Mechanical thrombectomy (MT) combined with intravenous thrombolysis (IVT) was confirmed to be superior to IVT alone for acute ischaemic stroke (AIS) caused by large vessel occlusion (LVO) in the anterior circulation in five randomized trials in 2015 (1). Direct Intra-arterial Thrombectomy to Revascularize Acute Ischaemic Stroke Patients with Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals: a Multicentre Randomized Clinical Trial (DIRECT-MT) pointed out that the effect and safety of direct MT was noninferior to bridging therapy for acute LVO patients eligible for IVT (2).

Cardioembolic (CE) stroke accounts for almost 30% of all ischaemic strokes (3), and the incidence is increasing (4). Cardioembolic stroke is usually more destructive than the nonembolic mechanisms of stroke, especially when considering that CE LVO is more likely to cause greater cerebral ischaemia (5). Approximately 50% of LVOs are caused by thrombi from cardioembolic (CE) sources such as atrial fibrillation (6), and the histopathologic composition of CE thrombi is different from that of noncardioembolic (N-CE) thrombi (7). The efficacy of endovascular treatment in CE LVO is higher than that in N-CE LVO (6). Alteplase is more effective in CE than in N-CE patients due to the clot composition and its dimensions (8). Our previous subgroup analysis indicated that there were no obvious differences in the modified Rankin Scale (mRS) score at 90 days and safety between the direct MT and bridging therapy groups in the different stroke etiology (9). However, we have not analyzed the effect of intravenous thrombolysis prior to endovascular treatment in the different subgroups of CE LVO in our main study.

In the DIRECT-MT trial, 44.2% of all enrolled patients were identified as having cardioembolic LVO (44.6% in the direct mechanical thrombectomy group and 43.8% in the bridging therapy). This study provided an opportunity to explore the benefit of intravenous alteplase before thrombectomy for the different subgroups of cardioembolic stroke.

This subgroup analysis within the DIRECT-MT cohort evaluated the effectiveness and safety of intravenous alteplase before endovascular thrombectomy in acute cardioembolic stroke patients. No statistically significant benefit was found in the treatment of bridging therapy for CE-LVO stroke patients. In the treatment-by-subgroup analysis for CE-LVO stroke patients, we found that age, the time from onset of symptoms to randomization, the occlusion location and the collateral grades did not affect the functional outcomes and safety of bridging therapy. However, in the treatment-by-baseline NIHSS analysis, it was found that patients with an NIHSS ≤ 15 in the direct MT group had better outcomes and lower mortality rates, while the efficacy and safety remained similar in the NIHSS > 15 CE-LVO stroke patients. This finding was different from previous studies, which indicated that LVO patients who underwent bridging therapy had better functional outcomes and lower mortality than patients who underwent direct MT treatment (15, 16).

Whether to initiate intravenous thrombolysis before mechanical thrombectomy for acute LVO is still controversial. It has been found that intravenous alteplase before MT can increase the early reperfusion rate and improve functional outcomes with the hypothesis that alteplase can reduce the hardness of the thrombi and can dissolve them (17, 18). On the other hand, intravenous alteplase was reported to cause thrombus fragmentation, thrombus migration and clot formation in new territories, which may lead to longer recanalization times and lower full reperfusion rates (19). In addition, intravenous alteplase may increase the incidence of symptomatic ICH (20). Our study found that higher percentages of sICH were more likely to occur in the patients treated with bridging therapy than in the patients with direct MT (aOR, 0.37 [0.125, 1.089]; p = 0.071). However, no significant differences were found in the patient functional outcome, final recanalization rate or the development of an embolism in new territory between the direct MT and bridging groups.

In our study, a better functional outcome and a lower mortality rate were observed in the CE-LVO patients with an NIHSS ≤ 15 in the direct MT group, while no difference in the functional outcome and mortality was found in the CE-LVO patients with an NIHSS > 15. Furthermore, a higher first-pass reperfusion rate was achieved in CE-LVO patients with an NIHSS ≤ 15 in the direct MT group, while there was no difference between the two treatment groups in the first-pass reperfusion rate in CE-LVO patients with an NIHSS > 15. As Zaidat et al. (21) reported, first-pass reperfusion was associated with higher rates of a better functional outcome and a lower mortality rate. This interaction was also found in the ETIS (endovascular treatment in ischaemic stroke) study (22) and was identified by Nikoubashman et al. (23). Therefore, we boldly inferred that first-pass reperfusion was the main cause for the difference in the effectiveness and safety between the two treatment groups in CE-LVO patients with NIHSS ≤ 15, while there were no differences in the other factors. On the one hand, first-pass reperfusion can reduce the time from onset to recanalization and limit the expansion of the infarct core volume (24). On the other hand, repeated mechanical thrombectomy would cause more injury to the vascular endothelium, which potentially has a negative impact on the efficacy and safety (25, 26). In addition, Chueh et al. (27) reported that thousands of tiny thrombus fragments were caused by any mechanical thrombectomy, and these tiny thrombus fragments could escape to small arterioles and capillaries and occlude them. These tiny thrombus fragments cannot be seen on digital subtraction angiography and magnetic resonance imaging, but they could lead to new small embolic infarctions and modify the clinical outcome (28). Moreover, as previous studies have described, the predictors of first-pass reperfusion included age, the occlusion sites, the combined first-line device strategy and so on. However, differences in these factors were not found in the two treatment groups in the CE-LVO patients with an NIHSS ≤ 15 in our study. A possible explanation could be that alteplase works better in medium vessel occlusions (29) or cardioembolic thrombi (8). In our study, more MCA occlusion occurred in the CE-LVO patients with an NIHSS ≤ 15 than in those with an NIHSS > 15. However, a very low percentage of patients were infused with a full dose of alteplase before MT (2). We hypothesized that inadequate alteplase before MT would not only reduce the effect of intravenous thrombolysis but would also destroy the stability of the thrombus (30). The decrease in thrombus stability will increase the incidence of thrombus fragmentation and subsequent distal embolism (31, 32), further reducing the rate of successful reperfusion after the first pass and complete recanalization. A higher first-pass rate and complete recanalization were associated with better neurologic outcomes (21, 33). Although there was no difference in the final complete recanalization between the two treatments, thrombus fragmentation and small distal emboli may be important factors affecting the clinical outcome (28).

This study has some limitations. One limitation is the small sample size. In the DIRECT-MT study, approximately 45% of strokes were caused by cardioembolism, and patients with an NIHSS < 15 accounted for only approximately one-third of the CE stroke patients, with ~50 patients per treatment group. And although the overall proportion of the site of the occlusion is not different, there were M2 patients of NIHSS ≤ 15 in the direct MT group which are more prone to be recanalized by IVT and associated with better prognosis. Second, almost all cardiogenic strokes (99%) are caused by atrial fibrillation, which is a relatively higher proportion than the real world. Previous studies have indicated that IVT for stroke patients with AF provided no benefit and potentially increased the risk of intracerebral hemorrhage and mortality (34). This may partially explain our results. In addition to atrial fibrillation, cardiogenic stroke can have many other causes, including foramen ovale, aortic arch atheroma, prosthetic heart valves and others (4). These patients were found to have an undetermined cause of stroke in the DIRECT-MT study through multimodal long-term vascular and cardiac examinations (35), although the thrombus composition could be similar to CE stroke (7). We might be able to generate more widely applicable theories when that data is available. In addition, the infusion of alteplase was completed before MT in only 4 of 53 patients of NIHSS ≤ 15 in the bridging group. DIRECT-MT study included no transit patients. The patients were all randomized at the main center. If the patient was randomly assigned to the bridging group, start using rt-PA and enter the operating room at the same time for thrombectomy. This may reduce the effect of alteplase and influence the results of this study.

In conclusion, thrombectomy alone might be a more reasonable choice for mild and moderate cardioembolic stroke patients. This need to be confirmed by further prospective studies in a larger number of patients.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The study was reviewed and approved by the ethics committees and research boards of the First People's Hospital of Changzhou and Naval Medical University Changhai hospital. Written informed consent was obtained before enrollment from all the patients or their legal representatives. The patients/participants provided their written informed consent to participate in this study.

YP, ML, and JL conceived and designed the study and including quality assurance and control. JC and PX collected the data and wrote the paper. PY and YZ designed the study's analytic strategy. ZL, WC, TL, and SW analyzed the data. XZ, RC, HS, JX, and TJ reviewed and edited the manuscript. All authors read and approved the manuscript.

This work was supported by a grant (GN-2017R0001) from the Stroke Prevention Project of the National Health Commission of the People's Republic of China and by the Wu Jieping Medical Foundation. This work was partly supported by the Basic Research Project of the Changzhou Science and Technology Bureau (No. CJ20200111).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.