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Clinical Investigations: CARDIOLOGY |

Cardiovascular Morbidity and Mortality in COPD* FREE TO VIEW

Laetitia Huiart, MD; Pierre Ernst, MD; Samy Suissa, PhD
Author and Funding Information

*From the Division of Clinical Epidemiology, Royal Victoria Hospital and Department of Epidemiology and Biostatistics, McGill University, Montreal, Canada; and Laboratoire de Santé Publique EA 3279, Université de la Méditerranée and Département d’Oncogénétique, Institut Paoli-Calmettes, Marseille, France.

Correspondence to: Samy Suissa, PhD, Division of Clinical Epidemiology, Royal Victoria Hospital, 687 Pine Ave West, Ross 4.29, Montreal, QC, Canada, H3A 1A1; e-mail: samy.suissa@clinepi.mcgill.ca



Chest. 2005;128(4):2640-2646. doi:10.1378/chest.128.4.2640
Text Size: A A A
Published online

Study objective: COPD and cardiovascular disease (CVD) share common risk factors. We undertook to estimate rates of hospitalization and death from CVD in COPD patients relative to the general population.

Design and setting: A cohort of patients ≥ 55 years old receiving a first treatment for COPD between 1990 and 1997 was formed from the Saskatchewan Health databases. All hospitalizations and deaths between cohort entry and the end of 1999 were identified.

Results: The cohort included 5,648 individuals and generated 23,426 person-years (PY) of follow-up. The overall rates of cardiovascular morbidity and mortality were 177.2 and 41 per 1,000 PY, respectively. Cardiovascular morbidity and mortality rates were higher in the COPD cohort than in the general population (standardized rate ratios of 1.9 and 2.0, respectively). More hospitalizations for CVD than for COPD itself were reported. Among CVDs, heart failure represented the most frequent cause of hospitalization (58.8 per 1,000 PY). CVD and more specifically ischemic heart disease (19.6 per 1,000 PY) were reported as a more frequent cause of death than COPD itself (15.5 per 1,000 PY).

Conclusion: CVD is more frequent in COPD patients than in the general population and may represent a burden greater than that of lung disease itself.

Figures in this Article

COPD is among the five most prevalent diseases and causes of death worldwide.1COPD is characterized by chronic inflammation in the airway and lung parenchyma most commonly caused by cigarette smoking.2In addition to smoking, a major risk factor for cardiovascular disease (CVD) and more specifically ischemic heart disease, COPD patients share other risk factors with CVD patients due to advanced age and decrease in physical activity caused by lung disease. Chronic bronchitis34 and lung function56 have also been identified as independent predictors of the occurrence of ischemic heart disease. Furthermore, therapy for COPD may increase CVD.79 Finally, once ischemic heart disease is present, CVD becomes an important comorbid factor predicting all-cause mortality in COPD patients.10Despite these observations, relatively minor attention has been paid to the cardiovascular status of patients with COPD. Little information is available in the literature to quantify the burden of illness that CVD represents in this population. Anthonisen et al11described the hospitalization and death rates for CVD in the Lung Health Study, which included smoking subjects 30 to 60 years old with mild-to-moderate lung function impairment. COPD, however, affects mostly older subjects,12 and thus the burden of CVD may be much more important, even when compared to an elderly population. We therefore conducted a study to quantify cardiovascular morbidity and mortality in a population-based cohort of COPD patients in comparison with the general population.

Source of Data

The health insurance databases of Saskatchewan were the primary source of data. The databases cover all residents eligible for health coverage, who represent approximately 99% of the population.13 Of these, approximately 91% are eligible for prescription drug benefits. These databases have been used extensively for research and provide valid information for each individual on prescriptions dispensed, hospital stay, use of physician services, and vital status.

Population

We defined a population-based cohort of new COPD patients based on medications dispensed: subjects entered the study cohort when dispensed a minimum of three prescriptions on two different dates in any 1-year period between January 1, 1990, and December 31, 1997, of inhaled or oral β2-agonist, xanthine, or ipratropium bromide (bronchodilators). To include only incident patients and distinguish between asthma and COPD, subjects had to be ≥ 55 years of age on the day of their first COPD agent prescription. In addition, patients who received any bronchodilator, antiasthma drug, or nasal or inhaled corticosteroid in the prior 5 years were excluded. Subjects were followed up until the earliest of the following events: December 31, 1999, end of coverage, or death.

Outcomes

All hospitalizations with a primary discharge diagnosis of CVD or COPD were compiled from the hospital separation database (International Classification of Diseases, ninth revision [ICD-9]14). The event date was the date of hospital admission. Subjects transferred from one hospital to another on the same day were counted as only one hospitalization when computing rates of hospitalizations and counted as two hospitalizations when comparing our rates to published provincial rates that count all hospitalizations.

The underlying cause of death was compiled from the vital statistics database using the ICD-9 codes. The underlying cause of death is determined from the causes listed on the death certificate by an automated program. It corresponds to the “the disease or injury which initiated the train of events leading directly to death, or the circumstances of the accident or violence that produced the fatal injury.”14

Comorbidities at Cohort Entry

Comorbid conditions were identified using either drugs dispensed within 12 months prior to cohort entry (diabetes, systemic hypertension, hyperlipidemia) or discharge diagnoses within 5 years before cohort entry (cardiomyopathy and dysrythmia, and pulmonary heart disease), or both (ischemic heart disease and heart failure).

Statistical Analysis

Rates were computed for hospitalization and death separately. The total amount of person-time was calculated from the cohort entry date to the exit date. To calculate the hospitalization rates, we subtracted the amount of person-time spent in hospital from the total person-time, as subjects were not at risk of being hospitalized at these times. All rates were stratified on gender, age, and time period. We compared death rates and hospitalization rates in our cohort with those of the Saskatchewan general population15 after adjusting for age and gender by indirect standardization. All confidence intervals (CIs) were computed assuming a Poisson distribution of the number of events. The hazard function of the first cardiovascular event was computed using the actuarial method. All analysis was performed using statistical software (SAS version 8.2; SAS Institute; Cary, NC). This study received ethical approval from Saskatchewan Health.

The population-based cohort of COPD patients comprised 5,648 subjects (53.9% male) with a mean age at cohort entry of 73.5 years (SD, 9.6 years). The mean duration of follow-up was 4.1 years (SD, 2.7 years), generating a total of 23,426 person-years (PY) of follow-up. At cohort entry, a large number of patients were being treated for some cardiovascular risk factors or had been previously hospitalized for a CVD (Table 1 ).

Morbidity

Overall, 22,083 hospitalizations occurred during follow-up, including 4,064 for CVD (18.4%) and 2,326 for COPD (10.5%). After subtracting the 486 PY of time spent in the hospital from the total number of PY generated by the entire cohort, 22,940 PY were at risk of hospitalization. Among women, 29.2% (n = 762) were hospitalized for CVD at least once, generating a total of 1,599 hospitalizations for CVD. Among men, a total of 2,465 hospitalizations for CVD were generated by 1,090 men (35.8%). The overall rate of CVD hospitalization was 177.2 per 1,000 PY (95% CI, 171.7 to 182.6 PY) [Table 2] . Heart failure and ischemic heart disease were the two most frequent specific CVDs (58.8 per 1,000 PY; 95% CI, 55.7 to 61.9 PY; and 42.0 per 1,000 PY; 95% CI, 39.3 to 44.6 PY, respectively).

In comparison, COPD itself was responsible for 812 hospitalizations among 399 women (15.3%) and 1,514 hospitalizations among 673 men (22.1%). The overall rate of hospitalization for COPD was 101.4 per 1,000 PY (95% CI, 97.3 to 105.5 PY) [Table 2]. Subjects with COPD were more often hospitalized for CVD than the general population when adjusting for age, gender, and calendar year (standardized rate ratio [SRR], 1.89; 95% CI, 1.83 to 1.94) [Table 3] . The largest increase was observed for heart failure, which was three times more frequent as a cause of hospitalization in COPD patients than in the general population (SRR, 3.07; 95% CI, 2.91 to 3.23).

Mortality

During follow-up, 2,553 deaths occurred. CVD was the underlying cause of death in 37.6% of cases (n = 960) and COPD in 14.3% (n = 364). Death rates are presented in Table 4 . The overall rate of CVD death was 41.0 per 1,000 PY (95% CI, 38.4 to 43.6 PY). Among CVD, ischemic heart disease is the first cause of death across all age groups (Fig 1 ). It represents nearly half of all cardiovascular deaths (19.6 per 1,000 PY; 95% CI, 17.8 to 21.4 PY) and is a more frequent cause of death than COPD itself (15.5 per 1,000 PY; 95% CI, 13.9 to 17.1 PY). CVD death rates increased more steeply with age than those of COPD in both men and women (Fig 2 ). CVD death rates were stable over time between 1990 and 1999, whereas COPD death rates appeared to increase slightly (Fig 3 ).

We compared the cardiovascular death rates in our cohort with death rates among the Saskatchewan general population adjusting for age, gender, and calendar time (Table 5 ). COPD patients presented a nearly twofold increase in CVD death rates compared to the general population (standardized mortality ratio [SMR], 1.95; 95% CI, 1.83 to 2.07). Among specific causes of CVD deaths, the largest SMR was observed for heart failure (2.83; 95% CI, 2.32 to 3.33).

Our study shows that CVD is an important cause of death and hospitalization among patients with COPD. The rate of hospitalization for CVD was higher than that for COPD itself. CVD, more specifically ischemic heart disease, was listed more often as the underlying cause of death than was COPD. Morbidity and mortality from CVD were nearly twice as high in our cohort as in the general population.

We used a population-based cohort compiled from administrative health services databases. The use of this source of data limits selection bias, as these databases cover most of the population. Indeed, 99% of Saskatchewan residents receive publicly funded health care and 91% are eligible for outpatient prescription drug benefits. Second, data on vital status, hospitalization, and dispensed prescriptions listed on the formulary are expected to be highly reliable. The recording of certain CVDs in the hospital separation database has been previously studied and found to be accurate.16 As for drugs, the Saskatchewan Prescription Drug Plan, the primary insurer of Saskatchewan formulary benefits in the province, requires that all claims be processed through the drug plan on-line system.

A weakness of the data source that we used is the absence of information on some important clinical data and confounders. Our study population was defined on drugs dispensed, and the distinction between COPD and asthma is difficult in this context. As the incidence of asthma in adults > 50 years of age is low,1718 we limited misdiagnosis by including only subjects having a new-onset respiratory disease after age ≥ 55 years and requiring more than occasional treatment. We also excluded prevalent asthma patients by excluding subjects who had received treatment for asthma in the 5 years prior to cohort entry. A clinical study19has pointed out that the frequency of asthma may be underestimated in elderly patients, although the onset of asthma later in life remained unusual. Misdiagnosis, therefore, certainly exists in our study but likely represents only a small portion of our population. A further limitation of our population definition is that COPD may be underdiagnosed and therefore undertreated.2021 Symptomatic or rapidly deteriorating patients are more likely to be treated. Therefore, although the use of a general population protects us from selection bias, our cohort likely comprises mostly patients with moderate-to-severe COPD. There is no direct method to assess patient severity in our study. Administrative databases do not provide information on measures of COPD severity such as spirometric values, arterial gas data, or smoking status, which are in turn important predictors of all-cause mortality.12,22 We can however use external information to assess the severity of disease in our cohort. Soriano et al12 defined a cohort of physician-diagnosed COPD patients and reported all-cause mortality rates ranging from 54.3 (women) and 73.5 (men) per 1,000 PY for mild COPD to 275.7 (women) and 380.2 (men) per 1,000 PY for severe COPD. The all-cause mortality rate in our cohort (109 per 1,000 per year) suggests that our results apply principally to moderate-to-severe COPD.

COPD was likely underreported on death certificates in our cohort since it was recorded as the underlying or a contributing cause of death in only 30.5% of all death certificates (data not shown). Among patients with COPD, Camilli et al23 found that COPD was reported more often on death certificates among patients with severe COPD than with less severe COPD. Moreover, whether COPD was reported as a contributing cause depended on which underlying cause was mentioned. For example, when ischemic heart disease was the underlying cause of death, COPD was mentioned in 50% of cases, as compared to 25% when malignancy was the underlying cause. Several studies2325 have described factors that determine whether COPD is listed as the underlying cause of death as opposed to a contributing cause of death. When COPD was listed on a death certificate, it was defined as the underlying cause of death in 43%24to 60%25of the time. In a cohort of COPD patients, Marcus et al26first recoded the underlying and the contributing cause of death and then compared their coding with the one from the health department that produces official statistics. In half of the cases, COPD was listed as the contributing cause by both sources. However, there was an agreement that COPD was the underlying cause in only 9% of the cases. This lack of agreement illustrates the difficulties in identifying the underlying cause of death in subjects with chronic disease and multiple comorbidities when there is no clear etiologic chain between the different coexisting conditions.27

Determining the degree to which COPD, in itself, is responsible for the death of COPD patients with cardiovascular comorbidities remains a major question. It is generally more difficult to determine the underlying cause of death among patients having multiple diseases, especially when a common risk factor such as tobacco use is responsible for several of the diseases. We used the underlying cause of death to calculate the death rate by cause, as the underlying and the contributing causes are competing. This may affect the cardiovascular mortality rate; if COPD is underestimated as an underlying cause of death, it implies that other causes, such as CVD, are overestimated. The increase in risk due to tobacco alone in an elderly population, such as our COPD cohort, is expected to be lower than the approximately twofold increase in cardiovascular morbidity and mortality we observed.28This increase is higher than expected even though our reference population contained smokers; 29% of the Saskatchewan population > 12 years of age were smokers in 1994/1995.29 This suggests the presence of risk factors for CVD other than tobacco in COPD patients.

In summary, our results underline the importance of CVD in COPD patients. Aside from smoking cessation, aggressive strategies to treat cardiovascular comorbidities should be considered after weighing the delayed benefit of some such strategies and the relatively short life expectancy of elderly COPD patients. On a broader perspective, this study highlights the underrepresentation of comorbidities in vital statistics. COPD comorbidities should be considered when estimating the social and economic burden of the disease. However, although COPD is projected to be the third-leading cause of death in 2020, ischemic heart disease will remain the number-one cause of death worldwide30 whether or not COPD comorbidities are taken into account.

Abbreviations: CI = confidence interval; CVD = cardiovascular disease; ICD-9 = International Classification of Diseases, ninth revision; PY = person-years; SMR = standardized mortality ratio; SRR = standardized rate ratio

This study is based in part on nonidentifiable data provided by the Saskatchewan Department of Health. The interpretations and conclusions contained herein do not necessarily represent those of the Government of Saskatchewan or the Saskatchewan Department of Health.

This study was funded by grants from the Canadian Institutes for Health Research, AstraZeneca, Boehringer-Ingelheim, and GlaxoSmithKline. Dr. Huiart was the recipient of a research fellowship, Bourse Lavoisier, from the French Foreign Affairs Ministry. Dr. Suissa is the recipient of a Distinguished Investigator award from the Canadian Institutes for Health Research. The McGill Pharmacoepidemiology Research Unit is funded by an infrastructure grant from the Fonds de la Recherche en Santé du Québec.

Table Graphic Jump Location
Table 1. Characteristics of the Study Subjects*
* 

Data are presented as No. (%) unless otherwise indicated.

 

Identified using drugs dispensed within 12 mo prior to cohort entry.

 

Identified using discharge diagnoses within 5 yr before cohort entry and drugs dispensed within 12 mo prior to cohort entry.

§ 

Identified using discharge diagnoses within 5 yr before cohort entry.

Table Graphic Jump Location
Table 2. Hospitalization Data for Patients with CVD and COPD
Table Graphic Jump Location
Table 3. SRRs for CVD Hospitalizations Adjusted for Age, Gender, and Calendar Year
* 

Including transfers between hospitals.

 

The reference population is the Saskatchewan general population.

Table Graphic Jump Location
Table 4. Death Rates per 1,000 PY for CVD and COPD
Figure Jump LinkFigure 1. Death rates by types of CVD according to age.Grahic Jump Location
Figure Jump LinkFigure 2. Deaths rates for COPD and CVD according to gender and age.Grahic Jump Location
Figure Jump LinkFigure 3. Trends over time in death rates for COPD and CVD.Grahic Jump Location
Table Graphic Jump Location
Table 5. SMRs for CVD Adjusted for Age, Gender, and Calendar Year
* 

The reference population is the Saskatchewan general population.

We thank Abbas Kezouh for database management and statistical advice. We also thank Caroline Quach and Mylene Kosseim for editorial comments.

 Life in the 21st century: a vision for all. 1998; World Health Organization. Geneva, Switzerland:.
 
Wright, JL, Lawson, LM, Pare, PD, et al Morphology of peripheral airways in current smokers and ex-smokers.Am Rev Respir Dis1983;127,474-477. [PubMed]
 
Haider, AW, Larson, MG, O’Donnell, CJ, et al The association of chronic cough with the risk of myocardial infarction: the Framingham Heart Study.Am J Med1999;106,279-284. [CrossRef] [PubMed]
 
Jousilahti, P, Vartiainen, E, Tuomilehto, J, et al Symptoms of chronic bronchitis and the risk of coronary disease.Lancet1996;348,567-572. [CrossRef] [PubMed]
 
Ebi-Kryston, KL Respiratory symptoms and pulmonary function as predictors of 10-year mortality from respiratory disease, cardiovascular disease, and all causes in the Whitehall Study.J Clin Epidemiol1998;41,251-260
 
Zureik, M, Kauffmann, F, Touboul, PJ, et al Association between peak expiratory flow and the development of carotid atherosclerotic plaques.Arch Intern Med2001;161,1669-1676. [CrossRef] [PubMed]
 
Suissa, S, Hemmelgarn, B, Blais, L, et al Bronchodilators and acute cardiac death.Am J Respir Crit Care Med1996;154,1598-1602. [PubMed]
 
Maxwell, SR, Moots, RJ, Kendall, MJ Corticosteroids: do they damage the cardiovascular system?Postgrad Med J1994;70,863-870. [CrossRef] [PubMed]
 
Sholter, DE, Armstrong, PW Adverse effects of corticosteroids on the cardiovascular system.Can J Cardiol2000;16,505-511. [PubMed]
 
Antonelli, I, Fuso, L, De Rosa, M, et al Co-morbidity contributes to predict mortality of patients with chronic obstructive pulmonary disease.Eur Respir J1997;10,2794-2800. [CrossRef] [PubMed]
 
Anthonisen, NR, Connett, JE, Enright, PL, et al Hospitalizations and mortality in the Lung Health Study.Am J Respir Crit Care Med2002;166,333-339. [CrossRef] [PubMed]
 
Soriano, JB, Maier, WC, Egger, P, et al Recent trends in physician diagnosed COPD in women and men in the UK.Thorax2000;55,789-794. [CrossRef] [PubMed]
 
Downey, W, Beck, P, McNutt, M, et al Health databases in Saskatchewan. Strom, BL eds.Pharmacoepidemiology 3rd ed.2000,325-345 John Wiley. New York, NY:
 
Manual of the international statistical classification of diseases, injuries and causes of death based on the recommendations of the ninth revision conference, 1975. Geneva, Switzerland: World Health Organization, 1977/OTHER-REF>.
 
Public Health Agency of Canada. Cardiovascular disease surveillance on-line. Available at: www.dsol-smed.hc-sc.gc.ca/dsol-smed/cvd/index. f.html. Accessed August 25, 2005.
 
Rawson, NS, Malcolm, E Validity of the recording of ischaemic heart disease and chronic obstructive pulmonary disease in the Saskatchewan health care datafiles.Stat Med1995;14,2627-2643. [CrossRef] [PubMed]
 
Yunginger, JW, Reed, CE, O’Connell, EJ, et al A community-based study of the epidemiology of asthma: incidence rates, 1964–1983.Am Rev Respir Dis1992;146,888-894. [PubMed]
 
McWhorter, WP, Polis, MA, Kaslow, RA Occurrence, predictors, and consequences of adult asthma in NHANES I and follow-up survey.Am Rev Respir Dis1989;139,721-724. [PubMed]
 
Bellia, V, Battaglia, S, Catalano, F, et al Aging and disability affect misdiagnosis of COPD in elderly asthmatics: the SARA study.Chest2003;123,1066-1072. [CrossRef] [PubMed]
 
Siafakas, NM, Vermeire, P, Pride, NB, et al Optimal assessment and management of chronic obstructive pulmonary disease (COPD): the European Respiratory Society Task Force.Eur Respir J1995;8,1398-1420. [CrossRef] [PubMed]
 
van den Boom, G, van Schayck, CP, van Mollen, MP, et al Active detection of chronic obstructive pulmonary disease and asthma in the general population: results and economic consequences of the DIMCA program.Am J Respir Crit Care Med1998;158,1730-1738. [PubMed]
 
Anthonisen, NR Prognosis in chronic obstructive pulmonary disease: results from multicenter clinical trials.Am Rev Respir Dis1999;140,S95-S99
 
Camilli, AE, Robbins, DR, Lebowitz, MD Death certificate reporting of confirmed airways obstructive disease.Am J Epidemiol1991;133,795-800. [PubMed]
 
Mannino, DM, Brown, C, Giovino, GA Obstructive lung disease deaths in the United States from 1979 through 1993: an analysis using multiple-cause mortality data.Am J Respir Crit Care Med1997;156,814-818. [PubMed]
 
Hansel, AL, Walk, JA, Soriano, JB What do chronic pulmonary disease patients die from? A multiple cause coding analysis.Am J Respir Crit Care Med2003;22,809-814
 
Marcus, EB, Buist, AS, Maclean, CJ, et al Twenty-year trends in mortality from chronic obstructive pulmonary disease: the Honolulu Heart Program.Am Rev Respir Dis1989;140,S64-S68. [PubMed]
 
Israel, RA, Rosenberg, HM, Curtin, LR Analytical potential for multiple cause-of-death data.Am J Epidemiol1986;124,161-179. [PubMed]
 
U.S.Department of Health and Human Services. The health consequences of smoking; cardiovascular disease: a report of the Surgeon General, 19831983,291-326 US Public Health Service, Office on Smoking and Health. Rockville, MD:
 
Saskatchewan Health. Annual report 2001–2002. Available at: www.health.gov.sk.ca/mc  dp  skhlth  2001–02  ar.pdf. Accessed August 25, 2005
 
Murray, CJ, Lopez, AD Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study.Lancet1997;349,1498-1504. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Death rates by types of CVD according to age.Grahic Jump Location
Figure Jump LinkFigure 2. Deaths rates for COPD and CVD according to gender and age.Grahic Jump Location
Figure Jump LinkFigure 3. Trends over time in death rates for COPD and CVD.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Characteristics of the Study Subjects*
* 

Data are presented as No. (%) unless otherwise indicated.

 

Identified using drugs dispensed within 12 mo prior to cohort entry.

 

Identified using discharge diagnoses within 5 yr before cohort entry and drugs dispensed within 12 mo prior to cohort entry.

§ 

Identified using discharge diagnoses within 5 yr before cohort entry.

Table Graphic Jump Location
Table 2. Hospitalization Data for Patients with CVD and COPD
Table Graphic Jump Location
Table 3. SRRs for CVD Hospitalizations Adjusted for Age, Gender, and Calendar Year
* 

Including transfers between hospitals.

 

The reference population is the Saskatchewan general population.

Table Graphic Jump Location
Table 4. Death Rates per 1,000 PY for CVD and COPD
Table Graphic Jump Location
Table 5. SMRs for CVD Adjusted for Age, Gender, and Calendar Year
* 

The reference population is the Saskatchewan general population.

References

 Life in the 21st century: a vision for all. 1998; World Health Organization. Geneva, Switzerland:.
 
Wright, JL, Lawson, LM, Pare, PD, et al Morphology of peripheral airways in current smokers and ex-smokers.Am Rev Respir Dis1983;127,474-477. [PubMed]
 
Haider, AW, Larson, MG, O’Donnell, CJ, et al The association of chronic cough with the risk of myocardial infarction: the Framingham Heart Study.Am J Med1999;106,279-284. [CrossRef] [PubMed]
 
Jousilahti, P, Vartiainen, E, Tuomilehto, J, et al Symptoms of chronic bronchitis and the risk of coronary disease.Lancet1996;348,567-572. [CrossRef] [PubMed]
 
Ebi-Kryston, KL Respiratory symptoms and pulmonary function as predictors of 10-year mortality from respiratory disease, cardiovascular disease, and all causes in the Whitehall Study.J Clin Epidemiol1998;41,251-260
 
Zureik, M, Kauffmann, F, Touboul, PJ, et al Association between peak expiratory flow and the development of carotid atherosclerotic plaques.Arch Intern Med2001;161,1669-1676. [CrossRef] [PubMed]
 
Suissa, S, Hemmelgarn, B, Blais, L, et al Bronchodilators and acute cardiac death.Am J Respir Crit Care Med1996;154,1598-1602. [PubMed]
 
Maxwell, SR, Moots, RJ, Kendall, MJ Corticosteroids: do they damage the cardiovascular system?Postgrad Med J1994;70,863-870. [CrossRef] [PubMed]
 
Sholter, DE, Armstrong, PW Adverse effects of corticosteroids on the cardiovascular system.Can J Cardiol2000;16,505-511. [PubMed]
 
Antonelli, I, Fuso, L, De Rosa, M, et al Co-morbidity contributes to predict mortality of patients with chronic obstructive pulmonary disease.Eur Respir J1997;10,2794-2800. [CrossRef] [PubMed]
 
Anthonisen, NR, Connett, JE, Enright, PL, et al Hospitalizations and mortality in the Lung Health Study.Am J Respir Crit Care Med2002;166,333-339. [CrossRef] [PubMed]
 
Soriano, JB, Maier, WC, Egger, P, et al Recent trends in physician diagnosed COPD in women and men in the UK.Thorax2000;55,789-794. [CrossRef] [PubMed]
 
Downey, W, Beck, P, McNutt, M, et al Health databases in Saskatchewan. Strom, BL eds.Pharmacoepidemiology 3rd ed.2000,325-345 John Wiley. New York, NY:
 
Manual of the international statistical classification of diseases, injuries and causes of death based on the recommendations of the ninth revision conference, 1975. Geneva, Switzerland: World Health Organization, 1977/OTHER-REF>.
 
Public Health Agency of Canada. Cardiovascular disease surveillance on-line. Available at: www.dsol-smed.hc-sc.gc.ca/dsol-smed/cvd/index. f.html. Accessed August 25, 2005.
 
Rawson, NS, Malcolm, E Validity of the recording of ischaemic heart disease and chronic obstructive pulmonary disease in the Saskatchewan health care datafiles.Stat Med1995;14,2627-2643. [CrossRef] [PubMed]
 
Yunginger, JW, Reed, CE, O’Connell, EJ, et al A community-based study of the epidemiology of asthma: incidence rates, 1964–1983.Am Rev Respir Dis1992;146,888-894. [PubMed]
 
McWhorter, WP, Polis, MA, Kaslow, RA Occurrence, predictors, and consequences of adult asthma in NHANES I and follow-up survey.Am Rev Respir Dis1989;139,721-724. [PubMed]
 
Bellia, V, Battaglia, S, Catalano, F, et al Aging and disability affect misdiagnosis of COPD in elderly asthmatics: the SARA study.Chest2003;123,1066-1072. [CrossRef] [PubMed]
 
Siafakas, NM, Vermeire, P, Pride, NB, et al Optimal assessment and management of chronic obstructive pulmonary disease (COPD): the European Respiratory Society Task Force.Eur Respir J1995;8,1398-1420. [CrossRef] [PubMed]
 
van den Boom, G, van Schayck, CP, van Mollen, MP, et al Active detection of chronic obstructive pulmonary disease and asthma in the general population: results and economic consequences of the DIMCA program.Am J Respir Crit Care Med1998;158,1730-1738. [PubMed]
 
Anthonisen, NR Prognosis in chronic obstructive pulmonary disease: results from multicenter clinical trials.Am Rev Respir Dis1999;140,S95-S99
 
Camilli, AE, Robbins, DR, Lebowitz, MD Death certificate reporting of confirmed airways obstructive disease.Am J Epidemiol1991;133,795-800. [PubMed]
 
Mannino, DM, Brown, C, Giovino, GA Obstructive lung disease deaths in the United States from 1979 through 1993: an analysis using multiple-cause mortality data.Am J Respir Crit Care Med1997;156,814-818. [PubMed]
 
Hansel, AL, Walk, JA, Soriano, JB What do chronic pulmonary disease patients die from? A multiple cause coding analysis.Am J Respir Crit Care Med2003;22,809-814
 
Marcus, EB, Buist, AS, Maclean, CJ, et al Twenty-year trends in mortality from chronic obstructive pulmonary disease: the Honolulu Heart Program.Am Rev Respir Dis1989;140,S64-S68. [PubMed]
 
Israel, RA, Rosenberg, HM, Curtin, LR Analytical potential for multiple cause-of-death data.Am J Epidemiol1986;124,161-179. [PubMed]
 
U.S.Department of Health and Human Services. The health consequences of smoking; cardiovascular disease: a report of the Surgeon General, 19831983,291-326 US Public Health Service, Office on Smoking and Health. Rockville, MD:
 
Saskatchewan Health. Annual report 2001–2002. Available at: www.health.gov.sk.ca/mc  dp  skhlth  2001–02  ar.pdf. Accessed August 25, 2005
 
Murray, CJ, Lopez, AD Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study.Lancet1997;349,1498-1504. [CrossRef] [PubMed]
 
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