Intervention Review

Regular treatment with salmeterol for chronic asthma: serious adverse events

  1. Christopher J Cates1,*,
  2. Matthew J Cates2

Editorial Group: Cochrane Airways Group

Published Online: 20 JAN 2010

Assessed as up-to-date: 17 AUG 2011

DOI: 10.1002/14651858.CD006363.pub2

Database Title

Additional Information

How to Cite

Cates CJ, Cates MJ. Regular treatment with salmeterol for chronic asthma: serious adverse events. Cochrane Database of Systematic Reviews 2008, Issue 3. Art. No.: CD006363. DOI: 10.1002/14651858.CD006363.pub2.

Author Information

  1. 1

    St George's, University of London, Population Health Sciences and Education, London, UK

  2. 2

    Torbay Hospital, Torquay, UK

*Christopher J Cates, Population Health Sciences and Education, St George's, University of London, Cranmer Terrace, London, SW17 0RE, UK. ccates@sgul.ac.uk.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 20 JAN 2010

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Abstract

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. 摘要

Background

Epidemiological evidence has suggested a link between beta2-agonists and increases in asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta2-agonists are safe.

Objectives

The aim of this review is to assess the risk of fatal and non-fatal serious adverse events in trials that randomised patients with chronic asthma to regular salmeterol versus placebo or regular short-acting beta2-agonists.

Search methods

We identified trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trial registers for unpublished trial data and FDA submissions in relation to salmeterol. The date of the most recent search was August 2011.

Selection criteria

We included controlled parallel design clinical trials on patients of any age and severity of asthma if they randomised patients to treatment with regular salmeterol and were of at least 12 weeks' duration. Concomitant use of inhaled corticosteroids was allowed, as long as this was not part of the randomised treatment regimen.

Data collection and analysis

Two authors independently selected trials for inclusion in the review. One author extracted outcome data and the second checked them. We sought unpublished data on mortality and serious adverse events.

Main results

The review includes 26 trials comparing salmeterol to placebo and eight trials comparing with salbutamol. These included 62,815 participants with asthma (including 2,599 children). In six trials (2,766 patients), no serious adverse event data could be obtained.

All-cause mortality was higher with regular salmeterol than placebo but the increase was not significant (Peto odds ratio (OR) 1.33 (95% CI 0.85 to 2.08)). Non-fatal serious adverse events were significantly increased when regular salmeterol was compared with placebo (OR 1.15 95% CI 1.02 to 1.29). One extra serious adverse event occurred over 28 weeks for every 188 people treated with regular salmeterol (95% CI 95 to 2606). There is insufficient evidence to assess whether the risk in children is higher or lower than in adults. We found no significant increase in fatal or non-fatal serious adverse events when regular salmeterol was compared with regular salbutamol.

We combined individual patient data from the two largest studies (SNS: n=25,180 and SMART: n=26,355), as all the asthma-related deaths in adults occurred in these studies. In patients who were not taking inhaled corticosteroids, compared to regular salbutamol or placebo, there was a significant increase in risk of asthma-related death with regular salmeterol (Peto OR 6.15 95% CI 1.73 to 21.84). The confidence interval for patients who were taking inhaled corticosteroids is wide and cannot rule in or out an increase in asthma mortality in the presence of an inhaled corticosteroid (Peto OR 2.03 95% CI 0.82 to 5.00).

Authors' conclusions

In comparison with placebo, we have found an increased risk of serious adverse events with regular salmeterol. There is also a clear increase in risk of asthma-related mortality in patients not using inhaled corticosteroids in the two large surveillance studies. Although the increase in asthma-related mortality was smaller in patients taking inhaled corticosteroids at baseline, the confidence interval is wide, so we cannot conclude that the inhaled corticosteroids abolish the risks of regular salmeterol. The adverse effects of regular salmeterol in children remain uncertain due to the small number of children studied.

 

Plain language summary

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. 摘要

Does daily treatment with salmeterol result in more serious adverse events compared with placebo or a salbutamol?

Asthma is a common condition that affects the airways – the small tubes that carry air in and out of the lungs. When a person with asthma comes into contact with an irritant (an asthma trigger), the muscles around the walls of the airways tighten, the airways become narrower, and the lining of the airways becomes inflamed and starts to swell. This leads to the symptoms of asthma - wheezing, coughing and difficulty in breathing. They can lead to an asthma attack or exacerbation. People can have underlying inflammation in their lungs and sticky mucus or phlegm may build up, which can further narrow the airways. There is no cure for asthma; however there are medications that allow most people to control their asthma so they can get on with daily life.

Long-acting beta2-agonists, such as salmeterol, work by reversing the narrowing of the airways that occurs during an asthma attack. These drugs - taken by inhaler - are known to improve lung function, symptoms, quality of life and reduce the number of asthma attacks. However, there are concerns about the safety of long-acting beta2-agonists, particularly in people who are not taking inhaled corticosteroids to control the underlying inflammation. We did this review to take a closer look at the safety of people taking salmeterol daily compared to people on placebo or the short acting beta2-agonist salbutamol.

There was no statistically significant difference in the number of people who died during treatment with salmeterol compared with placebo or salbutamol. Because so few people die of asthma, huge trials or observational studies are normally required to detect a difference in death rates from asthma. There were more non-fatal serious adverse events in people taking salmeterol compared to those on placebo; for every 188 people treated with salmeterol for 28 weeks, one extra non-fatal event occurred in comparison with placebo. There was no significant differences in serious adverse events in people on salmeterol compared to regular salbutamol.

In order to obtain individual patient data on asthma deaths, we looked separately at mortality in two large trials on over 51,000 patients who were not taking inhaled corticosteroids, and found that there was an increase in the number of asthma-related deaths among people on salmeterol.

We conclude that, for patients whose asthma is not well-controlled on moderate doses of inhaled corticosteroids, additional salmeterol can improve symptoms but this may be at the expense of an increased risk of serious adverse events and asthma related mortality. Salmeterol should not be used as a substitute for inhaled corticosteroids, and adherence with inhaled steroids should be kept under review if separate inhalers are used. Salmeterol should not be taken by people who are not taking regular inhaled steroids due to the increased risk of asthma-related death.

 

摘要

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. 摘要

背景

規律使用salmeterol來治療慢性氣喘：嚴重的不良事件

流行病學證據顯示betaagonists 和氣喘死亡率增加有關，不過其原因以及長效型beta2agonists的安全性仍有爭議。

目標

本文旨在評估隨機分配患有慢性氣喘的病患，規律服用salmeterol、安慰劑或規律使用短效型beta2agonists，造成死亡和未致死嚴重不良事件的風險。

搜尋策略

利用Cochrane Airways Group Specialised Register of trials資料庫篩選出試驗，並連結臨床試驗登錄中心(clinical trial registers)的網頁來以獲得未發表的數據，並且確認FDA(美國食品藥物管理局(Food and Drug Administration)salmeterol相關的意見書，最近一次的檢索時間為2009年8月。

選擇標準

納入針對任何年齡且不論氣喘嚴重程度患者所設計，只要隨機給予患者規律性服用salmeterol至少12個月，並具有平行對照設計的試驗，即使是伴隨著ICS的使用也可以被允許，只要這不是隨機治療過程的一部份即可。

資料收集與分析

有2位作者分別選擇被納入回顧的試驗，由1位作者取出成果數據，並且由另一位作者進行確認，並搜尋未公開的死亡率和嚴重不良事件數據。

主要結論

本回顧納入了26個針對salmeterol與安慰劑進行比較的試驗，8個針對salmeterol與salbutamol進行比較的試驗，這些試驗總共納入了62630位氣喘患者(包括2380位幼童)，在6個試驗(包括2766位患者)中，並沒有取得嚴重的不良事件數據。 規律使用salmeterol比使用安慰劑引發的的全原因致死率高，但是死亡率的增加並不明顯(OR值為0.33，95％的CI介於0.85至2.10之間)。此外，相對於安慰劑來說，因為規律使用salmeterol而使得非致命不良事件的發生明顯增加，(OR值為0.14，95％的CI介於1.01至1.28之間)，每188位規律使用salmeterol28週以上的患者都會額外出現一個嚴重的不良事件(95％的CI介於95至2606之間)。證據不夠充分評估發生在幼童身上的風險比發生在成人身上的風險高或低。針對規律使用salmeterol和規律使用salbutamol進行比較，兩者之間在引發致命性或非致命性嚴重不良事件的機率並沒有明顯的增加。由SNS試驗取得的個別患者數據會與SMART試驗的數據進行結合，當患者並沒有服用ICS與規律使用salmeterol或安慰劑進行比較時可以發現，規律使用salmeterol會使得與氣喘有關的死亡率明顯增加(OR值為0.52，95％的信賴區間介於1.24至73.09之間)，因為使用ICS進行試驗時所得到的信賴區間過於寬廣，所以在這個群組中排除有關氣喘致死率增加的數據。

作者結論

與安慰劑相比，我們發現規律使用salmeterol會增加嚴重不良事件的風險。在2個大型的監測試驗中，沒有使用ICS的患者引發與氣喘有關死亡的風險也明顯的增加，雖然患者使用基本劑量ICS所引發與有關的死亡機率較小，但是因為信賴區間的範圍過於寬廣，所以使用ICS的風險可以低於規律使用salmeterol的結果並不能被納入結論中，因為針對幼童試驗的樣本數較少，所以目前仍無法確定幼童規律使用salmeterol所引發的不良事件項目。

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

相要於安慰劑，規律使用SALMETEROL會增加臨床上嚴重不良事件的風險: 考慮到使用LABA治療氣喘的安全性，本研究由針對規律使用salmeterol和安慰劑或salbutamol進行比較的臨床試驗，集結了所有有關於全原因引發不良事件(致死性和非致死性)的有用資訊。 與安慰劑相較，死亡率會因為使用salmeterol而增加，但是這樣的增加情形在統計學上並不具有顯著性。非致死的嚴重不良事件也會因為使用salmeterol而增加，相對於安慰劑組來說，每188位接受salmeterol治療28週以上的患者便會多出現一個非致命的不良反應，針對規律使用salmeterol和salbutamol的組別中並沒有發現顯著差異，沒有使用ICS的患者中，透過2個大型的監控試驗可以發現與氣喘有關的死亡率增加速率十分類似，對於氣喘未獲得良好控制且使用中劑量ICS的患者來說，額外使用salmeterol可以對於氣喘症狀的控制上有所幫助，但是卻有可能增加嚴重不良反應的風險和氣喘相關死亡率情況，風險並未因為使用ICS而明確的消除，所以如果這樣的治療並未對症狀有所幫助，且製造者並未明確建議在症狀惡化期間增加salmeterol的使用劑量，便不應該連續性的規律使用salmeterol，salmeterol不應該被當作ICS的替代藥劑，如果如果使用分離式吸入劑時，便應該維持吸入性類固醇的使用。

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