4. Discussion
This research is a retrospective, real-world analysis focusing on recurrent stroke in AIS patients in our in-hospital cohort. Our study found that the in-hospital recurrence rate was reduced over time, especially in the minor stroke patients and large-artery atherosclerosis stroke patients. Infection was an obvious risk factor for in-hospital stroke recurrence. Diabetes may also be an influencing factor, especially in large-artery atherosclerosis stroke groups. A tendency of positive antiplatelet therapy was also presented over time.
Our results show that a decrease in in-hospital recurrence mainly occurred in patients with the LAA subtype. There is a consensus that LAA patients have a higher risk of early recurrence similar to the patients in our center during the early stage. However, we reached a different conclusion regarding patients admitted during the later stage (
Table 1,
p < 0.001 in Stage 1 vs.
p = 0.097 in Stage 2), although the absolute value of the recurrence rate was still higher in the patients with the LAA subtype. The subgroup analysis also revealed a reduction in the recurrence rate in the minor stroke patients. Increasing evidence suggests that DAPT with clopidogrel and aspirin provides greater protection against recurrent stroke than monotherapy, especially in minor stroke patients and patients with arterial stenosis. The CHANCE trial [
12] published in 2013 demonstrated the benefit of DAPT within 24 h of symptom onset in Chinese minor stroke patients despite the increased risk of bleeding. Subsequently, the POINT trial in 2018 [
15], which included multiracial patients across various centers, reported reductions in ischaemic stroke occurrence in the DAPT cohort. The THALES trial in 2020 extended the DAPT regimen as the combination of ticagrelor and aspirin could reduce the risk of the composite of stroke or death within 30 days in mild-to-moderate AIS patients [
16]. Nevertheless, in our study, the reduction in in-hospital recurrence was not related to DAPT, although the patients in those subgroups should have theoretically benefited from DAPT. Further analysis of the tendency of antiplatelet regimens showed that the patients with recurrence received more positive therapy. The patients with clinical features associated with atherosclerosis also received active antiplatelet treatment. Due to the limitations of retrospective studies, this result can only reveal a relationship in which patients with a higher risk of recurrent ischaemic stroke may also be treated more aggressively.
Our research also shows progress in comprehensive stroke management. The new version of Chinese stroke guideline pointed out the importance of treatment in acute phase. The guideline standardized the extended time window, indications and contraindications for intravenous thrombolysis. Apart from the early use of dual antiplatelet therapy, other treatments including anticoagulant therapy, blood pressure management, blood glucose management and the use of neuroprotective agents were also updated. In our center, the patients received more aggressive treatments and risk factor screening examinations in the later period. Although statins do not appear to be effective in preventing all types of strokes or reducing all-cause mortality, they might reduce the risk of recurrent ischaemic events with previous attacks [
17]. In-hospital statin initiation was linked to better early stroke outcomes [
18]. The early initiation of existing treatments, including antiplatelet therapy, statins and blood pressure control, after minor stroke could result in an 80% reduction in the risk of early recurrence [
19]. Some drug trials have revealed a beneficial effect of intensive glycemic control on risk of stroke although further high-quality studies are required to confirm that [
20]. Therefore, the clinical practice in our center reflected the effects of improved secondary prevention on the decrease in in-hospital recurrence. However, the number of patients with reperfusion therapy is limited. Improvement in reperfusion therapy is also not obvious in our center. Although the current study did not show any association between early reperfusion therapy and in-hospital recurrence in atherosclerotic stroke or minor stroke patients, reperfusion is still the primary goal of stroke treatment. Therefore, promotion of reperfusion therapy should be prioritized for improvement in future development efforts.
Despite the improvement in the awareness of secondary prevention, many patients had in-hospital recurrences. An alternative reason is the presence of antiplatelet nonresponsiveness. For example, polymorphisms in the CYP2C19 gene are strongly associated with the therapeutic effect of clopidogrel, and loss-of-function variants in the CYP2C19 gene are widespread in East Asian populations [
21]. Unfortunately, due to data deficiency in our center, these factors were not included in this analysis. Infection is another noteworthy topic. Yu F et al. [
9], Erdur et al. [
10] and Xu et al. [
22] analyzed the risk factors of in-hospital recurrence and noted that urinary or respiratory infections were associated with a higher risk of stroke recurrence. Infection may trigger the recurrence of stroke via infection-related platelet activation and aggregation, inflammation-induced thrombosis, impaired endothelial function, etc. [
23]. The glycoprotein (GP) Ib and GPVI-mediated pathways and the activation of coagulation factor XII, rather than GPIIb–IIIa-mediated aggregation, are the main checkpoints in inflammation-induced platelet activation [
24]. The current antiplatelet drugs have limited influence on the pathways mentioned above. Therefore, the common treatments may not be effective enough to prevent neothrombosis. However, the preventive use of antibiotic therapy in AIS patients cannot improve the clinical outcomes despite a reduction in urinary tract infections [
25]. Moreover, neuroinflammation has been recognized as a critical element in the onset and progression of ischaemic stroke. The role of platelet-immunocyte interactions during inflammation also contributes to atherosclerosis [
26]. Further studies should focus on biomarkers and interventions in thrombotic and neuroinflammatory pathways. The burden of diabetes is another important factor related to early recurrent stroke. A post hoc analysis of the CHANCE trial showed that diabetes was associated with an increased risk of recurrent stroke after a minor stroke or TIA after 3 months of follow-up. There was no difference in the effect of antiplatelet treatment in reducing these events in patients with or without diabetes [
27].
Our stratification of antiplatelet regimens was mainly based on the criterion used in the CHANCE trial, which was a coarse analysis. However, a trend of radical antiplatelet therapy was shown during the period of the guideline update. Kim et al. [
28] reported that a large atherosclerotic burden might affect the selection of a combination of DAPT. Similarly, the large-artery atherosclerosis patients in our study were likely to be treated positively. Patients who present with aphasia or coma may have intracranial or external vascular stenosis; thus, these patients may be treated aggressively even before a vascular examination. A previous study reported that the risk reduction in the subgroup with diabetes by antiplatelet treatment was only 7% compared with an average reduction of 22% in all patients [
29]. The patients with unstable blood glucose in our study were less likely to be undertreated, probably to prevent any form of deterioration, including recurrence. However, a potential risk of positive antiplatelet therapy exists. A post hoc analysis of the CHANCE trial revealed that compared with monotherapy, the benefit of clopidogrel-aspirin treatment was offset by the potential risk of hemorrhage after a short course of treatment, which was approximately 10 days [
30]. The rate of bleeding events increased during the second period in our center, although these patients already had a higher risk of hemorrhagic transformation considering the stroke subtype and severity of the index stroke (
Table S6).
Another aspect worthy of attention is that patients with cardioembolic stroke have a high risk of in-hospital recurrence during both periods. The risk of early recurrence in the first two weeks after cardioembolic ischaemic stroke is between approximately 0·5% and 1·3% per day [
31]. It seems that anticoagulant therapy is more widely used in our center, but there was no statistically significant decrease in recurrence. A previous study revealed that ischaemic stroke patients with atrial fibrillation shared similar risk factors with thrombotic stroke patients [
32]. Meanwhile, the risk factors for atherosclerosis, including diabetes and hypertension, are responsible for the development of atrial fibrillation. Infection is also related to atrial fibrillation in stroke patients [
33]. Therefore, potentially undiagnosed atrial fibrillation may also contribute to in-hospital recurrence. This finding highlights that long-term electrocardiographic (ECG) monitoring needs to be more widely adopted.
This study has some limitations. First, our study adopted a retrospective, single-center design and lacked out-of-hospital follow-up information. Our findings need to be further confirmed in a study with a larger sample size and prospective research. Second, the assessment of antiplatelet therapy adopted a crude approach. Vascular evaluation results are also important in choosing an antiplatelet regimen, and these data were not included during the grouping process. Third, we could only use the information in electronic medical records; as a result, some important information, such as the mechanism of recurrent stroke, was not included. The evaluations of other risk factors, treatments, comorbidities and complications are also insufficient. In Stage 2, the prescription of anticoagulants seemed to be related to ischaemic recurrence. However, accurate records of anticoagulation treatment after antiplatelet therapy are not available for all cardioembolic stroke cases; thus, we did not analyze the relationship between treatments and in-hospital recurrence in cardioembolic patients. Compared with Stage 1, more patients in Stage 2 received antihypertensive or hypoglycemic treatment. Further analysis needs to be broadened to include a more detailed therapy regimen and the effect on the outcome event. Fourth, the lack of detailed imaging data and vascular assessment results is another important limitation. Infarcts in different periods, multiple acute infarcts, lesions with different circulations, and isolated cortical lesions all indicate a higher risk of early recurrence [
8]. Minor stroke patients with acute large vessel occlusion are at risk of early recurrence, which may be caused by hypoperfusion [
34]. CTP changes can be used to predict subsequent ischaemic tissue injury on DWI in TIA/minor stroke patients and have been shown to be of value in predicting recurrence [
35]. The lack of relevant evaluation may lead to under-identification of risk populations. This population may have been undertreated in our study. The lack of advanced imaging may also deny a segment of patients access to a potentially beneficial reperfusion treatment. Therefore, the imaging features of the index stroke and evaluation of vascular stenosis should strongly be considered in subsequent studies.