Overview of the study

The Impairment of CognitiON and Sleep after acute ischemic stroke or transient ischemic attack study in Chinese patients (ICONS) is one of the research subgroups of China National Stroke Registry-III (CNSR-III).17 CNSR-III is a national prospective registry that recruited consecutive AIS or TIA in-hospital patients within 7 days after onset from 201 hospitals that cover 22 provinces and 4 municipalities in China.17

In 201 hospitals of the CNSR-III study, the steering committee of ICONS chose hospitals nationwide to represent the population from each region of east, south, west, north and centre of Mainland China. Fifty-two hospitals with the experience of cognition and sleep research were invited initially and 40 hospitals with qualified research capability and proved commitment to the study were ultimately selected. The complete list of ICONS members and sites could be found in online supplementary appendix S1, including 35 grade III hospitals (usually central hospitals for certain city or district) and five grade II hospitals (usually hospitals serving several communities). Figure 1 presented the geographical locations of all participating sites.

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Figure 1

The geographical locations of participating sites in ICONS. AIS, acute ischaemic stroke; TIA, transient ischaemic attack. Xiaoling Liao illustrated the figure 1.

The primary aim of this study is to investigate the occurrence and associated factors of cognitive impairment and sleep disorder after AIS or TIA.

Patient enrolment

Between August 2015 and January 2018, in 40 selected sites that joined both CNSR-III and ICONS study, all patients participating in CNSR-III study were screened. If the patient met the criteria of ICONS study and signed informed consent, the patient would be also enrolled to the ICONS study.

The inclusion criteria of ICONS were same as CNSR-III, including: age older than 18 years; in-hospital AIS or TIA patients within 7 days after onset. However, the following exclusion criteria were added to ICONS, including: prior diagnosis of cognitive impairment, schizophrenia or psychosis disease; illiterate patients; and concomitant neurological disorders that interfere with cognitive or sleep evaluation, for example, severe aphasia defined as National Institutes of Health Stroke Scale (NIHSS) item 9＞2, visual impairment, hearing loss, dyslexia, severe unilateral neglect or consciousness disorders. AIS and TIA were defined according to the WHO criteria and confirmed by brain MRI or CT.17 18 Cerebral infarction on MRI or CT without symptoms and signs were excluded.

Baseline data collection and data management

The baseline data collection and processing methods of the ICONS study were same as that of the CNSR-III study.17 The information was collected including patient demographics, education level, occupation, medical history, risk factor of stroke assessment, laboratory tests and NIHSS score, and in addition to all information in the CNSR-III study, patients enrolled in the ICONS study were supplemented with medical history information including cognitive impairment, insomnia, apnoea and restless legs syndrome. For physical examination, measurement of neck circumference was added.

An electronic data capture system (EDC) was developed by Zhinantech company and used for data collection. It provided the opportunity of simultaneous automatic data check for completeness and logical correction of the uploaded data and would be better to improve the data quality. Independent data monitoring was performed through EDC by an independent contract research organisation throughout the study period. All data were deidentified before data analysis to protect patient confidentiality.

Biological sample and imaging collection

Biological sample and imaging collection were also same as the CNSR-III study.17 Blood samples were collected within 24 hours of admission, at 3 months and 12 months after stroke. Urine samples were collected at the first day of enrolment (within 24 hours) and 3-month follow-up. In ICONS study, MRI was recommended for all patients, including diffusion-weighted imaging with apparent diffusion coefficient maps, T1 weighted, T2 weighted, fluid-attenuated inversion recovery, T2*/susceptibility-weighted imaging and magnetic resonance angiography. All MRI image data were collected in DICOM format on discs and sent to the image research centre in Beijing Tiantan Hospital for centralised quality control, privacy removal, standardised naming and double-blind manual interpretation analysis. If interpretation is in doubt, mediation analysis will be conducted by the committee of imaging experts.

Follow-up data collection and data management

Information including functional status, cardiovascular/cerebrovascular events, compliance of recommended secondary prevention medication and risk factor control was queried at 3 months, 6 months and 1–5 year annually follow-up by trained research coordinators together with CNSR-III study.17 In addition to those above, patients enrolled in the ICONS study were supplemented with the following information.

At 2 weeks or discharge, 3 months and 12 months, Montreal Cognitive Assessment (MoCA),19 20 Pittsburgh Sleep Quality Index,21 Epworth Sleeping Scale,22 Anxiety Disorder-7,23 Patient Health Questionnaire-9 (PHQ-9),24 Stroke Impact Scale and general 10 m walking speed test were evaluated face to face.25 26 All tests above were administered by trained examiners.

At 6 months, if patients could cooperate, comprehensive neuropsychological assessment would be performed face to face. The scales including MoCA, Auditory Verbal Learning Test, Symbol Digit Modalities Test, Verbal Fluency Test, Boston Naming Test, Rey-Osterrieth Complex Figure Test, Rey-Osterrieth Complex Figure Test, Stroop Color-Word Test-Chinese version, Chinese modified version of the Trail Making Test-A and B, PHQ-9, Informant Questionnaire on Cognitive Decline and activities of daily living. All tests were administered by trained examiners.

In the medication survey at each follow-up point, antidementia drugs, antidepressant drugs and insomnia treatment drugs were added in ICONS. The list of antidementia drug collection information includes donepezil, memantine hydrochloride, rivastigmine and galantamine. Selective serotonin reuptake inhibitor and selective serotonin–norepinephrine reuptake inhibitors antidepressant drugs were both collected., and the list of insomnia treatment drugs included 17 commonly used drugs, such as diazepam, estazolam, alprazolam, zolpidem tartrate and zopiclone.

Statistical analysis

The processing method for dropout were same as that of the CNSR-III study.17 Patients who were not eligible at the baseline or could not complete the scale evaluation at 2 weeks were excluded from the study. The association of most imaging and biological markers with the occurrence of cognitive impairment or sleep disorder will be performed by univariate and multivariate Cox proportional hazard regression model and HRs with their 95% CIs will be evaluated. For the outcome of poor functional outcome, univariate and multivariate logistic regression will be performed and ORs with their 95% CI will be evaluated.

In this article, the analyses focused on the baseline characteristics. Categorical variables were presented as percentages and continuous variables as mean with SD or median with IQR. Comparison of baseline variables among different groups were performed using χ² test or Fisher’s exact test for categorical variables and t test or Mann-Whitney test for continuous variables. The level of significance was p<0.05 (two sided). All analyses were conducted with SAS V.9.4.