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Risk of post-discharge fall-related injuries
among adult patients with syncope: A
nationwide cohort study
Anna-Karin Numé ID1*, Nicolas Carlson2,3, Thomas A. Gerds4, Ellen Holm5,
Jannik Pallisgaard1, Kathrine B. Søndergaard1, Morten L. Hansen1, Michael Vinther ID6,
Jim Hansen1, Gunnar Gislason1,2,7, Christian Torp-Pedersen8, Martin H. Ruwald1
1 Department of Cardiology, Copenhagen University Herlev Gentofte Hospital, Hellerup, Denmark, 2 The
Danish Heart Foundation, Copenhagen, Denmark, 3 Department of Internal Medicine, Holbæk Hospital,
Holbæk, Denmark, 4 Department of Public Health, Section of Biostatistics, University of Copenhagen,
Copenhagen, Denmark, 5 Department of Internal Medicine, Nykøbing Falster Hospital, Nykøbing Falster,
Denmark, 6 Department of Cardiology, Copenhagen University National Hospital, Copenhagen, Denmark,
7 The National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark,
8 Departments of Cardiology and Clinical Epidemiology, Aalborg University Hospital, Aalborg, Denmark
* [email protected]
Citation: Numé A-K, Carlson N, Gerds TA, Holm E,
Pallisgaard J, Søndergaard KB, et al. (2018) Risk of
post-discharge fall-related injuries among adult
patients with syncope: A nationwide cohort study.
PLoS ONE 13(11): e0206936.
Editor: Maw Pin Tan, University of Malaya,
Syncope could be related to high risk of falls and injury in adults, but documentation is
sparse. We examined the association between syncope and subsequent fall-related injuries
in a nationwide cohort.
Received: July 14, 2018
Accepted: October 21, 2018
By cross-linkage of nationwide registers, all residents �18 years with a first-time diagnosis
of syncope were identified between 1997–2012. Syncope patients were matched 1:1 with
individuals from the general population. The absolute one-year risk of fall-related injuries,
defined as fractures and traumatic head injuries requiring hospitalization, was calculated
using Aalen-Johansen estimator. Ratios of the absolute one-year risk of fall-related injuries
(ARR) were assessed by absolute risk regression analysis.
Published: November 21, 2018
Copyright: © 2018 Numé et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: Due to legal
restrictions pertaining to use of Danish registerbased data, these de-identified data are available
only upon request from Statistics Denmark
provided that relevant ethical and legal permissions
have been obtained, and that the researchers meet
the criteria for access to confidential data.
Funding: This study was supported by a research
grant from Lundbeckfonden (grant no. R108-
We identified 125,763 patients with syncope: median age 65 years (interquartile range 46–
78). At one year, follow-up was complete for 99.8% where a total of 8394 (6.7%) patients
sustained a fall-related injury requiring hospitalization, of which 1606 (19.1%) suffered hip
fracture. In the reference group, 4049 (3.2%) persons had a fall-related injury. The oneyear ARR of a fall-related injury was 1.79 (95% confidence interval 1.72–1.87, P<0.001) in patients with syncope compared with the reference group; however, increased ARR was not exclusively in older patients. Factors independently associated with increased ARR of fall-related injuries in the syncope population were: injury in past 12 months, 2.39 (2.26– PLOS ONE | November 21, 2018 1 / 15 Syncope and injuries A10415). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: AN has received research grants from P. Carl Petersen Foundation, Helsefonden, and the Department of Cardiology at Copenhagen University Gentofte Hospital. NC has received grants from The Danish Heart Foundation, The Danish Kidney Foundation, The Department of Cardiology at Gentofte Hospital and the Department of Nephrology at Herlev Hospital, Helen and Ejnar Bjoernows Foundation, The Danish Society of Nephrology and the Health Foundation. GG is supported by an unrestricted clinical research scholarship from the Novo Nordisk Foundation and has received research grants from AstraZeneca, Bristol Myers Squibb (BMS), Bayer, Boehringer-Ingelheim and Pfizer, and speaker honoraria from Pfizer, AstraZeneca and BMS, ouside the submitted work. CTP has received grants from Bayer and Biotronic outside the submitted work. JP has received grants from AstraZeneca, Bayer, Boehringer-Ingelheim, The Danish Heart Foundation, the Department of Cardiology at Copenhagen University Gentofte Hospital, and Axel Muusfeldt Foundation outside the submitted work. KBS has received unrestricted grants from Trygfonden Foundation outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials. 2.53, P<0.001), injury in relation to the syncope episode, 1.62 (1.49–1.77, P<0.001), and depression, 1.37 (1.30–1.45, P<0.001) Conclusion Patients with syncope were at 80% increased risk of severe fall-related injuries within the year following discharge. Notably, increased risk was not exclusively in older patients. Introduction Syncope episodes are frequent in both young and older adults, [1–3] and characterized by a total loss of consciousness due to transiently reduced cerebral blood flow with subsequent complete recovery. [4, 5] Nonetheless, episodes do often lead to falls, and syncope could be related to an increased risk of injuries. Falls and fall-related complications are a considerable public health concern in terms of morbidity, mortality, quality of life, and cost of health and social services, especially among older adults. [6–10] Over the last decade, the overlap in symptoms of syncope and falls, particularly in older persons, has received growing attention. [11–13] A number of age-related factors (physiological and pathological), in combination with amnesia for loss of consciousness, and lack of a witness account, may confound the assessment of syncope. [14] Consequently, persons with syncope are likely to present with an unexplained fall rather than syncope. [15, 16] Moreover, several studies have observed high prevalence of cardiovascular conditions among older persons presenting with unexplained falls. [17] Some of these conditions, particularly carotid sinus syndrome and orthostatic hypotension, are observed risk factors for unexplained falls and fall injuries, and also important causes of syncope in the elderly. [18–21] Yet, evidence on the associations between syncope syndromes and falls or injuries is sparse and mainly based on crosssectional studies in selected settings. One study among approximately 200 elderly patients with syncope reported a two-year incidence of fractures of 11%, but injury was a secondary outcome and further analysis was not undertaken. [22] Moreover, previous studies among adult patients with syncope report that 26% to 39% suffer from injuries in relation to their syncope episode, [23, 24] but whether this is exclusively in older adults is unknown. We conducted a nationwide study of adult patients with a first-time diagnosis of syncope, to provide longitudinal population-based data on the association between syncope and subsequent fall-related injuries. Our objectives were to assess the risk of fall-related injuries following syncope and evaluate if physical injury in this population occurs predominantly in older adults, and to compare the risk of fall-related injuries following syncope with that of the general population. Methods The study is a nationwide register-based cohort study from January 1, 1997 to December 31, 2013. The study was conducted in Denmark where health services are predominantly taxfunded, which ensures free access to healthcare for the entire population. Individual-level linkage of information between population-based registers is possible due to a unique and personal identification number, which is assigned to each resident at birth or upon immigration. [25] PLOS ONE | November 21, 2018 2 / 15 Syncope and injuries Registers The Civil Registration System holds information on the date of birth, death, sex, and migration for all residents. [25] Data on medical history and outcomes were retrieved from discharge diagnoses and claimed prescriptions as appropriate. The Danish National Patient Register holds data on all hospitalizations since 1977. [26] At discharge, each hospital contact is registered with one principal diagnosis, and if appropriate, one or several supplementary diagnoses according to the International Classification of Diseases (ICD). The Danish Register of Medicinal Product Statistics comprises information about claimed prescriptions, and each drug dispensing is registered according to the Anatomical Therapeutic Chemical classification system. [27] Partial reimbursement of drug expenses by the national healthcare system ensures complete registration by the pharmacies. Average five-year household income prior to study start served as a proxy of socioeconomic status, and information was obtained from Statistics Denmark. [28] Study population The study population comprised all residents �18 years with a first-time primary discharge diagnosis of syncope between 1997 and 2012. Both inpatient and emergency department (ED) encounters were included. Subjects with prior syncope outpatient contacts were excluded. The reference group was obtained with risk set matching: Each subject in the syncope population was matched with one subject from the general population without prior syncope hospitalizations by year of birth and sex. The ICD diagnosis of syncope (10th revision code R55.9) refers to the most common etiologies of syncope, [5] and has previously been validated with a positive predictive value of 96%.[29] Covariates Potential confounding factors were pre-specified and identification was based on current knowledge in combination with the construction of a model diagram. [30] The following medical variables were considered: cardiovascular disease (including ischemic heart disease or myocardial infarction, heart failure, cardiac arrhythmia, atrioventricular block or left bundle branch block, cerebral vascular disease, or peripheral vascular disease), pacemaker, diabetes mellitus, cancer, dementia, depression, Parkinson disease, and use of loop diuretic, antihypertensive, or anxiolytic drugs. Information was retrieved from diagnosis or surgical procedure codes up to ten years prior to inclusion, and from claimed prescriptions up to one year prior to inclusion (S1 Table). We considered combination treatment with at least two standard antihypertensive agents within a period of 90 days as use of antihypertensive drugs. [31] When appropriate, we combined diagnosis and prescription data of comorbidities such as diabetes mellitus, depression, and dementia, to increase the sensitivity of the covariates. Osteoporosis is a main risk factor of fragility-fractures, but because the association with syncope is unclear, it was not considered a principal confounder. Study outcome The primary outcome of a fall-related injury was defined as any hospital encounter (ED visit or inpatient admission) from fractures (femur, pelvis, shoulder or upper arm, elbow, forearm or wrist, and skull) or traumatic head injuries (S1 Table). The approach has been used previously as a proxy for serious falls. [9] The outcome of interest was post-discharge injuries, so documentation of an injury in relation to the syncope episode was not considered as an event PLOS ONE | November 21, 2018 3 / 15 Syncope and injuries (but evaluated in supplementary analyses). The study population was followed for one year, or until the occurrence of a fall-related injury, emigration, or death. Statistics Differences in baseline characteristics were compared using chi-squared test for categorical variables. We report loss to follow-up at one year. The level of significance was set at 5%. To assess the time-dependent absolute risk of fall-related injuries following syncope, we used the Aalen-Johansen estimator to account for the competing risk of death. [32] Furthermore, we report one-year risks separately for the syncope and reference group and according to age at baseline. The relation between the absolute risks and age (continuous scale) was obtained with the Aalen-Johansen estimate and kernel smoothing. In our main analysis, we performed absolute risk regression analysis, [33] and report absolute risk ratios (ARR) with 95% confidence intervals (CI) referring to the probability of sustaining a fall-related injury during the next year for persons with syncope compared to persons without syncope, given fixed values for the other predictor variables. Models were adjusted for age (five-year intervals), sex, calendar year (four-year intervals), and socioeconomic status in addition to comorbidities and pharmacotherapies. Effect modification was analyzed in subgroups defined by clinical relevance, thus the syncope-associated one-year risks of fall-related injuries were estimated in subgroups defined by age, sex, cardiovascular disease, arrhythmia, pacemaker, loop diuretic use, depression, and fall-related injury in the past 12 months. We further analyzed absolute risk ratios to associate changes in one-year risk of fall-related injuries with differences in person characteristics in the syncope population. Sensitivity analyses adjusted for osteoporosis and prior fall-related injury respectively, and in another analysis, we excluded all patients with fall-related injury in relation to the syncope episode. We also examined whether the risk was similar for patients with syncope who were admitted to hospital and patients discharged from the ED. All analyses were repeated with hip fracture as the outcome of interest; specifically, because hip fractures are both highly correlated with falls, and require hospitalization. Statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Gary, NC, USA) and R version 3.4. [34] Ethics. The study was approved by the Danish Data Protection Agency (ref. number: 2007-58-0015 / GEH-2014-013 I-Suite number: 02731). In Denmark, ethical approval is not required for retrospective register-based studies. All analyses were executed on servers placed at Statistics Denmark. Results In the period from 1997 through 2012, 125,763 adult patients with a first-time diagnosis for syncope were identified (n = 8288 were excluded due to prior syncope outpatient contacts), of which 68,671 (54.6%) represented inpatient admissions. The median age of patients with syncope was 65 years (interquartile range [IQR] 46–78) and 65,608 (52.2%) were women (Table 1). The most prevalent comorbidities were ischemic heart disease (n = 20,093, 16.0%), arrhythmia (n = 15,673, 12.5%), and depression (n = 22,415, 17.8%). Prevalence of comorbidities was greater in the syncope population compared with the matched reference group, as was the frequency of a prior fall-related injury (n = 7912, 6.3% versus n = 3774, 3.0%, P<0.001). Absolute one-year risk of fall-related injuries following syncope At one year, follow-up was complete for 99.8% of the syncope population (n = 199, 0.2% emigrated). A total of 8394 (6.7%, 95% CI, 6.6%-6.8%) patients had a fall-related injury requiring re-hospitalization, whereas 4049 (3.2%, 95% CI, 3.1%-3.3%) persons in the reference group PLOS ONE | November 21, 2018 4 / 15 Syncope and injuries Table 1. Baseline characteristics of the study populationa, b. Age, median [IQR], years Syncope (n = 125,763) No syncope (n = 125,763) 65 [46–78] 65 [46–78] 35,213 (28.0) 35,213 (28.0) 26,292 (20.9) Age groups, years 18–49 50–64 26,292 (20.9) 65–79 36,153 (28.7) 36,153 (28.7) �80 28,105 (22.3) 28,105 (22.3) Women 65,608 (52.2) 65,608 (52.2) Men 60,155 (47.8) 60,155 (47.8) Income groupc, quartiles Third quartile 22,781 (18.1) 27,524 (21.9) Cardiovascular disease 40,659 (32.3) 20,031 (15.9) Ischemic heart disease or MI 20,093 (16.0) 9428 (7.5) Comorbidity Heart failure 9053 (7.2) 4033 (3.2) Cardiac arrhythmia 15,673 (12.5) 6679 (5.3) Atrial fibrillation 11,688 (9.3) 5339 (4.2) 2576 (2.0) 691 (0.5) 12,875 (10.2) 5755 (4.6) AV block or LBBB Cerebral vascular disease Pacemaker Diabetes mellitus 3700 (2.9) 937 (0.7) 10,500 (8.3) 7123 (5.7) Cancer 10,378 (8.3) 7953 (6.3) Depression 22,415 (17.8) 12,806 (10.2) Parkinson disease 2760 (2.2) 1499 (1.2) Dementia 3981 (3.2) 2097 (1.7) Osteoporosis 5892 (4.7) 4779 (3.8) 25,480 (20.3) Pharmacotherapy Antihypertensive drugs 37,865 (30.1) Loop diuretic drugs 17,910 (14.2) 11,330 (9.0) Anxiolytic drugs 27,041 (21.5) 18,332 (14.6) 7912 (6.3) 3774 (3.0) Syncope inpatient admission Fall-injury in past 12 m 68,671 (54.6) NA Syncope ED visit 57,092 (45.4) NA 4601 (3.7) NA Syncope and injuryd Year of inclusion 1997–2000 29,776 (23.7) 29,776 (23.7) 2001–2004 32,640 (26.0) 32,640 (26.0) 2005–2008 31,171 (24.8) 31,171 (24.8) 2009–2012 32,176 (25.6) 32,176 (25.6) Abbreviations: IQR (interquartile range), MI (myocardial infarction), LBBB (left bundle branch block), ED (emergency department), NA (not applicable) Data are expressed as no. (%) unless otherwise indicated a b P values were <0.001 (except for age and sex) c Average five-year household income prior to inclusion d Documented fall-related injury in relation to the syncope episode PLOS ONE | November 21, 2018 5 / 15 Syncope and injuries Fig 1. Absolute risk of hospitalization due to fall-related injuries following syncope. Syncope population (red), matched reference group (black). One-year absolute risk of fall-related injuries was 6.7% (95% CI, 6.5%-6.8%) in the syncope population, and 3.2% (95% CI, 3.1%-3.3%) in the age- and sex matched reference group. had a fall-related injury (Fig 1). Hip fracture accounted for one out of five injury hospitalizations among persons with syncope (n = 1606, 19.1%) compared with n = 1016 in the reference group (S2 Table). Fig 2 shows the absolute one-year risks of fall-related injuries according to age in the syncope and reference population respectively. The absolute risk of a fall-related injury increased with advancing age, and was particularly high among elderly women; however, young men did also have a substantial risk of injury. Risk of fall-related injuries in patients with syncope compared to persons without syncope The one-year adjusted ARR of fall-related injuries was 1.79 (95% CI, 1.72–1.87, P<0.001) in patients with syncope compared with the reference group (unadjusted ARR, 1.85, 95% CI, 1.78–1.93, P<0.001). Fig 3 presents risk estimates stratified by age and sex. We found that the ARR decreased with advancing age. Also, in the older age groups, the relative importance of syncope was greater in men (65–79 years: ARR, 2.42, 95% CI, 2.11–2.77) compared with women (65–79 years: ARR, 1.73, 95% CI, 1.56–1.93). S1 Fig provides a summary of subgroup PLOS ONE | https://doi.o ... Purchase answer to see full attachment

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