Cardiovascular Comorbidity in COPD

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 independently. This study aimed to provide a systematic review of studies that investigated the association 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 individual 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

and cardiovascular disease (CVD) are leadCOPD ing causes of mortality globally. In 2005, COPD

and CVD caused an estimated 120,000 and 830,000 deaths, respectively, in the United States.1 Clinicians have long recognized that there is a very high prevalence of CVD among patients with COPD, and, indeed, CVD is the major contributor to morbidity

Manuscript received November 21, 2012; revision accepted April 15, 2013. Affiliations: From Worldwide Epidemiology (Dr Müllerova), GlaxoSmithKline R&D, Uxbridge, England; Thorax Institute (Dr Agusti), Hospital Clinic, IDIBAPS, Universitat de Barcelona and FISIB, CIBER Enfermedades Respiratorias (CIBERES), Mallorca, Spain; Weill Cornell Medical College (Dr Erqou), New York, NY; and Lovelace Clinic Foundation (Dr Mapel), Albuquerque, NM. Funding/Support: This study was sponsored by GlaxoSmithKline plc [study code WEUSKOP4140].

and mortality in patients with COPD.2-7 For example, Sidney et al7 reported a more than twofold increased risk for CVD-related hospitalization and CVD-related mortality in patients with COPD compared with those without COPD. The observed association between COPD and CVD may be explained, at least in part, by shared risk factors such as smoking, age, sex, and inactivity. However, it is also thought that systemic inflammatory changes Correspondence to: Hana Müllerova, PhD, Worldwide Epidemiology, GlaxoSmithKline R&D, Bldg 9, Iron Bridge Rd, Stockley Park W, Uxbridge, Middlesex, UB11 1BT, England; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.12-2847

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related to COPD may increase the risk of CVD independently.8 Additionally, pathophysiologic changes associated with COPD can directly impact heart function; for instance, emphysema and lung hyperinflation may impair left ventricular filling and lower cardiac output or cause pulmonary hypertension and rightsided heart failure.9 Studying the association between COPD and CVD is deemed important because the coexistence of COPD and CVD may have implications for the management of these patients. For example, systemic b-blockers that are very commonly used in CVD were at one time considered to be strictly contraindicated in COPD, but studies suggest that cardioselective b-blockers are safe and effective for most patients with COPD.10,11 Understanding the association between the two disease entities may enable improved CVD risk prediction in patients with COPD by identifying those individuals at higher risk of CVD morbidity and mortality. Finally, increasing our knowledge of an interaction between COPD and CVD may provide an opportunity to develop targeted therapies for the subset of patients with CVD and COPD as the nature of inflammation may be the same. The purpose of this report is to provide a systematic review of the available literature on the association between COPD and various CVD outcomes, including coronary heart disease (CHD), congestive heart failure (CHF), arrhythmias, stroke, arterial hypertension, and peripheral arterial disease (PAD).

or a reanalysis of clinical trials data where the study intervention 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 (eg, smoking, age, sex) for COPD and report at least one of the following cardiovascular outcomes of interest in relation to COPD: (1) CVD unspecified or aggregate (not otherwise specified, but referring to at least one of the following: CHD, arrhythmia, heart failure, and arterial hypertension); (2) CHD, including coronary stenosis, myocardial infarction (MI), coronary revascularization (coronary angioplasty or coronary artery bypass graft), angina, or coronary atherosclerosis; (3) arrhythmia (any type, including unspecified arrhythmias, irregular heart rhythm, atrial tachycardia or fibrillation or flutter, ventricular tachycardia or fibrillation, or conduction disorders); (4) CHF; (5) arterial hypertension; (6) PAD; and (7) stroke. Studies were considered if COPD was reported to have been diagnosed by spirometry or by the physician. Studies were further classified by their source as (1) health-care database (eg, insurance claims, electronic medical record data) or (2) cohorts collected as a part of chart review, survey, or patient registry. Based on these selection criteria, a final list of 25 studies was derived. The retrieval and selection of papers was conducted by two of the authors (S. E. for the period 1990-2009; H. M. for the period 2009-2012). One of the authors (H. M.) repeated the search process for the period 1990 to 1994, and no additional relevant papers were found.

Materials and Methods

Results

Data Sources and Searches An electronic literature search was conducted via PubMed (which comprises citations from MEDLINE, life science journals, and online books) for observational studies published between January 1990 and March 2012 reporting on CVD in patients with COPD or vice versa. Key terms used included medical subject headings and free texts related to CVD and its types (ie, coronary artery disease, myocardial infarction, heart failure, arrhythmia, and hypertension), and to COPD (specifically “Pulmonary disease, Chronic Obstructive,” COPD, emphysema, and “chronic obstructive”). The full list of search terms used is provided in e-Appendix 1. Searches were not restricted to the English language. The PubMed search was supplemented by manual screening of the reference lists of review articles. Study Selection PubMed searches identified 7,322 publications that were screened for relevance based on titles and abstracts. Of these, 257 potentially relevant publications were selected for closer review using their full text and/or abstracts. In all, 119 publications were excluded because they lacked relevant data, had low sample size (N , 100), or were reviews (Fig 1). For the remaining 138 studies that were fully abstracted, we used two major selection criteria. First, the study had to be observational with a prospective, retrospective, or cross-sectional design,

Data Analyses Association measures, that is, ORs, rate ratios (RRs), and hazard ratios (HRs), were abstracted overall and, where available, within subgroups. For adjusted estimates, information on adjustment variables was obtained. Due to the presence of substantial heterogeneity across the studies (design, population, and outcome definition), formal meta-analysis was not performed. Instead, the results were qualitatively described and compared. Tabular and graphic presentations are used to assist in interpretation of data.

In total, 25 studies were included in the current analysis; 22 studies provided an estimate for CVD risk in COPD, whereas four studies provided estimates of COPD risk in CVD (Table 1). Twelve studies used a cohort design, seven studies used nested case-control approach, and eight studies were cross-sectional. In the prospective studies, the duration of follow-up ranged from 1 to 27 years. The average age of participants ranged between 55 and 78 years. The percentage of male patients in the studies ranged between 45% and 96%. Unspecified CVD The prevalence of unspecified CVD among patients with COPD ranged from 28% to 70% (Table 2, Fig 2).4,18,19 Crude relative risk for CVD among patients with COPD was from 2.1 to 5.04,18 whereas the adjusted estimates was from 1.6 to 2.7.4,18,19 Two studies, using a similar data source, reported that the RR for CVD increased with increasing severity of airflow limitation.23,26 Johnston et al23 reported that the adjusted HR for incident CVD increased from 1.1 (95% CI,

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Original Research

Figure 1. Study flow diagram.

0.9-1.3) in patients with GOLD (Global Initiative for Chronic Obstructive Lung Disease) grade I to 1.5 (95% CI, 1.1-2.0) in patients with GOLD grade III/IV (airflow limitation) as compared with patients without COPD (N 5 8,193). Similarly, Mannino et al26 reported an increasing risk for prevalent CVD ranging from a RR of 1.7 (95% CI, 1.5-1.9) in GOLD grade I to 2.4 (95% CI 1.9-3.0) in GOLD grade III/IV, respectively. In contrast, a third study28 in a small cohort (N 5 100) of patients with COPD failed to demonstrate an association of prevalent CVD with the level of airflow limitation (Fig 2). The four studies reporting CVD hospitalization rates demonstrated that patients with COPD were at increased risk for hospitalization due to CVD compared with matched cohorts of individuals without COPD, with the RR ranging from 1.1 (95% CI, 0.9-1.3) to 2.2 (95% CI, 2.0-2.3).4,5,7,30 Overall, the associations between CVD and COPD remained statistically significant in eight of the 10 studies after adjustment for potential confounders (Table 2, Fig 2). Congestive Heart Failure The prevalence of CHF in patients with COPD ranged between 7.1% and 31.3%4,19,20,21,27; one study reported an annual incidence of 3.7%27 (Table 2). The adjusted RR of prevalent CHF in individuals with COPD compared with those without COPD ranged from 1.8 to 3.9; all associations remained significant

after adjustment for potential confounders (Fig 3). The adjusted RR for hospitalizations due to CHF in patients with COPD vs matched cohorts without COPD ranged from 1.2 to 3.8.4,5,7,13 Two studies reported an increased risk of COPD in patients with CHF with adjusted ORs of 2.4 and 2.1 compared with patients without CHF.20,32 Coronary Heart Disease The prevalence of CHD (a term that includes MI, angina, coronary artery disease, and ischemic heart disease) ranged between 4.7% and 60% among patients with COPD (Table 2)4,17,19,22,24,27,29; one study reported an incidence of acute MI in patients with COPD as 6.3 per 1,000 person-years.21 The adjusted RR for CHD ranged from 0.7 to 6.8 (Table 2).4,17,19,21,22,24,27,29,31 Five of nine studies reported a statistically significant positive association of increased CVD occurrence in COPD.4,19,24,27,31 Three studies explored an association between CHD and COPD severity15,25,31; two studies reported a numerically increased risk of CHD with increasing level of airflow limitation, one study reported a statistically significant association after adjustment for common risk factors between incident MI and COPD treatment intensity used as a surrogate for disease severity, from an OR of 1.8 (95% CI, 1.1-2.9) for mild to an OR of 3.0 (95% CI, 1.5-5.9) for severe disease.31 The risk for hospitalization due to CHD in patients with COPD

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Original Research

Case-control analysis of hospital-based cohort Cohort, general population based

Izquierdo et al22/2010 (Spain)c Johnston et al23/2008 (USA, 1986-2001)

Retrospective cohort

NCC, primary care EMR database NCC, Primary care EMR database Cohort, claims data

García Rodriguez et al20/ 2009c (UK, 1996) García Rodriguez et al21/2010 (UK, 1996-2001) Huiart et al5/2005 (Canada, 1990-1997)

Konecny et al24/2010 (USA, 1995-2008)

NCC, CCS

CCS, cohort

2,001

12,345

8,193

3,262

NS

5,648

234

16,108

1,927

70

16,546

2,975

1,174,240

10,048

890

0

22,986

1,927

2,975

29,870

860

111

Cohort, patient registry

Retrospective cohort

527

CCS, cohort

11,493

9,303

1,440

NCC, claims data

0

108,726

Cohort, hospital episodes database Cross-sectional, registry

726,588

Patients Without COPD, No.

169,328

Patients With COPD, No.

Cohort, claims data

Method, Population Source

Finkelstein et al19/2009 (USA, 2002)

Enriquez et al17/2011 (USA, 1999-2006) Feary et al18/2010 (UK, 2005)

de Lucas-Ramos et al15/2008 (Spain, NS) Dziewierz et al16/2010 (Poland, 2005-2008)

Allen et al12/ 2010 (USA, 2000-2002) Chen et al13/2009 (Canada, 1999-2000) Cordero et al14/2011 (Spain, 2009)c Curkendall et al4/ 2006 (Canada, 1998-2001)

Study/Year (Country, Study Period)

70

45

84

54

NS

53

46

51

65

54

85

54

50

55

57

Male Patients, %

Medical record

GOLD modified

GOLD criteria

Medical record and Rx Medical record and Rx Rx and age

Self report, smoking, age

Medical record

Medical record

Medical record

Medical record

ICD-9 and Rx

Medical record

ICD-9

ICD-9

COPD Ascertainment

AMI

Unspecified CVD

AMI, unspecified CVD, cerebrovascular disease, CHF, IHD COPD

AMI, CHF

CVD unspecified stroke (subarachnoid and intracranial hemorrhage and TIA) AMI, AP, arrhythmia, unspecified CVD, CHF, IHD, PAD, stroke CHF, HTN

MI

Arrhythmia

AMI, unspecified CVD, AP, arrhythmia, CHF, stroke IHD

COPD

Arrhythmia, IHD, CHF

Recurrent stroke

Comorbidity Assessed

(Continued)

1. Predefined clinical criteria 2. Incidence Medical record

Spirometry

1. Medical record 2. Incidence 1. Medical record 2. Incidence 1. ICD-9 2. Hospitalization episodes

1. Self report 2. Prevalence

Medial record

1. ICD-9 2. Period prevalence, and hospitalization episodes 1. Medical record 2. Prevalence 1. Predefined clinical criteria 2. Incidence Medical record

1. ICD-9 2. Hospitalization episodes 1. ICD-9 2. Hospitalization episodes Medical record

Comorbidity Assessment/Main Outcome

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

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 statistically significant in three of five studies (Fig 4).4,12,18,19,31 One study reported an increased RR trend by increasing 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 incidence. 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 cardiovascular 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 prevalence 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 five studies reporting statistically significant risk estimates.4,16,19,27,31 One study reported increased risk for arrhythmia with increasing GOLD grade of airflow

Figure 3. Forest plot of studies assessing a relationship between congestive heart failure and COPD (adjusted risk estimates). A, Risk estimates for hospitalization events incidence. B, Disease diagnosis incidence. C, Disease diagnosis prevalence.4,7,13,19,20,21,27 See Figure 2 legend for expansion of abbreviations.

1174

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1168

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Original Research

3,262

5,498

100

Johnston et al23/2008

Mannino et al26/2008

Methvin et al28/2009

CHF Curkendall et al4/2006 Finkelstein et al19/2009 García Rodriguez et al20/2009 García Rodriguez et al21/2010 Mapel et al27/2005

4,382

45,966

NS

22,986

ⵑ400

7,419

8,193

2,975

22,986 1,174,240

Patients Without COPD, No.

70,679 inpatients

308,275 inpatients

11,493 22,986 2,975 2,975 1,927 16,546 1,927 16,108 791,466 outpatients 35,839,862 outpatients

628

45,966

Sidney et al7/2005

Staszewsky et al30/2007

5,648

Huiart et al5/2005

11,493

2,975

Finkelstein et al19/2009

Curkendall et al4/2006

11,493 29,870

CV Unspecified Curkendall et al4/2006 Feary et al18/2010 (UK, 2005)

Study/Year

Patients With COPD, No.

NS NS NS NS Outpatients Prevalence Incidence Inpatients Prevalence Incidence

NS

NS

NS

GOLD I GOLD II GOLD III/IV GOLD I GOLD II GOLD III/IV GOLD I GOLD II GOLD III/IV NS

NS

NS NS

COPD Population Grading

24.5 3.7

14.1 4.6

31.3 11.4 7.1 NS

NS

6.4

18.4

1.0 1.7 2.0 18.7 19.4 22.1 33.7 30.3 41.3 11

56.5

70.4 28.0

Crude Rate in Patients With COPD, %

OR of heart disease in COPD (a,g,s)

NS NS NS NS

5.21 (4.86-5.58) OR of CHF in COPD (a,g,h) OR of CHF in COPD (a,g,h,s) OR of COPD in CHF (a,g,h,s) OR of CHF in COPD (a,g,h,s) OR and RR of CHF in COPD (a,g)

2.45 (2.27-2.65) RR of incident CVD hospitalization in COPD (a,g,h) NS RR of CVD hospitalizations in COPD (a,g) 2.33 (2.24-2.42) RR of CVD hospitalizations in COPD (a,g,h) NS HR of CVD hospitalization in COPD (a,g,h)

NS

(Continued)

1.81 (1.77-1.85) 1.46 (1.38-1.53)

7.94 (7.56, 8.35) 5.94 (5.50, 6.42)

3.84 (3.56-4.14) 3.9 (2.8-5.5) 2.38 (2.00-2.82) 2.54 (2.02-3.19)

1.08 (0.90-1.29)

1.96 (1.88-2.05)

1.89 (1.83-1.94)

2.5 (2.1-3.1) 2.7 (2.3-3.2) 1.1 (0.9-1.3) 1.2 (1.03-1.4) 1.5 (1.1-2.0) 1.7 (1.5-1.9) 2.2 (1.9-2.5) 2.4 (1.9-3.0) 1.4 (0.5-4.0 1.1 (0.5-2.7) 1.5 (0.4-4.9) 2.17 (2.00-2.33)

1.71 (1.61-1.81) Aged 65-74 y: never smokers: 2.2 (1.9-2.5); exsmokers: 1.7 (1.6-1.9), current smokers: 1.6 (1.5-1.7)

Maximally Adjusted Multivariate Model (Covariates)a Risk Estimate (95% CI)

2.09 (1.99-2.20) OR of CVD in COPD (a,g,h) OR 4.98 (4.85-5.81) OR of having COPD and previous diagnosis of CVD; multiple estimates stratified by age and smoking status, only age group 65-74 y listed, (a, h, s) NS HR of CVD in COPD OR of CVD in COPD (a,g,h,s) 1.4 (1.2-1.7) OR of CVD in COPD (a,g,h,s) 2.4 (2.1-2.7) 2.9 (2.2-3.9) NS OR of CVD in COPD (a,g,s)

Crude Risk Estimate (95% CI)

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

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4,854

12,345

2,975 16,108 234

10,048

22,986 0

2,178

45,966

NS

22,986

0

Patients Without COPD, No.

70,679 inpatients

308,275 inpatients

791,466 outpatients 35,839,862 outpatients

1,036

Lange et al25/2010

Mapel et al27/2005

2,001

2,975 1,927 70

860

11,493 527

Konecny et al24/2010

Finkelstein et al19/2009 García Rodriguez et al21/2010 Izquierdo et al22/2010

Enriquez et al17/2011

Coronary heart disease Curkendall et al4/2006 de Lucas-Ramos et al15//2008

514

45,966

Sidney et al7/2005

Tseng32/2011

5,648

11,493

Curkendall et al4/2006

Huiart et al5/2005

108,726

Chen et al13/2009

Study/Year

Patients With COPD, No.

GOLD I GOLD II GOLD III/IV Outpatients Prevalence Incidence Inpatients Prevalence Incidence

NS

NS NS NS

NS GOLD I GOLD II GOLD III GOLD IV NS

NS

NS

NS

NS

NS

COPD Population Grading

4.7 1.4

6.7 0.7

1.5 5.4 6.8

5.6 13.3 18.1 16.9 12.2 Rate at 1 y: 5.9 16.1 0.63 24% COPD in cases and 21% COPD in control subjects 61

19% COPD in CHF

1.8

18.4

3.2

19.3

Crude Rate in Patients With COPD, %

Table 2—Continued

NS

NS

NS

NS NS

OR and RR of CHD in COPD (a,g)

OR for occurrence of incident MI (a,g,s) OR of CHD in COPD (a,g)

OR of CHD in COPD (a,g,h,s) OR incident AMI in COPD 1.19 (0.67-2.13) OR for COPD in patients with and without IHD (a,g,s)

1.83 (1.64-2.05) OR of CHD in COPD (a,g,h) Reference OR of CHD in COPD (a,g,h,s) 1.43 (0.31-6.56) 1.32 (0.28-6.24) 0.9 (0.16-5.24) NS 1-y HR of CHD event (a,h)

(Continued)

1.06 (1.02-1.11) 1.28 (1.18-1.38)

6.75 (5.77-7.90) 5.31 (4.54-6.21)

0.3 (0.1, 0.8) 1.3 (0.8, 1.9) 1.4 (0.7-2.8)

1.30 (1.14-1.47)

2.0 (1.5-2.5) 0.93 (0.62-1.39) 1.14 (0.57-2.29)

1.61 (1.43-1.81) Reference 3.29 (0.38-28.18) 2.84 (0.32-25.09) 2.65 (0.25-28.56) 0.96 (0.70-1.30)

2.1 (1.9-2.4)

3.75 (3.39, 4.15)

1.89 (1.83-1.94)

3.45 (2.78-4.17)

1.20 (1.17-1.23)

Maximally Adjusted Multivariate Model (Covariates)a Risk Estimate (95% CI)

HR of COPD readmissions in COPD patients with and without CHF (a,g) 5.24 (4.42-6.20) RR of incident CHF hospitalization in COPD (a,g,h) NS RR of CHF hospitalizations in COPD (a,g) 5.55 (4.71-5.73) RR of CHF hospitalizations in COPD (a,g,h) OR for CHF hospitalization risk associated with COPD (a,g,h)

NS

Crude Risk Estimate (95% CI)

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35,772

108,726

11,493

45,966 313,958

4,568

11,493 111

2,975

Schneider et al31/2010

Chen et al13/2009

Curkendall et al4/2006 (Canada, 1998-2001)

Sidney et al7/2005

Sode et al29/2011

Wang et al33/2007

Arrhythmias Curkendall et al4/2006

Dziewierz et al16/2010

Finkelstein et al19/2009

Study/Year

Patients With COPD, No.

2,975

890

22,986

Not stated

7,105,833

45,966

22,986

0

35,772

Patients Without COPD, No.

NS

NS

NS

NS

NS

NS

NS

Any COPD Mild Moderate Severe NS

COPD Population Grading

29.2% with new onset AF had COPD 29.0

21.1

NA

27.20

0.95

1.1

NS

NS

Crude Rate in Patients With COPD, %

Table 2—Continued

OR of CHD in COPD (a,g,h,s)

NS

OR of arrhythmia in COPD (a,g,h,s)

2.09 (1.96-2.23) OR of arrhythmia in COPD (a,g,h) 3.46 (1.40-8.53) OR of incident atrial fibrillation in COPD (NS)

(Continued)

2.4 (2.0-2.8)

3.22 (1.22-8.51)

1.76 (1.64-1.89)

Before first COPD hospitalization: 1.47 (1.44-1.49); after first COPD hospitalization 0.74 (0.73-0.76) 1.38 (0.62-1.39)

1.89 (1.71, 2.09)

1.49 (0.71-3.13)

1.40 (1.13, 1.73) 1.79 (1.12, 2.86) 1.30 (1.04, 1.62) 3.00 (1.53, 5.86) 1.02 (0.99, 1.04)

Maximally Adjusted Multivariate Model (Covariates)a Risk Estimate (95% CI)

HR of COPD readmissions in COPD patients with and without CHD (a,g) 1.66 (1.34-2.05) RR of incident CHD hospitalization in COPD (a,g,h) 2.14 (1.95-2.36) RR of CHD hospitalizations in COPD (a,g,h) Before first COPD OR of AMI before first COPD hospitalization: hospitalization (a,g) 1.53 (1.50-1.56); after first COPD hospitalization 0.64 (0.85-0.87) NA OR of hospitalization for CAD (a,g,h)

NS

NS

Crude Risk Estimate (95% CI)

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11,493

45,966

169,328

Curkendall et al4/2006

Sidney et al7/2005

Stroke Allen et al12/2010

11,493

108,726

Chen et al13/2009

70,679 inpatients

35,772

Curkendall et al4/2006

4,854

Patients Without COPD, No.

22,986

726,588

45,966

22,986

0

35,772

308,275 inpatients

791,466 outpatients 35,839,862 outpatients

1,036

Schneider et al31/2010

Mapel et al27/2005

Lange et al25/2010

Study/Year

Patients With COPD, No.

NS

NS

NS

NS

GOLD I GOLD II GOLD III/IV Outpatients Prevalence Incidence Inpatients Prevalence Incidence Outpatients Prevalence Incidence Inpatients Prevalence Incidence Any COPD Mild Moderate Severe NS

COPD Population Grading

24.9% of recurrent stroke patients had COPD 9.6

0.01

0.6

1.6

15.9

1.6 0.48 7.2

0.29 0.15

14.3 2.3

6.4 2.05

1.5 2.9 5.5

Crude Rate in Patients With COPD, %

Table 2—Continued

OR and RR of VF in COPD (a,g)

OR and RR of AF in COPD (a,g)

OR of arrhythmia in COPD (a,g)

1.24 (1.15-1.34) OR of stroke in COPD (a,g,h)

1.00 (0.81-1.25) RR of recurrent stroke in COPD (a,g,h)

(Continued)

1.11 (1.02-1.21)

NS

2.80 (1.87-4.20)

1.98 (1.73, 2.25)

1.67 (1.27-2.22)

1.38 (1.28, 1.49) 1.35 (1.18, 1.55) 1.19 (0.98, 1.43) 1.64 (1.14, 2.34) 1.07 (0.86, 1.32) 1.29 (0.79, 2.11) 1.02 (1.00-1.06)

5.16 (3.88, 6.87) 4.47 (3.08, 6.49)

1.37 (1.33-1.41) 1.31 (1.23-1.39)

5.64 (5.29-6.01) 4.74 (4.27-5.26)

0.4 (0.2-1.1) 1.0 (0.6-1.7) 1.7 (0.8-3.8)

Maximally Adjusted Multivariate Model (Covariates)a Risk Estimate (95% CI)

1.42 (1.25-1.61) OR of arrhythmia in COPD (a,g,h,s) 1.42 (1.01-2.00) 1.39 (1.22-1.59) 2.10 (1.36-3.23) NS HR of COPD readmissions in COPD patients with and without arrhythmia (a,g) 2.01 (1.68-2.41) RR of incident CVD hospitalization in COPD (a,g,h) 2.42 (2.13-2.76) RR of AF hospitalizations in COPD (a,g,h) 4.17 (2.83-6.16) RR of VF hospitalizations in COPD (a,g,h)

NS

NS

Crude Risk Estimate (95% CI)

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2,975 1,036

35,772

11,493

5,648 45,966

1,440

Schneider et al31/2010

Curkendall et al4/2006

Huiart et al5/2005

Sidney et al7/2005

Arterial hypertension Cordero et al14/2011

29,870

Finkelstein et al19/2009 Lange et al25/2010

Feary et al18/2010

Study/Year

Patients With COPD, No.

9,303

45,966

NS

22,986

35,772

2,975 4,854

1,174,240

Patients Without COPD, No.

COPD

NS

NS

NS GOLD I GOLD II GOLD III/IV Any COPD Mild Moderate Severe NS

NS

COPD Population Grading

COPD in patients with: controlled BP 12.5; uncontrolled BP: 14.6 (P , .01)

0.8

2.1

1.2

6.9

8.0 NS

9.9

Crude Rate in Patients With COPD, %

Table 2—Continued

OR of stroke in COPD (a,g,h,s) OR of stroke in COPD (a,g)

NA

OR for presence of COPD for controlled vs uncontrolled BP: (a,g,s)

1.25 (1.05-1.49) OR of stroke in COPD (a,g,h,s) 1.28 (0.77-2.15) 1.26 (1.05-1.51) 0.98 (0.47-2.05) 1.27 (1.05-1.54) RR of incident stroke hospitalization in COPD (a,g,h) NS RR of stroke hospitalizations in COPD (a,g) 1.51 (1.37-1.66) RR of stroke hospitalizations in COPD (a,g,h)

NS NS

(Continued)

Presence of COPD for controlled vs uncontrolled BP: 1.17 (0.99-1.4)

1.33 (1.21 - 1.47)

1.27 (1.16-1.38)

Aged 65-74 y: never smokers: 1.6 (1.2-2.0); exsmokers: 1.1 (1.0-1.3); current smokers: 1.2 (1.1-1.3) 1.5 (1.1-2.1) 0.6 (0.3-1.1) 1.7 (1.1-2.5) 1.5 (0.7-3.0) 1.13 (0.92-1.38) 1.22 (0.71-2.09) 1.13 (0.92-1.38) 1.00 (0.47-2.15) 1.23 (0.68-2.22)

Maximally Adjusted Multivariate Model (Covariates)a Risk Estimate (95% CI)

OR 3.34 (3.21-3.48) OR of having COPD and previous diagnosis of stroke; multiple estimates stratified by age and smoking status, only age group 65-74 y listed, (a,h,s)

Crude Risk Estimate (95% CI)

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16,546 7,419

308,275 inpatients

70,679 inpatients

308,275 inpatients

2,975 2,975 791,466 outpatients 35,839,862 outpatients

70,679 inpatients

791,466 outpatients 35,839,862 outpatients

1,927 5,498

Patients Without COPD, No.

NS Outpatients Prevalence Incidence Inpatients Prevalence Incidence

NS GOLD I GOLD II GOLD III/IV Outpatients Prevalence Incidence Inpatients Prevalence Incidence

COPD Population Grading

2.9 0.7

1.9 0.9

33.8

46.6 4.2

51.2 8.8

23.8 40.4 43.8 51.1

Crude Rate in Patients With COPD, %

NS NS

NS

NS NS

Crude Risk Estimate (95% CI)

OR of PAD in COPD (a,g,h,s) OR and RR of PAD in COPD (a,g)

OR and RR of CVD in COPD (a,g)

OR of COPD in CVD (a,g,h,s) OR of CVD in COPD (a,g,s)

1.11 (1.05-1.19) 0.96 (0.85-1.09)

5.50 (4.90-6.18) 5.33 (4.54-6.27)

2.5 (2.0-3.0)

1.04 (1.03-1.06) 0.95 (0.91-0.99)

4.22 (4.14-4.31) 3.57 (3.41-3.74)

0.79 (0.70-0.90) 1.1 (0.9-1.2) 1.4 (1.3-1.6) 1.6 (1.3-1.9)

Maximally Adjusted Multivariate Model (Covariates)a Risk Estimate (95% CI)

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.

Peripheral arterial disease Finkelstein et al19/2009 Mapel et al27/2005

Mapel et al27/2005

García Rodriguez et al20/2009 Mannino et al26/2008

Study/Year

Patients With COPD, No.

Table 2—Continued

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 statistically significant in three of five studies (Fig 4).4,12,18,19,31 One study reported an increased RR trend by increasing 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 incidence. 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 cardiovascular 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 prevalence 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 five studies reporting statistically significant risk estimates.4,16,19,27,31 One study reported increased risk for arrhythmia with increasing GOLD grade of airflow

Figure 3. Forest plot of studies assessing a relationship between congestive heart failure and COPD (adjusted risk estimates). A, Risk estimates for hospitalization events incidence. B, Disease diagnosis incidence. C, Disease diagnosis prevalence.4,7,13,19,20,21,27 See Figure 2 legend for expansion of abbreviations.

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Discussion

Figure 4. Forest plot of studies assessing a relationship between stroke and COPD (adjusted risk estimates). A, Risk estimates for hospitalizations events incidence. B, Disease diagnosis prevalence.4,5,7,12,18,19,25,31 See Figure 2 legend for expansion of abbreviations.

RR of 1.5 (95% CI, 0.7-3.0) for patients with GOLD grade III/IV (Fig 4).25 The RR for hospitalization due to stroke was fairly consistent across studies, ranging from 1.2 to 1.3 in patients with COPD vs matched cohorts without COPD.4,5,7 Arterial Hypertension Two studies reported on hypertension prevalence among patients with COPD as an end point,26,27 both reporting a significantly increased risk of hypertension in COPD. In a cohort study reported by Mannino et al,26 the adjusted RR for hypertension increased from 1.1 (95% CI, 0.9-1.2) among those with GOLD grade I of airflow limitation, RR of 1.4 (95% CI, 1.3-1.6) among those with GOLD grade II, to 1.6 (95% CI, 1.3-1.9) among those with GOLD grade III/IV disease (Table 2). Two studies described the prevalence of COPD among patients with arterial hypertension14,20; both failed to show a significant association (Table 2). Peripheral Arterial Disease Two studies investigated the risk of PAD in patients with COPD and reported adjusted RR estimates of 1.11 (range: 1.05-1.19) and 5.50 (range: 4.90-6.18) in patients with COPD as compared with those without COPD (Table 2).19,27

In this study, we systematically reviewed the literature to estimate the risk of CVD overall and partitioned 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 available 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 differences between the highest and lowest estimates likely reflect differences in definition of the outcome, in ascertainment methods and study designs, population differences in underlying rates, and completeness of the databases used. Nevertheless, the majority of the RR estimates support a relationship between COPD and risk of CVD. It is of note that two studies reported a weak relationship between increasing severity of airflow limitation (reflected by the GOLD grade) and risk for CVD, CHD, arrhythmias, stroke, and hypertension.23,26 COPD and CVD share a number of risk factors, including smoking and aging, among others. In general, in studies that provided both adjusted and unadjusted RR estimates, the risk estimates persisted after adjustment for these shared risk factors.4,5,7,13,15,16,18,19,20,21,23,-27,29,31,32 A number of potential biologic mechanisms linking COPD and CVD have been proposed, including the proinflammatory milieu8,34,35 and increased oxidative stress36 that is common in both COPD and CVD. In addition, patients with COPD tend to have increased arterial stiffness37,38 and metabolic rate,39 and a sedentary lifestyle,40 which may predispose to increased risk of CVD. COPD can cause pulmonary hypertension, which overloads the right side of the heart, eventually leading to heart failure.41,42 In any case, the results presented here highlight the need to better investigate the pathobiology of the association of these two common and severe disease entities. From a clinical perspective, they support the need to consider CVD in the routine assessment of patients with COPD,43 and that patients with CVD should also be routinely screened for COPD.44

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Considering the specific CVDs explored in this review, a particularly strong association of RR ranging from 1.8 to 3.9 was found for heart failure and COPD, persisting after adjustment for age, sex, smoking history, history of CVD, and other study-specific confounders.19,20,21,27 An analysis of a population-based cohort reported a relationship between the lung function and incidence of heart failure.45 Studies have established a link for elevated inflammatory markers, specifically fibrinogen and IL-6, with incident heart failure as well as with incident COPD.46-48 These data further support a interrelationship of diseases of heart and lung based on inflammatory mechanisms. Further, inflammation was also implied in the etiology of atrial fibrillation49 and CHD.50 Nocturnal desaturation in COPD was associated with increased ventricular ectopy.51 Most studies on arrhythmia and COPD included in this review failed to control for smoking history; the two studies that did so resulted in inconsistent estimates.19,31 For coronary artery disease, the findings of our review are similarly inconsistent. Only about one-half of the studies reported here produced a significantly increased estimate.4,19,24,27,31 Some negative studies,15,17,22,25 tended to include smaller populations of patients with COPD, which may explain why they reported higher point estimates for the risk of CHD in COPD but were accompanied with wide confidence intervals.15,22, All the RR estimates for CHD hospitalization in patients with COPD were not significant.4,7,13 This finding may reflect a complex association between COPD and CVD events outlined in the study by Sode and colleagues,29 who reported a higher relative risk of acute MI before the first hospitalization for COPD, but lower risk after the first COPD hospitalization. The most important limitation of the current systematic review is that its findings are limited by the quality and consistency of the observational data available and, clearly, there was considerable variation in the method of data collection, study population, and analysis undertaken, including the relative-risk estimation methods and adjustment variables included. Few studies measured CVD as a part of predefined study design23,26 and the CVD ascertainment varied widely from patient self-report, to record of medical diagnosis, to objective diagnostic criteria. Similarly, COPD was most often assessed by a recorded medical diagnosis, but also by using spirometry (FEV1/FVC ratio , 0.7) and patient self-report. There were several other sources of heterogeneity: study setting (population-based or selective patients cohort vs health-care database records), outcome estimate (prevalent diagnosis, incident diagnosis, incident hospitalizations), and differences in adjustment of the relative risk estimates. Some of the studies were limited by the nature of the original data; for example, health-care databases usually do not con-

tain records of lung function tests, and some patient characteristics important for this analysis (eg, smoking status). Most of the patient-cohort studies addressed the relationship between COPD and CVD as an ad hoc question rather than a primary question. Studies primarily designed and focusing on a relationship between CVD and COPD are lacking. In conclusion, currently available observational data indicate that COPD is associated with a higher risk for CVD. In line with the GOLD 2011 recommendations, this highlights the importance of considering CVD in the clinical management of patients with COPD (and vice versa). Further study is needed to understand the nature and clinical utility of the association. Acknowledgments Authors contributions: Dr Müllerova had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr Müllerova: contributed to the literature search, creating the tables, and writing the manuscript and served as principle author. Dr Agusti: contributed to review of the study proposal and the interim results and writing the manuscript. Dr Erqou: contributed to the literature search, creating the initial review output, and writing the manuscript. Dr Mapel: contributed to review of the study proposal and the interim results and writing the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Müllerova is employed by GlaxoSmithKline R&D and owns shares and stock options of GlaxoSmithKline plc. Dr Agusti has received payment for speaking at meetings, attending advisory boards, and/or research projects from Almirall SA, AstraZeneca plc, Boehringer-Ingelheim GmBH, Chiesi Pharmaceuticals SpA, Esteve, GlaxoSmithKline plc, Merck Sharp & Dohme, Novartis AG, Procter and Gamble Co, and Takeda Pharmaceutical Company Ltd. Dr Erqou has been a paid consultant for GlaxoSmithKline plc for literature reviews. Dr Mapel has received research grants from and served as an advisor to GlaxoSmithKline plc, AstraZeneca plc, Pfizer Inc, and Boehringer Ingelheim GmBH. Role of sponsors: The study sponsor, GlaxoSmithKline R&D funded the literature retrieval and editorial assistance. The study was undertaken as a part of an employment at GlaxoSmithKline R&D (H. M.). Other contributions: We thank Stephanie Watkins, PhD (GlaxoSmithKline plc) who helped extract data from the published manuscripts identified during the selection step. Editorial support was provided by David Cutler, PhD, at Gardiner-Caldwell Communications and Louise Watson, PhD, at EPI PharmaCo and was funded by GlaxoSmithKline plc. Additional information: The e-Appendix can be found in the “Supplemental Materials” area of the online article.

References 1. National Heart, Lung, and Blood Institute. Morbidity and mortality: 2009 chart book on cardiovascular, lung, and blood diseases. 2009. National Heart, Lung, and Blood Institute website. http://www.nhlbi.nih.gov/resources/docs/2009_ChartBook.pdf. Accessed January 5, 2012. 2. Sin DD, Anthonisen NR, Soriano JB, Agusti AG. Mortality in COPD: role of comorbidities. Eur Respir J. 2006;28(6): 1245-1257. 3. McGarvey LP, John M, Anderson JA, Zvarich M, Wise RA; TORCH Clinical Endpoint Committee. Ascertainment of

1176

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

Original Research

4.

5. 6.

7.

8.

9. 10.

11.

12.

13. 14.

15.

16.

17.

18.

19.

20.

cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee. Thorax. 2007;62(5):411-415. 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(1):63-70. Huiart L, Ernst P, Suissa S. Cardiovascular morbidity and mortality in COPD. Chest. 2005;128(4):2640-2646. Macchia A, Monte S, Romero M, D’Ettorre A, Tognoni G. The prognostic influence of chronic obstructive pulmonary disease in patients hospitalised for chronic heart failure. Eur J Heart Fail. 2007;9(9):942-948. Sidney S, Sorel M, Quesenberry CP Jr, DeLuise C, Lanes S, Eisner MD. COPD and incident cardiovascular disease hospitalizations and mortality: Kaiser Permanente Medical Care Program. Chest. 2005;128(4):2068-2075. Agustí A, Edwards LD, Rennard SI, et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS ONE. 2012;7(5):e37483. Barr RG, Bluemke DA, Ahmed FS, et al. Percent emphysema, airflow obstruction, and impaired left ventricular filling. N Engl J Med. 2010;362(3):217-227. Short PM, Lipworth SI, Elder DH, Schembri S, Lipworth BJ. Effect of beta blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study. BMJ. 2011; 342:d2549. Hawkins NM, Petrie MC, Macdonald MR, et al. Heart failure and chronic obstructive pulmonary disease the quandary of beta-blockers and beta-agonists. J Am Coll Cardiol. 2011; 57(21):2127-2138. Allen NB, Holford TR, Bracken MB, et al. Geographic variation in one-year recurrent ischemic stroke rates for elderly Medicare beneficiaries in the USA. Neuroepidemiology. 2010; 34(2):123-129. Chen Y, Li Q, Johansen H. Age and sex variations in hospital readmissions for COPD associated with overall and cardiac comorbidity. Int J Tuberc Lung Dis. 2009;13(3):394-399. Cordero A, Bertomeu-Martínez V, Mazón P, et al. Factors associated with uncontrolled hypertension in patients with and without cardiovascular disease [in Spanish]. Rev Esp Cardiol. 2011;64(7):587-593. de Lucas-Ramos P, Izquierdo-Alonso JL, Rodríguez-González Moro JM, et al. Cardiovascular risk factors in chronic obstructive pulmonary disease: results of the ARCE study [in Spanish]. Arch Bronconeumol. 2008;44(5):233-238. Dziewierz A, Siudak Z, Rakowski T, Jakała J, Dubiel JS, Dudek D. Prognostic significance of new onset atrial fibrillation in acute coronary syndrome patients treated conservatively. Cardiol J. 2010;17(1):57-64. Enriquez JR, Parikh SV, Selzer F, et al. Increased adverse events after percutaneous coronary intervention in patients with COPD: insights from the National Heart, Lung, and Blood Institute dynamic registry. Chest. 2011;140(3):604-610. Feary JR, Rodrigues LC, Smith CJ, Hubbard RB, Gibson JE. Prevalence of major comorbidities in subjects with COPD and incidence of myocardial infarction and stroke: a comprehensive analysis using data from primary care. Thorax. 2010;65(11):956-962. Finkelstein J, Cha E, Scharf SM. Chronic obstructive pulmonary disease as an independent risk factor for cardiovascular morbidity. Int J Chron Obstruct Pulmon Dis. 2009;4: 337-349. García Rodríguez LA, Wallander MA, Tolosa LB, Johansson S. Chronic obstructive pulmonary disease in UK primary care: incidence and risk factors. COPD. 2009;6(5):369-379.

21. García Rodríguez LA, Wallander MA, Martín-Merino E, Johansson S. Heart failure, myocardial infarction, lung cancer and death in COPD patients: a UK primary care study. Respir Med. 2010;104(11):1691-1699. 22. Izquierdo JL, Martínez A, Guzmán E, de Lucas P, Rodríguez JM. Lack of association of ischemic heart disease with COPD when taking into account classical cardiovascular risk factors. Int J Chron Obstruct Pulmon Dis. 2010;5:387-394. 23. Johnston AK, Mannino DM, Hagan GW, Davis KJ, Kiri VA. Relationship between lung function impairment and incidence or recurrence of cardiovascular events in a middle-aged cohort. Thorax. 2008;63(7):599-605. 24. Konecny T, Somers K, Orban M, et al. Interactions between COPD and outcomes after percutaneous coronary intervention. Chest. 2010;138(3):621-627. 25. Lange P, Mogelvang R, Marott JL, Vestbo J, Jensen JS. Cardiovascular morbidity in COPD: A study of the general population. COPD. 2010;7(1):5-10. 26. Mannino DM, Thorn D, Swensen A, Holguin F. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J. 2008;32(4):962-969. 27. Mapel DW, Dedrick D, Davis K. Trends and cardiovascular co-morbidities of COPD patients in the Veterans Administration Medical System, 1991-1999. COPD. 2005;2(1):35-41. 28. Methvin JN, Mannino DM, Casey BR. COPD prevalence in southeastern Kentucky: the burden of lung disease study. Chest. 2009;135(1):102-107. 29. Sode BF, Dahl M, Nordestgaard BG. Myocardial infarction and other co-morbidities in patients with chronic obstructive pulmonary disease: a Danish nationwide study of 7.4 million individuals. Eur Heart J. 2011;32(19):2365-2375. 30. Staszewsky L, Wong M, Masson S, et al; Valsartan Heart Failure Trial Investigators. Clinical, neurohormonal, and inflammatory markers and overall prognostic role of chronic obstructive pulmonary disease in patients with heart failure: data from the Val-HeFT heart failure trial. J Card Fail. 2007;13(10): 797-804. 31. Schneider C, Bothner U, Jick SS, Meier CR. Chronic obstructive pulmonary disease and the risk of cardiovascular diseases. Eur J Epidemiol. 2010;25(4):253-260. 32. Tseng CH. Clinical features of heart failure hospitalization in younger and elderly patients in Taiwan. Eur J Clin Invest. 2011;41(6):597-604. 33. Wang YC, Lin JM, Li CY, Lee LT, Guo YL, Sung FC. Prevalence and risks of chronic airway obstruction: a population cohort study in Taiwan. Chest. 2007;131(3):705-710. 34. Agustí AG, Noguera A, Sauleda J, Sala E, Pons J, Busquets X. Systemic effects of chronic obstructive pulmonary disease. Eur Respir J. 2003;21(2):347-360. 35. Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax. 2004;59(7):574-580. 36. MacNee W. Pulmonary and systemic oxidant/antioxidant imbalance in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005;2(1):50-60. 37. Sabit R, Bolton CE, Edwards PH, et al. Arterial stiffness and osteoporosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175(12):1259-1265. 38. Maclay JD, McAllister DA, Mills NL, et al. Vascular dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;180(6):513-520. 39. Schols AM, Fredrix EW, Soeters PB, Westerterp KR, Wouters EF. Resting energy expenditure in patients with chronic obstructive pulmonary disease. Am J Clin Nutr. 1991;54(6):983-987. 40. Garcia-Aymerich J, Lange P, Benet M, Schnohr P, Antó JM. Regular physical activity modifies smoking-related lung function

journal.publications.chestnet.org

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

CHEST / 144 / 4 / OCTOBER 2013

1177

41. 42. 43.

44. 45.

46.

decline and reduces risk of chronic obstructive pulmonary disease: a population-based cohort study. Am J Respir Crit Care Med. 2007;175(5):458-463. Naeije R, Barberà JA. Pulmonary hypertension associated with COPD. Crit Care. 2001;5(6):286-289. Buch P, Friberg J, Scharling H, Lange P, Prescott E. Reduced lung function and risk of atrial fibrillation in the Copenhagen City Heart Study. Eur Respir J. 2003;21(6):1012-1016. Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. Global strategy for the diagnosis, management and prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease website.http://www.goldcopd.org/guidelinesglobal-strategy-for-diagnosis-management.html/. Accessed August, 2012. Soriano JB, Rigo F, Guerrero D, et al. High prevalence of undiagnosed airflow limitation in patients with cardiovascular disease. Chest. 2010;137(2):333-340. Agarwal SK, Heiss G, Barr RG, et al. Airflow obstruction, lung function, and risk of incident heart failure: the Atherosclerosis Risk in Communities (ARIC) study. Eur J Heart Fail. 2012;14(4):414-422. Barac A, Wang H, Shara NM, et al. Markers of inflammation, metabolic risk factors, and incident heart failure in

47.

48.

49.

50.

51.

American Indians: the Strong Heart Study. J Clin Hypertens (Greenwich). 2012;14(1):13-19. Bahrami H, Bluemke DA, Kronmal R, et al. Novel metabolic risk factors for incident heart failure and their relationship with obesity: the MESA (Multi-Ethnic Study of Atherosclerosis) study. J Am Coll Cardiol. 2008;51(18):1775-1783. Valvi D, Mannino DM, Müllerova H, Tal-Singer R. Fibrinogen, chronic obstructive pulmonary disease (COPD) and outcomes in two United States cohorts. Int J Chron Obstruct Pulmon Dis. 2012;7:173-182. Peña JM, MacFadyen J, Glynn RJ, Ridker PM. Highsensitivity C-reactive protein, statin therapy, and risks of atrial fibrillation: an exploratory analysis of the JUPITER trial. Eur Heart J. 2012;33(4):531-537. Emberson J, Bennett D, Link E, et al; Heart Protection Study Collaborative Group. C-reactive protein concentration and the vascular benefits of statin therapy: an analysis of 20,536 patients in the Heart Protection Study. Lancet. 2011; 377(9764):469-476. Shepard JW Jr, Garrison MW, Grither DA, Evans R, Schweitzer PK. Relationship of ventricular ectopy to nocturnal oxygen desaturation in patients with chronic obstructive pulmonary disease. Am J Med. 1985;78(1):28-34.

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