1. 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

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

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

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

5. 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.

6. 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.

7. 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.

8. 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.

9. 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

10. 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.

11. The current view: lung function loss is most accelerated in the early stages of COPD30 50 80
100
FEV1 (% predicted)
Years
GOLD 1
GOLD 2
GOLD 3
GOLD 4
D <35 mL/yr
D mL/yr
D 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.

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

13. 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)

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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: doi: /npjpcrm

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

21. 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

22. 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< for all comparisons.
Reference: Buhl RM, et al. Eur Respir J 2015; 45: 969–979.

23. 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).

24. 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.

25. 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.

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

27. 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.

28. 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.