Propranolol in the Prevention of First Upper Gastrointestinal Tract Hemorrhage in Patients with Cirrhosis of the Liver and Esophageal Varices

Abstract

We conducted a prospective, randomized, multicenter, single-blind trial of propranolol as compared with placebo in the prevention of first upper gastrointestinal tract bleeding in patients with cirrhosis of the liver. A total of 230 patients (90 percent with alcoholism and 46 percent with a Child-Pugh grade C classification) with large esophageal varices without previous bleeding were randomly assigned to receive either propranolol (n = 118) or placebo (n = 112), after they had been divided into two groups according to the severity of their liver disease. The end points of the study were bleeding and death. The dose of propranolol was progressively increased to decrease the heart rate by 20 to 25 percent. The final doses were 40 mg of conventional propranolol and 160 and 320 mg of long-acting propranolol daily in 22 percent, 60 percent, and 18 percent of patients, respectively. The mean (+/- SD) follow-up time among survivors without bleeding was 436 +/- 172 days. The cumulative percentages of patients free of bleeding two years after inclusion in the study were 74 percent (95 percent confidence limits, 61 and 83) in the propranolol group and 39 percent (95 percent confidence limits, 15 and 69) in the placebo group (P less than 0.05). Cumulative two-year survival was 72 percent (95 percent confidence limits, 60 and 81) in the propranolol group and 51 percent (95 percent confidence limits, 37 and 64) in the placebo group (P less than 0.05). The advantage of propranolol over placebo was maintained when potentially confounding variables were adjusted with use of the Cox model. Side effects occurred in 17 percent of the patients who received propranolol and led to the stopping of treatment in 11 percent. We conclude that propranolol can decrease the incidence of first bleeding and death during a period of two years in patients with cirrhosis and large varices.

Beta-Blockers to Prevent Gastroesophageal Varices in Patients With Cirrhosis

“…This reduction is smaller than the range of 20 to 26 percent (median, 24 percent) reported in studies of beta-blockers in the primary prophylaxis of variceal hemorrhage [16][17][18][19][20][21][22][23][24] and is probably due to the lower baseline heart rate (median, 73 beats per minute) in our study than in primary-prophylaxis studies of patients with varices (median, 80 beats per minute) 9,17-25 or secondaryprophylaxis studies of patients with varices (median, 84 beats per minute). [26][27][28][29] However, the absolute heart rate achieved is a better indicator of betablockade than the percent reduction in heart rate, 30 and the absolute heart rate in our study during timolol therapy (62 beats per minute) was similar discussion to the median heart rate of 60 beats per minute among patients receiving beta-blockers in previous studies.…”

Non-Selective Beta-Blockers in Liver Cirrhosis: Friends or Foes? A Review of the Literature

“…Similarly, these agents are used to treat extra-cardiac diseases such as migraine and glaucoma [7] , and in the 1980s they were introduced in the treatment of variceal hemorrhage in patients with cirrhosis and portal hypertension [8][9][10][11] .…”

Prevention of a first episode of variceal bleeding: role of duplex Doppler sonographic measurement of the acute response to beta-blockers.

“…[3][4][5][6] Several randomized controlled trials have demonstrated that the use of nonselective beta-adrenergic blockers (propranolol, nadolol) in patients at high risk for bleeding reduces the risk itself (by about 45%) [7][8][9][10] and tends to reduce the mortality rate. 11 Use of propranolol has resulted in a lower rate of bleeding when compared with sclerotherapy in one study 6 and a better survival time in another. 12 In most studies, recurrent bleeding is effectively prevented by administration of beta-blockers alone or in association with sclerotherapy.…”

“…11,15,-17 Two recent studies singled out the sequential measurement of the HPVG as the only parameter capable of predicting a reduction in the risk of first or recurrent bleeding in treated patients. A marked reduction in the occurrence of bleeding is guaranteed if the administration of the drug reduces the HPVG to below 12 mm Hg 11 or by more than 20% 12 after a period of treatment. This approach is fundamental because it can indicate the need for second-line treatment; however, owing to its being a complex and invasive technique, it has not found favor with clinicians.…”