Pharmacological treatment of COPD
Bronchodilation is the cornerstone of treatment
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
COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease
GOLD 2014 (http://www.goldcopd.org/)
REDUCE
RISK
3
The central role of airflow limitation leading to
symptoms in COPD
COPD
Expiratory flow limitation
Air trapping
Hyperinflation
Exercise
Exacerbations
Shortness of breath
Quality of life
Deconditioning
Inactivity
Reduced exercise capacity
Disability
COPD = chronic obstructive pulmonary disease
Adapted from Cooper CB. Respir Med 2009;103:325–34.
Disease progression
Death
4
Early intervention may interrupt the downward
spiral of activity-limiting symptoms
The dyspnea–inactivity downward spiral
Dyspnea with
activities
Becomes more
sedentary to avoid
dyspnea-producing
activity
(decreases activity)
Deconditioning
aggravates dyspnoea;
patients adjust by
reducing activity further
Reardon JZ et al. Am J Med 2006;119(10 Suppl 1):32–72
ZuWallack 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.
2.
3.
4.
5.
6.
GOLD 2014 (http://www.goldcopd.org/)
Barnes PJ. Life Sci 1993;52:521–7
Eglen RM et al. Pharmacol Rev 1996;48:531–65
Van Noord JA. Drugs 2002;62:1204–5
Caulfield MP and Birdsall NJM. Pharmacol Rev 1998;50:279–90
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.
2.
3.
4.
5.
6.
7.
8.
COMBIVENT Inhalation Solution Study Group. Chest 1997;112:1514–21
Mahler DA et al. Thorax 2012;67:781–8
van Noord JA et al. Eur Respir J 2005;26:214–22
Postma DS et al. Clin Sci 1985;69:251–8
Gaultier C et al. Respir Physiol 1977;31:169–82
Furlan R et al. Circulation 1990;81:537–47
Calverley PM et al. Thorax. 2003;58:659–64
Anthonisen N and Wright E. Am Rev Respir Dis 1986;133:814–9
9
GOLD 2014
Pharmacological management of COPD*
GOLD classification of
airflow limitation
GOLD Group C
GOLD Group D
GOLD Grade 3
ICS + LABA, or LAMA
LAMA + LABA or
LAMA + PDE-4i or
LABA + PDE-4i
ICS + LABA +/or LAMA
ICS + LABA + LAMA or
ICS + LABA + PDE-4i or
LAMA + LABA or
LAMA + PDE-4i
GOLD Group A
GOLD Group B
GOLD Grade 2
GOLD Grade 1
SAMA or SABA p.r.n.
LAMA or
LABA or
SABA + SAMA
LAMA or LABA
LAMA + LABA
CAT <10
CAT ≥10
mMRC 01
mMRC ≥2
≥2
or
≥1 leading to
hospital
admission
1 (not leading
to hospital
admission)
Risk
GOLD Grade 4
Recommended first choice
Alternative choice
Exacerbation history
Risk
Based on combined assessment of airflow limitation, symptoms and exacerbation risk
Symptoms
Breathlessness
*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)
Patients exacerbation-free (%)
100
Glycopyrronium 50 μg o.d.
Tiotropium
Placebo
90
80
70
60
50
Glycopyrronium vs placebo: HR 0.66 (95% CI 0.520–0.850); p=0.001
Tiotropium vs placebo: HR 0.61 (95% CI, 0.456–0.821); p=0.001
0
0
4
8
12
16
20
24
28
32
36
Time to first exacerbation (weeks)
40
44
 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
48
52
12
LAMA and LABA combination significantly improved lung function after first
dose (Day 1) and at Week 12 vs LABA alone
 Improvements in trough FEV1 were statistically significant with indacaterol + glycopyrronium*
vs indacaterol at Day 1 and Week 12 (both p<0.001)
1.55
Δ 64† mL
Δ 74† mL
Trough FEV1 (L)
1.50
1.45
1.40
1.35
1.30
1.25
1.20
1.15
0
1.496
1.422
Day 1
1.499
1.436
Week 12 (primary endpoint)
Indacaterol
µg o.d.+ glycopyrronium 50n=214
µg o.d.* n=214
Indacaterol 150 µg o.d.+ placebo
n=218 150n=213
*Open-label indacaterol and double-blind glycopyrronium were co-administered via separate Breezhaler® devices.
†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
Mean breathlessness symptom score
after 52 weeks
Inhaled corticosteroids do not improve symptoms of
breathlessness
2
p=ns
1
0
Fluticasone
propionate
ns = not significant
Calverley PMA et al. Lancet 2003;361:449–56
Placebo
14
Despite recommendations, ICS used often
in 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
GOLD Group C
GOLD Group D
13 patients
54% using ICS
604 patients
51% using ICS
GOLD Group A
GOLD Group B
152 patients
33% using ICS
739 patients
38% using ICS
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.
1. GOLD 2014 (http://www.goldcopd.org/)
2. Small M et al. Thorax 2012;67:A144–A145
3. 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
CI, confidence interval; COPD, chronic obstructive pulmonary disease; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist.
Singh S, et al. Arch Intern Med 2009;169:219–29
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;