Background: In Switzerland, about 5-7% of the population and certainly 28% of smokers suffer from COPD (“chronic obstructive pulmonary disease”). Acute exacerbation of COPD is a risk factor for further additional deterioration of the disease with correspondingly increased morbidity and mortality.
Specifically, patients with frequent exacerbations have increased mortality. Based on the Swiss COPD Cohort Study, 23-25% of patients annually suffer from COPD exacerbations requiring pharmacological treatment [1, 2]. Both Swiss and international guidelines recommend the use of systemic glucocorticoids (e.g., 30-40 mg oral prednisone for 10-14 days) in the treatment of COPD exacerbations [3, 4]. Randomized placebo-controlled trials showed over ten years ago that systemic glucocorticoids produced clinical improvement, shortened hospitalization time, and also improved pulmonary functional limitation [5]. However, the optimal duration and dose of this systemic glucocorticoid therapy is not known. A recently published Cochrane review of seven studies showed no clinical difference of glucocorticoid treatment of less or more than seven days in 281 patients with COPD exacerbations [6]. However, prolonged systemic glucocorticoid therapy is an independent risk factor for increased mortality in COPD and clearly leads to increased side effects such as the development of type 2 diabetes mellitus, osteoporosis, or development of adrenal insufficiency.
Question
With the REDUCE study (“Reduction in the Use of Corticosteroids in Exacerbated COPD”), we aimed to test the hypothesis whether five-day systemic glucocorticoid therapy is equally good and efficient as 14-day systemic glucocorticoid therapy (“non-inferiority”). Thus, we wondered whether a shorter course of systemic glucocorticoid therapy (5 days 40 mg/day) is equally good in terms of recurrence of exacerbation in the following six months compared with 14 days of therapy (14 days 40 mg/day).
Inclusion criterion
- Exacerbation of COPD defined by at least two of the following: change in dyspnea, cough, or sputum volume or color
- Age >40 years
- Smoker or ex-smoker of at least 20 py
Exclusion criteria
- History of known asthma
- No obstruction (FEV1/FVC >70%).
- Radiological diagnosis of pneumonia
- Expected survival of <6 months due to another comorbidity
- Pregnancy or breastfeeding
Study design
Randomized, double-blind, placebo-controlled, parallel-group study designed for non-inferiority. The study was multicenter.
Study location
- Cantonal Hospital Baselland at the Liestal and Bruderholz sites
- University Hospital Basel
- Biel Hospital Region
- Inselspital Bern
- Cantonal Hospital Lucerne
Groups
Group 1: Prednisone 40 mg/day from day 1-5 and placebo from day 6-14.
Group 2: Prednisone 40 mg/day from day 1-14.
The drugs administered were indistinguishable from each other (prednisone or placebo).
All patients received immediate-release bronchodilators during acute hospitalization, broad-spectrum antibiotic (Clamoxyl®/clavulanic acid type for 7 days), tiotropium bromide (Spiriva® 18 g 1×/day for 6 months), inhaled combination drug e.g. Symbicort® or Seretide® 2×/day for six months.
Measurement methods
Patients were examined before the start of prednisone administration (emergency department) or daily until hospital discharge and on days 6, 15, 30, 90, and 180. On days 15 and 90, this was done only via telephone interview.
The primary endpoint was the time to the next COPD exacerbation within the next six months (defined as acute worsening of a preexisting day-to-day variation in symptoms that required action by the treating physician). This could be done during the index exacerbation, i.e., over the course of the next six months.
Secondary endpoints were mortality, change in FEV1, cumulative corticosteroid dose, dyspnea, quality of life, and recording of steroid-related adverse events (such as increase in blood glucose or increase in blood pressure).
Sample calculation
Based on an assumed re-exacerbation rate of 50%, eleven different specialists (endocrinologists, internists, pulmonologists) judged an absolute difference of 15% between the two groups to be tolerable using the Delphi technique. Accordingly, according to the “non-inferiority” criteria, no more than 65% of patients in the short (5-day) corticosteroid arm were allowed to suffer an exacerbation in the following six months, which corresponded to a critical hazard ratio (HR) of 1.515. From this, we calculated that we needed to recruit 150 patients per arm.
Results
Side effects and adverse events were queried and recorded on the examination days.
- 770 patients were evaluated, 314 randomized.
- 3 patients were excluded after randomization in the blinded phase because of initial wrong COPD diagnosis.
- 311 patients could be used for the intention-to-treat analysis.
- 296 patients completed the 14-day treatment phase and could be included in the per protocol analysis.
- 12 patients (7.7%) in the 5-day glucocorticoid treatment arm and 13 patients (8.4%) in the 14-day glucocorticoid treatment arm were treated as outpatients.
- On average, the two treatment arms were comparable at baseline and did not differ in age, airway obstruction, or steroid pretreatment. However, there were more women in the 14-day glucocorticoid treatment arm compared to the five-day glucocorticoid treatment arm (46.5% vs. 32.7%, p=0.02).
- Fifty-six patients (35.9%) met the primary endpoint and experienced a new COPD exacerbation in the five-day glucocorticoid treatment arm compared with 57 patients (36.8%) in the 14-day glucocorticoid treatment arm. Thus, time to COPD exacerbation again was not different in the two treatment arms. Thus, we clearly demonstrated noninferiority of five-day glucocorticoid therapy compared with 14-day glucocorticoid therapy.
- In those patients who experienced a re-exacerbation during the six months studied, this exacerbation occurred after a median of 43.5 days in the 5-day glucocorticoid group and after 29 days in the 14-day glucocorticoid group.
- Secondary end points, such as death, occurred in 12 patients (7.7%) in the 5-day glucocorticoid treatment arm compared with 13 patients (8.4%) in the 14-day glucocorticoid treatment arm; the need for mechanical ventilation occurred in 17 patients (11%) in the 5-day glucocorticoid treatment arm compared with 21 patients (13.6%) in the 14-day glucocorticoid treatment arm.
- The cumulative prednisone dose was 200 mg in the 5-day glucocorticoid treatment arm compared with 560 mg in the 14-day glucocorticoid treatment arm. Thus, overall, a significantly lower prednisone dose was used in the shorter, five-day glucocorticoid treatment.
Discussion
Our study showed that five-day glucocorticoid treatment with 40 mg prednisone/day was equally good as 14-day glucocorticoid treatment in terms of time to next COPD exacerbation. About one-third of patients in both treatment arms experienced a new COPD exacerbation during the six-month observation period. There was no difference whether the COPD exacerbation was treated with 40 mg prednisone/day for 5 or for 14 days. Further, we also could not find any difference in terms of mortality, regardless of whether patients had been treated with 40 mg prednisone/day for 5 days or for 14 days.
“Less is more” certainly applies there. It should be noted, however, that we treated all patients simultaneously for seven days with a broad-spectrum antibiotic and immediate-release bronchodilators. We gave all patients a long-acting anticholinergic (tiotropium) and one of the inhaled combination drugs (Symbicort® or Seretide®) 2×/day for the six-month observation period, regardless of their COPD severity.
The majority of our patients suffered from severe to very severe COPD. Thus, the study cannot be automatically applied to all COPD stages. However, it is highly unlikely that patients with lower stages of COPD (1-2) would benefit from prolonged systemic steroid therapy.
Conclusions
The results of our study show that five-day glucocorticosteroid therapy (40 mg prednisone/day) is noninferior to longer-duration (14-day prednisone therapy) in the treatment of COPD exacerbation in a patient population with majority severe to very severe COPD. Thus, less is more or at least not worse. In patients with COPD exacerbation, it is sufficient to give systemic glucocorticoids for five days.
Prof. Dr. med. Jörg Daniel Leuppi
Source: Leuppi JD, et al: Short-term versus conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA 2013 Jun 5; 309(21): 2223-2231.
Literature:
- Jochmann A, et al: General practitioner’s adherence to the COPD GOLD guidelines: baseline data of the Swiss COPD Cohort Study. Swiss Med Wkly 2010 Apr 21; 140.
- Jochmann A, et al: Impact of adherence to the GOLD guidelines on symptom prevalence, lung function decline and exacerbation rate in the Swiss COPD cohort. Swiss Med Wkly 2012 Apr 5; 142.
- www.goldcopd.com
- Russi EW, et al: Diagnosis and management of chronic obstructive pulmonary disease: the Swiss guidelines. Official guidelines of the Swiss Respiratory Society. Respiration 2013; 85(2): 160-74.
- Niewoehner DE, et al: Department of Veterans Affairs Cooperative Study Group. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. N Engl J Med 1999; 340(25): 1941-1947.
- Walters JAE, et al: Different durations of corticosteroid therapy for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2011; 10: CD006897.
HAUSARZT PRAXIS 2014; 9(1): 36-38
