How best to Initiate COPD Treatment? Early intervention: Does is matter? Dr. Kevin Gruffydd-Jones Box Surgery, Wiltshire, England Respiratory Lead Royal College General Practitioners Joint Policy Lead PCRS-UK Member NICE COPD Guidelines and Quality Standards Committees

Conflicts of interest I have acted as a consultant and spoken on behalf of: AstraZeneca Boehringer Ingelheim Chiesi GSK Mundipharma/Napp Novartis Pfizer Teva

For your consideration What is ‘early’ disease? What can we do? Can we do better?

For your consideration What is ‘early’ disease? What can we do? Can we do better?

Symptoms but no diagnosis Spectrum of COPD The earliest point at which airflow obstruction may be detected by spirometry ‘Lower limits of normal’ ‘Upper limits of normal’ Damage Unaware of lung health Aware of lung health No symptoms Symptoms but no diagnosis MILD stage MODERATE stage SEVERE stage VERY SEVERE stage Well At-risk With COPD diagnosis This slide has been reproduced with permission from the Department of Health DRAFT NATIONAL STRATEGY 2010.

In patients with FEV1/FVC < 0.70: Global Strategy for Diagnosis, Management and Prevention of COPD Classification of Severity of Airflow Limitation in COPD* In patients with FEV1/FVC < 0.70: GOLD 1: Mild FEV1 ≥ 80% predicted GOLD 2: Moderate 50% ≤ FEV1 < 80% predicted GOLD 3: Severe 30% ≤ FEV1 < 50% predicted GOLD 4: Very Severe FEV1 < 30% predicted *Based on Post-Bronchodilator FEV1 Reference: © 2016 Global Initiative for Chronic Obstructive Lung Disease.

Global Strategy for Diagnosis, Management and Prevention of COPD Combined Assessment of COPD ≥ 2 or > 1 leading to hospital admission 1 (not leading admission) 4 (C) (D) 3 (GOLD Classification of Airflow Limitation) Risk (Exacerbation history) Risk 2 (A) (B) 1 CAT < 10 CAT > 10 Symptoms mMRC 0–1 mMRC > 2 Breathlessness Reference: © 2016 Global Initiative for Chronic Obstructive Lung Disease.

Or is it newly diagnosed COPD? Current and former smokers aged ≥40 years (n=818) with no prior COPD diagnosis (and no respiratory medications within the past year) were screened in primary care practices in Aberdeen, UK and Denver, USA Percentage of patients with/without COPD Percentage of patients with mild, moderate and severe COPD Reference: Tinkelman DG, et al. Prim Care Respir J 2007; 16: 41−48.

Mild disease? Patients with mild airflow limitation and symptoms have impaired quality of life, reduced physical activity and exercise tolerance Exacerbation rate 0.85/year “Eclipse” Agusti et al Resp Res 2010 Increased co-morbidities (Diabetes, Cardiovascular disease) Fabbri et al Lancet 2007

The traditional view: FEV1 declines progressively over time DISABILITY DEATH Smoked and susceptible to smoke Never smoked or not susceptible to smoke Traditional view by Fletcher and Peto: Lung function decline is slow in early-stage COPD and increases as disease progresses Cohort study with 792 working men, 8-year follow-up period, measurement of FEV1 every 6 months Modified version of the Fletcher & Peto graph showing the decline in FEV1 Reference: Fletcher C, Peto R. BMJ 1977; 1: 1645–1648.

The current view: lung function loss is most accelerated in the early stages of COPD 30 50 80 100 FEV1 (% predicted) Years GOLD 1 GOLD 2 GOLD 3 GOLD 4 D <35 mL/yr D 56 - 59 mL/yr D 47 - 79 mL/yr D 40 mL/yr Current view, informed by Tantucci & Modina: Loss of FEV1 in GOLD 2 COPD is greater than in more severe disease1,2 Analysis based on randomized control arms of longitudinal studies with a follow-up period ≥3 years Dashed lines indicate any stage or portion for which consistent information is lacking References: 1. Tantucci C, Modina D. Int J Chron Obstruct Pulmon Dis 2012; 7: 95–99; 2. Welte T, et al. Int J Clin Pract 2014; 69: 336–349.

For your consideration What is ‘early’ disease? What can we do? Can we do better?

Non-pharmacological Interventions Smoking cessation (reduces mortality and decline in FEV1) and reduced exposure to pollution Influenza and pneumococcal immunisation (reduce hospitalisations, exacerbations) Exercise promotion and pulmonary rehabilitation (improve exercise tolerance, HRQoL, reduce in-patient days)

The traditional view: FEV1 declines progressively over time Never smoked or not susceptible to smoke Smoked and susceptible to smoke DISABILITY DEATH Reference: Fletcher C, Peto R. BMJ 1977; 1: 1645–1648.

Probability of survival Physical activity is the strongest predictor of all-cause mortality in patients with COPD Higher risk of mortality for sedentary and very inactive patients than for active patients Probability of survival Chi-square=19.3 df=1 p<0.001 Months of follow-up Predominantly sedentary Active Very inactive Prospective observational study with 170 COPD patients (GOLD 1−4) followed for 4 years for all-cause mortality Physical activity was assessed by a multisensory armband according to World Health Organization categories of physical activity level Reference: Waschki B, et al. CHEST 2011; 140: 331−342.

Inactivity levels increase significantly from GOLD 2 to GOLD 3 Percentage of patients Increased inactivity INCREASED INACTIVITY GOLD 2 GOLD 1 GOLD 2 GOLD 3 − GOLD 4 Predominantly sedentary Active Very inactive 164 COPD patients monitored for physical activity parameters (steps per day, minutes of at least moderate activity, and 6-minute walking test) over 5 days Reference: Adapted from Watz H et al. Eur Respir J 2009; 33: 262−272.

Bronchodilator therapy combined with pulmonary rehabilitation can improve exercise endurance and dyspnoea Unlike lung impairment, which is largely irreversible, peripheral muscle dysfunction may be remedied with exercise training and therapeutic strategies1 Treadmill endurance at baseline and all post-treatment visits2 Mean weekly doses of rescue medication2 Endurance time (min) 24 8 10 12 14 16 18 20 22 *p<0.05 26 6 4 2 Weeks on treatment 4.5 *p<0.05 Doses/Day 4.0 3.5 3.0 2.5 2.0 1.5 26 24 22 20 18 16 14 12 10 8 6 4 2 Weeks on treatment * * * * * * * * * * * * * * * * * * * Tiotropium Placebo References: 1. Maltais F, et al. Clin Chest Med 2000; 21: 665−677; 2. Casaburi R, et al. CHEST 2005; 127: 809−817.

UPLIFT®: tiotropium reduces the rate of FEV1 decline in patients with GOLD 2 COPD 1.8 * * * * * * 1.6 * * * * * Postbronchodilator FEV1 * FEV1 (L) * * * 1.4 * * * Prebronchodilator FEV1 1.2 1 6 12 18 24 30 36 42 48 Day 30 (steady state) Month Tiotropium Control *p<0·0001 vs control Month 0: tiotropium, n=1196; control, n=1142. Month 48: tiotropium, n=925; control, n=859. Mean differences between groups range from 101 mL to 119 mL for prebronchodilator FEV1 and from 52 mL to 82 mL for postbronchodilator FEV1 Reference: Decramer M, et al. Lancet 2009; 374: 1171–1178.

Bronchodilator therapy in maintenance therapy-naïve patients with GOLD 2 COPD Randomized controlled trial: 457 patients receiving tiotropium 18μg once-daily (HandiHaler®) vs placebo over 24 weeks Mean FEV1 <66% predicted Mean increase in trough FEV1 = 140 ml Increase in Work Productivity Impairment Questionnaire 1.9 2.1 2.0 1.8 1.9 Trough FEV1 (I) FEV1 AUC0–3h (I) 1.8 1.7 1.7 1.6 Week 24 Difference in LS mean (95% CI): 0.14 (0.09, 0.18); p<0.001 1.6 Week 24 Difference in LS mean (95% CI): 0.23 (0.18, 0.27); p<0.001 8 16 24 8 16 24 Week Week Tiotropium Placebo Reference: Troosters T, et al. NPJ Prim Care Respir Med 2014; 24: 14003. doi: 10.1038/npjpcrm.2014.3.

For your consideration What is ‘early’ disease? What can we do? Can we do better?

Study design of TONADO® 1+2 Run-in (2–6 weeks) Treatment* period (52 weeks) Tiotropium/olodaterol 5/5 µg Tiotropium/olodaterol 2.5/5 µg Tiotropium 5 µg SCREENING R Tiotropium 2.5 µg Olodaterol 5 µg 24 weeks, coprimary endpoints: FEV1 AUC0–3 h (Day 169), trough FEV1 (Day 170), SGRQ (Day 169) *All treatments: two puffs once daily, administered via Respimat®. Reference: Buhl RM, et al. Eur Respir J 2015; 45: 969–979

Trough FEV1 at week 24 (day 169) Trough FEV1 change from baseline (mL) TONADO® 1+2 reported consistent and significant improvements in lung function for tiotropium/olodaterol 5/5 µg vs monotherapies Trough FEV1 at week 24 (day 169) 20 40 60 80 120 160 180 100 140 T/O 5/5 µg vs T 5 µg = 60mL (p<0.0001) T/O 5/5 µg vs O 5 µg = 85mL (p<0.0001) DAY 169 Trough FEV1 change from baseline (mL) 50 100 150 200 250 350 400 300 Test day Tiotropium 5 µg Olodaterol 5 µg Tiotropium/olodaterol 5/5 µg Combined data set for TONADO®1+2 (full analysis set); p<0.0001 for all comparisons. Reference: Buhl RM, et al. Eur Respir J 2015; 45: 969–979.

Trough FEV1, change from baseline (mL) TONADO® 1+2: confirmation of treatment benefits in GOLD 2, LABD-naïve patients Tiotropium 5 µg Trough FEV1 at Week 24 Tiotropium/ olodaterol 5/5 µg 50 100 150 200 156 * 146 148 118 95 79 Trough FEV1, change from baseline (mL) 68 76 n=237 n=226 n=275 n=270 n=206 n=193 n=299 n=328 LABD-naïve With prior LABD LABD-naïve With prior LABD GOLD 2 GOLD 3 – GOLD 4 *p<0·0001 References: Ferguson GT, et al. Adv Ther 2015; 32: 523–536; Ferguson GT, et al. Adv Ther 2015; 32: 523–536 (supplementary material).

OTEMTO® 1+2: meaningful QoL improvements with tiotropium/olodaterol 5/5 µg vs placebo in GOLD 2 SGRQ total score at Week 12 SGRQ responder* rate at Week 12 T+O vs T5 =19.1; p=0.0024 T+O vs T5 =2.51; p=0.0043 60 60 ‡ 52.8 = 4.0† 47.9 51.7 43.2 50 41.9 50 45.0 39.2 37.7 35.2 39.2 40 40 33.7 28.5 SGRQ total score ± SE (units) SGRQ responders (%) 30 30 20 20 10 10 GOLD 2 GOLD 3 GOLD 2 GOLD 3 Placebo Tiotropium 5 µg Tiotropium/olodaterol 5/5 µg Baseline SGRQ: GOLD 2, 39.9; GOLD 3, 47.4 *An SGRQ responder is defined as SGRQ total score ≥4.0 compared with baseline †p<0.001; ‡p<0.0001 Reference: Singh D, et al. Poster presented at the ERS International Congress 2015: Poster PA2958.

TDI responder rate at week 12# TDI focal score ± SE (units) OTEMTO® 1+2 also showed meaningful improvements in breathlessness with tiotropium/olodaterol vs placebo TDI focal score at week 12 TDI responder rate at week 12# = 1.62 * = 27.7 * TDI focal score ± SE (units) TDI responders (%) Tiotropium 5 µg Tiotropium/olodaterol 5/5 µg Placebo Combined dataset for OTEMTO®1+2 (full analysis set) *p<0.0001; #A TDI responder is defined as an improvement of ≥1.0 unit compared with baseline SE, standard error; TDI, Transition Dyspnea Index. Singh D, et al. Poster PA2958 presented at the ERS International Congress 2015 Reference: Singh D, et al. Poster PA2958 presented at the ERS International Congress 2015.

For your consideration What is ‘early’ disease? What can we do? Can we do better?

How should we best initiate maintenance treatment in COPD to optimize lung function and outcomes? Early detection and early treatment of COPD with smoking cessation and regular maintenance bronchodilator therapy can improve outcomes1,2 including slowing disease progression as measured by FEV1 decline3 References: 1. Welte T, et al. Int J Clin Pract 2014; 69: 336–349; 2. Kohansal R, et al. Am J Respir Crit Care Med 2009; 180: 3–10; 3. Tantucci C, Modina D. Int J Chron Obstruct Pulmon Dis 2012; 7: 95–99.

Early intervention with smoking cessation saves lives3 How should we best initiate maintenance treatment in COPD to optimize lung function and outcomes? Optimal bronchodilation is obtained with dual bronchodilator therapy with improvements in breathlessness and HRQoL1,2 Early intervention with smoking cessation saves lives3 Can early intervention with dual bronchodilation (plus pulmonary rehabilitation) improve long-term outcomes? References: 1. Ferguson GT, et al. Adv Ther 2015; 32: 523–536; 2. Ferguson GT, et al. Adv Ther 2015; 32: 523–536 (supplementary material); 3. Godtfredsen NS, et al. Eur Respir J 2008; 32: 844–853.