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Abstract

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Appendix
  8. References

Hyponatremia in cirrhosis is associated with significant morbidity and mortality and complicates ascites management. Vasopressin receptor antagonists improve serum sodium concentration by increasing renal solute-free water excretion, but their effects on the management of ascites have not been assessed. Our aim was to investigate the effects of satavaptan, a highly selective vasopressin V2 receptor antagonist, on ascites management and serum sodium in hyponatremic patients with cirrhosis. A total of 110 patients with cirrhosis, ascites, and hyponatremia (serum sodium ≤130 mmol/L) were included in a multicenter, double-blind, randomized, controlled study comparing three fixed doses of satavaptan (5 mg, 12.5 mg, or 25 mg once daily) versus placebo. Duration of treatment was 14 days and all patients received spironolactone at 100 mg/day. Satavaptan treatment was associated with improved control of ascites, as indicated by a reduction in body weight (mean change at Day 14 was +0.49 kg [±4.99] for placebo versus +0.15 kg [±4.23], −1.59 kg [±4.60] and −1.68 kg [±4.98] for the 5 mg, 12.5 mg, and 25 mg doses, respectively; P = 0.05 for a dose-effect relationship overall) and a parallel reduction in abdominal girth. This beneficial effect on ascites was associated with improvements in serum sodium (mean change from baseline to day 5 was 1.3 ± 4.2, 4.5 ± 3.5, 4.5 ± 4.8, and 6.6 ± 4.3 mmol/L for the placebo group and the groups on satavaptan at 5 mg, 12.5 mg, and 25 mg/day, respectively; P < 0.01 for all compared to placebo). Thirst was significantly more common in patients treated with satavaptan compared to those treated with placebo, whereas the frequency of other adverse events was similar among groups. Conclusion: The V2 receptor antagonist satavaptan improves the control of ascites and increases serum sodium in patients with cirrhosis, ascites, and hyponatremia under diuretic treatment. (HEPATOLOGY 2008.)

The development of ascites in cirrhosis is the result of an abnormal regulation of the extracellular fluid volume that causes a positive fluid balance due to a persistently increased renal sodium and water reabsorption. Several lines of evidence indicate that this renal dysfunction is related to impairment in circulatory function characterized by splanchnic arterial vasodilation, secondary to sinusoidal portal hypertension. This causes a reduction in the effective arterial blood volume and a subsequent homeostatic activation of vasoconstrictor and sodium-retaining and water-retaining systems, including the renin-angiotensin-aldosterone system, the sympathetic nervous system, and vasopressin, which are responsible for sodium and water retention.1, 2 According to this pathogenesis, the pharmacological approach to treatment of ascites has been based on the administration of spironolactone, a drug that antagonizes the effect of aldosterone, which reduces the increased extracellular fluid volume by increasing renal sodium and water excretion.3 However, a significant proportion of patients with ascites either do not respond to spironolactone or require the administration of high doses of the drug, which increases the risk of side effects.3–5 Therefore, there is a need for other effective drugs in the management of ascites in cirrhosis.

Recently, selective antagonists of the renal effects of vasopressin have been developed.6 These drugs are effective orally and act by antagonizing the vasopressin V2 receptors present in the principal cells of the collecting ducts in the kidney. The administration of these drugs to healthy subjects causes a striking increase in urine volume due to a marked increase in solute-free water excretion.6, 7 Considering that patients with cirrhosis and ascites have high vasopressin levels (due to a nonosmotic hypersecretion of vasopressin) that contribute to fluid retention,8 the administration of these drugs could in theory be effective in the management of ascites in these patients. A few studies have been reported recently which indicate that vasopressin V2 receptor antagonists are effective in improving serum sodium concentration in patients with cirrhosis and ascites and dilutional hyponatremia.9, 10 However, the effect of these drugs on ascites has not been assessed. Therefore, the current study was undertaken to evaluate whether the highly selective vasopressin V2 receptor antagonist satavaptan has beneficial effects in the management of ascites in patients with cirrhosis and hyponatremia. In addition, the effect of treatment on serum sodium concentration was also assessed.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Appendix
  8. References

Study Population.

A total of 145 patients with cirrhosis and ascites were evaluated for inclusion in the study, which was approved by the Investigational Review Board of each participating hospital. Criteria for inclusion were: (1) cirrhosis as diagnosed by liver biopsy or a combination of clinical, biochemical, ultrasonograpical, and endoscopical findings; (2) moderate or tense ascites defined as grade 2 or 3 ascites according to previously established criteria5; (3) hyponatremia defined as serum sodium concentration ≤ 130 mmol/L8; and (4) written informed consent. Criteria for exclusion were below the age of 19 years, serum bilirubin > 8 mg/dL (135 μmol/L), prothrombin time < 30% (international normalized ratio [INR] > 3), platelet count < 30,000/mm3, serum creatinine > 2 mg/dL (175 μmol/L), serum potassium ≥ 5.5 mmol/L, hepatocellular carcinoma exceeding the Milan criteria,11 hepatic encephalopathy > grade 1,12 bacterial infection or gastrointestinal bleeding within 10 days prior randomization, treatment with large-volume paracentesis within 7 days prior to randomization, cardiac disease, marked arterial hypotension (systolic pressure < 80 mmHg), and treatment with substances or drugs that may either induce or significantly inhibit cytochrome P450 CYP3A within 14 days prior to randomization.

Thirty-five of the 145 screened patients were excluded during the screening period for various reasons (spontaneous increase of serum sodium to > 130 mmol/L in nine patients, development of complications of cirrhosis in nine, laboratory abnormalities in seven, and miscellaneous reasons in the remaining patients). Therefore, 110 patients were randomized to one of the following four groups: (1) placebo (28 patients); (2) satavaptan 5 mg/day (28 patients); (3) satavaptan 12.5 mg/day (26 patients); and (4) satavaptan 25 mg/day (28 patients). The median number of patients included in the 30 participating centers was 3 (range 1 to 14). Each participating center received blocks of study treatment which contained equal numbers of each of the four therapies on a random sequence generated by a computer program. The chart flow of patients included into the study is summarized in Fig. 1. Overall, 99 of the 110 patients included in the study (90%) completed therapy. Reasons for discontinuation of therapy in the placebo group were lack of efficacy in two patients and side effects in another two; in the satavaptan 5 mg/day group: lack of efficacy in one patient; in the satavaptan 12.5 mg/day group: lack of efficacy in one patient and adverse events in three; and in the satavaptan 25 mg/day group: liver transplantation in one patient.

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Figure 1. Chart flow of patients included in the study. Overall, 99 of the 110 patients included in the study (90%) completed therapy. Reasons for discontinuation were adverse events in five patients, lack of efficacy in four patients, patient decision in one, and liver transplantation in one.

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Study Design and Organization.

This was a prospective, multicenter, randomized, double-blind, placebo-controlled efficacy study that was conducted between April 2004 and March 2005. Before randomization, all patients entered a 5-day to 7-day screening period during which they received spironolactone at 100 mg/day. Other diuretic agents were washed out during this period. Other drugs required for treatment of complications of liver disease, such as beta-blockers or fluoroquinolones (mainly norfloxacin), were not withdrawn. The number of patients receiving beta-blockers during the study was 11, 11, 7, and 13 for the placebo group and the groups receiving satavaptan at 5 mg, 12.5 mg, and 25 mg/day, respectively, and that of patients receiving fluoroquinolones was 8, 7, 9, and 11, respectively. Patients were then randomized to double-blind treatment for 14 days with either placebo or satavaptan at 5 mg, 12.5 mg or 25 mg in a single daily dose. These doses were selected on the basis of the results of previous studies in healthy subjects and patients with cirrhosis (unpublished data).

Patients were hospitalized to receive the first doses of the study medication and remained in hospital until hyponatremia was corrected (defined as two consecutive serum sodium values ≥ 135 mmol/L, at least 12 hours apart) or for a maximum of 5 days. Subsequently, they were treated as outpatients and returned for visits on day 5, if previously discharged, and day 14. This visit was also performed for patients who prematurely discontinued the study medication. At each visit (days 1, 5, 14, and 21) and daily for the duration of hospitalization, a complete physical examination was performed; vital signs, abdominal girth, and body weight were measured; and blood tests were performed. Study treatment was temporarily discontinued if a patient had a serum sodium value ≥ 145 mmol/day on two separate analyses, 12 hours apart. The treatment was withheld for at least 24 hours and could be restarted only when the serum sodium value was < 145 mmol/day. Body weight and abdominal girth were always measured in the morning at approximately the same time each day. Body weight was measured with the patient on an empty bladder and wearing the same amount of clothing on each occasion, with no shoes. The same calibrated scales (Seca 780/783; Seca Medizinische Waagen und Messysteme, Vogel und Halke GmbH & Co., Hamburg, Germany) were used for all participating centers throughout the study. Serum sodium and other laboratory parameters were measured in local laboratories, except for hormonal measurements which were done in a central laboratory. For the duration of the study, all patients were maintained on a low-sodium diet (90 mmol/day) and daily fluid intake was limited to 1.5 L unless patients were thirsty or there was a medical need to increase fluid intake. Compliance with the study medication was assessed by recording the contents of returned treatment wallet cards.

The sponsor, Sanofi-Aventis, and the academic principal investigator designed the study, developed the protocol, and prepared the first and subsequent drafts of the manuscript, with input from participant academic investigators. The sponsor and the academic principal investigator held and analyzed the data. Decisions related to the final draft of the manuscript were made by the academic principal investigator in consultation with all coauthors. All authors contributed to writing of the manuscript.

Endpoints and Definitions.

There were two primary efficacy endpoints reflecting the two objectives of the study: (1) change in body weight from baseline (day 1) to the end of the study treatment period (day 14); and (2) change in serum sodium from baseline (day 1) to day 5. Secondary efficacy endpoints were: (1) a composite endpoint of ascites worsening, defined by either need for therapeutic paracentesis or increase in diuretic dose or weight gain of ≥ 2 kg during the study period; (2) change in abdominal girth from baseline to the end of study treatment; and (3) response in terms of improved hyponatremia at day 5, defined as increase in serum sodium of ≥ 5 mmol/L (or at discharge if sooner) compared with baseline or serum sodium on day 5 (or at discharge if sooner) ≥ 135 mmol/L. Safety and tolerability were also assessed as well as changes in serum and urine osmolality, serum creatinine, estimated glomerular filtration rate, as assessed by the MDRD (Modification of Diet in Renal Disease) method,13 serum potassium, 24-hour urine volume, and the plasma levels of renin, aldosterone, and vasopressin.

Statistical Analysis.

Sample size calculation was based on a global type I error of 5% (two-sided) for the coprimary endpoint of change in body weight from baseline to end of study treatment period. A mean minimum difference of 3.0 kg between placebo and satavaptan and a standard deviation (SD) of 3.0 was set. The primary analysis was conducted on the intent-to-treat population, which included all randomized patients who received at least one dose of the study medication, had a baseline assessment, and at least one post-baseline assessment. Considering that 15% of patients would not be evaluable for the primary analysis, the calculated sample size was 108 patients (27 per treatment arm) with a power of 80%. In the analysis of primary endpoints in case of dropout or missing values, the value used in the analysis was the last post-baseline measurement available (last observation carried forward procedure). Coprimary endpoints were analyzed by means of analysis of covariance including treatment as fixed effect and baseline value as covariate in the model. In order to maintain an overall type I error of 5%, the Hochberg's modification of the Bonferroni procedure was used to account for multiplicity of doses. For categorical variables, each dose group of satavaptan was compared with placebo, by using the Fisher's exact test. Calculations were performed with the statistical program SAS 8.2 (SAS Institute Inc., Cary, NC). Results are presented as mean ± SD. P values less than 0.05 were considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Appendix
  8. References

Patient Characteristics.

The baseline characteristics of patients included in the study at the time of enrollment is shown in Table 1. Patients included had severe cirrhosis, as indicated by markedly impaired liver function tests and high Child-Pugh and Model for End-Stage Liver Disease (MELD) scores. The characteristics and management of ascites before enrollment in the study as well as the mean body weight change during the screening period are shown in Table 2.

Table 1. Baseline Characteristics of the 110 Patients Included in the Study According to the Assigned Treatment
CharacteristicPlacebo (n = 28)Satavaptan 5 mg/day (n = 28)Satavaptan 12.5 mg/day (n = 26)Satavaptan 25 mg/day (n = 28)
  1. Values are means ± SD. Abbreviations: INR, international normalized ratio; MELD, Model for End-Stage Liver Disease.

Age (years)55 ± 1057 ± 856 ± 959 ± 10
Sex (male/female)22/616/1219/720/8
Alcoholic cirrhosis, n (%)21 (70)21 (75)23 (85)20 (71)
Previous complications of cirrhosis    
 Hepatic encephalopathy, n (%)4 (14)6 (21)10 (38)10 (36)
 Variceal bleeding, n (%)3 (11)6 (21)5 (19)5 (18)
 Spontaneous bacterial peritonitis, n (%)4 (14)4 (14)6 (23)5 (18)
Serum bilirubin (μmol/mL)79 ± 6360 ± 3564 ± 3763 ± 43
Serum albumin (g/dL)28 ± 827 ± 626 ± 828 ± 7
INR1.7 ± 0.41.7 ± 0.41.6 ± 0.41.7 ± 0.3
Serum sodium (mmol/L)126 ± 4127 ± 5128 ± 4126 ± 6
Serum creatinine (μmol/mL)88 ± 2582 ± 2492 ± 4190 ± 30
Child-Pugh score10.1 ± 1.79.8 ± 1.49.8 ± 1.89.9 ± 1.6
MELD score18.1 ± 4.917 ± 4.416.9 ± 5.417.1 ± 3.9
Table 2. Characteristics and Management of Ascites Before Inclusion in the Study in the 110 Patients Included According to the Assigned Treatment
CharacteristicPlacebo (n = 28)Satavaptan 5 mg/day (n = 28)Satavaptan 12.5 mg/day (n = 26)Satavaptan 25 mg/day (n = 28)
  • Values are number of patients and percentages (in brackets) except for body weight change which are means ± SD.

  • *

    Up to 200 mg/day of spironolactone alone or 100 mg/day of spironolactone plus 40 mg/day of furosemide.

  • Spironolactone 200 mg/day plus furosemide 80 mg/day or greater.

Refractory ascites11 (39)14 (50)9 (35)13 (46)
Diuretic dosage    
 None8 (29)6 (21)10 (38)5 (18)
 Moderate*16 (57)15 (54)14 (54)18 (64)
 High4 (14)7 (25)2 (8)5 (18)
Large-volume paracentesis    
 Within the previous year    
  None14 (52)15 (56)13 (50)14 (52)
  ≤ 37 (26)5 (18)9 (35)8 (30)
  > 35 (22)7 (26)4 (15)5 (18)
 Within the previous 3 weeks8 (30)9 (33)3 (12)5 (19)
Body weight change during the screening period0.9 ± 2.40.8 ± 2.2−0.4 ± 2.90.1 ± 3.4

Effects of Treatment on Ascites.

With respect to the effects of treatment on ascites, the primary endpoint was the change in body weight from baseline to the end of the treatment period, whereas secondary endpoints were change in abdominal girth from baseline to the end of the treatment period and a composite endpoint of ascites worsening, defined by either need of therapeutic paracentesis or increase in diuretic dose or weight gain of ≥ 2 kg. Mean changes in body weight from baseline to day 14 for the placebo group and groups receiving satavaptan at 5, 12.5, and 25 mg/day were: 0.49 ± 4.99, 0.15 ± 4.23, −1.59 ± 4.6, and −1.68 ± 4.98 kg, respectively (P = 0.05, for a dose-effect relationship overall). When groups were compared between each other, there were no significant differences between the three groups of patients treated with satavaptan and the group of patients treated with placebo, probably due to the relatively low number of patients included in each group (least square mean difference versus placebo 5 mg/day: −0.54 (95% confidence interval −3.02, 1.93); 12.5 mg/day: −2.06 (−4.6, 0.48); 25 mg/day: −2.22 (−4.69, 0.24). The decrease in body weight in patients treated with the 12.5 and 25 mg/day doses occurred during the first days of therapy and was maintained thereafter (Fig. 2). Changes in body weight were associated with parallel changes in abdominal girth (mean changes in abdominal girth from baseline to day 14 for the placebo and satavaptan 5, 12.5, and 25 mg/day groups were: 1.4 ± 5.9, 0.0 ± 6.9, −3.0 ± 4.3, and −2.3 ± 6.4 cm, respectively; P < 0.05), which suggests that the reduction in body weight was at least in part due to reduction in ascites volume. Consistent with these findings, the percentage of patients with ascites worsening was greater in the group of patients treated with placebo than in those treated with satavaptan (placebo: 15/28 [54%], 5 mg/day: 11/28 [39%], 12.5 mg/day: 8/26 [32%], and 25 mg/day: 6/28 [21%], respectively), the difference reaching statistical significance for the 25 mg/day group compared to placebo (P = 0.026). The main reason for ascites worsening (28 of the 40 patients meeting this endpoint) was a weight gain of ≥ 2 kg during the study period. A total of 11 patients underwent interventions for treatment of ascites during the 15-day study period that were not allowed in the investigation protocol (one patient underwent a paracentesis and 10 patients had a modification of the diuretic treatment). An analysis made with these patients censored showed that these interventions had no effect on the results found in the intention-to-treat population.

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Figure 2. Mean changes of body weight in the four groups of patients included in the study from baseline to the end of treatment. Values under the graph are the number of patients at each time point.

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Effect of Treatment on Serum Sodium Concentration.

With respect to the effects of treatment on serum sodium concentration, the primary endpoint was the change in serum sodium from baseline to day 5, while the secondary endpoint was response in terms of improved hyponatremia at day 5, as defined by an increase in serum sodium ≥ 5 mmol/L compared with baseline or serum sodium ≥ 135 mmol/L. Overall, treatment with satavaptan was associated with an improvement in the low serum sodium concentration compared to placebo. Mean change in serum sodium concentration from baseline to day 5 was 1.3 ± 4.2, 4.5 ± 3.5, 4.5 ± 4.8, and 6.6 ± 4.3 mmol/L for the placebo and satavaptan 5, 12.5, and 25 mg/day groups, respectively (P < 0.01 for all doses of satavaptan compared to placebo) (Fig. 3). Likewise, a greater percentage of patients in the satavaptan groups compared to placebo group were responders in terms of improved hyponatremia at day 5: placebo: 5/28 (18%), 5 mg/day: 17/28 (61%), 12.5 mg/day: 14/26 (54%), and 25 mg/day: 18/28 (64%) (P < 0.02 for all satavaptan groups versus placebo). Corresponding values of responders at the end of treatment (day 14) were 7/28 (26%), 14/28 (50%), 14/26 (54%), and 23/28 (82%), respectively. The median time to response was very short: 1 day in the 25 mg/day satavaptan group and 2 days in the 5 and 12.5 mg/day groups. Changes in serum osmolality paralleled changes in serum sodium concentration (mean changes of serum osmolality from baseline to day 5 were: placebo: 2 ± 7; 5 mg/day: 8 ± 12; 12.5 mg/day: 11 ± 10; and 25 mg/day: 11 ± 12 mOsm/kg). It is important to emphasize that the improvement in serum sodium concentration was maintained in most patients throughout the study period (Fig. 3). Improvement in serum sodium concentration in patients treated with satavaptan occurred regardless the severity of hyponatremia. Mean change in serum sodium concentration in patients with baseline serum sodium < 125 mmol/L included in the three groups treated with satavaptan (n = 19) was 7.1±3.7 mmol/L. There was a trend for a lower baseline renin in responders versus nonresponders to satavaptan (median values 2608 versus 6428 ng/mL.hour, respectively). Other baseline parameters, including serum creatinine, MDRD, and vasopressin levels, were similar between responders and nonresponders. However, it should be kept in mind that patients were treated with different and fixed doses of satavaptan, which does not allow rigorous assessment of predictive factors of response, because response rate differed between doses.

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Figure 3. Mean serum sodium concentration in the four groups of patients included in the study from the screening period to the end of treatment. Values below graph are the number of patients at each time point.

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Effects of Treatment on Renal Function.

The administration of satavaptan was associated with a marked increase in urine volume and reduction in urine osmolality, findings consistent with an improvement in the renal solute-free water excretion (Table 3). The increase in urine volume occurred in most patients after the first dose of satavaptan and was maintained until the end of treatment. In some patients, the increase in urine volume was striking. In fact, 11 patients treated with satavaptan (one patient receiving 5 mg/day, four patients receiving 12.5 mg/day, and six patients receiving 25 mg/day) had a 24-hour urine volume of greater than 5 L at some point during the study (24-hour urine volume was measured at Day 1, daily during hospitalization, at Day 5, and at Day 14). No significant changes were observed in serum creatinine, glomerular filtration rate as estimated by the MDRD method, serum potassium concentration, and urinary potassium excretion throughout the study in any of the treatment groups (Table 3). Urinary sodium excretion increased significantly in the satavaptan 12.5 mg/day group.

Table 3. Effects of Treatment on Renal Function Parameters and Serum Potassium Concentration in the Four Groups of Patients
CharacteristicPlacebo (n = 28)Satavaptan 5 mg/day (n = 28)Satavaptan 12.5 mg/day (n = 26)Satavaptan 25 mg/day (n = 28)
  • Values are means ± SD except for urine sodium and urine potassium, which are medians and quartiles.

  • *

    End of treatment is day 14 or the last observation carried forward

  • **

    Available in 13 patients treated with placebo, 13 treated with Satavaptan 5 mg/day, 10 treated with Satavaptan 12.5 mg/day, and 12 treated with Satavaptan 25 mg/day.

  • ***

    Available in 19 patients treated with placebo, 21 treated with Satavaptan 5 mg/day, 18 treated with Satavaptan 12.5 mg/day, and 23 treated with Satavaptan 25 mg/day.

  • P = 0.06 versus placebo;

  • P < 0.01 versus placebo;

  • §

    P < 0.001;

  • P < 0.05 versus placebo.

Urine volume (mL/day)    
 Baseline1,372 ± 6371,420 ± 8431,602 ± 8551,774 ± 954
 End of treatment*1,316 ± 7162,177 ± 9303,246 ± 2,3852,763 ± 1,328
 Mean change−56 ± 739756 ± 7701,644 ± 2,183989 ± 1,470
Urine osmolality** (mOsm/kg)    
 Baseline527 ± 249432 ± 174416 ± 188517 ± 181
 End of treatment*563 ± 177284 ± 113241 ± 169187 ± 58
 Mean change36 ± 132−148 ± 182§−176 ± 161§−300 ± 173§
Serum creatinine (μmol/L)    
 Baseline88 ± 2582 ± 2492 ± 4190 ± 30
 End of treatment*102 ± 9189 ± 32106 ± 4794 ± 28
 Mean change14 ± 797 ± 1714 ± 424 ± 36
Estimated glomerular filtration rate (MDRD, mL/mm)    
 Baseline70 ± 2375 ± 2570 ± 2866 ± 20
 End of treatment*68 ± 2873 ± 3363 ± 2667 ± 19
 Mean change−0.4 ± 14−0.7 ± 14−7 ± 210.3 ± 23
Serum potassium (mmol/L)    
 Baseline4.6 ± 0.44.5 ± 0.74.4 ± 0.74.7 ± 0.7
 End of treatment*4.6 ± 0.74.6 ± 0.84.7 ± 0.64.7 ± 0.5
 Mean change−0.01 ± 0.80.1 ± 0.70.3 ± 0.50.1 ± 0.7
Urine sodium*** (mmol/day)    
 Baseline41 (13;114)84 (18;118)53 (11;85)57 (20;162)
 End of treatment*29 (11;81)62 (15;164)78 (16;155)92 (28;147)
 Median change−4 (−36;27)1 (−11;26)34 (−2;105)7 (−72;76)
Urine potassium*** (mmol/day)    
 Baseline35 (20;64)34 (21;70)36 (22;46)37 (24;62)
 End of treatment*41 (19;53)32 (22;44)35 (20;72)39 (28;56)
 Median change−0.4 (−7;16)−6 (−20;8)5 (−15;23)3 (−17;25)

Effects of Treatment on Circulatory Function and Vasoactive Hormones.

No significant changes were observed during therapy in systolic pressure, diastolic pressure, heart rate, and activity of the renin-angiotensin-aldosterone system in any of the treatment groups. By contrast, the administration of satavaptan was associated with an increase in plasma vasopressin concentration that paralleled the dose of satavaptan (Table 4).

Table 4. Effects of Treatment on Circulatory Function and Vasoactive Hormones in the Four Groups of Patients
CharacteristicPlacebo (n = 28)Satavaptan 5 mg/day (n = 28)Satavaptan 12.5 mg/day (n = 26)Satavaptan 25 mg/day (n = 28)
  • Values are mean ± SD, except for immunoreative renin, aldosterone, and vasopressin that are presented as median and quartiles.

  • *

    End of treatment is day 14 or the last observation carried forward.

  • P = 0.08 versus placebo.

  • P = 0.03 versus placebo.

  • §

    P = 0.057 versus placebo

Systolic pressure (mmHg)    
 Baseline116 ± 22115 ± 21113 ± 17120 ± 18
 End of treatment*114 ± 20116 ± 17115 ± 19117 ± 16
 Mean change−2 ± 150 ± 152 ± 16−3 ± 12
Diastolic pressure (mmHg)    
 Baseline69 ± 1168 ± 1368 ± 1069 ± 12
 End of treatment*68 ± 1169 ± 1170 ± 1168 ± 10
 Mean change−1 ± 100 ± 122 ± 9−1 ± 10
Heart rate (beats per minute)    
 Baseline83 ± 1479 ± 1478 ± 1379 ± 15
 End of treatment*81 ± 1383 ± 1480 ± 1580 ± 12
 Mean change−2 ± 93 ± 122 ± 101 ± 13
Immunoreactive renin (ng/mL.hour)    
 Baseline3784 (1440;14040)2464 (936;7952)4184 (2584;8120)5120 (1840;12072)
 End of treatment*5408 (3272;10664)3136 (1312;10080)3812 (2456;8056)3336 (1568;11272)
 Median368 (−4800;2240)576 (−504;2240)356 (−168;1384)−560 (−2432;1368)
Plasma aldosterone (pmol/L)    
 Baseline3650 (805;5495)1650 (830;5715)1945 (1180;3715)3440 (1330;5300)
 End of treatment*3010 (1390;5005)1690 (1180;6145)1955 (1195;4135)2250 (690;3940)
 Median90 (−940;900)280 (−30;960)135 (−455;1155)−360 (−2130;360)
Plasma vasopressin (ng/L)    
 Baseline1.7 (1.5;3)1.8 (1.7;2.9)2.1 (1.6;2.9)2.1 (1.5;3.1)
 End of treatment*1.9 (1.5;3)3 (2.4;3.8)3.6 (2.7;4.3)3.9 (2.7;5.6)
 Median0 (−0.2;0.5)0.9 (−0.1;1.7)1.2 (0.2;1.9)1 (0.1;3)§

Side Effects.

Overall, 61 of the 110 patients included experienced at least one treatment-emergent adverse event (TEAE) of any class. TEAEs as well as serious TEAEs were reported with a similar frequency in the placebo group compared to the satavaptan 5 mg, 12.5, and 25 mg groups (TEAEs: 17 [61%], 14 [50%], 14 [54%], and 16 patients [57%], respectively; serious TEAEs: 5 [18%], 4 [14%], 4 [15%], and 5 [18%], respectively). Thirst was more frequently reported in patients treated with satavaptan than in those treated with placebo and its occurrence was dose-related (one patient [4%] in the placebo group compared to 1 [4%], 2 [8%], and 8 patients [29%] in the 5 mg/day, 12.5 mg/day, and 25 mg/day groups). An increase in thirst in patients treated with satavaptan compared to those treated with placebo was also observed when thirst was analyzed with the use of a visual analog scale. Hypernatremia, as defined by a serum sodium concentration ≥ 145 mmol/L, occurred in two patients treated with satavaptan (one treated with 12.5 mg/day and one with 25 mg/day) and no patient treated with placebo. A rapid increase in serum sodium concentration (≥ 8 mmol/L in 24 hours) was observed during the first 5 days of therapy in four patients treated with placebo, two patients treated with satavaptan 5 mg/day, three patients treated with satavaptan 12.5 mg/day, and four patients treated with satavaptan 25 mg/day. None of these patients developed neurological symptoms. The number of patients who developed complications of cirrhosis during the study was similar among the four treatment groups: three in the placebo group, two in the 5 mg/day group, five in the 12.5 mg/day group, and five in the 25 mg/day group.

Discussion

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Appendix
  8. References

The main findings of the current study were that the highly selective vasopressin V2 receptor antagonist satavaptan, in addition to increasing serum sodium concentration, was effective in the management of ascites. The administration of satavaptan was associated with a reduction of body weight compared to placebo, indicating that it reduced the increased body fluid volume characteristic of cirrhosis with ascites. The doses of 12.5 and 25 mg/day were more effective than the 5 mg/day dose. Changes in abdominal girth paralleled those in body weight, suggesting that the reduction in body weight was probably due at least in part to a reduction in ascites volume. Moreover, a lower percentage of patients treated with satavaptan showed worsening of ascites during the study compared to placebo. Because the patient population included in the study (patients with ascites and dilutional hyponatremia) constitute a particularly difficult-to-treat population,14–16 the observed beneficial effects of satavaptan in the control of ascites are particularly relevant and suggest that treatment with vasopressin V2 receptor antagonists may represent a new pharmacological approach to management of ascites. Nevertheless, these results should be confirmed in further studies that include a larger number of patients and with longer treatment duration. Moreover, the effects of treatment on other patient populations should also be assessed.

A few previous studies have shown that vasopressin V2 receptor antagonists are effective in improving serum sodium concentration in patients with cirrhosis and ascites and dilutional hyponatremia with a low incidence of side effects.9, 10, 17 The current study extends these observations and shows that satavaptan is very effective in improving serum sodium concentration in this patient population compared to placebo (Fig. 3). The percentage of responders (that is, patients showing an increase in serum sodium of equal to or greater than 5 mmol/L compared with baseline after 5 days of therapy) was 61%, 54%, and 64% in the groups treated with satavaptan at 5 mg, 12.5 mg, and 25 mg/day, respectively, compared to 18% in the placebo group. Although there was no clear dose-effect relationship when the efficacy was analyzed after 5 days of treatment, the highest dose of satavaptan was more effective than the other two doses when changes in serum sodium were analyzed at day 14 (percentage of responders 50%, 54%, and 82% in the 5 mg, 12.5 mg, and 25 mg/day groups, respectively, compared to 26% in the placebo group). The improvement in serum sodium concentration in a low proportion of patients treated with placebo was probably due to restriction of fluid intake to 1.5 L/day. The increase in serum sodium concentration in patients treated with satavaptan was rapid in most patients and was likely due to a marked improvement in the renal solute-free water excretion. In fact, a marked increase in urine volume and decrease in urine osmolality were observed throughout treatment in the satavaptan-treated groups, whereas no changes were found in these parameters in patients treated with placebo. Average urine volumes in patients in the satavaptan groups ranged from 2.2–3.2 L/day. Very high urine volumes were relatively uncommon (13% of patients receiving satavaptan had a 24-hour urine volume of greater than 5 L at some point during the study). These high urine volumes should probably be avoided in clinical practice by reducing the dose of the drug because they may reduce patient compliance and theoretically be associated with a greater incidence of thirst and other potential side effects.

The reason for the lack of response to vasopressin V2 receptor antagonists in some patients with cirrhosis and ascites and dilutional hyponatremia cannot be ascertained from the current study. It may be that the dose of satavaptan and/or the duration of therapy were not sufficient. This possibility is supported by the fact that the percentage of responders increased up to 82% in patients treated with the highest dose for 14 days. Nevertheless, it is also possible that some patients are nonresponders because of factors related to renal function or hormonal parameters. This type of analysis, however, would require a study with a design different from the current one in which patients were treated with the same doses of satavaptan. Further studies should be performed to investigate the frequency and mechanism(s) of lack of response to vasopressin V2receptor antagonists in cirrhosis.

The administration of satavaptan at the different doses used in this study was safe and was not associated with a significant increase in the percentage of patients developing side effects during therapy compared to placebo. The only side effect that was significantly more frequent in patients treated with satavaptan was thirst, which is related to the intrinsic effect of the drug. Specific theoretical concerns of the treatment with vasopressin V2 receptor antagonists included: (1) rapid increase in serum sodium concentration, which could lead to neurological complications, particularly central pontine myelinolysis; (2) hypernatremia due to increased solute-free water excretion not compensated by increased fluid intake; and (3) renal failure due to contraction of intravascular volume secondary to large urine losses. None of these concerns proved to be true in the current investigation with the doses used and with the specific design of the study. A rapid and marked increase in serum sodium concentration which could be considered a risk factor for the development of neurological complications (≥ 8 mmol/L in 24 hours)18, 19 was observed very uncommonly and with a similar frequency in all treatment groups. Moreover, none of the patients developed neurological complications related to a rapid recovery of hyponatremia. This lack of neurological complications is in keeping with results from previous studies using vasopressin V2 receptor antagonists in patients with cirrhosis and ascites.9, 10, 17, 20, 21 In fact, to our knowledge, no single case of central pontine myelinolysis has so far been reported in studies evaluating the effects of vasopressin V2 receptor antagonists in cirrhosis. Hypernatremia was observed in two of the 82 patients (2%) treated with satavaptan and no patient treated with placebo. This relatively low frequency of hypernatremia was probably due to the fact that patients were allowed free access to fluids when they were thirsty. Finally, no significant changes in serum creatinine concentration or estimated glomerular filtration rate were found in any of the satavaptan-treated groups compared to placebo. Although plasma volume was not specifically measured in this study, the lack of significant changes in arterial pressure, heart rate, and activity of the renin-angiotensin-aldosterone system at the end of the study suggests that treatment with satavaptan, at the doses used and for a short duration of treatment, had no relevant effect on intravascular volume. Nevertheless, it should be pointed out that patients were treated with fixed doses of satavaptan, under a strict clinical surveillance, and with low doses of diuretics, which could have possibly reduced the incidence of these potential side effects. Therefore, it is not known whether the frequency of these complications would have been higher with different treatment conditions. Until more information is available, patients treated with vasopressin V2 receptor antagonists should be allowed a free access to fluids when they become thirsty and should be submitted for frequent clinical and analytical examinations to prevent rapid increases in serum sodium and development of hypernatremia and/or renal failure.

In conclusion, the results of this study show that a 14-day treatment with satavaptan, an orally active highly selective vasopressin V2 receptor antagonist, in patients with cirrhosis and ascites and hyponatremia is effective in increasing serum sodium concentration and improving the control of ascites. These results suggest that the use of vasopressin V2 receptor antagonists should be evaluated as a new pharmacological approach not only for the management of hyponatremia but also for the management of ascites in cirrhosis.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Appendix
  8. References

We thank Nathalie Bougon for work on the statistical analysis of the results.

Appendix

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Appendix
  8. References

Participating Investigators and Centers in the HypoCAT Multicenter Trial.

Paolo Angeli, Azienda Ospedaliera di Padova, Padova, Italy; Peter Angus, Austin Hospital, Heidelberg, Australia; Andres T. Blei, Northwestern University, Chicago, IL, USA; Radan Bruha, General Faculty Hospital, Prague, Czech Republic; Constantin Chira, D.Gerota Hospital, Bucharest, Romania; Juan Cordoba, Hospital Vall d'Hebron, Barcelona, Spain; Guy Decaux, Hôpital Universitaire Erasme, Brussels, Belgium; Daniela Dobru, County Hospital, Targu Mures, Romania; Alexandru Fraticiu, County Hospital, Sibiu, Romania; Adrian Gadano, Hospital Italiano, Buenos Aires, Argentina; Alexander Gerbes, University Hospital, Munich, Germany; Liliana Gheorge, Fundeni Clinical Institute, Bucharest, Romania; Pere Ginès, Hospital Clinic, Barcelona, Spain; Adrian Goldis, County Hospital, Timisoara, Romania; Yves Horsmans, Cliniques Universitaire St Luc, Brussels, Belgium; Janos Lonovics, Szegedi Tudomany Egyetem Áok, Szeged, Hungary; Michael Manns, University Hospital, Hannover, Germany; Claude Masliah, Hotel Dieu, Nantes Cedex, France; Timothy McCashland, University of Nebraska Medical Center, Nebraska, USA; Slobodan Milutinovic, Sveti Duh Clinical Hospital, Zagreb, Croatia; Dan Olteanu, University Hospital, Bucharest, Romania; Mohamed Ramdani, CHG Bezier, Beziers, France; Luis Ruiz del Arbol, Hospital Ramon y Cajal, Madrid, Spain; Arun J Sanyal, Virginia Commonwealth University Health System, Richmond, Virginia, USA; Si Nafa Siahmed, Hôpital de la Source, Orleans, France; Victor Stoica, Cantacuzino Hospital, Bucharest, Romania; Ruben Terg, Hospital Bonorino Udaondo, Buenos Aires, Argentina; Paul Thuluvath, Johns Hopkins Hospital, Baltimore, MD, USA; Mihail-Radu Voiosu, Colentina Hospital, Bucharest, Romania; Florence Wong, Toronto General Hospital, Toronto, Canada.

References

  1. Top of page
  2. Abstract
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. Appendix
  8. References
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