Am Fam Physician. 2009 Jun 1;79(11):957-958.
A middle-aged woman with daily coughing and wheezing from asthma requests an additional medication to help control her symptoms, but she is concerned about media reports that claim some medications may actually increase the risk of death from asthma.
Should salmeterol (Serevent) be used for long-term control of moderate to severe asthma symptoms?
Salmeterol may help improve asthma symptoms, but it should only be used as part of a comprehensive asthma management plan including inhaled corticosteroids and a short-acting beta agonist. There is currently insufficient evidence to confirm that salmeterol does not increase the risk of adverse events when used with inhaled corticosteroids for treatment of asthma. Current evidence is also insufficient to properly define the role of salmeterol for treatment of asthma in children.
Patients with daily asthma symptoms (e.g., coughing, wheezing, dyspnea, chest tightness) have moderate to severe disease. The National Heart, Lung, and Blood Institute recommends long-acting beta agonists (LABAs), such as salmeterol or formoterol (Foradil), plus inhaled corticosteroids, for long-term prevention and control of symptoms in moderate or severe persistent asthma.1
Adrenaline was the first beta agonist used for the relief of asthma symptoms, given subcutaneously in the early 1900s, then later by inhalation. In an effort to minimize adrenergic side effects, isoproterenol (Isuprel) and fenoterol (not available in the United States) were later introduced for asthma treatment. However, epidemiologic evidence suggested a link between the introduction of each of these three short-acting beta agonists and increased asthma mortality. The subsequent decrease in use of isoproterenol and fenoterol coincided with rising use of alternate beta agonists, including albuterol, and increased use of inhaled corticosteroids.2
LABAs were developed to allow longer-acting and more convenient symptom prevention and relief. Initial studies demonstrated beneficial effects of LABAs on lung function, symptoms, and quality of life, but there is concern about a possible increased risk of asthma mortality with LABAs.
In 2005, the U.S. Food and Drug Administration (FDA) called attention to a possible increased risk of worsening bronchospasm in some patients using LABAs for asthma treatment. In 2006, the FDA added a warning to the safety labeling for salmeterol and formoterol, stating that LABAs may increase the risk of asthma-related death.3,4
This Cochrane review's findings highlight the importance of proper patient education on the role of salmeterol in an asthma treatment plan.2 Salmeterol increases the risk of adverse events when compared with no asthma treatment; therefore, it must not be used alone as treatment for asthma. Salmeterol also is associated with increased risk of death from asthma in patients who are not taking inhaled corticosteroids, and, therefore, cannot be used as a replacement for inhaled corticosteroids for long-term asthma control.
Background: Epidemiological evidence has suggested a link between beta agonists and increases in asthma mortality. There has been much debate about possible causal links for this association, and whether regular (daily) long-acting beta agonists are safe.
Objectives: The aim of this review is to assess the risk of fatal and nonfatal serious adverse events in trials that randomized patients with chronic asthma to regular salmeterol (Serevent) versus placebo or regular short-acting beta agonists.
Search Strategy: Trials were identified using the Cochrane Airways Group Specialised Register of trials. Web sites of clinical trial registers were checked for unpublished trial data, and U.S. Food and Drug Administration submissions in relation to salmeterol were also checked. The date of the most recent search was July 2008.
Selection Criteria: Controlled parallel design clinical trials on patients of any age and severity of asthma were included if they randomized patients to treatment with regular salmeterol and were of at least 12 weeks in duration. Concomitant use of inhaled corticosteroids was allowed, as long as this was not part of the randomized treatment regimen.
Data Collection and Analysis: Two authors independently selected trials for inclusion in the review. Outcome data were extracted by one author and checked by the second author. Unpublished data on mortality and serious adverse events were sought.
Main Results: The review includes 26 trials comparing salmeterol with placebo and eight trials comparing it with albuterol. These included 62,630 participants with asthma (including 2,380 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 (odds ratio [OR] = 1.33; 95% confidence interval [CI], 0.85 to 2.10). Nonfatal serious adverse events were significantly increased when regular salmeterol was compared with placebo (OR = 1.14; 95% CI, 1.01 to 1.28). One extra serious adverse event occurred over 28 weeks for every 188 persons treated with regular salmeterol (95% CI, 95 to 2,606). There was insufficient evidence to assess whether the risk in children is higher or lower than in adults. No significant increase in fatal or nonfatal serious adverse events was found when regular salmeterol was compared with regular albuterol.
Individual patient data from the Serevent Nationwide Surveillance study have been combined with the results of the Salmeterol Multicenter Asthma Research Trial study. In patients who were not taking inhaled corticosteroids, compared with regular albuterol or placebo, there was a significant increase in risk of asthma-related death with regular salmeterol (OR = 9.52; 95% CI, 1.24 to 73.09). The CI for patients taking inhaled corticosteroids is too wide to rule out an increase in asthma mortality in this group.
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 it cannot be concluded that the inhaled corticosteroids abolish the risks of regular salmeterol. The adverse effects of regular salmeterol in children remain uncertain because of the small number of children studied.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (http://www.cochrane.org).
The absence of a statistically significant increased risk of death or adverse events is reassuring when salmeterol is compared with albuterol, or when salmeterol is used in conjunction with an inhaled corticosteroid. However, it is important for patients and physicians to be aware that no evidence was found indicating salmeterol would reduce asthma-related mortality, and the confidence interval did not exclude an increase in mortality.
Proper management of asthma can be complicated for patients. It may be inconvenient to always carry an inhaler for symptomatic relief. Patients with moderate to severe asthma may be confused by the different inhalers (with different colors and packaging) needed for each of their different asthma medications. Even well-educated patients may be easily confused as to which medication to use, when to use it, and for what purpose.
Patients with moderate to severe asthma must be educated continually on proper use of short-acting beta agonists, such as albuterol, for relief of acute asthma symptoms, and inhaled corticosteroids for long-term asthma prevention. Although salmeterol may provide additional long-term symptom relief, patients must be advised that this benefit comes with an associated increased risk of adverse events and may be associated with an increased risk of asthma-related death, especially if inhaled corticosteroids are not part of the asthma management plan. Patients also must be reminded to seek emergency care for escalating asthma symptoms unresponsive to usual outpatient treatment.
Address correspondence to William E. Cayley Jr., MD, at firstname.lastname@example.org. Reprints are not available from the author.
Author disclosure: Nothing to disclose.
1. National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR3): guidelines for the diagnosis and management of asthma. http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm. Accessed March 26, 2009.
2. Cates CJ, Cates MJ. Regular treatment with salmeterol for chronic asthma: serious adverse events. Cochrane Database Syst Rev. 2008;(3):CD006363.
3. U.S. Food and Drug Administration. Advair Diskus, Advair HFA, Brovana, Foradil, Perforomist, Serevent Diskus, and Symbicort information (long acting beta agonists). March 2006. http://www.fda.gov/cder/drug/infopage/LABA/default.htm. Accessed March 26, 2009.
4. U.S. Food and Drug Administration. FDA safety update: asthma medications. November 2008. http://www.fda.gov/consumer/updates/asthmameds051308.pdf. Accessed March 26, 2009.
The Cochrane Abstract is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Dr. Cayley presents a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a critique of the review. The practice recommendations in this activity are available at http://www.cochrane.org/reviews/en/ab006363.html.
The series coordinator for AFP is Clarissa Kripke, MD, Department of Family and Community Medicine, University of California, San Francisco.
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