SYSTEMIC INFLAMMATION LEADING TO

COMORBIDITIES 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
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

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

Leading Causes of
Death in U.S.

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

Cigarette Related Diseases

Leading Causes of
Death Worldwide 2010

What do COPD Patients Die From?

Mannino D.M., et al. Respiratory 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 DISEASE

COPD A COMPONENT OF THE CHRONIC DISEASE
COPD A SYSTEMIC DISEASE
Systemic inflammation
Cachexia
Skeletal muscle wasting
Osteoporosis
COPD A COMORBIDITY OF
Chronic heart failure
Coronary and peripheral arterial diseases
Lung cancer
Metabolic syndrome

Inhaled particles:
pulmonary and heart co-morbidity

SYSTEMIC INFLAMMATION LEADING TO

COMORBIDITIES 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

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

COPD
CAUSES OF HOSPITAL ADMISSION

CAUSES OF DEATH

Curkendall et al. Ann Epidemiol

Prevention of Exacerbations of Chronic Obstructive

Pulmonary Disease with Tiotropium, a Once-Daily
Inhaled Anticholinergic Bronchodilator

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

Coronary Artery Calcification in Older

Adults

Newman AB et al Circulation

Occurrence and Prognostic

Significance of Ventricular Arrhythmia
Is Related to Pulmonary Function
402 men, 68 yrs old 14 yrs follow-up

Engstrom G et al Circulation 2001

Percentuale di soggetti (maschi) con

una placca carotidea

Carotid Plaque, Intima Media Thickness,

Cardiovascular Risk Factors, and Prevalent
Cardiovascular Disease in Men and Women
800 soggetti, et media 66 anni

65.4 %

59.2%
50.4%
50%

FEV1 terzilies
Ebrahim S et al Stroke

FEV1 e risk of stroke:

the Copenhagen Stroke Study

Rischio Relativo

RR per maschi e femmine

RR per maschi

RR per femmine

2
1.5
1

0.5
100%

90-99%

80-89%

70-79%

60-69%

50-59%

<50%

Percentuale FEV1 rispetto al previsto

Truelsen T et al Int J Epidemiol

PULMONARY EMBOLISM IN PATIENTS WITH

UNEXPLAINED EXACERBATION OF CHRONIC
OBSTRUCTIVE PULMONARY DISEASE:
PREVALENCE AND RISK FACTORS

25% pulmonary embolism in patients

with COPD hospitalized for severe
exacerbation of unknown origin
Previous TEP, malignancy, low PaCO2
Tillie-Leblond et al, Ann Intern Med. 2006;144:390-396.

Cardiac infarction injury score

Cardiovascular morbidity in
COPD
P=0,001

High CRP

Severe
obstruction

High CRP
and severe
obstruction

Sin and Man, Circulation 2003

Inflammation, atherosclerosis and coronary artery disease

Hansson GK, N Engl J Med. 2005;352(16):1685-95

Activation 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 16.724.8)
had previously unrecognized heart failure

RECOGNISING HEART FAILURE IN ELDERLY PATIENTS

WITH STABLE CHRONIC OBSTRUCTIVE PULMONARY
DISEASE IN PRIMARY CARE

A limited number of items easily

available from history and physical examination,with
addition of NT-proBNP and electrocardiography, can
help general practitioners to identify concomitant
heart failure in individual patients with stable COPD

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

Peptidi natriuretici come marker

dello scompenso cardiaco cronico
Peptidi natriuretici

ANP

BNP

Peptide natriuretico atriale

Peptide natriuretico cerebrale

ANP
BNP

Cuore normale

ANP

BNP
Cuore scompensato

Breathing Not Properly Multinational Study

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

McCullough et al. Circ 2002

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

Utility of BNP in Differentiating Heart Failure from Lung

Disease in Patients Presenting
with Dyspnea

Morrison et al. JACC 2002

SYSTEMIC INFLAMMATION LEADING TO

COMORBIDITIES 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

Acute MI (0.510 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

Captopril 50 mg tid
(n = 4909)

Valsartan 160 mg bid

(n = 4909)

median duration: 24.7 months

event-driven
Primary Endpoint:
Secondary Endpoints:
Other Endpoints:

All-Cause Mortality
CV Death, MI, or HF
Safety and Tolerability

Captopril 50 mg tid +
Valsartan 80 mg bid
(n = 4885)

VALIANT Trial:
Prevalence of COPD
14703 patients included in the trial
1258 clinical diagnosis of COPD (8.6%)

Valsartan Heart Failure Trial

Study Design
HF patients 18 yr; NYHA IIIV
LVIDD> 2.9 cm/m BSA; EF<40%
Receiving Standard Therapy
including ACE inhibitors , diuretics
digoxin , -blockers

Randomized to

Valsartan
40 mg bid titrated
to160 mg bid

Placebo

906 deaths (events reported)

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

Val-HeFT Trial:
Prevalence of COPD
5010 patients included in the trial
628 clinical disgnosis of COPD (12.5%)

Val-HeFT Trial
Clinical events at 2 year follow-up

Mortality
P value

<0.0001

Hospitalization
<0.0001

Contributors to exercise intolerance in

COPD and CHF

Gosker et al. AJCN 1999

SYSTEMIC INFLAMMATION LEADING TO

COMORBIDITIES 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

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):2554-60

REDUCTION OF MORBIDITY AND MORTALITY BY STATINS, ANGIOTENSINCONVERTING ENZYME INHIBITORS, AND ANGIOTENSIN RECEPTOR
BLOCKERS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY
DISEASE

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

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

REDUCTION OF MORBIDITY AND MORTALITY BY STATINS,

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS, AND
ANGIOTENSIN RECEPTOR BLOCKERS IN PATIENTS WITH
CHRONIC OBSTRUCTIVE PULMONARY DISEASE

These agents may have dual cardiopulmonary

protective properties, thereby substantially
altering prognosis of patients with COPD
These findings need confirmation in randomized
clinical trials
Mancini GB, et al. J Am Coll Cardiol. 2006 Jun 20;47(12):2554-60

SYSTEMIC INFLAMMATION LEADING TO

COMORBIDITIES 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