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Low-Dose Inhaled Corticosteroid Therapy and Risk of Emergency Department Visits for Asthma
Don D. Sin, MD, MPH;
S. F. Paul Man, MD
Arch Intern Med. 2002;162:1591-1595.
ABSTRACT
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Background Patients who visit the emergency department (ED) because of asthma frequently
have a relapse. While the use of inhaled corticosteroids has been demonstrated
to improve asthma symptoms and lung function, it is not clear whether their
use after discharge from the ED reduces asthma relapse rates.
Objective To determine whether inhaled corticosteroid therapy reduces ED asthma
relapse rates.
Methods We analyzed ED visit and medication data on patients 5 to 60 years of
age who were enrolled in a government-sponsored drug plan and who visited
an ED because of asthma between April 1, 1997, and March 31, 1999, in Alberta,
Canada (N = 1293). Using a Cox proportional hazards model, we determined the
relative risk (RR) of relapse ED visits among users and nonusers of inhaled
corticosteroids after discharge from the ED. We also compared the RR of relapse
ED visits across different dose categories.
Results Users of inhaled corticosteroids after ED discharge had 45% fewer relapse
ED visits than did nonusers (adjusted RR, 0.55; 95% confidence interval [CI],
0.44-0.69). Low-, medium-, and high-dose therapies were associated with similar
reductions in the risk of relapse ED visits: low-dose therapy (RR, 0.52; 95%
CI, 0.39-0.68), medium-dose therapy (RR, 0.51; 95% CI, 0.34-0.76), and high-dose
therapy (RR, 0.67; 95% CI, 0.47-0.94).
Conclusions Inhaled corticosteroid therapy after ED discharge is associated with
a significant reduction in the risk of subsequent ED visits. Low-dose therapy
appears to be as effective as high-dose therapy. However, further studies
are needed to determine the optimal dosing regimen for inhaled corticosteroid
therapy for asthma.
INTRODUCTION
ASTHMA ACCOUNTS for nearly 2 million visits to the emergency department
(ED) per year, making it the leading cause of ED use among children and young
adults in the United States.1 Despite the "best"
in-hospital therapy, 30% of these patients will have a relapse within few
weeks to months of discharge, leading to recurrent use of EDs for rescue care
and necessitating frequent absenteeism from school or work.2
Moreover, once a relapse occurs, the risk of asthma-related morbidity and
mortality rises sharply.3
In randomized controlled trials, inhaled corticosteroid therapy has
been shown to increase lung function,4 to decrease
airway hyperresponsiveness,5 to reduce the
need for rescue bronchodilators,6 and to improve
asthma symptoms compared with treatment with placebo.4-6
Logically, inhaled corticosteroid therapy should also decrease the risk of
subsequent ED visits. However, the use of inhaled corticosteroids after ED
discharge remains controversial, as the published studies to date have produced
inconsistent and heterogeneous findings.7 The
inconsistent findings of published studies may in part be related to small
sample sizes and variable follow-up periods among these studies.7
Therefore, more data are needed to determine the utility of these medications
among patients with a recent ED visit for asthma.
Information concerning the effect of different doses of inhaled corticosteroids
on asthma exacerbation rates would also be useful. Recent studies suggest
that these medications, while efficacious, are also fraught with certain adverse
effects, including cataract formation,8-9
glaucoma,10 and bone demineralization,11 which occur in a dose-dependent fashion. Avoidance
of high-dose therapy, if it is not associated with better asthma control than
low-dose therapy, is desirable. A recently completed meta-analysis suggests
that low-dose therapy is as effective as high-dose therapy in reducing asthma
exacerbation rates and patient symptoms.12
However, owing to a number of methodological problems with the primary studies
included in this review,12 the relationship
between different dosing schedules of inhaled corticosteroids and clinical
outcomes in asthma remains unclear.
We used population-based data to determine whether long-term inhaled
corticosteroid therapy after ED discharge is associated with a lower risk
for subsequent visits to the ED. We also sought to compare ED relapse rates
among patients receiving low-, medium-, and high-dose therapies.
PATIENTS AND METHODS
STUDY POPULATION
We obtained ED discharge abstracts from Alberta Health and Wellness
through the Ambulatory Care Classification System database. Information from
this database included separations (discharges, hospital admissions, transfers,
or deaths) for all persons residing in the province of Alberta. For this study,
we included Alberta residents, 5 to 60 years of age, who had at least 1 ED
visit with asthma as the most responsible diagnosis from April 1, 1997, to
March 31, 1999. International Classification of Diseases,
Ninth Revision, Clinical Modification, codes
493.0, 493.1, and 493.9 were used to identify these patients.13
We chose this age cutoff to increase the diagnostic accuracy of the study
cohort.14 We further refined the study cohort
by including only patients who were enrolled in the government-sponsored supplementary
(nongroup) drug plan,15 as medication data
were available only for those residents. This group was composed mainly of
individuals (and their immediate family members) who were self-employed or
those who did not have supplementary drug coverage with their employer.15 We excluded those who died during the first (index)
ED visit or during the same hospitalization as part of the index visit. We
censored all ED visits that occurred after the first ED visit for each study
patient to avoid double counting of patients.
MEDICATION DATA
We merged the Ambulatory Care Classification System database with the
Alberta Blue Cross database to obtain information on medications prescribed
for the study cohort. All claims in this database contain a unique identification
number of the medication, as well as the quantity of drugs and the date dispensed.
For each study patient, we determined the use of all asthma medications (short-acting  2-agonists, ipratropium bromide, inhaled and oral corticosteroids, and
oral theophyllines) from April 1, 1997, to March 31, 2001. All medications
received before the patient's index ED visit were censored.
STUDY DESIGN
We followed up our study patients from the date of their first ED visit
for asthma to the date of a subsequent ED visit, or to March 31, 2001, whichever
came first. This ensured that all study patients had at least 2 years of potential
follow-up from their index ED visit. We considered a subsequent ED visit as
one in which asthma was the primary diagnosis for the visit.
Because Alberta Blue Cross provides data on the quantity of medications
dispensed rather than the daily dose, we imputed the average daily dose of
inhaled corticosteroids by using the following method: We first converted
all formulations of inhaled corticosteroids into beclomethasone dipropionate
equivalents based on equivalency calculations suggested by the Canadian Asthma
Consensus Report (Table 1).16 We then calculated the total dose of the first dispensing
of inhaled corticosteroids obtained by patients after their index ED visit.
We divided this sum by the elapsed number of days between the first and second
dispensings of these medications. For example, if a patient received 1 canister
of budesonide (200 µg per puff) containing 200 actuations during the
first pharmacy visit after the index ED visit, and if he or she did not refill
the next prescription for another 100 days, then the estimated average daily
dose for this patient was 500 µg/d. Based on this method, we categorized
the patients in our cohort into 5 mutually exclusive inhaled corticosteroid
categories: not dispensed, low dose ( 500 µg/d of beclomethasone
dipropionate or equivalent), medium dose (501-1000 µg/d), high dose
(>1000 µg/d), and indeterminate dose. The latter category included patients
who received only 1 dispensing of inhaled corticosteroids and, as such, we
could not estimate the daily dose of inhaled corticosteroids consumed by these
patients. This method of imputing average daily doses of medications has been
used previously.17
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Table 1. Dose Equivalencies for Various Inhaled Corticosteroids
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OTHER FACTORS
Comorbidities were determined using the Ambulatory Care Classification
System database. A modified Charlson comorbidity score was calculated for
each individual patient, using International Classification
of Diseases, Ninth Revision, Clinical Modification, codes in the 15 secondary-diagnosis fields.18
A Charlson comorbidity score of 0 denotes the absence of any comorbidities;
a higher number indicates an increasing burden of comorbidities.
STATISTICAL ANALYSIS
The means and SDs of continuous variables were compared using t tests. Ordinal and binary variables were compared using
a  2 test.
We defined inhaled corticosteroid users as patients who were receiving
low-, medium-, or high-dose therapy. Nonusers were patients who did not receive
any inhaled corticosteroid therapy during the follow-up period. Emergency
department visit rates between users and nonusers during the follow-up period
were compared using the Cox proportional hazards model. In this model, we
controlled for age, sex, Charlson comorbidity scores, whether patients were
hospitalized or discharged (home) from their index ED, and use of other asthma
medications (within the first 100 days of the index ED visit). We chose a
100-day frame because, in Alberta, pharmacies can fill prescriptions for a
maximum period of 100 days. We also used a Cox proportional hazards model
(with the same covariates) to determine the relationship between the average
daily doses and the risk of a subsequent ED visit in our cohort of patients.
All analyses were conducted with SAS software (Version 8.1; SAS Inc,
Carey, NC). All tests were 2-tailed, and P values
of less than .05 were considered.
RESULTS
STUDY POPULATION
We identified 1293 patients between 5 and 60 years of age who had at
least 1 ED visit for their asthma during the study period. Of these patients,
499 (38.6%) were men, and 158 (12.2%) were hospitalized during the index ED
visit. Only 20 (1.5%) patients had a Charlson comorbidity score of 1 or more.
The mean ± SD age of the cohort was 30.8 ± 17.7 years.
INHALED CORTICOSTEROID USE
Overall, 658 patients (50.9%) did not receive any inhaled corticosteroids
during the follow-up period; 241 (18.6%) received low-dose therapy; 96 (7.4%)
received medium-dose therapy; and 122 (9.4%) received high-dose therapy. We
could not calculate an average daily dose for 176 patients (13.6%) because
they received only 1 dispensing of inhaled corticosteroids during the follow-up
period. The baseline characteristics of those who did and did not receive
inhaled corticosteroids after ED discharge are shown in Table 2. Users of inhaled corticosteroids were older and more likely
to have received other asthma medications, including oral corticosteroids,
theophyllines, and ipratropium, during the first 100 days of follow-up. Since
these medications are generally reserved for treating those with moderate
to severe disease,16 it is likely that users
of inhaled corticosteroids had greater disease severity than nonusers.
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Table 2. Characteristics of Patients With Asthma Stratified According
to Use (or Nonuse) of Inhaled Corticosteroids*
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RISK OF SUBSEQUENT ED VISITS
During the follow-up period, 462 patients (35.7%) had a subsequent ED
visit for asthma. Crudely, inhaled corticosteroids were associated with a
36% (relative risk [RR], 0.64; 95% confidence interval [CI], 0.52-0.79) reduction
in the risk for a subsequent ED visit. After adjustment for all factors in
our model, users of inhaled corticosteroids after ED discharge had a 45% (RR,
0.55; 95% CI, 0.44-0.69) reduction in the risk for a subsequent ED visit compared
with nonusers of inhaled corticosteroids (Figure 1). Patients who received low-dose therapy had 48% (RR 0.52;
95% CI, 0.39-0.68) fewer subsequent ED emergency visits compared to nonusers.
Those receiving medium- and high-dose therapy also had fewer subsequent ED
visits (RR for medium dose, 0.51; 95% CI, 0.34-0.76; RR for high-dose 0.67;
95% CI, 0.47-0.94). Those in the indeterminate-dose group did not experience
any significant changes in their risk for subsequent ED visits compared with
nonusers (RR, 1.01; 95% CI, 0.78-1.32) (Table 3).
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Kaplan-Meier curve comparing proportion of patients with no subsequent
emergency department (ED) visits between users and nonusers of inhaled corticosteroids
after ED discharge (P<.001, Mantel log-rank test).
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Table 3. Relationship Between Subsequent Emergency Department (ED)
Visits and Inhaled Corticosteroid Therapy
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To determine the robustness of the relationship between inhaled corticosteroid
therapy and risk of a subsequent ED visit, we conducted a series of subgroup
analyses. Among those who received at least 1 dispensing of a bronchodilator
(ie, 2-adrenergics, ipratropium, or oral theophyllines),
users of inhaled corticosteroids were 45% less likely to experience a subsequent
ED visit than nonusers (RR, 0.55; 95% CI, 0.43-0.70). In this subgroup of
patients, low (RR, 0.53; 95% CI, 0.39-0.72), medium (RR, 0.48; 0.31-0.74),
and high (RR, 0.67; 95% CI, 0.46-0.98) dose therapy were all associated with
significant reductions in the risk for subsequent ED visits. A similar pattern
was observed when we restricted the analysis to patients who received oral
corticosteroid therapy within the first 100 days of the index ED visit. We
found that low (RR, 0.41; 95% CI, 0.26 -0.64), medium (RR, 0.46; 95% CI, 0.25-0.85),
and high (RR, 0.55; 95% CI, 0.34-0.88) dose therapy were all associated with
significant reductions in the risk for subsequent ED visits.
Since inhaled corticosteroid therapy before the index ED visit could
be a marker of more severe disease, we performed a subgroup analysis in patients
who did not receive any inhaled corticosteroids within 200 days before the
index ED date. In this "steroid-naive" group (n = 975), those who received
these medications after ED discharge had 49% fewer subsequent ED visits than
the nonusers (RR, 0.51; 95% CI, 0.32-0.76). Low, medium, and high doses were
associated with a 51% (RR, 0.49; 95% CI, 0.34-0.71), 44% (RR, 0.56; 95% CI,
0.34-0.92), and 48% (RR, 0.52; 95% CI, 0.31 0.89) reduction in the risk for
ED readmissions, respectively, in this subgroup of patients. Similar findings
were present in those who had used inhaled corticosteroids before the index
ED date (RR, 0.49; 95% CI, 0.39-0.68).
COMMENT
Our findings are consistent with a large body of evidence that inhaled
corticosteroid therapy produces clinical benefits for patients with asthma.19 In our study, users of inhaled corticosteroids had
45% fewer subsequent ED visits than nonusers, after adjustment for various
factors. However, we did not observe a dose-response relationship. Rates of
subsequent ED visits were similar among low-, medium-, and high-dose therapy
groups over a 2-year follow-up period.
Our findings provide new insights concerning the impact of inhaled corticosteroid
therapy on clinically important outcomes such as ED readmission rates that
prior randomized controlled trials have not been able to demonstrate. Because
prior research has focused on less sick asthmatic populations, risk of subsequent
visits to EDs could not be obtained. First, by targeting a sicker group of
patients, we were able to show an impressive benefit of inhaled corticosteroids
in reducing relapses to EDs, a finding that is consistent with the known effects
of these medications on lung mechanics and health outcomes of asthmatics.19 Second, owing to our large sample size and comprehensive
follow-up of patients, we were able to explore a dose-response relationship
between the use of inhaled corticosteroids and ED relapse rates. In the absence
of clear clinical data, some physicians may believe that "more is better"
when it comes to the use of inhaled corticosteroids in asthma. Our data, on
the other hand, suggest that even low doses are effective in lowering ED relapse
rates among persons with asthma.
Our findings are consistent with those of Hummel and Lehtonen,20 who showed that high-dose therapy offered no significant
advantages over low-dose therapy in reducing asthma symptoms, in the use of
on-demand rescue medications, or in improvement of lung function. These results
have been further supported by a recent meta-analysis that demonstrated only
marginal improvements in airway hyperresponsiveness but no appreciable benefits
on asthma symptoms or exacerbation rates with high-dose therapy (over low-dose
therapy).12
Because our study is observational in nature, relying on information
from administrative databases, confounding by indication is of concern. However,
users and nonusers of inhaled corticosteroids had similar rates of hospitalization
for their asthma (Table 2), suggesting
that there were no significant dissimilarities in disease severity between
these 2 groups. Moreover, users of inhaled corticosteroids were more likely
to be using bronchodilators and oral corticosteroids after discharge from
the ED than nonusers. Since these medications are markers of increased asthma
severity,21-22 it is highly unlikely
that confounding by indication could explain away our findings.
Based on our data, we cannot be certain on what the "optimal" dose of
inhaled corticosteroids ought to be. However, they do provide some assurances
for the practicing clinicians that in most cases low-dose inhaled corticosteroid
therapy could be used for long-term asthma control in patients who have recently
been discharged from EDs. Future randomized trials are required to confirm
our findings and to determine "best" doses of inhaled corticosteroids for
reducing asthma-related morbidity and mortality in this high-risk group of
patients.
AUTHOR INFORMATION
Accepted for publication November 20, 2001.
This project was sponsored in part through an unrestricted research
grant from the Alberta Lung Association, Edmonton.
Dr Sin is supported by a New Investigator Award from the Canadian Institutes
of Health Research, Ottawa, Ontario.
Corresponding author and reprints: Don D. Sin, MD, MPH, 2E4.29 Walter
C. Mackenzie Centre, University of Alberta, Edmonton, Alberta, Canada T6G
2B7 (e-mail: don.sin{at}ualberta.ca).
From the Division of Pulmonary Medicine, University of Alberta (Drs
Sin and Man), and the Institute of Health Economics (Dr Sin), Edmonton, Alberta.
REFERENCES
| |
1. Mannino DM, Homa DM, Pertowski CA, et al. Surveillance for asthma—United States, 1960-1995. Mor Mortal Wkly Rep CDC Surveill Summ. 1998;47:1-27.
2. McCarren M, McDermott MF, Zalenski RJ, et al. Prediction of repeat within eight weeks after an acute asthma exacerbation
in adults. J Clin Epidemiol. 1998;51:107-118.
FULL TEXT
|
ISI
| PUBMED
3. Crane J, Pearce N, Burgess C, et al. Markers of risk of asthma death or readmission in the 12 months following
a hospital admission for asthma. Int J Epidemiol. 1992;21:737-744.
FREE FULL TEXT
4. Haahtela T, Jarvinen M, Kava T, et al. Comparison of a beta 2-agonist, terbutaline, with an inhaled corticosteroid,
budesonide, in newly detected asthma. N Engl J Med. 1991;325:388-392.
ABSTRACT
5. Kerstjens HA, Brand PL, Hughes MD, et al. A comparison of bronchodilator therapy with or without inhaled corticosteroid
therapy for obstructive airways disease: Dutch Chronic Non-Specific Lung Disease
Study Group. N Engl J Med. 1992;327:1413-1419.
ABSTRACT
6. Lorentzson S, Boe J, Eriksson G, Persson G. Use of inhaled corticosteroids in patients with mild asthma. Thorax. 1990;45:733-735.
ABSTRACT
7. Rowe BH, Spooner CH, Ducharme FM, Bretzlaff JA, Bota GW. Corticosteroids for preventing relapse following acute exacerbations
of asthma. Cochrane Database Syst Rev. 2001;1:CD000195.
8. Cumming RG, Mitchell P, Leeder SR. Use of inhaled corticosteroids and the risk of cataracts. N Engl J Med. 1997;337:8-14.
FREE FULL TEXT
9. Garbe E, Suissa S, LeLorier J. Association of inhaled corticosteroid use with cataract extraction
in elderly patients. JAMA. 1998;280:539-543.
FREE FULL TEXT
10. Garbe E, LeLorier J, Boivin JF, Suissa S. Inhaled and nasal glucocorticoids and the risks of ocular hypertension
or open-angle glaucoma. JAMA. 1997;277:722-727.
ABSTRACT
11. Wong CA, Walsh LJ, Smith CJ, et al. Inhaled corticosteroid use and bone-mineral density in patients with
asthma. Lancet. 2000;355:1399-1403.
FULL TEXT
|
ISI
| PUBMED
12. Adams N, Bestall J, Jones P. Inhaled beclomethasone at different doses for long-term asthma. Cochrane Database Syst Rev. 2001;1:CD002879.
13. International Classification of Diseases, Ninth Revision, Clinical
Modification. Washington, DC: Public Health Service, US Dept of Health and Human
Services; 1988.
14. McFadden ER Jr, Gilbert IA. Asthma. N Engl J Med. 1992;327:1928-1937.
ABSTRACT
15. Alberta Health Care Insurance Plan/Supplementary Coverage. Available at: http://www.health.gov.ab.ca/ahcip/supplement.htm. Accessed April 15, 2002.
16. Boulet LP, Becker A, Berube D, Beveridge R, Ernst P. Canadian Asthma Consensus Report, 1999: Canadian Asthma Consensus Group. CMAJ. 1999;161(suppl):S1-S61.
17. Rochon PA, Tu JV, Anderson GM, et al. Rate of heart failure and 1-year survival for older people receiving
low-dose beta-blocker therapy after myocardial infarction. Lancet. 2000;356:639-644.
FULL TEXT
|
ISI
| PUBMED
18. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol. 1992;45:613-629.
FULL TEXT
|
ISI
| PUBMED
19. Barnes PJ. Inhaled glucocorticoids for asthma. N Engl J Med. 1995;332:868-875.
FREE FULL TEXT
20. Hummel S, Lehtonen L. Comparison of oral-steroid sparing by high-dose and low-dose inhaled
steroid in maintenance treatment of severe asthma. Lancet. 1992;340:1483-1487.
FULL TEXT
|
ISI
| PUBMED
21. Guite HF, Dundas R, Burney PG. Risk factors for death from asthma, chronic obstructive pulmonary disease,
and cardiovascular disease after a hospital admission for asthma. Thorax. 1999;54:301-307.
FREE FULL TEXT
22. Sin DD, Tu JV. Lack of association between ipratropium bromide and mortality in elderly
patients with chronic obstructive airway disease. Thorax. 2000;55:194-197.
FREE FULL TEXT
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