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Lixivaptan: a Vasopressin Receptor Antagonist for the Treatment of Hyponatremia

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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. summarizes the key characteristics and The introduction of medications that specifically antagonize the outcomes of both trials). Both studies vasopressin V2 receptor (vaptans) has provided a safe and effective are randomized, multinational, double- blinded placebo-controlled phase 3 trials. means of therapy. Lixivaptan is the newest of these agents that reliably In both studies, the dosage of lixivaptan increase serum sodium levels in patients with euvolemic hyponatremia. was titrated on the basis of daily serum However, significant questions remain regarding the specific indications sodium measurements. In both trials, for vaptans, and their potential impact on morbidity and mortality patients randomized to lixivaptan showed associated with hyponatremia. greater rises in serum sodium values at Kidney International (2012) 82, 1154–1156. doi:10.1038/ki.2012.317 day 7 after initiation of therapy, and were more likely to normalize their serum sodium, than those given placebo. Cessa- tion of lixivaptan in both trials led to Hyponatremia is the most common hyponatremia encountered in clinical worsening of hyponatremia, suggesting electrolyte disorder encountered in clini- practice are hypervolemic (due to con- that chronic therapy may be required in cal practice, and recent data have demon- gestive heart failure or cirrhosis) and some patients. strated that it is associated with an euvolemic (largely due to the syndrome Unique to the HARMONY study increase in mortality and morbidity even of inappropriate antidiuretic hormone was the avoidance of in-hospital drug in patients in whom overt clinical symp- action). Traditional therapies for hypo- initiation and titration, which is cur- toms may not be demonstrable.1–3 Typi- natremia have been limited, suboptimal, rently recommended with tolvaptan. cally, the evaluation of patients with unreliable, and potentiallytoxic(Table1). Using an outpatient strategy of starting hyponatremia relies on assessment of However, in 2005 the first drug that patients on the lowest possible dose of volume status and classifies patients into specifically antagonizes arginine vasopres- lixivaptan (25 mg) with point-of-care hypovolemic, euvolemic, and hyper- sinactionatthereceptorlevelwas testing of the serum sodium at 8 hours volemic states. This classification schema approved (the intravenous drug conivap- post-dose, the investigators demon- allows for determination of the under- tan, which antagonizes both the vaso- strated that only three patients in the lying cause as well as aiding the clinician pressin V1a and V2 receptors) (Figure 1). lixivaptan group (and one in the placebo in making decisions on appropriate In 2009, an oral vasopressin V2 receptor group) exceeded the desired sodium therapy. The most common forms of antagonist, tolvaptan, was also approved correction rates in the first 24 h; no sub- for the treatment of euvolemic and jects experienced an increase in serum 1Divison of Nephrology, University of Virginia hypervolemic hyponatremia. Both of sodium greater than 18 mmol/l within Health System, Charlottesville, Virginia, USA these agents (broadly termed ‘vaptans’) either a 48- or a 72-hour period; and Correspondence: Mitchell H. Rosner, Division of had clinical trial data demonstrating their no subjects had symptoms of osmotic Nephrology, Department of Internal Medicine, efficacy in increasing serum sodium levels University of Virginia Health System, Box 800133, demyelination syndrome. The ability to Charlottesville, Virginia 22908, USA. as well as increasing the percentage of initiate therapy for hyponatremia in the E-mail: [email protected] patients with hyponatremia who normali- outpatient setting is advantageous but 1154 Kidney International (2012) 82 commentary Table 1 | Available therapies for hyponatremia discretion of the treating physician and Therapy Benefits Drawbacks not prescribed by the protocol. Further- more, in the LIBRA trial there was a Fluid restriction Simple, easily implemented Minimally effective and requires Minimal cost several days to achieve correction large imbalance in the percentage of Can be useful in patients Hard for patients to remain patients who were on fluid restriction with urine osmolality compliant at baseline (65.4% in the placebo versus o400–600 mosmol/kg 37% in the lixivaptan group). This may Demeclocycline Effective in raising serum Slow response sodium Potentially nephrotoxic suggest that the patients in the lixivap- Expensive tan group had lower baseline urine Loop diuretics with May allow relaxation of fluid Requires careful titration and osmolalities and tolerated higher daily or without salt restriction and decreases monitoring water intakes, a factor that could supplementation urine-concentrating ability Risk for other electrolyte abnormalities confound the results of the study. Also Urea Effective and inexpensive Palatability of concern is that 33% of patients in the Limited availability LIBRA cohort and 46.3% of patients in Hypertonic (3%) saline Effective for severe acute Risk of overly rapid correction and symptomatic chronic Requires careful, intensive the HARMONY cohort were taking hyponatremia monitoring medications associated with hypona- Vasopressin receptor Targets excessive arginine Expensive tremia. Many of these patients might antagonists vasopressin Induces polyuria have had restoration of normonatremia Safe and effective Requires close monitoring of Predictable rise in sodium values serum sodium at initiation with simple cessation of the offen- No risk for concomitant electrolyte with inpatient admission ding medication and would not have disorders required therapy unless the medication was deemed indispensable. Wheredoesthisleaveus?Clearly Table 2 | Key characteristics and outcomes of LIBRA and HARMONY vaptan drugs are effective in antagoniz- LIBRA7 HARMONY8 ing the hydroosmotic effects of vasopres- Placebo Lixivaptan Placebo Lixivaptan sin and lead to a predictable rise in serum sodium levels in patients with No. of subjects 52 54 52 154 euvolemic or hypervolemic hypona- Mean age (years) 65.2 66.4 62.7 66.6 %onfluidrestrictionatbaseline 65.4 37 11.5 16.9 tremia. Lixivaptan (pending regulatory Dose at initiation None 50 mg None 25 mg approval) now joins tolvaptan and coni- (inpatient) (outpatient) vaptan in this group of drugs. How- Mean baseline sodium (mmol/l) 126.1 127.6 131.6 131.5 Increase in sodium at day 7 (mmol/l) 6.7±0.7 4.5±0.8 0.8±0.6 3.2±0.5 ever, as others have pointed out, there is % of subjects with normalized sodium 23.1 44.4 12.2 39.4 a large knowledge gap regarding key at day 7 clinical questions that would inform us on how best to use these agents.9 Most importantly, the indications for vaptans requires careful laboratory monitoring vaptans excluded such patients, and the in the treatment of chronic hyponatremia and the ability to obtain rapid outpatient indications for vaptan use in clinical remain uncertain. For instance: What measurements of serum sodium values practice are still uncertain. However, in symptoms associated with hyponatremia in order to assess for overly rapid both trials, in the lixivaptan treatment are indications for therapy? Is there an correction of the serum sodium. At this groups there were statistically signifi- absolute level of hyponatremia that time, such a strategy cannot be broadly cant improvements in the time required warrants therapy? What are the poten- recommended and requires further study to complete the Trail Making Test part B tial health-care-system cost savings asso- to ensure safety. (a neuropsychological test of visual ciated with therapy of hyponatremia? Also unique to both the LIBRA and attention and task switching), which Can treatment of hyponatremia
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