Prof Neil Barnes - GP CME South/Sun_Plenary_1130 Barnes - COPD CVS NZ.pdf · Professor Neil Barnes...
Transcript of Prof Neil Barnes - GP CME South/Sun_Plenary_1130 Barnes - COPD CVS NZ.pdf · Professor Neil Barnes...
Prof Neil Barnes Professor of Respiratory Medicine
London Chest Hospital &
The Royal London Hospital
United Kingdom
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 : [email protected] 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 : [email protected] 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