Pierluigi Paggiaro Cardio-Thoracic and Vascular Department, University of Pisa, Italy
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Transcript of Pierluigi Paggiaro Cardio-Thoracic and Vascular Department, University of Pisa, Italy
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
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
The natural history of FEV1 decline in COPD patients
Fletcher and Peto, BMJ 1977
Recent long-term trial have confirmed the progressive decline in FEV1 in untreated
moderate-severe COPD
Miravitlles et al, IJCOPD 2009
Long-term longitudinal studies have only partially confirmed the rate of FEV1 decline at
different baseline FEV1
Decramer and Cooper, Thorax 2010
GOLD stage II has a greater FEV1 decline than GOLD stage III and GOLD stage IV
Decramer and Cooper, Thorax 2010
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
Long-term smoking cessation may modify the FEV1 decline
Scanlon et al, AJRCCM 2000
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
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
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
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V1 (
L)
Tiotropium Control
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
Reversible and non reversible COPD patients had similar results from tiotropium addition
Hanania et al, Resp Res 2011
In moderate COPD, tiotropium significantly reduces the decline in post-bronc FEV1
Decramer et al, Lancet 2009
Celli et al, AJRCCM 2008
Post-hoc analysis of TORCH studySalm/Fluti decreases the decline in FEV1
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”
May early treatment effectively prevent progressive deterioration in COPD ?
Decramer et al, Respir Med 2011
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
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
Donaldson et al, Thorax 2002Donaldson et al, Thorax 2002
Frequent exacerbations are related to a greater decline in FEV1
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
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
Frequent exacerbators are represented in all GOLD stages
Hurst et al, NEJM 2010
Hurst et al, NEJM 2010
Frequent exacerbators represent a specificconstant phenotype
Alsaeedi et al, Am J Med 2002
Inhaled corticosteroids reduce the risk ofexacerbations in COPD
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
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
“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
Virus-induced exacerbations of COPD are associated with greater sputum eosinophilia
Papi et al, AJRCCM 2006
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 ?
High frequency of sputum eosinophilsin COPD patients
Papi et al, AJRCCM 2000
COPD patients with partial airway reversibilityhave higher levels of exhaled NO
Brightling et al,Thorax 2005
Sputum eosinophilia predicts a better response to CS in COPD patients
A strategy aiming to minimize sputum eosinophilia reduces the number of severe
exacerbations of COPD
Siva et al, ERJ 2007
Airway inflammation is present in COPD, also in earlier stages
Hogg et al, NEJM 2004
Malondealdehayde (MDA), a marker of oxidative stress in EBC, is increased in stable moderate
COPD patients
Bartoli et al,Med Inflamm 2011
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
A more flexible approach, based on symptoms and exacerbations, and not only on FEV1, has
been now considered in the future GOLD guidelines