Effect of intravenous thrombolysis combined with endovascular treatment on vascular recanalization rate and peak systolic velocity in patients with acute cerebral infarction

Objectives: To investigate the efficacy of intravenous thrombolysis (IVT) combined with endovascular treatment (EVT) on vascular recanalization rate and peak systolic velocity (PSV) in patients with acute cerebral infarction (ACI). Methods: A retrospective observational study was conducted from January 2019 to December 2021 in Chengdu First People’s Hospital. The clinical data of 96 patients with ACI were reviewed and the patients were assigned to either the control group (IVT alone, n=54) or the observation group (IVT+EVT, n=42). The vascular recanalization rate, PSV, neurological function, modified Rankin Scale (mRS) score and major adverse cardiovascular events (MACE) were compared between groups. Results: The vascular recanalization rate and PSV in the observation group were higher than the control group (P<0.05). The NIHSS scores of the observation group at 24 hour, one week and one month after treatment were significantly lower than those of the control group (P<0.05). The mRS scores of the observation group were significantly lower than the control group after treatment (P<0.05), while there was no difference in the incidence of MACE between groups (P>0.05). Conclusions: IVT combined with EVT can improve the vascular recanalization rate and PSV in patients with ACI, which is worthy of promotion in clinical practice.


INTRODUCTION
Acute cerebral infarction (ACI), or acute ischemic stroke, is one of the leading causes of disability and death worldwide, with 143 million disability-adjusted lifeyears and 6.55 million mortality in 2019, respectively. 1 ACI occurs when there is a cerebral artery thrombosis or embolic occlusion. 2 Treatment of ACI involves dredging of the obstructed blood vessels in time and restoring the oxygen and blood supply to the infarcted area.
Intravenous thrombolysis (IVT) is considered the gold standard treatment for ischemic stroke 3 and improves neurological function. 4 However, the recanalization rate of IVT on ACI with large vessel occlusion is low. 5 In recent years, significant progress has been made in endovascular treatment (EVT), which has greatly increased the recanalization rate and improved the prognosis of ACI patients with large vessel occlusion. 6 Many studies have investigated the effect of combined IVT with EVT (IVT+EVT) on patients with ACI, 7-9 however, results are conflicting. Our objective was to investigate the effect of IVT+EVT on recanalization rate and peak systolic velocity (PSV) to provide clinical reference for the treatment of patients with ACI.  11 First, 10% of the total dose was given as an initial bolus over one minute. Then the remaining 90% dose was infused intravenously over one hour. 11 Observation group: Patients in the observation group with arterial occlusion confirmed by magnetic resonance angiography (MRA) or CT angiography were treated with combined IVT and EVT. The IVT method was the same as the control group. After the completion of IVT, digital subtraction angiography (DSA) was performed to identify the occlusive site of the patients. According to the examination results, appropriate EVT interventions including mechanical thrombectomy, balloon dilation and stent placement were selected. The specific surgical procedures have been detailed in previous published literature. 12 After the operation, the patient was monitored for 24 hours by electrocardiogram. Patients in both groups underwent CT examination 24 hours after IVT. If there was no intracranial hemorrhage, patients were given combination antiplatelet therapy with aspirin (100 mg/d) and clopidogrel (75 mg/d). Follow up: Patients were followed up for three months post-treatment. Their neurological assessment was recorded at one month after treatment, and their modified Rankin Scale (mRS) score and major adverse cardiovascular events (MACE) were recorded at three months after treatment. Observational Indicators: Vascular recanalization rate: The recanalization of occluded blood vessels was examined by transcranial Doppler 24 hours post-treatment, and assessed according to the thrombolysis in cerebral infarction (TICI) grading system. 13 The TICI grading system is categorized into six levels: 13 Grade-0, no perfusion; Grade-1, penetration with minimal perfusion; Grade-2, partial perfusion; Grade-2a, partial perfusion (less than 2/3) of the affected territory; Grade-2b, complete perfusion of all the affected territory but the perfusion is slower than usual; Grade-3, complete perfusion. In our study, the TICI grading = 0, ≥2a and =3 was considered as vascular blocked, partial recanalization and complete recanalization, respectively.

Peak systolic velocity (PSV) of the vertebral artery:
Internal carotid artery and common carotid artery were measured by transcranial Doppler ultrasound in both groups before and 24 hours post-treatment. Neurological function: The National Institutes of Health Stroke Scale (NIHSS) 14,15 was used to assess the neurological function of patients in both groups before treatment, 24 hours post-treatment, one-week posttreatment and one-month post-treatment. The score range was 0 -42, with higher scores representing severer neurological deficits. It mRS is a 6-point disability scale with scores ranging between 0-5. A three months mRS score of ≤ 2 was considered a good outcome, while a score of 3-5 was considered a poor outcome. 16 Major adverse cardiovascular events (MACE): It includes death, intracranial hemorrhage, transient ischemic attack and cerebral infarction in new territory were recorded in the two groups three months post-treatment. Statistical Analysis: All data were analyzed using SPSS 23.0 (IBM, USA). Normally distributed and homogeneity of variance variables were described as mean ± SD and differences between the two groups were compared using Student's t-test. Not normally distributed variables were described as median (IQR) and differences between the two groups were compared using Mann-Whitney U-test. Paired-sample t-test was used to compare before and after treatment within a group. Repeated measures ANOVA was conducted for comparison of multiple time points. Qualitative variables were described as frequency and percentage (n, %), and differences between the two groups were compared by Chi-square test. P<0.05 indicated a statistically significant difference.

RESULTS
The control group included 35 males and 19 females aged 58-78 years (66.80±4.56 years) and the observation group included 26 males and 16 females aged 55-79 years (66.36 ± 6.59 years). There was no difference in baseline data between groups (P > 0.05; Table-I). The vascular recanalization rate in the observation group and the control group post-treatment were 85.7% and 61.1%, respectively. The vascular recanalization rate in the observation group was higher than that in the control group (P<0.05; Table-II).
There were no significant differences in PSV of vertebral artery, internal carotid artery and common carotid artery between groups before treatment (P>0.05). Post-treatment, the PSV of the arteries in each group was higher than that before treatment (P<0.001). The PSV of the arteries in the observation group post-treatment were significantly higher than those in the control group (P<0.001; Table-III).
There were no significant differences in NIHSS scores between groups before treatment (P>0.05). The NIHSS scores of the observation group at 24 hours, one week and one month post-treatment were significantly lower than the control group (P<0.001). The NIHSS scores in each group at these three time points were significantly lower than those before treatment within each group (P<0.001). When compared within the same group, the NIHSS scores at one week and one month post-treatment were significantly lower than those at 24 hours and one week post-treatment, respectively (P<0.001; Table-IV). The mRS scores of the observation group were significantly lower than the control group after three months of follow-up (P<0.05), but there was no difference in the incidence of MACE between the two groups (P>0.05; Table-V).

DISCUSSION
The results presented here show that the combination of IVT and EVT could significantly improve the vascular recanalization rate, neurological function, and PSV, in addition to reducing the incidence of MACE in patients with ACI.
Several studies have reported the effect of IVT+EVT in patients with ACI on the vascular recanalization rate and neurological function compared with patients treated with IVT or EVT alone. [7][8][9][17][18][19][20] Some studies have found that patients with ACI who received IVT+EVT had better recanalization rates. 8,12,17,20 A shorter time from symptom Data are presented as median (IQR) or mean ± SD. a , Mann-Whitney U-test; b , Student's t-test. Compared within the same group before treatment, *P < 0.001. onset to recanalization was associated with better clinical outcomes and neurological function in patients with ACI. 12 Further evidence shows that EVT following IVT may improve the vascular recanalization rate, subsequently improving survival and recovery in patients with acute ischemic stroke. 20 However, application of IVT+EVT may lead to higher hospital costs without improving the vascular recanalization or functional outcomes. 7 Our results confirm those in the literature, that patients receiving IVT+EVT had higher vascular recanalization rates and improved neurological function than those who received IVT alone. It is possible that the thrombolytic agent Alteplase promotes the conversion of plasminogen to plasmin, thereby dissolving the thrombus and unblocking the blood vessels. Also, the application of IVT before EVT can help to reduce the thrombus load in large vessels, improving the stability of stent and thrombus riveting. This combination may also help to dissolve secondary thrombus in collateral circulatory pathways slowing down the time of infarction and thus improving neurological function after thrombectomy. EVT can be directly applied to the vascular obstruction site which can shorten the vascular recanalization time.
In the present study, mRS was used to assess the neurological function recovery of the patients and we found that the mRS scores were lower in patients received the IVT+EVT approach, which is consistent with the findings by Huo et al 8 and Zhu et al 12 . In addition, our findings on the incidence of MACE after treatment support the study by Yang et al 21 that there was no significant difference in incidence rate of MACE in patients received EVT alone or IVT+EVT. It is suggested that IVT+EVT is as safe as IVT alone and it does not increase the risk of MACE.
Cerebral hemodynamic indexes can reflect the state of cerebral blood vessels and cerebral blood flow velocity, and PSV is a predictor of stroke. 22 There is limited data on the effect of IVT+EVT on PSV in patients with ACI. In our study, the PSV of patients receiving IVT+EVT was higher than patients receiving IVT alone, suggesting that IVT+EVT may improve cerebral blood flow perfusion in patients with ACI. As IVT+EVT can significantly shorten the vascular recanalization time, this may improve cerebral blood perfusion and avoid tissue hypoperfusion caused by vascular stenosis. Moreover, it can avoid plaque hemorrhage and thrombosis caused by the rupture of fibrous cap of unstable plaque.

Limitations of the study:
The sample size of the study was small, which may limit the generalization of the findings. Future studies with larger sample size should be conducted to further verify our observations. Moreover,

MACE, n(%)
Intracranial hemorrhage 2(4. it is a retrospective study with limited data, hence it is necessary to carry out randomized controlled trials to further confirm our findings. The follow-up period of the study was only three months, which could be further increased in future research.

CONCLUSION
The combination of IVT+EVT results in improved vascular recanalization rate, neurological function and PSV compared to IVT or EVT alone in patients with ACI.