Hugh Watson

Hyponatremia in cirrhosis: Results of a patient population survey.

Low serum sodium concentration is an independent predictor of mortality in patients with cirrhosis, but its prevalence and clinical significance is unclear. To evaluate prospectively the prevalence of low serum sodium concentration and the association between serum sodium levels and severity of ascites and complications of cirrhosis, prospective data were collected on 997 consecutive patients from 28 centers in Europe, North and South America, and Asia for a period of 28 days. The prevalence of low serum sodium concentration as defined by a serum sodium concentration ≤135 mmol/L, ≤130 mmol/L, ≤125 mmol/L, and ≤120 mmol/L was 49.4%, 21.6%, 5.7%, and 1.2%, respectively. The prevalence of low serum sodium levels (<135 mmol/L) was high in both inpatients and outpatients (57% and 40%, respectively). The existence of serum sodium <135 mmol/L was associated with severe ascites, as indicated by high prevalence of refractory ascites, large fluid accumulation rate, frequent use of large‐volume paracentesis, and impaired renal function, compared with normal serum sodium levels. Moreover, low serum sodium levels were also associated with greater frequency of hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome, but not gastrointestinal bleeding. Patients with serum sodium <130 mmol/L had the greatest frequency of these complications, but the frequency was also increased in patients with mild reduction in serum sodium levels (131‐135 mmol/L). In conclusion, low serum sodium levels in cirrhosis are associated with severe ascites and high frequency of hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome. (HEPATOLOGY 2006;44:1535–1542.)

Effects of satavaptan, a selective vasopressin V2 receptor antagonist, on ascites and serum sodium in cirrhosis with hyponatremia: A randomized trial†

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.)

Satavaptan for the management of ascites in cirrhosis: efficacy and safety across the spectrum of ascites severity

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.

Factors related to quality of life in patients with cirrhosis and ascites: Relevance of serum sodium concentration and leg edema

BACKGROUND & AIMS Hyponatremia is common in patients with cirrhosis and ascites and is associated with significant neurological disturbances. However, its potential effect on health-related quality of life (HRQL) in cirrhosis has not been investigated. We aimed at assessing the relationship between serum sodium concentration and other clinical and analytical parameters on HRQL in cirrhosis with ascites. METHODS A total of 523 patients with cirrhosis and ascites were prospectively investigated. Assessment of HRQL was done with the Medical Outcomes Study Short-Form 36 (SF-36) questionnaire, which is divided into 8 domains, summarized in two components: physical component score (PCS) and mental component score (MCS). Demographic, clinical, and analytical data at baseline were analyzed for their relationship with HRQL. RESULTS In multivariate analysis, independent predictive factors associated with an impaired PCS were non-alcoholic etiology of cirrhosis, severe ascites, history of previous episodes of hepatic encephalopathy and falls, presence of leg edema, and low serum sodium concentration. With respect to MCS, only two factors were associated with the independent predictive value: low serum sodium concentration and treatment with lactulose or lactitol. In both components, the scores decreased in parallel with the reduction in serum sodium concentration. Variables more commonly associated with the independent predictive value in the individual 8 domains of PCS and MCS were presence of leg edema and serum sodium concentration, 7 and 6 domains, respectively. CONCLUSIONS Serum sodium concentration and presence of leg edema are major factors of the impaired HRQL in patients with cirrhosis and ascites.

Effects of a selective vasopressin V2 receptor antagonist, satavaptan, on ascites recurrence after paracentesis in patients with cirrhosis

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 12 weeks. 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 17 days with satavaptan 5, 12.5, and 25mg, respectively, versus 14 days 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+/-0.48 L/week for placebo versus 2.12+/-0.40, 2.14+/-0.33, and 2.06+/-0.40 L/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.

Proton pump inhibitors as a risk factor for hepatic encephalopathy and spontaneous bacterial peritonitis in patients with cirrhosis with ascites.

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)

Non‐selective β‐blockers do not affect mortality in cirrhosis patients with ascites: Post hoc analysis of three RCTs with 1198 patients

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)

Nonselective β-blockers do not affect mortality in cirrhosis patients with ascites: Post Hoc analysis of three randomized controlled trials with 1198 patients.

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)

Diabetes as a risk factor for hepatic encephalopathy in cirrhosis patients

BACKGROUND & AIMS It remains unclear whether diabetes increases the risk for hepatic encephalopathy (HE) in cirrhotic patients. We examined this question using data from three randomized trials of satavaptan, a vasopressin receptor antagonist that does not affect HE risk, in cirrhotic patients with ascites. METHODS The trials included 1198 patients, and we excluded those with HE before or at randomization and followed the remaining patients for the one year duration of the trials. They were examined for HE regularly, and we compared rates of first-time overt HE between diabetics and non-diabetic patients using Cox regression, adjusting for gender, age, ascites severity, cirrhosis etiology, Child-Pugh class, creatinine, bilirubin, INR, sodium, potassium, albumin, platelets, lactulose use, benzodiazepine/barbiturate use, spironolactone dose, furosemide dose, potassium-sparing diuretic dose, and CirCom comorbidity score. RESULTS We included 862 patients of whom 193 (22%) had diabetes. In total, they experienced 115 first-time episodes of overt HE during the follow-up. Fewer diabetics than non-diabetic patients were in Child-Pugh class C at baseline (13% vs. 23%), yet they had higher cumulative risk of first-time overt HE (26.0% vs. 15.8% after 1 year), and their episodes of first-time overt HE were more likely to progress beyond grade 2 (64% vs. 42% of episodes progressed to grade 3 or 4, p=0.01 for independence between diabetes and highest HE grade). After the confounder adjustment, the hazard ratio of first-time overt HE for diabetics vs. non-diabetic patients was 1.86 (95% CI 1.20-2.87). CONCLUSIONS Diabetes increased the risk of first-time overt HE among cirrhotic patients with ascites.

O073 : Non-selective beta-blockers and mortality in cirrhosis patients with or without refractory ascites: Post hoc analysis of three large RCT’s with 1198 patients

comorbid conditions. As previously validated, decompensation was defined by the presence of one inpatient or two outpatient ICD-9 codes for esophageal varices with bleeding, ascites and/or spontaneous bacterial peritonitis. The association between statin use and decompensation and death was estimated using cox proportional hazards model with adjustment for age + Child score and age + MELD score. Results: Among 40,512 patients with HCV compensated cirrhosis (98% male, median age 56 years), 2,802 statin users were identified. From this group 685 statin users were propensity score matched with 2,062 non-users. Discrimination of propensity score model was excellent (c = 0.92). The figure shows plots of time to decompensation (A) or death (B) by statin use in the matched cohort. Statin use was associated with lower risk of decompensation [HR 0.55 (95%CI 0.39, 0.77)] or death [HR 0.56 (95%CI 0.46, 0.69)] compared to non-users. These findings persisted after adjustment for age + Child score [decompensation HR 0.53 (95%CI 0.37, 0.74); death HR 0.54 (95%CI 0.44, 0.66)] or age + MELD score [decompensation HR 0.53 (95%CI 0.38, 0.75); death HR 0.54 (95%CI 0.44, 0.66)]. Conclusions: Statin use in U.S. Veterans with HCV compensated cirrhosis is associated with over 40% lower risk of hepatic decompensation and death.