The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed [19]. The study protocol was pre-registered on PROSPERO (CRD42023443029).

A systematic search was performed using electronic databases (PubMed, Embase, Cochrane Library, and Web of Science) up to October 2023 to identify all available studies on anticoagulation for IDDVT classified as ADVT and MDVT. ClinicalTrials.gov was also searched to identify any ongoing randomized controlled trials (RCTs). Appropriate medical subject heading terms and free word searches were utilized. The full search strategy is available in Supplementary Material (Table S1). References for the included studies were screened for further eligible articles. No language restriction was used.

Two independent authors (WTY and ZYJ) analyzed the lists of retrieved articles and performed the study selection. Any disputes were resolved by a third reviewer (HLR).

The included articles had the following characteristics: (i) RCTs or prospective observational studies; (ii) objective diagnosis by ultrasonography (US) or venography of ADVT (i.e., posterior tibial, peroneal, and anterior tibial vein) and MDVT (soleal and gastrocnemius vein); (iii) intervention (anticoagulation for at least four weeks); (iv) availability of data on the incidence of DVT recurrence, proximal propagation, and/or PE; and (v) a minimum of 50 patients with ADVT or MDVT. Excluded articles had the following characteristics: (i) retrospective studies; (ii) < 3 months of follow-up; (iii) patients aged < 18 years; (iv) DVTs with proximal extension into popliteal, femoral, and oriliac segments; (v) endovascular or surgical interventions (e.g., catheter-directed thrombolysis); and (vi) case series, case reports, review articles, letters, and editorials.

The screening process was conducted using EndNote X9 (Clarivate, Chandler, AZ, USA). All titles and abstracts retrieved from the initial search were screened. Articles meeting the inclusion criteria were subjected to an independent full-text review for final eligibility and data extraction. Relevant articles with incomplete information based on the title or abstract were also subjected to a full-text evaluation.

All original articles selected for inclusion in the meta-analysis were reviewed and the following data were extracted when available: general data (year of publication, design), population characteristics (number and type of included patients), and method used for IDDVT diagnosis, treatment (types of anticoagulant, dose, and duration), and follow-up (duration, surveillance method). For patients with IDDVT who underwent anticoagulation, information on the following outcomes were collected: recurrent DVT, proximal extension of IDDVT, and PE. Two reviewers (WTY and ZYJ) extracted the data independently using a template in Microsoft Excel. If the pre-specified data elements were not found during the review of published trial results, the authors of the publications were contacted to obtain additional study-level summary information. Investigators from one trial [20] provided additional data upon request.

Quality assessment was performed independently by two reviewers (WTY and ZYJ) using the revised tool for risk of bias in randomized trials (RoB 2 tool). Prospective cohort study quality was assessed using the Newcastle–Ottawa Quality Assessment Scale (NOS). Any discrepancies were mediated by a third reviewer (HLR). The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) profiler tool was then used to assess the reporting quality of major study outcomes [21].

The primary outcome of our meta-analysis was recurrent VTE defined as the composite of progression of IDDVT, recurrent IDDVT, proximal DVT, and PE occurring during the study period. Progression of IDDVT was defined as a compression ultrasonography confirmed extension of isolated distal DVT to the calf trifurcation (if previously not involved), popliteal, femoral, or iliac vein using a standardised compression ultrasonography protocol. Recurrent IDDVT was defined as a new distal DVT in the contralateral leg, lack of compressibility of a previously compressible vein in the ipsilateral leg, or an increase of at least 2 mm in the diameter of the residual thrombus during compression in a previously non-compressible vein. Proximal DVT was defined by a new proximal DVT in the contralateral leg. US or venography were accepted for confirmation of recurrent VTE and a computed tomography scan or ventilation–perfusion scan for PE. In addition, subgroup analyses were performed based on the study type, with population excluding active cancer or previous VTE, and follow-up time.

The odds ratio (OR) and 95% confidence interval (CI) were calculated for each study. The results were compared using a fixed-effects model [22]. Cochran’s χ2 test and I2 test for heterogeneity were used to assess between-study heterogeneity [23]. Statistically significant heterogeneity was considered to be present at P < 0.10 and I2 > 50%. Analyses were performed with Review Manager 5.4 (The Cochrane Collaboration, Oxford, UK) and Stata version 17 (StataCorp LP, College Station, TX, USA).