Treatment for Stable COPD

Bartolome R. Celli, MDProfessor of Medicine

Tufts University. Boston

Objectives• COPD today• The course of the disease can be

modified with therapy• Outcomes can be impacted

COPD Today Inflammation

(Cosio,Hogg, Barnes Jeffery,Saetta,

Barbera, Rodriguez)

Hyperinflation

(Belman,O’Donnell, Casanova, Gea)

Autoimmunity? (Agusti and Mc Nee)

Apoptosis (Voelkel)

Systemic inflammation

(Maltais, Montes de Oca, Wouters)

Recommended Progression of COPD Pharmacotherapy

At Risk I: Mild II: Moderate

III: Severe IV: Very Severe

• Chronic symptoms

• Exposure to risk factors

• Normal spirometry

• FEV1 ≥80%

• With or without symptoms

• FEV1 50 -79%

• With or without symptoms

• FEV1 30 - 49%• With or without

symptoms

• FEV1 <30%• or presence of

chronic respiratory failure or right heart failure

20

40

60

80

100

Male

Female

Max

VO

2%

Pre

dict

ed

Control Stage 2Stage 1 Stage 4Stage 3

One-way ANOVA for groups <0.0001 Pinto-Plata et al CHEST 2007;132:1204

Peak O2 uptake in 256 men and 197 women

Muco-ciliarydysfunction

inflammation

Airflowlimitation Systemic

component

Structuralchanges

COPD: a phenotypic characterization

emphysema

Hyperinflation

Perception

0

10

20

30

40

50

60

70

80

90 HealthyGOLD I&IIGOLD IIIGOLD IV

Tim

e (m

in)

Physical Activity Declines With Progression of COPD

Pitta et al. Am J Respir Crit Care Med 2005;171:972

BODE ATS Staging

Celli et al. N EJ M 2004;350:1005

#625 #574 #454 #273 #80#625 #574 #454 #273 #80

III

III

Q1Q2Q3

Q4

0.0

0.2

0.4

0.6

0.8

1.0

0 26 520.0

0.2

0.4

0.6

0.8

1.0

0 26 52

Probability of Survival

Treatments:1. Pharmacotherapy2. Rehabilitation3. Lung Volume reduction4. Novel therapies

Clinical Course of COPD Defined FEV1 Decline

Annual visits

208152

134

124

26822335

2059

1652

1818

FEV 1

(% p

redi

cted

)

80

76

72

B/L AV 1 AV 2 AV 3 AV 4 AV 5

840 673599 541

50714654

3723

74

78

82

QuittersSmokers

Scanlon PD et al. Am J Respir Crit Care Med. 2000;161:381-90

IV: Very SevereIII: SevereII: ModerateI: Mild

Therapy at Each Stage of COPD

FEV1/FVC < 70%

FEV1 > 80% predicted

FEV1/FVC < 70%

50% < FEV1 < 80%predicted

FEV1/FVC < 70%

30% < FEV1 < 50% predicted

FEV1/FVC < 70%

FEV1 < 30% predicted

or FEV1 < 50% predicted plus chronic respiratory failure

Add regular treatment with one or more long-acting bronchodilators (when needed); Add rehabilitation

Add inhaled glucocorticosteroids if repeated exacerbations

Active reduction of risk factor(s); influenza vaccinationAdd short-acting bronchodilator (when needed)

Add long term oxygen if chronic respiratory failure. Consider surgical treatments

Pharmacotherapy of COPD

FEV

1(m

L)

1350

1300

1250

1200

1150

1100

0 24 48 72 96 120 156Weeks

No. of 1261 1248 1128 1049 979 906 819patients 1334 1317 1218 1127 1054 1012 934

1356 1346 1230 1157 1078 1006 9081392 1375 1281 1180 1139 1073 975

–39 mL/yr–42 mL/yr

–55 mL/yr

–42 mL/yr

PlaceboSALFPSFC

Vertical bars are standard errors

TORCH: Rate of decline in FEV1: effect of treatment

Celli et al for TORCH AJRCCM 2008;178:332

TORCH: Distribution of severity by post-bronchodilator FEV1 %

0

10

20

30

40

50

60

Very Severe Severe Moderate

% o

f pat

ient

s

Treatment effect was independent of baseline FEV1

Calverley et al for TORCH NEJM 2007;356:775

Out of these 34%, over 600 had FEV1 60-70%

1.00

1.10

1.20

1.30

1.40

1.50

1 6 12 18 24 30 36 42 48

Month

FEV 1

(L)

Tiotropium (n = 2498) Placebo (n = 2371)

UPLIFT: Trough FEV1

*

(Day 30,steady state)

* * * * * * * *

Tashkin et al NEJM 2008

1.20

1.40

1.60

1.80

FEV 1

(L)

Tiotropium Control

UPLIFT: Effect of Tiotropium on FEV1 decline

Post- Bronch FEV1

∆ Tio vs. control = 52 – 82 mL

Pre-Bronch FEV1

∆ Tio vs. control = 101 – 119 mL

* * **

** * *

** * *

* * ** * *

* p <0.0001 vs. control

2739 GOLD Stage II Randomized

Day 30(steady state)

6 12 18 24 30 36 42 480 1

Month

Tashkin DP et al. UPLIFT Study N E J M 2008;359: 1543

III IVGOLD stage

0

10

20

30

40

50

60

II

Rat

e of

dec

line

in F

EV1

(mL/

year

)

n=1158

∆=6 (3)P=0.02

Tiotropium Control

∆=0 (3)P=0.87

∆=-9 (7)P=0.24

n=1218 n=1031n=1104 n=194 n=185

Tashkin DP et al. UPLIFT Study N E J M 2008;359: 1543

UPLIFT: Effect of Tiotropium on FEV1 decline

35

40

45

50

SGR

Q T

otal

Sco

re (U

nits

)

Tiotropium Control

06 12 18 24 30 36 42 480

Month

Impr

ovem

ent

* **

* * * **

*P<0.0001 vs. control. Repeated measure ANOVA was used to estimate means. Estimated means are adjusted for baseline measurements. Patients with ≥2 acceptable SGRQ Total Scores after Month 6 were included in the analysis. Tiotropium: Month 0 n = 1179, Month 48 n = 908; Control: Month 0 n = 1119, Month 48 n = 839

∆ Tio vs. control = * p<0.0001

SGRQ in Stage II in UPLIFT

St George’s is 3.1 better than placebo and better than baseline

92 ml difference from placebo and changes rate of decline

25% reduction in exacerbations

St George’s is 3.3 units better than placebo and better than baseline

110 ml difference from placebo

16% reduction in exacerbations

UPLIFT®

Recently released or soon to appear medications

• Nebulized Formoterol (twice a day) • LAMA (Aclidinium)• Once a day LABA (Indacaterol, Carmuterol and

others)• Combination therapies:

ICS- LABA

Targets for New COPD Therapies

Barnes. Lancet. 2004;364:985-996.

Inhibitors of cell signalling• PDE4 inhibitors• p38 MAPK inhibitors• NFκB inhibitors• PIЗ Kγ inhibitors• PPA Rγ agonists

Protease inhibitors• NE inhibitors• Cathepsin inhibitors• MMP inhibitors• α1-antitrypsin• SLPI

Mucoregulators• EGF-receptor-kinase

inhibitors• CACC inhibitors

CD8-positivelymphocyte

Epithelial cells

Smoking cessation

Therapy directed against chemokines, cytokines, and adhesion molecules• CXCR2 and CCR2 antagonists• Selectin antagonists• Inhibition of ICAM1, CD11b• Anti-TNF-α• Interleukin 10

Antifibrotic therapy• TGFß1 inhibitors• FGF inhibitors• Tryptase and PA R2

inhibitors

Aveolar repair• Retinoids• HGF• Stem cells

LTB4 inhibitors

Proteases

Mucushypersecretion

Obstructivebronchiolitis Emphysema

Connective tissueproliferation and

fibrosis

AntioxidantsiNOS inhibitors

O2+–

O2+–

Interleukin 8TNF-α

Interleukin 8

LTB4

Alveolarmacrophage

NeutrophilFibroblast

ImmunosuppressantsCXCR3 antagonists

Targets for New COPD Therapies

Barnes. Lancet. 2004;364:985-996.

Inhibitors of cell signalling• PDE4 inhibitors• p38 MAPK inhibitors• NFκB inhibitors• PIЗ Kγ inhibitors• PPA Rγ agonists

Protease inhibitors• NE inhibitors• Cathepsin inhibitors• MMP inhibitors• α1-antitrypsin• SLPI

Mucoregulators• EGF-receptor-kinase

inhibitors• CACC inhibitors

CD8-positivelymphocyte

Epithelial cells

Smoking cessation

Therapy directed against chemokines, cytokines, and adhesion molecules• CXCR2 and CCR2 antagonists• Selectin antagonists• Inhibition of ICAM1, CD11b• Anti-TNF-α• Interleukin 10

Antifibrotic therapy• TGFß1 inhibitors• FGF inhibitors• Tryptase and PA R2

inhibitors

Aveolar repair• Retinoids• HGF• Stem cells

LTB4 inhibitors

Proteases

Mucushypersecretion

Obstructivebronchiolitis Emphysema

Connective tissueproliferation and

fibrosis

AntioxidantsiNOS inhibitors

O2+–

O2+–

Interleukin 8TNF-α

Interleukin 8

LTB4

Alveolarmacrophage

NeutrophilFibroblast

ImmunosuppressantsCXCR3 antagonists

New Target Studies• BRONCHUS (NAC)

Decramer et al Lancet 2005

• Roflumilast (PDE4 inhibitor)Rabe et al Lancet 2005

• Cilomilast (PDE4 inhibitor)Rennard et al CHEST 2006

• Anti IL-8 Monoclonal antibodyMahler et al. Chest 2004

• Anti TNF-α antibodyRennard et al AJRCCM 2007

Rehabilitation

Unbeatable

Evidence A

COPD Survival: Oxygen

0

20

40

60

80

100

0 12 18 24 36 44Months

Surv

ival

% MRC no O2 (80)MRC O2 (80)NOTT O2 (80)

Evidence on Effectiveness of RehabilitationComponent Current

Lower extremity training A

Upper extremity training B

Self Management B

Psychosocial, behavioral and educational components C

ATS/ERS and ACCP/ACCVPR statements

Evidence on Effectiveness of RehabilitationComponent/Outcome Current

Lower extremity training A

Upper extremity training B

Self Management B

Psychosocial, behavioral and educational components C

Dyspnea A

Health Status A

Health care utilization A

Survival C

ATS/ERS and ACCP/ACCVPR statements

Who?• PR should be considered for all patients with

respiratory disease with persistent symptoms, limited activity, and/or unable to adjust to illness despite otherwise optimal medical management

• Gains can be achieved from pulmonary rehabilitation regardless of age, sex, lung function, or smoking status.

ATS/ERS statement on P.R. AJRCCM 2006173;1390

Airflowlimitation Systemic

component

Pulmonary Rehabilitation

Hyperinflation

Perception

Effect of PR on BODE index

0

10

20

30

40

50

60

70

80

(-2) (-1) Same (+1) (+2)

% o

f pat

ient

s

Improvement Worsening

Cote et al ERJ 2005

N = 115

PR +32%

PR -68%

PR - 55%

PR +45%

Brooks et al ERJ 2002 Ries et al AJRCCM 2003

n = 340

Fail to Enrolln = 343

PR29%No

PR63%

PR +8%

S M -60%

S M +40%

Cote et al ERJ 2005Borbeau et al Arch Int Med 2003

n = 469

Fail to Enrolln = 246

F32%

C68%

Fail to Completen = 180

Fail to complete:

Exacerbations (66%)

Death (11%)

Distance (4%)

Quit or fed up (18%)

Sewell et al Chest 2005

26%

Characteristics of the Cohort

Characteristics of the Cohort

Characteristics of the Cohort

No PR PR

Multivariate analysis r2 = 26%

Adherence: 3 year mortality in TORCH

Adherence S F S/F Placebo

Good(>80%)

11 13 9.5 12

Poor(< 79%)

25 29 25 26

Vestbo et al Thorax (in press)

Novel Therapies

Circulation and possible effect of L to R shunt

Circulation and possible effect of L to R shunt

New Shunt Implant In-Vitro

Vein to Artery(Vein on Top)

Artery / Vein(Side by Side)

Artery to Vein(Artery on Top)

A V

Months since randomization0 12 24 36 48 60

0.0

0.1

0.2

0.3

0.40.5

0.6

0.7

High-risk patients excluded

Medical

Surgical

Prob

abili

ty o

f de

ath

Mortality: LVR NETT (5 years)

RR = 0.67

p = 0.02n = 1218

Naunheim et al Ann Thorac Surg 2006;82:431

Behavior modification

Intervention

Knowledge

SkillsSelf-efficacy Behaviour

changeHealth effect

Bourbeau J et al. Patient Educ Couns 2004;53:271

Self-management education for patients with COPD

Cochrane Database Syst Rev. 2007;4:CD002990

Assess the efficacy of COPD self-management education programs on:

health outcomesuse of health care services

Controlled trials of self-management education.

No P.R.

Number = 15 studies

Outcomes = multiple

OR 95 % CI NNT

Decrease admissions (1)

0.64 0.47-0.89 10

SGRQ - 2.58 -5.14 – 0.02

Borg dyspnea - 0.53 - 0.16 - -0.10

No impact on:AE’s. ER visits,

Exercise, Medications use

Develop a StrategyA strategy is a long term plan of action

designed to achieve a particular goal, most

often "winning" Strategy is

differentiated from tactics or immediate

actions with resources at hand

Conclusions• We have effective treatments for

COPD• Diagnosis has to be improved• A strategy to impact on disease is

needed

Thank You