Debating the use of inhaled corticosteroids in the treatment of COPD. COPD Epidemiology. A quick patient case. Risk Factors for COPD 1,2

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1 Debating the use of inhaled corticosteroids in the treatment of COPD Suzanne G. Bollmeier Pharm.D., BCPS, AE-C Associate Professor, St. Louis College of Pharmacy ACPE Guidelines on Non- Commercialism o I or my spouse/partner have no actual or potential conflict of interest in relation to this program. Lori Wilken Pharm.D., TT-S, AE-C, CDE Assistant Clinical Professor, University of Illinois at Chicago College of Pharmacy A quick patient case COPD Epidemiology COPD is currently the fourth leading cause of death in the U.S. 1 Data from prevalence surveys estimated ~25% of adults aged 40 and older may have Stage 1 COPD or higher. 1 Let s come back to TP Risk Factors for COPD 1,2 Smoking Age Gender Race Family history Alpha 1 antitrypsin deficiency Nutritional status Socioeconomic status Co-morbidities Respiratory infections Previous tuberculosis Airway hyperresponsiveness Impaired lung growth Occupational dusts and chemicals Oxidative stress Air pollution Signs / Symptoms 1 Dyspnea Cough Chronic sputum production Wheezing Chest tightness

2 Disease Assessment 1 Classification of disease severity STAGE 1: MILD STAGE 2: MODERATE STAGE 3: SEVERE STAGE 4: VERY SEVERE PFT result WITH OR WITHOUT SYMPTOMS 50% FEV1 < 80% predicted 30% FEV1 < 50% predicted FEV1 < 30% predicted OR FEV1 < 50% predicted WITH presence of chronic Stage 1: MILD Stage 2: Stage 3: Stage 4: Very /FVC< 70% /FVC < 70% /FVC< 70% /FVC< 70% 80%* 50 80%* 30 50% * < 30% OR < 50%* + chronic Avoidance of risk factors (smoking cessation) Influenza vaccination Pneumococcal vaccine (up to date) Add Short Acting Bronchodilator (SABA or SA AC) when needed (PRN) Stage 1: MILD Stage 2: Stage 3: Stage 4: Very /FVC< 70% /FVC < 70% /FVC< 70% /FVC< 70% 80% 50 80% 30 50% < 30% OR < 50% + chronic Avoidance of risk factors (smoking cessation) Influenza vaccination Pneumococcal vaccine (up to date) Add Short Acting Bronchodilator (SABA or SA AC) when needed (PRN) Stage 1: MILD Stage 2: FEV % Stage 3: FEV % Stage 4: Very 30 50% + chronic Add regular treatment with one or more long acting bronchodilators (LABA, LA AC) (when needed) Add pulmonary rehabilitation Add inhaled glucocorticosteroids if repeated Add long term oxygen if chronic Stage 1: MILD Stage 2: FEV % Guidelines: for example 3 in the past 3 years Stage 3: FEV % Stage 4: Very 30 50% + chronic Add regular treatment with one or more long acting bronchodilators (LABA, LA AC) (when needed) Add pulmonary rehabilitation Add inhaled glucocorticosteroids if repeated Add long term oxygen if chronic Stage 1: MILD Stage 2: Stage 3: FEV % FEV % Stage 4: Very 30 50% + chronic Add regular treatment with one or more long acting bronchodilators (LABA, LA AC) (when needed) Add pulmonary rehabilitation Add inhaled glucocorticosteroids if repeated Add long term oxygen if chronic

3 Primary Literature Review regarding inhaled corticosteroids (ICS) Primary outcome All-cause mortality 1 year after initiating ICS therapy Secondary outcomes (6 mo, 2 yr, 3 yr) Pneumonia Fractures Mortality Methods 11 randomized controlled trails,426 participants Mean study duration 2 months 3 ICS studied as monotherapy or in Fluticasone Triamcinolone Budesonide Results All cause mortality ICS use was NOT associated with a decreased risk of death at 1 year follow-up (RR 0.86; 95% CI )p=2.0 Pneumonia Pts receiving ICS had a higher incidence of pneumonia (RR, 1.34; 95% CI, p=0.03) Fracture No difference in risk of fracture between ICS vs nonusers (RR % CI, p=4.0) A higher risk of pneumonia was found in the following subgroups Highest ICS dose (RR 1.46; 95% CI p=0.08) Shorter ( 2 years) duration of ICS use (RR 2.12.; 95% CI )p< Higher baseline COPD severity ( < 40% PREDICTED) RR 1.90; 95% CI, p=0.002) Combo therapy (RR 1.57; 95% CI, p< 0.001) Supporting ICS use for COPD Limitations of Drummond 3 and colleagues meta-analysis Different definitions of pneumonia Could have overlap with clinical COPD exacerbation Differing inclusion criteria Could limit external validity of the findings Didn t provide information related to QOL or symptom scores

4 Pro ICS trials TORCH 4 (Towards a revolution in COPD Health) Primary endpoint: time to death from any cause 3 years) Mean baseline: 44% predicted Compared 500mcg + salmeterol 50mcg with each component alone and placebo Combination group: fewer, improved health status, and lung function. Number needed to prevent one exacerbation: 4; to prevent one hospitalization: 32. -Decreased in group --but frequent not part of the inclusion criteria ---Additional COPD pts may benefit from combo LABA + ICS even if they don t have frequent (as detailed in guidelines) Pro ICS trials Aaron SD 5 Ann Intern Med April 17, 2007; 6 (8): Primary outcome: Proportion of patients with at 1 year. Mean baseline FEV1: < 50% predicted. Compared tiotropium, tiotropium + salmeterol, and tiotropium + salmeterol + One exacerbation in the past year was required for entry into the study. 60% of patients overall experienced (not significantly different between groups) Tiotropium + salmeterol + group: lower rates of requiring hospitalization vs tiotropium alone Modest benefit in preventing hospitalizations and health related QOL scores in both groups. Pro ICS trials Sin DD, et al 6 Pooled data regarding allcause mortality from 7 randomized trials of ICS vs placebo. All trials lasted at least 1 year. Overall 4% patients died. Those in ICS group had a lower rate or mortality (hazard ratio = 0.75; 95% CI ). Subgroup analysis revealed mortality in ICS groups for those in stages 3 4 COPD, but not 1 2. Reinforces the GOLD guidelines that patients in stages 3-4 can have benefits of ICS. Pro ICS trials Wouters EFM, et al. 7 COSMIC trial Thorax 2005; 60: Evaluated the effects on 1 year after withdrawal of inhaled. Inclusion: FEV % predicted and at least 2 exac in previous year 3 month run-in period of then randomized to received either: 500mcg BID + salmeterol 50mcg BID vs salmeterol alone Baseline FEV1 (pre bronchodilator): 49% predicted (both groups) -Withdrawal of resulted in a decrease in FEV1 of ~50ml/year. -Annual rate of moderate to severe was not statistically significant. -Mild decreased by less than 1 / year in the group (p=0.020). Annual rate of moderate to severe was not statistically significant This study supports continuing inhaled corticosteroids for a modest effect on lung function and exacerbation rate. Back to TP our patient Clinical Case Use ICS for our patients in Stages 3 and 4 COPD with history of Monitoring Advocate for discontinuation if no benefits are seen Exacerbation frequency Hospitalizations Quality of life

5 Against the use of ICS Why not nicotine replacement gum? 8 Why not nicotine replacement gum? Is it asthma? Why not long-term oral corticosteroids? Are ICS effective in smokers? Do ICS decrease mortality? Why not a LABA? 26 COPD Neutrophils, Macrophages, CD8+(Tc1) /FVC <70%, DLCO, Small bronchodilator response Poor response to steroids Is it asthma? 1 Asthma Eosinophils, CD4 (Th2), Macrophages post bronchodilator >12% and 200 ml Good response to steroids Asthma Neutrophils, Macrophages, CD4+ and CD8+ Small bronchodilator response Reduced response to steroids Oral Corticosteroids Duration of an Exacerbation 9 Budesonide Bud +Pred Placebo Pre Study (0-84) 10 (0-168) (0-42) Year 1 (0-46) 15 (0-35) (0-54) Year 2 10 (0-45) 17.5 (0-41) 16 (0-87) Are ICS effective in smokers (with asthma)? 10 Do ICS Decrease Mortality? Why not a LABA? TORCH 4 Mortality Exacerbation Pneumonia Placebo 15.2% % Salmeterol 13.5% % Fluticasone 16% 0.93 Combo 12.6% (P=0.052) % 19.6% 30

6 Clinical Case TP is nota candidate for ICS Recommend tobacco dependence treatment for TP Recommend pneumococcal vaccine Recommend d/c combivent and switching to tiotropium 18 mcg daily and albuterol 2 puffs prn sob Continue Formoterol 12 mcg bid Questions /conversation Suzanne G. Bollmeier Pharm.D., BCPS, AE-C Associate Professor, St. Louis College of Pharmacy Lori Wilken Pharm.D., TT-S, AE-C, CDE Assistant Clinical Professor, University of Illinois at Chicago College of Pharmacy References 1. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the diagnosis, management, and prevention of COPD: NHLBI/WHO workshop report. Bethesda, MD: National Heart, Lung, and Blood Institute, April, 2001.(updated 2008) available at 2. Williams DM, Bourdet SV. Chronic obstructive pulmonary disease. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy A Pathophysiologic Approach. 7 th ed. New York, NY: McGraw-Hill: 2008; Drummond, et al. Inhaled Corticosteroids in patients with stable chronic obstructive pulmonary disease; A systematic review and meta-analysis. JAMA 2008;300(20): Calverley PMA, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, et al. Salmeterol and propionate and survival in chronic obstructive pulmonary disease (TORCH). N Engl J Med 2007; 356: Aaron SD, Vandemheen, KL, Fergusson D, Maltais F, Bourbeau J, Goldstein R, et al. Tiotropium in with placebo, salmeterol, or salmeterol for treatment of chronic obstructive pulmonary disease. Ann Intern Med 2007; 6: Sin DD, Wu, L, Anderson JA, Anthonisen NR, Buist AS, Burge PS, et al. Inhaled corticosteroids and mortality in chronic obstructive pulmonary disease. Thorax 2005; 60: References 7. Wouters EFM, Postma DS, Fokkens B, Hop WCJ, Prins J, Kuipers AF, et al. Withdrawal of propionate from combined salmeterol/ treatment in patients with COPD causes immediate and sustained disease deterioration: a randomized controlled trial (COSMIC). Thorax 2005; 60: Anthonisen NR, Skeans MA, Wise RA, et al. The effects of smoking cessation intervention on.5 year mortality: A randomized clinical trial. Ann Intern Med 2005;2: Renkema TE, Schouten JP, Koeter GH, et al. Effects of long-term treatment with corticosteroids in COPD. CHEST 1996;109(5): Tomlinson JEM, McMahon AD, Chaudhuri R, et al. Efficacy of low and high dose inhaled corticosteroids in smokers versus non-smokers with mild asthma. Thorax 2005;60:

7 Pro/con debate Debating the use of ICS for the treatment of COPD Learning objectives 1. To describe the current role of ICS for COPD treatment 2. To question the safety and efficacy of inhaled corticosteroids for COPD Post test Questions 1. JB is a 58y.o. WM who complains of being winded while grocery shopping and cutting his grass with a push mower. He quit smoking last year. JB s pulmonary function test results reveal: (post bronchodilator) : 58% predicted, /FVC: 64% predicted. He is not currently on any medications. Based upon the current GOLD guidelines, which medication regimen (in addition to albuterol 2 puffs q6h prn sob), would be most appropriate to initiate for JB? a. Fluticasone 220 mcg 2 puffs bid b. Prednisone 40 mg daily c. Fluticasone/salmeterol 250/50 mcg 1 inhalation bid d. Tiotropium 18 mcg inhalation daily 2. DR is a 70y.o. WF who presents for a follow up on her COPD. Current medications include: tiotropium 18mcg daily and albuterol 2 puffs q6h prn sob. The physician wants to add /salmeterol 250/50 mcg 1 inhalation bid based upon last month s PFT results post bronchodilator: /FVC: 58% predicted, : 39% predicted. Current literature supports the addition of this medication to a. Improve the decline of long term b. Improve DR s quality of life c. Decrease DR s mortality risk d. Decrease DR s risk of stroke 3. GG is a 64y.o. WF with COPD. She stopped smoking 10 years ago. She has complaints this year of being admitted to the hospital on 3 separate occasions for confirmed pneumonia. Current medications include: /salmeterol 250/50 mcg 1p BID, Tiotropium Handihaler 18 mcg 1p daily, and albuterol HFA 2p Q4 6HPRN SOB. What recommendation do you have to improve GG s COPD regimen? a. Discontinue /salmeterol 250/50 mcg 1p BID b. Discontinue tiotropium and add HFA 44mcg 1p BID c. Discontinue salmeterol and initiate arformoterol neb solution BID d. Add ipratropium/albuterol MDI 2p QID scheduled