Chronic obstructive pulmonary disease (COPD), peripheral arterial disease (PAD) and ischemic heart disease are considered to be a smoking-related triad.
內科學誌 2014：25：272-280
Chronic Obstructive Pulmonary Disease is Associated with an Increased Risk of Peripheral Arterial Disease Te-Chun Shen1,2, Wei Chen3,4, Cheng-Li Lin5,6, Kuo-Yang Huang1, Chia-Hung Chen1,4, Chih-Yen Tu1, Te-Chun Hsia1,4, Chuen-Ming Shih1,4, Wu-Huei Hsu1, and Yen-Jung Chang7 1Division
of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital and China Medical University, Taichung, Taiwan; 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chu Shang Show Chwan Hospital, Nantou, Taiwan; 3Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan; 4Department of Respiratory Therapy, 5Institute of Public Health, College of Public Health, China Medical University, Taichung, Taiwan; 6Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan; 7Department of Health Promotion and Health Education, National Taiwan Normal University, Taipei, Taiwan
Abstract Chronic obstructive pulmonary disease (COPD), peripheral arterial disease (PAD) and ischemic heart disease are considered to be a smoking-related triad. However, only a few studies investigated the relationship between COPD and PAD using limited study sample. We aimed to examine the risk of PAD among patients with COPD using a nationwide cohort database in Taiwan. We conducted a retrospective cohort study using data from the National Health Insurance system of Taiwan. The COPD cohort included 361,023 patients who were newly diagnosed and recruited between 1998 and 2008. Each patient with COPD was randomly frequency-matched with two participants without COPD on age, sex, and the year of index date. The newly diagnosis of PAD was followed up until the end of 2010. The relative risks of PAD were estimated using Cox proportional hazard models after adjusting for age, sex, index year and comorbidities. The overall incidence rate of PAD was 2.34–fold greater in the COPD cohort than in the non-COPD cohort (3.71 vs. 1.58 per 1000 person-years). Further analyses indicated that the risk of PAD was higher in males, individuals younger than 50 years, and without comorbidity among the subgroups. This nationwide population-based study indicates that the incidence of PAD is significantly higher in patients with COPD than in those without COPD and the hazard ratio was especially high in younger patients. Therefore, regular examination for PAD in patients with COPD may be considered. (J Intern Med Taiwan 2014; 25: 272-280)
Key Words: Peripheral arterial disease (PAD); Chronic obstructive pulmonary disease (COPD); Epidemiology Reprint requests and correspondence：Dr. Yen-Jung Chang Address：Department of Health Promotion and Health Education, National Taiwan Normal University, Taipei, Taiwan, No. 162, Heping East Road Section 1, Taipei, Taiwan
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PAD Risk in COPD
273
is a nationwide, large-scale cohort dataset, which
Introduction Chronic
provides reliable data and has been used for a variety
obstructive
pulmonary
disease
of studies over the course of many years.25-27
(COPD) is characterized by persistent airflow limi-
In the present study, we aim to determine
tation that is usually progressive and associated with
whether COPD is associated with an increased risk
an enhanced chronic inflammatory response in the
of PAD using this Taiwanese NHI dataset. To the
airways and the lung to noxious particles or gases.1
best of our knowledge, this is the first nationwide
It is the 4th leading cause of death worldwide, with
population-based study evaluating the relationship
reported prevalence rates between 5% and 13%.2-5
between COPD and the incidence of PAD.
Among the possible factors that influence the disease, cigarette smoking has the greatest impact
Materials and methods
have proposed mechanisms for the pathogenesis of
Data source Taiwan has launched a single-payer National
smoking-induced COPD, including deacetylases and
Health Insurance (NHI) program on March 1,
NF-kappaB in redox regulation,8 decreased airway
1995 and the coverage rate of the NHI is approxi-
factor,9
mately 99% of total population of 23.74 million.
and modulation of epithelial expression of toll-
The National Health Research Insurance (NHRI),
on the development of COPD.6,
7
Several studies
expression of vascular endothelial growth
In addition, the harmful
in cooperation with the National Health Insur-
effects of smoking are not limited to the lungs; it
ance Bureau (NHIB), has established a National
damages the cardiovascular system. This is a major
Health Insurance Research Database (NHIRD).
cormorbidity that must be managed in patients with
The NHIB has established a uniform system to
COPD.11-13 Recent studies have produced further
control the quality of medical services and coding.
evidence that COPD is an independent risk factor
The NHRI, which maintains the annual claims data
for cardiovascular diseases.11, 14-16 Consequently, the
of the NHIRD, scrambled the identification data
relationship between COPD and peripheral arterial
to protect the privacy of its beneficiaries before
disease (PAD) needs to be further investigated.
releasing the data for research use (http://nhird.
like receptor 4
(TLR4).10
PAD involves an atherosclerotic process
nhri.org.tw/en/index.htm). This study was exempted
caused by blockages of arteries that provide blood
from full review by the institutional Research Ethic
flow to the lower limbs.17 The prevalence of PAD
Committee (CMU-REC-101-012).
in general populations ranges widely, from 3% to populations.18-20 Previous studies also suggest that
Study population Patients with COPD (International Classifica-
the prevalence of PAD in patients with COPD also
tion of Diseases, 9th Revision, Clinical Modifica-
ranges widely due to varying numbers of addi-
tion [ICD-9-CM] codes 491, 492, and 496) were
tional cardiovascular risk factors in patients with
identified from the dataset. Patients aged 20 years
COPD.21-23 In a previous report, conducted in a
and more with an initial COPD diagnosis between
community hospital, Lin et al. found that the preva-
1998 and 2008 were recruited. The index date was
lence of asymptomatic PAD in patients with COPD
defined as the date for COPD diagnosis. Subjects
is 8.4%.24 Nevertheless, additional studies using
who had been diagnosed with PAD (ICD-9-CM code
nationally representative samples are required.
443.9, 444.21, 444.22 and 444.89) before index date
Taiwan’s National Health Insurance (NHI) database
were excluded. A non-COPD comparison cohort
20%, depending on the characteristics of the various
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T. C. Shen, W. Chen, C. L. Lin, K. Y. Huang, C. H. Chen, C. Y. Tu, T. C. Hsia, C. M. Shih, W. H. Hsu, and Y. J. Chang
was randomly selected from all NHI beneficiaries
the difference between two cohorts was compared
aged 20 years and more and was matched with the
using the log-rank test. All statistical analyses were
COPD cohort at a 2:1 ratio based on age (every 5
performed using SAS statistical software, version
years span), sex, and the year of COPD diagnosis.
9.2 (SAS Institute Inc., Cary, NC). A two-tailed
The same exclusion criteria were also applied to
probability was considered statistically significant
non-COPD subjects.
at p-value < 0.05.
Primary outcome and comorbidities The follow-up duration starts from the index
Results Table 1 compares the demographics and
date to the occurrence of PAD diagnosis, or to the
comorbidities between COPD cohort and non-COPD
time the subjects was lost of follow-up, due to death
cohort. Of the study subjects, 72.1% were male,
or withdrawal from NHI, or until the end of 2010.
with a predominance (74.7%) of elderly patients.
Baseline comorbidities including hypertension
The mean age of the COPD cohort was 69.9 years
(ICD-9-CM codes 401–405), diabetes (ICD-9-CM
(SD=11.7). Comorbidities were more prevalent in
code 250), hyperlipidemia (ICD-9-CM code 272),
the COPD cohort. The incidence and adjusted HRs
coronary artery disease (CAD) (ICD-9-CM codes
of PAD are shown in Table 2. The overall incidence
410–414), cerebrovascular disease (CVA) (ICD-
of PAD was 2.34–fold greater in the COPD cohort
9-CM codes 430–438), and chronic kidney disease
than in the non-COPD cohort (3.71 vs. 1.58 per 1000
(CKD) (ICD-9-CM codes 585) were identified
person-years), with an adjusted HRs of 1.48 (95%
according to the diagnosis records prior to the index date. In order to evaluate COPD severity to the risk of PAD, we defined patients in the COPD cohort who were hospitalized registered with any COPD
Table 1. Demographic characteristics and baseline comorbidities in patients with and without COPD COPD
codes as an inpatient admission. Variable
Statistical analysis Demographic and clinical characteristics of COPD patients and non-COPD comparison controls were compared using Chi-square test. The differences in continuous variables were evaluated using unpaired Student’s t test. The incidence densities were calculated for both cohorts, and the Poisson regression analysis was used to estimate incidence rate ratio (IRR) of the COPD cohort to the
Sex
No
Yes
N =722046
N =361023
n (%)
n (%)
Female
201244 (27.9) 100622 (27.9)
Male
520802 (72.1) 260401 (72.1)
p-value
0.99
Age stratified < 50 50–64 ≥ 65
53640 (7.43)
26820 (7.43)
128802 (17.8)
64401 (17.8)
0.99
539604 (74.7) 269802 (74.7) #
Age, mean(SD)
68.9 (11.7)
69.9 (11.7)
