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Hugh Watson - One of the best experts on this subject based on the ideXlab platform.

  • proton pump inhibitors as a risk factor for hepatic encephalopathy and spontaneous bacterial peritonitis in patients with cirrhosis with ascites
    Hepatology, 2016
    Co-Authors: Gitte Dam, Hugh Watson, Hendrik Vilstrup, Peter Uhd Jepsen
    Abstract:

    Proton pump inhibitors (PPIs) may be a risk factor for hepatic encephalopathy (HE) in patients with cirrhosis, possibly through translocation of gut bacteria, which can also lead to spontaneous bacterial peritonitis (SBP). We examined the associations between PPIs and development of HE or SBP in patients with cirrhosis with ascites. We used data from three 1-year trials of Satavaptan for ascites control. We used Cox regression to compare HE and SBP rates between users and nonusers of PPIs. At inclusion, 39% of the 865 patients with cirrhosis with ascites used PPIs, 52% used them at some point during the follow-up, and the proportion of current users was always in the 30%-39% range. There were 189 first-time HE episodes during the follow-up, and the cumulative 1-year risk was 31% for those who used PPIs at baseline versus 25% for those who did not. The confounder-adjusted hazard ratio (HR) of HE for current PPI use versus current nonuse was 1.36 (95% confidence interval [CI], 1.01-1.84). The HR for overt HE was higher (adjusted HR = 1.88; 95% CI, 1.21-1.91). During the follow-up, 86 patients developed SBP. The adjusted HR of SBP for current PPI users versus nonusers was 1.72 (95% CI, 1.10-2.69). Conclusion: PPIs were used by 52% of this international cirrhosis cohort during a 1-year period and was a risk factor for developing HE and SBP. These findings are consistent with the hypothesis that PPIs may increase translocation of gut bacteria. (Hepatology 2016;64:1265-1272)

  • nonselective β blockers do not affect mortality in cirrhosis patients with ascites post hoc analysis of three randomized controlled trials with 1198 patients
    Hepatology, 2016
    Co-Authors: Lars Bossen, Hugh Watson, Aleksander Krag, Hendrik Vilstrup, Peter Uhd Jepsen
    Abstract:

    The safety of nonselective β-blockers (NSBBs) in advanced cirrhosis has been questioned. We used data from three Satavaptan trials to examine whether NSBBs increase mortality in cirrhosis patients with ascites. The trials were conducted in 2006-2008 and included 1198 cirrhosis patients with ascites followed for 1 year. We used Cox regression to compare all-cause mortality and cirrhosis-related mortality between patients who did and those who did not use NSBBs at randomization, controlling for age, gender, Model for End-Stage Liver Disease score, Child-Pugh score, serum sodium, previous variceal bleeding, cirrhosis etiology, and ascites severity. Moreover, we identified clinical events predicting that a patient would stop NSBB treatment. At randomization, the 559 NSBB users were more likely than the 629 nonusers to have a history of variceal bleeding but less likely to have Child-Pugh class C cirrhosis, hyponatremia, or refractory ascites. The 52-week cumulative all-cause mortality was similar in the NSBB user and nonuser groups (23.2% versus 25.3%, adjusted hazard ratio = 0.92, 95% confidence interval 0.72-1.18), and NSBBs also did not increase mortality in the subgroup of patients with refractory ascites (588 patients, adjusted hazard ratio = 1.02, 95% confidence interval 0.74-1.40) or in any other subgroup. Similarly, NSBBs did not increase cirrhosis-related mortality (adjusted hazard ratio = 1.00, 95% confidence interval 0.76-1.31). During follow-up, 29% of initial NSBB users stopped taking NSBBs, and the decision to stop NSBB treatment marked a sharp rise in mortality and coincided with hospitalization, variceal bleeding, bacterial infection, and/or development of hepatorenal syndrome. Conclusion: This large and detailed data set on worldwide nonprotocol use of NSBBs in cirrhosis patients with ascites shows that NSBBs did not increase mortality; the decision to stop NSBB treatment in relation to stressful events may have added to the safety. (Hepatology 2016;63:1968-1976)

  • Satavaptan treatment for ascites in patients with cirrhosis a meta analysis of effect on hepatic encephalopathy development
    Metabolic Brain Disease, 2013
    Co-Authors: Hugh Watson, Pere Ginès, Florence Wong, Peter Uhd Jepsen, Juan Cordoba, Hendrik Vilstrup
    Abstract:

    Satavaptan, a vasopressin V2-receptor antagonist, has been shown to improve hyponatraemia in patients with cirrhosis. Hyponatraemia has been associated with an increased risk of hepatic encephalopathy. The objective is to evaluate the efficacy of Satavaptan in reducing the risk of new episodes of hepatic encephalopathy. 1,200 patients with cirrhosis and uncomplicated ascites were included in three randomised double-blind studies comparing Satavaptan (5-10 mg/day) vs placebo over a one-year treatment period. Effects on incidence of hepatic encephalopathy episodes in individual study and pooled databases were determined with analyses adjusted for hyponatraemia and previous episodes of encephalopathy. Hyponatraemia was improved by Satavaptan. Three hundred and ninety-five hepatic encephalopathy episodes were recorded. The risk of an episode and the mean number of episodes were not reduced by Satavaptan in any of the three studies in the overall population or in patients who were hyponatraemic on entry. These findings were confirmed in analysis of the pooled data. Satavaptan did not reduce the frequency of hepatic encephalopathy in patients with cirrhosis and ascites.

  • Satavaptan for the management of ascites in cirrhosis efficacy and safety across the spectrum of ascites severity
    Gut, 2012
    Co-Authors: Florence Wong, Hugh Watson, Mauro Bernardi, Hendrik Vilstrup, Alexander L Gerbes, Salvatore Badalamenti, Pere Ginès
    Abstract:

    Objective Satavaptan, a vasopressin V2 receptor antagonist, has been shown to improve the control of ascites in cirrhosis in short-term phase II studies. The aim of this study was to evaluate the efficacy and safety of Satavaptan in three different populations of patients with cirrhosis and ascites. Methods 1200 patients were included in three randomised double-blind studies comparing Satavaptan with placebo in uncomplicated ascites (study 1: n=463 patients) and difficult-to-treat ascites, with and without concomitant diuretic treatment (studies 2 and 3: n=497 and n=240 patients, respectively). Results Satavaptan was not more effective than placebo in the control of ascites in any of the populations studied as estimated by the primary efficacy endpoints: worsening of ascites (study 1) and the cumulative number of large-volume paracenteses during 12 weeks (studies 2 and 3). Nevertheless, some of the secondary efficacy endpoints related to the treatment of ascites were met in the three studies, suggesting a slight advantage of Satavaptan over placebo in delaying ascites formation. Moreover, Satavaptan was more effective than placebo in improving the serum sodium concentration in patients with hyponatraemia. The incidence of major complications of cirrhosis during follow-up did not differ significantly between the Satavaptan and placebo groups in the three studies. Overall, the rate of any treatment-related adverse events, serious treatment-related events and treatment-related events leading to permanent discontinuation of treatment did not differ significantly between the treatment groups. However, in study 2 mortality was higher in patients treated with Satavaptan compared with placebo (HR 1.47; 95% CI 1.01 to 2.15); no significant differences in mortality between the two groups were observed in the other two studies. No specific cause for the increased mortality was identified. Most deaths were associated with known complications of liver cirrhosis. Conclusion Satavaptan, alone or in combination with diuretics, is not clinically beneficial in the long-term management of ascites in cirrhosis.

  • effects of a selective vasopressin v2 receptor antagonist Satavaptan on ascites recurrence after paracentesis in patients with cirrhosis
    Journal of Hepatology, 2010
    Co-Authors: Florence Wong, Hugh Watson, Pere Ginès, Yves Horsmans, Paolo Angeli, Paul J Gow, Pascal Minini, Mauro Bernardi
    Abstract:

    Background & Aims Cirrhotic patients with recurrent ascites frequently require paracentesis despite diuretic therapy. Vasopressin receptor antagonists, by increasing free water clearance, may reduce the recurrence of ascites. To investigate the effects of the addition of a vasopressin V 2 receptor antagonist, Satavaptan, to 100mg spironolactone on ascites recurrence after a large volume paracentesis in patients with liver cirrhosis irrespective of the presence of hyponatraemia. Methods One hundred and fifty one cirrhotic patients with recurrent ascites with or without hyponatraemia, and normal to mildly abnormal renal function were randomised in a double-blind study to receive either 5mg ( n =39), 12.5mg ( n =36), 25mg ( n =40) of Satavaptan or placebo ( n =36) for 12weeks. Their Child–Pugh scores were 9.2±1.3, 8.7±1.7, 8.8±1.3, and 9.0±1.5, respectively. Results Median time to first paracentesis was 23, 26, and 17days with Satavaptan 5, 12.5, and 25mg, respectively, versus 14days with placebo (ns for all doses). The frequency of paracenteses was decreased significantly ( p 0.05) in all Satavaptan groups versus placebo. Mean increase in ascites was 2.82±0.48L/week for placebo versus 2.12±0.40, 2.14±0.33, and 2.06±0.40L/week for the 5, 12.5, and 25mg of Satavaptan, respectively (ns for all doses). Similar numbers of patients experienced major adverse events in all groups. Increases in serum creatinine, orthostatic changes in systolic pressure and thirst were more common with Satavaptan. Conclusions Satavaptan has the potential to reduce recurrence of ascites after a large volume paracentesis at doses from 5 to 25mg in cirrhotic patients with ascites.

Pere Ginès - One of the best experts on this subject based on the ideXlab platform.

  • Satavaptan treatment for ascites in patients with cirrhosis a meta analysis of effect on hepatic encephalopathy development
    Metabolic Brain Disease, 2013
    Co-Authors: Hugh Watson, Pere Ginès, Florence Wong, Peter Uhd Jepsen, Juan Cordoba, Hendrik Vilstrup
    Abstract:

    Satavaptan, a vasopressin V2-receptor antagonist, has been shown to improve hyponatraemia in patients with cirrhosis. Hyponatraemia has been associated with an increased risk of hepatic encephalopathy. The objective is to evaluate the efficacy of Satavaptan in reducing the risk of new episodes of hepatic encephalopathy. 1,200 patients with cirrhosis and uncomplicated ascites were included in three randomised double-blind studies comparing Satavaptan (5-10 mg/day) vs placebo over a one-year treatment period. Effects on incidence of hepatic encephalopathy episodes in individual study and pooled databases were determined with analyses adjusted for hyponatraemia and previous episodes of encephalopathy. Hyponatraemia was improved by Satavaptan. Three hundred and ninety-five hepatic encephalopathy episodes were recorded. The risk of an episode and the mean number of episodes were not reduced by Satavaptan in any of the three studies in the overall population or in patients who were hyponatraemic on entry. These findings were confirmed in analysis of the pooled data. Satavaptan did not reduce the frequency of hepatic encephalopathy in patients with cirrhosis and ascites.

  • Satavaptan for the management of ascites in cirrhosis efficacy and safety across the spectrum of ascites severity
    Gut, 2012
    Co-Authors: Florence Wong, Hugh Watson, Mauro Bernardi, Hendrik Vilstrup, Alexander L Gerbes, Salvatore Badalamenti, Pere Ginès
    Abstract:

    Objective Satavaptan, a vasopressin V2 receptor antagonist, has been shown to improve the control of ascites in cirrhosis in short-term phase II studies. The aim of this study was to evaluate the efficacy and safety of Satavaptan in three different populations of patients with cirrhosis and ascites. Methods 1200 patients were included in three randomised double-blind studies comparing Satavaptan with placebo in uncomplicated ascites (study 1: n=463 patients) and difficult-to-treat ascites, with and without concomitant diuretic treatment (studies 2 and 3: n=497 and n=240 patients, respectively). Results Satavaptan was not more effective than placebo in the control of ascites in any of the populations studied as estimated by the primary efficacy endpoints: worsening of ascites (study 1) and the cumulative number of large-volume paracenteses during 12 weeks (studies 2 and 3). Nevertheless, some of the secondary efficacy endpoints related to the treatment of ascites were met in the three studies, suggesting a slight advantage of Satavaptan over placebo in delaying ascites formation. Moreover, Satavaptan was more effective than placebo in improving the serum sodium concentration in patients with hyponatraemia. The incidence of major complications of cirrhosis during follow-up did not differ significantly between the Satavaptan and placebo groups in the three studies. Overall, the rate of any treatment-related adverse events, serious treatment-related events and treatment-related events leading to permanent discontinuation of treatment did not differ significantly between the treatment groups. However, in study 2 mortality was higher in patients treated with Satavaptan compared with placebo (HR 1.47; 95% CI 1.01 to 2.15); no significant differences in mortality between the two groups were observed in the other two studies. No specific cause for the increased mortality was identified. Most deaths were associated with known complications of liver cirrhosis. Conclusion Satavaptan, alone or in combination with diuretics, is not clinically beneficial in the long-term management of ascites in cirrhosis.

  • effects of a selective vasopressin v2 receptor antagonist Satavaptan on ascites recurrence after paracentesis in patients with cirrhosis
    Journal of Hepatology, 2010
    Co-Authors: Florence Wong, Hugh Watson, Pere Ginès, Yves Horsmans, Paolo Angeli, Paul J Gow, Pascal Minini, Mauro Bernardi
    Abstract:

    Background & Aims Cirrhotic patients with recurrent ascites frequently require paracentesis despite diuretic therapy. Vasopressin receptor antagonists, by increasing free water clearance, may reduce the recurrence of ascites. To investigate the effects of the addition of a vasopressin V 2 receptor antagonist, Satavaptan, to 100mg spironolactone on ascites recurrence after a large volume paracentesis in patients with liver cirrhosis irrespective of the presence of hyponatraemia. Methods One hundred and fifty one cirrhotic patients with recurrent ascites with or without hyponatraemia, and normal to mildly abnormal renal function were randomised in a double-blind study to receive either 5mg ( n =39), 12.5mg ( n =36), 25mg ( n =40) of Satavaptan or placebo ( n =36) for 12weeks. Their Child–Pugh scores were 9.2±1.3, 8.7±1.7, 8.8±1.3, and 9.0±1.5, respectively. Results Median time to first paracentesis was 23, 26, and 17days with Satavaptan 5, 12.5, and 25mg, respectively, versus 14days with placebo (ns for all doses). The frequency of paracenteses was decreased significantly ( p 0.05) in all Satavaptan groups versus placebo. Mean increase in ascites was 2.82±0.48L/week for placebo versus 2.12±0.40, 2.14±0.33, and 2.06±0.40L/week for the 5, 12.5, and 25mg of Satavaptan, respectively (ns for all doses). Similar numbers of patients experienced major adverse events in all groups. Increases in serum creatinine, orthostatic changes in systolic pressure and thirst were more common with Satavaptan. Conclusions Satavaptan has the potential to reduce recurrence of ascites after a large volume paracentesis at doses from 5 to 25mg in cirrhotic patients with ascites.

  • clinical trial short term effects of combination of Satavaptan a selective vasopressin v2 receptor antagonist and diuretics on ascites in patients with cirrhosis without hyponatraemia a randomized double blind placebo controlled study
    Alimentary Pharmacology & Therapeutics, 2010
    Co-Authors: Pere Ginès, Hugh Watson, Florence Wong, R Terg, R Bruha, J P Zarski, F Dudley
    Abstract:

    Aliment Pharmacol Ther 31, 834–845 Summary Background  There is little information on the effects of vaptans in patients with cirrhosis. Aim  To investigate the short-term effects of Satavaptan, a selective vasopressin V2 receptor antagonist on ascites in cirrhosis without hyponatraemia. Methods  A total of 148 patients with cirrhosis, ascites and serum sodium >130 mmol/L were included in a multicentre, double-blind, randomized, controlled study of 14 days comparing three fixed doses of Satavaptan (5 mg, 12.5 mg or 25 mg once daily) vs. placebo. Average MELD scores were: 13.4, 12.3, 13.8 and 13.1 respectively. All patients received spironolactone 100 mg/day plus furosemide 20–25 mg/day. Results  Satavaptan treatment was associated with a decrease in ascites (mean change in body weight was −0.36 kg (±3.03) for placebo vs. −2.46 kg (±3.11), −2.08 kg (±4.17) and −2.28 kg (±3.24) for the 5 mg, 12.5 mg and 25 mg doses respectively; P = 0.036, P = 0.041 and P = 0.036 for Satavaptan 5, 12.5 and 25 mg/day vs. placebo respectively). Thirst and slight increases in serum sodium were more common in patients treated with Satavaptan compared with placebo, while other adverse events were similar. Conclusions  The administration Satavaptan for a 14-day period is associated with reduction in ascites in patients with moderately severe cirrhosis without hyponatraemia under diuretic treatment.

  • effects of Satavaptan a selective vasopressin v2 receptor antagonist on ascites and serum sodium in cirrhosis with hyponatremia a randomized trial
    Hepatology, 2008
    Co-Authors: Pere Ginès, Slobodan Milutinovic, Luis Ruiz Del Arbol, Hugh Watson, Florence Wong, Dan Olteanu
    Abstract:

    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.)

Florence Wong - One of the best experts on this subject based on the ideXlab platform.

  • Satavaptan treatment for ascites in patients with cirrhosis a meta analysis of effect on hepatic encephalopathy development
    Metabolic Brain Disease, 2013
    Co-Authors: Hugh Watson, Pere Ginès, Florence Wong, Peter Uhd Jepsen, Juan Cordoba, Hendrik Vilstrup
    Abstract:

    Satavaptan, a vasopressin V2-receptor antagonist, has been shown to improve hyponatraemia in patients with cirrhosis. Hyponatraemia has been associated with an increased risk of hepatic encephalopathy. The objective is to evaluate the efficacy of Satavaptan in reducing the risk of new episodes of hepatic encephalopathy. 1,200 patients with cirrhosis and uncomplicated ascites were included in three randomised double-blind studies comparing Satavaptan (5-10 mg/day) vs placebo over a one-year treatment period. Effects on incidence of hepatic encephalopathy episodes in individual study and pooled databases were determined with analyses adjusted for hyponatraemia and previous episodes of encephalopathy. Hyponatraemia was improved by Satavaptan. Three hundred and ninety-five hepatic encephalopathy episodes were recorded. The risk of an episode and the mean number of episodes were not reduced by Satavaptan in any of the three studies in the overall population or in patients who were hyponatraemic on entry. These findings were confirmed in analysis of the pooled data. Satavaptan did not reduce the frequency of hepatic encephalopathy in patients with cirrhosis and ascites.

  • Satavaptan for the management of ascites in cirrhosis efficacy and safety across the spectrum of ascites severity
    Gut, 2012
    Co-Authors: Florence Wong, Hugh Watson, Mauro Bernardi, Hendrik Vilstrup, Alexander L Gerbes, Salvatore Badalamenti, Pere Ginès
    Abstract:

    Objective Satavaptan, a vasopressin V2 receptor antagonist, has been shown to improve the control of ascites in cirrhosis in short-term phase II studies. The aim of this study was to evaluate the efficacy and safety of Satavaptan in three different populations of patients with cirrhosis and ascites. Methods 1200 patients were included in three randomised double-blind studies comparing Satavaptan with placebo in uncomplicated ascites (study 1: n=463 patients) and difficult-to-treat ascites, with and without concomitant diuretic treatment (studies 2 and 3: n=497 and n=240 patients, respectively). Results Satavaptan was not more effective than placebo in the control of ascites in any of the populations studied as estimated by the primary efficacy endpoints: worsening of ascites (study 1) and the cumulative number of large-volume paracenteses during 12 weeks (studies 2 and 3). Nevertheless, some of the secondary efficacy endpoints related to the treatment of ascites were met in the three studies, suggesting a slight advantage of Satavaptan over placebo in delaying ascites formation. Moreover, Satavaptan was more effective than placebo in improving the serum sodium concentration in patients with hyponatraemia. The incidence of major complications of cirrhosis during follow-up did not differ significantly between the Satavaptan and placebo groups in the three studies. Overall, the rate of any treatment-related adverse events, serious treatment-related events and treatment-related events leading to permanent discontinuation of treatment did not differ significantly between the treatment groups. However, in study 2 mortality was higher in patients treated with Satavaptan compared with placebo (HR 1.47; 95% CI 1.01 to 2.15); no significant differences in mortality between the two groups were observed in the other two studies. No specific cause for the increased mortality was identified. Most deaths were associated with known complications of liver cirrhosis. Conclusion Satavaptan, alone or in combination with diuretics, is not clinically beneficial in the long-term management of ascites in cirrhosis.

  • effects of a selective vasopressin v2 receptor antagonist Satavaptan on ascites recurrence after paracentesis in patients with cirrhosis
    Journal of Hepatology, 2010
    Co-Authors: Florence Wong, Hugh Watson, Pere Ginès, Yves Horsmans, Paolo Angeli, Paul J Gow, Pascal Minini, Mauro Bernardi
    Abstract:

    Background & Aims Cirrhotic patients with recurrent ascites frequently require paracentesis despite diuretic therapy. Vasopressin receptor antagonists, by increasing free water clearance, may reduce the recurrence of ascites. To investigate the effects of the addition of a vasopressin V 2 receptor antagonist, Satavaptan, to 100mg spironolactone on ascites recurrence after a large volume paracentesis in patients with liver cirrhosis irrespective of the presence of hyponatraemia. Methods One hundred and fifty one cirrhotic patients with recurrent ascites with or without hyponatraemia, and normal to mildly abnormal renal function were randomised in a double-blind study to receive either 5mg ( n =39), 12.5mg ( n =36), 25mg ( n =40) of Satavaptan or placebo ( n =36) for 12weeks. Their Child–Pugh scores were 9.2±1.3, 8.7±1.7, 8.8±1.3, and 9.0±1.5, respectively. Results Median time to first paracentesis was 23, 26, and 17days with Satavaptan 5, 12.5, and 25mg, respectively, versus 14days with placebo (ns for all doses). The frequency of paracenteses was decreased significantly ( p 0.05) in all Satavaptan groups versus placebo. Mean increase in ascites was 2.82±0.48L/week for placebo versus 2.12±0.40, 2.14±0.33, and 2.06±0.40L/week for the 5, 12.5, and 25mg of Satavaptan, respectively (ns for all doses). Similar numbers of patients experienced major adverse events in all groups. Increases in serum creatinine, orthostatic changes in systolic pressure and thirst were more common with Satavaptan. Conclusions Satavaptan has the potential to reduce recurrence of ascites after a large volume paracentesis at doses from 5 to 25mg in cirrhotic patients with ascites.

  • clinical trial short term effects of combination of Satavaptan a selective vasopressin v2 receptor antagonist and diuretics on ascites in patients with cirrhosis without hyponatraemia a randomized double blind placebo controlled study
    Alimentary Pharmacology & Therapeutics, 2010
    Co-Authors: Pere Ginès, Hugh Watson, Florence Wong, R Terg, R Bruha, J P Zarski, F Dudley
    Abstract:

    Aliment Pharmacol Ther 31, 834–845 Summary Background  There is little information on the effects of vaptans in patients with cirrhosis. Aim  To investigate the short-term effects of Satavaptan, a selective vasopressin V2 receptor antagonist on ascites in cirrhosis without hyponatraemia. Methods  A total of 148 patients with cirrhosis, ascites and serum sodium >130 mmol/L were included in a multicentre, double-blind, randomized, controlled study of 14 days comparing three fixed doses of Satavaptan (5 mg, 12.5 mg or 25 mg once daily) vs. placebo. Average MELD scores were: 13.4, 12.3, 13.8 and 13.1 respectively. All patients received spironolactone 100 mg/day plus furosemide 20–25 mg/day. Results  Satavaptan treatment was associated with a decrease in ascites (mean change in body weight was −0.36 kg (±3.03) for placebo vs. −2.46 kg (±3.11), −2.08 kg (±4.17) and −2.28 kg (±3.24) for the 5 mg, 12.5 mg and 25 mg doses respectively; P = 0.036, P = 0.041 and P = 0.036 for Satavaptan 5, 12.5 and 25 mg/day vs. placebo respectively). Thirst and slight increases in serum sodium were more common in patients treated with Satavaptan compared with placebo, while other adverse events were similar. Conclusions  The administration Satavaptan for a 14-day period is associated with reduction in ascites in patients with moderately severe cirrhosis without hyponatraemia under diuretic treatment.

  • effects of Satavaptan a selective vasopressin v2 receptor antagonist on ascites and serum sodium in cirrhosis with hyponatremia a randomized trial
    Hepatology, 2008
    Co-Authors: Pere Ginès, Slobodan Milutinovic, Luis Ruiz Del Arbol, Hugh Watson, Florence Wong, Dan Olteanu
    Abstract:

    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.)

Hendrik Vilstrup - One of the best experts on this subject based on the ideXlab platform.

  • proton pump inhibitors as a risk factor for hepatic encephalopathy and spontaneous bacterial peritonitis in patients with cirrhosis with ascites
    Hepatology, 2016
    Co-Authors: Gitte Dam, Hugh Watson, Hendrik Vilstrup, Peter Uhd Jepsen
    Abstract:

    Proton pump inhibitors (PPIs) may be a risk factor for hepatic encephalopathy (HE) in patients with cirrhosis, possibly through translocation of gut bacteria, which can also lead to spontaneous bacterial peritonitis (SBP). We examined the associations between PPIs and development of HE or SBP in patients with cirrhosis with ascites. We used data from three 1-year trials of Satavaptan for ascites control. We used Cox regression to compare HE and SBP rates between users and nonusers of PPIs. At inclusion, 39% of the 865 patients with cirrhosis with ascites used PPIs, 52% used them at some point during the follow-up, and the proportion of current users was always in the 30%-39% range. There were 189 first-time HE episodes during the follow-up, and the cumulative 1-year risk was 31% for those who used PPIs at baseline versus 25% for those who did not. The confounder-adjusted hazard ratio (HR) of HE for current PPI use versus current nonuse was 1.36 (95% confidence interval [CI], 1.01-1.84). The HR for overt HE was higher (adjusted HR = 1.88; 95% CI, 1.21-1.91). During the follow-up, 86 patients developed SBP. The adjusted HR of SBP for current PPI users versus nonusers was 1.72 (95% CI, 1.10-2.69). Conclusion: PPIs were used by 52% of this international cirrhosis cohort during a 1-year period and was a risk factor for developing HE and SBP. These findings are consistent with the hypothesis that PPIs may increase translocation of gut bacteria. (Hepatology 2016;64:1265-1272)

  • nonselective β blockers do not affect mortality in cirrhosis patients with ascites post hoc analysis of three randomized controlled trials with 1198 patients
    Hepatology, 2016
    Co-Authors: Lars Bossen, Hugh Watson, Aleksander Krag, Hendrik Vilstrup, Peter Uhd Jepsen
    Abstract:

    The safety of nonselective β-blockers (NSBBs) in advanced cirrhosis has been questioned. We used data from three Satavaptan trials to examine whether NSBBs increase mortality in cirrhosis patients with ascites. The trials were conducted in 2006-2008 and included 1198 cirrhosis patients with ascites followed for 1 year. We used Cox regression to compare all-cause mortality and cirrhosis-related mortality between patients who did and those who did not use NSBBs at randomization, controlling for age, gender, Model for End-Stage Liver Disease score, Child-Pugh score, serum sodium, previous variceal bleeding, cirrhosis etiology, and ascites severity. Moreover, we identified clinical events predicting that a patient would stop NSBB treatment. At randomization, the 559 NSBB users were more likely than the 629 nonusers to have a history of variceal bleeding but less likely to have Child-Pugh class C cirrhosis, hyponatremia, or refractory ascites. The 52-week cumulative all-cause mortality was similar in the NSBB user and nonuser groups (23.2% versus 25.3%, adjusted hazard ratio = 0.92, 95% confidence interval 0.72-1.18), and NSBBs also did not increase mortality in the subgroup of patients with refractory ascites (588 patients, adjusted hazard ratio = 1.02, 95% confidence interval 0.74-1.40) or in any other subgroup. Similarly, NSBBs did not increase cirrhosis-related mortality (adjusted hazard ratio = 1.00, 95% confidence interval 0.76-1.31). During follow-up, 29% of initial NSBB users stopped taking NSBBs, and the decision to stop NSBB treatment marked a sharp rise in mortality and coincided with hospitalization, variceal bleeding, bacterial infection, and/or development of hepatorenal syndrome. Conclusion: This large and detailed data set on worldwide nonprotocol use of NSBBs in cirrhosis patients with ascites shows that NSBBs did not increase mortality; the decision to stop NSBB treatment in relation to stressful events may have added to the safety. (Hepatology 2016;63:1968-1976)

  • Satavaptan treatment for ascites in patients with cirrhosis a meta analysis of effect on hepatic encephalopathy development
    Metabolic Brain Disease, 2013
    Co-Authors: Hugh Watson, Pere Ginès, Florence Wong, Peter Uhd Jepsen, Juan Cordoba, Hendrik Vilstrup
    Abstract:

    Satavaptan, a vasopressin V2-receptor antagonist, has been shown to improve hyponatraemia in patients with cirrhosis. Hyponatraemia has been associated with an increased risk of hepatic encephalopathy. The objective is to evaluate the efficacy of Satavaptan in reducing the risk of new episodes of hepatic encephalopathy. 1,200 patients with cirrhosis and uncomplicated ascites were included in three randomised double-blind studies comparing Satavaptan (5-10 mg/day) vs placebo over a one-year treatment period. Effects on incidence of hepatic encephalopathy episodes in individual study and pooled databases were determined with analyses adjusted for hyponatraemia and previous episodes of encephalopathy. Hyponatraemia was improved by Satavaptan. Three hundred and ninety-five hepatic encephalopathy episodes were recorded. The risk of an episode and the mean number of episodes were not reduced by Satavaptan in any of the three studies in the overall population or in patients who were hyponatraemic on entry. These findings were confirmed in analysis of the pooled data. Satavaptan did not reduce the frequency of hepatic encephalopathy in patients with cirrhosis and ascites.

  • Satavaptan for the management of ascites in cirrhosis efficacy and safety across the spectrum of ascites severity
    Gut, 2012
    Co-Authors: Florence Wong, Hugh Watson, Mauro Bernardi, Hendrik Vilstrup, Alexander L Gerbes, Salvatore Badalamenti, Pere Ginès
    Abstract:

    Objective Satavaptan, a vasopressin V2 receptor antagonist, has been shown to improve the control of ascites in cirrhosis in short-term phase II studies. The aim of this study was to evaluate the efficacy and safety of Satavaptan in three different populations of patients with cirrhosis and ascites. Methods 1200 patients were included in three randomised double-blind studies comparing Satavaptan with placebo in uncomplicated ascites (study 1: n=463 patients) and difficult-to-treat ascites, with and without concomitant diuretic treatment (studies 2 and 3: n=497 and n=240 patients, respectively). Results Satavaptan was not more effective than placebo in the control of ascites in any of the populations studied as estimated by the primary efficacy endpoints: worsening of ascites (study 1) and the cumulative number of large-volume paracenteses during 12 weeks (studies 2 and 3). Nevertheless, some of the secondary efficacy endpoints related to the treatment of ascites were met in the three studies, suggesting a slight advantage of Satavaptan over placebo in delaying ascites formation. Moreover, Satavaptan was more effective than placebo in improving the serum sodium concentration in patients with hyponatraemia. The incidence of major complications of cirrhosis during follow-up did not differ significantly between the Satavaptan and placebo groups in the three studies. Overall, the rate of any treatment-related adverse events, serious treatment-related events and treatment-related events leading to permanent discontinuation of treatment did not differ significantly between the treatment groups. However, in study 2 mortality was higher in patients treated with Satavaptan compared with placebo (HR 1.47; 95% CI 1.01 to 2.15); no significant differences in mortality between the two groups were observed in the other two studies. No specific cause for the increased mortality was identified. Most deaths were associated with known complications of liver cirrhosis. Conclusion Satavaptan, alone or in combination with diuretics, is not clinically beneficial in the long-term management of ascites in cirrhosis.

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  • identification and characterization of an activating f229v substitution in the v2 vasopressin receptor in an infant with nsiad
    Journal of The American Society of Nephrology, 2012
    Co-Authors: E Carpentier, Daniel G. Bichet, Larry A Greenbaum, Driss Rochdi, Ravinder Abrol, William A Goddard, Michel Bouvier
    Abstract:

    Gain-of-function mutations in the gene encoding the V2 vasopressin receptor (V2R) cause nephrogenic syndrome of inappropriate antidiuresis. To date, reported mutations lead to the substitution of arginine 137 by either a cysteine or leucine (R137C/L). Here, we describe a 3-month-old hyponatremic infant found to have a phenylalanine 229 to valine (F229V) substitution in V2R. Characterization of this substitution in vitro revealed that it leads to high constitutive activity of the receptor, compatible with spontaneous antidiuresis. In contrast to R137C/L mutant receptors, F229V receptors do not undergo spontaneous desensitization, which results in sustained, high basal activity. Notably, the V2R-selective inverse agonists tolvaptan and Satavaptan completely silenced the constitutive signaling activity of the F229V mutant receptor, indicating that this substitution does not lock the receptor in an irreversible active state. Thus, inverse agonists might prove to be effective therapies for treating patients with this or other spontaneously activating mutations that do not lock the V2R in its active state. These results emphasize the importance of genetic testing and the functional characterization of mutant receptors for patients with nephrogenic syndrome of inappropriate antidiuresis because the results might inform treatment decisions.

  • functional characterization of vasopressin type 2 receptor substitutions r137h c l leading to nephrogenic diabetes insipidus and nephrogenic syndrome of inappropriate antidiuresis implications for treatments
    Molecular Pharmacology, 2010
    Co-Authors: Moulay Driss Rochdi, E Carpentier, Gabriel Vargas, Genevieve Olignylongpre, Stanford Chen, Abraham Kovoor, Stephen E Gitelman, Stephen M Rosenthal, Mark Von Zastrow, Michel Bouvier
    Abstract:

    Substitution of arginine-137 of the vasopressin type 2 receptor (V2R) for histidine (R137H-V2R) leads to nephrogenic diabetes insipidus (NDI), whereas substitution of the same residue to cysteine or leucine (R137C/L-V2R) causes the nephrogenic syndrome of inappropriate antidiuresis (NSIAD). These two diseases have opposite clinical outcomes. Still, the three mutant receptors were shown to share constitutive β-arrestin recruitment and endocytosis, resistance to vasopressin-stimulated cAMP production and mitogen-activated protein kinase activation, and compromised cell surface targeting, raising questions about the contribution of these phenomenons to the diseases and their potential treatments. Blocking endocytosis exacerbated the elevated basal cAMP levels promoted by R137C/L-V2R but not the cAMP production elicited by R137H-V2R, demonstrating that substitution of Arg137 to Cys/Leu, but not His, leads to constitutive V2R-stimulated cAMP accumulation that most likely underlies NSIAD. The constitutively elevated endocytosis of R137C/L-V2R attenuates the signaling and most likely reduces the severity of NSIAD, whereas the elevated endocytosis of R137H-V2R probably contributes to NDI. The constitutive signaling of R137C/L-V2R was not inhibited by treatment with the V2R inverse agonist Satavaptan (SR121463). In contrast, owing to its pharmacological chaperone property, SR121463 increased the R137C/L-V2R maturation and cell surface targeting, leading to a further increase in basal cAMP production, thus disqualifying it as a potential treatment for patients with R137C/L-V2R-induced NSIAD. However, vasopressin was found to promote β-arrestin/AP-2-dependent internalization of R137H/C/L-V2R beyond their already elevated endocytosis levels, raising the possibility that vasopressin could have a therapeutic value for patients with R137C/L-V2R-induced NSIAD by reducing steady-state surface receptor levels, thus lowering basal cAMP production.