Bronchodilation is the cornerstone of treatment

Pharmacological treatment of COPD

2

GOLD 2014: treatment goals for stable COPD

Relieve symptoms Improve exercise endurance Improve health status

REDUCE SYMPTOMS

AND

Prevent disease progression Prevent and treat exacerbations Reduce mortality

REDUCE RISK

COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease

GOLD 2014 (http://www.goldcopd.org/)

3

The central role of airflow limitation leading to symptoms in COPD

Disability Disease progression Death

Air trappingExpiratory flow limitation

Hyperinflation

Deconditioning Inactivity

Reduced exercise capacity

Exacerbations

COPD

Shortness of breath

Quality of life

Exercise

COPD = chronic obstructive pulmonary disease

Adapted from Cooper CB. Respir Med 2009;103:325–34.

4Early intervention may interrupt the downward spiral of activity-limiting symptoms

Becomes more sedentary to avoid dyspnea-producing

activity(decreases activity)

Dyspnea with activities

Deconditioning aggravates dyspnoea;

patients adjust by reducing activity further

The dyspnea–inactivity downward spiral

Reardon JZ et al. Am J Med 2006;119(10 Suppl 1):32–72ZuWallack R COPD 2007;4:293–7

5

Bronchodilators are the cornerstone of COPD management

Bronchodilators are central to the management of symptomatic COPD and comprise three different classes• Short-acting β2-agonists and muscarinic antagonists

(SABAs and SAMAs)1

• Long-acting β2-agonists and muscarinic antagonists (LABAs and LAMAs)1

Long-acting agents are more effective and convenient in maintenance control of symptoms, improving HRQoL, and preventing exacerbations than short-acting agents1–9

Drugs from different classes can be used alone or in combination1

COPD = chronic obstructive pulmonary disease; HRQoL = health-related quality of life; LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist; SABA = short-acting β2-agonist; SAMA = short-acting muscarinic antagonist

1. GOLD 2014 (http://www.goldcopd.org/); 2. Dahl R et al. Am J Respir Crit Care Med 2001;164:778–84; 3. Mahler D et al. Chest 1999;115:957–65; 4. Szafranski W et al. Eur Respir J 2003;21:74–81; 5. Calverley PMA et al. Eur Respir J 2003;22:912–9; 6. Rennard S et al. Am J Respir Crit Care Med 2001;163:1087–92; 7. Brusasco V et al. Thorax 2003;58:399–404; 8. Rutten van-Molken MPMH et al. Eur J Heath Econ 2007;8:123–35; 9. Vogelmeier C et al. N Engl J Med 2011;364:1093–103

6

Mechanism of action of bronchodilators

Alter airway smooth muscle tone, widening airways1

• Improves expiratory flow1

Reduce air trapping and improve lung emptying1–4

• Improves symptoms and exercise capacity1–4

Additional non-bronchodilator effects• Improves skeletal muscle function and mucociliary clearance5

1. GOLD 2014 (http://www.goldcopd.org/); 2. Hasegawa M et al. Thorax 2009;64:332–8; 3. Cooper CB. Respir Med 2009;103:325–34; 4. Calverley PMA. Eur Respir J 2005;26:190–1; 5. Johnson M, Rennard S. Chest 2001;120:258–70

7

Mechanism of action of LABAs and LAMAs

β2-adrenergic agonists• Stimulate β2-adrenergic receptors on airway smooth muscle1

- Causes muscle relaxation (i.e. bronchodilation)1

- Increases cAMP, antagonizing bronchoconstriction1

Anticholinergics• Block M3 receptors1

- Inhibits ACh-induced bronchoconstriction of airway smooth muscle2,3 - Inhibits mucus secretion at mucus glands2,3

• Non-selective agents also block M1 and M2 receptors1

- M2 receptor blockade may diminish original bronchodilatory effects, and produce adverse cardiac and urinary effects4–6

ACh = acetylcholine; cAMP = cyclic adenosine monophosphate; LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist; SABA = short-acting β2-agonist; SAMA = short-acting muscarinic antagonist

1. GOLD 2014 (http://www.goldcopd.org/)2. Barnes PJ. Life Sci 1993;52:521–73. Eglen RM et al. Pharmacol Rev 1996;48:531–654. Van Noord JA. Drugs 2002;62:1204–55. Caulfield MP and Birdsall NJM. Pharmacol Rev 1998;50:279–906. Hegde SS and Eglen RM. Life Sci 1999;64:419–28

8

Targeting two bronchodilatory pathways to improve bronchodilation

Targeting two bronchodilatory pathways can provide greater bronchodilation than one pathway alone1–3

Targeting two bronchodilatory pathways may also address diurnal variations in symptoms• Sympathetic activity may be more prominent during the day, and

parasympathetic activity more prominent during the night4–6

• Considerable intra-patient variability in reversibility testing has been observed7,8

1. COMBIVENT Inhalation Solution Study Group. Chest 1997;112:1514–212. Mahler DA et al. Thorax 2012;67:781–83. van Noord JA et al. Eur Respir J 2005;26:214–224. Postma DS et al. Clin Sci 1985;69:251–85. Gaultier C et al. Respir Physiol 1977;31:169–826. Furlan R et al. Circulation 1990;81:537–477. Calverley PM et al. Thorax. 2003;58:659–648. Anthonisen N and Wright E. Am Rev Respir Dis 1986;133:814–9

9

GOLD 2014 Pharmacological management of COPD*

Based on combined assessment of airflow limitation, symptoms and exacerbation risk

Risk

Exacerba

tion history

Ris

kG

OL

D c

lass

ifica

tion

of

airf

low

lim

itatio

n

GOLD Grade 4

GOLD Grade 2

GOLD Grade 1

GOLD Grade 3

GOLD Group C

ICS + LABA, or LAMALAMA + LABA or

LAMA + PDE-4i orLABA + PDE-4i

LAMA or LABA LAMA + LABA

SAMA or SABA p.r.n.LAMA orLABA or

SABA + SAMA

ICS + LABA +/or LAMAICS + LABA + LAMA orICS + LABA + PDE-4i or

LAMA + LABA orLAMA + PDE-4i

Recommended first choiceAlternative choiceGOLD Group D

GOLD Group A GOLD Group B

≥2 or

≥1 leading to hospital admission

1 (not leading to hospital admission)

SymptomsCAT ≥10CAT <10

mMRC 01 mMRC ≥2Breathlessness

*Medications in each box are in alphabetical order, and not necessarily in order of preference. Other possible treatments are not shown, but can be used alone or in combination with other options in the Recommended first choice and Alternative choice boxes.

CAT = COPD Assessment Test; COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease; HRQoL = health-related quality of life; ICS = inhaled corticosteroids; LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist; mMRC = modified Medical Research Council; PDE-4i = phosphodiesterase type 4 inhibitor; SABA = short-acting β2-agonist; SAMA = short-acting muscarinic antagonist

GOLD 2014 (http://www.goldcopd.org/)

10

LAMA therapies are established in COPD and can improve a range of clinical outcomes

Lung function1–7

Inspiratory capacity8–11

Exercise capacity9–11

Effectiveness of pulmonary rehabilitation12

Shortness of breath1,2,4–7,9

HRQoL*1–7

Exacerbations1,3,6,7,13

*St George's Respiratory Questionnaire1-7 and Short Form 36 Health Survey1

COPD = chronic obstructive pulmonary disease; HRQoL = health-related quality of life; LAMA = long-acting muscarinic antagonist

1. Casaburi R et al. Eur Respir J 2002;19:217–24; 2. Donohue J et al. Chest 2002;122:47–55; 3. Tashkin DP et al. N Engl J Med 2008;359:1543–54; 4. Kerwin EM et al. COPD 2012;9:90–101; 5. Jones PW et al. Eur Respir J 2012;40:830–6; 6. D'Urzo A et al. Respir Res 2011;12:156; 7. Kerwin E et al. Eur Respir J 2012;40:1106–14; 8. Celli B et al. Chest 2003;124:1743–8; 9. O’Donnell DE et al. Eur Respir J 2004;23:832–40;10. Maltais F et al. Chest 2005;128:1168–78; 11. Beeh KM et al. Int J Chron Obstruct Pulmon Dis 2012;7:503–13;12. Casaburi R et al. Chest 2005;127:809–17; 13. Niewoehner DE et al. Ann Intern Med 2005;143:317–26

11

LAMAs have demonstrated ability to reduce the risk of exacerbation vs placebo

Both glycopyrronium and tiotropium significantly reduced the risk of exacerbation (in terms of time to first moderate-to-severe exacerbation) vs placebo (p=0.001)

100

Pat

ient

s ex

acer

batio

n-fr

ee (

%)

Time to first exacerbation (weeks)

90

80

70

60

50

00 4 8 12 16 20 24 28 32 36 40 44 48 52

Glycopyrronium 50 μg o.d.

Tiotropium

Placebo

Glycopyrronium significantly reduced the rate of moderate-to-severe COPD exacerbations vs placebo

CI = confidence interval; COPD = chronic obstructive pulmonary disease; HR = hazard ratio; RR, rate ratio.

Kerwin E et al. Eur Respir J 2012;40:1106–14

Glycopyrronium vs placebo: HR 0.66 (95% CI 0.520–0.850); p=0.001Tiotropium vs placebo: HR 0.61 (95% CI, 0.456–0.821); p=0.001

12

Improvements in trough FEV1 were statistically significant with indacaterol + glycopyrronium* vs indacaterol at Day 1 and Week 12 (both p<0.001)

Day 1 Week 12 (primary endpoint)1.15

1.20

1.25

1.30

1.35

1.40

1.45

1.50

1.55

1.4961.498999999999

991.4221.435999999999

99

n=218 n=214n=213 n=214

Δ 74† mL Δ 64† mL

Tro

ugh

FE

V1 (

L)

0

LAMA and LABA combination significantly improved lung function after first dose (Day 1) and at Week 12 vs LABA alone

*Open-label indacaterol and double-blind glycopyrronium were co-administered via separate Breezhaler® devices.

Indacaterol 150 µg o.d.+ glycopyrronium 50 µg o.d.* Indacaterol 150 µg o.d.+ placebo

†p<0.001. Data are least squares mean ± standard error;. FEV1 = forced expiratory volume in 1s; o.d.,= once daily

Vincken et al. Int J Chron Obstruct Pulmon Dis 2014 (in press)

13

Inhaled corticosteroids do not improve symptoms of breathlessness

0

1

2

Fluticasone propionate

Mea

n br

eath

less

ness

sym

ptom

sco

re

afte

r 52

wee

ks

Placebo

p=ns

ns = not significant

Calverley PMA et al. Lancet 2003;361:449–56

14

Despite recommendations, ICS used oftenin early-stage COPD ICS plus LABA recommended for use only in patients in Groups C and D1

However, many patients in Groups A and B are treated with ICS2,3

Data were drawn from the Adelphi Respiratory Disease Specific Programme, a large multinational (France, Germany, Italy, Spain, UK, USA) cross-sectional survey generating real-world data based on actual clinical practice. N=1508.2,3 GOLD, Global Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist.

GOLD Group C

13 patients 54% using ICS

739 patients38% using ICS

152 patients33% using ICS

604 patients 51% using ICS

GOLD Group D

GOLD Group A GOLD Group B

1. GOLD 2014 (http://www.goldcopd.org/)2. Small M et al. Thorax 2012;67:A144–A1453. Higgins V et al. COPD8 2012. (Poster)

15

Increased risk of pneumonia with ICS use in patients with COPD: meta-analysis

Significantly increased risk of serious pneumonia for

• ICS vs placebo: risk ratio 1.51 (95%CI 1.08–2.10)285 events/3,881 patients vs 180 events/3,633 patients

• ICS + LABA vs LABA: risk ratio 1.72 (95%CI 1.28–2.30)356 events/4,754 patients vs 217 events/4,728 patients

• Total: ICS vs no ICS: risk ratio 1.60 (95%CI 1.33–1.92)641 events/8,635 patients vs 397 events/8,361 patients

Singh S, et al. Arch Intern Med 2009;169:219–29

CI, confidence interval; COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist.

16

Conclusions The key treatment goals for stable COPD are:1

• Reduce symptoms (improve symptoms, exercise endurance and health status)

• Reduce risk (prevent progression, prevent/treat exacerbations, reduce mortality)

Early intervention may interrupt the downward spiral of activity-limiting symptoms in COPD13,14(2,3)

Bronchodilators are central to the management of symptomatic COPD1

• Long-acting bronchodilators (LABAs and LAMAs) are preferred over short-acting agents

Long-acting bronchodilators have been shown to :• reduce airflow limitation2,3 (4,5)

• reduce hyperinflation and exercise endurance4 (6)

• improve HRQoL5(7)

• reduce exacerbations6–12(8-14)

Administration of a LAMA and a LABA provides incremental benefit on lung function (trough FEV1) compared with LABA alone(15)

ICS may reduce the risk of exacerbations in patients with severe COPD,15(16) but may also increase the risk of pneumonia16(17)

ICS are only recommended for high-risk patients1

COPD = chronic obstructive pulmonary disease; LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist; ICS = inhaled corticosteroids

1. GOLD 2014 (http://www.goldcopd.org/); 2. Reardon JZ et al. Am J Med 2006; 3. ZuWallack R COPD 2007; 4. Dahl R. et al. Am J Respir Crit Care Med 2001; 5. Donohue J et al. Chest 2002; 6. O’Donnell D et al. Eur Respir J 2004; 7. Calverley PMA et al. Eur Respir J 2003; 8. Calverley PMA et al. Lancet 2003; 9. Calverley PMA et al. New Engl J Med 2007; 10. Casaburi R, et al.. Eur Respir J 2002; 11. Vogelmeier C, et al. N Engl J Med 2011; 12. Vincken W, et al. Eur Respir J 2002; 13. Wedzicha JA, et al. Am J Respir Crit Care Med 2008; 14. Tashkin DP, et al. N Engl J Med 2008; 15. Vincken et al. Int J Chron Obstruct Pulmon Dis 2014 (in press); 16. Agarwal R, et al. Chest 2010; 17. Singh S, et al. Arch Intern Med 2009;