Saudi Journal of Gastroenterology
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Year : 2011  |  Volume : 17  |  Issue : 2  |  Page : 155-158
Carvedilol in the treatment of portal hypertension


Department of Hepatobiliary Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia

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Date of Submission05-Feb-2011
Date of Acceptance15-Feb-2011
Date of Web Publication2-Mar-2011
 

   Abstract 

Variceal bleeding is a major event in the natural history of end-stage liver disease with a subsequent high mortality rate. Non-selective β-blockers are currently the drugs of choice for preventing first variceal bleeding. Endoscopic rubber band ligation of high risk varices features as a first line option if cirrhotic patients cannot tolerate β-blockers. Despite adequate β-blockade, some patients may still present with variceal bleeding. The effect of carvedilol, a non-selective β and α-1 receptor-blocker, on lowering portal pressure has been investigated in several clinical trials and found to be superior to propranolol in both acute and chronic hemodynamic studies. Recently, carvedilol has also been compared with band ligation for primary prophylaxis against variceal bleeding with equivalent results to band ligation. Patient tolerance to carvedilol in advanced liver disease remains a source of concern. This review examines the place of carvedilol as an alternative to the currently recommended pharmacological therapy in prophylaxis against variceal bleeding.

Keywords: Band ligation, bleeding, carvedilol, portal hypertension, treatment, varices

How to cite this article:
Al-Ghamdi H. Carvedilol in the treatment of portal hypertension. Saudi J Gastroenterol 2011;17:155-8

How to cite this URL:
Al-Ghamdi H. Carvedilol in the treatment of portal hypertension. Saudi J Gastroenterol [serial online] 2011 [cited 2020 Oct 30];17:155-8. Available from: https://www.saudijgastro.com/text.asp?2011/17/2/155/77251



   Treatment Overview of Portal Hypertension Top


Hepatic hemodynamic studies enable us to indirectly estimate the degree of portal hypertension in cirrhotic patients. Clinically significant portal hypertension is defined as hepatic venous pressure gradient (HVPG) greater than 10 mmHg. [1] It is estimated that for every 1 mmHg increase in HVPG above a threshold level of 10 mmHg, an 11% increase in the risk of clinical decompensation could be expected. [2]

The clinical course of cirrhosis, commonly identified as compensated and decompensated forms, has recently been characterized into four prognostic stages. [3] Stage 1 is characterized by the absence of esophageal varices and ascites with an annual mortality rate of 1%; stage 2 is characterized by the appearance of esophageal varices without ascites and has an annual mortality rate of 3.4%, and stage 3 is characterized by ascites with or without esophageal varices and has an annual mortality rate of 20%. Finally, stage 4 is characterized by variceal bleeding, with or without ascites, and has 1-year mortality rate of 57%, with almost half of this occurring in the first 6 weeks of index bleeding. An increased portal pressure in cirrhotic patients plays a fundamental role in the development and rupture of varices and a HVPG over 12 mmHg was found to be a strong predictor for esophageal variceal bleeding. [4]

Given the significant mortality associated with variceal bleeding, and that varices may be present in a majority of cirrhotics, clinical trials dealing with portal pressure reduction have channeled their efforts into three main strategies. The first strategy (pre-primary prophylaxis) dealt with prevention of gastroesophageal varices development by using non-selective b-blockers. This strategy was eventually found to be ineffective in preventing development of varices. [5] The second strategy (primary prophylaxis) involved the prevention of variceal bleeding in patients who experienced no previous bleeding where high risk varices such as large varices (larger than 5 mm) or varices with red signs (red wales, cherry red spots, or hematocystic spots) had been identified at endoscopy. Non-selective b-blockers (propranolol and nadolol) demonstrated superiority to placebo in preventing variceal bleeding. [6] Endoscopic rubber band ligations of high risk varices were compared head-to-head with non-selective b-blockers in several randomized control studies as primary prophylaxis strategy. Several meta-analyses [7],[8],[9],[10] reported a small but significantly lower incidence of first variceal bleeding but no survival benefits were found in favor of band ligation. The third strategy (secondary prophylaxis) entails using non-selective b-blockers alone or in combination with endoscopic variceal band ligations/sclerotherapy for preventing rebleeding. The current evidence seems to favor combination therapy (non-selective b-blockers and variceal band ligation) over band ligation alone. [11].[12]

Salvage invasive techniques such as transjugular intrahepatic portosystemic shunt (TIPS) and surgical devascularization/shunting are typically reserved for refractory variceal bleeding when appropriately indicated.


   Pharmacological Aspects Top


Non-selective β-blockers exert their effects via blockade of both β1 and β2 receptors. The β1 receptors are located in the myocardium and their blockade results in a decrease in cardiac contractility and output. In the other hand, blockade of β2 receptors located in the splanchnic (mesenteric) vascular bed results in vasoconstriction due to unopposed activity of α1 adrenergic receptors with a net effect of reduction in portal blood inflow.

The intrahepatic vascular resistance represents another essential component in development and progress of portal hypertension in cirrhotic. It is caused by morphological changes in the hepatic microcirculation architecture due to pathological changes associated with cirrhosis. It is estimated that up to 40% of this intrahepatic vascular resistance is functionally reversible. [13] This reversible part is located in the contractile elements of the hepatic vascular bed. It pharmacologically represents another major site to modulate portal hypertension.

The α1 adrenergic receptors are distributed in both the systemic and splanchnic vascular smooth muscles and other sites such as smooth muscles of the genitourinary tract. Pharmacological antagonism of α1 adrenergic receptors would lead to a reduction in the intrahepatic vascular tone. Therefore, the addition of α1 blockers to non-selective β-blockers may attenuate portal pressure. In one trial, propranolol was combined with prazosin (n = 28), a selective α1 blocker, and compared to propranolol plus isosorbide-5-mononitrate (n = 28) for short-term use over 3 months. [14] The former combination showed a greater reduction in HVPG (24% vs 16%) but more hypotension events and less tolerance.

Carvedilol [15],[16] is a racemic mixture that has potent non-selective β-receptors and weak α-1 receptors blocking activity. It is two to four times more potent than propranolol as a β-receptor blocking drug. It has two enantiomeric forms, R (+) and S (-). The S (-) enantiomer is mainly responsible for the b-blocking effect of carvedilol, whereas both R (+) and S (-) contribute to the a1-blockade. It is rapidly absorbed following oral administration with a low absolute bioavailability, approximating to 25%. It has a rapid onset of action of 1-2 h. It undergoes extensive hepatic first-pass metabolism with plasma levels of R (+)-carvedilol two to fourfold higher than S (-)-carvedilol in healthy persons. The major P450 enzymes responsible for the metabolism of both R (+) and S (-) carvedilol in human liver microsomes are CYP2D6 and CYP2C9, and to a lesser extent CYP3A4, CYP2C19, and CYP2E1. The elimination half-life of carvedilol is 6-10 h. Drugs that inhibit CYP450 2D6 activity such as sertraline may increase plasma concentrations of R-carvedilol, in turn augmenting the systemic hypotensive effect of carvedilol. Drug excretion is mainly biliary and into feces, and renal elimination is minor requiring no dose adjustment in kidney impairment.

Carvedilol is available in various immediate release (used as once or twice daily) and extended release formulations (used as once daily). The drug is FDA approved for management of essential hypertension, congestive heart failure, and left ventricular dysfunction following myocardial infarction.


   Clinical Trials in Carvedilol Top


Due to its unique mechanism of action, carvedilol was compared to propranolol in several clinical trials. [17],[18],[19],[22] In the portal hemodynamic studies that evaluated the risk of variceal bleeding, responders to non-selective b-blockers were recognized if their HVPG dropped below 12 mmHg or by more than 20% from baseline.

Clinical trials evaluating the acute hemodynamic effects of carvedilol at a dose of 25 mg on portal pressure showed a reduction in HVPG by 17-27% from baseline measurements [17],[18],[19],[20] [Table 1]. In these trials, the incidence of systemic hypotension was significantly higher in the carvedilol group. On the other hand, hemodynamic effects of chronic administration of carvedilol were reported in several trials [19],[20],[21],[22],[23] using variable dosages between 12.5 and 50 mg/day. Banares et al, [22] reported the longest follow-up trial of 11.1 ± 4.1 weeks in 51 cirrhotic patients (26/carvidelol, 25/propranolol). The carvedilol doses were administrated at 12.5-50 mg (mean 31 ± 4 mg/d) starting at 6.25 mg and titrated up every 4 days according to blood pressure and heart rate. Chronic carvedilol administration resulted in 58% hemodynamic response rate compared to 23% response rate in the propranolol group. The mean arterial blood pressure (MAP) and systemic vascular resistance (SVR) weres not statistically different between baseline and end-of-study measurements in the carvedilol group. In acute carvedilol administration studies, there was a noticeable decrease in MAP and SVR. However, in this study carvedilol did not decrease SVR, but had a mild decrease in MAP. There was an increase in plasma volume and body weight that were statistically significant in the carvedilol group as observed in Child-Pugh class B and C patients. This required dose adjustment of diuretics. There were no changes in glomerular filtration rate (GFR) or urinary sodium excretion in either group. Carvedilol caused a greater decrease in HVPG in patients with Child-Pugh classes B and C, despite requiring lower doses, than Child-Pugh class A cirrhotic patients. Adverse events (orthostatic hypotension, encephalopathy, and discontinuation of the treatment) were not significantly different between the two treatment groups. The discontinuation rate of carvedilol was 8% as compared to 12% in the propranolol arm.
Table 1: Studies reporting on the effect of carvedilol in lowering hepatic venous pressure gradient


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Chronic carvedilol administration at lower doses of 12.5 mg was studied in two clinical trials. [19],[21] Both trials reported a reduction in HVPG by 23-43% from baseline measurements without a significant effect on MAP.

In the first and only randomized controlled trial comparing carvedilol with variceal band ligation for primary prophylaxis against variceal bleeding, [24] 152 cirrhotic patients with grade II or larger esophageal varices were randomized to either carvedilol 12.5 mg once daily (77 patients) or variceal band ligation (75 patients) every 2 weeks until eradication. On intention-to-treat analysis, carvedilol achieved lower rates of the first variceal bleed 10% versus 23% without differences in the overall mortality (35% vs 37%) or bleeding-related mortality (3% vs 1%). In this study, 15% of patients discontinued carvedilol due to intolerance. On per protocol analysis, there was however no difference between both groups in terms of first variceal bleeding, overall mortality, or bleeding-related mortality. There was no change in mean arterial pressure or serum creatinine in the carvedilol arm. Worsening of ascites was not different between carvedilol (18%) and band ligation (21%) arms.

It should be noted that in these clinical trials, the predominant liver dysfunction was Child-Pugh class A. Cirrhotic class B or C patients were more likely to suffer adverse effects, particularly when doses higher than 12.5 mg were used. It is also worth addressing that lower doses of carvedilol at 12.5 mg showed a comparable portal hemodynamic effect when administrated chronically as reported from at least two studies. [19],[21] Titration of carvedilol dose is perhaps the best strategy. Precipitating or worsening of hypotension, ascites, or renal function was noted in some but not all trials, particularly when doses of 25 mg or higher were administrated.

Given the powerful effect of carvedilol on portal hemodynamics, the question remains whether carvedilol should be the drug of choice in patients with varices who have non-cirrhotic portal hypertension? As of yet, this issue has not been addressed yet in this cohort of patients who may tolerate higher doses of carvedilol. Secondly, another question that remains unanswered is whether carvedilol should replace non-selective b-blockers in Child-Pugh class A cirrhotic patients presenting with variceal bleeding despite adequate b-blockade? Finally, despite of the promising results reported in these trials, larger randomized, controlled clinical trials comparing carvedilol with other non-selective b-blockers, or further head-to-head trials comparing carvedilol to band ligation must be conducted. Adequately powered trials with better patient selection, well-defined clinical end points, careful assessment of adverse events, and sufficient follow-up are required before we can advance carvedilol into an evidence-based treatment algorithm of portal hypertension.

 
   References Top

1.Feu F, Garcia-Pagan JC, Bosch J, Luca A. Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis. Lancet 1995;346:1056-9.  Back to cited text no. 1
    
2.Ripoll C, Groszmann RJ, Garcia-Tsao G, Grace N, Burroughs AK. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology 2007;133:481-8.  Back to cited text no. 2
    
3.D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: A systematic review of 118 studies. J Hepatol 2006;1:217-31.  Back to cited text no. 3
    
4.Casado M, Bosch J, Garcia-Pagan JC, Bru C. Clinical events after transjugular intrahepatic portosystemic shunt: Correlation with hemodynamic findings. Gastroenterology 1998;6:1296-303.  Back to cited text no. 4
    
5.Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med 2005;21:2254-61.  Back to cited text no. 5
    
6.Pagliaro L, D'Amico G, Sörensen TI, Lebrec D. Prevention of first variceal bleeding in cirrhosis. A meta-analysis of randomized trials of nonsurgical treatment. Ann Intern Med 1992;117:59-70.  Back to cited text no. 6
    
7.Imperiale TF, Chalasani N. A meta-analysis of endoscopic variceal ligation for primary prophylaxis of esophageal variceal bleeding. Hepatology 2001;33:802-7.  Back to cited text no. 7
[PUBMED]  [FULLTEXT]  
8.Khuroo MS, Khuroo NS, Farahat KL, Khuroo YS. Meta-analysis: Endoscopic variceal ligation for primary prophylaxis of oesophageal variceal bleeding. Aliment Pharmacol Ther 2005;21:347-61.  Back to cited text no. 8
    
9.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. 9
[PUBMED]  [FULLTEXT]  
10.Gluud LL, Klingenberg S, Nikolova D, Gludd 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. 10
    
11.Lo GH, Lai KH, Cheng JS, Chen MH. Endoscopic variceal ligation plus nadolol and sucralfate compared with ligation alone for the prevention of variceal rebleeding: A prospective, randomized trial. Hepatology 2000;3:461-5.  Back to cited text no. 11
    
12.De la PJ, Brullet E, Sanchez-Hernandez E, Rivero M. Variceal ligation plus nadolol compared with ligation for prophylaxis of variceal rebleeding: A multicenter trial. Hepatology 2005;3:572-8.  Back to cited text no. 12
    
13.Bathal PS, Grossmann HJ. Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators. J Hepatol 1985;1:325-9.  Back to cited text no. 13
    
14.Albillos A, García-Pagán JC, Iborra J, Bandi JC. Propranolol plus prazosin compared with propranolol plus isosorbide-5-mononitrate in the treatment of portal hypertension. Gastroenterology 1998;115:116-23.  Back to cited text no. 14
    
15.Carvedilol. In: Al-Shaqha WM, Hamdy A, Alnaim L, editors. Alphabetical listing of drugs. 4 th ed. Ohio: Lexi-Comp Inc; 2009. p. 432-5.   Back to cited text no. 15
    
16.Ruffolo RR Jr, Gellai M, Hiehle JP, Willette RN. The pharmacology of carvedilol. Eur J Clin Pharmacol 1990;38:S82-8.  Back to cited text no. 16
    
17.Banares R, Moitinho E, Piqueras B, Casado M. 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. 17
    
18.Lin HC, Yang YY, Hou MC, Huang YT. Acute administration of carvedilol is more effective than propranolol plus isosorbide-5- mononitrate in the reduction of portal pressure in patients with viral cirrhosis. Am J Gastroenterol 2004;99:1953-8.   Back to cited text no. 18
    
19.De BK, Das D, Sen S, Biswas PK. Acute and 7-day portal pressure response to carvedilol and propranolol in cirrhotics. J Gastroenterol Hepatol 2002;17:183-9.  Back to cited text no. 19
    
20.Forrest EH, Bouchier IA, Hayes PC. Acute haemodynamic changes after oral carvedilol, a vasodilating beta-blocker, in patients with cirrhosis. J Hepatol 1996;25:909-15.   Back to cited text no. 20
[PUBMED]    
21.Tripathi D, Therapondos G, Lui HF, Stanley AJ. Haemodynamic effects of acute and chronic administration of low-dose carvedilol, a vasodilating beta-blocker, in patients with cirrhosis and portal hypertension. Aliment Pharmacol Ther 2002;16:373-80.  Back to cited text no. 21
    
22.Banares R, Moitinho E, Matilla A, Garcia-Pagan JC. 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. 22
    
23.R Bruha, L Vitek, J Petrtyl, M Lenicek. Effect of carvedilol on portal hypertension depends on the degree of endothelial activation and inflammatory changes. Scand J Gastroenterol 2006;41:12.1454-63   Back to cited text no. 23
    
24.Tripathi D, Ferguson JW, Kochar N, Leithead JA. 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. 24
    

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Correspondence Address:
Hamdan Al-Ghamdi
Department of Hepatobiliary Sciences, (IMB 1440), PO Box 22490, King Abdulaziz Medical City, Riyadh 11426
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1319-3767.77251

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