Slowing the Deterioration of Asthma and Chronic Obstructive Pulmonary Disease Observed during Bronchodilator Therapy by Adding Inhaled Corticosteroids: A 4-Year Prospective Study

Rates of morbidity and mortality due to asthma and chronic obstructive pulmonary disease (COPD) have increased during the last two decades [1, 2]. These increases might be related to the use of bronchodilator therapy without anti-inflammatory medication [3, 4]. Recently, two studies found that regular bronchodilator treatment had adverse effects on the control of asthma [5] and the progression of asthma and COPD [6]. In a previous study of 160 patients with asthma or COPD [6], we found that continuous treatment with a bronchodilator (ipratropium bromide, 40 g, or salbutamol, 400 g, four times daily) was associated with a much higher annual decline in the forced expiratory volume in 1 second (FEV1) compared with treatment on demand. It is unclear whether an unfavorable course of asthma or COPD during bronchodilator therapy alone can be reversed or decelerated by additional anti-inflammatory therapy with inhaled corticosteroids. We studied 56 of the 160 patients who had an unfavorable disease course during bronchodilator therapy alone (an annual decline in FEV1 of at least 80 mL/y in combination with at least two exacerbations per year). These 56 patients (28 with asthma and 28 with COPD) were also treated with an inhaled corticosteroid (beclomethasone dipropionate, 800 g daily) during years 3 and 4 of the study. We assessed whether the worsening of their disease during bronchodilator therapy alone was reversed or decelerated by additional anti-inflammatory treatment with beclomethasone. The outcome measures were dynamic lung function indices (annual decline in pre- and postbronchodilator FEV1, peak expiratory flow rate [PEFR], and forced inspiratory volume in 1 second [FIV1]), static lung function indices (residual volume [RV], ratio of residual volume to total lung capacity (RV/TLC), inspiratory vital capacity [IVC]), nonspecific bronchial responsiveness (assessed by determining the concentration of histamine that provokes a 20% decrease in FEV1 [Pc 20]), exacerbations, and respiratory symptoms. Methods Patients Patient selection has been previously described [6]. In short, 29 family physicians in the catchment area of the University of Nijmegen, Nijmegen, the Netherlands, selected all patients who were 30 years or older and had symptoms of asthma or COPD. Only patients who showed mild-to-moderate airway obstruction (FEV1 > 50% of the predicted value [7]) or bronchial hyper-responsiveness to histamine (Pc 20 8 mg/mL) were included in the study. Patients dependent on inhaled corticosteroids who had chronic heart failure, malignant disorders, or other severe life-threatening diseases were excluded from the study. Of these patients, 160 (59 with asthma and 101 with COPD) completed the bronchodilator trial. During the 2 years of bronchodilator treatment, a rapid decline in FEV1 ( 80 mL/y) and a relatively high exacerbation rate ( 1/y) were observed in a subgroup of 56 patients (35%). Because of their unfavorable disease course, these patients were selected for additional treatment with inhaled beclomethasone for 2 years. The criteria for diagnosis of asthma or COPD were based on the standards of the American Thoracic Society [8]. Asthma was defined [6, 8] by a combination of factors: bronchial hyper-responsiveness to histamine (Pc 20 8 mg/mL); reversible obstruction (an improvement in FEV1 of more than 15% of the prebronchodilator value 60 minutes after the administration of both salbutamol, 400 g, and ipratropium bromide, 80 g); dyspnea; and allergy (defined as at least one positive result on seven radioallergosorbent tests that assessed sensitivity to pollen from weeds, grasses, and trees; cats and dogs; house dust mite; and Aspergillus fumigatus) or wheezing. Chronic obstructive pulmonary disease was defined [6, 8] by the combination of chronic cough or chronic sputum production for at least 3 months during at least 2 consecutive years; and continuous bronchus obstruction (FEV1 85% of the predicted value). The separate features of asthma and COPD overlap (for instance, some asthmatic patients had chronic cough, and some COPD patients had a Pc 20 8 mg/mL), but the definitions based on feature combinations ensured that no patients with asthma also had COPD and vice versa [6]. The study was approved by the Medical Ethics Committee of the University of Nijmegen. All patients gave informed consent. Study Design and Treatment At the start of the 4-year intervention study, the patients were randomly assigned to one of two parallel treatment regimens: continuous bronchodilator therapy (four times daily) or treatment on demand (dry powder inhalations during symptomatic periods) [6]. The patients used salbutamol, 400 g, during 1 year and ipratropium bromide, 40 g, during the other year; both were administered as dry powder inhalations. The sequence of the drugs was determined by random allocation. During years 3 and 4, the 56 patients received 400 g of beclomethasone, two times daily, in combination with 400 g of salbutamol or 40 g of ipratropium bromide, four times daily (all dry powder inhalations). The bronchodilator inhaled during year 2 was also used in years 3 and 4. During the first 2 years of the study, 27 of the 56 patients received bronchodilator therapy on demand (of the 27, 15 had asthma and 12 had COPD). For patients treated on demand, the mean (SE) daily number of dry powder inhalations of salbutamol or ipratropium bromide was 1.2 0.3 in those with asthma and 0.8 0.2 in those with COPD. During years 3 and 4, 28 patients received salbutamol (15 with asthma and 13 with COPD) and 28 received ipratropium bromide (13 with asthma and 15 with COPD). Once every 3 months, inhalation technique and compliance with the prescribed medication were checked. Patients were instructed to rinse their mouths after the dry powder inhalations. During the second year of beclomethasone therapy, a single-blind prospective study was done to assess patient compliance with beclomethasone and the additional bronchodilator. Compliance was measured by counting capsules at the end of a 4-month period. Patients were unaware that their medication was counted after this period. Lung Function, Nonspecific Bronchial Responsiveness, and Reversibility All measurements were carried out by two qualified laboratory assistants during exacerbation-free periods. No bronchodilator was inhaled for at least 8 hours before the pulmonary function tests. At the start and after 24 and 48 months of the study, the inspiratory vital capacity (IVC), residual volume (RV), functional residual capacity (FRC), and total lung capacity (TLC) were assessed using the wet Gould spirometer (Sensormedics, Bilthoven, the Netherlands) according to the standards of the European Coal and Steel Community [7]. The FEV1, bronchial responsiveness to histamine, and the reversibility of airway obstruction were assessed at 6-month intervals using the Microspiro HI-298 (Chest Corporation, Tokyo, Japan) [9]. Moreover, FEV1 and reversibility were also assessed after 1 and 13 months of study [6]. The best of three forced expiratory maneuvers, with the highest sum of the forced vital capacity (FVC) and FEV1, was used for data analysis. The bronchial responsiveness to histamine was measured according to the method described by Cockcroft and colleagues [10]. Results were expressed as the concentration of histamine that provoked a 20% decrease in FEV1 (Pc 20). After the FEV1 had returned to the baseline value, the bronchodilating response (reversibility) was assessed 60 minutes after the administration of both 80 g of ipratropium bromide and 400 g of salbutamol (metered dose aerosol) [6]. The bronchodilating response was expressed as the increase in FEV1 relative to the predicted value of the FEV1. Peak Expiratory Flow Assessments Once a week (on the same day and at the same time), peak expiratory flow rate (PEFR) was measured with the Assess peak flow meter (HealthScan Products, Cedar Grove, New Jersey) [11] in the morning and in the evening. The highest value of three measurements was included in the analysis. The diurnal PEFR index (absolute difference between the evening value and the morning value divided by the highest value) was calculated. Exacerbations Our definition of exacerbation was based on that of Fletcher as modified by Boman and colleagues [12]. When an exacerbation occurred, a 10-day course of oral prednisone was administered. Patients received 25 mg for 2 days, 20 mg for 2 days, 15 mg for 2 days, and so forth. Symptoms and Adverse Effects Using a scale of 0 to 4, all patients recorded, on a weekly basis, the presence and severity of symptoms (cough, phlegm, dyspnea, fatigue, disturbed sleep at night). The adverse effects of medication (dysphonia and oropharyngeal irritation) were recorded by the patients once every 3 months. Moreover, every 6 months, the presence and severity of oral candidiasis were assessed using a questionnaire (no, light, or severe symptoms). Smoking At the start of the study, smoking history was assessed in pack-years. During the study, the average number of cigarettes smoked per day was also recorded in weekly diary entries. Power Calculations Assuming that the clinically relevant, decreased annual decline in FEV1 during beclomethasone treatment is 25 mL/y and that the residual standard deviation is 50 mL/y, the coefficient of variation is 25/50 or 0.5. Based on an of 0.05 and a of 0.20 (power:1 0.2, or 0.8), the required number of patients for the study would be 51. Based on an estimated dropout rate of 10%, the required initial number of study patients would be 56. Statistical Analysis Data on outcome variables obtained before and during beclomethasone therapy were compared. Differences were tested by repeated-measures analysis of variance, the paired Student t-test for normally distributed variables, and the Wilcoxon paired signed-rank test for non-normally distributed variables. Before the analysis, the Pc 20 values were 2log transformed. The an