Modena, 6-7/8-9 Settembre 2011
CORSO DI FORMAZIONE PER PERSONALE MEDICO
Nycomed
Malattie cardiovascolari e BPCO
Pietro Roversi, Alessia Verduri e Fabrizio Luppi
Clinica di Malattie dell’Apparato Respiratorio
Azienda Ospedaliero – Universitaria
Policlinico di Modena
Muscle
Weakness / Wasting
TNFa
Metabolic Syndrome
Type 2 diabetes
IL-6
Local
Inflammation
Cardiovascular
Events
CRP
?
Osteoporosis
Liver
Fabbri LM, Luppi F et al, Eur Respir J 2008
Principali comorbilità
Insufficienza cardiaca cronica
Coronaropatia e Infarto miocardico
Vasculopatia periferica
Embolia polmonare
Aritmie
Neoplasia polmonare
Sindrome metabolica
Osteoporosi
Depressione
Prevalence of
Comorbid Diagnoses
and Symptoms
Among a National
Sample of Patients
with COPD
The American Journal
of Medicine
(2009) 122, 348-355
Frequency distribution of comorbid conditions
among patients with COPD.
Barr, The American Journal of Medicine, 2009
The high prevalence of comorbidity in COPD is likely multifactorial and
associated with age and multisystem impact of tobacco exposure
COPD was less commonly treated than less symptomatic and less
morbid conditions, such as hypertension and hypercholesterolemia,
despite the increasing number of proven medications for the treatment
of COPD
Patients with COPD demonstrated better recall of their blood pressure
and cholesterol than of their FEV1
This is not surprising in the context of the greater public education
regarding hypertension and hypercholesterolemia
Barr, The American Journal of Medicine, 2009
Prevention of exacerbations of chronic
obstructive pulmonary diseases with tiotropium,
a once-daily inhaled anticholinergic
bronchodilator: a randomized trial.
Co-morbilità
Vascolari (compresa l’ipertensione)
Cardiache
64%
38%
Gastrointestinali
48%
Metaboliche o nutrizionali
47%
Muscolo scheletriche o connettivali
46%
Genito-urinarie
27%
Neurologiche
22%
Niewoehner et al, Ann Intern Med 2005;143:317-326
Role of co-morbidities in a cohort of patients
with COPD undergoing pulmonary rehabilitation
• 51% of the patients reported at least one chronic
comorbidity added to COPD.
• Metabolic (systemic hypertension, diabetes and/or
dyslipidaemia) and heart diseases (chronic heart
failure and/or coronary heart disease) were the most
frequently reported co-morbid combinations (61% and
24%, respectively)
Crisafulli E, et al.,Thorax 2008;63: 487-492.
Screening della
comorbilità: alcuni esempi
Patologia
Identificazione
CHF
Rx torace, BNP
Osteoporosi
DEXA, morfometria colonna
dorsale
Geriatric Depression Scale
Depressione
Deficit
cognitivo
Glaucoma
MMSE, Clock Drawing test
Insufficienza
renale
MDRD (stima indiretta GFR)
Tonometria oculare
GOLD Linee guida BPCO 2010
Cause of death on treatment
Deaths (%)
Placebo
Cardiovascular
Pulmonary
SFC
Cancer
Other
Unknown
Calverley et al. NEJM 2007
What do COPD Patients Die
From?
Normal
Restricted
GOLD 2
GOLD 3/4
0%
20%
COPD
40%
ASCVD
60%
80%
Lung Cancer
100%
Other
Mannino et al, ERJ, 2007
Systemic Consequences of
COPD
Cardiovascular Morbidity
Cardiac infarction injury score
8
7
P=0.001
6
5
4
3
2
1
0
High CRP
Severe
obstruction
High CRP
and severe
obstruction
Sin and Man, Circulation. 2003
.
450 population
participants
without CVD
52 population
participants with
CVD,
119 hospital
patients with
CAD
Soriano , CHEST 2010
.
Soriano , CHEST 2010
1. One of every three patients with CAD recruited from the
hospital clinic, and one of every five patients with CVD
in the general population, suffer AL compatible with
COPD
2. The majority of them are not diagnosed, and, therefore,
they remain mostly untreated.
3. These observations are clinically relevant because
COPD is now considered a preventable and treatable
disease.
Soriano , CHEST 2010
Cardiovascular mortality in
COPD
For every 10% decrease in FEV1,
cardiovascular mortality increases by
approximately 28% and non-fatal
coronary event increases by
approximately 20% in mild to moderate
COPD
Anthonisen et al, Am J Respir Crit Care Med 2002
ARTERIAL STIFFNESS IS INDEPENDENTLY
ASSOCIATED WITH EMPHYSEMA SEVERITY IN
PATIENTS WITH CHRONIC OBSTRUCTIVE
PULMONARY DISEASE
Emphysema severity is associated with arterial
stiffness in patients with COPD
Similar pathophysiological processes may be
involved in both lung and arterial tissue
Further studies are now required to identify the
mechanism underlying this newly described
association
MacNee W et al, AJRCCM 2007; 176:1208-1214
RELATIONSHIP BETWEEN COPD AND
CARDIOVASCULAR DISEASE
Systemic
Inflammation
CRP
(FIBRINOGEN)
ENDOTELIN-1
IL-6
Cytokines
Complement
activation
ICAM VCAM
(adhesion molecules)
LDL
uptake
The risk ratio of developing CHF in COPD patients is 4.5
(compared with age-matched controls without COPD after
adjustments for cardiovascular risk factors ) (1)
The rate-adjusted hospital prevalence of CHF is 3 times
greater among patients discharged with a diagnosis of
COPD compared with patients discharged without mention
of COPD (2)
(1) Curkendall SM, DeLuise C, Jones JK, et al.
Cardiovascular disease in patients with chronic
obstructive pulmonary disease, Saskatchewan
Canada cardiovascular disease in COPD patients.
Ann Epidemiol 2006;16:63–70.
(2) Holguin F, Folch E, Redd SC, Mannino
DM. Comorbidity and mortality in COPDrelated hospitalizations in the United States,
1979 to 2001. Chest 2005;128:2005–11.
Prevalence (%)
Prevalence (%)
How common is HF in COPD?
Italian Health Search Database
n=341,329
Scottish Continuous Morbidity Record
n=377,439
7.9% prevalence
11.9% prevalence HF in COPD overall
HF in COPD
overall
Cazzola M. Respiration 2010; epub; Hawkins NM. Data on file.
Prevalence (%)
How common is LVSD in COPD?
Rutten FH. Eur J Heart Fail 2006: 8(7):706-711.
•
•
high prevalence
selected
populations
•
•
•
severe COPD
suspected LVSD
coronary disease
Kaplan–Meier event-free survival curves according to
chronic obstructive pulmonary disease coexistence
Mascarenhas, Am Heart J 2008
Why is heart failure important?
1.0
•
primary care patients with
COPD ≥ 65 years (n=404)
•
follow up for a mean
duration of 4.2 (SD 1.4)
years.
•
HF doubles mortality of
patients with COPD:
adjusted HR 2.1 (1.2–3.6
C.I.)
Survival
0.9
0.8
0.7
COPD
COPD GOLD
COPD + Heart failure
0.6
COPD GOLD + Heart Failure
0.5
0
12
24
36
48
60
72
Time (Months)
Boudestein LC. Eur J Heart Fail 2009; 11(12):1182-1188.
Mechanisms of Skeletal Muscle
Atrophy in Patients With CHF or COPD
M. Padeletti- LeJemtel : International Journal of Cardiology, 2008
PROGRESSION OF CHF AND COPD
M. Padeletti- LeJemtel : International Journal of Cardiology, 2008
Weight loss is a prognostic
factor in COPD
Survival
1.0
0.8
BMI > 29 Kg/m2
0.6
BMI 24-29 Kg/m2
0.4
BMI 20-24 Kg/m2
BMI < 20 Kg/m2
0.2
0.0
0
6
12
18
24
30
36
42
Follow-up, months
Schols et al. AJRCCM 1998; 157: 1791-7
48
INSULIN RESISTANCE AND INFLAMMATION A FURTHER SYSTEMIC COMPLICATION OF
COPD
This study demonstrates greater insulin
resistance in non-hypoxaemic patients
with COPD compared with healthy
subjects, which was related to systemic
inflammation. This relationship may
indicate a contributory factor in the
excess risk of cardiovascular disease
and type II diabetes in COPD
Bolton CE et al, COPD. 2007 Jun ;4(2):121-6
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).
a) diabetes,
b) hypertension
c) cardiovascular disease
Results from Cox proportional hazard
models (presented as hazard ratio with
95% confidence interval) that predict
death within 5 yrs by modified Global
Initiative for Obstructive Lung Disease
(GOLD) category and the presence of
a) diabetes, b) hypertension or c)
cardiovascular disease
a) diabetes,
b) hypertension
c) cardiovascular disease
Results from Cox proportional hazard
models (presented as hazard ratio with
95% confidence interval) that predict
time to first hospitalisation within 5 yrs
by modified Global Initiative for
Obstructive Lung Disease (GOLD)
category and the presence of a)
diabetes b) hypertension or c)
cardiovascular
REDUCTION OF MORBIDITY AND MORTALITY BY STATINS,
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS, AND
ANGIOTENSIN RECEPTOR BLOCKERS IN COPD
The combination of statins
and either ACE inhibitors or
ARBs is associated with a
reduction in COPD
hospitalization and total
mortality not only in the high
CV risk cohort but also in the
low CV risk cohort
Mancini JB, et al. J Am Coll Cardiol. 2006 Jun 20;47(12):2554-60
Challenges in patients with
coexistent COPD and CHF
• COPD is the one that most delays the diagnosis of
CHF
• COPD is most often advocated for nonadherence to
therapeutic guidelines, especially betablockade (BB)
• safety and efficacy of BB and bronchodilators in
patients with COPD and HF
M. Padeletti- LeJemtel : International Journal of Cardiology, 2008
gabbia
toracica
congestione
ematica
versamento
pleurico
Ridotta compliance
cardiomegalia
Aumento del lavoro
respiratorio
Limitazione del flusso espiratorio
bronchi
alveoli
Caution diagnosing COPD
in HF
Airway compression
Bronchial
hyperresponsiveness
overestimate
severity
inappropriate
avoidance
of β-blockers
misdiagnosis
always perform
Spirometry…
and always
when euvolaemic
inappropriate
bronchodilators
COPD masks or mimics heart
failure
pulmonary
vascular
remodeling
masks alveolar
shadowing
asymmetric
and regional
patterns
Gehlbach BK. Chest 2004; 125:669-682.
radiology
hyperinflation
reduces
cardiothoracic
ratio
vascular bed
loss causes
upper lobe
venous
diversion
COPD masks or mimics heart
failure
Why is diagnosis important?
Renin-angiotensinaldosterone system
inhibition
bronchodilators
beta-blockers
heart failure
OUTCOMES
COPD
beta-agonists
devices
smoking
cessation
THE IMPACT OF CARDIOSELECTIVE BETABLOCKERS ON MORTALITY IN PATIENTS WITH
COPD AND ATHEROSCLEROSIS
b-blockers are often withheld from patients with
chronic obstructive pulmonary disease (COPD)
because of fear of pulmonary worsening
Beta1-blockers may reduce mortality in COPD
patients undergoing vascular surgery (1)
In some patients with COPD selective beta1-blockers
are safe and may reduce mortality (2)
1) Van Gestel , Am J Respir Crit Care Med . 2008
2) Salpeter S Cardioselective beta-blockers for chronic obstructive pulmonary disease.
Cochrane Database Syst Rev 2005;4:CD003566.
Short PM et al., 2011
Baseline characteristics of 5977 patients at diagnosis of COPD, grouped
according to final treatment.
Short PM et al., 2011
Effect of different treatment regimens* on FEV1 of patients with COPD during
study period
Short PM et al., 2011
Adjusted hazard ratios for all cause mortality among patients with COPD in
reference to the control group (who received only inhaled therapy with short
acting β agonists or antimuscarinics)
Short PM et al., 2011
Kaplan-Meier estimate of probability of survival among patients
with COPD by use of β blockers
Β-blocker use was associated with a 22% reduction in mortality: hazard
ratio 0.78 (95% confidence interval 0.67 to 0.92)
Short PM et al., 2011
Conclusions
β blockers may reduce mortality and COPD
exacerbations when added to established
inhaled stepwise therapy for COPD,
independently of overt cardiovascular disease
and cardiac drugs, and without adverse effects
on pulmonary function.
Use of beta blockers and the risk of death in
hospitalised patients with acute exacerbations
of COPD
In-hospital mortality was 5.2%
Those receiving beta blockers (n = 142) were older and
more frequently had cardiovascular disease than those
who did not
Beta blocker use was associated with reduced
mortality (OR = 0.39; 95% CI 0.14 to 0.99)
The use of beta blockers by inpatients with
exacerbations of COPD is well tolerated and may be
associated with reduced mortality
Dransfield MT, Thorax. 2008 Apr;63(4):301-5.
1.0
CHARM trial: patients with
0.8
No bronchodilator
and beta-blocker
No bronchodilator
and no betablocker
Bronchodilator and
beta-blocker
0.7
Survival Rate
0.9
HF receiving bronchodilators
(n=674 of 7599)
0
0.5
1.0
1.5
2.0
Time (years)
Hawkins NM. Eur J Heart Fail 2010
2.5
3.0
3.5
Bronchodilator
and no betablocker
Cumulative frequency of cardiovascular endpoint event
Kaplan-Meier estimates of the probability of major and fatal CV events
in the placebo and tiotropium groups from the 30-trial pooled analysis.
0,1
0,09
0,08
0,07
Placebo
0,06
0,05
Tiotropium
0,04
0,03
0,02
0,01
Rate ratio = 0.83; 95% CI = (0.71-0.98)
0
0
6
12
10846
8699
6889
5506
4698
3599
Patients at risk
Tiotropium
Placebo
18
24
30
Time to first event (months)
2420
2240
2274
2068
2133
1917
36
42
48
2022
1787
1911
1681
1785
1571
Celli B. et al., Chest 2010; 137: 20-30.
Cumulative frequency of cardiovascular death
Kaplan-Meier estimates of the probability of major and fatal CV events
in the placebo and tiotropium groups from the 30-trial pooled analysis.
0,1
0,09
0,08
0,07
0,06
0,05
0,04
Placebo
0,03
Tiotropium
0,02
0,01
Rate ratio = 0.77; 95% CI = (0.60-0.98)
0
0
6
12
10846
8699
6933
5538
4737
3637
Patients at risk
Tiotropium
Placebo
18
24
30
Time to first event (months)
2456
2286
2322
2120
2193
1980
36
42
48
2087
1861
1986
1756
1863
1638
Celli B. et al., Chest 2010; 137: 20-30.
Primary analysis: all-cause mortality at 3 years
HR 0.825, p=0.052
17.5% risk reduction
Probability of death (%)
18
16
14
12
10
2.6%
absolute reduction
8
6
4
2
0
Number
alive
Placebo 15.2%
FSC
12.6%
0
1524
1533
12 24 36 48 60 72 84 96 108 120 132 144 156
Time to death (weeks)
1464
1487
Vertical bars are standard errors
1399
1426
1293 Plc
1339 SFC
Calverley et al, NEJM, 2007
Caratteristiche della TEP in
BPCO
1. Nearly 30% of all exacerbations of COPD do not have a
clear etiology
2. COPD patients are at a high risk for PE due to a variety of
factors including limited mobility, inflammation, and
comorbidities
3. Overall, the prevalence of PE was 19.9% (95% confidence
interval [CI], 6.7 to 33.0%; p 0.014).
4. In hospitalized patients, the prevalence was higher at
24.7% (95% CI, 17.9 to 31.4%; p 0.001) than those who
were evaluated in the emergency department (3.3%)
1. One of four COPD patients who require hospitalization for
an acute exacerbation may have PE.
2. A diagnosis of PE should be considered in patients with
exacerbation severe enough to warrant hospitalization,
especially in those with an intermediate-to-high pretest
probability of PE.
Endothelial-coagulative activation during COPD
exacerbations
IL-6: surrogate marker of
inflammation
vWF:Ag (von Willebrand
Factor antigen):
endothelium
activation
F1+2 (prothrombin
fragment 1+2 ): clotting
stimulation
D-Dimer : fibrinolytic
activation
Polosa et al: Haematologica , 2008
TEP in BPCO:
FATTORI DI RISCHIO
1. precedente storia di neoplasia maligna (rischio relativo, RR
1.82, 95% CI, 1.3-2.92)
2. storia di TVP o EP (RR 2.43, 95% CI, 1.49-3.49)
3. riduzione della PaCO2 > 5 mm Hg
COPATOLOGIE
1. cancro
2. scompenso cardiaco congestizio
Tillie-Leblond I : Ann Intern med 2006
Riztkallah, CHEST 2009
Riztkallah, CHEST 2009
Riztkallah, CHEST 2009
Riztkallah, CHEST 2009
Riztkallah, CHEST 2009
Riztkallah, CHEST 2009
AE-COPD
atypical
typical
Pre test probability for PE
TREATMENT
LOW
no improvement
INTERMEDIATE
NEG
creatinine
D-dimer
POS
improvement
HIGH
>1.5
Doppler US
<1.5
SPIRAL CT
V/Q scan
PE excluded
POS
PE confirmed
Kenneth E Wood International Journal of COPD 2008:3(2) 277–284
TEP in BPCO: messaggi chiave I
• La BPCO è uno dei fattori di rischio per tromboembolia
polmonare
• La TEP deve essere considerata tra le cause di
riacutizzazione di BPCO e la sua frequenza varia in
funzione della casistica studiata e del setting clinico,
potendo arrivare fino al 25% dei casi
• La diagnosi è resa difficile dall’aspecificità dei sintomi e
dalla possibile sovrapposizione con quelli di una
riacutizzazione e la formulazione di uno score clinico di
probabilità è utile sia per porre il sospetto sia per
l’accuratezza diagnostica.
• La performance clinica delle indagini diagnostiche, con
eccezione per la scintigrafia polmonare
perfusionale\ventilatoria, non è influenzata in modo
significativo dalla presenza di BPCO.
TEP in BPCO: messaggi chiave II
• Lo studio del circolo polmonare arterioso con tomografia
computerizzata (angioTC polmonare) è l’indagine di
riferimento
•
un eccessivo impiego di esami TC con mezzo di
contrasto può essere evitato escludendo i soggetti con
score di probabilità medio-basso associato a D-dimero
negativo.
• La valutazione del rischio di morte (stratificazione del
rischio con ricerca dei segni di disfunzione ventricolare
destra ) è utile a fini prognostici e terapeutici
DISSEZIONE
AORTICA