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Pentoxifylline for alcoholic hepatitis

  • Review
  • Intervention

Authors

  • Kate Whitfield,

    Corresponding author
    1. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 3344, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
    • Kate Whitfield, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 3344, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, DK-2100, Denmark. kate.whitfield@ctu.rh.dk.

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  • Andrea Rambaldi,

    1. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 3344, Rigshospitalet, Copenhagen University Hospital, Cochrane Hepato-Biliary Group, Copenhagen, Denmark
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  • Jørn Wetterslev,

    1. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 3344, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
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  • Christian Gluud

    1. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 3344, Rigshospitalet, Copenhagen University Hospital, Cochrane Hepato-Biliary Group, Copenhagen, Denmark
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Abstract

Background

Alcoholic hepatitis is a life-threatening disease, with an average mortality of approximately 40%. There is no widely accepted, effective treatment for alcoholic hepatitis. Pentoxifylline is used to treat alcoholic hepatitis, but there has been no systematic review to assess its effects.

Objectives

To assess the benefits and harms of pentoxifylline in alcoholic hepatitis.

Search methods

The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, clinicaltrials.gov, and full text searches were conducted until August 2009. Manufacturers and authors were contacted.

Selection criteria

All randomised clinical trials of pentoxifylline in participants with alcoholic hepatitis compared to control were selected for inclusion.

Data collection and analysis

Two authors extracted data and evaluated the risk of bias. RevMan Analysis was used for statistical analysis of dichotomous data with risk ratio (RR) and of continuous data with mean difference (MD), both with 95% confidence intervals (CI). Trial sequential analysis (TSA) was also used for statistical analysis of dichotomous and continuous data in order to control for random error. Where data were only available from one trial, we used Fisher's exact test or Student's t-test.

Main results

Five trials, with a total of 336 randomised participants, were included. A total of 105 participants (31%) died. Of the five included trials, four (80%) had a high risk of bias. Meta-analysis using all five trials showed that pentoxifylline reduced mortality compared with control (RR 0.64; 95% CI 0.46 to 0.89). However, this result was not supported by trial sequential analysis, which adjusts for multiple testing on accumulating data. Furthermore, four of the five trials were judged to have a high risk of bias, thus risking an overestimated intervention effect. Meta-analysis showed that pentoxifylline reduced the hepatic-related mortality due to hepatorenal syndrome (RR 0.40; 95% CI 0.22 to 0.71), but trial sequential analysis did not support this result. Data from one trial suggests that pentoxifylline may increase the occurrence of serious and non-serious adverse events compared to control.

Authors' conclusions

The current available data may indicate a possible positive intervention effect of pentoxifylline on all-cause mortality and mortality due to hepatorenal syndrome, and conversely, an increase in serious and non-serious adverse events. However, the evidence is not firm; no conclusions can be drawn regarding whether pentoxifylline has a positive, negative, or neutral effect on participants with alcoholic hepatitis.

摘要

背景

Pentoxifylline治療酒精性肝炎

酒精性肝炎是一種會危及生命的疾病,平均死亡率約為40%。目前還沒有廣為接受有效的酒精性肝炎治療。Pentoxifylline已被用來治療酒精性肝炎,但是尚未針對其成效進行系統性地評估。

目標

評估pentoxifylline治療酒精性肝炎的益處及害處。

搜尋策略

我們在Cochrane HepatoBiliary Group Controlled Trials Register、Cochrane Library的 Cochrane Central Register of Controlled Trials (CENTRAL)、MEDLINE、EMBASE、Science Citation Index Expanded、LILACS、clinicaltrials.gov的資料庫中,全文搜尋直到2009年8月的資料。我們也與製造商和作者聯繫。

選擇標準

所有以pentoxifylline治療酒精性肝炎病人,並與控制組比較的隨機臨床試驗。

資料收集與分析

本文2位作者摘錄數據,並評估發生偏誤的風險。我們使用Rev Man Analysis進行含風險比率(RR)之二元化數據及含平均差(MD)之連續數據的統計分析,兩者都採用95%的信賴區間(CI)。我們也使用試驗的序列分析(TSA)進行二元化及連續數據的統計分析,以控制隨機誤差。如果只能從一項試驗中取得數據,我們便使用費雪正確機率測驗(Fisher's exact test)或司徒頓t檢定(Student ttest)。

主要結論

我們收納共包含336位病人的5個試驗。共105位參加者(31%)死亡。在5個收納的試驗中,有4個有高偏誤風險(80%)。由這5個試驗的統合分析顯示,相較於控制組,pentoxifylline可以減少病人的死亡率(RR 0.64; 95% CI 0.46至 0.89)。然而試驗的序列分析並不支持這個結果,序列分析依累計數據的多次檢定而調整。此外,5個試驗中有4個判斷為高偏誤風險,因此有高估計療效的風險。統合分析顯示,pentoxifylline減少了因肝腎症候群導致肝臟相關的死亡率(RR 0.40; 95% CI 0.22 to 0.71),但是試驗序列分析並不支持這個結果。從1個試驗的數據顯示,相較於對照組,pentoxifylline可能會增加嚴重或不嚴重的不良反應之發生率。

作者結論

根據現有數據顯示pentoxifylline對於所有原因導致的死亡率及肝腎症候群導致的死亡率,可能具有正面的成效,但也增加嚴重和不嚴重的不良反應。然而,這證據仍未確定;尚無法對pentoxifylline對於酒精性肝炎病人是否為正面、負面或中立影響下結論。

翻譯人

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

沒有足夠的證據可得到pentoxifylline對於酒精性肝炎病人造成何種影響的結論。沒有足夠的證據可得到pentoxifylline對於酒精性肝炎病人造成何種影響的結論:肝炎是一種肝臟的發炎性損傷。酒精對於肝臟是有毒的,太多酒精可能會導致酒精性肝炎。嚴重的酒精性肝炎會威脅生命。根據目前獲得的最佳證據,仍無法支持或推翻使用pentoxifylline作為治療酒精性肝炎的療方。我們發現包括336位病人的5份文獻;其中一半以pentoxifylline治療,另外一半以安慰劑治療或是未給予治療。我們進行了這項系統性回顧和統計分析,但是無法找到確切的證據能證實pentoxifylline對於酒精性肝炎病人死亡率或肝臟疾病併發症是否產生有利的影響。Pentoxifylline似乎會導致更多嚴重和不嚴重的副作用。為了幫助判定是否應使用pentoxifylline治療酒精性肝炎,我們需要設計更良好、執行更順暢且大型的隨機臨床試驗,以獲得pentoxifylline之益處或害處的短期(1個月以內)或長期(1個月以上)數據。

Plain language summary

Not enough evidence to conclude the effect of pentoxifylline on patients with alcoholic hepatitis 

Hepatitis is inflammatory injury of the liver. Alcohol is toxic to the liver, and too much alcohol can cause alcoholic hepatitis. The severe form of alcoholic hepatitis is life-threatening. The use of pentoxifylline as a treatment for alcoholic hepatitis cannot be supported or rejected based on the best evidence available today. We found five randomised trials, which together included 336 participants; half received pentoxifylline, and the other half received placebo or no intervention. We performed this systematic review and statistical analyses but could not show firm evidence of beneficial effects of pentoxifylline on mortality or on complications of liver diseases in patients with alcoholic hepatitis. Pentoxifylline did appear to cause more serious and non-serious side effects. In order to help decide whether pentoxifylline should be used to treat alcoholic hepatitis or not, we need well-designed, well-conducted, large randomised clinical trials, with short-term (less than one month) and long-term (more than one month) data on benefits and harms.

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