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Scand J Rheumatol 2014;43:132–136
A nationwide population-based retrospective cohort study: increased risk of acute coronary syndrome in patients with ankylosing spondylitis C-H Chou1*, M-C Lin2*, C-L Peng3,4, Y-C Wu2, F-C Sung3,4, C-H Kao5,6, S-H Liu7,8 1
Division of Cardiology, Department of Internal Medicine, YuanSheng Hospital and Changhua Christian Hospital, Yunlin Branch, Yunlin, Department of Nuclear Medicine, E-DA Hospital, I-Shou University, Kaohsiung, 3Institute of Environmental Health, College of Public Health, China Medical University, Taichung, 4Management Office for Health Data, China Medical University Hospital, Taichung, 5 Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung, 6 Department of Nuclear Medicine and PET Centre, China Medical University Hospital, Taichung, 7Department of Health Care and Social Work, Yu Da University of Science and Technology, Miaoli, and 8Department of Public Health, China Medical University, Taichung, Taiwan Scand J Rheumatol Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/02/14 For personal use only.
2
Objectives: To compare the risk of acute coronary syndrome (ACS) between patients with and without ankylosing spondylitis (AS). Method: This retrospective cohort study identified all patients with AS aged 18 years newly diagnosed from 2000 to 2009, registered in the National Health Insurance Research Database (NHIRD) in Taiwan. The non-AS cohort consisted of fourfold randomly selected control patients free of AS, frequency matched by age, sex, and diagnosis year. The incidence of ACS was determined for both AS and non-AS cohorts. Results: We selected 6262 patients with AS and 25 048 patients without AS. The patients with AS were more prevalent than those without, with co-morbidities of hypertension, diabetes mellitus (DM), hyperlipidaemia, stroke, and peripheral vascular diseases. The overall incidence rate of ACS was higher in the AS cohort than in the non-AS cohort (4.4 vs. 2.9 per 1000 person-years), with an adjusted hazard ratio (aHR) of 1.36 [95% confidence interval (CI) 1.16–1.59]. AS patients with co-morbidities of hypertension, DM, and cancer had an aHR of 7.74 for ACS, compared to those without these comorbidities. Conclusions: AS patients are at higher risk of ACS compared with non-AS subjects. Management of CV risk factors should be taken into account for the treatment of patients with AS, especially for patients with co-morbidities of hypertension, DM, and cancer.
Acute coronary syndrome (ACS) includes conditions causing sudden reduced blood flow to the heart. ACS refers to unstable angina, non-ST-segment elevation myocardial infarction, and ST-segment elevation myocardial infarction (1, 2). The causes of cardiovascular disease (CVD) are multifactorial (3, 4); some of the CV risk factors are male gender, hypertension, smoking, hyperlipidaemia, and diabetes mellitis (DM). Ankylosing spondylitis (AS) is a chronic and systemic inflammatory condition that primarily affects the sacroiliac joints and the axial skeleton (5–8). Increased risk of CV-related morbidity and mortality has been reported in patients with inflammatory arthritis (9, 10). The inflammatory processes in rheumatoid arthritis (RA) are similar to atherosclerosis, including the formation of atheroma, plaque instability, and thrombus development Chia-Hung Kao, Department of Nuclear Medicine and PET Centre, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung 404, Taiwan. E-mail: [email protected] *These authors contributed equally to this work. Accepted 1 July 2013
(11). One study showed that an elevated C-reactive protein (CRP) concentration measured early in the disease process is a powerful predictor of death from CVD in inflammatory polyarthritis and RA (12). Data from USA have shown an increased prevalence of CV disease in AS patients compared with age- and gender-matched controls (13). Another study found a higher prevalence of spondyloarthropathies among patients receiving a coronary artery bypass graft (CABG) compared with control CABG patients, and demonstrated that spondyloarthropathy was a stronger risk factor for CABG than most traditional risk factors (14). Despite these studies, published reports of the relationships between AS and CV risk factors are limited (15). Hence, the aim of our study was to compare the incidence of ACS and CV risk factors between patients with and without AS.
Method Data sources Our retrospective cohort study used reimbursement data from National Health Insurance (NHI) electronic records
© 2014 Informa Healthcare on license from Scandinavian Rheumatology Research Foundation
www.scandjrheumatol.dk
DOI: 10.3109/03009742.2013.822097
Scand J Rheumatol Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/02/14 For personal use only.
Acute coronary syndrome in AS
system in Taiwan, which contains all medical claims from 1996 to 2009. In Taiwan, 99% of citizens are covered under the NHI and 90% of hospitals and clinics are NHI contracted providers. The National Health Research Institutes (NHRI) is responsible for managing the insurance claims data reported to the Bureau of Health Insurance. The NHRI has established electronic datasets for administrative and research purposes. We used a subset of data that comprises claims data from a random sample from the one million insured people in the nationwide database compiled by the NHRI and released for us to use in 2009. The diagnosis codes used in the NHRI are based on the International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM). Patients’ personal data are encrypted in this dataset for protection of privacy. This study was approved by the Ethics Review Board of the China Medical University and Hospital (CMU-REC-101-012).
Study subjects and outcome measures Our study consisted of an AS cohort and a non-AS cohort identified from the claims data of 2000–2009. Both cohorts were followed up until the end of 2009. The AS cohort consisted of patients aged 18 years newly diagnosed with AS in 2000–2009, identified from both ambulatory care and in-patient care units (ICD-9-CM codes 720 and 7200). The index date for an AS patient was the date of the first clinic visit with the diagnosis. Subjects with a history of ACS diagnosed (ICD-9-CM 410–411.1) before the index date or with missing information on age or sex were excluded. The comparison cohort was selected using a systematic random-sampling method in which four control patients, matched for age, sex, and year of index date, were selected for each corresponding AS patient. The follow-up person-years were calculated for each study participant from the index date to the date of withdrawal from the insurance system or to the end of 2009. All study subjects with a diagnosis of ACS or CVD risk factors were already confirmed by ICD-9 coding (ICD-9-CM 410–411.1) according to the study subject’s medical records in the National Health Insurance Research Database (NHIRD), based on based on validated definitions (16).
Statistical analysis The distributions of categorical sociodemographic characteristics were compared between the AS cohort and the non-AS cohort, and the differences were examined using the χ 2 test. The follow-up person-years were used for estimating the incidence density and the AS cohort to non-AS cohort incidence rate ratio (IRR) calculations used Poisson regression. Cox’s proportional hazards regressions were used to assess the risk of developing ACS that was associated with AS, while adjusting for variables that were significantly related to AS based on
133
the results of the χ 2 test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated in the model. All analyses were performed SAS version 9.2 (SAS Institute, Cary, NC, USA). A two-tailed p value < 0.05 was considered to be statistically significant.
Results We selected 6262 patients with AS for our study cohort and 25 048 control patients without AS for our comparison cohort. Among the study participants, 52.3% were women and 83.1% were younger than 65 years of age. The most common co-morbidities in the AS cohort compared with the non-AS cohort were hypertension (26.4% vs. 20.0%, p < 0.0001), DM (8.7% vs. 7.3%, p < 0.0001), hyperlipidaemia (23.3% vs. 15.8%, p < 0.0001), and stroke (14.3% vs. 10.0%, p < 0.0001) (Table 1). Table 2 shows the incidence rates of ACS for both cohorts, the AS cohort to the non-AS cohort IRRs and HRs by sex and age. The incidence rate of ACS was 1.5fold higher in the AS cohort than in the non-AS cohort (4.4 vs. 2.9 per 1000 person-years) with an adjusted HR (aHR) of 1.36 (95% CI 1.16–1.59). The sex-specific AS
Table 1. Demographic characteristics and co-morbidity in patients with and without ankylosing spondylitis (AS). AS cohort (n = 25 048) Variables Sex Male Female Age (years) 18–44 45–64 65–74 75 Hypertension Yes No Diabetes mellitus Yes No Hyperlipidaemia Yes No Stroke Yes No Cancer Yes No
n
%
Non-AS cohort (n = 6262) n
%
11 952 47.7 13 096 52.3
2988 3274
47.7 52.3
12 068 48.2 8740 34.9 2876 11.5 1364 5.4
3017 2185 719 341
48.2 34.9 11.5 5.4
5017 20.0 20 031 87.6
1652 4610
26.4 73.6
1818 7.3 23 230 92.7
546 5716
8.7 91.3
3966 15.8 21 082 84.2
1457 4805
23.3 76.7
2514 10.0 22 534 90.0
895 5367
14.3 85.7
348 1.4 24 700 98.6
81 6181
1.3 98.7
p-value* 1.00 1.00
< 0.0001 < 0.0001 < 0.0001 < 0.0001 0.5596
* χ 2 test. Hypertension ICD-9-CM (A-code): 401–405 (A260 and A269), admission more than three times; diabetes mellitus ICD-9-CM (A-code): 250 (A181), admission more than twice in the first year; hyperlipidaemia ICD-9-CM (A-code): 272 (A182), admission more than three times; stroke ICD-9-CM (A-code): 430–438 (A290– A299); cancer (HVfile) ICD-9-CM:140-208.
www.scandjrheumatol.dk
C-H Chou et al
cohort to non-AS cohort IRRs were similar for both men and women, as were the HRs. The incidence of ACS increased with age in both cohorts, being greater in those with AS and the highest in the oldest group. However, the age-specific AS cohort to non-AS cohort IRR and aHR of ACS were the greatest for the younger patients (aged 18–44 years). The age-specific aHR was not significant for the older groups. Figure 1 shows the Kaplan–Meier graph of ACS-free survival rates for AS patients and the comparison cohort. The results of the log-rank test indicate that patients with AS had a significantly lower ACS-free survival rate (95.8% vs. 97.1%, p < 0.001). Table 3 shows that subjects with co-morbidity had a higher incidence of ACS than those without co-morbidity, which was consistently higher in the AS cohort than in the non-AS cohort. Table 4 shows the interaction measures between AS and selected co-morbidities for the risk of ACS. Hypertension was most prevalent in both AS and non-AS cohorts, and was associated with an AS to non-AS aHR of 2.84. The corresponding aHR was 2.58 for those with DM. The aHR increased to 4.36 for those with both hypertension and DM. Cancer was the least prevalent in AS patients. However, AS patients with hypertension, DM, and cancer had an aHR of 7.74. Discussion In our study, the risk of ACS was higher in the AS cohort than the non-AS cohort. We also found a significantly higher prevalence of hypertension, DM, hyperlipidaemia, and stroke in patients with AS than in control patients. A previous meta-analysis showed that the risk of myocardial infarction in AS patients may be related to an increased frequency of dyslipidaemia (17). In a recent retrospective cohort study, although an increased risk of myocardial infarction in AS patients was not observed, the prevalence of DM and hypertension was higher for AS patients than for the controls (18). Health-care databases have been used in CV studies to assess disease prevalence and costs, and the reliability of
Probability of acute coronary syndrome 0.95 0.96 0.97 0.98 0.99 1.00
Scand J Rheumatol Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/02/14 For personal use only.
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Non-ankylosing spondylitis Ankylosing spondylitis Log-rank test, p
Scand J Rheumatol 2014;43:132–136
A nationwide population-based retrospective cohort study: increased risk of acute coronary syndrome in patients with ankylosing spondylitis C-H Chou1*, M-C Lin2*, C-L Peng3,4, Y-C Wu2, F-C Sung3,4, C-H Kao5,6, S-H Liu7,8 1
Division of Cardiology, Department of Internal Medicine, YuanSheng Hospital and Changhua Christian Hospital, Yunlin Branch, Yunlin, Department of Nuclear Medicine, E-DA Hospital, I-Shou University, Kaohsiung, 3Institute of Environmental Health, College of Public Health, China Medical University, Taichung, 4Management Office for Health Data, China Medical University Hospital, Taichung, 5 Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung, 6 Department of Nuclear Medicine and PET Centre, China Medical University Hospital, Taichung, 7Department of Health Care and Social Work, Yu Da University of Science and Technology, Miaoli, and 8Department of Public Health, China Medical University, Taichung, Taiwan Scand J Rheumatol Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/02/14 For personal use only.
2
Objectives: To compare the risk of acute coronary syndrome (ACS) between patients with and without ankylosing spondylitis (AS). Method: This retrospective cohort study identified all patients with AS aged 18 years newly diagnosed from 2000 to 2009, registered in the National Health Insurance Research Database (NHIRD) in Taiwan. The non-AS cohort consisted of fourfold randomly selected control patients free of AS, frequency matched by age, sex, and diagnosis year. The incidence of ACS was determined for both AS and non-AS cohorts. Results: We selected 6262 patients with AS and 25 048 patients without AS. The patients with AS were more prevalent than those without, with co-morbidities of hypertension, diabetes mellitus (DM), hyperlipidaemia, stroke, and peripheral vascular diseases. The overall incidence rate of ACS was higher in the AS cohort than in the non-AS cohort (4.4 vs. 2.9 per 1000 person-years), with an adjusted hazard ratio (aHR) of 1.36 [95% confidence interval (CI) 1.16–1.59]. AS patients with co-morbidities of hypertension, DM, and cancer had an aHR of 7.74 for ACS, compared to those without these comorbidities. Conclusions: AS patients are at higher risk of ACS compared with non-AS subjects. Management of CV risk factors should be taken into account for the treatment of patients with AS, especially for patients with co-morbidities of hypertension, DM, and cancer.
Acute coronary syndrome (ACS) includes conditions causing sudden reduced blood flow to the heart. ACS refers to unstable angina, non-ST-segment elevation myocardial infarction, and ST-segment elevation myocardial infarction (1, 2). The causes of cardiovascular disease (CVD) are multifactorial (3, 4); some of the CV risk factors are male gender, hypertension, smoking, hyperlipidaemia, and diabetes mellitis (DM). Ankylosing spondylitis (AS) is a chronic and systemic inflammatory condition that primarily affects the sacroiliac joints and the axial skeleton (5–8). Increased risk of CV-related morbidity and mortality has been reported in patients with inflammatory arthritis (9, 10). The inflammatory processes in rheumatoid arthritis (RA) are similar to atherosclerosis, including the formation of atheroma, plaque instability, and thrombus development Chia-Hung Kao, Department of Nuclear Medicine and PET Centre, China Medical University Hospital, No. 2, Yuh-Der Road, Taichung 404, Taiwan. E-mail: [email protected] *These authors contributed equally to this work. Accepted 1 July 2013
(11). One study showed that an elevated C-reactive protein (CRP) concentration measured early in the disease process is a powerful predictor of death from CVD in inflammatory polyarthritis and RA (12). Data from USA have shown an increased prevalence of CV disease in AS patients compared with age- and gender-matched controls (13). Another study found a higher prevalence of spondyloarthropathies among patients receiving a coronary artery bypass graft (CABG) compared with control CABG patients, and demonstrated that spondyloarthropathy was a stronger risk factor for CABG than most traditional risk factors (14). Despite these studies, published reports of the relationships between AS and CV risk factors are limited (15). Hence, the aim of our study was to compare the incidence of ACS and CV risk factors between patients with and without AS.
Method Data sources Our retrospective cohort study used reimbursement data from National Health Insurance (NHI) electronic records
© 2014 Informa Healthcare on license from Scandinavian Rheumatology Research Foundation
www.scandjrheumatol.dk
DOI: 10.3109/03009742.2013.822097
Scand J Rheumatol Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/02/14 For personal use only.
Acute coronary syndrome in AS
system in Taiwan, which contains all medical claims from 1996 to 2009. In Taiwan, 99% of citizens are covered under the NHI and 90% of hospitals and clinics are NHI contracted providers. The National Health Research Institutes (NHRI) is responsible for managing the insurance claims data reported to the Bureau of Health Insurance. The NHRI has established electronic datasets for administrative and research purposes. We used a subset of data that comprises claims data from a random sample from the one million insured people in the nationwide database compiled by the NHRI and released for us to use in 2009. The diagnosis codes used in the NHRI are based on the International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM). Patients’ personal data are encrypted in this dataset for protection of privacy. This study was approved by the Ethics Review Board of the China Medical University and Hospital (CMU-REC-101-012).
Study subjects and outcome measures Our study consisted of an AS cohort and a non-AS cohort identified from the claims data of 2000–2009. Both cohorts were followed up until the end of 2009. The AS cohort consisted of patients aged 18 years newly diagnosed with AS in 2000–2009, identified from both ambulatory care and in-patient care units (ICD-9-CM codes 720 and 7200). The index date for an AS patient was the date of the first clinic visit with the diagnosis. Subjects with a history of ACS diagnosed (ICD-9-CM 410–411.1) before the index date or with missing information on age or sex were excluded. The comparison cohort was selected using a systematic random-sampling method in which four control patients, matched for age, sex, and year of index date, were selected for each corresponding AS patient. The follow-up person-years were calculated for each study participant from the index date to the date of withdrawal from the insurance system or to the end of 2009. All study subjects with a diagnosis of ACS or CVD risk factors were already confirmed by ICD-9 coding (ICD-9-CM 410–411.1) according to the study subject’s medical records in the National Health Insurance Research Database (NHIRD), based on based on validated definitions (16).
Statistical analysis The distributions of categorical sociodemographic characteristics were compared between the AS cohort and the non-AS cohort, and the differences were examined using the χ 2 test. The follow-up person-years were used for estimating the incidence density and the AS cohort to non-AS cohort incidence rate ratio (IRR) calculations used Poisson regression. Cox’s proportional hazards regressions were used to assess the risk of developing ACS that was associated with AS, while adjusting for variables that were significantly related to AS based on
133
the results of the χ 2 test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated in the model. All analyses were performed SAS version 9.2 (SAS Institute, Cary, NC, USA). A two-tailed p value < 0.05 was considered to be statistically significant.
Results We selected 6262 patients with AS for our study cohort and 25 048 control patients without AS for our comparison cohort. Among the study participants, 52.3% were women and 83.1% were younger than 65 years of age. The most common co-morbidities in the AS cohort compared with the non-AS cohort were hypertension (26.4% vs. 20.0%, p < 0.0001), DM (8.7% vs. 7.3%, p < 0.0001), hyperlipidaemia (23.3% vs. 15.8%, p < 0.0001), and stroke (14.3% vs. 10.0%, p < 0.0001) (Table 1). Table 2 shows the incidence rates of ACS for both cohorts, the AS cohort to the non-AS cohort IRRs and HRs by sex and age. The incidence rate of ACS was 1.5fold higher in the AS cohort than in the non-AS cohort (4.4 vs. 2.9 per 1000 person-years) with an adjusted HR (aHR) of 1.36 (95% CI 1.16–1.59). The sex-specific AS
Table 1. Demographic characteristics and co-morbidity in patients with and without ankylosing spondylitis (AS). AS cohort (n = 25 048) Variables Sex Male Female Age (years) 18–44 45–64 65–74 75 Hypertension Yes No Diabetes mellitus Yes No Hyperlipidaemia Yes No Stroke Yes No Cancer Yes No
n
%
Non-AS cohort (n = 6262) n
%
11 952 47.7 13 096 52.3
2988 3274
47.7 52.3
12 068 48.2 8740 34.9 2876 11.5 1364 5.4
3017 2185 719 341
48.2 34.9 11.5 5.4
5017 20.0 20 031 87.6
1652 4610
26.4 73.6
1818 7.3 23 230 92.7
546 5716
8.7 91.3
3966 15.8 21 082 84.2
1457 4805
23.3 76.7
2514 10.0 22 534 90.0
895 5367
14.3 85.7
348 1.4 24 700 98.6
81 6181
1.3 98.7
p-value* 1.00 1.00
< 0.0001 < 0.0001 < 0.0001 < 0.0001 0.5596
* χ 2 test. Hypertension ICD-9-CM (A-code): 401–405 (A260 and A269), admission more than three times; diabetes mellitus ICD-9-CM (A-code): 250 (A181), admission more than twice in the first year; hyperlipidaemia ICD-9-CM (A-code): 272 (A182), admission more than three times; stroke ICD-9-CM (A-code): 430–438 (A290– A299); cancer (HVfile) ICD-9-CM:140-208.
www.scandjrheumatol.dk
C-H Chou et al
cohort to non-AS cohort IRRs were similar for both men and women, as were the HRs. The incidence of ACS increased with age in both cohorts, being greater in those with AS and the highest in the oldest group. However, the age-specific AS cohort to non-AS cohort IRR and aHR of ACS were the greatest for the younger patients (aged 18–44 years). The age-specific aHR was not significant for the older groups. Figure 1 shows the Kaplan–Meier graph of ACS-free survival rates for AS patients and the comparison cohort. The results of the log-rank test indicate that patients with AS had a significantly lower ACS-free survival rate (95.8% vs. 97.1%, p < 0.001). Table 3 shows that subjects with co-morbidity had a higher incidence of ACS than those without co-morbidity, which was consistently higher in the AS cohort than in the non-AS cohort. Table 4 shows the interaction measures between AS and selected co-morbidities for the risk of ACS. Hypertension was most prevalent in both AS and non-AS cohorts, and was associated with an AS to non-AS aHR of 2.84. The corresponding aHR was 2.58 for those with DM. The aHR increased to 4.36 for those with both hypertension and DM. Cancer was the least prevalent in AS patients. However, AS patients with hypertension, DM, and cancer had an aHR of 7.74. Discussion In our study, the risk of ACS was higher in the AS cohort than the non-AS cohort. We also found a significantly higher prevalence of hypertension, DM, hyperlipidaemia, and stroke in patients with AS than in control patients. A previous meta-analysis showed that the risk of myocardial infarction in AS patients may be related to an increased frequency of dyslipidaemia (17). In a recent retrospective cohort study, although an increased risk of myocardial infarction in AS patients was not observed, the prevalence of DM and hypertension was higher for AS patients than for the controls (18). Health-care databases have been used in CV studies to assess disease prevalence and costs, and the reliability of
Probability of acute coronary syndrome 0.95 0.96 0.97 0.98 0.99 1.00
Scand J Rheumatol Downloaded from informahealthcare.com by Karolinska Institutet University Library on 06/02/14 For personal use only.
134
Non-ankylosing spondylitis Ankylosing spondylitis Log-rank test, p
