INTRODUCTION

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Many patients with advanced chronic obstructive pulmonary disease (COPD) have respiratory symptoms that persist despite ongoing treatment with bronchodilators and inhaled corticosteroids. For these patients, extended treatment with oral corticosteroids is commonly prescribed in an attempt to reduce daily symptoms or to prevent COPD exacerbations. Although a brief course of high-dose oral corticosteroids improves spirometric values by a modest amount in patients with stable COPD (1), it is not known whether the improvement is sustained with chronic therapy or whether the short-term spirometric improvement is associated with other long-term clinical benefits. The only randomized trial of the effects of extended oral corticosteroid treatment showed that the addition of low dose (5 mg) daily prednisolone to inhaled corticosteroids in patients with relatively mild COPD did not result in additional improvement in pulmonary function, pulmonary symptom scores, or the frequency or duration of COPD exacerbations over a 2-yr period (2). Despite the paucity of evidence for its benefit, published guidelines recommend that chronic oral corticosteroid therapy be considered for patients with stable COPD who respond to a short-term trial of corticosteroids (3).

If chronic systemic corticosteroid treatment is effective in COPD, the benefit might be easier to demonstrate in patients taking daily oral corticosteroids, because such patients are thought to be "steroid-dependent." To test this hypothesis, we randomly assigned patients who were previously treated with long-term prednisone to either continue their usual maintenance dose for 6 mo, or to be gradually withdrawn from daily prednisone. The primary clinical outcome of the study was the average number of COPD exacerbations over a 6-mo study period. This preliminary investigation was conducted to examine the feasibility of the study design and to determine effect size in order to reliably calculate sample size requirements for a more definitive trial.

	METHODS

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Study Subjects

Potential study participants were identified by a review of computerized pharmacy records of patients who had received both inhaled -agonists and daily oral prednisone at a dose of at least 5 mg/d for the preceding 6 mo, without a reduction in their maintenance dose in the past month. Patients were invited by mail to participate. All study subjects had COPD by American Thoracic Society criteria (4). Other entry criteria were age  50 yr and a cigarette-smoking history of at least 20 pack-years. Exclusion criteria were: (1) a clinical diagnosis of asthma, including patients with normal or highly (> 50%) variable spirometric data within the previous 5 yr, a history of eosinophilia, a high IgE titer, or a strong family history of atopy; or (2) concomitant major illness that would probably preclude travel to monthly appointments or survival for 6 mo.

The study was conducted with approval by the Human Studies Institutional Review Board of the Minneapolis Veterans Administration Medical Center. Informed consent was obtained from all subjects.

Study Design

After a 1-wk run-in period in which all subjects received study capsules that contained their usual maintenance dose of prednisone, subjects were randomly assigned to receive identically packaged dose packs that contained either their usual maintenance dose of prednisone or capsules in which the daily maintenance prednisone dose was reduced by 5 mg/wk. In order to avoid an unplanned imbalance in baseline prednisone dose as a covariate that could be an indicator of the degree of steroid-dependency or severity of illness, patients were stratified according to whether their maintenance prednisone dose was: 5 to 10 mg/d or more than 10 mg/d. Patients were then randomly assigned to treatment so that predetermined, approximately equal proportions of patients from each stratum received each treatment. Study capsules were given for 6 mo. Patients in both study groups received open-label "demand" prednisone (40 mg/d for 10 d) as needed for COPD exacerbations (3). Patients hospitalized for COPD exacerbations were treated with open-label parenteral corticosteroids according to the individual preference of the patient's physician; patients completed the remainder of the 10-d course with prednisone at 40 mg/d. All subjects received inhaled triamcinalone acetonide (Azmacort; Rhone-Poulenc Roter, Collegeville, PA) 1,600 µg daily in divided doses. Other medications, including bronchodilators, were given at the discretion of the patient's primary physician. To assess our ability to maintain the double-blind study status, patients and study personnel were asked at each visit to judge the patients' treatment-group assignment. Patients were also queried at each visit about symptoms of corticosteroid withdrawal (weakness, fatigue, muscle or joint aches, and nausea).

The primary outcome measure was average number of COPD exacerbations during the 6-mo study period, on the basis of an intention-to-treat analysis. Exacerbations were defined as an increase in dyspnea or other pulmonary symptoms resulting in one or more of the following: administration of a higher dose of prednisone, administration of an antibiotic, emergency room (ER) or unscheduled clinic visit for COPD, hospitalization, intubation, or death due to COPD. When exacerbations meeting more than one of these definitions occurred during the same clinical episode, assignment to the category of exacerbation was hierarchical, as follows: death > intubation > hospitalization > ER visit > open-label corticosteroids > antibiotics. Secondary outcomes were the average daily systemic corticosteroid dose (including study drug, open-label prednisone, and parenteral corticosteroids), dyspnea index (5) and health-related quality of life (6), spirometric results, and changes in body weight. All outcome measures were assessed at baseline and again at 2 wk, 4 wk, and monthly for 6 mo after randomization. If the study drug was withdrawn before 6 mo, information about primary outcome measures and daily systemic steroid dose was collected for the full study period. If patients failed to come for visits, information was collected by telephone and review of the medical records.

Recorded values of FEV₁ and FVC were the best of those in three exhalations, as measured with a dry rolling-seal spirometer (Model 922; SensorMedics, Yorba Linda, CA) (4). The FEV₁ response to bronchodilator testing was measured 5 min after the inhalation of isoproterenol sulfate (0.08 mg). Compliance with dosing of the study drug was assessed by pill counting for both the continuous- and demand-dose regimens of prednisone. When the study drug was discontinued for any reason, it was not restarted, and usual medical care was resumed.

Statistical Analysis

Differences in the average number of COPD exacerbations, systemic corticosteroid dose, and body weight were analyzed with the Mann- Whitney two-sample rank-sum test. Differences in withdrawal rates and other proportions were analyzed with chi-square tests, and time to exacerbation and time on study drug were evaluated through Kaplan-Meier survival analysis. Differences in spirometric data, dyspnea, and quality of life indices were analyzed with unpaired t tests. Treatment outcomes relating to COPD exacerbations and systemic corticosteroid exposure were determined with an intention-to-treat analysis.

	RESULTS

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Of the 164 potential study patients identified, 122 declined enrollment because of logistical problems with participation in the study (42 patients), unwillingness to discontinue daily oral corticosteroids (24 patients), or for no given reason or no reply (56 patients). Of the 42 patients who agreed to participate, four did not complete the run-in period before randomization because of worsened respiratory symptoms; one of these patients died from COPD during the run-in period.

Thirty-eight patients, all men, were randomized, of whom 20 were randomized to continuous prednisone treatment and 18 to treatment with prednisone only on demand. Patients assigned to the two treatment groups were similar with regard to baseline characteristics including age, spirometric values, bronchodilator response, duration and dose of prior oral corticosteroid treatment, and use of inhaled corticosteroids (Table 1). Twelve patients (60%) receiving continuous prednisone, and eight patients (44%) receiving prednisone on demand, took the respective study drug for the full 6-mo study period (p = 0.34) (Table 2). For all subjects, the study drug was stopped at an average (± SD) of 129 ± 60 d in the continuous group and 103 ± 62 d in the demand group (p = 0.15). Study drug was withdrawn before 6 mo for the following reasons: worsened pulmonary status (two patients in each group); other intercurrent medical conditions (three patients in the continuous group, and four patients in the demand group); and anxiety about continued participation in the study (three patients in the continuous group, and four patients in the demand group). Compliance with the study drug regimen as determined from pill count per day before study drug was stopped was 88% in the continuous group and 76% in the demand group (p = 0.11).

The average (± SD) number of COPD exacerbations per patient during the 6-mo study period by intention-to-treat analysis was 2.7 ± 2.5 in the demand group and 2.5 ± 2.7 in the continuous group (p = 0.60, 95% confidence interval [CI] for the difference between demand and continuous dosing: 1.1 to 1.7) (Figure 1). There were no deaths or intubations due to COPD, and there were no significant differences between treatment groups in the number of hospitalizations caused by COPD (three in the continuous group and none in the demand group), unscheduled clinic visits or ER visits for COPD (one in the continuous group and four in the demand group), or average number of exacerbations that were treated only with antibiotics (1.1 ± 1.4 in the continuous group and 0.7 ± 0.8 in the demand group, p = 0.37) (Table 2). The number of patients with at least one COPD exacerbation (14 in each group), and the mean number of days until the first COPD exacerbation (49 ± 47 d in the continuous group and 42 ± 44 d in the demand group), also did not differ significantly in the two treatment groups. When we restricted the analysis to the period during which the patient was taking study drug, the frequency of COPD exacerbations was not significantly different (0.028/d while taking study drug in the continuous group and 0.032/d in the demand group, p = 0.69).

View larger version (26K): [in this window] [in a new window]   Figure 1.   Distribution of exacerbations per patient in COPD patients treated with systemic corticosteroids on demand only (top panel ) or continuously (bottom panel ) over a 6-mo period (p = 0.60, 95% CI for difference in mean number of exacerbations: 1.1 to 1.7).

Over the 6-mo study period, the average (± SD) daily systemic corticosteroid dose by intention-to-treat analysis was 10.7 ± 5.2 mg in the continuous group and 6.3 ± 6.4 mg in the demand group (p = 0.003). When we restricted the analysis to the period during which the patient was taking study drug, the average daily corticosteroid dose was 15.1 ± 8.1 mg in the continuous group and 7.7 ± 7.5 mg in the demand group (p = 0.002).

Dyspnea, quality of life indices, FEV₁, and FVC did not differ significantly in the two treatment groups or from baseline measurements at any visit. The presence or absence of a bronchodilator response was not associated with the frequency of COPD exacerbations in either treatment group. The body weights of patients who were treated with systemic corticosteroids on demand only decreased by 4.8 ± 2.2 kg after 6 mo, as compared with an increase in the continuous group of 0.5 ± 3.5 kg (p = 0.007).

Symptoms of steroid withdrawal were not significantly different with the two study treatments at any time while subjects were taking study drug. By the end of the study 38% (95% CI: 19 to 63%) of patients in the continuous group and 57% (95% CI: 30 to 78%) of patients in the demand group correctly guessed their treatment assignment, neither percentage of which differed significantly from the value of 50% expected by chance. However, the study coordinator (F.L.) correctly guessed the treatment assignment of 76% (95% CI: 51 to 91%) of the patients in the continuous group and of 85% (95% CI: 59 to 96%) of the patients in the demand group, both of which percentages are significantly better than would be expected by chance. Her judgment was based on subtle improvements in patients' appearance and affect in the demand group.

	DISCUSSION

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In this randomized double-blind trial, patients with steroid- dependent COPD who continued oral prednisone daily for 6 mo had a similar number of COPD exacerbations to that of patients using prednisone on demand. In addition, patients receiving continuous steroids did not have a reduction in dyspnea, improved subjective health ratings, or better spirometric values than patients who gradually stopped taking daily prednisone. Patients who took prednisone only on demand had a significantly lower total exposure to systemic corticosteroids over the 6-mo study period. They also had a significant reduction in body weight.

Randomized trials with hospitalized patients and outpatients have shown that a brief course of systemic corticosteroids for acute exacerbations of COPD improves outcomes (7- 9). The benefits of extended oral corticosteroid therapy for COPD have not been as well established. Trials of corticosteroids in stable COPD have usually employed high doses for short periods. In a meta-analysis of 10 such randomized trials of corticosteroids in stable COPD, Callahan and associates found that a brief course of oral prednisone resulted in a 20% or greater increase in baseline FEV₁ only 10% more often than did placebo (1). The effects of oral corticosteroids on functional status and on morbidity have been examined in only a few of the studies of their use in stable COPD, with contradictory results. In one study, short-term prednisone had positive effects on dyspnea, exercise capacity, and spirometric values (10). Prednisone had beneficial effects on 12-min walking distance and assessments of quality of life in another study, but did not have beneficial effects on dyspnea (11). Two other studies failed to show a beneficial effect of prednisone on exercise capacity (12, 13).

The results of retrospective studies suggest that treatment with daily prednisone over many years of patients with moderate to severe COPD may be associated with a reduced rate of decline in pulmonary function (14, 15). However, clinicians presumably prescribe chronic prednisone primarily for control of respiratory symptoms. The only published long-term randomized trial of chronic oral steroids in patients with COPD that resembled our study was done by Renkema and colleagues, and failed to demonstrate additional improvements in clinically relevant outcome measures, including respiratory symptoms and episodes of respiratory decompensation, when daily oral prednisone was added to treatment with inhaled corticosteroids (2). Although the results of our study and that of Renkema and colleagues are similar, the patient populations and study designs differed. By definition, all of our patients were regarded on clinical grounds as requiring daily prednisone treatment; patients receiving continuous systemic corticosteroid therapy were excluded from the study by Renkema and colleagues. In our study, the average daily prednisone dose during the 6-mo study period for patients assigned to continuous prednisone treatment (11 ± 5 mg) was approximately twice the dose used in the study by Renkema and colleagues. The average baseline FEV₁ of patients in our study was 0.94 ± 0.39 L, as might be expected in a study of patients with advanced, steroid-dependent COPD, whereas in the study by Renkema and colleagues it was 1.86 ± 0.56 L.

Consensus is lacking about predictors of steroid responsiveness in patients with COPD. Most of the factors that have been considered relate to the presence of occult asthma. In one trial of short-term prednisone in patients with stable COPD, it was reported that when patients with features of bronchial asthma were carefully excluded, there was no difference in the effect of prednisone and placebo on pulmonary function tests (16). In other studies, wheezing, variability in spirometric values, response to bronchodilators, sputum or blood eosinophilia, or positive skin tests have been variable predictors of a benefit from corticosteroids (17). In our study a  12% response to bronchodilators (4), which was present in 15% and 17% of the continuous and demand groups, respectively, was not associated with response to continuation or withdrawal of chronic oral corticosteroid therapy. From a practical standpoint, the distinction between asthma and COPD may be impossible in many older patients, since these conditions appear to overlap (21). Patients with longstanding asthma can develop irreversible airway obstruction from the narrowing of small airways (24), and as many as 50% of COPD patients have evidence of airway hyperresponsiveness as measured by histamine challenge (25).

Our study has several limitations. First, patients who had previously experienced relatively few benefits and more adverse effects of daily prednisone might have been more inclined to participate in the study, thus increasing the likelihood of selection bias. Second, although it is standard practice to prescribe inhaled steroids for patients with steroid-dependent COPD in an effort to reduce maintenance doses of systemic corticosteroids, the use of inhaled steroids could have masked differences between the demand and continuous treatment groups in our study. Third, this pilot study does not provide sufficient power to exclude a treatment difference of as many as 1.7 exacerbations over a 6-mo period. However, it should be noted that although there was a statistically nonsignificant trend in favor of continuous prednisone treatment for prevention of COPD exacerbations, there was an opposite trend in favor of demand treatment for subjective health and dyspnea ratings. These preliminary results may warrant a larger trial, which, although feasible, would probably present challenges in recruitment and subject retention.

Investigation of the long-term efficacy of systemic corticosteroids in COPD is critical, because prolonged treatment with oral corticosteroids of patients with obstructive lung disease can have serious adverse effects, including adverse psychiatric events, an increased frequency of infection, worsened control of diabetes mellitus, and especially osteoporosis (26). In a cross-sectional study that was adjusted for the severity of COPD, McEvoy and coworkers showed that patients with more than a 6-mo lifetime exposure to oral corticosteroids had a significantly increased risk of symptomatic vertebral-body fractures (27). Another potential adverse effect of chronic glucocorticoid administration is weight gain with redistribution of fat to truncal areas, and an associated negative nitrogen balance with catabolic effects on lean body mass (28). In the present study, although patients were obese at baseline (weight 88.9 ± 3.2 kg), and the weight loss in the demand group appeared to be evenly distributed across the range of baseline weights, we did not determine whether the weight loss was due to reductions in edema, fat, or lean body mass.

The results of this study provide clinicians with a preliminary estimate of the relative merits of chronic oral corticosteroid treatment versus treatment on demand only. Most patients maintained on daily oral corticosteroid therapy continue to experience frequent exacerbations of COPD. Daily oral corticosteroids may be successfully discontinued for many steroid-dependent patients without apparent harm, thereby reducing cumulative corticosteroid exposure and body weight.