EARLY TREATMENT: USE THE BEST FIRST
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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.

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Pierluigi paggiaro cardio thoracic and vascular department university of pisa italy

EARLY TREATMENT: USE THE BEST FIRSTEarly treatment with pharmacological approachFocus 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

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


Pierluigi paggiaro cardio thoracic and vascular department university of pisa italy

The natural history of FEV1 decline in COPD patients

Fletcher and Peto, BMJ 1977


Pierluigi paggiaro cardio thoracic and vascular department university of pisa italy

Recent long-term trial have confirmed the progressive decline in FEV1 in untreated moderate-severe COPD

Miravitlles et al, IJCOPD 2009


Pierluigi paggiaro cardio thoracic and vascular department university of pisa italy

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

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

Is it possible to modify the natural history of COPD ?


Long term smoking cessation may modify the fev1 decline

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

Short and long-term studies with inhaled corticosteroids (ICS)


No effect of regular use ics on fev1 decline in copd patients

No effect of regular use ICS on FEV1 decline in COPD patients

Soriano, Chest 2007


Pierluigi paggiaro cardio thoracic and vascular department university of pisa italy

In the Uplift study, tiotropium induces an important improvement in FEV1 which persists over 4 years

1,50

Tiotropium

Control

*

*

*

*

1,40

*

*

Post-Bronch FEV1

 = 47 – 65 mL

*

*

1,30

*

(L)

(n=2516)

*

1

*

*

*

FEV

(n=2374)

*

1,20

*

*

*

*

1,10

(n=2494)

Pre-Bronch FEV1

 = 87 – 103 mL

(n=2363)

1,00

0

1

0

6

42

48

12

18

24

30

36

Day 30

(steady state)

Month

*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.


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

Sub-analysis of the UPLIFT study


Reversible and non reversible copd patients had similar results from tiotropium addition

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

In moderate COPD, tiotropium significantly reduces the decline in post-bronc FEV1

Decramer et al, Lancet 2009


Pierluigi paggiaro cardio thoracic and vascular department university of pisa italy

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”

Rationale for early treatment in COPD


May early treatment effectively prevent progressive deterioration in copd

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

Factors contributing to the progression of COPD


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

COPD exacerbations represent an important outcome, among the PROs

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


Pierluigi paggiaro cardio thoracic and vascular department university of pisa italy

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

1–2 riacutizzazioni/anno

≥ 3 riacutizzazioni/anno

1,0

0,8

p<0,0002

0,6

p<0,0001

Probabilità di sopravvivenza

0,4

p=0,069

0,2

0

0

10

20

30

40

50

60

Tempo (mesi)

High frequency of exacerbations increases the risk of mortality in COPD

Soler-Cataluna JJ et al. Thorax 2005


Eclipse 3 year longitudinal observational study

ECLIPSE: 3-year longitudinal observational study

2165 COPD patients, GOLD II-IV

246 non smokers

336 ‘healthy’ smokers

baseline

3 Months

6 M

12 M

18 M

24 M

30 M

36 M

V1

V2

V3

V4

V5

V6

V7

V8

Vestbo et al. ERJ 2008


Frequent exacerbators are represented in all gold stages

Frequent exacerbators are represented in all GOLD stages

Hurst et al, NEJM 2010


Pierluigi paggiaro cardio thoracic and vascular department university of pisa italy

Frequent exacerbators represent a specific

constant phenotype

Hurst et al, NEJM 2010


Pierluigi paggiaro cardio thoracic and vascular department university of pisa italy

Inhaled corticosteroids reduce the risk of

exacerbations in COPD

Alsaeedi et al, Am J Med 2002


Moderate severe exacerbation in 3 yrs

Moderate-severe exacerbation in 3 yrs

Mean number of exacerbation/year

25% reduction

1.2

1.13

0.97*

0.93*

1

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

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

“Asthma” pattern in COPD


Virus induced exacerbations of copd are associated with greater sputum eosinophilia

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 ?

Sputum eosinophilia in stable COPD


Pierluigi paggiaro cardio thoracic and vascular department university of pisa italy

High frequency of sputum eosinophils

in COPD patients


Pierluigi paggiaro cardio thoracic and vascular department university of pisa italy

COPD patients with partial airway reversibility

have higher levels of exhaled NO

Papi et al, AJRCCM 2000


Pierluigi paggiaro cardio thoracic and vascular department university of pisa italy

Sputum eosinophilia predicts a better

response to CS in COPD patients

Brightling et al,

Thorax 2005


Pierluigi paggiaro cardio thoracic and vascular department university of pisa italy

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

Airway inflammation is present in COPD, also in earlier stages

Hogg et al, NEJM 2004


Pierluigi paggiaro cardio thoracic and vascular department university of pisa italy

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

Conclusions


Pierluigi paggiaro cardio thoracic and vascular department university of pisa italy

A more flexible approach, based on symptoms and exacerbations, and not only on FEV1, has been now considered in the future GOLD guidelines


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