role of inhaled corticosteroids in copd

Role of Inhaled Corticosteroids in COPD

Prof.Gamal Rabie,MD,FCCPProfessor of pulmonary medicine , Assuit

University

Agenda

• New Definition and overview.

• Diagnosis and assessment.

• Therapeutic Options.

• Manage stable COPD ( New pharmacological algorithms ).

• Role of Symbicort in the management of COPD.

Definition of COPD

COPD is a common preventable and treatable disease that is characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases.

Global Initiative for Chronic Obstructive Lung Disease 2017

2017

Mechanisms Underlying Airflow Limitation in COPD

Small Airways Disease•Airway inflammation•Airway fibrosis, luminal plugs•Increased airway resistance

( Chronic bronchitis )

Parenchymal Destruction•Loss of alveolar attachments•Decrease of elastic recoil

( Emphysema )

AIRFLOW LIMITATIONGlobal Initiative for Chronic Obstructive Lung Disease 2015

Emphysema

Loss of elasticity of the lung

Lung Hyperinflation

Etiology , pathobiology and pathology of COPD leading to airflow limitation and clinical manifestations

PathobiologyImpaired lung growthAccelerated declineLung injuryLung & systematic inflammation

EtiologySmoking & pollutantsHost factors

PathologySmall airway disorders or abnormalities EmphysemaSystemic effect

Air flow limitationPersistent airflow limitation

Clinical manifestationsSymptomsExacerbationsComorbidities


Burden & prevalence of COPD

• COPD is a leading cause of morbidity and mortality worldwide.

• The burden of COPD is projected to increase in coming decades due to continued exposure to COPD risk factors and the aging of the world’s population.

• COPD is associated with significant economic burden.

• Based on BOLD , it’s estimated that number of COPD cases was 384 million in 2010 , global prevalence 11.7 % , 3 million deaths annually.

• By 2030 there may be 4.5 million deaths annually from COPD & related conditions.

BOLD : Burden of obstructive lung diseases Global Initiative for Chronic Obstructive Lung Disease 2017

Risk Factors for COPD

GenesInfections

Socio-economic status

Aging PopulationsGlobal Initiative for Chronic Obstructive Lung Disease 2017

Asthma & airway hyper-reactivityChronic bronchitis

Agenda






Diagnosis and Assessment: Key Points

• COPD should be considered in any patient who had : 1) Dyspnea 2) Chronic cough 3) Sputum production and / or a history of

exposure to risk factors for the disease.• Spirometry is required to make the diagnosis .


Assessment of COPD

• Assess symptoms• Assess degree of airflow limitation using spirometry• Assess risk of exacerbations

• Assess comorbidities


The characteristic symptoms of COPD are chronic and progressive dyspnea, cough and sputum production that can be variable from day-to-day. Dyspnea: Progressive, persistent and characteristically worse with exercise.Chronic cough: May be intermittent and may be unproductive.Chronic sputum production: COPD patients commonly cough up sputum.

Symptoms of COPD


Assess symptoms

•COPD Assessment Test ( CAT).•Clinical COPD Questionnaire ( CCQ).•mMRC Breathlessness scale.


COPD Assessment Test (CAT)

An 8-item measure of health status impairment

in COPD.

Modified MRC (mMRC) Questionnaire


Self-

adm

inist

ered

que

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nnai

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ical c

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1) From your clinical practice , which patient questionnaire you rely on in the assessment of symptoms ?

A- COPD Assessment Test ( CAT).B- mMRC Breathlessness scale.C- Both of the above.D- Rely on presenting symptoms & history.

• Assess symptoms• Assess degree of airflow limitation using spirometry• Assess risk of exacerbations• Assess comorbidities

Use spirometry for grading severity according to spirometry, using four grades split at 80%, 50% and 30% of predicted value

Assessment of airflow limitation


Common FVL Shapes

Normal Young or quitter Poor effort

Hesitation Knee Coughing

Reporting Standards• Largest FVC obtained from all acceptable efforts should be

reported.• Largest FEV1 obtained from all acceptable trials should be

reported.• May or may not come from largest FVC effort.

• All other flows, should come from the effort with the largest sum of FEV 1 & FVC.

• PEF should be the largest value obtained from at least 3 acceptable maneuvers.

Results Reporting Example

Pre & Post Bronchodilator Studies: Withholding Medications

Reversibility

Reversibility of airways obstruction can be assessed with the use of bronchodilators.

• > 12% increase in the FEV1 and 200 ml improvement in FEV1

OR

• > 12% increase in the FVC and 200 ml improvement in FVC.

1-First Step, Check quality of the test1- Start:

Good start: Extrapolated volume (EV) < 5% of FVC or 0.15 LPoor start: Extrapolated volume (EV) ≥5% of FVC or ≥ 0.15 L

2- Termination:No early termination :Tex ≥ 6 s Early termination : Tex < 6 s

2- Look at …………FEV1/FVC

< LLN(70%)

Obstructive or Mixed

≥ LLN(70%)

Restrictive or Normal

3- Look at FEV1 To detect degreeMild > 70%Mod 50-69 %Severe 35-49%Very severe < 35%

3- Postbronchodilator FEV1/FVC

>LLN or 70%Asthma

< LLN or 70%COPD

4- Reversibility test of FEV1

> 12%, 200 mlReversible (Asthma)

< 12% ,200 mlIrreversible (COPD)

5- Look at TLC

≥80 – 120 % Pure

obstruction

< 80 % Mixed

Classification of Severity of Airflow Limitation in COPD*

In patients with FEV1/ FVC < 0.70:

GOLD 1: Mild FEV1 > 80% predicted

GOLD 2: Moderate 50% < FEV1 < 80% predicted

GOLD 3: Severe 30% < FEV1 < 50% predicted

GOLD 4: Very Severe FEV1 < 30% predicted

*Based on Post-Bronchodilator FEV1


2) From your clinical practice , what is the frequency of using spirometer in your diagnosis ?A- Very highB- HighC- MediumD- LowE- I don’t use

Assess Risk of Exacerbations

To assess risk of exacerbations use history of exacerbations and spirometry: •Two or more exacerbations within the last year or an FEV1 < 50 % of predicted value are indicators of high risk.•One or more hospitalizations for COPD exacerbation should be considered high risk.


Assess COPD ComorbiditiesCOPD patients are at increased risk for:

• Cardiovascular diseases• Osteoporosis• Respiratory infections• Anxiety and Depression• Diabetes• Lung cancer• Bronchiectasis

These comorbid conditions may influence mortality and hospitalizations and should be looked for routinely,

and treated appropriatelyGlobal Initiative for Chronic Obstructive Lung Disease 2015

Revised combined COPD assessment

• A refinement of the ABCD assessment tools is proposed that separates spirometric grades from the “ ABCD “ groups

• ABCD groups will be derived exclusively from patient symptoms & exacerbations history

• Spirometery in conjugation with patient symptoms & exacerbation history remains vital for :

1) Diagnosis 2) Prognostication 3) Therapeutic approaches


The refined ABCD assessmnet tool


Spirometrically confirmed diagnosis

Post-bronchodilatorFEV1/FVC < 0.7

Assessment of airflow

limitation

FEV1 ( % predicted )

GOLD 1 ≥ 80 GOLD 2 50 - 79 GOLD 3 30 - 49 GOLD 4 < 30

≥ 2or

≥ 1 leading to hospitaladmission

0 or 1 (not leading to hospitaladmission)

Assessment of Symptoms /

risk of exacerbations

C D

A B

mMRC 0 – 1

CAT ˂ 10

mMRC ≥ 2

CAT ≥ 10

Exacerbationhistory

Symptoms

Agenda






Therapeutic Options: COPD MedicationsBeta2-agonists Short-acting beta2-agonists Long-acting beta2-agonistsAnticholinergics Short-acting anticholinergics Long-acting anticholinergicsCombination short-acting beta2-agonists + anticholinergic in one inhaler MethylxanthinesInhaled corticosteroids Combination long-acting beta2-agonists + corticosteroids in one inhalerSystemic corticosteroidsPhosphodiesterase-4 inhibitors


• LABAs and LAMAs are preferred over short-acting agents except for patients with only occasional dyspnea (Evidence A).

• Patients may be started on single long-acting bronchodilator therapy or dual long-acting bronchodilator therapy, In patients with persistent dyspnea on one bronchodilator treatment should be escalated to two (Evidence A).

• Inhaled bronchodilators are recommended over oral bronchodilators (Evidence A).

• Theophylline is not recommended unless other long-term treatment bronchodilators are unavailable or unaffordable (Evidence B).

Key Points for the Use of bronchodilators


• Long-term treatment with ICS may be considered in association with LABAs for patients with a history of exacerbation despite appropriate treatment with long-acting bronchodilators (Evidence A).

• Long-term therapy with oral corticosteroids is not recommended (Evidence A).

• In patients with exacerbations despite LABA/ICS or LABA/LAMA/lCS, chronic bronchitis and severe to very severe airflow obstruction, the addition of a PDE4 inhibitor can be considered (Evidence B).

Key Points for the Use of anti- inflammatory agents


Key Points for the Use of anti- inflammatory agents

• In former smokers with exacerbations despite appropriate therapy, macrolides can be considered (Evidence B )

• Statin therapy is not recommended for prevention Of exacerbations (Evidence A).

• Antioxidant mucolytics are recommended on in selected patients (Evidence A).


• Patients with severe hereditary alpha-1 antitrypsin deficiency and established emphysema may be candidates for alpha-1 antitrypsin augmentation therapy

(Evidence B).

• Antitussives cannot be recommended (Evidence C).

• Drugs approved for primary pulmonary hypertension are not recommended for patients with pulmonary hypertension secondary to COPD (Evidence B).

• Low-dose long acting oral and parenteral opioids may be considered for treating dyspnea in COPD patients with severe disease (Evidence B).

Key Points for the Use of other pharmacological treatments


Agenda






• Relieve symptoms• Improve exercise tolerance• Improve health status

• Prevent disease progression• Prevent and treat exacerbations• Reduce mortality

Reducesymptoms

Reducerisk

Manage Stable COPD: Goals of Therapy


• Avoidance of risk factors : Smoking cessation Reduction of indoor pollution Reduction of occupational exposure• Influenza vaccination

Manage Stable COPD: All COPD Patients


Manage Stable COPD: Non-Pharmacological


Patient group Essential Recommended Depending on local guidelines

ASmoking cessation (can include pharmacologic treatment)

Physical activity Flu vaccinationPneumococcal vaccination

B - D

Smoking cessation (can include pharmacologic treatment)Pulmonary Rehabilitaion

Physical activity Flu vaccinationPneumococcal vaccination

3) From your clinical practice , Pulmonary Rehabilitaion palys any role in your non-pharmacological management of patinets group (B – D) ?

A- YesB-NO

Manage Stable COPD: Pharmacological treatment algorthmis by GOLD grade

2017

Highlighted boxes and arrows indicate preferred treatment pathways


• All Group A patients should be offered bronchodilators treatment based on it’s effect on breathlessness ( this can be either short- or long-acting bronchodilator ).

• This should be continued if symptomatic benefits is documented.

• Alternative mono bronchodilator class may be used if needed after evaluating effect on symptoms.


Bronchodilators

Continue , stop or try

alternative class of

bronchodilators Evaluate effect

Group A

• Initial therapy should consist of long-acting bronchodilator “ long-acting inhaled bronchodilators are superior to short-acting inhaled bronchodilators taken as needed ( prn) and are therefore recommended.

• There is no evidence to recommend one class of long-acting bronchodilators over another for initial relief of symptoms in this group of patients.

• In the individual patient, the choice should depend on the patient's perception of symptom relief.


Group B

A long – acting bronchodilators

( LABA or LAMA )

LAMA + LABA

PersistentSymptoms

• For patients with persistent breathlessness on monotherapy— the use of two bronchodilators is recommended.

• For patients with severe breathlessness initial therapy

with two bronchodilators may be considered.

• If the addition of a second bronchodilator does not improve symptoms, we suggest the treatment could be stepped down again to a single bronchodilator.

• Group B patients are likely to have comorbidities that may added to their symptomatology and impact their prognosis and these possibilities should be investigated.


Group B

A long – acting bronchodilators

( LABA or LAMA )

LAMA + LABA

PersistentSymptoms

• Initial therapy should consist of a single long acting bronchodilator, in two head to head comparisons the tested LAMA was superior to the LABA regarding exacerbation prevention, therefore we recommend starting therapy with a LAMA in this group. 1

• Patients with persistent exacerbations may benefit from adding a second long acting bronchodilator (LABA/LAMA) or using a combination of a long acting beta 2- agonist and an inhaled corticosteroid (LABA/ICS). 1

• As ICS increases the risk for developing pneumonia in some patients, our primary choice is LABA/LAMA. 1 EMA : Europe , Middle east & Asia

1-Global Initiative for Chronic Obstructive Lung Disease 20172-http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2016/04/WC500205577.pdf 6 December 20163-Suissaet al (2013) Thorax 2013;68:1029–1036

Group C

LAMA

LAMA + LABA

LABA + ICS

Further exacerbation

(s)

• EMA supports the risk/benefit profile of ICS-containing therapies in COPD “there should be no change to the way in which these medicines are used.” 2

• Risk of patients with COPD developing serious pneumonia is particularly elevated and dose-dependent with fluticasone propionate use, and comparatively much lower with budesonide. 3

• No prospective head-to-head studies have been performed to determine relative risk of adverse events between ICS-containing treatments

http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2016/04/WC500205577.pdf

We recommend starting therapy with a LABA/LAMA combination because:

•In studies with patient reported outcomes as the primary endpoint LABA/LAMA combinations showed superior results compared to the single substances. “If a single bronchodilator is chosen as Initial treatment, a LAMA is preferred for exacerbation prevention based on comparison to LABAs “

•A LABA/LAMA combination was superior to a LABA/ICS combination in preventing exacerbations other patient reported outcomes in Group D patients.

Global Initiative for Chronic Obstructive Lung Disease 2017Wedzicha et al. (2016) N Engl J Med. DOI: 10.1056/NEJMoa1516385

It is important to note:Three-quarters of patients in the FLAME study were in GOLD Group D, only 19.3% of patients overall had a history of 2 or more moderate or severe exacerbations in the previous 12 months

Group D

LAMA LAMA + LABA

LABA + ICS

LAMA+ LABA+ ICS

Consider Roflumilast

if FEV1 ˂ 50% pred.And patient has

chronic bronchitis

Consider macrolides in former smokers

Further exacerbation(s)


PersistentSymptoms /

further exacerbation(s)

• In some patients initial therapy with LABA/ICS may be the first choice.

• These patients may have a history and/or findings suggestive of asthma-COPD overlap.

• High blood eosinophil counts may also be considered as a parameter to support the use of ICS, although this is still under debate


Group D

LAMA

LAMA + LABA

LABA + ICS

LAMA+ LABA+ ICS


if FEV1 ˂ 50% pred.

And patient has chronic bronchitis



Further exacerbation(s

)



In patients who develop further exacerbations on LABA/LAMA therapy we suggest two alternative pathways:

•Escalation to LABA/LAMA/ICS. “Studies are underway comparing

the effects of LABA/LAMA vs. LABA/LAMA/ICS for exacerbation

prevention. “

•If LABA/ICS therapy does not positively impact exacerbations/symptoms a LAMA can be added.


Group D

LAMA

LAMA + LABA

LABA + ICS

LAMA+ LABA+ ICS







)



If patients treated with LABA/LAMA/ICS still have exacerbations the following options may

be considered: •Add roflumilast : This may be considered in patients with an FEVI < 50% predicted and chronic bronchitis, particularly if they have experienced at least one hospitalization for an exacerbation in the previous year.

•Add a macrolide : The best available evidence exists for the use of azithromycin.

Consideration to the development of resistant organisms should be factored into making

•Stopping ICS : Evidence showing no significant harm from withdrawal supports this recommendation .1-Global Initiative for Chronic Obstructive Lung Disease 2017

2-Kim et al (Magnussen et al (2014) Withdrawing ICS in COPD: WISDOM. N Engl J Med 2014;371:1285-943-Outcome of Inhaler Withdrawal in Patients Receiving Triple Therapy for COPD. Tuberc Respir Dis 2016;79:22-30

Group D

LAMA

LAMA + LABA

LABA + ICS

LAMA+ LABA+ ICS







)



Withdrawing ICS abruptly or inappropriately is associated with a significant decrease in lung function, quality of life and may precipitate

an increase in exacerbations and accelerate lung function decline

Withdrawing ICS from patients on triple:

•Significant decline in trough FEV1 of 43 ml (p < 0.01)2

•Significant decline in health status (p = 0.047)2

•Numerical increase in exacerbations2

•May also accelerate FEV1 decline (54.7 vs. 10.7 ml/year, p = 0.007)3

Does the inflammatory phenotype predict response to therapy?

In stable disease:

Phenotype Infrequent exacerbator ACOS Exacerbator with emphysema

Exacerbator with chronic bronchitis

Treatment strategy* Bronchodilators Bronchodilators + ICS

Bronchodilators (in some cases + ICS)

Bronchodilators + ICS

No Yes

ACOS? ACOS?

No Yes NoYes

Chronic cough?

YesNo

Diagnosis of COPD and ≥2 exacerbations per year?

*Choice of treatment should be based on clinical phenotype and the intensity determined by severity

• *Choice of treatment should be based on clinical phenotype and the intensity determined by severity • ACOS = asthma‒COPD overlap syndrome; GesEPOC = Guía Española de la EPOC [Spanish Guidelines for COPD]; ICS = inhaled corticosteroid

Miravitlles M, et al. Arch Bronconeumol 2012

Characterization of patients with COPD: GesEPOC

Sputum eosinophilia predicts response to corticosteroids in COPD

1. Brightling CE et al. Lancet 2000; 356: 1480–52. Brightling CE et al. Thorax 2005; 60: 193–8

-0.05

0.00

0.05

0.10

0.15

0.20

0.25*

Least to most eosinophilic tertile

*p < 0.01

-0.05

0.00

0.05

0.10

0.15

0.20

**

Least to most eosinophilic tertile

P

ost-

bron

chod

ilato

r FE

V 1 (

L)

**p < 0.05

Mometasone2

Mean absolute increase in FEV1 after corticosteroids, compared with placebo

Prednisolone1

WISDOM- Blood eosinophils predict exacerbation risk following ICS step-down

12 month double-blind parallel-group 6 week run-in LABA + LAMA + High dose ICS Step down ICS or continuation 500mcg FP- 250mcg- 100mcg stopped at week 12

Watz et al Lancet Resp Med 2016

Bronchodilators

Continue , stop or try alternative

class of bronchodilato

rs Evaluate effect

Group A

Group C

LAMA

LAMA + LABA LABA + ICS


Group B

A long – acting bronchodilators( LABA or LAMA )

LAMA + LABA

PersistentSymptoms

Group D

LAMA LAMA + LABA

LABA + ICS

LAMA+ LABA+ ICS


if FEV1 ˂ 50% pred.And patient has

chronic bronchitis







4) From your clinical practice , what is the first line of pharmacological therapy regarding group D patients ?A- LABA + ICSB- LABA + LAMAC- LABA + LAMA + ICSD- LAMA only

5) From your clinical practice , what is your goal of therapy in the management of severe or very severe COPD patients with a risk of exacerbations ?A- Maximise bronchodilation B- Control inflammation C-Both

Agenda






Role of Symbicort in

Chronic obstructive pulmonary disease Patients

Effect of treatment on lung function

SPEED study

Onset of effect: Increase in morning PEF and FEV1 after morning dose

ANOVA adjusted (for period and baseline) mean change from pre-treatment.bid, twice daily BUD/FORM, budesonide/formoterol FEV1, forced expiratory volume in 1 secondFLU/SAL, fluticasone/salmeterolPEF, peak expiratory flow

N : number of randomised patients.

0

20

40

60

80

100

120

0 5 10 15

p<0.001

p<0.001

PEF

chan

ge fr

om p

re-d

ose

(L/m

in)

Minutes after dose

FEV 1

cha

nge

from

pre

-dos

e (m

L)

p<0.001p<0.001

BUD/FORM 320/9 μg bid

0

2

4

6

8

10

12

14

16

18

0 5 10 15

FLU/SAL 500/50 μg bid FLU/SAL 500/50 μg bidBUD/FORM 320/9 μg bid

Adapted from Partridge et al. 2009

12.0 L/min

6.3 L/min

16.3 L/min

9.8 L/min

40 mL

100 mL

110 mL

40 mL

Minutes after doseAdapted from Partridge et al. 2009

Partridge MR, et al. Therapeutic Advances in Respiratory Disease 2009; 3: 147–157.

N = 442 N = 442

Effect of treatment on Physical Activity

CLIMB study

BUD/FORM + TIO improved change in total morning activity score versus TIO alone

BUD/FORM + TIOPlacebo + TIO

0

0.35

0.30

0.20

0.15

0.10

0.05

Cha

nge

in C

DLM

tota

l sc

ore

(0–5

) fro

m ru

n-in

1 2 3 4 5 6 7 8 9 10 11 12

p=0.027*

p<0.001†

Weeks

0.25

*Treatment comparison from randomisation to first week of treatment. †Treatment comparison from randomisation to last week of treatment. BUD/FORM, budesonide/formoterol CDLM: Capacity of Daily Living during the Morning questionnaire; TIO:tiotropiumN : number of randomised patients

Adapted from Welte et al. 2009

Welte T, et al. Am J Respir Crit Care Med 2009; 180: 741–750.

N= 660

SPEED study: Morning activities

BUD/FORM, budesonide/formoterol CDLM ; Capacity of Daily Living during the Morning; FLU/SAL :fluticasone/salmeterol; MID: minimal important differenceN : number of randomised patients.

MID Total Score

Cha

nge

in C

DLM

que

stio

nnai

re

scor

es fr

om ru

n-in

0

0.05

0.10

0.15

0.20

0.25

0.30

TOTAL SCORE

Was

h you

rself

Dry yo

urself

Get dre

ssed

Eat br

eakfa

st

Walk

early

Walk

late

BUD/FORM 320/9 µg bidFLU/SAL 500/50 µg bid

p<0.05p<0.02

p<0.02

Adapted from Partridge et al. 2009

Partridge MR, et al. Therapeutic Advances in Respiratory Disease 2009; 3: 147–157.

0.22

0.12

N = 442

Effect of treatment on quality of life

CLIMB studyGreater improvements in health status with BUD/FORM

+ TIO than TIO alone

-3.8

-1.5

-4

-3

-2

-1

0

Improved health status

Comparisons are from randomisation to last visit.

BUD/FORM + TIO Placebo + TIO

Adju

sted

mea

n ch

ange

in S

GRQ

-C s

core


BUD/FORM: budesonide/formoterol; SGRQ-C, St George’s Respiratory Questionnaire for patients with chronic obstructive pulmonary disease.TIO:tiotropiumN : number of randomised patients

p=0.023N= 660

Effect of treatment on exacerbation prevention

BUD/FORM reduces the number of exacerbations requiring medical intervention

Mea

n no

. of

exac

erba

tion

s/pa

tien

t/ye

ar

0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

BUD/FORM BUD FORM Placebo

*

*p<0.05 vs placebo p=0.043 BUD/FORM vs. FORM N=812

*p<0.05 vs placebo p=0.015 BUD/FORM vs. FORM N=1022

1.4

1.6

1.81.9

0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

BUD/FORMBUD FORM Placebo

*1.4

1.6

1.8 1.9

BUD, budesonideBUD/FORM, budesonide/formoterolFORM, formoterolN : number of randomised patients 1.Szafranski W, et al. Eur Respir J 2003; 21: 74–81; 2..Calverley PM, et al. Eur Respir J 2003; 22: 912–919.

Szafranski W, et al 1 Calverley PM, et al 2

CLIMB study: Rate of severe exacerbations reduced by 62% with BUD/FORM + TIO versus TIO

alone

Days since randomisation

0.4

0.2

0.1

0.0

Exac

erba

tion

s/pa

tien

t

0 15 30 45 60 75 90

0.3

BUD/FORM + TIOPlacebo + TIO

Cox-proportional hazards:

rate ratio 0.38 (95% CI 0.25, 0.57;

p<0.001)

BUD/FORM, budesonide/formoterolCI, confidence interval TIO, tiotropiumN : number of randomised patients


Adapted from Welte et al. 2009

N= 660

Pathos: COPD Exacerbations

3.4

21

54

85

109

2.7

15

38

63

80

0.0 20.0 40.0 60.0 80.0 100.0 120.0 140.0 160.0

Emergencyvisits

Hospitalisations

Antibiotics

Oral steroids

Allexacerbations

BUD/FORMSAL/FLU

Eventrate per 100 patient-years

**

**

**

**

*

Events per 100 patient/years for exacerbations in propensity matched COPD patients treated with BUD/FORM (n=2734) or FLU/SAL (n=2734)

**P<0.0001; *P=0.0003 for difference. CI :confidence intervals BUD/FORM :budesonide/formoterol FLU/SAL: fluticasone/salmeterol

27 %

26 %

29 %

29 %

21 %

Journal of internal medicine 2013

Rate ratio ( 95% CI)

0.74(0.69-0.79)

0.74(0.69-0.81)

0.70(0.66-0.75)

0.71(0.65-0.78)

0.79(0.71-0.89)

GenesGenes EnvironmentEnvironment

PathobiologyPathobiology

Clinical featuresClinical features

AmplifiedAmplifiedinflammationinflammation

Susceptibility genesSusceptibility genes• αα1-antitrypsin1-antitrypsin• TelomeraseTelomerase• Hedgehog signallingHedgehog signalling• Many minor genes?Many minor genes?

Treatment response genesTreatment response genes• Receptor polymorphismsReceptor polymorphisms• Metabolism polymorphismsMetabolism polymorphisms• Tissue response polymorphismsTissue response polymorphisms

Risk factorsRisk factors• Cig smokeCig smoke• Biomass fuelsBiomass fuels• Air pollutionAir pollution• Asthma?Asthma?

• NeutrophilsNeutrophils• EosinophilsEosinophils• MacrophagesMacrophages• Tc1 cellsTc1 cells• Th17 cellsTh17 cells

PathologyPathology• Small airway obstructionSmall airway obstruction• EmphysemaEmphysema• MixedMixed• Systemic inflammationSystemic inflammation

• SymptomsSymptoms• Mucus hypersecretionMucus hypersecretion• HyperinflationHyperinflation• Disease progressionDisease progression• Exacerbation frequencyExacerbation frequency• ComorbiditiesComorbidities

Treatment responseTreatment response• GenesGenes• EnvironmentEnvironment• PathobiologyPathobiology• Disease stageDisease stage• ComorbiditesComorbidites

TherapyTherapy

DETERMINANTS OF TREATMENT RESPONSE IN COPDDETERMINANTS OF TREATMENT RESPONSE IN COPD

Multiple disease phenotypesMultiple disease phenotypes

BiomarkersBiomarkersof responseof response

role of inhaled corticosteroids in copd

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