Combined corticosteroid and long-acting beta-agonist in one inhaler versus placebo for chronic obstructive pulmonary disease

 

Abstract

Background

Long-acting beta-agonists and inhaled corticosteroids have both been recommended in guidelines for the treatment of chronic obstructive pulmonary disease. Their co-administration in a combined inhaler may facilitate adherence to medication regimens, and improve efficacy.

Objectives

To assess the efficacy of combined inhaled corticosteroid and long-acting beta-agonist preparations, compared to placebo, in the treatment of adults with chronic obstructive pulmonary disease.

Search methods

We searched the Cochrane Airways Group Specialised Register of trials. The date of the most recent search is April 2007.

Selection criteria

Studies were included if they were randomised and double-blind. Studies could compare any combined inhaled corticosteroids and long-acting beta-agonist preparation with placebo.

Data collection and analysis

Two authors independently assessed study risk of bias and extracted data. The primary outcomes were exacerbations, mortality and pneumonia. Health-related quality of life (measured by validated scales), lung function and side-effects were secondary outcomes. Dichotomous data were analysed as fixed effect odds ratios or rate ratios with 95% confidence intervals, and continuous data as mean differences and 95% confidence intervals.

Main results

Eleven studies met the inclusion criteria (6427 participants randomised). Two different combination preparations (fluticasone/salmeterol and budesonide/formoterol) were used. Study quality was good. Fluticasone/salmeterol and budesonide/formoterol both reduced the rate of exacerbations. Pooled analysis of both combination therapies indicated that exacerbations were less frequent when compared with placebo, Rate Ratio: 0.74 (95% CI 0.7 to 0.8). The clinical impact of this effect depends on the frequency of exacerbations experienced by patients. The patients included in these trials had on average 1-2 exacerbations per year which means that treatment with combination therapy would lead to a reduction of one exacerbation every two to four years in these individuals. There is an overall reduction in mortality, but this outcome is dominated by the results of TORCH and further studies on budesonide/formoterol are required. The three year number needed to treat to prevent one extra death is 36 (95% CI 21 to 258), using a baseline risk of 15.2% from the placebo arm of TORCH. Both treatments led to statistically significant improvement in health status measurements, although the clinical importance of the differences observed is open to interpretation. Symptoms and lung function assessments favoured combination treatments. There was an increase in the risk of pneumonia with combined inhalers. The three year number needed to treat for one extra case of pneumonia is 13, using a baseline risk of 12.3% from the placebo arm of TORCH. Fewer participants withdrew from studies assessing combined inhalers due to adverse events and lack of efficacy.

Authors' conclusions

Compared with placebo, combination therapy led to a significant reduction of a quarter in exacerbation rates. There was a significant reduction in all-cause mortality with the addition of data from the TORCH trial. The increased risk of pneumonia is a concern, and better reporting of this outcome in future studies would be helpful. In order to draw firmer conclusions about the effects of combination therapy in a single inhaler more data are necessary, particularly in relation to the profile of adverse events and benefits in relation to different doses of inhaled corticosteroids.

 

Plain language summary

Combination therapy with inhaled corticosteroids and long-acting beta-agonists can reduce exacerbations and improve quality of life in people with chronic obstructive pulmonary disease (COPD) when compared to placebo treatment

Combinations of two classes of medication in one inhaler have been developed to treat people with COPD. Two types of combined inhaler exist currently: budesonide/formoterol (BDF - 'Symbicort'), and fluticasone/salmeterol (FPS - 'Advair' or 'Seretide'). The results of the studies showed that combined inhalers were effective and reduced the frequency of exacerbations compared with placebo medication to a level of three quarters of the previous rates. The patients included in these trials had on average 1-2 exacerbations per year which means that treatment with combination therapy would lead to a reduction of one exacerbation every two to four years in these individuals. Combination therapy led to a reduction in mortality over three years, and also led to improvements in lung function and symptoms. However, there was an increased risk of pneumonia associated with combined inhalers, and further monitoring of this outcome in future trials would provide valuable information for consumers and clinicians. Future research is required to show whether there is a difference between combination inhalers with different strengths of inhaled corticosteroids.

 

摘要

背景

合併皮質類固醇及長效beta促效劑於同一吸入器與安慰劑作比較其治療慢性阻塞性肺病之效果

長效beta促效劑及吸入式皮質類固醇兩者均在指引中被建議用作治療慢性阻塞性肺病。將其合併於同一吸入器中同時使用可促進用藥的遵從度並改良效益。

目標

評估合併吸入式皮質類固醇及長效beta促效劑與安慰劑相較，在治療成人慢性阻塞性肺病之效益。

搜尋策略

我們搜尋Cochrane Airways Group Specialised Register of trials。最近一次的搜尋日期是2007年4月。

選擇標準

若為隨機雙盲的研究則會被納入。研究可比較任何吸入式皮質類固醇及長效beta促效劑配方及安慰劑。

資料收集與分析

兩位作者獨立地評估試驗的品質及摘錄數據。一位作者輸入數據。

主要結論

有11項研究符合納入標準(6427名參與者接受隨機分配治療)。有兩種不同的組合配方(fluticasone/salmeterol及budesonide/formoterol)被使用。研究的品質良好。Fluticasone/salmeterol及budesonide/formoterol兩者均減低惡化率。將兩種組合治療作聯合分析，顯示與安慰劑相較呈現較少的惡化RR：0.74(95% CI 0.7至0.8)。這些效應的臨床影響是依據病人所經驗的惡化頻率而定，被納入這些試驗的病人每年平均惡化1至2次，這表示合併治療可導致這些病人每2至4年減少1次惡化。死亡率在整體中也減少，但主要是TORCH所呈現的結果，而budesonide/formoterol則需有進一步的研究。在TORCH試驗中以安慰劑組之基線風險為15.2%，三年減少一名死亡所需治療人數為36(95% CI 21至258)，兩種治療在健康狀態的測量項目中均有統計學上的意義，但這些觀察到的差異在臨床上的重要性仍有待解讀。症狀及肺功能評估皆以合併治療為優。使用合併藥物吸入器者肺炎的風險增加。在TORCH試驗中以安慰劑組的基線風險為12.3%，三年多一例肺炎所需治療人數為13(95% CI 9至20)。較少使用合併吸入器的病人因不良事件或缺乏療效而退出研究。

作者結論

與安慰劑相較，合併治療可有意義地減少四分之一的惡化率。自TORCH試驗提供額外的數據而顯著地減少總死亡率。增加肺炎風險受到關注，未來研究對此項結果提供更佳的報告將有所幫助。為要對此單一吸入器作合併治療的效果有更明確的結論，需要有更多的數據，特別是不同劑量的吸入式類固醇導致之不良事件與效益的概況。

翻譯人

本摘要由中國醫藥大學附設醫院陳祖裕翻譯。

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

總結

吸入式皮質類固醇及長效beta促效劑的合併治療，在與安慰劑相較下，能減少慢性阻塞性肺病(COPD)患者之惡化及改善生活品質。合併兩類藥物於單一吸入器已發展出來用於治療COPD患者。目前有兩型合併吸入器：budesonide/formoterol(BDFymbicort)及fluticasone/salmeterol(FPS dvair或″ Seretide)。與安慰劑相較的研究顯示合併吸入器是有效的且可減少惡化頻率至患者先前四分之三的水平。被納入這些試驗的病人每年平均有二至三次的惡化，這表示合併治療對這些病人每2至4年減少一次惡化。在三年的追蹤顯示合併治療可減少死亡率，且能改善肺部功能和症狀。然而，合併式吸入器卻伴隨肺炎風險的增加，而在未來的試驗對此結果作進一步的監測將可提供消費者及臨床醫師有價值的資料。未來研究須呈現出不同強度的吸入式皮質類固醇的合併吸入器之間是否有所差別。