Modena, 6-7/8-9 Settembre 2011
CORSO DI FORMAZIONE PER PERSONALE MEDICO Nycomed
Malattie cardiovascolari e BPCOPietro Roversi, Alessia Verduri e Fabrizio Luppi
Clinica di Malattie dell’Apparato RespiratorioClinica di Malattie dell’Apparato Respiratorio
Azienda Ospedaliero – Universitaria Azienda Ospedaliero – Universitaria
Policlinico di Modena Policlinico di Modena
MuscleWeakness / Wasting
Metabolic Syndrome Type 2 diabetes
Osteoporosis
CRP
CardiovascularEvents Liver
?LocalInflammation
TNF IL-6
Fabbri LM, Luppi F et al, Eur Respir J 2008
Insufficienza cardiaca cronicaCoronaropatia e Infarto miocardicoVasculopatia periferica Embolia polmonare AritmieNeoplasia polmonareSindrome metabolicaOsteoporosiDepressione
Principali comorbilità
The American Journal of Medicine (2009) 122, 348-355
Prevalence of Comorbid Diagnoses and SymptomsAmong a National Sample of Patients with COPD
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 pressureand 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-morbilitàCo-morbilità
Vascolari (compresa l’ipertensione) Vascolari (compresa l’ipertensione) 64%64%
Cardiache Cardiache 38%38%
Gastrointestinali Gastrointestinali
48%48%
Metaboliche o nutrizionali Metaboliche o nutrizionali
47%47%
Muscolo scheletriche o connettivali Muscolo scheletriche o connettivali
46% 46%
Genito-urinarie Genito-urinarie
27%27%
Neurologiche Neurologiche
22% 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
Crisafulli E, et al.,Thorax 2008;63: 487-492..
• 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)
• 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)
Screening della comorbilità: alcuni
esempiPatologia Identificazione
CHF Rx torace, BNP
Osteoporosi
DEXA, morfometria colonna dorsale
Depressione
Geriatric Depression Scale
Deficit cognitivo
MMSE, Clock Drawing test
Glaucoma Tonometria oculare
Insufficienza renale
MDRD (stima indiretta GFR)
GOLD Linee guida BPCO 2010GOLD Linee guida BPCO 2010
Cause of death on treatment
Cardio-vascular
Pulmonary Cancer Other Unknown
Deaths (%)
Placebo SFC
Calverley et al. NEJM 2007
0% 20% 40% 60% 80% 100%
GOLD 3/4
GOLD 2
Restricted
Normal
COPD ASCVD Lung Cancer Other
Mannino et al, ERJ, 2007
What do COPD Patients Die From?
High CRPHigh CRP Severe Severe obstructionobstruction
High CRP High CRP and severe and severe obstructionobstruction
Car
dia
c in
farc
tio
n in
jury
sc
ore
Car
dia
c in
farc
tio
n in
jury
sc
ore
P=0.001P=0.001
Sin and Man, Circulation. 2003Sin and Man, Circulation. 2003
0
1
2
3
4
5
6
7
8
Systemic Consequences of COPD
Cardiovascular Morbidity
.
Soriano , CHEST 2010
450 population participants without CVD
52 population participants with CVD,
119 hospital patients with CAD
.
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
For every 10% decrease in FEVFor every 10% decrease in FEV11, ,
cardiovascular mortality increases by cardiovascular mortality increases by approximately 28% and non-fatal approximately 28% and non-fatal
coronary event increases by coronary event increases by approximately 20% in mild to moderate approximately 20% in mild to moderate
COPDCOPD
Anthonisen et al, Am J Respir Crit Care Med 2002Anthonisen et al, Am J Respir Crit Care Med 2002
Cardiovascular mortality in Cardiovascular mortality in COPDCOPD
Emphysema severity is associated with arterial Emphysema severity is associated with arterial stiffness in patients with COPDstiffness in patients with COPD
Similar pathophysiological processes may be Similar pathophysiological processes may be involved in both lung and arterial tissueinvolved in both lung and arterial tissue
Further studies are now required to identify the Further studies are now required to identify the mechanism underlying this newly described mechanism underlying this newly described
associationassociation
MacNee W et al, AJRCCM 2007; MacNee W et al, AJRCCM 2007; 176:1208-1214176:1208-1214
ARTERIAL STIFFNESS IS INDEPENDENTLY ARTERIAL STIFFNESS IS INDEPENDENTLY ASSOCIATED WITH EMPHYSEMA SEVERITY IN ASSOCIATED WITH EMPHYSEMA SEVERITY IN
PATIENTS WITH CHRONIC OBSTRUCTIVE PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASEPULMONARY DISEASE
ENDOTELIN-1IL-6
LDL uptake
CRP(FIBRINOGEN)
RELATIONSHIP BETWEEN COPD ANDCARDIOVASCULAR DISEASE
ICAM VCAM(adhesion molecules)
CytokinesComplement
activation
Systemic Inflammation
The risk ratio of developing CHF in COPD patients is 4.5 (compared with age-matched controls without COPD afteradjustments 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 COPD-related hospitalizations in the United States,1979 to 2001. Chest 2005;128:2005–11.
How common is HF in COPD?
Cazzola M. Respiration 2010; epub; Hawkins NM. Data on file.
Italian Health Search Database
n=341,329
7.9% prevalence HF in COPD overall
Scottish Continuous Morbidity Record
n=377,439
11.9% prevalence HF in COPD overall
Pre
vale
nce
(%)
Pre
vale
nce
(%)
How common is LVSD in COPD?
Rutten FH. Eur J Heart Fail 2006: 8(7):706-711.
Pre
vale
nce
(%)
• 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?
• 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.)
0 12 24 36 48 60 72
0.5
0.6
0.7
0.8
0.9
1.0
Time (Months)
Su
rviv
al
COPD + Heart failure
COPD GOLD + Heart Failure
COPD
COPD GOLD
Boudestein LC. Eur J Heart Fail 2009; 11(12):1182-1188.
Mechanisms of Skeletal MuscleMechanisms of Skeletal MuscleAtrophy in Patients With CHF or COPDAtrophy in Patients With CHF or COPD
M. Padeletti- LeJemtel : International Journal of Cardiology, 2008M. Padeletti- LeJemtel : International Journal of Cardiology, 2008
PROGRESSION OF CHF AND COPD
M. Padeletti- LeJemtel : International Journal of Cardiology, 2008
BMI > 29 Kg/m2
BMI 24-29 Kg/m2
BMI 20-24 Kg/m2
BMI < 20 Kg/m2
Weight loss is a prognosticfactor in COPD
Schols et al. AJRCCM 1998; 157: 1791-7
0 6 12 18 24 30 36 42 480.0
0.2
0.4
0.6
0.8
1.0
Su
rviv
al
Follow-up, months
INSULIN RESISTANCE AND INFLAMMATION - INSULIN RESISTANCE AND INFLAMMATION - A FURTHER SYSTEMIC COMPLICATION OF A FURTHER SYSTEMIC COMPLICATION OF
COPDCOPD
Bolton CE et al, COPD. 2007 Jun ;4(2):121-6Bolton CE et al, COPD. 2007 Jun ;4(2):121-6
This study demonstrates greater insulin This study demonstrates greater insulin resistance in non-hypoxaemic patients resistance in non-hypoxaemic patients
with COPD compared with healthy with COPD compared with healthy subjects, which was related to systemic subjects, which was related to systemic
inflammation. This relationship may inflammation. This relationship may indicate a contributory factor in the indicate a contributory factor in the
excess risk of cardiovascular disease excess risk of cardiovascular disease and type II diabetes in COPD and type II diabetes in COPD
5-yrs mortality5-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
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
a) diabetes,
b) hypertension
c) cardiovascular disease
REDUCTION OF MORBIDITY AND MORTALITY BY STATINS, REDUCTION OF MORBIDITY AND MORTALITY BY STATINS, ANGIOTENSIN-CONVERTING ENZYME INHIBITORS, AND ANGIOTENSIN-CONVERTING ENZYME INHIBITORS, AND
ANGIOTENSIN RECEPTOR BLOCKERS IN COPDANGIOTENSIN 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):2554-60Mancini 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, M. Padeletti- LeJemtel : International Journal of Cardiology, 20082008
cardiomegaliacardiomegaliacardiomegaliacardiomegalia
congestionecongestioneematicaematicacongestionecongestioneematicaematica
versamentoversamentopleuricopleuricoversamentoversamentopleuricopleurico
gabbia toracicagabbia toracica
Ridotta compliance
Aumento del lavoro respiratorio
Ridotta compliance
Aumento del lavoro respiratorio
Limitazione del flusso espiratorio
alveolialveoli
bronchibronchi
Caution diagnosing COPD in HF
Airway compressionAirway compression
BronchialBronchialhyperresponsivenesshyperresponsiveness
always performalways performSpirometry…Spirometry…and alwaysand alwayswhen euvolaemicwhen euvolaemic
misdiagnosismisdiagnosisoverestimateoverestimateseverityseverity
inappropriateinappropriatebronchodilatorsbronchodilators
inappropriateinappropriateavoidanceavoidanceof of ββ-blockers-blockers
hyperinflation reduces cardiothoracic ratio
pulmonary
vascular
remodeling
masks alveolar
shadowing
asymmetric
and regional
patterns
vascular bed
loss causes
upper lobe
venous
diversion
Gehlbach BK. Chest 2004; 125:669-682.
radiology
COPD masks or mimics heart failure
COPD masks or mimics heart failure
OUTCOMES
bronchodilators
heart failure
devices smoking cessation
beta-blockers
Renin-angiotensin-aldosterone system inhibition
COPD
beta-agonists
Why is diagnosis important?
THE IMPACT OF CARDIOSELECTIVE BETA-THE IMPACT OF CARDIOSELECTIVE BETA-BLOCKERS ON MORTALITY IN PATIENTS WITH BLOCKERS ON MORTALITY IN PATIENTS WITH
COPD AND ATHEROSCLEROSISCOPD AND ATHEROSCLEROSIS
-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 Beta1-blockers may reduce mortality in COPD patients undergoing vascular surgery patients undergoing vascular surgery (1)(1)
In some patients with COPD selective beta1-blockers In some patients with COPD selective beta1-blockers are safe and may reduce mortality are safe and may reduce mortality (2)(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)
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.
Short PM et al., 2011
Use of beta blockers and the risk of death in Use of beta blockers and the risk of death in hospitalised patients with acute hospitalised patients with acute
exacerbations of COPDexacerbations of COPD
In-hospital mortality was 5.2%In-hospital mortality was 5.2%
Those receiving beta blockers (n = 142) were older and Those receiving beta blockers (n = 142) were older and more frequently had cardiovascular disease than those more frequently had cardiovascular disease than those
who did notwho did not
Beta blocker use was associated with reduced Beta blocker use was associated with reduced mortality (OR = 0.39; 95% CI 0.14 to 0.99) mortality (OR = 0.39; 95% CI 0.14 to 0.99)
The use of beta blockers by inpatients with The use of beta blockers by inpatients with exacerbations of COPD is well tolerated and may be exacerbations of COPD is well tolerated and may be
associated with reduced mortalityassociated with reduced mortality
Dransfield MT, Thorax. 2008 Apr;63(4):301-5.Thorax. 2008 Apr;63(4):301-5.
Hawkins NM. Eur J Heart Fail 2010
0.7
0.8
0.9
1.0
Su
rviv
al R
ate
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Time (years)
No bronchodilatorand beta-blocker
No bronchodilatorand no beta-blockerBronchodilator and beta-blocker
Bronchodilatorand no beta-blocker
CHARM trial: patients with HF receiving bronchodilators
(n=674 of 7599)
Celli B. et al., Chest 2010; 137: 20-30.Celli B. et al., Chest 2010; 137: 20-30.
Kaplan-Meier estimates of the probability of major and fatal CV events Kaplan-Meier estimates of the probability of major and fatal CV events in the placebo and tiotropium groups from the 30-trial pooled analysis.in the placebo and tiotropium groups from the 30-trial pooled analysis.
Cu
mu
lati
ve
fre
qu
en
cy
of
ca
rdio
va
sc
ula
r e
nd
po
int
ev
en
t
0
0,01
0,02
0,03
0,04
0,05
0,06
0,07
0,08
0,09
0,1
0 6 12 18 24 30 36 42 48
PlaceboPlacebo
TiotropiumTiotropium
Rate ratio = 0.83; 95% CI = (0.71-0.98)
Time to first event (months)Patients at risk
TiotropiumPlacebo
108468699
68895506
46983599
24202240
22742068
21331917
20221787
19111681
17851571
Celli B. et al., Chest 2010; 137: 20-30.Celli B. et al., Chest 2010; 137: 20-30.
Kaplan-Meier estimates of the probability of major and fatal CV events Kaplan-Meier estimates of the probability of major and fatal CV events in the placebo and tiotropium groups from the 30-trial pooled analysis.in the placebo and tiotropium groups from the 30-trial pooled analysis.
Cu
mu
lati
ve
fre
qu
en
cy
of
ca
rdio
va
sc
ula
r d
ea
th
0
0,01
0,02
0,03
0,04
0,05
0,06
0,07
0,08
0,09
0,1
0 6 12 18 24 30 36 42 48
PlaceboPlacebo
TiotropiumTiotropium
Rate ratio = 0.77; 95% CI = (0.60-0.98)
Time to first event (months)Patients at risk
TiotropiumPlacebo
108468699
69335538
47373637
24562286
23222120
21931980
20871861
19861756
18631638
Primary analysis: all-cause mortality at 3 years
Vertical bars are standard errorsVertical bars are standard errors
1524152415331533
1464146414871487
1399139914261426
1293 Plc1293 Plc1339 SFC1339 SFC
NumberNumberalivealive
00
2244
6688
10101212
1414
1616
1818
00 1212 2424 3636 4848 6060 7272 8484 9696 108108120120 132132144144156156Time to death (weeks)Time to death (weeks)
Probability of death (%)Probability of death (%)
FSC 12.6%FSC 12.6%Placebo 15.2%Placebo 15.2%
HR 0.825, p=0.052HR 0.825, p=0.05217.5% risk reduction17.5% risk reduction
2.6% 2.6% absolute reductionabsolute reduction
Calverley et al, NEJM, 2007Calverley et al, NEJM, 2007
Caratteristiche della TEP in BPCO
1.1. Nearly 30% of all exacerbations of COPD do not have a clear Nearly 30% of all exacerbations of COPD do not have a clear etiologyetiology
2.2. COPD patients are at a high risk for PE due to a variety of COPD patients are at a high risk for PE due to a variety of factors including limited mobility, factors including limited mobility, inflammation, and inflammation, and comorbiditiescomorbidities
3.3. Overall, the prevalence of PE was 19.9% (95% confidence Overall, the prevalence of PE was 19.9% (95% confidence interval [CI], 6.7 to 33.0%; p 0.014).interval [CI], 6.7 to 33.0%; p 0.014).
4.4. In hospitalized patients, the prevalence was higher at 24.7% In hospitalized patients, the prevalence was higher at 24.7% (95% CI, 17.9 to 31.4%; p 0.001) than those who were (95% CI, 17.9 to 31.4%; p 0.001) than those who were evaluated in the emergency department (3.3%)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.
Polosa et al: Haematologica , 2008
IL-6: surrogate marker of inflammation
vWF:Ag (von Willebrand Factor antigen): endotheliumactivation F1+2 (prothrombin fragment 1+2 ): clotting stimulation
D-Dimer : fibrinolyticactivation
Endothelial-coagulative activation during COPD exacerbations
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-COPDAE-COPD
typicaltypicalatypicalatypical
TREATMENTTREATMENT
improvementimprovement
no improvementno improvement
Pre test probability for PEPre test probability for PE
HIGHHIGHINTERMEDIATEINTERMEDIATELOWLOW
creatininecreatinine
>1.>1.55
<1.<1.55
SPIRAL CTSPIRAL CT
D-dimerD-dimer
NEGNEG
PE excludedPE excluded
POSPOS
PE confirmedPE confirmed
POSPOS
Doppler USDoppler US
V/Q scanV/Q scan
Kenneth E WoodKenneth E Wood International Journal of COPD 2008:3(2) 277–284 International Journal of COPD 2008:3(2) 277–284
• 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 I
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
DISSEZIONEAORTICA