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Source: Niewohner DE, et al. N Engl J Med 1999;340:1941-1947.
This large-scale clinical trial of the use of systemic corticosteroids in acute exacerbations of chronic obstructive pulmonary disease (COPD) was carried out at 25 VA medical centers across the United States. To be eligible, patients had to have COPD both clinically and by pulmonary function tests when available, have no prominent findings suggesting asthma, have no other imminently life-limiting diagnoses, be admitted because of an acute exacerbation, and not have used systemic corticosteroids in the preceding month.
All patients were treated with oxygen, antibiotics, and aerosolized beta-agonist and anticholinergic bronchodilators. They were randomized within 12 hours of admission to receive either eight weeks of systemic steroids (125 mg methylprednisolone IV every 6 hours for 72 hours, followed by a tapering course of oral prednisone that started with 60 mg daily for 4 days), two weeks of steroids (same regimen, truncated at 2 weeks), or placebo. All of the patients also received inhaled steroids beginning on day four of hospitalization. Theophylline was not used. Outcomes studied prospectively included death, the need for intubation, duration of hospitalization, and serial spirometry, with follow-up standardized over the six months following admission.
One thousand eight hundred forty patients were screened for the study, of whom 271 were enrolled. The main reasons for exclusion were recent systemic steroid use (50%), refusal to participate (23%), and the presence of severe comorbidity (18%). There were 80 patients in each of the steroid groups and 111 received placebo. The patient groups were reasonably matched. Rates of nonadherance to the protocol were low and comparable among the groups.
Overall, 26 of the 271 patients died during the six-month follow-up period, and there were no differences among the groups. Lung function, as measured by forced expired volume in the first second (FEV1), improved faster in the steroid-treated patients than in those who received placebo; the maximum difference was about 0.10 L, and this difference disappeared by two weeks. The average length of hospitalization was significantly longer in the placebo group than in the combined corticosteroid groups (9.7 days vs 8.5 days; P = 0.03). Data on deaths during hospitalization and the need for intubation are not explicitly provided in the paper, but these outcomes involved only small numbers of patients and were apparently not different in the treatment groups. About half of all the patients experienced a treatment failure, defined as death from any cause, the need for intubation, readmission because of COPD, or intensification of pharmacologic therapy, during the six-month follow-up period. Placebo-treated patients had more treatment failures than steroid-treated patients (33% vs 23% at 30 days, P = 0.04; 48% vs 37% at 90 days, P = 0.04). Duration of steroid treatment (2 vs 8 weeks) had no significant effect on treatment failures. More steroid-treated patients developed hyperglycemia that required treatment (15% vs 4% in the placebo group; P = 0.002).
Comment by David J. Pierson, MD, FACP, FCCP
Only a minority of patients with severe COPD (10-15%) benefit physiologically from systemic corticosteroids when clinically stable. However, the situation changes during acute exacerbations of the disease, when bronchospasm and inflammation presumably intensify, and short courses of systemic steroids have long been a cornerstone of therapy. A landmark 1980 study by Albert and associates, also conducted in a VA population, showed that steroid-treated patients with acute exacerbations of chronic bronchitis and/or COPD experienced more spirometric improvement in the first 72 hours of hospitalization than patients who received placebo.1 That study did not address length of stay or the patients’ subsequent clinical course. The present study, much larger in scope and involving many more patients, confirms and extends the findings of Albert et al. It shows that unselected, nonasthmatic COPD patients requiring emergency hospitalization for an acute exacerbation improve more rapidly, get out of the hospital faster, and do better clinically over the next six months if they are treated with systemic corticosteroids.
An overall management strategy for patients with COPD has evolved by which all patients with acute exacerbations are treated with short-course systemic steroids, but only those who demonstrate a substantial improvement in FEV1 during a two-week prednisone trial while clinically stable receive this drug long-term. Such a strategy should avoid most steroid-associated complications, while maximizing potential clinical benefit for the patient. Inhaled steroids are widely used in patients with COPD, as they were in this study. However, this expensive and intrusive therapy is based on unimpressive and, in my opinion, debatable evidence and I do not often prescribe these agents for my own patients.
1. Albert RK, et al. Ann Intern Med 1980;92:753-758.