Antegrade or Retrograde Approach for the Management of Tandem Occlusions in Acute Ischemic Stroke: Protocol for a Systematic Review and Meta-Analysis


 BackgroundAcute ischemic stroke (AIS) is a major contributor to global morbidity and mortality, and mechanical thrombectomy (MT) is an effective treatment for AIS. AIS caused by tandem intracranial and extracranial occlusions are not rare. Evidence for optimal MT strategy regarding order of treatment, including antegrade (extracranial first) or retrograde (intracranial first) approach is lacking. Therefore, a systematic review and meta-analysis is necessary to compare the two approaches for optimal management of tandem lesions in AIS.MethodsThis study will be performed with accordance to the PRISMA statement. Major databases including PubMed, Web of Science, Embase, and the Cochrane Library will be used for literature search. Randomized controlled trials and high-quality observational studies will be included. Risk of bias will be assessed using the Cochrane Collaboration criteria or Newcastle–Ottawa Scale according to type of study. Two reviewers will independently screen for eligible studies and perform data extraction. The primary outcomes are successful recanalization at post-intervention, and favorable outcome at 3-month follow-up. Secondary outcomes include duration of onset to arrival, onset to puncture, onset to recanalization, intracerebral hemorrhage, procedure and device related complications and mortality at 3-month follow-up. We will assess heterogeneity using the I2 statistic. Subgroup and sensitivity analyses will be performed to explore the sources of heterogeneity. Specific results will be described in narrative form when insufficient suitable studies are available for meta-analysis.DiscussionThis study will provide a reliable evidence base for antegrade or retrograde approach for the management of tandem lesions in AIS by synthesizing evidence from current pieces of literature comparing the two approaches, and also will provide updated clinical evidence of strategy selection and decision-making for this special group of patients. PROSPERO registration numberCRD42020199093

The treatment for this unique subgroup of patients is challenging. Achieving successful recanalization is still the primary goal of treatment and will increase the likelihood of favorable functional outcomes. Previous studies have shown that the rate of recanalization via intravenous tissue plasminogen activator (IV tPA) alone may be unsatisfactory [4,5]. Recently, the superiority of mechanical thrombectomy (MT) over IV tPA was established by clinical evidences from a series of randomized controlled trials (RCTs) [1,[6][7][8]. MT has been established as the primary care for intracranial occlusions out of IV tPA window, and recent study have shown MT alone is non-inferior to IV tPA even within 4.5-hour window [9].
For tandem occlusions occurring both at intracranial as well as extracranial locations (commonly the carotid artery), emergent carotid artery stenting-mechanical thrombectomy approach could achieve considerably high chance of recanalization and functional independence [10,11], and is considered an acceptable treatment modality for treatment of tandem occlusions [12,13]. Nevertheless, evidence for optimal strategy for order or treatment including antegrade (extracranial rst) and retrograde (intracranial rst) approach is lacking. Although comparable outcomes between the two approaches were found in previous meta-analysis by Wilson et al [14], the majority of recruited studies were single-armed, and many studies directly comparing the two approaches were published thereafter [15][16][17][18]. Some studies still showed comparable results between the two approaches [16,17]. In contrast, a better outcome of retrograde approach was found in the study of Maus et al and Yang et al [15,18]. Additionally, retrograde approach was adopted as the prior choice in some centers regarding its effectiveness and safety [17,19]. Therefore, it is necessary to summarize the current literatures comparing the two approaches for the management of tandem lesions in acute ischemic stroke, thus to provide updated clinical evidence of strategy selection and decision-making for this special group of patients.

Methods
This protocol is drafted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Protocols (PRISMA-P) guidelines (see online Additional le 1. PRISMA-P Checklist) [20]. The registration of this systematic review and meta-analysis is shown on the International Prospective Register of Systematic Reviews 'PROSPERO' database (CRD42020199093). If any modi cation is made to this protocol, the record will be updated in PROSPERO.

Search strategy
A literature search will be performed by two independent reviewers. We will search the following databases, including MEDLINE, EMBASE, Web of Science, and the Cochrane Library, for eligible studies. We will also search WHO trail register (https://www.who.int/ictrp/en/), for potential studies. The preliminary search terms, including stroke, large-vessel occlusion, acute ischemic stroke, tandem occlusion, internal carotid artery occlusion, and mechanical thrombectomy, will be utilized to capture all studies eligible for inclusion. The search strategy will be presented detailly on supplementary material (see online Additional le 2. Search strategy).

Study selection
The study selection will strictly follow criteria from the Population, Intervention, Comparison, Outcome (PICO) Model.

Patient
Inclusion criteria: aged 18 years or older with AIS with ≥70% stenosis or occlusion of the extracranial internal carotid artery (ICA) and concomitant occlusion of the intracranial ICA and/or proximal middle cerebral artery (MCA). Arterial stenosis or occlusion will be con rmed by imaging examinations such as computed tomographic angiography (CTA) or digital subtraction angiography (DSA). The grade of arterial stenosis will be measured according to NASCET (North American Symptomatic Carotid Endarterectomy) criteria.

Intervention
The intervention will be anterograde approach which is de ned as proximal-to-distal recanalization, with angioplasty and/or stenting of the extracranial lesion rst, followed by intracranial thrombectomy [15,18]. For this technique, a microwire followed by a microcatheter will pass the proximal occlusion at rst. If di cult to cross the extracranial occlusion site, intraarterial thrombolysis or balloon dilation will be performed to relieve occlusion and establish a narrow passage so that the microwire or the microcatheter could pass through the occlusion when necessary. Then angioplasty and/or stenting will be performed at the extracranial ICA lesion. The choice of stenting will be depended on the neurointerventionists. After extracranial occlusion is recanalized, intracranial thrombectomy will be conducted in terms of stent retrieval, intra-arterial thrombolysis, angioplasty and aspiration.

Comparator
The comparator will be retrograde approach, which is de ned as distal-to-proximal recanalization, with treatment of the intracranial occlusion with mechanical thrombectomy rst, followed by treatment of the extracranial ICA occlusion [15,18]. Once the proximal occlusion site was crossed with a microwire, intracranial occlusion thrombectomy was applied subsequently. Stent placement or balloon angioplasty of the extracranial ICA lesion was then performed after intracranial thrombectomy.

Outcomes
At least one of the following items should be reported: Primary outcomes: 1. Successful recanalization de ned as modi ed Thrombolysis in Cerebral Infarction scale (mTICI) 2b and 3, determined by post-interventional DSA 2. Favorable outcome de ned as the mRS (modi ed Rankin Score) ≤ 2 or equal to pre-stroke score at 3month follow-up RCTs and observational studies (cohort studies, case-control studies) will be included. The inclusion of observational studies is to gather su cient data for outcome evaluation and to minimize the type-II errors that can result from the lack of statistical power found in sole RCTs [22].
Exclusion criteria 1. Patients' age less than 18 years old 2. Patients with intracranial hemorrhage, signi cant cerebellar mass effect, and acute hydrocephalus on computed tomography or magnetic resonance imaging before stroke.
3. No report about aforementioned outcomes or an inability to extract the exact number of complications.
4. Unsuitable study types, such as case series report, and studies with unavailable full text.

Data selection and analysis
Selection of studies Two reviewers (RX and XQ) will screen and select the eligible studies, independently. First, the reviewers will screen titles, keywords, and abstracts among the initial searched studies, and the irrelevant studies will be excluded. We will then acquire the full texts of the rest of studies. Next, the reviewers will check the full-texted studies to evaluate their included eligibility and document the reasons for study exclusion. When data from the same trial are reported in more than one article, we will select the most recent study. A third reviewer (TW) will help to resolve any disagreements between the former two reviewers.

Data collection
Software of EndNote X9 (Clarivate Analytics, Philadelphia, USA) will be used for the management of included studies. A standardized form will be used for data extraction by two reviewers (YW and YF), independently. The extracted data will include the following information: 1. Study characteristics, such as type of study, authors, year of publication, sample size, and number of patients.
2. Patient characteristics, such as mean age, gender, medical history, site of occlusion, baseline NIHSS (National Institutes of Health Stroke Scale) score and the numbers of patients treated with IV thrombolysis.
3. Intervention characteristics, such as the time of onset to puncture or recanalization, numbers of patients treated with angioplasty or stent alone, numbers of patients treated anterograde or retrograde approach rst.
4. The aforementioned primary and secondary outcomes.
Discrepancy in data extraction between two reviewers will be resolved by a third reviewer (TW) when it cannot be settled by discussion. For unclear or missing data, we will contact the corresponding authors via email. If no responses after two emails, we will exclude this study for meta-analysis and record this case in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) ow chart [23].

Risk of bias assessment
Two review authors (KY and YM) will independently assess risk of bias in each included study. Reviewers will use risk of bias 2.0 tool of the Cochrane Collaboration criteria for RCTs and quasi-experimental studies, the Newcastle-Ottawa Scale (NOS, see Additional le 3) for observational studies including cohort study and case control study, and the Methodological Quality and Synthesis of Case Series and Case Reports for case series, respectively [24][25][26]. The following seven domains will be used as criteria to assess the risk of bias for RCTs and quasi-experimental studies:

Random sequence generation
Allocation concealment

Blinding of participants and personnel
Blinding of outcomes assessments Incomplete outcome data Selective outcome report Other possible bias The risk of bias for observational studies will be assessed by three domains including selection, compatibility and exposure. Each domain of included studies will be given a score based on the risk of bias. We will rank the level of risk of bias as low, unclear or high, and provide information from the study report together with a justi cation for our judgment in the 'Risk of bias' tables [27]. If there is opinion disagreement between the two reviewers, initial face-to-face discussion will be performed. Also, further team group discussion will be held if necessary.

Measures of treatment effect and data synthesis
Data analysis for outcomes of antegrade or retrograde approach for the management of tandem lesions in AIS is practical when there are two or more studies accessible for a speci c variable. The data analysis will be performed using Stata statistical software (version 15.0, Stata Corp, College station, Texas, USA). Treatment effect will be reported as relative risk (RR) with 95% CIs (con dence intervals) because most of the outcomes are dichotomous data. For continuous variables such as mean time of onset to recanalization, we will use mean differences (MDs) with 95% CIs. A narrative presentation of the study results will be provided under circumstance of lacking data.

Assessment of clinical and methodological heterogeneity
Assessment of heterogeneity Heterogeneity will be measured with the I 2 statistic before any outcome is pooled. The heterogeneity of mild (<40%), moderate (40-60%), or substantial (>60%) will be graded depending on the pooled results. On condition that the results with substantial heterogeneity and su cient number of included trials, we will use subgroup analysis to examine the reasonable origins of heterogeneity, which may include different study locations, patient characteristics, and endovascular treatments. Sensitivity analysis is also utilized to appreciate studies with high risk of bias through step-wise exclusion of studies and observation of combined bias in remaining studies.

Assessment of reporting biases
We will conduct a thorough protocol review of the included studies to evaluate reporting biases. Funnel plot and Egger's regression tests are suitable for assessing publication bias if the included studies exceed 10 [28]. If the included studies are less than 10, we will solely assess reporting bias qualitatively based on the characteristics of the included studies.

Assessment of pooled effect estimates
When the heterogeneity of results is high (>60%) in included studies, the DerSimonian and Laird method for random model will be applied; otherwise, the Mantel-Haenszel method for mixed model will be performed [29]. Statistical signi cance is de ned at p < 0.05.
We will evaluate the quality of evidence contributing to pooled effect estimates of the main outcomes with Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement for observational studies and the principle of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system for RCTs [30,31]. We will use methods and recommendations described in the Cochrane Handbook for Systematic Reviews of Intervention and the GRADEpro GDT software [27]. Eventually, we will construct a table summarizing the overall study results.

Discussion
The present study aims to provide a reliable evidence base for antegrade or retrograde approach for the management of tandem lesions in AIS by synthesizing evidence from current pieces of literature comparing the two approaches. Tandem vascular occlusions, including a proximal extracranial occlusion in conjunction with a downstream intracranial occlusion is not rare for patients with AIS. Currently, MT seems to be an effective technique for treating tandem vascular occlusions of AIS. However, tailored evidence for the optimal treatment order between antegrade and retrograde approach remain inconsistent and contradictory among studies and need to be clari ed. However, some limitations may exist. For example, heterogeneity among studies may be inevitable. In addition, most studies may be observational in nature and RCTs are rare. However, this study will provide updated clinical evidence of strategy selection and decision-making for this special group of patients, and will de nitely be helpful in summarizing the current clinical evidence and guiding future studies. Declarations YM, YC, LJ and KY contributed to the revision of the draft. XZ, XB, and XW contributed equally to this article. All of the authors approved the nal work prior to submission.

Funding
This work was supported by the Ministry of Science and Technology of the People's Republic of China (2016YFC1301700) and the Beijing Scienti c and Technologic Project (Z201100005520019).

Availability of data and material
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Ethics approval and consent to participate Not applicable

Consent for publication
Not applicable Figure 1 Flow diagram of literature for systematic review and meta-analysis.