1. USE OF STEROIDS IN PATIENTS WITH COPD EXACERBATION Richard C. Walls

2. Patient Case: JS  64 yo female who presented with increasing shortness of breath, wheezing, and hypoxia that did not adequately respond to oxygen supplementation and intensified bronchodilator therapy.  PMH and Home Medications  Atrial Fibrilation Aspirin 81 mg daily Digoxin 0.25 mg daily Diltiazem 240 mg daily  Depression/Anxiety Duloxetine 30 mg daily Lorazepam 1 mg BID prn Quetiapine 150 mg qhs  COPD Ipratropium 2.5 mL q6h prn  Hypothyroidism Levothyroxine 25 µg daily  Type II Diabetes Metformin 500 mg BID  Hyperlipidemia Simvastatin 20 mg qhs  Inpatient Medications  Albuterol 2.5 mg prn  Azithromycin 500 mg po  Methylprednisolone 60 mg IV

3. Why Steroids?  Niewoehner et al. (1999) 1  271 patients: 3 Treatment Groups Placebo (n=111) 3 days of methylprednisolone 125 mg q6h IV followed by Oral prednisone tapered over 2 weeks (n=80) Oral prednisone tapered over 8 weeks (n=80)  Primary outcome: death, intubation, readmission, or intensification of COPD therapy

4. Why Steroids? Percentage of Patients With a Primary Outcome Event 1 Placebo2 Weeks Steroids8 Weeks Steroids 30 days33% (3% death)24% (0%)22% (2%) 90 days48% (4%)38% (2%)36% (2%) 6 months54% (4%)49% (2%)52% (4%)  Fewer events with steroids after 30 & 90 days  No effect on mortality  No effect on all-cause mortality  No difference between duration of steroid treatment  Placebo length of stay 1.2 days longer than steroid  More adverse events with steroids  Hyperglycemia the most common significant adverse event

5. Why Steroids?  Davies et al. (1999) 2  14 days of 30 mg prednisone po (n=29) daily or placebo (n=27)  Greater increase FEV 1 with prednisone (92% vs. 85% at day 5 of treatment)  Placebo length of stay 2 days longer than steroid  GOLD guidelines 3  Recommend 30-40 mg prednisolone daily for 10-14 days in patients with COPD exacerbation  Recently updated (2013) to include all patients with COPD exacerbations  Recommendation graded Evidence Category D indicating a panel consensus judgment

6. Controversies  Is oral administration as effective as IV?  Is there a role for inhaled steroids in the treatment of COPD exacerbations?  Does the evidence support 30-40 mg prednisone daily for 10-14 days as an ideal regimen?

7. Oral vs. IV Steroids  de Jong et al. (2007) 4  5 days of 60 mg prednisolone daily either IV (n=107) or po (n=103)  Evaluated treatment failure: death, ICU admission, readmission to ICU due to COPD, or intensification of therapy within 90 days of treatment  Oral (56.3%) non-inferior to IV (61.7%) Overall treatment failure higher than 2 week regimen in Niewoehner trial (38%) 1 First three days of Niewoehner trial featured steroid doses 2.6 times higher 5  No data reported on adverse events  Ceviker, Sayiner (2013) 6 7 days of 32 mg methylprednisolone po daily (n=20) 4 days 1 mg/kg/day methylprednisolone IV then 3 days of 0.5 mg/kg/day (n=20)  Both groups showed improvement in FEV 1 (49.1% oral vs. 40.0% IV)  Less incidence of hyperglycemia in oral (22.2% vs. 55%)  Did not compare equipotent steroid doses

8. Systemic vs. Inhaled Steroids  Gunen et al. (2009) 7  Reviewed trials comparing nebulized budesonide to systemic steroids  No difference in efficacy, fewer adverse events (especially hyperglycemia) with budesonide  Only reviewed 7 trials Small trials (Averaged 88 patients) Short trials (Longest was 16 days) 3 of the trials were for asthma exacerbation

9. Implications for JS  Literature Summary  Suggest usefulness in COPD exacerbation  No clearly ideal dose, duration, or route of administration  Suggests dose-response/dose-toxicity relationship  Pertinent Patient Specific Factors  Type II Diabetes: Risk of hyperglycemia with high doses  Exacerbation possibly secondary to infection: Do we really want to expose JS to another route of infection?  JS is currently tolerating oral medications  Exacerbation is not so severe that it is immediately life threatening

10. Implications for JS  Given the patient’s clinical picture that puts her at risk for corticosteroid and IV access related complications, IV therapy at this point is likely inappropriate, and initiating a course of 30 mg oral prednisone daily would be more appropriate.

11. References 1. Niewoehner DE, Erbland ML, Deupree RH, Collins D, Gross NJ, Light RW, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med 1999 Jun 24;340(25):1941-1947. 2. 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 Aug 7;354(9177):456-460. 3. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. NHLBI/WHO workshop report. Bethesda, MD: National Heart, Lung, and Blood Institute; April 2001. Updated February 2013, http://www.goldcopd.com/.http://www.goldcopd.com/ 4. de Jong YP, Uil SM, Grotjohan HP, Postma DS, Kerstjens HA, van den Berg JW. Oral or IV prednisolone in the treatment of COPD exacerbations: a randomized, controlled, double-blind study. Chest 2007 Dec;132(6):1741-1747. 5. National Adrenal Diseases Foundation. Corticosteriod Comparison Chart. http://www.nadf.us/tools/adrenalhormone.pdf 6. Ceviker Y, Sayiner A. Comparison of two systemic steroid regimens for the treatment of COPD exacerbations. Pulm Pharmacol Ther 2013 Mar 18. 7. Gunen H, Mirici A, Meral M, Akgun M. Steroids in acute exacerbations of chronic obstructive pulmonary disease: are nebulized and systemic forms comparable? Curr Opin Pulm Med 2009 Mar;15(2):133-137.