google Scholar Excluding acute and chronic renal failure, the water-excreting defect of dilutional hyponatremia largely reflects elevated levels of arginine vasopressin. Currently, the cornerstone of treatment of the commonest causes of chronic hyponatremia of euvolemic (ie, syndrome of inappropriate antidiuretic hormone secretion [SIADH]) or hypervolemic (ie, chronic heart failure or cirrhosis) nature, when oligosymptomatic or asymptomatic, is water restriction.3Adrogué H.J. Madias N.E. Hyponatremia.N Engl J Med. 2000; 342: 1581-1589Crossref PubMed Scopus (1323) Google Scholar However, this often-harsh treatment is poorly tolerated and therefore ineffective. At best, it compensates for, rather than addresses, the underlying pathophysiology. In the November 16, 2006 issue of the New England Journal of Medicine, Schrier et al4Schrier R.W. Gross P. Gheorghiade M. et al.Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia.N Engl J Med. 2006; 355: 2099-2112Crossref PubMed Scopus (965) Google Scholar showed that tolvaptan, an oral vasopressin V2 receptor antagonist, was effective in raising serum sodium concentration in patients with euvolemic or hypervolemic hyponatremia. What Did This Important Study Show?The Study of Ascending Levels of Hyponatremia 1 and 2 (SALT-1 and SALT-2),4Schrier R.W. Gross P. Gheorghiade M. et al.Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia.N Engl J Med. 2006; 355: 2099-2112Crossref PubMed Scopus (965) Google Scholar 2 identically designed, multicenter, randomized, double-blind, placebo-controlled trials (1 carried out in the United States and the other at international sites), assigned patients with hyponatremia (serum sodium concentration less than 135 mEq/L [mmol/L]) due to SIADH, chronic heart failure, or cirrhosis to oral placebo (n = 223) or oral tolvaptan (n = 225) at a dose of 15 mg daily for up to 30 days. Study drug could be increased up to 60 mg daily during the first 4 days of therapy to achieve slow correction of serum sodium concentration to 135 mEq/L (mmol/L) or more. The study protocol did not require fluid restriction (although such was recommended in those with moderately severe hyponatremia) or change in medication regimen, including diuretics. Patients were hospitalized for the first day of study, and the majority were discharged by day 4. The 2 primary end points of the study were the change in the average daily area under the curve for the serum sodium concentration from baseline to day 4 and from baseline to day 30. For both primary endpoints, the increase in serum sodium concentration was greater in the tolvaptan group than in the placebo group (P < 0.001 for both). Absolute increases in serum sodium concentration were higher in the tolvaptan group than in the placebo group within 8 hours from drug administration and at all subsequent visits (P < 0.001 for all comparisons). Both on day 4 and day 30, more tolvaptan-treated patients had normal serum sodium concentration than patients assigned to placebo, and “marked” hyponatremia (serum sodium concentration less than 130 mEq/L [mmol/L]) was present in fewer tolvaptan recipients (P < 0.001 for all comparisons). For example, on day 30, 58% of the tolvaptan group in SALT-2 had normal serum sodium concentration compared with 25% in the placebo group (P < 0.001). However, efficacy results were not reported separately for each of the 3 causal groups of hyponatremia. A prespecified combined analysis of both trials showed improvement in the mental component scores of the SF-12 Health Survey on day 30 in the tolvaptan group (P < 0.02) but no difference in the physical component scores between groups. Hyponatremia recurred during the week after tolvaptan discontinuation. The difference between urine output and fluid intake, measured only during the first day of the study, was greater in the tolvaptan group than in the placebo group (P < 0.001). In 1.8% of the tolvaptan-treated patients, the correction of serum sodium concentration during the first 24 hours of study exceeded the predefined limit of 12 mEq/L (mmol/L), whereas 1.8% of tolvaptan recipients exceeded the predefined serum sodium concentration cutoff of 146 mEq/L (mmol/L) at some point during the entire study. Thirst and dry mouth were the most common adverse effects associated with tolvaptan treatment. Potentially study-related serious adverse effects developed in 8 patients assigned to tolvaptan (including dehydration with hypotension or dizziness, syncope, and acute renal failure) and in 10 patients assigned to placebo (including worsened cardiac failure, hepatic encephalopathy, acute renal failure, and acute dyspnea with edema). Fourteen tolvaptan-treated patients and 13 placebo-treated patients died. The Study of Ascending Levels of Hyponatremia 1 and 2 (SALT-1 and SALT-2),4Schrier R.W. Gross P. Gheorghiade M. et al.Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia.N Engl J Med. 2006; 355: 2099-2112Crossref PubMed Scopus (965) Google Scholar 2 identically designed, multicenter, randomized, double-blind, placebo-controlled trials (1 carried out in the United States and the other at international sites), assigned patients with hyponatremia (serum sodium concentration less than 135 mEq/L [mmol/L]) due to SIADH, chronic heart failure, or cirrhosis to oral placebo (n = 223) or oral tolvaptan (n = 225) at a dose of 15 mg daily for up to 30 days. Study drug could be increased up to 60 mg daily during the first 4 days of therapy to achieve slow correction of serum sodium concentration to 135 mEq/L (mmol/L) or more. The study protocol did not require fluid restriction (although such was recommended in those with moderately severe hyponatremia) or change in medication regimen, including diuretics. Patients were hospitalized for the first day of study, and the majority were discharged by day 4. The 2 primary end points of the study were the change in the average daily area under the curve for the serum sodium concentration from baseline to day 4 and from baseline to day 30. For both primary endpoints, the increase in serum sodium concentration was greater in the tolvaptan group than in the placebo group (P < 0.001 for both). Absolute increases in serum sodium concentration were higher in the tolvaptan group than in the placebo group within 8 hours from drug administration and at all subsequent visits (P < 0.001 for all comparisons). Both on day 4 and day 30, more tolvaptan-treated patients had normal serum sodium concentration than patients assigned to placebo, and “marked” hyponatremia (serum sodium concentration less than 130 mEq/L [mmol/L]) was present in fewer tolvaptan recipients (P < 0.001 for all comparisons). For example, on day 30, 58% of the tolvaptan group in SALT-2 had normal serum sodium concentration compared with 25% in the placebo group (P < 0.001). However, efficacy results were not reported separately for each of the 3 causal groups of hyponatremia. A prespecified combined analysis of both trials showed improvement in the mental component scores of the SF-12 Health Survey on day 30 in the tolvaptan group (P < 0.02) but no difference in the physical component scores between groups. Hyponatremia recurred during the week after tolvaptan discontinuation. The difference between urine output and fluid intake, measured only during the first day of the study, was greater in the tolvaptan group than in the placebo group (P < 0.001). In 1.8% of the tolvaptan-treated patients, the correction of serum sodium concentration during the first 24 hours of study exceeded the predefined limit of 12 mEq/L (mmol/L), whereas 1.8% of tolvaptan recipients exceeded the predefined serum sodium concentration cutoff of 146 mEq/L (mmol/L) at some point during the entire study. Thirst and dry mouth were the most common adverse effects associated with tolvaptan treatment. Potentially study-related serious adverse effects developed in 8 patients assigned to tolvaptan (including dehydration with hypotension or dizziness, syncope, and acute renal failure) and in 10 patients assigned to placebo (including worsened cardiac failure, hepatic encephalopathy, acute renal failure, and acute dyspnea with edema). Fourteen tolvaptan-treated patients and 13 placebo-treated patients died. How Does This Study Compare With Prior Studies?Conivaptan, a mixed vasopressin V1α and V2 receptor antagonist, is currently approved by the US Food and Drug Administration for intravenous treatment of euvolemic or hypervolemic hyponatremia in hospitalized patients for up to 4 days. In a double-blind, placebo controlled, randomized trial in euvolemic patients maintained on a fluid restriction of 2 liters or less per day, 28.6% of placebo-treated patients and 66.7% of conivaptan-treated patients (20 mg loading dose and 40 mg/day as a continuous infusion over 4 days) achieved at least a 6 mEq/L (mmol/L) increase in serum sodium concentration or normalization of serum sodium concentration to at least 135 mEq/L (mmol/L) on day 4 of treatment.5Astellas Pharma US, Inc: Vaprisol (conivaptan hydrochloride injection) product monograph. Deerfield, IL, 2006Google Scholar Similar results have been reported with lixivaptan, another oral vasopressin V2 receptor antagonist under development, in short-term trials in patients with euvolemic or hypervolemic hyponatremia.6Greenberg A. Verbalis J.G. Vasopressin receptor antagonists.Kidney Int. 2006; 69: 2124-2130Crossref PubMed Scopus (161) Google Scholar, 7Palm C. Pistrosch F. Herbrig K. Gross P. Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia.Am J Med. 2006; 119: S87-S92Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 8Gerbes A.L. Gülberg V. Ginès P. et al.Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: A randomized double-blind multicenter trial.Gastroenterology. 2003; 124: 933-939Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar Yet another oral vasopressin V2 receptor antagonist under development, satavaptan, showed a 79% (25 mg/day) and 83% (50 mg/day) efficacy rate (serum sodium concentration increased by 5 mEq/L [mmol/L] or more or normalized) in SIADH patients treated during a double-blind, in-hospital period of up to 5 days compared with 13% of placebo-treated patients.9Soupart A. Gross P. Legros J.-J. et al.Successful long-term treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion with satavaptan (SR121463B), an orally active nonpeptide vasopressin V2-receptor antagonist.Clin J Am Soc Nephrol. 2006; 1: 1154-1160Crossref PubMed Scopus (119) Google Scholar Of the 26 satavaptan-treated patients, several exceeded the predetermined rates of correction, reaching increases of serum sodium concentration of 14 to 16 mEq/L (mmol/L) during the first 24 hours (3 patients) and 19 mEq/L (mmol/L) during the first 48 hours of the study (1 patient). Nine patients exceeded the more conservative rate of correction of 8 mEq/L (mmol/L) during the first 24 hours of treatment. Hypernatremia (serum sodium concentration of greater than 145 mEq/L [mmol/L]) developed in 2 patients during the double-blind period and in 5 patients during a subsequent, open-label, 23-day dosage-adjustment period, reaching values up to 161 mEq/L (mmol/L). In an open-label, long-term extension of this trial, 10 patients have maintained normal levels of serum sodium concentration (136-145 mEq/L [mmol/L]) for 12 months on adjustable doses of satavaptan (12.5-50 mg/day) and fluid restriction of l.5 liters or less, without major side effects.9Soupart A. Gross P. Legros J.-J. et al.Successful long-term treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion with satavaptan (SR121463B), an orally active nonpeptide vasopressin V2-receptor antagonist.Clin J Am Soc Nephrol. 2006; 1: 1154-1160Crossref PubMed Scopus (119) Google ScholarSeveral studies have documented increased electrolyte-free water clearance and decreased urinary osmolality, as expected from the aquaretic effect of vasopressin V2 receptor antagonism.5Astellas Pharma US, Inc: Vaprisol (conivaptan hydrochloride injection) product monograph. Deerfield, IL, 2006Google Scholar, 6Greenberg A. Verbalis J.G. Vasopressin receptor antagonists.Kidney Int. 2006; 69: 2124-2130Crossref PubMed Scopus (161) Google Scholar, 7Palm C. Pistrosch F. Herbrig K. Gross P. Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia.Am J Med. 2006; 119: S87-S92Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 8Gerbes A.L. Gülberg V. Ginès P. et al.Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: A randomized double-blind multicenter trial.Gastroenterology. 2003; 124: 933-939Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar, 9Soupart A. Gross P. Legros J.-J. et al.Successful long-term treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion with satavaptan (SR121463B), an orally active nonpeptide vasopressin V2-receptor antagonist.Clin J Am Soc Nephrol. 2006; 1: 1154-1160Crossref PubMed Scopus (119) Google Scholar In addition to the relatively frequent occurrence of increased thirst and dry mouth, orthostatic hypotension has been observed in some patients. Conivaptan, a mixed vasopressin V1α and V2 receptor antagonist, is currently approved by the US Food and Drug Administration for intravenous treatment of euvolemic or hypervolemic hyponatremia in hospitalized patients for up to 4 days. In a double-blind, placebo controlled, randomized trial in euvolemic patients maintained on a fluid restriction of 2 liters or less per day, 28.6% of placebo-treated patients and 66.7% of conivaptan-treated patients (20 mg loading dose and 40 mg/day as a continuous infusion over 4 days) achieved at least a 6 mEq/L (mmol/L) increase in serum sodium concentration or normalization of serum sodium concentration to at least 135 mEq/L (mmol/L) on day 4 of treatment.5Astellas Pharma US, Inc: Vaprisol (conivaptan hydrochloride injection) product monograph. Deerfield, IL, 2006Google Scholar Similar results have been reported with lixivaptan, another oral vasopressin V2 receptor antagonist under development, in short-term trials in patients with euvolemic or hypervolemic hyponatremia.6Greenberg A. Verbalis J.G. Vasopressin receptor antagonists.Kidney Int. 2006; 69: 2124-2130Crossref PubMed Scopus (161) Google Scholar, 7Palm C. Pistrosch F. Herbrig K. Gross P. Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia.Am J Med. 2006; 119: S87-S92Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 8Gerbes A.L. Gülberg V. Ginès P. et al.Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: A randomized double-blind multicenter trial.Gastroenterology. 2003; 124: 933-939Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar Yet another oral vasopressin V2 receptor antagonist under development, satavaptan, showed a 79% (25 mg/day) and 83% (50 mg/day) efficacy rate (serum sodium concentration increased by 5 mEq/L [mmol/L] or more or normalized) in SIADH patients treated during a double-blind, in-hospital period of up to 5 days compared with 13% of placebo-treated patients.9Soupart A. Gross P. Legros J.-J. et al.Successful long-term treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion with satavaptan (SR121463B), an orally active nonpeptide vasopressin V2-receptor antagonist.Clin J Am Soc Nephrol. 2006; 1: 1154-1160Crossref PubMed Scopus (119) Google Scholar Of the 26 satavaptan-treated patients, several exceeded the predetermined rates of correction, reaching increases of serum sodium concentration of 14 to 16 mEq/L (mmol/L) during the first 24 hours (3 patients) and 19 mEq/L (mmol/L) during the first 48 hours of the study (1 patient). Nine patients exceeded the more conservative rate of correction of 8 mEq/L (mmol/L) during the first 24 hours of treatment. Hypernatremia (serum sodium concentration of greater than 145 mEq/L [mmol/L]) developed in 2 patients during the double-blind period and in 5 patients during a subsequent, open-label, 23-day dosage-adjustment period, reaching values up to 161 mEq/L (mmol/L). In an open-label, long-term extension of this trial, 10 patients have maintained normal levels of serum sodium concentration (136-145 mEq/L [mmol/L]) for 12 months on adjustable doses of satavaptan (12.5-50 mg/day) and fluid restriction of l.5 liters or less, without major side effects.9Soupart A. Gross P. Legros J.-J. et al.Successful long-term treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion with satavaptan (SR121463B), an orally active nonpeptide vasopressin V2-receptor antagonist.Clin J Am Soc Nephrol. 2006; 1: 1154-1160Crossref PubMed Scopus (119) Google Scholar Several studies have documented increased electrolyte-free water clearance and decreased urinary osmolality, as expected from the aquaretic effect of vasopressin V2 receptor antagonism.5Astellas Pharma US, Inc: Vaprisol (conivaptan hydrochloride injection) product monograph. Deerfield, IL, 2006Google Scholar, 6Greenberg A. Verbalis J.G. Vasopressin receptor antagonists.Kidney Int. 2006; 69: 2124-2130Crossref PubMed Scopus (161) Google Scholar, 7Palm C. Pistrosch F. Herbrig K. Gross P. Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia.Am J Med. 2006; 119: S87-S92Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 8Gerbes A.L. Gülberg V. Ginès P. et al.Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: A randomized double-blind multicenter trial.Gastroenterology. 2003; 124: 933-939Abstract Full Text Full Text PDF PubMed Scopus (271) Google Scholar, 9Soupart A. Gross P. Legros J.-J. et al.Successful long-term treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion with satavaptan (SR121463B), an orally active nonpeptide vasopressin V2-receptor antagonist.Clin J Am Soc Nephrol. 2006; 1: 1154-1160Crossref PubMed Scopus (119) Google Scholar In addition to the relatively frequent occurrence of increased thirst and dry mouth, orthostatic hypotension has been observed in some patients. What Should Clinicians and Researchers Do?Encouraging results to date suggest that aquaresis via nonpeptide vasopressin V2 receptor antagonists will emerge as the mainstay of treatment of euvolemic and hypervolemic hyponatremia. Conivaptan, the currently available mixed vasopressin V1α and V2 receptor antagonist, is an effective and well tolerated agent for the short-term management of moderately symptomatic or asymptomatic hyponatremia in hospitalized patients. Because of its effect on the vasopressin V1α receptor (which mediates vasoconstriction), special caution should be exercised in treating patients with low normal blood pressure, especially those with congestive heart failure or cirrhosis. Administration through large veins and change of the infusion site every 24 hours are recommended to minimize the risk of vascular irritation. When oral vasopressin V2 receptor antagonists become clinically available, practitioners would also be able to utilize aquaresis for the long-term management of hyponatremia and its consequences. Symptomatic relief from fluid overload would also be realized by hypervolemic patients (eg, decrease in dyspnea, edema, and tense ascites).6Greenberg A. Verbalis J.G. Vasopressin receptor antagonists.Kidney Int. 2006; 69: 2124-2130Crossref PubMed Scopus (161) Google Scholar, 7Palm C. Pistrosch F. Herbrig K. Gross P. Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia.Am J Med. 2006; 119: S87-S92Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 10Gheorghiade M. Konstam M.A. Burnett Jr, J.C. et al.Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: The EVEREST clinical status trials.JAMA. 2007; 297: 1332-1343Crossref PubMed Scopus (694) Google Scholar Vasopressin V2 receptor antagonists augment vasopressin levels and stimulate thirst. Therefore, their use would not eliminate the need for fluid restriction but rather lessen substantially its stringency.Additional investigative work is required in several areas. The efficacy (on hyponatremia and other clinical outcomes) and safety of vasopressin V2 receptor antagonists must be defined separately for SIADH, congestive heart failure, and cirrhosis. The potential consequences of the chronic activation of the unblocked vasopressin V1α receptor on the blood vessels (pressor effect) and the heart (mitogenic effect), especially in view of the variably heightened levels of arginine vasopressin resulting from vasopressin V2 receptor antagonism, require careful study. We need to understand better why hyponatremia fails to respond to these agents in a substantial minority of patients. Most of these cases likely reflect increased water intake in response to intense thirst. Nonetheless, hemodynamically induced decreased delivery of filtrate to the distal nephron, gain-of-function mutations in the vasopressin V2 receptor or other components of vasopressin’s intracellular signaling cascade including the aquaporin-2 water channel (nephrogenic syndrome of inappropriate antidiuresis),11Feldman B.J. Rosenthal S.M. Vargas G.A. et al.Nephrogenic syndrome of inappropriate antidiuresis.N Engl J Med. 2005; 352: 1884-1890Crossref PubMed Scopus (266) Google Scholar, 12Decaux G. Vandergheynst F. Bouko Y. Parma J. Vassart G. Vilain C. Nephrogenic syndrome of inappropriate antidiuresis in adults: High phenotypic variability in men and women from a large pedigree.J Am Soc Nephrol. 2007; 18: 606-612Crossref PubMed Scopus (111) Google Scholar or other antidiuretic principles might be at play. The range of correction rates of serum sodium concentration achieved by these agents requires careful definition given that a minority of patients has experienced faster-than-desirable rates and even frank hypernatremia. Although no clinical case of osmotic demyelination has been reported to date, there are firm reasons to expect that this dreaded complication is a potential adverse effect of these agents.3Adrogué H.J. Madias N.E. Hyponatremia.N Engl J Med. 2000; 342: 1581-1589Crossref PubMed Scopus (1323) Google Scholar, 13Soupart A. Silver S. Schroeder B. Sterns R. Decaux G. Comparison of mortality and brain composition in hyponatremic rats treated with vasopressin V1-V2 receptor antagonists or water diuresis.J Am Soc Nephol. 2003; 14 (abstr): A747Google Scholar Close monitoring of serum sodium concentration would be required in all patients during the early stages of treatment, and less intensive but regular oversight in the long term. Patients who cannot respond reliably to thirst (eg, frail or mentally compromised patients) would require particularly close follow up. All patients should also monitor their body weight closely. Defining the potential role of vasopressin V2 receptor antagonists in managing severely symptomatic hyponatremia and better understanding of their utility when co-administered with diuretics are additional areas of research. Because all current aquaretics are both substrates and inhibitors of the cytochrome P450 3A4 (family 3, subfamily A, polypeptide 4) system, the impact on efficacy and safety of their interaction with other drugs involved in this pathway needs careful definition. Encouraging results to date suggest that aquaresis via nonpeptide vasopressin V2 receptor antagonists will emerge as the mainstay of treatment of euvolemic and hypervolemic hyponatremia. Conivaptan, the currently available mixed vasopressin V1α and V2 receptor antagonist, is an effective and well tolerated agent for the short-term management of moderately symptomatic or asymptomatic hyponatremia in hospitalized patients. Because of its effect on the vasopressin V1α receptor (which mediates vasoconstriction), special caution should be exercised in treating patients with low normal blood pressure, especially those with congestive heart failure or cirrhosis. Administration through large veins and change of the infusion site every 24 hours are recommended to minimize the risk of vascular irritation. When oral vasopressin V2 receptor antagonists become clinically available, practitioners would also be able to utilize aquaresis for the long-term management of hyponatremia and its consequences. Symptomatic relief from fluid overload would also be realized by hypervolemic patients (eg, decrease in dyspnea, edema, and tense ascites).6Greenberg A. Verbalis J.G. Vasopressin receptor antagonists.Kidney Int. 2006; 69: 2124-2130Crossref PubMed Scopus (161) Google Scholar, 7Palm C. Pistrosch F. Herbrig K. Gross P. Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia.Am J Med. 2006; 119: S87-S92Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 10Gheorghiade M. Konstam M.A. Burnett Jr, J.C. et al.Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: The EVEREST clinical status trials.JAMA. 2007; 297: 1332-1343Crossref PubMed Scopus (694) Google Scholar Vasopressin V2 receptor antagonists augment vasopressin levels and stimulate thirst. Therefore, their use would not eliminate the need for fluid restriction but rather lessen substantially its stringency. Additional investigative work is required in several areas. The efficacy (on hyponatremia and other clinical outcomes) and safety of vasopressin V2 receptor antagonists must be defined separately for SIADH, congestive heart failure, and cirrhosis. The potential consequences of the chronic activation of the unblocked vasopressin V1α receptor on the blood vessels (pressor effect) and the heart (mitogenic effect), especially in view of the variably heightened levels of arginine vasopressin resulting from vasopressin V2 receptor antagonism, require careful study. We need to understand better why hyponatremia fails to respond to these agents in a substantial minority of patients. Most of these cases likely reflect increased water intake in response to intense thirst. Nonetheless, hemodynamically induced decreased delivery of filtrate to the distal nephron, gain-of-function mutations in the vasopressin V2 receptor or other components of vasopressin’s intracellular signaling cascade including the aquaporin-2 water channel (nephrogenic syndrome of inappropriate antidiuresis),11Feldman B.J. Rosenthal S.M. Vargas G.A. et al.Nephrogenic syndrome of inappropriate antidiuresis.N Engl J Med. 2005; 352: 1884-1890Crossref PubMed Scopus (266) Google Scholar, 12Decaux G. Vandergheynst F. Bouko Y. Parma J. Vassart G. Vilain C. Nephrogenic syndrome of inappropriate antidiuresis in adults: High phenotypic variability in men and women from a large pedigree.J Am Soc Nephrol. 2007; 18: 606-612Crossref PubMed Scopus (111) Google Scholar or other antidiuretic principles might be at play. The range of correction rates of serum sodium concentration achieved by these agents requires careful definition given that a minority of patients has experienced faster-than-desirable rates and even frank hypernatremia. Although no clinical case of osmotic demyelination has been reported to date, there are firm reasons to expect that this dreaded complication is a potential adverse effect of these agents.3Adrogué H.J. Madias N.E. Hyponatremia.N Engl J Med. 2000; 342: 1581-1589Crossref PubMed Scopus (1323) Google Scholar, 13Soupart A. Silver S. Schroeder B. Sterns R. Decaux G. Comparison of mortality and brain composition in hyponatremic rats treated with vasopressin V1-V2 receptor antagonists or water diuresis.J Am Soc Nephol. 2003; 14 (abstr): A747Google Scholar Close monitoring of serum sodium concentration would be required in all patients during the early stages of treatment, and less intensive but regular oversight in the long term. Patients who cannot respond reliably to thirst (eg, frail or mentally compromised patients) would require particularly close follow up. All patients should also monitor their body weight closely. Defining the potential role of vasopressin V2 receptor antagonists in managing severely symptomatic hyponatremia and better understanding of their utility when co-administered with diuretics are additional areas of research. Because all current aquaretics are both substrates and inhibitors of the cytochrome P450 3A4 (family 3, subfamily A, polypeptide 4) system, the impact on efficacy and safety of their interaction with other drugs involved in this pathway needs careful definition. Support: None. Financial Disclosure: Dr Madias has served as a consultant to and has received lecture fees from Astellas Pharma US, Inc (manufacturer of VAPRISOL [conivaptan hydrochloride injection]) and has served as a consultant to Sanofi-Aventis (manufacturer of satavaptan).