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Abstract & Commentary
Synopsis: Inhaled corticosteroids are the most effective pharmacologic agents in reducing exacerbations in asthmatics.
Source: Sin DD, et al. JAMA. 2004;292:367-376.
This paper is the product of a metanalysis. Sin and colleagues searched 3 major medical databases and consulted experts to identify trials evaluating pharmacologic treatment of asthma in adults. The review period was from January 1, 1980, until April 30, 2004. To be included in the analysis, trials had to be randomized, double-blind, include at least at 3 months of follow-up, and contain data about either exacerbations or change in forced expired volume in 1 second (FEV1), or both. Abstract reports and trials with poor follow-up were excluded. In general, an exacerbation was defined as an episode requiring oral or parenteral corticosteroids, emergency visits, hospitalization, or decrease in morning peak expiratory flow rates (PEFR). The analyses were conducted using Review Manager (from the Cochrane Collaboration), and controlled for many variables, including sample size, disease severity, and concomitant drug therapy. A varying number of trials were identified for each of the drug categories under investigation, but the numbers of participants from pooled studies was well over 2000 for each comparison.
Compared with placebo or short-acting beta agonists, inhaled corticosteroids were more effective in reducing asthma exacerbations (by 55%) and improving FEV1 (by 330 mL) than any other category of asthma medication. Long-acting beta agonists (LABA) reduced exacerbation rates by 25% and improved FEV1 by 330 units. In patients with persistent asthma symptoms despite inhaled steroids, the addition of LABA to inhaled steroids further reduced exacerbations (by 26%) compared with inhaled steroids alone, and this was better than doubling the inhaled steroid dose. The leukotriene modifiers reduced exacerbation rates by 41% and improved FEV1 by 250 units compared with placebo, but when directly compared with inhaled corticosteroids, these agents were inferior in reducing exacerbations or improving FEV1. When compared with the LABA (in patients already taking inhaled steroids), leukotriene modifiers were not significantly different. Recombinant monoclonal anti-IgE therapy was associated with a 45% reduction in exacerbations and improved FEV1 by 180 mL (in patients with positive allergy skin tests or other objective evidence of atopy). There are many caveats to this analysis, including the inability to evaluate long-term side effects of inhaled steroids (or any of the agents studied). Also of note is the fact that those studies evaluating LABA and steroids in combination included patients who were still symptomatic on steroids, so they cannot be generalized to steroid naïve patients. Those patients in the leukotriene modifier studies were proven to be allergic, and these results may not be generalizable to non-atopic asthmatic.
Comment by Barbara A. Phillips, MD, MSPH
Asthma is prevalent (5-12%),1 expensive ($11 billion per year in the United States)1,2 and deadly (4487 deaths in 2000).3 For reasons that are incompletely understood, both the prevalence and the death rate from asthma are increasing,1 despite a truly impressive expansion in our pharmacologic armamentarium and an NIH-backed health education effort.4 About 20% of asthmatics consume 80% of the resources expended on asthma; these patients are more likely to die and have the most frequent exacerbations.2,4 Thus, reduction in exacerbations is a critical aspect of therapeutic efficacy.
All of the drugs included in this metanalysis reduced the risk of exacerbations compared with placebo or short-acting beta agonists, but inhaled corticosteroids are clearly the most effective. Although the studies included in this metanalysis were not consistently long enough to compare long-term side effects of these agents with each other, inhaled beta agonists are associated with an increased risk of cardiac events,5,6 which does not appear to be the case with other agents. On the other hand, inhaled steroids, especially at high doses, may be associated with bone demineralization, cataracts, glaucoma, and adrenal suppression.7,8
The studies reviewed did not include enough long- term data for Sin et al of this metanalysis determine whether any agent reduced asthma-related mortality, but other observational studies suggest that inhaled steroids, but not other agents.9 In sum, as Sin et al put it, there is ". . . a wealth of evidence supporting the use of inhaled corticosteroids in low doses and first-line therapy for adult patients who require more than an occasional use of short-acting B2 agonistics for control of their disease."
So, how often does this happen? In an Internet survey of asthma treatment in Sweden, Jenson found that short-acting beta-agonists were used by 67% and inhaled steroids by 59% of those with daily symptoms.10
The reasons for our failure to optimally treat asthma are probably multiple, but chief among them is the difficulty in maintaining burdensome treatment to prevent a bad outcome. Use of antihypertensives or lipid-lowering agents are cases in point; compliance with these agents is relatively poor, despite strong evidence that they prevent bad outcomes, and despite the fact that they are pills, which are much less cumbersome to use than are inhaled medications. Our patients don't want to use an inhaler (or multiple inhalers) daily or several times a day when they are asymptomatic. But the data are clear that we need to work harder to try to get our asthmatics to do this, especially if they have exacerbations. The risk and cost of a single exacerbation generally outweighs the burden of daily preventive therapy.
Dr. Phillips, Professor of Medicine, University of Kentucky, Director, Sleep Disorders Center, Samaritan Hospital, Lexington, KY, is Associate Editor of Internal Medicine Alert.
1. Mannino DM, et al. MMWR CDC Surveill SUM. 1998;47:1-27.
2. Weiss KB, Sullivan SD. J Allergy Clin Immunol. 2001;107:3-8.
3. National Center for Health Statistics. Asthma prevalence, health care use and mortality, 2000-2001. www.cdc.gov/nchs/.
4. National Institutes of Health Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention: NHLBI/WHO Workshop Report. Bethesda, MD: National Heart, Lung and Blood Institute; January 1995. NIH Publication 02-3659.
5. Salpeter SR, et al. Drugs Aging. 2004;21:405-414.
6. Lemaitre RN, et al. Am J Med. 2002;113:711-716.
7. Wong CA, et al. Lancet. 2000;355:1399-1403.
8. Pasalacqua G, et al. Allergy. 2000;55:16-33.
9. Suissa S, et al. N Engl J Med. 2000;343:332-336.
10. Janson C, Wjst M. J Asthma. 2004;41:49-55.