Steroid Therapy for COPD Exacerbations: Getting By With Less

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Steroid Therapy for COPD Exacerbations: Getting By With Less

By Salynn Boyles
Reviewed by Rima R. Gidwani, MD, Assistant Professor, Critical Care Medicine, University of Texas Medical School at Houston

Take Note

• Systemic corticosteroids are widely used to treat COPD exacerbations, but there's been little consensus on the duration of therapy and patients have been treated from a few days to several months.
• The REDUCE trial, published in 2013, found 5-day treatment with systemic daily prednisone to be no less effective than 14-day treatment, with a similar rate of re-exacerbations within 6 months.
• Findings from the trial prompted the international COPD consortium GOLD to change its treatment guidelines to recommend the shorter, 5-day steroid course for COPD exacerbations.

Treating exacerbations of chronic obstructive pulmonary disease (COPD) with corticosteroids for 5 days is no less effective than treating patients for 1 or 2 weeks or even longer. In fact, 5-day treatment should be considered the norm for most patients, including those with the most severe disease.

Findings from the Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE) trial,¹ published in June 2013, prompted the Global Initiative for Chronic Obstructive Lung Disease (GOLD) to revise its guidelines for the treatment of COPD flare-ups and call for the shorter course of steroid therapy instead of the 7 to 14 days of treatment that GOLD had previously recommended.

According to the 2014 GOLD guidelines, “A dose of 40 mg prednisone per day for 5 days is recommended (Evidence B), although there are insufficient data to provide firm conclusions concerning the optimal duration of corticosteroid therapy for acute exacerbations of COPD. Therapy with oral prednisolone is preferable. Nebulized budesonide alone may be an alternative (although more expensive) to oral corticosteroids in the treatment of exacerbations. Nebulized magnesium as an adjuvant to salbutamol treatment in the setting of acute exacerbations of COPD has no effect on FEV₁.”²

Acute exacerbations of COPD are a major cause of hospitalization, lung function decline, and death. Treatment with corticosteroids can reduce the length of hospital stays and shorten recovery times, but long-term use has been associated with poorer patient outcomes and greater mortality.^3,4 Even steroid use to treat COPD flare-ups for as short as a few weeks has been linked to adverse outcomes, including hyperglycemia, weight gain, and insomnia. And since the majority of patients experience at least 1 exacerbation a year, and as many as 10% experience 2 or more annually, the risk for cumulative exposures may be great.^4,5

A 2011 Cochrane review of 7 studies including a total of 288 patients with COPD exacerbations showed no significant differences in clinical outcomes between patients treated with corticosteroids for more than 7 days and those treated for 7 days or less (5 studies used oral prednisolone and 2 used intravenous corticosteroids). But the Cochrane researchers concluded that the studies weren’t of sufficient quality to make firm recommendations regarding the duration of corticosteroid treatment during COPD exacerbations.⁶

“The beauty of the REDUCE trial is that it definitively told us whether we should be treating patients with a long or short course of therapy,” said Don D. Sin, MD, University of British Columbia professor of medicine and COPD researcher, in an interview. “In most cases, 5 days of prednisone at 40 mg per day is sufficient for acute exacerbation management. This is important to know because we don’t want to give these medications for longer periods or at higher doses than is necessary, because while they’re very effective, they also have severe toxicities.”

The REDUCE trial included 314 patients who presented with acute COPD exacerbations to 5 Swiss teaching hospital emergency departments between March 2006 and February 2011 and were randomized to treatment with 40 mg of prednisone daily for either 5 or 14 days in a placebo-controlled, double-blind fashion. The main outcome measure for the study was time to next exacerbation within 180 days.

A total of 289 patients (92%) were hospitalized after being seen in the ER; 311 were included in the intention-to-treat analysis and 296 were included in the per-protocol analysis. In the 5-day treatment group, 56 patients (35.9%) reached the main endpoint compared to 57 (36.8%) in the 14-day treatment group. Rates of re-exacerbation within 180 days were also similar in the 2 groups (37.2% [95% CI 29.5% to 44.9%] in the 5-day group and 38.4% [95% CI 30.6% to 46.3%] in the 14-day group, for a difference of -1.2% [95% CI -12.2% to 9.8%]).

Among patients with re-exacerbations, the median time to the event was 43.5 days (interquartile range [IQR], 13 to 118) in the 5-day treatment group and 29 days (IQR, 16 to 85) in the 14-day treatment group. No significant differences were seen among the 2 groups in time to death; the combined endpoint of exacerbation, death, or both; and recovery of lung function.

Not surprisingly, mean cumulative prednisone dose was significantly higher in the longer treatment group (793 mg [95% CI 710 to 876 mg] versus 379 mg [95% CI 311 to 446 mg], P<.001). Treatment-associated adverse reactions, however—including hyperglycemia and hypertension—were similar in both groups.

“Most of our patients had severe or very severe COPD: therefore, our results cannot necessarily be applied to less severe disease grades. However, it seems unlikely that patients with GOLD grades 1 and 2 would benefit from longer glucocorticoid treatment for COPD exacerbations,” lead researcher Jörg D. Leuppi, MD, PhD, and colleagues, wrote in the June 5, 2013 issue of JAMA.

Dr. Sin agrees. Although he wasn’t involved with the research, he wrote an editorial that was published with the Leuppi study. He noted that the 5-day treatment group had a 65% reduction in cumulative steroid exposure compared to the longer-treatment group (200 mg median prednisone exposure versus 560 mg).⁵

Dr. Sin said that while many clinicians had adopted the shorter course of steroid treatment for COPD exacerbations before the REDUCE trial, others—especially those trained decades ago when 6 to 8 weeks of treatment was the norm—still treat patients for 2 weeks or longer.

He added that although clinicians are doing a better job of treating COPD in general, this isn’t necessarily the case for COPD exacerbations.

“The sad reality is that the treatments we use for acute exacerbations today are no different from the ones we were using 20 years ago,” he said. “We used antibiotics then and we still do. We used oxygen and steroids then and we still do. The fundamental tenets of treatment haven’t changed over the past 20 or 30 years. We need better therapies.”

Published: 02/18/2014

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. 2013;309:2223-2231.
2. Global Strategy for the Diagnosis, Management, and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2014.
3. Davies L, Angus RM, Calverley PM. Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial.Lancet. 1999;354:456-460.
4. Groenewegen KH, Schols AM, Wouters EF. Mortality and mortality-related factors after hospitalization for acute exacerbation of COPD. Chest. 2003;124:459-467.
5. Sin DD, Park HY. Steroids for treatment of COPD exacerbations: less is clearly more. JAMA. 2013;309:2272-2273.
6. Walters JA, Wang W, Morley C, et al. Different durations of corticosteroid therapy for exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2011 Oct 5;(10):CD006897.

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