CHEST Original Research

COPD

Cardiovascular Comorbidity in COPD

Systematic Literature Review
Hana Müllerova, PhD; Alvar Agusti, MD, PhD; Sebhat Erqou, MD, PhD;
and Douglas W. Mapel, MD, MPH, FCCP

Background: Cardiovascular disease (CVD) is common among patients with COPD. However, it
is not clear whether this is due to shared risk factors or if COPD increases the risk for CVD inde-
pendently. This study aimed to provide a systematic review of studies that investigated the asso-
ciation between COPD and CVD outcomes, assessing any effect of confounding by common risk
factors.
Methods: A search was conducted in MEDLINE (via PubMed) for observational studies published
between January 1990 and March 2012 reporting cardiovascular comorbidity in patients with
COPD (or vice versa).
Results: Of the 7,322 citations identified, 25 studies were relevant for this systematic review.
Twenty-two studies provided an estimate for CVD risk in COPD, whereas four studies provided
estimates of COPD risk in CVD. The crude prevalence for the aggregate CVD category ranged
from 28% to 70%, likely due to differences in populations studied and CVD definitions; unadjusted
rate ratio (RR) estimates of unspecified CVD among patients with COPD compared with patients
without COPD ranged from 2.1 to 5.0. The association between COPD and CVD persisted after
adjustment for shared risk factors in the majority of the studies. Two studies found a relationship
between the severity of airflow limitation and CVD risk. Increased RRs were observed for indi-
vidual CVD types, but their estimates varied considerably for congestive heart failure, coronary
heart disease, arrhythmias, stroke, arterial hypertension, and peripheral arterial disease.
Conclusions: Available observational data support the hypothesis that COPD is associated with an
increased risk of CVD. CHEST 2013; 144(4):1163–1178

Abbreviations: CHD 5 coronary heart disease; CHF 5 congestive heart failure; CVD 5 cardiovascular disease;
GOLD 5 Global Initiative for Chronic Obstructive Lung Disease; HR 5 hazard ratio; MI 5 myocardial infarction;
PAD 5 peripheral arterial disease; RR 5 rate ratio

COPD and cardiovascular disease (CVD) are lead-

ing causes of mortality globally. In 2005, COPD
and mortality in patients with COPD.2-7 For example,
Sidney et al7 reported a more than twofold increased
and CVD caused an estimated 120,000 and 830,000 risk for CVD-related hospitalization and CVD-related
deaths, respectively, in the United States.1 Clinicians mortality in patients with COPD compared with those
have long recognized that there is a very high preva- without COPD.
lence of CVD among patients with COPD, and, The observed association between COPD and CVD
indeed, CVD is the major contributor to morbidity may be explained, at least in part, by shared risk fac-
tors such as smoking, age, sex, and inactivity. However,
Manuscript received November 21, 2012; revision accepted April 15, it is also thought that systemic inflammatory changes
2013.
Affiliations: From Worldwide Epidemiology (Dr Müllerova),
GlaxoSmithKline R&D, Uxbridge, England; Thorax Institute Correspondence to: Hana Müllerova, PhD, Worldwide Epide-
(Dr Agusti), Hospital Clinic, IDIBAPS, Universitat de Barcelona miology, GlaxoSmithKline R&D, Bldg 9, Iron Bridge Rd, Stockley
and FISIB, CIBER Enfermedades Respiratorias (CIBERES), Park W, Uxbridge, Middlesex, UB11 1BT, England; e-mail:
Mallorca, Spain; Weill Cornell Medical College (Dr Erqou), [email protected]
New York, NY; and Lovelace Clinic Foundation (Dr Mapel), © 2013 American College of Chest Physicians. Reproduction
Albuquerque, NM. of this article is prohibited without written permission from the
Funding/Support: This study was sponsored by GlaxoSmithKline American College of Chest Physicians. See online for more details.
plc [study code WEUSKOP4140]. DOI: 10.1378/chest.12-2847

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 related to COPD may increase the risk of CVD inde- or a reanalysis of clinical trials data where the study intervention
pendently.8 Additionally, pathophysiologic changes did not figure in the analysis. Second, the study had to report odds
or risk ratio estimates adjusted for at least one major risk factor
associated with COPD can directly impact heart func- (eg, smoking, age, sex) for COPD and report at least one of the
tion; for instance, emphysema and lung hyperinflation following cardiovascular outcomes of interest in relation to COPD:
may impair left ventricular filling and lower cardiac (1) CVD unspecified or aggregate (not otherwise specified, but
output or cause pulmonary hypertension and right- referring to at least one of the following: CHD, arrhythmia, heart
sided heart failure.9 failure, and arterial hypertension); (2) CHD, including coronary
stenosis, myocardial infarction (MI), coronary revascularization
Studying the association between COPD and CVD (coronary angioplasty or coronary artery bypass graft), angina,
is deemed important because the coexistence of COPD or coronary atherosclerosis; (3) arrhythmia (any type, including
and CVD may have implications for the management unspecified arrhythmias, irregular heart rhythm, atrial tachycardia
of these patients. For example, systemic b-blockers or fibrillation or flutter, ventricular tachycardia or fibrillation, or
that are very commonly used in CVD were at one time conduction disorders); (4) CHF; (5) arterial hypertension; (6) PAD;
and (7) stroke. Studies were considered if COPD was reported to
considered to be strictly contraindicated in COPD, but have been diagnosed by spirometry or by the physician. Studies
studies suggest that cardioselective b-blockers are were further classified by their source as (1) health-care database
safe and effective for most patients with COPD.10,11 (eg, insurance claims, electronic medical record data) or (2) cohorts
Understanding the association between the two dis- collected as a part of chart review, survey, or patient registry.
ease entities may enable improved CVD risk prediction Based on these selection criteria, a final list of 25 studies was
derived. The retrieval and selection of papers was conducted by
in patients with COPD by identifying those individ- two of the authors (S. E. for the period 1990-2009; H. M. for the
uals at higher risk of CVD morbidity and mortality. period 2009-2012). One of the authors (H. M.) repeated the search
Finally, increasing our knowledge of an interaction process for the period 1990 to 1994, and no additional relevant
between COPD and CVD may provide an opportu- papers were found.
nity to develop targeted therapies for the subset of
patients with CVD and COPD as the nature of inflam- Data Analyses
mation may be the same. The purpose of this report is Association measures, that is, ORs, rate ratios (RRs), and hazard
to provide a systematic review of the available literature ratios (HRs), were abstracted overall and, where available, within
on the association between COPD and various CVD subgroups. For adjusted estimates, information on adjustment vari-
ables was obtained. Due to the presence of substantial heteroge-
outcomes, including coronary heart disease (CHD), neity across the studies (design, population, and outcome definition),
congestive heart failure (CHF), arrhythmias, stroke, formal meta-analysis was not performed. Instead, the results were
arterial hypertension, and peripheral arterial disease qualitatively described and compared. Tabular and graphic pre-
(PAD). sentations are used to assist in interpretation of data.

Materials and Methods Results

Data Sources and Searches In total, 25 studies were included in the current
analysis; 22 studies provided an estimate for CVD risk
An electronic literature search was conducted via PubMed in COPD, whereas four studies provided estimates of
(which comprises citations from MEDLINE, life science journals,
and online books) for observational studies published between COPD risk in CVD (Table 1). Twelve studies used a
January 1990 and March 2012 reporting on CVD in patients with cohort design, seven studies used nested case-control
COPD or vice versa. Key terms used included medical subject head- approach, and eight studies were cross-sectional. In
ings and free texts related to CVD and its types (ie, coronary artery the prospective studies, the duration of follow-up ranged
disease, myocardial infarction, heart failure, arrhythmia, and hyper- from 1 to 27 years. The average age of participants
tension), and to COPD (specifically “Pulmonary disease, Chronic
Obstructive,” COPD, emphysema, and “chronic obstructive”). ranged between 55 and 78 years. The percentage of
The full list of search terms used is provided in e-Appendix 1. male patients in the studies ranged between 45%
Searches were not restricted to the English language. The PubMed and 96%.
search was supplemented by manual screening of the reference
lists of review articles. Unspecified CVD
Study Selection The prevalence of unspecified CVD among patients
PubMed searches identified 7,322 publications that were screened with COPD ranged from 28% to 70% (Table 2,
for relevance based on titles and abstracts. Of these, 257 poten- Fig 2).4,18,19 Crude relative risk for CVD among patients
tially relevant publications were selected for closer review using with COPD was from 2.1 to 5.04,18 whereas the adjusted
their full text and/or abstracts. In all, 119 publications were estimates was from 1.6 to 2.7.4,18,19 Two studies, using
excluded because they lacked relevant data, had low sample size a similar data source, reported that the RR for CVD
(N , 100), or were reviews (Fig 1).
For the remaining 138 studies that were fully abstracted, we increased with increasing severity of airflow limita-
used two major selection criteria. First, the study had to be obser- tion.23,26 Johnston et al23 reported that the adjusted
vational with a prospective, retrospective, or cross-sectional design, HR for incident CVD increased from 1.1 (95% CI,

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 Figure 1. Study flow diagram.

0.9-1.3) in patients with GOLD (Global Initiative for after adjustment for potential confounders (Fig 3).
Chronic Obstructive Lung Disease) grade I to 1.5 The adjusted RR for hospitalizations due to CHF in
(95% CI, 1.1-2.0) in patients with GOLD grade III/IV patients with COPD vs matched cohorts without COPD
(airflow limitation) as compared with patients without ranged from 1.2 to 3.8.4,5,7,13 Two studies reported an
COPD (N 5 8,193). Similarly, Mannino et al26 reported increased risk of COPD in patients with CHF with
an increasing risk for prevalent CVD ranging from a adjusted ORs of 2.4 and 2.1 compared with patients
RR of 1.7 (95% CI, 1.5-1.9) in GOLD grade I to without CHF.20,32
2.4 (95% CI 1.9-3.0) in GOLD grade III/IV, respec-
tively. In contrast, a third study28 in a small cohort Coronary Heart Disease
(N 5 100) of patients with COPD failed to demon-
The prevalence of CHD (a term that includes MI,
strate an association of prevalent CVD with the level
angina, coronary artery disease, and ischemic heart dis-
of airflow limitation (Fig 2).
ease) ranged between 4.7% and 60% among patients
The four studies reporting CVD hospitalization
with COPD (Table 2)4,17,19,22,24,27,29; one study reported
rates demonstrated that patients with COPD were at
an incidence of acute MI in patients with COPD as
increased risk for hospitalization due to CVD com-
6.3 per 1,000 person-years.21 The adjusted RR for
pared with matched cohorts of individuals without
CHD ranged from 0.7 to 6.8 (Table 2).4,17,19,21,22,24,27,29,31
COPD, with the RR ranging from 1.1 (95% CI, 0.9-1.3)
Five of nine studies reported a statistically significant
to 2.2 (95% CI, 2.0-2.3).4,5,7,30 Overall, the associations
positive association of increased CVD occurrence in
between CVD and COPD remained statistically sig-
COPD.4,19,24,27,31
nificant in eight of the 10 studies after adjustment for
Three studies explored an association between CHD
potential confounders (Table 2, Fig 2).
and COPD severity15,25,31; two studies reported a numer-
ically increased risk of CHD with increasing level of
Congestive Heart Failure
airflow limitation, one study reported a statistically
The prevalence of CHF in patients with COPD significant association after adjustment for common
ranged between 7.1% and 31.3%4,19,20,21,27; one study risk factors between incident MI and COPD treatment
reported an annual incidence of 3.7%27 (Table 2). intensity used as a surrogate for disease severity, from
The adjusted RR of prevalent CHF in individuals with an OR of 1.8 (95% CI, 1.1-2.9) for mild to an OR of
COPD compared with those without COPD ranged 3.0 (95% CI, 1.5-5.9) for severe disease.31 The risk for
from 1.8 to 3.9; all associations remained significant hospitalization due to CHD in patients with COPD

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 1166
Table 1—Summary of the Studies Assessing the Association Between CVD Comorbidities and COPD Controlled for Common Risk Factors That Were Included
in the Review

Study/Year Patients With Patients Without Comorbidity

(Country, Study Period) Method, Population Source COPD, No. COPD, No. Male Patients, % COPD Ascertainment Comorbidity Assessed Assessment/Main Outcome
Allen et al12/ 2010 Cohort, claims data 169,328 726,588 57 ICD-9 Recurrent stroke 1. ICD-9
(USA, 2000-2002) 2. Hospitalization episodes
Chen et al13/2009 Cohort, hospital episodes 108,726 0 55 ICD-9 Arrhythmia, IHD, CHF 1. ICD-9
(Canada, 1999-2000) database 2. Hospitalization episodes
Cordero et al14/2011 Cross-sectional, registry 1,440 9,303 50 Medical record COPD Medical record
(Spain, 2009)c
Curkendall et al4/ 2006 NCC, claims data 11,493 22,986 54 ICD-9 and Rx AMI, unspecified CVD, 1. ICD-9
(Canada, 1998-2001) AP, arrhythmia, 2. Period prevalence, and
CHF, stroke hospitalization episodes
de Lucas-Ramos et al15/2008 CCS, cohort 527 0 85 Medical record IHD 1. Medical record
(Spain, NS) 2. Prevalence
Dziewierz et al16/2010 Cohort, patient registry 111 890 54 Medical record Arrhythmia 1. Predefined clinical
(Poland, 2005-2008) criteria
2. Incidence
Enriquez et al17/2011 Retrospective cohort 860 10,048 65 Medical record MI Medical record
(USA, 1999-2006)
Feary et al18/2010 CCS, cohort 29,870 1,174,240 51 Medical record CVD unspecified stroke Medial record
(UK, 2005) (subarachnoid and
intracranial hemorrhage
and TIA)
Finkelstein et al19/2009 NCC, CCS 2,975 2,975 46 Self report, AMI, AP, arrhythmia, 1. Self report
(USA, 2002) smoking, age unspecified CVD, 2. Prevalence
CHF, IHD,
PAD, stroke
García Rodriguez et al20/ 2009c NCC, primary care 1,927 16,546 53 Medical record CHF, HTN 1. Medical record
(UK, 1996) EMR database and Rx 2. Incidence
García Rodriguez et al21/2010 NCC, Primary care 1,927 16,108 NS Medical record AMI, CHF 1. Medical record

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(UK, 1996-2001) EMR database and Rx 2. Incidence
Huiart et al5/2005 Cohort, claims data 5,648 NS 54 Rx and age AMI, unspecified CVD, 1. ICD-9
(Canada, 1990-1997) cerebrovascular 2. Hospitalization episodes
disease, CHF, IHD
Izquierdo et al22/2010 Case-control analysis of 70 234 84 GOLD criteria COPD Spirometry
(Spain)c hospital-based cohort
Johnston et al23/2008 Cohort, general 3,262 8,193 45 GOLD modified Unspecified CVD 1. Predefined clinical
(USA, 1986-2001) population based criteria
2. Incidence
Konecny et al24/2010 Retrospective cohort 2,001 12,345 70 Medical record AMI Medical record
(USA, 1995-2008)
(Continued)

Original Research
 limitation25 (OR 0.4 [95% CI, 0.2-1.1] for GOLD
grade I to OR of 1.7 [95% CI, 0.8-3.8] for GOLD
grades III/IV), although the risk estimates were not
significant. The adjusted RR for hospitalizations due
to arrhythmia ranged from 1.02 to 2.8 in patients
with COPD vs matched cohorts without COPD
(Table 2).4,7,13

Stroke
The prevalence of stroke in patients with COPD
was from 6.9% to 9.9% (Table 2).4,18,19,31 The adjusted
RR for stroke ranged from 1.0 to 1.6; it was statisti-
cally significant in three of five studies (Fig 4).4,12,18,19,31
One study reported an increased RR trend by increas-
ing grade of airflow limitation from RR of 0.6 (95% CI,
0.3-1.1) for patients with GOLD grade I, RR of 1.7
(95% CI, 1.1-2.5) for patients with GOLD grade II, to

Figure 2. Forest plot of studies assessing a relationship between

cardiovascular disease (unspecified) and COPD (adjusted risk
estimates). A, Risk estimates for hospitalization events inci-
dence. B, Disease diagnosis incidence. C, Disease diagnosis
prevalence.4,5,7,18,19,23,26,28,30 a 5 age; g 5 sex; h 5 past history of car-
diovascular disease; RR5 relative risk (includes odds, rate, and
hazard ratio estimates); s 5 smoking.

vs the matched cohorts without COPD ranged from

1.0 to 1.5; none of the associations was statistically
significant (Table 2).4,7,13

Arrhythmias
Nine studies explored a risk of arrhythmia (a term
that includes unspecified arrhythmias, irregular heart
rhythm, atrial tachycardia or fibrillation or flutter,
ventricular tachycardia or fibrillation, or conduction
disorders) in patients with COPD (Table 2). The prev-
alence of various types of arrhythmia among patients
with COPD was from 0.3% to 29%.4,19,27,31 The adjusted
RR for arrhythmia ranged from 1.2 to 5.6 with four of Figure 3. Forest plot of studies assessing a relationship between
five studies reporting statistically significant risk esti- congestive heart failure and COPD (adjusted risk estimates).
A, Risk estimates for hospitalization events incidence. B, Disease
mates.4,16,19,27,31 One study reported increased risk for diagnosis incidence. C, Disease diagnosis prevalence.4,7,13,19,20,21,27
arrhythmia with increasing GOLD grade of airflow See Figure 2 legend for expansion of abbreviations.

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 Table 2—Rate and Relative Risk Estimates of CVD in COPD or COPD in CVD Before and After Adjustment for Covariates in Studies Providing Incidence or

1168
Prevalence Estimates of CVD or COPD, and Incidence of Hospital Admission Due to CVD or COPD

Crude Rate in
Patients With Patients Without COPD Population Patients With Crude Risk Maximally Adjusted
Study/Year COPD, No. COPD, No. Grading COPD, % Estimate (95% CI) Multivariate Model (Covariates)a Risk Estimate (95% CI)
CV Unspecified
Curkendall et al4/2006 11,493 22,986 NS 70.4 2.09 (1.99-2.20) OR of CVD in COPD (a,g,h) 1.71 (1.61-1.81)
Feary et al18/2010 29,870 1,174,240 NS 28.0 OR 4.98 (4.85-5.81) OR of having COPD and Aged 65-74 y: never
(UK, 2005) previous diagnosis of CVD; smokers: 2.2 (1.9-2.5);
multiple estimates stratified exsmokers: 1.7 (1.6-1.9),
by age and smoking status, current smokers:
only age group 65-74 y 1.6 (1.5-1.7)
listed, (a, h, s)
Finkelstein et al19/2009 2,975 2,975 NS 56.5 NS HR of CVD in COPD 2.5 (2.1-3.1)
OR of CVD in COPD (a,g,h,s) 2.7 (2.3-3.2)
Johnston et al23/2008 3,262 8,193 GOLD I 1.0 1.4 (1.2-1.7) OR of CVD in COPD (a,g,h,s) 1.1 (0.9-1.3)
GOLD II 1.7 2.4 (2.1-2.7) 1.2 (1.03-1.4)
GOLD III/IV 2.0 2.9 (2.2-3.9) 1.5 (1.1-2.0)
Mannino et al26/2008 5,498 7,419 GOLD I 18.7 NS OR of CVD in COPD (a,g,s) 1.7 (1.5-1.9)
GOLD II 19.4 2.2 (1.9-2.5)
GOLD III/IV 22.1 2.4 (1.9-3.0)
Methvin et al28/2009 100 ⵑ400 GOLD I 33.7 NS OR of heart disease in 1.4 (0.5-4.0
GOLD II 30.3 COPD (a,g,s) 1.1 (0.5-2.7)
GOLD III/IV 41.3 1.5 (0.4-4.9)
Curkendall et al4/2006 11,493 22,986 NS 11 2.45 (2.27-2.65) RR of incident CVD 2.17 (2.00-2.33)
hospitalization in
COPD (a,g,h)
Huiart et al5/2005 5,648 NS NS 18.4 NS RR of CVD hospitalizations 1.89 (1.83-1.94)
in COPD (a,g)
Sidney et al7/2005 45,966 45,966 NS 6.4 2.33 (2.24-2.42) RR of CVD hospitalizations 1.96 (1.88-2.05)
in COPD (a,g,h)
Staszewsky et al30/2007 628 4,382 NS NS NS HR of CVD hospitalization 1.08 (0.90-1.29)

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in COPD (a,g,h)
CHF
Curkendall et al4/2006 11,493 22,986 NS 31.3 5.21 (4.86-5.58) OR of CHF in COPD (a,g,h) 3.84 (3.56-4.14)
Finkelstein et al19/2009 2,975 2,975 NS 11.4 NS OR of CHF in COPD (a,g,h,s) 3.9 (2.8-5.5)
García Rodriguez et al20/2009 1,927 16,546 NS 7.1 NS OR of COPD in CHF (a,g,h,s) 2.38 (2.00-2.82)
García Rodriguez et al21/2010 1,927 16,108 NS NS NS OR of CHF in COPD (a,g,h,s) 2.54 (2.02-3.19)
Mapel et al27/2005 791,466 outpatients 35,839,862 outpatients Outpatients NS OR and RR of CHF
Prevalence 14.1 in COPD (a,g) 7.94 (7.56, 8.35)
Incidence 4.6 5.94 (5.50, 6.42)
70,679 inpatients 308,275 inpatients Inpatients
Prevalence 24.5 1.81 (1.77-1.85)
Incidence 3.7 1.46 (1.38-1.53)

(Continued)

Original Research
 Table 2—Continued

Crude Rate in
Patients With Patients Without COPD Population Patients With Crude Risk Maximally Adjusted
Study/Year COPD, No. COPD, No. Grading COPD, % Estimate (95% CI) Multivariate Model (Covariates)a Risk Estimate (95% CI)
Chen et al13/2009 108,726 0 NS 19.3 NS HR of COPD readmissions 1.20 (1.17-1.23)
in COPD patients with
and without CHF (a,g)

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Curkendall et al4/2006 11,493 22,986 NS 3.2 5.24 (4.42-6.20) RR of incident CHF 3.45 (2.78-4.17)
hospitalization in
COPD (a,g,h)
Huiart et al5/2005 5,648 NS NS 18.4 NS RR of CHF hospitalizations 1.89 (1.83-1.94)
in COPD (a,g)
Sidney et al7/2005 45,966 45,966 NS 1.8 5.55 (4.71-5.73) RR of CHF hospitalizations 3.75 (3.39, 4.15)
in COPD (a,g,h)
Tseng32/2011 514 2,178 NS 19% COPD OR for CHF hospitalization 2.1 (1.9-2.4)
in CHF risk associated with
COPD (a,g,h)
Coronary heart disease
Curkendall et al4/2006 11,493 22,986 NS 5.6 1.83 (1.64-2.05) OR of CHD in COPD (a,g,h) 1.61 (1.43-1.81)
de Lucas-Ramos et al15//2008 527 0 GOLD I 13.3 Reference OR of CHD in COPD (a,g,h,s) Reference
GOLD II 18.1 1.43 (0.31-6.56) 3.29 (0.38-28.18)
GOLD III 16.9 1.32 (0.28-6.24) 2.84 (0.32-25.09)
GOLD IV 12.2 0.9 (0.16-5.24) 2.65 (0.25-28.56)
Enriquez et al17/2011 860 10,048 NS Rate at NS 1-y HR of CHD event (a,h) 0.96 (0.70-1.30)
1 y: 5.9
Finkelstein et al19/2009 2,975 2,975 NS 16.1 NS OR of CHD in COPD (a,g,h,s) 2.0 (1.5-2.5)
García Rodriguez et al21/2010 1,927 16,108 NS 0.63 NS OR incident AMI in COPD 0.93 (0.62-1.39)
Izquierdo et al22/2010 70 234 NS 24% COPD 1.19 (0.67-2.13) OR for COPD in patients 1.14 (0.57-2.29)
in cases and with and without IHD (a,g,s)
21% COPD
in control

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subjects
Konecny et al24/2010 2,001 12,345 NS 61 NS OR for occurrence of 1.30 (1.14-1.47)
incident MI (a,g,s)
Lange et al25/2010 1,036 4,854 GOLD I 1.5 NS OR of CHD in COPD (a,g) 0.3 (0.1, 0.8)
GOLD II 5.4 1.3 (0.8, 1.9)
GOLD III/IV 6.8 1.4 (0.7-2.8)
Mapel et al27/2005 791,466 outpatients 35,839,862 outpatients Outpatients NS OR and RR of CHD
Prevalence 6.7 in COPD (a,g) 6.75 (5.77-7.90)
Incidence 0.7 5.31 (4.54-6.21)
70,679 inpatients 308,275 inpatients Inpatients
Prevalence 4.7 1.06 (1.02-1.11)

CHEST / 144 / 4 / OCTOBER 2013

Incidence 1.4 1.28 (1.18-1.38)
(Continued)

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 1170
Table 2—Continued

Crude Rate in
Patients With Patients Without COPD Population Patients With Crude Risk Maximally Adjusted
Study/Year COPD, No. COPD, No. Grading COPD, % Estimate (95% CI) Multivariate Model (Covariates)a Risk Estimate (95% CI)
Schneider et al31/2010 35,772 35,772 Any COPD NS NS OR of CHD in COPD (a,g,h,s) 1.40 (1.13, 1.73)
Mild 1.79 (1.12, 2.86)
Moderate 1.30 (1.04, 1.62)
Severe 3.00 (1.53, 5.86)
Chen et al13/2009 108,726 0 NS NS NS HR of COPD readmissions 1.02 (0.99, 1.04)
in COPD patients with
and without CHD (a,g)
Curkendall et al4/2006 (Canada, 11,493 22,986 NS 1.1 1.66 (1.34-2.05) RR of incident CHD 1.49 (0.71-3.13)
1998-2001) hospitalization in
COPD (a,g,h)
Sidney et al7/2005 45,966 45,966 NS 0.95 2.14 (1.95-2.36) RR of CHD hospitalizations 1.89 (1.71, 2.09)
in COPD (a,g,h)
Sode et al29/2011 313,958 7,105,833 NS 27.20 Before first COPD OR of AMI before first COPD Before first COPD
hospitalization: hospitalization (a,g) hospitalization:
1.53 (1.50-1.56); 1.47 (1.44-1.49);
after first COPD after first COPD
hospitalization hospitalization
0.64 (0.85-0.87) 0.74 (0.73-0.76)
Wang et al33/2007 4,568 Not stated NS NA NA OR of hospitalization for 1.38 (0.62-1.39)
CAD (a,g,h)
Arrhythmias
Curkendall et al4/2006 11,493 22,986 NS 21.1 2.09 (1.96-2.23) OR of arrhythmia in 1.76 (1.64-1.89)

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COPD (a,g,h)
Dziewierz et al16/2010 111 890 NS 29.2% with 3.46 (1.40-8.53) OR of incident atrial 3.22 (1.22-8.51)
new onset fibrillation in COPD (NS)
AF had
COPD
Finkelstein et al19/2009 2,975 2,975 NS 29.0 NS OR of arrhythmia in 2.4 (2.0-2.8)
COPD (a,g,h,s)
(Continued)

Original Research
 Table 2—Continued

Crude Rate in
Patients With Patients Without COPD Population Patients With Crude Risk Maximally Adjusted
Study/Year COPD, No. COPD, No. Grading COPD, % Estimate (95% CI) Multivariate Model (Covariates)a Risk Estimate (95% CI)
Lange et al25/2010 1,036 4,854 GOLD I 1.5 NS OR of arrhythmia in 0.4 (0.2-1.1)

journal.publications.chestnet.org
GOLD II 2.9 COPD (a,g) 1.0 (0.6-1.7)
GOLD III/IV 5.5 1.7 (0.8-3.8)
Mapel et al27/2005 791,466 outpatients 35,839,862 outpatients Outpatients NS OR and RR of AF in
Prevalence 6.4 COPD (a,g) 5.64 (5.29-6.01)
Incidence 2.05 4.74 (4.27-5.26)
Inpatients
Prevalence 14.3 1.37 (1.33-1.41)
Incidence 2.3 1.31 (1.23-1.39)
70,679 inpatients 308,275 inpatients Outpatients
Prevalence 0.29 OR and RR of VF 5.16 (3.88, 6.87)
Incidence 0.15 in COPD (a,g) 4.47 (3.08, 6.49)
Inpatients
Prevalence 1.6 1.38 (1.28, 1.49)
Incidence 0.48 1.35 (1.18, 1.55)
Schneider et al31/2010 35,772 35,772 Any COPD 7.2 1.42 (1.25-1.61) OR of arrhythmia 1.19 (0.98, 1.43)
Mild 1.42 (1.01-2.00) in COPD (a,g,h,s) 1.64 (1.14, 2.34)
Moderate 1.39 (1.22-1.59) 1.07 (0.86, 1.32)
Severe 2.10 (1.36-3.23) 1.29 (0.79, 2.11)
Chen et al13/2009 108,726 0 NS 15.9 NS HR of COPD readmissions 1.02 (1.00-1.06)
in COPD patients with
and without arrhythmia (a,g)
Curkendall et al4/2006 11,493 22,986 NS 1.6 2.01 (1.68-2.41) RR of incident CVD 1.67 (1.27-2.22)
hospitalization in
COPD (a,g,h)

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Sidney et al7/2005 45,966 45,966 NS 0.6 2.42 (2.13-2.76) RR of AF hospitalizations 1.98 (1.73, 2.25)
in COPD (a,g,h)
0.01 4.17 (2.83-6.16) RR of VF hospitalizations 2.80 (1.87-4.20)
in COPD (a,g,h)
Stroke
Allen et al12/2010 169,328 726,588 NS 24.9% of 1.00 (0.81-1.25) RR of recurrent stroke NS
recurrent in COPD (a,g,h)
stroke patients
had COPD
Curkendall et al4/2006 11,493 22,986 NS 9.6 1.24 (1.15-1.34) OR of stroke in COPD (a,g,h) 1.11 (1.02-1.21)

CHEST / 144 / 4 / OCTOBER 2013

(Continued)

1171
 1172
Table 2—Continued

Crude Rate in
Patients With Patients Without COPD Population Patients With Crude Risk Maximally Adjusted
Study/Year COPD, No. COPD, No. Grading COPD, % Estimate (95% CI) Multivariate Model (Covariates)a Risk Estimate (95% CI)
Feary et al18/2010 29,870 1,174,240 NS 9.9 OR 3.34 (3.21-3.48) OR of having COPD and Aged 65-74 y: never
previous diagnosis of stroke; smokers:
multiple estimates stratified 1.6 (1.2-2.0);
by age and smoking status, exsmokers:
only age group 65-74 y 1.1 (1.0-1.3);
listed, (a,h,s) current smokers:
1.2 (1.1-1.3)
Finkelstein et al19/2009 2,975 2,975 NS 8.0 NS OR of stroke in COPD (a,g,h,s) 1.5 (1.1-2.1)
Lange et al25/2010 1,036 4,854 GOLD I NS NS OR of stroke in COPD (a,g) 0.6 (0.3-1.1)
GOLD II 1.7 (1.1-2.5)
GOLD III/IV 1.5 (0.7-3.0)
Schneider et al31/2010 35,772 35,772 Any COPD 6.9 1.25 (1.05-1.49) OR of stroke in COPD (a,g,h,s) 1.13 (0.92-1.38)
Mild 1.28 (0.77-2.15) 1.22 (0.71-2.09)
Moderate 1.26 (1.05-1.51) 1.13 (0.92-1.38)
Severe 0.98 (0.47-2.05) 1.00 (0.47-2.15)
Curkendall et al4/2006 11,493 22,986 NS 1.2 1.27 (1.05-1.54) RR of incident stroke 1.23 (0.68-2.22)
hospitalization in
COPD (a,g,h)
Huiart et al5/2005 5,648 NS NS 2.1 NS RR of stroke hospitalizations 1.27 (1.16-1.38)
in COPD (a,g)
Sidney et al7/2005 45,966 45,966 NS 0.8 1.51 (1.37-1.66) RR of stroke hospitalizations 1.33 (1.21 - 1.47)
in COPD (a,g,h)

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Arterial hypertension
Cordero et al14/2011 1,440 9,303 COPD COPD in NA OR for presence of Presence of COPD
patients with: COPD for controlled for controlled
controlled vs uncontrolled BP: (a,g,s) vs uncontrolled
BP 12.5; BP: 1.17 (0.99-1.4)
uncontrolled
BP: 14.6
(P , .01)
(Continued)

Original Research
 journal.publications.chestnet.org
Table 2—Continued

Crude Rate in
Patients With Patients Without COPD Population Patients With Crude Risk Maximally Adjusted
Study/Year COPD, No. COPD, No. Grading COPD, % Estimate (95% CI) Multivariate Model (Covariates)a Risk Estimate (95% CI)
García Rodriguez et al20/2009 1,927 16,546 NS 23.8 NS OR of COPD in CVD (a,g,h,s) 0.79 (0.70-0.90)
Mannino et al26/2008 5,498 7,419 GOLD I 40.4 NS OR of CVD in COPD (a,g,s) 1.1 (0.9-1.2)
GOLD II 43.8 1.4 (1.3-1.6)
GOLD III/IV 51.1 1.6 (1.3-1.9)
Mapel et al27/2005 791,466 outpatients 35,839,862 outpatients Outpatients NS OR and RR of CVD
Prevalence 51.2 in COPD (a,g) 4.22 (4.14-4.31)
Incidence 8.8 3.57 (3.41-3.74)
70,679 inpatients 308,275 inpatients Inpatients
Prevalence 46.6 1.04 (1.03-1.06)
Incidence 4.2 0.95 (0.91-0.99)
Peripheral arterial disease
Finkelstein et al19/2009 2,975 2,975 NS 33.8 NS OR of PAD in COPD (a,g,h,s) 2.5 (2.0-3.0)
Mapel et al27/2005 791,466 outpatients 35,839,862 outpatients Outpatients NS OR and RR of PAD
Prevalence 1.9 in COPD (a,g) 5.50 (4.90-6.18)
Incidence 0.9 5.33 (4.54-6.27)
70,679 inpatients 308,275 inpatients Inpatients
Prevalence 2.9 1.11 (1.05-1.19)

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Incidence 0.7 0.96 (0.85-1.09)
a 5 age; AF 5 atrial fibrillation; CAD 5 coronary artery disease; CV 5 cardiovascular; g 5 sex; h 5 past history of cardiovascular disease; HR 5 hazard ratio; NA 5 not applicable; RR 5 rate ratio; s 5 smoking;
VF 5 ventricular fibrillation. See Table 1 legend for expansion of other abbreviations.
aMost studies detailed other covariates, but age, sex, past history of cardiovascular disease, and smoking were the four key covariates we selected to summarize.

CHEST / 144 / 4 / OCTOBER 2013

1173
 limitation25 (OR 0.4 [95% CI, 0.2-1.1] for GOLD
grade I to OR of 1.7 [95% CI, 0.8-3.8] for GOLD
grades III/IV), although the risk estimates were not
significant. The adjusted RR for hospitalizations due
to arrhythmia ranged from 1.02 to 2.8 in patients
with COPD vs matched cohorts without COPD
(Table 2).4,7,13

Stroke
The prevalence of stroke in patients with COPD
was from 6.9% to 9.9% (Table 2).4,18,19,31 The adjusted
RR for stroke ranged from 1.0 to 1.6; it was statisti-
cally significant in three of five studies (Fig 4).4,12,18,19,31
One study reported an increased RR trend by increas-
ing grade of airflow limitation from RR of 0.6 (95% CI,
0.3-1.1) for patients with GOLD grade I, RR of 1.7
(95% CI, 1.1-2.5) for patients with GOLD grade II, to

Figure 2. Forest plot of studies assessing a relationship between

cardiovascular disease (unspecified) and COPD (adjusted risk
estimates). A, Risk estimates for hospitalization events inci-
dence. B, Disease diagnosis incidence. C, Disease diagnosis
prevalence.4,5,7,18,19,23,26,28,30 a 5 age; g 5 sex; h 5 past history of car-
diovascular disease; RR5 relative risk (includes odds, rate, and
hazard ratio estimates); s 5 smoking.

vs the matched cohorts without COPD ranged from

1.0 to 1.5; none of the associations was statistically
significant (Table 2).4,7,13

Arrhythmias
Nine studies explored a risk of arrhythmia (a term
that includes unspecified arrhythmias, irregular heart
rhythm, atrial tachycardia or fibrillation or flutter,
ventricular tachycardia or fibrillation, or conduction
disorders) in patients with COPD (Table 2). The prev-
alence of various types of arrhythmia among patients
with COPD was from 0.3% to 29%.4,19,27,31 The adjusted
RR for arrhythmia ranged from 1.2 to 5.6 with four of Figure 3. Forest plot of studies assessing a relationship between
five studies reporting statistically significant risk esti- congestive heart failure and COPD (adjusted risk estimates).
A, Risk estimates for hospitalization events incidence. B, Disease
mates.4,16,19,27,31 One study reported increased risk for diagnosis incidence. C, Disease diagnosis prevalence.4,7,13,19,20,21,27
arrhythmia with increasing GOLD grade of airflow See Figure 2 legend for expansion of abbreviations.

1174 Original Research

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 Discussion
In this study, we systematically reviewed the litera-
ture to estimate the risk of CVD overall and parti-
tioned into more specific disease types (CHF, CHD,
arrhythmias, stroke, arterial hypertension, and PAD)
in patients with COPD. To our knowledge, it provides
the most comprehensive and systematic review of avail-
able information on the topic to date. Main results
support that COPD is associated with an increased
risk of CVD, with the risk of CVD increasing with the
severity of airflow limitation (reflected by the GOLD
grade).
The prevalence estimate of CVD in COPD varied
depending on the specific disease type considered
(eg, CHF). For CVD unspecified, the crude prevalence
ranged from 28% to 70%.4,18,19 The RR for overall
CVD among patients with COPD also showed wide
variation and ranged from 1.6 to 2.7 compared with
patients without COPD.4,18,19 Similarly, there was a
considerable variation in both the crude RRs (where
available) and the adjusted estimates for the specific
CVD outcomes assessed. These considerable differ-
Figure 4. Forest plot of studies assessing a relationship between ences between the highest and lowest estimates likely
stroke and COPD (adjusted risk estimates). A, Risk estimates reflect differences in definition of the outcome, in
for hospitalizations events incidence. B, Disease diagnosis pre- ascertainment methods and study designs, population
valence.4,5,7,12,18,19,25,31 See Figure 2 legend for expansion of
abbreviations. differences in underlying rates, and completeness of
the databases used. Nevertheless, the majority of the
RR estimates support a relationship between COPD
RR of 1.5 (95% CI, 0.7-3.0) for patients with GOLD and risk of CVD. It is of note that two studies reported
grade III/IV (Fig 4).25 The RR for hospitalization due a weak relationship between increasing severity of
to stroke was fairly consistent across studies, ranging airflow limitation (reflected by the GOLD grade)
from 1.2 to 1.3 in patients with COPD vs matched and risk for CVD, CHD, arrhythmias, stroke, and
cohorts without COPD.4,5,7 hypertension.23,26
COPD and CVD share a number of risk factors,
Arterial Hypertension including smoking and aging, among others. In gen-
Two studies reported on hypertension prevalence eral, in studies that provided both adjusted and
among patients with COPD as an end point,26,27 both unadjusted RR estimates, the risk estimates per-
reporting a significantly increased risk of hypertension sisted after adjustment for these shared risk fac-
in COPD. In a cohort study reported by Mannino et al,26 tors.4,5,7,13,15,16,18,19,20,21,23,-27,29,31,32 A number of potential
the adjusted RR for hypertension increased from biologic mechanisms linking COPD and CVD have
1.1 (95% CI, 0.9-1.2) among those with GOLD grade I been proposed, including the proinflammatory
of airflow limitation, RR of 1.4 (95% CI, 1.3-1.6) among milieu8,34,35 and increased oxidative stress36 that is com-
those with GOLD grade II, to 1.6 (95% CI, 1.3-1.9) mon in both COPD and CVD. In addition, patients
among those with GOLD grade III/IV disease (Table 2). with COPD tend to have increased arterial stiffness37,38
Two studies described the prevalence of COPD among and metabolic rate,39 and a sedentary lifestyle,40 which
patients with arterial hypertension14,20; both failed to may predispose to increased risk of CVD. COPD can
show a significant association (Table 2). cause pulmonary hypertension, which overloads the
right side of the heart, eventually leading to heart fail-
ure.41,42 In any case, the results presented here high-
Peripheral Arterial Disease
light the need to better investigate the pathobiology
Two studies investigated the risk of PAD in patients of the association of these two common and severe
with COPD and reported adjusted RR estimates of disease entities. From a clinical perspective, they sup-
1.11 (range: 1.05-1.19) and 5.50 (range: 4.90-6.18) in port the need to consider CVD in the routine assess-
patients with COPD as compared with those without ment of patients with COPD,43 and that patients with
COPD (Table 2).19,27 CVD should also be routinely screened for COPD.44

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 Considering the specific CVDs explored in this tain records of lung function tests, and some patient
review, a particularly strong association of RR rang- characteristics important for this analysis (eg, smoking
ing from 1.8 to 3.9 was found for heart failure and status). Most of the patient-cohort studies addressed
COPD, persisting after adjustment for age, sex, smok- the relationship between COPD and CVD as an ad
ing history, history of CVD, and other study-specific hoc question rather than a primary question. Studies
confounders.19,20,21,27 An analysis of a population-based primarily designed and focusing on a relationship
cohort reported a relationship between the lung func- between CVD and COPD are lacking.
tion and incidence of heart failure.45 Studies have In conclusion, currently available observational data
established a link for elevated inflammatory markers, indicate that COPD is associated with a higher risk
specifically fibrinogen and IL-6, with incident heart for CVD. In line with the GOLD 2011 recommenda-
failure as well as with incident COPD.46-48 These data tions, this highlights the importance of considering
further support a interrelationship of diseases of heart CVD in the clinical management of patients with COPD
and lung based on inflammatory mechanisms. Fur- (and vice versa). Further study is needed to understand
ther, inflammation was also implied in the etiology of the nature and clinical utility of the association.
atrial fibrillation49 and CHD.50 Nocturnal desatura-
tion in COPD was associated with increased ventric-
ular ectopy.51 Most studies on arrhythmia and COPD Acknowledgments
included in this review failed to control for smoking Authors contributions: Dr Müllerova had full access to all of the
history; the two studies that did so resulted in incon- data in the study and takes responsibility for the integrity of the
data and the accuracy of the data analysis.
sistent estimates.19,31 Dr Müllerova: contributed to the literature search, creating the
For coronary artery disease, the findings of our review tables, and writing the manuscript and served as principle author.
are similarly inconsistent. Only about one-half of the Dr Agusti: contributed to review of the study proposal and the
interim results and writing the manuscript.
studies reported here produced a significantly increased Dr Erqou: contributed to the literature search, creating the initial
estimate.4,19,24,27,31 Some negative studies,15,17,22,25 tended review output, and writing the manuscript.
to include smaller populations of patients with COPD, Dr Mapel: contributed to review of the study proposal and the
interim results and writing the manuscript.
which may explain why they reported higher point Financial/nonfinancial disclosures: The authors have reported
estimates for the risk of CHD in COPD but were to CHEST the following conflicts of interest: Dr Müllerova is
accompanied with wide confidence intervals.15,22, All employed by GlaxoSmithKline R&D and owns shares and stock
options of GlaxoSmithKline plc. Dr Agusti has received payment
the RR estimates for CHD hospitalization in patients for speaking at meetings, attending advisory boards, and/or research
with COPD were not significant.4,7,13 This finding may projects from Almirall SA, AstraZeneca plc, Boehringer-Ingelheim
reflect a complex association between COPD and CVD GmBH, Chiesi Pharmaceuticals SpA, Esteve, GlaxoSmithKline plc,
Merck Sharp & Dohme, Novartis AG, Procter and Gamble Co,
events outlined in the study by Sode and colleagues,29 and Takeda Pharmaceutical Company Ltd. Dr Erqou has been a
who reported a higher relative risk of acute MI before paid consultant for GlaxoSmithKline plc for literature reviews.
the first hospitalization for COPD, but lower risk after Dr Mapel has received research grants from and served as an
advisor to GlaxoSmithKline plc, AstraZeneca plc, Pfizer Inc, and
the first COPD hospitalization. Boehringer Ingelheim GmBH.
The most important limitation of the current system- Role of sponsors: The study sponsor, GlaxoSmithKline R&D
atic review is that its findings are limited by the quality funded the literature retrieval and editorial assistance. The study
was undertaken as a part of an employment at GlaxoSmithKline
and consistency of the observational data available and, R&D (H. M.).
clearly, there was considerable variation in the method Other contributions: We thank Stephanie Watkins, PhD
of data collection, study population, and analysis under- (GlaxoSmithKline plc) who helped extract data from the published
manuscripts identified during the selection step. Editorial support
taken, including the relative-risk estimation methods was provided by David Cutler, PhD, at Gardiner-Caldwell Com-
and adjustment variables included. Few studies mea- munications and Louise Watson, PhD, at EPI PharmaCo and was
sured CVD as a part of predefined study design23,26 funded by GlaxoSmithKline plc.
Additional information: The e-Appendix can be found in the
and the CVD ascertainment varied widely from patient “Supplemental Materials” area of the online article.
self-report, to record of medical diagnosis, to objec-
tive diagnostic criteria. Similarly, COPD was most often
assessed by a recorded medical diagnosis, but also by References
using spirometry (FEV1/FVC ratio , 0.7) and patient
1. National Heart, Lung, and Blood Institute. Morbidity and mor-
self-report. There were several other sources of het- tality: 2009 chart book on cardiovascular, lung, and blood dis-
erogeneity: study setting (population-based or selec- eases. 2009. National Heart, Lung, and Blood Institute website.
tive patients cohort vs health-care database records), http://www.nhlbi.nih.gov/resources/docs/2009_ChartBook.pdf.
outcome estimate (prevalent diagnosis, incident diag- Accessed January 5, 2012.
nosis, incident hospitalizations), and differences in 2. Sin DD, Anthonisen NR, Soriano JB, Agusti AG. Mortality
in COPD: role of comorbidities. Eur Respir J. 2006;28(6):
adjustment of the relative risk estimates. Some of the 1245-1257.
studies were limited by the nature of the original data; 3. McGarvey LP, John M, Anderson JA, Zvarich M, Wise RA;
for example, health-care databases usually do not con- TORCH Clinical Endpoint Committee. Ascertainment of

1176 Original Research

Downloaded From: http://journal.publications.chestnet.org/ by a Georgia State University User on 10/31/2013

 cause-specific mortality in COPD: operations of the TORCH 21. García Rodríguez LA, Wallander MA, Martín-Merino E,
Clinical Endpoint Committee. Thorax. 2007;62(5):411-415. Johansson S. Heart failure, myocardial infarction, lung cancer
4. Curkendall SM, DeLuise C, Jones JK, et al. Cardiovascular and death in COPD patients: a UK primary care study. Respir
disease in patients with chronic obstructive pulmonary dis- Med. 2010;104(11):1691-1699.
ease, Saskatchewan Canada cardiovascular disease in COPD 22. Izquierdo JL, Martínez A, Guzmán E, de Lucas P, Rodríguez
patients. Ann Epidemiol. 2006;16(1):63-70. JM. Lack of association of ischemic heart disease with COPD
5. Huiart L, Ernst P, Suissa S. Cardiovascular morbidity and when taking into account classical cardiovascular risk factors.
mortality in COPD. Chest. 2005;128(4):2640-2646. Int J Chron Obstruct Pulmon Dis. 2010;5:387-394.
6. Macchia A, Monte S, Romero M, D’Ettorre A, Tognoni G. The 23. Johnston AK, Mannino DM, Hagan GW, Davis KJ, Kiri VA.
prognostic influence of chronic obstructive pulmonary dis- Relationship between lung function impairment and inci-
ease in patients hospitalised for chronic heart failure. Eur J dence or recurrence of cardiovascular events in a middle-aged
Heart Fail. 2007;9(9):942-948. cohort. Thorax. 2008;63(7):599-605.
7. Sidney S, Sorel M, Quesenberry CP Jr, DeLuise C, Lanes S, 24. Konecny T, Somers K, Orban M, et al. Interactions between
Eisner MD. COPD and incident cardiovascular disease hos- COPD and outcomes after percutaneous coronary interven-
pitalizations and mortality: Kaiser Permanente Medical Care tion. Chest. 2010;138(3):621-627.
Program. Chest. 2005;128(4):2068-2075. 25. Lange P, Mogelvang R, Marott JL, Vestbo J, Jensen JS. Car-
8. Agustí A, Edwards LD, Rennard SI, et al; Evaluation of COPD diovascular morbidity in COPD: A study of the general popu-
Longitudinally to Identify Predictive Surrogate Endpoints lation. COPD. 2010;7(1):5-10.
(ECLIPSE) Investigators. Persistent systemic inflammation 26. Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence
is associated with poor clinical outcomes in COPD: a novel and outcomes of diabetes, hypertension and cardiovascular
phenotype. PLoS ONE. 2012;7(5):e37483. disease in COPD. Eur Respir J. 2008;32(4):962-969.
9. Barr RG, Bluemke DA, Ahmed FS, et al. Percent emphysema, 27. Mapel DW, Dedrick D, Davis K. Trends and cardiovascular
airflow obstruction, and impaired left ventricular filling. N Engl co-morbidities of COPD patients in the Veterans Adminis-
J Med. 2010;362(3):217-227. tration Medical System, 1991-1999. COPD. 2005;2(1):35-41.
10. Short PM, Lipworth SI, Elder DH, Schembri S, Lipworth BJ. 28. Methvin JN, Mannino DM, Casey BR. COPD prevalence
Effect of beta blockers in treatment of chronic obstructive in southeastern Kentucky: the burden of lung disease study.
pulmonary disease: a retrospective cohort study. BMJ. 2011; Chest. 2009;135(1):102-107.
342:d2549. 29. Sode BF, Dahl M, Nordestgaard BG. Myocardial infarction
11. Hawkins NM, Petrie MC, Macdonald MR, et al. Heart fail- and other co-morbidities in patients with chronic obstructive
ure and chronic obstructive pulmonary disease the quandary pulmonary disease: a Danish nationwide study of 7.4 million
of beta-blockers and beta-agonists. J Am Coll Cardiol. 2011; individuals. Eur Heart J. 2011;32(19):2365-2375.
57(21):2127-2138. 30. Staszewsky L, Wong M, Masson S, et al; Valsartan Heart Fail-
12. Allen NB, Holford TR, Bracken MB, et al. Geographic vari- ure Trial Investigators. Clinical, neurohormonal, and inflamma-
ation in one-year recurrent ischemic stroke rates for elderly tory markers and overall prognostic role of chronic obstructive
Medicare beneficiaries in the USA. Neuroepidemiology. 2010; pulmonary disease in patients with heart failure: data from
34(2):123-129. the Val-HeFT heart failure trial. J Card Fail. 2007;13(10):
13. Chen Y, Li Q, Johansen H. Age and sex variations in hospital 797-804.
readmissions for COPD associated with overall and cardiac 31. Schneider C, Bothner U, Jick SS, Meier CR. Chronic obstruc-
comorbidity. Int J Tuberc Lung Dis. 2009;13(3):394-399. tive pulmonary disease and the risk of cardiovascular diseases.
14. Cordero A, Bertomeu-Martínez V, Mazón P, et al. Factors asso- Eur J Epidemiol. 2010;25(4):253-260.
ciated with uncontrolled hypertension in patients with and 32. Tseng CH. Clinical features of heart failure hospitalization
without cardiovascular disease [in Spanish]. Rev Esp Cardiol. in younger and elderly patients in Taiwan. Eur J Clin Invest.
2011;64(7):587-593. 2011;41(6):597-604.
15. de Lucas-Ramos P, Izquierdo-Alonso JL, Rodríguez-González 33. Wang YC, Lin JM, Li CY, Lee LT, Guo YL, Sung FC. Prev-
Moro JM, et al. Cardiovascular risk factors in chronic obstruc- alence and risks of chronic airway obstruction: a population
tive pulmonary disease: results of the ARCE study [in Spanish]. cohort study in Taiwan. Chest. 2007;131(3):705-710.
Arch Bronconeumol. 2008;44(5):233-238. 34. Agustí AG, Noguera A, Sauleda J, Sala E, Pons J, Busquets X.
16. Dziewierz A, Siudak Z, Rakowski T, Jakała J, Dubiel JS, Systemic effects of chronic obstructive pulmonary disease.
Dudek D. Prognostic significance of new onset atrial fibril- Eur Respir J. 2003;21(2):347-360.
lation in acute coronary syndrome patients treated conserva- 35. Gan WQ, Man SF, Senthilselvan A, Sin DD. Association
tively. Cardiol J. 2010;17(1):57-64. between chronic obstructive pulmonary disease and systemic
17. Enriquez JR, Parikh SV, Selzer F, et al. Increased adverse inflammation: a systematic review and a meta-analysis. Thorax.
events after percutaneous coronary intervention in patients 2004;59(7):574-580.
with COPD: insights from the National Heart, Lung, and 36. MacNee W. Pulmonary and systemic oxidant/antioxidant
Blood Institute dynamic registry. Chest. 2011;140(3):604-610. imbalance in chronic obstructive pulmonary disease. Proc Am
18. Feary JR, Rodrigues LC, Smith CJ, Hubbard RB, Gibson JE. Thorac Soc. 2005;2(1):50-60.
Prevalence of major comorbidities in subjects with COPD 37. Sabit R, Bolton CE, Edwards PH, et al. Arterial stiffness and
and incidence of myocardial infarction and stroke: a com- osteoporosis in chronic obstructive pulmonary disease. Am J
prehensive analysis using data from primary care. Thorax. Respir Crit Care Med. 2007;175(12):1259-1265.
2010;65(11):956-962. 38. Maclay JD, McAllister DA, Mills NL, et al. Vascular dysfunc-
19. Finkelstein J, Cha E, Scharf SM. Chronic obstructive pul- tion in chronic obstructive pulmonary disease. Am J Respir
monary disease as an independent risk factor for cardiovas- Crit Care Med. 2009;180(6):513-520.
cular morbidity. Int J Chron Obstruct Pulmon Dis. 2009;4: 39. Schols AM, Fredrix EW, Soeters PB, Westerterp KR, Wouters EF.
337-349. Resting energy expenditure in patients with chronic obstruc-
20. García Rodríguez LA, Wallander MA, Tolosa LB, Johansson S. tive pulmonary disease. Am J Clin Nutr. 1991;54(6):983-987.
Chronic obstructive pulmonary disease in UK primary care: 40. Garcia-Aymerich J, Lange P, Benet M, Schnohr P, Antó JM.
incidence and risk factors. COPD. 2009;6(5):369-379. Regular physical activity modifies smoking-related lung function

journal.publications.chestnet.org CHEST / 144 / 4 / OCTOBER 2013 1177

Downloaded From: http://journal.publications.chestnet.org/ by a Georgia State University User on 10/31/2013

 decline and reduces risk of chronic obstructive pulmonary American Indians: the Strong Heart Study. J Clin Hypertens
disease: a population-based cohort study. Am J Respir Crit (Greenwich). 2012;14(1):13-19.
Care Med. 2007;175(5):458-463. 47. Bahrami H, Bluemke DA, Kronmal R, et al. Novel metabolic
41. Naeije R, Barberà JA. Pulmonary hypertension associated risk factors for incident heart failure and their relationship with
with COPD. Crit Care. 2001;5(6):286-289. obesity: the MESA (Multi-Ethnic Study of Atherosclerosis)
42. Buch P, Friberg J, Scharling H, Lange P, Prescott E. Reduced study. J Am Coll Cardiol. 2008;51(18):1775-1783.
lung function and risk of atrial fibrillation in the Copenhagen 48. Valvi D, Mannino DM, Müllerova H, Tal-Singer R. Fibrinogen,
City Heart Study. Eur Respir J. 2003;21(6):1012-1016. chronic obstructive pulmonary disease (COPD) and outcomes
43. Global Initiative for Chronic Obstructive Lung Disease (GOLD) in two United States cohorts. Int J Chron Obstruct Pulmon
2011. Global strategy for the diagnosis, management and pre- Dis. 2012;7:173-182.
vention of COPD. Global Initiative for Chronic Obstructive 49. Peña JM, MacFadyen J, Glynn RJ, Ridker PM. High-
Lung Disease website.http://www.goldcopd.org/guidelines- sensitivity C-reactive protein, statin therapy, and risks of atrial
global-strategy-for-diagnosis-management.html/. Accessed fibrillation: an exploratory analysis of the JUPITER trial. Eur
August, 2012. Heart J. 2012;33(4):531-537.
44. Soriano JB, Rigo F, Guerrero D, et al. High prevalence of 50. Emberson J, Bennett D, Link E, et al; Heart Protection
undiagnosed airflow limitation in patients with cardiovascular Study Collaborative Group. C-reactive protein concentration
disease. Chest. 2010;137(2):333-340. and the vascular benefits of statin therapy: an analysis of
45. Agarwal SK, Heiss G, Barr RG, et al. Airflow obstruction, 20,536 patients in the Heart Protection Study. Lancet. 2011;
lung function, and risk of incident heart failure: the Atheroscle- 377(9764):469-476.
rosis Risk in Communities (ARIC) study. Eur J Heart Fail. 51. Shepard JW Jr, Garrison MW, Grither DA, Evans R, Schweitzer
2012;14(4):414-422. PK. Relationship of ventricular ectopy to nocturnal oxygen
46. Barac A, Wang H, Shara NM, et al. Markers of inflamma- desaturation in patients with chronic obstructive pulmonary
tion, metabolic risk factors, and incident heart failure in disease. Am J Med. 1985;78(1):28-34.

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