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The aim of this study was to evaluate the efficacy of pentoxifylline in patients with severe acute alcoholic hepatitis. Pentoxifylline is a nonselective phosphodiesterase inhibitor that decreases tumor necrosis factor (TNF) gene transcription. Elevated TNF levels have been found in the sera of patients with alcoholic hepatitis, and hence the rationale for this large scale study was to definitively address the therapeutic role of pentoxifylline in this disease. The study was conducted in the liver unit at the University of Southern California in patients with a history of heavy alcohol abuse and a clinical diagnosis of acute alcoholic hepatitis. Inclusion criteria for patients in the study were jaundice; Maddrey discriminant factor (DF) of ≥32 and one or more of the clinical or laboratory parameters of fever, palpable tender hepatomegaly, white blood cell count of >12,000/ml3 with predominantly neutrophilic differentiation, hepatic encephalopathy, and hepatic systolic bruit. Enrollment into the study was attempted within the first 10 days after admission. Exclusion criteria included concomitant bacterial infections, active GI hemorrhage, or severe cardiopulmonary disease, and clinical evidence of advanced alcoholic cirrhosis. A histological diagnosis was not required for inclusion in the study, as the investigators feared that severely ill, coagulopathic patients might not be able to undergo a percutaneous liver biopsy. The study was a prospective, double blind, randomized, placebo-controlled study. The two primary endpoints were the effect of pentoxifylline on 1) the short term survival (during the index hospitalization or over the 28-day study period) and 2) progression to hepatorenal syndrome (HRS). Secondary endpoints were the effect of pentoxifylline on 1) the course of laboratory parameters, including serum TNF levels, and 2) development of clinical complications of liver disease. One hundred two patients were enrolled and randomized to receive either pentoxifylline 400 mg t.i.d. for 4 wk or a placebo. Patients with previous hepatic decompensation (n = 22), hepatic encephalopathy (n = 10), and renal impairement (serum creatinine of >2.4 mg/dl, n = 9 patients) were also included. There were no significant differences between the two groups for any of the demographic or clinical variables. Among the pentoxifylline group, 78% received medication until the completion of 28 days or until death, whereas in the control group 92% received placebo capsules for 28 days or until death. The mean period of treatment was 21 (21.5 ± 9.5) days for both groups, thereby providing active treatment for a sufficient period. Reasons for discontinuation in the pentoxifylline group included headache, GI symptoms, and generalized skin rash. Plasma TNF levels were available for 60 patients (29 in the pentoxifylline group and 31 in the control group). Baseline TNF levels were above the normal range in all patients from both groups. There were no differences between the two groups at randomization or at any time during the treatment period in absolute values or in changes from baseline when all patients or only survivors of the two groups were compared. When only the nonsurvivors were compared, control patients had higher TNF values than pentoxifylline-treated patients at wk 1, 2, and 4. In this study, 25% and 46% in the pentoxifylline and control arms died (p = 0.037, reluctant risk [RR] = 0.59, 95% CI = 0.35–0.97) after a range of 5–54 days and 7–139 days, respectively. In the patients who died, hepatic failure with HRS had developed in 50% in the pentoxifylline group and 92% in the control group. New onset renal failure occurred in 11% and 43% in the pentoxifylline and control groups, respectively (p = 0.001, RR = 0.35, 95% CI = 0.15–0.77), and progressed to HRS in 80% and 90% of patients, respectively, in the two groups (p = 0.0015, RR = 0.32, 95% CI = 0.13–0.79). In multiple logistic regression analysis, two variables (DF and age) were independently associated with survival in the control group, and one variable (creatinine) in the pentoxifylline group. Three variables (creatinine, age, and treatment with pentoxifylline) were independently associated with survival in the two groups combined. |
