HEPATOLOGY ELSEWHERE
Is Petoxifylline Still an Option in Severe Alcoholic Hepatitis? Park SH, Kim DJ, Kim YS, Yim HJ, Tak WY, Lee HJ, et al. Pentoxifylline vs. corticosteroid to treat severe alcoholic hepatitis: a randomized, non-inferiority, open trial. J Hepatol 2014;61:792-798. (Reprinted with permission.)
Abstract Background & Aims: Both corticosteroids and pentoxifylline reduce short-term mortality in severe alcoholic hepatitis. However, few studies have directly compared the efficacy of pentoxifylline and corticosteroids in patients with this condition. Methods: In this multicentre, open-labelled, randomized non-inferiority trial, we assigned 121 patients with severe alcoholic hepatitis (Maddrey’s discriminant function >32) to receive either pentoxifylline (400 mg, three times daily, in 62 subjects) or prednisolone (40 mg daily, in 59 subjects). The primary end point was non-inferiority in survival at the 1 month time point for the pentoxifylline treatment compared with prednisolone. Results: The 1-month survival rate of patients receiving pentoxifylline was 75.8% (15 deaths) compared with 88.1% (7 deaths) in those taking prednisolone, for a treatment difference of 12.3% (95% confidence interval, 24.2% to 28.7%; p 5 0.08). The 95% confidence interval for the observed difference exceeded the predefined margin of non-inferiority (15%) and included zero. The 6-month survival rate was not significantly different between the pentoxifylline and prednisolone groups (64.5% vs 72.9%; p 5 0.23). At 7 days the response to therapy assessed by the Lille model was significantly lower in the prednisolone group (n 5 58) than in the pentoxifylline group (n 5 59): 0.35 vs 0.50 (p 5 0.012). Hepatitis complications, including hepatorenal syndrome and side effects such as infection and gastrointestinal bleeding, were similar in the two groups. Conclusions: The findings demonstrate that the efficacy of the pentoxifylline is not statistically equivalent to the efficacy of prednisolone, supporting the use of prednisolone as a preferred treatment option in patients with severe alcoholic hepatitis.
Comment Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease. It is characterized by an acute decompensation of liver function that can occur at
EDITORS Roberto J. Groszmann, New Haven, CT Yasuko Iwakiri, New Haven, CT Tamar H. Taddei, New Haven, CT
any stage of the disease in patients with active alcohol consumption. The clinical spectrum of AH can range from asymptomatic forms to severe liver failure with a 6-month mortality higher than 40%. Despite the progress in the knowledge of the pathogenesis of AH, corticosteroids, in addition to alcohol abstinence, nutritional support, and prevention of complications, have been the treatment of choice for more than 30 years and are still recommended in the recent American Association for the Study of Liver Diseases and European Association for the Study of the Liver clinical guidelines.1,2 However, only approximately 40% of patients respond to corticosteroids, and many patients have contraindications to corticosteroid therapy, such as active infection or gastrointestinal bleeding. Some physicians are reluctant to give corticosteroids to these patients because of the risk of infection, although the impact of infection mainly depends on the degree of liver impairment and response to treatment.3 For these reasons clinical guidelines also recommend pentoxifylline as an alternative to corticosteroid therapy. Pentoxifylline is a phosphodiesterase inhibitor with anti–tumor necrosis factor action. In 1991 McHutchison and colleagues4 suggested that pentoxifylline could be useful to prevent the development of hepatorenal syndrome (HRS) in patients with severe AH. Ten years later, Akriviadis et al.5 performed a randomized, double-blind controlled trial comparing the administration of 1200 mg/day of pentoxifylline versus placebo for 28 days and showed a significantly lower mortality in the group of patients treated with pentoxifylline. This beneficial effect was related to a significantly lower incidence of HRS, without differences in blood levels of tumor necrosis factor between the two groups. Hepatorenal syndrome is one of the factors with a major impact on early mortality.6 Pentoxifylline has been used in different scenarios for the treatment of severe AH: comparing its efficacy versus placebo,5,7 versus prednisolone,8 in addition to prednisolone versus prednisolone alone,9 and as a rescue treatment in patients with no response to corticosteroids.10 The design and quality of these studies are heterogeneous, including in general a low number of 1425
1426
HEPATOLOGY ELSEWHERE
patients, different end points, and not always being double-blind, as well as only two requiring histological diagnosis. Among these studies, one of the largest and best designed is that of Mathurin and colleagues9 comparing the combination of pentoxifylline and prednisolone versus prednisolone and placebo, which showed an identical 69% 6-month survival in both groups and demonstrated that pentoxifylline does not improve the effect of prednisolone. The conclusions of a recent meta-analysis were that pentoxifylline reduced the incidence of HRS with respect to placebo without clear effects on survival and that there were no significant differences in survival between pentoxifylline administered alone or combined with corticosteroids versus corticosteroids.11 This meta-analysis also showed that the incidence of HRS was usually higher in patients treated with corticosteroids, but the differences were not always statistically significant. In a recent issue of the Journal of Hepatology, Park and colleagues12 published the results of a noninferiority trial in 124 patients with severe AH comparing the short-term mortality among those randomized to pentoxifylline versus prednisolone. Conventional doses of pentoxifylline or prednisolone were recommended, 1200 mg/day and 40 mg/day, respectively, for 28 days. One-month survival, the primary end point of the study, was 75.8% in the pentoxifylline-treated group and 88.1% in the prednisolone group, a difference that exceeded the limit of noninferiority. Six-month survival was 64% in the pentoxifylline group and 72% in the prednisolone group, close to the survival rate obtained in other similar studies. The authors concluded that the efficacy of pentoxifylline is lower than that of prednisolone and, consequently, that corticosteroids must continue to be the first-choice treatment of severe AH. Interestingly, the percentage of complications was low with no significant differences between the two groups, including the incidence of HRS. Furthermore, in this study the Lille score was a good predictor of response to treatment, confirming its clinical value. The study by Park and colleagues12 was well designed and included a large number of patients. However, as pointed out by the authors, it was not double-blind, did not include a placebo group, and lacked histological confirmation of the diagnosis. Although the diagnosis of AH can be suspected by clinical and analytical data, a definitive diagnosis requires histological confirmation. While the need for liver biopsy to diagnose AH in clinical practice is a still matter of controversy, the European Association for the Study of the Liver clinical guidelines state that
HEPATOLOGY, April 2015
clinical trials evaluating new strategies for severe AH should be based on histological confirmation of the diagnosis. In a recent multicenter study, Altamirano and colleagues13 analyzed liver biopsies of 326 patients from six centers in Europe and the United States and developed a histological score capable of predicting short-term survival in patients with AH. This score included four histological parameters: degree of fibrosis, degree of neutrophil infiltration, type of bilirubinostasis, and presence of megamitochondria. It was capable of identifying patients with a low, moderate, or high risk of death within 90 days. Interestingly, the score allows a more accurate prediction of survival of patients with age–bilirubin–international normalized ratio–creatinine class B14 or with a MELD (Model for End-Stage Liver Disease) score
Is Petoxifylline Still an Option in Severe Alcoholic Hepatitis? Park SH, Kim DJ, Kim YS, Yim HJ, Tak WY, Lee HJ, et al. Pentoxifylline vs. corticosteroid to treat severe alcoholic hepatitis: a randomized, non-inferiority, open trial. J Hepatol 2014;61:792-798. (Reprinted with permission.)
Abstract Background & Aims: Both corticosteroids and pentoxifylline reduce short-term mortality in severe alcoholic hepatitis. However, few studies have directly compared the efficacy of pentoxifylline and corticosteroids in patients with this condition. Methods: In this multicentre, open-labelled, randomized non-inferiority trial, we assigned 121 patients with severe alcoholic hepatitis (Maddrey’s discriminant function >32) to receive either pentoxifylline (400 mg, three times daily, in 62 subjects) or prednisolone (40 mg daily, in 59 subjects). The primary end point was non-inferiority in survival at the 1 month time point for the pentoxifylline treatment compared with prednisolone. Results: The 1-month survival rate of patients receiving pentoxifylline was 75.8% (15 deaths) compared with 88.1% (7 deaths) in those taking prednisolone, for a treatment difference of 12.3% (95% confidence interval, 24.2% to 28.7%; p 5 0.08). The 95% confidence interval for the observed difference exceeded the predefined margin of non-inferiority (15%) and included zero. The 6-month survival rate was not significantly different between the pentoxifylline and prednisolone groups (64.5% vs 72.9%; p 5 0.23). At 7 days the response to therapy assessed by the Lille model was significantly lower in the prednisolone group (n 5 58) than in the pentoxifylline group (n 5 59): 0.35 vs 0.50 (p 5 0.012). Hepatitis complications, including hepatorenal syndrome and side effects such as infection and gastrointestinal bleeding, were similar in the two groups. Conclusions: The findings demonstrate that the efficacy of the pentoxifylline is not statistically equivalent to the efficacy of prednisolone, supporting the use of prednisolone as a preferred treatment option in patients with severe alcoholic hepatitis.
Comment Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease. It is characterized by an acute decompensation of liver function that can occur at
EDITORS Roberto J. Groszmann, New Haven, CT Yasuko Iwakiri, New Haven, CT Tamar H. Taddei, New Haven, CT
any stage of the disease in patients with active alcohol consumption. The clinical spectrum of AH can range from asymptomatic forms to severe liver failure with a 6-month mortality higher than 40%. Despite the progress in the knowledge of the pathogenesis of AH, corticosteroids, in addition to alcohol abstinence, nutritional support, and prevention of complications, have been the treatment of choice for more than 30 years and are still recommended in the recent American Association for the Study of Liver Diseases and European Association for the Study of the Liver clinical guidelines.1,2 However, only approximately 40% of patients respond to corticosteroids, and many patients have contraindications to corticosteroid therapy, such as active infection or gastrointestinal bleeding. Some physicians are reluctant to give corticosteroids to these patients because of the risk of infection, although the impact of infection mainly depends on the degree of liver impairment and response to treatment.3 For these reasons clinical guidelines also recommend pentoxifylline as an alternative to corticosteroid therapy. Pentoxifylline is a phosphodiesterase inhibitor with anti–tumor necrosis factor action. In 1991 McHutchison and colleagues4 suggested that pentoxifylline could be useful to prevent the development of hepatorenal syndrome (HRS) in patients with severe AH. Ten years later, Akriviadis et al.5 performed a randomized, double-blind controlled trial comparing the administration of 1200 mg/day of pentoxifylline versus placebo for 28 days and showed a significantly lower mortality in the group of patients treated with pentoxifylline. This beneficial effect was related to a significantly lower incidence of HRS, without differences in blood levels of tumor necrosis factor between the two groups. Hepatorenal syndrome is one of the factors with a major impact on early mortality.6 Pentoxifylline has been used in different scenarios for the treatment of severe AH: comparing its efficacy versus placebo,5,7 versus prednisolone,8 in addition to prednisolone versus prednisolone alone,9 and as a rescue treatment in patients with no response to corticosteroids.10 The design and quality of these studies are heterogeneous, including in general a low number of 1425
1426
HEPATOLOGY ELSEWHERE
patients, different end points, and not always being double-blind, as well as only two requiring histological diagnosis. Among these studies, one of the largest and best designed is that of Mathurin and colleagues9 comparing the combination of pentoxifylline and prednisolone versus prednisolone and placebo, which showed an identical 69% 6-month survival in both groups and demonstrated that pentoxifylline does not improve the effect of prednisolone. The conclusions of a recent meta-analysis were that pentoxifylline reduced the incidence of HRS with respect to placebo without clear effects on survival and that there were no significant differences in survival between pentoxifylline administered alone or combined with corticosteroids versus corticosteroids.11 This meta-analysis also showed that the incidence of HRS was usually higher in patients treated with corticosteroids, but the differences were not always statistically significant. In a recent issue of the Journal of Hepatology, Park and colleagues12 published the results of a noninferiority trial in 124 patients with severe AH comparing the short-term mortality among those randomized to pentoxifylline versus prednisolone. Conventional doses of pentoxifylline or prednisolone were recommended, 1200 mg/day and 40 mg/day, respectively, for 28 days. One-month survival, the primary end point of the study, was 75.8% in the pentoxifylline-treated group and 88.1% in the prednisolone group, a difference that exceeded the limit of noninferiority. Six-month survival was 64% in the pentoxifylline group and 72% in the prednisolone group, close to the survival rate obtained in other similar studies. The authors concluded that the efficacy of pentoxifylline is lower than that of prednisolone and, consequently, that corticosteroids must continue to be the first-choice treatment of severe AH. Interestingly, the percentage of complications was low with no significant differences between the two groups, including the incidence of HRS. Furthermore, in this study the Lille score was a good predictor of response to treatment, confirming its clinical value. The study by Park and colleagues12 was well designed and included a large number of patients. However, as pointed out by the authors, it was not double-blind, did not include a placebo group, and lacked histological confirmation of the diagnosis. Although the diagnosis of AH can be suspected by clinical and analytical data, a definitive diagnosis requires histological confirmation. While the need for liver biopsy to diagnose AH in clinical practice is a still matter of controversy, the European Association for the Study of the Liver clinical guidelines state that
HEPATOLOGY, April 2015
clinical trials evaluating new strategies for severe AH should be based on histological confirmation of the diagnosis. In a recent multicenter study, Altamirano and colleagues13 analyzed liver biopsies of 326 patients from six centers in Europe and the United States and developed a histological score capable of predicting short-term survival in patients with AH. This score included four histological parameters: degree of fibrosis, degree of neutrophil infiltration, type of bilirubinostasis, and presence of megamitochondria. It was capable of identifying patients with a low, moderate, or high risk of death within 90 days. Interestingly, the score allows a more accurate prediction of survival of patients with age–bilirubin–international normalized ratio–creatinine class B14 or with a MELD (Model for End-Stage Liver Disease) score
