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

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fre

qu

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cy

of

ca

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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