Increased Risk of Stroke Among Hip Fracture Patients: A Nationwide Cohort Study
Running title: Increased Risk of Stroke Among Hip Fracture Patients
Chun-Hao Tsai 1,2, Cheng-Li Lin 3,4, Horng-Chang Hsu 1,2, Wei-Sheng Chung5,6*
1 Graduate Institute of Clinical Medicine, China Medical University, Taichung, Taiwan; 2 Department of Orthopedics, China Medical University Hospital, Taichung, Taiwan; 3
Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan; 4 Department of Public health, China Medical University, Taichung, Taiwan; 5 Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan; 6 Department of Health Services Administration, China Medical University, Taichung, Taiwan
Correspondence to: *Wei-Sheng Chung, M.D., Ph.D., Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare, Taichung, Taiwan; No. 199, Section 1, San-Min Road, Taichung City 40343, Taiwan Tel: 886-4-22294411. Fax: 886-4-22290020. E-mail: chung.w53@msa.hinet.net
All authors have contributed significantly, and that all authors are in agreement with the content of the manuscript: Conception/Design: Wei-Sheng Chung, Chun-Hao Tsai; Collection and/or assembly of data: All authors; Data analysis and interpretation: Wei-Sheng Chung, Chun-Hao Tsai, Cheng-Li Lin; Manuscript writing: All authors; Final approval of manuscript: All authors
Acknowledgments: This work received administrative support from the Management Office for Health Data, China Medical University Hospital. No additional external funding was received for this study.
Disclosure Statement: Chun-Hao Tsai, Cheng-Li Lin, Horng-Chang Hsu, Wei-Sheng Chung declare that they have no conflicts of interest.
Mini-abstract
Our study indicates hip fracture is independently associated with increased risk of developing stroke. In addition, the risk of stroke following incidence of hip fracture is more prominent in younger patients, men, those with cardiovascular comorbidities, and in patients using specific medication, such as diuretics and ABRs.
ABSTRACT
Purpose: Hip fractures are associated with increased risk of major morbidity. However, few data are available on the risk of stroke after hip fracture. Therefore, we investigated whether hip fracture increases the risk of stroke in a large nationwide cohort study.
Methods: Using universal insurance claims data, we identified a study cohort comprising 6013 newly diagnosed hip fracture patients from 2000 to 2010 and a nonhip-fracture cohort of 23 802 participants. Incidence and risk of stroke were estimated for both cohorts until the end of 2011. Results: Stroke incidence was 1.69-fold (95% confidence interval [CI] = 1.56–1.83) higher in the hip fracture cohort than in the comparison cohort with an adjusted hazard ratio (HR) of 1.54 (95% CI = 1.42–1.67) for the hip fracture cohort. The hip fracture patients were at higher risk of developing ischemic stroke (HR = 1.55, 95% CI = 1.42–1.69) and hemorrhagic stroke (HR = 1.55, 95% CI = 1.16–1.89), respectively. At an incidence of 64.6 per 1000 person-years, the adjusted HR of stroke increases to 3.10 (95% CI = 2.47–3.90) for patients with coexisting diabetes, hypertension, and heart failure compared with those without these 3 conditions. At an incidence of 60.4 per 1000 person-years, the adjusted HR of stroke increases to 2.92 (95% CI = 2.43–3.51) for hip fracture patients prescribed diuretics and angiotensin II receptor blockers (ARBs) compared with those without hip fracture or prescriptions for diuretics or ARBs.
Conclusions: Hip fracture is independently associated with a subsequent risk of stroke. Keywords: hip fracture, stroke, diabetes, hypertension, heart failure, cohort study
Introduction
Hip fracture is a traumatic event that causes major morbidity and mortality, particularly among elderly populations.1,2,3 Worldwide, the total number of hip fractures is anticipated to
exceed 6 million by a year.4 Previous studies have reported that the lifetime risk of hip fracture is
17.5% for women and 6% for men.5 Recently, the association between cardiovascular disease and
hip fracture has become a research topic of interest. Previous studies have proposed that several factors concurrently affect the vascular system and regulation of bone formation.Bone and vasculature are regulated by several shared factors, and calcification of the vascular walls resembles the bone formation process in numerous ways.9 A recent study reported that hip
fracture is associated with an increased risk of subsequent acute myocardial infraction.10 Stroke is
a well-known risk factor of hip fracture. However, only one study has assessed the risk of stroke among patients within one year of hip fracture. Long-term medication after hip fracture also plays a role in stroke risk; therefore, we also assessed the risk among patients prescribed various medications. This study investigates the frequency and risk of stroke after hip fracture by using a nationwide population-based cohort study.
Methods Data Source
In 1995, Taiwan launched the National Health Insurance (NHI) program, providing insurance coverage for approximately 99% of Taiwan’s population. The Bureau of NHI makes patient data electronically accessible through the NHI Research Database (NHIRD) project. The NHIRD contains comprehensive patient information, such as demographic characteristics, diagnoses, medical expenditures, and prescription claims, including the date and duration of prescriptions, type of medications, and dosages. Diseases are coded according to the International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM). Previous studies
have confirmed the high accuracy and validity of ICD-9-CM diagnoses in the NHIRD. In this study, we used the Longitudinal Health Insurance Database 2000 (LHID2000), which is a subset of the NHIRD, comprising patient data from 1996 to 2011. The LHID2000 comprises data on 1 000 000 beneficiaries randomly sampled from the original NHIRD. According to the National Health Research Institutes, no statistically significant difference exists in the age, sex, or
healthcare costs between the sample group in the LHID and all enrollees. The NHIRD contains depersonalized secondary data that were released for research purposes. This study was approved by the Institutional Review Board of China Medical University and Hospital (CMU-REC-101-012).
Study population
We conducted a retrospective cohort study from January 1, 2000, to December 31, 2010. We identified newly diagnosed hip fracture (ICD-9-CM Code 820) patients aged 20 years and older as the hip fracture cohort. The first hospitalization for hip fracture was selected as the index date. Patients those with a history of stroke prior to the index date, diagnosis of pathological fracture (ICD-9-CM Code 733.1), fractures from transport-related accidents (E800-E848), aged less than 20 years, or with incomplete demographic information were excluded from this study. Patients with no record of hip fracture were randomly selected from the LHID2000 and used as the comparison cohort and. Each hip fracture case was frequency-matched with 4 controls by sex, age (in 5-y bands), and index year. The same exclusion criteria were applied to the comparison cohort.
Baseline variables
We obtained baseline variable data including the patients’ age; sex; comorbidities of diabetes (ICD-9-CM Code 250), hypertension (ICD-9-CM Codes 401–405), hyperlipidemia (ICD-9-CM Code 272), osteoporosis (ICD-9-CM Code 733.0), coronary artery disease (CAD;
ICD-9-CM Codes 410–414), and heart failure (ICD-9-CM Code 428); and medication,
specifically, aspirin, clopidogrel, warfarin, proton pump inhibitors (PPIs), statins, estrogen (only for women), prednisolone, bisphosphonates, and antihypertensive agents (calcium channel blockers [CCBs], angiotensin-converting enzyme inhibitors [ACEIs], angiotensin II receptor blockers [ARBs], alpha blockers, beta blockers, and diuretics).
Outcome measurement
The endpoint of interest was set as the development of stroke (ICD-9-CM Codes 430–438). Stroke was classified into 2 subtypes; ischemic (ICD-9-CM Codes 433–438) and hemorrhagic (ICD-9-CM Codes 430–432). All patients were followed from the index date to the endpoint, withdrawal from the insurance program, or December 31, 2011, whichever was first.
Statistical analysis
SAS for Windows (Version 9.1.3, SAS Institute Inc., Cary, NC, USA) was used to perform all statistical analyses. A 2-tailed probability was considered statistically significant where P < .05. Distribution of sex, age (20–49, 50–64, 65–79, and ≤ 80 y), comorbidity, and medication was compared between the hip fracture cohort and the comparison cohort, and subsequently examined using the chi-square test and t test for categorical and continuous variables, respectively.
Subsequently, we plotted the cumulative incidence curves of stoke during the follow-up period by using the Kaplan–Meier method, and the differences between the 2 cohorts were examined using the log-rank test. The variable-specific (sex, age, comorbidity, and follow-up years) incidence densities of stroke were estimated for both cohorts. Univariable and multivariable Cox proportional hazards regression models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of stroke among the hip fracture cohort relative to that among the comparison cohort. The baseline characteristic variables (sex, age, comorbidities, and
the comorbidities in the multivariable model showed that diabetes, hypertension, and heart failure were significant,associated with stroke risk, we further analyzed to evaluate the interactive effect of diabetes, hypertension, and heart failure on stroke risk. In the multivariable model, diuretics and ARBs exhibited a statistically significant relationship with incidence of stroke. Subsequent data analysis was also performed to evaluate the interaction among hip fracture, diuretics, and ARB.
Results
This study examined a cohort of hip fracture (n = 6013) and nonhip-fracture (n = 23 802) patients (Table 1). Among the hip fracture patients, most were women (55.2%) and adults older than 65 years (76.5%). The mean age of the hip fracture cohort and the comparison cohort was 72.4 years (SD = 16.1) and 71.2 years (SD = 15.9), respectively. Patients with hip fracture exhibited a higher incidence of diabetes, hypertension, osteoporosis, CAD, and heart failure (P < .001). Compared with the comparison cohort, all medications were more prevalent among the hip fracture cohort at the baseline (P < .001). During the mean follow-up period for the hip fracture cohort (3.78 y) and the comparison cohort (4.86 y), the overall incidence of stroke per 1000 person-years was 35.6 and 20.8, respectively (Table 2). Figure 1 depicts the cumulative stroke incidence curve for the 2 cohorts. The figure shows that the incidence curve of the hip fracture cohort is significantly higher than that of the comparison cohort (log-rank test P < .001). After adjusting the model to control the effects of age, sex, and comorbidities (diabetes,
hypertension, hyperlipidemia, osteoporosis, CAD, and heart failure) and medications (aspirin, clopidogrel, warfarin, PPIs, statins, estrogen in women, prednisolone, bisphosphonates, CCBs, ACEIs, ARBs, alpha blockers, beta blockers, and diuretics), the hip fracture patients exhibited a 1.54-fold increased risk of stroke (95% CI = 1.42–1.67) compared with the comparison cohort. The hip fracture patients also exhibited higher incidences of ischemic and hemorrhagic stroke. In
both cohorts, stroke incidence was higher in women than in men. Compared with the comparison cohort, the relative incidence of stroke in the hip fracture cohort was significantly higher for both women (adjusted HR = 1.47, 95% CI = 1.32–1.63) and men (adjusted HR = 1.64, 95%
CI = 1.44–1.86). In both cohorts, the incidence of stroke increased in conjunction with age. The age-specific analysis results showed that the incidence of stroke development is higher in the hip fracture patients than in the comparison cohort for all age groups. Among patients with any comorbidity, the risk of stroke was 1.50-fold higher in the hip fracture cohort than in the comparison cohort (95% CI = 1.38–1.64). The highest risk occurred during the first year of the follow-up period (adjusted HR = 1.96, 95% CI = 1.67–2.28), reducing to 1.29 as the follow-up period increased to for 4 to 5 years of up. The risk persisted beyond the 5 years of follow-up.
Table 3 shows that the stroke incidence was considerably higher in patients with diabetes, hypertension, and heart failure. Compared with the patients without diabetes, hypertension, and heart failure, those with diabetes, hypertension, and heart failure exhibited an adjusted HR of 3.10 (95% CI = 2.47–3.90). Table 4 lists the interactive effect of hip fracture, diuretics, and ARBs on stroke risk. Compared with the comparison cohort who were not prescribed diuretics and ARBs, the hip fracture patients who were prescribed diuretics exhibited a significantly higher risk of stroke (adjusted HR = 3.28, 95% CI = 2.89–3.71), followed by those who were prescribed both diuretics and ARBs (adjusted HR = 2.92, 95% CI = 2.43–3.51).
Discussion
After adjustment for potential confounding factors, the results of this study indicated that hip fracture patients are at a 1.54-fold risk of developing stroke compared the comparison cohort. This finding is consistent with that reported in previous studies. However, Kang et al and Popa et al reported an increased risk of stroke within the first year following incidence of hip fracture.
Our study results showed that the risk of stroke can persist throughout and beyond a 5-year follow-up period. The highest risk of stroke was observed during a follow-up period of 1 year (adjusted HR = 1.96, 95% CI = 1.67–2.28), followed by 2 to 3 years (adjusted HR = 1.45), 4 to 5 years (adjusted HR = 1.29), and more than 5 years (adjusted HR = 1.46).
The cause of stroke occurrence in hip fracture patients remains unclear. Numerous factors might be involved in the association between hip fracture and stroke. Potential genetic factors include telomere length as well as specific genes involved in cellular mechanisms shared by vasculature and bone. Matrix proteins supporting bone, vessel walls, and the myocardium might be of particular relevance. Other potential factors include calcification regulatory hormones, gonadal steroids, proteins related to lipid metabolism, oxidative stress, and chronic inflammation. Physical inactivity, psychological distress, and pain are typical after incidence of hip fracture,20
and disruption or deterioration of preexisting cardiovascular risk can be triggered under such circumstances. Previous studies have reported that the systemic migration of emboli to the brain through intracardiac or extracardiac right-to-left shunts (resulting in stroke) occurs more
frequently than previously considered.21,22 In addition, the hospitalization and surgery required
for hip fracture treatment are associated with unfavorable physiological changes that exacerbate the predisposing factor in stroke patients.
In this study, the risk of stroke after hip fracture was more prominent among young patients, men, those using diuretics and ABRs, and patients with comorbidities. The higher risk observed for the presence of hip fracture and comorbid medical disorders might indicate that a synergistic effect exists between these risk factors. The incidence of stroke after hip fracture increased as age increased. However, the younger adults aged 20 to 49 years exhibited the greater risk of stroke compared to the middle-aged and older adults after adjusting for covariates. This might be because older adults have a higher proportion of comorbidities interacting with hip fracture,
leading to development of stroke. In addition, the relatively increased risk of younger age might contribute to the genetic factor. The relationship between sex and stroke risk remain
controversial. Antihypertensive medications were associated with an increased risk of hip fracture.25 The findings of this study also indicate that using diuretics and ABRs concurrently increases the risk of stroke, which might be related to the dehydration and hypercoagulative status of patients after hip fracture, which is a documented complication that can trigger a stroke.26 This study did not investigate the impact of the type of hip fracture, anesthesia, or
surgery. Dehydration is frequently observed in elderly patients; dehydration before surgery nearly quadrupled the number of postoperative complications following hip fracture surgery.27
Thus, awareness of the hydration status of patients is a crucial measure for mitigating the risk of subsequent complications. During acute and postoperative periods, embolic events from fat embolism, deep vein thrombosis, and pulmonary embolism are not uncommon in hip fracture patients.28 Our study shows that the highest risk of stroke is within the first year after hip fracture,
and the risk remains high throughout the following years, indicating the need for short-term prophylaxis for cerebrovascular event in primary care after fracture and long-term preventative measures.
The strength of this study is the use of a large population-based data set. The current cohort study confirms that hip fractures are associated with an increased risk of stroke development. However, several limitations must be considered when interpreting these findings. First, because a claims database was used, our study was unable to investigate the effects of various risk factors, such as body mass index, dietary habits, exercise capacity, and cigarette smoking status, in the regression model, which might have compromised our findings. Because nutritional supplements are not covered by the NHI program in Taiwan, information on vitamin D and calcium
comorbidity. Bisphosphonate is widely used in the treatment of osteoporosis and also after hip fracture. This study adjusted the risk between bisphosphonates and stroke. Although bisphosphate use was unrelated to stroke risk in our study, the cardiovascular safety of bisphosphonates for the treatment of osteoporosis remains a concern.29–32 Further research on the dosage and course of
various bisphosphonates, as well as the risk of stroke after hip fracture and surgery is warranted. After adjusting the regression model to control the effect of these cofounders, hip fracture remained independently associated with increased risk of stroke throughout follow-up.
In conclusion, hip fracture is independently associated with increased risk of developing stroke. In addition, the risk of stroke following incidence of hip fracture is more prominent in younger patients, men, those with cardiovascular comorbidities, and in patients using specific medication, such as diuretics and ABRs. Given the subsequent higher risk of stroke among patients with hip fracture, our study results indicate that physicians should be proactive to prevent strokes. A multidisciplinary approach, including medical, orthopedic, and rehabilitative collaboration is recommended to address both short-term and long-term stroke risk. Controlling cerebrovascular risks, early mobilization, hypertension medication adjustment, and adequate hydration can be pivotal in decreasing the risk of stroke after hip fracture.
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Table 1. Comparison of demographics and comorbidity between hip fracture patients and controls Hip fracture No(N=23802) Yes(N=6013) n % n % p-value Sex 0.53 Women 13022 54.7 3317 55.2 Men 10780 45.3 2696 44.8 Age, year 0.81 20-49 2680 11.3 670 11.1 50-64 2992 12.6 748 12.4 65-79 9354 39.3 2337 38.9 80+ 8776 36.9 2258 37.6 Mean (SD) 71.2 15.9 72.4 16.1 <0.001† Comorbidity Diabetes 3390 14.2 1368 22.8 <0.001 Hypertension 14096 59.2 3959 65.8 <0.001 Hyperlipidemia 6509 27.4 1457 24.2 <0.001 Osteoporosis 3614 15.2 1395 23.2 <0.001 CAD 7565 31.8 2059 34.2 <0.001 Heart failure 1975 8.30 689 11.5 <0.001 Medications Aspirin 11749 49.4 3559 59.2 <0.001 Clopidogrel 634 2.66 241 4.01 <0.001 Warfarin 400 1.68 135 2.25 0.003 PPIs 3608 15.2 1307 21.7 <0.001 Statins 3725 15.7 953 15.9 0.70
Estrogen (only women) 3246 13.6 762 12.7 0.05 Prednisolone 12779 53.7 3428 57.0 <0.001 Bisphosphonates 456 1.92 243 4.04 <0.001 Calcium channel blocker (CCB) 12231 51.4 3772 62.7 <0.001 ACEI 8127 34.1 2436 40.5 <0.001 ARB 4372 18.4 1326 22.1 <0.001 Alpha blocker 4380 18.4 1340 22.3 <0.001 Beta blocker 11182 47.0 3197 53.2 <0.001 Diuretics 9669 40.6 3300 54.9 <0.001
Table 2. Incidence and adjusted hazard ratio of stroke stratified by sex, age and comorbidity compared between with hip fracture and without hip fracture
Hip fracture
Compared to without Non- fracture
No Yes
Variables Case PY Rate# Case PY Rate# Crude HR
＊ (95% CI) Adjusted HR† (95% CI) All 2411 115760 20.8 809 22755 35.6 1.69(1.56, 1.83)*** 1.54(1.42, 1.67)*** Ischemic stroke 2128 18.4 722 31.7 1.71(1.57, 1.86)*** 1.55(1.42, 1.69)*** Hemorrhagic stroke 283 2.44 87 3.82 1.55(1.22, 1.98)*** 1.48(1.16, 1.89)*** Sex Women 1371 62397 22.0 469 12521 37.5 1.70(1.53, 1.89)*** 1.47(1.32, 1.63)*** Men 1040 53363 19.5 340 10234 33.2 1.68(1.49, 1.90)*** 1.64(1.44, 1.86)*** Age 20-49 19 16983 1.12 21 3947 5.32 4.76(2.56, 8.86)*** 2.31(1.14, 4.70)* 50-64 113 16956 6.66 64 3537 18.1 2.71(1.99, 3.69)*** 1.82(1.31, 2.52)*** 65-79 1025 49287 20.8 388 9159 42.4 2.07(1.84, 2.33)*** 1.75(1.55, 1.98)*** 80+ 1254 32533 38.6 336 6111 55.0 1.43(1.27, 1.61)*** 1.35(1.19, 1.52)*** Comorbidity No 355 42872 8.28 98 7547 13.0 1.56(1.25, 1.96)*** 1.25(0.99, 1.57) Yes 2056 72887 28.2 711 15207 46.8 1.65(1.52, 1.80)*** 1.50(1.38, 1.64)***
Follow time, years
≤1 484 23021 21.0 256 5346 47.9 2.28(1.96, 2.65)*** 1.96(1.67, 2.28)***
2-3 788 37484 21.0 272 7817 34.8 1.65(1.44, 1.90)*** 1.45(1.26, 1.67)***
4-5 547 25523 21.4 143 4766 30.0 1.40(1.16, 1.68)*** 1.29(1.07, 1.56)**
>5 592 29732 19.9 138 4826 28.6 1.44(1.19, 1.73)*** 1.46(1.20, 1.76)***
Adjusted HR† : multivariable analysis including age, sex, co-morbidities of diabetes, hypertension,
hyperlipidemia, osteoporosis, CAD, and heart failure, medications of aspirin, clopidogrel, warfarin, PPIs, statins, estrogen (only women), prednisolone, bisphosphonates, calcium channel blocker (CCB), ACEI, ARB, Alpha blocker, Beta blocker, and diuretics; *p<0.05, **p<0.01, ***p<0.001
Comorbidity‡: Only to have one of comorbidities (including diabetes, hypertension, hyperlipidemia,
Table 3. Development of stroke in patients with hip fracture by interaction of diabetes, hypertension, heart failure
stroke Adjusted HR†
Variables N n PY Rate# (95% CI)
Diabetes Hypertension Heart failure
- - - 10850 557 58578 9.51 1(Reference) + - - 647 66 2748 24.0 2.10(1.62, 2.71)*** - + - 12171 1629 54578 29.9 1.65(1.46, 1.86)*** - - + 240 20 934 21.4 1.14(0.73, 1.79) + + - 3483 540 13761 39.2 2.30(1.98, 2.66)*** + - + 23 2 77 26.0 1.66(0.41, 6.67) - + + 1796 293 6087 48.1 2.10(1.77, 2.49)*** + + + 605 113 1751 64.6 3.10(2.47, 3.90)***
N, sample size; n, events of stroke; Rate#, incidence rate, per 1,000 person-years; Adjusted HR†:
multivariable analysis including age, sex, co-morbidities of hyperlipidemia, osteoporosis, and CAD, medications of aspirin, clopidogrel, warfarin, PPIs, statins, estrogen (only women), prednisolone, bisphosphonates, calcium channel blocker (CCB), ACEI, Alpha blocker, and Beta blocker; *p<0.05, **p<0.01, ***p<0.001
Table 4. Development of stroke in patients with hip fracture associated with Medications of Diuretics and ARB
stroke Adjusted HR†
Variables N n PY Rate# (95% CI)
Hip fracture Diuretics ARB
- - - 12832 734 70166 10.5 1(Reference) + - - 2436 174 11379 15.3 1.51(1.28, 1.78)*** - + - 6598 1181 29901 39.5 2.19(1.98, 2.41)*** - - + 1301 90 5214 17.3 0.99(0.79, 1.24) + + - 2251 438 7702 56.9 3.28(2.89, 3.71)*** + - + 277 30 907 33.1 2.06(1.42, 2.97)*** - + + 3071 406 10479 38.8 1.85(1.61, 2.12)*** + + + 1049 167 2767 60.4 2.92(2.43, 3.51)***
N, sample size; n, events of stroke; Rate#, incidence rate, per 1,000 person-years; Adjusted HR†:
multivariable analysis including age, sex, co-morbidities of diabetes, hypertension, hyperlipidemia, osteoporosis, CAD, and heart failure, medications of aspirin, clopidogrel, warfarin, PPIs, statins, estrogen (only women), prednisolone, bisphosphonates, calcium channel blocker (CCB), ACEI, Alpha blocker, and Beta blocker; *p<0.05, **p<0.01, ***p<0.001
Figure 1. Cumulative incidence of stroke for patients with (dashed line) and without (solid line) hip fracture
