Reversibility: Redefining Airflow Obstruction in COPD /09 ©AstraZeneca LP. All rights reserved.

Current Definition and Diagnosis of COPD A preventable and treatable diseaseA preventable and treatable disease Associated with significant extrapulmonary effects and important comorbid conditionsAssociated with significant extrapulmonary effects and important comorbid conditions Characterized by airflow limitation that isCharacterized by airflow limitation that is –Partially reversible –Usually progressive –Associated with an abnormal inflammatory response to noxious particles or gases Postbronchodilator FEV 1 /FVC <0.7 used to help establish diagnosisPostbronchodilator FEV 1 /FVC <0.7 used to help establish diagnosis Global Initiative for Chronic Obstructive Lung Disease. Accessed November 21, 2008.

How is Reversibility of Airflow Obstruction Defined? Defined by ATS/ERS Task Force on Lung Function Testing 1Defined by ATS/ERS Task Force on Lung Function Testing 1 Postbronchodilator FEV 1 and/or FVC ≥200 mL and 12% improvement over baseline is considered significant bronchodilation 1Postbronchodilator FEV 1 and/or FVC ≥200 mL and 12% improvement over baseline is considered significant bronchodilation 1 GOLD COPD Guidelines have adopted this standard 2GOLD COPD Guidelines have adopted this standard 2 1. Pellegrino R, Viegi G, Brusasco V et a. Eur Respir J. 2005;26:948– Global Initiative for Chronic Obstructive Lung Disease. Accessed November 21, 2008.

Hyperinflation Is a Hallmark of COPD Increases FRC (EELV)Increases FRC (EELV) Decreases ICDecreases IC Increases volume at which tidal breathing occursIncreases volume at which tidal breathing occurs Worsens with exercise and reduces exercise tolerance (dynamic hyperinflation)Worsens with exercise and reduces exercise tolerance (dynamic hyperinflation) Total Lung Capacity Tidal Ventilation Healthy Patients Patients With COPD Patients With COPD During Exercise No Bronchodilator With Bronchodilator FRC (EELV) (EELV) IC = inspiratory capacity; FRC/EELV = functional residual capacity/end expiratory lung volume. Adapted with permission from Sutherland ER et al. N Engl J Med. 2004;350: IC

Understanding Changes in Lung Volumes Ferguson GT. Proc Am Thorac Soc. 2006;3: Time Volume TLC VC TLC IC FRC IRV VTVTVTVT ERV RVRV

Airflow Obstruction Is a Central Feature of COPD 1,2 Dyspnea Dyspnea Exercise Tolerance Airflow Limitation, Air Trapping, Lung Hyperinflation, Mucus Hypersecretion Decline in Lung Function Deterioration in Health Status in Health Status Premature Mortality Inactivity Exacerbations 1. Global Initiative for Chronic Obstructive Lung Disease. Accessed November 21, American Thoracic Society, European Respiratory Society. Accessed November 19, 2008.

Patients With COPD Ipratropium (anticholinergic) Patients With COPD Albuterol (β 2 -Agonist) ▲ Asthma and COPD Have Varying Degrees of Bronchodilator Responsiveness n=19. Adapted with permission from Higgins BG et al. Eur Resp J. 1991;4: Patients With Asthma Ipratropium (anticholinergic) Patients With Asthma Albuterol (β 2 -Agonist) ■ Cumulative Dose (µg) Δ FEV 1 ■ ■ ■ ■ ▲ ▲ ▲ ▲

COPD Previously Defined as “Irreversible” Airway Obstruction Note: Actual subset sizes were not proportional relative to the subset images. Adapted from American Thoracic Society. Am J Respir Crit Care Med. 1995;152(5 pt 2):S77-S121. Chronic Bronchitis Emphysema Airflow Obstruction Asthma COPD(Irreversible) (Reversible)

Mean Reversibility ~4% Baseline Characteristics Study Group SIA (n=1961) SIP (n=1962) UC (n=1964) Mean (SD) age, years 48.4 (6.8) 48.6 (6.8) 48.4 (6.9) Male, % Mean (SD) pack-years of cigarette smoking 40.4 (19.7) 40.4 (18.8) 40.5 (18.9) Mean (SD) FEV 1 L (prebronchodilator) 2.62 (0.61) 2.64 (0.59) 2.65 (0.59) Mean (SD) FEV 1 L (postbronchodilator) 2.73 (0.64) 2.75 (0.62) 2.76 (0.62) Mean (SD) FEV 1, predicted % 75.1 (8.8) 75.2 (8.8) 75.1 (8.8) Mean (SD) FEV 1 /FVC, % 62.9 (5.6) 63.0 (5.5) 62.9 (5.5) Mean (SD) bronchodilator response (% of FEV 1 ) 4.2 (5.2)4.4 (5.1)4.2 (5.1) Patient Populations Included in COPD Studies Were Largely “Irreversible” n=5887. SIA=smoking intervention and inhaled bronchodilator ipratropium bromide. SIP = smoking intervention plus placebo. UC=usual care. Anthonisen NR et al. JAMA. 1994;272: Lung Health Study Subject Demographics and Baseline Characteristics

“Irreversible” Patients Can Change Their Reversibility Status Over Time Study Population: 660 Patients Meeting Both ERS and ATS Criteria for Irreversible COPD, Years of Age, Current or Ex-tobacco Smokers N = 660 Visit 0: 58% Visit 1: 62% Visit 2: 59% 52% of Patients Changed Bronchodilator Responder Status Over a 2-month Period per ATS Criteria Total % Not Reversible at Each Visit Calverley PM et al. Thorax. 2003;58: = Positive responders = Negative responders

73% of Patients Show Reversibility to Short-acting Bronchodilators* 27% 11% (n=280) 27% 35% (n=217) (n=222) (n=91) N=813. *Reversibility defined as ≥12% and >200 mL increase in FEV 1. Donohue J et al. Presented at the 1997 International Conference of the American Thoracic Society. San Francisco, CA; May 18-21, Reversibility Varies by Patient and Bronchodilator Both Neither Albuterol only Ipratropium only

A Recent Study Also Demonstrates Reversibility in Many Patients With COPD Postbronchodilator FEV 1 measured after administration of 80 µg ipratropium and 400 µg albuterol. Adapted with permission from Tashkin DP et al. Eur Resp J. 2008;31: Change in FEV 1 % Patients, % Degree of Reversibility ~54% of Patients Met ATS Reversibility Criteria (≥12% + ≥200 mL) *65.6% showed a >15% increase in FEV 1 *

Bronchodilators Play an Important Role in COPD Treatment Algorithms ATS/ERS Guidelines SA-BD = short-acting bronchodilator; LA-BD = long-acting bronchodilator;ICS = inhaled corticosteroid. SA-BD = short-acting bronchodilator; LA-BD = long-acting bronchodilator; ICS = inhaled corticosteroid. Adapted from Celli B et al. Eur Respir J. 2004;23: Intermittent Sx Intermittent Sx (cough, wheeze, dyspnea) Persistent Sx Persistent Sx (dyspnea, pm awakenings) SA-BD p.r.n. LA-BD/SA-BD q.i.d. with rescue Alternative class/combination ( LA-BD /ICS) Add/substitute oral theophylline Limited Benefit? Limited Benefit? AE? Yes Yes Confirm Dx Confirm Dx of COPD

Bronchodilatory Response Varies in COPD Long-acting β 2 -agonist vs Long-acting Anticholinergic AUC FEV hours; Formoterol +114 mL vs tiotropium (P=0.014) n=81. Form = formoterol. Tio = tiotropium. Richter K et al. Respiration. 2006;73: Time (min) FEV 1 (mL) FEV 1 (mL) Form 12 µg bid Tio 18 µg qd

n=80. T = tiotropium; P = placebo; FRC = functional residual capacity. *P<0.01. Celli B et al. Chest. 2003;124: Significant Improvements in Volume-based Measurements After Bronchodilator FVCICFRC Difference (T – P) at Day 28 (mL) FEV 1 * * FlowVolume PredosePostdose 800 * * * * * *

What Is a Meaningful Improvement in FEV 1 for Patients with COPD? Minimal clinically important difference (MCID) is the smallest difference patients perceive as beneficial and which would mandate a change in management 1Minimal clinically important difference (MCID) is the smallest difference patients perceive as beneficial and which would mandate a change in management 1 From a patient perspective, 4% or 112 mL increase in FEV 1 has been associated with improved dyspnea 2From a patient perspective, 4% or 112 mL increase in FEV 1 has been associated with improved dyspnea 2 Current recommendations suggest postdose FEV 1 improvement of 100 to 140 mL as an appropriate MCID range 1,2Current recommendations suggest postdose FEV 1 improvement of 100 to 140 mL as an appropriate MCID range 1,2 1. Donohue JF. COPD Mar;2(1): Cazzola M et al. Eur Respir J. 2008;31:

Patients May Respond to Long-term Bronchodilator Therapy, Regardless of Initial Reversibility Status n=921. *P<.001 vs placebo at all time points following drug administration. Tashkin D, Kesten S. Chest. 2003;123: FEV 1 (liters) PlaceboTiotropium Time (minutes) FEV 1 (liters) PlaceboTiotropium Time (minutes) 1.4 Day 1 Day 344 Responders Poor Responders * *

Understanding Reversibility in COPD Professional guidelines and clinical data demonstrate that airflow obstruction in COPD is at least partially reversibleProfessional guidelines and clinical data demonstrate that airflow obstruction in COPD is at least partially reversible Studies show that bronchodilators can improve lung function in COPD patientsStudies show that bronchodilators can improve lung function in COPD patients Reversibility status may vary in response to different bronchodilators, and may change over timeReversibility status may vary in response to different bronchodilators, and may change over time Patients may respond to long-term bronchodilator therapy, regardless of short-term reversibilityPatients may respond to long-term bronchodilator therapy, regardless of short-term reversibility