Prof Neil Barnes Professor of Respiratory Medicine

London Chest Hospital &

The Royal London Hospital

United Kingdom

neil.barnes@bartshealth.nhs.uk

COPD A MODIFIABLE RISK

FACTOR IN COPD?

South GPCME Meeting,Dunedin

Sunday 18th August 2013

Professor Neil Barnes

Consultant Respiratory Physician

London Chest Hospital,Bart`s Health

Bart`s and the London

School of Medicine and Dentistry

DISCLAIMER

Professor Neil Barnes, has been

appointed GSK Global Respiratory

Medical Head effective 1st October 2013.

WHO Global Burden of Disease study

LEADING CAUSES OF DEATH

1990

1

2

6 3

10

9

7

14

Ischemic heart disease

Cerebrovascular disease

COPD Lower respiratory infection

Lung cancer

Road traffic accidents

Tuberculosis

Stomach cancer

2020

1

2

3 4

5

6

7

8

FEV1 AS A RISK FACTOR FOR

CVS DISEASE Ranked second to smoking1

2 to 5 fold increase in cardiovascular

mortality2 independent of smoking and other risk factors for

coronary artery disease

Incidence of ventricular arrhythmia3

1. Manino et al ERJ 2006

2. Friedman, NEJM, 1976

3. Gulsvik, Scand J Respir Dis, 1978

CO-MORBIDITIES

Cardiac

Hypertension

Diabetes

Metabolic syndrome

Osteoporosis

Muscle wasting

Depression

Anxiety

Lung cancer

7

WHAT DO COPD PATIENTS DIE

FROM?

0% 20% 40% 60% 80% 100%

GOLD 2/3/4

GOLD 1

No COPD

COPD ASCVD Lung Cancer Pneum/Inf Other

Mannino, Thorax

2003

8

TORCH STUDY COMORBIDITIES

53

34

2521

18 18 1714 14

12 11 10 10 9

4 4

% t

ota

l po

pu

lati

on

GSK, Data on file.

n=6112

9

CARDIOVASCULAR DISEASE

IN COPD AND CONTROLS

Curkendall SM, et al. Am J Epidemiol. 2006;16:63-70.

*

*

* *

*

*

*

21.1

11.2

5.6

31.3

9.6

70.4

22.8

11.7

6.4 3.2

9 7.9

54

11.2

0

10

20

30

40

50

60

70

80

Arrhythmia Angina Acute MI CHF Stroke Other CVD CVD

Hospitalisation

Pe

rce

nt

of

Su

bje

cts

COPD (N=11,493)

Controls (N=22,986)

10

37

25

22.5

19

1312

11

5

22

14

1012

8.56.5

10

3

0

5

10

15

20

25

30

35

40

RF Pneumonia Heart Failure IHD Hypertension TM Diabetes PVD

In H

osp

ital

Mo

rtali

ty (

as %

of

dis

ch

arg

es)

COPD

No COPD

Holguin F, et al. Chest. 2005;128:2005

IN-HOSPITAL MORTALITY &

COMORBIDITIES IN COPD

11

REDUCED LONG-TERM SURVIVAL OF

PATIENTS WITH COPD AFTER ANGIOPLASTY

Berger J Am Card 2004

Figure 1. Kaplan-Meier curve for long-term survival in

patients with and without COPD who underwent PCI.

Time (days)

Cu

mu

lative

Su

rviv

al

1.0

0.9

0.8

0.7

0 200 400 600 800 1000 1200 1400

No COPD

Log-rank P<0.001

COPD

ASSESSMENT OF COPD

GOLD 2013

GOLD 2013; www.goldcopd.org

RIS

K*

(GO

LD

Cla

ssif

icat

ion

of

Air

flow

Lim

itat

ion

)

4

(C) (D) 2 or more

or 1 hospitalisation

RIS

K*

(Exa

cerb

atio

n h

isto

ry)

3

2

(A) (B) Less than 2

1

mMRC 0-1 mMRC > 2

CAT <10 CAT >10

SYMPTOMS†

(mMRC or CAT score)

Lower Risk

Higher Risk

Severity assessed using the new system

Low Symptoms Higher Symptoms

Worsening

COPD

Lower Risk

Higher Risk

Diabetes 4% Diabetes 16%

Diabetes 29%

Patients in European 1y and 2y care survey (n=1191)

‘New’ GOLD classified – co-morbidity

Low Symptoms Higher Symptoms

Jones et al ERS 2012

ANOVA p values

Diabetes p<0.0001

Lower Risk

Higher Risk

Diabetes 4%

Hypertension 38%

Diabetes 16%

Hypertension 55%

Diabetes 29%

Hypertension 65%

Patients in European 1y and 2y care survey (n=1191)

‘New’ GOLD classified – co-morbidity

Low Symptoms Higher Symptoms

Jones et al ERS 2012

ANOVA p values

Diabetes p<0.0001

Hypertension p<0.0001

Lower Risk

Higher Risk

Diabetes 4%

Hypertension 38%

Hyperlipidaemia 13%

Diabetes 16%

Hypertension 55%

Hyperlipidaemia 30%

Diabetes 29%

Hypertension 65%

Hyperlipidaemia 37%

Patients in European 1y and 2y care survey (n=1191)

‘New’ GOLD classified – co-morbidity

Low Symptoms Higher Symptoms

Jones et al ERS 2012

ANOVA p values

Diabetes p<0.0001

Hypertension p<0.0001

Hyperlipidaemia p<0.0001

Lower Risk

Higher Risk

Diabetes 4%

Hypertension 38%

Hyperlipidaemia 13%

Coronary artery disease 3%

Diabetes 16%

Hypertension 55%

Hyperlipidaemia 30%

Coronary artery disease 6%

Diabetes 29%

Hypertension 65%

Hyperlipidaemia 37%

Coronary artery disease 9%

Patients in European 1y and 2y care survey (n=1191)

‘New’ GOLD classified – co-morbidity

Low Symptoms Higher Symptoms

Jones et al ERS 2012

ANOVA p values

Diabetes p<0.0001

Hypertension p<0.0001

Hyperlipidaemia p<0.001

Coronary disease p=0.06

18

POSSIBLE MECHANISM OF LINK

BETWEEN COPD AND CVS DISEASE

Coincidence

Smoking

Hypoxia

Shared genetic risk

Hyperinflation

Inflammation

19

POSSIBLE MECHANISM OF LINK

BETWEEN COPD AND CVS DISEASE

Coincidence

Smoking

Hypoxia

Shared genetic risk

Hyperinflation

Inflammation

Can be ruled out

20

POSSIBLE MECHANISM OF LINK

BETWEEN COPD AND CVS DISEASE

Coincidence

Smoking

Hypoxia

Shared genetic risk

Hyperinflation

Inflammation

21

SHARED GENETIC RISK

* After multivariate adjustment, Increase in % emphysema was associated with a

4.1 ml decrease in LVEDV.

Barr et al , NEJM 2010

22

POSSIBLE MECHANISM OF LINK

BETWEEN COPD AND CVS DISEASE

Coincidence

Smoking

Hypoxia

Shared genetic risk

Hyperinflation

Inflammation

23

Stiffness of the parietal pleura, the walls of the cardiac

fossa.

? contribute to left and right diastolic dysfunction

in the absence of pulmonary hypertension3

Reduction in intrathoracic blood volume related to

increased PEEPi4

CONSEQUENCES OF

HYPERINFLATION

3. Butler J , Chest 1990

4. Jorgensen Chest 2007

25

CONSEQUENCES OF

HYPERINFLATION

Significantly impaired LV diastolic

filling pattern compared with a

ratio of >0.25 2

2x all cause mortality1

IC/TLC <0.25 vs IC/TLC > 0.25

1. Casanova et al AJRCCM 2005

2. Watz et al Chest 2010

26

POSSIBLE MECHANISM OF LINK

BETWEEN COPD AND CVS DISEASE

Coincidence

Smoking

Hypoxia

Shared genetic risk

Hyperinflation

Inflammation

COPD DEFINITION GOLD 2006

COPD is a preventable and treatable

disease with some extrapulmonary effects

that may contribute to the severity in

individual patients. Its pulmonary

component is characterized by airflow

limitation that is not fully reversible. The

airflow limitation is usually progressive and

associated with an abnormal response of

the lungs to noxious particles or gases.

MULTI-COMPONENT

PATHOPHYSIOLOGY OF COPD

Muco-ciliary

dysfunction

Airway

inflammation Airflow

limitation Systemic

component

Structural

changes

29

ARTERIAL STIFFNESS

Pulse wave velocity

V I C O R D E R

Skidmore Medical Ltd 1 The Old Estate Yard Office, North Stoke Lane, Upton Cheyney, Bristol, BS30 6NG, UK

Local Representative

AORTIC PULSE WAVE VELOCITY AND ABI MEASUREMENT

PWV MEASUREMENT ABI MEASUREMENT

Fast

Neckpad placement Brachial cuff and PPG placement

Portable

Non-invasive

Operator Independent

Thigh cuff placement

Ankle cuff and PPG placement

Aortic path length

Press Space bar and GO

PWV and Transit Time ABI and Pressures

Contact us : Tel : +44 (0)1179 324612 Fax : +44 (0)1179 323943

e-mail : enquiries@skidmoremedical.com www.skidmoremedical.com

V I C O R D E R

Skidmore Medical Ltd 1 The Old Estate Yard Office, North Stoke Lane, Upton Cheyney, Bristol, BS30 6NG, UK

Local Representative

AORTIC PULSE WAVE VELOCITY AND ABI MEASUREMENT

PWV MEASUREMENT ABI MEASUREMENT

Fast

Neckpad placement Brachial cuff and

PPG placement Portable

Non-invasive

Operator Independent

Thigh cuff placement

Ankle cuff and PPG placement

Aortic path length

Press Space bar and GO

PWV and Transit Time ABI and Pressures

Contact us : Tel : +44 (0)1179 324612 Fax : +44 (0)1179 323943

e-mail : enquiries@skidmoremedical.com www.skidmoremedical.com

30

SIGNIFICANCE OF PULSE

WAVE VELOCITY Independent predictor of coronary artery

disease

– In hypertensive patients

– In diabetic patients

– In a general population including the elderly.

– Associated with disease duration and the

presence of inflammatory mediators CRP and

interleukin (IL) 6

31

ARTERIAL STIFFNESS THE HEALTH ABC STUDY

Relative Risk 95 % CI

Total mortality

1.45 0.98 - 2.16

CV mortality

2.13* 1.07 – 4.24

Coronary HD

1.48* 1.05 – 2.09

Stroke

2.93* 1.37 – 6.27

CHF 0.99 0.62 – 1.58

Data adjusted for age, gender, race, systolic BP & other variables including

smoking, cholesterol, HR, ankle/arm index etc.

Associations between aPWV and events (aPWV Q2 vs Q1)

Sutton-Tyrrell et al Circulation 2005

32 INCREASED ARTERIAL STIFFNESS

(APWV) IN COPD

control

COPD

Sabit et al AJRCCM 2007

Age associated with aPWV

aPWV greater in successive decades

In both Control & COPD groups:

In all subjects:

An inverse relationship between aPWV & FEV1

N = 75 patient (64.5 9.5 y)

vs

N = 42 control (62.0 10.5 y)

PERCENTAGE CHANGE FROM

BASELINE IN BIOPSY AND SPUTUM

ENDPOINTS

-80

-60

-40

-20

0

20

40

60

80

CD68+ Total

neutrophils

CD45+ CD4+ Mast

cells

IFNg TNFa Med

ian

perc

en

tag

e c

han

ge f

rom

baselin

e

CD8+

-36%

(-56,-16%)

p=0.001

-24%

(-74, 21%)

p=0.29

-53%

(-111,-1%)

p<0.05

-35%

(-60, -14%)

p=0.001

-27%

(-48, -4%)

p=0.02

-26%

(-72, 0%)

p=0.06

-40%

(-71, 14%)

p=0.002

-30%

(-58, -8%)

p=0.007

Primary endpoints Other biopsy endpoints

Placebo SALM/FP

p-values relate to median difference between SALM/FP and placebo. No adjustments made for multiplicity

EFFECT OF TREATMENT ON

PULSE WAVE VELOCITY

Randomized Salm/FP 250 vs Placebo

Primary endpoint change in PWV at 12/52 For those who remained on study treatment reduction of 0.49 m/s – p=0.045 CI:-0.098,-0.01

Post-hoc analysis in those with higher PWV

Impact on cardiac function not known

Dransfield et al, Respiratory Medicine 2010

A STUDY OF TREATMENT OF COPD

ON CARDIAC FUNCTION

7 day run-in once

washed out

2 x 7-14 day treatment

periods

1 week washout period

at cross-over

Minimum of 4 visits (+ 2

telephone consults)

CARDIAC MRI

No geometric

assumptions

Highly accurate

and reproducible

Limitations with

ECHO due to

emphysema do

not apply

EFFECT OF TREATMENT ON

CARDIAC MORBIDITY AND

MORTALITY ICS/LABA

Anticholinergics

Phosphodiesterase 4 inhibitors

Novel agents

39

TORCH: STUDY DESIGN

SFC 500/50 bd

FP 500 bd

Salmeterol 50 bd

Placebo

Duration = 3 years

1,533

1,534

1,524

1,521

6112 patients

*All ICS and inhaled LABA discontinued before run-in ITT population

2 week

run-in*

Calverley et al NEJM 2007

PRIMARY ANALYSIS: ALL-CAUSE

MORTALITY AT 3 YEARS

1524

1533

1464

1487

1399

1426

1293

1339

Number

alive

0 2 4 6 8

10 12 14 16 18

0 12 24 36 48 60 72 84 96 108 120 132 144 156 Time to death (weeks)

Probability of death (%)

SALM/FP Placebo

Calverley et al NEJM 2007

CAUSE OF DEATH

ON TREATMENT (ADJUDICATED BY

CEC)

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

Cardio-

vascular

Pulmonary Cancer Other Unknown

Deaths (%)

Placebo SALM/FP

Placebo + Any Respiratory Medications * ‡

Tiotropium 18 µ g + Concomitant Medications * ‡

4 years

Randomized

UPLIFT: STUDY DESIGN

Decramer M et al. J COPD 2004; 1: 303 – 312

* Includes ICS,SABA, LABA,ICS/LABA

‡ No restrictions for medications

prescribed for treatment of

exacerbations

Four - year, randomized, double - blind, double - dummy

N=5993

Screening Spirometry

ipratropium

30 days

Spirometry SGRQ

Pt. Diary

2 weeks

Day 30 Spirometry

Every 6 mos Spirometry

SGRQ Pt. Diary

1.00

1.10

1.20

1.30

1.40

1.50

FE

V1 (

L)

Tiotropium Control

*

Day 30

(steady state)

* *

* *

* *

* *

0

6 12 18 24 30 36 42 48 0 1

Months

* * * *

* * * *

*

Post-Bronch FEV1

= 47 – 65 mL

Pre-Bronch FEV1

= 87 – 103 mL

(n=2516)

(n=2374)

(n=2494)

(n=2363)

N Eng J Med 2008: 359(Suppl 15):1543-1554.

IMPROVEMENT IN FEV1

SERIOUS ADVERSE EVENTS Incidence rate of serious adverse events per 100 patient-years*

Adverse Event

Tiotropium

(n=2986)

Placebo

(n=3006)

Relative Risk for

Tiotropium vs. Placebo

(95% CI)

Cardiac 3.56 4.21 0.84 (0.73–0.98)†

Angina 0.51 0.36 1.44 (0.91–2.26)

Atrial fibrillation 0.74 0.77 0.95 (0.68–1.33)

Cardiac failure 0.61 0.48 1.25 (0.84–1.87)

Congestive heart failure 0.29 0.48 0.59 (0.37–0.96)†

Coronary artery disease 0.21 0.37 0.58 (0.33–1.01)

Myocardial infarction 0.69 0.97 0.71 (0.52–0.99)†

Lower respiratory 11.32 13.47 0.84 (0.77–0.92)†

Bronchitis 0.37 0.31 1.20 (0.73–1.98)

COPD exacerbation 8.19 9.70 0.84 (0.76–0.94)†

Dyspnea 0.38 0.62 0.61 (0.40–0.94)†

Pneumonia 3.28 3.46 0.95 (0.81–1.11)

Respiratory failure 0.9 1.31 0.69 (0.52–0.92)†

ROFLUMILAST: TIME TO ONSET OF FIRST

MAJOR ADVERSE CV EVENT (MACE*)

Roflumilast 500 mcg, od, p.o. + Roflumilast 250 mcg, od p.o.

Placebo, od, p.o.

Pro

bab

ility

of

even

t

0.00

0.02

0.04

0 30 60 90 120 150 180 210 240 270 300 330 360 390

Days post-randomisation

0.01

0.03

*MACE : CV death, non-fatal MI, non-fatal stroke

HR 0.65; p=0.019

White WB, et al. Am J Respir Crit Care Med 183;2011:A3092.

EFFECT OF MAP KINASE INHIBITOR ON

SERUM FIBRINOGEN & IL-8 IN COPD

Day 28 Estimate 95% CI p

Fibrinogen

Ratio SB/Plac

0.89

(0.81, 0.98)

0.020

IL-8

Ratio SB/Plac

1.22

(0.79, 1.89)

0.360

Fibrinogen Pbo baseline mean 3.45 d 14 3.57 day 28 3.64 g/L

‘323 baseline mean 3.59, d 14 3.27, day 28 3.32 g/L

IL-8 Pbo baseline mean 3312 d 14 3609 day 28 3205 ng/mL

‘323 baseline mean 2310, d 14 1849, day 28 2554 ng/mL

Barnes et al ERS 2009

SUMMARY

COPD is an independent risk factor for

cardiovascular disease

There are multiple mechanisms which may

link COPD and cardiovascular disease

There is emerging evidence that treatment

of COPD may reduce cardiovascular

morbidity and mortality