Abstract
Background: Co-morbidities are common in COPD; however, there is a lack of population-based studies evaluating the health economic impact of co-morbid diseases for subjects with COPD. The main objective of this study was to estimate annual direct health-care costs, divided into costs due to non-respiratory and respiratory conditions, comparing subjects with and without COPD. Methods: Subjects with and without COPD derived from population-based cohorts in northern Sweden have been invited to annual examinations involving spirometry and structured interviews since 2005. This paper is based on data from 1472 subjects examined in 2006. COPD classification was based on spirometry. Results: Mean annual costs for both respiratory and non-respiratory conditions were significantly higher for subjects with COPD than non-COPD subjects, in total USD 2139 vs. USD 1276 (p = 0.026), and COPD remained significantly associated with higher costs also after adjustment for common confounders as age, smoking habits, BMI and sex. The mean total cost increased with COPD disease severity and was higher for all severity stages (GOLD) than for non-COPD subjects. Hospitalization due to non-respiratory diseases was the main cost driver in COPD, after adjustment for common confounders amounting to about 46% (unadjusted 62%) of the total COPD-costs. Conclusions: Costs were higher for COPD than non-COPD. In COPD, costs for co-morbid conditions were higher than those for respiratory conditions, and hospitalization due to co-morbid conditions was the main cost driver also when adjusted for common confounders.
Introduction
Chronic obstructive pulmonary disease (COPD) is one of the most common chronic and disabling diseases with substantial morbidity and mortality (Citation1). Worldwide, the prevalence is approximately 10% among people above 40 years of age (Citation2–5). The main risk factors are smoking and increasing age; and about every other elderly smoker fulfill the spirometric criteria for COPD (Citation6,7). However, COPD has also been reported among non-smokers, and is related to environmental tobacco smoke exposure (Citation8).
COPD causes impaired health-related quality of life (Citation9) and places a considerable burden on the health-care systems contributing to high costs for the society (Citation10–21). Most health economic studies of COPD are top-down studies based on registers and health statistics. However, epidemiological studies have shown that only 20–35% of all subjects with COPD are identified by the health-care (Citation4,Citation22), and this under-diagnosis leads register-based studies to underestimate the costs (Citation10,Citation23–25). The impact of under-diagnosis is illustrated by the fact that the estimated societal costs of COPD in Sweden from a population-based study conducted in 1999 were three times higher than those obtained in a register-based study even though only resource usage that was directly due to COPD was included (Citation23).
Co-morbidities are common in COPD (Citation2,Citation26–35); around two-thirds of COPD patients are affected by at least one co-morbid disease (Citation26). Actually, cardiovascular disease is the major contributor to morbidity and mortality in subjects with COPD (Citation32,33). Consequently, costs for co-morbid diseases are important to consider when evaluating total health-care costs among subjects with COPD. This co-morbidity may also contribute to the under-diagnosis of COPD, because the co-morbid diseases may overshadow the presence of COPD (Citation36). However, there are hardly any population-based studies estimating the magnitude of the health-care costs for subjects with COPD, including the costs arising from co-morbid conditions.
The main objective of this study was to estimate the annual total direct health-care costs for hospitalizations and outpatient visits divided into costs due to non-respiratory and respiratory conditions comparing subjects with and without COPD. A secondary aim was to analyze the prevalence of co-morbid diseases among subjects with COPD as well as the use of medicines due to respiratory and non-respiratory diseases.
Methods
Study population
In 2002–2004, previously examined subjects from four adult population-based cohorts within the OLIN (Obstructive Lung Disease in Northern Sweden) studies were invited to a re-examination. All subjects with COPD were identified (n = 993) together with an age- and gender-matched cohort of equal size without obstructive lung function impairment. Since 2005, the study population (n = 1986) has been invited to annual examinations with a basic program including structured interviews and spirometry (Citation37). The Ethics Committee at the University Hospital of northern Sweden in Umeå approved the study (EPN Dnr 04-045M).
This article is based on data collected in 2006. As of December 31, 2005, 89 subjects from the initial cohort had died. In total, 1598 subjects (84% of those still alive) participated in 2006, whereof 126 not able to attend the examination were telephone interviewed. The analyses presented herein are based on data from the 1472 subjects examined in 2006 (n = 599 COPD, n = 873 non-COPD).
Methods
The questions regarding respiratory symptoms and conditions included in the interview questionnaire were developed from the British Medical Research Council questionnaire and have been validated in several studies (Citation38,39). In addition; self-reported data on respiratory diseases, non-respiratory diseases and use of medicine were collected. Heart disease was defined as at least one of the following: angina pectoris, myocardial infarction, cardiac insufficiency, a coronary artery bypass or a Percutaneous Coronary Intervention (PCI) procedure. Cardiovascular disease was defined as any of heart disease, intermittent claudication or stroke. Specific questions relating to annual health-care resource consumption were also included.
COPD classification was based on spirometry; FEV1/best of FVC and SVC <0.70 using the highest values pre- or post broncho-dilation. Reversibility-testing was performed if the quotation was <0.70 or FEV1 <80% predicted. Disease severity was classified by FEV1 percent predicted according to the Global Initiative for Obstructive Lung Disease (GOLD) spirometric criteria (Citation40); GOLD 1: FEV1 ≥80% predicted, GOLD 2: ≥ 50 and < 80% predicted, GOLD 3: ≥ 30 and < 50% predicted and GOLD 4: < 30% predicted.
Costs
Mean annual costs per subject for outpatient visits and hospitalizations due to both COPD and non-respiratory conditions were estimated over the last 12 months by multiplying their resource consumption and the corresponding unit costs, based on the exchange rates at the time of submission (USD 1 = SEK 6.57, USD 1 = 0.73 Euro) (Citation41). All analyses were performed for subjects with and without COPD and also by COPD disease severity (GOLD 3 and 4 were grouped together due to a low number of cases). The unit costs for health-care resources were obtained from the Northern health-care region's price list of 2013 (Citation42), which includes all costs for the health-care sector per visit to outpatient care or per day in hospital (e-Table ).
Table 1. Basic characteristics of the study population
Statistical analysis
Statistical analyses were performed with the IBM Statistical Package for the Social Sciences (SPSS) Statistics 20. As the distribution of the costs was skewed and not normally distributed (a majority of the subjects had low or zero costs), the non-parametric Mann-Whitney U-test was used to test differences in costs between groups. The Chi-square test was used to test differences in proportion between groups. Differences between the non-COPD and COPD groups were regarded as significant if p < 0.050, and differences between non-COPD and GOLD stages were regarded as significant if p < 0.017 (based on the Bonferroni correction for multiple testing, i.e., 0.050/3 = 0.017) when tested by Mann-Whitney U-test or Chi-square test. Differences in mean age and BMI (Body Mass Index) between the non-COPD and COPD groups were tested with the Independent T-test, while differences between non-COPD and GOLD stages were tested by One-way ANOVA with the Dunnett Post Hoc test for multiple comparisons. A significance threshold of < 0.050 was applied in all of these tests.
Multivariable regression models were utilized to adjust the estimate for COPD (non-COPD as reference) for age, smoking habits (smokers and ex-smokers respectively, non-smokers as reference), BMI and male sex (female sex as reference) as possible confounders. To adjust prevalence estimates, odds ratios for COPD (non-COPD as reference) from binary logistic regression models were estimated. To adjust health-care utilization and costs, generalized linear models assuming a negative binomial distribution with a log link was utilized to account for the highly skewed data. The exponents of the estimates for COPD from these generalized linear models equal the ratios between the estimates of COPD and the estimates of non-COPD. For example, an Exp(estimate) of 1.67 implies 67% higher costs for COPD compared to non-COPD.
Results
Study population
Basic characteristics of the study population are shown in Table . Cardiovascular disease was significantly more common among subjects with COPD compared to non-COPD subjects, 25.2% and 20.6%, respectively, p = 0.038 (Table ). All cardiovascular diseases other than stroke increased with COPD severity, but only the prevalence of heart disease and intermittent claudication in GOLD 2, were significantly higher compared to non-COPD subjects; p = 0.005 and p = 0.002, respectively. The prevalence of vertebral compression and depression/anxiety was also significantly higher among subjects with COPD; p = 0.044 and p = 0.008, respectively (Table ). However, when adjusting prevalence data of co-morbidities in COPD for age, smoking habits, BMI and sex, no differences compared to non-COPD remained significant, with the exception of rheumatic disease (p = 0.018).
Table 2. Prevalence (%) of non-respiratory conditions in non-COPD, COPD and by COPD disease severity (GOLD stage)
Non-participants (n = 298) had a higher mean age and a greater proportion of females than the study population (66.7 vs. 63.3 years, p < 0.001 and 51.0% vs. 43.9%, p = 0.025). Cardiovascular disease was significantly more common among non-participants (28.5% vs. 20.8%, p = 0.003). There were no differences between non-participants and the study population with respect to smoking habits or the prevalence of COPD.
Health-care resource consumption; outpatient visits and hospitalizations
The annual number of outpatient visits to specialists in hospitals due to non-respiratory conditions was significantly higher for subjects with COPD than those without, p = 0.026 (Table ). Subjects with COPD had significantly higher numbers of hospitalized days per subject and year than non-COPD subjects, due to both respiratory (0.11 vs. 0.04) and non-respiratory diseases (1.21 vs. 0.55); p = 0.015 and p = 0.017, respectively.
Table 3. Average annual resource use, hospitalizations and outpatient care, in the health-care sector per subject with and without COPD caused by respiratory, non-respiratory and all diseases
When adjusting health-care resource consumption for age, smoking habits, BMI and sex, COPD remained significantly associated with increased consumption compared to non-COPD in the same parameters as in the unadjusted analyses. In addition, COPD became significantly associated with increased consumption of outpatient visits to specialist due to respiratory diseases and with general practitioner due to non-respiratory diseases when adjusted for confounders.
Health-care costs
The mean annual total costs for all conditions (respiratory and non-respiratory) were significantly higher for subjects with COPD than non-COPD subjects, USD 2139 vs. USD 1276, p = 0.026 (Table ). Subjects with COPD had about 39% higher total costs for non-respiratory conditions than non-COPD subjects. Hospitalization due to non-respiratory diseases (COPD USD 1321 vs. non-COPD USD 564, p = 0.012) was the main cost driver among COPD subjects, amounting to about 62% of the total costs (Figure ).
Figure 1. Distribution of health-care costs among subjects with and without COPD. (a) Mean annual total health-care costs.
Table 4. Mean annual health-care costs (hospitalizations and outpatient care) (USD) per subject in non-COPD, COPD and by COPD disease severity (GOLD stage)
In the adjusted analyses, COPD remained significantly associated with higher costs in the same cost elements as for unadjusted costs, and in addition, also to total cost for non-respiratory diseases. Unadjusted estimates of costs are shown in Table and cost estimates adjusted for age, smoking habits, BMI and sex are presented in e-Table . The adjusted total costs for COPD were approximately 33% higher than non-COPD. The main cost driver was non-respiratory diseases, and hospitalization due to non-respiratory diseases was the major single cost driving parameter, amounting to 85%, respectively, 46% of the total adjusted costs.
Subjects with COPD had significantly higher costs for total outpatient visits due to respiratory diseases, p < 0.001 (Table ). The total costs for outpatient visits due to non-respiratory conditions were similar in subjects with and without COPD (Table ), but the costs for outpatient visits at hospital due to non-respiratory conditions were significantly higher for subjects with COPD, p = 0.023 (Table ). Also for adjusted cost estimates COPD remained significantly associated with increased costs in the same cost elements as unadjusted costs, and in addition also costs due to outpatient visits for respiratory diseases at hospital. In contrast, adjusted costs due to outpatient visits for non-respiratory diseases in primary care became associated with significantly lower costs in COPD compared to non-COPD.
Table 5. Mean annual costs for outpatient care (USD) per subject in non-COPD, COPD and by COPD disease severity (GOLD stage)
Costs by COPD disease severity
The mean annual total cost for all diseases (respiratory and non-respiratory) increased with COPD disease severity and was higher for each GOLD stage compared to non-COPD subjects, significantly so for GOLD ≥2 (Table , Figure ). A similar pattern was observed in the total costs of hospitalization (Table , Figure ) but costs for outpatient care were only significantly higher when comparing GOLD 3+4 to non-COPD subjects, p = 0.002 (Table , Figure ). Hospitalizations due to non-respiratory disease yielded the highest cost in all GOLD stages of COPD and the costs increased with disease severity.
Figure 2. hospitalizations and outpatient care, (USD) per subject in non-COPD and COPD by disease severity (GOLD stage). (b) Mean annual costs for hospitalizations (USD) per subject in non-COPD and COPD by disease severity (GOLD stage). (c) Mean annual costs for outpatient care (USD) per subject in non-COPD and COPD by disease severity (GOLD stage).
Use of medicines
The proportion of subjects using any medicine for respiratory conditions was significantly higher among subjects with COPD compared to non-COPD subjects, 37.1% vs. 16.2%, p < 0.001 (e-Table ). The use of respiratory medicines increased with COPD severity, and was significantly higher in each GOLD stage compared to non-COPD subjects. The same trend was seen for most medicines due to non-respiratory conditions, besides diabetes where there was an inverse relationship, i.e., being more common among non-COPD subjects, however non-significantly so (p = 0.052) Notably, none of the subjects in GOLD stage 3+4 used medicines for depression/anxiety even though 14.3% reported such condition (e-Table ).
Discussion
The total health-care costs including both respiratory and non-respiratory diseases, i.e. co-morbidities, were higher for subjects with COPD than those for non-COPD subjects. In addition, costs increased with increasing disease severity (i.e. GOLD stage) among COPD subjects. Hospitalizations were more frequent and contributed to higher costs not only for respiratory but also non-respiratory conditions among subjects with COPD. Actually, hospitalization due to non-respiratory conditions, i.e., co-morbid diseases, was the main cost driver among COPD subjects, and unadjusted amounted to 62% of the total costs, which corresponded to 46% when adjusted for age, smoking habits, BMI and sex as confounding factors.
In keeping with previous reports (Citation2,Citation26–35), we found that co-morbidities are common among subjects with COPD. Every fourth COPD subject reported cardiovascular disease compared to every fifth among those without COPD. Besides cardiovascular disease, also anxiety/depression and vertebral compression were more common among subjects with COPD, while rheumatic disease had an inverse relationship. Use of respiratory and non-respiratory medicines followed an almost similar pattern. Co-morbid diseases can be expected to increase utilization of health-care resources. However, most previous cost-of-illness studies have only included costs due to respiratory diseases without considering the impact of co-morbidity on the health economic burden of COPD.
A Danish register-based health economic study included also costs of co-morbidities and found that the number of hospitalizations was almost four times higher for subjects with COPD than a control group. Only about 30% of the total costs for COPD were due to COPD as the primary diagnosis (Citation13), with two-thirds being attributed to other diseases. In a Spanish primary care based study, the health-care costs were significantly higher for COPD-patients with heart disease than for those without (Citation43). Unfortunately no control group without COPD was included, which complicates comparison with our study. These register-based studies confirm that co-morbid diseases have a large impact on the health economic costs of COPD. However, in order to estimate the true societal costs of COPD, it is important to account for the under-diagnosis.
A population-based study conducted in USA found that lung function impairment was associated with more frequent co-morbid diseases, and that the risk of hospitalization (and mortality) increased with the number of co-morbid diseases among subjects with COPD (Citation30). The increased health-care consumption among subjects with COPD was clearly related to co-morbidities, as in our study, but the referred study (Citation30) did not include any health economic cost estimates. Our results verify the expected increased costs due to co-morbidities, and actually hospitalization due to co-morbid diseases was the main cost driver in COPD, also when adjusted for confounders. Compared to non-COPD subjects, these costs were almost twice as high in GOLD 1, and more than three times higher in GOLD 3+4.
Smoking is, besides age, the most important risk factor for COPD, and smoking is associated not only with presence but also prognosis of co-morbid conditions such as cardiovascular disease. Smoking cessation is good not only for the individual patient's health but may also reduce health economic costs through reduced total disease burden. Prevalence data on co-morbidities adjusted for amongst all smoking habits show that the prevalence of most co-morbid conditions actually was not significantly different when comparing COPD and non-COPD. However, most previous cost-of-illness studies of COPD where costs for co-morbidities are included have not adjusted for smoking habits (Citation13,Citation43), and in our study most of health-care resource consumption and cost estimates remained associated with higher burden in COPD compared to in non-COPD also when adjusted for confounders such as smoking habits.
Comparison between countries is difficult due to differences in health-care systems and since unit costs within health-care systems differ between countries. Further, structural changes within the health-care sector in Sweden during the last years have resulted in fewer hospital beds and thus generally shortened treatment time at hospital. These factors should be considered when interpreting results in our study, but we do not expect that our primary aim, comparison between COPD and non-COPD, is substantially affected even though the health cost estimates may differ not only between countries but also by time in Sweden.
We have previously shown that indirect costs are the main cost drivers of COPD (Citation10,Citation23), although only costs for respiratory disease were taken into account. In the current paper, we analyzed the direct costs of outpatient care and hospitalizations due to respiratory and non-respiratory conditions but did not consider the costs of medication or indirect costs due to early retirement and sick leave. Thus, the health economic impact of co-morbidity among subjects with COPD would probably have been even greater if these costs had been taken into account.
Due to the substantial under-diagnosis of COPD (Citation22), the best available method for estimating the true costs is to collect data from a well-defined sample that is representative of the general population. The distribution of the GOLD stages in our study corresponds well with the distribution of COPD disease severity found in other population-based studies (Citation4,Citation44–45), consequently our COPD cohort can be considered representative of COPD in the society. Another strength of this study is that it includes a control group with a similar age distribution. The study design thus makes it possible to consider the impact of non-respiratory conditions on the excessive costs of COPD when compared to subjects without COPD. In addition, data were gathered using well-validated methods (i.e. spirometry and structured interviews) and the resulting data is more detailed than data from official registers.
The use of lower limit of normal (LLN) should be strongly considered to define COPD in epidemiological studies (Citation46) due to the known overestimation of COPD among elderly and underestimation among younger subjects related to the fixed ratio criterion (FEV1/FVC <0.70). However, the current study was designed just after the shift of the millennium when, after the launch of the GOLD guidelines in 1997, the fixed ratio was recommended to define COPD. Since the fixed ratio still is commonly used in health-care, the results can be interpreted in relation to clinical practice, even though the drawbacks of the fixed ratio criterion always have to be taken into account.
Another possible weakness of our study is the risk of recall bias because the questions refer to contacts with the health-care sector over a period of one year; a period of three months has been regarded as a more suitable time period to avoid this risk, but the possible recall bias would be expected to cause an underestimation of costs rather than overestimation. Furthermore, subjects not participating in the 2006 examinations were older, and had more cardiovascular diseases at recruitment, supporting a hypothesis of a healthy survivor effect in this study, contributing to additional underestimation of costs. However, since the main aim of this study was to compare costs between COPD and non-COPD, and not to evaluate the absolute cost-level, bias is not expected, and significant differences between COPD and non-COPD remained also after adjustment for age, BMI, smoking habits and sex. Notably, the estimations rely on self-reported health-care resource consumption without having been validated by medical records, but the precision of categorical data related to health-care resource use by subjects with COPD is considered to be high (Citation46). Further, population-based studies will include mainly GOLD 1 and 2 and only a low proportion of GOLD 3 and 4, and although the costs are highest in GOLD 3+4 the power was not sufficient to establish statistical significance for this group.
Conclusions
Our population-based study revealed that the total costs for all diseases were higher among subjects with COPD than non-COPD subjects. Costs for non-respiratory conditions were higher than those for respiratory disease among subjects with COPD, and hospitalization due to co-morbid diseases was the main cost driver for health-care consumption for all COPD severity stages, also when adjusted for age, smoking habits, BMI and sex. However, additional studies that account for costs of medicines and indirect costs will be required to estimate the total health economic costs for subjects with COPD.
Declaration of Interest Statement
Eva Rönmark has from AstraZeneca received research funding to the OLIN studies. The other authors have no conflicts of interest to declare. The authors alone are responsible for the content and writing of the paper.
Acknowledgments
Financial support from The Swedish Heart & Lung Foundation, Swedish Research Council, ALF –Umeå university, and Visare Norr (a research foundation sponsored by the Northern Sweden health-care authority and Umeå University) and AstraZeneca is gratefully acknowledged.
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