Patients With Ankylosing Spondylitis Have Increased Cardiovascular and Cerebrovascular Mortality

Editors' Notes Context Although prior studies have shown an association between ankylosing spondylitis (AS) and cardiovascular morbidity, few have examined the relationship between AS and mortality from vascular disease. Contribution The authors analyzed administrative health data to examine the risk for vascular death (from either cardio-vascular or cerebrovascular disease) among patients with AS compared with matched controls without AS. Caution The administrative database lacked information on such risk factors as smoking status, diet, physical activity, and lipid levels. Prescription data were not available for patients younger than 65 years. Implication Patients who had AS had greater risk for vascular death than those without AS. Patients with chronic inflammatory diseases have adverse cardiovascular outcomes. Inflammation is associated with accelerated atherosclerosis and endothelial dysfunction (1, 2). Preclinical studies have highlighted the importance of inflammatory mediators in atherogenesis (3, 4). Ankylosing spondylitis (AS) is a chronic inflammatory arthritis that predominantly affects the spine. Several studies have shown that patients with AS have a high risk for cardiovascular disease (514). Ischemic heart disease and myocardial infarction occur at a higher rate in patients with AS (15, 16), and AS is an independent risk factor for early coronary artery bypass graft surgery (17). However, a population-based study from Wales concluded that vascular morbidity was not significantly increased in AS after correction for age and sex (18). Patients with AS have higher mortality risk than the general population (1922). Infections were reported as the most frequent cause of death in patients with AS (23). In a hospital-based study, the most frequent cause was vascular disease (24). However, most of these studies were conducted well before the biologic era. Tumor necrosis factor inhibitors have revolutionized the management of AS and are disease-modifying (25, 26). In addition, better management has decreased vascular deaths in the general population. Contemporary large-scale studies on vascular mortality in AS are lacking. Given the relatively low prevalence of AS, validated administrative databases are a valuable resource for research. We conducted a population-based study to assess whether patients with AS are at increased risk for cardiovascular and cerebrovascular mortality. We also sought to identify the risk factors for vascular mortality in patients with AS. Methods This study was approved by the research ethics board at Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. Study Setting and Data Sources We conducted a population-based study by using provincial health administrative data in Ontario, Canada. The 13.5 million Ontario residents receive health services coverage under a publicly funded universal health care system. Ontario's provincial health administrative databases, which are held securely in a linked, coded form and analyzed at the Institute for Clinical Evaluative Sciences (ICES) (www.ices.on.ca), carry details of each resident's health care utilization. We used 4 core data sets: 1) the Ontario Health Insurance Plan (OHIP) Registered Persons Database, which contains demographic, place of residence, and vital status information on persons with insured health services; 2) the OHIP Claims History Database, which captures information on physician billing claims (27); 3) the Canadian Institute for Health Information (CIHI) Discharge Abstract Database (DAD), which contains diagnostic and procedural information regarding all acute hospital admissions (28); and the Ontario Registrar General Death Database, with information regarding all deaths, including primary cause of death. Study Cohort Ankylosing spondylitis was defined among Ontario residents aged 15 years or older who had at least 2 OHIP claims with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM), diagnosis code of 720 (AS) over 2 years, with at least 1 claim by a rheumatologist; or at least 1 CIHI-DAD record with an ICD-9-CM code 720 or an International Classification of Diseases, 10th Revision (ICD-10), code M45 (AS). From this cohort, we identified all Ontarians with incident AS between 1 April 1995 and 31 March 2011. The date of the first eligible diagnosis code served as the cohort entry date. To help minimize the misclassification of prevalent cases as incident, we applied our case detection algorithm beginning at the earliest date possible in our data (1 April 1992), and any patients in whom AS was diagnosed during the first 3 years of accrual were treated as prevalent cases. We identified a comparison cohort comprising Ontarians without AS and matched them to patients with AS for age (365 days), sex, and Local Health Integration Networks in Ontario. Each person with AS was matched to 4 comparators, who were assigned the same cohort entry date. Outcomes Our primary outcome was vascular mortality, defined by using a composite primary cause of cardiovascular death (ICD-9-CM codes 410 through 414) or cerebrovascular death (ICD-9-CM codes 431, 434, and 436) as recorded in the Ontario Registrar General's Database. The ICD-9-CM codes chosen have been used in several studies to identify vascular events (2932). Covariates We collected data on baseline comorbidities for people in both the AS and comparison groups by using a 36-month look-back window. The baseline comorbidities studied were hypertension, peripheral vascular disease (PVD), chronic kidney disease (CKD), diabetes, inflammatory bowel disease (IBD), cancer, and dementia. Because the outcome was vascular mortality, we excluded patients with coronary artery disease (CAD) and cerebrovascular disease (CVD) at baseline. We used previously validated diagnostic algorithms for identifying hypertension (33), diabetes (34), and IBD (35). The data sources and ICD codes for the other disease covariates are provided in the Appendix and Appendix Tables 1, 2, and 3. Chinese and South Asian ethnicity were defined by using a validated surname algorithm (36). Finally, because individual-level income data were not available in our data sources, we used each person's neighborhood median household income from the Statistics Canada census (28, 37, 38). Appendix Table 1. Ontario Health Insurance Plan Fee Codes for Renal Dialysis Appendix Table 2. ICD and OHIP Diagnosis Codes for CKD* Appendix Table 3. Algorithm for Diagnosing Adult-Onset IBD* Statistical Analysis Participant characteristics were summarized by age, sex, income quintile, ethnicity, and baseline comorbid illness at the time of cohort entry. Given the large size of the cohorts, we used standardized differences to compare baseline characteristics of patients with AS and matched comparators. Standardized differences less than 0.1 are not considered important (39). In the primary analysis, we followed patients with AS and comparators from their cohort entry date until 31 December 2011, censoring them when they experienced the primary outcome (vascular mortality), died of another cause, or left the province. Persons in the comparison group were additionally censored upon diagnosis of AS but were eligible to enter the AS cohort. We then calculated the incidence rates for vascular mortality. We used strata statement in PHREG to fit a Cox proportional hazards model that was stratified on the matched pairs, and we calculated hazard ratios (HRs) that were adjusted for baseline cancer, diabetes mellitus, dementia, IBD, PVD, hypertension, and CKD. Patients who had CAD or CVD at baseline were excluded in the primary analysis. To identify predictors of vascular mortality among patients with AS, we performed a separate Cox regression model including only patients with AS. Finally, we constructed survival curves adjusted for covariates by using the KaplanMeier method and tested for survival differences by using the log-rank test (40). Vascular disease could be a direct effect of AS-related inflammation. If so, excluding patients with CAD and CVD from the multivariable analysis of vascular mortality would be an overcorrection. We separately calculated HRs for vascular mortality in patients with AS compared with controls in a model that included patients with baseline CAD and CVD. Because any effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on vascular events could alter our results, we separately analyzed the effect of medications on vascular mortality in patients with AS. Prescription drug claims from the Ontario Drug Benefit Program were available for patients aged 65 years or older. We assessed the effect of exposure to statins, traditional NSAIDs, cyclooxygenase-2 (COX-2) inhibitors, and antihypertensive drugs on vascular mortality among persons aged 66 years or older. To account for the total duration of drug intake and avoid survival bias, we treated drug exposure as a time-dependent variable (41). The number of patients receiving tumor necrosis factor inhibitors was insufficient for us to assess the effect of these agents on vascular mortality. All analyses were conducted at ICES by using SAS, version 9.3 (SAS Institute). Role of the Funding Source This study was supported by the Arthritis Program, University Health Network, Toronto; The Arthritis Society, Canada; and ICES, which is funded by a grant from the Ontario Ministry of Health and Long-Term Care. The sponsors had no role in the design and conduct of the study; collection, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. Results Cohort Characteristics We identified 21 473 Ontarians aged 15 years or older who were diagnosed with AS between 1 April 1995 and 31 March 2011, and 86 606 individuals were matched to the patients with AS by age, sex, and health planning region of residence (Table 1). Table 1. Demographic and Clinical Characteristics of Persons With and Without AS at