BACKGROUND: International guidelines advocate a 10 to 14-day course of systemic glucocorticoid therapy in the management of COPD exacerbations. The optimal duration of therapy is unknown and glucocorticoids have serious adverse effects. The aim of this trial is to demonstrate non-inferiority of a five-day compared to a 14-day course of systemic glucocorticoids with respect to COPD outcome, thereby significantly reducing steroid exposure and side effects in patients with COPD exacerbations.
METHODS:This is arandomised,placebo-controlled, non-inferiority multicentre trial. Patients with acute COPD exacerbation are randomised to receive 40 mg of prednisone-equivalent daily for 14 days (conventional arm) or glucocorticoid treatment for 5 days, followed by placebo for another 9 days (intervention arm). Follow-up is 180 days. The primary endpoint is time to next exacerbation. Secondary endpoints include cumulative glucocorticoid dose, time to open-label glucocorticoid therapy, glucocorticoid-associated side effects and complications, duration of hospital stay, death, change in FEV1, need for assisted ventilation, clinical outcome assessed by standardised questionnaires, and suppression of the hypothalamic-pituitary-adrenal axis.
RESULTS: Mean age (± SD) of patients who finished the study was 70 ± 11 years. 12% had mild or moderate disease, whereas severe and very severe stages were found in 30 and 58%, respectively. At the time of inclusion, 20% of patients were under treatment with systemic glucocorticoids.
CONCLUSIONS: If the strategy of significantly reducing cumulative exposure to glucocorticoids while taking advantage of their beneficial short-term effects proves to be successful, it will warrant a change in common glucocorticoid prescription practice, thereby improving the management of COPD.
Keywords: COPDexacerbationsteroidsglucocorticoidsside effects
List of abbreviations
COPD chronic obstructive pulmonary disease
GOLD Global Initiative for Chronic Obstructive Lung Disease
HPA axis hypothalamic-pituitary-adrenal axis
Chronic obstructive pulmonary disease (COPD) is the fourth commonest cause of death worldwide, posing a large socioeconomic burden [1, 2] . In Switzerland, it has been estimated that 5–7% of the population and 28% of the current smokers suffer from COPD . The clinical course of the disease is characterised by progressive, irreversible airflow obstruction associated with chronic inflammation of the respiratory tract. Acute exacerbations are triggered mainly by respiratory tract infections. According to evidence-based reviews and current guidelines, systemic glucocorticoid therapy is an integral part of the management of COPD exacerbations [1, 2, 4–10] . Randomised, controlled trials suggests that systemic glucocorticoid therapy accelerates the recovery of the FEV1 [11–16] , decreases the length of hospital stay [12, 15, 16] , and improves clinical outcome [14–17] . However, the optimal dose and duration of glucocorticoid therapy remain unknown. The SCCOPE trial, the largest placebo-controlled study, used cumulative prednisone doses as high as roughly 2000 and 2600 mg in the two active treatment arms, respectively, but the clinical outcomes of the active and placebo arms did not differ after 6 months of follow-up  . The benefit of glucocorticoids on FEV1 improvement lasts for 3 to 5 days and levels off thereafter [15, 16] . Thus, there are no data yet to suggest a benefit of treatment beyond 5 days.
As patients with COPD frequently experience exacerbations, many will be exposed to large cumulative doses of glucocorticoids during the course of their disease. A significant number of patients remain steroid-dependent beyond the acute exacerbation. Thus, approximately 50% of eligible patients had to be excluded from the SCCOPE study because of systemic glucocorticoid use in the 30 days prior to enrolment.
The side-effects and dangers of treatment with systemic glucocorticoids are well known. Their use in patients with COPD is independently associated with increased mortality in models adjusting for multiple confounders . Moreover, these patients are at enhanced risk for osteoporosis, in part due to decreased muscle mass, physical inactivity, and cigarette smoking. In a cohort of individuals with chronic pulmonary diseases, including COPD, the cumulative dose of glucocorticoids strongly correlated with vertebral fracture risk due to loss of bone mineral density  . Glucocorticoids contribute to muscle catabolism in COPD , and the cumulative dose has been found to correlate with muscle weakness . In the SCCOPE study, hyperglycaemia was seen significantly more often in glucocorticoid- as compared to placebo-treated patients, and rehospitalisation rates due to serious infections, particularly pneumonia, were high in the long-term active treatment group  . Moderate to high-dose (i.e., ≥25 mg/d prednisone equivalent) systemic glucocorticoid treatment, even if prescribed for a relatively short period (i.e., 5–30 days), may suppress the hypothalamic-pituitary-adrenal (HPA) axis as assessed by the low-dose (1 µg) ACTH stimulation test in almost half the patients . Although the clinical significance of this finding is unclear, a suppressed HPA axis may be potentially hazardous in stressful situations such as an acute exacerbation of COPD.
Thus, in order to alleviate these multiple adverse effects of glucocorticoid therapy, a strong effort should be made to minimise its cumulative dose in patients with COPD.
Recruitment started in March 2006. So far, 211 patients have been randomised, and a total of 127 have completed the 180 days follow-up. Their mean (± SD) age was 70 ± 11 years. Patients had smoked 50 ± 23 (mean ± SD) pack-years. 58% of the study subjects had very severe (GOLD stage IV) and 30% had severe (GOLD stage III) COPD; the remainder (12%) had mild or moderate airway obstruction (GOLD stage I and II, respectively). 20% of patients had received systemic glucocorticoids before entering the study, either for the index exacerbation or as part of their chronic COPD therapy.
The data safety and monitoring board carried out a pre-planned interim safety analysis after about 50% of the originally planned number of patients had completed the study. Based on the results of this analysis, the board recommended continuation of the trial without safety concerns.
A 10 to 14 day course of systemic corticosteroids in patients with acute COPD exacerbations is an evidence-based treatment recommendation and has become common clinical practice. Systemic glucocorticoids improve lung function, reduce hospital stay, and decrease treatment failure. However, randomised clinical trials addressing the use of systemic glucocorticoids are relatively sparse and heterogeneous in their designs and settings [7, 10] . Notably, the optimal dose and duration of treatment remains unknown. The benefits of glucocorticoids on recovery of lung function appear to level off after 3 to 5 days [15, 16] and are compromised by complications, notably a higher rate of hyperglycaemia requiring treatment, osteoporotic bone disease, muscle catabolism, and suppression of the endogenous cortisol production. Most importantly, prolonged use of glucocorticoids raises mortality in patients with COPD . This therapeutic dilemma prompted the initiation of the present multicentre trial aiming to demonstrate non-inferiority of a short course of systemic glucocorticoids as compared to a standard course, thereby significantly reducing steroid exposure. Some considerations made during the planning phase of this trial warrant additional comment.
Previous studies examined the effects of systemic corticosteroids in acute exacerbations of COPD and used spirometric improvement (FEV1) as a main outcome parameter [11, 12, 16] . However, FEV1 is not closely associated with the perception of dyspnoea or with exercise limitation  and is therefore of limited patient relevance. In the SCCOPE study  , treatment failure rates in the placebo and glucocorticoid groups were identical after 6 months of follow-up, and the primary outcome of treatment failure was defined as a composite of multiple clinical events of varying significance. We therefore decided to use “time to next exacerbation” as our primary endpoint and assess other clinical data, including FEV1, as secondary endpoints.
In our trial, the cumulative prednisone dose in the standard arm will be 560 mg. The cumulative dose used in the largest available study for hospitalised patients (the SCCOPE study ) amounts to ~2000 mg prednisone-equivalent in the short (2 weeks) and ~2600 mg in the long (8 week) treatment arm. We did not see a rationale to use such high dosage in our trial other than the attempt to rigorously copy the study design used in that trial. Thus, we decided to use a more practical and ethically more justifiable dose, although this will result in a treatment difference in the standard arm as compared to the SCCOPE study.
Apart from the intervention, we decided to rigorously standardise COPD medication, particularly inhaled steroids and bronchodilators, and the use of antibiotics during the initial treatment phase. At the time our study was designed, the fixed combined use of long-acting beta agonists, inhaled steroids, and tiotropium was beyond generally accepted treatment recommendations. However, we wanted to minimise any treatment bias that might have lead to falsification of the effects of systemic glucocorticoids. After our study had been initiated, the TORCH trial was published showing that, compared to placebo, inhaled long-acting beta-agonists combined with inhaled glucocorticoids reduce exacerbation rate, improve health status, and preserve lung function  . Similarly, in the UPLIFT study, tiotropium was shown to improve lung function and quality of life as well as reduce COPD exacerbations  . These results are reassuring in view of the treatment plan chosen in our study protocol. As for antimicrobial therapy, broad spectrum antibiotics have been shown to improve clinical outcome and, in hospitalised patients, reduce mortality .
Three previous trials conducted at the University Hospital Basel advocate procalcitonin-guided antibiotic treatment in patients with lower respiratory tract infections and exacerbated COPD [28, 29, 37] . The introduction of a procalcitonin-based treatment algorithm would have complicated our study protocol substantially. Also, published guidelines recommend antibiotic use in patients with altered sputum characteristics [2, 8] , but there is a large scope for discretion as to the choice of the antibiotic and the duration of treatment [7, 36] . In the present study, an unbalanced distribution of antibiotic use in the two treatment arms has to be avoided, especially as physicians are likely to prescribe antibiotics more frequently in patients with slow improvement, which could be the case in the short treatment arm. Thus, antibiotic treatment bias could compromise our non-inferiority design and obscure the true treatment effects from systemic corticosteroids.
We were confronted with doubts whether in the emergency room setting, the execution of an ACTH test prior to the initiation of glucocorticoid therapy is feasible. However, in a smaller trial studying the HPA axis in nine patients with exacerbated COPD, we were able to demonstrate the feasibility of this approach . The low-dose (1 µg) ACTH test measures plasma cortisol at baseline and 30 min. after stimulation, omitting the value 60 min. after stimulation, which is usually measured in the conventional (250 µg) ACTH test. Thus, the low-dose ACTH test does not cause a relevant delay in treatment.
In conclusion, the REDUCE study aims to clarify whether a 5-day course of systemic glucocorticoid therapy is non-inferior to a 14-day course for COPD patients with an acute exacerbation. The trial will add significant evidence regarding the treatment of exacerbated COPD with systemic glucocorticoids. Furthermore, the study addresses other important therapeutic issues, such as the practice of glucocorticoid withdrawal and adverse effects of systemic glucocorticoids.
PD Dr. Jonas Rutishauser
Clinic of Internal Medicine
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