Title: Steroids for Acute Exacerbation of Chronic Obstructive Pulmonary Disease – Five days is enough
Contributor Citation Information (Name, Degrees, Affiliation, AND EMAIL)
Author: Gary N. Asher, MD, MPH
Department of Family Medicine, University of North Carolina
Co-Author: Anne Mounsey MD. University of North Carolina at Chapel Hill. ()
Editor: James J. Stevermer, MD, MSPH ()
Department of Family and Community Medicine
University of Missouri - Columbia
Practice Changer
Five-day steroid treatment works as well as 14-day treatment for acute COPD exacerbation. (SOR B: Based on a single, well done, RCT)
Leuppi JD, Schuetz P, Bingisser R, et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial.JAMA. 2013;309(21):2223-2231.1
Illustrative Case
A 55-year-old man with COPD presents to the Emergency Department because of progressive shortness of breath, cough, and sputum production over the past 4 days. He is diagnosed with a COPD exacerbation, treated with corticosteroids, and admitted to the inpatient service. His hospital treatment includes antibiotics, inhaled albuterol and atrovent, supplemental oxygen, and oral corticosteroids.
How many days of oral steroids should he be given?
Clinical Context
Severe exacerbations of COPD are independently associated with mortality regardless of baseline COPD severity.2 Furthermore, nearly 60% of the cost of the disease is associated with acute exacerbations, particularly those episodes requiring hospitalization.3 Guidelines and systematic reviews advise use of oral glucocorticoids in the management of acute COPD exacerbation because they shorten recovery time and length of hospital stay, improve lung function, and reduce the risk of early relapse and treatment failure.4-6 However, it is unknown how long the steroid course should be. Data supporting a 14-day course compared to longer duration comes from the Systematic Corticosteroids in COPD Exacerbations (SCCOPE) trial.7 The current GOLD criteria suggest a dose of 30-40 mg daily for 10-14 days, but the report recognizes there are insufficient data from clinical and observational studies to support this recommendation.4 A recent Cochrane review compared short course treatment (3-7 days) to longer duration treatment (10-15 days) and judged the current evidence as inconclusive to recommend a clinical practice change.6
The REDUCE study is adouble-blinded,randomized, controlled trial that compared the use of 5-day verses 14-day oral steroid treatment in patients hospitalized for acute COPD exacerbation.1
Study Summary
Five-day steroid treatment (40 mg) may be sufficient for most patients with acute COPD exacerbations.
The REDUCE study used a non-inferiority methodology to compare5versus 14day courses of prednisone (40 mg daily) in treating patients with COPD exacerbations. A patient was considered to have a COPD exacerbation if he or she had a change from baseline in at least 2 of the following: dyspnea, cough, sputum quantity or purulence. Participants were consecutive patientswho presented to the Emergency Department at 1 of 5 Swiss teaching hospitals between March 2006 and February 2011. They were eligible if they were 40 years or older and had at least 20 pack-years of smoking. The investigators excluded patients with asthma, mild obstruction (FEV1:FVC > 70%), pneumonia, an estimated survival less than 6 months, pregnancy or lactation.All patients (n=311) received 40 mg methylprednisolone IV on day 1, and then prednisone 40 mg orally on each of days 2 through5.The researchers then randomly allocated participants into 2 groups and treated one group with prednisone 40mg daily and the other with matching placebo for a further 11 days. Participants also received seven days of antibiotics, twice daily inhaled steroids, daily tiotropium, and nebulized albuterol as needed.
The primary outcome was the time to next COPD exacerbation (up to 180 days). Non-inferiority between the groups was defined as no more than a 15% absolute increase in exacerbations. The dropout rate was 5.7% and evenly divided between groups. Intention-to-treat and per-protocol analyses were conducted, and hazard ratios were calculated using the Kaplan-Meier method and Cox proportional hazard models.
The time to next COPD exacerbation did not differ between the study groups (HR 0.95, 90% CI: 0.70 – 1.29). Sensitivity analyses adjusting for baseline characteristics provided similar results as did the per-protocol analysis.Secondary outcomes (overall survival, need for mechanical ventilation, need for additional corticosteroids, and clinical performance measures, such as dyspnea score and quality of life) also did not differ between groups. There were no between-group differences for hyperglycemia, worsening hypertension, infection, or other adverse effects typically associated with glucocorticoid use. The active treatment group took over 400 mg more prednisone than the placebo group (mean 793 mg vs.379 mg; p<0.001).
What’s New
While randomized trials demonstrate glucocorticoids improve COPD symptoms we don’t know the best treatment dose or duration. All current guidelines recommend treatment for longer than 5 days. This trial clearly demonstrated that 40 mg of prednisone for 5 days is at least as good as a 14-day treatment course. Furthermore, it is unnecessary to taper the short-course therapy, simplifying the treatment regimen.
Caveats
More than 80% of patients with acute COPD exacerbation can be managed in the outpatient setting.4 However, participants in this trial were hospitalized for a median of 8.5 days and most had severe or very severe COPD, which doesn’t fully represent the typical COPD population seen in outpatient practice. Fortunately, patients with less severe disease are probably at least as likely to respond to short course steroids as those with more severe disease. Importantly, participants in this study all received optimal guideline-based therapies during hospitalization, which may be difficult to achieve for some patients treated in the outpatient setting. Finally, treatment adherence observed during the hospitalization period in this trial is unlikely to be replicated in the outpatient setting.
Challenges to Implementation
For patients with new COPD exacerbation, or those successfully treated using short course treatment in the past, a 5-day regimen may be appropriate. For patients who have failed prior attempts at short course treatment, a 14-day regimen may be more advisable. However, there is no guideline to help choose which patients previously treated with longer course regimens may fail on short-course regimens.
Acknowledgement
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
References
1.Leuppi JD, Schuetz P, Bingisser R, et al. Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA. Jun 5 2013;309(21):2223-2231.
2.Soler-Cataluna JJ, Martinez-Garcia MA, Roman Sanchez P, Salcedo E, Navarro M, Ochando R. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. Nov 2005;60(11):925-931.
3.Hilleman DE, Dewan N, Malesker M, Friedman M. Pharmacoeconomic evaluation of COPD. Chest. Nov 2000;118(5):1278-1285.
4.Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for Diagnosis, Management, and Prevention of COPD (Updated 2013). Available online at
5.Quon BS, Gan WQ, Sin DD. Contemporary management of acute exacerbations of COPD: a systematic review and metaanalysis. Chest. Mar 2008;133(3):756-766.
6.Walters JA, Wang W, Morley C, Soltani A, Wood-Baker R. Different durations of corticosteroid therapy for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011(10):CD006897.
7.Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med. Jun 24 1999;340(25):1941-1947.