Gastroenterology

Gastroenterology

Volume 127, Issue 2, August 2004, Pages 476-484
Gastroenterology

Clinical-liver, pancreas, and biliary tract
A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis 1,

https://doi.org/10.1053/j.gastro.2004.05.004Get rights and content

Abstract

Background & Aims: Beta-blockers are extensively used to prevent variceal bleeding in patients with large esophageal varices. It is not established if beta-blockers delay the growth of small varices. Methods: A total of 161 patients with cirrhosis and small esophageal varices (F1 according to the classification of Beppu et al.) without previous bleeding were enrolled. A total of 83 patients were randomized to nadolol (dose adjusted to decrease resting heart rate by 25%; mean dose given, 62 ± 25 mg/day) and 78 to placebo. The principal end point was occurrence of large esophageal varices (F2 or F3 according to the classification of Beppu et al.). Endoscopic examination was performed after 12, 24, 36, 48, and 60 months of follow-up. Mean follow-up was 36 months. Results: The 2 groups were well matched for demographic and clinical characteristics. During the study period, 9 patients randomized to nadolol and 29 randomized to placebo had growth of esophageal varices. At the end of follow-up, the cumulative risk was 20% versus 51% (P < 0.001) (absolute risk difference, 31%; 95% confidence interval, 17%–45%). When possible confounding factors were taken into account, treatment was a significant factor predicting growth of varices (odds ratio, 4.0; 95% confidence interval, 1.95–8.4). The cumulative probability of variceal bleeding was also lower in patients randomized to nadolol (P = 0.02). Survival was not different (P = 0.33). Adverse effects resulting in withdrawal of drug occurred in 9 in the nadolol group and one in the placebo group (P = 0.01). Conclusions: This study suggests that beta-blocker prophylaxis of variceal bleeding in patients with compensated cirrhosis should be started when small esophageal varices are present.

Section snippets

Patients and methods

The study was a multicenter randomized clinical trial coordinated by the Department of Clinical and Experimental Medicine of the University of Padua (Padua, Italy). Seven further departments of medicine of general hospitals in the northeastern part of Italy participated in the study.

Results

Randomization resulted in 83 patients in the nadolol group and 78 patients in the placebo group; these 2 groups were well matched for demographic and clinical characteristics (Table 1 and Figure 1).

During follow-up, 11 patients randomized to nadolol and 10 patients randomized to placebo were lost to follow-up (P = 0.91) after a mean of 8 ± 6 and 11 ± 8 months of follow-up, respectively (range, 3–24 and 3–30 months; P = 0.30).

Nine patients in the nadolol group had to be withdrawn from treatment

Discussion

In the present trial, we observed that the administration of nonselective beta-blockers in patients with cirrhosis and small esophageal varices at low risk of bleeding markedly decreased the risk of growth of esophageal varices to large varices at relevant risk of bleeding. When designing the study protocol, we had to face the problem of whether it would be better to use a double-blind trial design, which minimizes bias in assessment of outcome but implies evident difficulties in the management

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    Supported by grants from the Italian Ministry of Education, University and Research (Rome, Italy) (National Project “Portal hypertension in cirrhosis”) and from the Veneto Region (Venezia, Italy) (Regional Center for Epidemiology and Treatment of Liver Diseases).

    1

    Members of the Gruppo Triveneto per l’Ipertensione Portale are as follows. Steering committee: A. Gatta and C. Merkel (University of Padua, Padua, Italy); V. Donadon (General Hospital of Pordenone, Pordenone, Italy); P. Spandri (General Hospital of Thiene, Thiene, Italy); F. Tremolada (General Hospital of Belluno, Belluno, Italy); and G. Marin (General Hospital of Dolo, Dolo, Italy). Clinical investigators: E. Bernardinello, L. Chemello, and F. Vescovi (University of Padua, Padua, Italy); G. Marin (General Hospital of Dolo, Dolo, Italy); P. Spandri (General Hospital of Thiene, Thiene, Italy); L. Zancanella (General Hospital of Bolzano, Bolzano, Italy); C. Costan (General Hospital of Chioggia, Chioggia, Italy); C. Mazzaro (General Hospital of Pordenone, Pordenone, Italy); P. Torboli (General Hospital of Trento, Trento, Italy); and F. Tremolada (General Hospital of Belluno, Belluno, Italy). Endoscopists: P. Angeli (University of Padua, Padua, Italy); R. Marin (General Hospital of Dolo, Dolo, Italy); P. Zanella (General Hospital of Thiene, Thiene, Italy); M. Felder (General Hospital of Bolzano, Bolzano, Italy); G. Cavallarin (General Hospital of Chioggia, Chioggia, Italy); C. Donada (General Hospital of Pordenone, Pordenone, Italy); I. Avancini (General Hospital of Trento, Trento, Italy); and G. Sebastianelli (General Hospital of Belluno, Belluno, Italy). Statistical analysts: M. Bolognesi, B. Bellini, and C. Merkel (University of Padua, Padua, Italy).

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