The Efficacy and Safety of Mechanical Thrombectomy in Posterior Circulation Large Vessel Occlusion as Compared to Anterior Circulation Large Vessel Occlusion: A Systematic Review

Mechanical thrombectomy (MT) has been established as a standard of care for patients with stroke due to anterior circulation large vessel occlusion (AC-LVO). Due to a lack of robust evidence for the effectiveness of mechanical thrombectomy, intravenous thrombolysis (IVT) is still the only approved first-line acute reperfusion strategy for posterior circulation large vessel occlusion (PC-LVO). This systematic review analyzes and reports on the effectiveness and safety of MT in PC-LVO. A literature review was performed to identify all studies of patients with acute ischemic stroke due to PC-LVO who underwent MT with second-generation devices (stent retrievers and/or aspiration devices) that were reported between January 2017 and January 2023. The primary outcome was functional independence at 90 days, defined as a modified Rankin (mRS) score of ≤2. Secondary outcomes were successful recanalization (modified treatment in cerebral infarction score (mTICI) 2b/3), symptomatic intracerebral hemorrhage (sICH), and mortality at 90 days post-procedure. We looked at 13 studies with a total of 30,407 participants in four meta-analyses and 5951 participants in nine observational studies. In most studies, patients in the PC-LVO group were male and younger than the AC-LVO group. Higher baseline National Institutes of Health Stroke Scale (NIHSS) score, lower rates of IVT, longer onset-to-groin puncture time, lower likelihood of sICH, higher 90-day mortality rates, and higher futile recanalization rates were frequently observed in the PC-LVO group with a large discrepancy in the likelihood of functional independence at 90 days with majority studies showing comparable rates. Hence, in patients with acute ischemic stroke caused by the PC-LVO, successful reperfusion can be achieved via MT, though at the cost of higher mortality rates. Such futile recanalization can be avoided with the refinement of procedures through technical improvements, skills training, and recognition of reliable predictors associated with it, which might help increase the efficacy of MT in PC-LVO. Additionally, future large-scale RCTs comparing patient selection and interventional strategies to avoid futile interventions are also needed.


Introduction And Background
Stroke is ranked as the second leading cause of death with an annual mortality rate of about 5.5 million, and it is the leading cause of disability worldwide [1].It can be classified into anterior circulation stroke (ACS) and posterior circulation stroke (PCS) according to vascular territory involvement, with PCS responsible for 20% of cases [2].
Due to its varied presentation, PCS is more likely to be misdiagnosed than ACS.Depending on the blood supply and collateral status, the presentation can vary from subtle findings to devastating neurological deficits [3].The basilar artery, which supplies most of the brain stem, occipital lobes, and part of the cerebellum and thalami, is the main artery of the posterior circulation.Patients with acute basilar artery occlusion (BAO) present with symptoms varying from isolated cranial nerve palsies or hemiplegia to lockedin syndrome, often leading to delays in reaching hospitals within golden hours of treatment [4].
The treatment strategy for acute ischemic stroke (AIS) is opening the occluded blood vessels to reestablish blood flow.The National Institute of Neurological Disorders and Stroke (NINDS) trial revolutionalized the management of AIS using recombinant tissue plasminogen activator (tPA) within three hours [5].Eventually, the treatment window period was increased to 4.5 hours after the European Cooperative Acute Stroke Study (ECASS) III trial [6].Currently recommended first-line therapy for AIS is still intravenous thrombolysis (IVT) using tPA when a patient reaches within 4.5 hours [7].However, less than 10% of patients are eligible for IVT because the efficacy of IVT is time-dependent, and patients who have contraindications to tPA, received major surgery recently, or have a history of intracranial hemorrhage are ineligible [8,9].In addition, IVT is less effective in patients with proximal large-vessel occlusion (LVO), mainly in the terminal internal carotid artery, proximal middle cerebral artery, and basilar artery, rather than in more distal occlusion [10,11].Therefore, clinical worsening is expected in many cases of LVO unless endovascular mechanical thrombectomy (MT) is initiated.
To improve the low rates of recanalization, several new thrombolytic drugs and treatment strategies, especially mechanical thrombectomy, emerged and were proven effective [12,13].In 2015, five randomized clinical trials (SWIFT PRIME (Solitaire™ with the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke), REVASCAT (Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours), MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands), EXTEND-IA (Extending the Time for Thrombolysis in Emergency Neurological Deficits -Intra-Arterial), and ESCAPE (Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke)) conducted across Europe, North America, and Australia reported an overwhelming benefit of the second-generation mechanical thrombectomy devices compared to IVT in opening occluded vessels [14][15][16][17][18].A subsequent meta-analysis indicated that MT was associated with significantly higher rates of angiographic revascularization and functional independence compared to standard medical care with tPA alone [12].These findings have led to a major shift in managing patients with LVO, and MT is gradually being adopted worldwide.
However, the vessel occlusion location of patients included in the above trials was mainly in the anterior circulation, based on which American Heart Association/American Stroke Association (AHA/ASA) guidelines published in 2015 established MT as the management of choice in a patient with anterior circulation LVO (AC-LVO).No high-class evidence exists for posterior circulation LVO (PC-LVO) [19].IVT is still the standard of care in patients with acute BAO and other large vessel occlusions in the posterior circulation [20].
Though initial studies like the Basilar Artery Occlusion Endovascular Intervention Versus Standard Medical Treatment (BEST) and the Basilar Artery International Cooperation Study (BASICS) trials both failed to demonstrate the efficacy of MT for PC-LVO, multicenter randomized control trial (RCT) of endovascular treatment for acute ischemic stroke in the Netherlands registry showed that high rates of favorable clinical outcomes and successful reperfusion could be achieved with MT for PCS despite high mortality [21][22][23][24].The prospective multicenter Revascularization in Ischemic Stroke Patients (REVASK) registry also showed that MT in PCS had a lower risk of symptomatic intracerebral hemorrhage (sICH) and similar effectiveness compared to ACS [24].It has also been shown that PCS patients benefit from MT beyond six hours after symptom onset and even up to 24 hours using advanced brain imaging [21].Given the success in MT treatment of AC-LVO, neuro-interventionists routinely perform MT in PC-LVO in the absence of level-1 evidence supporting the use of thrombectomy after PCS.
Hence, this present systematic review is aimed at analyzing the available resources and evidence to determine the efficacy and safety of MT in PC-LVO as compared to AC-LVO.

Data Extraction
Two writers independently carried out the data extraction.From all qualifying studies, demographic and baseline data were gathered, including first author, publication date, participant count, age, sex, initial National Institutes of Health Stroke Scale (NIHSS), site of LVO, therapy intervention tools, onset-topuncture time, passes, and start to reperfusion time.

Study Quality Assessment and Reducing the Risk of Bias
The Newcastle-Ottawa Scale was employed to assess the quality of the included observational studies semiquantitatively.The maximum number of stars was nine on the Newcastle-Ottawa scale.A study with ≥ 7 stars was of high quality; otherwise, it was of low quality.Similarly, the AMSTAR checklist was used to assess the quality of the systematic review and meta-analysis.The maximum number of stars was 11 on the AMSTAR checklist.A study with ≥ 8 was of high quality; otherwise, it is of low quality.The quality of the included study was high.

Study Identification and Selection
We identified a total of 4759 relevant articles reported between 2017 and 2023 using all databases.In total, 2802 duplicate articles were removed before screening them in detail.One hundred and eighty-eight articles were shortlisted after screening these articles by going through titles and abstracts and retrieving full texts.The shortlisted full-text articles were assessed for eligibility and quality, and 13 articles were finalized for review.The selection process of the studies is shown in Figure 1 in the PRISMA flowchart.

Outcomes Measured
Primary outcome was functional independence (defined as an mRS score of ≤2) at 90 days after the procedure.Secondary outcomes were successful recanalization (mTICI 2b/3), mortality at 90 days after the procedure, and sICH.

Study Characteristics
We examined 13 studies, of which four were systematic reviews and meta-analyses, and nine were prospective/ retrospective observational studies.Out of nine observational studies, five were multicenter, and four were single-center.All of them included acute ischemic stroke patients presenting with isolated AC-LVO or PC-LVO undergoing MT with or without IVT and were assessed as separate treatment arms.In each study, a comparison of baseline characteristics like patient numbers, age, gender, baseline NIHSS score, site of LVO, initial treatment with intravenous tPA, onset to groin puncture time and outcomes in the form of successful recanalization (TICI 2b/3), sICH, functional independence at 90 days (mRS 0-2) and mortality at 90 days post-procedure was made between both arms.A total of 5951 patients were reviewed in nine observational studies where 733 patients with PC-LVO and 5218 patients with AC-LVO underwent MT.In four meta-analyses, a total of 30,407 patients were reviewed.Table 1 shows a summary and characteristics of all included studies.Performing mechanical thrombectomy on PC strokes is more time-consuming and laborious than AC strokes.Older age and longer procedure duration make it more likely that the procedure will be unsuccessful in BAO cases.

Discussion
Strokes occurring due to PC-LVO and AC-LVO differ in terms of their pathophysiology, clinical features, and the outcome of their acute management with endovascular MT.Limited sample size and few RCTs including PC-LVO patients make the safety and efficacy of MT difficult to assess in the PC-LVO group, which has been confirmed in AC-LVO.
The morbidity and mortality rates of conservatively managed acute BAO (largest subgroup in PC-LVO) can reach up to 80-90% [39], which is the highest among all types of ischemic stroke.Patients who enroll in RCTs are seeking treatment and hence, they should not be randomized to a conservative treatment group which is logically known to be inferior to MT, given its success in AC-LVO.In AC-LVO, MT has been accepted in most clinical settings as the best way to obtain recanalization.Therefore, randomizing patients with PC-LVO into groups including no-MT is considered mostly unethical.
Among the few RCTs that focused on PCS, the BEST RCT was terminated due to loss of equipoise, resulting from a high crossover rate and was topped by a small sample size.This trial reported no difference in favorable outcomes between MT patients and those receiving only standard medical treatment, including IVT [22].Similarly, another RCT, the BASICS trial, failed to demonstrate MT's efficacy for PC-LVO.
Recently, a few studies have shown that MT in the posterior circulation appears to have a similar safety and efficacy profile in carefully selected patients.Still, such studies are underpowered and provide lower-quality evidence to guide PC-LVO treatment decisions [23,24].
Therefore, we conducted a systemic review of studies done over five years (2017 to 2023) to study the extent to which MT in PC-LVO differs from that in AC-LVO.Patients in these studies underwent MT using secondgeneration MT devices which were introduced in the last decade with proven superiority to first-generation MT devices.

Baseline Characteristics of PC-LVO versus AC-LVO
Results of characteristics like age, gender, baseline NIHSS, and site of LVO for the included studies are reported in Table 2 and Table 3.   [27,30].In the meta-analysis by Wang et al., baseline pre-thrombectomy NIHSS varied [35].The reason for this discrepancy could be partly explained by the NIHSS being highly weighted toward deficits occurring in AC-LVO, such as aphasia and hemiparesis, and neglecting PC-LVO symptomatology, such as unsteady gait, dysphagia, and oculomotor deficits [24].On the other hand, once posterior circulation occlusion (PCO) leads to a disturbance of consciousness, the NIHSS score will increase significantly.Therefore, for a given NIHSS score, patients with PC-LVO may have a more serious condition than patients with AC-LVO.

Studies
IVT rates: PC-LVO patients received IVT less often than AC-LVO patients, as shown in all the included nine observational studies and meta-analyses by Wang et al. and Mbroh et al. [35,38].The most reasonable explanation for this is IVT being a time-dependent treatment and the varied symptomatology of PC-LVO strokes.Prodromal symptoms are seen in up to 60% of cases of PC-LVO, which is a reason for misdiagnosis and wrong specialty consultation in many cases [4,40].Visual deficits, ataxia, giddiness, and decreased level of consciousness, the most common signs and symptoms of acute PC-LVO, can confuse clinicians with "stroke chameleons" [41][42][43].As a result, PC-LVO patients may not succeed in presenting within the widely accepted 4.5-hour time window to receive IVT [44].Also, patients with PCS are often in severe condition when admitted to the hospital, often missing the opportunity for acute treatment [45].
Onset-to-groin puncture times: Delay in MT in patients with PC-LVO was reflected in the longer onset-togroin puncture times, which was observed in all the included observational studies.[27,29,31,32].A meta-analysis by Mbroh et al. also showed significantly longer onset-to-groin puncture time in the PC-LVO group (standardized mean difference (SMD) = 0.59, 95%CI 0.33-0.85,p < 0.00001) [38].The same argument for why PC-LVO patients present as stroke chameleons and are misdiagnosed, delaying definitive care, can be used to explain this observation.

PC-LVO versus AC-LVO Thrombectomy: Technical Efficacy
Successful recanalization (mTICI 2b/3 grade recanalization): As shown in Table 4, there was no statistically significant difference in rates of successful recanalization (defined as mTICI 2b/3 grade recanalization) between PC-LVO and AC-LVO cohorts in all the observational studies included in this analysis except Meinel et al., where they showed higher odds of successful recanalization in PC-LVO cohort (OR=2.740,95%CI 1.145-6.554,p=0.011) [31].This exceptionally high rate was explained by advances in MT technique, operator adjudication, use of thrombolysis in cerebral infarction (TICI) score in PC-LVO in their registry, and different patient selection methods [31].Also, successful recanalization rates were comparable in all four meta-analyses included in the review as shown in Table 5.    [30][31][32].

Studies
PCO versus ACO Thrombectomy: Safety sICH: The likelihood of sICH, which was defined as any intracranial hemorrhage associated with an increase of 4 points or more on the NIHSS score, was significantly lower in PC-LVO compared to AC-LVO as shown in all the four included meta-analyses.A similar finding was observed in all the included observational studies, although not in a statistically significant range.
We can try to explain why patients with PC-LVO receiving MT have a lower rate of sICH than patients with AC-LVO with the following points: (a) compared to anterior circulation, posterior circulation vessels are mostly small end-arteries, with relatively less high perfusion and less reperfusion injury than anterior circulation vessels [46,47], (b) there is more hemodynamic flow in the carotid artery than the vertebral artery; thus, the vascular bed pressure is higher in the anterior circulation system, (c) the infarction area occurred in PCS is usually relatively small than that in ACS, which may decrease the risk of bleeding events [48,49], (d) abundance of collateral circulation existing in posterior circulation leads to slower evolution of irreversible ischemia and, 5) lower IVT rate in PC-LVO group leading to fewer rates of sICH.Favorable functional outcome (mRS 0-2) at 90 days: There was a large discrepancy in the likelihood of favorable functional outcomes seen after MT in PC-LVO compared to AC-LVO, as shown in Table 4 and Table 5. showed worse 90-day functional outcomes after MT for PC-LVO, which could be due to higher baseline severity of stroke at admission, laborious and time-consuming endovascular procedures, a tendency towards a higher rate of complications related with the procedures and higher mortality rates in studied patients [29,30].

PC-LVO versus AC-LVO
Mortality (mRS 6) at 90 days: MT in PC-LVO was associated with a significantly higher mortality likelihood than AC-LVO, as shown in all four meta-analyses.Similarly, 90-day mortality rates were also significantly higher in the PC-LVO group in all the observational studies except Weber et al., Alaweih et al., and Uno et al., where the rates were comparable [27,28,34].This higher 90-day mortality in PC-LVO patients can result from higher baseline NIHSS, which is suggestive of higher stroke severity on admission.It has been consistently shown as an important predictor of bad stroke outcomes, especially in the posterior circulation [50,51].Here, many studies only included patients with BAO for the PC-LVO group, and in the rest of the others, the basilar artery was the most frequent site of PC-LVO.Stroke due to BAO has been described as the most severe in relation to other occlusion sites in PC-LVO, which may explain this higher mortality [52].In addition, the higher mortality rate in PC-LVO might be attributable to the damage occurring to the vital brainstem centers leading to a deep comatose state, dysphagia, respiration difficulties leading to ventilatory support, tracheostomy, pneumonia, and complications due to long-term bedridden state.Although it is agreed upon that younger patients tend to have a better stroke outcome than older patients, this study demonstrates that although PC-LVO patients are younger, they have a greater mortality rate than AC-LVO patients.
Futile recanalization: Futile recanalization, defined as the poor functional outcome with mRS 4-6, despite successful recanalization by MT, has been reported in individual studies as being significantly higher in PC-LVO than AC-LVO [31,35].In the study by Meinel et al., futile recanalization was found more often in BAO, with 47% and 34% of patients achieving futile recanalization in PC-LVO and AC-LVO groups, respectively (adjusted OR (aOR)=2.146,95%CI 1.267-3.633,p=0.002) [31].Similar results were found in a meta-analysis by Wang et al., who found that the PC-LVO group had a 1.75 times higher risk of futile recanalization (OR-1.75;95%CI 1.30-2.37,p=0.003) [35].
With such a higher rate of futile recanalization associated with MT in PC-LVO, ethics and patient preferences should be considered when considering the risk of subjecting patients to a treatment that may avoid death but instead creates long-term dependence.Recognition of factors associated with futile recanalization in PC-LVO might help increase the efficacy of MT in such patients.Efforts have been made to identify predictors of futile recanalization in PC-LVO and it has been shown that age, stroke severity on admission, duration of the procedure, and intracranial stenting are significant predictors [31,30].
Thus, the most important question is not whether to treat PC-LVO patients with MT or not, but rather which patients' recanalization would be futile and cause long-term dependence.Consequently, conducting RCTs that compare patient selection strategies with advanced imaging methods and concurrent medical therapy is vitally necessary.

Limitations
In our systemic review, most of the studies included were retrospective and observational, which does not allow for the generalization of our results.Also, there was a huge disparity in the number of PC-LVO and AC-LVO patients.The fact that thrombectomy is less commonly performed in PCS than in ACS patients resulted in fewer patients in the PC-LVO group.This leads to inadequate statistical power to assess the impact of endovascular treatment on major clinical outcomes between the two groups, especially in mortality.
Apart from that, non-transparent patient selection with disparities in patient inclusion criterion and definition of outcomes, different baseline characteristics, and heterogeneous endovascular treatments are the potential sources of bias.Apart from the type of devices used, the prognosis of patients could also be affected by the different perioperative management and procedures of MT.Therefore, follow-up multicenter randomized controlled studies are needed to validate the findings presented in this work.

Conclusions
Outcomes of MT in PC-LVO are far from ideal, with higher 90-day mortality rates and higher futile recanalization rates, although the rates of sICH appear to be lower compared to AC-LVO.On the other hand, the morbidity and mortality rates of conservatively managed acute BAO can reach up to 80-90%, which is the highest among all types of ischemic stroke.Hence, MT in PC-LVO can become a gold standard procedure if refinements can be made through technical improvements and skills training, as well as recognition of reliable predictors associated with futile recanalization, leading to increased overall efficacy.To achieve these goals, large-scale RCTs comparing patient selection and interventional strategies to avoid futile interventions are needed in the future.

[
Majr] OR "Brain Infarction/complications"[Majr] OR "Brain Infarction/diagnosis"[Majr] OR "Brain Infarction/diagnostic imaging"[Majr] OR "Brain Infarction/drug therapy"[Majr] OR "Brain Infarction/etiology"[Majr] OR "Brain Infarction/mortality"[Majr] OR "Brain Infarction/physiopathology" [Majr] OR "Brain Infarction/therapy"[Majr] ) Eligibility Criteria Studies were included based on the following criteria: (1) acute ischemic stroke patients presenting with isolated AC-LVO or PC-LVO undergoing MT with or without IVT; (2) prospective or retrospective cohort studies with patients stratified by AC-LVO and PC-LVO and a combined sample size of at least 40; (3) study must have compared baseline characteristics and reported functional outcomes using the modified Rankin Scale; (4) only English language; (5) only human studies Studies were excluded based on the following criteria: (1) patients involved in the study received only IVT and not undergoing MT; (2) duplicated articles; (3) grey literature; (4) insufficient data for comparison purposes; (5) study with AC-LVO and PC-LVO combined into one treatment arm; (6) use of the firstgeneration devices (MERCI (Mechanical Embolus Removal in Cerebral Ischemia) retriever) for MT Two researchers reviewed each study for relevance.Studies from reference lists of relevant articles were also manually searched to avoid omitting essential details.All disagreements were resolved by consensus.

FIGURE 1 :
FIGURE 1: The PRISMA flowchart PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses Thrombectomy: Outcome 2023 Patel et al.Cureus 15(9): e45861.DOI 10.7759/cureus.45861 A meta-analysis by Mbroh et al. and all the included observational studies except Huo et al. and De Lecinana et al.showed comparable rates of functional independence at 90 days, which means that a favorable functional outcome in PC-LVO is equally possible just as in AC-LVO despite the longer onset-to-IVT and onset-to-groin puncture times.Penumbra in posterior circulation stroke persists for a longer time compared to anterior circulation stroke, possibly due to better collateralization in the brainstem, which was the hypothesis put forward to explain this finding[48].Hence, shorter onset-to-IVT and onset-to-groin puncture times could influence a better functional MT outcome in PC-LVO.Huo et al. and De Lecinana et al.
It varied between 225 minutes (Weber et al.) to 480.3 minutes (Alaweih et al.) [27,28].It was also statistically significant in studies by Weber et al., Huo et al., Meinel et al., and Hu et al.

TABLE 5 : Safety and Outcomes -meta-analyses AC
[35,38]30,32,34]irculation large vessel occlusion, CI: confidence interval, mTICi: modified treatment in cerebral infarction, OR: odds ratio, PC-LVO: posterior circulation large vessel occlusion Time from onset to recanalization (OTR): There was a significant difference in OTR between both arms ranging 329 to 434 minutes for PC-LVO and 274 to 360 minutes for AC-LVO, as reflected in studies done by Weber et al., Huo et al., De Lecinana et al., and Hu et al..An exception was the observational study by Uno et al.where OTR was 200 minutes (160-262) for PC-LVO and 220 minutes (174-297.5)forAC-LVO[27,29,30,32,34].This difference reflects the long delay from onset-to-groin puncture times and the higher complexity of the procedures, including the need for stenting in those with BAO.The meta-analysis by Wang et al. and Mbroh et al. also showed similar findings[35,38].