Springer 2006

European Journal of Epidemiology (2006) 21:803813

DOI 10.1007/s10654-006-9066-1

CARDIOVASCULAR DISEASES

Chronic obstructive pulmonary disease severity and cardiovascular outcomes

Suellen M. Curkendall1, Stephan Lanes2, Cynthia de Luise3, Mary Rose Stang4,
Judith K. Jones5, Dewei She6 and Earl Goehring Jr.5
1

Cerner LifeSciences, 1953 Gallows Road, Suite 570, Vienna, VA, 22182, USA; 2Epidemiology, Boehringer-Ingelheim Pharmaceuticals, Inc., Ridgeeld, CT, USA; 3Global Epidemiology NY, Pzer Inc., New York, NY, USA; 4Saskatchewan Health,
Regina, Saskatchewan, Canada; 5The Degge Group, Ltd., Arlington, VA, USA; 6The EMMES Corporation, Rockville, MD,
USA
Received: 12 January 2006/Accepted in revised form 14 September 2006

Abstract. Objective: To identify predictors of chronic

obstructive pulmonary disease (COPD) severity and
assess the relation between COPD severity and risk of
cardiovascular outcomes. Study design and setting:
A cohort of patients with diagnosed and treated
COPD was compiled from the Saskatchewan Health
longitudinal databases. We used multivariate modeling to identify predictors of hospitalization for
COPD as an indicator of COPD severity, and we
used the model to characterize patients according to
quintiles of COPD severity. These severity levels were
used as independent variables in multivariate models
of cardiovascular outcomes. Results: Determinants of
COPD severity included emphysema, recent nebulizer

use, home oxygen services, corticosteroid use, frequent bronchodilator use, pneumonia and prior
COPD exacerbation. The 20% of patients with the
highest COPD severity were 1.27 (CI: 1.071.50)
times more likely to have arrhythmia, 1.25 (CI: 1.07
1.46) times more likely to have ischemic heart disease,
1.38 (CI: 1.111.71) times more likely to have angina,
2.28 (CI: 1.952.66) times more likely to have congestive heart failure, and 1.63 (CI: 1.222.16) times
more likely to die of cardiovascular causes than the
least severe 20% of patients. Conclusions: Patients
with more severe COPD, as dened by our model,
had higher cardiovascular morbidity and mortality
than patients with less severe COPD.

Key words: Cardiovascular comorbidities, Chronic obstructive pulmonary disease, Mortality, Severity,
Saskatchewan, Longitudinal
Abbreviations COPD = Chronic obstructive pulmonary disease; GOLD = Global initiative for chronic
obstructive lung disease; FEV = Forced expiratory volume; FEV1 = Forced expiratory volume in one second;
PaO2 = Arterial oxygen tension; PaCO2 = Arterial carbon dioxide tension; BMI = Body mass index;
ECG = Electrocardiogram; LVD = Left ventricular dysfunction

Introduction
Patients with impaired pulmonary function have an
elevated risk of cardiovascular disease [14]. A study
in the Saskatchewan population provided evidence
that the prevalence of cardiovascular diseases and
incidence of hospitalization due to cardiovascular
diseases is higher among patients with chronic
obstructive pulmonary disease (COPD) [5]. At the
same time, the relationship between the degree of
severity of COPD and cardiovascular outcomes is
unclear.
In current clinical guidelines, such as the Global
Initiative for chronic obstructive lung disease
(GOLD) [6], spirometry results have been used to
assign severity levels to COPD, which have been
incorporated in treatment guidelines [7, 8]. Additionally, severity graded using forced expiratory
volume (FEV) and forced expiratory volume in one

second (FEV1), similar to the GOLD guidelines, has

been shown to be related to functional limitations
such as inability to walk a quarter of a mile [9]. FEV1
has also been shown to be related to cardiovascular
outcomes [3], and low FEV1 levels have been shown
to predict mortality among patients with obstructive
lung disease [10].
Other variables have also been investigated as
potential predictors of mortality in COPD, including
low values on a 6- or 12-min walk test, patientreported level of dyspnea, modied Medical Research
Council (MMRC) dyspnea scale, low diusion
capacity of the lung for carbon monoxide as a
percentage of alveolar volume, low arterial oxygen
tension (PaO2), high arterial carbon dioxide tension
(PaCO2) low body mass index (BMI), high number of
medications, cor pulmonale, age, and continued
smoking [1014]. Studies of COPD patients
discharged from the hospital have identied the

804
following variables as predictors of mortality:
PaCO2, maintenance use of glucocorticosteroids,
chronic renal failure, electrocardiogram (ECG) signs
of right ventricular hypertrophy, FEV1 below 590 ml,
ECG signs of ischemic heart disease, and age [15, 16].
The objectives of the present study were twofold:
(1) determine how to measure severity of COPD
using data elements that are available in administrative data, and (2) dene the relationship between the
degree of severity of COPD and cardiovascular
outcomes.

Materials and methods

Subjects
The Province of Saskatchewan funds medical benets
of 99% (approximately 1 million) of its residents. As
a result, Saskatchewan Health, a provincial government department, has accumulated and maintains
longitudinal, centralized databases of health care
information. The databases include health insurance
registration data, physician claims, hospital separations, outpatient prescription drugs and vital statistics, including date and cause of deaths registered in
Saskatchewan [17]. These data have been widely used
for epidemiologic studies, including studies of drug
exposure and health outcomes [18, 19], chronic
diseases [20, 21], and drug utilization [22].
A cohort of patients with COPD was selected from
among all individuals in the database eligible for
prescription drug benets (approximately 90% of the
covered population). Inclusion criteria were as follows: (1) at least one study diagnosis (chronic
airway obstruction, emphysema or chronic bronchitis
ICD-9 codes 491.0 492.8 or 496) was present in
the physician claims or hospital separation databases
any time during the period 19972000; (2) at least two
prescriptions for an inhaled bronchodilator (anticholinergic, b-agonist or corticosteroid) during the
period 19972000 and within 6 months of a study
diagnosis; and (3) 40 years old or older at the time
he or she qualied. All hospital and home oxygen
service records, prescription and physician claims,
eligibility information, and vital statistics were
obtained for the cohort for the period 19972001.
Each patient was assigned a study index date, the
earliest date between January 1, 1998 and December
31, 2000 by which time the patient fully met the
COPD diagnostic and treatment criteria.
Methods
Developing a measure of COPD severity
The study consisted of two analyses. The rst analysis
dened COPD severity as the likelihood of being
hospitalized for COPD. In order to determine the
likelihood of COPD hospitalization, a nested

casecontrol analysis was performed within the

COPD cohort. Cases were patients with a COPD
hospitalization (primary inpatient diagnoses of
chronic airway obstruction, emphysema, chronic
bronchitis, or bronchitis not specied as acute or
chronic) during the period beginning with their study
index date and ending December 31, 2001. The date
of the patients rst hospitalization during this period
was dened as the event date for COPD hospitalization. Two controls without COPD hospitalizations, matched on gender and age group (5-year
categories between ages 40 and 80 and a single group
over age 80), were randomly selected for each case.
An additional requirement for controls was that each
control must have survived long enough past its study
entry date to have had the hospitalization event of its
corresponding case.
Potential severity markers were examined for their
contribution to COPD hospitalization using a logistic
regression analysis. There are three categories of
potential severity variables: (1) pre-existing chronic
conditions, (2) recent acute conditions, and (3) recent
high use of bronchodilators (see Appendix Table A1
for variable denitions). Each patients available
diagnostic history prior to the event date was searched for the following chronic conditions: cor
pulmonale, chronic airway obstruction, chronic
bronchitis, emphysema, other lung disease due to
external agents, and obesity. Variables representing
acute conditions, recent home oxygen service, recent
COPD hospitalization, recent ventilation or intubation, and recent use of bronchodilators were created
by searching specic periods of 90, 180 and 365 days
prior to each patients COPD hospitalization date.
The bronchodilator use variables identied
patients who were using above-average amounts of
these medications, using the assumption that severely
ill patients may require more respiratory medications
than other patients. Although the medication
amounts consumed were not known, the amount of
medication dispensed during the months prior to a
hospitalization was used to indicate how much was
consumed or anticipated. The cut-o points for
dening high drug use during 180 days are shown in
Appendix Table A2. These cut-o points were
determined by analyzing the combined data for cases
and controls during the period 180 days before the
event date (an estimated event date was used for
controls). Each drug and dose form was analyzed
separately. For example, separate cut-o points were
tabulated for salbutamol puers, salbutamol solution
for nebulization and salbutamol powder for inhalation. Patients were ranked according to the total
dosage dispensed during 180 days. For each drug/
dose form, the cut-o point was set at the amount
above which only 40% of the patients were ranked.
A conditional logistic regression model of the
COPD hospitalizations was constructed [23] using
the chronic condition, acute condition and

805
bronchodilator use variables. Since bronchodilator
variables were correlated with one another, they
could not all be used in the same specication. We
searched for the specication that provided the most
predictive power while including variables for the
major classes of medications (anticholinergics,
xanthines, short-acting b-agonists and steroids).
Variables that were not statistically signicant at the
5% level were not included in the nal specication.
The estimated values of the endogenous variable in
this model were used to determine patients relative
likelihood of having a COPD hospitalization.
The patients were ranked according to lowest to
highest likelihood of COPD hospitalization and
stratied into quintiles based on the models estimates in a manner similar to the creation of propensity scores. Patients with the highest likelihood of
having a COPD hospitalization were dened as the
most severely ill.
Relationship of COPD severity and cardiovascular
outcomes
The second analysis estimated the relationships
between the estimated COPD severity level and risk
for cardiovascular outcomes. The period prevalence of
cardiovascular diseases and incidence rates of hospitalization for selected cardiovascular causes were
computed for the period beginning with each patients
study index date and ending on December 31, 2001, or
when the patient died or became ineligible for coverage. The following cardiovascular outcomes were
investigated (identied using the ICD-9 codes shown
in parentheses): arrhythmia (426, 427), acute myocardial infarction (410), ischemic heart disease other
than acute myocardial infarction (411, 412, 413, 414),
angina (413), congestive heart failure (428), and other
cardiovascular disease (391398, 401405, 415417,
420425, 429438, 440444, 446448, 451459, 798).
Incident hospitalizations for cardiovascular conditions were determined using the primary diagnosis for
each hospitalization. Chart review was conducted on a
sample of incident cardiovascular hospitalizations [5].
Cardiovascular mortality was determined using the
underlying cause of death.
Multivariate logistic regression models of prevalence and Poisson models of incidence of each
cardiovascular outcome were constructed. Severity of
COPD was an independent variable in each model. A
class variable (high, medium, low) was used to specify
severity. Two dierent specications of this variable
were used: in the rst, the two quintiles of patients
(40%) with the highest severity were dened as high,
those in the middle quintile (20%) were dened as
medium, and those in the lowest two quintiles (40%)
were dened as low. In the second, the breakout used
the top 20% for high, the middle 60% for medium,
and the bottom 20% for low. Age group and gender
were included in all models. Additionally, the
following cardiovascular risk factors, computed

during each patients baseline year prior to the

beginning of the prevalence / incidence period, were
included when signicant at the 5% level: diabetes,
hypertension, hypercholesterolemia, and obesity.

Results
Measure of COPD severity
The original cohort of 11,493 patients diagnosed with
and treated for COPD comprised 46% females. The
cohort was largely made up of elderly people,
including 25.0% over 80, 34.4% ages 7079, 24.8%
ages 6069, 11.1% ages 5059 and 4.8% ages 4049.
Of the original COPD cohort, 2525 cases with a
COPD hospitalization were identied. Follow-up
time from index date to COPD hospitalization was
90 days for 40% of cases, 91 days to 1 year for
25%, between 1 and 2 years for 22%, between 2 and
3 years for 13% and between 3 and 4 years for 6%.
Females comprised 44% of the cases. The cases were
slightly older than the overall COPD cohort with
27.7% over 80, 39.8% ages 7079, 23.1% ages 6069,
7.6 ages 5059 and 1.8% ages 4049.
The distributions of the variables tested in the
model of COPD hospitalization are shown in
Table 1. The results of the nal model of COPD
hospitalization are shown in Table 2. Of the variables
representing chronic and acute conditions, those that
were signicant were recent home oxygen services,
recent pneumonia diagnosis, recent acute exacerbation of COPD, recent COPD hospitalization, and
emphysema diagnosis. Chronic bronchitis was marginally signicant in some formulations but was not
signicant in the presence of previous COPD hospitalization. Very low proportions of patients had
codes for cachexia, intubation procedures, ventilation, cor pulmonale, and other lung diseases due to
external agents. Consequently, these variables were
not signicant in the models. Obesity and pulmonary
congestion/hypostasis diagnoses were also not
signicant. Two related variables were investigated to
represent COPD exacerbations; recent antibiotic use
and antibiotic use in the presence of a respiratory
diagnosis. Both were signicant on their own but
antibiotic use was not signicant when the two variables were used in the same model. Antibiotic use in
the presence of a respiratory diagnosis was chosen
because it is more specic.
The bronchodilator drug use variables were all signicant except any long-acting b-agonist. However,
many were collinear and were not all signicant when
used together. The model specications with the most
overall predictive power included variables representing all therapeutic classes (anticholinergics, xanthines,
short-acting b-agonists and steroids). The bronchodilator variable specications that made the most signicant contribution to the overall predictive power of

806
Table 1. Distributions of binary variables tested in regression models of chronic obstructive pulmonary disease (COPD)
hospitalization
Cases (N = 2525)
Condition (ICD-9 code), procedure or prescription

Chronic conditions occurring any time in the patients available history

Cor pulmonale (415.0)
15
Chronic airway obstruction (496)
2207
Chronic bronchitis (491)
645
Emphysema (492.)
668
Other lung disease due to external agents (500508)
7
Obesity (278.)
61
Indicators of acute conditions occurring within 365 days prior to event
Acetylcysteine Rx
16
Acute exacerbation
1050
Antibiotic Rx
1705
Cachexia diagnosis (799.4)
0
Home oxygen
786
Intubation procedure
4
Pneumonia diagnosis (480486)
720
Previous COPD hospitalization
279
Pulmonary congestion & hypostasis diagnosis (514)
97
Ventilator
29
COPD drug use variables 180 days prior to event
Any nebulizer Rx
906
Any inhaled corticosteroid
1670
Any long-acting inhaled b-agonist
153
Any oral corticosteroid
926
High ipratropium or high xanthine
832
High combivent
434
High ipratropium
723
High short-acting inhaled b-agonist
1097
High xanthine
209

% Yes

Controls (N = 5050)
N

% Yes

0.6
87.4
25.5
26.5
0.3
2.4

7
4279
909
767
14
173

0.1
84.7
18.0
15.2
0.3
3.4

0.6
41.6
67.5
0.0
31.1
0.16
28.5
11.0
3.8
1.1

7
1623
2971
1
645
3
932
190
113
33

0.1
32.1
58.8
0.02
12.8
0.1
18.5
3.8
2.2
0.7

35.9
66.1
6.1
36.7
33.0
17.2
28.6
43.4
8.3

891
2610
219
890
724
424
588
1038
190

17.6
51.7
4.3
17.6
14.3
8.4
11.6
20.6
3.8

Table 2. Results of conditional logistic regression model of chronic obstructive pulmonary disease (COPD) hospitalization*

Variable
Any inhaled corticosteroid during past 180 days
Any oral corticosteroid during past 180 days
High amount of ipratropium or xanthine
dispensed during past 180 days
High amount of combivent dispensed during past 180 days
High amount of short-acting inhaled b-agonists
dispensed during past 180 days
Any nebulizer dispensed during past 180 days
Previous COPD hospitalization during past 365 days
Home oxygen use during past 180 days
Acute exacerbation during past 180 days
Pneumonia diagnosis during past 365 days
Emphysema diagnosis during patients available history

Parameter
estimate

p-Valuea

Hazard
ratio

HR
95% CI

0.291
0.498
0.470

<0.0001
<0.0001
<0.0001

1.338
1.645
1.600

1.1901.505
1.4481.870
1.3821.851

0.960
0.736

<0.0001
<0.0001

2.611
2.087

2.2013.099
1.8292.382

0.339
0.906
0.599
0.326
0.261
0.387

<0.0001
<0.0001
<0.0001
<0.0001
0.0001
<0.0001

1.403
2.474
1.820
1.385
1.299
1.473

1.2241.608
1.9573.128
1.5762.103
1.2161.578
1.1371.484
1.2821.694

*This model was estimated using conditional logistic regression (PHREG in SAS) with 7575 patients. A model t statistic
()2 log likelihood) was 5548 without covariates and 4328 with covariates. The unconditional logistic regression version of
the same model had a C statistic of 0.741 with 73.2% concordant pairs, 25.0% discordant pairs and 1.8% ties.
a
p-Value of v2 statistic for coecient estimate.

the model were used. High amount of steroids dispensed was signicant on its own, but not in the
presence of any oral steroids and any inhaled steroids which together added more to the predictive

power of the model. Additionally, the 90, 180 and 365day use variables were highly correlated and had very
similar results. The nal model used 180 days for all
drug use variables.

807

Figure 1. Proportion of patients with each severity indicator in each severity quintile.

The predicted values of the model in Table 2 were

used to separate patients into ve quintiles of
increasing severity. Figure 1 shows the proportions of
patients in each severity quintile that had a yes
value for each indicator. By construction, the COPD
severity level generally increased with these yes
proportions. Also by construction, the rate of COPD
hospitalization increased with higher levels of severity
(Table 3).

Relationship of COPD severity and cardiovascular

disease
COPD severity was related to each of the cardiovascular diseases (Table 4). With few exceptions, the
odds ratios exceeded one, indicating that the prevalence of cardiovascular disease increased with the
COPD severity level, after adjusting for age, gender
and cardiovascular risk factors. Comparing extreme

Table 3. Rate ratios of chronic obstructive pulmonary disease (COPD) hospitalization for dierent levels of COPD severity

High vs. low

High vs. middle
Middle vs. low

Severity categories* 40, 20, 40%

Severity categories* 20, 60, 20%

RR

95% CI

RR

95% CI

4.48
2.20
2.03

(3.905.14)
(1.912.55)
(1.692.45)

7.29
2.62
2.78

(5.958.94)
(2.332.94)
(2.293.37)

*Severity categories refers to the proportions of patients in each severity category. For example, a category labeled 40, 20,
40% means that high includes the most severe 40% of patients, middle includes the next 20% of patients and low
includes the least severe 40% of patients.

*Odds ratios (OR) were adjusted for gender, age group and, where signicant, diabetes, hypertension, hypercholesterolemia, and obesity, using logistic regression.
a
Severity categories refers to the proportions of patients in each severity category. For example, a category labeled 40, 20, 40% means that high includes the most severe 40% of
patients, middle includes the next 20% of patients and low includes the least severe 40% of patients. Average follow-up time per patient was 905 days overall, 933 in the top 40%,
889 in the middle 20%, 886 in the bottom 40%, 922 in the top 20%, 904 in the middle 60% and 894 in the bottom 20%.
b
The number of patients with prevalent cardiovascular diseases is listed in this column. For example, of 7575 patients with COPD, 1806 had prevalent arrhythmia.

0.901.19
0.861.42
0.911.19
0.891.28
1.201.56
0.881.12
0.791.04
1.04
1.11
1.04
1.07
1.37
0.99
0.91
1.071.40
0.921.47
1.061.36
1.091.53
1.471.89
0.861.10
1.021.35
1.23
1.16
1.20
1.29
1.67
0.98
1.18
1.071.50
0.961.73
1.071.46
1.111.71
1.952.66
0.831.12
0.901.26
1.27
1.29
1.25
1.38
2.28
0.97
1.07
0.791.07
0.861.45
0.861.13
0.751.12
1.131.49
0.881.14
0.831.12
0.92
1.12
0.98
0.92
1.30
1.00
0.97
1.21
1.13
1.09
1.22
1.32
1.01
1.11
1.11
1.26
1.07
1.12
1.71
1.02
1.07
Arrhythmia (n = 1806)
Acute myocard. infarction (n = 919)
Ischemic heart disease (n = 2276)
Angina (n = 919)
Congestive heart failure (n = 2731)
Other cardiovas. dis. (n = 5021)
Any cardiovas. hosp. (n = 1780)

0.981.25
1.021.56
0.961.20
0.961.30
1.531.91
0.911.13
0.951.21

1.041.40
0.871.45
0.951.25
1.001.48
1.151.51
0.891.16
0.961.29

95% CI
OR
95% CI
OR
95% CI
OR
95% CI
RR
95% CI
OR

High vs. middle

95% CI
OR
Cardiovascular diseasesb

Middle vs. low

High vs. middle
High vs. low
High vs. low

Middle vs. low

Severity categoriesa 20, 60, 20%

Severity categoriesa 40, 20, 40%

Table 4. Relationship of Severity of chronic obstructive pulmonary disease (COPD) to prevalence of cardiovascular diseases* in a cohort of 7575 patients with COPD

808
levels of COPD severity produced the strongest
relationships. Adjusted odds ratios comparing the
most severe 20% with the least severe 20% of patients
were associated with prevalence of arrhythmia,
ischemic heart disease, angina and congestive heart
failure, but not acute myocardial infarction, other
cardiovascular disease, or any cardiovascular
hospitalization. The prevalence of congestive heart
failure had the strongest relationship with COPD
severity: all adjusted odds ratios for congestive heart
failure were signicant and the 20% of patients with
the most severe COPD were more than twice as likely
to have congestive heart failure as the 20% with the
lowest severity.
The relationship of COPD severity levels to
hospitalization and mortality due to cardiovascular
diseases are shown in Table 5. The incidence rates of
hospitalization due to acute myocardial infarction,
ischemic heart disease, angina, and congestive heart
failure were higher among patients with the highest
severity than in patients with the lowest severity,
although the relationship was signicant at the 95%
level only for congestive heart failure. Both cardiovascular mortality and overall mortality were positively and highly signicantly related to COPD
disease severity. The cardiovascular mortality rate
ratio (RR) was 1.27 for the 40% with the most severe
COPD compared with the least severe 40% and 1.63
for the most severe 20% versus the least severe 20%.
Very low severity was associated with lower cardiovascular mortality than moderate severity, with a rate
ratio of 1.39 for medium (middle 60%) versus low
severity (bottom 20%). Overall mortality risk increased signicantly from low to middle to high
COPD severity level, regardless of the specication
used. The most severe 40% of patients had a mortality rate twice that of patients in the least severe
40%, and the most severe 20% had a mortality rate
three times that of the least severe 20%.

Discussion
Our study describes a method of assigning severity of
COPD in a population of patients with diagnosed
and treated COPD using frequently available utilization data: recent intensity of use of drug therapies
for COPD, recent hospitalizations for COPD and
COPD exacerbations, home oxygen services, recent
pneumonia, and presence of emphysema. The
strength of this study is that it used a clinical outcome, COPD hospitalizations, in a larger COPD
population than previously studied. The validity of
COPD hospitalization as a severity indicator is
enhanced by its relationship with mortality. The
method is particularly applicable for use in administrative data where spirometry results are unavailable.
It diers from a method developed for use in the UK
General Practice Research Database, which had a

0.80
1.12
0.99
1.22
1.24
1.00
0.99
1.27
2.02

Arrhythmia (n = 338)
Acute myocardial infarction (n = 208)
Ischemic heart disease (n = 371)
Angina (n = 116)
Congestive heart failure (n = 651)
Other cardiovas. Dis. (n = 717)
Any cardiovas. hosp. (n = 1780)
Cardiovascular mortality (n = 590)
Overall mortality (n = 1975)

0.601.07
0.831.51
0.721.35
0.801.85
1.041.48
0.831.20
0.881.11
1.021.59
1.762.31

95% CI
1.05
0.99
1.09
1.95
1.08
1.00
1.04
0.98
1.36

RR
0.711.54
0.691.40
0.741.62
1.053.65
0.871.33
0.791.25
0.901.20
0.761.26
1.171.58

95% CI
0.77
1.14
0.91
0.62
1.15
1.01
0.95
1.30
1.48

RR
0.521.12
0.791.64
0.611.35
0.331.18
0.921.43
0.801.26
0.821.10
0.991.70
1.251.76

95% CI
0.80
1.18
1.17
1.71
1.42
0.96
1.00
1.63
3.07

RR
0.541.18
0.771.81
0.851.62
0.953.08
1.061.90
0.751.24
0.831.21
1.222.16
2.453.86

95% CI
0.98
1.24
1.30
2.16
1.22
1.08
1.11
1.17
1.79

RR

0.701.38
0.871.75
1.001.70
1.353.45
0.971.52
0.871.33
0.961.30
0.951.43
1.562.07

95% CI

0.81
0.95
0.90
0.79
1.17
0.90
0.90
1.39
1.71

RR

0.591.11
0.661.37
0.681.19
0.451.38
0.911.50
0.731.11
0.771.05
1.091.79
1.382.13

95% CI

Middle vs. low

*All rate ratios (RR) were adjusted for gender and age group using multivariate Poisson regression. Additionally, the AMI and angina risk ratios were adjusted for hypertension, the
arrhythmia, other CVD and CVD hospitalization risk ratios were adjusted for diabetes, the CHF risk ratio was adjusted for diabetes and hypertension, and the ischemic heart disease
risk ratio was adjusted for diabetes, hypertension and hypercholesterolemia.
a
Severity categories refers to the proportions of patients in each severity category. For example, a category labeled 40, 20, 40% means that high includes the most severe 40% of
patients, middle includes the next 20% of patients and low includes the least severe 40% of patients.
b
The number of patients with a rst hospitalization for each cardiovascular disease and the number of mortalities are listed in this column. For example, of 7575 patients with COPD,
338 were hospitalized at least once with arrhythmia, 1975 died during the follow-up period and 590 of these died of cardiovascular causes.

RR

Cardiovascular diseasesb

High vs. middle

High vs. low

Middle vs. low

High vs. low

High vs. middle

Severity categoriesa 20, 60, 20%

Severity categoriesa 40, 20, 40%

Table 5. Relationship of severity of chronic obstructive pulmonary disease (COPD) to incidence of hospitalization and mortality* due to cardiovascular diseases

809

810
broader inclusion criterion and was validated using a
physician questionnaire [24]. However, our results
conrm their result that oxygen services and nebulizer therapy are markers of more severe COPD.
A limitation of this study is that our method
denes severity of COPD relative to other patients in
the study data. Overall severity may be higher in the
Saskatchewan COPD cohort than in sources with
younger populations, such as those identied in US
managed care data sources. Additionally, since dispensing data were used as a proxy for drug
consumption, the categorization of patients as high
bronchodilator users may be an imprecise surrogate
for each patients actual bronchodilator use. Similarly, the use of monthly nancial claims for oxygen
services does not capture exact timing or intensity of
use. However, both high bronchodilator use and
oxygen services were predictors of COPD hospitalization in the cohort as a whole. Another limitation is
that some diagnoses and procedures that may be
markers of COPD are not routinely captured in this
data. Specically, cachexia, cor pulmonale, intubation and ventilation were not signicant in our model
because they were recorded for very few patients.
Regarding cardiovascular comorbidities, COPD
severity was signicantly related to cardiovascular
disease prevalence and cardiovascular mortality.
Although the study does not consider the temporal
sequence of the onset of COPD and cardiovascular
diseases, it demonstrates that patients with higher
COPD severity are more likely to have coexisting
cardiovascular diseases and more likely to be hospitalized with or die from cardiovascular causes.
Evidence is accumulating that cardiovascular disease
contributes to poorer prognosis among patients with
COPD. Render et al found that 32% of COPD out-

patients presenting with symptomatic deterioration

had left ventricular dysfunction (LVD) and that these
patients had signicantly worse functional limitations
than patients with deterioration but no LVD [25].
Incalzi et al. [16] found that ECG evidence of right
ventricular hypertrophy and of ischemic heart disease
were among the ve signicant predictors of mortality among patients discharged from a hospital after
an acute exacerbation of COPD. One likely explanation for the relationship between COPD and
cardiovascular disease, in addition to the presence of
chronic hypoxia, is the presence of persistent systemic
inammation in patients with COPD [26] and in
persons with cardiovascular diseases. At the same
time, increased inammatory markers have been
shown to be linked with accelerated decline in lung
function [3, 26, 27].

Conclusions
Severity of COPD can be measured in administrative
data using recent prescription information for
bronchodilators and evidence of emphysema,
home oxygen services, recent exacerbations, pneumonia and recent hospitalizations for COPD.
Severity of COPD is positively related to the prevalence of arrhythmia, acute myocardial infarction,
ischemic heart disease, angina and congestive
heart failure. With the exception of arrhythmia,
COPD severity is positively related to the incidence
of hospitalization due to these cardiovascular diseases. There is a positive and highly signicant
relationship between severity of COPD and mortality due to cardiovascular causes, as well as overall
mortality.

Appendix
Table A1. Denitions of binary variables tested in casecontrol model of COPD hospitalization*
Variable
Variables tabulated any time in the
patients available prior history
Cor pulmonale
Emphysema diagnosis
Chronic bronchitis diagnosis
Chronic airways obstruction
Other lung disease due to external agents
Obesity
Variables tabulated for 90, 180 and
365 days prior to the event
Acetylcysteine prescription
Acute exacerbation

Antibiotic prescription

Denition

ICD-9 415.0
ICD-9 492
ICD-9 491
ICD-9 496
ICD-9s 500508
ICD-9 278

Prescription for acetylcysteine, a mucolytic agent.

Prescription for an antibiotic on the same day as a respiratory diagnosis or
within 2 days after a respiratory diagnosis. Physician and hospital records
were searched for any of the following respiratory diagnoses, ICD-9 codes
460462, 464466, 487, 490492, 494, 496.
Outpatient prescription for any antibiotic

811
Table A1. continued
Variable
Cachexia diagnosis
Home oxygen services

Intubation procedure performed during

a recent hospitalization
Pneumonia diagnosis
Previous recent COPD hospitalization
Pulmonary congestion and
hypostasis diagnosis
Ventilator or emergency resuscitation

COPD drug treatment variables tabulated

for 90, 180 and 365 days prior to the event
Any nebulizer prescription

Any long-acting inhaled beta agonist

Any inhaled corticosteroid

Any oral corticosteroid

High amount of steroids dispensed

relative to the overall COPD cohort
High amount of ipratropium dispensed
High amount of combivent dispensed
High amount of xanthine
bronchodilators dispensed
High amount of short-acting
inhaled beta agonist dispensed
High ipratropium or xanthine

Denition
ICD-9 799.4 on a hospital record.
Monthly record indicating that invoices were submitted by a supplier of
home oxygen services for a particular beneciary, including equipment
repair, during the specied 90, 180 or 365 day period. Oxygen services data
are monthly and do not have daily dates. If the record was in the same
month as the event, it was not counted because it may have followed the
event in time.
Hospital procedure code (CCPa code) 10.0110.05 nonoperative intubation of respiratory tract.
ICD-9 480486
Previous hospitalization with a primary diagnosis that is the same as the
event diagnosis. ICD-9s 491., 492., 496, 490
ICD-9 514
Hospital CCP procedure code 13.62 mechanical assistance to respiration
or Physician fee for service code 922A or 923A emergency resuscitation
may or may not involve mechanical ventilation.

Prescription for nebulizer form of an anticholinergic or beta agonist. The

drugs of this type in the data that were prescribed in nebulizer forms are
ipratropium, combivent, fenoterol, salbutamol, and budesonide.
During the study period, Saskatchewans formulary coverage of long-acting inhaled beta agonists was restricted. These drugs had exception drug
status, whereby a physician or pharmacist was required to apply for approval for coverage for an individual patient. The long-acting inhaled beta
agonist prescriptions in the data were for the following drugs: formoterol,
salmeterol, and salmeterol/uticasone.
Prescription for inhaled corticosteroid. Inhaled corticosteroids present in
the data are: beclomethasone, budesonide, uticasone, unixolide, triamcinolone.
Prescription for oral corticosteroid. Most of the oral corticosteroid prescriptions in this population were for prednisone. However, other oral
corticosteroids used were vbetamethasone, cortisone, dexamethasone,
hydrocortisone, methylprednisolone, prednisolone and triamcinonlone.
The dose form and strength of each steroid was converted to its methylprednisolone equivalent and each patients use was compared with the
overall COPD cohort during the same amount of time.
Patient received a high amount of ipratropium prior to the event date.
Patient received a high amount of combivent prior to the event date.
Patient received a high amount of aminophylline, oxtriphylline or theophylline prior to the event date.
Patient received a high amount of short-acting inhaled fenoterol, salbutamol or terbutaline prior to the event date.
Patient qualies either for high ipratropium or high xanthine.

*In the Saskatchewan data, outpatient physician visits are coded using 3-digit ICD-9 codes and hospital visits are coded
using 4-digit codes (or 3-digit codes where a 4-digit code does not exist, such as 496).
a
CCP = Canadian Classication of Diagnostic, Therapeutic and Surgical Procedures 1986.

812
Table A2. Denitions of high drug use during 180 days
Puers 4 or
Nebulizer dose 60 or
If patient is taking both puers
and nebules,
Puers 3 or
Nebulizer dose* 60
Xanthines
Aminophylline pills 82,500 mg or
Oxtriphylline pills 72,000 mg or
Theophylline pills 68,000 mg or
Liquid oxtriphylline 6,000 mg
Combination
Puers 4 or
ipratropium/albuterol Nebulizer dose* 240
Short-acting beta
Salbutamol
agonists
Puers 4 or
Nebulizer dose* 360 or
Inhaler capsules 40 mg or
Fenoterol
Puers 7 or
Nebulizer dose* 150 or
Terbutaline
Puers 2

Ipratropium

*Cut-o points were set at the highest 40% of dispensings

during a specic 180 day period
Ipratropium nebulizer dose = reported quantity strength
(mg per ml)
Combination ipratropium/albuterol nebulizer
dose = number of 2.5 ml doses 0.2 mg
Salbutamol nebulizer dose = number of 2.5 ml doses
strength (mg per ml)
Fenoterol nebulizer dose = number of 2 ml doses
strength (mg per ml)
Quantity of 0.25 strength ipratropium nebulizer was
reported as either number of 2 ml nebules or number of ml
of multidose solution, depending on which preparation was
dispensed. The computation was done twice, using 2 ml and
1 ml for quantity. There was no dierence in the nal
result.

Acknowledgements
The authors would like to thank cardiologist Toby
Barbey, M.D. for adjudication of medical charts and
Miriam Gabrysh and Leanne Stricker for abstracting
medical records at Saskatchewan hospitals.
Funding: This study was funded by Pzer, Inc. and
Boehringer-Ingelheim Pharmaceuticals. It is based in
part on de-identied data provided by the Saskatchewan Department of Health. The interpretation and
conclusions contained herein do not necessarily represent those of the Government of Saskatchewan or
the Saskatchewan Department of Health.

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Address for correspondence: Suellen M. Curkendall , Cerner LifeSciences, 1953 Gallows Road, Suite 570, Vienna, VA, 22182, USA
Phone: +1-703-2458150; Fax: +1-816-9367450;
E-mail: Suellen.Curkendall@cerner.com

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