Transcript Slide 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
COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease
GOLD 2014 (http://www.goldcopd.org/)
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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
COPD, chronic obstructive pulmonary disease.
1. Seemungal TA. Int J Chron Obstruct Pulmon Dis 2009;4:203–23
2. Tashkin DP. N Engl J Med 2008;359:1543–54
3. Wedzicha JA. Am J Respir Crit Care Med 2008;177:19–26
4. Soler-Cataluña JJ and Rodriguez-Roisin R. COPD 2010;7:276–84
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Seasonality of COPD exacerbations
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Northern* and Southern† regions
Patients reporting an exacerbation (%)
Patients reporting an exacerbation (%)
 COPD exacerbations are more frequent in winter months than in summer months
12
10
8
6
4
2
0
Tropics‡
14
12
10
8
6
4
2
0
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
1. Jenkins CR et al. Eur Respir J 2012;39:38-45
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Exacerbation triggers and effects
Triggers
Viruses
Pollutants
Bacteria
Effects
Inflamed
COPD airways
Greater airway
inflammation
Systemic
inflammation
Bronchoconstriction
edema, mucus
Expiratory flow
limitation
Cardiovascular
comorbidity
COPD = chronic obstructive pulmonary disease
Wedzicha JA, Seemungal TA. Lancet 2007;370:786–96
Exacerbation
symptoms
Dynamic
hyperinflation
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Risk factors for an exacerbation
 COPD severity (GOLD stage)1
 Older age2
 Degree of FEV1 impairment2
 Chronic bronchial mucus
hypersecretion
2
Proportion of COPD patients reporting exacerbation
by GOLD severity stage1
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
 Frequent past exacerbations2
 Daily cough and wheeze
Exacerbation
within past yr
 Persistent symptoms of chronic
bronchitis2
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
Ever had
exacerbation
0
10
20
30
40
50
60
Proportion of subjects (%)
COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease; FEV1 = forced expiratory volume in 1 s
1. De Oca MM, et al. Chest 2009;136:71–78;
2. Anzueto A, et al. Proc Am Thorac Soc 2007;4:554–64
70
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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
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
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‘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
0
Exacerbations/year
Year 1
0
Percentage
20 40 60 80 100
20
Year 2
Year 3
Percentage
Percentage
40
60
80
100
0
0
0
1
1
≥2
≥2
20
40
60
80
100
80
100
0
Percentage
1
0
≥2
Data are for 1679 patients with
COPD who completed the study
COPD = chronic obstructive pulmonary disease
Hurst J, et al. N Engl J Med 2010:363:1128–38
20
40
60
Percentage
80
100
0
0
0
1
1
≥2
≥2
20
40
60
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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
COPD = chronic obstructive pulmonary disease; GOLD = Global Initiative for Chronic Obstructive Lung Disease; HRQoL, health-related quality of life
1. Wilkinson TM et al. Am J Respir Crit Care Med 2004;169:1298–303
2. Xu W et al. Eur Respir J 2010;35:1022–30
3. Langsetmo L et al. Am J Respir Crit Care Med 2008;177:396–401
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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
More hospital
admissions
COPD = chronic obstructive pulmonary disease
1. Wedzicha JA, Seemungal TA. Lancet. 2007;370:786–96
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COPD exacerbations worsen airflow obstruction,
cause hyperinflation and contribute to inactivity
COPD
Exercise
Expiratory flow limitation
Air trapping
Hyperinflation
Exacerbations
Shortness of breath
Deconditioning
Quality of life
Inactivity
Reduced exercise capacity
Disability
Disease progression
COPD = chronic obstructive pulmonary disease; HRQoL = health-related quality of life
1. Cooper CB. Respir Med 2009;103:325–34
Death
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COPD exacerbations have a significant impact
on personal well being
Due to flare-ups
Had to cancel public outings
33%
Lost energy/interest of doing what I had planned
32%
Was frightened of the onset of winter
30%
Wanted to be alone/with few close friends/family
27%
I was very frustrated with myself
27%
22%
I was very scared
I was bed-ridden/hospitalized
Intimacy with my partner was impossible
Results from 1,100 patient interviews, in five European countries and the USA.
COPD = chronic obstructive pulmonary disease
1. Miravitlles M et al. Respir Med 2007;101:453–60
19%
17%
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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
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
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COPD exacerbations increase mortality risk
Group A: no exacerbations
Group B: 1–2 exacerbations
Group C: ≥3 exacerbations
1.0
Survival probability
0.8
A
p<0.0002
0.6
B
p=0.069
0.4
C
0.2
0
0
10
20
COPD = chronic obstructive pulmonary disease
1. Soler-Cataluña JJ et al. Thorax 2005;60:925–31
30
40
Time (months)
50
60
p<0.0001
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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
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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
Tiotropium 18 μg o.d. (n=665)
2.0
Salmeterol/fluticasone 50/500 μg
b.i.d. (n=658)
p=ns
Rate per year
1.5
1.32
1.28
p=0.028
p=0.039
0.97
1.0
0.82
0.85
0.69
0.5
0
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
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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
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52
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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 (http://www.goldcopd.org/); 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