COPD and cardiovascular diseases (CVDs) are

COPD and Incident Cardiovascular

Disease Hospitalizations and Mortality:

Kaiser Permanente Medical Care

Program*

Stephen Sidney, MD, MPH; Michael Sorel, MPH;

Charles P. Quesenberry, Jr., PhD; Cynthia DeLuise, RPA-C, MPH;

Stephan Lanes, PhD; and Mark D. Eisner, MD, MPH, FCCP

Study objectives:

To determine the relationship between diagnosed and treated COPD and the

incidence of cardiovascular disease (CVD) hospitalization and mortality.

Design:

Retrospective matched cohort study.

Setting:

Northern California Kaiser Permanente Medical Care Program (KPNC), a

comprehen-sive prepaid integrated health-care system.

Patients or participants:

Case patients (n

ⴝ

45,966) were all KPNC members with COPD who

were identified during a 4-year period from January 1996 through December 1999. An equal

number of control subjects without COPD were selected from KPNC membership and were

matched for gender, year of birth, and length of KPNC membership.

Measurements and results:

Follow-up conducted for hospitalization and mortality from CVD end

points through December 31, 2000. CVD study end points included cardiac arrhythmias, angina

pectoris, acute myocardial infarction, congestive heart failure (CHF), stroke, pulmonary

embo-lism, all of the aforementioned study end points combined, other CVD, and all CVD end points.

The mean follow-up time was 2.75 years for case patients and 2.99 years for control subjects. The

risk of hospitalization was higher in COPD case patients than in control subjects for all CVD

hospitalization and mortality end points. The relative risk (RR) for hospitalization for the

composite measure of all study end points was 2.09 (95% confidence interval [CI], 1.99 to 2.20)

after adjustment for gender, preexisting CVD study end points, hypertension, hyperlipidemia,

and diabetes, and ranged from 1.33 (stroke) to 3.75 (CHF). The adjusted RR for mortality for the

composite measure of all study end points was 1.68 (95% CI, 1.50 to 1.88), ranging from 1.25

(stroke) to 3.53 (CHF). Younger patients (

ie

, age

<

65 years) and female patients had higher risks

than older and male participants.

Conclusions:

COPD was a predictor of CVD hospitalization and mortality over an average

follow-up time of nearly 3 years. The finding of a stronger relationship of COPD to CVD

outcomes in patients

<

65 years of age suggests that CVD risk should be monitored and treated

with particular care in younger adults with COPD.

(CHEST 2005; 128:2068 –2075)

Key words:cardiovascular disease; COPD; mortality

Abbreviations: AMI⫽acute myocardial infarction; CHF⫽congestive heart failure; CI⫽confidence interval; CVD⫽cardiovascular disease; ICD-9⫽International Classification of Diseases, ninth revision; ICD-10⫽ Interna-tional Classification of Diseases, 10th revision; KPNC⫽Northern California Kaiser Permanente Medical Care Program; MI⫽myocardial infarction; OR⫽odds ratio; RR⫽relative risk; VF⫽ventricular fibrillation; VT⫽ventricular tachycardia

C

OPD and cardiovascular diseases (CVDs) are

two of the leading causes of morbidity and

mortality in the United States. The estimated total

annual cost to the United States for CVDs is $368.1

billion, and for COPD $32.1 billion.

The incidence of

and mortality from these diseases increase with age.

A number of studies have shown an association

*From the Division of Research (Drs. Sidney and Quesenberry, and Mr. Sorel), Kaiser Permanente Northern California, Oak-land, CA; Pfizer, Inc. (Ms. DeLuise), New York, NY; Boehringer Ingelheim, Inc. (Dr. Lanes), Ridgefield, CT, and the University of California San Francisco (Dr. Eisner), San Francisco, CA. This research was funded by grants from Pfizer, Inc. and Boehringer Ingelheim, Inc.

Manuscript received December 17, 2004; revision accepted April 20, 2005.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml).

Correspondence to: Stephen Sidney, MD, MPH, Kaiser Perma-nente Medical Care Program, Division of Research, 2000 Broad-way, Oakland, CA 94612; e-mail: sxs@dor.kaiser.org

between COPD and selected CVD end points

in-cluding total cardiac mortality,

mortality from acute

myocardial infarction (AMI),

mortality after

coro-nary artery bypass graft,

and pulmonary

embo-lism.

Low FEV

1

is associated with all-cause

mortal-ity, CVD mortalmortal-ity, nonfatal and fatal myocardial

infarction (MI), nonfatal and fatal stroke,

and

atrial fibrillation.

There are several reasons for a

COPD-CVD association, including a major shared

risk factor (smoking) and a number of factors that

may lead to increased stress on the cardiovascular

system or to cardiac arrhythmias (eg, use of

␤

-agonist

medications that may stimulate the cardiovascular

system, hypoxemia, hyperventilation leading to

respi-ratory alkalosis, and inflammation).

There is little in the published literature on the

risk of CVD in persons with COPD, and we are

unaware of studies that have prospectively examined

the relationship of clinically diagnosed COPD with

the incidence and mortality from CVD relative to an

appropriately matched comparison group of

individ-uals without COPD. In order to increase knowledge

of the association between COPD and CVD, we

examined the relationship of clinically diagnosed

COPD to the incidence of several CVD end points in

the Kaiser Permanente Medical Care Program of

Northern California (KPNC), a large integrated

health-care system.

Materials and Methods

Study Setting

The study population was drawn from members of the KPNC, agedⱖ40 years. The KPNC provides comprehensive prepaid integrated health care to its approximately 3.2 million subscrib-ers, who comprise⬎25% of the population in the areas served. The subscribers are ethnically, racially, and socioeconomically heterogeneous, and are reflective of the local population except for being somewhat more educated, on average, and underrep-resentative of the extremes of income.12 _{In the age group}

targeted for this study, there were approximately 1.3 million members during the year 2000.

Data Sources

We utilized the following computerized administrative data-bases to obtain study data, all of which could be linked utilizing a unique eight-digit number assigned to each KPNC health plan member. The membership database included date of birth, gender, and other demographic data. The overnight hospitaliza-tion database includes race, dates of hospitalizahospitaliza-tion, and all hospital discharge codes. The outpatient visit database includes diagnostic codes for conditions noted at the visit. The mortality database for KPNC contains linked death certificate information for members who have died in California since 1970. Each year, all active KPNC members are linked to California state death certificates using the following identifiers: social security number; name; date of birth; ethnicity; and place of residence. The

pharmacy database includes all prescriptions filled at KPNC pharmacies. At the time of the study, approximately 93% of KPNC members had a prescription benefit for KPNC pharma-cies.

Study Population

Case Patients: All COPD case patients who were age ⱖ40 years were identified during the 4-year period from January 1, 1996, through December 31, 1999. All case patients met the following criteria: (1) hospitalization with a primary hospital discharge diagnosis or an outpatient visit diagnosis with Interna-tional Classification of Diseases, ninth revision, (ICD-9) dis-charge codes for COPD (491, chronic bronchitis; 492, emphy-sema; or 496, COPD), and two prescriptions for COPD medications (ie, inhaled anticholinergics, inhaled ␤-adrenergic steroids, a combination of inhaled anticholinergic and␤ -adren-ergic agonists, and methylxanthines) within the 12-month win-dow that began 6 months prior to the index date, where the index date was the date of the first hospital admission or outpatient diagnosis that met the criterion for a COPD case patient; (2) age at least 40 years on the index date; and (3) at least 12 months of KPNC membership prior to the index date.

Control Subjects: Control subjects were selected from the membership of KPNC in a 1:1 ratio to case patients and met the following conditions: (1) random selection from KPNC member-ship groupings matched to COPD case patients on gender, year of birth, and length of KPNC membership (1 to 4.9 years, 5 to 9.9 years, and ⱖ10 years); (2) no outpatient visits or hospital discharges with COPD codes either in the 6-month period prior to the index date or during follow-up; and (3) at least 12 months of KPNC membership prior to the index date. Matching took place sequentially based on case patient entry into the cohort. A total of 5,880 COPD case patients and 1,285 control subjects were excluded from analyses that were limited to those without prevalent CVD.

Validation of COPD Diagnosis

One hundred twenty records of COPD cohort members were randomly selected for medical record review (96 outpatient records; 24 hospitalization records). A medical record abstractor obtained and abstracted the Kaiser Permanente medical records for a 12-month period of time prior to and subsequent to the date of COPD diagnosis. We defined spirometrically determined categories of airflow as follows: normal; mild airflow obstruction (FEV₁/FVC ratio,⬍70% predicted; FEV₁,ⱖ80% predicted); or airway obstruction (FEV₁/FVC ratio,⬍70% predicted; FEV₁, ⬍80% predicted) according to the Global Initiative for Chronic Obstructive Lung Disease criteria.13_{Tobacco smoking, chronic}

cough, exertional dyspnea, asthma, chronic bronchitis, emphy-sema, and COPD medications were considered to be present if noted in the medical record during this time period. Medication was recorded if noted in the medical record, including inhaled anticholinergic agents, inhaled␤-adrenergic steroids, a combina-tion of inhaled anticholinergic agents and␤-adrenergic agonists, and methylxanthine agents.

Chronic cough (68%) and exertional dyspnea (52%) were frequently noted. A diagnosis of chronic bronchitis was found in 39% of the records, and a diagnosis of emphysema was found in 17.5%. Spirometry was found in only 31% of the records, and airflow obstruction was found in 92% of the spirometry records. Medication was recorded from 77% of the records. We devel-oped a composite index of COPD, including the presence of at least one of the following conditions: chronic cough; chronic bronchitis; emphysema; or any degree of airflow obstruction. This

composite finding was present in 84% of the records (hospital-ization records, 77%; outpatient records, 86%).

Follow-up

Follow-up was conducted for the following CVD hospitaliza-tion and mortality end points: ventricular tachycardia (VT)/ ventricular fibrillation (VF)/cardiac arrest (ICD-9 codes 427.1, 427.41, and 427.5;International Classification of Diseases, 10th revision [ICD-10] codes I46.2 and I49.0), atrial fibrillation and flutter (ICD-9 codes 427.31 and 427.32; ICD-10 codes I48.0 and I48.1), other arrhythmia (ICD-9 codes 427.x except those noted above; ICD-10 codes I47.x and I49.x except I49.0x), angina pectoris (ICD-9 code 413.x; ICD-10 codes I20.1, I20.8, or I20.9 plus prescription for nitroglycerine within a 3-month period after hospital admission), AMI (ICD-9 code 410.x; ICD-10 codes I21.x to I22.x), congestive heart failure (CHF) [ICD-9 codes 428.x and 402.x1; ICD-10 codes I50.x], stroke (ICD-9 codes 431.x to 434.x, and 436.0; ICD-10 codes I60.x, I61.x, I63.x, and I64.x), pulmo-nary embolism (ICD-9 code 415.1; ICD-10 code I26.x with prescription for enoxaparin and/or warfarin), all CVD (ICD-9 codes 390.x to 459.x; ICD-10 codes I00.x to I99.x). For hospital-ization incidence analyses, follow-up was conducted to the first of the following dates: date of hospitalization for end point; death; end of membership; or December 31, 2000. For mortality analyses, follow-up was conducted to the first of the following dates: date of death; or December 31, 2000. We excluded all deaths occurring more than 1 month after the date of member-ship termination. The mean length of follow-up (to the end of membership or to December 31, 2000) was 2.75 years for case patients and 2.99 years for control subjects.

Validation of Hospital Discharge Codes

We validated the following primary hospital discharge diag-noses in a sample of case patients by medical record abstraction using a trained medical record analyst, with review of the findings by one of the study authors (S.S.): (1) unstable angina (ICD-9 codes 411.1 primary, or 414.xx primary and 411.x secondary) was validated in 75 of 88 case patients (85.2%), with most of the remaining case patients having AMI or stable angina; (2) angina (stable), which was defined as ICD-9 code 413.x in the primary hospital discharge code position, was validated in nine of nine case patients (100%) and was also reliably coded in the setting of 414.xx primary and 413.x secondary hospital discharge codes with a 93.7% validation rate (36 of 37 case patients); (3) arrhythmia, which was defined as ICD-9 code 427.x in the primary hospital discharge code position, included several different arrhythmias. The paroxysmal supraventricular tachycardia code had a high validation rate (91.7%), while all other arrhythmia groupings had validation rates in the range of 54 to 67%. We did not validate atrial fibrillation/atrial flutter because of previous validation work at the Division of Research showing these to be reliable codes (ICD-9 codes 427.31 and 427.32 had a validation rate of⬎95%). Validation rates for the other CVD end points have been determined for other studies at the Division of Research and include rates of⬎96% for AMIs, approximately 78 to 80% for ischemic stroke, 96% for CHF,14 _and ⬎_{90% for pulmonary}

embolism (personal communication).

Statistical Analysis

Disease incidence rates were determine by direct age adjust-ment using the 2000 KPNC membership as the standard. Age-adjusted rate ratios and multivariable relative risks (RRs)

were determined using proportional hazard models. Multivari-able models included case-control status, age, gender, and car-diovascular risk morbidities (ie, diabetes, hypertension, and hyperlipidemia) and the presence of baseline CVD detected during the 6-month period prior to the index date (eg, MI or stroke). Two-way interactions were tested for age⫻case-control status, and gender⫻case-control status. All data analysis was performed utilizing a statistical software package (SAS; SAS Institute; Cary, NC).

Results

We identified a total of 45,966 persons, age

ⱖ

40

years who satisfied the case definition for COPD.

The gender and age distribution of case patients and

control subjects are shown in Table 1. Fifty-five

percent of the case patients were men. The mean age

of case patients and control subjects was 64.4 years

(SD, 12.2 years).

The prevalence at baseline of comorbidities in

case patients and control subjects is shown in Table

2. The COPD case group had a higher prevalence of

each of the comorbid conditions. The most striking

prevalence differences between the case and control

groups were for a concomitant diagnosis of asthma

(40.0% vs 2.6%, respectively; odds ratio [OR], 24.71;

95% confidence interval [CI], 23.27 to 26.24), CHF

(7.2% vs 0.9%, respectively; OR, 8.48; 95% CI, 7.65

to 9.40), and atrial fibrillation (4.7% vs 1.1%,

respec-tively; OR, 4.41; 95% CI, 4.00 to 4.87).

The incidence of hospitalization for study end

points is shown in Table 3. The overall incidence rate

of CVD end points was 6,402 per 100,000

years in case patients and 2,793 per 100,000

person-years in control subjects. For study end points, the

rates were 4,557 per 100,000 person-years in case

patients and 1,837 per 100,000 person-years in

con-Table 1—Distribution of Case Patients and Control

Subjects by Age and Gender

Variables

Case Patients Control Patients

No. % No. % Gender Men 25,468 55.4 25,468 55.4 Women 20,498 44.6 20,498 44.6 Age, yr 40–44 3,024 6.6 3,025 6.6 45–49 3,712 8.1 3,710 8.1 50–54 4,349 9.5 4,350 9.5 55–59 4,901 10.7 4,908 10.7 60–64 5,698 12.4 5,727 12.5 65–69 6,799 14.8 6,771 14.7 70–74 7,102 15.5 7,132 15.5 75–79 5,679 12.4 5,652 12.3 80–84 3,151 6.9 3,140 6.8 85⫹ 1,552 3.4 1,552 3.4

trol subjects. Among the study end points, heart

failure was the leading cause of hospitalization in

case patients, followed by MI and stroke. For control

subjects, stroke was the leading cause of

hospitaliza-tion followed by MI and heart failure. Age-adjusted

rates were higher in COPD case patients than in

control subjects for all CVD end points. The

age-adjusted risks for case patients relative to control

subjects were generally in the 2 to 3 range, with the

exception of heart failure (RR, 5.55; 95% CI, 4.71 to

5.73), VT/VF/cardiac arrest (RR, 4.17; 95% CI, 2.83

to 6.16), and stroke (RR, 1.51; 95% CI, 1.37 to 1.66).

The RRs did not change substantially when the

analysis was limited to those who did not have

preexisting study end points.

The mortality from diagnoses at the study end

point is shown in Table 4. For many diagnostic

categories, the age-adjusted RRs were in the range of

2 to 3, except for stroke (RR, 1.46; 95% CI, 1.21 to

1.75) and CHD (RR, 4.93; 95% CI, 3.36 to 7.24).

The RRs did not change substantially when the

analysis was limited to those who did not have

preexisting study end points. There were too few

case patients and control subjects in the categories of

VT/VF/cardiac arrest, atrial fibrillation, other

ar-rhythmia, and pulmonary embolism to report

mean-ingful rates and rate ratios.

We tested interactions with gender

⫻

case-control

status and age

⫻

case-control status terms to

deter-mine whether the RR differed by gender and by age.

Table 2—Prevalence of Baseline Comorbidities, Case Patients, and Control Subjects

Comorbidities

Case Patients Control Subjects

OR (95% CI) No. % No. % Obesity 3,779 8.2 1,398 3.0 2.86 (2.68–3.04) Diabetes 753 1.6 501 1.1 1.51 (1.35–1.69) Hypertension 8,387 18.2 5,163 11.2 1.76 (1.70–1.83) Hyperlipidemia 3,998 8.7 3,279 7.1 1.24 (1.18–1.30) VT/VF/cardiac arrest 347 0.8 44 0.1 7.94 (5.80–10.87) Atrial fibrillation 2,169 4.7 510 1.1 4.41 (4.00–4.87) Other arrhythmia 1,254 2.7 310 0.7 4.13 (3.65–4.68) Angina 461 1.0 106 0.2 4.38 (3.55–5.42) MI 823 1.8 189 0.4 4.42 (3.77–5.17) Stroke 553 1.2 228 0.5 2.44 (2.09–2.85) Pulmonary embolism 117 0.3 25 0.1 4.69 (3.04–7.22) CHF 3,311 7.2 417 0.9 8.48 (7.65–9.40) Renal disease 259 0.6 101 0.2 2.57 (2.04–3.24) Asthma 18,371 40.0 1,206 2.6 24.71 (23.27–26.24)

Table 3—Incidence of Hospitalization During Longitudinal Follow-up for Study End Points in Case Patients and

Control Subjects Outcome Case Patients, No. Case Patient Rate* Control Subjects, No. Control Subject Rate* Age-Adjusted

Rate Ratio† Model†‡

Model Excluding CVD Prevalent at Baseline†‡ VT/VF/cardiac arrest 123 97.5 32 23.3 4.17 (2.83–6.16) 2.80 (1.87, 4.20) 2.78 (1.75, 4.42) Atrial fibrillation 741 592.1 342 249.7 2.42 (2.13–2.76) 1.98 (1.73–2.25) 2.11 (1.82–2.44) Other arrhythmia 372 295.9 206 151.1 2.04 (1.72–2.41) 1.71 (1.43–2.03) 1.70 (1.41–2.06) Angina 664 530.6 319 232.9 2.32 (2.03–2.66) 1.98 (1.73–2.27) 2.03 (1.75–2.35) MI 1,184 949.6 619 453.1 2.14 (1.95–2.36) 1.89 (1.71–2.09) 1.87 (1.69–2.08) CHF 2,233 1,807.3 482 352.0 5.55 (4.71–5.73) 3.75 (3.39–4.15) 3.85 (3.44–4.32) Stroke 1,010 808.1 753 551.7 1.51 (1.37–1.66) 1.33 (1.21–1.47) 1.39 (1.25–1.54) Pulmonary embolism 163 129.4 59 42.9 3.03 (2.25–4.08) 2.72 (2.00–3.68) 2.74 (1.99–3.76) Other CVD§ 2,846 2,333.9 1,477 1,092.9 2.16 (2.03–2.30) 1.85 (1.73–1.97) 1.86 (1.74–1.99) Any study end point㛳 5,410 4,557.3 2,460 1,837.3 2.53 (2.42–2.66) 2.09 (1.99–2.20) 2.09 (1.98–2.21) Any CVD 7,378 6,401.8 3,678 2,792.5 2.33 (2.24–2.42) 1.95 (1.88–2.03) 1.96 (1.88–2.05)

*Age-adjusted rate per 100,000 person-years. †Values given as RR (95% CI).

‡Model includes the independent variables age, gender, hypertension, hyperlipidemia, and diabetes.

§Includes all CVD diagnostic codes (ICD-9 codes 390x to 459x) not included in the main study end points (ie, the first eight end points on the list in this table).

The risks of hospitalizations for MI, stroke, any study

end point, and any CVD were modestly higher in

women compared with men (Table 5). The risks of

hospitalization for MI, CHF, stroke, other CVD, any

study end point, and any CVD were higher among

those persons 40 to 64 years old compared with those

ⱖ

65 years. The risk of mortality did not differ by

gender for any of the study end points (Table 6). The

risk of mortality from MI, other CVD, any study

end point, and any CVD were higher among those

persons 40 to 64 years old compared with those

⬎

65 years.

Discussion

The main finding of this study was that persons

with diagnosed and treated COPD identified in this

large integrated health-care population had a higher

risk of incident hospitalization and mortality for each

of the CVD end points studied, relative to

age-matched and gender-age-matched control subjects. All

rates for CVD end points were substantially higher in

case patients than in control subjects, most notably

so for CHF. Relative to the control subjects, the

prevalence of baseline medical conditions was

par-ticularly high for asthma and for CHF.

The findings of higher incidences of

hospitaliza-tion for and mortality from cardiovascular end points

in COPD patients may be, in part, due to the higher

prevalence of preexisting CVD in the COPD

pa-tients. However, the restriction of our analyses to

those persons without known preexisting CVD did

not substantively alter the RRs for any of the end

points examined. We controlled in our analyses for

some of the known CVD risk factors, including high

BP, hyperlipidemia, and diabetes. While these risk

factors were more prevalent in the COPD case

group than in the control group, controlling for them

Table 4 —Mortality Rates in Case Patients and Control Subjects

Outcomes Case Patients, No. Case Patient Rate* Control Subjects, No. Control Subject Rate* Age-Adjusted

Rate Ratio† Model†‡

Model Excluding CVD Prevalent at Baseline†‡ MI 487 385.8 241 213.8 2.27 (1.95–2.65) 1.81 (1.54–2.12) 1.85 (1.55–2.21) CHF 138 109.3 32 30.5 4.93 (3.36–7.24) 3.53 (2.38–5.25) 3.50 (2.22–5.50) Stroke 260 206.0 204 171.6 1.46 (1.21–1.75) 1.25 (1.03–1.51) 1.35 (1.09–1.66) Pulmonary embolism 29 19.8 12 10.2 2.35 (1.18–4.67) 1.89 (0.93–3.85) 1.54 (0.72–3.31) Other CVD§ 1,407 1,114.7 614 542.0 2.59 (2.35–2.84) 1.96 (1.77–2.16) 1.95 (1.74–2.18) Any study end points㛳 918 727.2 498 434.9 2.09 (1.87–2.33) 1.68 (1.50–1.88) 1.71 (1.51–1.94) All CVD 2,325 1,842.2 1,112 977.2 2.36 (2.20–2.54) 1.84 (1.70–1.98) 1.84 (1.69–2.00)

*Age-adjusted rate per 100,000 person-years. †Values given as RR (95% CI).

‡Model includes independent variables age, gender, hypertension, hyperlipidemia, and diabetes.

§Includes all CVD diagnostic codes (ICD-9 codes 390x to 459x) not included in the main study end points (ie, the first eight end points on the list in this table).

㛳Any study end point refers to the first eight end points on the list in this table.

Table 5—Incidence of Hospitalization for Study End Points by Gender and by Age*

Outcome Men Women p Value 40–64 yr ⱖ65yr p Value

VT/VF/cardiac arrest 2.99 (1.82–4.89) 2.43 (1.21–4.90) 0.70 2.17 (1.08–4.37) 3.10 (1.89–5.08) 0.80 Atrial fibrillation 2.20 (1.83–2.64) 1.75 (1.44–2.11) 0.15 2.19 (1.65–2.91) 1.90 (1.64–2.21) 0.94 Other arrhythmia 1.78 (1.38–2.30) 1.64 (1.29–2.09) 0.94 1.69 (1.15–2.48) 1.70 (1.39–2.07) 0.58 Angina 1.79 (1.50–2.19) 2.31 (1.85–2.89) 0.05 2.42 (1.86–3.15) 1.81 (1.54–2.13) 0.07 MI 1.77 (1.56–2.01) 2.09 (1.78–2.46) 0.01 2.43 (1.98–2.98) 1.73 (1.54–1.94) ⬍0.001 CHF 3.78 (3.30–4.33) 3.71 (3.19–4.31) 0.79 7.89 (5.89–10.58) 3.24 (2.91–3.62) ⬍0.001 Stroke 1.21 (1.06–1.37) 1.50 (1.30–1.74) 0.01 2.01 (1.57–2.56) 1.22 (1.09–1.35) 0.01 Pulmonary embolism 3.46 (2.11–5.68) 2.32 (1.58–3.41) 0.35 2.67 (1.59–4.48) 2.72 (1.87–3.96) 0.86 Other CVD† 1.85 (1.70–2.02) 1.84 (1.67–2.03) 0.34 2.57 (2.26–2.91) 1.61 (1.50–1.74) ⬍0.001 Any study end point‡ 2.02 (1.89–2.16) 2.18 (2.02–2.37) 0.01 2.71 (2.43–3.02) 1.93 (1.83–2.04) ⬍0.001 Any CVD 1.89 (1.79–1.99) 2.03 (1.91–2.16) 0.003 2.49 (2.29–2.71) 1.79 (1.71–1.88) ⬍0.001

*Values given as RR (95% CI), unless otherwise indicated. Model includes independent variables age, gender, hypertension, hyperlipidemia, and diabetes.

†Other CVD includes all CVD diagnostic codes (ICD-9 codes 390x to 459x) not included in the main study end points (ie, the first eight end points on the list in this table).

attenuated, but did not eliminate, the increased risk

of CVD end points associated with COPD. Thus,

COPD was a risk factor for CVD end points

regard-less of whether or not CVD comorbidity was present

at baseline and traditional risk factors explained

some, but not all, of the increased risk of CVD end

points in patients with COPD. However, our

data-bases did not include information on smoking, which

is an important risk factor for both CVD and COPD,

nor did we have data on body mass index. Cigarette

smoking is the most powerful predictor of COPD

and is also an important risk factor for CVD.

Al-though it could not be ascertained from medical

record review, we would assume that smoking rates

were higher in COPD patients than in control

subjects, an observation that is supported by our

phone survey (separate report) of a subset of the

cohort (21.9% in COPD patients vs 8.8% in control

subjects for current use) and is supported by another

study

of individuals hospitalized for AMI, which

showed that the prevalence of current smoking was

44% higher among AMI patients who had COPD

than in patients without COPD. Thus, cigarette

smoking undoubtedly contributed to higher CVD

rates in COPD patients. The prevalence of cigarette

smoking in case patients was lower than that in two

other studies that reported smoking in 32%

and

30%

of COPD case patients, while the prevalence

of smoking in the control group was somewhat lower

than that reported by participants in the 1998

Na-tional Health Interview Survey

(40 to 64 years of

age, 25.0%;

ⱖ

65 years of age, 10.9%).

Another potential mechanism for increased CVD

risk from COPD is inflammation. COPD is

charac-terized by chronic pulmonary inflammation

and

high levels of cytokines in exhaled breath

conden-sate,

and is associated with general systemic

in-flammation.

Systemic inflammation has emerged

as a causative factor for CVD. For example, the

blood level of C-reactive protein, a marker of

sys-temic inflammation, is a risk factor for cardiovascular

events.

Atrial fibrillation and heart failure were

more common in COPD case patients than in

con-trol subjects. Both of these conditions are related to

the risk of stroke

and probably contribute to the

higher rate of stroke in COPD patients.

COPD patients use medications that stimulate the

cardiovascular system, including anticholinergic

agents and sympathomimetic medications. These

medications may contribute to increased heart rate

and BP, which might instigate an ischemic episode of

heart disease (eg, angina or MI) or cerebrovascular

disease (transient ischemic attack or stroke).

Cardio-vascular stimulation may also lead to arrhythmias,

including potentially lethal arrhythmias such as VT

or VF. A graded increase in the risk of acute

coronary syndrome was demonstrated for a number

of metered-dose inhalers of

␤

-agonists prescribed in

the 90 days prior to hospitalizations in a Department

of Veterans Affairs study,

with the risk nearly

doubling for those receiving six or more canisters.

However, a Canadian study

showed no overall risk

of fatal or nonfatal MI associated with

␤

-agonist use

in the year prior to the event, although a small

increased risk (11%) was noted for each 10 canisters

dispensed during this time period. An alternative

explanation for an association of

␤

-agonist use with

CVD is that the intensity of use reflects the severity

of COPD.

COPD patients, especially in cases of more

ad-vanced disease, may manifest hypoxemia.

Hypox-emia may contribute to episodes of ischemic CVD

(eg, angina, MI, transient ischemic attack, or stroke)

and may instigate cardiac arrhythmias.

Hyperventi-lation in COPD patients may lead to respiratory

alkalosis, a disturbance in metabolic parameters that

may contribute to cardiac arrhythmias. Since FEV

in mid-life is a predictor of later CVD and of

mortality, it is possible that there are other factors

that are specifically related to chronic lung disease

(eg, inflammation or smoking) that contribute to

CVD.

Table 6 —Mortality for Study End Points by Gender and by Age*

Outcome Men Women p Value 40–64 yr ⱖ65 yr p Value

MI 1.91 (1.57–2.34) 1.62 (1.25–2.11) 0.74 4.08 (2.30–6.94) 1.62 (1.37–1.92) 0.002 CHF 2.76 (1.66–4.56) 5.00 (2.60–9.60) 0.16 4.97 (0.58–42.46) 3.48 (2.33–5.21) 0.49 Stroke 1.09 (0.84–1.41) 1.47 (1.11–1.94) 0.09 1.72 (0.78–3.76) 1.13 (1.00–1.48) 0.65 Pulmonary embolism 1.86 (0.61–5.70) 1.92 (0.76–4.80) 0.74 2.42 (0.46–12.69) 1.76 (0.80–3.88) 0.61 Other CVD† 1.93 (1.71–2.18) 2.00 (1.70–2.35) 0.35 2.68 (1.97–3.65) 1.87 (1.69–2.08) 0.007 Any study end point‡ 1.64 (1.41–1.90) 1.73 (1.45–2.07) 0.31 3.26 (2.16–4.91) 1.57 (1.39–1.76) 0.001 Any CVD 1.81 (1.64–1.98) 1.87 (1.66–2.11) 0.22 2.89 (2.26–3.70) 1.74 (1.60–1.88) ⬍0.001

*Values given as RR (95% CI), unless otherwise indicated.

†Includes all CVD diagnostic codes (ICD-9 codes 390x to 459x) not included in the main study end points (ie, the first eight end points on the list in this table).

We do not have an explanation for the slightly

higher risks for hospitalization for some of the CVD

end points in women compared to men. We

specu-late that the higher rates of CVD hospitalization and

mortality end points in younger members of the

cohort (ie, those 40 to 64 years of age) vs older

members (ie, those

ⱖ

65 years of age) mean that

COPD reflects earlier and more serious diseases in

younger adults, making it more important as a risk

factor in this age group. Alternatively, COPD in

younger adults may act in part as a confounder,

reflecting a more intense (ie, longer and/or more

frequent) smoking history, with smoking being a

known risk factor for CVD.

The major strength of this study is its large size,

the high comparability of the KPNC population to

the local population that it serves, the data

availabil-ity on a number of comorbidities, and the availabilavailabil-ity

of validation studies on several of the hospital

out-comes that were assessed from administrative

data-bases. Limitations include reliance on an

administra-tive database that lacks data on cigarette smoking;

the lack of systematic information on comorbidities

for all patients, since the assessment of comorbidity

required a medical encounter during the 6-month

period prior to the index date; and the lack of

spirometry data for use in defining COPD case

patients. The low prevalence of spirometry in the

subset of case patients for which medical record

review may potentially reflect a lack of precision in

case patient definition in this cohort, or,

alterna-tively, may indicate that spirometry is not frequently

used in the management of case patients with

chronic disease and was not performed during the

24-month period that was covered by the review.

However, almost all of the spirometry tests reviewed

showed evidence of airflow obstruction. The high

prevalence of asthma in COPD patients also raises

questions about the specificity of the COPD and

asthma diagnoses. However, the RRs of COPD in

relation to CVD outcomes were generally similar in

analyses that excluded patients with concomitant

asthma (data not shown).

In conclusion, we found COPD to be a predictor

of CVD hospitalization and mortality over an average

follow-up time of nearly 3 years. The relationship of

COPD to CVD outcomes was stronger in adults who

were

⬍

65 years of age. These data suggest that CVD

risk should be monitored and treated with particular

care in younger adults with COPD.

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