Vaptans and Hyponatremia in Critical Patients

Translational Medicine @ UniSa, - ISSN 2239-9747 2012, 3(1): 1-14

VAPTANS AND HYPONATREMIA IN CRITICAL PATIENTS

David D’Auria, Geremia Zito Marinosciˡ, Giuseppe De Benedictis, Ornella Piazza²

1 Department of Anesthesia and Intensive Care, Federico II University, Napoli, Italy ² Department of Medicine, University of Salerno, Salerno, Italy

ABSTRACT: Hyponatremia is the most frequent manifestation depend on many factors (time of duration, fluid and electrolyte disorder in hospitalized patients velocity of sodium decrease, sodium levels, patients age, (20%), particularly in ICU, associated with an increase comorbidities) (3) and can give few and aspecific signs in morbility and mortality. While hypovolaemic and symptoms (fatigue, anorexia, nausea, behavioral hyponatremia needs to be corrected with the alterations) when sodium level is higher than 125 mEq/l or replacement of the lost extracellular fluid by isotonic the hyponatremia is chronic or it may cause more serious saline, euvolaemic (SIADH) and hypervolaemic derangements when sodium level is below 120 mEq/l or hyponatremia (oedematous states like decompensated hyponatremia is acute (cerebral edema, encephalopathy, heart failure, liver cirrhosis, i.e.) are treated by seizures, coma) (3, 4). Nevertheless, hyponatremia is a restriction of fluid intake, loop diuretics and predictor of poor outcomes in patients with heart failure. hypertonic saline. A novel approach consists in use of Patients with heart failure and hyponatremia often have vaptans, non-peptide arginine vasopressin (AVP) inappropriately elevated plasma vasopressin levels and receptor antagonists. Vaptans cause “aquaresis”, significantly poorer long-term prognosis than those with which results in the correction of plasma osmolality heart failure and normal serum sodium levels. (5) and serum sodium levels, without activation of the renin-angiotensin-aldosterone system or changes in With regard to the osmolality, except for a few cases of blood pressure and renal function. In this paper we hyperosmolality hyponatremia (due to hyperglycemia or critically reviewed the results of the available mannitol or other osmotic agents that cause a shift of randomized controlled critical trials, discussing the water from the intracellular to the extra-cellular effectiveness and safety of vaptans in treating compartment), it is more frequently hypoosmolar (i.e. hypervolaemic and euvolaemic hyponatremia in renal failure, liver cirrhosis, cardiac failure, states of critical patients. hypovolemia, SIADH).

The commonest classification of hyponatremia refers to volaemic state: a) “hypovolaemic hyponatremia” due to Keywords- AVP receptor antagonists, hyponatremia, extracellular fluid loss (vomiting, diarrhea, excessive vaptans, vasopressin. sweating, use of diuretics, salt wasting syndromes, adrenal insufficiency); b) “euvolaemic hyponatremia” observed in primary polydipsia, hypothyroidism and in SIADH, a disorder determined by an excessive hypothalamic or I.INTRODUCTION ectopic secretion of vasopressin, which can be caused by a large number of pathologies (pituitary adenoma, HYPONATREMIA: DEFINITION, SYMPTOMS encephalitis, other CNS disorders; cancer such as lung AND CLASSIFICATIONS. cancer, pancreatic carcinoma, thymoma; pulmonary Hyponatremia, defined as a serum sodium level below 135 inflammatory states; drugs as DDAVP, oxytocin, mEq/l, is the most frequent electrolyte disorder and occurs carbamazepine, tryciclics, cyclophosphamide, tioridazine) in 3-15 % of hospitalized patients, especially in the ; c) “hypervolaemic hyponatremia”, also called diluitional, departments of Intensive Care, Cardiology, Pulmonology, observed in oedematous states that cause a fluid overload: Internal Medicine, Surgery (1, 2). acute or chronic congestive heart failure (CHF), liver cirrhosis, acute and chronic renal failure. (Table I). (6) It is defined as acute or chronic if its duration is shorter or longer than 48 hours respectively (3). Its clinical

1 Università degli Studi di Salerno Translational Medicine @ UniSa, - ISSN 2239-9747 2012, 3(1): 1-14

TABLE I.

CLASSIFICATION OF HYPONATREMIA ACCORDING TO VOLAEMIC STATE

Volemic Hypovolemia Euvolemia Hypervolemia state Related ECF loss, diarrhea, Salt wasting Adrenal Hypotiroidism, Drug, nausea, SIADH CHF, liver Diseases diuretics. syndromes. insufficiency. primary hypocortisolemia. cirrhosis, polydipsia. nephrotic syndrome. Edema ------+ Blood Low low low normal/low Normal/low normal low pressure Urine Low high high low high high (low low sodium in type C) excretion Plasma High high high low low low high renin activity Others hypercloremic response to hormone hormone dosing hormone dosing low blood typical metabolic acidosis in saline dosing, urea and alterations: diarrhea; infusion hyperkalemia uricemia hypokaliemic metabolic alkalosis in diuretics.

HYPONATREMIA: CONVENTIONAL THERAPY hemiplegia or quadriplegia, convulsions, coma, death (3). Other conventional treatments used in managing The conventional treatments of hyponatraemia differ hyponatremia consist in water restriction and loop according to the underlying disease. diuretics (oedematous states). Lithium and Demeclocycline, capable of correcting hyponatremia Hypovolaemic hyponatremia simply requires the causing nephrogenic insipidus diabetes, are rarely used administration of lost fluids in the form of isotonic saline. because of their side effects and only under certain As far as euvolaemic and hypervolaemic hyponatremia are conditions (SIADH). Mannitol and urea (12) can be used concerned, the use of hypertonic saline solution is to induce osmotic diuresis with increased excretion of free reserved for severe hyponatremia with neurological water. symptoms. The correction of the sodium intake should be slow and gradual and not exceed 8-12 mEq/l in the first 24 Most of these therapies are of moderate efficacy. In any hours in case of acute hyponatremia, even slower in case it is important to monitor blood volume and assess correcting chronic hyponatraemia (maximum 8 mEq/l in frequently sodium levels (i.e. more a day by ABG), as 24 h). Overly rapid correction, in fact, can cause serious well as other electrolytes, urine output, renal and and irreversible neurological disorders, such as the cardiovascular function when correcting the serum pontine myelinolysis due to brain glial damage sodium. None of the conventional therapies directly (oligodendrocytes) (7, 8, 9, 10, 11). Osmotic addresses the effects of elevated vasopressin levels, which demyelination syndrome results in confusion, behavioral is the underlying cause of many cases of hyponatremia. changes, dysphagia, dysarthria, mutism, spastic

2 Università degli Studi di Salerno Translational Medicine @ UniSa, - ISSN 2239-9747 2012, 3(1): 1-14

ARGININE VASOPRESSIN AND VAPTANS Until now two vaptans have been released for clinic use: conivaptan, as an intravenous preparation, and tolvaptan, Arginine Vasopressin or ADH (Antidiuretic hormone) is a as an oral tablet. cyclic peptide (9 amino-acids) with a disulfide bridge. It is synthesized in the hypothalamus (sopraoptic and Conivaptan (Vaprisol®) was the first medication of this paraventricular nuclei) and transported along the axons to class to be approved by the FDA in 2005 for the treatment the posterior lobe of hypophysis. It is released into the of hyponatremia in SIADH, hypothyroidism, pulmonary circulation in response to a number of stimuli (13). These disorders and adrenal insufficiency in hospitalized patients stimuli can be osmotic (osmoreceptors situated in the (22) and two years later, in 2007, also for hypervolemic anterior hypothalamus) or non-osmotic (low-pressure hyponatremia in hospitalized patients (23). The loading baroreceptors, present in large veins, right and left atrium, dose is 20 mg i.v. over 30 min and the maintenance dose lungs; high-pressure receptors, present in the carotid is 20-40 mg i.v. for continuous infusion over 24h up to sinuses and aortic arch). Other non-osmotic stimuli are 96h. Differently from all the other vaptans, which are hypovolemia, stress, hypoglycemia, nausea and vomiting, selective V2-receptor antagonists, conivaptan acts like a drugs. Circulating ADH is metabolized by a V1a-receptor and V2-receptor antagonist. This singularity vasopressinase (also called oxytocinase or placental could be investigated in a randomized trial to show if leucine aminopeptidase), widely expressed on cellular conivaptan is better than other vaptans in treating membrane. Well known ADH receptors are: V1a, V1b hyponatremic patients with CHF thanks to its (also known as V3), V2. They belong to G-protein- cardiovascular action (V1a-receptor blockage causes coupled receptor superfamily. V1a and V1b receptors reduction of vascular peripheral resistance and inhibits activate the phospholipase C/protein kinase C pathway, unfavorable myocardial remodeling). It is metabolized by while V2 receptor activates the cAMP/protein kinase A CYP3A4. Common side effects are infusion site reactions, pathway. fever, hypokalemia, hypotension, gastrointestinal disturbances. Udelson reported that a single iv dose of V1a receptor (expressed on surface of vascular smooth conivaptan increased urine output and reduced PCWP muscle cells, cardiomyocytes, platelets, hepatocytes, brain (pulmonary capillary wedge pressure) in patients with and muscle uterine cells) regulates vasoconstriction, advanced heart failure (NYHA class III or IV) (46). inotropic effect, platelets aggregation, glycogenolysis, anxiety and stress, myocyte hypertrophy (14). V1b Tolvaptan (Samsca®) was approved by FDA for treatment receptor, found in anterior pituitary gland, increases of euvolemic and hypervolemic hyponatremia in HF, release of ACTH (15). V2 receptor is expressed on cirrhosis and SIADH, and by EMEA for treatment of endothelial cells, where it determines release of von SIADH (24, 25) only. The initial dosage is 15 mg once Willebrand factor, and on the basolateral membrane of the daily, increasing to 30-60 mg/day depending on clinical principal cells of the renal collecting ducts, where response. Like conivaptan it is metabolized largely by determines a water reabsorbition through the synthesis and CYP3A4, so there are some warnings about interactions. insertion in the luminal membrane of the water channel The main adverse reactions are weakness, dry mouth, aquaporina-2 (AQP2) (16). thirst, constipation, hyperglycemia.

According to antidiuretic action of V2 receptor, since the 80’s a large number of vasopressin antagonists has been investigated to treat hyponatremia. Because of limits linked to their peptide structure, the first peptide vasopressin antagonists were abandoned in favor of non- peptide vasopressin antagonists, also known as vaptans.

Non-peptidic vasopressin antagonists (i.e. vaptans) are: mozavaptan (OPC 31260) (17), lixivaptan (VPA 985) (18), conivaptan (YM 087) (19), satavaptan (SR 121463) (20), tolvaptan (OPC 41061) (21). (TABLE II).

3 Università degli Studi di Salerno Translational Medicine @ UniSa, - ISSN 2239-9747 2012, 3(1): 1-14

TABLE II.

VAPTANS

Lixivaptan Tolvaptan Conivaptan Satavaptan V1a:V2 affinity 1:100 1:29 10:1 1:112

Route of oral oral intravenous oral administration Dosage twice a day once a day continuous once a day infusion Na⁺ excretion/24 h ↔ (small dose) ↔ ↔ ↔ ↑ (bigger dose)

Aquaresis effect + + + +

Administration SIADH, CHF, SIADH, CHF, SIADH, CHF, SIADH cirrhosis cirrhosis cirrhosis

II. METHODOLOGY

SEARCH STRATEGY

We searched CENTRAL (The Cochrane Central Register In table III (Results) these studies, sorted in chronological of Controlled Trials) and PubMed databases from January order, are described and commented in a systematic 2000 to January 2012. We searched for “vasopressin manner, according to a scheme that shows references; the receptor antagonists” AND “hyponatremia”. In PubMed typology of study; the vaptan used, the population we applied filter for “Randomized Clinical Trial” and enrolled and size of the two groups (drug versus placebo); “Controlled Clinical Trial”. No language restrictions were the pharmacological intervention and the primary and imposed. According to these criteria 17 trials are secondary outcomes (when provided); results; described in this review. observations.

III. RESULTS a) Reference a) Vaptan a) Interventation Results Observations b) Typology of study b) Population b) Time

c) Number of c) Main Outcome patients

4 Università degli Studi di Salerno Translational Medicine @ UniSa, - ISSN 2239-9747 2012, 3(1): 1-14

a) Gheorghiade M a) Tolvaptan a) fixed doses of 30, 45, 60 A decrease in -A significant (Circulation 2003). (26) mg/die without fluidic body weight and number of b) Hyponatremia in restriction and with stable an increase in patients had only b) double-blind, chronic HF. furosemide doses. urine output mild CHF and multicentric, RCCT. doses-related modest volume c) n=254 patients: b) 25 days. (p<0.001 for all overload. treated vs - n=191 tolvaptan c) Primary efficacy placebo). -Necessity of (n=64: 30 mg variable: change in body further studies n=64: 45 mg weight at day 1 vs Decrease in with NYHA- n=63: 60 mg). baseline. edema and status normalization of stratification. - n=63 placebo. s[Na⁺ ] in the tolvaptan group -Focused only on but not in the diuretic placebo group. properties of tolvaptan witout Not significant mentioning changes in HR, neurohormonal AP, s[K⁺ ], renal effects. function. a) Gerbes AL a) Lixivaptan. a) Primary end-point: Normalization in -little study. (Gastroenterology s[Na⁺ ] ≥ 136 mmol/l. 27% 100 mg/die 2003). (27) b) Hyponatremia in group vs 50% in -lixivaptan liver cirrhosis and 100mg/die per os vs 200 mg/die vs 0% treatment was b) double-blind, ascites . 200mg/die per os vs in placebo, associated with a multicentric, RCCT. placebo respectively slight decline c) n=60 patients: with p<0.05 and 0.001 (8%) of the GFR. water restriction (max . - n=40 lixivaptan 1l/die). (n=22: 100 mg n=18. 200mg). b) 7 days.

- n=20 placebo. c) s[Na⁺ ] normalization in 2 following measurements. a) Wong F (Hepatolgy a) Lixivaptan. a) fixed doses of 25mg/bid Primary end- -little study. 2003). (28) vs 125 mg/bid vs 250 point: increase b) Hyponatremia in mg/bid per os vs placebo dose-dependent -with higher b) double-blind, liver cirrhosis, HF, with aquaresis doses appeared multicentric,RCCT. SIADH. water restriction (max 1.5 (p<0.05). side effects that l/die) determined c) n=44 patients: and suspension of diuretics. treatment in 5 - n=33 lixivaptan patients. (n=12: 25 mg b)7 days . n=11: 125 mg n=10: 250 mg). c) changes in s[Na⁺ ], body weight, AP, diuresis. - n=11 placebo. a) Schrier RW ( Study of a) Tolvaptan. a) increasing doses of -Tolvaptan is - The trial was Ascending Levels of tolvaptan 15, 30, 60 effective in conducted Tolvaptan in b) Hyponatremia in mg/die per os in 30 days. normalize s[Na⁺ ] without fluidic Hyponatremia (SALT liver cirrhosis, HF, vs placebo (134- restriction. I+II); N Engl J Med SIADH. b) 37 days (30 days of 135 vs 130 mEq/l 2006). (29) terapy and 7 days at the 4th day and -After c) n=448 patients: observation after 136 vs 131 mEq/l discontinuation, b) double-blind, discontinuation). at 30th day). hyponatremia multicentric, RCCT. - n=225 tolvaptan (p<0.001 for all recurred.

5 Università degli Studi di Salerno Translational Medicine @ UniSa, - ISSN 2239-9747 2012, 3(1): 1-14

c) -Mean outcome: daily comparisons). - n=223 placebo. s[Na⁺ ] -The correction -Dry mouth and of hyponatremia -Secondary Outcome: thrist s(Na⁺ )≥146 in patients changes in body weight, mEq/l in the first assuming total changes in s[Na⁺ ]. day (1.6%). tolvaptan was associated with a significant improvement of the mental health status measured by the SF-12 Questionnaire.

This was the first study showing the benefits of a long-term treatment of hyponatremia with an oral vaptan. a) Gheorghiade M (Am J a) Tolvaptan. a) increasing doses of Tolvaptan appears -little study Cardiol 2006). (30) tolvaptan 15, 30, 45, 60 to be more b) Hyponatremia in mg/die per os in 14 days. effective than b) prospective, liver cirrhosis, HF, Follow up in out-patient fluid restriction at multicenter, randomized, SIADH. clinic. correcting active-controlled, open- hyponatremia in label trial. c) n=28 patients: b) 65 days. hospitalized subjects, without - n=17 tolvaptan. c) - Primary outcome: an increase in normalization of or a adverse events. - n=11 placebo + s[Na⁺ ] ≥10% increase (p<0.05). water restriction. from baseline.

-Secondary outcome: changes in s[Na⁺ ], CH2O, plasma osmolarity and thrist. a) Soupart A (Clin J Am a) Satavaptan. a) 1st phase: fixed dose of Significative -The first trial Soc Nephrol 2006). (31) satavaptan 25 or 50 mg/die increase in s(Na⁺ ) showing a long- b) Hyponatremia in per os . in patients term b) double-blind (1st SIADH. 2nd phase: increasing doses assuming effectiveness. phase) and open-label of 12.5, 25, 50 mg/die satavaptan 25 mg (2nd phase), C) with (p<0.01) and 50 -However 10% multicentric, RCCT. c.1) 1st phase. fluidic restriction (< 1.5 mg (p<0.001) vs of treated patients (phase II). n=34 patients: l/die). placebo. reported an overly rapid - n=26 satavaptan b) 1 st phase: 7-30 days During the long- correction of (n=14: 25 mg 2nd phase: 12 months term treatment, 15 s[Na⁺ ] (> 12 n=12: 50 mg). of 18 enrolled mEq/l/day), no c) s[Na⁺ ] normalization in patients achieved osmotic first 24h, body weight, AP. 6 mo and 10 demyelisation - n=8 placebo. achieved 12 mo of syndrome was treatment. observed.

-No drug-related

6 Università degli Studi di Salerno Translational Medicine @ UniSa, - ISSN 2239-9747 2012, 3(1): 1-14

c.2) 2nd phase: serious adverse n=22 patients. events were recorded during the long-term treatment and the s(Na⁺ ) response was maintained with a good tolerance.

a) Ghali J (J Clin a) Conivaptan a) fixed doses of conivaptan shows Thirst not Endocrinol Metab 2006). conivaptan 40 and 80 a dose dependent included in side (32) b) Hyponatremia in mg/die in two doses. Max increasing s[Na⁺ ] effects. liver cirrhosis, HF, water intake 2 l/die vs placebo b) double-blind, SIADH. (p<0.001). multicentric, RCCT. b) 5 days. c) n=74 patients: Headache, c) change from baseline in hypotension, - n=51conivaptan s[Na⁺ ] area under the nausea, (n=24: 40 mg curve. constipation, and n=27: 80 mg). postural hypotension were - n=23 placebo. the most common adverse events.

a) Konstam MA (The a) Tolvaptan. a) fixed doses tolvaptan 30 During a median In this trial Efficacy of Vasopressin mg/die or placebo in follow-up of 9.9 tolvaptan was Antagonism in Heart b) Patients addition to standard months, 537 initiated for acute Failure Outcome Study hospitalized for therapy. patients (25.9%) treatment of With Tolvaptan exacerbation of in the tolvaptan patients (EVEREST), JAMA chronic HF with b) at least 60 days group and 543 hospitalized with 2007). (33) signs of volume (26.3%) in the heart failure. overload, ejection c) Outcomes placebo group b) event-driven, double- fraction ≤40%, c.1) Dual Primary died. The study, with a blind, multicentric, NYHA class III or outcomes: large number of RCCT. IV simptoms. -1) all-cause mortality The end points of patients and a (superiority and cardiovascular long-term follow- c) n=4133 patients: noninferiority) mortality, up, shows that -2) cardiovascular death cardiovascular tolvaptan has no - n=2072 tolvaptan. or hospitalization for heart death or effect on long- failure (superiority only). hospitalization, term mortality or and worsening heart failure- - n=2061 placebo. c.2) Secondary outcomes: heart failure were related morbidity; - changes in dyspnea, body not different. but it also shows weight, and edema. that tolvaptan is Tolvaptan the first drug ever significantly evaluated in improved patients secondary end hospitalized for points of day 1 worsening HF for patient-assessed which dyspnea, day 1 combination of body weight, and short-term day 7 edema. In symptomatic

7 Università degli Studi di Salerno Translational Medicine @ UniSa, - ISSN 2239-9747 2012, 3(1): 1-14

patients with benefits (↓ hyponatremia, dyspnea, edema, serum sodium body weight) and levels long-term safety significantly has been increased. established.

Tolvaptan caused increased thirst and dry mouth, but frequencies of major adverse events were similar in the 2 groups.

a) Zelster D (Am J a) Conivaptan. a) 20 mg i.v. bolus Both conivaptan -This trial shows Nephrol 2007). (34) followed by a continuos doses increased the rapid b) Hyponatremia in 96h i.v. infusion of 40 area under the effectiveness of c) double-blind, liver cirrhosis, HF, mg/die and 80 mg/die with [Na+]-time curve the conivaptan in multicentric, RCCT. SIADH. fluidic restriction (max 2 during the 4-day the short-term l/die). treatment (p < treatment of c) n=84 patients: 0.0001 vs. hyponatremia. b) 96 h placebo). - n=55 conivaptan -Thirst’s increase (n=29: 40 mg c) Primary outcome: Conivaptan is not considered. n=26: 80 mg). change in s[Na⁺ ], significantly measured by the baseline- improved all - n=29 placebo. adjusted area under the secondary s[Na⁺ ]-time efficacy measures curve. (p < 0.001 vs. placebo, both Secondary outcome: doses). changes in s[Na⁺ ], osmolarity, ADH, vasoactives hormones. a) Ginès P (HypoCAT; a) Satavaptan. a) fixed doses of Improved control -The trial shows Hepatology 2008). (35) satavaptan 5, 12.5, 25 of ascites, as that satavaptan b) Hyponatremia in mg/die of with fluidic indicated by a improves the b) double-blind, liver cirrhosis with restriction (max 1.5 l/die). reduction in body control of ascites multicentric, RCCT. ascites. All patients received weight (p = 0.05 in cirrhotic spironolactone at 100 for a dose-effect patients under c) n=110 patients: mg/day. relationship diuretic treatment overall) and and serum - n=82 satavaptan b) 14 days. improvements in sodium dose- (n=28: 5 mg/die serum sodium (p< dependently. n=26: 12.5 mg/d c) Main Outcome: changes 0.01 for all groups n=28: 25 mg/di) in body weight from compared to baseline (day 1) to the end placebo). - n=28 placebo of treatment (day 14) and -Short-term chenges in s[Na⁺ ] from Thirst study. baseline to day 5. significantly more common in patients treated with satavaptan compared to

8 Università degli Studi di Salerno Translational Medicine @ UniSa, - ISSN 2239-9747 2012, 3(1): 1-14

placebo.

The frequency of other adverse events was similar among groups. a) Annane D (Am J Med a) Conivaptan a) fixed doses of oral A normal s[Na⁺ ] - Short-term Sci 2009). (36) conivaptan 40 and 80 or an increase study. b) Hyponatremia in mg/die with oral fluidic from baseline ≥ 6 b) double-blind, liver cirrhosis, HF, restriction (max 2l/die). mEq/L was -Not evaluated multicentric, RCCT. SIADH. significantly the effects of b) 5 days. higher among other drugs c) n=83 patients: patients given allowed. c) Main outcome: baseline- conivaptan 40 and - n=53 conivaptan adjusted area under the 80 mg/die (67% (n=27: 40 mg s[Na⁺ ]-time curve. and 88%, n=26: 80 mg). respectively) than placebo (20%; P < - n=30 placebo. 0.001). a) Wong F (J Hepatol a) Satavaptan a) fixed doses of The frequency of The trial included 2010). (37) satavaptan 5, 12.5, 25 paracentesis was patients with or b) Ascites mg/die or placebo and decreased without b) double-blind, recurrence after spironolactone 100 mg/die. significantly (n all hyponatraemia, multicentric, RCCT. paracentesis in satavaptan groups and normal to cirrhotic patients. b) 12 weeks. vs placebo mildly abnormal (p<0.05). renal function. c) n=151 patients: c) frequency of paracentesis Increases in - n=115satavapta serum creatinine, (n=39: 5 mg orthostatic n=36: 12.5 mg changes in n=40: 25 mg). systolic pressure and thirst were - n=36 placebo more common with satavaptan. a) Naidech AM a) Conivaptan. a) Conivaptan bolus (20 Conivaptan led to Recruitment (Neurocritic Care 2010). mg iv) followed by 20 mg higher s[Na⁺ ] according to (38) b) neuro-ICU IV over 24 h. compared to usual inclusion-criteria patients with severe care at 6, 24, 36 h was difficult: the b) prospective, hyponatremia (< b) 36h (p<0.05). study was randomized pilot (goal N 130 mE/l) or terminated after 6 = 20) trial Hyponatremia c) changes in serum and patients were (<135 mEq/l) with urine electrolytes and enrolled. depressed GCS. clinical examinations. Not conclusive c) n= 20 results.

a) Abraham WT (The a) Lixivaptan. a) doses of lixivaptan or Lixivaptan led to BALANCE seeks BALANCE Study: placebo adjusted on higher s[Na⁺ ] to address unmet Treatment of b) patients s[Na⁺ ] or volume status. and reduce body questions Hyponatremia Based on hospitalized for weight, without regarding the use Lixivaptan in NYHA CHF (NYHA III- b) 60 days. renal dysfunction of vasopressin Class III/IV Cardiac IV). or hypokalemia. antagonists Patient Evaluation; Clin c) Increase in s[Na⁺ ] including their Transl Sci 2010). (39) c) n=652 patients: from baseline. Body effects on

9 Università degli Studi di Salerno Translational Medicine @ UniSa, - ISSN 2239-9747 2012, 3(1): 1-14

- n=326 lixivaptan weight and clinical cognitive b) double-blind, - n=326 placebo measures. function multicentric, RCCT. (phase III trial). a) Aronson D (Short- a) Satavaptan. a) Satavaptan 25 mg/die vs The response rate The long-term and long-term treatment 50 mg/die vs placebo. was significantly open-label of dilutional b)diluitional (p<0.05) and treatment results hyponatraemia with hyponatremia b) 4 days (double-blind doses-related demonstrate satavaptan: the DILIPO (<135 mEq/l) in treatment), followed by higher with sustained efficacy study; Eur J Heart Fail CHF. non-comparative open- satavaptan than of satavaptan in 2011). (40) label satavaptan therapy with placebo. maintaining c) n= 118 for up to 343 days. normal sodium b) double-blind, Sodium responses levels. multicentric, RCCT. c) s[Na⁺ ]≥ 135 mEq/l maintained during and/or an increase in ≥ 5 open-label mEq/l above baseline. therapy. Clinical measures. Higher rates of adverse events with the 50 mg/day dose.

a) Galton C (Neurocrit a) Conivaptan a) a single dose 20 mg At 4 h, serum - non- Care 2011). (41) conivaptan. sodium was hyponatremic b) Within 24 h of higher (P = 0.02) patients enrolled. b) Open-label severe traumatic b) 48 h and ICP was randomized controlled brain injury. lower (P = 0.046) - little study. trial. c) s[Na⁺ ], sodium load, in the conivaptan c) n=10 patients: change in ICP, urine group. - further - n=5: conivaptan output. investigations are - n=5: only usual 24-h but not 48-h needed to assess care urine output was the role of different between conivaptan in the the two groups (P management of < 0.01 and P = intracranial 0.20, hypertension. respectively).

No drug-related serious adverse events a) Koren MJ (Am J a) Conivaptan. a) Conivaptan 20 mg/die Changes were Health Syst Pharm, or 20 mg/bid or placebo significantly 2011). (42) b) Euvolemic or via 30-minute i.v. infusion. greater and dose- hypervolemic related compared b) RCCT. hyponatremia. b) 48 h. with those in the placebo group. c) n=49 patients. c) Change in s[Na⁺ ] from baseline to 48 hours. Both conivaptan regimens were more efficacious than placebo in all secondary efficacy outcomes.

Conivaptan was

10 Università degli Studi di Salerno Translational Medicine @ UniSa, - ISSN 2239-9747 2012, 3(1): 1-14

generally well tolerated, with infusion-site reactions being the most common adverse effects .

IV. DISCUSSION hyponatremia in paraneoplastic SIADH)also block the V1a receptors, they may have superior efficacy compared The analysis of the mentioned trials shows that non- to satavaptan, tolvaptan and lixivaptan (which are peptide vasopressin antagonists are safe and effective selective V2-receptor antagonists) in patients with heart drugs in the short-term correction of hyponatremia in both failure. the states of hypervolemia (liver cirrhosis and heart failure) and euvolemia (SIADH). All vaptans induce thirst and this effect is very important Certainly vaptans have a number of limitations. First of for compliance to therapy. Without doubt, the thirst is all, trials presented a percentage of 10-20% of patients explained by the increased plasma osmolality that they who do not respond to treatment. The reason for this determine, but it may be also linked to a direct action on phenomenon has not yet been studied well. This can be vasopressin receptors of “thirst” in hypothalamic neurons. partly attributed to altered pharmacokinetics (altered volume of distribution in oedematous states and water In recent years the use of vaptans for treatment of ingestion), in part to polymorphisms and mutations in the emergency hyponatremia (45) and for the control of serum vasopressin receptors (43, 44). On the other hand, vaptans sodium and intracranial hypertension in neurosurgical may be associated with rapid correction of sodium values patients has been discussed (38, 41). For the correction of (> 12 h mEq/l/24) with potential risk of pontine emergency hyponatremia, hypertonic saline remains the myelinolysis, although the literature has not reported any treatment of choice, but it has been hypothesized that cases of this complication in patients treated with these vaptans could at least be taken into account to give a drugs. slower correction of sodium rate than hypertonic saline and no risk of pulmonary edema (45). With regard to the Clinical response to vaptans in terms of aquaresis and treatment of cerebral edema and intracranial hypertension hyponatremia correction is not the same in all subsets of in neurosurgical patients, the current target is to keep the patients. Patients with SIADH are those that respond best, patient “salty and full”, with careful monitoring and rapid while those with liver cirrhosis worse. Probably in the intervention to keep within normal limits the plasma state of hypervolemia (CHF, liver cirrhosis) proximal osmolality and serum sodium (as well as the optimization tubular reabsorption reduces the effect that vaptans cause of respiratory and cardiovascular functions, in addition to in distal tubular ducts. Further studies are needed to sedation, to guaranty an adequate DO₂ /VO₂ ) through the clarify this point. So clinicians need to keep in mind that consolidated use of mannitol, hypertonic saline, diuretics. therapy with vaptans should be individualized for each To the best of our knowledge, there are still no conclusive patient. studies on these two issues and we wait for results in the coming years. All studies were short term. Only Soupart (31) and Aronson (40) studied the effectiveness of satavaptan for one year, in SIADH and CHF respectively, demonstrating the efficacy and good tolerability in long-term treatment.

There are no studies comparing the efficacy between vaptans and traditional treatment (diuretics, hypertonic saline, urea,…) or between two different vaptans. This last point is considerable because, whereas conivaptan and V. CONCLUSIONS mozavaptan (used in Japan for the treatment of

11 Università degli Studi di Salerno Translational Medicine @ UniSa, - ISSN 2239-9747 2012, 3(1): 1-14

Vaptans are safe and effective drugs in the short-term on pathogenesis and prevention of neurologic treatment of hyponatremia due to hypervolaemic complications. Clin Nephrol. 1996; 46: 149-169. edematous states (liver cirrhosis, heart failure) and euvolaemic states (SIADH). They are contraindicated in 9. Yeates KE, Morton AR Vasopressin antagonists: role hypovolaemic hyponatremia. About superiority of one in the management of hyponatremia. Am J Nephrol. 2006; vaptan above the other and comparison between vaptans 26: 348-355. and conventional therapy, questions are still open. 10. Yeates KE, Singer M, Morton AR. Salt and water: a simple approach to hyponatremia. CMAJ. 2004; 170: 931.

11. Adrogue HJ. Consequences of inadequate management of hyponatremia. Am J Nephrol. 2005; 25: ACKNOWLEDGMENT 240-249.

The authors declare no conflicts of interest. 12. Decaux G, Brimioulle S, Genette F, et al. Treatment of the syndrome of inappropriate secretion of antidiuretic hormone by urea. Am J Med 69: 99-106, 1980.

13. Schally AV: Hormones of the neurohypophysis; in Lock W, Schally AV (eds): The Hypothalamus and BIBLIOGRAPHY Pituitary in Health and Disease. Springfield, Thomas, 1. Hoorn EJ, Lindemans J, Zietse R. Development of 1972, pp 154–171. severe hyponatremia in hospitalized patients: treatment- 14. Thibonnier M, Conarty DM, Preston JA, et al: related risk factors and inadequate management. Nephrol Molecular pharmacology of human vasopressin receptors. Dial Transplant 21: 70-76, 2006. Adv Exp Med Biol 1998; 449: 251–276. 2. Adrogué HJ, Madias NE. Hyponatremia. New Engl J 15. Du Pasquier D, Loup F, Dubois-Dauphin M, et al: Med 21: 1581-1589, 2000. Binding sites for vasopressin in the human pituitary are 3. Janicic N, Verbalis JG. Evaluation and management of associated with corticotrophs and may differ from other hypo-osmolality in hospitalized patients. Endocrinol known vasopressin receptors. J Neuroendocrinol 1991;3: Metab Clin North Am. 2003; 32: 459-481. 237–247.

4. Hawkins RC. Age and gender as risk factors for 16. Nielsen S, Frokler J, Marples D, Kwon T, et al: hypernatremia and hyponatremia. Clin Chim Acta. 2003; Aquaporins in the kidney from molecules to medicine. 337: 169- 172. Physiol Rev 2002; 82: 205–244.

5. Gheorghiade M, Hellkamp AS, Pina IL, et al. 17. Yamamura Y, Ogawa H, Yamashita H, et al. Hemodynamic characterization and prognostic value of Characterization of a novel aquaretic agent OPC 31260, as persistent hyponatremia in patients with severe heart an orally effective, nonpeptide vasopressin V2 receptor failure in the ESCAPE trial. J Am Coll Cardiol. antagonist. Br J Pharmacol 105: 787-791, 1992. 2005;(Suppl):145A. 18. Chan PS, Coupet J, Park HC, et al. VPA-985, a 6. Esposito P, Piotti G et al. The Syndrome of nonpeptide orally active and selective vasopressin V2 Inappropriate Antidiuresis: Pathophysiology, Clinical receptor antagonist. In: Zingg HH, Bourque CW, Bichet Management and New Therapeutic Options. Nephron Clin DG, Eds. Vasopressin and Oxytocin; Molecular, Cellular Pract 2011; 119: c69-c73. and Clinical Advances. Raven Press, New York, 1998: 439-443. 7. Goh KP. Management of hyponatremia. Am Fam Physician. 2004; 69: 2387-2394. 19. Tahara A, Tomura Y, Wada K, et al. Pharmacological profile of YM 087, a novel potent 8. Soupart A, Decaux G. Therapeutic recommendations nonpeptide vasopressin V1a and V2 receptor antagonist, for management of severe hyponatremia: current concepts in vitro and in vivo. J Pharmacol Exp Ther 282: 301-306, 1997.

12 Università degli Studi di Salerno Translational Medicine @ UniSa, - ISSN 2239-9747 2012, 3(1): 1-14

20. Serradeil-LeGal C, Lacour C, Valette G, et al. 31. Soupart A, Gross P, Legros JJ, et al. Successful long- Characterisation of SR 121 463 A, a highly potent and term treatment of hyponatremia in syndrome of selective, orally active vasopressin V2 receptor antagonist. inappropriate antidiuretic hormone secretion with J Clin Invest 98: 2729-2738, 1996. Satavaptan (SR-121463B), an orally active non-peptide vasopressin V2-receptor antagonist. Clin J Am Soc 21. Yamamura Y, Nakamura S, Itoh S, et al. OPC 41061, Nephrol. 2006; 1:1154–1160. a highly potent human vasopressin V-2 receptor antagonist:pharmacological profile and aquaretic effect by 32. Ghali JK, Koren MJ, Tylor JR, et al; Conivaptan single and multiple oral dosing in rats. J Pharmacol Exp Study Group. Efficacy and safety of oral conivaptan: a Ther 287: 860-867, 1998. V1A/V2 vasopressin receptor antagonist, assessed in a randomized, placebo-controlled trial in patients with 22. Vaprisol (conivaptan HCl injection). Package insert. euvolemic or hypervolemic hyponatremia. J Clin Deerfield IL: Astellas Tokai Co.; February 2006. Endocrinol Metab. 2006;91:2145–2152.

23. Ghali JK, Farah JO, Daifallah S, et al:Conivaptan and 33. Konstam MA, Gheorghiade M, Burnett JC, et al. its role in the treatment of hyponatremia. Drug Des Devel Effects of oral tolvaptan in patients hospitalized for Ther 2009; 3: 253–268. worsening heart failure. JAMA 297: 1319-1931, 2007

24. Samsca (Tolvaptan): US Prescribing Information. 34. Zeltser D, Rosansky S, van Rensburg H, Verbalis JG, Rockville, Otsuka America Pharmaceutical Inc, 2009. Smith N; Conivaptan Study Group. Assessment of the efficacy and safety of intravenous conivaptan in 25. Samsca (Tolvaptan): EU Summary of Product euvolemic and hypervolemic hyponatremia. Am J Nephrol Characteristics. Uxbridge, Otsuka Pharmaceutical Europe 2007;27:447-57. Ltd, 2009. 35. Gines P, Wong F, Watson H, et al: Effects of 26. Gheorghiade M, Niazi I, Ouyang J, Czerwiec F, satavaptan, a selective vasopressin V2 receptor antagonist, Kambayashi J, Zampino M, Orlandi C; Tolvaptan on ascites and serum sodium in cirrhosis with Investigators. Vasopressin V2-receptor blockade with hyponatremia: a randomized trial. Hepatology 2008; 48: tolvaptan in patients with chronic heart failure: results 204–213. from a double-blind, randomized trial. Circulation. 2003 Jun 3;107(21):2690-6. 36. Annane D, Decaux G, Smith N: Efficacy and safety of oral conivaptan, a vasopressin-receptor antagonist, 27. Gerbes AL, Gulberg V, Gines P, et al; The VPA evaluated in a randomized, controlled trial in patients with study group. Therapy of hyponatremia in cirrhosis with a euvolemic or hypervolemic hyponatremia. Am J Med Sci vasopressin receptor antagonist: a randomized double- 2009; 337: 28–36. blind multicenter trial. Gastroenterology. 2003;124:933– 939. 37. Wong F et al. Effects of a selective vasopressin V2 receptor antagonist, satavaptan, on ascites recurrence after 28. Wong F, Blei AT, Blendis LM, Thuluvath PJ. A paracentesis in patients with cirrhosis. J Hepatol. 2010 vasopressin receptor antagonist (VPA-985) improves Aug;53(2):283-90. serum sodium concentration in patients with hyponatremia: a multicenter, randomized, placebo- 38. Naidech AM et al. Use of Conivaptan (Vaprisol) for controlled trial. Hepatology. 2003;37:182–191. hyponatremic neuro-ICU patients. Neurocrit Care. 2010 Aug;13(1):57-61. 29. Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V2-receptor 39. Abraham WT, Aranda JM, Boehmer JP, Elkayam U, antagonist, for hyponatremia. N Engl J Med. Gilbert EM, Gottlieb SS, Hasenfuss G, Kukin M, Lowes 2006;355:2099–2112. BD, O'Connell JB, Tavazzi L, Feldman AM, Ticho B, Orlandi C. Rationale and design of the treatment of 30. Gheorghiade M, Gottlieb SS, Udelson JE, et al. hyponatremia based on lixivaptan in NYHA class III/IV Vasopressin V2 receptor blockade with tolvaptan versus cardiac patient evaluation (THE BALANCE) study. Clin fluid restriction in the treatment of hyponatremia. Am J Transl Sci. 2010 Oct;3(5):249-53. Cardiol 97: 1064-1067, 2006.

13 Università degli Studi di Salerno Translational Medicine @ UniSa, - ISSN 2239-9747 2012, 3(1): 1-14

40. Aronson D, Verbalis JG, Mueller M, Krum H; 43. Feldman BJ, Rosenthal SM et al. Nephrogenic DILIPO investigators. Short- and long-term treatment of syndrome of inappropriate antidiuresis. N Engl J Med dilutional hyponatraemia with satavaptan, a selective 2005; 352: 1884–1890. arginine vasopressin V2-receptor antagonist: the DILIPO study. Eur J Heart Fail. 2011 Mar;13(3):327-36. Epub 44. Decaux G, Vandergheynst et al. Nephrogenic 2011 Jan 3. syndrome of inappropriate antidiuresis in adults: high phenotypic variability in men and women from a large 41. Galton C, Deem S, Yanez ND, Souter M, Chesnut R, pedigree. J Am Soc Nephrol 2007; 18: 606–612. Dagal A, Treggiari M. Open-label randomized trial of the safety and efficacy of a single dose conivaptan to raise 45. Lehrich RW, Greenberg A. When is it appropriate to serum sodium in patients with traumatic brain injury. use vasopressin receptor antagonists? J Am Soc Nephrol Neurocrit Care. 2011 Jun;14(3):354-60. 2008; 19: 1054–1058.

42. Koren MJ, Hamad A, Klasen S, Abeyratne A, 46. Udelson JE, Smith WB, Hendrix GH, Painchaud CA, McNutt BE, Kalra S. Efficacy and safety of 30-minute Ghazzi M, Thomas I, Ghali JK, Selaru P, Chanoine F, infusions of conivaptan in euvolemic and hypervolemic Pressler ML, Konstam MA 2001 Acute hemodynamic hyponatremia. Am J Health Syst Pharm. 2011 May effects of conivaptan, a dual V1A and V2 vasopressin 1;68(9):818-27. receptor antagonist, in patients with advanced heart failure. Circulation 104:2417–2423.

14 Università degli Studi di Salerno