Update on steroid recommendations for COPD exacerbations

Let’s start with a patient case.  An elderly patient is admitted through the emergency department with markedly worsening dyspnea and purulent sputum production over the last three days.  When reviewing his history, you find that he has GOLD grade 4 (very severe) COPD and experiences roughly one exacerbation per year that requires hospitalization.  His home medications for COPD include tiotropium (Spiriva) 18 mcg/inhalation once daily, albuterol MDI (Proventil HFA, ProAir HFA, or Ventolin HFA) 90 mcg/inhalation 2 inhalations every 4-6 hours as needed for dyspnea, and fluticasone/salmeterol (Advair Diskus) 250/50 mcg inhaled twice daily.  You are now deciding what steroid regimen should be initiated to manage this exacerbation.

Background

The use of corticosteroids for COPD exacerbations has been a long-standing practice but the ideal dose, duration, and route has not been confirmed.  The first and one of the most referenced studies that examined the efficacy of different steroid regimens was published in 1999.  It compared placebo with either a 2- or 8-week course of glucocorticoids in 271 patients with COPD exacerbations.  In this study, both steroid groups first received methylprednisolone 125 mg IV every 6 hours for 72 hours, followed by tapering doses of oral prednisone (60 mg daily tapered to 5 mg daily in the 8-week group and 60 mg daily tapered to 20 mg daily in the 2-week group).  All patients received a week of antibiotics and a specific regimen of inhalers.  Treatment failure at 30 and 90 days was higher in the placebo group and length of stay was longer by 1.2 days.  There was no difference between the 2- and 8-week courses of prednisone with regards to death, intubation, readmission for COPD, or need for intensification of therapy.

After this study was published, several smaller studies were carried out and were collectively analyzed in a Cochrane review in 2011 (7 studies totaling 288 patients).  This review concluded that outcomes were no worse for patients with COPD exacerbations who received shorter course (≤7 days) versus longer course (>7 days) of systemic steroid treatment.  

Namely for these reasons, through 2013, the GOLD guidelines recommendation for the management of COPD exacerbation recommended 30-40 mg of prednisolone daily for 10-14 days at Evidence category D (Panel Consensus Judgment).

Recent developments

Last year, a randomized double-blind placebo controlled noninferiority study was published in JAMA called the REDUCE trial (Reduction in the Use of Corticosteroids in Exacerbated COPD).  The study compared a 5- versus 14-day course of prednisone 40 mg orally once daily on the outcome of time to next COPD exacerbation in addition to other outcomes such as all-cause mortality, change in FEV₁, cumulative glucocorticoid dose, clinical performance, a quality of life score, and overall performance during 6 months of follow up.  The first dose in both groups was methylprednisolone 40 mg IV to facilitate administration in patients in distress.  All patients received 7 days of antibiotics, short-acting bronchodilators as needed, inhaled glucocorticoids twice daily, and tiotropium once daily.  

In the 5-day course, 35.9% of patients reached the primary outcome compared to 36.8% in the 14-day course.  There were no differences in time to reexacerbation, overall survival, need for mechanical ventilation during the initial exacerbation, improvement in FEV₁, dyspnea, quality of life, or overall performance.  In fact, the only differences between the study groups were the cumulative steroid dose (median 200 mg in the 5-day course vs. 560 mg in the 14-day course) and a shorter length of stay (by 1 day) in the 5-day course.  There were no significant differences in side effects either, including hypertension, hyperglycemia, infection rates, GI bleeding, insomnia, fractures, psychiatric symptoms, or heart failure.  It is noteworthy that more than 50% of the patients in both study groups were grade 4 (very severe) COPD.  

So to summarize, REDUCE was a robustly performed study of a 5- versus 14-day course of oral prednisone 40 mg daily (without a taper) in patients with COPD exacerbations with baseline severe to very severe COPD with the result of no meaningful difference in any objective or subjective study endpoints.  The shorter course had a shorter length of stay and lower cumulative steroid consumption.

Because of this study, the 2014 GOLD Guidelines revised their recommendations on the use of steroids in management of COPD exacerbations.  The current recommendation is a dose of prednisone 40 mg per day for 5 days with upgraded Evidence from D to B.  

Back to the patient case

Seeing how our patient is already on the correct inhaled medications for his severity at home (as per the GOLD guidelines), they should be continued during the acute exacerbation (short-acting bronchodilator, long-acting bronchodilator, and inhaled corticosteroid).  The patient should also receive 5-10 days of antibiotics because he meets two of the cardinal symptoms.  Lastly, a 5-day course of prednisone 40 mg orally daily should be initiated with the option of substituting the first dose with IV methylprednisolone 40 mg.  Monitoring for adverse effects such as hypertension, hyperglycemia, psychiatric symptoms, heart failure, and GI bleeding should be done (in addition to electrolytes, fluid retention, and drug interactions which was not mentioned in the REDUCE study).

Take home points:

• Systemic corticosteroids for COPD exacerbations are well established in reducing recovery time, improving FEV₁, PaO₂, risk of early relapse, length of stay, and treatment failure.
• The new recommendations from this year’s GOLD guidelines are prednisone 40 mg daily for 5 days.
• Ensure the patient is also taking the correct regimen of inhalers for their COPD severity (available in the GOLD guidelines).
• The equivalent doses to prednisone 40 mg are approximately methylprednisolone 32 mg, dexamethasone 6 mg, and hydrocortisone 160 mg.
• Prednisone oral bioavailability is 92% and can be administered once daily.  Morning administration is considered optimal to reduce the risk of HPA-axis suppression (this mimics the diurnal secretion of ACTH where concentrations are usually highest in the morning).
• To see how to convert systemic corticosteroids, see this post.

References:

1.  Neiwoehner DE, Erbland ML, Deupree RH, et al.  Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease.  N Engl J Med 1999;340:1941-7.

2.  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).

3.  Global Strategy for Diagnosis, Management, and Prevention of COPD.  2013.

4.  Leuppi JD, Schuetz P, Bingisser R, et al.  Short-term vs conventional glucocorticoid therapy in acute exacerbations of chronic obstructive pulmonary disease.  JAMA 2013;309(21):2223-31.
5.  Global Strategy for Diagnosis, Management, and Prevention of COPD.  2014.  Available at: http://www.goldcopd.org/Guidelines/guidelines-resources.html.  Accessed May, 2014.