SGK/SGP 2016

Dyspnea in COPD

Prof. Michael TammHead of Pneumology and Comprehesive

Lung Center University Hospital Basel

GOLD GuidelinesFE

V1

% p

red

> 8

0%

50

-80

%

30

-50

%<3

0%

MMRC0 – 1 2 – 4

Nu

mb

er o

f A

ECO

PD

0 –

1=

>2

Assessments:

- Symptoms

- Airflow obstruction

- Risk of AECOPD

- Comorbidities

A) Low risk, less symptoms

B) Low risk, more symptoms

C) High risk, less symptoms

D) High risk, more symptoms

Dyspnea in COPD

• Bodyplethysmography

– FEV1 ? reversibility ? NO ?

– hyperinflation ?

• Diffusion capacity

– proportional/disproportional ?

• Blood gases

– pO2 pCO2

• CT thorax

– bronchiectasis/mucuspluging/emphysema

Dyspnea in COPD

• Echo

– LEF

– Diastolic dysfunction

– Pulmonary hypertension

• Ev MPS

• SPECT

– thromboembolic disease

– potential for LVR

PH-COPD in end-stage COPD

PH-COPD in end-stage COPD

210 199

16

25 35

PAH vs. PH-COPD

PAH vs. PH-COPD

PAH vs. PH-COPD: CPET

PAH vs. PH-COPD: CPET

PAH vs. PH-COPD: CPET

PAH vs. PH-COPD: CPET

PH-COPD: Endothelin ReceptorAntagonists

• Distance walked in 6 min– Bosentan group: 339 ± 81 to 329 ± 94 m at week 12; p = 0.040)

– Placebo group: 331 ± 116 to 331 ± 123 m at week 12; p = 0.100)

• Arterial PO2– Bosentan group: 65.2 ± 10.5, 58.8 ± 8.6 and 60.7 ± 7.5 mmHg at

baseline, 4 weeks and 12 weeks, respectively

– Placebo group: 66.1 ± 15.1, 64.4 ± 6.9 and 65.7 ± 10.9 mmHg, respectively.

• FEV1: 51.3 ± 31,4 %pred

• mPAP at rest: 31.3 ± 7.3 mmHg

• PCWP: 12.8 ± 5.6 mmHg

PH-COPD: aerosolized Iloprost

Hyperinflation in COPD= Dyspnea

TORCH Study

• 6000 Patients 3 years

• Primary endpoint:

Mortality

• Sekundary endpoints:

– Exacerbations

– Lung function

– Quality of life /Dyspnea

Fluticason

Fluticason + Salmeterol

Calverley et al, NEJM 2007

Calverley et al. NEJM 2007

Calverley et al. NEJM 2007

Calverley et al. NEJM 2007

ICS/LABA TORCH

• Quality of Life Scores yes

• FEV1 yes

• FEV1 decline no

• Hyperinflation ?

• VO2/endurance/6 min distance?

• Exacerbations yes

• Comorbidities ?

• Mortality no/yes

UPLIFT Study

Primary endpoint:

– FEV1 (Slope of decline)

Sekundary endpoints:

– Quality of life

– Exacerbations

– Mortality

6000 Patients 4 years Tiotropium versus Placebo

70% ICS and/or LABA

Tiotropium

Control

0 6 12 24 30 36 42 4818

Hazard ratio = 0.87

95% CI: (0.76, 0.99)

P = 0.034 (log-rank test)

20

15

10

5

0

Pro

ba

bil

ity o

f d

ea

th f

rom

an

y c

au

se

[%

]

Months

Mortality

Exacerbations

0

20

40

60

80

0 6 12 18 24 30 36 42 48

Pro

ba

bilit

y o

f e

xa

ce

rba

tio

n (

%)

Tiotropium Control

Hazard ratio = 0.86,

(95% CI, 0.81, 0.91)

p < 0.0001 (log-rank test)

Month

FEV1

1.00

1.10

1.20

1.30

1.40

1.50

FE

V1 (

L)

Tiotropium Control

* **

**

**

**

0

6 12 18 24 30 36 42 480 1

Month

* * **

** * *

*

Post-Bronch FEV1

= 47 – 65 mL

Pre-Bronch FEV1

= 87 – 103 mL

*P<0.0001 vs. control

Quality of Life

35

40

45

50

SG

RQ

To

tal

Sc

ore

(U

nit

s) Tiotropium (n = 2478) Control (n = 2337)

0

6 12 18 24 30 36 42 480

Month

* **

** *

**

Imp

rovem

en

t

SGRQ Total Score = 2.3 units

*P<0.0001 vs. control

Tiotropium UPLIFT

• Quality of Life Scores yes

• FEV1 yes

• FEV1 decline no

• Hyperinflation ?

• VO2/endurance/6 min distance ?

• Exacerbations yes

• Comorbidities ?

• Mortality no/yes

WISDOM Studie

Primary endpoint

Time to 1st moderate or severe on-treatment exacerbation during 12-month randomised period

Magnussen H et al. Withdrawal of Inhaled Glucocorticoids and Exazerbations of COPD. Respir Med 2014;108:593-9

Secondary endpoints

Included lung function, health status (SGRQ) and dyspnea (mMRC)

Estimated probability of moderate or severe COPD exacerbation

1243

1242

1059

1090

927

965

827

825

763

740

646

646

694

688

615

607

581

570

14

19

No. at risk

ICS

ICS withdrawal

0.6

0.4

0.2

0.0

0 6 12 18 24 30 36 42 48 54

ICS

ICS withdrawalEstim

ate

d p

rob

ab

ility

Time to events (weeks)

0.1

0.3

0.5

Hazard ratio, 1.06 (95% CI, 0.94–1.19)

P=0.35 by Wald’s chi-squared test

Magnussen H et al. Withdrawal of Inhaled Glucocorticoids and Exazerbations of COPD. Respir Med 2014;108:593-9

Adju

ste

d m

ean (

SE

) change

from

baselin

e in

FE

V1

(mL)

**p<0.01; ***p<0.0001 vs ICS; restricted maximum likelihood repeated measures model; baseline values 970 mL for ICS, 981 mL for ICS withdrawal

Week

ICS

ICS withdrawal

***

**

1223

1218

1135

1135

1114

1092

1077

1058

970

935

n

ICS withdrawal

ICS

38 mL

43 mL

100 µg BID 0 µg (placebo)250 µg BID

Mean change from baseline in lung function: FEV1

ICS withdrawal

Magnussen H et al. Withdrawal of Inhaled Glucocorticoids and Exazerbations of COPD. Respir Med 2014;108:593-9

FLAME STUDY

0 6 12 19 26 32 38 5245

0

10

20

30

40

50

60

70

80

90

100

Wa

hrs

ch

ein

lic

hk

eit

fü

r e

ine

Ex

aze

rba

tio

n (

%)

Hazard ratio, 0.84

(95% CI, 0.78-0.91) P<0.001

Alle

16%

Risiko-

Reduktion

Hazard ratio, 0.78

(95% CI, 0.70-0.86) P<0.001

Moderate oder schwere

22%

Risiko-

Reduktion

Hazard ratio, 0.81

(95% CI, 0.66-1.00) P=0.046

schwere

(Hospitalisationen)

19%

Risiko-

Reduktion

Indacaterol/Glycopyrr. 110/50 μg, 1x tgl.

Salmeterol/Fluticason 50/500 μg, 2x tgl.

Wedzicha, J., et al., NEJM, 2016

Zeit (Tage)

An

ge

pa

sste

r m

ittle

rer

SG

RQ

-C-

Ge

sa

mts

co

re

48

47

46

45

44

43

42

Tag 0

(Baseline)

0Tag 29 Tag 85 Tag 183 Tag 267 Tag 365

Mittlerer LS-

Unterschied = -

1,3

P < 0,001

Mittlerer LS-

Unterschied = -

1,2

P = 0,001

Mittlerer LS-

Unterschied = -

1,3

P = 0,003

Mittlerer LS-

Unterschied = -

1,8

P < 0,001

Mittlerer LS-

Unterschied =

0

P = NS

Salmeterol/Fluticason 50/500 μg 2x tgl. (n = 1593)

Indacaterol/Glycopyrronium 110/50 μg 1x tgl. (n = 1602)

Verb

esseru

ng

SGRQ-C-Responder*: Indacaterol/Glycopyrronium 49,2 %; Salmeterol/Fluticason 43,7 %

(OR 1,30; P < 0,001)Analyse der mITT. *Ansprechen definiert als eine Verbesserung von ≥ 4 Einheiten im SGRQ-C

LABA/LAMA significantly improved Quality of Life as compared to LABA/ICS

Wedzicha, J., et al., NEJM, 2016

∆=–0.25, P<0.001

Ad

just

ed m

ean

ch

ange

in r

escu

e m

edic

atio

n u

se f

rom

b

asel

ine

(pu

ffs/

day

)

0

–0.25

–0.50

–0.75

–1.0

–1.25

–1.5

32

Baseline rescue medication use was 4 puffs per day, on average, in both treatment groups

LABA/LAMA significantly decreased rescue medication use compared with LABA/ICS at Week 52

Wedzicha et al. N Engl J Med, 2016

Exercise ToleranceTiotropium vs. Placebo

Maltais F et al. Chest 2005; 128: 1168-1178

450

550

650

750

850

-10 0 10 20 30 40 50

Sekunden

Belastungsdauer

+ 236 s

+ 41,5%

* *

#

# p < 0,05

* p < 0,01

Tiotropium (n = 131)

Placebo (n = 130)

Studientag

Exercise ToleranceTiotropium plus Rehabilitation vs. Placebo plus Reha

Casaburi R et al. Chest 2005; 127:809-817

Belastungsdauer

* * * p < 0,05 Tiotropium ( 55)

Placebo (n = 53)

Studienwoche

+ 42%+ 32%

+ 16%

Rehabilitation8

12

16

20

24

0 4 8 12 16 20 24

Min

ute

n

LVR Indication

• FEV1 < 35 % • TLC > 125 %• RV > 200 %• RV/TLC > 0.6• 6’ Gehtest < 300 m• VO2max < 12 ml/kg/min

SPECT

National Emphysema Treatment Trial

LVRS – FEV1

15

20

25

30

35

40

45

50

Prä OP 3M 6M 9 M 12M 15M 18M

Verlauf

FE

V1%

FEV1 % VC MAX

LVRS – Air Trapping

40

50

60

70

Prä OP 3M 6M 9 M 12M 15M 18M

Verlauf

RV

% T

LC

Mean RV % TLC

Bronchoscopic LVR

Valves: efficacy predictors

Coils: Long term Follow-up

Summary

• Dyspnea in COPD can be caused by

– Hyperinflation

– Emphysema/ diffusion problem

– Pulmonary hypertension

– Comorbidities

• Treatment is mainly based on bronchodilatation and REHAB

• In specific cases, oxygen, lung volume reduction, transplantation