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Mortality in patients with schizophrenia admitted for incident ischemic stroke: A population-based cohort study
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European Neuropsychopharmacology (2019) 000, 1–6
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SHORT COMMUNICATION
Mortality in patients with schizophrenia admitted for incident ischemic stroke: A population-based cohort study Nicholas Chak Lam Yung a, Corine Sau Man Wong a, Joe Kwun Nam Chan a, Philip Chi Fai Or b, Eric Yu Hai Chen a,c, Wing Chung Chang a,c,∗ a
Department of Psychiatry, The University of Hong Kong, Queen Mary Hospital, Hong Kong Department of Psychiatry, Queen Mary Hospital, Hospital Authority, Hong Kong c State Key Laboratory of Brain and Cognitive Sciences, the University of Hong Kong, Hong Kong b
Received 10 October 2019; received in revised form 21 November 2019; accepted 8 December 2019 Available online xxx
KEYWORDS Ischemic stroke; Mortality; Population-based study; Schizophrenia; Stroke
Abstract Evidence shows that schizophrenia is associated with increased incidence of stroke. However, relationship between schizophrenia and short-term mortality risk is understudied, and mixed findings were observed. In this retrospective population-based cohort study, we identified individuals admitted for incident ischemic stroke between 2006 and 2016 using a territory-wide electronic medical record database of public healthcare system in Hong Kong to examine 30day and 1-year mortality rates in 817 schizophrenia patients compared with 8170 patients without psychotic disorder (10:1 matched to schizophrenia patients on demographics, treatment sites and calendar-period for index admission). Multivariate regression analyses adjusting for medical comorbidities revealed that schizophrenia patients experienced elevated 1-year (16.9% vs 12.1%; p < 0.001) and 30-day mortality (7.2% vs 5.3%; p = 0.053) relative to control group. Additional age- and gender-stratified analyses revealed even more pronounced effect of schizophrenia on raised mortality risk, as indicated by higher odds, in younger-age (<65 years) group and men. Our results indicate that schizophrenia is associated with heightened shortterm mortality following incident ischemic stroke. Further research is warranted to identify factors contributing to excess post-stroke deaths among schizophrenia patients to facilitate development of effective interventions for mortality risk reduction. © 2019 Elsevier B.V. and ECNP. All rights reserved.
1. ∗ Corresponding
author at: Department of Psychiatry, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong. E-mail address: [email protected] (W.C. Chang).
Introduction
People with schizophrenia experience markedly elevated risk of premature mortality (Hjorthøj et al., 2017;
https://doi.org/10.1016/j.euroneuro.2019.12.107 0924-977X/© 2019 Elsevier B.V. and ECNP. All rights reserved. Please cite this article as: N.C.L. Yung, C.S.M. Wong and J.K.N. Chan et al., Mortality in patients with schizophrenia admitted for incident ischemic stroke: A population-based cohort study, European Neuropsychopharmacology, https://doi.org/10.1016/j.euroneuro.2019.12. 107
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N.C.L. Yung, C.S.M. Wong and J.K.N. Chan et al.
Oakley, et al., 2018). Evidence indicates that the vast majority of excess deaths in schizophrenia are attributable to physical diseases (Walker et al., 2015). Cardiovascular diseases (CVD), including stroke and ischemic heart disease (IHD), are a major contributor to premature mortality in schizophrenia. Recent meta-analytic reviews further show that schizophrenia is associated with increased incidence of stroke and IHD (Correll et al., 2017; Li et al., 2014). In fact, a substantial body of literature demonstrates raised mortality after acute coronary syndrome among schizophrenia patients relative to the general population (Shao et al., 2020). Conversely, the relationship between schizophrenia and post-stroke mortality risk is understudied. Until now, there are only four published reports in this respect. One of these studies examined 5-year post-stroke mortality and reported that schizophrenia patients exhibited heightened mortality compared with non-schizophrenia controls (Tsai et al., 2012). The remaining three studies focused on short-term post-stroke mortality with mixed findings being observed (Kang et al., 2011; Kisley et al., 2009; Willers et al., 2018). Among those two studies investigating both 1-month and 1-year mortality after stroke, one revealed that schizophrenia was associated with increased 1year mortality (Kisley et al., 2009), while the other failed to find any significant differences in mortality rates between patients with and without psychotic disorders (Willers et al., 2018). Another study even observed that schizophrenia patients had lower 90-day post-stroke mortality rate than those without schizophrenia (Kang et al., 2011). Of note, half of these reports comprised patients presenting with incident stroke and those with previous stroke history which may confound the study results (Kang et al., 2011; Willers et al., 2018). Additionally, most studies treated stroke as a single disease category without taking into consideration its subtypes in mortality analysis. Only one prior study assessed mortality rate specifically following ischemic stroke (Willers et al., 2018), which accounts for over 85% of acute strokes (Hankey, 2017), in schizophrenia. To this end, we conducted a retrospective populationbased cohort study with an aim to examine short-term (30-day and 1-year) mortality rates after admission for incident ischemic stroke in schizophrenia patients compared with those without psychotic disorders in Hong Kong (HK). Clinical data of the current investigation was retrieved from a territory-wide electronic medical record database of public healthcare services which provide governmentsubsidized, universal health coverage to 7.5 million HK residents. The potential confounding effects of medical comorbidities including hypertension, diabetes, hyperlipidemia, alcohol and substance use disorders on mortality outcome were adjusted to enable a better estimation of the relationship between schizophrenia and short-term mortality risk after stroke.
2. 2.1.
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Methods Data source
This study was conducted using Clinical Data Analysis and Reporting System (CDARS; Cheung et al., 2007), a territory-wide electronic health record database developed by the Hospital Authority (HA)
which provides public healthcare services to HK residents by managing all public hospitals, specialist and general outpatient clinics in HK. Detailed description of CDARS has been reported elsewhere (Cheung et al., 2007). Briefly, CDARS is an integrated, longitudinal patient electronic record system capturing clinical data across all healthcare settings of HA facilities since 1995. The database contains patients’ demographic and clinical information of their diagnoses, hospital admissions, visits to outpatient clinics and emergency department, to name a few. It also contains data on deaths through its internal linkage to regional deaths registry from the Immigration Department. Clinical data are collected and entered into the computerized clinical management system by treating clinicians and other healthcare professionals, and are then transferred to CDARS for audit and research purposes. CDARS generates unique, anonymized patient-identifiers to protect patient confidentiality and to link all medical records. This database has been used to conduct high-quality population-based studies for various physical and neuropsychiatric diseases (Wong et al., 2016; Man et al., 2017).
2.2.
Study sample
This was a retrospective study. We identified all individuals aged ≥18 years who had a public hospital admission for first-recorded ischemic stroke in HK during a period between 1 January 2006 and 31 December 2016. Diagnosis of ischemic stroke was identified by ICD9-CM code (433–434). Patients with past record of stroke diagnosis (ICD9-CM codes: 430–438) before an index admission were excluded. Within the incident stroke cohort, we identified a group of patients who had a principal ICD10 diagnosis of schizophrenia (F20) or schizoaffective disorder (F25) (termed schizophrenia henceforth) recorded in psychiatric inpatient and / or outpatient settings (with inpatient discharge diagnosis taking precedence over outpatient diagnosis in determining final diagnosis) prior to an index admission. CDARS-derived diagnostic ascertainment has been used for patient-sample identification in previous retrospective studies for psychotic disorders (e.g., Man et al., 2017). We then derived a “control” comparison group by randomly selecting patients from the remainder of the incident stroke cohort matched 10:1 to schizophrenia group on gender, age, calendar-year period and catchment area of healthcare services for index admission. Patients with psychiatric diagnosis of other non-affective psychoses, mania or bipolar disorder (ICD10 codes: F22-24, F28-29, F30-31) recorded preceding an index admission were excluded from control sample selection. The study was approved by the local institutional review board.
2.3.
Statistical analysis
The primary analysis was to compare schizophrenia group with control group in 30-day and 1-year mortality after admission for incident ischemic stroke. Multivariate logistic regression analyses were performed to examine the associations between schizophrenia and mortality rates, adjusting for medical comorbidities which included hypertension, diabetes, hyperlipidemia, other physical comorbidities as quantified by Charlson-Deyo comorbidity index (Deyo et al., 1992), alcohol and substance use disorders. In addition, we conducted age- (<65 years vs ≥65 years) and gender-stratified analyses to examine whether there were differential effects of schizophrenia on post-stroke mortality between age-groups and gender. Level of statistical significance for all analyses was set at p < 0.05.
3.
Results
Demographics and baseline characteristics of the study cohort (schizophrenia group, N = 817; control group,
Please cite this article as: N.C.L. Yung, C.S.M. Wong and J.K.N. Chan et al., Mortality in patients with schizophrenia admitted for incident ischemic stroke: A population-based cohort study, European Neuropsychopharmacology, https://doi.org/10.1016/j.euroneuro.2019.12. 107
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Mortality in patients with schizophrenia admitted for incident ischemic stroke: A population-based cohort study
Table 1
3
Demographics and baseline characteristics of patients admitted for ischemic stroke.
Variablesa
Schizophrenia (N = 817)
Control comparison (N = 8170)
P value
Age, mean (SD) Male gender, N (%) Calendar-year period (2006–2011),b N (%) Medical comorbidity Hypertension, N (%) Diabetes, N (%) Hyperlipidemia, N (%) Charlson comorbidity index,c mean (SD) Alcohol use disorder, N (%) Substance use disorder, N (%) Catchment areas of public health service,d N (%) Hong Kong East Hong Kong West Kowloon Central Kowloon East Kowloon West New Territories East New Territories West
67.0 (11.4) 382 (46.8) 505 (61.8)
67.0 (11.4) 3820 (46.8) 5050 (61.8)
0.995 1.000 1.000
409 (50.1) 284 (34.8) 112 (13.7) 3.1 (1.9) 14 (1.7) 8 (1.0)
3772 (46.2) 1991 (24.4) 1431 (17.5) 2.9 (1.9) 8 (0.1) 19 (0.2)
0.033 <0.001 0.006 0.093 <0.001 <0.001 1.000
61 (7.5) 48 (5.9) 134 (16.4) 95 (11.6) 217 (26.6) 115 (14.1) 147 (18.0)
610 (7.5) 480 (5.9) 1340 (16.4) 950 (11.6) 2170 (26.6) 1150 (14.1) 1470 (18.0)
a Potential group differences were examined using independent-samples t tests and chi-square tests for continuous and categorical variables, separately. b Calendar-year period of index admission was categorized into 2006–2011 and 2012–2016 periods. c Age-adjusted adapted Charlson-Deyo comorbidity index (CCI) was computed (Deyo et al., 1992). As diabetes was already treated as a medical comorbidity for covariate analysis, it was thus excluded from CCI score calculation. Cerebrovascular disease, which was the study disease of interest, was also excluded. d In Hong Kong, the Hospital Authority manages public healthcare service delivery (inpatient and specialist/general outpatient services) which is organized into 7 clusters based on geographical locations (i.e., catchment areas).
N = 8170) are summarized in Table 1. Schizophrenia patients had higher prevalence of hypertension, diabetes, alcohol and substance use disorders, but lower rate of hyperlipidemia than controls. As shown in Table 2, schizophrenia patients exhibited significantly higher 1-year mortality rate than controls (16.9% vs 12.1%). The association between schizophrenia and 30day mortality also approached significance (p = 0.053; schizophrenia patients vs controls: 7.2% vs 5.3%). Our ageand gender-stratified analyses revealed similar results as observed in full-cohort analyses, with schizophrenia being found to be associated with increased 1-year mortality in each of the stratified samples (Table 2; please also refer to supplementary Table S1 and S2 for baseline characteristics of age- and gender-stratified samples, respectively). However, the effect of schizophrenia on heightened mortality was even more pronounced, as indicated by higher odds, in younger (<65 years) age-group and men. Additionally, significant association between raised 30-day mortality and schizophrenia was only found in younger and male patients.
4.
Discussion
The current study sought to investigate the short-term mortality after admission for incident ischemic stroke in schizophrenia patients relative to those without psychotic disorders. Our results showed that schizophrenia was associated with increased 1-year and 30-day poststroke mortality risk (albeit approaching significance in
the latter) after adjusting for medical comorbidities. This is thus consistent with the only previous study which also examined short-term mortality among patients presenting with incident acute stroke and demonstrated that patients with psychotic disorders experienced significantly elevated 1-year mortality compared with those without psychotic disorders (Kisley et al., 2009). Of note, although older age was linked to higher mortality irrespective of comorbid schizophrenia diagnosis, our age-stratified analyses revealed that the influence of schizophrenia on heightened mortality was even more pronounced among patients aged under 65 years. In particular, schizophrenia was found to be associated with 2-fold increased odds of 1-year post-stroke morality in this younger-age group. This is in keeping with the widely replicated findings of markedly shortened lifespan in schizophrenia patients relative to the general population (Hjorthøj et al., 2017). Alternatively, our multivariate regression analyses (full data not shown) indicated that male gender was significantly related to 1-year mortality (adjusted OR [95% CI]: 1.15 [1.00–1.33]; p = 0.046), but not 30-day mortality (p = 0.274), for the entire study cohort. This latter finding in fact concurs with an earlier study which reported generally comparable 30-day mortality rates between men and women (aged <85 years) after first hospitalization for stroke in Hong Kong (during 2000–2007; Wu et al., 2012). Our gender-stratified analyses further showed that the association between schizophrenia and increased mortality was more prominent in men (both 30-day and 1-year mortality) than in women (1-year mortality only). However, owing to the paucity of
Please cite this article as: N.C.L. Yung, C.S.M. Wong and J.K.N. Chan et al., Mortality in patients with schizophrenia admitted for incident ischemic stroke: A population-based cohort study, European Neuropsychopharmacology, https://doi.org/10.1016/j.euroneuro.2019.12. 107
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Table 2
Mortality of patients admitted for ischemic stroke.
Outcome
Schizophrenia N (%)
Control comparison N (%)
Unadjusted OR (95% CI)
P value
Adjusted OR (95% CI)a
P value
59 (7.2)
436 (5.3)
0.025
985 (12.1)
1.34 (1.00–1.79) 1.51 (1.22–1.85)
0.052
138 (16.9)
1.38 (1.04–1.83) 1.48 (1.22–1.80)
1.89 (1.15–3.13) 2.11 (1.47–3.02)
0.013
1.75 (1.04–2.95) 2.02 (1.38–2.96)
0.036
1.22 (0.87–1.72) 1.32 (1.04–1.67)
0.254
1.19 (0.84–1.70) 1.35 (1.05–1.73)
0.327
1.72 (1.14–2.60) 1.55 (1.16–2.08)
0.010
1.63 (1.06–2.50) 1.54 (1.13–2.11)
0.027
1.17 (0.80–1.72) 1.43 (1.10–1.86)
0.428
1.13 (0.76–1.69) 1.47 (1.11–1.94)
0.553
Full-cohort analyses A full cohort 30-day mortality 1-year mortality
<0.001
<0.001
Age-stratified analyses Patients < 65 yearsb 30-day mortality
19 (5.5)
103 (3.0)
1-year mortality
40 (11.5)
202 (5.8)
Patients ≥ 65 yearsc 30-day mortality
40 (8.5)
333 (7.1)
1-year mortality
98 (20.9)
783 (16.7)
<0.001
0.021
<0.001
0.018
Gender-stratified analyses Male patientsd 30-day mortality 1-year mortality Female patientse 30-day mortality 1-year mortality a b c d e
28 (7.3)
168 (4.4)
61 (16.0)
417 (10.9)
31 (7.1)
268 (6.2)
77 (17.7)
568 (13.1)
0.003
0.007
0.007
0.007
Multivariate regression analyses were adjusted for medical comorbidities. There were 347 schizophrenia patients and 3468 controls included in the analyses. There were 470 schizophrenia patients and 4702 controls included in the analyses. There were 382 schizophrenia patients and 3820 controls included in the analyses. There were 435 schizophrenia patients and 4350 controls included in the analyses.
existing data, further investigations are needed to verify our findings and to disentangle the relationships between schizophrenia, gender and short-term post-stroke mortality. It is suggested that raised CVD-related mortality associated with schizophrenia, including stroke, might be attributable to inequitable medical care (Lawrence and Kisely, 2010). In fact, several previous studies found that schizophrenia patients had significantly lower receipt of post-stroke reperfusion treatment and secondary preventive medications than the general population (Kisley et al., 2009; Laursen et al., 2014; Willers et al., 2018). Substantial evidence also showed that schizophrenia patients underwent inadequate guideline-recommended screening and follow-up monitoring of CVD risk factors and metabolic parameters (Ayerbe et al., 2018; Mitchell et al., 2012), as well as lower utilization of primary healthcare and medical specialist services compared with the general population (Copeland et al., 2009; Swildens et al., 2016). A recent study further reported under-diagnosis of CVD prior to CVDrelated death among schizophrenia patients (Heiberg et al., 2019). Alternatively, factors other than deficits in medical care might also contribute to heightened post-stroke mortality associated with schizophrenia including antipsychotic
treatment (Prior et al., 2014) and unhealthy lifestyle patterns such as physical inactivity, poor diet and smoking. Hence, further research is warranted to clarify the relationship between these risk factors and post-stroke mortality risk among patients with schizophrenia. There are several limitations in the study. First, a number of CVD risk factors including lifestyle patterns (e.g. smoking and physical activity levels), obesity and family history of CVD were not adequately recorded in medical database and thus were not included in the current analysis. Second, we did not have prescription data on psychotropic medications including antipsychotics which are found to be related to increased risk of stroke (Hsu et al., 2017). Third, our lack of information on receipt of post-stroke reperfusion treatment and secondary preventive medications precludes us from verifying whether schizophrenia patients receive inferior post-stroke treatment relative to control group, and whether such treatment disparity (if present) is associated with increased mortality. Fourth, given the short follow-up period, we were not able to examine the relationship between schizophrenia and longer-term post-stroke mortality. In conclusion, in this population-based cohort study of patients admitted for incident ischemic stroke, our results in-
Please cite this article as: N.C.L. Yung, C.S.M. Wong and J.K.N. Chan et al., Mortality in patients with schizophrenia admitted for incident ischemic stroke: A population-based cohort study, European Neuropsychopharmacology, https://doi.org/10.1016/j.euroneuro.2019.12. 107
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Mortality in patients with schizophrenia admitted for incident ischemic stroke: A population-based cohort study dicate that comorbid diagnosis of schizophrenia is associated with increased short-term mortality, with its effect on raised mortality risk being more prominent among younger age-group and men. Given that the causes for heightened post-stroke mortality among schizophrenia patients remain unknown, more research is required to identify factors contributing to such increased mortality risk so as to facilitate development of effective strategies for outcome improvement following stroke in this vulnerable population.
CRediT authorship contribution statement Nicholas Chak Lam Yung: Data curation, Writing - original draft, Writing - review & editing, Funding acquisition. Corine Sau Man Wong: Conceptualization, Writing - review & editing. Joe Kwun Nam Chan: Writing - review & editing. Philip Chi Fai Or: Writing - review & editing. Eric Yu Hai Chen: Writing - review & editing. Wing Chung Chang: Conceptualization, Funding acquisition, Data curation, Writing - review & editing.
Role of funding source The study was supported by the funding from the State Key Laboratory of Brain & Cognitive Sciences and the Master Research in Medicine Programme, University of Hong Kong.
Conflict of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Acknowledgment The authors would like to thank the colleagues in Hospital Authority for their kind assistance in data retrieval for the current investigation.
Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.euroneuro. 2019.12.107.
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Correll, C.U., Solmi, M., Veronese, N., et al., 2017. Prevalence, incidence and mortality from cardiovascular disease in patients with pooled and specific severe mental illness: a large-scale meta-analysis of 3211768 patients and 113383368 controls. World Psychiatry 16, 163–180. Deyo, R.A., Cherkin, D.C., Ciol, M.A., 1992. Adapting a clinical comorbidity index for use with ICD9-CM administrative databases. J. Clin. Epidemiol. 45, 613–619. Hankey, G.J., 2017. Stroke. Lancet 389, 641–654. Heiberg, I.H., Jacobsen, B.K., Balteskard, L., et al., 2019. Undiagnosed cardiovascular disease prior to cardiovascular death in individuals with severe mental illness. Acta Psychiatr. Scand. 139, 558–571. Hjorthøj, C., Stürup, A.E., McGrath, J.J., Nordentoft, M., 2017. Years of potential life lost and life expectancy in schizophrenia: a systematic review and meta-analysis. Lancet Psychiatry 4, 295–301. Hsu, W.T., Esmaily-Fard, A., Lai, C.C., et al., 2017. Antipsychotics and the risk of cerebrovascular accident: a systematic review and meta-analysis of observational studies. J. Am. Med. Dir. Assoc. 18, 692–699. Kang, J.H., Xirasagar, S., Lin, H.C., 2011. Lower mortality among stroke patients with schizophrenia: a nationwide population-based study. Psychosom. Med. 73, 106–111. Kisley, S., Campbell, L.A., Want, Y., 2009. Treatment of ischaemic heart disease and stroke in individuals with psychosis under universal healthcare. Br. J. Psychiatry 195, 545–550. Laursen, T.M., Mortensen, P.B., MacCabe, J.H., Gasse, C., 2014. Cardiovascular drug use and mortality in patients with schizophrenia or bipolar disorder: a Danish population-based study. Psychol. Med. 44, 1625–1637. Lawrence, D., Kisely, S., 2010. Inequalities in healthcare provision for people with severe mental illness. J. Psychopharmacol. 24 (suppl.4), 61–68. Li, M., Fan, Y.L., Tang, Z.Y., Cheng, X.S., 2014. Schizophrenia and risk of stroke: a meta-analysis of cohort studies. Int. J. Cardiol. 173, 588–590. Man, K.K.C., Chan, D.W., Ip, P., et al., 2017. Prenatal antidepressant use and risk of attention-deficit/hyperactivity disorder in offspring: population based cohort study. BMJ 357, j2350. Mitchell, A.J., Delaffon, V., Vancampfort, D., Correll, C.U., De Hert, M., 2012. Guideline concordant monitoring of metabolic risk in people treated with antipsychotic medication: systematic review and meta-analysis of screening practices. Psychol. Med. 42, 125–147. Oakley, P., Kisely, S., Baxter, A., et al., 2018. Increased mortality among people with schizophrenia and other non-affective psychotic disorders in the community: a systematic review and meta-analysis. J. Psychiatr. Res. 102, 245–253. Prior, A., Laursen, T.M., Larsen, K.K., et al., 2014. Post-stroke mortality, stroke severity, and preadmission antipsychotic medicine use – a population-based cohort study. PLoS ONE 9, e84103. Shao, M., Tian, H., Wang, L., Jiang, D., Ji, F., Zhuo, C., 2020. Mortality risk following acute coronary syndrome among patients with schizophrenia: a meta-analysis. Prog. Neuropsychopharmacol. Biol. Psychiatry 96, 109737. Swildens, W., Termorshuizen, F., de Ridder, A., Smeets, H., Engelhard, I.M., 2016. Somatic care with a psychotic disorder: lower somatic health care utilization of patients with a psychotic disorder compared to other patient groups and to controls without a psychiatric diagnosis. Adm. Policy Ment. Health 4, 650–662. Tsai, K.Y., Lee, C.C., Chou, Y.M., Su, C.Y., Chou, F.H.C., 2012. The incidence and relative risk of stroke in patients with schizophrenia: a five-year follow-up study. Schizophr. Res. 138, 41– 47. Walker, E.R., McGee, R.E., Druss, B.G., 2015. Mortality in mental disorders and global disease burden implications: a sys-
Please cite this article as: N.C.L. Yung, C.S.M. Wong and J.K.N. Chan et al., Mortality in patients with schizophrenia admitted for incident ischemic stroke: A population-based cohort study, European Neuropsychopharmacology, https://doi.org/10.1016/j.euroneuro.2019.12. 107
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Please cite this article as: N.C.L. Yung, C.S.M. Wong and J.K.N. Chan et al., Mortality in patients with schizophrenia admitted for incident ischemic stroke: A population-based cohort study, European Neuropsychopharmacology, https://doi.org/10.1016/j.euroneuro.2019.12. 107
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European Neuropsychopharmacology (2019) 000, 1–6
www.elsevier.com/locate/euroneuro
SHORT COMMUNICATION
Mortality in patients with schizophrenia admitted for incident ischemic stroke: A population-based cohort study Nicholas Chak Lam Yung a, Corine Sau Man Wong a, Joe Kwun Nam Chan a, Philip Chi Fai Or b, Eric Yu Hai Chen a,c, Wing Chung Chang a,c,∗ a
Department of Psychiatry, The University of Hong Kong, Queen Mary Hospital, Hong Kong Department of Psychiatry, Queen Mary Hospital, Hospital Authority, Hong Kong c State Key Laboratory of Brain and Cognitive Sciences, the University of Hong Kong, Hong Kong b
Received 10 October 2019; received in revised form 21 November 2019; accepted 8 December 2019 Available online xxx
KEYWORDS Ischemic stroke; Mortality; Population-based study; Schizophrenia; Stroke
Abstract Evidence shows that schizophrenia is associated with increased incidence of stroke. However, relationship between schizophrenia and short-term mortality risk is understudied, and mixed findings were observed. In this retrospective population-based cohort study, we identified individuals admitted for incident ischemic stroke between 2006 and 2016 using a territory-wide electronic medical record database of public healthcare system in Hong Kong to examine 30day and 1-year mortality rates in 817 schizophrenia patients compared with 8170 patients without psychotic disorder (10:1 matched to schizophrenia patients on demographics, treatment sites and calendar-period for index admission). Multivariate regression analyses adjusting for medical comorbidities revealed that schizophrenia patients experienced elevated 1-year (16.9% vs 12.1%; p < 0.001) and 30-day mortality (7.2% vs 5.3%; p = 0.053) relative to control group. Additional age- and gender-stratified analyses revealed even more pronounced effect of schizophrenia on raised mortality risk, as indicated by higher odds, in younger-age (<65 years) group and men. Our results indicate that schizophrenia is associated with heightened shortterm mortality following incident ischemic stroke. Further research is warranted to identify factors contributing to excess post-stroke deaths among schizophrenia patients to facilitate development of effective interventions for mortality risk reduction. © 2019 Elsevier B.V. and ECNP. All rights reserved.
1. ∗ Corresponding
author at: Department of Psychiatry, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong. E-mail address: [email protected] (W.C. Chang).
Introduction
People with schizophrenia experience markedly elevated risk of premature mortality (Hjorthøj et al., 2017;
https://doi.org/10.1016/j.euroneuro.2019.12.107 0924-977X/© 2019 Elsevier B.V. and ECNP. All rights reserved. Please cite this article as: N.C.L. Yung, C.S.M. Wong and J.K.N. Chan et al., Mortality in patients with schizophrenia admitted for incident ischemic stroke: A population-based cohort study, European Neuropsychopharmacology, https://doi.org/10.1016/j.euroneuro.2019.12. 107
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N.C.L. Yung, C.S.M. Wong and J.K.N. Chan et al.
Oakley, et al., 2018). Evidence indicates that the vast majority of excess deaths in schizophrenia are attributable to physical diseases (Walker et al., 2015). Cardiovascular diseases (CVD), including stroke and ischemic heart disease (IHD), are a major contributor to premature mortality in schizophrenia. Recent meta-analytic reviews further show that schizophrenia is associated with increased incidence of stroke and IHD (Correll et al., 2017; Li et al., 2014). In fact, a substantial body of literature demonstrates raised mortality after acute coronary syndrome among schizophrenia patients relative to the general population (Shao et al., 2020). Conversely, the relationship between schizophrenia and post-stroke mortality risk is understudied. Until now, there are only four published reports in this respect. One of these studies examined 5-year post-stroke mortality and reported that schizophrenia patients exhibited heightened mortality compared with non-schizophrenia controls (Tsai et al., 2012). The remaining three studies focused on short-term post-stroke mortality with mixed findings being observed (Kang et al., 2011; Kisley et al., 2009; Willers et al., 2018). Among those two studies investigating both 1-month and 1-year mortality after stroke, one revealed that schizophrenia was associated with increased 1year mortality (Kisley et al., 2009), while the other failed to find any significant differences in mortality rates between patients with and without psychotic disorders (Willers et al., 2018). Another study even observed that schizophrenia patients had lower 90-day post-stroke mortality rate than those without schizophrenia (Kang et al., 2011). Of note, half of these reports comprised patients presenting with incident stroke and those with previous stroke history which may confound the study results (Kang et al., 2011; Willers et al., 2018). Additionally, most studies treated stroke as a single disease category without taking into consideration its subtypes in mortality analysis. Only one prior study assessed mortality rate specifically following ischemic stroke (Willers et al., 2018), which accounts for over 85% of acute strokes (Hankey, 2017), in schizophrenia. To this end, we conducted a retrospective populationbased cohort study with an aim to examine short-term (30-day and 1-year) mortality rates after admission for incident ischemic stroke in schizophrenia patients compared with those without psychotic disorders in Hong Kong (HK). Clinical data of the current investigation was retrieved from a territory-wide electronic medical record database of public healthcare services which provide governmentsubsidized, universal health coverage to 7.5 million HK residents. The potential confounding effects of medical comorbidities including hypertension, diabetes, hyperlipidemia, alcohol and substance use disorders on mortality outcome were adjusted to enable a better estimation of the relationship between schizophrenia and short-term mortality risk after stroke.
2. 2.1.
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Methods Data source
This study was conducted using Clinical Data Analysis and Reporting System (CDARS; Cheung et al., 2007), a territory-wide electronic health record database developed by the Hospital Authority (HA)
which provides public healthcare services to HK residents by managing all public hospitals, specialist and general outpatient clinics in HK. Detailed description of CDARS has been reported elsewhere (Cheung et al., 2007). Briefly, CDARS is an integrated, longitudinal patient electronic record system capturing clinical data across all healthcare settings of HA facilities since 1995. The database contains patients’ demographic and clinical information of their diagnoses, hospital admissions, visits to outpatient clinics and emergency department, to name a few. It also contains data on deaths through its internal linkage to regional deaths registry from the Immigration Department. Clinical data are collected and entered into the computerized clinical management system by treating clinicians and other healthcare professionals, and are then transferred to CDARS for audit and research purposes. CDARS generates unique, anonymized patient-identifiers to protect patient confidentiality and to link all medical records. This database has been used to conduct high-quality population-based studies for various physical and neuropsychiatric diseases (Wong et al., 2016; Man et al., 2017).
2.2.
Study sample
This was a retrospective study. We identified all individuals aged ≥18 years who had a public hospital admission for first-recorded ischemic stroke in HK during a period between 1 January 2006 and 31 December 2016. Diagnosis of ischemic stroke was identified by ICD9-CM code (433–434). Patients with past record of stroke diagnosis (ICD9-CM codes: 430–438) before an index admission were excluded. Within the incident stroke cohort, we identified a group of patients who had a principal ICD10 diagnosis of schizophrenia (F20) or schizoaffective disorder (F25) (termed schizophrenia henceforth) recorded in psychiatric inpatient and / or outpatient settings (with inpatient discharge diagnosis taking precedence over outpatient diagnosis in determining final diagnosis) prior to an index admission. CDARS-derived diagnostic ascertainment has been used for patient-sample identification in previous retrospective studies for psychotic disorders (e.g., Man et al., 2017). We then derived a “control” comparison group by randomly selecting patients from the remainder of the incident stroke cohort matched 10:1 to schizophrenia group on gender, age, calendar-year period and catchment area of healthcare services for index admission. Patients with psychiatric diagnosis of other non-affective psychoses, mania or bipolar disorder (ICD10 codes: F22-24, F28-29, F30-31) recorded preceding an index admission were excluded from control sample selection. The study was approved by the local institutional review board.
2.3.
Statistical analysis
The primary analysis was to compare schizophrenia group with control group in 30-day and 1-year mortality after admission for incident ischemic stroke. Multivariate logistic regression analyses were performed to examine the associations between schizophrenia and mortality rates, adjusting for medical comorbidities which included hypertension, diabetes, hyperlipidemia, other physical comorbidities as quantified by Charlson-Deyo comorbidity index (Deyo et al., 1992), alcohol and substance use disorders. In addition, we conducted age- (<65 years vs ≥65 years) and gender-stratified analyses to examine whether there were differential effects of schizophrenia on post-stroke mortality between age-groups and gender. Level of statistical significance for all analyses was set at p < 0.05.
3.
Results
Demographics and baseline characteristics of the study cohort (schizophrenia group, N = 817; control group,
Please cite this article as: N.C.L. Yung, C.S.M. Wong and J.K.N. Chan et al., Mortality in patients with schizophrenia admitted for incident ischemic stroke: A population-based cohort study, European Neuropsychopharmacology, https://doi.org/10.1016/j.euroneuro.2019.12. 107
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Mortality in patients with schizophrenia admitted for incident ischemic stroke: A population-based cohort study
Table 1
3
Demographics and baseline characteristics of patients admitted for ischemic stroke.
Variablesa
Schizophrenia (N = 817)
Control comparison (N = 8170)
P value
Age, mean (SD) Male gender, N (%) Calendar-year period (2006–2011),b N (%) Medical comorbidity Hypertension, N (%) Diabetes, N (%) Hyperlipidemia, N (%) Charlson comorbidity index,c mean (SD) Alcohol use disorder, N (%) Substance use disorder, N (%) Catchment areas of public health service,d N (%) Hong Kong East Hong Kong West Kowloon Central Kowloon East Kowloon West New Territories East New Territories West
67.0 (11.4) 382 (46.8) 505 (61.8)
67.0 (11.4) 3820 (46.8) 5050 (61.8)
0.995 1.000 1.000
409 (50.1) 284 (34.8) 112 (13.7) 3.1 (1.9) 14 (1.7) 8 (1.0)
3772 (46.2) 1991 (24.4) 1431 (17.5) 2.9 (1.9) 8 (0.1) 19 (0.2)
0.033 <0.001 0.006 0.093 <0.001 <0.001 1.000
61 (7.5) 48 (5.9) 134 (16.4) 95 (11.6) 217 (26.6) 115 (14.1) 147 (18.0)
610 (7.5) 480 (5.9) 1340 (16.4) 950 (11.6) 2170 (26.6) 1150 (14.1) 1470 (18.0)
a Potential group differences were examined using independent-samples t tests and chi-square tests for continuous and categorical variables, separately. b Calendar-year period of index admission was categorized into 2006–2011 and 2012–2016 periods. c Age-adjusted adapted Charlson-Deyo comorbidity index (CCI) was computed (Deyo et al., 1992). As diabetes was already treated as a medical comorbidity for covariate analysis, it was thus excluded from CCI score calculation. Cerebrovascular disease, which was the study disease of interest, was also excluded. d In Hong Kong, the Hospital Authority manages public healthcare service delivery (inpatient and specialist/general outpatient services) which is organized into 7 clusters based on geographical locations (i.e., catchment areas).
N = 8170) are summarized in Table 1. Schizophrenia patients had higher prevalence of hypertension, diabetes, alcohol and substance use disorders, but lower rate of hyperlipidemia than controls. As shown in Table 2, schizophrenia patients exhibited significantly higher 1-year mortality rate than controls (16.9% vs 12.1%). The association between schizophrenia and 30day mortality also approached significance (p = 0.053; schizophrenia patients vs controls: 7.2% vs 5.3%). Our ageand gender-stratified analyses revealed similar results as observed in full-cohort analyses, with schizophrenia being found to be associated with increased 1-year mortality in each of the stratified samples (Table 2; please also refer to supplementary Table S1 and S2 for baseline characteristics of age- and gender-stratified samples, respectively). However, the effect of schizophrenia on heightened mortality was even more pronounced, as indicated by higher odds, in younger (<65 years) age-group and men. Additionally, significant association between raised 30-day mortality and schizophrenia was only found in younger and male patients.
4.
Discussion
The current study sought to investigate the short-term mortality after admission for incident ischemic stroke in schizophrenia patients relative to those without psychotic disorders. Our results showed that schizophrenia was associated with increased 1-year and 30-day poststroke mortality risk (albeit approaching significance in
the latter) after adjusting for medical comorbidities. This is thus consistent with the only previous study which also examined short-term mortality among patients presenting with incident acute stroke and demonstrated that patients with psychotic disorders experienced significantly elevated 1-year mortality compared with those without psychotic disorders (Kisley et al., 2009). Of note, although older age was linked to higher mortality irrespective of comorbid schizophrenia diagnosis, our age-stratified analyses revealed that the influence of schizophrenia on heightened mortality was even more pronounced among patients aged under 65 years. In particular, schizophrenia was found to be associated with 2-fold increased odds of 1-year post-stroke morality in this younger-age group. This is in keeping with the widely replicated findings of markedly shortened lifespan in schizophrenia patients relative to the general population (Hjorthøj et al., 2017). Alternatively, our multivariate regression analyses (full data not shown) indicated that male gender was significantly related to 1-year mortality (adjusted OR [95% CI]: 1.15 [1.00–1.33]; p = 0.046), but not 30-day mortality (p = 0.274), for the entire study cohort. This latter finding in fact concurs with an earlier study which reported generally comparable 30-day mortality rates between men and women (aged <85 years) after first hospitalization for stroke in Hong Kong (during 2000–2007; Wu et al., 2012). Our gender-stratified analyses further showed that the association between schizophrenia and increased mortality was more prominent in men (both 30-day and 1-year mortality) than in women (1-year mortality only). However, owing to the paucity of
Please cite this article as: N.C.L. Yung, C.S.M. Wong and J.K.N. Chan et al., Mortality in patients with schizophrenia admitted for incident ischemic stroke: A population-based cohort study, European Neuropsychopharmacology, https://doi.org/10.1016/j.euroneuro.2019.12. 107
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N.C.L. Yung, C.S.M. Wong and J.K.N. Chan et al.
Table 2
Mortality of patients admitted for ischemic stroke.
Outcome
Schizophrenia N (%)
Control comparison N (%)
Unadjusted OR (95% CI)
P value
Adjusted OR (95% CI)a
P value
59 (7.2)
436 (5.3)
0.025
985 (12.1)
1.34 (1.00–1.79) 1.51 (1.22–1.85)
0.052
138 (16.9)
1.38 (1.04–1.83) 1.48 (1.22–1.80)
1.89 (1.15–3.13) 2.11 (1.47–3.02)
0.013
1.75 (1.04–2.95) 2.02 (1.38–2.96)
0.036
1.22 (0.87–1.72) 1.32 (1.04–1.67)
0.254
1.19 (0.84–1.70) 1.35 (1.05–1.73)
0.327
1.72 (1.14–2.60) 1.55 (1.16–2.08)
0.010
1.63 (1.06–2.50) 1.54 (1.13–2.11)
0.027
1.17 (0.80–1.72) 1.43 (1.10–1.86)
0.428
1.13 (0.76–1.69) 1.47 (1.11–1.94)
0.553
Full-cohort analyses A full cohort 30-day mortality 1-year mortality
<0.001
<0.001
Age-stratified analyses Patients < 65 yearsb 30-day mortality
19 (5.5)
103 (3.0)
1-year mortality
40 (11.5)
202 (5.8)
Patients ≥ 65 yearsc 30-day mortality
40 (8.5)
333 (7.1)
1-year mortality
98 (20.9)
783 (16.7)
<0.001
0.021
<0.001
0.018
Gender-stratified analyses Male patientsd 30-day mortality 1-year mortality Female patientse 30-day mortality 1-year mortality a b c d e
28 (7.3)
168 (4.4)
61 (16.0)
417 (10.9)
31 (7.1)
268 (6.2)
77 (17.7)
568 (13.1)
0.003
0.007
0.007
0.007
Multivariate regression analyses were adjusted for medical comorbidities. There were 347 schizophrenia patients and 3468 controls included in the analyses. There were 470 schizophrenia patients and 4702 controls included in the analyses. There were 382 schizophrenia patients and 3820 controls included in the analyses. There were 435 schizophrenia patients and 4350 controls included in the analyses.
existing data, further investigations are needed to verify our findings and to disentangle the relationships between schizophrenia, gender and short-term post-stroke mortality. It is suggested that raised CVD-related mortality associated with schizophrenia, including stroke, might be attributable to inequitable medical care (Lawrence and Kisely, 2010). In fact, several previous studies found that schizophrenia patients had significantly lower receipt of post-stroke reperfusion treatment and secondary preventive medications than the general population (Kisley et al., 2009; Laursen et al., 2014; Willers et al., 2018). Substantial evidence also showed that schizophrenia patients underwent inadequate guideline-recommended screening and follow-up monitoring of CVD risk factors and metabolic parameters (Ayerbe et al., 2018; Mitchell et al., 2012), as well as lower utilization of primary healthcare and medical specialist services compared with the general population (Copeland et al., 2009; Swildens et al., 2016). A recent study further reported under-diagnosis of CVD prior to CVDrelated death among schizophrenia patients (Heiberg et al., 2019). Alternatively, factors other than deficits in medical care might also contribute to heightened post-stroke mortality associated with schizophrenia including antipsychotic
treatment (Prior et al., 2014) and unhealthy lifestyle patterns such as physical inactivity, poor diet and smoking. Hence, further research is warranted to clarify the relationship between these risk factors and post-stroke mortality risk among patients with schizophrenia. There are several limitations in the study. First, a number of CVD risk factors including lifestyle patterns (e.g. smoking and physical activity levels), obesity and family history of CVD were not adequately recorded in medical database and thus were not included in the current analysis. Second, we did not have prescription data on psychotropic medications including antipsychotics which are found to be related to increased risk of stroke (Hsu et al., 2017). Third, our lack of information on receipt of post-stroke reperfusion treatment and secondary preventive medications precludes us from verifying whether schizophrenia patients receive inferior post-stroke treatment relative to control group, and whether such treatment disparity (if present) is associated with increased mortality. Fourth, given the short follow-up period, we were not able to examine the relationship between schizophrenia and longer-term post-stroke mortality. In conclusion, in this population-based cohort study of patients admitted for incident ischemic stroke, our results in-
Please cite this article as: N.C.L. Yung, C.S.M. Wong and J.K.N. Chan et al., Mortality in patients with schizophrenia admitted for incident ischemic stroke: A population-based cohort study, European Neuropsychopharmacology, https://doi.org/10.1016/j.euroneuro.2019.12. 107
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Mortality in patients with schizophrenia admitted for incident ischemic stroke: A population-based cohort study dicate that comorbid diagnosis of schizophrenia is associated with increased short-term mortality, with its effect on raised mortality risk being more prominent among younger age-group and men. Given that the causes for heightened post-stroke mortality among schizophrenia patients remain unknown, more research is required to identify factors contributing to such increased mortality risk so as to facilitate development of effective strategies for outcome improvement following stroke in this vulnerable population.
CRediT authorship contribution statement Nicholas Chak Lam Yung: Data curation, Writing - original draft, Writing - review & editing, Funding acquisition. Corine Sau Man Wong: Conceptualization, Writing - review & editing. Joe Kwun Nam Chan: Writing - review & editing. Philip Chi Fai Or: Writing - review & editing. Eric Yu Hai Chen: Writing - review & editing. Wing Chung Chang: Conceptualization, Funding acquisition, Data curation, Writing - review & editing.
Role of funding source The study was supported by the funding from the State Key Laboratory of Brain & Cognitive Sciences and the Master Research in Medicine Programme, University of Hong Kong.
Conflict of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Acknowledgment The authors would like to thank the colleagues in Hospital Authority for their kind assistance in data retrieval for the current investigation.
Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.euroneuro. 2019.12.107.
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Please cite this article as: N.C.L. Yung, C.S.M. Wong and J.K.N. Chan et al., Mortality in patients with schizophrenia admitted for incident ischemic stroke: A population-based cohort study, European Neuropsychopharmacology, https://doi.org/10.1016/j.euroneuro.2019.12. 107