Diminishing Returns with Long-term Steroids in COPD Exacerbations
ABSTRACT & COMMENTARY
By Barbara A. Phillips, MD, MSPH
Professor of Medicine, University of Kentucky; Director, Sleep Disorder Center, Samaritan Hospital, Lexington
Dr. Phillips serves on the speakers bureau for PotomaCME.
This article originally appeared in the July 15, 2013, issue of Internal Medicine Alert. It was edited by Stephen Brunton, MD, and peer reviewed by Gerald Roberts, MD. Dr. Brunton is Adjunct Clinical Professor, University of North Carolina, Chapel Hill, and Dr. Roberts is Senior Attending Physician, Long Island Jewish Medical Center, NS/LIJ Health Care System, New Hyde Park, NY. Dr. Brunton serves on the advisory board for Abbott, Amarin, Boehringer Ingelheim, Duchesnay, Janssen, Lilly, Novo Nordisk, Sunovion, and Teva; he serves on the speakers bureau of Boehringer Ingelheim, Janssen, Lilly, Novo Nordisk, and Teva. Dr. Roberts reports no financial relationship to this field of study.
SYNOPSIS: Five days of steroid treatment was as effective as 14 days of treatment in preventing repeat exacerbations of COPD in patients presenting to the emergency department with COPD exacerbations.
SOURCE:Leuppi JD, et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease. The REDUCE randomized clinical trial. JAMA 2013;309:2223-2231.
The Swiss investigators who conducted this trial set out to determine if there would be important clinical differences for patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) who were treated with 5 days of oral steroids compared with those who were treated with the currently recommended 14 days.
They recruited consecutive patients with COPD exacerbations from emergency departments of teaching hospitals. COPD was defined by the presence of at least two of the following: change in baseline dyspnea, cough, or sputum quantity or purulence; age older than 40 years; and a smoking history of 20 pack-years or more. People were not eligible for this study if they had asthma, normal spirometry, pneumonia, terminal illness, or were pregnant. Patients were randomized to either 5 or 14 days of systemic glucocorticoids. Randomization was designed to match patients for age, use of steroids before the study, severity of COPD, and trial site. All patients received 40 mg of intravenous methylprednisolone on day 1, followed by 40 mg of oral prednisone daily from day 2 through 5. From day 6 through 14, patients received either 40 mg of oral prednisone or matching placebo once daily. In addition, all patients received a broad-spectrum antibiotic for 7 days and a nebulized, short-acting bronchodilator 4 to 6 times daily as needed while hospitalized. Inhaled glucocorticoids twice daily combined with inhaled ß2-agonist twice daily plus tiotropium 18 μg once daily were also used. Physiotherapy, supplemental oxygen, and ventilatory support were administered according to guidelines.1 Additional steroids could be administered at the discretion of the treating physicians. Endpoints were assessed daily during hospitalization, then on days 6, 15, 30, 90, and 180.
The primary endpoint was time to next COPD exacerbation over the next 6 months. Secondary endpoints were all-cause mortality, change in FEV1, cumulative steroid dose, clinical performance, quality of life, duration of hospital stay, time to open-label steroid use therapy (generally given in cases of another exacerbation), need for mechanical ventilation during the index exacerbation, and glucocorticoid-associated adverse effects (including hyperglycemia, hypertension, and infection).
After exclusions, data from 311 patients were used in an intention-to-treat analysis. A total of 296 patients completed the 14-day treatment period according to study protocol and were included in the per-protocol analysis. In other words, they were hospitalized for 14 days and definitely received the study medications, whereas the 25 patients who were treated in the ED and discharged without hospitalization may not have. There were more women in the conventional (long-term) group than in the short-term treatment group (46.5% vs 32.7%; P = 0.02), but otherwise, the two treatment groups were well balanced in terms of age, severity of airway obstruction, and pretreatment with glucocorticoids. In the 25 people who did not require hospitalization, 12 were in the short-term and 13 in the long-term steroid groups.
Overall, 56 patients (35.9%) reached the primary endpoint of COPD exacerbation in the short-term treatment group compared with 57 patients (36.8%) in the conventional treatment group. Time to re-exacerbation did not differ between groups. Among patients who experienced a re-exacerbation during follow-up, the median time to the event was 43.5 days in the short-term and 29 days in the conventional treatment group. Statistical adjustment for baseline variables, including sex, provided similar results. Overall survival did not differ between the treatment groups. For those who were hospitalized, patients who received short-term treatment had a shorter hospital stay with a median of 8 days compared with 9 days in the conventional treatment group (P = 0.04). The FEV1 improved significantly in both groups between baseline and the sixth day, and then remained stable. In addition, improvement in breathlessness, quality of life, and patient-assessed performance did not differ between treatment groups.
The number of patients receiving open-label steroid treatment (presumably for an exacerbation) during the study did not differ between treatment groups, but the total amount of steroids received was substantially different. The short-term group had a mean cumulative prednisone dose of 379 mg and the conventional treatment group had a mean cumulative prednisone dose of 793 mg.
However, there did not appear to be differences in short-term side effects in this study. There were not statistically significant differences between the short-term and long-term groups in terms of blood glucose levels, hyperglycemia, and worsening or new development of hypertension.
Commentary
This changes everything! COPD exacerbations are a very difficult, expensive, and destructive part of the disease. Exacerbations are a risk factor for loss of pulmonary function2 and death,3 and account for up to 70% of the cost of caring for the disease.4 Corticosteroids are a mainstay of treatment of COPD exacerbations, but the best dose and duration of treatment is unknown. Several guidelines recommend treatment with oral prednisone for 10-14 days,5,6 but evidence to support this is lacking. While steroids have well-documented benefits in treating exacerbations, those of us who have cared for patients who have had frequent exacerbations have witnessed the appalling side effects of serious long-term steroid toxicity, including weight gain, diabetes, osteoporosis, fractures, adrenal suppression, and ocular complications. Steroid toxicity is dose and duration dependent, so providing the lowest possible dose for the shortest possible time is clearly a benefit to patients.
While differences in steroid-induced side effects were not seen in this study, this was a relatively short (6 months) protocol and was not designed to assess this outcome. As Don Sin wrote in the accompanying editorial, "The clinical implications of this study are clear. Most patients with acute COPD exacerbations can be treated with a 5-day course of prednisone or equivalent (40 mg daily). Furthermore, this regimen can be applied across all...categories of disease severity."7
References
1.Celli BR, MacNee W.ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: A summary of the ATS/ERS position paper. Eur Respir J 2004;23:932-946.
2.Hansel TT, Barnes PJ. New drugs for exacerbations of chronic obstructive pulmonary disease. Lancet 2009; 374:744-755.
3.Soler-Cataluña JJ, et al. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax 2005;60:925-931.
4.Vestbo J, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013;187:347-365.
5.O’Donnell DE, et al. Canadian Thoracic Society recommendations for management of chronic obstructive pulmonary disease — 2007 update. Can Respir J 2007;
14(Suppl B): 5B-32B.
6.Walters JAE, et al. Different durations of corticosteroid therapy for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev2011; (10):CD006897.
7.Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management and prevention of COPD. http://www.goldcopd.org/guidelines/guidelines-resources.html. Accessed April 18, 2013.
8.Sin DD, Park HY. Steroids for treatment of COPD exacerbations: Less is clearly more. JAMA 2013;309:2272-2273.