Rationale and design of the GOLDEN BRIDGE II: a cluster-randomised multifaceted intervention trial of an artificial intelligence-based cerebrovascular disease clinical decision support system to improve stroke outcomes and care quality in China

Study design

The GOLDEN BRIDGE II trial is a multicentre, open-labelled, cluster-randomised multifaceted intervention study designed to evaluate the effects of cerebrovascular disease AI-CDSS on new composite vascular events (including ischaemic stroke, haemorrhagic stroke, myocardial infarction or vascular death) at 3 months in patients who had an AIS. The cerebrovascular disease AI-CDSS will provide AI-assisted imaging analysis, auxiliary stroke aetiology and pathogenesis analysis, and guideline-based treatment recommendations for patients in the intervention group. On the other hand, patients in the control group will receive usual care. All patients will be enrolled sequentially and receive follow-ups at 3, 6 and 12 months after stroke onset. The flow chart of the study is shown in figure 1. The study was registered on ClinicalTrials.gov (NCT: 04524624).

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Participants

To ensure diversity, the geographical location and grade of hospitals were considered. The included hospitals cover the eastern, central and western regions of China, with proportional recruitment of secondary and tertiary hospitals. A total of 80 hospitals located across 23 provinces, autonomous regions or municipalities in mainland China were included. The criteria for hospital inclusion and exclusion are shown in table 1.

This trial is specifically designed for patients over the age of 18 with AIS confirmed by imaging of the brain within 7 days of symptom onset, and excludes those with the diagnosis of transient ischaemic attack (TIA), haemorrhagic stroke or non-cerebrovascular diseases. The inclusion and exclusion criteria for the participants are shown in table 2.

Intervention

The clustered randomisation will be completed before each hospital is enrolled in the study, and the eligible participants with AIS in the intervention group will receive the AI-based analysis and the recommended treatment provided by the cerebrovascular disease AI-CDSS. The specific AI-CDSS intervention protocol includes AI-assisted imaging analysis, auxiliary analysis of ischaemic stroke aetiology and pathogenesis, and guideline-based treatment recommendations for acute and secondary prevention.

The AI-CDSS obtains patients’ clinical data and imaging data from the hospital information system and uses the method of stroke image automatic interpretation technology based on deep learning combined with a stroke clinical knowledge base to provide assistant clinical decisions including imaging diagnosis, aetiological classification and treatment decision of ischaemic stroke (figure 2 and online supplemental material).

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The neurologists in the intervention hospitals will complete training on cerebrovascular disease AI-CDSS before the start of this study. A 2-week transition phase of AI-CDSS intensive intervention will be completed before the patients are enrolled. All participants in the hospital of the control group received normal routine diagnosis and treatment (figure 3).

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Randomisation

The computer-generated random number sequence will be used for cluster randomisation at the hospital level, and two independent biostatisticians (YJ and H-QG) will be aware of it. Participating hospitals are randomly grouped on a 1:1 basis. To prevent imbalance, hospital location and grade are matched during randomisation. A confirmation letter will be provided to each hospital 1 month before the intervention’s implementation to assure readiness. If the chosen hospital could not complete the study, it was replaced with another one of equivalent capacity and economic–geographic region strata.

Primary outcome

The primary outcome is a new composite vascular event (including ischaemic stroke, haemorrhagic stroke, myocardial infarction or vascular death) at 3 months after stroke onset.

Secondary outcomes

The secondary outcomes include: (1) the composite measure score of medical service indicators for AIS care quality, (2) a new composite vascular event at 6 and 12 months after stroke onset, (3) disability based on the modified Rankin Scale (mRS=3–6) at 3, 6 and 12 months after stroke onset and (4) average hospitalisation days, average total hospitalisation cost, average hospitalisation drug cost and average hospitalisation examination cost.

Safety outcomes

The primary safety outcome refers to the occurrence of moderate or severe bleeding events as defined by the Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) within 3 months after stroke onset. The secondary safety outcomes include severe or moderate bleeding (as defined by GUSTO) within 6 and 12 months. In addition, all bleeding events (including severe or moderate bleeding) within 3, 6 and 12 months are included.

Study organisation

The International Academic Steering Committee is comprised of the cochief investigators and members. It provides the scientific basis and strategic guidance for the trial, overseeing research design, execution and publication-related activities. Additionally, the Academic Steering Committee chairs meetings of the Senior Management Group. The Executive Committee, comprised of experienced experts guided by the International Academic Steering Committee, aims to monitor the trial’s progress, ensure participants’ safety and provide scientifically grounded decisions on whether to terminate, modify or continue the trial. The Data Safety Monitoring Board regularly monitors the progress of the study to ensure adherence to the highest ethical and patient safety standards. Furthermore, it provides written recommendations to the Chair of the Trial Steering Committee following each meeting. The Quality Improvement Committee, consisting of clinical specialists and experts in stroke quality improvement, is responsible for supervising adherence to stroke care quality standards.

Data collection

The executive committee has approved the case report form.10 11 Baseline data include demographic information, medical history, medication history, prestroke mRS Score, time of stroke onset, baseline National Institutes of Health Stroke Scale (NIHSS) Score and imaging data. Trained clinical research coordinators at each site are responsible for collecting this information on admission. Subsequently, data collected at discharge including final aetiological classification, in-hospital treatments, in-hospital complications, NIHSS Score at discharge, mRS score at discharge, medications for secondary prevention at discharge, hospitalisation costs and other data. A face-to-face interview is conducted at 3 months after stroke onset, followed by concentrated telephone follow-ups at 6 and 12 months after stroke onset. The data collected at 3, 6 and 12 months include current mRS Score, medication adherence, stroke recurrence, all-cause mortality and other clinical events. All interviewers will be oblivious to the patients’ cluster assignment.

Sample size

The main null hypothesis of this study was that, compared with those who receive traditional routine diagnosis and treatment, there would be no difference in the incidence of new vascular events observed at 3 months among patients who had a stroke treated with interventions recommended by the cerebrovascular disease AI-CDSS.

According to the findings of the third China National stroke Registry study, patients who had an AIS or TIA had a 3-month new composite vascular event rate of 6.4%.10 We assumed that the rate of 3-month new composite vascular events would be reduced to 4.7% (relative decrease of 26%) by using multiple quality-improving interventions with AI-CDSS, which decrease rate was made based on data from the GOLDEN BRIDGE trial.³ We initiated the trial with a target sample size of 21 689 participants from 80 hospitals with a 2-sided significance level of 5%, with 80% power to see a reduction of 26% in new composite vascular events, 10% of people not being followed up with and an intraclass correlation coefficient of 0.01.

Statistical analyses

In this study, efficacy analysis will be performed using intention-to-treat analysis.12 Categorical variables are typically presented in the form of counts and percentages, whereas continuous variables are commonly displayed as means and SD or alternatively as medians accompanied by IQRs. For continuous variables, t-tests or Wilcoxon Rank Sum tests will be used, and for categorical variables, the χ² t-test or Fisher’s exact test will be used. The primary outcome will be tested using a mixed effects logistic regression with a random effect or generalized estimating equation for the cluster (hospital). The methodology employed for the primary outcome will be used for the analysis of the categorical secondary outcomes. Mixed effects linear regression model incorporating a random effect or generalized estimating equation for the cluster (hospital) will be employed to analyse continuous secondary outcomes. All statistical analyses will be performed by using SAS V.9.4 software.