systemic inflammation leading to comorbidities associated with copd leonardo m. fabbri

SYSTEMIC INFLAMMATION LEADING TO SYSTEMIC INFLAMMATION LEADING TO COMORBIDITIES ASSOCIATED WITH COPDCOMORBIDITIES ASSOCIATED WITH COPD

Leonardo M. Fabbri

Comorbidities and systemic effects of COPD

Cardiovascular diseases in COPD

COPD in Chronic Heart Failure

Cardiovascular drugs in COPD

CHRONIC DISEASE IN THE ELDERLY:

Back to the Future of Internal Medicine

LM Fabbri and R Ferrari, Breathe, 2006, in press

Two or more chronic diseases almost invariably develop together in the same patient, particularly in the elderly, often making it difficult to

establish a proper diagnosis and assessment of severity

Patient-oriented approach that takes into account the several coexisting components of chronic disease is required

This “change of concept” implies the need for medical specialists to extend their expertise to broader diagnostic and treatment

approaches that are traditionally the purview of internal medicine

Leading Causes of Death in U.S.

#1. MI#2. CA#3. CVA#4. COPD

Cigarette Related DiseasesLeading Causes of

Death Worldwide 2010

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

GOLD 3/4

GOLD 2

Restricted

Normal

COPD ASCVD Lung Cancer Other

What do COPD Patients Die From?

Mannino D.M., Mannino D.M., et al. et al. Respiratory Medicine 2006; 100:115Respiratory Medicine 2006; 100:115

Chronic diseases represent a huge proportion of human illness

58 million deaths in 2005:

Cardiovascular disease 30%

Cancer 13%

chronic respiratory diseases 7%

Diabetes 2%

Horton R. Lancet, 2006

COPD AS A SYSTEMIC DISEASECOPD AS A SYSTEMIC DISEASECOPD A COMPONENT OF THE CHRONIC DISEASECOPD A COMPONENT OF THE CHRONIC DISEASE

COPD A SYSTEMIC DISEASE

•Systemic inflammation•Cachexia

•Skeletal muscle wasting•Osteoporosis

COPD A COMORBIDITY OFChronic heart failure

Coronary and peripheral arterial diseasesLung cancer

Metabolic syndrome

?

=

?

?

Inhaled particles:pulmonary and heart co-morbidity






Leonardo M. Fabbri

Cardiovascular mortality in Cardiovascular mortality in COPDCOPD

For every 10% decrease in FEVFor every 10% decrease in FEV11, ,

cardiovascular mortality increases by cardiovascular mortality increases by approximately 28% and non-fatal coronary approximately 28% and non-fatal coronary event increases by approximately 20% in event increases by approximately 20% in

mild to moderate COPD.mild to moderate COPD.

Anthonisen et al, Am J Respir Crit Care Med 2002Anthonisen et al, Am J Respir Crit Care Med 2002

Curkendall et al. Ann Epidemiol

2006;16:63–70.

COPD

CAUSES OF HOSPITAL ADMISSION

CAUSES OF DEATH

Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease with Tiotropium, a Once-Daily

Inhaled Anticholinergic Bronchodilator

Niewoehner,et al, Ann Intern Med. 2005;143:317-326

COEXISTING ILLNESSES

Vascular (including hypertension) 64%Cardiac 38%

Gastrointestinal 48%Musculoskeletal or connective tissue 46%

Metabolic or nutritional 47%Reproductive or urinary 27%

Neurologic 22%

Coronary Artery Calcification in Older Adults

Newman AB et al Circulation 2001

Occurrence and Prognostic Significance of Ventricular Arrhythmia Is Related to Pulmonary Function

Engstrom G et al Circulation 2001

402 men, 68 yrs old – 14 yrs follow-up

Carotid Plaque, Intima Media Thickness, Cardiovascular Risk Factors, and Prevalent Cardiovascular Disease in Men and Women

65.4 %

59.2%

50.4%

Perc

en

tuale

di sog

gett

i (m

asch

i) c

on

u

na p

lacca c

aro

tid

ea

50%

FEV1 terzilies

800 soggetti, età media 66 anni

Ebrahim S et al Stroke 1999

FEV1 e risk of stroke:the Copenhagen Stroke Study

≥100% 90-99% 80-89% 70-79% 60-69% 50-59% <50%

Percentuale FEV1 rispetto al previsto

Ris

ch

io R

ela

tivo

4

2

1.5

0.5

1

RR per maschi e femmine RR per maschi RR per femmine

Truelsen T et al Int J Epidemiol 2001

PULMONARY EMBOLISM IN PATIENTS WITH UNEXPLAINED EXACERBATION OF CHRONIC

OBSTRUCTIVE PULMONARY DISEASE: PREVALENCE AND RISK FACTORS

Tillie-Leblond et al, Ann Intern Med. 2006;144:390-396.

25% pulmonary embolism in patientswith COPD hospitalized for severe

exacerbation of unknown origin

Previous TEP, malignancy, low PaCO2

Cardiovascular morbidity in Cardiovascular morbidity in COPDCOPD

0

1

2

3

4

5

6

7

8

High CRPHigh CRP Severe Severe obstructionobstruction

High CRP High CRP and severe and severe obstructionobstruction

Car

dia

c in

farc

tio

n in

jury

sco

reC

ard

iac

infa

rcti

on

inju

ry s

core

P=0,001P=0,001

Sin and Man, Circulation 2003Sin and Man, Circulation 2003

Inflammation, atherosclerosis and coronary artery disease Inflammation, atherosclerosis and coronary artery disease Hansson GK, N Engl J Med. 2005;352(16):1685-95Hansson GK, N Engl J Med. 2005;352(16):1685-95

Activation of a type 1 immune response in atheroma formationActivation of a type 1 immune response in atheroma formation

Cross-sectional study, patients 65 years of age

Of 405 participating patients with a diagnosis of chronic obstructive pulmonary disease, 83 (20.5%, 95% CI 16.7–24.8) had previously unrecognized heart failure

RECOGNISING HEART FAILURE IN ELDERLY PATIENTS WITH STABLE CHRONIC OBSTRUCTIVE PULMONARY

DISEASE IN PRIMARY CARE

F H Rutten et al, BMJ 2005, Dec;331(4):1379-81

A limited number of items easilyavailable from history and physical examination,withaddition of NT-proBNP and electrocardiography, can

help general practitioners to identify concomitantheart failure in individual patients with stable COPD

Peptidi natriuretici come marker dello scompenso cardiaco cronico

ANP

Cuore normaleCuore normale Cuore scompensatoCuore scompensato

ANP

BNP

ANPANPPeptide natriuretico atrialePeptide natriuretico atriale

BNP

Peptidi natriureticiPeptidi natriuretici

BNPBNPPeptide natriuretico cerebralePeptide natriuretico cerebrale

Breathing Not Properly Multinational Study

McCullough et al. Circ 2002

1586 participants who presented with acute dyspnea

1538 (97%) had clinical certainty of CHF determined by the attending physician in the emergency department

Participants underwent routine care and had BNP measured in a blinded fashion

~ 37 % COPD comorbidity

Breathing Not Properly (BNP) Multinational Study

McCullough et al. Circ 2002

Utility of BNP in Differentiating Heart Failure from Lung Disease in Patients Presenting

with Dyspnea

Morrison et al. JACC 2002






Leonardo M. Fabbri

Primary Endpoint: All-Cause MortalitySecondary Endpoints: CV Death, MI, or HFOther Endpoints: Safety and Tolerability

Captopril 50 mg tid(n = 4909)

Valsartan 160 mg bid(n = 4909)

Captopril 50 mg tid + Valsartan 80 mg bid

(n = 4885)

Acute MI (0.5–10 days)—SAVE, AIRE or TRACE eligible(either clinical/radiologic signs of HF or LV systolic dysfunction)

Major Exclusion Criteria:— BP 100 mm Hg— Serum creatinine 2.5 mg/dL— Prior intolerance of an ARB or ACEI— Nonconsent

double-blind active-controlled

median duration: 24.7 monthsevent-driven

VALIANT Trial:Prevalence of COPD

• 14703 patients included in the trial

• 1258 clinical diagnosis of COPD (8.6%)

Valsartan Heart Failure Trial

Study Design

J. N. Cohn et. al, J. Card. Fail. 1999; 5: 155-160

HF patients 18 yr; NYHA II–IV

LVIDD> 2.9 cm/m² BSA; EF<40%

Valsartan40 mg bid titrated

to160 mg bid

906 deaths (events reported)

Randomized to

Receiving Standard Therapyincluding ACE inhibitors , diuretics digoxin , -blockers

Placebo

Val-HeFT Trial:Prevalence of COPD

• 5010 patients included in the trial

• 628 clinical disgnosis of COPD (12.5%)

0

5

10

15

20

25

30

Mortalità totale Ospedal per HF

No COPD COPD

Val-HeFT TrialClinical events at 2 year follow-up

<0.0001 <0.0001P value

Mortality Hospitalization

Contributors to exercise intolerance in

COPD and CHF

Gosker et al. AJCN 1999






Leonardo M. Fabbri

METHODS

Case-control study of two population-based retrospective cohorts

1) COPD patients having undergone coronary revascularization (high CV risk cohort)

2) COPD patients without previous myocardial infarction (MI) and newly treated with nonsteroidal anti-inflammatory drugs (low CV

risk cohort)

Outcomes: COPD hospitalization, MI, and total mortality

Mancini GB, et al. J Am Coll Cardiol. 2006 Jun 20;47(12):2554-60Mancini GB, et al. J Am Coll Cardiol. 2006 Jun 20;47(12):2554-60

REDUCTION OF MORBIDITY AND MORTALITY BY STATINS, ANGIOTENSIN-REDUCTION OF MORBIDITY AND MORTALITY BY STATINS, ANGIOTENSIN-CONVERTING ENZYME INHIBITORS, AND ANGIOTENSIN RECEPTOR CONVERTING ENZYME INHIBITORS, AND ANGIOTENSIN RECEPTOR

BLOCKERS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY BLOCKERS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASEDISEASE

These drugs reduced both CV and pulmonary outcomes

Largest benefits with statins combined with ACEin or ARBs

This combination reduces COPD hospitalization and mortality in the high and low CV risk cohort

The combination also reduced MI in the high CV risk cohort

Benefits were similar when steroid users were included


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 PATIENTS WITH ANGIOTENSIN RECEPTOR BLOCKERS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASECHRONIC OBSTRUCTIVE PULMONARY DISEASE

These agents may have dual cardiopulmonary These agents may have dual cardiopulmonary protective properties, thereby substantially protective properties, thereby substantially altering prognosis of patients with COPDaltering prognosis of patients with COPD

These findings need confirmation in randomized These findings need confirmation in randomized clinical trialsclinical trials







Leonardo M. Fabbri

systemic inflammation leading to comorbidities associated with copd leonardo m. fabbri

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