Invasive Management of Vertebrobasilar Artery Stenosis and Occlusion: A Meta-Analysis on Efficacy and Safety Endpoints

Vertebrobasilar angioplasty and stenting or mechanical thrombectomy (MT) using a stent retriever or suction thrombectomy are effective interventions in managing acute ischemic stroke caused by vertebrobasilar artery occlusion (VBAO). This study aims to investigate the safety and efficacy of self-expanding stents and balloon angioplasty in managing ischemic stroke. We reviewed the literature for relevant clinical trials and included those reporting the following primary outcomes: successful recanalization, favorable clinical outcome, and stenosis degree change. We included 24 studies (858 patients). In the subgroup analysis, participants were divided into three main subgroups based on the type of intervention: mechanical thrombectomy (MT), percutaneous transluminal angioplasty and stenting (PTAS), and MT+PTAS. Regarding overall mortality, the incidence was 34.5%, 9.9%, and 28.9% in the MT, PTAS, and MT+PTAS groups, respectively. The incidence of arterial dissection was 3.6% in the MT group, 3.1% in the PTAS group, and 16.7% in the MT+PTAS group. Incidence of distal embolization, MT, PTAS, and MT+PTAS groups had 3.4%, 5.8%, and 9.5% incidence rates, respectively. Favorable clinical outcomes were reported in 42.8% of subjects in the MT+PTAS group, 64.7% in the PTAS group, and 39.2% in the MT group. The incidence of intracranial hemorrhage was 5.2%, 4.5%, and 15.3% in the MT, PTAS, MT + PTAS groups, respectively. The incidence of successful recanalization was 85.3% in the MT group, 99.4% in the PTAS group, and 92.7% in the MT+PTAS group. Our analysis concludes that PTAS is the most effective intervention for VBAO and is associated with a lower rate of mortality compared to mechanical thrombectomy alone.

Many cases of VBAO are undiagnosed or misdiagnosed [9]. This is likely because the most common initial symptoms are nonspecific, including but not limited to vertigo, dizziness, vomiting, and head or neck pain [9,10]. Further, CT or MR angiography reveals stenosis or occlusion of the affected artery in about 25% of posterior circulation strokes [11,12]. Currently, the standard care varies depending on the location of the occlusion. Due to the lack of data from randomized clinical trials, decisions regarding extradural occlusion are mostly dependent upon clinician judgment. In addition to risk factor modification, management options include single antiplatelet therapy and PTAS [13]. Unfortunately, antithrombotic agents and intravenous thrombolytics have yielded poor results in achieving recanalization of affected vasculature [14][15][16][17][18]. Several studies suggest that mechanical thrombectomy (MT) using devices such as stent retriever or suction thrombectomy is a safe and effective treatment for acute ischemic stroke caused by vertebrobasilar artery occlusion [19][20][21]. Vertebrobasilar angioplasty and stenting are effective options for patients with atherosclerotic vertebrobasilar disease [22]. There are various methods for achieving successful recanalization, including intra-arterial thrombolysis and percutaneous transluminal angioplasty (PTA) [23]. Although surgical management is a well-known and effective treatment option for intracranial vertebrobasilar atherosclerosis, there are high morbidity and mortality rates [24,25]. While the percutaneous management of vertebral artery occlusion was associated with lower morbidity than surgical repair [26], VBAO is generally associated with a relatively good prognosis. The only factor favoring better outcomes and prognosis is early recanalization of the occluded vessels [27][28][29].
A limited number of studies have been conducted regarding the safety and efficacy of self-expanding stents and balloon angioplasty in the management of ischemic stroke secondary to VBAO. Therefore, we conducted this systematic review and meta-analysis.

Methodology
We followed the criteria of preferred reporting items for systematic reviews and meta-analyses (PRISMA) in designing our systematic review and meta-analysis [30].

Literature Search
We searched the following databases for relevant articles published through November 2020: PubMed, Cochrane Central, Scopus, and Web of Science. We used the following keywords "basilar," "vertebral," "vertebra-basilar," "recanalization," "revascularization," "occlusion," "stenosis," "thrombosis," "stent," "thrombectomy," and "angioplasty." All authors screened the titles and abstracts of the obtained records independently according to the eligibility criteria, followed by full-text screening, and when there was a conflict about the inclusion decision, it was solved by discussion.

Eligibility Criteria
We included one-arm retrospective and prospective observational cohort studies of patients with basilar, vertebral, or vertebral-basilar artery occlusion who had undergone an invasive intervention: mechanical thrombectomy or angioplasty with or without a stent. Our primary outcomes were successful recanalization, favorable clinical outcome, and stenosis degree change. Secondary outcomes included mortality, postoperative complications, NIHSS (National Institute of Health Stroke Scale) score change, need for retreatment, and Modified Rankin Scale (MRS) score change.

Data Extraction
We independently extracted data related to patient characteristics, procedure-related complications, and outcomes. Patient characteristics included age, gender, presenting symptoms, comorbidities, and site of occlusion. Procedure outcomes were post-procedure successful recanalization rate, favorable recanalization at three months, post-procedure NIHSS change, post-procedure MRS change, and post-procedural stenosis change. Post-procedure-related complications were the need for retreatment, infarction, intracranial hemorrhage (ICH), stent embolism, re-occlusion, restenosis, artery dissection, distal emboli, transient ischemic attack, and stroke. Successful recanalization was defined as a Modified Treatment in Cerebral Ischemia (mTICI) score of 2B or 3 measured after procedure performance or technical success. A favorable outcome was defined as the MRS between (0-2) at three months of follow-up.

Quality Assessment
We assessed the quality of the included studies by the Newcastle Ottawa scale (NOS). The NOS contains three main domains: selection, comparability, and ascertainment of the outcome. It is based on reviewer judgment by marking stars on specific items under each domain if matched in the included studies. A high number of total stars represents good quality.

Meta-Analysis
We calculated the qualitative outcomes by pooling each study's proportions by the untransformed proportion equation, and the pooled proportion was presented with a 95% confidence interval (95% CI). Regarding quantitative outcomes, we calculated the change in MRS and NIHSS according to the Cochrane Handbook for Systematic Reviews of Interventions [31], then a meta-analysis was performed by pooling mean change values of each study using the inverse-variance method, and the pooled mean change value was presented with 95% CI. Results were considered significant when the p-value was less than 0.05. We used OpenMeta [Analyst] (an open source software available at http://www.cebm.brown.edu/openmeta/) to perform this meta-analysis.

Heterogeneity
We used the random-effects model as the existent difference between studies on patient characteristics, severity, site of occlusion, and various procedures. We tested heterogeneity by the chi-square test. Outcomes were considered homogenous if the P-value was more than 0.1 and I2 was less than 50%. In the case of heterogeneous outcomes, we performed a sensitivity test and searched for the cause of heterogeneity.

Search results
Our search of four databases revealed 1219 results. By Endnote software, 449 studies were excluded due to duplication. We performed title and abstract screening for the remaining 770 results. Study outcomes that were irrelevant to our study, posthoc analyses, non-English language studies, review articles, conference abstracts, editorials, or individual case reports were excluded. Only 29 of them were eligible for full-text screening. After the full-text screening, we included 24 studies according to our inclusion criteria. Twentytwo studies were retrospective cohort studies, and the two studies were prospective cohorts. We searched all references included in each study manually, but no further records were added to the included studies. We excluded five studies in the full-text screening for reasons including stenting of other cranial vessels. The PRISMA flow diagram is shown in Figure 1.

Characteristics of included studies
The 22 cohort studies recruited 864 participants. The earliest of them was published in 1999 and the latest in 2019. Six studies were conducted in China, four in Germany, three in the USA, three in Australia, two in Japan, and one study in each of these countries: the UK, Turkey, Korea, and Spain. According to the type of treatment, three subgroups were defined: Percutaneous transluminal angioplasty with or without stenting (PTAS), Mechanical thrombectomy (MT), and combination PTAS+MT. A detailed summary of the characteristics of both included studies and the participants is illustrated in Table 1.

Comorbidities
Eighteen studies reported the presence of baseline comorbidities with the potential to influence the success of intervention or contribute to further complications. These comorbidities included hyperlipidemia/ hypercholesterolemia, hypertension, diabetes mellitus, coronary artery disease, peripheral vascular disease, smoking, and alcohol consumption. This is summarized in Table 2.

Risk of bias assessment
The quality of the included studies ranged from moderate to high, as shown in the risk of bias graph, and summary ( Figure 2).

FIGURE 2: A summary and a graph showing the risk of bias in the included studies
Selection: Regarding the representativeness of the exposed cohort, all studies are of low risk of bias. The same was found to be true of the non-exposed cohort. Concerning the ascertainment of exposure, the presence of surgical records and follow-up interviews confer a low risk of bias. Finally, regarding the demonstration that the outcome of interest was not present at the start of the study, all studies are of low risk of bias.
Outcome: Regarding confidence in assessing outcomes, all studies were of low risk of bias as an independent blind assessment was conducted. As for follow-up, all studies are of low risk of bias. Regarding the adequacy of cohorts' follow-up, 13 studies [13,22,[32][33][34]37,40,42,44,45,47,48,50] reported adequate details suggesting no missing data or the missed data is not enough to have a significant impact on the intervention. Therefore, they were considered at low risk of bias. However, nine studies [31,35,36,38,39,41,43,46,49] did not report enough data about this outcome; thus, they were put at unclear risk of bias.

Discussion
Our analysis found that the use of mechanical thrombectomy alone is associated with the highest rates of adverse events and mortality. Percutaneous transluminal angioplasty with or without stenting is the most effective and least associated with mortality. Additionally, we found that the intervention led to a significant increase in NIHSS score but did not significantly increase the MRS score at discharge.
Endovascular therapy includes balloon-mounted stents, balloon angioplasty alone, and self-expandable stents with or without prior angioplasty [51]. Zhang et al. found that treatment with self-expanding stents has a higher risk of restenosis and longer operative time than treatment with balloon-mounted stents in patients with symptomatic intracranial vertebrobasilar arterial stenosis [50].
A review by Luo et al. suggested endovascular treatment as an effective and safe option for the management of intracranial atherosclerotic stenosis if it is used in selected patients and performed with an experienced team who could carefully manage the patients before, during, and after the procedure [51]. These results appear inconsistent with our results. Nevertheless, Goyal et al., in their review, presented challenges with the implementation of endovascular therapy that needed to be resolved. The first, viable implementation of the outcomes across a large number of people; the second, observing, empowering, and approving the new treatments that bring about additional improvements; and third, making a framework to permit induction of outcomes of trials on patients that were not previously tested. Finally, increasing the accessibility of endovascular therapy in developing countries [52].
Thrombolysis, either intravenous thrombolysis or local intra-arterial thrombolysis are among the treatments used to manage vertebrobasilar system stenosis or occlusion. They are considered the most treatment used for revascularization of acute vertebrobasilar artery occlusion. Intra-arterial thrombolysis (IAT) achieves a higher rate of revascularization than intravenous thrombolysis (IVT), but there is not much difference between the efficacy of both [53,54]. Moreover, there is a strong relationship between the occlusion site and the efficacy of intravenous thrombolysis to achieve revascularization and earlier neurological recovery successfully. The chance for successful revascularization is least with terminal internal carotid artery occlusion, but a higher chance for revascularization is with smaller and more distal occlusion [55,56]. Lindeberg et al. revealed that the recanalization rate is higher in patients treated with intravenous thrombolysis than those treated with endovascular techniques [53].
Endarterectomy and reconstruction are surgical treatments offered for the management of atherosclerotic stenosis of the vertebral artery. However, their performance has been diminished in recent years and replaced with endovascular interventions for refractory cases to medical treatment [57].
Our analysis's main strength is the inclusion of a large number of studies performed in different countries and the absence of any evidence of heterogeneity in the analysis. Conversely, cohort design, either retrospective or prospective with a moderate to high risk of bias, is considered the main limitation. We used subgroup analysis to overcome the inconsistency among the included studies. Further studies are recommended to compare the efficacy and safety of the medical treatment and endovascular therapy in managing vertebrobasilar system stenosis or occlusion.

Conclusions
With regard to VBAO, we conclude that PTA with or without stenting is associated with better outcomes and a lower rate of mortality when compared to MT alone.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.