“How your approach in COPD might change in 2012” INTRODUCTION GOLD 2007 CAT (COPD Assessment Test) HEED study ECLIPSE study GOLD 2012 POSITION OF COMBINATION THERAPY CONCLUSION

Definition of COPD (GOLD 2012) Chronic obstructive pulmonary disease (COPD), a common preventable and treatable disease, is characterized by persistant airflow limitation: not fully reversible usually progressive associated with an enhanced chronic inflammatory response in the airways and the lungs to noxious particles or gases. Comorbidities and exacerbations contribute to the overall severity in individual patients. www.goldcopd.org

COPD: epidemiology Bousquet J. et al, Eur Respir J 2010; 36: 995-1001.

COPD: epidemiology US / Europe: smoking cigarettes cigars Asia / Africa: cooking and heating biomass fuel

COPD: the third biggest killer by 2020 1990 2020 Ischemic heart disease CVD disease Lower respiratory infection Diarrhoeal disease Perinatal disorders COPD Tuberculosis Measles Road traffic accident Lung cancer 3rd 6th Stomach cancer HIV Suicide As part of the Global Burden of Disease Study, Murray and Lopez1 projected future mortality rates based on the most common causes of death in 1990. The top 10 most important causes of death are presented in this slide. The majority of these leading causes of deaths are projected to remain stable or decline. Notably, COPD is expected to rise from the sixth biggest killer in 1990 to the third in 2020. Of the top 10 leading causes of death in 1990, only deaths caused by COPD, lung cancer and road traffic accidents are projected to rise. Reference Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet 1997;349:1498–504. Murray & Lopez, Lancet 1997.

INFLAMMATION AIRFLOW LIMITATION Small airways disease Bronchiolitis Emphysema Small airways disease Airway inflammation Airway remodeling Parenchymal destruction Loss of alveolar attachments Decrease of elastic recoil AIRFLOW LIMITATION www.goldcopd.org GOLD 2001

indoor/outdoor pollution SPIROMETRY IS REQUIRED Diagnosis of COPD EXPOSURE TO RISK FACTORS SYMPTOMS cough tobacco sputum occupation dyspnea indoor/outdoor pollution è : FEV1/FVC < 70% Post bronchodilatation! SPIROMETRY IS REQUIRED TO MAKE DIAGNOSIS www.goldcopd.org

“How your approach in COPD might change in 2012” INTRODUCTION GOLD 2007 CAT (COPD Assessment Test) HEED study ECLIPSE study GOLD 2012 POSITION OF COMBINATION THERAPY CONCLUSION

Previous GOLD guidelines Therapy at Each Stage of COPD I: Mild II: Moderate III: Severe IV: Very Severe FEV1/FVC < 70% FEV1 < 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure FEV1/FVC < 70% 30% < FEV1 < 50% predicted FEV1/FVC < 70% 50% < FEV1 < 80% predicted FEV1/FVC < 70% FEV1 > 80% predicted Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation Add inhaled glucocorticosteroids if repeated exacerbations Add long term oxygen if chronic respiratory failure. Consider surgical treatments www.goldcopd.org Report GOLD 2009 (Updated)

“How your approach in COPD might change in 2012” INTRODUCTION GOLD 2007 CAT (COPD Assessment Test) HEED study ECLIPSE study GOLD 2012 POSITION OF COMBINATION THERAPY CONCLUSION

Breathless walking on level ground Health status, FEV1 and GOLD stage: Staging by FEV1 neglects patient outcomes Lung function measurements do not reflect the impact of COPD 20 40 60 80 100 10 30 50 70 90 Upper limit of normal SGRQ score Stage 4 Stage 3 Stage 2 FEV1 (% predicted) Breathless walking on level ground r =–0.23 P<0.0001 Lung function measurements do not completely reflect the impact of COPD. The St George’s Respiratory Questionnaire (SGRQ) is considered to be a good tool for measuring the overall impact of COPD on patients’ health. However, as this slide shows, the correlation between FEV1 and health status measured using the SGRQ is weak, with a correlation coefficient of only −0.23.1 In addition, the utility of the SGRQ in everyday practice is limited because it is a 76-item questionnaire and requires a computer to score it.2 These problems resulted in an attempt to develop a new COPD assessment questionnaire. 1. Jones PW. Thorax 2001;56:880–887. 2. Jones PW et al. Am Rev Respir Dis 1992;145:1321–1327. Jones P. Thorax 2001;56:880-887. 11

Medical Research Council (mMRC) Dyspnea Score Dyspnea was defined as a score of 2 or higher on mMRC scale Airflow limitation: (FEV1) mMRC 4: I am to breathless to leave the house…; mMRC 3: I stop for breath after walking about 100 yards…; mMRC 2: I walk slower than other people…; mMRC 1: Short of breath when hurrying; mMRC 0: Breathless with strenuous exercise Adapted from Jones P. et al, ERJ 2011; 34: 29-35

Aims of the COPD Assessment Test (CAT) a patient-completed questionnaire a short, simple and reliable test: To improve the assessment of COPD patients To grade the impact of COPD on health status. Jones P. et al, ERJ 2009; 34: 648-654.

COPD Assessment Test (CAT) ✗ 1 2 4 3 5 22 Jones P. et al, ERJ 2009; 34: 648-654. Scoring range 0–40

Impact of COPD on daily life CAT score Light Moderate Important Very important 10 20 30 40 www.CATestonline.org

CAT: correlation with SGRQ P<0.0001 Jones P. et al, ERJ 2009; 34: 648-654.

“How your approach in COPD might change in 2012” INTRODUCTION GOLD 2007 CAT (COPD Assessment Test) HEED study ECLIPSE study GOLD 2012 POSITION OF COMBINATION THERAPY CONCLUSION

HEED study: Health related quality of life in European COPD patients A large cross-sectional observational study to evaluate health status in patients with COPD in primary care. COPD patients: Age: 40-80 years COPD: all severities Current or ex-smokers with a smoking history of ≥ 10 pack-years 7 Countries: Belgium, France, Germany, Italy, the Netherlands, Spain and UK. Real Life Jones P. et al, Resp Medicine 2011.

European COPD Quality of Life Survey Total: n = 1.787 Jones P. et al, Resp Medicine 2011.

European COPD Quality of Life Survey: SGRQ Jones P. et al, Resp Medicine 2011.

European COPD Quality of Life Survey: CAT Jones P., Brusselle G. et al, ERJ 2011.

European COPD Quality of Life Survey: CAT correlation with SGRQ HEED EU patients: r = 0.84, p<0.001 r=0.80* * P<0.0001 Jones P., Brusselle G. et al, ERJ 2011. *Jones PW et al. Eur Respir J 2009

“How your approach in COPD might change in 2012” INTRODUCTION GOLD 2007 CAT (COPD Assessment Test) HEED study ECLIPSE study GOLD 2012 POSITION OF COMBINATION THERAPY CONCLUSION

ECLIPSE study: Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints

The ECLIPSE Study: Objectives of this 3-yrs observational study To define clinically relevant COPD subtypes in individuals with GOLD stage II–IV COPD To define the parameters that predict disease progression over 3 years in the clinically relevant COPD subtypes To acquire data on known clinical biomarkers in order to identify those that correlate with clinically relevant COPD subtypes To identify novel genetic factors and/or biomarkers that correlate with clinically relevant COPD subtypes and with markers of disease progression Vestbo J, et al. Eur Respir J. 2008;31:869-873 25

ECLIPSE: Study Design 46 Centres;12 Countries Analysis GOLD stage II (FEV1 50–80% pred.) GOLD stage IV (FEV1 <30% pred.) GOLD stage III (FEV1 30–50% pred.) 2180 COPD subjects** 343 smoking controls 223 non-smoking controls 566 control subjects** Planned Recruitment 0 3 6 12 18 24 30 36 Months Analysis FSFV* Dec 19 2005 LSLV* Feb 19 2010 46 Centres;12 Countries Each visit captured: Lung Function; Impulse Oscillometry; Exhaled CO, Resting Oxygen Saturation; Blood samples; Exacerbation assessment Annual visits captured: Pulmonary plethysmography; Body composition; Fat-free mass; Exercise capacity; Induced sputum; Health status (SGRQ,BODE); Dyspnoea Year 1 and 3 Visits captured: Chest computed tomography Year 3 visit captured: Depression; Fatigue Vestbo J, et al. Eur Respir J. 2008;31:869-873.

Definition of COPD exacerbation according to GOLD guidelines An exacerbation of COPD is: “an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day- to-day variations and leads to a change in medication.” www.goldcopd.org 27

The ‘frequent exacerbator phenotype’: ECLIPSE Susceptibility to Exacerbation in Chronic Obstructive Pulmonary Disease John R. Hurst, Jørgen Vestbo, Antonio Anzueto, Nicholas Locantore, Hana Mϋllerova, Ruth Tal-Singer, Bruce Miller, David A. Lomas, Alvar Agusti, William MacNee, Peter Calverley, Stephen Rennard, Emiel F.M. Wouters and Jadwiga A. Wedzicha New England Journal of Medicine 2010;363:1128-38 Hurst JR, et al. N Engl J Med. 2010;363:1128-38.

The ‘frequent exacerbator phenotype’: ECLIPSE: Introduction Background Exacerbations of COPD are a major part of the natural history of COPD: Accelerate decline in lung function Reduce physical activity and QoL Increase risk of hospitalization and death Increased significantly healthcare costs Rationale The ECLIPSE cohort was used to test the hypothesis of a frequent exacerbation phenotype Is the most reliable predictor of exacerbations in an individual patient a history of prior exacerbations? Hurst JR, et al. N Engl J Med. 2010;363:1128-38 29

What are the predictors of exacerbation frequency? The ‘frequent exacerbator phenotype’: ECLIPSE Frequency/Severity of Exacerbations by GOLD stage (1) p<0.01 Exacerbations are more frequent and more severe with increasing COPD severity What are the predictors of exacerbation frequency? THIS SLIDE CONTAINS 3 BUILDS Hospitalised for exacerbation in yr 1 Frequent exacerbations (2 or more) ECLIPSE 1 year data Hurst et al. N Engl J Med 2010

The ‘frequent exacerbator phenotype’: ECLIPSE: Stability of the Exacerbator Phenotype 71% of Frequent Exacerbators in Year 1 and Year 2 were Frequent Exacerbators in Year 3 THIS SLIDE CONTAINS 7 BUILDS 74% of patients having no exacerbations in Years 1 and Year 2 had no exacerbations in Year 3 ECLIPSE 3 year data Hurst JR, et al. N Engl J Med. 2010;363:1128-38. 31

Conclusions (1) ECLIPSE and HEED confirm Disease severity (breathlessness, exercise capacity, exacerbations, health status degradation) increases with GOLD stage FEV1 poorly related with other parameters COPD is highly heterogeneous Within GOLD stage there is substantial variation in: Breathlessness Exercise capacity Exacerbation frequency Health status “Airflow limitation alone does not provide an accurate measure of disease severity or activity” New GOLD guidelines must include other parameters: QoL, symptoms and exacerbation rate Si l'obstruction bronchique était significativement lié à l'essoufflement, l'état de santé, 6MWD et nombre d'exacerbations, il y avait un chevauchement considérable entre les stades du GOLD, confirment l’hétérogéinicité de la BPCO et les faibles corrélations. Peu de bronchiectasies. Les donnés sur la distribution en fonction du BODE index n’a pas été présentée. Agusti A, et al. Resp Res. 2010;11:122 32 32

Exacerbation rate must be integrated in GOLD guidelines Conclusions (2) ECLIPSE confirms Exacerbations become more frequent and more severe as COPD severity increases Frequent exacerbator is an independent disease phenotype That can be identified by patient self-report about previous exacerbations Stable over time (3 yrs) Patients with moderate COPD may be frequent exacerbators (22%) Exacerbation in prior year is the best predictor of occurrence of exacerbation Exacerbation rate must be integrated in GOLD guidelines

“How your approach in COPD might change in 2012” INTRODUCTION GOLD 2007 CAT (COPD Assessment Test) HEED study ECLIPSE study GOLD 2012 POSITION OF COMBINATION THERAPY CONCLUSION

Approaches of COPD treatment according to GOLD guidelines Timeline Unidimensional approach Multidimensional approach GOLD 2001 GOLD 2012 1) Risk: FEV1 Rate of exacerbations 2) Symptoms: CAT score, mMRC scale 35

Management of COPD according to Symptoms, Spirometric classification and Future Risk of Exacerbations 4 (C) (D) ≥ 2 3 (GOLD Classification of Airflow Limitation) Spirometry (Exacerbation history) Risk 2 1 (A) (B) 1 mMRC < 2 CAT < 10 mMRC ≥ 2 CAT ≥ 10 Symptoms (mMRC or CAT score) www.goldcopd.org

Combined Assessment of COPD Assess symptoms first If mMRC 0-1 or CAT < 10: Less Symptoms (A or C) If mMRC > 2 or CAT > 10: More Symptoms (B or D) (C) (D) (A) (B) mMRC 0-1 CAT < 10 mMRC > 2 CAT > 10 Symptoms (mMRC or CAT score)) www.goldcopd.org

Combined Assessment of COPD Assess risk of exacerbations next If GOLD 1 or 2 and only 0 or 1 exacerbations per year: Low Risk (A or B) If GOLD 3 or 4 or two or more exacerbations per year: High Risk (C or D) 4 (C) (D) > 2 3 (GOLD Classification of Airflow Limitation) Risk (Exacerbation history) Risk 2 1 (A) (B) 1 mMRC 0-1 CAT < 10 mMRC > 2 CAT > 10 Symptoms (mMRC or CAT score)) www.goldcopd.org

The four COPD patient groups according to GOLD 2012 (summary) When assessing risk, choose the highest risk according to GOLD grade or exacerbation history Patient Characteristic Spirometric Classification Exacerbations per year mMRC CAT A Low Risk Less Symptoms GOLD 1-2 ≤ 1 0-1 < 10 B More Symptoms >2 ≥ 10 C High Risk GOLD 3-4 D www.goldcopd.org

Management of COPD according to Symptoms, Spirometric classification and Future Risk of Exacerbations ICS + LABA or LAAC 2) LAAC + LABA ICS + LABA or LAAC ICS + LABA + LAAC 4 ≥ 2 3 (GOLD Classification of Airflow Limitation) Spirometry (Exacerbation history) Risk 2 1)LAAC or LABA 2) LAAC + LABA 1 SAAC prn or SAAB prn 1 mMRC < 2 CAT < 10 mMRC ≥ 2 CAT ≥ 10 Symptoms (mMRC or CAT score) www.goldcopd.org

“How your approach in COPD might change in 2012” INTRODUCTION GOLD 2007 CAT (COPD Assessment Test) HEED study ECLIPSE study GOLD 2012 POSITION OF COMBINATION THERAPY CONCLUSION

TORCH: Post-bronchodilator FEV1 Adjusted mean change FEV1 (mL) –150 –100 –50 50 100 *† SFC SALM FP * Placebo Descriptive statistics of actual FEV1 and change from baseline FEV1 were reported for baseline and all subsequent visits and at withdrawal. Change from baseline FEV1 was compared between treatment groups using a repeated measures analysis. Treatment group was fitted as the explanatory variable, and smoking status, age, gender, baseline FEV1, region, visit, baseline FEV1 by visit and treatment by visit were fitted as covariates. Supportive analyses were also performed at each visit. The ANCOVA fitted change in FEV1 as the response variable, treatment group as the predictor variable and also adjusted for smoking status, age, gender, region and baseline FEV1. The adjusted mean change in post-bronchodilator FEV1 averaged over the 3-year treatment period was calculated for each treatment group: –62 mL for placebo –21 mL for SALM –15 mL for FP 29 mL for SFC. Average treatment differences were: 92 mL for SFC vs placebo (p < 0.001) 50 mL for SFC vs SALM (p < 0.001) 44 mL for SFC vs FP (p < 0.001) 42 mL for SALM vs placebo (p < 0.001) 47 mL for FP vs placebo (p < 0.001) In all cases, SFC significantly increased post-bronchodilator FEV1 compared with the other treatment arms. The true treatment effect may be larger, since there was differential drop out with placebo patients more likely to drop out, therefore this is likely to produce a conservative treatment effect of SFC. Reference Calverley PMA, Anderson JA, Celli B. for the TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. NEJM 2007; 356(8): 775-789 & Online Supplement 24 48 72 96 120 156 Time (weeks) *p < 0.001 vs placebo; †p < 0.001 vs SALM and FP Calverley et al. NEJM 2007 42

TORCH: SFC significantly reduces exacerbations over 3 years 0.2 0.4 0.6 0.8 1.0 1.2 Placebo Annualised exacerbation rate Salmeterol FP SFC 25% (p<0.001) 1.13 0.97 0.93 0.85 Treatment effect p-value SFC vs placebo 25% <0.001 SFC vs salmeterol 12% 0.002 SFC vs FP 9% 0.02 Calverley N Eng J Med 2007

Annualised exacerbation rate TORCH: SFC reduces rate of exacerbations requiring systemic corticosteroids over 3 years –0.05 0.15 0.35 0.55 0.75 0.95 1.15 Placebo Salmeterol FP SFC 43% (p<0.001) 0.80 0.64 0.52 0.46 Annualised exacerbation rate Moderate and severe p-value Treatment effect SFC vs placebo 43% <0.001 SFC vs salmeterol 29% <0.001 SFC vs FP 13% 0.02 Calverley N Eng J Med 2007

Annualised exacerbation rate TORCH: SFC reduces the rate of severe exacerbations requiring hospitalisation over 3 years 0.05 0.10 0.15 0.20 SFC FP Salmeterol Placebo 17% (p=0.03) 0.19 0.16 0.17 Annualised exacerbation rate p-value Treatment effect SFC vs placebo 17% 0.03 SFC vs salmeterol –2% 0.79 SFC vs FP 5% 0.56 Calverley N Eng J Med 2007

SFC reduces dyspnea 691 COPD (mean FEV1: 41%) with mMRC≥2 - results at 24 weeks * p<0.05 Mahler DA et al AJRCCM 2002

“How your approach in COPD might change in 2012” INTRODUCTION GOLD 2007 CAT (COPD Assessment Test) HEED study ECLIPSE study GOLD 2012 POSITION OF COMBINATION THERAPY CONCLUSION

Take home message COPD is highly heterogeneous (HEED and ECLIPSE) Former management of COPD (GOLD 2007): Unidimensional approach: spirometry: FEV1 (FEV1/FVC):  Diagnosis New management of COPD (GOLD 2012): Multidimensional approach: FEV1; mMRC, CAT and exacerbations  Diagnosis (and phenotyping)  Prognosis  Monitoring Aim: Optimal Management and Treatment ICS/LABA combination is effective in COPD patient groups C and D

Questions? 49