Asthma in US Seniors: Part 2. Treatment. Seeing Through the Glass Darkly

REVIEW

Asthma in US Seniors: Part 2. Treatment. Seeing Through the Glass Darkly Richard D. deShazo, MD,a J. Eric Stupka, MDb a

Divisions of Clinical Immunology-Allergy and Geriatrics, Department of Medicine, University of Mississippi Medical Center, Jackson; Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Texas Health Sciences Center at San Antonio, San Antonio. b

ABSTRACT BACKGROUND: We sought to identify the best evidence for treatment of asthmatic patients aged 65 years or more. METHODS: We used computer-assisted searches to identify randomized, controlled trials for asthma in the elderly that were published in English between 1950 and 2008. RESULTS: Small trials of an inhaled corticosteroid versus a leukotriene antagonist and an oral beta2-agonist versus placebo compose the controlled trial data on asthma therapy in seniors. Epidemiologic evidence suggests that the side effects of corticosteroids and beta-agonists may be more common in the elderly than in younger populations. CONCLUSION: Seniors with asthma or comorbid conditions that are common in the elderly have been systematically excluded from asthma treatment trials. There is no compelling evidence to demonstrate the superiority of any pharmacologic therapy in these asthmatic patients. Evaluation of response to asthma treatment in clinical trials remains primarily symptom-based when symptoms have been shown to underestimate the severity of disease in seniors. © 2009 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2009) 122, 109-113 KEYWORDS: Aging; Asthma; Elderly; Obstructive lung disease; Treatment

We sought to identify the best evidence for treatment in the growing population of adults with asthma who are aged more than 65 years and to place those data in the context of the present treatment recommendations.

MATERIALS AND METHODS We searched the PubMed/MEDLINE databases and included citations from 1950 to 2008. Our search strategy combined Medical Subject Headings or the text words for asthma, humans, English, aged (65⫹years), and the publication type: randomized controlled trial. To identify studies exclusive to the target population, we excluded the age groups: child, adolescent, adult (19-44 years), or middleaged (45-64 years). In addition, we searched databases speFunding: none. Conflict of Interest: none. Requests for reprints should be addressed to Richard D. deShazo, MD, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216. E-mail address: [email protected]

0002-9343/$ -see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2008.09.019

cific to clinical trials. These sources included the Cochrane Database of Systematic Reviews (established 1994), the Cochrane Central Register of Controlled Trials (1991 to 2008), and the Database of Abstracts of Reviews of Effects (DARE) (1991 to the present). Our search strategy for these databases was composed of variations on the text words for asthma and the aged or elderly. Finally, we reviewed 5 published asthma treatment guidelines.1-5

RESULTS Results of Literature Review Our review focused on those studies specifically designed to investigate asthma in elderly asthmatic patients, rather than larger asthma studies that included small subsets of elderly patients. A PubMed search for randomized controlled studies yielded no results. The search of the Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and DARE revealed 35 citations remained: 2 from DARE, 2 from the Cochrane Central Register of Controlled Trials, and 31 from the Cochrane Database of Sys-

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tributed in part to the systematic exclusion of the elderly and tematic Reviews. These articles were further screened to persons with medical conditions common to the elderly from eliminate studies that did not focus on asthma in the elderly clinical trials of asthma therapy. but simply included asthma, elderly, or aged somewhere in Similar consensus recommendations for treatment of the text of the article. When the search was completed, adult asthmatic patients were published in 1997 and 2007.2,4 using all databases, we found only 4 controlled studies that The 2007 Expert Panel Report 3 focused exclusively on asthma in included a section, “Special Issues patients aged more than 65 years. for Older Adults,” to specifically Two studies focused on pharmaCLINICAL SIGNIFICANCE address asthma in seniors.4 Becotherapy, one on a beta2-agonist6 and the other on a leukotriene recause of the high prevalence of ● The population of seniors with asthma ceptor antagonist.7 The largest of chronic bronchitis and emphyis rapidly increasing in the United these studies enrolled 73 patients.6 sema among the elderly, a 2- to States. One study focused on medication 3-week trial of systemic cortico● These patients have a high level of mordelivery systems,8 and one study steroids was suggested to detect bidity and mortality from their asthma. focused on exercise testing.9 The “significant reversibility of airway published randomized, controlled disease” in patients thought to ● Seniors with asthma have been extreatment trials of asthma included have asthma who fail to demoncluded from clinical trials of asthma small numbers of individuals aged strate reversibility on pulmonary management by their age or comorbid more than 65 years, whereas the function testing. Because seniors conditions. largest trials in adult patients inhave decreased awareness of cluded patients with both asthma bronchoconstriction, decreased ● We present evidence that a new apand chronic obstructive pulmophysiologic responses to hypoxproach to this chronic disease is nary disease (COPD). Thus, the emia and hypercapnia, and more warranted. information to follow was, for the advanced airway obstruction than younger asthmatic patients, pulmost part, derived from less rigormonary function testing could be ous data. more appropriate to use than symptoms as the primary guide for treatment.11-14

PRESENT TREATMENT OF ASTHMA IN SENIORS Asthma Guidelines

Which Medications, When?

Asthma treatment guidelines are symptom based (Table 1). Because most older adult asthmatic patients seem to be undertreated, what is the best treatment?10 The 1996 National Asthma Education and Prevention Program Report, Considerations for Diagnosis and Managing Asthma in the Elderly, concluded that “no new guidelines for the management of asthma in the elderly are necessary or possible” because more detail related to the diagnosis, pharmacologic therapy, and asthma education was necessary.5 The lack of an evidence-based approach to asthma in the elderly was at-

The 2007 Expert Panel Report 3 included special treatment concerns about the more prominent adverse effects of asthma medications in seniors and the potential deleterious effects of drugs used to treat comorbid conditions on asthma management (Table 2).4

Table 1 Impairment Components Recommended for Use in the Assessment of Severity and Control of Asthma in Adults by the Expert Panel Symptoms Night-time awakenings Interference with normal activity Short-acting beta2-agonists Other FEV1 or peak flow Validated questionnaires FEV1 ⫽ forced expiratory volume in 1 second; PEFR ⫽ peak expiratory flow rate. Adapted from National Heart, Lung, and Blood Institute Expert Panel Report 3: Guidelines for Diagnosis and Management of Asthma, page 345.4 Symptoms Nocturnal FEV1/PEFR.

Beta-Agonists Beta-adrenergic agonist medications have been surrounded in controversy since the early 1970s.15 Hypokalemia, QT prolongation, and tachycardia occur in association with these agents.16 Clinical trials have not specifically addressed the use of short- or long-acting beta-agonists in elderly asthmatic patients. This is unfortunate, because the most worrisome side effects of these agents involve cardiac events, particularly arrhythmias. A meta-analysis of 33 randomized placebo-controlled trials investigated the link between long and short-acting beta2-agonist medications and cardiovascular events in patients with obstructive lung disease.17 The analysis included several heterogeneous studies, the largest of which contained 1068 patients and the smallest of which contained only 8 patients. Participants’ ages ranged from 11 to 67 years, with a trend toward younger patients in most trials. Five of the studies focused on older patients, but all of the patients in those studies had COPD rather than asthma. The results of this meta-analysis showed an increased risk of adverse cardiovascular events in pa-

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Table 2 Special Issues for Older Adults Published in the 2007 Asthma Guidelines Assessment Treatment

Importance of pulmonary function testing to demonstrate reversibility Concerns about beta2-agonist response and side effects of beta2-agonists, theophylline, and systemic corticosteroids Possibility that co-administration of an inhaled beta2-agonist and anticholinergic may be beneficial Concerns about osteoporosis with inhaled corticosteroids, exacerbation of asthma by medications for comorbid conditions, or technical problems with inhalation devices

Adapted from Section 4. Managing Asthma Long Term—Youth ⬎ 12 years of Age and Adults. National Heart, Lung, and Blood Institute Expert Panel Report 3: Guidelines for Diagnosis and Management of Asthma.4

tients receiving beta-agonists that was thought to be related to the increased heart rates and hypokalemia.17 There was a statistically significant increase in “minor” cardiovascular events, such as sinus tachycardia. The relative risk for “major” cardiovascular events (eg, other arrhythmias, congestive heart failure, or acute coronary syndromes) was 1.66 and did not reach statistical significance. Because almost all of the studies excluded patients with known cardiovascular disease, the risk of adverse events in the elderly is likely underestimated in this analysis. The Salmeterol Multicenter Asthma Research Trial investigated the possible link between long-acting beta2-agonists and respiratory-related deaths in asthmatic patients aged 12 years or more.18 There was a small but significant increase in respiratory-related deaths in study subjects using long-acting beta2-agonists without inhaled corticosteroids compared with placebo. This occurred primarily in African Americans.4

Anticholinergic Medications Concerns about beta2-agonists and the possibility of some fixed bronchoconstriction in this population make anticholinergic medications of special interest.19 A Cochrane review analyzed data from 22 studies involving the use of inhaled anticholinergic agents for maintenance therapy of chronic asthma in adults.20 No study contained only adults aged more than 65 years. There were 2 arms to the Cochrane review. The first analysis compared the effects of inhaled anticholinergic medications with placebo and included 13 studies and 205 individuals. Patients’ ages ranged from 18 to 77 years. There were small but statistically significant improvements in daytime dyspnea and peak flow measurements in those patients treated with inhaled anticholinergic agents compared with placebo. The second arm of the study, composed of 9 studies and 440 patients, compared anticholinergic medications plus a short-acting beta2-agonist versus a short-acting beta-agonist alone. There was no difference between these regimens in the improvement of symptoms or

111 peak flow rates. Thus, inhaled anticholinergic agents provided symptomatic improvement that was substantiated by improvement of peak flow when compared with placebo, but the combination of inhaled anticholinergics with beta2agonists was unlikely to provide significant additional benefit in maintenance therapy. These data suggest that anticholinergic agents require evaluation as quick-relief medications in seniors who cannot tolerate short-acting beta-agonists. Although the combination of inhaled anticholinergic agents and short-acting beta2-agonists does not seem to be beneficial in maintenance therapy, the combination of shortacting beta-agonists and anticholinergic drugs may provide benefit in treatment of acute asthma exacerbations in emergency settings. A meta-analysis of 23 randomized control trials, none of which included only seniors, showed a reduction in hospitalization and improved spirometric function with combination therapy when compared with shortacting beta2-agonists alone.21 On the basis of this evidence, the 2007 asthma guidelines recommend combining inhaled ipratropium with short-acting beta2-agonist therapy in moderate or severe asthma exacerbations.4 Patients with more severe obstruction may benefit most, a finding that could be particularly important in older asthmatic patients.21

Corticosteroids There are no controlled trials confirming the benefits of inhaled maintenance corticosteroid therapy in elderly asthmatic patients. There is some evidence that inhaled corticosteroids improve both morbidity and mortality in patients with obstructive lung disease who are aged more than 65 years. A retrospective cohort study of 22,620 patients aged more than 65 years who were discharged from the hospital after COPD exacerbations found that those discharged with inhaled corticosteroids had 24% fewer repeat hospitalizations for COPD than those who were not.22 There also was a 29% reduction in all-cause mortality with inhaled corticosteroid treatment. Inhaled formulations of corticosteroids have some systemic absorption, so the potential for side effects is present. An analysis from several cross-sectional and retrospective cohort studies, none of which focused specifically on asthmatic patients aged more than 65 years, found that adult patients with asthma in those studies did not sustain a significant loss of bone mineral density from inhaled corticosteroid use.23 However, the authors conceded that adverse effects may be seen only after many years of high-dose inhaled corticosteroid use. A case-control study of 38,325 individuals aged 66 years or more using inhaled or nasal glucocorticoids, reported an increased risk (odds ratio 1.44; 95% confidence limit, 1.01-2.06) of ocular hypertension and open-angle glaucoma with prolonged administration of high doses of inhaled corticosteroids.24 A case-control study of 3677 patients with cataracts and 21,868 control subjects aged 70 years or more reported an increased risk for cataracts (odds ratio 3.40; 95% confidence limit, 1.49-7.76) after more than 2 years of daily high-dose (⬎1 mg) inhaled beclomethasone or budesonide.25

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Concerns over costs (because there are no generic inhaled corticosteroids for asthma in the United States) and adverse effects in elderly populations likely contribute to underuse of inhaled corticosteroids in seniors. A retrospective cohort study of 6254 asthmatic patients found that 40% of patients discharged from the hospital after asthma exacerbations had not received inhaled corticosteroids by the time of discharge.26 The expert panel concluded that potential side effects of inhaled corticosteroids in elderly patients are offset by the efficacy of inhaled steroids in asthma treatment.4 The guidelines suggested spacer devices, the lowest possible dose of inhaled corticosteroids, and postinhalation mouth rinsing to minimize systemic absorption. The expert panel also suggested that calcium and vitamin D supplementation be considered to prevent osteoporosis.

Leukotriene Receptor Antagonists The effect of age was a prospectively evaluated primary end point in a 4-week open-label trial of zafirlukast that included 321 asthmatic patients aged 66 years or more.27 Approximately two thirds of the elderly asthmatic patients were receiving an inhaled corticosteroid and some form of an inhaled beta-agonist. The study excluded individuals with hepatic dysfunction or those receiving warfarin or betablockers. There were statistically significant improvements in symptoms and morning peak expiratory flow with zafirlukast, although less so than those seen in younger groups. Side effects in seniors were only slightly more common than in younger adults (17.5% vs 18.8%). A small controlled study from Japan found that the oral leukotriene antagonist, pranlukast, was equal in efficacy to inhaled fluticasone and was preferred by the elderly patients.7

Anti-immunoglobulin-E Therapies Monoclonal antibodies against immunoglobulin-E are a novel therapy for difficult to control asthma. A review of pooled analysis data from 7 randomized, controlled studies evaluated the effectiveness of omalizumab on asthma exacerbations in 2511 asthmatic patients aged 6 to 75 years.28 Omalizumab use was associated with a reduction of asthma exacerbations by 38% and emergency department visits by 47%. Although subgroup analysis showed beneficial effects among all age groups, improvements in patients aged more than 65 years did not reach statistical significance. This could reflect the fact that only 241 treated study subjects were aged more than 65 years. There are no controlled trials of allergen immunotherapy in elderly asthmatic patients.

Medicine Delivery Systems in Seniors with Asthma Some observational studies have suggested that seniors without cognitive impairment have difficulty with the use of various inhalation devises used for medication delivery in asthma,29 whereas others suggest there is little effect of age, asthma, or COPD on metered dose inhaler (MDI) technique.30 There are no large randomized, controlled trials to

address these issues in seniors. However, 2 systematic reviews of controlled trials and other systematic reviews in adults with asthma and COPD provide some insight. One study found no differences in treatment responses for inhaled corticosteroids or beta-agonists delivered by MDIs compared with chlorofluorocarbon-free inhalers using hydrofluoroalkanes, dry powder inhalers, autohaler devices, or nebulizers.31 A second study, which accepted 59 of an available 394 randomized controlled trials in patients with asthma and COPD, showed no differences in effectiveness among MDIs, MDIs with spacers or holding chambers, dry powder inhalers or nebulizers for inhaled beta-agonists, anticholinergic drugs, or corticosteroids.32 The study did recommend consideration of “patient age and the ability to use the selected device adequately” among the variables for device selection. The limited data available suggest that the ability to learn inhaler techniques in the elderly is more related to cognitive function than to age.33

DISCUSSION Although additional studies may be available in proprietary or archival sources, it is clear that there are few randomized, controlled treatment trials in seniors to support present recommendations for treatment. In this regard, limited progress has been made in providing the evidence required to make the treatment of asthma evidence based (Table 3).5 There is some evidence for the effectiveness of inhaled corticosteroids in chronic asthma in the elderly, but little is

Table 3 Research Recommendations for Understanding Asthma in Seniors from the 1996 National Asthma Education and Prevention Program Working Group Report Increase knowledge of epidemiology Clarify familial and genetic factors Evaluate immune factors Better understand relationship between histopathology and fixed obstruction Understand cellular and molecular mechanisms of airway inflammation Evaluate differences in function, disease severity, comorbidity, emotional and cognitive status, and treatment expectations among younger and older asthmatic patients Determine the specificity and sensitivity of pulmonary function tests in patients Determine the sensitivity and specificity of bronchial provocation tests Evaluate MDI vs nebulizers in the emergency setting Evaluate long-term safety of inhaled corticosteroids Determine effectiveness of nedocromil Reevaluate exclusion criteria for elderly patients in clinical trials of asthma and statistical methods to control for confounding variables related to age MDI ⫽ metered dose inhaler. Summarized from the 1996 National Asthma Education and Prevention Program Working Group Report National Institutes of Health Publication 96-3662, page 51.

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known about their effects on osteoporosis and fracture risk or how often to monitor for cataracts and glaucoma while on therapy. The side effects of chronic use of both short- and long-acting beta2-agonists in the increasing population of elderly asthmatic patients require both investigation and vigilance with their present empiric use. Theophylline has a risk profile that might preclude use in the elderly.

CONCLUSIONS Evidence to support the effectiveness of the present approach to pharmacologic management of asthma in seniors is suboptimal because there are few prospective controlled trials on drug treatment. We hypothesize that the use of a symptom-based evaluation approach for asthma in the elderly when recognition of airways obstruction is blunted may be a confounding variable in drug trials and clinical practice. Objective surrogates for airway obstruction seem to be necessary to access therapeutic responses in the elderly and when symptom score data are suspect.

ACKNOWLEDGMENTS The authors thank Leigh Wright, BA, for assistance with the preparation of this article, and Helvi McCall Price, MLS, AHIP, for assistance with the literature search.

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