The authors have declared that no competing interests exist.
Conceived and designed the experiments: MEL SJT WCC WPC CHH. Performed the experiments: MEL SJT TL KSH WPC. Analyzed the data: MEL SJT WCC WPC. Contributed reagents/materials/analysis tools: MEL WCC WTC WPC. Wrote the paper: MEL SJT WCC WPC.
This study estimates the risk of stroke within 5 years of newly diagnosed dementia among elderly persons aged 65 and above. We examined the relationship between antipsychotic usage and development of stroke in patients with dementia.
We conducted a nationwide 5-year population-based study using data retrieved from the Longitudinal Health Insurance Database 2005 (LHID2005) in Taiwan. The study cohort comprised 2243 patients with dementia aged ≥65 years who had at least one inpatient service claim or at least 2 ambulatory care claims, whereas the comparison cohort consisted of 6714 randomly selected subjects (3 for every dementia patient) and were matched with the study group according to sex, age, and index year. We further classified dementia patients into 2 groups based on their history of antipsychotic usage. A total of 1450 patients were classified into the antipsychotic usage group and the remaining 793 patients were classified into the non-antipsychotic usage group. Cox proportional-hazards regressions were performed to compute the 5-year stroke-free survival rates after adjusting for potentially confounding factors.
The dementia patients have a 2-fold greater risk of developing stroke within 5 years of diagnosis compared to non-dementia age- and sex-matched subjects, after adjusting for other risk factors (95% confidence interval (CI) = 2.58–3.08;
Dementia may be an independent risk factor for stroke, and the use of antipsychotics may further increase the risk of stroke in dementia patients.
The frequency of stroke increases with age. Therefore, these disorders have become major health problems worldwide because the increasing number of elderly and stroke patients contributes to disability in old age
On the other hand, antipsychotics are frequently and increasingly prescribed for the treatment of behavioral and psychological symptoms associated with dementia
Therefore, this nationwide population study was conducted to estimate the relationship between dementia and the subsequent development of stroke within 5 years of follow-up. We further examined whether the use of antipsychotic medications potentially increases the risk of stroke among dementia patients.
Our study used the data obtained through the Longitudinal Health Insurance Database 2005 (LHID2005), from the National Health Insurance Research Database (NHIRD), which is managed by the Taiwanese National Health Research Institutes (NHRI). These claims data included registration and medical claims for 1 000 000 randomly sampled patients from the total number of NHRI enrollees. The data set contained the entire medical claims data of 1 million beneficiaries from 1996 to 2010. The NHRI informs that there were no statistical differences in age and sex between the sampled group and all enrollees. Because the LHID2005 comprises secondary data (that cannot be used to identify patients) released to the public for research purposes, this study was exempt from full review by the Institutional Review Board. To our knowledge, the LHID2005 data set is one of the largest nationwide population-based databases in the world, and numerous scientific studies are published using its data
The study cohort consists of dementia patients aged 65 years or above who were newly diagnosed with dementia [ICD-9-Code 290.0 (Senile dementia, uncomplicated), 290.1x (Presenile dementia), 290.2x (Senile dementia with delusional or depressive features), 290.3 (Senile dementia with delirium), 290.4x (Arteriosclerotic dementia), 294.1 (Dementia in conditions classified elsewhere), 331.0 (Alzheimer disease), 331.1 (Pick disease), and 331.2 (Senile degeneration of brain)] between January 2003 and December 2005. Cases were only included if patients obtained ≥2 dementia diagnoses in outpatient visits or 1≥ inpatient service because the diagnostic accuracy of the administrative data set was criticized. Between January 2003 and December 2005, the initial diagnosis date of dementia was assigned as the index date for each patient. Patients with dementia before or after the enrollment period and patients who previously experienced strokes (ICD-9-CM codes 430–438) were excluded.
Our comparison cohort was randomly sampled from the remaining subjects of the LHID2005 data set. Subjects were excluded if they were diagnosed with or had a history of any other dementia disease or stroke. The final comparison cohort was chosen from this representative data set through random selection to match a control-to-case ratio of 3 on the basis of age, sex, and index year. Each subject was followed-up for up to five years. The cohort study censored follow-up only on the following conditions: when the subjects expired, on the dates of outcome incidence (i.e. stroke), or at the end of this cohort. Theoretically, loss of follow up would only occur if the patient refused to seek medical service at all upon having a stroke and still stayed in the insurance system for a long time, which is very unlikely.
Several co-variables such as age, sex, hypertension (ICD-9-CM 401.X-405.X), diabetes mellitus (ICD-9-CM 250.X), and hyperlipidemia (ICD-9-CM 272.X) were adopted in our analytical model to examine the relationship between stroke and particular comorbidities. We defined antipsychotics (N05A) according to the Anatomical Therapeutic Chemical (ATC) Classification System
The Taiwanese NHRI used cluster analysis to examine urbanization levels. They divided 359 towns in Taiwan into 7 strata, with 1 indicating “most urbanized” and 7 indicating “least urbanized”. The categorization of these urbanization levels into 7 clusters were based on Taiwanese census data from 2000. Nevertheless, few dementia cases were in levels 4, 5, 6 and 7; thus, these 4 levels were combined into a single group. Hence, we have 4 strata in urbanization levels.
All data processing and statistical analyses were performed with the Statistical Package for Social Science (SPSS) software, version 17 (SPSS Inc). Pearson
A total of 2243 patients diagnosed with dementia matched the inclusion criteria; 6714 subjects were included in the comparison cohort. The distributions of sociodemographic characteristics and the comorbid medical disorders for the dementia and comparison groups are shown in
Patients with Dementia(n = 2243) | Patients without Dementia(n = 6714) | P value | |||
n | % | n | % | ||
Gender | 0.95 | ||||
Male | 1048 | 46.7 | 3132 | 46.6 | |
Female | 1195 | 53.3 | 3582 | 53.4 | |
AGE(Years), mean (SD) | 0.79 | ||||
> = 65 | 77.85 | (7.16) | 77.80 | (7.09) | |
Follow-up, year, mean (SD) | <0.001 | ||||
2.61 | (2.34) | 4.45 | (1.28) | ||
Urbanization level | 0.776 | ||||
1(most urbanized) | 595 | 26.5 | 1805 | 26.9 | |
2 | 553 | 24.7 | 1582 | 23.6 | |
3 | 338 | 15.1 | 1028 | 15.3 | |
4(least urbanized) | 758 | 33.7 | 2299 | 34.2 | |
Monthly income | <0.001 | ||||
No income | 791 | 35.3 | 2352 | 35.0 | |
NT$ 1–15840 | 630 | 28.1 | 1603 | 23.9 | |
NT$ 15841–25000 | 787 | 35.1 | 2661 | 39.6 | |
NT$≧25001 | 35 | 1.6 | 98 | 1.5 | |
Geographic region | <0.05 | ||||
North | 894 | 39.9 | 2892 | 43.1 | |
Central | 623 | 27.8 | 1747 | 26.0 | |
South | 565 | 25.2 | 1644 | 24.5 | |
Eastern | 161 | 7.2 | 431 | 6.4 | |
Hypertension | <0.001 | ||||
Yes | 1906 | 85.0 | 5413 | 80.6 | |
No | 337 | 15.0 | 1301 | 19.4 | |
Hyperlipidemia | 0.58 | ||||
Yes | 974 | 43.4 | 2960 | 44.1 | |
No | 1269 | 56.6 | 3754 | 55.9 | |
Diabetes | <0.001 | ||||
Yes | 1147 | 51.1 | 2630 | 39.2 | |
No | 1096 | 48.9 | 4084 | 60.8 | |
Antipsychotic usage | <0.001 | ||||
Yes | 1450 | 64.7 | 1904 | 28.4 | |
No | 792 | 35.3 | 4803 | 71.6 |
Total | Patients with Dementia | Patients without Dementia | ||||
Development of Stroke | NO. | (%) | NO. | (%) | NO. | (%) |
5-year follow-up period | ||||||
Yes | 2161 | 24.1 | 811 | 36.2 | 1350 | 20.1 |
No | 6796 | 75.9 | 1432 | 63.8 | 5364 | 79.9 |
Crude HR (95% CI) | 2.88(2.63–3.14) |
1.00 | ||||
Adjusted HR (95% CI) | 2.82(2.58–3.08) |
1.00 |
Total sample number = 8957. Both crude and adjusted HRs were calculated by Cox proportional hazard regressions, and stratified by age and sex. Adjustments are made for age, sex, monthly income, geographic region, hypertension, diabetes, Using antipsychotic drugs.
Indicates p<0.001.
Dementia patients were divided into 2 groups according to antipsychotic usage for further analysis. A total of 1450 patients had used antipsychotics, and 793 patients had never used antipsychotics. Cox regression model analysis demonstrated that the adjusted HR of stroke was 1.17 times greater for patients with dementia and patients using antipsychotics (95% CI = 1.01–1.40) compared to patients who did not use antipsychotics (
Total | Dementia Patients with using antipsychotic | Dementia Patients without using antipsychotic | ||||
Development of Stroke | NO. | (%) | NO. | (%) | NO. | (%) |
Yes | 811 | 36.2 | 547 | 37.7 | 264 | 33.3 |
No | 1432 | 63.8 | 903 | 62.3 | 529 | 66.7 |
Crude HR (95% CI) | 1.18 (1.02–1.35) |
1 | ||||
Adjusted HR (95% CI) | 1.17 (1.01–1.40) |
1 |
Total patients with dementia number = 2243.Adjustments are made for age, sex, monthly income, geographic region, hypertension, diabetes.
Indicates p<0.05.
The main findings from our study of elderly Taiwanese people may be summarized in the following points: (1) Dementia patients have a more than 2-fold greater risk of developing stroke within 5 years of diagnosis compared to non-dementia age- and sex-matched subjects, after adjusting for other risk factors, and (2) antipsychotic usage increases the risk of stroke in dementia patients.
The association between dementia and stroke originated mainly from community-based studies of people with cognitive dysfunction rather than dementia. A large-scale community- based study in Italy indicated that elevated stroke risk is associated with cognitive impairment
Several explanations are plausible for the increased risk of stroke in dementia patients. First, dementia patients have an increased burden of cerebrovascular disease. Several studies have suggested that a significant number of dementia patients suffer from a combination of both degenerative and vascular pathology; thus, a combination of cerebral hypoperfusion, culmination of vascular pathology, and senescence leads to a neuroglial energy crisis, neuronal injury, cognitive impairment, and ultimately, dementia
Second, patients with dementia may be more vulnerable to the complications that are associated with cardiovascular diseases
On the other hand, we identified that stroke risk with antipsychotic usage was higher among dementia patients compared to patients who did not receive antipsychotics. This finding was consistent with previous reports
Our study has several limitations. First, all administrative databases are subject to possible coding errors and under- or over-coding problems. The definitions of dementia and stroke relied solely on the coding of hospital diagnoses, but the accuracy of the diagnosis and coding were not verified. Second, information regarding the degree or stage of dementia was unavailable in this database, and the subtypes of dementia were not considered in the analyses of this study. All of these factors may affect the degree of stroke risk. Third, stroke is a heterogeneous disease that includes large-artery atherosclerosis, cardioembolism, small-artery occlusion, and other subtypes
We identified dementia as an independent risk factor for stroke using a large-scale population-based study. The use of antipsychotic agents in dementia patients may increase the risk of stroke. Further studies are required to replicate these findings and examine whether preventing cognition decline or discontinuing antipsychotic usage can modify the risk of stroke in dementia patients.
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This study is partially based on the National Health Insurance Research Database data provided by the Bureau of National Health Insurance, Department of Health, and managed by the National Health Research Institutes, Taiwan. The results and explanations in this study do not represent the views of the Bureau of National Health Insurance, Department of Health, or National Health Research Institutes.