Efficacy and Safety of Endovascular Therapy for 34 cases of Progressive Ischemic Stroke in Posterior Circulation with Large Artery Stenosis/Occlusion

Abstract

Introduction

The incidence of posterior circulation progressive ischemic stroke (PIS) can reach 34%¹. When the lesions involve the reticular activation system, circulation center and respiratory system, once the disease progresses, it is very dangerous and endangers the life safety of patients. PIS in posterior circulation has been mainly treated with drugs, despite active treatment, there is still a high rate of disability and mortality. With the improvement of thrombectomy devices, the time window of endovascular therapy (ET) has been extended from 6 hours to 24 hours in just 5 years for anterior circulation^2-3. Up to now, DIRECT-MT study has shown that it is possible to skip intravenous thrombolysis (IVT) and direct mechanical thrombectomy⁴. However, there are few large randomized clinical trials studies on posterior circulation treated with ET. The BEST⁵ study led by Chinese scholars published in 2019 provided the highest level of evidence for vertebro-basilar artery ET, however, whether ET can improve the prognosis of PIS patients in posterior circulation is unclear. Patients with PIS of posterior circulation can only present with dizziness and unstable walking, insidious onset and easy to be ignored. When these patients come to the hospital with worsening condition, they have missed the time window of IVT and ET within 24 hours^2–3. For patients with PIS of posterior circulation caused by stenosis or occlusion of large vessels, the response to drug therapy is poor. What is the effect of ET within the time window? And what is the effect of out-of-time window? These are all questions we need to explore. Currently, there have been studies of anterior circulation comparing the effects of ET in early (within 6 hours) and late (6-72 hours), and the results prove that patients can still benefit from late revascularization⁶, while there are few reports on the effect of ET beyond the time window of the posterior circulation. The success of ET in the anterior circulation brings more treatment options for patients with PIS of posterior circulation. In this study, PIS of posterior circulation patients were selected as the research objects, and a single-center observational study was conducted to evaluate the effect of ET for PIS of posterior circulation, so as to provide evidence for the treatment direction and improve prognosis of PIS in posterior circulation.

Methods

Patients

Patients with posterior circulation PIS who were hospitalized in the Department of Neurology, The Second Affiliated Hospital of Nanchang University from May 2020 to December 2021 were consecutively enrolled, aggravating patients were treated with intravascular interventional + standard medical therapy (SMT) as the ET+SMT group, treated with pure standard drug treatment as the SMT group. All methods were approved and were performed in accordance with guidelines and regulations set by the Second Affiliated Hospital of Nanchang University Medical Research Ethics Committee, and have been performed in accordance with the Declaration of Helsinki. Informed consent was obtained from all participants and/or their legal guardians. The PIS of posterior circulation was associated with the following conditions: (1) MRI confirmed posterior circulation cerebral infarction; Meet PIS of posterior circulation definition; (2) Onset-to-ET time was beyond 6 hours; (3) MRA/CTA/DSA suggested intracranial/extracranial large artery stenosis or occlusion; (4) Patients with informed consent can cooperate to complete the study indicators; (5) modified Rankin Scale (mRS) score was 0-2 before stroke. And Exclusion criteria include: (1) Patients with cerebral hemorrhage or hemorrhage transformation after infarction; (2) Exceeded 7 days when aggravation; (3) Patients received IVT; (4) Patients who did not cooperate with follow-up; (5) Patients with malignant tumors, infectious diseases, autoimmune diseases or other serious diseases; (6) Patients with anterior circulation cerebral infarction.

Definition of PIS in posterior circulation

The widely used definition of PIS is the aggravation of the patient's condition within 24 hours of onset, and the increase of ≥4 points in the National Institutes of Health Stroke Scale (NIHSS) score is defined as PIS⁷. In our view, PIS of posterior circulation defined as within 7 days of onset, after conventional treatment such as anti-platelet, anticoagulant, lipid regulation, improve circulation, nerve protection, et al., neurological impairment still made progress, ∆NIHSS score increased ≥4 points, and lesions only involved in posterior circulation. When ∆NIHSS score <4 points, but with new lesions on imaging could still be functionally meaningful⁸.

Study design

Treatment options

The ET+SMT group received Solitaire thrombectomy, angioplasty and standard drug therapy. After mechanical thrombectomy, significant vascular stenosis still existed, such as stenosis > 70% or stenosis affects distal flow [modified Thrombolysis In Cerebral Infarction scale(mTICI)<2b] or lead to repeated reocclusion, angioplasty (balloon dilation and/or stent placement)^9-10 can be considered. The SMT group received aspirin 100 mg/d + clopidogrel 75 mg/d, continuous treatment for 3 months, or tirofiban 0.1 μg/kg/min, continuous treatment for 3-5 days, sequential aspirin+ clopidogrel, or argatroban/argatroban + clopidogrel for 7 days, sequential aspirin+ clopidogrel. When the cause is considered as cardiogenic embolism, only single antiplatelet therapy can be used after surgery, according to the condition switched to anticoagulant therapy at the later stage. It is recommended to re-examine CT 24 hours after intervention to exclude hemorrhage transformation and then give bigeminy antiplatelet therapy when considering the formation of atherosclerosis. During the treatment of both groups, statins were given to strengthen lipid-lowering, blood glucose and blood pressure would be control, dehydration and reduces intracranial pressure could be performed if necessary. If the condition is stable or improved, head CT examination can be performed within 36 hours after interventional treatment to evaluate intracranial hemorrhage. CT or MRI were used to assess posterior circulation Acute Stroke Prognosis Early CT score (pc-ASPECTS) and intracranial hemorrhage.

Data gathering

Basic information of the two groups was collected, including age, sex, medical history, history of alcohol and tobacco, etiology of cerebral infarction, responsible vessels, NIHSS score at onset, NIHSS score at exacerbation, pc-ASPECTS, complications, rate of vascular recanalization, and clinical outcome, NIHSS score and mRS score at 90 days. The main clinical outcome of the study was the proportion of patients with mRS 0-3 at 90 days; secondary clinical outcomes included the proportion of patients with mRS 0-2 at 90 days, NIHSS score at 90 days, and the distribution of mRS score. Secondary imaging outcomes included the rate of vascular recanalization (mTICI≥2b) in two groups, brain CTA/MRA showing severe stenosis/occlusion at admission was regarded as mTICI<2b. The primary endpoint for safety outcome was mortality at 90 days. Secondary endpoints were rate of symptomatic intracranial hemorrhage (sICH), and other serious adverse events included stroke-associated pneumonia (SAP) and heart failure. All images were read separately by two experienced neurologists, differences between the two were resolved by consensus. Clinical data and images informed consent was obtained from all participants and/or their legal guardians.

Statistical Analysis

Continuous variables were analyzed with the Student t test or Mann–Whitney U test according to their normality of distribution. Categorical variables were analyzed with χ² or Fisher exact tests. The primary and secondary outcomes, safety events and adverse events were analyzed by linear regression analysis or Logistic regression analysis, and the survival analysis was analyzed by K-M curve analysis. We selected these confounders on the basis of their associations with the outcomes of interest or a change in effect estimate of more than 10%. P < 0.05 in data comparison indicated that the difference was statistically significant. Statistical analysis were performed using R version 3.4.3(www.R-project.org)and Empower States（www.Empowerstats.com).

Results

Of the 36 patients were included. According to literature review during the collection process, 1 case in the ET + SMT did not meet the inclusion criteria, and 1 case in the ET + SMT had a history of lung cancer during the follow-up, which was excluded according to the exclusion criteria. In the final, 21 cases into ET + SMT, and no case was lost to follow-up, 13 cases in the SMT, and 1 case was lost to follow-up(Fig. 1).

Discussion

There was no significant difference in baseline data between ET + SMT group and SMT group, which made it possible to compare the treatment effects between the two groups. In the ET + SMT group, mRS 0–2 and mRS score in multivariate Logistic regression analysis and linear regression analysis were better than those in the SMT group. ET did significantly improve the living quality of patients with PIS of posterior circulation, and have improved neurologic impairment and survival of patients with a higher deteriorative NIHSS score (NIHSS ≥ 15). Traditional antiplatelet, anticoagulant, reduce blood lipids, improve circulation, difficult to dissolve the mass of stearic plaque or large thrombi, ET can increase the rate of vascular recanalization in patients with low-perfusion watershed infarction caused by large artery stenosis/occlusion, and did not increase the risk of symptomatic intracranial hemorrhage. The risk of SAP and heart failure was similar in both groups. The brain tissue of ischemic penumbra was not completely necrotic, recanalization and blood flow reperfusion were achieved in the early stage of ET. The symptoms of dizziness, paralysis and consciousness disturbance were improved, and the patient could take the initiative to recover, reduce time of ventilator use, bed time and complications, and improve the survival rate. The follow-up results of the two groups showed that patients with low NIHSS score at the time of progression tended to have lower or no significant increase NIHSS score and mRS score 90 days later, with a better prognosis. Conservative treatment could be selected for these patients, but longer follow-up time is needed to verify the long-term prognosis. In this study, 9 patients died, which may be related to the change of the patient's consciousness level affecting swallowing function, vomiting and aspiration, and long-term bed rest, combined with SAP and heart failure during hospitalization. The mortality of patients in the ET + SMT group was lower than that in SMT group, which was statistically different from the previous results of BEST⁵. This may be related to the small sample size, which needs to be verified by further large-scale studies. In addition, the cases collected during the same period were more willing to choose interventional, which may also result in fewer cases in SMT group than in ET + SMT group. Previous studies on intravascular therapy for ischemic stroke did not include patients with posterior circulation vascular diseases in order to promote intravascular therapy in pursuit of better therapeutic effect. Based on the study of anterior circulation endovascular therapy, the BEST⁵ study provided the highest level of evidence for thrombectomy for vertebro-basilar artery occlusion, suggesting that ET for stroke patients with acute vertebro-basilar artery occlusion may be safe and feasible. The guidelines suggest that mechanical thrombectomy should be considered after imaging evaluation in patients with acute basilar artery occlusion within 6–24 hours of onset. For patients with large vessel occlusion more than 24 hours after onset, the benefit of mechanical thrombectomy is not clear¹¹. In our study, as a result of some patients have mild onset symptoms, they didn't take it seriously, when they came to the hospital for aggravation, they had missed the best time for treatment, or a lesser degree of disability when aggravated, the patient and his family members did not agree to ET because of the risk of operation, when the pros and cons were weighed again or the disease got worse again, they decided to have ET treatment, the onset-to-ET time tend to be more than 24 hours, deterioration-to-ET time was also more than 24 hours, but we did it to save the ischemic penumbra rather than the core infarct. Animal experiments have shown that the volume of ischemic penumbra changes dynamically and can be identified by MRI¹². Due to the existence of collateral circulation, penumbra can persist for a period of time, therefore, delayed reperfusion of ischemic stroke can also improve neurological dysfunction by restoring blood flow to penumbra¹³, and clinical cases reported that patients can still benefit from ET 3 months or more after onset¹⁴. Infarct core was populated by microglial cells, endothelial cells, neural progenitor cells, and neural stem cells after recanalization, additionally, the penumbral region was abundant with neurons and astrocytes, cells in the area around the infarction might help remove debris and release pro-angiogenic, anti-inflammatory, and neuroprotective factors, neural stem cells can differentiate into new blood vessels, astrocytes and neurons, all of these will contribute to the recovery of brain tissue¹⁵. Another mechanism for protection of ischemic area is that permanent occlusion can stimulate the liver produce hepatocyte growth factor (HGF), serum release of fibroblast growth factor 21 (FGF21), FGF21 activated the FGFR1/PI3K/Caspase-3 signaling pathway, which attenuated neuronal apoptosis. A similar mechanism was observed for HGF. Bone marrow stem cells can be converted into new neurons, spleen macrophages can remove cellular debris, when recanalization, these beneficial cells and secreted factors reach the infarct area through blood flow and promote the repair of brain tissue^16–17. Our research shows that beyond the guidelines for 24 hours, ET can still improve the symptoms of patients with nerve function defect, has potential therapeutic value. MRI/CT perfusion was used in our study, Flair-DWI mismatches¹⁸ and ASL-DWI mismatches¹⁹ can reveal penumbra, which is conducive to ET. If ET is selected based on the presence of ischemic penumbra, it may be safe and feasible for PIS beyond the traditional 6 hours⁶. Since NIHSS scores are not sensitive to the posterior circulation, more studies are needed to better define PIS of posterior circulation. At this point, we can use MRI/CT perfusion mismatches to screen patients eligible for ET²⁰. With the improvement of the ability of more accurate and personalized measurement tools to identify the penumbra, it is valuable for suitable patients to ET even days or months after aggravation. Patients with delayed recanalization should be carefully selected according to their condition and be performed by an experienced clinician. For chronic stenosis or occlusion caused by atherosclerosis, ischemic area has certain compensatory ability, symptoms can be mild, there was no significant difference between angioplasty treatment and conservative treatment in these patients^21–22, the operation may be delayed after acute phase if the condition was stable and ET was required, but for associated with severe neurologic deficits, especially acute stroke caused by large artery embolism, lack of collateral compensatory, patients with onset nasty, serious, soon consciousness obstacle, reperfusion of the occluded artery should proceed as soon as possible. As a small sample study on the safety of ET for PIS of posterior circulation, linear regression analysis showed that among patients with severe neurological deficits at the time of deterioration (NIHSS ≥ 15), 90-day mRS scores in ET + SMT were 3.33 points lower than those in SMT, and delayed recanalization still benefited, which was consistent with the study on anterior circulation^6,23, but the indications for ET should be strictly controlled, age, underlying diseases, baseline NIHSS score, time window of ET, vascular lesions, related risk, willingness of patients and their families and cost of operation should be considered.

Some limitations of the present study must be addressed when interpreting the results. First of all, our study was a retrospective study, reviewing a small sample size database, which limited the ability to rectify differences between the two groups, in this study, only age, sex were adjusted. However, all data were measured by clinicians who were trained to record the data according to hospital standards. Secondly, we assumed that aspirin and clopidogrel were taken regularly for 90 days in two groups, although most of the follow-up of patients with long-term use of antiplatelet drugs or anticoagulant drugs, we don't know whether patients to stop taking one of antiplatelet drugs or replace other antiplatelet drugs, it is impossible to judge whether patients' medication compliance interferes with the study results.

Conclusions

In conclusion, our study provided evidence of a significant advantage in favourable neurological outcomes in patients treated with interventional therapy plus standard drug therapy compared with those treated with standard drug therapy alone. For PIS of posterior circulation due to large vessel stenosis/occlusion with severe neurological impairment, ET is preferred after aggressive conservative therapy, improves those patients outcome and survival. Delayed recanalization still has better therapeutic effect. It is hoped that this study will be validated and evaluated in a larger prospective, multicenter, randomized controlled trial.

Declarations

Acknowledgements

The authors want to thank all the patients and participants involved in the study. Special thanks are due to Key R&D Plan of Jiangxi Provincial Department of Science and Technology - general project, for the fnancial support.

Author contributions

Dandan Li: Methodology, Formal analysis, Investigation, Data curation, Writing e original draft, Writing e review & editing, Visualization, Supervision. Yang Chen: Data curation, Methodology, Formal analysis, Supervision. Xin Luo: Data curation, Writing-original draft, Writing-review & editing. Zhijuan Cheng: Writing-original draft, Writing guidance. Keqi Lei: Data collection, Investigation, Visualization. Weiping Chen: Data curation, Data interpretation, Writing-review & editing. Min Yin: Data curation, Data interpretation. Fang Li, Kai Wang: Data collection, Writing-original draft. Jianglong Tu: Methodology, Writing guidance, Writing-review & editing, Supervision.

Competing interests 

The authors declare no competing interests.

Availability of data and materials

Correspondence and requests for materials should be addressed to Jianglong Tu. 

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