bmj open€¦ · risk of epilepsy in stroke patients receiving acupuncture treatment: a nationwide...
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Risk of epilepsy in stroke patients receiving acupuncture treatment: a nationwide retrospective matched-cohort
study
Journal: BMJ Open
Manuscript ID bmjopen-2015-010539
Article Type: Research
Date Submitted by the Author: 13-Nov-2015
Complete List of Authors: Weng, Shu-Wen; Taichung Hospital, Ministry of Health and Welfare, Department of Chinese Medicine Liao, Chien-Chang; Taipei Medical University Hospital, Department of
Anesthesiology Yeh, Chun-Chieh; University of Illinois, Department of Surgery Chen, Ta-Liang; Taipei Medical University Hospital, Department of Anesthesiology Lane, Hsin-Long; I-Shou University, School of Chinese Medicine for Post-Baccalaureate Lin, Jaung-Geng; China Medical University, School of Chinese Medicine Shih, Chun-Chuan; I-Shou University, School of Chinese Medicine for Post-Baccalaureate
<b>Primary Subject Heading</b>:
Complementary medicine
Secondary Subject Heading: Epidemiology, Public health, Neurology, Health services research
Keywords: Acupuncture, Stroke < NEUROLOGY, Epilepsy < NEUROLOGY
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Risk of epilepsy in stroke patients receiving acupuncture treatment: a nationwide
retrospective matched-cohort study
Short title: Acupuncture reduces post-stroke epilepsy
Shu-Wen Weng,1,2 Chien-Chang Liao,1,3,4,5 Chun-Chieh Yeh,6,7 Ta-Liang Chen,3,4,5,
Hsin-Long Lane,8 Jaung-Geng Lin,1 Chun-Chuan Shih8,9
1School of Chinese Medicine, China Medical University, Taichung, Taiwan
2Department of Chinese Medicine, Taichung Hospital, Ministry of Health and Welfare,
Taichung, Taiwan
3Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan
4School of Medicine, Taipei Medical University, Taipei, Taiwan
5Health Policy Research Center, Taipei Medical University Hospital, Taipei, Taiwan
6Department of Surgery, China Medical University Hospital, Taichung, Taiwan
7Department of Surgery, University of Illinois, Chicago, Illinois, USA
8School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung City,
Taiwan
9Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, Taipei
Medical University
*Chien-Chang Liao contributed equally with first author; Jaung-Geng Lin contributed equally
with the corresponding author.
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Correspondence:
Chun-Chuan Shih, MD, PhD
Associate professor
School of Chinese Medicine for Post-Baccalaureate, I-Shou University
No.8, Yida Rd., Jiaosu Village, Yanchao District, Kaohsiung 82445, Taiwan
Tel: 886-2-2765-1125
Fax: 886-2-2765-3230
E-mail: [email protected]; [email protected]; [email protected]
Abstract: 250 words; Text: 2184; Tables: 3; Figures: 1
Keywords: Stroke, epilepsy, acupuncture
List of abbreviations: CI=confidence intervals; HR=hazard ratio; ICD-9-CM=International
Classification of Diseases, 9th Revision, Clinical Modification; NHIRD=National Health
Insurance Research Database
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ABSTRACT
Objective: To investigate the risk of epilepsy for stroke patients with and without receiving of
acupuncture treatment.
Design: Retrospective cohort study.
Setting: This study was based on Taiwan’s National Health Insurance Research Database that
included stroke patients who hospitalized between January 1, 2000 and December 31, 2004.
Participants: We identified 60820 patients with new-diagnosed stroke hospitalization who
aged 20 years and older.
Primary and secondary outcome measures: We compared the incident epilepsy during the
follow-up period until the end of 2009 in stroke patients with and without receiving
acupuncture. The adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of epilepsy
associated with acupuncture were calculated in multivariate Cox proportional hazard
regressions.
Results: Stroke patients who received acupuncture treatment (11.2 per 1,000 person-years)
experienced a reduced incidence of epilepsy compared to those who did not receive
acupuncture treatment (13.4 per 1,000 person-years), with a HR of 0.81 (95% CI, 0.76 to 0.86)
after adjustment for sociodemographics and coexisting medical conditions. Acupuncture
treatment was associated with a decreased risk of epilepsy, particularly among stroke patients
aged 20-59 years and individuals with hemorrhagic stroke. The probability curve with
log-rank test indicated that stroke patients receiving acupuncture treatment experienced a
reduced probability of epilepsy compared with individuals who did not receive acupuncture
treatment during the follow-up period (p<0.0001).
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Conclusions: Stroke patients who received acupuncture treatment experienced a reduced risk
of epilepsy compared with those without receiving acupuncture treatment. However, these
protective effects associated with acupuncture treatment require further validation using
randomized clinical trials.
Key Words: Acupuncture, epilepsy, stroke, cohort study
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Strengths of this study
First, we used matching procedure with propensity score to reduce the confounding effects.
Second, the multivariate Cox proportional hazard models were use to control the residual
confounding bias. Third, our study had no selection bias because all hospitalized stroke
patients in 2000-2004 in Taiwan were analyzed.
Limitations of this study
First, our data lack of clinical risk scores (such as the National Institute of Health Stroke Scale
or the Barthel index), lesion characteristics (location or size), biochemical measures, and
patients’ lifestyles. Second, preventive administration of antiepileptic medications or other
rehabilitation programs were not considered during the follow-up period. Third, the validity
of diagnostic codes of diseases is also a limitation of the study. In addition, our study could
not validate the actual acupuncture points used in treatment. Finally, the mode of acupuncture
treatment for stroke patients varied among TCM physicians.
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INTRODUCTION
Stroke remains the leading cause of adult disability and death worldwide.[1,2]
Approximately global 5.8 million deaths were attributed to stoke and the one-year cost of
stroke is approximately 30,000 US dollars per patient in 2010 in countries worldwide.[2,3]
Given that strokes occur in 2.8% of adults in the United States, the economic burden of stroke
was $36.5 billion in 2010.[4] In Taiwan, the average of the first-year medical costs after
stroke was 5,679 US dollars per patient.[5] Epilepsy, depression, headache, acute myocardial
infarction, sleep disorders, pneumonia, gastrointestinal bleeding, urinary tract infection,
musculoskeletal pain, recurrent stroke, and post-stroke falls are common medical
complications observed after stroke.[6-8]
Acupuncture plays a major role in traditional Chinese medicine (TCM), and it is widely
used in many countries.[9] A previous study found that TCM is commonly used for stroke
patients in Asian countries,[10] and several investigations have demonstrated that acupuncture
treatment may improve dysphagia,[11] shoulder pain,[12] spasticity,[13] disability, and
quality of life in stroke patients.[14,15] Epilepsy frequently occurs after patients suffer from
hemorrhagic stroke, with an estimated prevalence ranging from 4.1% to 11.3%.[16,17] After
the first seizure, patients may develop recurrent seizures and exhibit increased fatality.[17,18]
Although acupuncture treatment is helpful and potentially reduces seizure frequency in
epilepsy patients,[19] limited information is available regarding whether acupuncture
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treatment is beneficial in reducing epilepsy in stroke patients.
Using the Taiwan National Health Insurance Research Database (NHIRD), we conducted a
nationwide, propensity score-matched, population-based, retrospective cohort study to
investigate the risk of epilepsy for stroke patients with and without receiving of acupuncture
treatment.
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METHODS
Source of data
Research data were obtained from reimbursement claims of the Taiwan National Health
Insurance Program, which was implemented in March 1995 and insures greater than 99% of
the 23 million Taiwan residents. The National Health Research Institute in Taiwan established
the National Health Insurance Research Database (NHIRD); this database records all
beneficiaries’ medical services, including inpatient and outpatient demographics, primary and
secondary diagnoses, procedures, prescriptions, and medical expenditures, for public research
interest. The validity of this database has been favorably evaluated, and research articles that
have used this database have been published in prominent scientific journals
worldwide.[10,20-23]
Ethical statements
The insurance reimbursement claims used in this study were from Taiwan’s National
Health Insurance Research Database. To ensure privacy, the patients were de-identified in the
electronic database. This study was evaluated and approved by the Institutional Review Board
of Taiwan’s National Health Research Institutes (NHIRD-100-122) and E-DA Hospital,
Kaohsiung, Taiwan (2014012). Informed consent was not required because the patients’
identities were decoded and scrambled. This study was conducted in accordance with the
Declaration of Helsinki.[10,20-23]
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Study design
We identified patients ≥20 years in age with newly diagnosed stroke who were hospitalized
between 2000 and 2004 as eligible study subjects. Each subject either received follow-up
from the index date until December 31, 2009 or was censored. To confirm that all stroke
patients in our study were incident cases, only new-onset stroke cases were included in this
study; patients with a diagnosis of stroke within a 4-year period prior to the study were not
included. Overall, we identified 226,699 new-onset stroke survivors ≥20 years in age among
the 23 million people in Taiwan; 37,687 of these patients had received at least two courses
(one course including six consecutive treatments) of acupuncture treatment after being
discharged. We compared stroke patients receiving at least two courses of acupuncture
treatment with patients not receiving acupuncture treatment. We randomly selected stroke
patients who had not received acupuncture treatment as controls; these patients were matched
according to age, sex, low income, urbanization, intensive care unit stay, neurosurgery, and
coexisting medical conditions, such as diabetes mellitus, hypertension, hyperlipidemia, head
injury, malignant neoplasm of brain, mental disorder, Parkinson’s disease, and stroke subtype.
Criteria and definition
We defined stroke according to the International Classification of Diseases, 9th Revision,
Clinical Modification (ICD-9-CM 430-438). The eligible study participants included 226,699
patients in the stroke cohort. Coexisting medical conditions included diabetes (ICD-9-CM
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250), hypertension (ICD-9-CM 401-405), hyperlipidemia (ICD-9-CM 272.0–272.4), mental
disorder (ICD-9-CM 290-319), head injury (ICD-9-CM 800-805, 850-854), malignant
neoplasm of brain (ICD-9-CM 191), Parkinson’s disease (ICD-9-CM 332), and Alzheimer’s
disease (ICD-9-CM 331). Regular renal dialysis (including hemodialysis and/or peritoneal
dialysis), which was identified from the individuals’ health reimbursement claims, was also
considered a medical condition among stroke patients in this study. Under the condition of not
experiencing previous epilepsy before stroke admission through January 1, 1996, cases of
newly diagnosed epilepsy (ICD-9-CM 345) were further defined as at least one medical visit
(including inpatient and outpatient care) with a physician’s diagnosis after stroke admission.
Statistical analysis
We conducted our analysis using a propensity score matched-pair procedure. A
nearest-neighbor algorithm was applied to construct matched pairs, assuming that a
proportion of 0.95 to 1.0 is perfect. The follow-up time, in person-years, was calculated for
each subject until the diagnosis of epilepsy or until being censored because of death,
withdrawal from the insurance system, or loss to follow-up. The outcome of this study was
the person-years of new-onset epilepsy for stroke patients. This study’s objective was to
determine whether using acupuncture was associated with reduced the incidence of epilepsy
in stroke patients.
We first compared the distribution of sociodemographic factors and coexisting medical
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conditions between the stroke cohorts with and without acupuncture treatment using
chi-square tests and t-tests. We calculated hazard ratios (HRs) with 95% confidence intervals
(CIs) for the risk of epilepsy after stroke associated with acupuncture treatment, adjusting for
age, sex, low income, and urbanization in multivariate Cox proportional hazard regression
models. The duration of observation for each person was calculated until the individual was
diagnosed with epilepsy or censored for death, migration, or discontinued enrollment in the
insurance system. Adjusted HRs with 95% CIs for epilepsy associated with acupuncture
treatment were calculated using multivariate Cox proportional hazard analyses with the
variables categorized. We also performed age- and sex-stratified analyses to investigate the
association between epilepsy and the use of acupuncture. SAS software version 9.1 (SAS
Institute, Inc.) was used for data analyses with a two-tailed probability, and P<.05 was
considered statistically significant.
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RESULTS
After the propensity score matching procedure, no significant differences in sex, age, stroke
subtype, low income, urbanization, coexisting medical condition, ICU stay, neurosurgery, or
length of stay were noted between stroke patients with and without acupuncture treatment
(Table 1). Compared to stroke patients who did not receive acupuncture treatment, stroke
patients receiving acupuncture treatment exhibited a reduced epilepsy incidence (7.5% vs.
5.5%, p<0.0001).
After adjustment for sex, age, stroke subtype, low income, urbanization, coexisting medical
condition, ICU stay, neurosurgery, and length of stay (Table 2), stroke patients receiving
acupuncture treatment exhibited a decreased risk of epilepsy (HR=0.81; 95% CI 0.76 to 0.86)
compared with those not receiving acupuncture treatment. The association between
acupuncture treatment and reduced risk of post-stroke epilepsy was significant in men
(HR=0.86; 95% CI 0.79 to 0.93) and women (HR=0.74; 95% CI 0.69 to 0.82) 20 to 59 years
of age as well as in individuals who had suffered from hemorrhagic stroke (HR=0.70; 95% CI
0.61 to 0.80). The HR values of post-stroke epilepsy were 0.21 (95% CI 0.10 to 0.43), 0.61
(95% CI 0.43 to 0.85), 0.61 (95% CI 0.51 to 0.73), and 0.72 (95% CI 0.63 to 0.83) in stroke
patients aged 20-29 years, 30-39 years, 40-49 years, and 50-59 years, respectively.
As shown in Table 2, patients who had suffered from hemorrhagic stroke and received
acupuncture treatment exhibited a decreased risk of post-stroke epilepsy (HR=0.70; 95% CI
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0.61 to 0.80). Among stroke patients, the risk of epilepsy exhibited a dose-dependent decrease
with increasing use of acupuncture treatment (Table 3). Figure 1 shows that the probability of
epilepsy in patients receiving acupuncture was reduced compared to that in patients not
receiving acupuncture.
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DISCUSSION
In this nationwide, propensity score-matched, retrospective cohort study, we observed that
stroke patients receiving acupuncture treatment exhibited a significantly lower risk of
epilepsy during the follow-up period compared to those not receiving acupuncture treatment.
A decreased risk of epilepsy after receiving acupuncture treatment was exclusively noted only
among hemorrhagic stroke patients 20 to 59 years of age. To our knowledge, this study is the
first to report the association between using acupuncture and reduced risk of post-stroke
epilepsy.
Older age, male sex, urbanization, hypertension, diabetes mellitus, mental disorders,
Parkinson’s disease and Alzheimer’s disease are known risk factors associated with
stroke.[24,25] These sociodemographics and coexisting medical conditions are also
associated with epilepsy.[6-28] Neurosurgery, ICU stay, and length of hospital stay have also
been shown to exhibit impacts on post-stroke epilepsy.[7,29] To reduce bias, we used
propensity score matching and multivariate regression to control for potential confounders.
Our study demonstrated that acupuncture treatment is associated with a decreased risk of
epilepsy among male and female stroke patients aged 20 to 59 and among those who have
experienced hemorrhagic stroke. Age and sex have been previously shown to determine the
medical conditions and complications of individuals suffering from stroke.[20] For instance,
older populations exhibit an increased mortality rate and poorer outcomes after stroke.[30]
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Young and middle-aged adults have less coexisting medical conditions; have better
knowledge, attitudes, and practice; and more commonly use TCM or acupuncture treatment
compared with older individuals.[10,31] These findings may partly explain why we observed
enhanced effects of acupuncture treatment on decreasing the risk of post-stroke epilepsy in
young and middle-aged adults.
The incidence of post-stroke epilepsy varied based on the stroke type.[16,32] Consistent
with previous reports,[16,17] the present study also demonstrated that patients who
experienced hemorrhagic stroke exhibited an increased risk for developing seizures compared
to those who experienced ischemic stroke or other stroke subtypes. Nevertheless, our
investigation indicated the beneficial effects of acupuncture treatment in reducing the risk of
epilepsy for patients with every stroke subtype.
Acupuncture treatment is one option among rehabilitation programs,[33] particularly for
stroke patients.[34] We propose three possible explanations for the association between
acupuncture treatment and the decreased risk of post-stroke epilepsy that was demonstrated in
this study. First, acupuncture intervention involves multiple levels of differential activities
over a wide range of brain networks.[35] and this modulation and sympathovagal response
may relate to acupuncture analgesia and other potential therapeutic effects.[35] Second,
depression is a frequent co-existing condition in stroke patients. Indeed, a meta-analysis
reported that acupuncture exhibits a beneficial effect on patients with depression.[36] Stroke
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patients with coexisting medical conditions, such as dementia or Alzheimer’s disease, are also
more likely to develop epilepsy,[37] and an interventional trial reported that acupuncture
treatment potentially improves cognitive function and quality of life in vascular dementia
patients.[38] Third, stroke patients who receive acupuncture treatment may possess more
knowledge about and better attitudes toward physical rehabilitation, which are helpful in
reducing post-stroke epilepsy, compared to patients not receiving acupuncture treatment.
The first advantage of this study was its large sample size and reduced selection bias.
Second, our study consisted of a retrospective cohort design using the NHIRD; this design
provides stronger causal inference than case-control and cross-sectional designs. Third, to
eliminate the interference of sociodemographics and coexisting medical conditions between
stroke patients receiving acupuncture treatment and those not receiving such treatment, we
used a propensity score matched-pair procedure to select acupuncture and non-acupuncture
treatment controls. To control for residual confounding effects in the association between a
decreased risk of post-stroke epilepsy and acupuncture treatment, we applied multivariable
Cox proportional hazard models to calculate adjusted HRs and 95% CIs of epilepsy
associated with acupuncture treatment. Finally, immortal time in observational studies may
bias the results in favor of the treatment group, thereby overestimating the beneficial effects.
To reduce such bias, we calculated person-years by correcting for immortal time in the
acupuncture treatment group.
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Nevertheless, this study had certain limitations. First, we used insurance claims data, which
lack information on clinical risk scores (such as the National Institute of Health Stroke Scale
or the Barthel index), lesion characteristics (location or size), biochemical measures, and
patients’ lifestyles, which have been reported as predictors of post-stroke epilepsy. Thus, this
study does not provide information regarding the severity-dependent relationship between
epilepsy and stroke. Second, preventive administration of antiepileptic medications or other
rehabilitation programs were not considered during the follow-up period. Thus, we were
unable to evaluate the influence of these factors on the association between acupuncture and
the decreased risk of post-stroke epilepsy. Third, although the accuracy of diagnosis codes in
the database has been validated in previous studies,[10] the validity of co-morbidity codes is
one potential limitation of the study. The prevalence of epilepsy may also have been
underestimated, given that patients experiencing mild symptoms may not seek medical
treatment; however, these effects appear minimal in our population-based study. In addition,
our study could not validate the actual acupuncture points used in treatment, given the limited
information provided by the reimbursement claims of Taiwan’s NHIRD. Finally, the mode of
acupuncture treatment for stroke patients varied among TCM physicians. Thus, we could not
confirm that all TCM physicians performed the same procedures and used the same
acupuncture points for stroke patients.
In conclusion, stroke patients receiving acupuncture treatment exhibited a reduced risk of
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epilepsy compared to patients not receiving acupuncture treatment. The association between
decreased epilepsy risk and acupuncture use was observed in men, women, younger adults,
and patients suffering from hemorrhagic stroke. However, this associated protective effect
must be further assessed in randomized clinical trials to provide direct evidence regarding the
effectiveness and mechanisms of acupuncture treatment on post-stroke epilepsy.
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injuries and risk factors study. Eur J Intern Med 2014;25:1-5.
2. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes
of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden
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3. Luengo-Fernandez R, Gray AM, Rothwell PM. Costs of stroke using patient-level data: a
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a report from the American Heart Association. Circulation 2014;129:e28-292.
5. Lee HC, Chang KC, Huang YC, et al. Readmission mortality, and first-year medical costs
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7. Ingeman A, Andersen G, Hundborg HH, et al. In-hospital medical complications, length
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8. Tong X, Kuklina EV, Gillespie C, et al. Medical complications among hospitalizations for
ischemic stroke in the United States from 1998 to 2007. Stroke 2010;41:980-6.
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United States, 2007. J Altern Complement Med 2014;20:32-9.
10. Liao CC, Lin JG, Tsai CC, et al. An investigation of the use of traditional Chinese
medicine in stroke patients in Taiwan. Evid Based Complement Alternat Med
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11. Long YB, Wu XP. A meta-analysis of the efficacy of acupuncture in treating dysphagia in
patients with a stroke. Acupunct Med. 2012;30:291-7.
12. Lee JA, Park SW, Hwang PW, et al. Acupuncture for shoulder pain after stroke: a
systematic review. J Altern Complement Med. 2012;18:818-23.
13. Wayne PM, Krebs DE, Macklin EA, et al. Acupuncture for upper-extremity rehabilitation
in chronic stroke: a randomized sham-controlled study. Arch Phys Med Rehabil
2005;86:2248-55.
14. Shen PF, Kong L, Ni LW, et al. Acupuncture intervention in ischemic stroke: a
randomized controlled prospective study. Am J Chin Med 2012;40:685-93.
15. Wu P, Mills E, Moher D, et al. Acupuncture in poststroke rehabilitation: a systematic
review and meta-analysis of randomized trials. Stroke 2010;41:e171-9.
16. Labovitz DL, Hauser WA, Sacco RL. Prevalence and predictors of early seizure and status
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17. Arntz R, Rutten-Jacobs L, Maaijwee N, et al. Post-stroke epilepsy in young adults: a
long-term follow-up Study. PLoS One 2013;8:e55498.
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18. Knake S, Rochon J, Fleischer S, et al. Status epilepticus after stroke is associated with
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19. Cheuk DKL, Wong V. Acupuncture for epilepsy. Cochrane Database Syst Rev
2008;4:CD005062.
20. Liao CC, Su TC, Sung FC, et al. Does hepatitis C virus infection increase risk for stroke?
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21. Yeh CC, Chen TL, Hu CJ, et al. Risk of epilepsy after traumatic brain injury: a
retrospective population-based cohort study. J Neurol Neurosurg Psychiatry
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22. Liao CC, Shen WW, Chang CC, et al. Surgical adverse outcomes in patients with
schizophrenia: a population-based study. Ann Surg 2013;257:433-8.
23. Liao CC, Lin CS, Shih CC, et al. Increased risk of fracture and postfracture adverse events
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24. Peters SA, Huxley RR, Woodward M. Comparison of the sex-specific associations
between systolic blood pressure and the risk of cardiovascular disease: a systematic
review and meta-analysis of 124 cohort studies, including 1.2 million individuals. Stroke
2013;44:2394-2401.
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25. Kumar S, Selim MH, Caplan LR. Medical complications after stroke. Lancet Neurol
2010;9:105-18.
26. De Herdt V, Dumont F, Hénon H, et al. Early seizures in intracerebral hemorrhage:
incidence, associated factors, and outcome. Neurology 2011;77:1794-1800.
27. Roivanen R, Haapaniemi E, Putaala J, et al. Young adult ischaemic stroke related acute
symptomatic and late seizures: risk factors. Eur J Neurol 2013;20:1247-55.
28. Addo J, Ayerbe L, Mohan KM, et al. Socioeconomic status and stroke: an updated review.
Stroke 2012;43:1186-91.
29. Burneo JG, Fang J, Saposnik G. Impact of seizures on morbidity and mortality after stroke:
a Canadian multi-centre cohort study. Eur J Neurol 2010;17:52-8.
30. van Wijk I, Kappelle LJ, van Gijn J, et al. Long-term survival and vascular event risk after
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2005;365:2098-104.
31. Shih CC, Liao CC, Su YC, et al. Gender Differences in Traditional Chinese Medicine Use
among Adults in Taiwan. PLoS One 2012;7:e32540.
32. Beghi E, D'Alessandro R, Beretta S, et al. Incidence and predictors of acute symptomatic
seizures after stroke. Neurology 2011;77:1785-93.
33. Wong V, Cheuk DK, Lee S, et al. Acupuncture for acute management and rehabilitation
of traumatic brain injury. Eur J Phys Rehabil Med 2012;48:71-86.
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34. Yam W, Wilkinson JM. Is acupuncture an acceptable option in stroke rehabilitation? A
survey of stroke patients. Complement Ther Med 2010;18:143-9.
35. Li QQ, Shi GX, Xu Q, et al. Acupuncture effect and central autonomic regulation. Evid
Based Complement Alternat Med 2013;2013:267959.
36. Wang H, Qi H, Wang BS, et al. Is acupuncture beneficial in depression: a meta-analysis
of 8 randomized controlled trials? J Affect Disord 2008;111:125-34.
37. Imfeld P, Bodmer M, Schuerch M, et al. Seizures in patients with Alzheimer's disease or
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38. Shi GX, Liu CZ, Li QQ, et al. Influence of acupuncture on cognitive function and markers
of oxidative DNA damage in patients with vascular dementia. J Tradit Chin Med
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Acknowledgments: This study is based in part on data obtained from the National Health
Insurance Research Database provided by the Bureau of National Health Insurance, Ministry
of Health and Welfare, and managed by the National Health Research Institutes. The
interpretation and conclusions contained herein do not represent those of the Bureau of
National Health Insurance, Ministry of Health and Welfare, or National Health Research
Institutes.
Competing interests: None.
Financial support: This research was supported in part by Shuang Ho Hospital, Taipei
Medical University (104TMU-SHH-23), and by Taiwan’s Ministry of Science and
Technology (MOST104-2314-B-038-027-MY2; MOST103-2320-B-214-010-MY2;
NSC102-2314-B-038-021-MY3).
Contributorship Statement: The conception or design of the work: SWW, CCL, CCS; The
acquisition and analysis of data: CCL, HLL, CCS; Interpretation of data: SWW, CCL, CCY,
TLC, HLL, JGL, CCS; Drafting the work: SWW, CCL; Revising it critically for important
intellectual content: SWW, CCL, CCY, TLC, HLL, JGL, CCS; Final approval of the version
to be published: SWW, CCL, CCY, TLC, HLL, JGL, CCS; Agreement to be accountable for
all aspects of the work in ensuring that questions related to the accuracy or integrity of any
part of the work are appropriately investigated and resolved: SWW, CCL, CCY, TLC, HLL,
JGL, CCS.
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Data sharing statement: dataset available from the Taiwan’s National Health Research
Institutes (http://nhird.nhri.org.tw/index1.php).
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Fig 1 The epilepsy-free proportions estimated for post-stroke patients with and without
acupuncture treatment using the Kaplan-Meier method.
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Table 1 Baseline Characteristics of Stroke Patients With and Without Acupuncture
Treatment
Acupuncture use
No (N = 30410) Yes (N = 30410) P value
n (%) n (%)
Female 13615 (44.8) 13615 (44.8) 1.0000
Age, years 1.0000
20-29 186 (0.6) 186 (0.6)
30-39 723 (2.4) 723 (2.4)
40-49 3441 (11.3) 3441 (11.3)
50-59 6582 (21.6) 6582 (21.6)
60-69 9843 (32.4) 9843 (32.4)
70-79 8156 (26.8) 8156 (26.8)
≥80 1479 (4.9) 1479 (4.9)
Stroke subtype 1.0000
Hemorrhage 4014 (13.2) 4014 (13.2)
Ischemic 16597 (54.6) 16597 (54.6)
Other 9799 (32.2) 9799 (32.2)
Low income 546 (1.8) 546 (1.8) 1.0000
Urbanization 1.0000
Low 1108 (3.6) 1108 (3.6)
Moderate 10302 (33.9) 10302 (33.9)
High 19000 (62.5) 19000 (62.5)
Coexisting medical condition
Hypertension 22458 (73.9) 22458 (73.9) 1.0000
Mental disorder 12570 (41.3) 12570 (41.3) 1.0000
Diabetes mellitus 11755 (38.7) 11755 (38.7) 1.0000
Hyperlipidemia 5739 (18.9) 5739 (18.9) 1.0000
Head injury 3441 (11.3) 3441 (11.3) 1.0000
Parkinson’s disease 1389 (4.6) 1389 (4.6) 1.0000
Alzheimer’s disease 51 (0.2) 51 (0.2) 1.0000
Brain cancer 36 (0.1) 36 (0.1) 1.0000
ICU stay 3465 (11.4) 3465 (11.4) 1.0000
Neurosurgery 850 (2.8) 850 (2.8) 1.0000
Length of stay, days 7.74±6.12 7.77±6.15 0.4919
ICU = intensive care unit.
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Table 2 Incidence and Risk of Epilepsy for Stroke Patients With and Without Acupuncture Treatment by Age, Sex, and Stroke
Type
No acupuncture Acupuncture use
n Events Person-year Incidence n Events Person-year Incidence HR (95% CI)
All* 30,410 2,270 169,235 13.4 30,410 1,663 147,859 11.2 0.81 (0.76-0.86)
Female 13,615 907 79,068 11.5 13,615 592 67,584 8.0 0.74 (0.69-0.82)
Male 16,795 1,363 90,167 15.1 16,795 1,071 80,275 13.3 0.86 (0.79-0.93)
Age, years‡
20-29 186 38 1,000 38.0 186 9 913 9.9 0.21 (0.10-0.43)
30-39 723 89 4,046 22.0 723 56 3,474 16.1 0.61 (0.43-0.85)
40-49 3,441 346 20,733 16.7 3,441 199 17,419 11.4 0.61 (0.51-0.73)
50-59 6,582 489 39,817 12.3 6,582 320 33,835 9.5 0.72 (0.63-0.83)
60-69 9,843 654 56,976 11.5 9,843 537 48,718 11.0 0.95 (0.84-1.06)
70-79 8,156 566 40,936 13.8 8,156 457 37,720 12.1 0.90 (0.79-1.02)
≥80 1,479 88 5,726 15.4 1,479 85 5,779 14.7 1.04 (0.77-1.40)
Type of stroke§
Hemorrhage 4,014 559 20,851 26.8 4,014 389 19,766 19.7 0.70 (0.61-0.80)
Ischemic 16,597 1,137 91,134 12.5 16,597 934 80,840 11.6 0.93 (0.85-1.01)
Other 9,799 574 57,250 10.0 9,799 340 47,253 7.2 0.70 (0.61-0.81)
CI = confidence interval, HR = hazard ratio. *Adjusted for sociodemographics, hypertension, mental disorders, diabetes, hyperlipidemia, traumatic brain injury, Parkinson’s
disease, Alzheimer’s disease, brain cancer, type of stroke, admission to intensive care unit, neurosurgery, and length of stay. †Adjusted for covariates in the full model with the exception of sex. ‡Adjusted for covariates in the full model with the exception of age. §Adjusted for covariates in the full model with the exception of stroke subtype.
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Table 3 Risk of Epilepsy and Number of Acupuncture Treatment Packages in Stroke Patients
Number of packages n Events Person-years Incidence HR (95% CI)*
0 30410 2270 169235 10.9 1.00 (reference)
2 6118 316 25653 12.3 0.81 (0.72-0.91)
3 4051 235 17829 13.2 0.87 (0.76-0.99)
4 2888 157 13536 11.6 0.78 (0.66-0.91)
5 2203 114 10676 10.7 0.71 (0.59-0.86)
6 1673 82 8005 10.2 0.70 (0.56-0.87)
≥7 13477 759 72160 10.5 0.69 (0.63-0.74)
CI = confidence interval, HR = hazard ratio. *Adjusted for sociodemographics, hypertension, mental disorders, diabetes, hyperlipidemia,
traumatic brain injury, Parkinson’s disease, Alzheimer’s disease, brain cancer, type of stroke,
admission to intensive care unit, neurosurgery, and length of stay.
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STROBE 2007 (v4) checklist of items to be included in reports of observational studies in epidemiology*
Checklist for cohort, case-control, and cross-sectional studies (combined)
Section/Topic Item # Recommendation Reported on page #
Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the abstract 1, 3
(b) Provide in the abstract an informative and balanced summary of what was done and what was found 3
Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 5
Objectives 3 State specific objectives, including any pre-specified hypotheses 6
Methods
Study design 4 Present key elements of study design early in the paper 7
Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data
collection 7, 8
Participants 6 (a) Cohort study—Give the eligibility criteria, and the sources and methods of selection of participants. Describe
methods of follow-up
Case-control study—Give the eligibility criteria, and the sources and methods of case ascertainment and control
selection. Give the rationale for the choice of cases and controls
Cross-sectional study—Give the eligibility criteria, and the sources and methods of selection of participants
8, 9
(b) Cohort study—For matched studies, give matching criteria and number of exposed and unexposed
Case-control study—For matched studies, give matching criteria and the number of controls per case 8, 9
Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic
criteria, if applicable 8, 9
Data sources/ measurement 8* For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe
comparability of assessment methods if there is more than one group 8, 9
Bias 9 Describe any efforts to address potential sources of bias 9, 10
Study size 10 Explain how the study size was arrived at 9, 10
Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen
and why 9, 10
Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding 9, 10
(b) Describe any methods used to examine subgroups and interactions 9, 10
(c) Explain how missing data were addressed 9, 10
(d) Cohort study—If applicable, explain how loss to follow-up was addressed
Case-control study—If applicable, explain how matching of cases and controls was addressed 9, 10
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Cross-sectional study—If applicable, describe analytical methods taking account of sampling strategy
(e) Describe any sensitivity analyses 9, 10
Results
Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility,
confirmed eligible, included in the study, completing follow-up, and analysed 11, 12
(b) Give reasons for non-participation at each stage 11, 12
(c) Consider use of a flow diagram 11, 12
Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and
potential confounders 11, 12
(b) Indicate number of participants with missing data for each variable of interest 11, 12
(c) Cohort study—Summarise follow-up time (eg, average and total amount) 11, 12
Outcome data 15* Cohort study—Report numbers of outcome events or summary measures over time 11, 12
Case-control study—Report numbers in each exposure category, or summary measures of exposure 11, 12
Cross-sectional study—Report numbers of outcome events or summary measures 11, 12
Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95%
confidence interval). Make clear which confounders were adjusted for and why they were included 11, 12
(b) Report category boundaries when continuous variables were categorized 11, 12
(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period 11, 12
Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses 11, 12
Discussion
Key results 18 Summarise key results with reference to study objectives 13
Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction
and magnitude of any potential bias 16
Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results
from similar studies, and other relevant evidence 13-17
Generalisability 21 Discuss the generalisability (external validity) of the study results 13-17
Other information
Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on
which the present article is based 18
*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.
Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE
checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at
http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org.
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Risk of epilepsy in stroke patients receiving acupuncture treatment: a nationwide retrospective matched-cohort
study
Journal: BMJ Open
Manuscript ID bmjopen-2015-010539.R1
Article Type: Research
Date Submitted by the Author: 07-Apr-2016
Complete List of Authors: Weng, Shu-Wen; Taichung Hospital, Ministry of Health and Welfare, Department of Chinese Medicine Liao, Chien-Chang; Taipei Medical University Hospital, Department of
Anesthesiology Yeh, Chun-Chieh; University of Illinois, Department of Surgery Chen, Ta-Liang; Taipei Medical University Hospital, Department of Anesthesiology Lane, Hsin-Long; I-Shou University, School of Chinese Medicine for Post-Baccalaureate Lin, Jaung-Geng; China Medical University, School of Chinese Medicine Shih, Chun-Chuan; I-Shou University, School of Chinese Medicine for Post-Baccalaureate
<b>Primary Subject Heading</b>:
Complementary medicine
Secondary Subject Heading: Epidemiology, Public health, Neurology, Health services research
Keywords: Acupuncture, Stroke < NEUROLOGY, Epilepsy < NEUROLOGY
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Risk of epilepsy in stroke patients receiving acupuncture treatment: a nationwide
retrospective matched-cohort study
Short title: Acupuncture reduces post-stroke epilepsy
Shu-Wen Weng,1,2
Chien-Chang Liao,1,3,4,5
Chun-Chieh Yeh,6,7
Ta-Liang Chen,3,4,5
,
Hsin-Long Lane,8 Jaung-Geng Lin,
1 Chun-Chuan Shih
8,9
1School of Chinese Medicine, College of Chinese Medicine, China Medical University,
Taichung, Taiwan
2Department of Chinese Medicine, Taichung Hospital, Ministry of Health and Welfare,
Taichung, Taiwan
3Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan
4Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical
University, Taipei, Taiwan
5Health Policy Research Center, Taipei Medical University Hospital, Taipei, Taiwan
6Department of Surgery, China Medical University Hospital, Taichung, Taiwan
7Department of Surgery, University of Illinois, Chicago, Illinois, USA
8School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung City,
Taiwan
9Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, Taipei
Medical University
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*Chien-Chang Liao contributed equally with first author; Jaung-Geng Lin contributed equally
with the corresponding author.
Correspondence:
Chun-Chuan Shih, MD, PhD
Associate professor
School of Chinese Medicine for Post-Baccalaureate, I-Shou University
No.8, Yida Rd., Jiaosu Village, Yanchao District, Kaohsiung 82445, Taiwan
Tel: 886-2-2765-1125
Fax: 886-2-2765-3230
E-mail: [email protected]; [email protected]; [email protected]
Abstract: 250 words; Text: 2184; Tables: 3; Figures: 1
Keywords: Stroke, epilepsy, acupuncture
List of abbreviations: CI=confidence intervals; HR=hazard ratio; ICD-9-CM=International
Classification of Diseases, 9th Revision, Clinical Modification; NHIRD=National Health
Insurance Research Database
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ABSTRACT
Objective: To investigate the risk of epilepsy for stroke patients with and without receiving of
acupuncture treatment.
Design: Retrospective cohort study.
Setting: This study was based on Taiwan’s National Health Insurance Research Database that
included stroke patients who hospitalized between January 1, 2000 and December 31, 2004.
Participants: We identified 42040 patients with new-diagnosed stroke hospitalization who
aged 20 years and older.
Primary and secondary outcome measures: We compared the incident epilepsy during the
follow-up period until the end of 2009 in stroke patients with and without receiving
acupuncture. The adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of epilepsy
associated with acupuncture were calculated in multivariate Cox proportional hazard
regressions.
Results: Stroke patients who received acupuncture treatment (11.2 per 1,000 person-years)
experienced a reduced incidence of epilepsy compared to those who did not receive
acupuncture treatment (13.4 per 1,000 person-years), with a HR of 0.81 (95% CI, 0.76 to 0.86)
after adjustment for sociodemographics and coexisting medical conditions. Acupuncture
treatment was associated with a decreased risk of epilepsy, particularly among stroke patients
aged 20-69 years. The probability curve with log-rank test indicated that stroke patients
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receiving acupuncture treatment experienced a reduced probability of epilepsy compared with
individuals who did not receive acupuncture treatment during the follow-up period
(p<0.0001).
Conclusions: Stroke patients who received acupuncture treatment experienced a reduced risk
of epilepsy compared with those without receiving acupuncture treatment. However, these
protective effects associated with acupuncture treatment require further validation using
randomized clinical trials.
Key Words: Acupuncture, epilepsy, stroke, cohort study
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Strengths of this study
(1) We used matching procedure with propensity score to reduce the confounding effects.
(2) The multivariate Cox proportional hazard models were use to control the residual
confounding bias.
(3) Our study had no selection bias because all hospitalized stroke patients in 2000-2004 in
Taiwan were analyzed.
Limitations of this study
(1) Our data lack of clinical risk scores, lesion characteristics, biochemical measures, and
lifestyles of stroke patients.
(2) Preventive administration of antiepileptic medications or other rehabilitation programs
were not considered during the follow-up period.
(3) The validity of diagnostic codes of diseases is also a limitation of the study.
(4) Our study could not validate the actual acupuncture points used in treatment.
(5) The mode of acupuncture treatment for stroke patients varied among TCM physicians.
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INTRODUCTION
Stroke remains the leading cause of adult disability and death worldwide.[1,2]
Approximately global 5.8 million deaths were attributed to stoke and the one-year cost of
stroke is approximately 30,000 US dollars per patient in 2010 in countries worldwide.[2,3]
Given that strokes occur in 2.8% of adults in the United States, the economic burden of stroke
was $36.5 billion in 2010.[4] In Taiwan, the average of the first-year medical costs after
stroke was 5,679 US dollars per patient.[5] Epilepsy, depression, headache, acute myocardial
infarction, sleep disorders, pneumonia, gastrointestinal bleeding, urinary tract infection,
musculoskeletal pain, recurrent stroke, and post-stroke falls are common medical
complications observed after stroke.[6-8]
Acupuncture plays a major role in traditional Chinese medicine (TCM), and it is widely
used in many countries.[9] A previous study found that TCM is commonly used for stroke
patients in Asian countries,[10] and several investigations have demonstrated that acupuncture
treatment may improve dysphagia,[11] shoulder pain,[12] spasticity,[13] disability, and
quality of life in stroke patients.[14,15] Epilepsy frequently occurs after patients suffer from
hemorrhagic stroke, with an estimated prevalence ranging from 4.1% to 11.3%.[16,17] After
the first seizure, patients may develop recurrent seizures and exhibit increased fatality.[17,18]
Although acupuncture treatment is helpful and potentially reduces seizure frequency in
epilepsy patients,[19] limited information is available regarding whether acupuncture
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treatment is beneficial in reducing epilepsy in stroke patients.
Using the Taiwan National Health Insurance Research Database (NHIRD), we conducted a
nationwide, propensity score-matched, population-based, retrospective cohort study to
investigate the risk of epilepsy for stroke patients with and without receiving of acupuncture
treatment.
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METHODS
Source of data
Research data were obtained from reimbursement claims of the Taiwan National Health
Insurance Program, which was implemented in March 1995 and insures greater than 99% of
the 23 million Taiwan residents. The National Health Research Institute in Taiwan established
the National Health Insurance Research Database (NHIRD); this database records all
beneficiaries’ medical services, including inpatient and outpatient demographics, primary and
secondary diagnoses, procedures, prescriptions, and medical expenditures, for public research
interest. The validity of this database has been favorably evaluated, and research articles that
have used this database have been published in prominent scientific journals
worldwide.[10,20-23]
Ethical statements
The insurance reimbursement claims used in this study were from Taiwan’s National
Health Insurance Research Database. To ensure privacy, the patients were de-identified in the
electronic database. This study was evaluated and approved by the Institutional Review Board
of Taiwan’s National Health Research Institutes (NHIRD-100-122) and E-DA Hospital,
Kaohsiung, Taiwan (2014012). Informed consent was not required because the patients’
identities were decoded and scrambled. This study was conducted in accordance with the
Declaration of Helsinki.[10,20-23]
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Study design
We identified patients ≥20 years in age with newly diagnosed stroke who were hospitalized
between 2000 and 2004 as eligible study subjects. Each subject either received follow-up
from the index date until December 31, 2009 or was censored. To confirm that all stroke
patients in our study were incident cases, only new-onset stroke cases were included in this
study; patients with a diagnosis of stroke within a 4-year period prior to the study were not
included. Overall, we identified 226,699 new-onset stroke survivors ≥20 years in age among
the 23 million people in Taiwan; 21020 of these patients had received at least two courses
(one course including six consecutive treatments) of acupuncture treatment after being
discharged. We compared stroke patients receiving at least two courses of acupuncture
treatment with patients not receiving acupuncture treatment. We randomly selected stroke
patients who had not received acupuncture treatment as controls (case-control ratio=1:1);
these patients were matched according to age, sex, stroke subtype, low income, urbanization,
hypertension, mental disorder, diabetes, hyperlipidemia, head injury, Parkinson’s disease,
Alzheimer’s disease, brain cancer, renal dialysis, rehabilitation, anti-epilepsy drugs,
anticoagulant, anti-platelet agents, lipid-lowering agents, stay of intensive care unit,
neurosurgery, and length of stay.
Criteria and definition
We defined stroke according to the International Classification of Diseases, 9th Revision,
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Clinical Modification (ICD-9-CM 430-438). The eligible study participants included 226,699
patients in the stroke cohort. Coexisting medical conditions included hypertension
(ICD-9-CM 401-405), mental disorder (ICD-9-CM 290-319), diabetes (ICD-9-CM 250),
hyperlipidemia (ICD-9-CM 272.0–272.4), head injury (ICD-9-CM 800-805, 850-854),
Parkinson’s disease (ICD-9-CM 332), Alzheimer’s disease (ICD-9-CM 331), brain cancer
(ICD-9-CM 191), and. regular renal dialysis (administration code, D8, D9). Using
rehabilitation, anti-epilepsy drugs, anticoagulant, anti-platelet agents, lipid-lowering
agents,during the follow-up period were also considered in this study During the index stroke
admission, we identified stay of intensive care unit, neurosurgery, and length of stay as
potential confounding factors for the association between acupuncture treatment and
post-stroke epilepsy. Under the condition of not experiencing previous epilepsy before stroke
admission through January 1, 1996, cases of newly diagnosed epilepsy (ICD-9-CM 345) were
further defined as at least one medical visit (including inpatient and outpatient care) with a
physician’s diagnosis after stroke admission.
Statistical analysis
We used propensity score-matched pair method combined frequency matching to analyze
patients with and without acupuncture treatment. We developed a non-parsimonious
multivariable logistic regression model to estimate a propensity score for patients with and
without acupuncture treatment, irrespective of outcome. Clinical significance guided the
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initial choice of covariates in this model: age, sex, stroke subtype, low income, urbanization,
hypertension, mental disorder, diabetes, hyperlipidemia, head injury, Parkinson’s disease,
Alzheimer’s disease, brain cancer, renal dialysis, rehabilitation, anti-epilepsy drugs,
anticoagulant, anti-platelet agents, lipid-lowering agents, stay of intensive care unit,
neurosurgery, and length of stay. We matched patients with acupuncture to no-acupuncture
patients using a greedy-matching algorithm with best to next-best until no more match. In the
1:1 matching procedure, all cases are initially matched to their “best” control in the first
iteration of the 8 to 1 digit match. The set of matched cases is then matched to the set of
un-matched controls in N-1 additional iterations of the 8 to 1 Digit Match. If a case does not
have 1 matched controls, it is removed from the set of matches at the time it fails to receive a
matched control. The corresponding control is also removed from the set of matches. The
control is added back to the pool of un-matched controls, and allowed to match to another
case. This method could remove 98% of the bias from measured covariates. The chi-square
tests were used to measure covariate balance and a p-value <0.05 was suggested to represent
meaningful covariate imbalance.
The follow-up time, in person-years, was calculated for each subject until the diagnosis of
epilepsy or until being censored because of death, withdrawal from the insurance system, or
loss to follow-up. The outcome of this study was the person-years of new-onset epilepsy for
stroke patients. This study’s objective was to determine whether using acupuncture was
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associated with reduced the incidence of epilepsy in stroke patients.
We first compared the distribution of sociodemographic factors and coexisting medical
conditions between the stroke cohorts with and without acupuncture treatment using
chi-square tests and t-tests. We calculated hazard ratios (HRs) with 95% confidence intervals
(CIs) for the risk of epilepsy after stroke associated with acupuncture treatment, adjusting for
age, sex, low income, and urbanization in multivariate Cox proportional hazard regression
models. The duration of observation for each person was calculated until the individual was
diagnosed with epilepsy or censored for death, migration, or discontinued enrollment in the
insurance system. Adjusted HRs with 95% CIs for epilepsy associated with acupuncture
treatment were calculated using multivariate Cox proportional hazard analyses with the
variables categorized. We also performed age- and sex-stratified analyses to investigate the
association between epilepsy and the use of acupuncture. SAS software version 9.1 (SAS
Institute, Inc.) was used for data analyses with a two-tailed probability, and P<.05 was
considered statistically significant.
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RESULTS
After the propensity score matching procedure, no significant differences in sex, age, stroke
subtype, low income, urbanization, coexisting medical condition, ICU stay, neurosurgery, or
length of stay were noted between stroke patients with and without acupuncture treatment
(Table 1).
Compared to stroke patients who did not receive acupuncture treatment (Table 2), stroke
patients receiving acupuncture treatment exhibited a reduced epilepsy incidence (9.8 vs. 11.5
per 1000 person-years, p<0.0001). After adjustment for sex, age, stroke subtype, low income,
urbanization, coexisting medical condition, rehabilitation, anti-epilepsy drugs, anticoagulant,
anti-platelet agents, lipid-lowering agents, ICU stay, neurosurgery, and length of stay, stroke
patients receiving acupuncture treatment exhibited a decreased risk of epilepsy (HR=0.74;
95% CI 0.68 to 0.80) compared with those not receiving acupuncture treatment. The
association between acupuncture treatment and reduced risk of post-stroke epilepsy was
significant in men (HR=0.77; 95% CI 0.69 to 0.85) and women (HR=0.70; 95% CI 0.61 to
0.81), stroke patients aged 20-69 years as well as in individuals who had suffered from
hemorrhagic stroke (HR=0.60; 95% CI 0.50 to 0.73), ischemic stroke (HR=0.86; 95% CI 0.78
to 0.96) and other stroke (HR=0.62; 95% CI 0.52 to 0.74). The HR values of post-stroke
epilepsy were 0.16 (95% CI 0.04 to 0.68), 0.39 (95% CI 0.21 to 0.73), 0.51 (95% CI 0.39 to
0.66), 0.66 (95% CI 0.54 to 0.80) and 0.79 (95% CI 0.68 to 0.91) in stroke patients aged
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20-29 years, 30-39 years, 40-49 years, 50-59 years, and 60-69 years, respectively.
Among stroke patients, the risk of epilepsy exhibited a dose-dependent decrease with
increasing use of acupuncture treatment (Table 3). Figure 1 shows that the probability of
epilepsy in patients receiving acupuncture was reduced compared to that in patients not
receiving acupuncture.
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DISCUSSION
In this nationwide, propensity score-matched, retrospective cohort study, we observed that
stroke patients receiving acupuncture treatment exhibited a significantly lower risk of
epilepsy during the follow-up period compared to those not receiving acupuncture treatment.
A decreased risk of epilepsy after receiving acupuncture treatment was exclusively noted only
among stroke patients aged 20 to 69 years. To our knowledge, this study is the first to report
the association between using acupuncture and reduced risk of post-stroke epilepsy.
Older age, male sex, urbanization, hypertension, diabetes mellitus, mental disorders,
Parkinson’s disease and Alzheimer’s disease are known risk factors associated with
stroke.[24,25] These sociodemographics and coexisting medical conditions are also
associated with epilepsy.[6-28] Neurosurgery, ICU stay, and length of hospital stay have also
been shown to exhibit impacts on post-stroke epilepsy.[7,29] To reduce bias, we used
propensity score matching and multivariate regression to control for potential confounders.
Our study demonstrated that acupuncture treatment is associated with a decreased risk of
epilepsy among male and female stroke patients aged 20 to 69 years. Age and sex have been
previously shown to determine the medical conditions and complications of individuals
suffering from stroke.[20] For instance, older populations exhibit an increased mortality rate
and poorer outcomes after stroke.[30] Young and middle-aged adults have less coexisting
medical conditions; have better knowledge, attitudes, and practice; and more commonly use
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TCM or acupuncture treatment compared with older individuals.[10,31] These findings may
partly explain why we observed enhanced effects of acupuncture treatment on decreasing the
risk of post-stroke epilepsy in young and middle-aged adults.
The incidence of post-stroke epilepsy varied based on the stroke type.[16,32] Consistent
with previous reports,[16,17] the present study also demonstrated that patients who
experienced hemorrhagic stroke exhibited an increased risk for developing seizures compared
to those who experienced ischemic stroke or other stroke subtypes. Nevertheless, our
investigation indicated the beneficial effects of acupuncture treatment in reducing the risk of
epilepsy for patients with every stroke subtype.
Acupuncture treatment is one option among rehabilitation programs,[33] particularly for
stroke patients.[34] We propose three possible explanations for the association between
acupuncture treatment and the decreased risk of post-stroke epilepsy that was demonstrated in
this study. First, acupuncture intervention involves multiple levels of differential activities
over a wide range of brain networks and this modulation and sympathovagal response may
relate to acupuncture analgesia and other potential therapeutic effects.[35] Second, depression
is a frequent co-existing condition in stroke patients. Indeed, a meta-analysis reported that
acupuncture exhibits a beneficial effect on patients with depression.[36] Stroke patients with
coexisting medical conditions, such as dementia or Alzheimer’s disease, are also more likely
to develop epilepsy,[37] and an interventional trial reported that acupuncture treatment
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potentially improves cognitive function and quality of life in vascular dementia patients.[38]
Third, stroke patients who receive acupuncture treatment may possess more knowledge about
and better attitudes toward physical rehabilitation, which are helpful in reducing post-stroke
epilepsy, compared to patients not receiving acupuncture treatment.
By using functional magnetic resonance imaging, previous studies indicated that laser
acupuncture activated the precuneus relevant to mood in the posterior default mode network
while needle acupuncture activated the parietal cortical region associated with the primary
motor cortex.[39] In addition, laser stimulation of acupoints lead to activation of
frontal-limbic-striatal brainregions, with the pattern of neural activity somewhat different for
each acupuncture point.[40] The activation in under activated brain regions, deactivation
where there is overload and over activation and so on. This may be one of the reasons why
there is a reduction of epilepsy. Therefore, we believe that laser acupuncture may be also
helpful during the rehabilitation for stroke patients.
The first strength of this study was its large sample size and reduced selection bias. Second,
our study consisted of a retrospective cohort design using the NHIRD; this design provides
stronger causal inference than case-control and cross-sectional designs. Third, to eliminate the
interference of sociodemographics and coexisting medical conditions between stroke patients
receiving acupuncture treatment and those not receiving such treatment, we used a propensity
score matched-pair procedure to select acupuncture and non-acupuncture treatment controls.
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To control for residual confounding effects in the association between a decreased risk of
post-stroke epilepsy and acupuncture treatment, we applied multivariable Cox proportional
hazard models to calculate adjusted HRs and 95% CIs of epilepsy associated with
acupuncture treatment. Finally, immortal time in observational studies may bias the results in
favor of the treatment group, thereby overestimating the beneficial effects. To reduce such
bias, we calculated person-years by correcting for immortal time in the acupuncture treatment
group.
Nevertheless, this study had certain limitations. First, we used insurance claims data, which
lack information on clinical risk scores (such as the National Institute of Health Stroke Scale
or the Barthel index), lesion characteristics (location or size), biochemical measures, and
patients’ lifestyles, which have been reported as predictors of post-stroke epilepsy. Thus, this
study does not provide information regarding the severity-dependent relationship between
epilepsy and stroke. Second, preventive administration of antiepileptic medications or other
rehabilitation programs were not considered during the follow-up period. Thus, we were
unable to evaluate the influence of these factors on the association between acupuncture and
the decreased risk of post-stroke epilepsy. Third, although the accuracy of diagnosis codes in
the database has been validated in previous studies,[10] the validity of co-morbidity codes is
one potential limitation of the study. The prevalence of epilepsy may also have been
underestimated, given that patients experiencing mild symptoms may not seek medical
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treatment; however, these effects appear minimal in our population-based study. In addition,
our study could not validate the actual acupuncture points used in treatment, given the limited
information provided by the reimbursement claims of Taiwan’s NHIRD. Finally, the mode of
acupuncture treatment for stroke patients varied among TCM physicians. Thus, we could not
confirm that all TCM physicians performed the same procedures and used the same
acupuncture points for stroke patients.
In conclusion, stroke patients receiving acupuncture treatment exhibited a reduced risk of
epilepsy compared to patients not receiving acupuncture treatment. The association between
decreased epilepsy risk and acupuncture use was observed in men, women, younger adults,
and patients suffering from any subtypes of stroke. However, this associated protective effect
must be further assessed in randomized clinical trials to provide direct evidence regarding the
effectiveness and mechanisms of acupuncture treatment on post-stroke epilepsy.
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25. Kumar S, Selim MH, Caplan LR. Medical complications after stroke. Lancet Neurol
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seizures after stroke. Neurology 2011;77:1785-93.
33. Wong V, Cheuk DK, Lee S, et al. Acupuncture for acute management and rehabilitation
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34. Yam W, Wilkinson JM. Is acupuncture an acceptable option in stroke rehabilitation? A
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Acknowledgments: This study is based in part on data obtained from the National Health
Insurance Research Database provided by the Bureau of National Health Insurance, Ministry
of Health and Welfare, and managed by the National Health Research Institutes. The
interpretation and conclusions contained herein do not represent those of the Bureau of
National Health Insurance, Ministry of Health and Welfare, or National Health Research
Institutes.
Competing interests: None.
Financial support: This research was supported in part by Shuang Ho Hospital, Taipei
Medical University (104TMU-SHH-23), Taiwan’s Ministry of Science and Technology
(MOST104-2314-B-038-027-MY2; MOST103-2320-B-214-010-MY2;
NSC102-2314-B-038-021-MY3), and Taiwan’s Ministry of Health and Welfare Clinical Trial
and Research Center of Excellence (MOHW105-TDU-B-212-133019).
Data sharing statement: dataset available from the Taiwan’s National Health Research
Institutes (http://nhird.nhri.org.tw/index1.php).
Author contribution: All the authors revised and approved the contents of the submitted
article. CCL and CCS created the idea of the manuscript. CCL and HLL conducted statistical
analysis of data. SWW and CCL wrote the manuscript. All the authors made substantial
contributions to interpretation of data and carried out a critical revision of the manuscript for
important intellectual content.
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Fig 1 The epilepsy-free proportions estimated for post-stroke patients with and without
acupuncture treatment using the Kaplan-Meier method.
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Table 1 Baseline Characteristics of Stroke Patients With and Without Acupuncture
Treatment
Acupuncture use
No (N = 21020) Yes (N = 21020) P value
N (%) n (%)
Female 9272 (44.1) 9272 (44.1) 1.0000
Age, years 1.0000
20-29 75 (0.4) 75 (0.4)
30-39 284 (1.4) 284 (1.4)
40-49 1878 (8.9) 1878 (8.9)
50-59 4320 (20.6) 4320 (20.6)
60-69 7080 (33.7) 7080 (33.7)
70-79 6311 (30.0) 6311 (30.0)
≥80 1072 (5.1) 1072 (5.1)
Stroke subtype 1.0000
Hemorrhage 1775 (8.4) 1775 (8.4)
Ischemic 12285 (58.4) 12285 (58.4)
Other 6960 (33.1) 6960 (33.1)
Low income 184 (0.9) 184 (0.9) 1.0000
Urbanization 1.0000
Low 582 (2.8) 582 (2.8)
Moderate 7247 (34.5) 7247 (34.5)
High 13191 (62.8) 13191 (62.8)
Coexisting medical condition
Hypertension 15887 (75.6) 15887 (75.6) 1.0000
Mental disorder 8144 (38.7) 8144 (38.7) 1.0000
Diabetes mellitus 8048 (38.3) 8048 (38.3) 1.0000
Hyperlipidemia 3403 (16.2) 3403 (16.2) 1.0000
Head injury 1659 (7.9) 1659 (7.9) 1.0000
Parkinson’s disease 656 (3.1) 656 (3.1) 1.0000
Alzheimer’s disease 13 (0.1) 13 (0.1) 1.0000
Brain cancer 4 (0.0) 4 (0.0) 1.0000
Renal Dialysis 304 (1.5) 304 (1.5) 1.0000
Rehabilitation 13803 (46.6) 13803 (46.6) 1.0000
Anti-epilepsy drugs 6170 (29.4) 6170 (29.4) 1.0000
Anticoagulant 1599 (7.6) 1599 (7.6) 1.0000
Anti-platelet agents 20016 (95.2) 20016 (95.2) 1.0000
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Lipid-lowering agents 11307 (53.8) 11307 (53.8) 1.0000
ICU stay 1412 (6.7) 1412 (6.7) 1.0000
Neurosurgery 318 (1.5) 318 (1.5) 1.0000
Length of stay, days 6.92±5.19 6.93±5.25 0.7302
ICU = intensive care unit.
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Table 2 Incidence and Risk of Epilepsy for Stroke Patients With and Without Acupuncture Treatment by Age, Sex, and Stroke
Type
No acupuncture Acupuncture use
n Events Person-year Incidence n Events Person-year Incidence HR (95% CI)
All* 21020 1382 120164 11.5 21020 993 101044 9.8 0.74 (0.68-0.80)
Female 9272 525 55162 9.5 9272 343 45620 7.5 0.70 (0.61-0.81)
Male 11748 857 65001 13.2 11748 650 55424 11.7 0.77 (0.69-0.85)
Age, years‡
20-29 75 9 408 22.1 75 3 369 8.1 0.16 (0.04-0.68)
30-39 284 31 1632 19.0 284 16 1363 11.7 0.39 (0.21-0.73)
40-49 1878 165 11601 14.2 1878 90 9357 9.6 0.51 (0.39-0.66)
50-59 4320 263 26875 9.8 4320 166 22064 7.5 0.66 (0.54-0.80)
60-69 7080 444 42234 10.5 7080 332 34762 9.6 0.79 (0.68-0.91)
70-79 6311 403 33073 12.2 6311 341 29006 11.8 0.88 (0.76-1.02)
≥80 1072 67 4340 15.4 1072 45 4123 10.9 0.71 (0.48-1.04)
Type of stroke§
Hemorrhage 1775 253 9355 27.0 1775 179 8501 21.1 0.60 (0.50-0.73)
Ischemic 12285 764 68961 11.1 12285 615 59265 10.4 0.86 (0.78-0.96)
Other 6960 365 41848 8.7 6960 199 33277 6.0 0.62 (0.52-0.74)
CI = confidence interval, HR = hazard ratio. *Adjusted for all covariates in Table 1. †Adjusted for covariates in Table 1 except sex. ‡Adjusted for covariates in Table 1 except age. §Adjusted for covariates in Table 1 except stroke subtype.
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Table 3 Risk of Epilepsy and Number of Acupuncture Treatment Packages in Stroke Patients
Number of packages n Events Person-years Incidence HR (95% CI)*
0 21020 1382 120164 11.5 0.77 (0.66-0.90)
2 4385 182 18258 10.0 1.06 (0.91-1.25)
3 2907 164 12720 12.9 0.84 (0.69-1.02)
4 2040 104 9597 10.8 0.75 (0.59-0.95)
5 1545 72 7271 9.9 0.74 (0.55-0.98)
6 1168 48 5464 8.8 0.64 (0.57-0.71)
≥7 8975 423 47734 8.9 0.69 (0.63-0.74)
CI = confidence interval, HR = hazard ratio. *Adjusted for age, sex, stroke subtype, low income, urbanization, hypertension, mental
disorder, diabetes, hyperlipidemia, head injury, Parkinson’s disease, Alzheimer’s disease,
brain cancer, renal dialysis, rehabilitation, anti-epilepsy drugs, anticoagulant, anti-platelet
agents, lipid-lowering agents, stay of intensive care unit, neurosurgery, and length of stay.
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339x254mm (300 x 300 DPI)
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STROBE 2007 (v4) checklist of items to be included in reports of observational studies in epidemiology*
Checklist for cohort, case-control, and cross-sectional studies (combined)
Section/Topic Item # Recommendation Reported on page #
Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the abstract 1, 3
(b) Provide in the abstract an informative and balanced summary of what was done and what was found 3
Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 5
Objectives 3 State specific objectives, including any pre-specified hypotheses 6
Methods
Study design 4 Present key elements of study design early in the paper 7
Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data
collection 7, 8
Participants 6 (a) Cohort study—Give the eligibility criteria, and the sources and methods of selection of participants. Describe
methods of follow-up
Case-control study—Give the eligibility criteria, and the sources and methods of case ascertainment and control
selection. Give the rationale for the choice of cases and controls
Cross-sectional study—Give the eligibility criteria, and the sources and methods of selection of participants
8, 9
(b) Cohort study—For matched studies, give matching criteria and number of exposed and unexposed
Case-control study—For matched studies, give matching criteria and the number of controls per case 8, 9
Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic
criteria, if applicable 8, 9
Data sources/ measurement 8* For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe
comparability of assessment methods if there is more than one group 8, 9
Bias 9 Describe any efforts to address potential sources of bias 9, 10
Study size 10 Explain how the study size was arrived at 9, 10
Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen
and why 9, 10
Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding 9, 10
(b) Describe any methods used to examine subgroups and interactions 9, 10
(c) Explain how missing data were addressed 9, 10
(d) Cohort study—If applicable, explain how loss to follow-up was addressed
Case-control study—If applicable, explain how matching of cases and controls was addressed 9, 10
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Cross-sectional study—If applicable, describe analytical methods taking account of sampling strategy
(e) Describe any sensitivity analyses 9, 10
Results
Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility,
confirmed eligible, included in the study, completing follow-up, and analysed 11, 12
(b) Give reasons for non-participation at each stage 11, 12
(c) Consider use of a flow diagram 11, 12
Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and
potential confounders 11, 12
(b) Indicate number of participants with missing data for each variable of interest 11, 12
(c) Cohort study—Summarise follow-up time (eg, average and total amount) 11, 12
Outcome data 15* Cohort study—Report numbers of outcome events or summary measures over time 11, 12
Case-control study—Report numbers in each exposure category, or summary measures of exposure 11, 12
Cross-sectional study—Report numbers of outcome events or summary measures 11, 12
Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95%
confidence interval). Make clear which confounders were adjusted for and why they were included 11, 12
(b) Report category boundaries when continuous variables were categorized 11, 12
(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period 11, 12
Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses 11, 12
Discussion
Key results 18 Summarise key results with reference to study objectives 13
Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction
and magnitude of any potential bias 16
Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results
from similar studies, and other relevant evidence 13-17
Generalisability 21 Discuss the generalisability (external validity) of the study results 13-17
Other information
Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on
which the present article is based 18
*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.
Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE
checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at
http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org.
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