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Scand J Rheumatol 2015;44:42–47
Increased subsequent risk of acute coronary syndrome for patients with dermatomyositis/polymyositis: a nationwide population-based retrospective cohort study Y-N Lin1, C-L Lin2, K-C Chang1, C-H Kao3,4 Division of Cardiology, Department of Internal Medicine, 2Management Office for Health Data, 3Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, and 4Department of Nuclear Medicine and PET Centre, China Medical University Hospital, Taichung, Taiwan
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1
Objectives: The aim of this study was to explore the possible association between dermatomyositis/polymyositis (DM/PM) and subsequent acute coronary syndrome (ACS) risk. Method: We used data from the National Health Insurance (NHI) system of Taiwan to address the research topic. The exposure cohort contained 2029 patients with new diagnoses of DM/PM. Each patient was randomly frequency-matched according to sex and age with four participants from the general population who did not have a history of ACS at the index date (control group). Cox proportional hazard regression analyses were conducted to estimate the relationship between DM/PM and subsequent ACS risk. Results: Among patients with DM/PM, the overall risk for developing subsequent ACS was significantly higher than that of the control group [adjusted hazard ratio (aHR) 1.98, 95% confidence interval (CI) 1.17–3.35]. Further analysis indicated a higher risk in patients who were male, older, or diagnosed with comorbidities. Conclusions: The findings from this population-based retrospective cohort study suggest that DM/PM is associated with an increased subsequent ACS risk.
Dermatomyositis and polymyositis (DM/PM) are rare systemic autoimmune rheumatic diseases characterized by chronic inflammatory myopathies. Until modern treatments became available, the fatality related to these conditions was as high as 45% (1, 2). Previous studies have estimated that approximately 15–55% of deaths in patients with DM are caused by cardiovascular disease (3, 4). Acute coronary syndrome (ACS), a cardiac manifestation in patients with chronic inflammatory myopathies (5), remains a leading cause of morbidity and mortality worldwide despite advances in management. Chronic inflammation in connective tissue disease plays a crucial aetiopathological role in causing accelerated atherosclerosis (5, 6). A prevalence of cardiovascular risk factors and side-effects of therapies such as corticosteroid therapy also contribute to cardiovascular disease (7). Rheumatoid arthritis (8, 9), systemic sclerosis (10), and systemic lupus erythematosus (11) have all been reported to be associated with an increased risk of ACS. However, epidemiological
Chia-Hung Kao, Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 404, Taiwan. E-mail: [email protected] Accepted 22 April 2014
studies regarding ACS risk in patients with inflammatory myopathy are rare. Studies have indicated that approximately one-fifth of DM hospitalizations were associated with an atherosclerotic cardiovascular diagnosis or procedure and doubled the risk of in-hospital deaths (12). Tisseverasinghe et al indicated an increased incidence of ACS in patients with inflammatory myopathies (13). However, their study lacked a matched control group and hence the relative risk of cardiovascular events was difficult to estimate. To address this relationship, a prospective cohort study using the National Health Insurance (NHI) database showed that the adjusted hazard ratio (aHR) for developing ACS in patients with DM was 3.37 (14). This study enrolled only patients with incident DM and excluded those with a history of stroke, which reduced the sample size. PM, an inflammatory myopathy, shares similar characteristics to DM and should not be neglected. Therefore, we evaluated the risk of ACS in patients with inflammatory myopathies, including DM/PM, by using the Taiwan NHI database. Method Data sources The NHI program was implemented in Taiwan on 1 March 1995, and by the end of 2009, it covered over
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DOI: 10.3109/03009742.2014.918652
DM/PM and acute coronary syndrome
99% of the 23.74 million Taiwanese residents (15). In this study, we used the NHI Research Database (NHIRD), which is managed and released for research purposes by the National Health Research Institutes (NHRI). To protect personal privacy, patient identifications in the database were decoded and scrambled for research access. The NHIRD has been described in detail in previous studies (16, 17). The accuracy of diagnoses of major diseases, such as stroke and venous thromboembolism, in the NHIRD has been validated (18, 19). This study was approved by the Institutional Review Board of China Medical University (CMU-REC-101-012).
43
follow-up, death, withdrawal from the insurance programme, or the end of 2010. The primary outcome was newly diagnosed ACS, obtained from hospital records. ACS comorbidities were identified according to hospital admissions prior to the index date as potential confounding factors. These comorbidities included hypertension (ICD-9: 401–405), diabetes (ICD-9: 250), hyperlipidaemia (ICD-9: 272), cerebrovascular accident (CVA) (ICD-9: 430–438), chronic obstructive pulmonary disease (COPD) (ICD-9: 490–496), and end-stage renal disease (ESRD) (ICD-9: 585).
Statistical analysis
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Participants A diagnosis of DM/PM (ICD-9-CM codes 710.3 and 710.4) was defined according to ACR diagnostic criteria, and was confirmed through the Registry for Catastrophic Illness Patient Database (RCIPD, including inpatients and outpatients), a subsection of the NHIRD. Patients in the RCIPD with newly identified DM/PM from 1998 to 2010 were selected as the DM/PM cohort. The index date for patients with DM/PM was the date of DM/PM registration. A comparison cohort was randomly selected from the whole insured population with a non-DM/PM status, who were frequency-matched according to age (a 5-year span), sex, and index year of patients in the DM/PM cohort. The DM/PM and non-DM/PM cohorts were selected in a ratio of 1:4 to increase the statistical power and control potential confounding. In both cohorts, patients who were diagnosed with ACS (ICD-9 code 410) before the index date or were missing information for age and sex were excluded from the data analysis. The Taiwan NHI is a single-payer universal health insurance programme established by the Ministry of Health in 1995, with more than 99% of Taiwan’s population covered. For research purposes, the Taiwan NHRI has been authorized to establish the Taiwan NHIRD for researchers. We used claims data that included the entire population of Taiwan. Information on basic demographic status, outpatient visits, hospital admissions, prescriptions, and disease diagnosis were available for the period 1998–2010. Missing data were low (< 0.1%), based on sex and age. Subjects with missing data were excluded from the study. The follow-up rate should be good because the NHI insurance programme is compulsory. Approximately 14.7% of subjects were lost to follow-up and they were censored for follow-up time estimation from 1998 to 2010. Therefore, over 85% of subjects had completed the follow-up during this study. Most of the subjects were lost to follow-up due to death. The other uncommon reasons for the discontinuity of NHI included withdrawal of insurance, immigration, and prison sentence.
Outcome measurements Person-years of the follow-up were calculated for each patient until ACS diagnosis or censored for loss of
Independent t tests and χ 2 tests were used to examine the differences in the demographic characteristics and comorbidities between the DM/PM and non-DM/PM cohorts. The incidence of newly diagnosed ACS in the DM/PM and non-DM/PM cohorts was calculated and the incidence rate ratio (IRR) of the DM/PM cohort to the nonDM/PM cohort with 95% confidence intervals (CIs) was evaluated using Poisson regression analyses. Multivariate Cox proportional hazard regression analysis was used to assess the risk of developing ACS associated with DM/ PM compared with the non-DM/PM cohort after controlling for age, sex, and comorbidities. The HRs and 95% CIs were estimated in the Cox model. Further analysis was performed to assess whether the association of ACS varied according to the duration of follow-up after DM/ PM diagnosis. The Kaplan–Meier method was used to estimate the cumulative incidence of ACS for the DM/PM and non-DM/PM cohorts, and the log-rank test was used to test the difference between the curves. Data analyses were performed using SAS version 9.2 (SAS Institute Inc, Cary, NC, USA), and the significance level was set at p < 0.05 for two-sided testing.
Results Table 1 shows comparisons of the demographic characteristics and comorbidities of the DM/PM and non-DM/ PM patients. Our sample comprised 2029 patients with DM/PM and 81 166 comparison patients without DM/ PM, of whom 67.8% were women. Approximately 55% of the patients were 49 years of age. A higher proportion of patients with DM/PM experienced hypertension (12.6% vs. 5.32%), diabetes (5.96% vs. 2.98%), hyperlipidaemia (5.17% vs. 1.55%), and COPD (4.29% vs. 1.13%) compared with the non-DM/PM cohort. Table 2 shows the ACS incidence densities in the DM/PM and non-DM/PM cohorts and the IRRs of the DM/PM cohort relative to the non-DM/PM cohort for ACS. Overall, the incidence of ACS was 1.74 times greater in the DM/PM cohort than in the non-DM/PM cohort (2.00 vs. 1.15 per 1000 person-years). The cumulative incidence of ACS was 1.00% greater in the DM/PM cohort than in the non-DM/PM cohort (2.00% vs. 1.00%, p ¼ 0.035) by
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Y-N Lin et al
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Variable
Without DM/PM With DM/PM
n Sex, n (%) Female Male Age (years), mean (SD) Age group 34 years 35–49 years 50–64 years 65 years Comorbidity, n (%) Hypertension Diabetes Hyperlipidaemia CVA COPD ESRD
Cumulative incidence with acute coronary syndrome
Table 1. Demographic characteristics and comorbidity in patients with and without dermatomyositis/polymyositis (DM/PM). p-value
8116
2029
5504 (67.8) 2612 (32.2) 45.7 (18.1)
1376 (67.8) 653 (32.2) 46.1 (18.0)
0.99*
2008 (24.7) 2480 (30.6) 2400 (29.6) 1228 (15.1)
502 (24.7) 620 (30.6) 600 (29.6) 307 (15.1)
0.99*
432 (5.32) 242 (2.98) 126 (1.55) 157 (1.93) 92 (1.13) 23 (0.28)
256 (12.6) 121 (5.96) 105 (5.17) 43 (2.12) 87 (4.29) 7 (0.34)
< 0.0001* < 0.0001* < 0.0001* 0.59* < 0.0001* 0.65*
0.37*
0.000 0.005 0.010 0.015 0.020 0.025 0.030
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Non-dermatomyositis/polymyositis cohort Dermatomyositis/polymyositis cohort Long-rank Test: p-value = 0.035
0
2
4
6 8 years
10
12
14
Figure 1. Cumulative incidence comparison of acute coronary syndrome (ACS) between the dermatomyositis/polymyositis (DM/ PM) and non-DM/PM cohorts using the Kaplan–Meier method.
CVA, Cerebrovascular accident; COPD, chronic obstructive pulmonary disease; ESRD, end-stage renal disease. * Two-sample t-test.
patients aged 49 years. After adjusting for cofactors, the risk of developing ACS increased with age (patients 49 years of age were the reference group), and the patients 65 years exhibited an aHR of 17.4 (95% CI 8.24–36.9). A comorbidity-specific analysis showed a greater incidence of ACS for patients with comorbidities in both cohorts (Table 3). The incidence of ACS was 1.75 (95% CI 1.48–2.07) times greater among DM/PM patients without any comorbidities than among nonDM/PM patients without any comorbidities. When stratified according to comorbidities, patients with hypertension and ESRD showed significantly greater risks of developing ACS than did those without (aHR 2.48, 95% CI 1.37–4.52 for hypertension; aHR 4.86, 95% CI 1.41– 16.88 for ESRD). The incidence and HR of ACS were calculated according to the year of follow-up (Table 4).
the end of follow-up (Figure 1). After adjusting for age, sex, and comorbidities, the HR for developing ACS during the follow-up period was 1.98 times greater (95% CI 1.17–3.35) for patients with DM/PM than for non-DM/ PM patients. The sex-specific analyses showed a greater incidence rate for men than women in both cohorts (2.96 vs. 1.58 per 1000 person-years for the DM/PM cohort; 2.08 vs. 0.73 per 1000 person-years for the non-DM/PM cohort, respectively). However, compared with women, men showed a greater risk of ACS (HR 2.13, 95% CI 1.34–3.36). The age-specific analysis showed that the incidence of ACS increased with age in both cohorts, and the IRR of 8.69 (95% CI 7.12–10.6) indicated that the age-specific relative risk of ACS was greatest for
Table 2. Comparison of incidence and hazard ratios of acute coronary syndrome (ACS) stratified by sex and age between patients with and without dermatomyositis/polymyositis (DM/PM). Without DM/PM Variables All Sex Female Male Stratify age 49 50–64 65
With DM/PM
Event
PY
Rate†
Event
PY
Rate†
IRR (95% CI)
Adjusted HR‡ (95% CI)
55
47 892
1.15
20
10 000
2.00
1.74 (1.50–2.03)***
1.98 (1.17–3.35)*
24 31
32 968 14 924
0.73 2.08
11 9
6960 3040
1.58 2.96
2.17 (1.82–2.59)*** 1.43 (1.09–1.87)*
1 (Reference) 2.13 (1.34–3.36)**
3 15 37
28 487 13 184 6221
0.11 1.14 5.95
6 7 7
6554 2587 858
0.92 2.71 8.16
8.69 (7.12–10.6)*** 2.38 (1.83–3.09)*** 1.37 (0.91–2.06)
1 (Reference) 4.86 (2.22–10.6)*** 17.4 (8.24–36.9)***
PY, person-years; IRR, incidence rate ratio; CI, confidence interval; HR, hazard ratio. † Incidence rate per 1000 person-years. ‡ Multivariable analysis including age, sex, hypertension, diabetes, hyperlipidaemia, cerebrovascular accident (CVA), and chronic obstructive pulmonary disease (COPD). * p < 0.05, ** p < 0.01, *** p < 0.001.
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DM/PM and acute coronary syndrome
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Table 3. Comparison of incidence and hazard ratios of acute coronary syndrome (ACS) stratified by comorbidity between patients with and without dermatomyositis/polymyositis (DM/PM). Without DM/PM
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Variables
With DM/PM
Event
PY
Rate†
Event
PY
Rate†
38
45 095
0.84
12
8154
1.47
1.75 (1.48–2.07)***
-
39 16
46 216 1676
0.84 9.55
13 7
9060 940
1.43 7.44
1.70 (1.45–2.00)*** 0.78 (0.48–1.27)
1 (Reference) 2.48 (1.37–4.52)**
47 8
46 863 1028
1.00 7.78
18 2
9538 462
1.89 4.33
1.88 (1.61–2.19)*** 0.56 (0.26–1.20)
1 (Reference) 1.54 (0.74–3.21)
52 3
47 309 582
1.10 5.15
19 1
9483 517
2.00 1.94
1.82 (1.57–2.12)*** 0.38 (0.14–1.04)
1 (Reference) 0.84 (0.30–2.38)
49 6
47 305 587
1.04 10.2
20 0
9859 141
2.03 0.00
1.96 (1.69–2.27)*** –
1 (Reference) 1.18 (0.47–2.93)
53 2
47 530 362
1.12 5.53
19 1
9695 305
1.96 3.27
1.76 (1.51–2.05)*** 0.59 (0.22–1.59)
1 (Reference) 0.67 (0.20–2.22)
53 2
47 806 85
1.11 23.5
19 1
9980 20
1.90 50.5
1.72 (1.48–2.00)*** 2.15 (0.24–18.9)
1 (Reference) 4.86 (1.41–16.8)*
Without comorbidity§ Hypertension No Yes Diabetes No Yes Hyperlipidaemia No Yes CVA No Yes COPD No Yes ESRD No Yes
IRR (95% CI)
Adjusted HR‡ (95% CI)
PY, person-years; IRR, incidence rate ratio; CI, confidence interval; HR, hazard ratio; CVA, cerebrovascular accident; COPD, chronic obstructive pulmonary disease; ESRD, end-stage renal disease. † Incidence rate per 1000 person-years. ‡ Multivariable analysis including age, sex, and comorbidities. § Without any comorbidity (including hypertension, diabetes, hyperlipidemia, CVA, COPD, and ESRD) classified as the without comorbidity group. * p < 0.05, ** p < 0.01, *** p < 0.001.
We observed a 4.35 times significantly greater relative risk of developing ACS after a 5-year follow-up period (95% CI 1.78–10.6).
Discussion Our study is the first Asian nationwide population-based study to investigate the risk for ACS among patients with DM/PM. During a 10-year follow-up, we documented 20 (2.00%) and 55 (1.15%) ACS episodes among DM/PM patients and non-DM/PM patients, respectively. We associated a diagnosis of depression with a nearly 1.98-fold increased risk of ACS during the 10-year follow-up, after
adjusting for comorbid medical disorders and sociodemographic characteristics. Men were at higher risk for ACS than women (HR 2.13). The association persisted in further analyses stratified according to age, particularly at ages 65 years (HR 17.4). Finally, compared with the non-DM/PM cohort, DM/PM patients without comorbid medical diseases exhibited a higher risk of ACS occurrence (HR 1.75). DM/PM may cause ACS through independent mechanisms other than common cardiovascular risk factors, particularly after the 5-year follow-up (aHR 4.35 vs. 1.30 compared with the patients followed up for 5 years). Our study results are consistent with those of previous studies that have identified DM/PM as a risk factor for
Table 4. Trends of acute coronary syndrome (ACS) risk by stratified follow-up years. Non-DM/PM cohort Follow-up (years)† 5 >5
DM/PM cohort
Event
PY
Rate‡
Event
PY
Rate‡
42 13
31 583 16 308
1.33 0.80
11 9
6756 3244
1.63 2.77
IRR (95% CI)
Adjusted HR§ (95% CI)
1.22 (1.03–1.45)* 3.48 (2.87–4.22)***
1.30 (0.66–2.58) 4.35 (1.78–10.6)**
PY, person-years; IRR, incidence rate ratio; CI, confidence interval; HR, hazard ratio. † Partitioned into two segments ( 5 and > 5) by median. ‡ Incidence rate per 1000 person-years. § Multivariable analysis including age and sex. * p < 0.05, ** p < 0.01, *** p < 0.001.
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ACS (12–14). DM/PM is an independent risk factor for developing ACS. This phenomenon is attributed to possible accelerated atherosclerosis associated with DM/PM and the undertreatment of cardiovascular risk factors in DM/PM patients. DM/PM is a chronic systemic inflammatory disorder similar to other connective tissue diseases, and is associated with prothrombotic factors and endothelial dysfunction in the development of atherosclerotic cardiovascular diseases (20, 21). Previous studies have shown inflammatory myopathies to be associated with vasculopathy, thereby causing local hypoperfusion, thrombosis, and heart infarction (14, 22, 23). In addition, the myocardium may be attacked during myositis progression (24). Corticosteroids, widely used in DM/PM, are associated with hypertension, hyperglycaemia, dyslipidaemia, and an increased risk of cardiovascular events (25, 26). However, corticosteroids may have an anti-inflammatory effect and provide cardiovascular protection (27, 28). Whether anti-inflammatory properties of corticosteroids counteract their adverse cardiovascular effects remains unclear. In patients with DM/PM, the female to male predominance is approximately 2 to 1. The peak incidence in adults occurs between 40 and 50 years of age. A recent large cohort study did not discuss the epidemiology of ACS in DM/PM patients. In our study, the risk for ACS increased in both sexes. After adjusting for age and other comorbidities, men with DM/PM had a higher risk of developing ACS than women. The effect of DM/PM on ACS risk was higher in young adults, whereas ACS risk increased with age after adjusting for sex and comorbidities. The cumulative incidence of ACS increased in the years following DM/PM diagnosis, particularly after 5 years of follow-up. Based on these findings, we recommend aggressive control of DM/PM activity and an annual cardiovascular risk assessment for all patients with DM/PM, particularly for older men within the first 5 years of diagnosis. Our study also showed that the incidence of ACS increased in patients with comorbidities. After adjusting for sex and age, patients diagnosed with DM/PM and ESRD had the highest risk (4.86-fold higher than that of the control patients) for developing ACS. The other risk was hypertension, which caused a 2.48-fold higher risk of developing ACS in DM/PM patients. This indicates the importance of blood pressure control in patients with DM/PM. The ICD-9 diagnosis of some major diseases had been validated with good accuracy. Cheng et al (18) validated the diagnosis of stroke with an accuracy of 97.85%, while the diagnosis of venous thromboembolism was validated by Yu et al (19). The ICD-9 diagnosis ACS has been validated with 100% accuracy (29). Although the diagnoses of PM and DM have not been validated, both diseases have been used in several previous studies (14, 30). In addition, with regard to disease definition and register, DM/PM was classified as a catastrophic illness in the Taiwan NHI system. In Taiwan, people who are diagnosed with DM/PM have the right to apply for a special
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Y-N Lin et al
‘catastrophic illness card’ and the benefit of getting a medical discount for treatment of this disease. There is a conscientious and careful process to distribute this card. Only rheumatologists can help to apply for the card for DM/PM. Another specialized expert (also a rheumatologist) also reviews the medical records, serological reports, or pathology following the criteria for the classification of DM/PM. Our DM/PM cohort is based only on people who newly applied for the ‘catastrophic illness card’. The strength of this study is that it was a nationwide population-based longitudinal cohort study of Asian people with DM/PM on the risk of experiencing ACS events. However, several limitations merit attention. First, the data used in this study were retrieved from the NHIRD and lacked specific social and personal information and drug histories. Therefore, we could not evaluate all possible impacts, including smoking, body mass index, dietary habits, physical exercise, medication interaction, patients’ drug compliance, and treatment response. Second, we could not obtain information regarding the individual severity of DM/PM. People with DM/PM who had never sought medical attention were overlooked. In addition, approximately one-quarter of myocardial infarctions are ‘silent’ and might be overlooked in claims. Third, although the full regression models were specified after adjusting for certain concurrent illnesses, the patients with DM/PM could have been less healthy and could have had higher rates of comorbid medical problems than indicated in the data, which could have affected the calculation of the patients’ risk for ACS. Finally, the evidence derived from a cohort study is generally of lower methodological quality than that obtained from randomized trials, because a cohort study design is subject to numerous biases related to adjusting for confounders. Despite our meticulous study design involving adequate control of confounding factors, a key limitation was that bias may remain because of possible unmeasured or unknown confounders. Nevertheless, apart from these potential problems, the data on DM/PM and ACS diagnoses were highly reliable.
Conclusions This national population-based retrospective cohort study indicates that there is a significant association between DM/PM and subsequent ACS risk in Taiwan. Aggressive control of DM/PM activity and an annual cardiovascular risk assessment are recommended, particularly for older men with hypertension or ESRD within the first 5 years of diagnosis. Further study is required to extend this positive link to clinical practice and to enable preventative treatment to be established. Acknowledgements This work was supported by study grants (DMR-102-014 and DMR102-023) from our hospital, from the Clinical Trial and Research Centre of the Taiwanese Department of Health (DOH102-TD-B-111-004), and
DM/PM and acute coronary syndrome Taiwan Ministry of Health and Welfare Clinical Trail and Research Center of Excellence (MOHW103-TDU-B-212-113002), Health and welfare surcharge of tobacco products, China Medical University Hospital Cancer Research Center of Excellence (MOHW103-TD-B111-03, Taiwan).
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Scand J Rheumatol 2015;44:42–47
Increased subsequent risk of acute coronary syndrome for patients with dermatomyositis/polymyositis: a nationwide population-based retrospective cohort study Y-N Lin1, C-L Lin2, K-C Chang1, C-H Kao3,4 Division of Cardiology, Department of Internal Medicine, 2Management Office for Health Data, 3Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, and 4Department of Nuclear Medicine and PET Centre, China Medical University Hospital, Taichung, Taiwan
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Objectives: The aim of this study was to explore the possible association between dermatomyositis/polymyositis (DM/PM) and subsequent acute coronary syndrome (ACS) risk. Method: We used data from the National Health Insurance (NHI) system of Taiwan to address the research topic. The exposure cohort contained 2029 patients with new diagnoses of DM/PM. Each patient was randomly frequency-matched according to sex and age with four participants from the general population who did not have a history of ACS at the index date (control group). Cox proportional hazard regression analyses were conducted to estimate the relationship between DM/PM and subsequent ACS risk. Results: Among patients with DM/PM, the overall risk for developing subsequent ACS was significantly higher than that of the control group [adjusted hazard ratio (aHR) 1.98, 95% confidence interval (CI) 1.17–3.35]. Further analysis indicated a higher risk in patients who were male, older, or diagnosed with comorbidities. Conclusions: The findings from this population-based retrospective cohort study suggest that DM/PM is associated with an increased subsequent ACS risk.
Dermatomyositis and polymyositis (DM/PM) are rare systemic autoimmune rheumatic diseases characterized by chronic inflammatory myopathies. Until modern treatments became available, the fatality related to these conditions was as high as 45% (1, 2). Previous studies have estimated that approximately 15–55% of deaths in patients with DM are caused by cardiovascular disease (3, 4). Acute coronary syndrome (ACS), a cardiac manifestation in patients with chronic inflammatory myopathies (5), remains a leading cause of morbidity and mortality worldwide despite advances in management. Chronic inflammation in connective tissue disease plays a crucial aetiopathological role in causing accelerated atherosclerosis (5, 6). A prevalence of cardiovascular risk factors and side-effects of therapies such as corticosteroid therapy also contribute to cardiovascular disease (7). Rheumatoid arthritis (8, 9), systemic sclerosis (10), and systemic lupus erythematosus (11) have all been reported to be associated with an increased risk of ACS. However, epidemiological
Chia-Hung Kao, Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 404, Taiwan. E-mail: [email protected] Accepted 22 April 2014
studies regarding ACS risk in patients with inflammatory myopathy are rare. Studies have indicated that approximately one-fifth of DM hospitalizations were associated with an atherosclerotic cardiovascular diagnosis or procedure and doubled the risk of in-hospital deaths (12). Tisseverasinghe et al indicated an increased incidence of ACS in patients with inflammatory myopathies (13). However, their study lacked a matched control group and hence the relative risk of cardiovascular events was difficult to estimate. To address this relationship, a prospective cohort study using the National Health Insurance (NHI) database showed that the adjusted hazard ratio (aHR) for developing ACS in patients with DM was 3.37 (14). This study enrolled only patients with incident DM and excluded those with a history of stroke, which reduced the sample size. PM, an inflammatory myopathy, shares similar characteristics to DM and should not be neglected. Therefore, we evaluated the risk of ACS in patients with inflammatory myopathies, including DM/PM, by using the Taiwan NHI database. Method Data sources The NHI program was implemented in Taiwan on 1 March 1995, and by the end of 2009, it covered over
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DOI: 10.3109/03009742.2014.918652
DM/PM and acute coronary syndrome
99% of the 23.74 million Taiwanese residents (15). In this study, we used the NHI Research Database (NHIRD), which is managed and released for research purposes by the National Health Research Institutes (NHRI). To protect personal privacy, patient identifications in the database were decoded and scrambled for research access. The NHIRD has been described in detail in previous studies (16, 17). The accuracy of diagnoses of major diseases, such as stroke and venous thromboembolism, in the NHIRD has been validated (18, 19). This study was approved by the Institutional Review Board of China Medical University (CMU-REC-101-012).
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follow-up, death, withdrawal from the insurance programme, or the end of 2010. The primary outcome was newly diagnosed ACS, obtained from hospital records. ACS comorbidities were identified according to hospital admissions prior to the index date as potential confounding factors. These comorbidities included hypertension (ICD-9: 401–405), diabetes (ICD-9: 250), hyperlipidaemia (ICD-9: 272), cerebrovascular accident (CVA) (ICD-9: 430–438), chronic obstructive pulmonary disease (COPD) (ICD-9: 490–496), and end-stage renal disease (ESRD) (ICD-9: 585).
Statistical analysis
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Participants A diagnosis of DM/PM (ICD-9-CM codes 710.3 and 710.4) was defined according to ACR diagnostic criteria, and was confirmed through the Registry for Catastrophic Illness Patient Database (RCIPD, including inpatients and outpatients), a subsection of the NHIRD. Patients in the RCIPD with newly identified DM/PM from 1998 to 2010 were selected as the DM/PM cohort. The index date for patients with DM/PM was the date of DM/PM registration. A comparison cohort was randomly selected from the whole insured population with a non-DM/PM status, who were frequency-matched according to age (a 5-year span), sex, and index year of patients in the DM/PM cohort. The DM/PM and non-DM/PM cohorts were selected in a ratio of 1:4 to increase the statistical power and control potential confounding. In both cohorts, patients who were diagnosed with ACS (ICD-9 code 410) before the index date or were missing information for age and sex were excluded from the data analysis. The Taiwan NHI is a single-payer universal health insurance programme established by the Ministry of Health in 1995, with more than 99% of Taiwan’s population covered. For research purposes, the Taiwan NHRI has been authorized to establish the Taiwan NHIRD for researchers. We used claims data that included the entire population of Taiwan. Information on basic demographic status, outpatient visits, hospital admissions, prescriptions, and disease diagnosis were available for the period 1998–2010. Missing data were low (< 0.1%), based on sex and age. Subjects with missing data were excluded from the study. The follow-up rate should be good because the NHI insurance programme is compulsory. Approximately 14.7% of subjects were lost to follow-up and they were censored for follow-up time estimation from 1998 to 2010. Therefore, over 85% of subjects had completed the follow-up during this study. Most of the subjects were lost to follow-up due to death. The other uncommon reasons for the discontinuity of NHI included withdrawal of insurance, immigration, and prison sentence.
Outcome measurements Person-years of the follow-up were calculated for each patient until ACS diagnosis or censored for loss of
Independent t tests and χ 2 tests were used to examine the differences in the demographic characteristics and comorbidities between the DM/PM and non-DM/PM cohorts. The incidence of newly diagnosed ACS in the DM/PM and non-DM/PM cohorts was calculated and the incidence rate ratio (IRR) of the DM/PM cohort to the nonDM/PM cohort with 95% confidence intervals (CIs) was evaluated using Poisson regression analyses. Multivariate Cox proportional hazard regression analysis was used to assess the risk of developing ACS associated with DM/ PM compared with the non-DM/PM cohort after controlling for age, sex, and comorbidities. The HRs and 95% CIs were estimated in the Cox model. Further analysis was performed to assess whether the association of ACS varied according to the duration of follow-up after DM/ PM diagnosis. The Kaplan–Meier method was used to estimate the cumulative incidence of ACS for the DM/PM and non-DM/PM cohorts, and the log-rank test was used to test the difference between the curves. Data analyses were performed using SAS version 9.2 (SAS Institute Inc, Cary, NC, USA), and the significance level was set at p < 0.05 for two-sided testing.
Results Table 1 shows comparisons of the demographic characteristics and comorbidities of the DM/PM and non-DM/ PM patients. Our sample comprised 2029 patients with DM/PM and 81 166 comparison patients without DM/ PM, of whom 67.8% were women. Approximately 55% of the patients were 49 years of age. A higher proportion of patients with DM/PM experienced hypertension (12.6% vs. 5.32%), diabetes (5.96% vs. 2.98%), hyperlipidaemia (5.17% vs. 1.55%), and COPD (4.29% vs. 1.13%) compared with the non-DM/PM cohort. Table 2 shows the ACS incidence densities in the DM/PM and non-DM/PM cohorts and the IRRs of the DM/PM cohort relative to the non-DM/PM cohort for ACS. Overall, the incidence of ACS was 1.74 times greater in the DM/PM cohort than in the non-DM/PM cohort (2.00 vs. 1.15 per 1000 person-years). The cumulative incidence of ACS was 1.00% greater in the DM/PM cohort than in the non-DM/PM cohort (2.00% vs. 1.00%, p ¼ 0.035) by
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Y-N Lin et al
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Variable
Without DM/PM With DM/PM
n Sex, n (%) Female Male Age (years), mean (SD) Age group 34 years 35–49 years 50–64 years 65 years Comorbidity, n (%) Hypertension Diabetes Hyperlipidaemia CVA COPD ESRD
Cumulative incidence with acute coronary syndrome
Table 1. Demographic characteristics and comorbidity in patients with and without dermatomyositis/polymyositis (DM/PM). p-value
8116
2029
5504 (67.8) 2612 (32.2) 45.7 (18.1)
1376 (67.8) 653 (32.2) 46.1 (18.0)
0.99*
2008 (24.7) 2480 (30.6) 2400 (29.6) 1228 (15.1)
502 (24.7) 620 (30.6) 600 (29.6) 307 (15.1)
0.99*
432 (5.32) 242 (2.98) 126 (1.55) 157 (1.93) 92 (1.13) 23 (0.28)
256 (12.6) 121 (5.96) 105 (5.17) 43 (2.12) 87 (4.29) 7 (0.34)
< 0.0001* < 0.0001* < 0.0001* 0.59* < 0.0001* 0.65*
0.37*
0.000 0.005 0.010 0.015 0.020 0.025 0.030
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Non-dermatomyositis/polymyositis cohort Dermatomyositis/polymyositis cohort Long-rank Test: p-value = 0.035
0
2
4
6 8 years
10
12
14
Figure 1. Cumulative incidence comparison of acute coronary syndrome (ACS) between the dermatomyositis/polymyositis (DM/ PM) and non-DM/PM cohorts using the Kaplan–Meier method.
CVA, Cerebrovascular accident; COPD, chronic obstructive pulmonary disease; ESRD, end-stage renal disease. * Two-sample t-test.
patients aged 49 years. After adjusting for cofactors, the risk of developing ACS increased with age (patients 49 years of age were the reference group), and the patients 65 years exhibited an aHR of 17.4 (95% CI 8.24–36.9). A comorbidity-specific analysis showed a greater incidence of ACS for patients with comorbidities in both cohorts (Table 3). The incidence of ACS was 1.75 (95% CI 1.48–2.07) times greater among DM/PM patients without any comorbidities than among nonDM/PM patients without any comorbidities. When stratified according to comorbidities, patients with hypertension and ESRD showed significantly greater risks of developing ACS than did those without (aHR 2.48, 95% CI 1.37–4.52 for hypertension; aHR 4.86, 95% CI 1.41– 16.88 for ESRD). The incidence and HR of ACS were calculated according to the year of follow-up (Table 4).
the end of follow-up (Figure 1). After adjusting for age, sex, and comorbidities, the HR for developing ACS during the follow-up period was 1.98 times greater (95% CI 1.17–3.35) for patients with DM/PM than for non-DM/ PM patients. The sex-specific analyses showed a greater incidence rate for men than women in both cohorts (2.96 vs. 1.58 per 1000 person-years for the DM/PM cohort; 2.08 vs. 0.73 per 1000 person-years for the non-DM/PM cohort, respectively). However, compared with women, men showed a greater risk of ACS (HR 2.13, 95% CI 1.34–3.36). The age-specific analysis showed that the incidence of ACS increased with age in both cohorts, and the IRR of 8.69 (95% CI 7.12–10.6) indicated that the age-specific relative risk of ACS was greatest for
Table 2. Comparison of incidence and hazard ratios of acute coronary syndrome (ACS) stratified by sex and age between patients with and without dermatomyositis/polymyositis (DM/PM). Without DM/PM Variables All Sex Female Male Stratify age 49 50–64 65
With DM/PM
Event
PY
Rate†
Event
PY
Rate†
IRR (95% CI)
Adjusted HR‡ (95% CI)
55
47 892
1.15
20
10 000
2.00
1.74 (1.50–2.03)***
1.98 (1.17–3.35)*
24 31
32 968 14 924
0.73 2.08
11 9
6960 3040
1.58 2.96
2.17 (1.82–2.59)*** 1.43 (1.09–1.87)*
1 (Reference) 2.13 (1.34–3.36)**
3 15 37
28 487 13 184 6221
0.11 1.14 5.95
6 7 7
6554 2587 858
0.92 2.71 8.16
8.69 (7.12–10.6)*** 2.38 (1.83–3.09)*** 1.37 (0.91–2.06)
1 (Reference) 4.86 (2.22–10.6)*** 17.4 (8.24–36.9)***
PY, person-years; IRR, incidence rate ratio; CI, confidence interval; HR, hazard ratio. † Incidence rate per 1000 person-years. ‡ Multivariable analysis including age, sex, hypertension, diabetes, hyperlipidaemia, cerebrovascular accident (CVA), and chronic obstructive pulmonary disease (COPD). * p < 0.05, ** p < 0.01, *** p < 0.001.
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DM/PM and acute coronary syndrome
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Table 3. Comparison of incidence and hazard ratios of acute coronary syndrome (ACS) stratified by comorbidity between patients with and without dermatomyositis/polymyositis (DM/PM). Without DM/PM
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Variables
With DM/PM
Event
PY
Rate†
Event
PY
Rate†
38
45 095
0.84
12
8154
1.47
1.75 (1.48–2.07)***
-
39 16
46 216 1676
0.84 9.55
13 7
9060 940
1.43 7.44
1.70 (1.45–2.00)*** 0.78 (0.48–1.27)
1 (Reference) 2.48 (1.37–4.52)**
47 8
46 863 1028
1.00 7.78
18 2
9538 462
1.89 4.33
1.88 (1.61–2.19)*** 0.56 (0.26–1.20)
1 (Reference) 1.54 (0.74–3.21)
52 3
47 309 582
1.10 5.15
19 1
9483 517
2.00 1.94
1.82 (1.57–2.12)*** 0.38 (0.14–1.04)
1 (Reference) 0.84 (0.30–2.38)
49 6
47 305 587
1.04 10.2
20 0
9859 141
2.03 0.00
1.96 (1.69–2.27)*** –
1 (Reference) 1.18 (0.47–2.93)
53 2
47 530 362
1.12 5.53
19 1
9695 305
1.96 3.27
1.76 (1.51–2.05)*** 0.59 (0.22–1.59)
1 (Reference) 0.67 (0.20–2.22)
53 2
47 806 85
1.11 23.5
19 1
9980 20
1.90 50.5
1.72 (1.48–2.00)*** 2.15 (0.24–18.9)
1 (Reference) 4.86 (1.41–16.8)*
Without comorbidity§ Hypertension No Yes Diabetes No Yes Hyperlipidaemia No Yes CVA No Yes COPD No Yes ESRD No Yes
IRR (95% CI)
Adjusted HR‡ (95% CI)
PY, person-years; IRR, incidence rate ratio; CI, confidence interval; HR, hazard ratio; CVA, cerebrovascular accident; COPD, chronic obstructive pulmonary disease; ESRD, end-stage renal disease. † Incidence rate per 1000 person-years. ‡ Multivariable analysis including age, sex, and comorbidities. § Without any comorbidity (including hypertension, diabetes, hyperlipidemia, CVA, COPD, and ESRD) classified as the without comorbidity group. * p < 0.05, ** p < 0.01, *** p < 0.001.
We observed a 4.35 times significantly greater relative risk of developing ACS after a 5-year follow-up period (95% CI 1.78–10.6).
Discussion Our study is the first Asian nationwide population-based study to investigate the risk for ACS among patients with DM/PM. During a 10-year follow-up, we documented 20 (2.00%) and 55 (1.15%) ACS episodes among DM/PM patients and non-DM/PM patients, respectively. We associated a diagnosis of depression with a nearly 1.98-fold increased risk of ACS during the 10-year follow-up, after
adjusting for comorbid medical disorders and sociodemographic characteristics. Men were at higher risk for ACS than women (HR 2.13). The association persisted in further analyses stratified according to age, particularly at ages 65 years (HR 17.4). Finally, compared with the non-DM/PM cohort, DM/PM patients without comorbid medical diseases exhibited a higher risk of ACS occurrence (HR 1.75). DM/PM may cause ACS through independent mechanisms other than common cardiovascular risk factors, particularly after the 5-year follow-up (aHR 4.35 vs. 1.30 compared with the patients followed up for 5 years). Our study results are consistent with those of previous studies that have identified DM/PM as a risk factor for
Table 4. Trends of acute coronary syndrome (ACS) risk by stratified follow-up years. Non-DM/PM cohort Follow-up (years)† 5 >5
DM/PM cohort
Event
PY
Rate‡
Event
PY
Rate‡
42 13
31 583 16 308
1.33 0.80
11 9
6756 3244
1.63 2.77
IRR (95% CI)
Adjusted HR§ (95% CI)
1.22 (1.03–1.45)* 3.48 (2.87–4.22)***
1.30 (0.66–2.58) 4.35 (1.78–10.6)**
PY, person-years; IRR, incidence rate ratio; CI, confidence interval; HR, hazard ratio. † Partitioned into two segments ( 5 and > 5) by median. ‡ Incidence rate per 1000 person-years. § Multivariable analysis including age and sex. * p < 0.05, ** p < 0.01, *** p < 0.001.
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ACS (12–14). DM/PM is an independent risk factor for developing ACS. This phenomenon is attributed to possible accelerated atherosclerosis associated with DM/PM and the undertreatment of cardiovascular risk factors in DM/PM patients. DM/PM is a chronic systemic inflammatory disorder similar to other connective tissue diseases, and is associated with prothrombotic factors and endothelial dysfunction in the development of atherosclerotic cardiovascular diseases (20, 21). Previous studies have shown inflammatory myopathies to be associated with vasculopathy, thereby causing local hypoperfusion, thrombosis, and heart infarction (14, 22, 23). In addition, the myocardium may be attacked during myositis progression (24). Corticosteroids, widely used in DM/PM, are associated with hypertension, hyperglycaemia, dyslipidaemia, and an increased risk of cardiovascular events (25, 26). However, corticosteroids may have an anti-inflammatory effect and provide cardiovascular protection (27, 28). Whether anti-inflammatory properties of corticosteroids counteract their adverse cardiovascular effects remains unclear. In patients with DM/PM, the female to male predominance is approximately 2 to 1. The peak incidence in adults occurs between 40 and 50 years of age. A recent large cohort study did not discuss the epidemiology of ACS in DM/PM patients. In our study, the risk for ACS increased in both sexes. After adjusting for age and other comorbidities, men with DM/PM had a higher risk of developing ACS than women. The effect of DM/PM on ACS risk was higher in young adults, whereas ACS risk increased with age after adjusting for sex and comorbidities. The cumulative incidence of ACS increased in the years following DM/PM diagnosis, particularly after 5 years of follow-up. Based on these findings, we recommend aggressive control of DM/PM activity and an annual cardiovascular risk assessment for all patients with DM/PM, particularly for older men within the first 5 years of diagnosis. Our study also showed that the incidence of ACS increased in patients with comorbidities. After adjusting for sex and age, patients diagnosed with DM/PM and ESRD had the highest risk (4.86-fold higher than that of the control patients) for developing ACS. The other risk was hypertension, which caused a 2.48-fold higher risk of developing ACS in DM/PM patients. This indicates the importance of blood pressure control in patients with DM/PM. The ICD-9 diagnosis of some major diseases had been validated with good accuracy. Cheng et al (18) validated the diagnosis of stroke with an accuracy of 97.85%, while the diagnosis of venous thromboembolism was validated by Yu et al (19). The ICD-9 diagnosis ACS has been validated with 100% accuracy (29). Although the diagnoses of PM and DM have not been validated, both diseases have been used in several previous studies (14, 30). In addition, with regard to disease definition and register, DM/PM was classified as a catastrophic illness in the Taiwan NHI system. In Taiwan, people who are diagnosed with DM/PM have the right to apply for a special
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Y-N Lin et al
‘catastrophic illness card’ and the benefit of getting a medical discount for treatment of this disease. There is a conscientious and careful process to distribute this card. Only rheumatologists can help to apply for the card for DM/PM. Another specialized expert (also a rheumatologist) also reviews the medical records, serological reports, or pathology following the criteria for the classification of DM/PM. Our DM/PM cohort is based only on people who newly applied for the ‘catastrophic illness card’. The strength of this study is that it was a nationwide population-based longitudinal cohort study of Asian people with DM/PM on the risk of experiencing ACS events. However, several limitations merit attention. First, the data used in this study were retrieved from the NHIRD and lacked specific social and personal information and drug histories. Therefore, we could not evaluate all possible impacts, including smoking, body mass index, dietary habits, physical exercise, medication interaction, patients’ drug compliance, and treatment response. Second, we could not obtain information regarding the individual severity of DM/PM. People with DM/PM who had never sought medical attention were overlooked. In addition, approximately one-quarter of myocardial infarctions are ‘silent’ and might be overlooked in claims. Third, although the full regression models were specified after adjusting for certain concurrent illnesses, the patients with DM/PM could have been less healthy and could have had higher rates of comorbid medical problems than indicated in the data, which could have affected the calculation of the patients’ risk for ACS. Finally, the evidence derived from a cohort study is generally of lower methodological quality than that obtained from randomized trials, because a cohort study design is subject to numerous biases related to adjusting for confounders. Despite our meticulous study design involving adequate control of confounding factors, a key limitation was that bias may remain because of possible unmeasured or unknown confounders. Nevertheless, apart from these potential problems, the data on DM/PM and ACS diagnoses were highly reliable.
Conclusions This national population-based retrospective cohort study indicates that there is a significant association between DM/PM and subsequent ACS risk in Taiwan. Aggressive control of DM/PM activity and an annual cardiovascular risk assessment are recommended, particularly for older men with hypertension or ESRD within the first 5 years of diagnosis. Further study is required to extend this positive link to clinical practice and to enable preventative treatment to be established. Acknowledgements This work was supported by study grants (DMR-102-014 and DMR102-023) from our hospital, from the Clinical Trial and Research Centre of the Taiwanese Department of Health (DOH102-TD-B-111-004), and
DM/PM and acute coronary syndrome Taiwan Ministry of Health and Welfare Clinical Trail and Research Center of Excellence (MOHW103-TDU-B-212-113002), Health and welfare surcharge of tobacco products, China Medical University Hospital Cancer Research Center of Excellence (MOHW103-TD-B111-03, Taiwan).
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