COPD and cardiovascular diseases (CVDs) are

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1 COPD and Incident Cardiovascular Disease Hospitalizations and Mortality: Kaiser Permanente Medical Care Program* Stephen Sidney, MD, MPH; Michael Sorel, MPH; Charles P. Quesenberry, Jr., PhD; Cynthia DeLuise, RPA-C, MPH; Stephan Lanes, PhD; and Mark D. Eisner, MD, MPH, FCCP Study objectives: To determine the relationship between diagnosed and treated COPD and the incidence of cardiovascular disease (CVD) hospitalization and mortality. Design: Retrospective matched cohort study. Setting: Northern California Kaiser Permanente Medical Care Program (KPNC), a comprehensive prepaid integrated health-care system. Patients or participants: Case patients (n 45,966) were all KPNC members with COPD who were identified during a 4-year period from January 1996 through December An equal number of control subjects without COPD were selected from KPNC membership and were matched for gender, year of birth, and length of KPNC membership. Measurements and results: Follow-up conducted for hospitalization and mortality from CVD end points through December 31, CVD study end points included cardiac arrhythmias, angina pectoris, acute myocardial infarction, congestive heart failure (CHF), stroke, pulmonary embolism, all of the aforementioned study end points combined, other CVD, and all CVD end points. The mean follow-up time was 2.75 years for case patients and 2.99 years for control subjects. The risk of hospitalization was higher in COPD case patients than in control subjects for all CVD hospitalization and mortality end points. The relative risk (RR) for hospitalization for the composite measure of all study end points was 2.09 (95% confidence interval [CI], 1.99 to 2.20) after adjustment for gender, preexisting CVD study end points, hypertension, hyperlipidemia, and diabetes, and ranged from 1.33 (stroke) to 3.75 (CHF). The adjusted RR for mortality for the composite measure of all study end points was 1.68 (95% CI, 1.50 to 1.88), ranging from 1.25 (stroke) to 3.53 (CHF). Younger patients (ie, age < 65 years) and female patients had higher risks than older and male participants. Conclusions: COPD was a predictor of CVD hospitalization and mortality over an average follow-up time of nearly 3 years. The finding of a stronger relationship of COPD to CVD outcomes in patients < 65 years of age suggests that CVD risk should be monitored and treated with particular care in younger adults with COPD. (CHEST 2005; 128: ) Key words: cardiovascular disease; COPD; mortality Abbreviations: AMI acute myocardial infarction; CHF congestive heart failure; CI confidence interval; CVD cardiovascular disease; ICD-9 International Classification of Diseases, ninth revision; ICD-10 International Classification of Diseases, 10th revision; KPNC Northern California Kaiser Permanente Medical Care Program; MI myocardial infarction; OR odds ratio; RR relative risk; VF ventricular fibrillation; VT ventricular tachycardia COPD and cardiovascular diseases (CVDs) are two of the leading causes of morbidity and mortality in the United States. The estimated total annual cost to the United States for CVDs is $368.1 *From the Division of Research (Drs. Sidney and Quesenberry, and Mr. Sorel), Kaiser Permanente Northern California, Oakland, CA; Pfizer, Inc. (Ms. DeLuise), New York, NY; Boehringer Ingelheim, Inc. (Dr. Lanes), Ridgefield, CT, and the University of California San Francisco (Dr. Eisner), San Francisco, CA. This research was funded by grants from Pfizer, Inc. and Boehringer Ingelheim, Inc. billion, and for COPD $32.1 billion. 1,2 The incidence of and mortality from these diseases increase with age. A number of studies have shown an association Manuscript received December 17, 2004; revision accepted April 20, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). Correspondence to: Stephen Sidney, MD, MPH, Kaiser Permanente Medical Care Program, Division of Research, 2000 Broadway, Oakland, CA 94612; sxs@dor.kaiser.org 2068 Clinical Investigations

2 between COPD and selected CVD end points including total cardiac mortality, 3 mortality from acute myocardial infarction (AMI), 4 mortality after coronary artery bypass graft, 5,6 and pulmonary embolism. 7 Low FEV 1 is associated with all-cause mortality, CVD mortality, nonfatal and fatal myocardial infarction (MI), nonfatal and fatal stroke, 8 10 and atrial fibrillation. 11 There are several reasons for a COPD-CVD association, including a major shared risk factor (smoking) and a number of factors that may lead to increased stress on the cardiovascular system or to cardiac arrhythmias (eg, use of -agonist medications that may stimulate the cardiovascular system, hypoxemia, hyperventilation leading to respiratory alkalosis, and inflammation). There is little in the published literature on the risk of CVD in persons with COPD, and we are unaware of studies that have prospectively examined the relationship of clinically diagnosed COPD with the incidence and mortality from CVD relative to an appropriately matched comparison group of individuals without COPD. In order to increase knowledge of the association between COPD and CVD, we examined the relationship of clinically diagnosed COPD to the incidence of several CVD end points in the Kaiser Permanente Medical Care Program of Northern California (KPNC), a large integrated health-care system. Study Setting Materials and Methods The study population was drawn from members of the KPNC, aged 40 years. The KPNC provides comprehensive prepaid integrated health care to its approximately 3.2 million subscribers, who comprise 25% of the population in the areas served. The subscribers are ethnically, racially, and socioeconomically heterogeneous, and are reflective of the local population except for being somewhat more educated, on average, and underrepresentative of the extremes of income. 12 In the age group targeted for this study, there were approximately 1.3 million members during the year Data Sources We utilized the following computerized administrative databases to obtain study data, all of which could be linked utilizing a unique eight-digit number assigned to each KPNC health plan member. The membership database included date of birth, gender, and other demographic data. The overnight hospitalization database includes race, dates of hospitalization, and all hospital discharge codes. The outpatient visit database includes diagnostic codes for conditions noted at the visit. The mortality database for KPNC contains linked death certificate information for members who have died in California since Each year, all active KPNC members are linked to California state death certificates using the following identifiers: social security number; name; date of birth; ethnicity; and place of residence. The pharmacy database includes all prescriptions filled at KPNC pharmacies. At the time of the study, approximately 93% of KPNC members had a prescription benefit for KPNC pharmacies. Study Population Case Patients: All COPD case patients who were age 40 years were identified during the 4-year period from January 1, 1996, through December 31, All case patients met the following criteria: (1) hospitalization with a primary hospital discharge diagnosis or an outpatient visit diagnosis with International Classification of Diseases, ninth revision, (ICD-9) discharge codes for COPD (491, chronic bronchitis; 492, emphysema; or 496, COPD), and two prescriptions for COPD medications (ie, inhaled anticholinergics, inhaled -adrenergic steroids, a combination of inhaled anticholinergic and -adrenergic agonists, and methylxanthines) within the 12-month window that began 6 months prior to the index date, where the index date was the date of the first hospital admission or outpatient diagnosis that met the criterion for a COPD case patient; (2) age at least 40 years on the index date; and (3) at least 12 months of KPNC membership prior to the index date. Control Subjects: Control subjects were selected from the membership of KPNC in a 1:1 ratio to case patients and met the following conditions: (1) random selection from KPNC membership groupings matched to COPD case patients on gender, year of birth, and length of KPNC membership (1 to 4.9 years, 5 to 9.9 years, and 10 years); (2) no outpatient visits or hospital discharges with COPD codes either in the 6-month period prior to the index date or during follow-up; and (3) at least 12 months of KPNC membership prior to the index date. Matching took place sequentially based on case patient entry into the cohort. A total of 5,880 COPD case patients and 1,285 control subjects were excluded from analyses that were limited to those without prevalent CVD. Validation of COPD Diagnosis One hundred twenty records of COPD cohort members were randomly selected for medical record review (96 outpatient records; 24 hospitalization records). A medical record abstractor obtained and abstracted the Kaiser Permanente medical records for a 12-month period of time prior to and subsequent to the date of COPD diagnosis. We defined spirometrically determined categories of airflow as follows: normal; mild airflow obstruction (FEV 1 /FVC ratio, 70% predicted; FEV 1, 80% predicted); or airway obstruction (FEV 1 /FVC ratio, 70% predicted; FEV 1, 80% predicted) according to the Global Initiative for Chronic Obstructive Lung Disease criteria. 13 Tobacco smoking, chronic cough, exertional dyspnea, asthma, chronic bronchitis, emphysema, and COPD medications were considered to be present if noted in the medical record during this time period. Medication was recorded if noted in the medical record, including inhaled anticholinergic agents, inhaled -adrenergic steroids, a combination of inhaled anticholinergic agents and -adrenergic agonists, and methylxanthine agents. Chronic cough (68%) and exertional dyspnea (52%) were frequently noted. A diagnosis of chronic bronchitis was found in 39% of the records, and a diagnosis of emphysema was found in 17.5%. Spirometry was found in only 31% of the records, and airflow obstruction was found in 92% of the spirometry records. Medication was recorded from 77% of the records. We developed a composite index of COPD, including the presence of at least one of the following conditions: chronic cough; chronic bronchitis; emphysema; or any degree of airflow obstruction. This CHEST / 128 / 4/ OCTOBER,

3 composite finding was present in 84% of the records (hospitalization records, 77%; outpatient records, 86%). Follow-up Follow-up was conducted for the following CVD hospitalization and mortality end points: ventricular tachycardia (VT)/ ventricular fibrillation (VF)/cardiac arrest (ICD-9 codes 427.1, , and 427.5; International Classification of Diseases, 10th revision [ICD-10] codes I46.2 and I49.0), atrial fibrillation and flutter (ICD-9 codes and ; ICD-10 codes I48.0 and I48.1), other arrhythmia (ICD-9 codes 427.x except those noted above; ICD-10 codes I47.x and I49.x except I49.0x), angina pectoris (ICD-9 code 413.x; ICD-10 codes I20.1, I20.8, or I20.9 plus prescription for nitroglycerine within a 3-month period after hospital admission), AMI (ICD-9 code 410.x; ICD-10 codes I21.x to I22.x), congestive heart failure (CHF) [ICD-9 codes 428.x and 402.x1; ICD-10 codes I50.x], stroke (ICD-9 codes 431.x to 434.x, and 436.0; ICD-10 codes I60.x, I61.x, I63.x, and I64.x), pulmonary embolism (ICD-9 code 415.1; ICD-10 code I26.x with prescription for enoxaparin and/or warfarin), all CVD (ICD-9 codes 390.x to 459.x; ICD-10 codes I00.x to I99.x). For hospitalization incidence analyses, follow-up was conducted to the first of the following dates: date of hospitalization for end point; death; end of membership; or December 31, For mortality analyses, follow-up was conducted to the first of the following dates: date of death; or December 31, We excluded all deaths occurring more than 1 month after the date of membership termination. The mean length of follow-up (to the end of membership or to December 31, 2000) was 2.75 years for case patients and 2.99 years for control subjects. Validation of Hospital Discharge Codes We validated the following primary hospital discharge diagnoses in a sample of case patients by medical record abstraction using a trained medical record analyst, with review of the findings by one of the study authors (S.S.): (1) unstable angina (ICD-9 codes primary, or 414.xx primary and 411.x secondary) was validated in 75 of 88 case patients (85.2%), with most of the remaining case patients having AMI or stable angina; (2) angina (stable), which was defined as ICD-9 code 413.x in the primary hospital discharge code position, was validated in nine of nine case patients (100%) and was also reliably coded in the setting of 414.xx primary and 413.x secondary hospital discharge codes with a 93.7% validation rate (36 of 37 case patients); (3) arrhythmia, which was defined as ICD-9 code 427.x in the primary hospital discharge code position, included several different arrhythmias. The paroxysmal supraventricular tachycardia code had a high validation rate (91.7%), while all other arrhythmia groupings had validation rates in the range of 54 to 67%. We did not validate atrial fibrillation/atrial flutter because of previous validation work at the Division of Research showing these to be reliable codes (ICD-9 codes and had a validation rate of 95%). Validation rates for the other CVD end points have been determined for other studies at the Division of Research and include rates of 96% for AMIs, approximately 78 to 80% for ischemic stroke, 96% for CHF, 14 and 90% for pulmonary embolism (personal communication). Statistical Analysis Disease incidence rates were determine by direct age adjustment using the 2000 KPNC membership as the standard. Age-adjusted rate ratios and multivariable relative risks (RRs) were determined using proportional hazard models. Multivariable models included case-control status, age, gender, and cardiovascular risk morbidities (ie, diabetes, hypertension, and hyperlipidemia) and the presence of baseline CVD detected during the 6-month period prior to the index date (eg, MIor stroke). Two-way interactions were tested for age case-control status, and gender case-control status. All data analysis was performed utilizing a statistical software package (SAS; SAS Institute; Cary, NC). Results We identified a total of 45,966 persons, age 40 years who satisfied the case definition for COPD. The gender and age distribution of case patients and control subjects are shown in Table 1. Fifty-five percent of the case patients were men. The mean age of case patients and control subjects was 64.4 years (SD, 12.2 years). The prevalence at baseline of comorbidities in case patients and control subjects is shown in Table 2. The COPD case group had a higher prevalence of each of the comorbid conditions. The most striking prevalence differences between the case and control groups were for a concomitant diagnosis of asthma (40.0% vs 2.6%, respectively; odds ratio [OR], 24.71; 95% confidence interval [CI], to 26.24), CHF (7.2% vs 0.9%, respectively; OR, 8.48; 95% CI, 7.65 to 9.40), and atrial fibrillation (4.7% vs 1.1%, respectively; OR, 4.41; 95% CI, 4.00 to 4.87). The incidence of hospitalization for study end points is shown in Table 3. The overall incidence rate of CVD end points was 6,402 per 100,000 personyears in case patients and 2,793 per 100,000 personyears in control subjects. For study end points, the rates were 4,557 per 100,000 person-years in case patients and 1,837 per 100,000 person-years in con- Table 1 Distribution of Case Patients and Control Subjects by Age and Gender Variables Case Patients Control Patients No. % No. % Gender Men 25, , Women 20, , Age, yr , , , , , , , , , , , , , , , , , , , , Clinical Investigations

4 Table 2 Prevalence of Baseline Comorbidities, Case Patients, and Control Subjects Case Patients Control Subjects Comorbidities No. % No. % OR (95% CI) Obesity 3, , ( ) Diabetes ( ) Hypertension 8, , ( ) Hyperlipidemia 3, , ( ) VT/VF/cardiac arrest ( ) Atrial fibrillation 2, ( ) Other arrhythmia 1, ( ) Angina ( ) MI ( ) Stroke ( ) Pulmonary embolism ( ) CHF 3, ( ) Renal disease ( ) Asthma 18, , ( ) trol subjects. Among the study end points, heart failure was the leading cause of hospitalization in case patients, followed by MI and stroke. For control subjects, stroke was the leading cause of hospitalization followed by MI and heart failure. Age-adjusted rates were higher in COPD case patients than in control subjects for all CVD end points. The ageadjusted risks for case patients relative to control subjects were generally in the 2 to 3 range, with the exception of heart failure (RR, 5.55; 95% CI, 4.71 to 5.73), VT/VF/cardiac arrest (RR, 4.17; 95% CI, 2.83 to 6.16), and stroke (RR, 1.51; 95% CI, 1.37 to 1.66). The RRs did not change substantially when the analysis was limited to those who did not have preexisting study end points. The mortality from diagnoses at the study end point is shown in Table 4. For many diagnostic categories, the age-adjusted RRs were in the range of 2 to 3, except for stroke (RR, 1.46; 95% CI, 1.21 to 1.75) and CHD (RR, 4.93; 95% CI, 3.36 to 7.24). The RRs did not change substantially when the analysis was limited to those who did not have preexisting study end points. There were too few case patients and control subjects in the categories of VT/VF/cardiac arrest, atrial fibrillation, other arrhythmia, and pulmonary embolism to report meaningful rates and rate ratios. We tested interactions with gender case-control status and age case-control status terms to determine whether the RR differed by gender and by age. Table 3 Incidence of Hospitalization During Longitudinal Follow-up for Study End Points in Case Patients and Control Subjects Outcome Case Patients, No. Case Patient Rate* Control Subjects, No. Control Subject Rate* Age-Adjusted Rate Ratio Model Model Excluding CVD Prevalent at Baseline VT/VF/cardiac arrest ( ) 2.80 (1.87, 4.20) 2.78 (1.75, 4.42) Atrial fibrillation ( ) 1.98 ( ) 2.11 ( ) Other arrhythmia ( ) 1.71 ( ) 1.70 ( ) Angina ( ) 1.98 ( ) 2.03 ( ) MI 1, ( ) 1.89 ( ) 1.87 ( ) CHF 2,233 1, ( ) 3.75 ( ) 3.85 ( ) Stroke 1, ( ) 1.33 ( ) 1.39 ( ) Pulmonary embolism ( ) 2.72 ( ) 2.74 ( ) Other CVD 2,846 2, ,477 1, ( ) 1.85 ( ) 1.86 ( ) Any study end point 5,410 4, ,460 1, ( ) 2.09 ( ) 2.09 ( ) Any CVD 7,378 6, ,678 2, ( ) 1.95 ( ) 1.96 ( ) *Age-adjusted rate per 100,000 person-years. Values given as RR (95% CI). Model includes the independent variables age, gender, hypertension, hyperlipidemia, and diabetes. Includes all CVD diagnostic codes (ICD-9 codes 390x to 459x) not included in the main study end points (ie, the first eight end points on the list in this table). Refers to the first eight end points on the list in this table. CHEST / 128 / 4/ OCTOBER,

5 Table 4 Mortality Rates in Case Patients and Control Subjects Outcomes Case Patients, No. Case Patient Rate* Control Subjects, No. Control Subject Rate* Age-Adjusted Rate Ratio Model Model Excluding CVD Prevalent at Baseline MI ( ) 1.81 ( ) 1.85 ( ) CHF ( ) 3.53 ( ) 3.50 ( ) Stroke ( ) 1.25 ( ) 1.35 ( ) Pulmonary embolism ( ) 1.89 ( ) 1.54 ( ) Other CVD 1,407 1, ( ) 1.96 ( ) 1.95 ( ) Any study end points ( ) 1.68 ( ) 1.71 ( ) All CVD 2,325 1, , ( ) 1.84 ( ) 1.84 ( ) *Age-adjusted rate per 100,000 person-years. Values given as RR (95% CI). Model includes independent variables age, gender, hypertension, hyperlipidemia, and diabetes. Includes all CVD diagnostic codes (ICD-9 codes 390x to 459x) not included in the main study end points (ie, the first eight end points on the list in this table). Any study end point refers to the first eight end points on the list in this table. The risks of hospitalizations for MI, stroke, any study end point, and any CVD were modestly higher in women compared with men (Table 5). The risks of hospitalization for MI, CHF, stroke, other CVD, any study end point, and any CVD were higher among those persons 40 to 64 years old compared with those 65 years. The risk of mortality did not differ by gender for any of the study end points (Table 6). The risk of mortality from MI, other CVD, any study end point, and any CVD were higher among those persons 40 to 64 years old compared with those 65 years. Discussion The main finding of this study was that persons with diagnosed and treated COPD identified in this large integrated health-care population had a higher risk of incident hospitalization and mortality for each of the CVD end points studied, relative to agematched and gender-matched control subjects. All rates for CVD end points were substantially higher in case patients than in control subjects, most notably so for CHF. Relative to the control subjects, the prevalence of baseline medical conditions was particularly high for asthma and for CHF. The findings of higher incidences of hospitalization for and mortality from cardiovascular end points in COPD patients may be, in part, due to the higher prevalence of preexisting CVD in the COPD patients. However, the restriction of our analyses to those persons without known preexisting CVD did not substantively alter the RRs for any of the end points examined. We controlled in our analyses for some of the known CVD risk factors, including high BP, hyperlipidemia, and diabetes. While these risk factors were more prevalent in the COPD case group than in the control group, controlling for them Table 5 Incidence of Hospitalization for Study End Points by Gender and by Age* Outcome Men Women p Value yr 65yr p Value VT/VF/cardiac arrest 2.99 ( ) 2.43 ( ) ( ) 3.10 ( ) 0.80 Atrial fibrillation 2.20 ( ) 1.75 ( ) ( ) 1.90 ( ) 0.94 Other arrhythmia 1.78 ( ) 1.64 ( ) ( ) 1.70 ( ) 0.58 Angina 1.79 ( ) 2.31 ( ) ( ) 1.81 ( ) 0.07 MI 1.77 ( ) 2.09 ( ) ( ) 1.73 ( ) CHF 3.78 ( ) 3.71 ( ) ( ) 3.24 ( ) Stroke 1.21 ( ) 1.50 ( ) ( ) 1.22 ( ) 0.01 Pulmonary embolism 3.46 ( ) 2.32 ( ) ( ) 2.72 ( ) 0.86 Other CVD 1.85 ( ) 1.84 ( ) ( ) 1.61 ( ) Any study end point 2.02 ( ) 2.18 ( ) ( ) 1.93 ( ) Any CVD 1.89 ( ) 2.03 ( ) ( ) 1.79 ( ) *Values given as RR (95% CI), unless otherwise indicated. Model includes independent variables age, gender, hypertension, hyperlipidemia, and diabetes. Other CVD includes all CVD diagnostic codes (ICD-9 codes 390x to 459x) not included in the main study end points (ie, the first eight end points on the list in this table). Any study end point refers to the first eight end points on the list in this table Clinical Investigations

6 Table 6 Mortality for Study End Points by Gender and by Age* Outcome Men Women p Value yr 65 yr p Value MI 1.91 ( ) 1.62 ( ) ( ) 1.62 ( ) CHF 2.76 ( ) 5.00 ( ) ( ) 3.48 ( ) 0.49 Stroke 1.09 ( ) 1.47 ( ) ( ) 1.13 ( ) 0.65 Pulmonary embolism 1.86 ( ) 1.92 ( ) ( ) 1.76 ( ) 0.61 Other CVD 1.93 ( ) 2.00 ( ) ( ) 1.87 ( ) Any study end point 1.64 ( ) 1.73 ( ) ( ) 1.57 ( ) Any CVD 1.81 ( ) 1.87 ( ) ( ) 1.74 ( ) *Values given as RR (95% CI), unless otherwise indicated. Includes all CVD diagnostic codes (ICD-9 codes 390x to 459x) not included in the main study end points (ie, the first eight end points on the list in this table). Refers to the first eight end points on the list in this table. attenuated, but did not eliminate, the increased risk of CVD end points associated with COPD. Thus, COPD was a risk factor for CVD end points regardless of whether or not CVD comorbidity was present at baseline and traditional risk factors explained some, but not all, of the increased risk of CVD end points in patients with COPD. However, our databases did not include information on smoking, which is an important risk factor for both CVD and COPD, nor did we have data on body mass index. Cigarette smoking is the most powerful predictor of COPD and is also an important risk factor for CVD. Although it could not be ascertained from medical record review, we would assume that smoking rates were higher in COPD patients than in control subjects, an observation that is supported by our phone survey (separate report) of a subset of the cohort (21.9% in COPD patients vs 8.8% in control subjects for current use) and is supported by another study 4 of individuals hospitalized for AMI, which showed that the prevalence of current smoking was 44% higher among AMI patients who had COPD than in patients without COPD. Thus, cigarette smoking undoubtedly contributed to higher CVD rates in COPD patients. The prevalence of cigarette smoking in case patients was lower than that in two other studies that reported smoking in 32% 15 and 30% 16 of COPD case patients, while the prevalence of smoking in the control group was somewhat lower than that reported by participants in the 1998 National Health Interview Survey 17 (40 to 64 years of age, 25.0%; 65 years of age, 10.9%). Another potential mechanism for increased CVD risk from COPD is inflammation. COPD is characterized by chronic pulmonary inflammation 18 and high levels of cytokines in exhaled breath condensate, 19 and is associated with general systemic inflammation. 20 Systemic inflammation has emerged as a causative factor for CVD. For example, the blood level of C-reactive protein, a marker of systemic inflammation, is a risk factor for cardiovascular events. 21 Atrial fibrillation and heart failure were more common in COPD case patients than in control subjects. Both of these conditions are related to the risk of stroke 22 and probably contribute to the higher rate of stroke in COPD patients. COPD patients use medications that stimulate the cardiovascular system, including anticholinergic agents and sympathomimetic medications. These medications may contribute to increased heart rate and BP, which might instigate an ischemic episode of heart disease (eg, angina or MI) or cerebrovascular disease (transient ischemic attack or stroke). Cardiovascular stimulation may also lead to arrhythmias, including potentially lethal arrhythmias such as VT or VF. A graded increase in the risk of acute coronary syndrome was demonstrated for a number of metered-dose inhalers of -agonists prescribed in the 90 days prior to hospitalizations in a Department of Veterans Affairs study, 23 with the risk nearly doubling for those receiving six or more canisters. However, a Canadian study 24 showed no overall risk of fatal or nonfatal MI associated with -agonist use in the year prior to the event, although a small increased risk (11%) was noted for each 10 canisters dispensed during this time period. An alternative explanation for an association of -agonist use with CVD is that the intensity of use reflects the severity of COPD. COPD patients, especially in cases of more advanced disease, may manifest hypoxemia. Hypoxemia may contribute to episodes of ischemic CVD (eg, angina, MI, transient ischemic attack, or stroke) and may instigate cardiac arrhythmias. Hyperventilation in COPD patients may lead to respiratory alkalosis, a disturbance in metabolic parameters that may contribute to cardiac arrhythmias. Since FEV 1 in mid-life is a predictor of later CVD and of mortality, it is possible that there are other factors that are specifically related to chronic lung disease (eg, inflammation or smoking) that contribute to CVD. CHEST / 128 / 4/ OCTOBER,

7 We do not have an explanation for the slightly higher risks for hospitalization for some of the CVD end points in women compared to men. We speculate that the higher rates of CVD hospitalization and mortality end points in younger members of the cohort (ie, those 40 to 64 years of age) vs older members (ie, those 65 years of age) mean that COPD reflects earlier and more serious diseases in younger adults, making it more important as a risk factor in this age group. Alternatively, COPD in younger adults may act in part as a confounder, reflecting a more intense (ie, longer and/or more frequent) smoking history, with smoking being a known risk factor for CVD. The major strength of this study is its large size, the high comparability of the KPNC population to the local population that it serves, the data availability on a number of comorbidities, and the availability of validation studies on several of the hospital outcomes that were assessed from administrative databases. Limitations include reliance on an administrative database that lacks data on cigarette smoking; the lack of systematic information on comorbidities for all patients, since the assessment of comorbidity required a medical encounter during the 6-month period prior to the index date; and the lack of spirometry data for use in defining COPD case patients. The low prevalence of spirometry in the subset of case patients for which medical record review may potentially reflect a lack of precision in case patient definition in this cohort, or, alternatively, may indicate that spirometry is not frequently used in the management of case patients with chronic disease and was not performed during the 24-month period that was covered by the review. However, almost all of the spirometry tests reviewed showed evidence of airflow obstruction. The high prevalence of asthma in COPD patients also raises questions about the specificity of the COPD and asthma diagnoses. 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