SEPAR 44th National Congress Oviedo, 17 June 2011

Management of COPD: GOLD guidelines

Leonardo M. Fabbri
Clinica di Malattie dellApparato Respiratorio Universit degli Studi di Modena e Reggio Emilia Azienda Ospedaliero-Universitaria - Policlinico di Modena

MANAGEMENT OF COPD Leonardo M. Fabbri

COPD and chronic comorbidities Exacerbations in COPD Current and future treatment Treatment of co-morbidities of COPD Futuristic treatments

Aggiornamento concetti generali sulla componente respiratoria della BPCO Leonardo M. Fabbri
DEFINIZIONE Chronic Obstructive Pulmonary Disease (COPD) is a common preventable and treatable disease. It is characterized by chronic respiratory symptoms, particularly dyspnea and persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response of the airways and the lung to cigarette smoke and/or other noxious particles or gases. Exacerbations, significant concomitant disorders contribute to the overall severity in individual patients.

Bologna 8 Febbraio 2011

CHANGING CONCEPTS IN COPD ASSESSMENT OF SEVERITY AND MANAGEMENT OF COPD

Courtesy of PW Jones, 2011

COMPLEX CHRONIC COCO-MORBIDITIES OF COPD

Fabbri, Beghe, Luppi and Rabe, Eur Respir J 2008;31:204-212

5-yrs mortality

The present study analysed data from 20,296 subjects aged >45 yrs at baseline in the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS).

Clinical practice guidelines (CPGs) and quality of care for older patients with multiple comorbid diseases: implications for pay for performance
This review suggests that adhering to current CPGs in caring for an older person with several comorbidities may have undesirable effects Basing standards on existing CPGs could lead to inappropriate judgment of the care provided to older individuals with complex comorbidities  Developing measures of the quality of the care needed by older patients with complex comorbidities is critical to improving their care

Boyd C et al JAMA. 2005 Aug 10;294(6):716-24 10;294(6):716-

Management of COPD: GOLD guidelines Leonardo M. Fabbri COPD and chronic comorbidities Exacerbations in COPD Current and future treatment Treatment of co-morbidities of COPD Futuristic treatments

OUTCOME OF COPD EXACERBATIONS

In ICU patients
Hospital mortality
20%20%-24%
(1 year)

In hospitalized patients In ER patients

Hospital mortality

2.5%2.5%-10%
(5 days)

Relapse (repeat ER visit)

22%22%-32%
(14 days)

In outpatients

Treatment failure rate

13%13%-33%
(14 days)

Seneff et al. JAMA. 1995; 274:1852-1857; Murata et al. Ann Emerg Med. 1991;20:125-129; Adams et al. Chest. 2000; 117:1345-1352; Patil et al. Arch Int Med. 2003; 163:1180-1186.

CAUSES OF EXACERBATION OF RESPIRATORY SYMPTOMS IN CHRONIC PATIENTS

PNEUMONIA THROMBOEMBOLISM ACUTE HEART FAILURE METABOLIC ACIDOSIS ANEMIA

THE PROGNOSTIC IMPORTANCE OF LUNG FUNCTION IN PATIENTS ADMITTED WITH HEART FAILURE

Prognostic importance for all-cause mortality allof lung function variables obtained by spirometry in an unselected group of patients admitted with heart failure (HF)

Iversen KK et al, Eur J Heart Fail. 2010 Jul;12(7):685-91. Jul;12(7):685-

BIOCHEMICAL MARKERS OF CARDIAC DYSFUNCTION PREDICT MORTALITY IN ACUTE EXACERBATIONS OF COPD

Elevated levels of NT-proBNP and troponin T are strong predictors of early mortality among patients admitted to hospital with acute exacerbations of COPD independently of other known prognostic indicators The pathophysiological basis for this is unknown, but indicates that cardiac involvement in exacerbations of COPD may be an important determinant of prognosis

Chang CL et al, Thorax in press

CARDIOVASCULAR MECHANISMS OF DEATH IN SEVERE COPD EXACERBATION: TIME TO THINK AND ACT BEYOND GUIDELINES
Patients hospitalized because of ECOPD should be carefully examined for the relevant biomarkers and for any concomitant abnormality that may call for specific therapy This in line with the recent editorial of FitzGerald20 and comment by the Editors of Thorax who recommends replacing the term exacerbations with the term lung attacks to emphasise their severity, dramatic consequences, and need for more aggressive, comprehensive and prolonged treatment

Fabbri LM, Beghe B and Agusti A, Thorax, June 2011 Thorax,

Goal of COPD Management

Overall COPD Control
achieving Current Control defined by
Symptoms Reliever use

reducing Future Risk defined by Exacerbations

Mortality
Medication adverse effects

Activity

Lung function

Progression of the disease

????? GOLD 2011 www.goldcopd.org

COPD exacerbations

COPD
Chronic disease
progressive nature lung function symptoms comorbidities

Exacerbations
typically 1 - 3 per year frequency proportional to COPD severity the frequent exacerbator chronic decline resulting in poorer prognosis  q HRQL  o hospitalizations  o mortality

Tashkin D. N Engl J Med 2010; 363: 1184

Hurst et al, N Engl J Med 2010; 363: 1128-38

ASSOCIATION OF DISEASE SEVERITY WITH THE FREQUENCY AND SEVERITY OF EXACERBATIONS DURING THE FIRST YEAR OF FOLLOW-UP IN PATIENTS WITH COPD
50
Hospitalized for exacerbation in yr 1
47

% of patients

40 30

Frequent exacerbations
33 33

22

20 10 0 GOLD 2
(N=945)

18

GOLD 3
(N=900)

GOLD 4
(N=293)

Hurst J.R. et al., N Engl J Med 2010; 363: 1128-38

STABILITY OF THE FREQUENT-EXACERBATION PHENOTYPE IN THE 1679 PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE WHO COMPLETED THE STUDY
Year 1
Patients with no exacerbation Patients with 1 exacerbation Patients with 2 exacerbations 0 20 40 60 80 100 Percent 0 20 40 60 80 100
5% 3% 1%

Year 2
0

Year 3
20 40 60 80 100

23 % 6% 2% 6% 3% 2% 2% 1%

20 40 60

80 100 2%

20 40 60

80 100 3%
2% 2%

0 0 20 40 60 80 100 Percent 0 20 40 60 80 100 Percent 0

20 40 60

80 100

2% 2% 3% 2% 1% 1%

20 40 60

80 100

20 40 60

80 100 2% 80 100
2% 3% 1% 4% 12 %

0 0 20 40 60 80 100 Percent 0

20 40 60

20 40 60 80 100 Percent

Hurst J.R. et al., N Engl J Med 2010; 363: 1128-38

Breast Cancer Diseases - 2015

ER+ 65-75%
PI3Kmut 10% HER3+ IGFR1+

All Breast Cancers

HER2+ 15-20%

p95+ 4% P53mut 30-40 % FGFR1 Ampl 8%

Triple negative 15% PTENloss

30-50% BRCAMut 8%

TARGETED THERAPIES IN A-NSCLC Positive Phase III Studies

Erlotinib BR.21 Gefitinib IPASS/INTEREST/NEJG002 EGFR Mut+ EGFR Mut+ All lines 2007 2008 2009

Monotherapy

2nd /3rd Line 2005

A-NSCLC

ComboTherapy

1st Line Bevacizumab ECOG 4599/AVAiL

Not Registere Cetuximab d! FLEX

Management of COPD: GOLD guidelines Leonardo M. Fabbri COPD and chronic comorbidities Exacerbations in COPD Current and future treatment Treatment of co-morbidities of COPD Futuristic treatments

Therapy at Each Stage of COPD

I: Mild II: Moderate III: Severe
y y y FEV1/FVC < 70%
> 80% predicted FEV1/FVC < 70% 50% < FEV1 < 80% predicted

IV: Very Severe

FEV1/FVC < 70%

y y

FEV1/FVC < 70% 30% < FEV1 < 50% predicted

y FEV1

FEV1 < 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure

Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) Add one or more long-acting bronchodilators (when needed); Add rehabilitation Add inhaled glucocorticosteroids if repeated exacerbations
Add long term oxygen if chronic respiratory failure. Consider surgical treatments

Therapy at Each Stage of COPD

I: Mild II: Moderate III: Severe
y y y FEV1/FVC < 70%
> 80% predicted FEV1/FVC < 70% 50% < FEV1 < 80% predicted

IV: Very Severe

FEV1/FVC < 70%

y y

FEV1/FVC < 70% 30% < FEV1 < 50% predicted

y FEV1

FEV1 < 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure

Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) Add one or more long-acting bronchodilators (when needed); Add rehabilitation Add inhaled glucocorticosteroids if repeated exacerbations
Add long term oxygen if chronic respiratory failure. Consider surgical treatments

Comprehensive Management of COPD

Optimal Pharmacotherapy

CHANGING CONCEPTS IN COPD ASSESSMENT OF SEVERITY AND MANAGEMENT OF COPD

Courtesy of PW Jones, 2011

Calverley PMA et al, NEJM 2007; 356:775-78

Rate of Exacerbations
1.13

number/patient/year

0.97 *

0.93 *

0.85 * #

0.5

0
Plc
* p< 0.001 vs Plc, p=0.002 vs SAL, # p=0.024 vs FP

SAL

FP

SFC

Calverley PMA et al, N Engl J Med. 356(8): 775-89.

THE OPTIMAL STUDY: Effects on Exacerbations

N=449 No significant differences among groups

Assumes all patients lost to follow-up did not have exacerbations (4 for tiotropium, 2 for tiotropium + salmeterol, 2 for tiotropium + salmeterol/fluticasone)

Aaron SD, et al. Ann Intern Med. 2007;146:545-555.

EFFICACY AND TOLERABILITY OF BUDESONIDE/FORMOTEROL ADDED TO TIOTROPIUM IN PATIENTS WITH COPD

0.4

Mean number of severe exacerbations

Bud/form + TIO PBO + TIO

0.3 Exacerbations/patient

0.2

0.1

0.0 0 15 30 45 60 75 90 Days since randomisation

Welte T, et al. Am J Respir Crit Care Med. 2009 Oct 15;180(8):741-50

Increased risk of pneumonia in COPD patients treated with ICS

Placebo SAL FP SFC (N = 1544) (N = 1542) (N = 1552) (N = 1546)

Adverse event rate* Serious adverse event rate*

0.052 0.030

0.052 0.030

0.084 0.052

0.088 0.055

Fatal serious AE rate*

0.0031

0.0031

0.0042

0.0032

* Rate per treatment year

Torch Study, 2008

POET-COPD: A Double-Blind, Double-Dummy Study

Run in 2 weeks Treatment period 12 months Follow-up SAEs 30 days

Tiotropium 18 g Handihaler once daily + Placebo MDI twice daily

All previously prescribed COPD medications permitted (except anticholinergics and beta-agonists, but salbutamol)

Salmeterol 50 g MDI twice daily + Placebo Handihaler once daily

Screening Day 1 2 months 4 months Randomization 8 months 12 months End of trial

Exacerbations at Clinic Visits/Vital Status

MDI=metered-dose inhaler; SAE=serious adverse event.

Vogelmeier C et al N Engl J Med 2011, 24 March 2011

Tiotropium Significantly Delayed Time to First Exacerbation

Probability of COPD exacerbation (%) 50 45 40 35 30 25 20 15 10 5 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days)
No. of patients at risk: Tiotropium 3707 3369 3136 2955 2787 2647 2561 2455 2343 2242 2169 2107 1869 Salmeterol 3669 3328 3028 2802 2605 2457 2351 2251 2137 2050 1982 1915 1657 *Cox regression adjusted for (pooled) centre and treatment.

Tiotropium Salmeterol

17% Risk difference

Hazard ratio = 0.83* (95% CI, 0.77, 0.90) P<0.001 (log-rank test)

Vogelmeier C et al N Engl J Med 2011, 24 March 2011

Reduced Risk of Premature Discontinuation with Tiotropium

Probability of premature discontinuation of trial medication (%) 20 Tiotropium Salmeterol 15

12% Risk difference

10
*Cox regression adjusted for (pooled) centre and treatment.

Hazard ratio = 0.88* (95% CI, 0.78, 0.98) P=0.02 (log-rank test) 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days)

No. of patients at risk: Tiotropium 3707 3592 3501 3429 3382 3330 3299 3268 3225 3186 3158 3138 2841 Salmeterol 3669 3541 3436 3337 3291 3209 3181 3151 3111 3074 3054 3037 2703

Vogelmeier C et al N Engl J Med 2011, 24 March 2011

INSPIRE: Study Endpoints (I)

Primary Objective

y To study the effect of SALMETEROL/FLUTICASONE combination

vs TIOTROPIUM in reducing the rate of healthcare utilisation COPD exacerbations over 104 weeks in subjects with severe COPD. Main Secondary Endpoints

y Rate of symptom-defined exacerbations y Time to withdrawal y Post-dose FEV1

Main Other Endpoints
Total exacerbation rate TDI, All-cause Mortality

Health Outcomes
SGRQ

Safety
Adverse events AEs of special interest All-cause Mortality

Other lung function parameters

INSPIRE: Study Design

Prednisolone 30mg/day + salmeterol 50mcg bd

SFC combination 50/500mcg bd via DISKUS

Any COPD therapy

tiotropium bromide 18mcg od

2 weeks Run-in

20

32

44

56

68

80

92 104

106 Follow-up

Treatment

Exacerbation rates
SFC (n=641) Rate of all HCU exacerbations HCU exacerbations using OCS HCU exacerbations (ab) Symptom defined exacerbations Total exacerbatoins 1.28 0.69 Tio (n=650) 1.32 0.85 0.976 (0.836,1.119)
0.814 (0.670,0.990)

Rate Ratio (CI)

P value 0.651
0.039

0.97
3.04

0.82 3.02

1.186 (1.019,1.381) 1.006 1.000 (0.901,1.123) (0.904,1.107)

0.028 0.913 0.995

3.37

3.37

Time to Withdrawal
44 40 36 Probability of Event (%) 32 28 24 20 16 12 8 4 0 Number 656 at Risk 663 0 560 547 13 531 501 26 510 474 39 494 450 52 476 434 65 456 415 78 445 397 91 160 SFC 50/500 140 TIO 18 104

Probability of wd prior to wk 104 SFC 34.5% TIO 41.7%

Cox Hazard Ratio SFC vs TIO 0.776

95% CI

p-value 0.005

(0.651,0.926)

Time to Event (Weeks) Treatment: SFC 50/500 TIO 18

Time to Withdrawal due to an Exacerbation

15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 Number 656 at Risk 663 Probability of Event (%) 0

Probability of wd prior to wk 104 SFC 9.5% TIO 12.8%

Cox Hazard Ratio 95% CI SFC vs TIO

560 547 13 531 501 26 510 474 39 494 450 52 476 434 65

p-value 0.088

0.736
456 415 78

(0.518,1.046)
445 397 91 160 SFC 50/500 140 TIO 18 104

Time to Event (Weeks) Treatment: SFC 50/500 TIO 18

INVOLVE: 52-week efficacy and safety

Double-blind, randomized, placebo-controlled, parallel-group study

Indacaterol 300 g o.d. (n=437) Indacaterol 600 g o.d. (n=428)

Screening period

Placebo

(n=432)

Formoterol 12 g b.i.d. (n=435)

2 weeks

Baseline

52 weeks
Dahl et al. Thorax 2010

N.B. Indacaterol 150 g and 300 g once-daily are registered doses The recommended dose strength is 150 g once-daily, to be increased only on medical advice

Indacaterol 300 g provided significant improvement in trough FEV1 over 52 weeks, superior to formoterol
Placebo Indacaterol 300 g o.d. 1.55 1.50 Trough FEV1 (L) 1.45 1.40 1.35 1.30 1.25 1.20 1.15 Day 2 Week 12 Primary endpoint Week 52
1.31 1.31 1.28 1.43

Formoterol 12 g b.i.d.

***

1.45 1.38 1.38 * 1.32

***

1.48

***

1.43

***

***

*p<0.05, ***p<0.001 vs placebo; p<0.05, p<0.001 vs formoterol Data are LSM in the modified intent-to-treat population Trough = average of 23 h 10 min and 23 h 45 min post-dose values

Dahl et al. Thorax 2010

Improvements in trough FEV1 were sustained over 52 weeks of treatment

FEV1 (mL): differences between indacaterol and placebo 250

200

***

*** ***

***

***

*** *** ***

150 ***

***

100

Indacaterol 150 g 50 After 1 day Day 15

Indacaterol 300 g Week 12 Week 26 Week 52

***p<0.001 vs placebo. Data are LSM with 95% confidence intervals. The study was powered to detect an indacaterol-placebo difference of 120 mL (dotted line)

Chapman et al. Chest 2011

Symptom summary: Indacaterol vs twice a day beta agonists

 Indacaterol is superior to salmeterol and formoterol for

Dyspnoea score Quality of life

 The improvements in lung function translate into

clinically meaningful changes

Summary: comparison with beta agonists

 Indacaterol

significantly improved lung function compared with salmeterol and formoterol



Improved clinical outcomes for patients: breathlessness significant improvements compared with formoterol (300 g) and salmeterol (150 g) health related quality of life Significant improvements compared with placebo significant improvements compared with salmeterol and numerical improvements vs formoterol reduction in need for rescue medication compared with salmeterol, formoterol and placebo

Markers of hyperinflation and exercise endurance

Indacaterol improved inspiratory capacity which is sustained over 24 hours

Indacaterol 300 g o.d. Open-label Salmeterol 50 g b.i.d. Placebo * * ** * * * * * *

2.2 Inspiratory capacity (L) 2.1 2.0 1.9 1.8 1.7 1.6
2

Indacaterol Salmeterol (1st dose)

Salmeterol (2nd dose)

10 12 14 16 18 20 22 24

Time post-dose
*p<0.05 indacaterol vs salmeterol; p0.015 for indacaterol vs placebo at all time points; p<0.05 for salmeterol vs placebo at all time points except 50 minutes, 3 hours, 8 hours, 10 hours, 11 hours 10 minutes LaForce et al. Pulm Pharmacol Ther 2011 and 23 hours 45 minutes. Data are LSMSE

INABLE 1: 21-day exercise endurance study

Indacaterol 300 g o.d.

Indacaterol 300 g o.d.

n=90

Placebo

Placebo

21 days Screening Treatment 1

21 days Washout

21 days Treatment 2

ODonnell et al. Respir Med 2011 (accepted)

Indacaterol improved exercise endurance time on Days 1 and 21, compared with placebo
Placebo 12 Exercise endurance time (mins) 1.68 *** 11 10 9 8 7 6 5 Day 1
*p=0.011, ***p<0.001 Data are LSM and SE

Indacaterol 300 g o.d. 1.85 * 9.77

9.75

8.07

7.92

Day 21

ODonnell et al. Respir Med 2011 (accepted)

Indacaterol improved inspiratory capacity at the end of exercise

Placebo End-exercise inspiratory capacity (L) 2.5 190 mL * 2.3 2.1 1.9 1.7 1.5 Day 1
*p=0.04, **p=0.002 Data are LSM and SE

Indacaterol 300 g o.d. 280 mL ** 2.22

2.17 1.98 1.94

Day 21

ODonnell et al. Respir Med 2011 (accepted)

INDORSE: 52-week safety and efficacy

Dose selection

Stage I
Indacaterol 75 g o.d. Indacaterol 150 g o.d. Indacaterol 300 g o.d. Indacaterol 600 g o.d. Placebo Formoterol 12 g b.i.d. Tiotropium* 18 g o.d.

Stage II

Stage III extension

Indacaterol 150 g Indacaterol 300 g

Indacaterol 150 g Indacaterol 300 g

Placebo

Placebo

Tiotropium* 18 g

Stage I: 2 weeks, seven treatment arms Stage II: 26 weeks, four treatment arms (efficacy and safety) Stage III: 52 weeks, three treatment arms (safety and efficacy) *Open-label All drugs were delivered via proprietary SDDPIs

Rennard et al. ACCP 2009; Chapman et al. Chest 2011

BLINDED 12 WEEK COMPARISON OF ONCE DAILY INDACATEROL AND TIOTROPIUM IN COPD Both bronchodilators demonstrated spirometric efficacy The two treatments were well tolerated with similar adverse event profiles Compared with tiotropium, indacaterol provided significantly greater improvements in clinical outcomes
Buhl R et al, Eur Respir J 2011, 24 May 2011

ONCE-DAILY BRONCHODILATORS FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE: indacaterol versus tiotropium

Indacaterol was an effective once-daily oncebronchodilator As effective as tiotropium in improving clinical outcomes for patients with COPD

Donohue JF et al, Am J Respir Crit Care Med Vol 182. pp 155162, 2010

Summary: comparison with tiotropium

 Improved lung function at least as effectively as

tiotropium
 Improved clinical outcomes for patients for patients treated with

indacaterol compared to tiotropium: breathlessness health related quality of life reduction in need for rescue medication
 Indacaterol has faster onset of action

INDORSE

INDORSE: 52-week safety and efficacy

Dose selection

Stage I
Indacaterol 75 g o.d. Indacaterol 150 g o.d. Indacaterol 300 g o.d. Indacaterol 600 g o.d. Placebo Formoterol 12 g b.i.d. Tiotropium* 18 g o.d.

Stage II

Stage III extension

Indacaterol 150 g Indacaterol 300 g

Indacaterol 150 g Indacaterol 300 g

Placebo

Placebo

Tiotropium* 18 g

*Open-label All drugs were delivered via proprietary SDDPIs

Rennard et al. ACCP 2009; Chapman et al. Chest 2011 (accepted)

LONG-TERM SAFETY AND EFFICACY OF INDACATEROL, A NOVEL LONG-ACTING 2AGONIST, IN SUBJECTS WITH COPD: A RANDOMIZED, PLACEBO-CONTROLLED STUDY

During 1 year of treatment: indacaterol was well tolerated provided significant and well-maintained bronchodilation that was accompanied by improved clinical outcomes
Chapman et et al, Chest 24 february 2011

BRONCHODILATORS ARE ASSOCIATED WITH INCREASED MORTALITY

1.0

CHARM trial: patients with HF

receiving bronchodilators (n=674 of 7599)

Survival Rate

0.8

0.9

No bronchodilator and beta-blocker betaNo bronchodilator and no betabetablocker Bronchodilator and betabeta-blocker Bronchodilator and no betabetablocker

0.7 0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Time (years)

Hawkins NM et al Eur J Heart Fail 2010;12:557-65 2010;12:557-

HEART FAILURE AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE: THE QUANDARY OF BETABLOCKERS AND BETA-AGONISTS
-agonists are associated with incident heart failure in patients with pulmonary disease, and with increased mortality and hospitalization in those with existing heart failure. These purported adverse effects require further investigation In the meantime, clinicians should consider carefully the etiology of dyspnea and obtain objective evidence of airflow obstruction before prescribing -agonists to patients with heart failure. Hawkins N et al, Am J Coll Cardiologist, 2011, in press

MORTALITY ASSOCIATED WITH TIOTROPIUM MIST INHALER IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE: SYSTEMATIC REVIEW AND METAANALYSIS OF RANDOMISED CONTROLLED TRIALS

Our meta-analysis suggests an increased risk of mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease Clinicians should inform patients about the possibility of this increased risk and exercise caution when prescribing tiotropium mist inhaler, particularly in patients with possible underlying cardiac disease

Singh S,et al, BMJ 2011, 342:d3215

Therapy at Each Stage of COPD

I: Mild II: Moderate III: Severe
y y y FEV1/FVC < 70%
> 80% predicted FEV1/FVC < 70% 50% < FEV1 < 80% predicted

IV: Very Severe

FEV1/FVC < 70%

y y

FEV1/FVC < 70% 30% < FEV1 < 50% predicted

y FEV1

FEV1 < 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure

Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) Add one or more long-acting bronchodilators (when needed); Add rehabilitation Add inhaled glucocorticosteroids if repeated exacerbations
Add long term oxygen if chronic respiratory failure. Consider surgical treatments

ROFLUMILAST IN CLINICAL PRACTICE

Clinical benefits
 Roflumilast is an anti-inflammatory drug and not a bronchodilator  In patients with severe COPD with chronic bronchitis  prevention of exacerbations  improvement of lung function  Add-on to bronchodilator maintenance treatment with additive effects

PDE4 inhibition

 Specific safety profile

Calverley PMA et al, Lancet 2009;374:685-694. Fabbri LM et al, Lancet 2009;374:695-703.

Therapy at Each Stage of COPD

I: Mild II: Moderate III: Severe
y y y FEV1/FVC < 70%
> 80% predicted FEV1/FVC < 70% 50% < FEV1 < 80% predicted

IV: Very Severe

FEV1/FVC < 70%

y y

FEV1/FVC < 70% 30% < FEV1 < 50% predicted

y FEV1

FEV1 < 30% predicted or FEV1 < 50% predicted plus chronic respiratory failure

Active reduction of risk factor(s); influenza vaccination Add short-acting bronchodilator (when needed) Add one or more long-acting bronchodilators (when needed); Add rehabilitation Add ICS OR/AND ROFLUMILAST in exacerbators
Add long term Add ROFLUMILAST oxygen if chronic respiratory failure. Consider surgical treatments

Management of COPD: GOLD guidelines Leonardo M. Fabbri COPD and chronic comorbidities Exacerbations in COPD Current and future treatment Treatment of co-morbidities of COPD Futuristic treatments

SYSTEMIC EFFECTS AND COMORBIDITIES OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Barnes PJ et al., Eur Respir J 2009;33:11651185 2009;33:1165

REDUCTION OF MORBIDITY AND MORTALITY BY STATINS, ACE INHIBITORS, AND ARBS IN PATIENTS WITH COPD These agents may have dual cardiopulmonary protective properties, thereby substantially altering prognosis of patients with COPD. These findings need confirmation in randomized clinical trials.

Mancini JB et al. J Am Coll Cardiol 2006;47(12):2554-60

EFFECT OF BLOCKERS IN TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE: A RETROSPECTIVE COHORT STUDY blockers (predominantly cardioselective) may confer reductions in mortality, exacerbations, and hospital admissions in patients with COPD, in addition to the benefits attributable to addressing cardiovascular risk These additive benefits were seen on top of inhaled therapy, including inhaled corticosteroids and did not result in any worsening of pulmonary function
Philip M Short et Al BMJ 2011;342:d2549

Management of COPD: GOLD guidelines Leonardo M. Fabbri COPD and chronic comorbidities Exacerbations in COPD Current and future treatment Treatment of co-morbidities of COPD Futuristic treatments

EMERGING PHARMACOTHERAPIES FOR COPD

Barnes PJ. Chest 2008; 134:1278-1286

Management of COPD: GOLD guidelines Leonardo M. Fabbri COPD and chronic comorbidities Exacerbations in COPD Current and future treatment Treatment of co-morbidities of COPD Futuristic treatments

SEPAR 44th National Congress Oviedo 17 June 2011

Management of COPD: GOLD guidelines
Leonardo M. Fabbri
Clinica di Malattie dellApparato Respiratorio Universit degli Studi di Modena e Reggio Emilia Azienda Ospedaliero-Universitaria - Policlinico di Modena

VIZI E VIRTU Giotto, Cappella degli Scrovegni, Padova

Obaji A, Sethi S. Drugs and Aging 2001;18:1-11.

INVIDIA Giotto, Padova, Scrovegni

Obaji A, Sethi S. Drugs and Aging 2001;18:1-11.