Risk factors for ischemic stroke post bone fracture

Journal of Clinical Neuroscience xxx (2018) xxx–xxx

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Clinical study

Risk factors for ischemic stroke post bone fracture Qi An a,b, Zhe Chen a, Kang Huo a, Hua Su c, Qiu-Min Qu a,⇑ a

Department of Neurology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China Department of Rheumatology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China c Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, CA, USA b

a r t i c l e

i n f o

Article history: Received 17 March 2018 Accepted 24 September 2018 Available online xxxx Keywords: Ischemic stroke Post fracture stroke Risk factor

a b s t r a c t Stroke is one of the most devastating complications after bone fracture. However, due to the rarity of the complication, the risk factor for post fracture stroke remains unknown. We retrospectively reviewed 2914 fractured adults referred to the first affiliated hospital of Xi’an Jiaotong University, a regional referral center of China, from January 2008 to May 2013. As a result, among the 2914 patients, 13 of them had newly onset stroke within a median of 4 days after bone fractures (ranging from 1 to 25 days). The overall prevalence of post fracture stroke was 0.446%. The post fracture stroke prevalence in patients older than 68 years old was 3.542%. Compared to patients with vertebral (0.124%) and femur (0.619%) fractures, patients with hip fractures had a higher prevalence of post fracture stroke (2.320%) (P < 0.001). Univariate analysis showed that hyperlipidemia, history of prior fracture, more comorbidities, higher CHADS2 score and higher neutrophil counts at admission were more often observed among patients who had post fracture stroke (P < 0.05). With the multiple logistic regression analysis, we identified that history of prior fracture was an independent risk factor for post fracture ischemic stroke (OR = 6.417, 95% CI = 1.581–26.051, P = 0.009). Our study illustrates that the history of prior fracture is associated with a 6.4-fold increase in the risk of post fracture ischemic stroke. Ó 2018 Elsevier Ltd. All rights reserved.

1. Introduction Bone fracture is a common health problem that can cause longterm disability. After adjusting for competing risks of death, the residual life time risk of fracture for women and men from age of 60 was 44% and 25%, respectively [1]. Some types of fractures, such as vertebral fractures, hip fractures, wrist-forearm fractures, are osteoporosis-related and increasing with age [2,3]. Worldwide, the disability adjusted life years (DALYs) lost due to osteoporotic fracture is 5.8 million, accounting for 0.83% of the global burden of noncommunicable diseases [4]. Stroke is another common cause of disability [5,6]. Moreover, stroke, per se, is one of the most devastating complications for bone fractured patients. Research on the prevalence of stroke after bone fractures is rare. Bone fractured patients with post fracture stroke have poorer functional recovery and require more care during the 1st year than those without [7]. In addition, the treatments for post fracture stroke are challenging. Currently, intravenous thrombolysis is widely accepted and is still the leading therapy approved by the US Food and Drug Administration for the manage-

⇑ Corresponding author at: 277 West Yanta Road, Xi’an, Shaanxi, China. E-mail address: [email protected] (Q.-M. Qu).

ment of acute ischemic stroke [8,9]. However, fracture is a contraindication for thrombolysis. For these who have not received thrombolysis, either antiplatelet or anticoagulation therapy is recommended to decrease the prevalence of recurrent stroke [8,10,11]. Meanwhile, all these therapies might increase the risk of hemorrhage after fractures. Thus, it is a better alternative medical strategy to prevent post fracture stroke through identifying and interfering with related risk factors. However, to the best of our knowledge, there was rare research on risk factors of post fracture stroke. The aim of this study was to identify these risk factors for post fracture stroke.

2. Methods This was a retrospective study and included patients hospitalized for fracture in the First Affiliated Hospital of Xi’an Jiaotong University, a regional referral center in China, from January 1st, 2008, to May 31st, 2013. All fractures were confirmed by radiology (i.e. X-ray or computed tomography). The exclusion criteria were: younger than 18 years of age, diagnosed as pathological fractures, and with delayed bone healing. Patients with fracture caused by excessive trauma (e.g., motor vehicle accident) were also excluded. This study was approved by the Ethics Committee of The First

https://doi.org/10.1016/j.jocn.2018.09.017 0967-5868/Ó 2018 Elsevier Ltd. All rights reserved.

Please cite this article in press as: An Q et al. Risk factors for ischemic stroke post bone fracture. J Clin Neurosci (2018), https://doi.org/10.1016/j. jocn.2018.09.017

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Q. An et al. / Journal of Clinical Neuroscience xxx (2018) xxx–xxx

Fig. 1. Study flow diagram.

Affiliated Hospital of Xi’an Jiaotong University. Written informed consent was signed by each patient before entering into this study. We searched the hospital information system in our center. In the study period, a total of 3605 patients were diagnosed as ‘‘fracture” and admitted. After eliminating 691 patients according to the exclusion criteria, 2914 patients were enrolled in the present study ultimately, including 806, 323 and 431 patients who fractured their vertebral, femur and hip, respectively (Fig. 1). The median following-up time was 20 days (ranging from 4 to 90 days). We extracted demographic and medical records in the hospital information system, including age, gender and fracture type etc. History of hypertension, diabetes mellitus, hyperlipidemia, stroke, fracture and routine examination and biochemistry results were also recorded. The results of routine examination and biochemistry, including levels of white blood cell (WBC), neutrophile, hemoglobin, platelet, albumin, fibrinogen, D-dimer, etc., were tested within 24 h after admission. Brain computed tomography (CT) or magnetic resonance imaging (MRI) was conducted among patients who were suspected to have post fracture stroke based on symptoms and physical examinations. And all these patients satisfied the World Health Organization criteria for acute stroke [12]. All the ischemic strokes were further classified based on the Oxford shire Community Stroke Project (OCSP) criteria: total anterior circulation infarction (TACI), partial anterior circulation infarction (PACI), posterior circulation infarction (POCI), and lacunar infarction (LACI) [13]. The diagnostic criteria of the complications are demonstrated in Table 1. CHADS2 and its derived scales were first designed to predict the risk of ischemic stroke among patients with chronic atrial fibrillation and to guide the antithrombotic treatment [14,15]. Recently,

several studies showed that CHADS2 and its derived scales were still simple and reliable methods for predicting ischemic stroke risks in patients with a history of coronary artery disease, and those without atrial fibrillation [16,17]. The CHADS2 scores in patients with hip fractures were evaluated according to the medical records, and were further classified as Group 0–1 and Group 2– 6 for clinical purposes, respectively. Statistical analyses were conducted by SPSSÒ software (version 13.0). Numerical data was expressed as mean ± SD (standard deviation) or median (range min–max), while categorical data was expressed as percentages or numbers. Numerical data was compared with the independent sample t-test. Categorical data was compared with the Chi-square test or the Fisher’s exact test, where appropriate. Finally, we used Multiple Logistic Regression analysis to determine independent factors for post-fracture ischemic stroke. Enter method of Logistic Regression was used. The enter and removal levels were 0.05 and 0.10, respectively. For the Logistic Regression analysis, continuous neutrophil cell counts were transformed into Dichotomous variables based on the cutoff point of 75th percentile (i.e. 7.34  109/L) for clinical purposes. P < 0.05 was deemed to indicate a significant difference.

3. Results A total of 13 patients had post fracture stroke during our study period. And all strokes were ischemic. The prevalence of stroke after fracture was 0.446%. Table 2 shows the clinical characteristics of the 13 patients. Compared to patients with vertebral (0.124%) and femur (shaft/ distal, 0.619%) fractures, patients with hip fractures had a higher prevalence of stroke (2.320%) (P < 0.001). The median time between fracture and the onset of stroke was 4 days (ranging from 1 to 25 days). LACI was the most common stroke type (7 out of 13 patients), no TACI was observed. Concerning about the test validity, the following study was focused on patients with hip fractures only. Among these 431 hip-fractured patients, the median age were 76 years old (ranging from 34 to 101 years old). The demographic characteristics and comorbidities of hip fractured patients at admission are shown in Table 3. There were more females (59%) than males. About 25% (1 0 9) patients had a history of prior stroke, 89 were ischemic stroke, 16 were haemorrhagic stroke, and 4 had both. Most patients had fractures on left hips (54.52%). However, the stroke prevalence was not correlated with gender and the location of hip fractures (P = 0.95 and P = 0.76, respectively). Hyperlipidemia, previous fracture and comorbidities were more common in patients with post fracture stroke compared to those without (P = 0.027, P = 0.004, P = 0.036, respectively, Table 3). Most of the

Table 1 The diagnostic criteria of the complications. Items

Definition

Hypertension Diabetes Mellitus Hyperlipidemia Coronary Heart Disease Atrial Fibrillation History of Stroke Congestive Heart Failure

BP >140/90 mmHg on repeated measurements during the hospitalization or on antihypertensive medication a history of diabetes mellitus, or FBG 7.0 mmol/L or use of antidiabetic drugs TC >5.18 mmol/L or use of lipid-lowering agents a history of myocardial infarction or angina pectoris, or cardiac bypass surgery or stent angioplasty a history of atrial fibrillation, or diagnosed using the patient’s in-hospital EKG a history of stroke, including IS, TIA, ICH or SAH a history of congestive heart failure, or with symptoms of heart failure and at least one echocardiographic abnormality in hospital smoking at the time of fracture or quit smoking <1 year a history of discontinuousness of bone cortex, including primary fracture and discontinuousness secondary to medical procedures, joint arthroplasty, etc eGFR <60 mL/min/1.73 m2 [19,20] a history of COPD [21]

Current Smoking History of Fracture Comorbidities

CKD COPD

BP, blood pressure; FBG, fasting blood glucose; TC, total cholesterol; IS, ischemic attack; TIA, transient ischemic attack; ICH, intracerebral hemorrhage; SAH, subarachnoid hemorrhage; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; COPD, Chronic Obstructive Pulmonary Disease.

Please cite this article in press as: An Q et al. Risk factors for ischemic stroke post bone fracture. J Clin Neurosci (2018), https://doi.org/10.1016/j. jocn.2018.09.017

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Q. An et al. / Journal of Clinical Neuroscience xxx (2018) xxx–xxx Table 2 Characteristics of patients with post-bone fracture stroke. No.

Gender

Age

Fracture type

Comorbidities

Fracture to IS (day)

OCSP

1 2 3 4 5 6 7 8 9 10 11 12 13

F F F M M F M F M F M F M

88 84 80 73 84 80 79 76 75 68 81 78 77

Hip Hip Hip Hip Hip Hip Hip Hip Hip, Humerus Hip, Radial Femur Shaft Femur Distal Vertebral

N N N N Y N N N Y Y N N N

9 7 20 25 2 3 4 2 1 13 13 2 2

LACI LACI POCI LACI LACI LACI POCI PACI PACI PACI LACI LACI POCI

IS, ischemic stroke; N, without comorbidities; Y, with comorbidities; OCSP, Oxfordshire Community Stroke Project; LACI, lacunar infarction; POCI, posterior circulation infarction; PACI, partial anterior circulation infarction.

Table 3 Demographic Characteristics and Comorbid Medical Disorders of Hip-Fracture at hospital admission. Patients with post fracture IS (n = 10)

Patients without post fracture IS (n = 421)

Variable

Mean/n

SD/%

Mean/n

SD/%

P value

Female Age Left Side Multiple Fractures Hypertension Diabetes Mellitus Coronary Heart Disease Atrial Fibrillation Congestive Heart Failure Hyperlipidemia Previous Stroke Previous Fractures Current Smoking Comorbidities

6 78.70 6 2 8 3 0 1 0 4 2 5 1 4

60 5.91 60 20 70 30 0 10 0 40 20 50 10 40

248 75.97 229 34 218 128 85 25 11 49 107 5 9 52

58.91 8.49 54.39 8.08 51.78 30.40 20.19 5.94 2.61 11.64 25.42 1.88 2.14 12.35

0.945 0.230 0.761 0.442 0.148 0.978 0.222 0.594 1.000 0.027 0.983 0.004 0.692 0.036

Table 4 Relationship between CHADS2 score and post hip fracture IS. CHADS2 Score

0–1 2–6

Patients with post fracture IS (n = 10)

Patients without post fracture IS (n = 421)

n

%

n

%

1 9

10 90

196 225

46.56 53.44

patients with post fracture stroke had a CHADS2 score  2 (P = 0.049, Table 4). Patients with post fracture ischemic stroke had significantly higher neutrophile counts than those without (7.76 ± 3.59  109/ L VS 6.04 ± 2.54  109/L, P = 0.037). Meanwhile, the hip-fractured patients had higher WBC and platelet levels. However, no statistical difference was observed (9.59 ± 3.85  109/L VS

p value

0.049

P = 0.074; 221.20 ± 83.74  109/L VS 7.98 ± 2.79  109/L, 9 177.77 ± 75.41  10 /L, P = 0.073). Patients with and without post fracture stroke had similar levels on hemoglobin, albumin, fibrinogen and D-dimer. In multiple logistic regression analysis, the only independent predictor of ischemic stroke was history of prior fracture (OR = 6.417, 95% CI = 1.581–26.051, P = 0.009) (Table 5).

Table 5 Multivariate logistic regression for prediction of post-fracture stroke. Model variables

Coefficient

SE

Wald

P

OR (95% CI)

Hyperlipidemia Prior fracture More comorbidities CHADS2 score 2-6 Higher neutrophile count Constant

1.390 1.859 1.268 2.053 1.226 7.008

0.736 0.715 0.748 1.105 0.696 1.268

3.564 6.763 2.874 3.455 3.107 30.526

0.059 0.009 0.090 0.063 0.078 0.000

4.016(0.948–17.008) 6.417(1.581–26.051) 3.554(0.820–15.392) 7.793(0.894–67.922) 3.409(0.872–13.330)

SE, standard error; OR, odds ratio; CI, credit interval.

Please cite this article in press as: An Q et al. Risk factors for ischemic stroke post bone fracture. J Clin Neurosci (2018), https://doi.org/10.1016/j. jocn.2018.09.017

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Q. An et al. / Journal of Clinical Neuroscience xxx (2018) xxx–xxx

4. Discussion In our study, the prevalence of post fracture stroke was 0.446%, which is higher than 0.104% of the general population [18]. Patients with advanced age and hip fractures were more likely to have post fracture stroke. In multiple logistic regression analysis, we found that history of prior fracture was an independent risk factor for post fracture stroke. To the best of our knowledge, this is the first study analyzed the prevalence and risk factors of post fracture stroke among Chinese populations. The etiology of post fracture ischemic stroke is largely unclear. Fat embolism could be one of the causative factors, especially in long bone and pelvic fractures [19]. The general prevalence of fat embolism after hip fractures varies from 0.7 to 3.3% [20]. The risk of fat embolism is highest with the first 3–4 days after trauma [21]. In our study, the results that patients with post hip fracture ischemic stroke had higher lipid levels than those without implied fat embolism might be a latent etiology. However, only about half of our patients (7 out of 13) developed ischemic stroke within 4 days, suggesting existence of other mechanisms. Paradoxical embolism of vein thrombosis is an underlying etiology for ischemic stroke [22]. We reviewed the transthoracic echocardiography of our 10 patients with post hip fracture ischemic stroke, however, no proof of intracardiac right-to-left shunts were recorded. Thus, paradox embolism might not be the etiology for post fracture ischemic stroke among our patients. As suspected, older patients had higher risks for post bone fracture ischemic stroke. After long bone or proximal femur fractures, interleukin 6 (IL-6) was significantly increased only in older patients [23]. Fornage et al found that IL-6 was associated with white matter leisions (WML) and brain infarcts among elderly participants of the Cardiovascular Health Study [24]. Furthermore, fractures could stimulate hematopoietic marrow resulting in augmented inflammation through HMGB1 (high mobility group box 1) and macrophage/microglia infiltration in brain tissue [25]. It’s worth noting that WML and lacunar infarction are correlated tightly with each other and both are associated with cerebral small vessel disease [26,27]. These intriguing results could partially explain why elderly patients were more vulnerable to post fracture ischemic stroke and lacunar infarction was the most common ischemic stroke type among our patients. The prevalence of post hip fracture stroke in our study is 2.320%, which is comparable to previous reports (ranging from 0.2% to 4.1%) [28–30]. Similar to the published studies, we observed that hip fractured patients were more likely to have post fracture ischemic stroke as well [28]. The following three factors might be responsible for this result. First, hip fracture occurs mostly in patients with advanced age. In our research, all post hip fracture stroke patients were no younger than 68 years old. Advanced age is an important risk factor for ischemic stroke [31,32]. It has also been shown that advanced age (older than 75 years) was associated with increased risk of ischemic stroke after hip surgery [29]. Elder patients are more likely to combine with other diseases and their general conditions are likely to be poorer. Our study showed that patients with post fracture ischemic stroke had more comorbidities and higher CHADS2 scores than those without. Second, immobility and life style change after hip fracture. Epidemiology shows that fractures in the thoracolumbar spine, hip and distal radius are the top three causes of fracture types in the elder [33]. It was reported that both vertebral and hip fractures increased the risk of ischemic stroke [28,34]. As far as we know, there is no research suggesting that distal radius fracture increases the risk of ischemic stroke. The American Heart Association (AHA) and American Stroke Association (ASA) have listed physical activity

as a modifiable risk factor for primary ischemic stroke [35]. In the vertebral or hip fractured patients, ambulation is markedly limited because of pain and disability. Further studies are needed to determine whether the incidence of ischemic stroke after fractures would decrease by improving the mobility. Third, hip has unique anatomical and histological structures. Compared with vertebral and femur shaft and radius, hip has rich hematopoietic cells in bone marrow cavity [36]. As mentioned previously, fractures could stimulate hematopoietic marrow resulting in augmented inflammation [25]. Thus, it seems rational to predict more severe inflammatory reactions after hip fractures. In our study, we noted that prior fracture was an independent risk factor for post hip fracture ischemic stroke. It was an intriguing result and had never been mentioned before. The relationship between previous fracture and subsequent post fracture ischemic stroke remains unclear. Further studies are needed to verify the relationship between prior fracture and post fracture ischemic stroke. Our study had some limitations. First, our study only included patients in the First Affiliated Hospital of Xi’an Jiaotong University, where patients are likely to have more severe and complex conditions. The incidence of post fracture ischemic stroke might be overestimated. Second, due to the retrospective nature of the study, we may have missed some mild strokes if they were not recognized and recorded, which would lead to underestimation. Third, we only recorded the stroke during in hospital period. Patients who had stroke after discharging were not included. Fourth, the patient sample is small due to the low events incidence. Further studies with larger patients in multiple hospitals are needed to verify the result obtained in this study. 5. Conclusions Hip fractured patients with advanced age are prone to post fracture ischemic stroke. Hyperlipidemia, history of prior fracture, more comorbidities, higher CHADS2 score and neutrophil counts are related to post fracture ischemic stroke. History of prior fracture is an independent risk factor for ischemic stroke. These findings could help doctors identify fractured patients who are at high risks for post fracture ischemic stroke and provide them with prompt therapies in order to prevent the complex clinical entity. Conflict of interest statement All the authors declare that they have no conflict of interest. Funding This work was supported by grants to Hua Su from the National Institutes of Health (R01 NS027713 and R21 NS083788) and from the Michael Ryan Zodda Foundation and UCSF Research Evaluation and Allocation Committee (REAC). Acknowledgements We should thank Professor Yu-sheng Qiu in the Orthopedic department and Mrs. Rong Peng in the Archive department of the First Affiliated Hospital of Xi’an Jiaotong University for their helps in data collection. Appendix A. Supplementary material Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2018.09.017.

Please cite this article in press as: An Q et al. Risk factors for ischemic stroke post bone fracture. J Clin Neurosci (2018), https://doi.org/10.1016/j. jocn.2018.09.017

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Please cite this article in press as: An Q et al. Risk factors for ischemic stroke post bone fracture. J Clin Neurosci (2018), https://doi.org/10.1016/j. jocn.2018.09.017