Are beta blockers indicated in cirrhotics with small varices?

August 1, 2007

evarices.jpgCommentary by Bani Chander MD, PGY-2

Esophageal varices are a common complication of cirrhosis and approximately one-third of all cirrhotic patients with varices will develop a variceal bleed [1]. Each episode of variceal hemorrhage is associated with a 15 to 20 percent risk of mortality in patients with severe liver dysfunction.  The risk of bleeding is related to the location, size, and appearance of the varix, presence of red wale markings, variceal pressure, prior history of variceal bleeding, as well as the severity of hepatic dysfunction (classified by Child-Pugh class.)

In patients with cirrhosis, elevated portal pressure develops as a result of both increased portal inflow due to splanchnic arteriolar vasodilatation in combination with an elevated resistance to outflow through hepatic sinusoids.  Varices develop when the hepatic venous pressure gradient or HVPG (pressure between the portal and hepatic veins) rises above 12 mmHg, as a compensatory mechanism to decompress the portal vein and return blood to the systemic circulation. In a review of 12 studies, including 943 patients, D’Amico and colleagues showed that reducing HPVG<12mmHg significantly reduced the risk of variceal bleeding in cirrhotics. [2]

Non-selective beta-blockers impair the formation of varices by decreasing the β-2 receptor mediated vasodilatory tone in mesenteric arterioles.  This results in unopposed alpha vasoconstriction and therefore a decrease in portal venous inflow. In addition, the systemic effects of beta blockers on cardiac output via β-1 receptor blockade also contributes to the reduction of portal venous inflow.

It is well known that non-selective beta- blockers prevent variceal bleeding in patients with moderate to large varices [3-9], however, primary prophylaxis in cirrhotics without varices has not been shown to be beneficial nor does it appear to prevent the formation of varices [10]. 

The current screening guidelines recommend that all cirrhotics have endoscopy at the time of diagnosis; β-blockers should be initiated in those patients with moderate or large varices who have no contraindications.  It is recommended that patients with small varices follow up with yearly endoscopy; however, given the high incidence of bleeding and mortality in patients with esophageal varices, it is important to identify preventative measures to delay the progression and prevent hemorrhage in this group of patients.

To date, few studies have looked at primary prophylaxis with beta-blockers in patients with small varices, however, a handful of studies have suggested some benefit in these patients, especially in those with progressive liver disease. Merckel et al, [11] in a multicenter, single blind, randomized placebo controlled clinical trial, compared nadolol with placebo in the prevention of growth of small esophageal varices  in 161 patients with cirrhosis and small esophageal varices (F1, Beppu Classification*, [12] ) who had no prior bleed history.  The principal end point in this trial was the occurrence of large esophageal varices (F2 or F3 classification), with endoscopic follow up at 12, 24, 36, 48, and 60 months.  After 5 year follow up, progression to large varices occurred in 20% of the nadolol group as compared to 51% in the placebo group, with an absolute risk reduction of 31%.  In addition, the probability of variceal bleed in the nadolol group was significantly lower (12%) than in the placebo group (22%).  Of note, there was no significant difference in survival between the two groups. The authors of this study suggest that β-blocker prophylaxis should be started in patients with compensated cirrhosis at the stage of small esophageal varices. 

While patients with small varices may benefit from beta blockers, it is important to recognize that treatment is associated with a higher risk of adverse complications (9 complications in the nadolol group including hypotension, asthma, and heart failure vs. 1 in the placebo group).  Further studies are needed to confirm the efficacy of beta blockers as primary prophylaxis to prevent growth or variceal hemorrhage in cirrhotic patients with small varices. In the interim, some hepatologists are recommending treatment with non selective beta blockers in any patient with small varices, especially in those who do not comply with yearly endoscopy [13]. 

*BEPPU CLASSIFICATION

Esophageal varices are classified as: F1(flatten/disappear with insuflation), F2 (tortuous, protrude less than a third of esophageal lumen) and F3 (pseudotumorous). Bleeding risk increases from F1 to F3 and is greater if varices show red spots.

References:

1- Prediction of the first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. A prospective multicenter study. The North Italian Endoscopic Club for the Study and Treatment of Esophageal Varices. N Engl J Med 1988; 319:983-989.

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

3- Conn HO, Grace ND, Bosch J, Groszmann RJ, Rodés J, Wright SC, Matloff DS, Garcia-Tsao G, Fisher RL, Navasa M, et al. Propranolol in the prevention of the first hemorrhage from esophagogastric varices: A multicenter, randomized clinical trial. The Boston-New Haven-Barcelona Portal Hypertension Study Group. Hepatology. 1991 May;13(5):902-12.

4- Lebrec, D, Poynard, T, Capron, JP, et al. Nadolol for prophylaxis of gastrointestinal bleeding in patients with cirrhosis. A randomized trial. J Hepatol 1988; 7:118.

5- Andreani, T, Poupon, RE, Balkau, GB, et al. Preventive therapy of first gastrointestinal bleeding in patients with cirrhosis: Results of a controlled trial comparing propranolol, endoscopic sclerotherapy, and placebo. Hepatology 1990; 12:1413.

6- Propranolol prevents first gastrointestinal bleeding in non-ascitic cirrhotic patients. Final report of a multicenter randomized trial. The Italian Multicenter Project for Propranolol in Prevention of Bleeding. J Hepatol 1989; 9:75.

7- Prophylaxis of first hemorrhage from esophageal varices by sclerotherapy, propranolol or both in cirrhotic patients: A randomized multicenter trial. The PROVA Study Group. Hepatology 1991; 14:1016.

8- Ideo, G, Bellati, G, Fesce, E, Grimoldi, D. Nadolol can prevent the first gastrointestinal bleeding in cirrhotics: A prospective randomized study. Hepatology 1988; 8:6.

9- Sanyal, AJ, Shiffman, ML. The pharmacologic treatment of portal hypertension. Annu Rev Gastrointest Pharmacol 1996; 242.

10- Groszmann, RJ, Garcia-Tsao, G, Bosch, J, et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med 2005; 353:2254.

11- Merkel, C, marin, R, Angeli, P, et al. A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis. Gastroenterology 2004; 127:476.

12- Beppu et al, “Prediction of variceal hemorrhage by esophageal endoscopy,” Gastrointestinal Endosc 1981; 27: 213-218 

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One Response to Are beta blockers indicated in cirrhotics with small varices?

  1. Joseph E. Glaser, MD on August 6, 2007 at 1:36 pm

    I was looking around the internet for some other references, and happened to find this article. Since I had taken care of a bad cirrhotic (albeit in a trauma setting) lately, I thought I would share some thoughts.
    I would think most cirrhotics have other indications for beta-blockers as well, as many will have heart disease. Additionally, if their kidneys are beginning to suffer from the liver disease, they may develop CHF. This is all independent of varices.

    Since you mentioned Child’s class, have you found any correlation(s) with the MELD scoring of patients (which is what is used to classify patients as suitable for transplant)?

    Octreotide is also commonly used in these patients, as well as well as diuretics to remove all the ascites and third-spaced fluid cirrhotics tend to have. Anything that reduces portal hypertension will reduce the risk of bleeding.

    Another thing to consider in cirrhotics at general risk for bleeding varices is their natural coagulopathy. Since they don’t make normal clotting factors due to their impaired synthetic function, at the same time that they are at risk for bleeding, they are coagulopathic and need to be monitored and corrected to prevent this as well. If they start to bleed, it is a disaster needing interventions including aggressive coagulation correction with blood products, and anything ranging from endoscopic intervention, a Blakemore or Minnesota tube, and possible operation.

    Nice article, Bani.

    Joey Glaser

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