Refractory ascites occurs in less than 10% of patients with cirrhosis and ascites.1 Refractory ascites is defined as a lack of response to high doses of diuretics or as the recurrence of side effects when lower doses of diuretics are given.2, 3 Patients with refractory ascites have a poor outcome.2-4 The first-line treatment for refractory ascites is repeated large-volume paracentesis.2-4 In patients with cirrhosis, the administration of nonselective beta-blockers for the prevention of gastrointestinal hemorrhaging is frequent when esophageal varices are present.5-7 However, this treatment may have deleterious effects on patients with ascites treated by large-volume paracentesis. In particular, it may contribute to limiting the compensatory increase in cardiac output.8, 9 The aim of the present study was to evaluate the effect of the administration of nonselective beta-blockers on long-term survival in patients with cirrhosis and refractory ascites. In addition, the predictive factors of mortality in these patients were studied.
Beta-blockers may have a negative impact on survival in patients with cirrhosis and refractory ascites. The aim of this study was to evaluate the effect of the administration of beta-blockers on long-term survival in patients with cirrhosis and refractory ascites. We performed a single-center, observational, case-only, prospective study of patients with cirrhosis and refractory ascites who did or did not receive beta-blockers for the prevention of gastrointestinal bleeding; 151 patients were included. The mean Model for End-Stage Liver Disease score was 18.8 ± 4.1. All patients regularly underwent large-volume paracentesis and intravenous albumin administration. Seventy-seven patients (51%) were treated with propranolol (113 ± 46 mg/day). The median follow-up for the whole group was 8 months. The median survival time was 10 months [95% confidence interval (CI) = 8-12 months]. The probability of survival at 1 year was 41% (95% CI = 33%-49%). The clinical characteristics and laboratory values at enrolment were not significantly different between patients who were receiving propranolol and those who were not. The median survival time was 20.0 months (95% CI = 4.8-35.2 months) in patients not treated with propranolol and 5.0 months (95% CI = 3.5-6.5 months) in those treated with propranolol (P = 0.0001). The 1-year probability of survival was significantly lower in patients who received propranolol [19% (95% CI = 9%-29%)] versus those who did not [64% (95% CI = 52%-76%), P < 0.0001]. The independent variables of mortality were Child-Pugh class C, hyponatremia and renal failure as causes of refractory ascites, and beta-blocker therapy. Conclusion: The use of beta-blockers is associated with poor survival in patients with refractory ascites. These results suggest that beta-blockers should be contraindicated in these patients. HEPATOLOGY 2010
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Patients and Methods
The study was a single-center, observational, case-only, prospective study. From January 2004 to December 2008, all consecutive patients who had cirrhosis, were older than 18 years, and were admitted to our liver unit for refractory ascites were studied. The criteria for refractory ascites were based on International Ascites Club criteria.2, 3 Patients were considered to have refractory ascites when they had either diuretic-resistant or diuretic-intractable ascites. Refractory ascites was qualified as diuretic-resistant when ascites could not be stabilized despite intensive diuretic therapy (e.g., 400 mg of spironolactone with 160 mg of furosemide per day) associated with dietary sodium restriction (90 mmol of sodium per day). Refractory ascites was qualified as diuretic-intractable when metabolic disturbances made it impossible to administer or increase diuretic therapy. For the purpose of this study, these metabolic abnormalities were diuretic-induced hepatic encephalopathy, hyponatremia (defined as a serum sodium level ≤ 125 mmol/L), renal impairment (defined as a serum creatinine level ≥ 1.5 mg/dL), and abnormal serum potassium levels (defined as a serum potassium level ≤ 3 or ≥ 6 mmol/L).
The time of entry into the study was the date on which the criteria for refractory ascites were first fulfilled. Patients were divided into two groups according to whether they were receiving beta-blockers or not.
The following information was collected at entry: demographic data, etiology of cirrhosis, physical examination findings, biochemical values, Child-Pugh score, Model for End-Stage Liver Disease (MELD) score, presence of diabetes, and type of treatment. In addition, because both the MELD score and serum sodium levels were available for all patients, the newly described Model for End-Stage Liver Disease with sodium (MELD-Na) score10 was calculated. The hospital course, laboratory values, and outcomes (renal dysfunction development, liver transplantation, or death) were determined during regular follow-up. Wedged and free hepatic venous pressures were measured, and the hepatic venous pressure gradient (HVPG) was calculated for 27 patients receiving beta-blockers and for 29 patients who did not receive beta-blockers.
Continuous data that were not normally distributed are reported as median and ranges (minimum to maximum). The distribution of the variables was tested with the Shapiro-Wilk test. Group comparisons were made with the Wilcoxon-Mann-Whitney test. Categorical variables are reported as counts and percentages. Group comparisons were made with the χ2 test or Fisher's exact test. Survival was assessed with the Kaplan-Meier nonparametric survivorship function, and group comparisons were made with the log-rank test. Univariate and multivariate Cox regression analyses were performed to detect the independent predictors of survival. In all survival analyses, the follow-up period ended either on the day of the last visit for nontransplant patients or on the day of transplantation for transplant patients. The multivariate model was built with the backward elimination technique with P < 0.10 for entering the model and P < 0.05 for staying in the model. The results are presented as crude hazard ratios (HRs) with 95% confidence intervals (CIs) in univariate analyses and as adjusted HRs with 95% CIs in multivariate analyses. Crude HRs indicate the relationship between mortality and a single predictor. Adjusted HRs indicate the relationship between mortality and a predictor and take into account the other independent predictors. A P value < 0.05 was considered significant. Analyses were performed with the PASW statistical package (SPSS version 18.0, SPSS, Chicago, IL).
Characteristics of the Patients.
A total of 151 patients were enrolled. Clinical characteristics, biochemical values, and treatment at inclusion are summarized in Table 1. One hundred four patients (68.9%) had diuretic-intractable ascites: renal dysfunction was found at entry in 46 patients (30.5%), and hyponatremia was found in 58 patients (38.4%). None of the patients had diuretic-intractable ascites due to abnormal serum potassium levels. Forty-seven patients (31.1%) had diuretic-resistant ascites. All patients were regularly treated with large-volume paracentesis and intravenous albumin. Seventy-seven patients (51%) were treated with nonselective beta-blockers (propranolol) for the prevention of gastrointestinal hemorrhage. Among these patients, 9 (11.7%) were given 40 mg of propranolol per day, 31 (40.3%) were given 80 mg, 1 (1.3%) was given 120 mg, and 36 (46.7%) were given 160 mg.
|Whole Group (n = 151)||No–Beta-Blocker Group (n = 74)||Beta-Blocker Group (n = 77)||P Value|
|Gender, male||122 (80.8)||60 (81.1)||62 (80.5)||0.93|
|Age, years||60.4 ± 11.8||59.8 ± 11.4||60.9 ± 12.2||0.56|
|Weight, kg*||75.0 (40-132)||75.5 (51-132)||74 (40-103)||0.87|
|Heart rate, bpm||70 (54-89)||77 (63-89)||65 (54-79)||<0.0001|
|Arterial systolic pressure, mm Hg||114 (91-139)||123 (11-139)||103 (91-119)||<0.0001|
|Arterial diastolic pressure, mm Hg||73 (55-89)||73 (64-89)||73 (55-89)||0.95|
|Cause of cirrhosis||0.32|
|Hepatitis C virus||30 (19.9)||13 (17.6)||17 (22.1)|
|Hepatitis B virus||17 (11.3)||5 (6.8)||12 (15.6)|
|Alcoholic||85 (56.3)||49 (66.2)||36 (46.8)|
|B||49 (32.5)||29 (39.2)||20 (26.0)|
|C||102 (67.5)||45 (60.8)||57 (74.0)|
|MELD score||18.8 ± 4.1||18.9 ± 4.2||18.8 ± 4.0||0.89|
|MELD-Na score*||22 (11-31)||22 (11-31)||22 (14-30)||0.69|
|Presence of hepatocellular carcinoma||41 (27.2)||17 (23)||24 (31.2)||0.26|
|Presence of esophageal varices||74 (49)||3 (4.1)||77 (100)||<0.001|
|Presence of hepatic encephalopathy||57 (37.8)||24 (32.4)||33 (42.8)||0.38|
|Diabetes||32 (21.2)||15 (20.3)||17 (22.1)||0.78|
|Prothrombin time, % of normal||45 (30-90)||45 (31-90)||45 (30-90)||0.69|
|International normalized ratio||1.80 (1.00-2.50)||1.8 (1-2.5)||1.8 (1.0-2.5)||0.15|
|Platelet count, ×10−3/mm3||78 (27-359)||74 (29-359)||78 (27-270)||0.92|
|White cell count, ×10−3/mm3||6.8 (0.25-26)||6.9 (0.34-26)||6.7 (0.25-12.3)||0.69|
|Creatinine, mg/dL||0.89 (0.42-3.40)||0.86 (0.45-3.40)||0.89 (0.42-2.56)||0.83|
|Renal dysfunction||51 (33.8)||30 (41)||21 (27.3)||0.07|
|Serum sodium, mmol/L||132 (112-145)||133 (118-140)||125 (112-145)||0.09|
|Serum potassium, mmol/L||4 (2.5-5.4)||4.1 (2.5-5.1)||4.0 (2.9-5.4)||0.29|
|Total bilirubin, mg/dL||53 (11-340)||48 (11-340)||56 (17-125)||0.01|
|Serum albumin, g/L||28 (4-47)||29 (20-42)||26 (4-47)||0.12|
|Aspartate aminotransferase, U/L||56 (21-360)||54 (21-360)||58 (22-142)||0.16|
|Alanine aminotransferase, U/L||48 (11-183)||45 (12-183)||49 (11-156)||0.68|
|Ascitic fluid protein concentration, g/L||11 (0.9-25)||12 (0.9-22)||11 (0.9-25)||0.12|
Outcome and Follow-Up of the Whole Group of Patients.
The median follow-up time was 8 months (1-47 months). The median survival time was 10 months (95% CI = 8-12 months). The probability of survival was 41% at 1 year (95% CI = 33%-49%) and 28% at 2 years (95% CI = 20%-36%; Fig. 1).
Ninety-seven patients (64.2%) died. Causes of death were sepsis in 50 patients (spontaneous bacterial peritonitis in 11 cases) and progression of hepatocellular carcinoma in 13. Twenty-five patients died at home of unspecified causes. Twenty-six patients underwent liver transplantation during the study period.
Outcome According to Beta-Blocker Therapy.
At enrollment, no significant difference was observed between the two groups except for serum bilirubin and esophageal varices, which were present in all patients treated with beta-blockers and in only three patients in the other group (Table 1). The frequency of paracentesis was not significantly different between patients treated with beta-blockers (2.0 ± 1.1 per month) and those who were not (2.0 ± 1.8 per month). The heart rate and arterial pressure were also significantly different between the two groups. The HVPG was not significantly different between the two groups; it was 20.0 ± 4.5 mm Hg in patients treated with beta-blockers and 19.1 ± 5.0 mm Hg in those who were not (P = 0.49).
Sixty-three patients treated with beta-blockers died, and 34 patients died in the other group. The median survival time was 5.0 months (95% CI = 3.5-6.5 months) in patients treated with beta-blockers and 20.0 months (95% CI = 4.8-35.2 months) in patients not treated with beta-blockers. The difference was significant between the two groups (P < 0.0001).
In patients not treated with beta-blockers, the 1-year probability of survival was 64% (95% CI = 52%-76%), and in patients treated with beta-blockers, it was 19% (95% CI = 9%-29%; Fig. 2). In patients not treated with beta-blockers, the 2-year probability of survival was 45% (95% CI = 31%-59%), and in patients treated with beta-blockers, it was 9% (95% CI = 0%-19%; Fig. 2). The differences were significantly different (P < 0.0001). The causes of death were not significantly different between the two groups.
Factors Associated With Mortality.
Results of the univariate analysis of factors associated with mortality are found in Table 2. Significant univariate predictors of death were introduced into the multivariate Cox regression model. The independent factors predicting death were the presence of hepatocellular carcinoma, Child-Pugh class C, underlying etiologies of refractory ascites, and beta-blocker therapy (Fig. 3).
|Variable||HR (95% CI)||P Value|
|Age, years||1.02 (1.00-1.03)||0.0402|
|MELD-Na score||1.11 (1.01-1.21)||0.0254|
|Esophageal varices, presence of||2.11 (1.70-2.61)||<0.0001|
|Beta-blockers, presence of||4.00 (2.58-6.20)||<0.0001|
|Child-Pugh class C||2.41 (1.51-3.85)||0.0002|
|Hepatocellular carcinoma, presence of||2.13 (1.39-3.26)||0.0005|
|Cause of cirrhosis||1.15 (1.05-1.25)||0.0028|
|Prothrombin time, % of normal||0.98 (0.96-0.99)||0.0132|
|International normalized ratio||2.46 (1.44-4.20)||0.0010|
|Serum bilirubin concentration, mg/dL||1.01 (1.00-1.01)||0.0201|
|Etiology of refractory ascites||3.03 (2.28-4.02)||<0.0001|
|Renal impairment||3.10 (1.65-5.85)||0.0005|
|Severe hyponatremia (≤125 mEq/L)||9.26 (5.05-16.98)||<0.0001|
|Ascitic fluid protein concentration, g/L||0.93 (0.88-0.98)||0.0072|
|Serum sodium concentration, mEq/L||0.92 (0.89-0.95)||<0.0001|
|Heart rate, bpm||0.94 (0.91-0.96)||<0.0001|
|Arterial systolic blood pressure, mm Hg||0.97 (0.95-0.98)||<0.0001|
The present prospective observational study shows that patients with cirrhosis and refractory ascites who were treated with beta-blockers had a significantly higher mortality rate than those who were not. In addition, the median survival time was four times lower in the group with beta-blockers versus the group without beta-blockers. This difference was highly significant. The median survival time for all patients was 10 months, and this period was similar to those observed in previous studies.11, 12 There is no clear explanation for our finding of deleterious effects of beta-blocker treatment on mortality in patients with cirrhosis and refractory ascites. However, certain comments can be made. In fact, the effects of beta-blocker treatment in these patients have never been studied. Only one meta-analysis of four trials of beta-blockers in the prevention of initial episodes of gastrointestinal bleeding has been reported, and it showed that advanced cirrhosis and especially the presence of ascites were associated with death in both treated and untreated patients and that the mortality rate in the treated group was significantly lower than that in the placebo group.13 Patients with refractory ascites were not, however, included in these four trials. In the present series of patients, the severity of cirrhosis estimated by the Child-Pugh score and MELD score and the etiology of cirrhosis were not different between the two groups. The degree of portal hypertension estimated by the HVPG also does not explain the difference in mortality because the HVPG values were not different between the two groups. The slightly elevated serum bilirubin levels observed in patients treated with beta-blockers suggest subtle differences in liver function but cannot explain the higher mortality rate in beta-blocker–treated patients. Similarly, the presence of esophageal varices in treated patients does not seem to explain the higher mortality rate in this group. Although the occurrence of varices is associated with the severity of cirrhosis, in this study, the severity of cirrhosis was similar in the two groups. In contrast, the low arterial pressure measured in patients treated with beta-blockers may explain, at least in part, the higher mortality rate because it has been shown that low arterial pressure is an independent predictor of death in patients with cirrhosis and ascites.14 In the present study, our finding of low arterial pressure in patients with refractory ascites treated with beta-blockers is in contrast to observations in most patients with cirrhosis, in whom beta-blockers have no effect on arterial pressure.15 The relationship between low arterial pressures and mortality risk, independent of the severity of cirrhosis, remains, however, to be determined. Finally, beta-blocker administration may contribute to the development of postparacentesis-induced circulatory dysfunction, a syndrome associated with low survival in patients with cirrhosis and tense ascites.16-19 In patients with cirrhosis treated with beta-blockers, the development of the postparacentesis circulatory dysfunction may be secondary to the limitation of increased cardiac output. The survival rate in patients with refractory ascites and esophageal varices treated by band ligation is unknown. If beta-blockers are responsible for postparacentesis-induced circulatory dysfunction, the survival rate of patients treated by band ligation should be better than that of those treated with beta-blockers. The present study, however, makes it impossible to respond to this hypothesis and indicates that studies are needed to compare the two groups of treated patients.
Multivariate analysis showed that there were four independent predictors of death for the whole group of patients: the presence of hepatocellular carcinoma, Child-Pugh score class C, underlying etiologies of refractory ascites, and beta-blocker therapy. It should be emphasized that, unlike the Child-Pugh score, neither the MELD score nor the MELD-Na score was able to predict mortality in patients with cirrhosis and refractory ascites. In fact, in this series of patients, the MELD score was relatively low, whereas more than two-thirds of the patients had Child-Pugh class C cirrhosis. The discordance between these two prognostic indicators may be explained by the fact that ascites is taken into account in the Child-Pugh score but not in the MELD score.20, 21 In fact, patients with refractory ascites may have an elevated or low MELD score. Thus, the risk of premature death in patients with cirrhosis, refractory ascites, and preserved liver function is underestimated by the MELD score.21, 22 In other words, the MELD score cannot be used to predict mortality in patients with cirrhosis and refractory ascites. Because there is a strong correlation between the presence of ascites and hyponatremia in patients with cirrhosis, previous studies have shown that the serum sodium concentration has an independent prognostic value.23, 24 Several alternative models have suggested that the incorporation of sodium into the MELD score provides a more accurate prediction of survival than the MELD score alone in patient with ascites.10, 23 However, these new models do not take into account ascites itself and have been developed only for patients on the list for liver transplantation.
In multivariate analysis, severe hyponatremia (a reason for not using diuretic therapy) was a significant predictor of mortality. Even if hyponatremia has been clearly identified as a poor prognostic factor in cirrhosis,21, 23, 25, 26 the exact relationship between hyponatremia and the prognosis of cirrhosis remains unclear. Hyponatremia could be a reflection of systemic hemodynamic disorders related to the severity of cirrhosis.11 In addition, renal impairment (a reason for not using diuretic therapy) was an independent predictor of mortality. Renal impairment is known to be an indicator of poor prognosis in cirrhosis.4 Together, these findings suggest that diuretic-intractable refractory ascites (due to severe hyponatremia or renal impairment) may be worse than diuretic-resistant refractory ascites.
In conclusion, the present study shows that the use of nonselective beta-blockers is associated with poor survival in patients with cirrhosis and refractory ascites and suggests that these drugs should be contraindicated in these patients. This study also shows that the Child-Pugh score (but not MELD score) is a predictive factor of mortality in patients with cirrhosis and refractory ascites.