【medical-news】沙美特罗可能增加哮喘病人发生严重不良事件的危险
发布于 2008-08-10 · 浏览 1659 · IP 安徽安徽
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July 18, 2008 — Salmeterol increases the risk for serious adverse events in patients with asthma, according to a review published in the July 16 Online First issue of the Cochrane Database of Systematic Reviews.
"Epidemiological evidence has suggested a link between beta-agonists and increases in asthma mortality," write Christopher J. Cates, from St. George's, University of London, London, United Kingdom, and Matthew J. Cates, from Bristol Royal Infirmary, Bristol, United Kingdom. "There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta2-agonists are safe. 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."
The authors identified trials using the Cochrane Airways Group Specialised Register of trials through October 2007, consulted Web sites of clinical trial registers for unpublished trial data, and reviewed US Food and Drug Administration submissions regarding salmeterol. Inclusion criteria were controlled, parallel-design, clinical trials in patients of any age and asthma severity, provided these trials randomized patients to treatment with regular salmeterol and were of at least 12 weeks' duration. Participants were permitted concomitant use of inhaled corticosteroids, provided this was not part of the randomized treatment regimen.
Both authors independently selected trials for inclusion in the review. One author extracted outcome data, including unpublished data on mortality rates and serious adverse events, and the second author checked these data.
Identified trials meeting criteria included 26 trials comparing salmeterol vs placebo and 8 trials comparing salmeterol vs salbutamol. These enrolled a total of 62,630 participants with asthma, of whom 2380 were children. No serious adverse event data could be obtained in 6 trials enrolling a total of 2766 patients.
Although all-cause mortality rate was higher with regular salmeterol vs placebo, the difference was not significant (odds ratio [OR], 1.33; 95% CI, 0.85 - 2.10). Compared with placebo, nonfatal serious adverse events were significantly increased with regular salmeterol (OR, 1.14; 95% CI, 1.01 - 1.28). For every 188 people treated with regular salmeterol, 1 extra serious adverse event occurred at 28 weeks (95% CI, 95 - 2606). Evidence was insufficient to determine whether the risk in children is higher or lower vs adults.
Compared with regular salbutamol, regular salmeterol was not associated with a significant increase in fatal or nonfatal serious adverse events in patients not taking inhaled corticosteroids.
Individual patient data from a nationwide surveillance study were combined with those from the Salmeterol Multi-Center Asthma Research Trial study, showing that in patients who were not taking inhaled corticosteroids, there was a significant increase in the risk for asthma-related death with regular salmeterol vs regular salbutamol or placebo (OR, 9.52; 95% CI, 1.24 - 73.09).
For patients taking inhaled corticosteroids, the CI was too wide to rule out an increase in asthma mortality rate in this group.
"In comparison with placebo, we have found an increased risk of serious adverse events with regular salmeterol," the reviewers write. "There is also a clear increase in risk of asthma-related mortality in patients not using inhaled corticosteroids in the two large surveillance studies."
Limitations of this review include selective reporting in that serious adverse events were not well reported in the journal publications but were available from the controlled trial register on the GlaxoSmithKline Web site, financial support for all but 1 of the included studies provided by GlaxoSmithKline, and use of independent outcome assessors in only the 2 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 it cannot be concluded that the inhaled corticosteroids abolish the risks of regular salmeterol," the reviewers write. "The adverse effects of regular salmeterol in children remain uncertain due to the small number of children studied."
Clinical implications of this review are that for patients with asthma that is poorly controlled with moderate doses of inhaled corticosteroids, additional salmeterol can give symptomatic benefit. However, this may be at the expense of an increased risk for serious adverse events and asthma-related mortality. Use of inhaled corticosteroids does not clearly reduce these risks.
"Therefore regular salmeterol should be discontinued if no symptomatic benefit is achieved and the manufacturers' advice not to increase the dose of salmeterol during exacerbations should be made clear," the reviewers conclude. "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."
Coch Database Syst Rev. Published online July 16, 2008.
Salmeterol May Increase Risk for Serious Adverse Events in Patients With Asthma
"Epidemiological evidence has suggested a link between beta-agonists and increases in asthma mortality," write Christopher J. Cates, from St. George's, University of London, London, United Kingdom, and Matthew J. Cates, from Bristol Royal Infirmary, Bristol, United Kingdom. "There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta2-agonists are safe. 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."
The authors identified trials using the Cochrane Airways Group Specialised Register of trials through October 2007, consulted Web sites of clinical trial registers for unpublished trial data, and reviewed US Food and Drug Administration submissions regarding salmeterol. Inclusion criteria were controlled, parallel-design, clinical trials in patients of any age and asthma severity, provided these trials randomized patients to treatment with regular salmeterol and were of at least 12 weeks' duration. Participants were permitted concomitant use of inhaled corticosteroids, provided this was not part of the randomized treatment regimen.
Both authors independently selected trials for inclusion in the review. One author extracted outcome data, including unpublished data on mortality rates and serious adverse events, and the second author checked these data.
Identified trials meeting criteria included 26 trials comparing salmeterol vs placebo and 8 trials comparing salmeterol vs salbutamol. These enrolled a total of 62,630 participants with asthma, of whom 2380 were children. No serious adverse event data could be obtained in 6 trials enrolling a total of 2766 patients.
Although all-cause mortality rate was higher with regular salmeterol vs placebo, the difference was not significant (odds ratio [OR], 1.33; 95% CI, 0.85 - 2.10). Compared with placebo, nonfatal serious adverse events were significantly increased with regular salmeterol (OR, 1.14; 95% CI, 1.01 - 1.28). For every 188 people treated with regular salmeterol, 1 extra serious adverse event occurred at 28 weeks (95% CI, 95 - 2606). Evidence was insufficient to determine whether the risk in children is higher or lower vs adults.
Compared with regular salbutamol, regular salmeterol was not associated with a significant increase in fatal or nonfatal serious adverse events in patients not taking inhaled corticosteroids.
Individual patient data from a nationwide surveillance study were combined with those from the Salmeterol Multi-Center Asthma Research Trial study, showing that in patients who were not taking inhaled corticosteroids, there was a significant increase in the risk for asthma-related death with regular salmeterol vs regular salbutamol or placebo (OR, 9.52; 95% CI, 1.24 - 73.09).
For patients taking inhaled corticosteroids, the CI was too wide to rule out an increase in asthma mortality rate in this group.
"In comparison with placebo, we have found an increased risk of serious adverse events with regular salmeterol," the reviewers write. "There is also a clear increase in risk of asthma-related mortality in patients not using inhaled corticosteroids in the two large surveillance studies."
Limitations of this review include selective reporting in that serious adverse events were not well reported in the journal publications but were available from the controlled trial register on the GlaxoSmithKline Web site, financial support for all but 1 of the included studies provided by GlaxoSmithKline, and use of independent outcome assessors in only the 2 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 it cannot be concluded that the inhaled corticosteroids abolish the risks of regular salmeterol," the reviewers write. "The adverse effects of regular salmeterol in children remain uncertain due to the small number of children studied."
Clinical implications of this review are that for patients with asthma that is poorly controlled with moderate doses of inhaled corticosteroids, additional salmeterol can give symptomatic benefit. However, this may be at the expense of an increased risk for serious adverse events and asthma-related mortality. Use of inhaled corticosteroids does not clearly reduce these risks.
"Therefore regular salmeterol should be discontinued if no symptomatic benefit is achieved and the manufacturers' advice not to increase the dose of salmeterol during exacerbations should be made clear," the reviewers conclude. "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."
Coch Database Syst Rev. Published online July 16, 2008.
Salmeterol May Increase Risk for Serious Adverse Events in Patients With Asthma
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