“How your approach in COPD might change in 2012”

“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.

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

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 Murray & Lopez, Lancet 1997.

INFLAMMATION 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

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

Previous GOLD guidelinesTherapy at Each Stage of COPD I: Mild II: Moderate III: Severe IV: Very Severe Active reduction of risk factor(s); influenza vaccination Addshort-acting bronchodilator (when needed) Addregular treatment with one or more long-acting bronchodilators (when needed);Addrehabilitation Addinhaled glucocorticosteroids if repeated exacerbations Addlong term oxygenif chronic respiratory failure. Considersurgical treatments www.goldcopd.org Report GOLD 2009 (Updated)

Health status, FEV1 and GOLD stage:Staging by FEV1 neglects patient outcomes Stage 4 Stage 3 Stage 2 Breathless walking on level ground Lung function measurements do not reflect the impact of COPD 100 80 60 SGRQ score 40 20 Upper limit of normal 0 r=–0.23 P<0.0001 10 20 30 40 50 60 70 80 90 FEV1 (% predicted) Jones P. Thorax 2001;56:880-887.

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) 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 ✗ 1 ✗ 2 4 ✗ 3 ✗ 4 ✗ 2 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 r-=0.80 P<0.0001 Jones P. et al, ERJ 2009; 34: 648-654.

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 inprimary 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. 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

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 factorsand/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

ECLIPSE: Study Design • Months • 0 3 6 12 18 24 30 36 46 Centres;12 Countries FSFV* Dec 19 2005 LSLV* Feb 19 2010 • GOLD stage II (FEV1 50–80% pred.) • 2180 COPD subjects** • GOLD stage III (FEV1 30–50% pred.) • GOLD stage IV (FEV1 <30% pred.) • Analysis • Planned Recruitment • 343 smoking controls • 566 control subjects** • 223 non-smoking controls • 0 3 6 12 18 24 30 36 • Year 1 and 3 Visits captured: • Chest computed tomography • Year 3 visit captured: • Depression; Fatigue 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 Vestbo J, et al. Eur Respir J. 2008;31:869-873.

Definition of COPD exacerbationaccording 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

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

The ‘frequent exacerbator phenotype’: ECLIPSEFrequency/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? 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 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.

Conclusions (1) “Airflow limitation alone does not provide an accurate measure of disease severity or activity” • 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 New GOLD guidelines must include other parameters: QoL, symptoms and exacerbation rate 32 Agusti A, et al. Resp Res. 2010;11:122

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

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

Management of COPD according to Symptoms, Spirometric classification and Future Risk of Exacerbations 4 (C) (D) ≥ 2 3 Risk (Exacerbation history) Spirometry (GOLD Classification of Airflow Limitation) 2 1 (A) (B) 1 0 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 > 2or 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 andonly 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 Risk (GOLD Classification of Airflow Limitation) Risk (Exacerbation history) 2 1 (A) (B) 0 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 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 Risk (Exacerbation history) Spirometry (GOLD Classification of Airflow Limitation) 2 1 1)LAAC or LABA 2) LAAC + LABA SAAC prn or SAAB prn 1 0 mMRC < 2 CAT < 10 mMRC ≥ 2 CAT ≥ 10 Symptoms (mMRC or CAT score) www.goldcopd.org

TORCH: Post-bronchodilator FEV1 100 50 0 *† –50 * –100 * –150 Placebo SALM FP SFC Adjusted mean change FEV1 (mL) 0 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

TORCH: SFC significantly reduces exacerbations over 3 years 25% (p<0.001) 1.2 1.13 1.0 0.97 0.93 0.8 0.85 Annualised exacerbation rate 0.6 0.4 0.2 0 Placebo Salmeterol FP SFC Treatment effect p-value 25% <0.001 SFC vs placebo 12% 0.002 SFC vs salmeterol SFC vs FP 9% 0.02 Calverley N Eng J Med 2007

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

TORCH: SFC reduces the rate of severe exacerbations requiring hospitalisation over 3 years 17% (p=0.03) Treatment effect p-value 0.20 0.19 0.15 0.17 0.16 0.16 0.10 0.05 0 Placebo Salmeterol FP SFC Annualised exacerbation rate SFC vs placebo 17% 0.03 0.79 SFC vs salmeterol –2% SFC vs FP 5% 0.56 Calverley N Eng J Med 2007

Take home message • COPD is highly heterogeneous (HEED and ECLIPSE) • Former management of COPD (GOLD 2007): Unidimensionalapproach: spirometry: FEV1 (FEV1/FVC):  Diagnosis • New management of COPD (GOLD 2012): Multidimensionalapproach: 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

“How your approach in COPD might change in 2012”