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Multicenter randomized placebo-controlled trial of non-selective beta-blockers in the prevention of the complications of portal hypertension Final results and identification of a predictive factor



Multicenter randomized placebo-controlled trial of non-selective beta-blockers in the prevention of the complications of portal hypertension Final results and identification of a predictive factor



Hepatology 38(4 Suppl 1): 206A, October



The aims of this multicenter, randomized, double-blind, placebo-controlled trial performed in cirrhotic patients without varices were to investigate: 1) whether a non-selective beta-adrenergic blocker (timolol) given early in the course of cirrhosis can prevent the development of varices or variceal hemorrhage (VH). 2) whether sequential measurements of hepatic venous pressure gradient (HVPG) can predict the development of varices/VH, thereby constituting a prognostic tool in the management of these patients. Methods: Patients with biopsy-proven cirrhosis and no varices but with portal hypertension (i.e. HVPG >6 mmHg) were candidates for the study. The individual dose of timolol was determined prior to randomization by titrating it until one of the following was achieved: a 25% reduction in resting heart rate (HR) from baseline, a HR <55 beats/min or a maximal dose of 80 mg/day. Once the dose was determined, the patient was randomized to timolol or placebo. Patients were followed with yearly endoscopies, and HVPG measurements. The presence or absence of varices was determined by two independent observers. The primary end-point was the development of varices/VH and the time to occurrence of varices/VH. The occurrence of treatment "failures" (primary end-point, transplant or death) and the time to treatment failure were also analyzed. Sequential HVPG measurements were compared between study groups and were correlated to the occurrence of primary, secondary (ascites and encephalopathy) and terminating events. Data analysis was determined pre-hoc and performed on an intent-to-treat basis. Results: 780 pts were screened and 213 were randomized (108 to timolol, 105 to placebo). Etiology of cirrhosis was hepatitis C in 53%, alcohol in 20%, alcohol+hepatitis C in 15% and other etiologies in 12%. The majority (88%) were Child A and 12% were Child B. No differences in baseline parameters (age, gender, race, etiology of cirrhosis, Child score, liver tests or HVPG) were identified between study groups. Patients were stratified by etiology (alcoholic vs. non-alcoholic) and by HVPG (<10 mmHg vs. gtoreq10 mmHg). Median followup was 4.2 years (range 0 to 8.2 years). In the timolol group, the mean daily dose of timolol was 10.8 mg (range 1.25-80.0) and this group exhibited a significant reduction in HR compared to placebo group at all time-points (p<0.01). No statistically significant differences were found between study groups regarding the development or the time to occurrence of primary events or treatment failures. There were 84 primary end-points (78 varices, 6 VH; equally distributed between study groups), 25 deaths (15 placebo, 10 timolol; ns) and 9 transplants (7 timolol, 2 placebo; ns). Ascites and/or encephalopathy occurred in 56 patients (32 timolol, 24 placebo; ns). There was a significantly higher number of adverse events and serious adverse events (20 vs. 6) in the timolol group (p<0.01). No significant differences in HVPG were detected between both study groups. An HVPG>10 mmHg at baseline and at year 1 after inclusion in the study was highly predictive of the development of primary, secondary and terminating events (p<0.0001). Conclusions: 1) In cirrhotic patients without varices, non-selective beta-blockers are not useful in the prevention of the development of varices/VH and are associated with a higher proportion of adverse events, 2) An HVPG>10 mmHg is a powerful prognostic predictor of the development of complications of portal hypertension.

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