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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 5  |  Issue : 1  |  Page : 1-8

Does acute response to safe dose of carvedilol vary across different child class of liver disease: A large cohort hemodynamic study


1 Department of Gastroenterology, ILBS, New Dehli, India
2 Department of Health and Medical Education, Health Services, Kashmir, India
3 Department of Gastroenterology, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, India
4 Department of Preventive Medicine, ILBS, New Dehli, India

Date of Web Publication13-Jan-2016

Correspondence Address:
Riyaz Ahmad Bhat
Department of Health and Medical Education, Health Services, Kashmir
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-344X.173883

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  Abstract 

Background: Carvedilol is a nonselective beta-blocker with an additional alpha 1 adrenoceptor blocking action, causing a much greater decrease in portal pressure as compared to propranolol. Materials and Methods: One hundred two consecutive patients of cirrhosis of the liver with significant portal hypertension were included, and hepatic venous pressure gradient (HVPG) was measured at the baseline and after 90 min of administration of 12.5 mg carvedilol. Results: A total of 102 patients with mean age of 58.3 ± 6.6 years were included. A total of 42.2%, 31.9%, and 26.6% patients had child Class A, child Class B, and Child Class C cirrhosis, respectively. Mean baseline HVPG was 16.75 ± 2.12 mmHg that dropped to 13.07 ± 2.32 mmHg, after 90 min of administration of 12.5 mg of carvedilol. The mean drop of HVPG was 4.5 ± 2.2 mmHg and 2.4 ± 1.9 mmHg between responders and nonresponders, respectively. Overall, 52 patients (51%) showed acute response while 50 (49%) were nonresponders. Baseline low cardiac output (CO) and high mean arterial pressure (MAP) were significant predictors of acute response on univariate analysis. On multivariate analysis, low baseline CO was found as an independent predictor. Conclusion: Carvedilol is a drug of choice among beta-blockers for primary prophylaxis of variceal bleed. Hemodynamic parameters like baseline low CO high MAP are significantly predicting acute response while as etiology, child class, and variceal size are not significantly associated with acute response to a safe dose of carvedilol.

Keywords: Cardiac output, hepatorenal syndrome, variceal band ligation


How to cite this article:
Wani ZA, Bhat RA, Maiwall R, Andrabi Ru, Yatoo GN, Shah MA, Bhadoria AS. Does acute response to safe dose of carvedilol vary across different child class of liver disease: A large cohort hemodynamic study. Int J Health Allied Sci 2016;5:1-8

How to cite this URL:
Wani ZA, Bhat RA, Maiwall R, Andrabi Ru, Yatoo GN, Shah MA, Bhadoria AS. Does acute response to safe dose of carvedilol vary across different child class of liver disease: A large cohort hemodynamic study. Int J Health Allied Sci [serial online] 2016 [cited 2021 Sep 27];5:1-8. Available from: https://www.ijhas.in/text.asp?2016/5/1/1/173883


  Introduction Top


Serious complications of portal hypertension (PTH) are esophageal and gastric variceal bleeding, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, portal hypertensive gastropathy, cytopenia, and portosystemic encephalopathy.[1] Recent studies have shown that for these complications to develop, hepatic venous pressure gradient (HVPG) should increase above 10 mmHg and should be above 12 mmHg for variceal bleeding.[2],[3] The overall prevalence of varices in an asymptomatic compensated patient is 40%[2] while the incidence of variceal development is 6% per year and it doubles if HVPG rises above 10 mmHg and thus cirrhotics with HVPG of >10 mmHg represent higher risk group. HVPG >10 mmHg also correlates with higher risk of decompensation and hepatocellular carcinoma (HCC).[4],[5] A good number of meta-analysis has shown that prognosis of cirrhotics patients improves with a significant decrease in portal pressure, i.e., when target decrease in HVPG (>20% from baseline or to <12 mmHg) is achieved.[6] In practice, all patients with varices should be treated except for child A patients with small varices without red color signs.[7] Current therapy with propranolol results in a reduction in first variceal bleed and mortality compared with placebo.[8] Analysis of two recent meta-analysis with 16 trials do not show the difference in bleeding.[9] one meta-analysis has shown variceal band ligation (VBL) as more effective intervention than drug therapy (beta-blocker) in primary prevention of variceal bleeding, although there was no difference in survival.[10] The other meta-analysis also showed similar results. Here, the trials with follow-up <20 months and unclear bias control were excluded, and it clearly makes no difference in bleeding between VBL and beta-blocker group.[11]

Nonselective beta-blockers (NSBBs) propranolol and nodolol achieve HVPG response in 30–40% of patients but the reduction in risk of bleeding is to the tune of 45–50% that has been ascribed to the decline of azygous blood flow and variceal pressure as well as decreasing the intestinal transit time.[12],[13]

HVPG can be further reduced when drugs such as isosorbide −5 mononitrate, prazosin, or statins are added to NSBBs.

The hemodynamic response to carvedilol has been assessed in many earlier studies. A pilot trial on 16 patients demonstrated fall in HVPG from 16.7 to 13.6 mmHg without significant reduction in azygous blood flow. In this trial, mean arterial pressure (MAP) dropped from 94.8 to 84 mmHg and heart rate (HR) decrease only in ascites patients. No changes in cardiac output (CO), renal blood flow or systemic vascular resistance (SVR) were observed.[14]

A randomized trial comparing the acute administration of carvedilol to propranolol has shown a more effective reduction in portal pressure with carvedilol than propranolol, in this study, carvedilol was shown to cause a greater reduction in MAP.[15] From this study, it was concluded that arterial hypotension may eventually prevent its long-term use in cirrhotic patients with hyperdynamic circulation and impaired renal function.

Bañares et al. in 2002 compared carvedilol to propranolol in portal hypertensive patients and showed that proportion of patients achieving hemodynamic response was greater with carvedilol, but an follow-up carvedilol caused a significant decrease in MAP, increase in plasma volume, in the study, it was shown that glomerular filtration rate (GFR) remained unchanged with carvedilol and dose of diuretics where more frequently increased in carvedilol group.[16] The long-term randomized study using carvedilol for primary prophylaxis of variceal bleeding compared with endoscopic band ligation (EBL) showed significantly lower bleeding rates in carvedilol limb compared to EBL, in this study, hemodynamic response was not evaluated by HVPG measurements and a fixed dose of carvedilol (12.5 mg) was used.[17]

Recently, a study evaluated hemodynamic response to carvedilol in propranolol nonresponders and concluded that carvedilol leads to a significantly greater decrease in HVPG than propranolol, using carvedilol for primary prophylaxis; a substantial portion of propranolol nonresponders achieved a hemodynamic response with improved outcome with regard to prevention of variceal bleeding, hepatic decompensation, and death. The study also showed that increasing the dose of carvedilol above 12.5 mg may just increase unwanted systemic and renal side effects while lacking a greater portal hypertensive effect and thus a need for optimal dose of carvedilol needs separate studies, further optimal dose across different child class may vary and thus responses with respect to optimal dose across different child class may also vary.[18]

Therefore, primary aim of our study was to assess the effect of reasonably safe dose of (12.5 mg) of carvedilol in an acute reduction of portal pressure and to see the response across different child class of liver disease. The significant clinical hemodynamic parameters for acute response were also assessed, so that, future studies can be conducted to evaluate the further response of higher and properly optimized doses of carvedilol and level of higher dose tolerability across different class of liver disease.


  Materials and Methods Top


A prospective cohort study was conducted at Tertiary Care Centre of North India. The study was approved by local Ethics Committee and Review Board of the Institute. Cirrhotic patients referred for hemodynamic evaluation were included in the study. Appropriate consent was sought from the patients after explaining them the nature of the study.

Inclusion criteria were the presence of esophageal varices on upper gastrointestinal (GI) endoscopy, without a previous history of hemorrhage and a baseline HVPG of >12 mmHg.

Exclusion criteria's were age below 18 years; severe liver failure international normalized ratio >2.5, or bilirubin >5 mg/dl; active alcohol consumption (patient with cirrhosis with alcohol abuse have to be abstinent for 3 months); intravenous drug abuse; renal failure, i.e., creatinine >1.5 mg/dl; HCC; contraindication to NSBB; Pre- or post-hepatic cause of PHT; refusal to participate in study. Well informed and written consent was obtained from all the participants in the study.

A patient who was eligible for the study were first assessed for acute response to carvedilol, i.e., after baseline HVPG measurement, patients were given 12.5 mg of carvedilol per oral and HVPG was again measured after 90 min to see the acute response to carvedilol.

The acute response was defined as a drop in HPVG of >20% from baseline and or <12 mmHg after seeing baseline HVPG and administration of 12.5 mg of carvedilol.

The study design is shown in [Figure 1].
Figure 1: Study design of the studied population

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Hemodynamic measurements

The standards outlined by Bosch et al., were employed for hepatic vein catheterization.[19] Under fluoroscopic control, 7F balloon-tipped catheter was advanced to the main right hepatic vein to measure wedged hepatic pressure (WHP). The difference between WHP and free hepatic pressure was taken as HVPG. Swangaz catheter was advanced to pulmonary artery for measurement of cardiopulmonary pressures such as pulmonary artery pressure, wedged pulmonary pressures, and right atrial pressure (RAP). All measurements were repeated thrice, and tracing were taken. MAP was measured noninvasively by automatic sphygmomanometer. HR was derived by continuous electrocardiographic monitoring and SVR as (MAP − RAP/CO ×80).

Statistical analysis

Statistical analysis was done by using IBM Statistical Package for Social Sciences (SPSS) version 22.0. Descriptive statistics was presented as proportion, mean ± standard deviation (SD) and median with inter-quartile range. Comparative analysis was done by utilizing Student's t-test and Chi-square test. The univariate and multivariate logistic regression was also used for finding the predictors. A P value less 0.05 was considered significant.


  Results Top


During the study period, 200 patients of cirrhosis with different etiology were referred for evaluation of PHT with no history of variceal hemorrhage. Among these patients, 35 patients had no esophageal varices, and 25 patients had HVPG <12 mmHg and were excluded from the study. Other 38 patients, were excluded from the study in view of, HCC (10), PVT (8), renal failure (10), and refusal to participate (10) in the study. Finally, 102 patients with cirrhosis of the liver and esophageal varices and with baseline HVPG >12 mmHg were included in the study.

Of 102 patients, 63 (61.85%) were males, and 39 (38.2%) were female patients with the mean age of 58.35 ± 6.62 years. The mean age of female and male patients was 59.3 ± 6.3 and 57.8 ± 6.8 years, respectively.

Main etiologies of cirrhosis were an autoimmune liver disease (ALD) (30.4%), nonalcoholic steatohepatitis (NASH) (25.5%), hepatitis C virus (HCV) (19.6%), and hepatitis B virus (HBV) (16.7%). Out of these, 43 patients (42.2%) were child A, 32 patients (31.4%) were child B, and 27 patients (26.5%) were child C cirrhosis.

A total of 68 patients (66.7%) had large varices, and 34 patients (33.3%) had small varices on upper GI endoscopy and 63 (61.8%) patients had no ascites while others had mild to moderate ascites. The baseline parameters are shown in [Table 1].
Table 1: Baseline characteristics of 102 patients

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Effects of carvedilol on acute reduction of portal pressure

A fixed dose of 12.5 mg was given to 102 consecutive patients who fulfilled the inclusion criteria. The acute reduction in portal pressure was assessed after 90 min of therapy. Mean predrug HVPG was 16.75 ± 2.12 mmHg, which dropped to 13.07 ± 2.32 mmHg, after 90 min of administration of 12.5 mg of carvedilol.

The mean drop of HVPG was 4.5 ± 2.2 mmHg and 2.4 ± 1.9 mmHg among responders and nonresponders, respectively. Overall 52 patients (51%) showed acute response, i.e., <12 mmHg or 20% drop in HVPG from baseline while 50 patients, i.e., (49%) were nonresponders.

Mean (±SD) hemodynamic parameters for predrug and postdrug are shown in [Table 2].
Table 2: Pre- and post-therapy (after 90 min) comparison of hemodynamic parameters

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In univariate analysis, we found that the baseline low CO and MAP were significantly predicting the acute response. Gender, child class, etiology, variceal size, presence or absence of ascites, and other biochemical parameters were not found to be statistically significant between responders and nonresponders [Table 3]. On multivariate analysis low baseline CO (odds ratio [OR] 1.39, 95% confidence interval [CI]; 1.11–1.76) and high MAP (OR 0.04, 95% CI; 0.01–0.67) were found as an independent predictors for acute response (P < 0.05).
Table 3: Predictors of acute response (responders (n=52) vs. nonresponders (n=50))

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  Discussion Top


This is among few studies which tried to see the acute response on the safe dose of carvedilol and assess whether response among different child class varies or not further this study tried to assess significant hemodynamic and clinical prediction for an acute response. Further, this study can guide the treatment with carvedilol for PTH in following ways:

  • What is the minimum percentage of patients who showed acute response on safe dose
  • What is the magnitude of response on this safe dose
  • It is expected that chronic response further increases in terms of percentage of patients because a proper dose optimization can further increase the response and more ever higher number of patients are protected from variceal bleed due to declining variceal pressure and increase in intestinal transit time
  • On chronic studies, one can assess the predictors of response to those acute nonresponders who became responders on a chronic basis. Further, it is possible that dose across different child class and patients with higher blood pressure can be optimized to higher doses to achieve better response
  • The magnitude of response on acute reduction is also important so that a drug which has no effect on MAP, HR, CO can be added to those nonresponders and it can be expected that they turn responders. Those patients whose decline in HVPG is reasonably good but not to the level of response can be selected for adding a drug like simvastatin which has no effect on MAP, CO, and HR and can turn many nonresponders to responders without hypertension and renal failure.


Carvedilol is a third generation noncardio selective beta-blocker with weak 1 blocking actions and calcium channel blockade at high doses. It has also been reported to have antioxidant properties and beneficial effects on mitochondrial function. Carvedilol is rapidly absorbed as a result of good lipid solubility, with peak levels detected 25–120 min after oral dosing and a half-life of 6–8 h. Carvedilol undergoes extensive first-pass metabolism in the liver through oxidation and conjugation and is excreted in bile as glucuronide conjugates. Carvedilol, like propranolol, is extensively protein bound. The stereoisomer R-carvedilol has equal β and α-β1 antagonism, whereas S-carvedilol has only nonselective beta antagonism in healthy individuals. R-carvedilol has twice the bioavailability of S-carvedilol, whereas patients with liver disease has equal and increased availability of both stereoisomers as some of the metabolites excreted in bile are active. Severe cholestasis may affect the efficacy of carvedilol. Furthermore, low albumin levels in advanced cirrhosis may increase the bioavailability of carvedilol.

Carvedilol is 2-4 times more potent than propranolol in its actions on blocking β receptors, and also has α-blocking properties somewhat less than labetalol. Carvedilol blocks β1 receptors to reduce CO and splanchnic blood flow. By blocking β2 receptors, it promotes unopposed splanchnic vasoconstriction mediated by α1 receptors. It is also thought to reduce intrahepatic resistance by its α-blocking actions as has been shown with prazosin. It is likely that this is through its actions on activated hepatic stellate cells lining the hepatic sinusoids.

It is interesting that the net effect of α1 antagonism in the presence of nonselective β blockade is a reduction in portal pressure. Potentially, the beneficial effects of unopposed α receptor stimulation on the splanchnic circulation may be somewhat less with carvedilol. However, animal studies have shown that splanchnic blood flow is reduced with carvedilol. This may reflect the relatively weak and incomplete α-blocking actions of carvedilol on the splanchnic circulation, not enough to counteract the strong blockade of β2 receptors. The effect of reduced intrahepatic resistance may have an additional portal hypotensive effect. Animal studies using bile duct ligated rats have shown that carvedilol reduces portocollateral resistance and endothelial-related vasodilation in the splanchnic circulation because of reduced expression of endothelial nitric oxide synthase. The effect of the carvedilol on the splanchnic circulation probably reflects a dynamic interplay between α receptor-mediated vasoconstriction and endothelial related vasodilation, with the net effect being splanchnic vasoconstriction. It is recognized that increased portocollateral resistance is often responsible for poor response to propranolol observed with some patients, and carvedilol could be more effective than propranolol in reducing portal pressure on account of the reduced portocollateral resistance observed with α1 blockade. The acute hemodynamic studies on carvedilol are shown in [Table 4]. Furthermore, a comparative analysis is presented in [Table 5].
Table 4: Acute hemodynamic studies of carvedilol in patients with portal hypertension

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Table 5: Hemodynamic studies of carvedilol versus propranolol in patients with portal hypertension

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Two randomized trials, one comparing the acute administration of carvedilol to propranolol has shown a more effective reduction in portal pressure with carvedilol than with propranolol while carvedilol caused a more fall in MAP.[15] Second trial assessed the efficacy and safety of long-term use of carvedilol compared to propranolol in portal hypertensive patients.[16] This trial showed hemodynamic response was greater with carvedilol and after a median observation period of 3 months, carvedilol caused significant decrease in MAP and significant increase in plasma volume and body weight with no change in GFR, another long-term randomized trial using carvedilol for primary prophylaxis of variceal bleeding compared with EBL demonstrated lower bleeding rate under carvedilol than EBL limb.[17] In this study, fixed dose of carvedilol was used, i.e. 12.5 mg possibly keeping in mind the hemodynamic background of above two studies mentioned, this fixed dose may be considered safe dose and with this background.

We performed hemodynamic evaluation of 102 consecutive patients of cirrhosis of liver with significant portal pressure using acute administration of fixed dose of carvedilol (12.5 mg) on group of patients with different etiology of liver disease such as ALD (30.4%), NASH (25.5%), HCV (19.6%), HBV (16.5%), autoimmune hepatitis (4.9%), and cryptogenic (2.9%) and different child class such as child Class A (42.2%), child Class B (31.9%), and child Class C (26.6%). We found mean predrug HVPG was (16.75 ± 2.12 mmHg) which dropped to 13.07 ± 2.32 mmHg, after 90 min of administration of 12.5 mg of oral carvedilol. Overall, 52 patients (51%) were responders while as 50 (49%) were nonresponders. The mean drop of HVPG was 4.5 ± 2.2 mmHg and 2.4 ± 1.9 mmHg among responders and nonresponders, respectively. Univariate analysis found that the baseline low CO and MAP were significantly predicting the acute response, while as gender, child class, etiology, variceal size, presence, and absence of ascites were not found to be statistically significant. On multivariate analysis, low baseline CO was found as an independent predictor.

Carvedilol low dose (<25 mg) is as effective as relatively high dose (25–50 mg/day) in decreasing HVPG, with lower risk of causing arterial hypotension and dose adjustment in most cases is limited to (6.25–125.5 mg/day).[20] As discussed by Bosch [20] that low dose of carvedilol <25 mg/day is as effective as high dose (25–50 mg/day) can be further assessed in the study.


  Conclusion Top


We have shown that carvedilol is an excellent drug in terms of acute response in decreasing PHT significantly. Does increased dose in child A, help to turn many acute nonresponders to responders without side effects especially in that group who had more decrease in HR needs further studies and larger group. However, it seems from the study that a dose >18.5 mg, especially in child A, is a reasonably good policy. This study is further evidence of the fact that carvedilol should be beta-blocker of choice except in hypotensive and refractory ascites patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Bosch J, Berzigotti A, Garcia-Pagan JC, Abraldes JG. The management of portal hypertension: Rational basis, available treatments and future options. J Hepatol 2008;48 Suppl 1:S68-92.  Back to cited text no. 1
    
2.
Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Planas R, et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med 2005;353:2254-61.  Back to cited text no. 2
    
3.
Groszmann RJ, Bosch J, Grace ND, Conn HO, Garcia-Tsao G, Navasa M, et al. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology 1990;99:1401-7.  Back to cited text no. 3
    
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Ripoll C, Groszmann R, Garcia-Tsao G, Grace N, Burroughs A, Planas R, et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology 2007;133:481-8.  Back to cited text no. 4
    
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Ripoll C, Groszmann R, Garcia Tsao G, Grace N, Burroughs A, Planas R, et al. Portal hypertension collaborative group; hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis. J Hepatol 2009;50:923-8.  Back to cited text no. 5
    
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Abraldes JG, Tarantino I, Turnes J, Garcia-Pagan JC, Rodés J, Bosch J. Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis. Hepatology 2003;37:902-8.  Back to cited text no. 6
    
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Albillos A, Bañares R, González M, Ripoll C, Gonzalez R, Catalina MV, et al. Value of the hepatic venous pressure gradient to monitor drug therapy for portal hypertension: A meta-analysis. Am J Gastroenterol 2007;102:1116-26.  Back to cited text no. 7
    
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Hayes PC, Davis JM, Lewis JA, Bouchier IA. Meta-analysis of value of propranolol in prevention of variceal haemorrhage. Lancet 1990;336:153-6.  Back to cited text no. 9
    
10.
Tripathi D, Graham C, Hayes PC. Variceal band ligation versus beta-blockers for primary prevention of variceal bleeding: A meta-analysis. Eur J Gastroenterol Hepatol 2007;19:835-45.  Back to cited text no. 10
    
11.
Gluud LL, Klingenberg S, Nikolova D, Gluud C. Banding ligation versus beta-blockers as primary prophylaxis in esophageal varices: Systematic review of randomized trials. Am J Gastroenterol 2007;102:2842-8.  Back to cited text no. 11
    
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Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med 2010;362:823-32.  Back to cited text no. 12
    
13.
Tsochatzis EA, Bosch J, Burroughs AK. New therapeutic paradigm for patients with cirrhosis. Hepatology 2012;56:1983-92.  Back to cited text no. 13
    
14.
Bosch J, García-Pagán JC. Complications of cirrhosis. I. Portal hypertension. J Hepatol 2000;32 1 Suppl: 141-56.  Back to cited text no. 14
    
15.
Bañares R, Moitinho E, Piqueras B, Casado M, García-Pagán JC, de Diego A, et al. Carvedilol, a new nonselective beta-blocker with intrinsic anti- alpha1-adrenergic activity, has a greater portal hypotensive effect than propranolol in patients with cirrhosis. Hepatology 1999;30:79-83.  Back to cited text no. 15
    
16.
Bañares R, Moitinho E, Matilla A, García-Pagán JC, Lampreave JL, Piera C, et al. Randomized comparison of long-term carvedilol and propranolol administration in the treatment of portal hypertension in cirrhosis. Hepatology 2002;36:1367-73.  Back to cited text no. 16
    
17.
Tripathi D, Ferguson JW, Kochar N, Leithead JA, Therapondos G, McAvoy NC, et al. Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed. Hepatology 2009;50:825-33.  Back to cited text no. 17
    
18.
Reiberger T, Ulbrich G, Ferlitsch A, Payer BA, Schwabl P, Pinter M, et al. Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic non-response to propranolol. Gut 2013;62:1634-41.  Back to cited text no. 18
    
19.
Bosch J, Garcia-Pagán JC, Berzigotti A, Abraldes JG. Measurement of portal pressure and its role in the management of chronic liver disease. Semin Liver Dis 2006;26:348-62.  Back to cited text no. 19
    
20.
Bosch J. Carvedilol: The ß-blocker of choice for portal hypertension? Gut 2013;62:1529-30.  Back to cited text no. 20
    


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  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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