Oral deferiprone for iron chelation in people with thalassaemia

  • Review
  • Intervention

Authors


Abstract

Background

Thalassaemia major is a genetic disease characterised by a reduced ability to produce haemoglobin. Management of the resulting anaemia is through transfusions of red blood cells.

Repeated transfusions result in excessive accumulation of iron in the body (iron overload), removal of which is achieved through iron chelation therapy. A commonly used iron chelator, deferiprone, has been found to be pharmacologically efficacious. However, important questions exist about the efficacy and safety of deferiprone compared to another iron chelator, desferrioxamine.

Objectives

To summarise data from trials on the clinical efficacy and safety of deferiprone and to compare the clinical efficacy and safety of deferiprone for thalassaemia with desferrioxamine.

Search methods

We searched the Group's Haemoglobinopathies Trials Register, MEDLINE, EMBASE, Biological Abstracts, ZETOC, Current Controlled Trials and bibliographies of relevant publications. We contacted the manufacturers of deferiprone and desferrioxamine.

Most recent searches: June 2006.

Selection criteria

Randomised controlled trials comparing deferiprone with another iron chelator; or comparing two schedules of deferiprone, in people with transfusion-dependent thalassaemia.

Data collection and analysis

Two authors independently assessed trial quality and extracted data. Missing data were requested from the original investigators.

Main results

Ten trials involving 398 people (range 10 to 144 people) were included. Nine trials compared deferiprone with desferrioxamine or a combination of deferiprone and desferrioxamine and one compared different schedules of deferiprone. There was little consistency between outcomes and little information to fully assess the methodological quality of most of the included trials.

No trial reported long-term outcomes (mortality and end organ damage). There was no consistent effect on reduction of iron overload between all treatment comparisons, with the exception of urinary iron excretion in comparisons of deferiprone with desferrioxamine. An increase in iron excretion levels favoured deferiprone in one trial and desferrioxamine in three trials, even though measurement of urinary iron excretion underestimates total iron excretion by desferrioxamine.

Adverse events were recorded in trials comparing deferiprone with desferrioxamine. There was evidence of adverse events in all treatment groups. Adverse events in one trial were significantly more likely with deferiprone than desferrioxamine, risk ratio 2.24 (95% confidence interval 1.19 to 4.23).

Authors' conclusions

We found no reason to change current treatment recommendations, namely deferiprone is indicated for treating iron overload in people with thalassaemia major when desferrioxamine is contraindicated or inadequate. However, there is an urgent need for adequately-powered, high quality trials comparing the overall clinical efficacy and long-term outcome of deferiprone with desferrioxamine.

摘要

背景

口服deferiprone用於海洋性貧血(thalassaemia)患者的鐵螯合治療

重度海洋性貧血(thalassemia major)是一種血紅素製造能力下降的遺傳性疾病;其所造成的貧血,要透過紅血球輸血來處理。反覆輸血會造成鐵質在身體裡過度堆積(鐵負荷過多[iron overload]),得藉由鐵螯合治療將之排除。Deferiprone是一種常用的鐵螯合劑(譯者按:iron chelation,即我國俗稱的「排鐵劑」),其藥效已確立。然而,與另一鐵螯合劑desferrioxamine相比,deferiprone的療效與安全性仍有疑問。

目標

由來自試驗的資料中,整理deferiprone在海洋性貧血的臨床療效與安全性,並與desferrioxamine做比較。

搜尋策略

我們搜尋了Cochrane Haemoglobinopathies Trials Register、MEDLINE、EMBASE、Biological Abstracts, ZETOC、Current Controlled Trials等資料庫以及相關文獻的參考書目。我們也與deferiprone和desferrioxamine的製造商連絡。最近搜尋時間:2006年6月。

選擇標準

針對輸血依賴型海洋性貧血患者,比較deferiprone與其他鐵螯合劑,或比較兩種不同的deferiprone給藥時程的隨機對照試驗(randomised controlled trials)。

資料收集與分析

由2位作者獨立評估試驗品質並擷取數據。若資料有缺,則向原研究者索取。

主要結論

共引入包含398人(範圍從10到144人)的10個試驗。有9個試驗比較deferiprone與desferrioxamine或兩者併用,另1個則比較deferiprone的不同給藥時程。其結果的一致性偏低,且本文引入的大部分試驗只有少量資訊可完整分析其方法學品質(methodological quality)。沒有試驗有報告長期預後(死亡率及目標器官損傷[end organ damage])。各種治療在降低鐵負荷過多方面,也沒有一致的療效,但deferiprone與desferrioxamine的尿液裡的鐵排出量比較則例外。儘管測量尿液裡的鐵排出量會低估desferrioxamine的整體鐵排出量,desferrioxamine仍在3個試驗中勝出,只有1個試驗發現deferiprone的鐵排出較佳。在比較deferiprone與desferrioxamine的試驗中,都有紀錄藥物不良反應(adverse events)。實際上,所有的治療組都有藥物不良反應。在1個試驗中,deferiprone的藥物不良反應發生率顯著高於desferrioxamine (RR 2.24, 95% CI 1.19 to 4.23)。

作者結論

我們找不到改變現有治療建議的理由。也就是說,當重度海洋性貧血患者使用desferrioxamine有禁忌症或效果不彰時,才適合使用deferiprone治療鐵負荷過多。然而,亟需強度充分的高品質試驗來比較deferiprone與desferrioxamine的整體臨床療效與長期預後。

翻譯人

本摘要由臺灣大學附設醫院劉彥麟翻譯。

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

總結

使用鐵螯合劑deferiprone治療輸血依賴型海洋性貧血患者。 海洋性貧血是一種血紅素製造能力下降的遺傳性疾病,其治療需常規輸血,但會造成體內鐵質過多。移除這些過量的鐵對於預防重要器官損傷相當重要,需透過鐵螯合治療來達成,其中常用的一種是 deferiprone。不過,與最廣為使用的鐵螯合劑desferrioxamine (DFO)相比,deferiprone在排鐵方面的效果與安全性仍有疑問。我們找到了10個隨機對照試驗,比較deferiprone與DFO用於治療輸血依賴型海洋性貧血。這些研究利用下列幾種方式來分析過多的鐵的排除:測量血液與肝臟的鐵濃度、測量心臟功能、測量尿中的鐵排除量等。然而,deferiprone或DFO的鐵排除量測量結果並不一致,有些研究測出deferiprone排出較多鐵,有些則測出DFO排出較多鐵。造成這種差異的原因之一,是由於引用試驗所採用的各種測量與分析方法相去甚遠之故。這些試驗也有比較deferiprone與DFO的副作用;各試驗中都有發生的藥物不良反應包括:噁心、關節痛、胃痛、deferipeone造成白血球數量下降、DFO注射部位疼痛或皮膚起反應。有1個試驗顯示deferiprone的副作用顯著地比DFO多,使用deferiprone患者出現藥物不良反應的危險性比使用DFO患者多了兩倍(RR 2.24; 95% CI 1.19 to 4.23)。本回顧受限於引用試驗用來評估治療成果的方法各有不同,因此很難比較不同試驗的結果。我們找不到改變現有治療建議的證據。也就是說,當重度海洋性貧血患者使用desferrioxamine有禁忌症或效果不彰時,才適合使用deferiprone治療鐵負荷過多。針對鐵的排除量應如何測量,且其結果對一位輸血依賴型海洋性貧血患者究竟有何意義,還需更多研究來探討。

Plain language summary

The use of the iron chelator deferiprone in people with thalassaemia who are dependent on blood transfusions

Thalassaemia is a genetic disease in which there is a reduced ability to produce haemoglobin. Management by regular blood transfusions results in excess iron in the body. Removal of excess iron is vital to prevent damage to major organs. This is achieved through iron chelation therapy; one common iron chelator is deferiprone. Questions exist about whether deferiprone is as good at removing excess iron, and as safe as the most widely used iron chelator desferrioxamine (DFO).

Ten randomised controlled trials were identified that compared deferiprone with DFO for the treatment of transfusion-dependent thalassaemia. Removal of excess iron was assessed in a number of ways by these trials: measuring iron concentration in the blood and in the liver; measuring how well the heart functions; and measuring the amount of iron that is excreted in urine. However, there was little consistency in the amount of iron removed with either deferiprone or DFO; for some of these measures the amount of iron removed was greater with deferiprone, for other measures the amount of iron removed was greater with DFO. One of the reasons for this inconsistency is that there were many differences in how these measures were made and assessed in the included trials.

Adverse events were recorded in trials comparing deferiprone with DFO. The range of adverse events that occurred across all trials included nausea, joint pain, stomach upsets and low white blood cell count with deferiprone and pain or skin reactions at the injection site and joint pain with DFO. In one trial, adverse events were significantly more likely with deferiprone than DFO, the risk of experiencing an adverse event with deferiprone was twice that of the risk of experiencing an adverse event with DFO (risk ratio 2.24 (95% confidence interval 1.19 to 4.23)).

A limitation to this review is the difference in the ways outcomes were measured by the included trials. This makes it difficult to compare results between the different trials.

We have found no evidence to change current treatment recommendations, namely that deferiprone is indicated for treating iron overload in people with thalassaemia major when desferrioxamine is contraindicated or inadequate. There is a need for more research that considers how the removal of excess iron is measured by trials and what the results of these measurements mean to a person with transfusion-dependent thalassaemia.

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