1. The burden of COPD
Exacerbations

2. GOLD 2014 definition of exacerbations
GOLD defines an exacerbation as an acute event characterized by worsening of respiratory symptoms
Worsening must be beyond normal day-to-day variations
Worsening must lead to a change in medication
Diagnosis relies on patient presentation
An important goal of COPD treatment is to minimize impact of current exacerbation and prevent development of subsequent exacerbations
Reference
GOLD Available from:
COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease
GOLD 2014 (

3. Epidemiology of COPD exacerbations
On average, 0.85–3.00 exacerbations are reported per patient per year1
The average number of days with an exacerbation(s) was 12–14 per patient per year2
60%–70% of patients have an exacerbation over 2–4 years2,3
On average, 3 days are spent in hospital per patient per year2
‘Frequent exacerbator’ COPD phenotype4
Is prone to frequent exacerbations
Uses considerable healthcare resources
Experiences higher morbidity and mortality
References
Seemungal TA et al. Int J Chron Obstruct Pulmon Dis. 2009;4:203–23.
Tashkin DP et al. N Engl J Med. 2008;359:1543–54.
Wedzicha JA et al. Am J Respir Crit Care Med 2008;177:19–26.
Soler-Cataluña JJ and Rodriguez-Roisin R. COPD 2010;7:276–84.
COPD, chronic obstructive pulmonary disease.
1. Seemungal TA. Int J Chron Obstruct Pulmon Dis 2009;4:203– Tashkin DP. N Engl J Med 2008;359:1543– Wedzicha JA. Am J Respir Crit Care Med 2008;177:19– Soler-Cataluña JJ and Rodriguez-Roisin R. COPD 2010;7:276–84

4. Seasonality of COPD exacerbations
COPD exacerbations are more frequent in winter months than in summer months
Northern* and Southern† regions
Tropics‡ 14 14 12 12 10 10 8 8
Patients reporting an exacerbation (%)
Patients reporting an exacerbation (%) 6 6 4 4 2 2
Reference
Jenkins CR et al. Eur Respir J 2012;39:38-45.
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec
Month
Month
Northern
Southern
Tropics
*Canada, China, eastern/western Europe and USA; †Argentina, Australia, Brazil, Chile, New Zealand and South Africa; ‡Hong Kong, Malaysia, Mexico, Philippines, Singapore, Taiwan and Thailand
COPD = chronic obstructive pulmonary disease
Jenkins CR et al. Eur Respir J 2012;39:38-45

5. Exacerbation triggers and effects
Viruses
Pollutants
Bacteria
Inflamed
COPD airways
Effects
Greater airway
inflammation
Systemic
inflammation
Bronchoconstriction
edema, mucus
Reference
Wedzicha JA, Seemungal TA. Lancet 2007;370:786–96.
Expiratory flow
limitation
Cardiovascular
comorbidity
Exacerbation
symptoms
Dynamic
hyperinflation
COPD = chronic obstructive pulmonary disease
Wedzicha JA, Seemungal TA. Lancet 2007;370:786–96

6. Risk factors for an exacerbation
Proportion of COPD patients reporting exacerbation by GOLD severity stage1
COPD severity (GOLD stage)1
Older age2
Degree of FEV1 impairment2
Chronic bronchial mucus hypersecretion2
Frequent past exacerbations2
Daily cough and wheeze
Persistent symptoms of chronic bronchitis2
Exacerbation requiring hospitalization within past yr
GOLD Stage 4
GOLD Stage 3
GOLD Stage 2
GOLD Stage 1
Exacerbation requiring doctor visit within past yr
Exacerbation within past yr
Patients with GOLD Stage 3 or 4 (severe or very severe) COPD are much more likely to have exacerbations and be hospitalized for an exacerbation than those with mild to moderate disease.1 Additionally, older age, severity of forced expiratory volume in 1 second (FEV1) impairment, chronic bronchial mucus hypersecretion, frequent past exacerbations, daily cough and wheeze, and persistent symptoms of chronic bronchitis increase the likelihood of exacerbations, and have been found to be risk factors for more than 2 exacerbations per year.2
References
de Oca MM, Talamo C, Halbert RJ, et al. Frequency of self-reported COPD exacerbation and airflow obstruction in five Latin American cities: the Proyecto Latinoamericano de Investigacion en Obstruccion Pulmonar (PLATINO) study. Chest. 2009;136(1):71-78.
Anzueto A, Sethi S, Martinez FJ. Exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2007;4(7):
Ever had exacerbation
Ever had an exacerbation, p<0.0001; Exacerbation within past year, p=0.0002;
Exacerbation requiring doctor visit, p=0.0001
Exacerbation requiring hospitalization, p=0.0077
COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease; FEV1 = forced expiratory volume in 1 s
De Oca MM, et al. Chest 2009;136:71–78;
Anzueto A, et al. Proc Am Thorac Soc 2007;4:554–64
Proportion of subjects (%)

7. The best predictor of future exacerbations is a history of previous exacerbations
Exacerbations during previous year
OR [95% CI] (≥2 versus 0 exacerbations): 5.72 [4.47, 7.31], p<0.001
100 mL decrease in FEV1
OR: 1.11 [1.08, 1.14], p<0.001
4-point increase in SGRQ-C
OR: 1.07 [1.04, 1.10], p<0.001
History of reflux/heartburn
OR: 2.07 [1.58, 2.72], p<0.001
1x109 increase in white blood cell count
OR: 1.08 [1.03, 1.14], p=0.007
In the ECLIPSE study, the occurrence of exacerbations during the previous year was the best predictor of future exacerbations. Individuals who had had two or more exacerbations in the past year were almost six fold more likely to have an exacerbation (odds ratio 5.72), compared with individuals who had not had an exacerbation in the past year. Other significant predictors of exacerbations included a 100 mL decrease in FEV1 (11% increase in risk), a 4-point decrease in St George’s Respiratory Questionnaire score (7% increase), history of reflux/heartburn (two-fold increase) and 1 x 109 increase in white blood cells (8% increase).
Reference
Hurst JR, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med 2010:363:1128–38.
FEV1 = forced expiratory volume in 1 s; OR = odds ratio; SGRQ-C = St George’s Respiratory Questionnaire for COPD patients
Hurst J, et al. N Engl J Med 2010:363:1128–38

8. ‘Frequent exacerbator’ and ‘non exacerbator’ are stable phenotypes
71% of frequent exacerbators in Years 1 and 2 were frequent exacerbators in Year 3
74% of patients with no exacerbations in Years 1 and 2 had no exacerbations in Year 3
Year 2
Year 3
Percentage
Percentage
Year 1
Percentage 1 1 ≥2 ≥2
Exacerbations/year
Percentage
Percentage 1 ≥2
Reference
Hurst JR, et al. N Engl J Med 2010;363:1128–38. 1 1
Data are for 1679 patients with COPD who completed the study ≥2 ≥2
COPD = chronic obstructive pulmonary disease
Hurst J, et al. N Engl J Med 2010:363:1128–38

9. Importance of accurate recognition and prompt reporting of exacerbations
There are limitations to the GOLD 2014 criteria
Exacerbations do not always fulfil these criteria
Furthermore, exacerbations are not always recognized or reported by patients1–3
Under-recognition, under-reporting and delayed treatment can impact negatively on outcomes
Slower recovery1
Increased hospitalization risk1
Worse HRQoL1,2
References
Wilkinson TM et al. Am J Respir Crit Care Med 2004;169:1298–303.
Xu W et al. Eur Respir J 2010;35:1022–30.
Langsetmo L et al. Am J Respir Crit Care Med 2008;177:396–401.
COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease; HRQoL, health-related quality of life
Wilkinson TM et al. Am J Respir Crit Care Med 2004;169:1298–303
Xu W et al. Eur Respir J 2010;35:1022–30
Langsetmo L et al. Am J Respir Crit Care Med 2008;177:396–401

10. COPD exacerbations have a significant impact on clinical outcomes
Patients with frequent exacerbations
Greater airway inflammation
Faster decline in lung function
Poorer quality of life
Higher mortality
Reference
Wedzicha JA, Seemungal TA. Lancet. 2007;370:786–96.
More hospital
admissions
COPD = chronic obstructive pulmonary disease
Wedzicha JA, Seemungal TA. Lancet. 2007;370:786–96

11. Reduced exercise capacity
COPD exacerbations worsen airflow obstruction, cause hyperinflation and contribute to inactivity
COPD
Expiratory flow limitation
Exercise
Exacerbations
Air trapping
Hyperinflation
Shortness of breath
Deconditioning
Quality of life
Inactivity
Reference
Cooper CB. Respir Med 2009;103:325–34.
Reduced exercise capacity
Disability
Disease progression
Death
COPD = chronic obstructive pulmonary disease; HRQoL = health-related quality of life
Cooper CB. Respir Med 2009;103:325–34

12. COPD exacerbations have a significant impact on personal well being
Due to flare-ups
Had to cancel public outings
Lost energy/interest of doing what I had planned
Was frightened of the onset of winter
Wanted to be alone/with few close friends/family
I was very frustrated with myself
I was very scared
I was bed-ridden/hospitalized
A random telephone contact survey in six countries was performed. From the 83,592 households screened, 1100 patients with symptoms compatible with COPD were identified.1
Reference
Miravitlles M et al. Respir Med 2007;101:453–60 [data depicted are from a personal communication].
Intimacy with my partner was impossible
Results from 1,100 patient interviews, in five European countries and the USA.
COPD = chronic obstructive pulmonary disease
Miravitlles M et al. Respir Med 2007;101:453–60

13. Implications of exacerbations for prognosis of COPD
Hospitalization (3–16% of patients)1
Death (8–14% of hospitalized patients)2–4
Pulmonary embolism, myocardial infarction, stroke5–7
Worsening lung function8
Impaired quality of life 9,10
Frequent exacerbations
Worsening lung function
Between 3 and 16% of patients experiencing an exacerbation require hospitalization, and some of these will develop respiratory failure and require ICU admission.1 Between 8% and 14% of patients hospitalized with acute COPD exacerbations will die during their admission.2–4 Patients with COPD exacerbation are also at high risk of venous thromboembolism, pulmonary embolism, myocardial infarction and stroke.5–7 The prognosis is particularly poor for patients who require ICU admission and mechanical ventilation. More frequent exacerbations are also associated with more rapid decline in lung function8 and QoL.9,10
References
1. MacIntyre N, Huang YC. Acute exacerbations and respiratory failure in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2008;5(4):
2. Fuso L, et al. Predicting mortality of patients hospitalized for acutely exacerbated chronic obstructive pulmonary disease. Am J Med. Mar 1995;98(3):
3. Connors AF, Jr., et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments). Am J Respir Crit Care Med. 1996;154(4 Pt 1):
4. Gunen H, et al. Factors affecting survival of hospitalized patients with COPD. Eur Respir J. 2005;26(2):
5. Gunen H, et al. Venous thromboemboli and exacerbations of COPD. Eur Respir J 2010;35:
6. Rizkallah J, et al. Prevalence of pulmonary embolism in acute exacerbations of COPD: a systematic review and metaanalysis. Chest. 2009;135(3):
7. Donaldson GC, et al. Increased risk of Myocardial Infarction and Stroke following Exacerbation of Chronic Obstructive Pulmonary Disease. Chest. 2010;137(5):
8. Donaldson GC, et al. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57(10):
9. Llor C, et al. Exacerbations worsen the quality of life of chronic obstructive pulmonary disease patients in primary healthcare. Int J Clin Pract. 2008;62(4):
10. Spencer S, Calverley PM, Burge PS, Jones PW. Impact of preventing exacerbations on deterioration of health status in COPD. Eur Respir J. 2004;23(5):
COPD = chronic obstructive pulmonary disease
1. MacIntyre N, Huang YC. Proc Am Thorac Soc. 2008;5:530–535; 2. Fuso L, et al. Am J Med. 1995;98:272–77; 3. Connors AF Jr, et al. Am J Respir Crit Care Med. 1996;154:959–67; 4. Gunen H, et al. Eur Respir J. 2005;26:234–21; 5. Gunen H, et al. Eur Respir J 2010;35:1243–8; 6. Rizkallah J, et al. Chest. 2009;135:786–93; 7. Donaldson GC, et al. Chest. 2010;137:1091–97; 8. Donaldson GC, et al. Thorax. 2002;57:847–52; 9. Llor C, et al. Int J Clin Pract. 2008;62:585–92; 10. Spencer S, et al. Eur Respir J. 2004;23:698–702

14. COPD exacerbations increase mortality risk
Group A: no exacerbations
Group B: 1–2 exacerbations
Group C: ≥3 exacerbations
1.0
0.8 A
p<0.0002
0.6
Survival probability B
p<0.0001
0.4
p=0.069 C
Reference
Soler-Cataluña JJ et al. Thorax 2005;60:925–31.
0.2
Time (months)
COPD = chronic obstructive pulmonary disease
Soler-Cataluña JJ et al. Thorax 2005;60:925–31

15. Treatment challenges of COPD exacerbations
Identifying the frequent exacerbator
Especially in early-stage disease
Treating exacerbations
Patients need to report promptly to ensure rapid recovery
Detecting exacerbations
Exacerbations may cluster, be seasonal and be relatively uncommon
Control of symptoms, especially dyspnea, is key to reducing exacerbations and their severity
COPD = chronic obstructive pulmonary disease

16. Limited evidence for reduction in exacerbation rate with salmeterol/fluticasone vs tiotropium
In the INSPIRE study, rates of ‘All exacerbations’ at 2 years were similar between tiotropium and salmeterol/fluticasone treatment groups
2.0
Tiotropium 18 μg o.d. (n=665)
Salmeterol/fluticasone 50/500 μg b.i.d. (n=658)
p=ns
1.5
p=0.028
p=0.039
Rate per year
1.0
For the primary efficacy endpoint, tiotropium and salmeterol/fluticasone (SFC) had similar impacts on healthcare-utilization exacerbations (defined as those that required treatment with oral corticosteroids and/or antibiotics or required hospitalization). Estimated exacerbation rates per year were 1.28 for SFC and 1.32 for tiotropium (rate ratio [RR]: [95% CI, to 1.119], p=0.656).1
Exacerbations requiring antibiotics occurred more frequently in patients treated with SFC (SFC, 0.97/yr; tiotropium, 0.82/yr; RR: 1.19 [95% CI, 1.02 to 1.38], p=0.028), but those requiring systemic corticosteroids were less frequent than in the tiotropium-treated patients (SFC, 0.69/yr; tiotropium, 0.85/yr; RR: 0.81 [95% CI, 0.67 to 0.99], p=0.039).1
Reference
1. Wedzicha JA et al. Am J Respir Crit Care Med 2008;177:19–26.
0.5
All exacerbations
Exacerbations requiring antibiotics
Exacerbations requiring systemic corticosteroids
b.i.d. = twice daily; ICS = inhaled corticosteroid; LABA = long-acting β2-agonist; LAMA = long-acting muscarinic antagonist; o.d. = once daily
Wedzicha JA et al. Am J Respir Crit Care Med 2008;177:19–26 16

17. 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
Glycopyrronium 50 μg o.d.
Tiotropium
Placebo 90 80
Patients exacerbation-free (%) 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
Glycopyrronium significantly reduced the risk of exacerbations (in terms of time to first moderate or severe exacerbation) by 34% vs placebo (HR, 0.66; 95% CI 0.520–0.850; p=0.001).1
Comparable to tiotropium, which provided a 39% risk reduction vs placebo (HR, 0.61; 95% CI, 0.456–0.821; p=0.001).1
Glycopyrronium reduced the rate of moderate or severe COPD exacerbations by 35% vs placebo (0.54/yr vs 0.80/yr; rate ratio 0.66; CI 0.496–0.869; p=0.003).1
The effect of tiotropium was not significantly different from placebo (rate ratio 0.80; CI 0.586–1.105; p=0.179).1
Glycopyrronium 50 μg and tiotropium 18 μg once daily were comparable and were both superior to placebo in reducing moderate exacerbations requiring systemic corticosteroids (glycopyrronium/placebo OR, 0.61; 95% CI, 0.434–0.870; p=0.006; tiotropium/placebo OR, 0.62; 95% CI 0.413–0.930; p=0.021) and those requiring treatment with antibiotics (glycopyrronium/placebo OR, 0.69; 95% CI 0.495–0.957; p=0.026; tiotropium/placebo OR, 0.65; 95% CI 0.438–0.949; p=0.026).1
GLOW2 study details
Design: 52-week, randomized, double-blind, placebo-controlled, parallel-group, open-label tiotropium.1
Patient population: N=1066.1
Key inclusion criteria: moderate to severe COPD (GOLD Stage II–III), age ≥40 years, at least 10-pack-year smoking history, post-bronchodilator FEV1 of <80% and ≥30% of predicted normal and post-bronchodilator FEV1/FVC ratio of <0.7.1
Key exclusion criteria: history/diagnosis of asthma, history of clinically significant cardiac abnormalities/prolongation of QTc interval1
Treatment groups: Seebri Breezhaler o.d., open-label tiotropium 18 µg o.d. and placebo (2:1:1).1
Primary outcome measure: trough FEV1 at 12 weeks.1
Key/important secondary outcome measures: TDI at 26 weeks, SGRQ at 52 weeks, time to first COPD exacerbation over 52 weeks, and daily rescue medication over 52 weeks.1
Additional secondary variables: trough FEV1 at Day 1, Week 26 and Week 52; serial spirometry on Day 1 and Weeks 12 and 52 (at time points 5, 15, 30 mins and 1,2,3 and 4 h post-dose); IC on Day 1 and Weeks 12 and 52 (time points 25 mins, 1 h 55mins and 3 h 55 mins post dose); rate of COPD exacerbations in the 52 weeks.1
76% completed the study.1
Reference
Kerwin E et al. Eur Respir J 2012;40:1106–14.
Time to first exacerbation (weeks)
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

18. Conclusions
Exacerbations are characterized by worsening of respiratory symptoms beyond normal day-to-day variation and requiring a change in medication1
60–70% of patients with COPD will have an exacerbation over 2–4 years2,3
Risk factors for exacerbations include:
COPD severity (GOLD stage)4
Older age5
Degree of FEV1 impairment5
Frequent past exacerbations (the best predictor of future exacerbations)5,6
‘Frequent exacerbators’ and ‘non-exacerbators’ are stable phenotypes6
Patients with frequent exacerbations have poorer clinical outcomes7
Failure to identify and treat exacerbations promptly can adversely affect outcomes8,9
COPD exacerbations significantly affect clinical outcomes7 and personal well being,10 result in an increased mortality risk,11 and lead to hyperinflation and inactivity12
There is limited evidence that LABA/ICS therapy reduces exacerbation rates compared with a LAMA3
LAMAs have been shown to reduce the risk of exacerbations vs placebo13
COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease; ICS= inhaled corticosteroid; LABA = long-acting β2 agonist; LAMA = long-acting muscarinic antagonist
1. GOLD 2014 ( 2. Tashkin DP, et al. N Engl J Med 2008;359:,1543–54; 3. Wedzicha JA ,et al. Am J Respir Crit Care Med 2008;177:19–26; 4. De Oca MM, et al. Chest 2009;136:71–78; 5. Anzueto A, et al. Proc Am Thorac Soc 2007;4:554–64; 6. Hurst J, et al. N Engl J Med 2010:363:1128–38; 7. Wedzicha JA, Seemungal TA. Lancet. 2007;370:786–96; 8. Wilkinson TM et al. Am J Respir Crit Care Med 2004;169:1298–303; 9. Xu W et al. Eur Respir J 2010;35:1022–30; 10. Miravitlles M et al. Respir Med 2007;101:453–60; 11. Soler-Cataluña JJ et al. Thorax 2005;60:925–31;
12. Cooper CB. Respir Med 2009;103:325–34; 13. Kerwin E et al. Eur Respir J 2012;40:1106–14