early treatment: use the best first early treatment with pharmacological approach focus on copd...
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EARLY TREATMENT: USE THE BEST FIRST
Early treatment with pharmacological approachFocus on COPD Stage II
Pierluigi PaggiaroCardio-Thoracic and Vascular Department, University of Pisa, Italy
Annual Meeting ACCP – Capitolo ItalianoHonolulu, Hawaii, 23 oct 2011
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Main characteristics of COPD
• Non completely reversible airway obstruction• Variable combination of chronic bronchitis
and emphysema• Progressive decline in FEV1• Progressive deterioration in
– dyspnoea– exercise limitation
• Relevant role of exacerbations– in progression of the disease– in quality of life
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The natural history of FEV1 decline in COPD patients
Fletcher and Peto, BMJ 1977
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Recent long-term trial have confirmed the progressive decline in FEV1 in untreated
moderate-severe COPD
Miravitlles et al, IJCOPD 2009
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Long-term longitudinal studies have only partially confirmed the rate of FEV1 decline at
different baseline FEV1
Decramer and Cooper, Thorax 2010
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GOLD stage II has a greater FEV1 decline than GOLD stage III and GOLD stage IV
Decramer and Cooper, Thorax 2010
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Is it possible to modify the natural history of COPD ?
• Several interventional studies– Lung Health Study I (ipratropium bromide)– ICS treatment
• Euroscope (budesonide)• Copenhagen City Heart Study (budesonide)• LHS II (triamcinolone)• ISOLDE(fluticasone)
– UPLIFT study (tiotropium)– TORCH study (Salm/Fluti)
• Negative results in the primary outcome
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Long-term smoking cessation may modify the FEV1 decline
Scanlon et al, AJRCCM 2000
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Short and long-term studies with inhaled corticosteroids (ICS)
• Effective in reducing number and/or severity of exacerbations
– Several studies, with different but consistent results (Paggiaro et al, Lancet 1997)
• Effect associated with:
– Improvement in FEV1
– Improvement in quality of life
– In subjects with FEV1 < 50% and frequent exacerbations
• Studies over 3-4 years, with the aim to modify natural history of the disease
– All studies negative on improving the progressive decline of FEV1 (Euroscop, ISOLDE, LHS-II, CCLS)
– Confirmation of the positive effect on exacerbations and other secondary outcomes
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Soriano, Chest 2007Soriano, Chest 2007
No effect of regular use ICS on FEV1 decline in COPD patients
No effect of regular use ICS on FEV1 decline in COPD patients
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In the Uplift study, tiotropium induces an important improvement in FEV1 which persists
over 4 years
*
Day 30(steady state)
* ** *
* **
*
06 12 18 24 30 36 42 480 1
Month
* * ** * * * * *
Post-Bronch FEV1
= 47 – 65 mL
Pre-Bronch FEV1
= 87 – 103 mL
(n=2516)
(n=2374)
(n=2494)
(n=2363)
*P<0.0001 vs. control. Repeated measure ANOVA was used to estimate means. Means are adjusted for baseline measurements. Baseline trough FEV1 (observed mean) = 1.116 (trough), 1.347 (peak). Patients with ≥3 acceptable PFTs after day 30 were included in the analysis.
1,00
1,10
1,20
1,30
1,40
1,50
FE
V1 (
L)
Tiotropium Control
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Sub-analysis of the UPLIFT study
• Different response to tiotropium, according to:
– Gender: male vs female• Tashkin et al, Respir Med 2010
– Smoking habit: current vs ex vs intermittent• Tashkin et al, ERJ 2010
– GOLD II stage **• Decramer et al, Lancet 2009
– Acute reversibility; reversible vs non reversible• Hanania et al, Resp Res 2011
– No additional therapies (ICS/LABA) **• Troosters et al, ERJ 2010
– Age: lower than 50 yrs vs higher than 50 yrs **• Morice et al, Respir Med 2010
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Reversible and non reversible COPD patients had similar results from tiotropium addition
Hanania et al, Resp Res 2011
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In moderate COPD, tiotropium significantly reduces the decline in post-bronc FEV1
Decramer et al, Lancet 2009
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Celli et al, AJRCCM 2008
Post-hoc analysis of TORCH studySalm/Fluti decreases the decline in FEV1
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Rationale for early treatment in COPD
• Symptoms and limitation in daily life– Present also in mild airway obstruction and/or
hyperinflation
• Decline in FEV1– Greater in early phases– Positive effect of treatment easier to be observed
• Airway and lung inflammation / exacerbations– Present in the early stages– More steroid-sensitive in early stage (?)
• Need to identify “rapid decliners”
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May early treatment effectively prevent progressive deterioration in COPD ?
Decramer et al, Respir Med 2011
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Factors contributing to the progression of COPD
• Persistence of smoking habit• Pulmonary function
– FEV1– IC
• Exercise capacity– 6MWT, physical activity
• Nutritional status– BMI, FFM
• Rate of exacerbations
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COPD exacerbations represent an important outcome, among the PROs
– COPD patients may have exacerbations, which increase in number and severity with the increase in the severity of the pathology of the disease
– The impact of exacerbations increases over time, leading to:
• Greater decline in pulmonary function 1 • Increase in symptoms 2
• Deterioration in health status 3 • Increased risk of hospitalization 4
– Severe exacerbations increase the risk of mortality 4,5
1. Donaldson GC et al. Thorax 2002; 57: 847-852; 2. Donaldson GC et al. Eur Respir J 2003; 22: 931-936;3. Seemungal TA et al. Am J Respir Crit Care Med 1998; 157: 1418-1422; 4. Groenewegen KH et al. Chest 2003; 124: 459-467; 5. Soler-Cataluna JJ et al. Thorax 2005; 60: 925-931
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Donaldson et al, Thorax 2002Donaldson et al, Thorax 2002
Frequent exacerbations are related to a greater decline in FEV1
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High frequency of exacerbations increases the risk of mortality in COPD
Soler-Cataluna JJ et al. Thorax 2005
≥ 3 riacutizzazioni/anno
0
0,2
0,4
0,6
0,8
1,0
Pro
babili
tà d
i so
pra
vviv
enza
50
0 riacutizzazioni/anno 1–2 riacutizzazioni/anno
60403020100
Tempo (mesi)
p<0,0002
p=0,069
p<0,0001
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ECLIPSE: 3-year longitudinal observational study
Vestbo et al. ERJ 2008
2165 COPD patients, GOLD II-IV
336 ‘healthy’ smokers 246 non smokers
baseline 3 Months 6 M 12 M 18 M 24 M 36 M30 MV1 V2 V3 V4 V5 V6 V7 V8
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Frequent exacerbators are represented in all GOLD stages
Hurst et al, NEJM 2010
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Hurst et al, NEJM 2010
Frequent exacerbators represent a specificconstant phenotype
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Alsaeedi et al, Am J Med 2002
Inhaled corticosteroids reduce the risk ofexacerbations in COPD
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Moderate-severe exacerbation in 3 yrs
*p < 0.001 vs placebo; †p = 0.002 vs SALM; ‡p = 0.024 vs FP
Mean number of exacerbation/year
1.13
0.97*0.93*
0.85*†‡
25% reduction
0
0.2
0.4
0.6
0.8
1
1.2
Placebo SALM FP SALM/FP
Trattamenti
Calverly et al, NEJM 2007
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Salm/Fluti reduces all causes of mortality of Salm/Fluti reduces all causes of mortality of COPD in comparison with placeboCOPD in comparison with placebo
Calverly et al, NEJM 2007
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“Asthma” pattern in COPD
• Sputum eosinophilia
• During acute exacerbations– In up to 50% of AE– Mainly in virus-induced AE
• In stable COPD– In 30% about of patients– Associated with exhaled NO, acute reversibility (?)– Non associated with age, smoke, atopy, etc
• Different response to inhaled or oral CS
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Virus-induced exacerbations of COPD are associated with greater sputum eosinophilia
Papi et al, AJRCCM 2006
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Sputum eosinophilia in stable COPD
• Observed in up to 30-40% of patients• Lower than in asthma• Not related to other clinical features
– Chronic bronchitis ?– Acute reversibility ?
• How to select these patients ?
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High frequency of sputum eosinophilsin COPD patients
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Papi et al, AJRCCM 2000
COPD patients with partial airway reversibilityhave higher levels of exhaled NO
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Brightling et al,Thorax 2005
Sputum eosinophilia predicts a better response to CS in COPD patients
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A strategy aiming to minimize sputum eosinophilia reduces the number of severe
exacerbations of COPD
Siva et al, ERJ 2007
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Airway inflammation is present in COPD, also in earlier stages
Hogg et al, NEJM 2004
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Malondealdehayde (MDA), a marker of oxidative stress in EBC, is increased in stable moderate
COPD patients
Bartoli et al,Med Inflamm 2011
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Conclusions
• Progression of COPD is more evident in early phase– In GOLD I-II stages
• Exacerbations represent a major target of treatment– Efficacy of ICS and ICS/LABA– Also in earlier stages
• Early treatment– Better chance of modifying natural history
• Phenotyping of COPD– “asthmatic” feature role of ICS
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A more flexible approach, based on symptoms and exacerbations, and not only on FEV1, has
been now considered in the future GOLD guidelines