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1 February 1997 | Volume 126 Issue 3 | Pages 177-183
Background: The increasing costs of managing asthma are due in part to the introduction of new medications, such as leukotriene receptor antagonists. These antagonists interfere with the action of leukotrienes, which are implicated in bronchoconstriction and the formation of airway edema in patients with asthma. Leukotriene receptor antagonists must be shown to be clinically and economically effective for their clinical use to be justified.
Objective: To assess the clinical and economic effectiveness of zafirlukast, a leukotriene receptor antagonist, in patients with mild-to-moderate asthma who might benefit from regular anti-inflammatory therapy.
Design: Randomized, double-blind, multicenter, placebo-controlled trial.
Setting: 28 outpatient clinics.
Patients: 146 patients with mild-to-moderate asthma who were 12 years of age or older, had not smoked cigarettes in the previous 6 months, had a smoking history of less than 10 pack-years, had an FEV1 at least 55% of the predicted value with no upper limit, had demonstrated bronchial hyperresponsiveness, and were symptomatic during the 7-day run-in period. All patients were seen every 2 to 3 weeks for 13 weeks.
Intervention: 103 patients received zafirlukast (20 mg twice daily), and 43 patients received placebo (twice daily). All patients received inhaled ß-agonists as needed.
Measurements: Data were obtained from medical examinations, patient questionnaires, and daily diaries. The clinical effectiveness outcomes were days per month without asthma symptoms, limitation of activity, use of ß-agonists, sleep disturbance, and episodes of asthma (the latter was a composite measure made up of the first four outcomes plus the occurrence of adverse events). The economic effectiveness outcomes were frequency and type of unscheduled health care contacts, use of ß-agonist inhalers, consumption of nonasthma medications, and days of absence from work or school.
Results: The zafirlukast group had 89% more days without symptoms (adjusted rates, 7.0 compared with 3.7 days per month; P = 0.03), 89% more days without use of ß-agonists (adjusted rates, 11.3 compared with 6.0 days per month; P = 0.001), and 98% more days without episodes of asthma (adjusted rates, 10.1 compared with 5.1 days per month; P = 0.003). They also had 55% (95% CI, 19% to 74%) fewer health care contacts (18.5 compared with 40.7 per 100 per month; P = 0.007) and 55% (CI, 3% to 79%) fewer days of absence from work or school (15.6 compared with 35.0 per 100 per month; P = 0.04). They used 17% fewer canisters of inhaled ß-agonists (P = 0.17) and 19% less nonasthma medication (P > 0.2).
Conclusions: A daily regimen of zafirlukast added to as-needed inhaled ß-agonists is more effective than ß-agonists alone in treating mild-to-moderate asthma. The clinical and economic effectiveness of zafirlukast, a potential alternative to inhaled corticosteroids, provides further impetus to use regular "preventive" therapy in patients with mild-to-moderate asthma.
The effect of a new drug on relevant and costly outcomes now needs to be shown during the introduction of that drug. As of 1992, no studies of the economic effectiveness of either existing or new drugs for the treatment of asthma had been done [5]. Recently, studies assessing the effect of inhaled corticosteroids in patients with asthma and chronic obstructive pulmonary disease have shown that the higher initial costs of these drugs may be offset by the savings generated by reduced use of health care [6, 7].
Leukotriene receptor antagonists, a new generation of asthma medications, are being developed because they interfere with the action of leukotrienes. Leukotrienes are implicated in bronchoconstriction and the formation of airway edema, which result from the inflammatory process in patients with asthma. Several leukotriene receptor antagonists are currently at different stages of development and testing [8]. Zafirlukast (ICI-204, 219, or ACCOLATE [Zeneca Pharmaceuticals, Wilmington, Delaware]) is one such compound; it acts through selective leukotriene receptor antagonism. It has been shown to block both early and late asthmatic responses to inhaled allergens [9]. In phase II dose-ranging studies, it was found to decrease the use of concurrent asthma medication, improve FEV1 and the morning peak expiratory flow rate, and decrease the incidence of asthma symptoms [10].
The effect of zafirlukast on clinical and economic outcomes has yet to be examined. We studied the clinical and economic effectiveness of zafirlukast among patients with mild-to-moderate asthma who were receiving only ß-agonists as needed (the need was frequent) and who therefore might have obtained benefit from additional regular medication. We focus particularly on clinical effectiveness outcomes (such as symptoms, limitation of activity, and sleep disturbance) and economic effectiveness outcomes (such as health care use, the need for other medications, and absence from work or school).
Clinical Protocol
The trial from which this study arose was designed to compare zafirlukast plus as-needed ß-agonist therapy with placebo plus as-needed ß-agonist therapy in patients with mild-to-moderate asthma who needed additional treatment but would not have been unduly put at risk if such treatment were to be delayed for 3 months. After an initial 1-week observation period (visits 1 and 2) and a 7- to 14-day placebo run-in period (visit 3), the patients were randomly assigned in a 2 to 1 ratio to receive either zafirlukast and ß-agonists (albuterol from a metered-dose inhaler, 100 µg per inhalation) or placebo and ß-agonists. Patients were then followed every 2 weeks for visits 4 and 5 and every 3 weeks thereafter (visits 6 through 8), for a total of 13 weeks. The initial 1-week period was devoted to observation, screening, eligibility testing, and instruction about questionnaires and the general structure of the trial. The run-in period, during which both groups received placebo, was used to assess final eligibility criteria and compliance with study procedures. After randomization, patients received zafirlukast, 20 mg, or placebo orally in a double-blind manner twice daily. With the exception of ß-agonists, no concurrent medications for asthma were permitted.
Patients were eligible for the study if they were 12 years of age or older, had not smoked cigarettes in the previous 6 months, had a smoking history of less than 10 pack-years, and had an FEV1 at least 55% of the predicted value. They had to 1) have a 15% or greater improvement in FEV1 after inhalation of a bronchodilator within the previous 6 months or 2) show bronchial hyperresponsiveness (a decrease in FEV1
The occurrence of more than one visit to an emergency department, one hospitalization for asthma, or the worsening of asthma necessitating therapy with agents other than ß-agonists resulted in the termination of follow-up for treatment failure. Follow-up was also terminated for severe adverse reactions, development of concurrent severe disease unrelated to asthma, voluntary withdrawal, and noncompliance with study procedures. Information on pulmonary function, daytime symptoms (classified as none, mild, moderate, or severe), nighttime awakenings, symptoms on arising, the occurrence and duration of adverse events, the use of other medications (type and duration), and the use of ß-agonist inhalers (number of puffs per day) was collected daily using patient report forms. Physical and physiologic data were obtained at each visit.
Outcomes Subprotocol
We obtained data through an extended patient report form, which was given to each participant for the purpose of collecting daily information on major clinical and economic effectiveness outcomes, such as activity limitation due to asthma; absence from work or school due to asthma; and additional clinic visits, hospital visits, and contacts with health care personnel outside of the scheduled protocol structure. All procedures done and medications given outside of the trial structure were also described on the form. Data on quality of life were obtained but are not presented here; they will be combined with data from an ongoing study of patient preferences in a separate quality-of-life and cost–utility analysis.
Clinical and Economic Effectiveness Outcomes
Days without symptoms, days without limitation of activity, days without use of ß-agonists, days without sleep disturbance, and days without episodes of asthma were selected as measures of clinical effectiveness because they were simple and clinically relevant. We obtained information on the daily occurrence of asthma symptoms, asthma-related limitation of activity, use of ß-agonists, and sleep disturbance due to asthma directly from the daily patient report forms to compute the number of days per month that were free of each outcome. A composite outcome variable, "episode-free days," was defined as the number of days without an asthma attack (severe symptoms), without the use of ß-agonists, without sleep disturbance due to asthma, and without an adverse event [12].
The economic effectiveness outcomes included the use of health services and resources as well as the extent of absenteeism. Only the health services that varied between arms of the trial were considered; thus, the protocol-driven resources incurred by each patient (which were theoretically equal between the arms of the trial) were ignored. These resources were the frequency of unscheduled health care visits and contacts, the total number of ß-agonist inhalers used, and the number of prescriptions for all nonasthma medications consumed. Absenteeism was quantified as the number of days of absence from work or school due to asthma.
Statistical Analysis
Measures were computed across patient-days. Patient-days for which data were missing during follow-up were not directly included in the calculations, but estimates derived from nonmissing data were extrapolated to the totality of all follow-up days for a given patient. This was done by imputing the average for the days that were not missing data to the days that were missing data. For all outcome variables, the individual approach to data analysis was used, with the patient as the unit of analysis. For the clinical effectiveness outcomes, for which the patient either had or did not have a clinical event reported daily, the measure was based on the proportion of relevant days (for example, days without symptoms) of all of the patient's follow-up days of treatment. These were standardized into mean days per month by multiplying by 30. For these clinical effectiveness measures, multiple linear regression was used to estimate the mean differences between the two groups and to assess the statistical significance of those differences [13]. These estimates were adjusted for baseline differences and for baseline values of the effectiveness measures to increase precision. In addition, a generalized linear regression model with a logarithmic link was used for these outcomes to estimate the percentage change for each mean outcome [14].
For the economic effectiveness outcomes, which were based on infrequent events, a Poisson regression model with a logarithmic link and with variances adjusted for between-subject overdispersion by the deviance was used to estimate the percentage change in the outcome rate between groups [14]. To improve precision, these Poisson regression models were kept parsimonious by adjustment for only those baseline factors that were significant. The statistical significance of differences between groups at baseline was assessed by using the chi-square test and the Wilcoxon rank-sum test [13].
Role of Sponsor
The sponsor who funded this study, Zeneca Pharmaceuticals, coordinated all aspects of data collection. The authors verified, analyzed, and interpreted the data at the Royal Victoria Hospital, Montreal, independently of the sponsor. According to McGill University regulations, the authors had complete freedom with regard to the decision to seek publication, the content of the paper, and the choice of the journal in which to publish the study results.
Table 1 shows the baseline characteristics of the study participants. Unexpectedly, the mean percent predicted FEV1 at baseline was significantly lower in the zafirlukast group (74.2%) than in the placebo group (83.7%). This difference can only be random because randomization and consent to participate occurred after these measures were obtained. The two groups did not differ in mean age, sex, or prevalence of symptoms at night or early in the morning. ARTICLE
Effectiveness of the Leukotriene Receptor Antagonist Zafirlukast for Mild-to-Moderate Asthma
A Randomized, Double-Blind, Placebo-Controlled Trial
In 1990, the total cost of asthma in the United States was estimated to be more than $6 billion per year, of which some $1.1 billion, or almost 20%, was spent on drug therapy [1]. Moreover, the overall cost of drugs for the treatment of asthma is expected to increase substantially as a result of a greater emphasis on expensive anti-inflammatory agents, such as inhaled corticosteroids and cromolyn [2-4], and the introduction of new drugs, such as long-acting ß-agonists. It is hoped, however, that the higher initial costs will be offset by the reduction in morbidity and absence from work that may result from the use of these newer, more effective medications.
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The data for this effectiveness study originated from a large, randomized, double-blind, multicenter trial designed to assess the efficacy of zafirlukast in 762 patients with mild-to-moderate asthma who were followed for 13 weeks [11]. Of the 63 centers participating in that trial, 28 agreed to collect the additional outcome data needed for our study. Of the 335 patients from those 28 centers, 150 agreed to participate; these 150 patients are the subject of our analysis. 
20% at an inhaled concentration 
8.0 mg/mL of histamine or methacholine). Patients also had to be symptomatic (defined as a 7-day asthma symptom score 8) during the run-in period. The asthma symptom score was the sum over 7 days of an overall assessment of asthma symptoms, which were rated daily by the patient as 0 = none, 1 = mild (no interference with activities), 2 = moderate (interference with some activities), or 3 = severe (interference with many activities).
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The baseline characteristics of the 150 patients who agreed to participate in this outcomes substudy were similar to those of the 185 patients who did not participate, except that the participants were an average of 4.3 years older than the nonparticipants. Of the 150 initial participants, 4 later declined to participate. Of the 146 patients remaining, 103 were randomly assigned to the zafirlukast group and 43 were randomly assigned to the placebo group. In the zafirlukast group, 4 (3.9%) of the 7 (6.8%) patients who did not complete the study withdrew because their asthma worsened or because they used other asthma drugs; in the placebo group, 4 (9.3%) of the 5 (11.6%) patients who did not complete the study withdrew because their asthma worsened or because they used other asthma drugs. Information for these persons up to the point of withdrawal was used. Of the 9373 possible patient-days of treatment in the zafirlukast group, data were missing for 6.0% to 8.9%, depending on the outcome in question. In the placebo group, data were missing for 4.9% to 10.7% of the 3913 possible patient-days. Thus, analyses are based on a rate of data availability greater than 90%.
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Table 2 shows values for each group for the principal measures of clinical effectiveness at baseline, expressed as the time spent (in days per month) in those specific health states during the 7 days immediately before randomization. Overall, both groups were similar, although our data suggest that the patients assigned to receive zafirlukast may have been slightly sicker than those assigned to receive placebo.
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As shown in Table 3, patients in the zafirlukast group had significantly more time without symptoms (Figure 1), without the use of ß-agonists, and without episodes of asthma. The adjusted differences, corrected for baseline differences in percent predicted FEV1 and in the baseline measures of clinical effectiveness themselves, indicate that zafirlukast produced 89% more days without symptoms (adjusted rates, 7.0 compared with 3.7 days per month; P = 0.03), 89% more days without the use of ß-agonists (adjusted rates, 11.3 compared with 6.0 days per month; P = 0.001), and 98% more days without episodes of asthma (adjusted rates, 10.1 compared with 5.1 days per month; P = 0.003). An additional 2.2 days without limitations (P = 0.10) and 1.2 days without sleep disturbance (P > 0.2) were seen in the zafirlukast group, but the differences between the groups were not statistically significant. Table 4, for the symptom-free days outcome of Table 3, contrasts the magnitude of the crude and multivariate effects of the adjustment factors with the effect of zafirlukast. The mean number of days without symptoms per month increased by 0.7 for every 10% increase in the baseline percent predicted FEV1 and by 0.9 for every day without symptoms per month during the baseline period; it increased by 3.1 as a result of the use of zafirlukast.
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Table 5 shows that zafirlukast reduced all resource-consumption measures of economic effectiveness. All health care contacts were combined because 70% of these were office visits to physicians. In the zafirlukast group, the frequency of these contacts was reduced by 55% (18.5 compared with 40.7 contacts per 100 per month; P = 0.007), as was asthma-related absenteeism from work or school (15.6 compared with 35.0 days per 100 per month; P = 0.04). The patients receiving zafirlukast used 17% fewer canisters of inhaled ß-agonists (47.5 compared with 57.1 per 100 per month; P = 0.17) and 19% fewer nonasthma medications (70.4 compared with 87.4 per 100 per month; P > 0.2).
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Discussion
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Results from studies of the efficacy of leukotriene receptor antagonists in asthma are not yet generally available. Israel and coworkers [15] reported on the efficacy of zileuton, a 5-lipoxygenase inhibitor that was thought to have important similarities to leukotriene antagonists. These investigators found decreases in symptoms and in the use of inhaled ß-agonists in patients receiving zileuton compared with patients receiving placebo. These results, in combination with our own, provide further impetus to use regular "preventive" therapy in patients with mild-to-moderate asthma, as recent guidelines suggest [16].
Our evaluation of economic effectiveness showed that zafirlukast reduced health care contacts by 54% and absenteeism by 55%. The value of considering this latter economic outcome (days lost from work or school because of asthma) in assessing the economic effectiveness of a drug is debatable [17]. However, because absenteeism in the workplace is a major concern of employers, who are currently the predominant payers for health care in the United States, it appears relevant to study and incorporate this outcome when evaluating the effects of a treatment.
Our analysis of clinical and economic effectiveness outcomes was done using data from a subprotocol of a multicenter clinical trial of a new therapeutic agent. We show the usefulness of such outcomes analyses in the evaluation of new therapies for asthma, and we suggest that such evaluations be done for most new asthma treatments. Nevertheless, the actual effect of zafirlukast on disease cannot be precisely estimated from our study for three major reasons. First, the small number of patients that we examined over a relatively short span of time did not incur any of the major expenses often associated with asthma [1], such as death (13% of the total cost of the disease) and hospitalization (33% of the total cost), and only one patient visited an emergency department. Second, because the study was controlled, we could not observe actual patterns of drug use-including lack of compliance, overuse, and underuse-that may have led to different cost effects. Zafirlukast is an oral preparation and must be taken daily, and these factors can play a role in its real-life effectiveness.
Third, the effect favoring zafirlukast may have been underestimated because of the imbalance of treatment failures between the study groups (4% of the zafirlukast group and 10% of the placebo group had treatment failures); it is likely that treatment failures will be followed by such major outcomes as treatments, visits to emergency departments, hospitalizations, and absence from work or school. Because no data were collected for this post-failure follow-up period, we did not consider such outcomes in our analysis. In addition, the mean percent predicted FEV1 at baseline was lower in the zafirlukast group (74.2%) than in the placebo group (83.7%), and this may have biased our results despite randomization and statistical adjustment.
Finally, the fact that several measures of outcome are based on self-reports by patients limits the generalizability of the absolute rates. Nevertheless, randomization has ensured that such self-reports did not affect the validity of the comparative effectiveness measures, although their statistical precision may be reduced. Therefore, a larger study with more participants that is conducted over a longer period (thus increasing the chance that events will occur) must be done. Such a study should reduce control of actual drug use and should follow patients after treatment failure to obtain a more accurate estimate of true economic effect. This would provide a more realistic picture of the overall effect of zafirlukast and would show whether the effectiveness found in this study persists. Such a study should be randomized, should focus on a few major outcomes (such as those reported here and visits to emergency departments and hospitalizations), and should concentrate on obtaining accurate data to reduce the magnitude of measurement error.
Our study assessed the clinical and economic effectiveness of a new drug for asthma before approval for marketing worldwide. Our results indicate that this new drug improves clinical effectiveness and has an important effect in decreasing major economic outcomes. Future studies should quantify this effect in economic terms and incorporate into the analysis the intangible but real value that patients would attribute to the alleviation of symptoms, greater ease in performing daily activities, and the absence of adverse events. Such a cost–utility study of zafirlukast is currently under way. Furthermore, it would be of interest to compare the clinical and economic effectiveness of zafirlukast with that of other available preventive medications, such as inhaled corticosteroids.
Dr. Dennis: Hospital San Ignacio, Carrera 7, 40-62, Piso 2, Bogota, Columbia.
Dr. Ernst: Respiratory Epidemiology Unit, McGill University, 1110 Pine Avenue West, Montreal, Quebec H3A 1A3, Canada.
Dr. Wood-Dauphinee: Physical and Occupational Therapy, McGill University, Davis House, 3654 Drummond, Montreal, Quebec H3G 1Y5, Canada.
Author and Article Information
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References
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1. Welss KB, Gergen PJ, Hodgson TA. An economic evaluation of asthma in the United States. N Engl J Med. 1992; 326:862-6.
2. Guidelines for the Diagnosis and Management of Asthma: Expert Panel Report. Bethesda, MD: National Asthma Education Program, Office of Prevention, Education, and Control, National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services, Public Health Service; 1991.
3. International consensus report on diagnosis and treatment of asthma. National Heart, Lung, and Blood Institute, National Institutes of Health. Bethesda, Maryland 20892. Publication no. 92-3091, March 1992. Eur Respir J. 1992; 5:601-41.
4. Hargreave FE, Dolovich J, Newhouse MT. The assessment and treatment of asthma: a conference report. J Allergy Clin Immunol. 1990; 85:1098-111.
5. Rutten-van Molken MP, Van Doorslaer EK, Rutten FF. Economic appraisal of asthma and COPD care: a literature review 1980-1991. Soc Sci Med. 1992; 35:161-75.
6. Rutten-van Molken MP, Van Doorslaer EK, Jansen M, Van Essen-Zandvliel EE, Rutten FF. Cost-effectiveness of inhaled corticosteroid plus bronchodilator therapy versus monotherapy in children with asthma. Pharmacoeconomics. 1993; 4:257-70.
7. Rutten-van Molken MP, Van Doorslaer EK, Jansen MC, Kerstjens HA, Rutten FF. Costs and effects of inhaled corticosteroids and bronchodilators in asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1995; 151:975-82.
8. Chung KF. Leukotriene receptor antagonists and biosynthesis inhibitors: potential breakthrough in asthma therapy. Eur Respir J. 1995; 8:1203-13.
9. Taylor IK, O'Shaughnessy KM, Fuller RW, Dollery CT. Effect of cysteinylleukotriene receptor antagonist ICI 204.219 on allergen-induced bronchoconstriction and airway hyperreactivity in atopic subjects. Lancet. 1991; 337:690-4.
10. Spector SL, Smith LJ, Glass M. Effects of 6 weeks of therapy with oral doses of ICI 204,219, a leukotriene D4 receptor antagonist, in subjects with bronchial asthma. ACCOLATE Asthma Trialists Group. Am J Respir Crit Care Med. 1994; 150:618-23.
11. ICI Pharma. A multicenter double-blind placebo controlled trial of Accolate in mild to moderate asthmatic patients needing chronic treatment. Trial number 9188IL/0029. Canada, 1992.
12. Sculpher MJ, Buxton MJ. The episode-free day as a composite measure of effectiveness. Pharmacoeconomics. 1993; 4:345-52.
13. Armitage P, Berry G. Statistical Methods in Medical Research. Boston: Blackwell Scientific; 1987.
14. McCullagh P, Nelder JA, eds. Generalized Linear Models. 2d ed. London: Chapman & Hall; 1989.
15. Israel E, Rubin P, Kemp JP, Grossman J, Plerson W, Siegel SC, et al. The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma. Ann Intern Med. 1993; 119:1059-66.
16. Global strategy for asthma management and prevention. WHO/NHLBI workshop In: National Institutes of Health, National Heart, Lung and Blood Institute, Publication no. 95-3659; 1995.
17. Henry D. Economic analysis as an aid to subsidization decisions: the development of Australian guidelines for pharmaceuticals. Pharmacoeconomics. 1992; 1:54-67.
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