A Vasopressin Receptor Antagonist (VPA-985)

Improves Serum Sodium Concentration in Patients

With Hyponatremia: A Multicenter, Randomized,

Placebo-Controlled TrialFlorence Wong,1 Andres T. Blei,2 Laurence M. Blendis,1 and Paul J. Thuluvath,3 for

The North American VPA-985 Study Group

Hyponatremia in advanced cirrhosis and ascites or congestive heart failure (CHF) is theresult of an inappropriate increase in vasopressin secretion, which acts through activation ofspecific V2 receptors in the distal renal nephron to increase water reabsorption. This studyinvestigates the efficacy and safety of 3 different doses of the V2 receptor antagonist, VPA-985, in correcting hyponatremia over a 7-day inpatient study period. Forty-four hospitalizedpatients (33 patients with cirrhosis, 6 with CHF, and 5 with syndrome of inappropriateantidiuretic hormone (SIADH) were studied on a constant sodium intake, with VPA doses of25, 125, and 250 mg twice daily or placebo. Serum sodium measurements were repeated afterevery daily dose, and the next dose withheld for excessive serum sodium rises. Fluid intakewas adjusted according to previous 24-hour urinary outputs. Adverse events were based onclinical signs of dehydration or encephalopathy. VPA-985 produced a significant overallaquaretic response compared with placebo, with significant dose related increases in freewater clearance (P < .05) and serum sodium (P < .05), without significant changes inorthostatic blood pressure or serum creatinine levels. Five patients (50%) on 250 mg twicedaily had to have medication withheld on multiple occasions. End-of-study plasma vaso-pressin levels increased significantly in the 2 larger dose groups. In conclusion, VPA-985appears effective and safe in appropriate doses in correcting abnormal renal water handlingand hyponatremia in conditions associated with water retention. Higher doses of VPA-985may produce significant dehydration and will require close monitoring with their use.(HEPATOLOGY 2003;37:182-191.)

See Editorial on Page 13

Patients with advanced cirrhosis and ascites or withcongestive heart failure (CHF) have a disturbancein water metabolism, resulting in decreased renal

free water excretion and dilutional hyponatremia.1 The

presence of hyponatremia in hospitalized patients withalcoholic cirrhosis or CHF is associated with a signifi-cantly increased mortality.2,3 The inability of these pa-tients to excrete an appropriate amount of free water isrelated to many factors, the most important of which isthe nonosmotic stimulation of vasopressin release.4-6

Plasma vasopressin levels are increased despite low plasmaosmolality,7 reflecting the resetting of the osmostat to alower osmolar threshold for vasopressin suppression.8

Vasopressin exerts its effects on water metabolismthrough the activation of specific V2 receptors, which areexpressed on the cells of the ascending limb of the loop ofHenle and on the cells of the collecting duct of thenephron.9 In the collecting duct, the activation of the V2

receptor increases water reabsorption directly through theinsertion of water channels into the otherwise water-im-permeable collecting duct cells.10 V2 receptor antagonists,by competitive binding to the V2 receptor, can displacevasopressin and, therefore, decrease water reabsorption at

Abbreviations: CHF, congestive heart failure; SIADH, syndrome of inappropri-ate antidiuretic hormone; CORE, Computerized Randomization/Enrollment;aldo, aldosterone.

From the 1Department of Medicine, Toronto General Hospital, University ofToronto, Toronto, Canada; 2Department of Medicine, Northwestern University,Chicago, IL; 3Department of Medicine, The Johns Hopkins University School ofMedicine, Baltimore, MD.

Received March 19, 2002; accepted October 23, 2002.This study was sponsored by Wyeth-Ayerst Laboratories, USA.Address reprint requests to: Florence Wong, M.D., Room 220, 9th Floor, Eaton

Wing, Toronto General Hospital, 200 Elizabeth St., Toronto M5G 2C4, Ontario,Canada. E-mail: florence.wong@utoronto.ca; fax: 416-340-5019.

Copyright © 2003 by the American Association for the Study of Liver Diseases.0270-9139/03/3701-0026$35.00/0doi:10.1053/jhep.2003.50021

182

the renal collecting tubule.11 VPA-985 is a nonpeptide,highly selective, orally active V2 receptor antagonist. It is acompetitive inhibitor of vasopressin binding to V2 recep-tors.12 It has been shown to promote renal water excretionwithout affecting renal electrolyte excretion, thereby im-proving serum sodium concentration.13 Therefore, theaims of this study were to assess (1) the safety and efficacyof different doses of VPA-985 in correcting hyponatremiain patients with edematous states, including liver cirrhosiswith ascites and heart failure and syndrome of inappro-priate antidiuretic hormone (SIADH), and (2) the effectof VPA-985 on overall patient symptomatology.

Patients and Methods

Institutional approval for the study was granted by theEthics Committees of all participating centers. All pa-tients gave informed consent for the study.

PatientsFrom January, 1998 to January, 1999, 44 hospitalized

patients with stable hyponatremia of �130 mmol/L for 3consecutive days were enrolled into a multicenter ran-domized placebo controlled trial assessing the safety andefficacy of different doses of VPA-985. The study groupconsisted of 33 patients with cirrhosis and ascites, 1 pa-tient with cirrhosis and CHF, 5 patients with CHF, and 5patients with SIADH unrelated to the presence of tumor.The etiology of the liver cirrhosis was related to heavyalcohol use with (2 patients) or without hepatitis C infec-tion (14 patients), hepatitis C infection alone (8 patients),hepatitis B infection (2 patients), cryptogenic cirrhosis (6patients), and primary sclerosing cholangitis (1 patient).All patients with CHF had ischemic heart disease,whereas the patient with both CHF and cirrhosis hadidiopathic dilated cardiomyopathy. All 5 patients withSIADH had either idiopathic SIADH (4 patients), orlong-standing medication-induced hyponatremia (car-bamazepine) (1 patient) which was continued throughoutthe study, and none had any evidence of malignancy.There were 31 men and 13 women with a mean age of51.3 � 1.6 (mean � SEM) years. All patients with cir-rhosis either had biopsy-proven cirrhosis or clinical andlaboratory evidence of cirrhosis. Of those patients whohad cirrhosis and ascites, 12 were Child-Pugh class B pa-tients with a mean score of 8.4 � 0.2, whereas the remain-ing 21 patients belonged to Child-Pugh class C with amean score of 10.9 � 0.2. Of the 6 patients who hadCHF (1 with cirrhosis as well), 1 had New York class Isymptoms, and 2 had class III symptoms, whereas theother 3 patients had class IV symptoms. None of thepatients with CHF was on inotropic drugs. The patientwho had cirrhosis and CHF had a Child-Pugh score of 5.

Patients with advanced liver cirrhosis (Child-Pugh score�12), significant renal impairment (serum creatinine�265 �mol/L in patients without cirrhosis, or serumcreatinine �176 �mol/L in patients with cirrhosis), ad-renal insufficiency, hypothyroidism or hyperthyroidism,or unstable diabetes (fasting blood glucose �13.8mmol/L) were excluded. Likewise, patients who had re-cent infection (�2 weeks), myocardial infarction (�2months), surgery, or head trauma were excluded. Otherexclusion criteria included evidence of intravascular hy-povolemia as indicated by a systolic blood pressure of�80 mm Hg or symptomatic orthostatic hypotensionor the use of therapeutic agents such as lithium, vasopres-sin analogs, demeclocycline, DDAVP, oncologic agents,salt tablets, or hypertonic saline that could affect watermetabolism. The baseline characteristics of all study pa-tients, including baseline diuretic use, are presented inTable 1.

ProtocolAll patients were maintained on their usual doses of

medications, including diuretics and 1.5-L fluid restric-tion during the 3-day screening period and throughoutthe study period of 8 inpatient days. The dietary sodiumrestriction of each patient was determined by each inves-tigator and remained constant for that patient throughoutthe study period. On day 1 of the study, patients wererandomized at a central site by the Computerized Ran-domization/Enrollment (CORE) system to receive twicedaily per os either placebo, 25 mg VPA-985, 125 mgVPA-985 or 250, mg VPA-985 after ascertaining thatserum [Na] had remained at less than 130 mmol/L. Afterrandomization and the initial medication, administrationof further study medication was always preceded by mea-surement of serum [Na]. If the serum [Na] had risen to�142 mmol/L or by �8 mmol/L from the previous mea-surement, the next dose of the study medication was with-held. Study medication was resumed when the serum[Na] had returned to �142 mmol/L or when the increasein serum [Na] was �8 mmol/L from the previous read-ing.

Patients were monitored throughout the study periodfor evidence of intravascular volume depletion. Ortho-static heart rate and blood pressure were monitored twicedaily, together with daily accounts of fluid intake andoutput as well as weight measurement. In addition, pa-tients were assessed twice daily for thirst with a thirst scale.Patients who had a urine output of �3 L in the 8 hoursafter a dose of VPA-985 would increase their fluid intakefrom 1.5 L to 2 L for the next 24 hours and the next doseof VPA-985 withheld. Patients who had a urine output of

HEPATOLOGY, Vol. 37, No. 1, 2003 WONG ET AL. 183

�4 L in any 24-hour period would increase their fluidintake to 2.5 L for the next 24 hours.

Baseline biochemistry, including serum electrolytes,osmolality, creatinine, urea, glucose, and liver enzymes aswell as complete blood count and prothrombin time wereperformed before enrollment. Serum electrolytes were re-peated daily, whereas serum osmolality, creatinine, andurea were repeated on days 3, 5, and 7 of the study period.Twenty-four–hour urine collections for measurements ofurine electrolytes, creatinine, and osmolality also wereperformed at baseline, days 3, 5, and 7. Free water clear-ance was measured on days 3, 5, and 7.

Neurohormones, including plasma renin activity, al-dosterone (Aldo) and norepinephrine were measured atbaseline, days 1 and 7 of the study period after patientshave been supine for at least 30 minutes. Vasopressinlevels were assessed on days 1, 4, and 7. On completion ofthe 7-day inpatient period, patients were discharged onday 8, and were reviewed on day 9 as outpatients.

Safety AssessmentEvaluation of the safety of VPA-985 was based on the

results of a daily physical examination for signs of dehy-dration and evidence of encephalopathy, subjective symp-toms, and twice daily orthostatic pulse and blood pressurereadings. Patients also were required to complete a dailythirst score, which was measured using a 100-mm visual

analog scale,14 with 0 being least and 100 being mostthirsty. Electrocardiogram was obtained at baseline, days3 and 7.

Analytical Techniques and Assays. Serum and uri-nary electrolytes, complete blood count, prothrombintime, and liver function tests were performed withstandard automated laboratory techniques. Blood sam-ples for vasopressin, norepinephrine, plasma renin ac-tivity, and Aldo determinations were collected on ice.Plasma was separated by refrigerated centrifugationand stored at �70°C until assay. Serum and urinaryosmolality were measured with a freezing point os-mometer. Plasma renin activity was estimated by theimmunoassay of angiotensin I generated from plasmaafter 1-hour incubation at pH 5.5 and at 37°C in con-ditions inhibiting further conversion of angiotensin 1(GammaCoat Plasma Renin Activity; DiaSorin, Still-water, MN). Samples that yielded values �0.1 ng/L/swere then reassayed and incubated for 3 hours. PlasmaAldo was assayed with a radioimmunoassay techniquewith a commercial kit (Coat-A-Count Aldosterone kit;Diagnostic Products Corp., Los Angeles, CA). Plasmanon-epinephrine concentrations were determined withhigh performance liquid chromatography using a com-mercial kit (Lyphochek Endocrine Control; Bio-Rad,Hercules, CA). Plasma vasopressin was assayed by ra-

Table 1. Baseline Demographics of the 4 Study Groups

Placebo 25 mg bid 125 mg bid 250 mg bid

n 11 12 11 10

Age (yr) 51.5 � 2.9 48.1 � 3.2 54.8 � 4.0 51.3 � 3.3

Gender (M/F) 10/1 5/7 8/3 8/2

Etiology

Cirrhosis 8 8 10 7

Alcohol 3 4 4 3

Alcohol � HCV 1 — — 1

HCV 2 3 2 1

HBV — — 1 1

Cryptogenic 2 1 3 —

PSC — — — 1

Cardiac failure 1 1 1 2

Cardiac failure and cirrhosis 1 — — —

SIADH 1 3 — 1

Child-Pugh score (in cirrhosis) 9.1 � 0.7 11.0 � 0.4 10.0 � 0.5 9.6 � 0.6

Serum Na (135-145 mmol/L) 127 � 1 126 � 0.4 121 � 1 126 � 1

Serum creatinine (57-110 �mol/L) 95.4 � 11.6 72.0 � 11.5 84.4 � 5.8 104.3 � 14.0

Serum osmolality (278-305 mosm/kg) 273 � 5 271 � 4 263 � 6 269 � 4

Urinary Na (mmol/d) 107 � 21 120 � 43 71 � 19 110 � 37

Urinary osmolality (50-1,200 mosm/kg) 410 � 48 334 � 41 430 � 49 439 � 42

Diuretic use

Furosemide

Amiloride 6 8 9 7

Spironolactone 3 — 1 —

Metolazone 7 6 8 6

Hydrochlothiazide 1 1 — 1

1 — — 2

184 WONG ET AL. HEPATOLOGY, January 2003

dioimmunoassay (Renal Research Laboratory, Mel-bourne, FL).

Statistical Analysis. Data were collected centrally atWyeth-Ayerst Laboratories and initially analyzed atWyeth-Ayerst. The raw data were retrieved from thesponsor and reanalyzed at one of the investigator’s re-search centers with 1-way analysis of variance, withTukey’s test for comparison between groups. Baseline ver-sus final comparison within each group was made usingStudent’s t test. All results were expressed as mean �

SEM.

Results

Thirty-two patients completed the study. Twelve pa-tients (placebo group, 2 patients; 25 mg twice per daygroup, 2 patients; 125 mg twice per day group, 2 patients;250 mg twice per day group, 6 patients) exited the studyat a mean time of 5.3 � 0.6 days. Exits occurred on day 2(25 mg twice per day, 1 patient), day 3 (25 mg twice perday group, 1 patient; 250 mg twice per day group, 2patients), day 5 (placebo group, 1 patient), day 6 (250 mgtwice per day group, 2 patients), day 7 (placebo group, 1patient; 125 mg twice per day group, 2 patients; 250 mgtwice per day group, 2 patients), and were related to de-hydration as indicated by systemic postural hypotensionin 6 patients (25 mg twice per day group, 1 patient; 125mg twice per day group, 2 patients; 250 mg twice per daygroup, 3 patients), whereas the remainder of the patientsexited early for other medical (ruptured umbilical hernia,2 patients; spontaneous bacterial peritonitis, 1 patient;upper gastrointestinal bleed, 1 patient) or nonmedicalreasons (inability to obtain blood samples, 1 patient; fail-ure of the institution’s pharmacy to store the drugs prop-erly, 1 patient). For the patients who exited the studyearly, comparisons were made between the baseline mea-surements and those of the last inpatient day. Throughoutthe study, all patients were maintained on their usualdoses of diuretic(s), which were not different between the4 patient groups (Table 1).

Renal Water HandlingVPA-985 produced an overall significant aquaretic re-

sponse compared with placebo in edematous patients whowere on diuretic therapy, as well as in patients withSIADH who were not on diuretics. There was a dose-related significant increase in the net fluid volume (urineoutput-fluid intake) and free water clearance (Fig. 1),leading to dose-related significant increases in serum [Na](Fig. 2) and serum osmolality (Fig. 3). There was an as-sociated significant decrease in urinary osmolality (Fig. 3)without any change in urinary sodium excretion (Table

2). There was an overall decrease in body weight in all 4study groups, but the difference was only statistically sig-nificant in the 25 mg twice per day group (P � .02)(Table 3). Because 5 of the 250 mg twice per day grouphad withdrawn from the study by day 7, the mean weightappears to be markedly decreased compared with baseline(Table 3); however, when correcting the baseline weightfor dropouts, the difference was not statistically differentin the 250 mg twice per day group. Serum creatinine didnot change in any of the patient groups throughout thestudy period (Table 2).

On analyzing the patients with cirrhosis as a separategroup, the serum [Na] levels were 127 � 1 mmol/L onday 1 versus 126 � 1 mmol/L (P � .05) on last inpa-tient day for the placebo group; 126 � 1 mmol/Lversus 129 � 2 mmol/L (P � .05) for the 25 mg twiceper day group; 122 � 2 mmol/L versus 127 � 3mmol/L (P � .05) for the 125 mg twice per day group;

Fig. 1. (A) Twenty-four–hour net fluid volume (urine output minus fluid

intake) and (B) renal free water clearance in the 4 study groups. (‚)

Placebo; (●) 25 mg twice daily; (■) 125 mg twice daily; (Œ) 250 mg

twice daily. *, P � .05 versus placebo; **, P � .01 versus placebo; #,

P � .05 versus 25 mg twice per day; ‚, P � .01 versus 25 mg twice

per day; ¶, P � .05 versus 125 mg twice per day.

HEPATOLOGY, Vol. 37, No. 1, 2003 WONG ET AL. 185

and 125 � 1 mmol/L versus 132 � 1 mmol/L (P �

.003) for the 250 mg twice per day group. The serumcreatinine readings for the patients with cirrhosis were82.5 � 2.9 �mol/L on day 1 versus 88.4 � 6.4 �mol/Lon day 7 for the placebo group; 67.0 � 14.3 �mol/Lversus 75.1 � 9.3 �mol/L for the 25 mg twice per daygroup; 83.1 � 6.2 �mol/L versus 107.1 � 15.9�mol/L for the 125 mg twice per day group; and109.9 � 19.2 �mol/L versus 77.7 � 6.6 �mol/L forthe 250 mg twice per day group. There was no signif-icant difference in the serum creatinine levels betweenday 1 and day 7 in the 4 patient groups.

In the 5 patients with SIADH, 1 received placebo,whereas 3 patients received 25 mg twice per day, and the fifthpatient received 250 mg twice per day. Analysis of the resultsof the 4 patients who received active medication showed thattheir serum sodium increased from 127 � 3 mmol/L on day1 to 139 � 1 mmol/L on day 7 (P � .01). There was nosignificant change in their body weight (62.7 � 5.9 kg onday 1 versus 61.9 � 6.3 kg on day 7; p � .05) nor in their

serum creatinine levels (62 � 6 �mol/L on day 1 versus75 � 7 �mol/L on day 7; P � .05).

Systemic HemodynamicsThe baseline supine and standing mean arterial pres-

sures were not significantly different between the 4 studygroups (80 � 3 mm Hg and 82 � 3 mm Hg, respectively,for the placebo group; 75 � 4 mm Hg and 74 � 3 mmHg for the 25 mg twice per day group; 79 � 3 mm Hgand 77 � 4 mm Hg for the 125 mg twice per day group;and 78 � 4 mm Hg and 74 � 3 mm Hg for the 250 mgtwice per day group). Likewise, the baseline supine andstanding heart rates were not significantly different be-tween the 4 study groups (79 � 3 beats/min and 83 � 4beats/min, respectively, for the placebo group; 80 � 4beats/min and 86 � 5 beats/min for the 25 mg twice perday group; 80 � 4 beats/min and 94 � 4 beats/min forthe 125 mg twice per day group; and 81 � 4 beats/minand 93 � 4 beats/min for the 250 mg twice per day

Fig. 2. (A) Serum [Na] and (B) change in serum [Na] in the 4 study

groups. Change in serum sodium value represents the difference between

the day in question and previous days’ serum sodium values. (‚)

Placebo; (●) 25 mg twice daily; (■) 125 mg twice daily; (Œ) 250 mg

twice daily. *, P � .05 versus placebo; **, P � .01 versus placebo; #,

P � .05 versus 25 mg twice per day; ‚, P � .01 versus 25 mg twice

per day; ¶, P � .05 versus 125 mg twice per day.

Fig. 3. (A) Serum osmolality and (B) urinary osmolality in the 4 study

groups. (‚) Placebo; (●) 25 mg twice daily; (■) 125 mg twice daily; (Œ)

250 mg twice daily.*, P � .05 versus placebo; **, P � .01 versus

placebo; #, P � .05 versus 25 mg twice per day; ‚, P � .01 versus 25

mg twice per day; ¶, P � .05 versus 125 mg twice per day.

186 WONG ET AL. HEPATOLOGY, January 2003

group). There were no overall changes in the orthostaticmean arterial pressures or the heart rate after the admin-istration of VPA-985 in the 4 study groups throughoutthe entire study period (Table 2).

Hormonal ProfileThere was no significant change in plasma renin activ-

ity, norepinephrine, or Aldo throughout the study periodin any of the patient groups. In contrast, plasma vasopres-sin increased significantly at the end of the study periodfor both the VPA-985 125 mg twice per day group andthe 250 mg twice per day group (Table 4).

Symptoms and Safety ProfileFor symptoms related to dehydration, the thirst score

was used. The thirst score was not significantly differentbetween the 4 study groups at baseline; however, patientsin the VPA-985 250 mg twice per day group consistentlycomplained of increased thirst, and this was reflected intheir significantly increased thirst score throughout thestudy period (Table 4). None of the patients in the pla-cebo group had their medication (VPA-985) withheldbecause of an increase in serum [Na] by �8 mmol/L or toa value of �142 mmol/L. In contrast, 1 patient in the 25mg twice per day group (SIADH patient) had his VPA-

Table 2. Changes in Systemic Hemodynamics, Renal Fucntion, and Sodium Excretion Following the Administration of

VPA-985 in the 4 Study Groups

Day �1 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7

�MAP (mm Hg)

Placebo 2.8 � 2.3 2.7 � 1.9 6.9 � 2.3 4.6 � 2.5 4.9 � 3.3 1.8 � 4.1 3.2 � 2.0 0.4 � 3.4

25 mg bid �1.3 � 2.6 �0.8 � 2.9 �5.9 � 2.9† �3.2 � 3.2 �3.4 � 3.8 0.3 � 2.2 �1.5 � 2.6 0.3 � 2.0

125 mg bid �3.3 � 3.5 �4.5 � 2.3 �3.1 � 1.7* 1.6 � 2.7 �5.7 � 2.3* �1.8 � 2.2 �1.9 � 2.8 �2.4 � 2.7

250 mg bid �3.3 � 1.8 �4.7 � 2.3 �1.1 � 2.3* �0.6 � 1.3 �1.4 � 2.4 �1.4 � 1.9 �1.7 � 4.3 �5.7 � 4.4

�Heart rate (beats/min)

Placebo 6 � 4 8 � 4 10 � 2 9 � 1 12 � 3 11 � 2 10 � 2 11 � 2

25 mg bid 6 � 2 6 � 2 12 � 3 8 � 2 5 � 2 9 � 2 5 � 4 13 � 4

125 mg bid 13 � 4 13 � 4 9 � 2 11 � 3 12 � 1 6 � 3 12 � 3 10 � 2

250 mg bid 11 � 3 12 � 4 15 � 5 11 � 4 18 � 5‡ 9 � 4 8 � 3 11 � 3

Urinary sodium (mmol/d)

Placebo 107 � 21 — — 82 � 12 — 93 � 17 — 102 � 28

25 mg bid 120 � 43 — — 56 � 23 — 44 � 14 — 46 � 11

125 mg bid 71 � 19 — — 64 � 15 — 51 � 17 — 57 � 20

250 mg bid 110 � 37 — — 50 � 11 — 52 � 12 — 51 � 16

Serum creatinine (57-110 �mol/L)

Placebo 95.4 � 10.5 — — 96.8 � 14.1 — 95.3 � 13.3 — 97.2 � 12.2

25 mg bid 72.0 � 10.0 — — 80.1 � 9.7 — 75.7 � 9.5 — 76.0 � 6.5

125 mg bid 84.4 � 5.8 — — 95.6 � 6.6 — 97.7 � 10.1 — 105.2 � 14.3

250 mg bid 104.3 � 14.0 — — 111.4 � 12.4 — 91.7 � 5.8 — 87.3 � 8.4

NOTE. � � difference between supine and standing values.

*P � .05 versus placebo, †P � .01 versus placebo, ‡P � .01 versus 25 mg bid.

Table 3. Overall Thirst Score and Weight With the Administration of VPA-985 in the 4 Study Groups

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7

Thirst score

Placebo (n � 11) 60.3 � 7.8 58.3 � 7.0 62.3 � 7.1 64.2 � 8.2 64.7 � 7.7 79.0 � 7.6 79.2 � 7.6

25 mg bid (n � 11) 47.7 � 7.4 57.3 � 6.9 57.2 � 7.7 49.8 � 8.6 48.4 � 8.5 50.1 � 7.6 51.9 � 7.5

125 mg bid (n � 11) 57.1 � 8.5 56.5 � 6.9 62.0 � 7.0 71.9 � 8.1 67.2 � 8.0 67.9 � 7.4 62.9 � 7.3

250 mg bid 35.3 � 8.7 60.2 � 7.4*† 55.1 � 7.4* 70.4 � 9.5*† 67.5 � 8.9* 78.3 � 8.9* 54.4 � 10.5

(n � 10) (n � 10) (n � 10) (n � 8) (n � 8) (n � 7) (n � 5)

Weight (kg)

Placebo (n � 11) 83.8 � 6.0 83.6 � 6.0 83.1 � 6.0 82.9 � 6.0 82.5 � 6.0 85.0 � 5.9 84.9 � 6.1

25 mg bid (n � 11) 69.2 � 3.9 68.3 � 3.9 68.7 � 4.2 70.9 � 4.0 68.6 � 4.4 68.3 � 4.4 68.7 � 4.3

125 mg bid (n � 11) 77.8 � 3.5 76.8 � 3.6 76.0 � 3.4 75.8 � 3.5 75.6 � 3.5 75.6 � 3.4 75.4 � 3.3

250 mg bid 72.3 � 7.2 70.7 � 7.2 70.5 � 7 68.4 � 8.7 68.2 � 8.7 72.3 � 9.3 58.0 � 3.4

(n � 10) (n � 10) (n � 10) (n � 8) (n � 8) (n � 7) (n � 5)

NOTE. Values on day 1 were taken prior to administration of medications. The total number of patients (n) for each study day for the 250 mg bid group is shown

underneath the mean � SEM value.

*P � .05 versus day 1 (baseline), †P � .05 versus placebo.

HEPATOLOGY, Vol. 37, No. 1, 2003 WONG ET AL. 187

985 withheld on day 2 because of an increase in serum[Na] by more than 8 mmol/L and again on days 3 and 5because the serum [Na] had increased to �142 mmol/L.One patient in the 125 mg twice per day group (patientwith cirrhosis) had his VPA-985 withheld on day 2, andagain on days 4 to 7 because his serum [Na] had increasedto �142 mmol/L. In the 250 mg twice per day group, 5patients had to have their VPA-985 withheld on 11 occa-sions. Two patients (with cirrhosis) in this group had theirVPA-985 withheld once because of an increase in serum[Na] by �8 mmol/L, 2 (1 patient with CHF and 1 patientwith SIADH) had their VPA-985 withheld on 2 separatedays because of either an increase in serum [Na] by �8mmol/L or to a value of �142 mmol/L, whereas the fifthpatient (with cirrhosis patient) had his VPA-985 withheldfor 5 of his 7 inpatient days because of serum [Na] levels�142 mmol/L. In the same group, VPA-985 was firstwithheld on the second day in 2 patients, and thereafteron day 3 (1 patient), day 4 (2 patients), day 5 (2 patients),day 6 (2 patients), and day 7 (2 patients). One patient inthe 25 mg twice per day group and another patient in the250 mg twice per day group developed worsening en-cephalopathy that was reversed easily with lactulose. Onepatient died after aspiration pneumonia. None of the pa-tients with cirrhosis with ascites had any apparent reduc-tion in the amount of ascites.

Discussion

The development of hyponatremia and hypo-osmola-lity in cirrhosis and CHF is a hallmark of advanced dis-ease.15-17 It represents a progressive deterioration ofhemodynamics with consequent activation of variouscompensatory neurohormonal mechanisms, which di-

rectly or indirectly participate in the abnormal renal waterhandling. The increased reabsorption of sodium in theproximal tubule of the nephron, leading to a decreaseddistal sodium delivery, results in an inability of thenephron to generate free water. In addition, the nonos-motic release of vasopressin through osmoreceptor andnonosmoreceptor pathways18,19 further impairs free waterclearance, ultimately resulting in hyponatremia. In themanagement of patients with cirrhosis and severe hypo-natremia, the usual practice is to expand the intravascularvolume of these patients in an attempt to counteract thehemodynamic abnormalities; or to correct the causes ofsystemic vasodilatation such as infection; or to eliminatethe causes of dehydration such as diuretic therapy or ex-cessive diarrhea from over-zealous use of lactulose. How-ever, in patients whose serum [Na] cannot be normalizedby these measures, the improvement in serum [Na] can beachieved by either reducing vasopressin release or by in-hibiting the renal effects of vasopressin with �-opioid re-ceptor agonists, which reduce vasopressin release. Thelatter has proved to be successful in inducing an aquaresisin both animal models20,21 and patients22 with cirrhosis;however, the aquaretic effect was not sustained in patientswith cirrhosis.22 Preliminary studies of vasopressin recep-tor antagonists, which competitively block the effects ofvasopressin at the renal collecting tubules, also have beenshown to be effective in producing an aquaresis in bothanimal models23,24 and patients25 with heart failure. Stud-ies in animal models26,27 and patients28 with cirrhosishave yielded similar results.

VPA-985 is a recently developed, orally active, non-peptide selective V2 vasopressin receptor antagonist.12 Ithas the advantage over other vasopressin receptor antag-

Table 4. Hormonal Profile of the 4 Study Groups

Placebo 25 mg bid 125 mg bid 250 mg bid

Vasopressin

(0.47-8.52 pmol/L)

Day 1 1.00 � 0.20 1.27 � 0.67 0.79 � 0.17 1.86 � 0.63

Last inpatient day 1.02 � 0.20 0.86 � 0.14 1.70 � 0.30*†‡ 2.80 � 0.82*†‡

Nonrepinphrine

(0.65-4.14 nmol/L)

Day 1 7.02 � 1.57 4.96 � 0.59 7.10 � 1.23 5.71 � 1.92

Last inpatient day 6.12 � 0.77 5.33 � 0.92 7.31 � 1.46 7.36 � 1.55

Plasma renin activity

(0.2-7.7 �g/L/h)

Day 1 26.18 � 5.02 15.45 � 3.42 25.20 � 3.40 24.37 � 7.29

Last inpatient day 22.11 � 5.37 17.10 � 3.82 20.24 � 3.13 23.80 � 6.47

Aldosterone

(0.11-0.86 nmol/L)

Day 1 4.52 � 1.35 2.70 � 1.03 4.97 � 0.79 3.33 � 1.37

Last inpatient day 5.29 � 1.29 3.35 � 1.11 4.85 � 1.00 2.63 � 1.02

NOTE. Values on day 1 were taken before administration of medication.

*P � .05 versus baseline, †P � .05 versus placebo, ‡P � .05 versus 25 mg bid.

188 WONG ET AL. HEPATOLOGY, January 2003

onists of a greater specific selectivity for the V2 receptorsin the renal collecting tubule29 and, therefore, increasedpotency of action.13 The lack of agonist action furtherenhances its potency.13 In patients with cirrhosis, VPA-985 produced a dose-dependent aquaresis after single oraldoses of up to 300 mg.30 We have shown in this study thatthe beneficial effects of VPA-985 in improving renal wa-ter handling was maintained with continued administra-tion for 7 days in patients with hyponatremia in differentdisease groups, including cirrhosis or CHF, with diuretictherapy and SIADH, resulting in a dose-dependent sus-tained increase in renal free water clearance together witha significant improvement in serum osmolality and serum[Na]. None of the patients received intravascular volumeexpansion to counteract the hyponatramia, so that a cor-rect evaluation of the aquaretic effects of VPA985 couldbe made. Despite this, improvement in renal water han-dling was achieved without any significant changes in re-nal electrolyte excretion, systemic hemodynamics, orrenal function. The higher dose of 250 mg twice per daywas less well tolerated and was associated with significantdehydration as indicated by increased thirst and markedincreases in serum sodium concentration, necessitatingfrequent dose withdrawals. The corollary from this obser-vation is that the administration of high doses of VPA-985 requires careful monitoring for signs of dehydration,and should not be given to patients without easy access towater.

The aquaretic effects of VPA-985 were anticipatedfrom its known mechanisms of action. Unlike traditionaldiuretics, which increase sodium excretion together withwater excretion, VPA-985 selectively increased the renalfree water clearance without affecting the renal sodiumexcretion, resulting in the serum [Na] returning to nor-mal levels. The competitive binding of VPA-985 to thevasopressin V2 receptor also explains the increased efficacyof higher doses of VPA-985. The aquaretic effects ofVPA-985 are dependent on the generation of free water inthe thick ascending limb of the Loop of Henle, which, inturn, is dependent on the reabsorption of NaCl at thesame site.12 Therefore, theoretically, the inhibition ofNaCl reabsorption in the thick ascending limb of theLoop of Henle such as the concomitant administration offurosemide should reduce the efficacy of VPA-985. Innormal anesthetized rats, VPA-985 and furosemide de-creased urinary osmolality to a similar extent, whereas thecombination produced a slightly greater decrease in uri-nary osmolality.12 Therefore, it appears that the aquareticeffect of VPA-985 is independent of the NaCl reabsorp-tion proximal to the renal collecting tubules. This offersthe potential for combination therapy in conditions ofsodium retention and hyponatremia, such as liver cirrho-

sis with ascites. However, the doses of both VPA-985 andfurosemide will have to be adjusted carefully to avoidoverdiuresis if this combination is to be used, becausehigh doses of both agents can produce marked water loss.

The aquaretic effects of VPA-985, as indicated by thefree water clearance, although well maintained, appearedto plateau with repeated administrations for several days,especially with the higher doses. Similar findings also wereobserved in rats with cirrhosis that received a 10-daycourse of another vasopressin receptor antagonist,SR121463,26 with the aquaretic effects being moremarked during the first 5 days of drug administration.This may be explained by the significant increase in theplasma vasopressin levels after continued VPA-985 ad-ministration in the higher doses groups. Similar increasesin plasma vasopressin levels also have been observed withother V2 receptor antagonists.23,27,31 High plasma levels ofvasopressin have been shown to down-regulate V2 recep-tors, especially after dehydration.32 The down-regulationof V2 receptors may well represent the body’s in-builtdefense mechanism against excessive fluid loss and furtherdehydration. Indeed, plasma renin activity and plasmanorepinephrine levels, indirect indicators of the fullness ofthe effective arterial blood volume, did not increase sig-nificantly with repeated administration of VPA-985. Thislack of continued fluid loss also might have protected thepatient against a continued rise in serum [Na], therebyreducing the risk of demyelination33 as well as any signif-icant deterioration in renal function. The same mecha-nism also might be responsible for maintaining meanarterial blood pressure throughout the study. The poten-tial for escape from the aquaretic effects of VPA-985 willawait clarification from long-term studies.

Despite the fact that the total body fluid loss appeared tohave plateaued with repeated administration of VPA-985,many patients reported significant increase in thirst, espe-cially with the higher doses of VPA-985. Thus, the physicianwho administers VPA-985 must be aware of the side effect ofsignificant dehydration, especially with the higher doses.Measurement of fluid intake is no guarantee against dehy-dration, because this can be difficult even in the hospitalsetting. Therefore, other parameters, such as increased thirstor frequent serum [Na] estimations, require monitoring. In-deed, many patients in the higher dose groups required dosesof VPA-985 to be withheld because of significant increases inserum [Na]. The careful monitoring of the study patientswith provisions for withholding VPA-985 doses might havecontributed to the favorable safety profile. Deterioration ofrenal function was not observed in any of the study patients,and hepatic encephalopathy was reported only in a smallpercentage of patients. However, the potential for excessiveaquaretic effects of VPA-985, especially with the higher

HEPATOLOGY, Vol. 37, No. 1, 2003 WONG ET AL. 189

doses, demands careful selection of doses and close monitor-ing to prevent extreme water diuresis and dehydration. Thefrequent association of significant side effects with 250 mgtwice per day would suggest that its use should be discour-aged. Future studies with VPA-985 will need to assess lowerdoses in patients with less degree of hemodynamic instabilityto benefit from its aquaretic effects without the patients suf-fering from unwanted side effects. In conclusion, VPA-985is effective in correcting renal water handling and hypona-tremia in conditions associated with water retention. Thepotential for combination therapy with the appropriate doseof VPA that will permit an aquaresis without too many sideeffects may permit diuretics to be continued, and hence ef-fect a better fluid loss, thereby providing an advantage overtraditional diuretics in the management of sodium and waterretention in cirrhosis and cardiac failure. However, care mustbe taken to avoid rapid overaquaresis because this may pre-dispose the patient to unwanted side effects such as renalfailure, encephalopathy, and possibly central pontine myeli-nosis.

Acknowledgment: The authors thank Jeanne Gottsteinof Northwestern University, Chicago, IL, for her tireless ef-forts in performing the statistical analysis for the study.

Appendix

The North American VPA-985 Study Group is Vin-cent Bain, M.D., University of Alberta, Edmonton, Al-berta, Canada; David Barnes, M.D., Cleveland ClinicFoundation, Cleveland, OH; Daniel Bichet, M.D., Ho-pital du Sacre-Couer de Montreal, Montreal, Quebec,Canada; Stephen H. Caldwell, M.D., University of Vir-ginia, Charlottesville, VA; Daniel Ganger, M.D., St.Luke’s Medical Centre, Chicago, IL, Thomas Gonwa,M.D., Baylor University Medical Centre, Dallas, TX;Ray E. Hershberger, M.D., Oregon Health Sciences Uni-versity, Portland, OR; Peter Liu, M.D., Toronto GeneralHospital, University of Toronto, Toronto, Ontario, Can-ada; Anna S. F. Lok, M.D., University of Michigan Med-ical Centre, Ann Arbor, MI; Gerald Minuk, M.D.,Health Sciences Centre, Winnipeg, Manitoba, Canada;Kevin Mullen, M.D., Metro Health Medical Centre,Cleveland, OH; Gary L. Robertson, M.D., NorthwesternUniversity, Chicago, IL; Arun J. Sanyal, M.D., MedicalCollege of Virginia, Richmond, VA.

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