Steroid Treatment for COPD Exacerbations: Five Days Just as Effective as 14 Days

Patients with chronic obstructive pulmonary disease (COPD), sometimes known as emphysema, often experience acute exacerbations (or flare-ups) of lung symptoms, such as shortness of breath, coughing and sputum (phlegm) production. The conventional treatment for such COPD exacerbations typically involves a seven-to-14-day course of systemic glucocorticosteroids (also called glucocorticoids), a family of adrenal steroid drugs with anti-inflammatory effects.

Results from a well-designed clinical trial recently published in the Journal of the American Medical Association (JAMA) demonstrated that a five-day course of glucocorticoids for treating acute COPD exacerbations appears to work just as well as a 14-day course. Because many COPD patients suffer multiple acute exacerbations over a period of years and thus require repeated courses of glucocorticoids, the ability to safely reduce the duration of these treatments should help limit the frequency and severity of side effects caused by long-term cumulative exposure to these drugs.

What is COPD?

COPD is a common chronic, progressive lung disease characterized by difficulty moving air into and out of the lungs. The condition may be treated with bronchodilator medications, but it is not fully reversible. Smoking is the leading cause of COPD, by far. The disease classically can present either as emphysema (replacement of normal lung tissue with large air pockets) or chronic bronchitis (inflammation of the airways in the lungs), although some patients can have clinical features of both.

Common symptoms of COPD include coughing (with mucus or phlegm production), shortness of breath, wheezing and chest tightness. In mild COPD, shortness of breath may occur only with exertion. As COPD progresses, the shortness of breath may occur with minimal activity, such as slow walking, or even at rest.

Smoking cessation is the most important first step in slowing the progression of COPD. The primary chronic treatments for COPD include inhaled beta-agonist bronchodilators (such as albuterol [COMBIVENT, which also contains ipratropium, or PROVENTIL, VENTOLIN, VOLMAX and VOSPIRE], salmeterol [SEREVENT and ADVAIR] and formoterol [DULERA, FORADIL, PERFOROMIST and SYMBICORT]), inhaled anticholinergic bronchodilators such as ipratropium (ATROVENT, COMBIVENT and DUONEB) and tiotropium (SPIRIVA), inhaled steroids, systemic steroids given orally, pulmonary physical rehabilitation and home oxygen.

Acute COPD exacerbations can cause severe symptoms, are a common cause of hospitalization in COPD patients, and can lead to respiratory failure and death. Infections, either viral or bacterial, and exposure to air pollutants are considered to be common triggers of these exacerbations.[1]

Not surprisingly, the likelihood of having an acute exacerbation rises as COPD severity increases. For example, one study found that 22 percent of patients with moderate COPD, 33 percent with severe COPD and 47 percent with very severe COPD experienced frequent acute exacerbations (defined as two or more during the first year of follow-up).[2] The same study found that a history of prior exacerbations was the single best predictor of new exacerbations across all levels of COPD severity.[3]

Currently, treatment guidelines for COPD recommend a seven-to-14-day course of an oral glucocorticoid — such as prednisone (PREDNISONE INTENSOL, RAYOS) or prednisolone (FLO-PRED, ORAPRED, PRELONE) at a dose of 30 to 40 mg daily — for treatment of acute COPD exacerbations.[4],[5] Data from earlier studies indicate that such steroid treatment — in comparison to no steroid treatment at all — shortens recovery time and the duration of hospitalization, improves lung function and blood oxygen levels, and reduces the risks of both treatment failure and a recurrent exacerbation in the short-term.[6]

Seven small randomized clinical trials comparing short duration (ranging from three to seven days) and conventional duration (ranging from 10 to 15 days) for treatment of acute COPD exacerbations have previously been published.[7] The results of these studies, which involved a combined total of 288 patients, suggested that short courses of steroids were just as effective as the conventional longer courses.[8] However, conclusive recommendations could not be drawn from these studies because they were small and of relatively low quality.[9]

In contrast to these earlier studies, the recently published JAMA study was well-designed, high-quality and very large, with a total subject enrollment greater than the seven prior studies combined.

JAMA study overview

Researchers at five teaching hospitals in Switzerland conducted a randomized, placebo-controlled study comparing short-term (five days) and conventional (14 days) treatment with systemic glucocorticoids in patients with acute COPD exacerbations.[10] The study, published on June 25, 2013, was designed as a noninferiority trial, which means that researchers wanted to determine whether the short-term course of steroids was significantly worse, or not, than a conventional duration of treatment. Patients were enrolled in the study between March 2006 and February 2011.[11]

The subjects were COPD patients who came into the hospital emergency department (ED) with worsening of at least two of the following symptoms: shortness of breath, cough, or sputum quantity or purulence (change from clear or white sputum to sputum appearing yellow, green or brown).[12] To be included in the trial, patients had to be older than age 40 and have a history of smoking the equivalent of one pack of cigarettes per day for at least 20 years.[13] Patients with a history of asthma, X-ray evidence of pneumonia in the ED and near normal lung function tests were excluded from the trial.[14]

The subjects were randomly assigned to either five or 14 days of systemic glucocorticoids. All subjects in both groups were given an initial 40-mg intravenous dose of methylprednisolone on day one of the study, followed by a daily 40-mg oral dose of prednisone on study days two through five. From study day 6 through 14, subjects were given either 40 mg of prednisone (the conventional treatment group) or a matching placebo (short-term treatment group) once daily.[15] The study was double-blinded, meaning the patients, their doctors and the researchers did not know the study group to which each patient was assigned.[16]

All subjects in both groups received other standard treatments, including a seven-day course of antibiotics, inhaled short-acting bronchodilators administered with a nebulizer device while subjects were hospitalized, and inhaled glucocorticoids combined with beta-agonists twice daily plus inhaled tiotropium once daily. Subjects also received oxygen and mechanical ventilation (treatment with an artificial breathing machine) as needed.[17] Finally, additional glucocorticoids could be given to any subject in either group if the subject’s treating physician felt it necessary.[18]

The subjects were then monitored for up to six months. The researchers primarily evaluated how long it took for the next exacerbation to occur following treatment. They also looked at death from any cause, changes in lung function tests and the total cumulative glucocorticoid dose. Finally, they measured the length of hospital stay related to the initial COPD exacerbation and short-term side effects commonly associated with glucocorticoids (new or worsening hyperglycemia [high blood sugar] during hospitalization, new or worsening hypertension during hospitalization, and newly diagnosed infections during the six-month follow-up period).[19]

Study results

A total of 311 COPD patients were included in the study, with 155 randomly assigned to the conventional treatment group and 156 to the short-term treatment group.[20] Of these subjects, more than 90 percent were admitted to the hospital.[21] The average age of the subjects in both groups was 70 years.[22] Women comprised 47 percent of the conventional treatment group subjects and 33 percent of short-term group subjects.[23] There were fewer current smokers in the conventional treatment group than the short-term treatment group (40 percent versus 49 percent, respectively), a difference that could have favored the conventional treatment group. Other baseline clinical characteristics were similar between the two groups.[24]

The major study results are summarized in the table below. With respect to the primary outcome being studied, there was no difference seen in the time it took for the next COPD exacerbation to occur. During the six-month follow-up period, another COPD exacerbation occurred in 56 subjects (36 percent) in the short-term treatment group versus 57 subjects (37 percent) in the conventional treatment group.[25] On the basis of this result, the short-term course of glucocorticoids was found to be noninferior to (not significantly worse than) conventional treatment.

There also were no differences between the two study groups with respect to the rates of death, newly diagnosed infections, or new or worsening hyperglycemia.[27] Although a higher percentage of patients in the conventional treatment group experienced new or worsening hypertension than the short-term treatment group, this difference was not statistically significant.[28] Tests of lung function improved significantly in both groups between the time of initial presentation to the ED and day six of hospitalization.[29] No significant differences in lung function tests were seen between the two study groups during the follow-up period.

Predictably, the average total cumulative dose of prednisone taken by the conventional treatment group subjects was significantly, more than two times, higher than that of the short-term treatment group (793 mg versus 379 mg, respectively).[30]

Also, the median length of hospital stay was slightly longer for the conventional treatment group compared with the short-term treatment group, and this difference was found to be statistically significant.[31]

Summary of Major JAMA Study Outcomes[26]

*Number and percentage of subjects experiencing listed outcome in each group

Implications of the JAMA study

The study’s results underscore one of the 10 rules for safer drug use published on WorstPills.org:

Rule 5: Stopping a drug is as important as starting it. Do not take a drug any longer than is necessary.

With respect to effectiveness, the JAMA study provides strong evidence that a short, five-day course of glucocorticoid therapy for acute COPD exacerbations works just as well as a 14-day course for most patients.

In terms of risks, although no significant differences were seen between the study groups in the occurrence of short-term adverse events associated with glucocorticoid steroids, shortening the duration of the course of glucocorticoids for each COPD exacerbation likely will limit longer-term toxicities that are associated with these drugs in patients who suffer frequent exacerbations. Adverse events associated with increasing cumulative exposure to glucocorticoids include osteoporosis, fractures, avascular necrosis of the hip or other joints (a type of destructive arthritis), and cataracts.

A JAMA editorial entitled “Steroids for Treatment of COPD Exacerbations: Less Is Clearly More” noted the following:[32]

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. This is welcome news for patients with COPD who experience multiple exacerbations annually and are exposed to repeated courses of systemic corticosteroids. These findings will enable clinicians to minimize steroid exposure and reduce the risk of steroid-related toxicity in these patients.

We agree with this assessment.

What You Can Do

If you have COPD and continue to smoke, one of the most important steps you can take to manage your disease is to stop smoking. Consult with your doctor about smoking cessation programs and interventions.

If you develop a COPD exacerbation and your doctor prescribes a course of glucocorticosteroids, confirm how long the course will be. If the course is to be longer than five days, ask your doctor about limiting it to five days. You might consider taking this article with you to facilitate the discussion.

References

[1] Wouters EF. Management of severe COPD. Lancet. 2004;364(9437):883-895.

[2] Hurst JR, Vestbo J, Anzueto A, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12):1128-1138.

[3] Ibid.

[4] Vestbo J, Hurd SS, Agustí AG, 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(4):347-365.

[5] Walters JAE, 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; Issue 10. Art. No.: CD006897. DOI:10.1002/14651858.CD006897.pub2.

[6] Vestbo J, Hurd SS, Agustí AG, 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(4):347-365.

[7] Walters JAE,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; Issue 10. Art. No.: CD006897. DOI:10.1002/14651858.CD006897.pub2.

[8] Ibid.

[9] Ibid.

[10] 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.

[11] Ibid.

[12] Ibid.

[13] Ibid.

[14] Ibid.

[15] Ibid.

[16] Ibid.

[17] Ibid.

[18] Ibid.

[19] Ibid.

[20] Ibid.

[21] Ibid.

[22] Ibid.

[23] Ibid.

[24] Ibid.

[25] Ibid.

[26] Ibid.

[27] Ibid.

[28] Ibid.

[29] Ibid.

[30] Ibid.

[31] Ibid.

[32] Ibid.

[33] Sin DD, Park HY. Steroids for treatment of COPD exacerbations: less is clearly more. JAMA. 2013;309(21):2272-2273.