Development of Ascites in Compensated Cirrhosis With Severe Portal Hypertension Treated With...

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The American Journal of GASTROENTEROLOGY VOLUME 107 | MARCH 2012 www.amjgastro.com

INTRODUCTION Th e natural history of cirrhosis involves the progression from

a compensated to a decompensated stage characterized by the

development of complications, such as ascites, variceal bleeding,

or encephalopathy ( 1,2 ). Decompensation is a key event herald-

ing the onset of signifi cant morbidity and mortality. Portal hyper-

tension (PHT), usually estimated by the hepatic venous pressure

gradient (HVPG), is involved in the development of most com-

plications of cirrhosis and is the strongest predictor of clinical

decompensation ( 2 ). Even in the compensated phase of cirrhosis,

two stages with diff erent probability of survival have been deline-

ated based on the presence or absence of varices ( 1 ). Clinically

signifi cant PHT is diagnosed when HVPG is ≥ 10 mm Hg as both

varices and decompensation of cirrhosis may appear at this point

( 3,4 ). However, once this threshold has been reached the relation-

ship between changes in HVPG (such as those induced by drug

therapy) and development of decompensation has not been suffi -

ciently investigated. Th e prognostic value of HVPG monitoring to

predict bleeding is well established ( 5 ), but its utility in the predic-

tion of other complications is unclear. Ascites is the most frequent

complication of cirrhosis and is oft en the fi rst decompensation

to appear ( 6 – 8 ). It has been demonstrated that, in patients with

decompensated cirrhosis receiving drug therapy to prevent

variceal rebleeding, a reduction of HVPG to < 12 mm Hg or ≥ 20 %

from baseline, in addition to a marked decrease in rebleeding

risk, is also associated with a signifi cant reduction of the risk of

Development of Ascites in Compensated Cirrhosis With Severe Portal Hypertension Treated With β -Blockers Virginia Hern á ndez-Gea , MD 1 , Carles Aracil , MD 2 , Alan Colomo , MD 1 , 3 , Isabel Garupera , MD 1 , Maria Poca , MD 1 , Xavier Torras , MD 1 , 3 , Josep Mi ñ ana , MD 2 , Carlos Guarner , MD 1 , 3 and C à ndid Villanueva , MD 1 , 3

OBJECTIVES: In compensated cirrhosis, a threshold value of hepatic venous pressure gradient (HVPG) ≥ 10 mm Hg is required for the development of decompensation. However, whether the treatment of portal hypertension (PHT) can prevent the transition into development of ascites once this level has been reached is unclear. Our aim was to assess the relationship between changes in HVPG induced by β -blockers and development of ascites in compensated cirrhosis with severe PHT.

METHODS: Eighty-three patients without any previous decompensation of cirrhosis, with large esophageal varices and HVPG ≥ 12 mm Hg were included. After baseline hemodynamic measurements nadolol was administered and a second hemodynamic study was repeated 1 – 3 months later.

RESULTS: During 53 ± 30 months of follow-up, decompensation occurred in 52 patients (62 % ) and in 81 % of them ascites was the fi rst manifestation. Using receiver operating characteristic curve analysis a decrease in HVPG ≥ 10 % was the best cutoff to predict ascites. As compared with nonresponders, patients with an HVPG decrease ≥ 10 % had a lower probability of developing ascites (19 % vs. 57 % at 3 years, P < 0.001), refractory ascites ( P = 0.007), and hepatorenal syndrome ( P = 0.027). By Cox regression analysis hemodynamic nonresponse was the best predictor of ascites. By stepwise logistic regression, development of ascites was independently associated with nonresponse, whereas refractory ascites, hepatorenal syndrome, and spontaneous bacterial peritonitis were not.

CONCLUSIONS: In patients with compensated cirrhosis and large varices treated with β -blockers, an HVPG decrease ≥ 10 % signifi cantly reduces the risk of developing ascitic decompensation and other related compli-cations such as refractory ascites or hepatorenal syndrome.

Am J Gastroenterol 2012; 107:418–427; doi: 10.1038/ajg.2011.456; published online 14 February 2012

1 Gastrointestinal Bleeding Unit, Department of Gastroenterology, Servei de Patologia Digestiva, Hospital de la Santa Creu i Sant Pau, Universidad Autonoma de Barcelona , Barcelona , Spain ; 2 Department of Gastroenterology, Hospital Arnau de Vilanova , Lleida , Spain ; 3 Centro de Investigaci ó n Biom é dica en Red de Enfermedades Hep á ticas y Digestivas (CIBERehd) , Barcelona , Spain . Correspondence: C à ndid Villanueva, MD , Gastrointestinal Bleeding Unit, Department of Gastroenterology, Servei de Patologia Digestiva, Hospital de la Santa Creu i Sant Pau, Avgda, Universidad Autonoma de Barcelona , Sant Antoni M Claret, 167, Barcelona 08025 , Spain . E-mail: [email protected] Received 11 April 2011; accepted 11 October 2011

see related editorial on page 428

© 2012 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

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Development of Ascites in Compensated Cirrhosis

ascites, spontaneous bacterial peritonitis (SBP), hepatorenal syn-

drome, and also with an improvement in survival ( 9,10 ). However,

whether pharmacological treatment of PHT by reducing portal

pressure can prevent the transition of compensated cirrhosis into

development of ascites is unclear, particularly in the stage with

varices in which the risk of decompensation is higher. Further-

more, predictors of development of ascites in patients with com-

pensated cirrhosis and severe PHT remain undefi ned.

Th e aim of this study was to elucidate the relationship between

the changes in induced by β -blocker on PHT and development of

fi rst ascitic decompensation in patients with compensated cirrho-

sis, severe PHT, and large esophageal varices treated for primary

prophylaxis of bleeding. Other predictive factors of development

of ascites were also investigated.

METHODS All consecutive patients referred to our Hepatic Hemodynamic

Laboratory for entering into a program of prevention of fi rst

variceal bleeding episode were considered for inclusion in this

study. Patients were enrolled between January 2001 and January

2008, and were followed up until July 2009. Informed consent was

obtained from all the patients and the hospital ’ s ethics committee

approved the protocol.

Selection of patients Cirrhotic patients with large esophageal varices and without any

previous episode of gastrointestinal bleeding or previous his-

tory of ascites, jaundice, or encephalopathy were eligible. Cir-

rhosis was diagnosed by liver biopsy or by unequivocal clinical

and echographic fi ndings. Esophageal varices were diagnosed

by endoscopy performed in the previous 6 months by any of the

members of our bleeding unit and those with a diameter > 5 mm

were defi ned as large.

Th e NIEC (North Italian Endoscopie Club) index, a score which

includes Child-Pugh class and endoscopic parameters (size of

varices and red wale marks), was used to predict variceal bleeding

risk ( 11,12 ).

Exclusion criteria included contraindications to β -blockers,

hepatocellular carcinoma, Child-Pugh score > 10, splanchnic

venous thrombosis, age < 18 or > 80 years, treatment with diuret-

ics or with vasoactive drugs, and comorbidity expected to decrease

life expectancy to < 1 year.

Hemodynamic measurements and study design Hemodynamic studies were performed aft er an overnight fast.

Under local anesthesia, a catheter introducer was placed in the

right internal jugular vein using the Seldinger technique and was

used to advance, under fl uoroscopic guidance, a 7-F balloon-

tipped catheter into the right main hepatic vein and a Swan-Ganz

catheter into the pulmonary artery. Portal pressure was measured

as the HVPG, which is the diff erence between wedged and free

hepatic venous pressure. All intravascular pressure measurements

were performed in triplicate using a previously calibrated, highly

sensitive transducer, with external zero at the mild-axiliary line.

Permanent recording of tracings was obtained. Th e occluded

position was checked by the absence of refl ux aft er injection of

contrast medium. Cardiopulmonary pressures and cardiac out-

put were also measured. Electrocardiography, arterial pressure,

heart rate, and oxygen saturation were monitored noninvasively

throughout the study with an automatic monitor. To assess the

prognostic value of acute β -blockers test in a single hemody-

namic study, aft er completing baseline hemodynamic measure-

ments, a single intravenous bolus of 0.15 mg / kg of propranolol

was administered and 20 min later hemodynamic measurements

were repeated.

Continuous treatment with nadolol was started immediately aft er

the baseline hemodynamic study. Nadolol was administered orally

with a starting dose of 40 mg once daily. Th is was subsequently

adjusted over 1 – 2 weeks, with a stepwise increase or decrease of

20 mg every 2 – 3 days up to the maximum tolerate dose without

reducing resting heart < 50 beats per minute or up to 240 mg per day.

A second hemodynamic study was repeated 1 – 3 months later to

evaluate chronic response. Hemodynamic response was not pre-

defi ned.

Sodium restricted diet, without fl uid restriction, was indicated

in all cases. Nadolol was used for primary prophylaxis of variceal

bleeding. Endoscopic variceal ligation was indicated in case of

intolerance to β -blockers.

Follow-up Aft er inclusion, patients were followed at months 1 and 3, and

every 6 months thereaft er. Each visit included physical examina-

tion, blood tests, and abdominal ultrasound. Treatment adher-

ence was assessed by extensive interrogation with the patient and

relatives and by heart rate measurements. Follow-up data were

gathered for at least 18 months or until liver transplantation or

death. Th e end points evaluated were development of ascites or

complications of ascites (refractory ascites, SBP, hepatorenal syn-

drome). Development of other decompensations (bleeding and

encephalopathy) and death from any cause were also evaluated.

Ascites were defi ned by the presence of signs and symptoms

suggestive of ascites on physical examination and was always con-

fi rmed on ultrasonography or paracentesis. Th e diagnostic criteria

for refractory ascites, hepatorenal syndrome, and SBP were those

proposed by the International Ascites Club ( 13 ). Gastrointestinal

bleeding was defi ned as any episode of hematemesis or melena,

or both, that occurred during the follow-up and was evaluated by

emergency endoscopy. Variceal bleeding was defi ned according to

the Baveno IV criteria ( 14 ). Any death occurring during follow-up

was recorded. Patients lost to follow-up were censored as alive the

day of the last visit.

Statistical analysis Statistical analysis was performed according to an intention-to-

treat strategy.

Categorical variables, which are reported as frequencies, were

compared using the Fisher exact test. Continuous variables, which

were reported as mean values ± standard deviations, were com-

pared using the unpaired Student ’ s t -test or the nonparametric


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Hern á ndez-Gea et al.

Mann – Witney rank-sum test. Actuarial probabilities were calcu-

lated according to the Kaplan – Meier method and compared using

the Long-rank test. Follow-up was censored at the time of death,

liver transplantation, or last visit. Th e possible role of confound-

ing variables was investigated with the Cox proportional hazards

regression analysis or with stepwise logistic regression (SLR) anal-

ysis, by introducing covariates that were related to the analyzed

events in a univariate analysis ( P ≤ 0.1). Th e maximum number of

variables included in the multivariate analysis was 1 per 5 – 10 out-

comes. Th e contribution of each signifi cant variable to the risk of

reaching the end point was estimated by the relative hazard with

its 95 % confi dence interval (CI). Stratifi cation according to diff er-

ent risk subsets groups, with respect to ascites development, was

made by classifi cation-and-regression-tree analysis. All P values

were two-tailed and the level of values of less statistical signifi -

cance was taken at P < 0.05. Th e relationship between the sensitiv-

ity and specifi city of the HVPG value at diff erent cutoff points, as

a predictor of ascites development during follow-up, was evalu-

ated from a receiver operating characteristic (ROC) curve. Cal-

culations were performed with SPSS18 statistical package (SPSS,

Chicago, III).

RESULTS From a group of 204 patients eligible for the study, 121 had one

or more exclusion criteria of whom 94 had previous history of

ascites. Th e remaining 83 were fi nally included. During a mean

follow-up of 53 ± 30 months, 52 patients (62 % ) decompensate. Th e

fi rst decompensation to appear was ascites in 42 / 52 cases (81 % ),

variceal bleeding in 9 / 52 (17 % ), and encephalopathy in only 1.

Overall, 49 patients (59 % ) developed ascites, 13 patients (16 % )

SBP, and 11 (13 % ) patients hepatorenal syndrome. In all, 14

patients (17 % ) had a fi rst variceal bleed, hepatocellular carcinoma

occurred in 12 (14 % ), 5 underwent liver transplantation and 25

patients (30 % ) died.

Nine patients (11 % ) did not receive nadolol. Th is was because

of treatment nonadherence in two patients and due to complica-

tions in seven patients. Th e second hemodynamic study was not

performed in fi ve patients because of decision of the attending

physician in three and refusal to in two. Four of them developed

ascites.

Hemodynamic response to β -blockers and decompensation of cirrhosis Th e diagnostic accuracy to predict development of ascites

as measured by changes in HVPG while receiving chronic

treatment with nadolol was evaluated using ROC curve analysis

( Figure 1 ) and discriminative ability was good ( c statistic, 0.84;

95 % CI, 0.73 – 0.92). Th e optimal cutoff point was a ≥ 10 % reduc-

tion in HVPG, with 87 % sensitivity and 80 % specifi city. Accord-

ingly, patients were classifi ed as hemodynamic responders when

the HVPG decreased by ≥ 10 % from baseline.

Compared with nonresponders, responders had better NIEC

index, better degree of β -blockade, and a trend toward better

adherence to treatment with nadolol. Th ere were no other

diff erences between responders and nonresponders in baseline

data ( Table 1 ).

Compared with nonresponders, responders had a lower risk

of developing ascites ( Figure 2 ). In all, 11 responders (27 % ) and

34 nonresponders (89 % ) had ascites during the follow-up period

( P < 0.001). Th e likelihood of ascites was also lower in responders in

an analysis excluding the nine patients (three responders) who did

not receive nadolol due to complications or nonadherence (48 %

vs. 18 % at 2 years, P = 0.001). To treat ascites, diuretics were used

in 32 (74 % ) nonresponders vs. 11 (27 % ) responders ( P < 0.001). As

compared with nonresponders, responders also have a lower prob-

ability of developing refractory ascites ( Figure 2 ) and hepatorenal

syndrome. Transient hypovolemia-induced renal failure occurred

in two responders (5 % ) and in fi ve nonresponders (13 % ; P = 0.28).

Th ere was a trend toward a lower probability of developing SBP in

responders (7 % vs. 2 % at 2 years, P = 0.4).

As expected, the likelihood of fi rst bleeding was signifi cantly

higher in nonresponders (17 % vs. 5 % at 2 years, P = 0.001), as

well as the likelihood of a fi rst variceal bleeding (14 % vs. 5 % at 2

years, P = 0.01). Th e probability of developing encephalopathy was

slightly lower in responders, although the diff erence was not sig-

nifi cant (16 % vs. 6 % at 2 years, P = 0.14).

By SLR, both fi rst bleeding (hazard ratio (HR) = 6.3, 95 % CI = 1.1 –

35; P = 0.03) and ascites (HR = 14.5, 95 % CI = 4 – 53; P < 0.001) were

independently associated with hemodynamic nonresponse. In

another SLR model that included ascites, refractory ascites, hepa-

torenal syndrome, and SBP, only development of ascites was inde-

pendently associated with hemodynamic nonresponse (HR = 22,

95 % CI = 7 – 77; P < 0.001).

Acute hemodynamic response to β -blockers and development of ascites Using ROC curve analysis, the discriminative ability of acute

HVPG changes aft er intravenously administration of propranolol

Sen

sitiv

ity

1 - Specificity

1.0

0.8

0.6

0.4

0.2

0.0

0.0 0.2 0.4 0.6 0.8 1.0

Figure 1 . Receiver operating characteristic curves of acute and chronic response to β -blockers for development of ascites. Continuous line repre-sents hepatic venous pressure gradient (HVPG) changes after the chronic administration of nadolol and discontinuous line represents HVPG changes after the acute administration of intravenously propranolol. The diagnostic performance of chronic changes was better than that of acute changes, with c statistic of 0.84 (0.73 – 0.92) vs. 0.74 (0.61 – 0.84), P = 0.04.


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Table 1 . Characteristics of chronic hemodynamic responders and nonresponders at admission and during follow-up a

Responders �

( N =40)

Non-responders ( N =38) P value

Sex (M / F) 21 / 19 17 / 21 0.32

Age (years) 62 ± 10 63 ± 10 0.83

Cause of cirrhosis ( % ) 0.21

Alcohol 7 (17) 7 (18)

HCV 25 (62) 23 (60)

Alcohol + HCV 7 (17) 4 (10)

Associated diseases ( % ) 19 (47) 17 (45) 0.82

Albumin (g / l ) 35 ± 6 34 ± 5 0.15

Bilirubin ( μ mol / l) 35 ± 60 36 ± 26 0.93

Prothrombin time, INR 1.24 ± 0.5 1.27 ± 0.5 0.21

Creatinine ( μ mol / l) 85 ± 16 82 ± 13 0.38

Hemoglobin (g / l) 124 ± 19 116 ± 22 0.11

Platelet count ( × 10 − 3 ) 102 ± 50 104 ± 53 0.86

Child-Pugh class, A / B / C ( % ) 37 (92) / 2 (5) / 1 (2)

32 (84) / 6 (16) / 0

0.19

Child-Pugh score 6.5 ± 1.6 7.2 ± 1.7 0.10

MELD score 10 ± 4 12 ± 4 0.09

NIEC index 27 ± 4 31 ± 5 0.001

Variceal grade, II / III ( % ) b 35 (87) / 5 (13)

35 (92) / 3 (8)

0.49

Red weal marks ( % ) 15 (37) 16 (42) 0.82

Gastric varices ( % ) c 3 (7) 1 (3) 0.62

Hemodynamic variables (baseline values and chronic changes) d

Baseline pulmonary artery pressure (mm Hg)

17.9 ± 5 16.3 ± 4 0.14

Change from baseline ( % ) + 21 ± 47 + 12 ± 37 0.39

Baseline pulmonary wedge pressure (mm Hg )

11.1 ± 5 9.8 ± 4 0.19


Baseline right atrial pressure (mm Hg )

6.5 ± 3 5.5 ± 3 0.49


Baseline heart rate (beats / min)

77 ± 13 77 ± 11 0.86

Change from baseline ( % ) − 27 ± 13 − 12 ± 20 0.001

Decrease by > 10 % from baseline ( % )

39 (97) 24 (63) < 0.001


23 (58) 11 (29) 0.01

Baseline mean arterial pressure (mm Hg)

89 ± 12 87 ± 11 0.44


Baseline cardiac output (l / min) 7.1 ± 1.7 7.3 ± 1.9 0.42


Table 1 . Continued

Responders

( N =40)

Non-responders ( N =38) P value


33 (85) 21 (58) 0.02

Systemic vascular resistance (dyn.s / cm 5 )

1,000 ± 336 951 ± 303 0.51


Baseline WHVP (mm Hg) 27.0 ± 5 25.1 ± 5 0.11

Change from baseline ( % ) − 5 ± 15 + 5 ± 22 0.02

Baseline FHVP (mm Hg) 9.6 ± 3 8.3 ± 4 0.15


Baseline HVPG (mm Hg) 17.4 ± 3 16.8 ± 3 0.45

Change from baseline ( % ) − 19 ± 6 + 1 ± 13 < 0.001

Decrease by 20 % from baseline ( % )

17 (42) 0 < 0.001

Decrease to < 12 mm Hg ( % ) e 12 (30) 1 (3) 0.002

Follow-up

Nadolol dose (mg per day) 73 ± 35 64 ± 48 0.41

Withdrawal of nadolol ( % ) f 2 (5) 7 (8) 0.08

Compliance: good / fair / poor ( % ) g

33 (83) / 5 (12) / 2 (5)

23 (60) / 9 (24) / 6 (16)

0.08

Abstinence from alcohol ( % ) 9 / 14 (64) 6 / 11 (54) 0.69

Hepatocellular carcinoma ( % ) 6 (15) 6 (16) 0.99

Duration of follow-up (months) 0.43

Mean 54 ± 30 59 ± 30

Median 52 63

Range 6 – 96 9 – 96

Lost of follow-up ( % ) h 4 (10) 1 (3) 0.61

F, female; FHVP, free hepatic venous pressure; INR, International Normalized Ratio; M, male; HVPG, hepatic venous pressure gradient; NIEC, North Italian Endoscopie Club; WHVP, wedge hepatic venous pressure . a Patients were considered responders when in the second hemodynamic study, performed after 1 – 3 months of treatment with nadolol, the HVPG decreased by > 10 % from baseline. Plus-minus values are means ± s.d. b Grade I denotes varices that were fl attened by insuffl ation (all had red weal marks), grade II varices that were not fl attened by insuffl ation and were sepa-rated by areas of normal mucosa, and grade III confl uent varices that were not fl attened by insuffl ation. c Patients with esophageal and fundal varices (gastroesophageal varices type 2 according to Sarin’s classifi cation). d Baseline values and values obtained in the second hemodynamic study. e The fi nal value of HVPG was < 12 mm Hg in 13 patients. Only in 1 of them (of the responders group) the fi nal value of HVPG was < 10 mm Hg. f Two patients among responders and seven patients among nonresponders did not receive nadolol because of side-effects (six nonresponders) or nonadher-ence (two nonresponderss). These nine patients received endoscopic variceal ligation for primary prophylaxis of bleeding. g Adherence to treatment was considered good when doses of nadolol were rarely or never missed, fair when one or less doses were missed per week on average, and poor when ≥ 2 doses were missed per week. h Three patients in the responders group were lost to follow-up between at 31 and 60 months, and 1 patient in the nonresponders group was lost to follow-up at 41 month. � Patients were considered acute hemodynamic responders when the HVPG decreased by ≥ 10 % from baseline in the acute test to intravenous propranolol performed during the baseline study.


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independent predictors of development of ascites, whereas base-

line glomerular fi ltration rate and systemic vascular resistance

were not. Th e classifi cation-and-regression-tree method identi-

fi ed chronic hemodynamic response as the best single predictor

for development of acites ( Figure 3 ). In responders, the MELD

score provided additional prognostic value. A simple risk tree

identifi ed groups with ascites development ranging from 18 to

89 % ( Figure 3 ).

Patients who develop ascites had a signifi cantly higher rate of

fi rst variceal bleeding and of encephalopathy, than patients with-

out ascites. In all, 13 patients developed both ascites and variceal

bleeding. In seven of them (54 % ), ascites occurred before bleeding

and in three patients (23 % ) both decompensations occurred at the

same time. In all, 18 patients developed both ascites and encepha-

lopathy. In nine of them (50 % ), ascites occurred before and in six

patients (33 % ) both decompensations occurred at the same time.

Survival and development of decompensation Th e probability of survival was signifi cantly better in patients who

remained compensated than in those who developed an initial

decompensation of PHT (ascites, bleeding, or encephalopathy;

Figure 4 ). Twenty-three decompensated patients (44 % ) died (all

had ascites), as compared with two (6 % ) compensated. Death was

related to liver failure in 13 patients, to hepatocellular carcinoma

in 5, to bleeding in 4, sepsis in 2, and was unrelated with liver

disease in 1 patient.

Th e probability of survival was lower in patients who developed

ascites than in those who did not ( Figure 4 ), in patients who had

was good ( c statistic, 0.74; 95 % CI, 0.61 – 0.84; Figure 1 ). Th e

diagnostic performance of acute HVPG changes was worse than

that of chronic changes (diff erence between areas = 0.12 ± 0.05,

P = 0.04). Th e optimal cutoff point for acute changes was a > 9 %

reduction in HVPG and this threshold was used to defi ne acute

response. As compared with nonresponders, acute respond-

ers had a signifi cantly lower risk of developing a fi rst episode of

ascites (17 % vs. 49 % at 2 years, P = 0.005), lower risk of refractory

ascites (5 % vs. 18 % at 2 years, P = 0.03), and a trend toward lower

probability of developing hepatorenal syndrome (11 % vs. 0 % at 2

years, P = 0.3).

Predictors of risk of fi rst ascitic decompensation Patients who developed fi rst ascitic decompensation had lower

baseline systemic vascular resistance and lower glomerular fi ltra-

tion rate than patients who remained compensated. Th e baseline

MELD score was also signifi cantly higher in patients who devel-

oped ascites. Th ere were no other diff erences in baseline clinical

and hemodynamic parameters between patients who develop

ascites and patients compensated ( Table 2 ). Both, the rate of acute

and chronic hemodynamic response were signifi cantly lower in

patients who developed ascites. Th e incidence of fi rst variceal

bleeding and the incidence of encephalopathy were signifi cantly

higher in patients who had ascites than in those who had not. No

other parameters during follow-up were diff erent between patients

who had or had not ascites ( Table 2 ). In the multivariate analysis,

chronic hemodynamic nonresponse (HR = 3.2; 95 % CI = 1.5 – 6.4)

and baseline MELD score < 9 (HR, 1.9; 95 % CI = 1.0 – 3.50) were

Pro

babi

lity

of b

eing

free

of a

scite

s

1.0a

b c

0.8

0.6

0.4

0.2

0.0

040

Patients at riskResponders

Nonresponders

Responders

Nonresponders

32 26 21 18 16 11 8 6 41236111315192438

12 24 36 48 60 72 84 96 108 120 Months

Pro

babi

lity

of b

eing

free

of r

efra

ctor

y as

cite

s

Pro

babi

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epat

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yndr

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0.8

0.6

0.4

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1.0

0.8

0.6

0.4

0.2

0.0

Responders

Nonresponders

Responders

Nonresponders

0 12 24 36 48 60 72 84 96 108

120 Months 0 12 24 36 48 60 72 84 96 10

812

0 Months

Figure 2 . Probability of ascites ( a ), refractory ascites ( b ), and hepatorenal syndrome ( c ) according to hemodynamic response (defi ned as a decrease in hepatic venous pressure gradient decrease > 10 % from baseline). As compared with nonresponders (dashed line), hemodynamic responders (continuous line) have a signifi cantly higher probability of developing: ( a ) ascites ( P < 0.001), ( b ) refractory ascites ( P = 0.007), and ( c ) hepatorenal syndrome ( P = 0.027).


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Table 2 . Characteristics of patients who developed a fi rst ascitic decompensation and patients who remained compensated, at admission and during follow-up a

Remained compensated

( N =34)

Developed ascites ( N =49) P value

Sex (M / F) 20 / 14 20 / 29 0.12

Age (years) 63 ± 12 66 ± 9 0.18

Cause of cirrhosis ( % ) 0.53

Alcohol 8 (23) 7 (14)

HCV 18 (53) 33 (67)

Alcohol + HCV 5 (15) 6 (12)

Associated diseases ( % ) 18 (53) 29 (59) 0.60

Albumin (g / l) 38 ± 6 37 ± 5 0.26

Bilirubin ( μ mol / l) 22 ± 28 24 ± 14 0.77

Prothrombin time, INR 1.2 ± 1.6 1.2 ± 1.5 0.62

Urea (mmol / l) 6.1 ± 1.9 5.9 ± 2.9 0.77

Creatinine ( μ mol / l) 85 ± 16 82 ± 13 0.38

Glomerular fi ltration rate (ml / min per 1.73 m 2 ) b

83 ± 15 73 ± 15 0.007

Serum sodium (mmol / l) 140 ± 3 139 ± 3 0.29

Hemoglobin (g / l) 125 ± 24 126 ± 20 0.93

Platelet count ( × 10 − 3 ) 97 ± 42 87 ± 47 0.77

Child-Pugh class, A / B / C ( % ) 31 (91) / 2 (6) / 1 (3)

40 (82) 9 (18) / 0

0.13

Child-Pugh score 5.6 ± 1.2 5.8 ± 0.9 0.31

MELD score 7.4 ± 3 8.8 ± 3 0.05

NIEC index 25 ± 3 24 ± 3 0.42

Variceal grade, II / III ( % ) 28 (76) / 6 (18)

47 (90) / 2 (4)

0.12

Red weal marks ( % ) 16 (47) 16 (33) 0.14

Gastric varices ( % ) 2 (6) 2 (4) 0.99

Hemodynamic variables (baseline values and chronic changes) c

Baseline pulmonary artery Pressure (mm Hg)

17.9 ± 5 17.43 ± 5 0.68

Change from baseline ( % ) 15 ± 48 18 ± 38 0.77

Baseline pulmonary wedge pressure (mm Hg)

11.4 ± 4 10.1 ± 4 0.14


Baseline right atrial pressure (mm Hg)

6.8 ± 3 5.6 ± 3 0.15


Baseline heart rate (beats / min)

75 ± 11 79 ± 12 0.21



23 (85) 32 (80) 0.35


11 (41) 16 (40) 0.32

Table 2 . Continued

Remained compensated

( N =34)

Developed ascites ( N =49) P value

Baseline mean arterial pressure (mm Hg)

89 ± 12 86 ± 11 0.28


Baseline cardiac output (l / min) 6.9 ± 1.8 7.5 ± 1.9 0.13



16 (67) 23 (62) 0.07

Systemic vascular resistance (dyn.s / cm 5 )

1053 ± 383 908 ± 263 0.05


Baseline WHVP (mm Hg) 26.6 ± 5 26.0 ± 5 0.62

Change from baseline ( % ) − 6 ± 14 4 ± 21 0.03

Baseline FHVP (mm Hg) 10.2 ± 3 8.6 ± 3 0.09


Baseline HVPG (mm Hg) 16.4 ± 3 17.5 ± 3 0.11

Change from baseline ( % ) − 18 ± 9 − 4 ± 15 < 0.001

Decrease by 10 % from baseline ( % )

29 (88) 11 (24) < 0.001

Decrease to < 12 mm Hg ( % ) d 11 (33) 2 (4) 0.0012

Follow-up

Nadolol dose (mg per day) 64 ± 35 82 ± 39 0.34

Withdrawal of nadolol ( % ) e 3 (9) 6 (12) 0.39

Compliance: good / fair / poor ( % ) 28 (82) / 4 (12) / 2 (6)

32 (65) / 11 (23) / 6 (12)

0.23

Abstinence from alcohol ( % ) 9 / 12 (75) 8 / 13 (61) 0.67

Variceal bleeding 1 (3) 13 (26 % ) 0.006

Encephalopathy 5 (16) 18 (39) 0.04

Hepatocellular carcinoma ( % ) 4 (12) 8 (16) 0.64

Duration of follow-up (months) 0.22

Mean 47 ± 29 57 ± 30

Median 48 60

Range 6 – 96 6 – 96

Lost of follow-up ( % ) f 3 (9) 2 (5) 0.58

F, female; FHVP, free hepatic venous pressure; INR, International Normalized Ratio; M, male; HVPG, hepatic venous pressure gradient; NIEC, North Italian Endoscopie Club; WHVP, wedge hepatic venous pressure. a Patients included had not previous decompensations. Development of ascites was always confi rmed by ultrasonography or paracentesis. Plus-minus values are means ± s.d. See footnotes in Table 1 . b Glomerular fi ltration rate was estimated from serum creatinine with the Modifi -cation of Diet in Renal Disease equation. c Baseline values and values obtained in the second study performed after 1 – 3 months of treatment with nadolol. d Only in one patient (of the compensated group) the fi nal value of HVPG was < 10 mm Hg. e Three patients of the compensated group and six of the ascites group did not receive nadolol because of side-effects. These nine patients received endo-scopic variceal ligation for primary prophylaxis of bleeding. f Three patients in the compensated group were lost to follow-up between at 31 and 60 months, and two patients in the ascites group were lost to follow-up at 41 and 47 months.


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in HVPG and ascites development. Heterogeneous stages of cir-

rhosis, with diff erent prognosis, were included in these studies,

meaning patients with compensated and decompensated disease,

with previous history of ascites in many cases. Another impor-

tant limitation of these studies was the subjective defi nition used

for ascites development, even including worsening of preexisting

ascites. To deal with these limitations the current study specifi -

cally select an homogeneous group of patients with compensated

cirrhosis and without any previous decompensation, but at high

risk of decompensation indicated by the presence of HVPG

≥ 12 mm Hg and large varices, who were treated with nonselective

β -blockers for primary prophylaxis of bleeding. Our results pro-

vide additional evidence on the contribution of PHT to the pro-

gression of cirrhosis, showing that once clinically signifi cant PHT

is reached, it is still possible to reduce the probability of develop-

ing ascites by achieving a decrease in HVPG ≥ 10 % from baseline.

Otherwise ascites will develop in the majority of patients (up to

90 % ) without such a reduction in HVPG. In agreement with pre-

vious observations ( 9,10,15 ), the current study shows that hemo-

dynamic response also decreases the risk of refractory ascites and

hepatorenal syndrome. However, SLR analysis showed that only

ascites, and neither hepatorenal syndrome nor refractory ascites,

was independently associated with hemodynamic response. Th is

suggests that, in compensated cirrhosis, hemodynamic response

reduces the risk of complications related with ascites by decreas-

ing the probability of developing ascites.

Predictors of ascites development have not been clearly estab-

lished. Previous studies have shown that several parameters refl ect-

ing liver and circulatory dysfunction, such as bilirubin, MELD,

arterial hypotension, urinary sodium excretion, or plasma renin

activity, provide prognostic information on development of ascites

( 4,7,8,16 – 18 ). Th is is clinically sound because both, liver and cir-

culatory dysfunction, are involved in the development of ascites as

well as PHT ( 16 – 18 ). In keeping with this, the current study clearly

demonstrates that lack of hemodynamic response is a strong pre-

dictor of ascites. We also found that patients who developed ascites

had worse liver function, as indicated by a higher MELD score, and

had changes related to the circulatory dysfunction that accompanies

the progression of cirrhosis, such as a greater arterial vasodilatation

indicated by a lower systemic vascular resistance. However, clas-

sifi cation-and-regression-tree analysis showed that hemodynamic

nonresponse provides the strongest prognostic information on the

risk of developing ascites, whereas MELD score may be helpful to

identify patients at risk despite achieving a hemodynamic response.

Th e defi nition of response in this study diff ers from the tradi-

tional criteria of an HVPG decrease > 20 % . However, this criterion

was established in decompensated cirrhosis with previous variceal

bleeding and frequently also with ascites ( 19,20 ). In keeping with

our results, several studies have shown that in earlier stages of cir-

rhosis, with less severe PHT, a lower threshold reduction in HVPG

may be enough to prevent decompensation ( 4,21 ). In compensated

cirrhosis with moderate PHT (HVPG > 6 mm Hg) and absence of

varices, a 10 % threshold reduction in HVPG was independently

associated with a reduced risk of developing either varices or

variceal bleeding and also lower risk of cirrhotic decompensation

hepatorenal syndrome than in those who had not (70 % vs. 90 % at

3 years, P < 0.001) and in patients who had SBP vs. those who had

not (82 % vs. 89 % at 3 years, P = 0.03). Th e probability of survival

was also lower in patients who had a fi rst variceal bleeding than

in non-bleeders ( Figure 4 ), in patients who had encephalopathy

vs. those who had not (85 % vs. 90 % at 3 years, P = 0.004), and in

chronic hemodynamic nonresponders vs. responders ( Figure 4 ).

Among the diff erent causes of decompensation, development

of ascites (HR = 7.7, 95 % CI = 1.8 – 23.3; P < 0.01) and fi rst bleeding

(HR = 5.01, 95 % CI = 2.1 – 11.3; P < 0.01), but not encephalopathy,

were independent predictors of death by backward stepwise Cox

proportional hazards regression analysis. Among the complica-

tions of ascites, development of refractory ascites (HR = 4.1, 95 %

CI = 1.8 – 9.3; P < 0.01) was the only independent predictor of death,

whereas hepatorenal syndrome and SBP were not.

DISCUSION Th is study shows that in compensated cirrhosis with severe PHT

and large esophageal varices a reduction in HVPG > 10 % from

the baseline (considered hemodynamic response) lowers the risk

of decompensation. In addition to a reduced risk of fi rst variceal

bleeding, hemodynamic responders had lower probability of fi rst

ascitic decompensation. Complications of ascites, such as refrac-

tory ascites and hepatorenal syndrome, were also less frequent

in responders. Previous studies have shown that development of

ascites is mainly dependent on the progression of PHT ( 2 ). An

increase in HVPG above 10 mm Hg dramatically increases the

risk of transition from a compensated to a decompensated stage

( 4 ). However, beyond this threshold the contribution of changes

in HVPG to the risk of ascites has not been clearly established.

Previous studies focused on the prevention of variceal hemor-

rhage have shown that a reduction in HVPG to < 12 mm Hg or

≥ 20 % from baseline, in addition to lower risk of bleeding, is also

associated with a decreased risk of ascites ( 9,10 ). However, con-

troversial results have been reported ( 15 ). Th is may be due to

methodological diff erences among studies. None of them was

specifi cally designed to evaluate the relationship between changes

Overall83 cases,

49 (59%) developed ascitic decompensation

Hemodynamic responders40 cases

11 (27%) developed ascites

MELD score >107 cases


MELD score >1033 cases


Hemodynamic nonresponders38 cases


Figure 3 . Classifi cation-and-regression-tree (CART) analysis for develop-ment of ascites. CART analysis identifi ed hemodynamic nonresponse as the most effi cient fi rst splitting variable of risk of developing ascites. MELD score provides additional prognostic value in responders. In 5 of the 83 patients included, hemodynamic response could not be assessed because the second hemodynamic study was not performed (4 of them developed ascites).


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( 3,4 ). In a recent study from our unit, this threshold reduction was

the best cutoff to predict fi rst bleeding in patients with large varices

under primary prophylaxis ( 21 ). In that study, we also observed

that hemodynamic responders had a lower risk of development or

worsening of ascites ( 21 ). However, more than 50 % of the patients

included had previous history of ascites precluding an appropriate

evaluation of the relationship between changes in HVPG and pro-

gression into decompensation.

Another relevant fi nding in this study was the prognostic value of

acute response to β -blockers on long-term risk of ascites. Although

the prognostic ability was inferior than that of chronic response, as

indicated by a lower area under ROC curve, the predictive value of

acute response, in a single hemodynamic study, on long-term risk of

decompensation was accurate as shown in previous studies ( 21,22 ).

Both endoscopic variceal ligation and β -blockers are currently rec-

ommended as fi rst-line option in primary prophylaxis of bleeding

( 23 ). Our fi ndings show that a single hemodynamic study with an

acute test is able to predict patients in whom β -blockers may pro-

vide relevant additional benefi t. Th is in turn suggests that restricting

EVL, a therapy with potential for severe side-eff ects, to acute non-

responders may improve the effi cacy of prophylactic treatment in

compensated cirrhosis, but requires further investigation.

In compensated cirrhosis mortality largely depends on the pro-

gression of liver disease to decompensation ( 1,2 ). Accordingly, in the

current study the majority of deaths occurred aft er either ascites or

bleeding and as expected we found that development of decompen-

1.0

0.8

0.6

0.4

0.2

0.0

0 12 24 26 48 60 72 84 96 108 120

Decompensted

Compensted1.0

0.8

0.6

0.4

0.2

0.0

0 12 24 26 48 60 72 84 96 108 120

Non-ascitic

Ascitic

1.0

0.8

0.6

0.4

0.2

0.0

0 12 24 26 48 60 72 84 96 108 120

1.0

0.8

0.6

0.4

0.2

0.0

0 12 24 26 48 60 72 84 96 108 120

RespondersNon-bleeders

Bleeders

Pro

babi

lity

of s

urvi

val

Pro

babi

lity

of s

urvi

val

Pro

babi

lity

of s

urvi

val

Pro

babi

lity

of s

urvi

val

Non responders

a b

c d

Figure 4 . Probability of survival according to development of any fi rst decompensation ( a ), development of ascites ( b ), development of fi rst bleeding ( c ), and according to hemodynamic response ( d ). ( a ) The probability of survival was signifi cantly better in patients who remained compensated (continu-ous line) than in those who did not (dashed line) and developed a fi rst decompensation of portal hypertension (ascites, bleeding, or encephalopathy; P = 0.008). ( b ) Survival was worse in patients who developed ascites (dashed line) than in those who did not (continuous line; P = 0.006). ( c ) Survival was worse in patients with fi rst bleeding (dashed line) than in non-bleeders (continuous line; P = 0.01). ( d ) Survival was worse in hemodynamic nonresponders (dashed line) than in responders (continuous line; P = 0.04).

sation had a robust predictive value of mortality. Both development

of ascites and bleeding had independent predictive value of death.

In keeping with previous studies ( 5,9,10,19,20 ), we also found that

hemodynamic response was the strongest predictor of decompensa-

tion of cirrhosis, which will ultimately determine survival.

A possible limitation of this study is related to the population

investigated. We included patients in compensated phase of cir-

rhosis and in the stage with large esophageal varices. Whether the

results can be applied to patients without varices or with decom-

pensated cirrhosis remains to be determined. However, it has been

shown that an HVPG decrease ≥ 10 % is an independent predictor

of decompensation in compensated cirrhosis without varices and

with mild PHT (with HVPG ≥ 6 mm Hg) ( 4 ). In decompensated cir-

rhosis, it has been shown that an HVPG decrease ≥ 20 % may avoid

complications such as ascites ( 9,10 ). Whether a lesser decrease in

HVPG may be enough to prevent ascites in these patients remains

to be determinate. Another potential limitation is related to the fact

that the study was not blinded and this may have introduced a bias.

It is unlikely, however, as the hemodynamic response was not pre-

defi ned and all consecutive patients referred primary prevention of

bleeding were included and prospectively followed for development

of decompensation. Th e absence of a control group, without treat-

ment with β -blockers, does not allow to ascertaining whether other

cofactors may have induce an improvement of PHT or may have

account for development of ascites. However, it has been shown that

hemodynamic response, either induced by therapy or spontaneous,


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WHAT IS NEW HERE 3 In compensated cirrhosis with severe portal hypertension

(indicated by the presence of large esophageal varices), when β -blockers achieve a reduction in HVPG > 10 % , the risk of progress to decompensation decreases signifi cantly.

3 In addition to a lower probability of fi rst variceal bleeding, hemodynamic responders (with an HVPG reduction > 10 % ) had a signifi cantly lower probability of developing ascites, refractory ascites, and hepatorenal syndrome.

3 Hemodynamic nonresponse provides the strongest prog-nostic information on the risk of develop ascites, whereas MELD score may be helpful to identify patients at risk despite achieving a hemodynamic response

3 The prognostic value of acute hemodynamic response to β -blockers on long-term risk of ascites was accurate, although it was inferior to that of chronic response.

REFERENCES 1 . D ’ Amico G , Garcia-Tsao G , Pagliaro L . Natural history and prognostic indi-

cators of survival in cirrhosis: a systematic review of 118 studies . J Hepatol 2006 ; 44 : 217 – 31 .

2 . Garcia-Tsao G , Friedman S , Iredale J et al. Now there are many (stages) where before there was one: In search of pathophysiological classifi cation of cirrhosis . Hepatology 2010 ; 51 : 1445 – 9 .

3 . Groszmann RJ , Garcia-Tsao G , Bosch J , et al. , for the Portal Hypertension Collaborative Group . Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis . N Engl J Med 2005 ; 353 : 2254 – 61 .

4 . Ripoll C , Groszmann R , Garcia-Tsao G et al. Hepatic venous pressure gardient predicts clinical descompensation in patients with compensated cirrhosis . Gastroenterology 2007 ; 133 : 481 – 8 .

5 . D ’ Amico G , Garcia-Pagan JC , Luca A et al. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review . Gastroenterology 2006 ; 131 : 1611 – 24 .

6 . Gines P , Quintero E , Arroyo V et al. Compensated cirrhosis: natural history and prognostic factors . Hepatology 1987 ; 7 : 122 – 8 .

7 . Sangiovanni A , Prati GM , Fasani P et al. Th e natural history of compensat-ed cirrhosis due to hepatitis C virus: a 17-year cohort study of 214 patients . Hepatology 2006 ; 43 : 1303 – 10 .

8 . Sanyal AJ , Banas C , Sargeant C et al. Similarities and diff erences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C . Hepatology 2006 ; 43 : 682 – 9 .

9 . Villanueva C , L ó pez-Balaguer JM , Aracil C et al. Maintenance of hemo-dynamic response to treatment for portal hypertension and infl uence on complications of cirrhosis . J Hepatol 2004 ; 40 : 757 – 65 .

10 . Abraldes JG , Tarantino I , Turnes J et al. Hemodynamic response to phar-macological treatment of portal hypertension and long-term prognosis of cirrhosis . Hepatology 2003 ; 37 : 902 – 8 .

11 . Beppu K , Inokuchi K , Koyanagi N et al. Prediction of variceal hemorrhage by esophageal endoscopy . Gastrointest Endosc 1981 ; 27 : 213 – 8 .

12 . Th e North Italian Endoscopic Club for the study and treatment of esophageal varices . Prediction of the fi rst variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices . N Engl J Med 1988 ; 319 : 983 – 9 .

13 . Arroyo V , Gin è s P , Gerbes AL et al. Defi nition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis . Hepatology 1996 ; 23 : 164 – 76 .

14 . De Franchis R . Evolving consensus in portal hypertension. Report of the Baveno III consensus workshop on methodology of diagnosis and therapy in portal hypertension . J Hepatol 2005 ; 43 : 167 – 76 .

15 . Turnes J , Garcia-Pagan JC , Abraldes JG et al. Pharmacological reduction of portal pressure and long-term risk of fi rst variceal bleeding in patients with cirrhosis . Am J Gastroenterol 2006 ; 101 : 506 – 12 .

16 . Wong F , Liu P , Allidina Y et al. Pattern of sodium handling and its consequences in patients with preascitic cirrhosis . Gastroenterology 1995 ; 108 : 1820 – 7 .

17 . Wong F , Liu P , Blendis L . Sodium homeostasis in the chronic sodium load-ing in pre-ascitic cirrhosis . Gut 2001 ; 49 : 847 – 51 .

is an independent predictor of decompensation in compensated

cirrhosis without varices ( 4 ). Whether treatment of PHT, with

β -blockers or other drugs, can prevent the development of ascites as

suggested by our study should be confi rmed in future randomized

control trial.

In conclusion, the results of this study indicate that in patients with

compensated cirrhosis and severe PHT with large varices, achieving

an HVPG decrease > 10 % from baseline with β -blockers provides

a signifi cant reduction on the risk of fi rst ascitic decompensation.

Hemodynamic responders also have lower risk of other decompen-

sations related with ascites, such as refractory ascites and hepato-

renal syndrome, in addition to lower risk of variceal bleeding.

ACKNOWLEDGMENTS We thank the nursing and medical staff of the Gastrointestinal

Bleeding Unit and the Semi-Critical Unit of the Hospital de la Santa

Creu i Sant Pau for their cooperation in this study. We also thank

Mr X. Diez for his technical support in hemodynamic studies.

CONFLICT OF INTEREST Guarantor of the article: Candid Villanueva, MD.

Specifi c author contributions: All authors have contributed to

data interpretation and approved the fi nal version of the manuscript.

Virginia Hernández-Gea was responsible for study design, data

acquisition, draft ing of the manuscript, and data analysis. Carles

Aracil and Alan Colomo were responsible for study design,

manuscript revision, and data analysis. Isabel Graupera and Maria

Poca were responsible for data acquisition. Carlos Guarner, Josep

Miñana, and Xavier Torras were responsible for critical review of

the study design and manuscript revision. Candid Villanueva made

substantial contribution to the conception and design of the project,

interpretation of the data, manuscript draft ing, and overall supervi-

sion of the project.

Financial support: Th is study has been supported in part by a Grant

from the Fondo de Investigaciones Sanitarias (EC08 / 00087) and by

the Fundaci ó Investigaci ó Sant Pau (CAIBER).

Potential competing interests: None.

Study Highlights

WHAT IS CURRENT KNOWLEDGE 3 Ascites is the most frequent complication of cirrhosis and

is often the fi rst decompesation to appear. Predictors of ascites development are not known.

3 In compensated cirrhosis, the risk of developing ascites appears when the hepatic venous pressure gradient (HVPG) is 10 mmHg.

3 Once this threshold has been reached the relationship between changes in HVPG and development of decompen-sation has not been clarifi ed.

3 In patients with decompensated cirrhosis receiving drug therapy to prevent variceal rebleeding, a reduction of HVPG 20 % from baseline is associated with a signifi cant reduction of the risk of ascites. Whether changes in HVPG (induced by treatment) can prevent the transition of compensated cir-rhosis into development of ascites has not been established.


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18 . Blendis L , Wong F . Th e natural history and management of hepatorenal disorders: from pre-ascites to hepatorenal syndrome . Clin Med 2003 ; 3 : 154 – 9 .

19 . Feu F , Garc í a-Pag á n JC , Bosch J et al. Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis . Lancet 1995 ; 346 : 1056 – 9 .

20 . Villanueva C , Mi ñ ana J , Ortiz J et al. Endoscopic ligation compared with combined treatment with nadolol plus isosorbide mononitrate to prevent recurrent variceal bleeding . N Engl J Med 2001 ; 345 : 647 – 55 .

21 . Villanueva C , Aracil C , Colomo A et al. Acute hemodynamic response to beta-blockers and prediction of long-term outcome

in primary prophylaxis of variceal bleeding . Gastroenterology 2009 ; 137 : 119 – 28 .

22 . La Mura V , Abraldes JG , Raff a JC et al. Prognostic value of acute hemo-dynamic response to i.v. propranolol in patients with cirrhosis and portal hypertension . J Hepatol 2009 ; 51 : 279 – 87 .

23 . Garcia-Tsao G , Sanyal A , Grace ND , et al. , and the Practice Guidelines Committee of the American Association for the Study of Liver Diseases, the Practice Parameters Committee of the American College of Gastroenterology . Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis . Hepatology 2007 ; 46 : 922 – 38 .

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