Discussion
In the current study, we found substantial differences between centralised and non-centralised aetiological classifications of stroke subtypes in China. Factors related to the heterogeneity between centralised and non-centralised subtyping included the hospital level, geographical region/location and area of the admitting hospital; the admitting department and stroke severity. Incomplete aetiological investigation during hospitalisation and inadequate secondary prevention strategies were observed in patients with inconsistent classification by site evaluators (non-centralised) using centralised adjudication. Furthermore, we found that both a high baseline NIHSS score and admission to a stroke unit were each associated with a more consistent aetiological diagnosis between centralised and non-centralised stroke subtyping. Thus, differences in evaluation and care quality among patients with different severities might lead to inaccurate aetiological diagnoses in patients with mild neurological deficits.
The proportion of distribution of each subtype after centralised and non-centralised TOAST classification was similar to those reported in a previous registry,28 with LAA accounting for a large proportion of ischaemic stroke and CE accounting for a small proportion. The particularly high prevalence of intracranial artery stenosis in Chinese patients with stroke29 might explain the high-ranking proportion of the LAA subtype relative to the other subtypes. However, the proportion of LAA subtype among all patients classified by the non-centralised or centralised designations was different (60.8% vs 26.7%). A strict application of the TOAST classification criteria can lead to the designation of a significant number of strokes as an undetermined cause category.14 A neurologist’s ‘clinical opinion’, based on experience, might help to assign a high degree of confidence to one specific stroke cause in a particular patient when facing competing evidence of different aetiologies. Recent subtyping systems, such as the Chinese Ischaemic Stroke Subclassification (CISS) criteria, emphasise underlying pathological mechanisms and contain revised standards for categorising the LAA subtype.19 According to CISS criteria, patients with infarct in the territory of an isolated penetrating artery and evidence of atherosclerotic plaque or any degree of stenosis in the parent artery are categorised into the LAA subtype, regardless of the degree of luminal stenosis of the clinically relevant artery. With the continuously increasing development of novel techniques for plaque detection and vessel wall imaging, mild intracranial artery stenosis (<50% luminal stenosis) or non-stenotic atherosclerotic plaques are being recognised in >50% of patients with ischaemic symptoms.30 These new subtyping criteria have had a profound influence on Chinese neurologists and might bias their ‘clinical opinions’ towards the LAA subtype.
Unlike the considerably high incidence of the CE subtype in the Caucasian population,31 CE stroke accounts for only 5.7% of ischaemic strokes among Chinese patients, even with a complete aetiological investigation. Disagreements between non-centralised and centralised aetiological diagnosis of the CE subtype were mainly caused by the detection of atrial fibrillation (AF) after ischaemic stroke. AF is a well-established predictor of stroke recurrence and has a validated association with cardiogenic embolism.32 The AF-SCREEN International Collaboration recommends 72-hour electrocardiographic monitoring for AF detection.33 Because the CNSR-III protocol was written before publication of the white paper,33 a stepwise approach was used to evaluate AF using resting EKG followed by 24-hour Holter monitoring. The current diagnostic approach detected AF-related stroke in 252 patients and reassigned them to the CE category. Another reason for subtyping inconsistency might be the availability of complementary information from the centralised data collection. Newly observed high-risk or medium-risk cardiac embolism sources within centralised data contributed to 62.3% of cardioembolic stroke classifications.
Inconsistency between non-centralised and centralised classifications of the CE subtype was associated with inadequate guideline-recommended secondary prevention strategy, especially with regard to indications for treatment with oral anticoagulants. Among patients with ischaemic stroke with non-valvular atrial fibrillation (NVAF) in the CNSR without contraindications to anticoagulation, only 16.2% received warfarin therapy as secondary prevention.34 In the second CNSR (CNSR-II), the prescription rate of warfarin for patients with stroke with NVAF remained low (19.4%).35 Although an overall increase was observed in the use of oral anticoagulants in the current analysis, we found that the prescription rate in patients with unrecognised CE with indications of anticoagulation treatment (15.3%) was even lower than that reported in previous studies.34 35 Inaccurate diagnosis of CE aetiology could cause suboptimal anticoagulation treatment in patients with CE indicated for anticoagulant therapy. Enhancing the accuracy and reliability of aetiological diagnosis is an essential step to improve adherence to guideline-recommended secondary prevention treatment.
Our study has several strengths. We used an algorithm for centralised adjudication of aetiology categories, which integrated all necessary data elements collected and processed centrally by trained specialists. Furthermore, this study was based on a cohort in which >94% of all included patients underwent complete aetiological examinations. The centralised aetiology classification was reproducible and stable because it eliminated any disagreements between evaluators in the judgement step.
However, this study had certain limitations. First, the algorithm was designed based on previously published rules.12 New perspectives to stratify the sources of cardiac embolism risk are continually being updated.36 Efficient treatments for different potential embolic sources continue to be developed, such as percutaneous patent foramen ovale (PFO) closure for PFO-related stroke.37–39 For future use, the algorithm employed in the current study needs to be updated with the most recent knowledge. Second, many patients in the current study were assigned to the undetermined causes category with ≥1 competing mechanism after completing the diagnostic workup. It is thus essential to refine the hierarchical competing standard among subtype elements. Third, the standard evaluation process in the current study lacked cardiac MRI, 72-hour EKG monitoring and specific biomarkers for cardiac function. Fourth, the evaluators at each study site were trained in the use of videotape. The intra-rater and inter-rater reliabilities were not centrally assessed before aetiological diagnosis was performed. However, this reflects a real-world challenge of evaluating interobserver and intraobserver agreements of aetiological diagnoses owing to the large scale of neurological departments and constantly rotating physicians in the many hospitals in China. Efforts to improve the quality of centralised training processes and constant interactive feedback are needed to narrow the gap between non-centralised and centralised subtyping in future multicentre studies.