Propranolol prevents first gastrointestinal bleeding in non-ascitic cirrhotic patients

Final report of a multicenter randomized trial
  • Affiliations
    Divisione di Medicina, Istituto di Medicina Generale e Pneumologia, Ospedale V. Cervello, Palermo, Italy

    Istituto di Gastroenterologia, Università di Modena, Modena, Italy

    Divisione di Gastroenterologia, Ospedale Generale Regionale, Bolzano, Italy

    Divisione di Medicina, Instituti Ospedalieri S. Corona, Pietra Ligure, Italy

    Istituto di Biometria, Università di Milano, Milano, Italy
  • Author Footnotes
    ∗ The following participated in the Italian Multizenter Project for Propranolol in Bleeding: Planning committee. Luigi Pagliaro, Professor of Medicine, Gennaro D'Amico MD, Linda Pasta MD, M. Gabriella Filippazzo MD, Federico Manenti, Professor of Gastroenterology, Giorgio Dobrilla MD and Giorgio Marenco MD. Steering committee: Linda Pasta MD, Gennaro D'Amico MD, Salvatore Le Moli MD, Alberto Ferrari MD, Giovanni De Pretis MD, Federico Oberhollenzer MD and Giorgio Marenco MD. Writing committee: Gennaro D'Amico MD. Luigi Pagliaro, Professor of Medicine and Linda Pasta MD. Other participants: Mariano Amuso MD, Sonia Di Piazza MD, Giovanna Gatto MD, Ga. dolfo Giannuoli MD, Alberto Maringhini MD, Ugo Palazzo MD, Giovambattista Pinzello MD, R Giovanna Simonetti MD, Maria Caltagirone MD, Silvio Magrin MD, M. Pia Marceno' MD, Mario Traina MD, Miriam Turri MD, Maria Vinci MD, Roberto Virdone MD, Giovanni Vizzini MD, Mario Cottone MD, Elio Sciarrino MD, Alberto Merighi MD, Giampiero Rigo MD, Lucia Piazzi MD, Maurizio Valentini MD, Harald Steiner MD, Antonio Giudici Cipriani MD, Gianluigi Dante MD and Giorgio Menardo MD. Statistical analysis: Alberto Morabito, Professor of Biomathematics, Gennaro D'Amico MD and Fabio Tine MD.
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      We report here the final analysis of a multicentre randomized, single-blind trial of propranolol for prophylaxis of first bleeding in cirrhosis. One hundred and seventy-four consecutive patients with large esophageal varices were randomly assigned to either propranolol in doses reducing the resting heart rate by 25% (85 patients) or to a placebo (vitamin K: 89 patients). Three were lost to follow-up and 26 had to be withdrawn from propranolol because of side effects (n = 23) or low compliance (n = 3). The cumulative value over 42 months of patients free of bleeding was 74% (95% confidence interval = 85%-63%) in the propranolol and 59% (95% CI = 79%-43%) in the control group and the corresponding survival figures were 51% (95% CI = 63%-39%) and 59% (95% CI = 75%-43%): neither of the differences was significant. A retrospective analysis according to the presence of ascites at randomization showed that In the subset without ascites the proportion of patients free of bleeding was significantly higher in the propranolol group than in the control group (83% vs. 61%: 95% CI = 97%-69% and 78%-44%, respectively; P = 0.028); this difference was even more evident in the ascites-free period (94% vs. 58%; 95% CI = 100%-86% and 76%-40%, respectively; P = 0,002). No differences were found in patients with ascites at randomization. Survival was not significantly affected by treatment in any subgroup, although it was shorter in the ascitic patients given propranolol than in controls (33% vs. 49%; 95% CI = 51%-15% and 71%-27%, respectively; P = 0.07) Our conclusion was that propranolol prevents first bleeding in cirrhotic patients with large varices and without ascites. Further studies are needed to assess its effectiveness and safely in ascitic patients.
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        • The Italian Multicenter Project tor Propranolol in Prevention of Bleeding
        Propranolol for prophylaxis of bleeding in cirrhotic patients with large varices: a multicenter, randomized clinical trial.
        Hepatology. 1938; 8: 1-5
        • Italian Liver Cirrhosis Project
        Reliability of endoscopy in the assessment of variceal features.
        J Hepatol. 1987; 4: 93-98
        • Cox DR
        Regression models and life-tables.
        GR Stat Soc (B). 1972; 34: 187-220
        • Conn HO
        • Lindenmuth WW
        • May CJ
        • Ramsby GR
        Prophylactic portatcaval anastomosis. A tale of two studies.
        Medicine. 1972; 51: 27-40
        • Collins R
        • Yusuf S
        • Peto R
        Overview of randomized trials of diuretics in pregnancy.
        Br Med J. 1985; 290: 17-23
        • Pascal JP
        • Cales P
        • The Multicenter Study Group
        Propranolol in the prevention of first upper gastrointestinal tract hemorrhage in patients with cirrhosis of the liver and esophageal varices.
        N Engl J Med. 1987; 317: 856-861
        • Idèo G
        • Bellati G
        • Pesce E
        • Grimoldi D
        Nadolol can prevent the first gastrointestinal bleeding in cirrhotics: a prospective randomized study.
        Hepatology. 1988; : 6-8
        • Lebrec D
        • Poynard T
        • Capron JP
        • Hillon P
        • Geoffroy P
        • Roulot D
        • Chaput JL
        • Benhamou JP
        Nadolol for prophylaxis of gastrointestinal bleeding in patients with cirrhosis. A randomized trial.
        J Hepatol. 1988; 7: 118-125
        • Bosch J
        • Groszmann RJ
        • Grace N
        • Navasa M
        • Mastai R
        • Conn HO
        • Rodes J
        Propranolol in the prevention of the first hemorrhage from esophageal varices: results of a randomized double blind cooperative clinical trial.
        J Hepatol. 1988; 7 (suppl): S12
        • D'Amico G
        • Malinia G
        • Mon F
        Therapeutic end points for prophylaxis of variceal bleeding.
        in: Burroughs AK Methodology and Reviews of Clinical Trials in Portal Hypertension. Excerpta Medica, Amsterdam1987: 237-248
        • Lebrec D
        • Poynard T
        • Hillon P
        • Benhamou JP
        Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis. A controlled study.
        N Engl J Med. 1981; 305: 1371-1374
        • Burroughs AK
        • Jenkins WJ
        • Sherlock S
        • et al.
        Controlled thal of propranolol for the prevention of recurrent variceal hemorrhage in patients with cirrhosis.
        N Engl J Med. 1983; 309: 1539-1542
        • Villeneuve JP
        • Pomier Layragues G
        • Infante-Rivard C
        • et al.
        Propranolol for the prevention of recurrent variceal hemorrhage: a controlled trial.
        Hepatology. 1986; 6: 1239-1243
        • Queuniet AM
        • Czernichow P
        • Lerebourus E
        • Ducrotte P
        • Tranvouez JL
        • Colin R
        Étude contrôlée du propranolol dans la prevention des récidives hémorragiques chez les patients cirrhotiques.
        Gastroenterol Clin Biol. 1987; 11: 41-47
        • Gerbes AL
        • Remien J
        • Jungst D
        • Sauerbruch T
        • Paumgartner G
        Evidence for down-regulation of beta-2-adrenoceptors in cirrhotic patients with severe ascites.
        Lancet. 1986; i: 1409-1410
        • Colman JC
        • Jennings GL
        • McLean AJ
        • Mignot PR
        • Dudley FJ
        Propranolol in decompensated alcoholic cirrhosis.
        Lancet. 1982; ii: 1040-1041
        • Rector WG
        Propranolol for portal hypertension. Evaluation of therapeutic response by direct measurement of portal vein pressure.
        Arch Intern Med. 1985; 145: 648-650
        • Braillon A
        • Cales P
        • Valla D
        • Gaudy D
        • Geoffry P
        • Lebrec D
        Influence of the degree of liver failure on systemic and splanchnic haemodynamics and on response to propranolol in patients with cirrhosis.
        Gut. 1986; 27: 1204-1209
        • Garcia-Tsao G
        • Grace ND
        • Groszman R
        • et al.
        Short-term effects of propranolol on portal venous pressure.
        Hepatology. 1986; 6: 101-106
        • Vorobioff J
        • Picabea E
        • Villavicencio R
        • et al.
        Acute and chronic hemodynamic effects of propranolol in unselected cirrhotic patients.
        Hepatology. 1987; 7: 648-653
        • Lobrec D
        • Bernuau J
        • Rueff B
        • Benhamou JP
        Gastrointestinal bleeding after abrupt cessation of propranolol administration in cirrhosis.
        N Engl J Med. 1982; 307: 560
        • Maringhini A
        • Simonetti RM
        • Marcenó MP
        • Pagliaro L
        Propranolol for gastrointestinal bleeding in cirrhosis.
        N Engl J Med. 1982; 307: 1710
        • Gatta A
        • Sacerdoti D
        • Merkel C
        • Milani L
        • Battaglia G
        • Zuin R
        Effects of nadoiol treatment on renal and hepatic hemodynamics and function in cirrhotic patients with portal hypertension.
        Am Heart J. 1984; 108: 1167-1172
        • Gatta A
        • Sacordoti D
        • Merkel C
        • Rossoni R
        • Finucci G
        • Bolognesi M
        • Zuin R
        Use of a non-selective beta-blocker, nadolol, in the treatment et portal hypertension in cirrhotics.
        Int J Clin Pharmacol Res. 1985; 57: 413-418