Effectiveness of the Leukotriene Receptor Antagonist Zafirlukast for Mild-to-Moderate Asthma

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 -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. 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 -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). Methods 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. Clinical Protocol The trial from which this study arose was designed to compare zafirlukast plus as-needed -agonist therapy with placebo plus as-needed -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 -agonists (albuterol from a metered-dose inhaler, 100 g per inhalation) or placebo and -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 -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 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). 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 -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 -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 costutility analysis. Clinical and Economic Effectiveness Outcomes Days without symptoms, days without limitation of activity, days without use of -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 -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 -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 -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 im