Studies that work on the stent patency rate in venous stent with DOAC / NOAC will be included. The below outcomes are NOT mandatory but, if the any secondary outcomes were reported, we will record them: bleeding (major/minor), other vascular accidents like hemorrhagic cardiovascular accidents (CVA), perioperative complications: thrombotic events and non-thrombotic complications (access site complications, stent migration, back pain, retroperitoneal bleeding, and contrast extravasation), clinical outcomes (included pain and edema relief, ulcer healing, recurrence, and clinical–etiology–anatomy–pathophysiology (CEAP) clinical classification before and after procedure), and death.
Type of studies
The primary studies (Cohort, case control, case-series or randomized/ non-randomized trials) will be included if the participants / patients have had acute or chronic DVT, with venous stenting (at least one study group or all of study subjects) who have received DOAC / NOAC agents. The stent patency rate should be reported in all of study subjects within a follow-up time, minimum for 12 months (1 year).
Type of participants
This systematic review will focus on studies that evaluate the rate of stent patency in acute or chronic DVT patients (inpatients or outpatients) with venous stenting (at least one study group or all of study subjects) who have received DOAC / NOAC agents.
The relevant animal studies or review articles will be excluded
We will perform an electronic search on published or in press articles, which have been published in MEDLINE / PubMed, Embase, the online Cochrane database, CENTRAL and searches of clinical trial registries: clinicalTrials.gov, EU Clinical Trials, ISRCTN registry, WHO network registry for trials. PROSPERO databases will be manually searched for protocols. Reference lists of previous systematic reviews and the primary articles will be also checked manually. No geographical restrictions will be applied. Language restriction will not be applied, and non-English studies will be included if at least an English abstract is available. Mesh search and free-text method (asking experts’ opinion, checking previous review articles, and similar systematic review) will be applied to find synonyms and related terms: due to the primary searches there are few primary articles in this field, so following searches will be carried out for “All fields” with no field restrictions to achieve the most comprehensive search.
"Deep Vein Thrombosis", “venous stenting” and "post thrombotic syndrome" will be the main components and important related terms including: Iliofemoral DVT, Anticoagulation therapy, valve incompetence, venous patency, Thrombolytic therapy, Catheter-directed Thrombolysis (CDT), Catheter-based Thrombectomy, Post-thrombotic Syndrome (PTS), Pharmacomechanical Thrombectomy (PMT), VKA (Vitamin K Antagonists): such as Warfarin; Coumarin; Acenocoumarol; NOAC (Non-VKA Oral Anticoagulants), DOAC (Direct Oral Anticoagulant). Search syntax for these keywords and/or Medical Subject Headings (MeSH) terms and free text method will be selected and combined by Boolean operators and applied in PUBMED. Search terms will be adjusted for other electronic databases. The following syntax will be used in the PubMed database:
((("Deep Venous" OR deep-vein OR "Deep Vein") AND Thrombos*) OR "Deep-Vein Thrombos*" OR Phlebothrombos* OR "Deep Venous Thrombos*" OR "venous thrombos*" OR "vein thrombos*" OR Postthrombotic OR Post-thrombotic OR "venous stasis") AND stent* AND "post thrombotic syndrome"
It is noteworthy that prior to any screening, reviewers will undergo training to ensure a comprehensive understanding of the review question, and the inclusion and exclusion criteria.
In the first step, after exporting the search outputs into Endnote software, any duplicates will be removed. After that, the studies will be screened based on titles and /or abstracts for the relevant topic by two reviewers (S.B. and A.K.).
Selection of studies
Two reviewers (S.B. and A.K) will independently screen all articles through the inclusion criteria and independently classify the articles into three groups based on the eligibility criteria: relevant, irrelevant, and unsure. Irrelevant studies, which selected by both reviewers, will remove from the study. A third reviewer will decide against the final decision whenever the two reviewers had disagreement.
Assessing risk of bias
The eligible primary studies (Cohort or Follow-up studies) will be assessed by Newcastle-Ottawa Scale tool (Cohort version) (8). The included trials or experimental studies will be assessed by Cochrane Risk of Bias (ROB) assessment tool (version-1) (9).
The ROB assessment will be independently performed by two reviewers and any disagreements will be resolved by third expert reviewer.
Data extraction and Data synthesis
Two reviewers will independently extract data from papers using a template created in Microsoft Excel. Data extraction form for this review will include general information, study eligibility, method, the risk of bias assessment, and results of studies. Any discrepancies in the data will be addressed by a third expert reviewer who will check these two forms and their differences. An email will be sent to corresponding authors of studies for missing, unclear, and unreliable data. From each article, the following information will be extracted.
General information: first author name, publication year, journal title, volume and issue, article title, reference numbers
Study eligibility: location, time and duration of the study (name of country, total study duration), type of participants, sample size (total population recruited in the study), inclusion and exclusion criteria (in the study), age and gender of study population, procedure performed in the study, side of the limb where the intervention has been performed (left, right), technical success rate, access site, stent style, stent size, stent number, Imaging during the operation, randomization method, inclusion criteria, interventions performed, assessor blinding, follow-up, outcomes / end-points, rate of post thrombotic syndrome, statistical analysis, loss to follow-up, procedural complications
Method: Study design (traditional case-control, Nested case-control, any type of cohort study), ethical approval obtained for the study.
Risk of bias assessment (mentioned above).
Results of studies: (Odds Ratio, Risk Ratio, Rate Ratio, 95% confidence intervals, standardized mean differences).
If there are clinical trials and observational studies included in this study, they will not be combined and the analysis will be performed separately. Based on data analysis in majority of the eligible primary studies (Time-to-event or survival analysis), we will use “Hazard Ratio” (HR) as the optimum Effect Size (ES) in this meta-analysis. We convert the survival graph extracted data (usually Kaplan-Meier graph) and the findings of Log-rank test (Chi square and …) into HR based on previous method (10,11).
In the absence of survival analysis in the eligible studies, we will use or calculate “Risk Ratio” (RR) or “Odds Ratio” (OR) ES measures as the selected study specific ES. Furthermore the rare outcome assumption is addressed (the outcome frequency < 10%), we will combine the different types of “Relative Risk” ES family such as HR, RR, OR (12).
We will assess heterogenity using Q Cochrane test and I squared measure. We will categorize I squared measure into 4 categories; mild (0-24.9%), moderate (25-49.9%), severe (50-74.9%) and highly severe (75-100%) based on Higgin’s suggestion (13).
We will explore the source(s) of heterogenity using “Sub-group analysis” or “Meta-regression” based on the covariate data type.
The sensitivity analysis will be performed by two approaches. First, we will use one-out remove method for the influence of any primary studies on the combined ES. Secondly, we will evaluate the effect(s) of methodological quality (score or categorical data) on the primary studies ES by sub-group analysis.
We will assess reporting bias using the Funnel plot and Egger’s test and plot (14). If the Egger’s test has the p value < 0.10, we will use Trim & Fill method (15) for evaluating the publication bias effect.
Analysis of subgroups or subsets:
We consider the study type (observational versus interventional), the ROB status categories (Low ROB vs High ROB) and the different follow-up time in the included studies (1-3 years vs > 3 years) as sub-group variables.
If there are the minimum criteria of quantitative data synthesis (minimum 5 primary studies in one of cohort or trial studies AND no highly severe methodological heterogenity), we will perform Meta-analysis.
Assessing certainity of evidence:
We will grade the strength of evidence as high, moderate, low, or very-low using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) rating system. In the GRADE system, RCTs begin as high-quality evidence but may be downrated according to the risk of bias assessment, inconsistency, indirectness, imprecision in the results, and publication bias. Certainty is uprated for estimates with large (RR > 2.0 or RR < 0.5) or very-large (RR > 5.0 or RR < 0.2) magnitude of effect (16).