View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Elsevier - Publisher Connector review http://www.kidney-international.org & 2011 International Society of Nephrology

Vaptans are not the mainstay of treatment in hyponatremia: perhaps not yet Peter A. Gross1, Andrea Wagner1 and Guy Decaux2

1Division of Nephrology, Department of Medicine III, Universita¨tsklinikum C. G. Carus, Dresden, Germany and 2Department of General Internal Medicine, Hoˆpital Erasme, Universite´ Libre de Bruxelles, Bruxelles, Belgium

Two antagonists (‘vaptans’) are now in the Imagine for a moment that you were with a car dealer, market for the treatment of euvolemic (Europe) or euvolemic looking for a replacement of your ramshackle old model. The and hypervolemic (United States) hyponatremia: dealer offers a great new—somewhat expensive—solar-driven for intravenous use and for oral application. replacement. When you ask how (in which gear) to drive it, Although their specificity and effectiveness are considered where (on which type of road) to run it, and how much cost established, their indications are not. At present, we do not you might incur from using that car, he would be vague, know which symptoms of hyponatremia and which degree of unable to answer your questions precisely. Would you hyponatremia should serve as indications for vaptans. Other consider that car? We would be very hesitant. We would areas of uncertainty relate to the following unanswered probably tell the dealer to come back later when he would be questions: do vaptans shorten the duration of certain of the answers. This we think is the situation of the hospitalization? Is it justifiable to use them to prevent relapse vaptans at present, as pointed out by others before.1 of hyponatremia in (chronic) SIAD(H)? (In this text we use the Hyponatremia has been known for some time as the most abbreviation SIAD(H) instead of the recently proposed frequent electrolyte disorder encountered.2,3 It is seen abbreviation SIAD to emphasize that vaptans will work only primarily in hospitals, but it occurs in outpatients as well.3,4 in the presence of ADH (‘SIADH’) but not in the syndrome of Hyponatremia may cause symptoms and sometimes they are nephrogenic antidiuresis.) Do they decrease the high as severe as coma and grand mal seizures.5 It has been shown mortality associated with hyponatremia? How do we justify many times that hyponatremia is associated with increased the cost of chronic vaptan therapy? The optimal vaptan mortality.6–11 However, the therapy has been lagging behind. regimen (dose, timing of controls) to treat SIAD(H) is Indirect measures such as (1) fluid restriction, (2) currently not established, as is the procedure to be carbonate, (3) hydrochloride, (4) urea, (5) recommended in a too rapid correction rate of (chronic) 3% saline, (6) loop in SIAD (syndrome of hyponatremia. Until these requirements shall be met by inappropriate antidiuresis) and (7) CVVH (continuous additional studies, we are hesitant to consider vaptans a venovenous hemofiltration), or (8) SLED (sustained low- treatment of choice for the appropriate hyponatremias. efficiency dialysis) in select circumstances have all been Kidney International (2011) 80, 594–600; doi:10.1038/ki.2011.78; utilized for years. They have major drawbacks. Fluid published online 30 March 2011 restriction (1) is often of limited effectiveness, although KEYWORDS: conivaptan; hyponatremia; tolvaptan physicians may not always try hard enough to implement it or to convince the patient of its usefulness. Fluid restriction in principle is promising in patients with a urinary osmolality of o400–500mOsm/kg, indicating that these patients probably have a fluid intake in excess of 1.5 l/day. The other measures are often unreliable and/or potentially toxic (3 and 4), not suitable for chronic outpatient therapy (5), too cumbersome (6), or too invasive and expensive (7 and 8) for everyday treatment of hyponatremia. Clearly then, there is an unmet need for a specific, direct, easy, titratable therapy of hyponatremia—something comparable with for edematous disorders. Hence, it was considered a break- 12 Correspondence: Peter A. Gross, Medicine and Nephrology, Medizinische through when vaptans, effective oral (tolvaptan )or 13 Klinik III, Universita¨tsklinikum C.G. Carus, Fetscherstrasse 74, D-01307 parenteral (conivaptan ) antagonists of the hydroosmotic Dresden, Germany. E-mail: [email protected] effects of vasopressin in the kidney, met with regulatory Received 29 August 2010; revised 21 December 2010; accepted 5 approval recently. Vaptans are now available in the drug January 2011; published online 30 March 2011 market. In phase II and III trials, vaptans have been shown to

594 Kidney International (2011) 80, 594–600 PA Gross et al.: Vaptans and the treatment of hyponatremia review

correct hyponatremia of euvolemic and hypervolemic states same vein, the natural history of patients with severe effectively.12,14 Although this applies to scientific trials, the asymptomatic hyponatremia (arbitrarily defined here as question is of whether vaptans are really clinical therapeutic a serum sodium o120 mmol/l) has not been studied breakthroughs as well. either. We do not know their quality of life, their medical In the following we shall discuss the role of vaptan complications, or their readmission rate to hospital treatment in chronic but not acute hyponatremia because the because of worsened hyponatremia. Together, we lack latter is rarely addressed in published literature. We shall information on which degree of severity of hyponatremia consider the hyponatremias of SIAD(H), cardiac failure, and should give us reason to consider vaptan treatment. liver cirrhosis together—although vaptan treatment differs somewhat between them—because reported vaptan trials did Third, work by Gankam Kengne et al.28 suggested that not analyze these entities separately. However, we included a patients with mild chronic hyponatremia fall to the ground table with an overview of the major vaptan trials to facilitate more often than matched normonatremic controls (see also finding more information pertaining to different indications Figure 1). (In the present communication we arbitrarily for the reader (Table 1). define mild hyponatremia as a serum sodium between 128 and 134 mmol/l.) They appeared to fracture a bone THE INDICATIONS FOR VAPTANS ARE NOT CLEAR approximately four times more often than their normona- In medical school, doctors are trained to treat patients—not tremic counterparts. This was retrospective work.28 We do lab results on paper. Treatments are usually reserved for not know if comparable results would hold up in a symptomatic patients. In this field, vaptans let the physician prospective randomized controlled trial. We are unable to encounter a bunch of stumbling blocks: answer the question of whether elderly patients with chronic First, we do not know how to distinguish between mild hyponatremia should be treated, for example, by a symptoms that are an indication for vaptan and those that vaptan to correct hyponatremia and prevent fractures. are not. Given the high cost of vaptan therapy consider this: Fourth, in terms of indication for vaptan, the area least would headache—when associated with hyponatremia—be controversial might appear to be that of severe symptomatic an indication for vaptan? Or what about the likes of (chronic) hyponatremia. A ‘hyponatremia-naive’ physician is weakness, apathy, depressed mood, change of taste, or likely to conclude that vaptans if anything should be reduced fine motor movements? There are no published promising in severe symptomatic hyponatremia. However, studies that evaluate the gain in quality of life from treating there are literally no published data on this. Clinical trials of such symptoms by vaptan vs their cost. In other words, we do vaptans12,14,16,29 have consistently excluded severe sympto- not know which symptoms are indications for vaptan matic hyponatremia from study because of ethical concerns treatment. (risk of worsening of severe symptoms when receiving Second, a given degree of chronic hyponatremia does not placebo). A recent expert panel suggested that in severe necessarily cause comparable symptoms in different patients. symptomatic (chronic) hyponatremia, infusions of hyper- We (PAG) have recorded a patient with chronic hypoosmolar tonic saline should have priority over vaptan.30 This is an hyponatremia of 109 mmol/l and no discernable symptoms at area of significant uncertainty. It has been pointed out that the bedside, whereas others with chronic hypoosmolar 3% NaCl may correct hyponatremia too quickly,31 or it may hyponatremia of ‘only’ 118 mmol/l were confined to bed, occasionally lead to pulmonary edema in SIAD(H). On the unsteady, confused, and unable to concentrate. This brings other hand, we have personal experience (PAG) that SIAD(H)- up two unanswerable questions: related severe symptomatic hyponatremia is a rewarding indication for vaptan. Thus, in the absence of a trial comparing (1) should we treat the patients at 118 mmol/l, but not the one fluid restriction plus 3% saline with vaptans in severe at 109 mmol/l, because of the clinical symptomatology? symptomatic hyponatremia, we do not have a database to (2) or, conversely, should we treat almost all hyponatremic make specific recommendations for or against vaptans. patients who are under 130 mmol/l, even if they appear Taken together, there is considerable uncertainty at to be clinically asymptomatic? Renneboog et al.27 were present as to which symptoms, which setting, and what able to demonstrate neurocognitive defects literally in all degree of severity of a hyponatremia should be considered of them.26,27 These authors26 subjected 16 patients with indications for vaptan treatment. mild chronic hyponatremia of 128±3 mmol/l related to SIAD(H) to formal testing before and after correction of IT IS NOT PROVEN THAT VAPTANS SAVE MONEY the hyponatremia. It was found that this mild hypona- In a study of chronic heart failure termed EVEREST,11 tremia reduced the tested abilities as follows: attention patients receiving tolvaptan were able to leave the hospital (10% reduced), unsteadiness of gait (20% increased; B2 days earlier than control patients. It was concluded that Figure 1), and total error rate (20% increased). Yet, the tolvaptan could shorten hospitalization and save money. Was findings of Renneboog et al.27 have not been translated this because of better treatment of hyponatremia? Not into a prospective study with clinical end points. We do automatically, because EVEREST was a study of mostly not know the meaning of the findings in real life. In the normonatremic heart failure and not one primarily of

Kidney International (2011) 80, 594–600 595 review PA Gross et al.: Vaptans and the treatment of hyponatremia

Table 1 | Overview of major reported studies of the use of vaptans in different hyponatremic states Number and kind of patients included; duration Study Study; reference End point of study design Main results

(1) A Efficacy and safety of n=44, with RCT appeared effective and safe in antagonist improves serum lixivaptan in euvolemic and hyponatremia; correcting hyponatremia. High doses risked sodium concentration in hypervolemic hyponatremia 7 days producing significant dehydration. patients with hyponatremia15

(2) Therapy of hyponatremia Efficacy of lixivaptan in n=60, with RCT Lixivaptan was effective in improving the in cirrhosis with lixivaptan16 hyponatremia of cirrhosis hyponatremia; hyponatremia of cirrhosis. 7 days

(3) Vasopressin blockade Short-term effects of n=254, with normo- RCT Tolvaptan decreased the body weight by with tolvaptan in chronic tolvaptan in chronic and hyponatremia; 0.84 kg and improved hyponatremia. heart failure17 heart failure 25 days

(4) Tolvaptan in patients Short-term and n=310, with normo- RCT At 24 h, body weight decreased by 1.4 kg versus hospitalized with worsening intermediate effects and hyponatremia; placebo. At 60 days, no difference in worsening heart failure18 of tolvaptan 60 days heart failure.

(5) Aquaretic effect of Short-term renal effects n=42, with normo- RCT Lixivaptan, 400 mg, increased aquaresis by lixivaptan in chronic of lixivaptan and hyponatremia; 2.1 l and raised the serum sodium significantly. heart failure19 24 h

(6) Conivaptan, a V1A/V2 Efficacy and safety n=74, with RCT Conivaptan increased serum sodium in a antagonist in euvolemic and of (oral) conivaptan hyponatremia; dose-dependant manner. Headache, hypertension, hypervolemic hyponatremia14 5 days nausea, and constipation were noted as side effects.

(7) Long-term treatment Efficacy and safety n=18, with Open-label The improvement of the serum sodium was of hyponatremia in SIADH of satavaptan hyponatremia; observation maintained over the duration of 12 months with satavaptan20 12 months or longer and was safe.

(8) Tolvaptan for Improvement of n=448, with RCT Tolvaptan was effective in increasing the serum hyponatremia12 hyponatremia with hyponatremia; sodium at days 4 and 30. tolvaptan 30 days

(9) EVEREST clinical Short-term effects of n=4133, with normo- RCT Greater improvement of congestion with tolvaptan status trials21 tolvaptan on congestion and hyponatremia; than with placebo. More weight loss on day 7 with of heart failure 7 days tolvaptan (À3.3 kg) than with placebo (À2.7 kg). (10) Intravenous conivaptan Efficacy and tolerability n=84, with RCT Four days of i.v. conivaptan significantly increased in euvolemic and of i.v. conivaptan hyponatremia; serum sodium. Adverse events were injection site hypervolemic hyponatremia22 4 days phlebitis and postural hypotension. (11) EVEREST outcome trial11 All-cause mortality in n=4133, with normo- RCT Mortality in treated and untreated patients cardiac failure receiving and hyponatremia; was comparable. tolvaptan 9.8 months

(12) Effects of satavaptan Effects on ascites and n=110, with RCT Satavaptan improved hyponatremia and the control on ascites and serum hyponatremia in cirrhosis hyponatremia; of ascites. sodium in cirrhosis with 14 days hyponatremia23

(13) Oral conivaptan in Efficacy and safety of oral n=83, with RCT Oral conivaptan was effective and increased euvolemic and hypervolemic conivaptan in hyponatremia hyponatremia; serum sodium in patients with euvolemic or hyponatremia24 5 days hypervolemic hyponatremia.

(14) Intravenous conivaptan Clinical experience using n=18, with Retrospective Lower serum sodium at baseline and higher for the treatment i.v. conivaptan hyponatremia; analysis eGFR were correlated with larger response of hyponatremia13 72 h to conivaptan.

(15) SALTWATER25 Safety and efficacy of n=111, with Open-label Normonatremia was maintained throughout. tolvaptan during long-term hyponatremia; observation Only 1 patient developed hypernatremia. treatment 1.5 years Abbreviations: eGFR, estimated glomerular filtration rate; i.v., intravenous; RCT, randomized controlled trial. hyponatremia. Another publication used computer modeling would be a major achievement if these amounts of money to calculate the annual cost of hyponatremia to the US could be saved. However, we lack a study with vaptans health-care system.32 The study came up with an amount of proving that they actually would. Skepticism also applies to 1.6 to 3.6 billion US dollars.32 These are staggering figures. It the following work: a retrospective analysis by Shea et al.33

596 Kidney International (2011) 80, 594–600 PA Gross et al.: Vaptans and the treatment of hyponatremia review

[Na+]=130 mEq/I [Na+]=139mEq/I

80 80

40 40

0 0 –500 –400 –300 –200 –100 0 –100 –200 –500 –400 –300 –200 –100 0 –100 200 300 –40 –40

–80 –80

–120 –120

[Na+]=126 mEq/I [Na+]=136 mEq/I 80 80

40 40

0 0 –400 –300 –200 –100 0 100 200 –400 –300 –200 –100 0 100 200

–40 –40

–80 –80

–120 –120

[Na+]=124 mEq/I [Na+]=135 mEq/I 140 100 120 80 100 60 80 40 60 40 20 20 0 – 400 – 300 – 200 – 100 0 100 200 0 –20 – 500 – 400 – 300 – 200 – 100 0 – 100 – 200 –40 –40 –60 –80 –80 – 100 – 120 – 120 Figure 1 | Instability of gait by three patients in hyponatremia (left three panels) and improvement of gait in the same patients after correction of hyponatremia (right three panels). In each example, the patient was asked to walk from left to right (reprinted from reference Renneboog et al.27; with permission from Elsevier). indicated that the use of resources by patients with there is an increased sensitivity to vaptan in that setting.) hyponatremia was B100% higher than that by matched Such costs are in excess of those for a month of chronic patients with normonatremia. This is impressive. But is it hemodialysis for instance. Conivaptan therapy is even costlier guaranteed that normalization of natremia with vaptan will than tolvaptan in Europe. There is no published prospective take the excessive expense away? We will not know unless the evidence demonstrating how such costs can be justified question is tested prospectively in a study. Yet another issue in terms of benefit to the patient and to the health-care related to cost has to do with discontinuation of vaptan system. It is not known what kind of symptoms a therapy. Unless the underlying condition has been corrected, hyponatremic patient would have to exhibit to justify such hyponatremia is likely to return. This could cause recurrent treatment costs. morbidity and expense, making the use of vaptan proble- In fact, considering that the majority of hyponatremic matic. Together, do vaptans save money when used to treat patients will have mild hyponatremia and will be clinically hyponatremia? There are suggestive, although retrospective, oligosymptomatic or asymptomatic, would it not make more data; we are lacking prospective work. sense to test alternative therapies for chronic hyponatremia in them like urea? Urea has been used for a long time as an IT IS DIFFICULT TO JUSTIFY THE COST OF LONG-TERM agent that induces an osmotic diuresis—when given in VAPTAN TREATMENT sufficient quantities. It may be used orally, by nasogastric Otsuka (Otsuka Pharmaceutical, Osaka, Japan) recommends tube, or intravenously. It has been shown that urea is able to a standard regimen for hyponatremia of 15 or 30 mg of correct hyponatremia in SIAD(H), even when patients were tolvaptan once daily p.o. In Germany, a tablet (15 or 30 mg in intensive care for hyponatremia.34,35 The major advantage alike) is presently sold for 103h, roughly equivalent to US of urea is its very low cost. A potential disadvantage may be $130. In the United States, a tablet reportedly costs its taste. However, if pharmacological grade urea is used approximately US $244. In other words, a month of vaptan in quantities of 15–30g/day or more, it may be dissolved in treatment—if that was ever to be given to a patient—could orange juice, which will make the taste palatable. A study cost as much as 3150h in Europe or US $7200 in the United comparing urea treatment with vaptan therapy, done in States (These high amounts may primarily apply to patients with mild hyponatremia, is probably indicated to hypervolemic hyponatremia. In euvolemic hyponatremia, compare the efficacy, the quality-of-life aspects, and the cost treatment costs for vaptans are likely to be lower because of both treatments in that specific setting.

Kidney International (2011) 80, 594–600 597 review PA Gross et al.: Vaptans and the treatment of hyponatremia

IT HAS NOT BEEN SHOWN THAT VAPTANS SAVE LIVES stay (8.6 vs 7.2 days) were significantly increased in those This is an important but controversial issue. The association with admission hyponatremia when compared with normo- of hyponatremia with increased mortality is well documented natremic patients. in the literature,6–10,36 but its meaning is disputed. Some An even more detailed study was reported recently.39 interpret this literature to suggest that hyponatremia actually It represents a prospective cohort study of 98 411 hospital causes increased mortality. Hence, a few years ago, a finding admissions of two teaching hospitals in Boston, MA, between from a trial termed ACTIVE in CHF37 met with interest. In a 2000 and 2003. Patients with hyponatremia were older post hoc analysis of a subgroup of 69 study participants with (67 vs 63.1 years) and had more comorbid conditions hyponatremia (total number of participants: 319, normo- than normonatremic patients (index: 1.9 vs 1.4). Patients and hypo-natremic, tolvaptan vs placebo), ACTIVE found with hyponatremia had an increased risk of death in the mortality to be significantly lower in those in whom hospital (odds ratio 1.47), at 1 year after discharge (hazard hyponatremia improved (usually receiving tolvaptan) when ratio 1.38), and at 5 years (hazard ratio 1.25). The relation- compared with the remainder 69 in whom hyponatremia ship between hyponatremia and mortality was pronounced remained unchanged (usually receiving placebo). The reduc- in patients with cardiovascular disease, metastatic cancer, tion of mortality amounted to B50%. This was a post hoc and musculoskeletal disorders. Resolution of hyponatremia analysis of a subgroup from a larger trial, and hence there was during hospitalization attenuated the increased mortality risk a possibility that the results could have been fortuitous. conferred by hyponatremia. Subsequently, a randomized controlled trial termed EVER- These are intriguing studies. Do they clarify whether EST11 was set up to probe the question of tolvaptan with patients die from hyponatremia or with hyponatremia? In respect to mortality more rigorously. EVEREST gave our opinion this question cannot be answered at the present tolvaptan (30 mg q.d. p.o.) versus placebo for up to 24 time. Prospective interventional work will eventually have to months in 4133 patients with cardiac failure. The primary resolve this issue. end point was mortality. However, the resulting mortality curves for tolvaptan- and placebo-treated patients were not QUESTIONS ABOUT THE SAFETY OF VAPTAN TREATMENTS different from each other (Figure 2). In a recent publication of work reporting the use of Another report addressed the role of hyponatremia on conivaptan in everyday medicine, B50% of treatments admission for the hospital course and outcome.38 Data were corrected hyponatremia too fast. Treatment regimens had obtained in a retrospective manner from a large adminis- to be interrupted, halted, or even reversed to prevent adverse trative database representing 198,281 discharges from 39 US outcomes.13 One out of 18 treated patients experienced hospitals in 2004 and 2005. Patients with hyponatremia were transient symptomatic hypotension and required a bolus of older (65.7 vs 61.5 years) and had a higher comorbidity score 250 ml of normal saline. Two out of four patients receiving (1.8±2.1 vs 1.3±1.8) than their normonatremic counter- conivaptan through a peripheral venous line had injection parts. A higher proportion of hyponatremic patients required site reactions, whereas 14 patients receiving conivaptan intensive care within the first 48 h of hospitalization (17.3 vs through central venous catheters had no such reactions. 10.9%). Hospital mortality (5.9 vs 3%) and mean length of Two patients met the criteria for a significant rise in serum creatinine although their peak serum creatinine remained 1.0 All-cause mortality o1.0 mg/dl. One patient fulfilled the criteria for azotemia 13 0.9 and his blood urea nitrogen level rose from 22 to 40 mg/dl. 0.8 Although these observations may be consequences of the 0.7 efficiency of conivaptan, they do illustrate that caution is 0.6 warranted in using this agent. 0.5 In terms of tolvaptan, the manufacturer recommends 0.4 beginning treatment with 15 or 30 mg q.d. Our own (PAG) 0.3 preliminary experience in SIAD(H) is that 7.5 mg q.d. may

Proportion surviving suffice. It is unclear at which time points after the start of a 0.2 Log-rank test: P=0.76 0.1 Peto-Peto-Wilcoxon test: P=0.68 vaptan therapy, controls of the serum sodium should be done Stratified Peto-Peto-Wilcoxon test: P=0.68 to provide for safety of the correction rate. Last, there is no 03691215 18 21 24 published experience on how to proceed when ‘back- Months in study titration’ of natremia becomes necessary. No. at Risk Tolvaptan 2072 1812 1446 1112 859 589 404 239 97 Taken together, optimal dosing, monitoring, and adequate Placebo 2061 1781 1440 1109 840 580 400 233 95 precautions in the use of vaptans should be better defined. Figure 2 | Kaplan–Meier analysis of all-cause-mortality in the EVEREST study. There was no difference in mortality between VAPTANS AS A PROPHYLAXIS AGAINST RELAPSE INTO tolvaptan- and placebo-treated participants (reproduced from 11 HYPONATREMIA: IN WHICH PATIENTS WILL IT PAY? reference Konstam et al. ; with permission from American 25 Medical Association; Copyright 2007 American Medical A study termed SALTWATER has recently reported safe and Association. All rights reserved). successful long-term tolvaptan treatment in 111 patients with

598 Kidney International (2011) 80, 594–600 PA Gross et al.: Vaptans and the treatment of hyponatremia review

euvolemic and hypervolemic hyponatremia over B2 years. ACKNOWLEDGMENTS We are indebted to Richard Sterns, MD, who contributed by reading Hypernatremia leading to discontinuation was noted in a the manuscript and making helpful suggestions. single patient only. SALTWATER probably proved the principle, but will it work in everyday medicine as well and REFERENCES will it be as safe as under scientific observation? In addition, 1. Lehrich RW, Greenberg A. When is it appropriate to use vasopressin what frequency of naturally occurring relapses into hypona- receptor antagonist? J Am Soc Nephrol 2008; 19: 1054–1058. 2. Hoorn EJ, Lindemans J, Zietse R. Development of severe hyponatremia tremia that lead to hospital admission would be required to in hospitalized patients: treatment-related risk factors and inadequate justify chronic vaptan treatment in such patients? What kind management. Nephrol Dial Transplant 2006; 21: 70–76. of chronic symptoms, significantly lowering the quality of life 3. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia. Am J Med 2006; 119: S30–S35. should a hyponatremic patient exhibit for the same reasons? 4. Miller M, Morley JE, Rubenstein LZ. Hyponatremia in a nursing home Clearly, more data are necessary about this possible population. JAGS 1995; 43: 1410–1413. 5. Arieff AI. Hyponatremia, convulsions, respiratory arrest and permanent indication before it can be generally recommended. brain damage after elective surgery in healthy women. N Engl J Med 1986; 314: 1529–1535. ARE WE CRITICIZING VAPTANS UNFAIRLY? 6. Goldberg A, Hammerman H, Petcherski S et al. Prognostic importance of hyponatremia in acute ST-elevation myocardial infarction. Am J Med It could be said that our proposals are asymmetrical and 2004; 117: 242–248. biased, as we do not postulate comparable trials to be done 7. Heuman DM, Abou-assi SG, Habib A et al. Persistent ascites and for the other measures to treat hyponatremia, such as fluid low serum sodium identify patients with cirrhosis and low MELD scores who are at high risk for early death. Hepatology 2004; 40: restriction or lithium treatment, for instance. We would 802–810. disagree. Besides being of some vintage, these much older 8. Klein L, O’ Connor CM, Leimberger JD et al. Lower serum sodium is approaches do not qualify for being directed, highly potent, associated with increased short-term mortality in hospitalized patients with worsening heart failure: results from the outcomes of a prospective specifically designed, and pathophysiologically focused novel trial of intravenous milrinone for exacerbations of chronic heart failure treatments of hyponatremia. But vaptans do. Hence, the (OPTIME-CHF) Study. Circulation 2005; 111: 2454–2460. usual present standard of scrutiny applies more to vaptans 9. Elsayem A, Mori M, Parsons HA et al. Predictors of inpatient mortality in an acute palliative care unit at a comprehensive cancer center. Support than to the other methods. Care Cancer 2009; 18: 67–76. 10. Asadollahi K, Beeching N, Gill G. Hyponatremia as a risk factor for hospital CONCLUDING COMMENTS mortality. QJMed2006; 99: 877–880. 11. Konstam MA, Gheorghiade M, Burnett Jr JA et al. Effects of oral tolvaptan Based on the foregoing we believe that research into the in patients hospitalized for worsening heart failure: the EVEREST outcome appropriate indications for vaptans is urgently needed. There trial. JAMA 2007; 297: 1319–1331. 12. Schrier RW, Gross P, Gheorghiade M et al. Tolvaptan, a selective oral is significant uncertainty at this time concerning when, how, vasopressin V2-receptor antagonist, for hyponatremia. N Engl J Med 2006; and for how long to use vaptans. These issues may be 355: 2099–2112. resolvable in future randomized controlled trials. At the 13. Velez JCQ, Dopson SJ, Sanders DS et al. Intravenous conivaptan for the treatment of hyponatremia caused by the syndrome of inappropriate present time, for the reasons presented here, vaptans cannot secretion of antidiuretic hormone in hospitalized patients: a single-centre (yet?) constitute the mainstay of therapy in hyponatremia. experience. Nephrol Dial Transplant 2010; 25: 1524–1531. Having said this, we would like to add that we (PAG) use 14. Ghali JK, Koren MJ, Taylor JR et al. Efficacy and safety of oral conivaptan: a V1a/V2 vasopressin receptor antagonist, assessed in a randomized, vaptans in the permitted settings. We find them to be of placebo-controlled trial in patients with euvolemic or hypervolemic advantage to physicians and patients alike—if great caution is hyponatremia. J Clin Endocrinol Metab 2006; 91: 2145–2152. 15. Wong F, Blei AT, Blendis LM et al. A vasopressin receptor antagonist applied in terms of frequent controls and dosing and if (VPA-985) improves serum sodium concentration in patients with demonstrable symptoms are present. hyponatremia: a multicenter, randomized, placebo-controlled trial. To return to the car dealer business, the metaphor that we Hepatology 2003; 37: 182–191. 16. Gerbes AL, Gu¨lberg V, Gines P et al. Therapy of hyponatremia in cirrhosis used in the beginning of this communication; we did not with a vasopressin receptor antagonist: a randomized double- blind stick to our guns, instead we got that great new car. It multicenter trial. Gastroenterology 2003; 124: 933–939. surprised us in several ways: the actual speed differed at times 17. Gheorghiade M, Niazi I, Ouyang J et al. Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: from what it was meant to be; we were not always sure results from a double-blind, randomized trial. Circulation 2003; whether we should take that car or walk by our feet; the 107: 2690–2696. 18. Gheorghiade M, Gattis WA, O’Connor CM et al. Effects of tolvaptan, brakes did not always work as anticipated—but then the a vasopressin antagonist, in patients hospitalized with worsening maintenance turned out cheaper than expected. And so on. heart failure. JAMA 2004; 291: 1963–1971. Are these nothing but teething problems? Possible, more time 19. Abraham WT, Shamshirsaz AA, McFann K et al. Aquaretic effect of lixivaptan, an oral, non-peptide, selective V2 receptor vasopressin and studies will be needed to tell. Do not give up, stay tuned. antagonist in New York Heart Association functional class II and III chronic heart failure patients. JACC 2006; 47: 1615–1621. DISCLOSURE 20. Soupart A, Gross P, Legros JJ et al. Successful long-term treatment of GD was a trialist in studies of lixivaptan (Wyeth), conivaptan (Astellas), hyponatremia in syndrome of inappropriate antidiuretic hormone tolvaptan (Otsuka), and satavaptan (Sanofi). PAG has been involved in secretion with satavaptan (SR 121463B), an orally active nonpeptide vasopressin V2-receptor antagonist. Clin J Am Soc Nephrol 2006; 1: phase II and III trials of vaptans, performed by Otsuka, Astellas, and 1154–1160. CardioKine, and has received fees for study-related work. He was 21. Gheorghiade M, Konstam MA, Burnett JC et al. Short-term clinical effects given honoraria for scientific presentations for GE Healthcare and of tolvaptan, an oral vasopressin antagonist, in patients hospitalized Otsuka. He presently serves on committees of Otsuka related to for heart failure: the EVEREST clinical status trials. JAMA 2007; 297: vaptans. AW declared no competing interests. 1332–1343.

Kidney International (2011) 80, 594–600 599 review PA Gross et al.: Vaptans and the treatment of hyponatremia

22. Zeltser D, Rosansky S, van Rensburg H et al. Assessment of the efficacy of 31. Mohmand HK, Issa D, Akmad Z et al. Hypertonic saline for hyponatremia: intravenous conivaptan in euvolemic and hypervolemic hyponatremia. risk of inadvertent overcorrection. Clin J Am Soc Nephrol 2007; 2: Am J Nephrol 2007; 27: 447–457. 1110–1117. 23. Gines P, Wong F, Watson H et al. Effects of satavaptan, a selective 32. Boscoe A, Paramore C, Verbalis JG. Cost of illness of hyponatremia in the vasopressin V2 receptor antagonist, on ascites and serum sodium in United States. Cost Eff Resou Alloc 2006; 4: 10. cirrhosis with hyponatremia. Hepatology 2008; 48: 204–213. 33. Shea AM, Hammill BG, Curtis LH et al. Medical cost of abnormal serum 24. Annane D, Decaux G, Smith N. Efficacy and safety of oral conivaptan, a sodium levels. J Am Soc Nephrol 2008; 19: 764–770. vasopressin-receptor antagonist, evaluated in a randomized, controlled 34. Decaux G, Andres C, Gankam Kengne F et al. Treatment of euvolemic trial in patients with euvolemic or hypervolemic hyponatremia. Am J Med hyponatremia in the intensive care unit by urea. Crit Care 2010; 14: R184. Sci 2009; 337: 28–36. 35. Soupart A, Decaux G. Efficacy and tolerance of vaptans compared to urea 25. Berl T, Quittnat-Pelletier F, Verbalis JG et al. Oral tolvaptan is safe for longterm treatment of patients with SIADH. A prospective study. Acta and effective in chronic hyponatremia. J Am Soc Nephrol 2010; 21: Clin Belgica 2009; 64-6: 563 Abstract. 705–712. 36. Lee WH, Packer M. Prognostic importance of serum sodium 26. Decaux G. Is asymptomatic hyponatremia really asymptomatic? Am J Med concentration and its modification by converting-enzyme inhibition 2006; 119: S79–S82. in patients with severe chronic heart failure. Circulation 1986; 73: 27. Renneboog B, Musch W, Vandemergel X et al. Mild chronic hyponatremia 257–267. is associated with falls, unsteadiness, and attention deficits. Am J Med 37. Rossi J, Bayram M, Udelson JE et al. Improvement in hyponatremia during 2006; 119: 71.e1–71.e8. hospitalization for worsening heart failure is associated with improved 28. Gankam Kengne FG, Andres C, Sattar L et al. Mild hyponatremia and risk outcomes: insights from the Acute and Chronic Therapeutic Impact of a of fracture in the ambulatory elderly. QJMed2008; 101: 583–588. Vasopressin Antagonist in Chronic Heart Failure (ACTIV in CHF) trial. Acute 29. Gheorghiade M, Gottlieb SS, Udelson JE et al. Vasopressin V2 receptor Cardiac Care 2007; 9: 82–86. blockade with tolvaptan versus fluid restriction in the treatment of 38. Zilberberg MD, Exuzides A, Spalding J et al. Epidemiology, clinical and hyponatremia. Am J Cardiol 2006; 97: 1064–1067. economic outcomes of admission hyponatremia among hospitalized 30. Verbalis JG, Goldsmith SR, Greenberg A et al. Hyponatremia treatment patients. Curr Med Res Opin 2008; 24: 1601–1608. guidelines 2007: expert panel recommendations. Am J Med 2007; 120: 39. Waikar SS, Mount DB, Curhan GC. Mortality after hospitalisation with S1–S21. mild, moderate and severe hyponatremia. Am J Med 2009; 122: 857–865.

600 Kidney International (2011) 80, 594–600