Original ArticleAtrial fibrillation, CHA2DS2-VASc score, antithrombotics and risk of non-traffic-, non-cancer-related bone fractures: A population-based cohort study
Introduction
Accidental bone fractures are a major cause of human disability [1]. These accidents incur considerable medical costs [2] and compromise the life quality of patients [3], [4] leading to mortality in a substantial portion of fracture patients [5], [6], [7]. The causes of accidental fracture are thought to be multifactorial, but major contributing factors include physical impact, most commonly from an incidental fall [8], and weakening of the compact bony tissue, often due to loss of bone mass from osteoporosis [9], [10]. Medical conditions [11], [12], [13] that provoke falls or weaken bones can trigger bone fractures, and thus knowledge of these causative factors may help prevent occurrence of such fractures.
Atrial fibrillation (AF) is the most common arrhythmic disease in adults. This cardiac disorder can exert disadvantageous hemodynamic and thromboembolic effects on the nervous system and disturb postural steadiness [14], rendering affected individuals vulnerable to incidental falls [15], [16]. The potential deleterious effect of AF on the whole-body vasculature with respect to thromboembolism may also be harmful to the osseous structure via the bone-vascular axis [17], thereby reducing bone mass due to deficit of blood supply. These effects therefore increase risk of falls, osteoporosis, and in turn bone fracture in AF patients. As such, medications that prevent AF-related embolic stroke could play a role in the reduction of such accidents. To test this hypothesis, this study was designed to investigate whether patients with AF are more prone to accidental fracture of bones, and use of antithrombotics, including oral antiplatelet and anticoagulant agents, is associated with occurrence of such events in these patients. The research was conducted by examining a large-scale database maintained by Taiwan's National Health Research Institutes (NHRI) [18], [19] to follow up the incidence of hospitalization-requiring non-traffic-, non-cancer-related bone fractures in patients with AF. The aim of this study was to determine the potential relationship between AF and the risk of bone fractures and then the correlation of antithrombotics with such events in AF patients.
Section snippets
Research database
The National Health Insurance (NHI) program in Taiwan provides comprehensive health care coverage for about 99% of the nation's 23.74 million residents . The claims records from all medical facilities are stored by Taiwan's NHRI in the National Health Insurance Research Database (NHIRD) [18], [19]. The present study collected data from the Longitudinal Health Insurance Database 2005 (LHID 2005), which contains the original claims data of 1 million patients randomly sampled from the 2005
Definition of non-traffic-, non-cancer-related bone fracture
Bone fracture caused by physical injury other than traffic accidents are classified by the NHI into 4 major categories: skull, neck and trunk, upper limb, and lower limb. The possibility of pathological fracture due to involvement or metastasis of any malignant disease was excluded, as no patients were included in the study if there was a record of cancer diagnosis during enrollment or follow-up.
Antithrombotic medications for atrial fibrillation
Contemporarily available oral antithrombotic drugs for AF, including antiplatelet (aspirin, ticlopidine, dipyridamole, and clopidogrel) and oral anticoagulant (OAC, i.e., warfarin) agents, were retrieved from outpatient and inpatient claims data in the LHID 2005. The proportion of days covered (PDC) by OAC within the entire follow-up period was divided into four categories (1–25%, 26–50%, 51–75%, and 76–100%) to correlate drug adherence level with the incidence of bone fractures.
Statistical analysis
Continuous variables were expressed as mean (SD). Normally distributed continuous data in both cohorts were compared by unpaired Student's t test, while non-parametric continuous data were compared by Mann–Whitney U test. Categorical variables were compared by χ2 analysis with Fischer's exact correction. Kaplan–Meier survival curves for non-traffic-, non-cancer-related bone fractures were constructed for the two patient cohorts and compared in-between with the log-rank test. Multivariate Cox
Patients' characteristics
Of the 1,000,000 representative subjects included in the LHID 2005, there were 998,695 patients who had consumed at least an NHI-reimbursed medical service between 2005 and 2009. Among them, 790,808 subjects aged ≧ 18 years were investigated. After further excluding 5042 subjects with a tentative (once to twice) or definite (≧ 3 times) outpatient diagnosis of AF or cancer between 1998 and 2004, as well as 5126 patients ever admitted due to AF, traffic accident, or any malignant disease, there
Discussion
Bone fractures impose a considerable financial and physical burden on patients and may lead to premature disability and death in a substantial portion of victims. This is the first study to investigate whether the most common cardiac arrhythmic disease, AF, is associated with future occurrence of accidental bone fractures, and the results demonstrate that such patients have a 1.84-fold risk of bone fracture-related hospitalization compared to those without AF. The risk of bone fracture was even
Conclusions
Patients with AF are at a higher risk of non-traffic-, non-cancer-related bone fractures. Female gender, previous stroke and higher CHA2DS2-VASc scores are risk predictors for such events, whereas use of oral anticoagulant but not antiplatelet therapy represents a negative predictor, especially when given to patients with CHA2DS2-VASc score ≧ 1 point. Thus, for patients with AF, bone fracture should be viewed as a potential adverse event of concern, and anticoagulant therapy might be warranted
Study limitations
There were four limitations in this study. First, minor bone fractures without the need for hospitalization were not collected in the NHIRD. Second, the true rate of osteoporosis could not be inferred from the NHIRD, as this disease was often overlooked by patients or treated by self-medication or traditional herbal therapy not covered by NHI. Third, the NHIRD does not provide data on time in therapeutic range (TTR), [50] so only PDC could be used to represent treatment adequacy of OAC. Fourth,
Conflicts of interest
None.
Acknowledgments
This study is based in part on data from the National Health Insurance Research Database provided by the National Health Insurance Administration, Ministry of Health and Welfare, and managed by National Health Research Institutes. The interpretation and conclusions contained herein do not represent those of the National Health Insurance Administration, Ministry of Health and Welfare, or the National Health Research Institutes.
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H.-C. Lai and W.-C. Chien contributed equally to this work.