EARLY TREATMENT: USE THE BEST FIRST
Early treatment with pharmacological approach
Focus on COPD Stage II
Pierluigi Paggiaro
Cardio-Thoracic and Vascular Department, University of Pisa, Italy
Annual Meeting ACCP – Capitolo Italiano
Honolulu, 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
No effect of regular use ICS on FEV1
decline in COPD patients
Soriano, Chest 2007
In the Uplift study, tiotropium induces an
important improvement in FEV1 which persists
over 4 years
1,50
Tiotropium
*
*
FEV1 (L)
1,40
*
*
*
*
Control
*
1,30
*
*
1,20
*
*
*
Post-Bronch FEV1
*
 = 47 – 65 mL
*
(n=2516)
(n=2374)
*
*
*
1,10
*
(n=2494)
Pre-Bronch FEV1
(n=2363)
1,00
0
01
Day 30
(steady state)
6
12
18
24
30
Month
*P<0.0001 vs. control. Repeated measure ANOVA was used to estimate means.
Means are adjusted for baseline measurements. Baseline trough FEV 1 (observed
mean) = 1.116 (trough), 1.347 (peak). Patients with ≥3 acceptable PFTs after day
30 were included in the analysis.
36
42
48
 = 87 – 103 mL
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
Post-hoc analysis of TORCH study
Salm/Fluti decreases the decline in FEV1
Celli et al, AJRCCM 2008
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
Frequent exacerbations are related to
a greater decline in FEV1
Donaldson et al, Thorax 2002
High frequency of exacerbations
increases the risk of mortality in COPD
0 riacutizzazioni/anno
≥ 3 riacutizzazioni/anno
1–2 riacutizzazioni/anno
Probabilità di sopravvivenza
1,0
0,8
p<0,0002
0,6
p<0,0001
0,4
p=0,069
0,2
0
0
10
20
30
40
50
60
Tempo (mesi)
Soler-Cataluna JJ et al. Thorax 2005
ECLIPSE: 3-year longitudinal observational study
2165 COPD patients,
GOLD II-IV
baseline 3 Months 6 M
V1
V2
V3
336 ‘healthy’ smokers
12 M
V4
18 M
V5
246 non smokers
24 M
V6
30 M
V7
36 M
V8
Vestbo et al. ERJ 2008
Frequent exacerbators are represented in
all GOLD stages
Hurst et al, NEJM 2010
Frequent exacerbators represent a specific
constant phenotype
Hurst et al, NEJM 2010
Inhaled corticosteroids reduce the risk of
exacerbations in COPD
Alsaeedi et al, Am J Med 2002
Moderate-severe exacerbation in 3 yrs
Mean number of exacerbation/year
1.2
1.13
25% reduction
0.97*
1
0.93*
0.85*†‡
0.8
0.6
0.4
0.2
0
Placebo
SALM
FP
SALM/FP
Trattamenti
*p < 0.001 vs placebo; †p = 0.002 vs SALM; ‡p = 0.024 vs FP
Calverly et al, NEJM 2007
Salm/Fluti reduces all causes of mortality of
COPD 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 eosinophils
in COPD patients
COPD patients with partial airway reversibility
have higher levels of exhaled NO
Papi et al, AJRCCM 2000
Sputum eosinophilia predicts a better
response to CS in COPD patients
Brightling et al,
Thorax 2005
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