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Treatment Strategies for Proximal Deep Vein Thrombosis: A Network Meta-analysis of Randomised Controlled Trials

  • Author Footnotes
    ‡ These authors contributed equally to the manuscript.
    Mohammed Ashrafi
    Footnotes
    ‡ These authors contributed equally to the manuscript.
    Affiliations
    Department of Vascular and Endovascular Surgery, Manchester University NHS Foundation Trust, Manchester, UK
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  • Author Footnotes
    ‡ These authors contributed equally to the manuscript.
    Saad B. Ahmad
    Footnotes
    ‡ These authors contributed equally to the manuscript.
    Affiliations
    Department of Vascular and Endovascular Surgery, Manchester University NHS Foundation Trust, Manchester, UK
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  • Stavros A. Antoniou
    Affiliations
    Department of Surgery, Mediterranean Hospital of Cyprus, Limassol, Cyprus
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  • Taha Khan
    Affiliations
    Department of Vascular and Endovascular Surgery, Manchester University NHS Foundation Trust, Manchester, UK
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  • George A. Antoniou
    Correspondence
    Corresponding author. The Royal Oldham Hospital, Room G37, Vascular Offices, J Block, Rochdale Road, Oldham OL1 2JH, UK.
    Affiliations
    Department of Vascular and Endovascular Surgery, Manchester University NHS Foundation Trust, Manchester, UK

    Division of Cardiovascular Sciences, School of Medical Sciences, The University of Manchester, Manchester, UK
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  • Author Footnotes
    ‡ These authors contributed equally to the manuscript.
Published:January 24, 2022DOI:https://doi.org/10.1016/j.ejvs.2021.10.058

      Objective

      To investigate the outcomes of treatment strategies for proximal and iliofemoral deep vein thrombosis (DVT).

      Methods

      Randomised controlled trials (RCTs) investigating outcomes of catheter directed thrombolysis (CDT), ultrasound assisted CDT (USCDT), percutaneous aspiration thrombectomy (PAT), and best medical therapy (BMT) for proximal DVT from 2000 onwards were considered. MEDLINE, EMBASE, and CINAHL were searched using the Healthcare Databases Advanced Search interface developed by the National Institute for Health and Care Excellence. The primary outcome was the rate of post-thrombotic syndrome (PTS), which was defined using the Villalta scoring system (score of ≥5). Secondary outcomes included vessel patency, recurrence, bleeding, and mortality. The network of evidence was summarised using network plots, and random effects network meta-analyses were performed. The certainty of evidence was assessed using the Certainty In Network Meta-Analysis (CINeMA) approach.

      Results

      Seven RCTs meeting the inclusion criteria were identified. There were direct comparisons between medical therapy, CDT, and USCDT across outcomes, except for patency. There were no direct comparisons between medical therapy and PAT (except for patency), and USCDT and PAT. There was no significant difference observed in PTS between the treatment modalities for proximal and iliofemoral DVT (low certainty). There was a significant difference in patency rates between medical therapy and USCDT (odds ratio [OR] 9.46, 95% confidence interval [CI] 3.05 – 29.35; low certainty) and CDT (OR 2.03, 95% CI 1.46 – 2.80; low certainty) in favour of USCDT and CDT, respectively, for proximal DVT. USCDT significantly improved patency rates compared with CDT (OR 4.67, 95% CI 1.58 – 13.81; very low certainty) for proximal DVT. There was no significant difference in DVT recurrence, bleeding, or mortality between treatment groups for proximal and iliofemoral DVT (low to moderate certainty for most comparisons).

      Conclusion

      USCDT may improve patency rates compared with BMT and the other interventional treatment modalities used for the management of proximal DVT. However, no treatment modality showed superiority with regard to a reduction in PTS, and overall, the quality of available evidence is poor.

      Keywords

      This network meta-analysis provides a robust review of current randomised controlled trials investigating the optimum management of proximal and iliofemoral deep vein thrombosis (DVT). Multiple interventional treatment strategies, including catheter directed thrombolysis (CDT), ultrasound assisted CDT (USCDT), percutaneous aspiration thrombectomy, and best medical therapy (BMT), were compared to identify the best treatment for proximal and iliofemoral DVT. USCDT may improve patency rates, compared with BMT and other interventional treatment modalities used for the management of proximal and iliofemoral DVT. However, no treatment modality showed superiority with regard to a reduction in post-thrombotic syndrome. It must be noted that the overall quality of available evidence is poor.

      Introduction

      Deep vein thrombosis (DVT) is a serious condition with an incidence of 1.6 per 1 000/year and can have long term sequelae.
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      Comparison of clear effect and the complications, and short and mid-term effects between ultrasound-guided and non-guided catheter-directed thrombolysis in the treatment of deep venous thrombosis of lower extremity.
      However, long term venous insufficiency and obstruction can lead to ulceration, pain, and oedema. A proximal DVT is defined as a thrombus involving one or more of the more central veins, including the popliteal, femoral, common femoral, profunda femoris, external iliac, internal iliac, and common iliac veins, and the inferior vena cava. Iliofemoral DVT is defined as thrombus involving the iliac and/or common femoral veins, with or without extension to the inferior vena cava. DVT frequently affects the lower limb, with proximal vessels being common sites affected: common femoral, 20%; femoral, 20%; iliac, 4%; and popliteal, 16%. Distal veins comprise 40% of all cases.
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      PTS negatively affects the quality of life and imposes substantial costs on healthcare systems.
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      Our early experience with iliofemoral vein stenting in patients with post-thrombotic syndrome.
      Therefore, appropriate therapy is vital in preventing and reducing the incidence of PTS.
      The mainstay of treatment for DVT is medical therapy, which involves anticoagulation for three to six months,
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      Use of percutaneous aspiration thrombectomy vs. anticoagulation therapy to treat acute iliofemoral venous thrombosis: 1-year follow-up results of a randomised, clinical trial.
      along with the use of compression therapy to help prevent PTS in the long term.
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      Catheter-directed Venous Thrombolysis in acute iliofemoral vein thrombosis-the CaVenT Study: rationale and design of a multicenter, randomized, controlled, clinical trial (NCT00251771).
      However, previous individual trials have shown patients with proximal DVT who are managed with medical therapy only are at a higher risk of PTS vs. interventions aimed at deep vein recanalisation,
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      Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis.
      with more than half of these patients developing the syndrome.
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      • Sandvik L.
      • Ghanima W.
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      Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial.
      As a result, patients with proximal DVT may benefit from invasive interventional treatment.
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      • et al.
      Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis.
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      Predictors of the post-thrombotic syndrome with non-invasive venous examinations in patients 6 weeks after a first episode of deep vein thrombosis.
      ,
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      • Wittens C.H.
      Validation of the LET classification.
      This enables early removal of the thrombus, thereby improving vessel patency and restoring function, which may help with the long term outcome.
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      • Haig Y.
      • Kløw N.-E.
      • Slagsvold C.-E.
      • Sandvik L.
      • Ghanima W.
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      Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial.
      ,
      • Comerota A.J.
      • Paolini D.
      Treatment of acute iliofemoral deep venous thrombosis: a strategy of thrombus removal.
      Interventional treatment options include, but are not limited to, catheter directed thrombolysis (CDT), ultrasound assisted CDT (USCDT), and percutaneous aspiration thrombectomy (PAT). These may be particularly beneficial, as medical therapy alone does not offer a thrombolytic effect.
      • Cakir V.
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      • Gencpinar T.
      • Kucuk B.
      • et al.
      Use of percutaneous aspiration thrombectomy vs. anticoagulation therapy to treat acute iliofemoral venous thrombosis: 1-year follow-up results of a randomised, clinical trial.
      A recent Cochrane review compared thrombolytic clot removal strategies with anticoagulation against anticoagulation alone for the management of acute lower limb DVT.
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      • Watson L.
      • Armon M.P.
      Thrombolytic strategies versus standard anticoagulation for acute deep vein thrombosis of the lower limb.
      Nineteen randomised controlled trials (RCTs) were included. It was found that complete clot lysis occurred more frequently after thrombolysis (with or without additional clot removal strategies) and the incidence of PTS was slightly reduced.
      • Broderick C.
      • Watson L.
      • Armon M.P.
      Thrombolytic strategies versus standard anticoagulation for acute deep vein thrombosis of the lower limb.
      However, this review grouped all thrombolysis interventions, including systemic, locoregional and CDT, as well as pharmacomechanical thrombolysis together in comparison to anticoagulation alone. Lichtenberg et al. undertook a systematic review and meta-analysis comparing percutaneous mechanical thrombectomy with thrombolysis alone and concluded that percutaneous mechanical thrombectomy offered better patency of vessels at six months compared with thrombolysis alone.
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      • Gagne P.
      • Razavi M.K.
      • et al.
      Endovascular mechanical thrombectomy versus thrombolysis in patients with iliofemoral deep vein thrombosis – a systematic review and meta-analysis.
      However, this review included observational studies, as well as RCTs. In another meta-analysis, Tang et al. compared percutaneous mechanical thrombectomy to CDT and concluded that percutaneous mechanical thrombectomy groups had reduced PTS rates with a shorter hospital stay and thrombolysis time compared with CDT.
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      • Chen L.
      • Chen J.
      • Mei T.
      • Lu Y.
      Pharmacomechanical thrombectomy versus catheter-directed thrombolysis for iliofemoral deep vein thrombosis: a meta-analysis of clinical trials.
      However, this meta-analysis only included retrospective studies.
      Given the recommendation that early thrombus removal strategies should be considered in selected patients,
      • Kakkos S.K.
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      • Baekgaard N.
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      • Black S.A.
      • et al.
      Editor's Choice - European Society for Vascular Surgery (ESVS) 2021 clinical practice guidelines on the management of venous thrombosis.
      there remains uncertainty surrounding the optimum treatment strategy. Therefore a network meta-analysis was conducted to investigate the outcomes of early thrombus removal treatment strategies for proximal and iliofemoral DVT. This study is the first of its kind to compare all invasive treatment options for proximal and iliofemoral lower limb DVT.

      Methods

      Design

      The study followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses for Network Meta-Analysis (PRISMA-NMA) framework.
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      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
      The objective of the study, the search design, inclusion, and exclusion criteria, and methods of analysis were pre-specified.

      Criteria for considering studies

      Only RCTs comparing any of the interventions of CDT, USCDT, PAT, and medical therapy for proximal DVT from 2000 onwards were considered for this review. RCTs focusing on DVT situated in any other anatomical site and those solely investigating medical intervention were excluded. In addition, studies in languages other than English were excluded. RCTs that included any patients (no age or sex restriction) diagnosed with acute proximal DVT (within the past 21 days) were included. The data were further separated into patients diagnosed with acute iliofemoral DVT (within the past 21 days).

      Types of outcomes

      The primary outcome was the incidence of PTS defined using the Villalta scoring system for PTS.
      • Villalta S.
      • Bagatella P.
      • Piccioli A.
      • Lensing A.
      • Prins M.
      • Prandoni P.
      Assessment of validity and reproducibility of a clinical scale for the post-thrombotic syndrome (abstract).
      All levels of PTS with a score of five or above were included. PTS was assessed at the end of follow up for each individual study. Secondary outcomes included vessel patency (partial or complete patency rates were combined), bleeding, DVT recurrence, and death. Clinically important effect sizes were set at an odds ratio (OR) of 1.1 for PTS, 1.5 for patency, 1.1 for bleeding, 1.3 for DVT recurrence, and 1.1 for death. The clinical importance of effect sizes was determined by two experienced vascular surgeons (G.A. and T.K.), one of whom (T.K.) is a clinical expert in the field.

      Search methods for study identification

      The literature search strategy was developed by a review author (G.A.) with experience in outreach, knowledge, and evidence search. Relevant studies were identified by searching electronic information sources and reference lists of articles. The search strategy was based on a PICOS style (patient, intervention, comparison, outcome, study design) approach.
      A literature search was run on PubMed in April 2021 applying the search syntax presented in Supplementary Table S1. Subsequently, the Healthcare Databases Advanced Search (HDAS) interface developed by the National Institute for Heath and Care Excellence was used to search the following electronic bibliographic databases: MEDLINE, EMBASE, and CINAHL.
      The following trial registries were also searched as part of the search strategy: https://www.isrctn.com/ and https://clinicaltrials.gov/.
      A combination of thesaurus and free text terms was used to search the electronic databases. Thesaurus headings, search operators, and search limits in each of the databases were adapted accordingly. The search of HDAS was last run on 4 May 2021. The electronic search strategy is presented in Supplementary Table S1.

      Data extraction and management

      Three review authors (S.B.A., M.A., and T.K.) independently performed the literature search, and independently evaluated the studies and selected the studies that fulfilled the inclusion criteria for this review. A fourth author (G.A.) then assessed all the selected studies and ensured their eligibility against the inclusion criteria and also acted as an adjudicator in the event of disagreement. Local hospital library services were contacted for articles that were not accessible and a request was sent for electronic copies to be emailed.
      A spreadsheet was then used for data extraction. This was a two step process: the initial step was to identify data categories from the studies and then actual data were collected. This was performed by two authors (S.B.A. and M.A.). The final data were presented to G.A. who further analysed the data. The data collected included study information (i.e., year, journal, country, multicentre or single centre, patient recruitment dates, intention to treat, and types of intervention compared); patient characteristics (i.e., age, sex, past medical and surgical history, body mass index [BMI], pregnancy, smoking status, combined oral contraceptive/hormone replacement therapy [COC/HRT] use, thrombophilia, trauma, inflammatory bowel disease, cancer, previous DVT, previous surgery, and infection); and outcome data as outlined above.

      Assessment of bias risk in the included studies

      Version 2 of the Cochrane risk of bias tool for randomised trials (Rob2) was used for the assessment of the risk of bias of the selected trials for each outcome.
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      • Blencowe N.S.
      • Boutron I.
      • et al.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      Briefly, this tool evaluates five domains: randomisation process; deviations from the intended interventions; missing outcome data; measurement of the outcome; and selection of the reported result. For each individual domain, studies were classified into low risk of bias, some concerns, or high risk of bias.

      Publication bias

      The effect was plotted by the inverse of its standard error in pairwise comparisons and publication bias was assessed visually by evaluating the symmetry of the funnel plot for outcomes reported by at least 10 trials.

      Certainty of the evidence

      The certainty of the evidence was assessed using Certainty In Network Meta-Analysis (CINeMA).
      • Owen R.K.
      • Bradbury N.
      • Xin Y.
      • Cooper N.
      • Sutton A.
      MetaInsight: an interactive web-based tool for analyzing, interrogating, and visualizing network meta-analyses using R-shiny and netmeta.

      Methods of analysis

      Statistical analyses were performed with the MetaInsight platform and the R packages netmeta: Network Meta-Analysis using Frequentist Methods, version 0.9-8 and gemtc: Network Meta-analysis using Bayesian Methods, version 0.8-2.
      • Nikolakopoulou A.
      • Higgins J.P.T.
      • Papakonstantinou T.
      • Chaimani A.
      • Del Giovane C.
      • Egger M.
      • et al.
      CINeMA: an approach for assessing confidence in the results of a network meta-analysis.
      Frequentist pairwise meta-analyses of competing interventions were conducted by calculating the OR and 95% confidence interval (CI) under a random effects assumption. The network of evidence was summarised using network plots, and random effects network meta-analyses were performed. Pairwise and network meta-analyses were summarised in forest plots and league tables. When both direct and indirect evidence was present, the difference between direct and indirect estimates was calculated with respective CIs and quantified using p values. Ranking tables were constructed, summarising the probability of each treatment being the best, second best, third best, etc., within a Bayesian framework.

      Results

      Literature search results

      After the initial search, 12 762 articles were identified. This was reduced to 797 articles as only RCTs were employed in this network meta-analysis. These articles were assessed for eligibility and 755 articles were excluded as they were deemed not relevant to the review. Full texts were obtained for the remaining 43 articles and further evaluation narrowed the research results to seven studies (16 articles).
      • Zhu C.
      • Zhuo H.
      • Qin Y.
      • Zhang W.
      • Qiu J.
      • Ran F.
      Comparison of clear effect and the complications, and short and mid-term effects between ultrasound-guided and non-guided catheter-directed thrombolysis in the treatment of deep venous thrombosis of lower extremity.
      ,
      • Cakir V.
      • Gulcu A.
      • Akay E.
      • Capar A.E.
      • Gencpinar T.
      • Kucuk B.
      • et al.
      Use of percutaneous aspiration thrombectomy vs. anticoagulation therapy to treat acute iliofemoral venous thrombosis: 1-year follow-up results of a randomised, clinical trial.
      • Enden T.
      • Sandvik L.
      • Kløw N.-E.
      • Hafsahl G.
      • Holme P.A.
      • Holmen L.O.
      • et al.
      Catheter-directed Venous Thrombolysis in acute iliofemoral vein thrombosis-the CaVenT Study: rationale and design of a multicenter, randomized, controlled, clinical trial (NCT00251771).
      • Enden T.
      • Haig Y.
      • Kløw N.-E.
      • Slagsvold C.-E.
      • Sandvik L.
      • Ghanima W.
      • et al.
      Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial.
      ,
      • Elsharawy M.
      • Elzayat E.
      Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis. A randomised clinical trial.
      • Notten P.
      • Ten Cate-Hoek A.J.
      • Arnoldussen C.
      • Strijkers R.H.W.
      • de Smet A.
      • Tick L.W.
      • et al.
      Ultrasound-accelerated catheter-directed thrombolysis versus anticoagulation for the prevention of post-thrombotic syndrome (CAVA): a single-blind, multicentre, randomised trial.
      • Haig Y.
      • Enden T.
      • Grøtta O.
      • Kløw N.-E.
      • Slagsvold C.-E.
      • Ghanima W.
      • et al.
      Post-thrombotic syndrome after catheter-directed thrombolysis for deep vein thrombosis (CaVenT): 5-year follow-up results of an open-label, randomised controlled trial.
      • Enden T.
      • Kløw N.E.
      • Sandvik L.
      • Slagsvold C.E.
      • Ghanima W.
      • Hafsahl G.
      • et al.
      Catheter-directed thrombolysis vs. anticoagulant therapy alone in deep vein thrombosis: results of an open randomized, controlled trial reporting on short-term patency.
      • Comerota A.J.
      The ATTRACT trial: rationale for early intervention for iliofemoral DVT.
      • Vedantham S.
      • Goldhaber S.Z.
      • Julian J.A.
      • Kahn S.R.
      • Jaff M.R.
      • Cohen D.J.
      • et al.
      Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis.
      • Weinberg I.
      • Vedantham S.
      • Salter A.
      • Hadley G.
      • Al-Hammadi N.
      • Kearon C.
      • et al.
      Relationships between the use of pharmacomechanical catheter-directed thrombolysis, sonographic findings, and clinical outcomes in patients with acute proximal DVT: results from the ATTRACT Multicenter Randomized Trial.
      • Kearon C.
      • Gu C.S.
      • Julian J.A.
      • Goldhaber S.Z.
      • Comerota A.J.
      • Gornik H.L.
      • et al.
      Pharmacomechanical catheter-directed thrombolysis in acute femoral-popliteal deep vein thrombosis: analysis from a stratified randomized trial.
      • Magnuson E.A.
      • Chinnakondepalli K.
      • Vilain K.
      • Kearon C.
      • Julian J.A.
      • Kahn S.R.
      • et al.
      Cost-effectiveness of pharmacomechanical catheter-directed thrombolysis versus standard anticoagulation in patients with proximal deep vein thrombosis: results from the ATTRACT Trial.
      • Engelberger Rolf P.
      • Spirk D.
      • Willenberg T.
      • Alatri A.
      • Do D.-D.
      • Baumgartner I.
      • et al.
      Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis.
      • Engelberger R.P.
      • Stuck A.
      • Spirk D.
      • Willenberg T.
      • Haine A.
      • Périard D.
      • et al.
      Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis: 1-year follow-up data of a randomized-controlled trial.
      These were incorporated in this study. Figure 1 summarises the literature search results.
      Figure 1
      Figure 1Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagram of randomised controlled trials (RCTs) investigating outcomes of treatment strategies for proximal and iliofemoral deep vein thrombosis. The electronic databases were searched individually, and thesaurus headings, search operators, and search limits were adapted in each of them.

      Network structure

      Medical therapy, CDT, and USCDT formed a closed loop across outcomes, meaning that all interventions were directly compared with each other, except for patency, where there were direct comparisons between medical therapy – CDT, medical therapy – PAT, and CDT – USCDT. There were no direct comparisons between medical therapy and PAT (except for patency), and USCDT and PAT. Network plots for each outcome are provided in Figure 2.
      Figure 2
      Figure 2Network plots from a CINeMA approach
      • Nikolakopoulou A.
      • Higgins J.P.T.
      • Papakonstantinou T.
      • Chaimani A.
      • Del Giovane C.
      • Egger M.
      • et al.
      CINeMA: an approach for assessing confidence in the results of a network meta-analysis.
      for the outcomes of (A) post-thrombotic syndrome (PTS); (B) patency; (C) bleeding; (D) deep vein thrombosis recurrence; and (E) mortality for different treatment strategies for proximal and iliofemoral deep vein thrombosis. Node size is proportional to the cumulative sample size of the studies; the coloured area within the nodes is proportional to the overall risk of bias of the studies (green, low risk; yellow, some concerns; red, high risk). Edge width is proportional to the number of studies contributing data to the comparison; edge colour represents the average risk of bias of the studies contributing to the comparison. CDT = catheter directed thrombolysis, PAT = percutaneous aspiration thrombectomy, USCDT = ultrasound assisted catheter directed thrombolysis.

      Description of studies

      The characteristics of the selected studies and the specific study population baseline demographics and clinical characteristics are summarised in Table 1 and Supplementary Table S2, respectively. All studies but the ATTRACT trial (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter Directed Thrombolysis) reported iliofemoral DVT, and the ATTRACT trial reported separate results for proximal and iliofemoral DVT.
      • Comerota A.J.
      • Kearon C.
      • Gu C.S.
      • Julian J.A.
      • Goldhaber S.Z.
      • Kahn S.R.
      • et al.
      Endovascular thrombus removal for acute iliofemoral deep vein thrombosis.
      Table 1Study characteristics of randomised controlled trials (RCTs) investigating outcomes of treatment strategies for proximal and iliofemoral deep vein thrombosis (DVT)
      RCTRecruitment periodITTPatients – nPatient groupsInclusion criteriaPrimary endpointFollow up
      CaVenT 2007, 2009, 2012, 2013, 2016; 24 centres, Norway
      • Enden T.
      • Sandvik L.
      • Kløw N.-E.
      • Hafsahl G.
      • Holme P.A.
      • Holmen L.O.
      • et al.
      Catheter-directed Venous Thrombolysis in acute iliofemoral vein thrombosis-the CaVenT Study: rationale and design of a multicenter, randomized, controlled, clinical trial (NCT00251771).
      ,
      • Enden T.
      • Haig Y.
      • Kløw N.-E.
      • Slagsvold C.-E.
      • Sandvik L.
      • Ghanima W.
      • et al.
      Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial.
      ,
      • Haig Y.
      • Enden T.
      • Grøtta O.
      • Kløw N.-E.
      • Slagsvold C.-E.
      • Ghanima W.
      • et al.
      Post-thrombotic syndrome after catheter-directed thrombolysis for deep vein thrombosis (CaVenT): 5-year follow-up results of an open-label, randomised controlled trial.
      ,
      • Enden T.
      • Kløw N.E.
      • Sandvik L.
      • Slagsvold C.E.
      • Ghanima W.
      • Hafsahl G.
      • et al.
      Catheter-directed thrombolysis vs. anticoagulant therapy alone in deep vein thrombosis: results of an open randomized, controlled trial reporting on short-term patency.
      Jan 2006 – Dec 2009Yes189CDT: 90

      BMT: 99
      18–75 y; first time iliofemoral DVT; duration < 21 dPTS (Villalta ≥ 5 or leg ulcer) at 2 y; deep venous patency at 6 mo6 mo

      2 y

      5 y
      Engelberger 2015, 2017; 1 centre, Switzerland
      • Engelberger Rolf P.
      • Spirk D.
      • Willenberg T.
      • Alatri A.
      • Do D.-D.
      • Baumgartner I.
      • et al.
      Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis.
      ,
      • Engelberger R.P.
      • Stuck A.
      • Spirk D.
      • Willenberg T.
      • Haine A.
      • Périard D.
      • et al.
      Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis: 1-year follow-up data of a randomized-controlled trial.
      Nov 2011 – Nov 2013Yes48CDT: 24

      USCDT: 24
      18–75 y; iliofemoral DVT; duration ≤ 14 dThrombus load reduction; PTS (Villalta ≥ 5 or leg ulcer); deep venous patency15 h

      3 mo

      1 y
      Cakir 2014; 1 centre,

      Turkey
      • Cakir V.
      • Gulcu A.
      • Akay E.
      • Capar A.E.
      • Gencpinar T.
      • Kucuk B.
      • et al.
      Use of percutaneous aspiration thrombectomy vs. anticoagulation therapy to treat acute iliofemoral venous thrombosis: 1-year follow-up results of a randomised, clinical trial.
      Mar 2010 – Apr 2011Yes42PAT: 21

      BMT:21
      Involving iliofemoral–popliteal veins; duration ≤ 14 dDeep venous patency; clinical symptoms score1 mo

      3 mo

      1 y
      Zhu 2019; 1 centre,

      China
      • Zhu C.
      • Zhuo H.
      • Qin Y.
      • Zhang W.
      • Qiu J.
      • Ran F.
      Comparison of clear effect and the complications, and short and mid-term effects between ultrasound-guided and non-guided catheter-directed thrombolysis in the treatment of deep venous thrombosis of lower extremity.
      Aug 2015 – Apr 2016Yes60CDT: 30

      USCDT: 30
      Duration ≤ 14 dPTS (Villalta ≥ 5 or leg ulcer); deep venous patency1 mo

      2 mo

      6 mo

      1 y
      CAVA 2020; 15 centres, the Netherlands
      • Notten P.
      • Ten Cate-Hoek A.J.
      • Arnoldussen C.
      • Strijkers R.H.W.
      • de Smet A.
      • Tick L.W.
      • et al.
      Ultrasound-accelerated catheter-directed thrombolysis versus anticoagulation for the prevention of post-thrombotic syndrome (CAVA): a single-blind, multicentre, randomised trial.
      May 2010 – Sep 2017Yes152USCDT: 75

      BMT: 75
      18–85 y; first time iliofemoral DVT; duration ≤ 14 dPTS (Villalta ≥ 5 or leg ulcer)1 y
      ATTRACT 2009, 2017, 2019, 2019, 2019, 2019; 56 centres, USA
      • Comerota A.J.
      The ATTRACT trial: rationale for early intervention for iliofemoral DVT.
      • Vedantham S.
      • Goldhaber S.Z.
      • Julian J.A.
      • Kahn S.R.
      • Jaff M.R.
      • Cohen D.J.
      • et al.
      Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis.
      • Weinberg I.
      • Vedantham S.
      • Salter A.
      • Hadley G.
      • Al-Hammadi N.
      • Kearon C.
      • et al.
      Relationships between the use of pharmacomechanical catheter-directed thrombolysis, sonographic findings, and clinical outcomes in patients with acute proximal DVT: results from the ATTRACT Multicenter Randomized Trial.
      • Kearon C.
      • Gu C.S.
      • Julian J.A.
      • Goldhaber S.Z.
      • Comerota A.J.
      • Gornik H.L.
      • et al.
      Pharmacomechanical catheter-directed thrombolysis in acute femoral-popliteal deep vein thrombosis: analysis from a stratified randomized trial.
      • Magnuson E.A.
      • Chinnakondepalli K.
      • Vilain K.
      • Kearon C.
      • Julian J.A.
      • Kahn S.R.
      • et al.
      Cost-effectiveness of pharmacomechanical catheter-directed thrombolysis versus standard anticoagulation in patients with proximal deep vein thrombosis: results from the ATTRACT Trial.
      ,
      • Comerota A.J.
      • Kearon C.
      • Gu C.S.
      • Julian J.A.
      • Goldhaber S.Z.
      • Kahn S.R.
      • et al.
      Endovascular thrombus removal for acute iliofemoral deep vein thrombosis.
      Dec 2009 – Dec 2014Yes691CDT: 336

      BMT: 355
      16–70 y; symptomatic proximal DVT involving iliac vein, CFV, or FV; duration ≤ 14 dPTS (Villalta ≥ 5 or leg ulcer)10 d

      30 d

      6 mo

      1 y

      1.5 y

      2 y
      Elsharawy 2002; 1 centre, Egypt
      • Elsharawy M.
      • Elzayat E.
      Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis. A randomised clinical trial.
      1 Apr 2000 – 1 Apr 2001Yes35CDT: 18

      BMT: 17
      < 70 y; iliofemoral DVT; duration ≤ 10 dDeep venous patency6 wk

      3 mo

      6 mo
      BMT = best medical therapy; CDT = catheter directed thrombolysis; CFV = common femoral vein; FV = femoral vein; ITT = intention to treat; PAT = percutaneous aspiration thrombectomy; PTS = post-thrombotic syndrome; USCDT = ultrasound assisted catheter directed thrombolysis.

      Catheter directed thrombolysis vs. medical therapy

      Three studies compared the outcomes of CDT with medical therapy.
      • Enden T.
      • Sandvik L.
      • Kløw N.-E.
      • Hafsahl G.
      • Holme P.A.
      • Holmen L.O.
      • et al.
      Catheter-directed Venous Thrombolysis in acute iliofemoral vein thrombosis-the CaVenT Study: rationale and design of a multicenter, randomized, controlled, clinical trial (NCT00251771).
      ,
      • Enden T.
      • Haig Y.
      • Kløw N.-E.
      • Slagsvold C.-E.
      • Sandvik L.
      • Ghanima W.
      • et al.
      Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial.
      ,
      • Elsharawy M.
      • Elzayat E.
      Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis. A randomised clinical trial.
      ,
      • Haig Y.
      • Enden T.
      • Grøtta O.
      • Kløw N.-E.
      • Slagsvold C.-E.
      • Ghanima W.
      • et al.
      Post-thrombotic syndrome after catheter-directed thrombolysis for deep vein thrombosis (CaVenT): 5-year follow-up results of an open-label, randomised controlled trial.
      • Enden T.
      • Kløw N.E.
      • Sandvik L.
      • Slagsvold C.E.
      • Ghanima W.
      • Hafsahl G.
      • et al.
      Catheter-directed thrombolysis vs. anticoagulant therapy alone in deep vein thrombosis: results of an open randomized, controlled trial reporting on short-term patency.
      • Comerota A.J.
      The ATTRACT trial: rationale for early intervention for iliofemoral DVT.
      • Vedantham S.
      • Goldhaber S.Z.
      • Julian J.A.
      • Kahn S.R.
      • Jaff M.R.
      • Cohen D.J.
      • et al.
      Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis.
      • Weinberg I.
      • Vedantham S.
      • Salter A.
      • Hadley G.
      • Al-Hammadi N.
      • Kearon C.
      • et al.
      Relationships between the use of pharmacomechanical catheter-directed thrombolysis, sonographic findings, and clinical outcomes in patients with acute proximal DVT: results from the ATTRACT Multicenter Randomized Trial.
      • Kearon C.
      • Gu C.S.
      • Julian J.A.
      • Goldhaber S.Z.
      • Comerota A.J.
      • Gornik H.L.
      • et al.
      Pharmacomechanical catheter-directed thrombolysis in acute femoral-popliteal deep vein thrombosis: analysis from a stratified randomized trial.
      • Magnuson E.A.
      • Chinnakondepalli K.
      • Vilain K.
      • Kearon C.
      • Julian J.A.
      • Kahn S.R.
      • et al.
      Cost-effectiveness of pharmacomechanical catheter-directed thrombolysis versus standard anticoagulation in patients with proximal deep vein thrombosis: results from the ATTRACT Trial.
      In the ATTRACT and CaVenT (Catheter directed Venous Thrombolysis in acute iliofemoral vein thrombosis) studies, medical therapy involved the use of low molecular weight heparin (LMWH) (dalteparin [Pfizer, New York, NY, USA] or enoxaparin [Sanofi, Paris, France]) initially; thereafter, patients were switched to a long term oral anticoagulation agent. The patients were also encouraged to wear compression stockings for the duration of treatment. For Elsharawy and Elzayat,
      • Elsharawy M.
      • Elzayat E.
      Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis. A randomised clinical trial.
      patients received an unfractionated heparin (UFH) bolus followed by continuous infusion. They were then started on warfarin. For the intervention group, ATTRACT employed recombinant tissue plasminogen activator (rt-PA). Balloon venoplasty and stenting were also used as part of the intervention to reach maximum patency. The intervention was stopped after 90% vessel patency was achieved. In the CaVenT trial, the intervention group initially received a UFH bolus followed by an alteplase infusion. As with ATTRACT, vessel patency was improved by angioplasty or stenting. Elsharawy and Elzayat used streptokinase as the thrombolytic agent using a pulse spray.
      • Elsharawy M.
      • Elzayat E.
      Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis. A randomised clinical trial.
      Treatment was stopped when complete lysis was achieved.

      Catheter directed thrombolysis vs. ultrasound assisted catheter directed thrombolysis

      Two studies compared the outcomes of CDT with USCDT.
      • Zhu C.
      • Zhuo H.
      • Qin Y.
      • Zhang W.
      • Qiu J.
      • Ran F.
      Comparison of clear effect and the complications, and short and mid-term effects between ultrasound-guided and non-guided catheter-directed thrombolysis in the treatment of deep venous thrombosis of lower extremity.
      ,
      • Engelberger Rolf P.
      • Spirk D.
      • Willenberg T.
      • Alatri A.
      • Do D.-D.
      • Baumgartner I.
      • et al.
      Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis.
      ,
      • Engelberger R.P.
      • Stuck A.
      • Spirk D.
      • Willenberg T.
      • Haine A.
      • Périard D.
      • et al.
      Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis: 1-year follow-up data of a randomized-controlled trial.
      For Engelberger et al.,
      • Engelberger Rolf P.
      • Spirk D.
      • Willenberg T.
      • Alatri A.
      • Do D.-D.
      • Baumgartner I.
      • et al.
      Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis.
      ,
      • Engelberger R.P.
      • Stuck A.
      • Spirk D.
      • Willenberg T.
      • Haine A.
      • Périard D.
      • et al.
      Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis: 1-year follow-up data of a randomized-controlled trial.
      patients in each intervention group were initiated on a bolus of UFH, followed by continuous infusion; they were then switched onto LMWH and then a long term anticoagulant. During CDT, patients were given rt-PA. For those in the USCDT group, intravascular ultrasound energy was switched on. Zhu et al. used urokinase initially,
      • Zhu C.
      • Zhuo H.
      • Qin Y.
      • Zhang W.
      • Qiu J.
      • Ran F.
      Comparison of clear effect and the complications, and short and mid-term effects between ultrasound-guided and non-guided catheter-directed thrombolysis in the treatment of deep venous thrombosis of lower extremity.
      which was delivered directly to the thrombus through the thrombolytic catheter. Thereafter, a maintenance dose of urokinase was infused every six hours. The catheter remained in place for four to six days. In addition to the thrombolytic agent, LMWH, aspirin, and horse chestnut seed extract tablets (aescuven forte) were also given to all patients. After a week of LWMH, patients were started on warfarin. Thrombolytic agents were stopped at complete or near complete lysis, if there was no effect seen at 72 hours, or if a major complication had occurred. The treatment remained the same between the two intervention groups, although ultrasound was used to identify the vessel for cannulation in the USCDT group.

      Percutaneous aspiration thrombectomy vs. medical therapy

      Only one RCT was identified comparing PAT with medical therapy.
      • Cakir V.
      • Gulcu A.
      • Akay E.
      • Capar A.E.
      • Gencpinar T.
      • Kucuk B.
      • et al.
      Use of percutaneous aspiration thrombectomy vs. anticoagulation therapy to treat acute iliofemoral venous thrombosis: 1-year follow-up results of a randomised, clinical trial.
      Medical therapy involved patients receiving LMWH (Clexane 6000 anti Xa/0.6 mL bit subcutaneously) and warfarin (coumadin 5 mg/day orally), whereby LMWH was discontinued after five days. Patients were also encouraged to mobilise early, and compression stockings were recommended to all patients. The intervention group received medical therapy in addition to PAT. During PAT, after access to the vein was achieved, non-ionic contrast was injected to obtain ascending venographic images of the deep venous system. Intravenous heparin, bolus and maintenance, was used during PAT. Thereafter, a 9 F catheter was passed through the thrombus segment and negative pressure was applied using a syringe for aspiration. Once free flowing blood was seen in the syringe, the procedure was stopped. Balloon venoplasty and stenting were considered for residual stenosis.

      Ultrasound assisted catheter directed thrombolysis vs. medical therapy

      The CAVA trial (ultrasound accelerated catheter directed thrombolysis vs. anticoagulation for the prevention of post-thrombotic syndrome) compared USCDT to medical therapy.
      • Haig Y.
      • Enden T.
      • Grøtta O.
      • Kløw N.-E.
      • Slagsvold C.-E.
      • Ghanima W.
      • et al.
      Post-thrombotic syndrome after catheter-directed thrombolysis for deep vein thrombosis (CaVenT): 5-year follow-up results of an open-label, randomised controlled trial.
      Patients in both groups received LMWH or oral anticoagulation with compression stockings. For the intervention group, a urokinase bolus followed by a maintenance infusion was used, and at the same time, a heparin infusion was also given. The delivery of the thrombolytic agent was achieved using a drug delivery catheter with a microsonic core containing ultrasound transducers. Patients were followed up from three to 12 months. If additional interventions, such as stenting, were required for residual stenosis, these patients were followed up earlier, at two and six weeks.

      Risk of bias assessment

      Random sequence generation and allocation concealment methods were adequately described in all but three of the trials.
      • Zhu C.
      • Zhuo H.
      • Qin Y.
      • Zhang W.
      • Qiu J.
      • Ran F.
      Comparison of clear effect and the complications, and short and mid-term effects between ultrasound-guided and non-guided catheter-directed thrombolysis in the treatment of deep venous thrombosis of lower extremity.
      ,
      • Cakir V.
      • Gulcu A.
      • Akay E.
      • Capar A.E.
      • Gencpinar T.
      • Kucuk B.
      • et al.
      Use of percutaneous aspiration thrombectomy vs. anticoagulation therapy to treat acute iliofemoral venous thrombosis: 1-year follow-up results of a randomised, clinical trial.
      ,
      • Weinberg I.
      • Vedantham S.
      • Salter A.
      • Hadley G.
      • Al-Hammadi N.
      • Kearon C.
      • et al.
      Relationships between the use of pharmacomechanical catheter-directed thrombolysis, sonographic findings, and clinical outcomes in patients with acute proximal DVT: results from the ATTRACT Multicenter Randomized Trial.
      ,
      • Kearon C.
      • Gu C.S.
      • Julian J.A.
      • Goldhaber S.Z.
      • Comerota A.J.
      • Gornik H.L.
      • et al.
      Pharmacomechanical catheter-directed thrombolysis in acute femoral-popliteal deep vein thrombosis: analysis from a stratified randomized trial.
      In two of the trials,
      • Zhu C.
      • Zhuo H.
      • Qin Y.
      • Zhang W.
      • Qiu J.
      • Ran F.
      Comparison of clear effect and the complications, and short and mid-term effects between ultrasound-guided and non-guided catheter-directed thrombolysis in the treatment of deep venous thrombosis of lower extremity.
      ,
      • Cakir V.
      • Gulcu A.
      • Akay E.
      • Capar A.E.
      • Gencpinar T.
      • Kucuk B.
      • et al.
      Use of percutaneous aspiration thrombectomy vs. anticoagulation therapy to treat acute iliofemoral venous thrombosis: 1-year follow-up results of a randomised, clinical trial.
      blinding of outcome assessors was inadequately described. One RCT was found to have incomplete outcome data.
      • Elsharawy M.
      • Elzayat E.
      Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis. A randomised clinical trial.
      • Notten P.
      • Ten Cate-Hoek A.J.
      • Arnoldussen C.
      • Strijkers R.H.W.
      • de Smet A.
      • Tick L.W.
      • et al.
      Ultrasound-accelerated catheter-directed thrombolysis versus anticoagulation for the prevention of post-thrombotic syndrome (CAVA): a single-blind, multicentre, randomised trial.
      • Haig Y.
      • Enden T.
      • Grøtta O.
      • Kløw N.-E.
      • Slagsvold C.-E.
      • Ghanima W.
      • et al.
      Post-thrombotic syndrome after catheter-directed thrombolysis for deep vein thrombosis (CaVenT): 5-year follow-up results of an open-label, randomised controlled trial.
      • Enden T.
      • Kløw N.E.
      • Sandvik L.
      • Slagsvold C.E.
      • Ghanima W.
      • Hafsahl G.
      • et al.
      Catheter-directed thrombolysis vs. anticoagulant therapy alone in deep vein thrombosis: results of an open randomized, controlled trial reporting on short-term patency.
      • Comerota A.J.
      The ATTRACT trial: rationale for early intervention for iliofemoral DVT.
      Three of the trials did not provide a pre-specified analysis plan that was finalised before unblinded outcome data were available for analysis.
      • Zhu C.
      • Zhuo H.
      • Qin Y.
      • Zhang W.
      • Qiu J.
      • Ran F.
      Comparison of clear effect and the complications, and short and mid-term effects between ultrasound-guided and non-guided catheter-directed thrombolysis in the treatment of deep venous thrombosis of lower extremity.
      ,
      • Cakir V.
      • Gulcu A.
      • Akay E.
      • Capar A.E.
      • Gencpinar T.
      • Kucuk B.
      • et al.
      Use of percutaneous aspiration thrombectomy vs. anticoagulation therapy to treat acute iliofemoral venous thrombosis: 1-year follow-up results of a randomised, clinical trial.
      ,
      • Engelberger Rolf P.
      • Spirk D.
      • Willenberg T.
      • Alatri A.
      • Do D.-D.
      • Baumgartner I.
      • et al.
      Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis.
      ,
      • Engelberger R.P.
      • Stuck A.
      • Spirk D.
      • Willenberg T.
      • Haine A.
      • Périard D.
      • et al.
      Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis: 1-year follow-up data of a randomized-controlled trial.
      No RCTs were terminated early. The risk of bias assessment of the RCTs is summarised in Figure 3, Figure 4.
      Figure 3
      Figure 3Contribution risk of bias chart for the outcomes of (A) post-thrombotic syndrome (PTS); (B) patency; (C) bleeding; (D) deep vein thrombosis recurrence; and (E) mortality for different treatment strategies for proximal and iliofemoral deep vein thrombosis, indicating the proportional risk of bias of studies contributing to the comparisons (green, low risk; yellow, some concerns; red, high risk). CDT = catheter directed thrombolysis, PAT = percutaneous aspiration thrombectomy, USCDT = ultrasound assisted catheter directed thrombolysis.
      Figure 4
      Figure 4Risk of bias summary based on review authors’ judgements about each risk of bias item for each included study for (A) post-thrombotic syndrome (PTS); (B) patency; (C) bleeding; (D) deep vein thrombosis recurrence; and (E) mortality for randomised controlled trials on different treatment strategies for proximal and iliofemoral deep vein thrombosis.

      Assessment of transitivity and inconsistency

      There was non-homogeneous distribution of underlying diagnoses (effect modifiers) across trial arms, which is referred to as intransitivity; several studies did not provide relevant information. Notably, thrombophilia was the underlying diagnosis in 43.3% of patients undergoing CDT in the CaVenT study and in no patients undergoing CDT in the study of Engelberger et al.
      • Engelberger Rolf P.
      • Spirk D.
      • Willenberg T.
      • Alatri A.
      • Do D.-D.
      • Baumgartner I.
      • et al.
      Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis.
      ,
      • Engelberger R.P.
      • Stuck A.
      • Spirk D.
      • Willenberg T.
      • Haine A.
      • Périard D.
      • et al.
      Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis: 1-year follow-up data of a randomized-controlled trial.
      Similarly, COC/HRT accounted for 7.8% – 37.5% of patients in different study arms. There was relative consistency in age, sex distribution, and BMI. There was some intransitivity with regard to duration of follow up, with most studies providing one to two year data. Analytical data are provided Table 2. Inconsistency testing was not suggestive of significant inconsistency, although this may be masked in smaller networks.
      Table 2Network meta-analysis league table for proximal deep vein thrombosis
      PTS
      Medical1.58 (0.62–4.01)1.33 (0.32–5.45)
      1.42 (0.61–3.32)
      Significant results.
      CDT1.58 (0.35–7.22)
      1.69 (0.56–5.13)
      Significant results.
      1.19 (0.38–3.69)USCDT
      Patency
      USCDT4.67 (1.58–13.81)
      Significant results.
      1.18 (0.10– 14.37)
      Significant results.
      PAT8.00 (0.86–74.11)
      4.67 (1.58–13.81)3.95 (0.42–37.46)CDT2.03 (1.46–2.80)
      Significant results.
      9.46 (3.05–29.35)8.00 (0.86–74.11)2.03 (1.46–2.80)
      Significant results.
      Medical
      Bleeding
      USCDT1.57 (0.04–58.99)9.24 (0.13–660.59)
      1.59 (0.09–29.65)
      Significant results.
      CDT5.68 (0.46–69.89)
      9.09 (0.42–195.23)
      Significant results.
      5.71 (0.58–56.45)Medical
      DVT recurrence
      USCDT1.23 (0.24–6.43)1.57 (0.19–12.95)
      1.35 (0.36–5.11)
      Significant results.
      Medical0.99 (0.44–2.22)
      1.36 (0.34–5.43)
      Significant results.
      1.01 (0.46–2.19)CDT
      Mortality
      Medical1.08 (0.39–3.02)3.17 (0.32–31.15)
      1.11 ( 0.42–2.97)
      Significant results.
      CDT2.09 (0.18–24.73)
      2.75 (0.48–15.63)
      Significant results.
      2.47 (0.42–14.32)USCDT
      Effect estimates are provided as odds ratio (OR; 95% confidence interval). An OR > 1 indicates that the intervention in the respective column is superior; an OR < 1 indicates that the intervention in the respective row is superior. The upper right half (above the diagonal defined by the interventions) lists direct effect estimates and the lower left half (below the diagonal) lists network estimates. PTS = post-thrombotic syndrome; CDT = catheter directed thrombolysis; USCDT = ultrasound assisted catheter directed thrombolysis; PAT = percutaneous aspiration thrombectomy; DVT = deep vein thrombosis.
      Significant results.

      Effects of interventions and certainty in the evidence

      There was no significant difference in PTS observed between the treatment modalities (low certainty). There was a significant difference in patency rates between medical therapy and USCDT (OR 9.46, 95% CI 3.05 – 29.35; low certainty) and CDT (OR 2.03, 95% CI 1.46 – 2.80; low certainty) in favour of USCDT and CDT, respectively. USCDT significantly improved patency rates compared with CDT (OR 4.67, 95% CI 1.58 – 13.81; very low certainty). There was no significant difference in DVT recurrence, bleeding, and mortality between the treatment groups (low to moderate certainty for most comparisons) (Figure 5, Table 2, Supplementary Table S3).
      Figure 5
      Figure 5Forest plots of comparison for other treatment strategies vs. catheter directed thrombolysis (CDT) for proximal and iliofemoral deep vein thrombosis for (A) post-thrombotic syndrome (PTS); (B) patency; (C) bleeding; (D) deep vein thrombosis recurrence; and (E) mortality. CI = confidence interval, OR = odds ratio, PAT = percutaneous aspiration thrombectomy, USCDT = ultrasound assisted catheter directed thrombolysis.

      Analysis of iliofemoral deep vein thrombosis

      There was no significant difference in PTS observed between the treatment modalities. Subanalysis of patency could not be undertaken owing to limitations in data availability. There was no significant difference in DVT recurrence, bleeding, and mortality between treatment groups (Supplementary Table S4).

      Discussion

      A network meta-analysis was conducted to evaluate different treatment modalities (USCDT, CDT, PAT, and medical therapy alone) for the management of acute proximal and iliofemoral DVT. This network meta-analysis is the first of its kind to compare all invasive treatment options for proximal and iliofemoral lower limb DVT. A total of 1 217 patients from seven RCTs were included. There was no statistically significant difference in the incidence of PTS between treatment modalities. The network meta-analysis identified a statistically significant difference in vein patency rates between the different treatment modalities. The most effective modality in improving patency was USCDT, which was superior to CDT, and CDT was subsequently superior to medical therapy alone. There was no statistically significant difference across the treatment modalities for DVT recurrence, bleeding, and mortality.
      The absence of a statistically significant difference in the incidence of PTS between treatment modalities is in keeping with the individual outcomes of ATTRACT, Engelberger et al., and CAVA,
      • Notten P.
      • Ten Cate-Hoek A.J.
      • Arnoldussen C.
      • Strijkers R.H.W.
      • de Smet A.
      • Tick L.W.
      • et al.
      Ultrasound-accelerated catheter-directed thrombolysis versus anticoagulation for the prevention of post-thrombotic syndrome (CAVA): a single-blind, multicentre, randomised trial.
      ,
      • Comerota A.J.
      The ATTRACT trial: rationale for early intervention for iliofemoral DVT.
      • Vedantham S.
      • Goldhaber S.Z.
      • Julian J.A.
      • Kahn S.R.
      • Jaff M.R.
      • Cohen D.J.
      • et al.
      Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis.
      • Weinberg I.
      • Vedantham S.
      • Salter A.
      • Hadley G.
      • Al-Hammadi N.
      • Kearon C.
      • et al.
      Relationships between the use of pharmacomechanical catheter-directed thrombolysis, sonographic findings, and clinical outcomes in patients with acute proximal DVT: results from the ATTRACT Multicenter Randomized Trial.
      • Kearon C.
      • Gu C.S.
      • Julian J.A.
      • Goldhaber S.Z.
      • Comerota A.J.
      • Gornik H.L.
      • et al.
      Pharmacomechanical catheter-directed thrombolysis in acute femoral-popliteal deep vein thrombosis: analysis from a stratified randomized trial.
      • Magnuson E.A.
      • Chinnakondepalli K.
      • Vilain K.
      • Kearon C.
      • Julian J.A.
      • Kahn S.R.
      • et al.
      Cost-effectiveness of pharmacomechanical catheter-directed thrombolysis versus standard anticoagulation in patients with proximal deep vein thrombosis: results from the ATTRACT Trial.
      • Engelberger Rolf P.
      • Spirk D.
      • Willenberg T.
      • Alatri A.
      • Do D.-D.
      • Baumgartner I.
      • et al.
      Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis.
      • Engelberger R.P.
      • Stuck A.
      • Spirk D.
      • Willenberg T.
      • Haine A.
      • Périard D.
      • et al.
      Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis: 1-year follow-up data of a randomized-controlled trial.
      which found no difference in the incidence of PTS between the compared treatment modalities. On the contrary, CAVENT did support a reduction in the incidence of PTS in patients treated with CDT, compared with medical therapy alone at the two and five year follow ups.
      • Enden T.
      • Sandvik L.
      • Kløw N.-E.
      • Hafsahl G.
      • Holme P.A.
      • Holmen L.O.
      • et al.
      Catheter-directed Venous Thrombolysis in acute iliofemoral vein thrombosis-the CaVenT Study: rationale and design of a multicenter, randomized, controlled, clinical trial (NCT00251771).
      ,
      • Enden T.
      • Haig Y.
      • Kløw N.-E.
      • Slagsvold C.-E.
      • Sandvik L.
      • Ghanima W.
      • et al.
      Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial.
      ,
      • Notten P.
      • Ten Cate-Hoek A.J.
      • Arnoldussen C.
      • Strijkers R.H.W.
      • de Smet A.
      • Tick L.W.
      • et al.
      Ultrasound-accelerated catheter-directed thrombolysis versus anticoagulation for the prevention of post-thrombotic syndrome (CAVA): a single-blind, multicentre, randomised trial.
      ,
      • Enden T.
      • Kløw N.E.
      • Sandvik L.
      • Slagsvold C.E.
      • Ghanima W.
      • Hafsahl G.
      • et al.
      Catheter-directed thrombolysis vs. anticoagulant therapy alone in deep vein thrombosis: results of an open randomized, controlled trial reporting on short-term patency.
      However, at five years there was a dropout rate of 16% and, as with the other studies, the authors concluded that the patients’ quality of life was not improved. Zhu et al. showed the superiority of USCDT over CDT in reducing PTS,
      • Zhu C.
      • Zhuo H.
      • Qin Y.
      • Zhang W.
      • Qiu J.
      • Ran F.
      Comparison of clear effect and the complications, and short and mid-term effects between ultrasound-guided and non-guided catheter-directed thrombolysis in the treatment of deep venous thrombosis of lower extremity.
      but follow up was limited to 12 months. The other two RCTs did not compare the effect of treatment on the incidence of PTS.
      • Cakir V.
      • Gulcu A.
      • Akay E.
      • Capar A.E.
      • Gencpinar T.
      • Kucuk B.
      • et al.
      Use of percutaneous aspiration thrombectomy vs. anticoagulation therapy to treat acute iliofemoral venous thrombosis: 1-year follow-up results of a randomised, clinical trial.
      ,
      • Elsharawy M.
      • Elzayat E.
      Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis. A randomised clinical trial.
      The network meta-analysis showed that the most effective modality in improving patency was USCDT, which was superior to CDT, and CDT subsequently superior to medical therapy alone. The value of patency rates on patients’ quality of life remains unclear. In 2017, Gombert et al. compared patency rates and the quality of life in patients suffering from iliofemoral DVT.
      • Gombert A.
      • Gombert R.
      • Barbati M.E.
      • Bruners P.
      • Keszei A.
      • Wittens C.
      • et al.
      Patency rate and quality of life after ultrasound-accelerated catheter-directed thrombolysis for deep vein thrombosis.
      Patients with patent veins reported a better quality of life; however, the study size was small, with only 30 patients completing the survey. They concluded that prospective studies are needed to better evaluate the value of patency rates in acute proximal DVT. Although USCDT and CDT significantly improved vein patency rates compared with each other with medical therapy alone, this did not translate into a reduction in the incidence of PTS.
      Abraham et al. compared the effects of CDT in acute DVT.
      • Abraham B.
      • Sedhom R.
      • Megaly M.
      • Saad M.
      • Elbadawi A.
      • Elgendy I.Y.
      • et al.
      Outcomes with catheter-directed thrombolysis compared with anticoagulation alone in patients with acute deep venous thrombosis.
      They performed a systematic review and meta-analysis of 11 studies, concluding that CDT reduced PTS and improved vessel patency in the long term. However, the review included seven observational studies and, as with such studies, overestimation can occur due to confounding and selection bias.
      • Abraham B.
      • Sedhom R.
      • Megaly M.
      • Saad M.
      • Elbadawi A.
      • Elgendy I.Y.
      • et al.
      Outcomes with catheter-directed thrombolysis compared with anticoagulation alone in patients with acute deep venous thrombosis.
      Therefore, the authors concluded that the review could be used as a hypothesis generating study and that CDT may be used in patients with extensive proximal acute DVT. A systematic review and meta-analysis by Wang and Deng comparing the effects of percutaneous endovenous intervention to anticoagulation concluded that percutaneous endovenous intervention confers reduced incidence of PTS and DVT recurrence, and improved vessel patency.
      • Wang C.N.
      • Deng H.R.
      Percutaneous endovenous intervention plus anticoagulation versus anticoagulation alone for treating patients with proximal deep vein thrombosis: a meta-analysis and systematic review.
      However, bleeding was increased with interventional treatment compared with medical therapy alone. These results contrast with the present results, although the Wang and Deng study employed only four RCTs from 2016, and the TORPEDO trial (Thrombus Obliteration by Rapid Percutaneous Endovenous intervention in Deep venous Occlusion) was excluded from the analysis as that trial combined multiple interventional treatments into a single group termed percutaneous endovenous intervention.
      • Sharifi M.
      • Mehdipour M.
      • Bay C.
      • Smith G.
      • Sharifi J.
      Endovenous therapy for deep venous thrombosis: the TORPEDO trial.
      ,
      • Sharifi M.
      • Bay C.
      • Mehdipour M.
      • Sharifi J.
      Thrombus obliteration by rapid percutaneous endovenous intervention in deep venous occlusion (TORPEDO) trial: midterm results.
      A risk of bias assessment was conducted and found that five of the seven studies had some concerns, with the Elsharawy and Elzayat study and the CAVA trial being of low risk of bias.
      • Elsharawy M.
      • Elzayat E.
      Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis. A randomised clinical trial.
      ,
      • Notten P.
      • Ten Cate-Hoek A.J.
      • Arnoldussen C.
      • Strijkers R.H.W.
      • de Smet A.
      • Tick L.W.
      • et al.
      Ultrasound-accelerated catheter-directed thrombolysis versus anticoagulation for the prevention of post-thrombotic syndrome (CAVA): a single-blind, multicentre, randomised trial.
      ATTRACT (the largest trial) had incomplete outcome data. In addition, two trials (that of Cakir et al. and Zhu et al.),
      • Zhu C.
      • Zhuo H.
      • Qin Y.
      • Zhang W.
      • Qiu J.
      • Ran F.
      Comparison of clear effect and the complications, and short and mid-term effects between ultrasound-guided and non-guided catheter-directed thrombolysis in the treatment of deep venous thrombosis of lower extremity.
      ,
      • Cakir V.
      • Gulcu A.
      • Akay E.
      • Capar A.E.
      • Gencpinar T.
      • Kucuk B.
      • et al.
      Use of percutaneous aspiration thrombectomy vs. anticoagulation therapy to treat acute iliofemoral venous thrombosis: 1-year follow-up results of a randomised, clinical trial.
      did not adequately describe the blinding of outcome assessors. From the studies used in this network meta-analysis, ATTRACT, CAVENT, and CAVA were multicentre trials carried out across 56, 24, and 15 centres, respectively. The other four studies were single centre trials. The CaVenT trial followed patients up to five years, with ATTRACT having a two year follow up. However, Elsharawy and Elzayat only followed up patients to six months.
      • Elsharawy M.
      • Elzayat E.
      Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis. A randomised clinical trial.
      Furthermore, ATTRACT had the largest number of patient participants (n = 691), whereas Elsharawy and Elzayat only recruited 32 patients.
      • Elsharawy M.
      • Elzayat E.
      Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis. A randomised clinical trial.
      ,
      • Comerota A.J.
      The ATTRACT trial: rationale for early intervention for iliofemoral DVT.
      There was also inconsistency with underlying diagnoses; for example, thrombophilia was the underlying diagnosis in 43.3% of patients in CaVenT but in none of the patients studied by Engelberger et al.
      • Engelberger Rolf P.
      • Spirk D.
      • Willenberg T.
      • Alatri A.
      • Do D.-D.
      • Baumgartner I.
      • et al.
      Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis.
      ,
      • Engelberger R.P.
      • Stuck A.
      • Spirk D.
      • Willenberg T.
      • Haine A.
      • Périard D.
      • et al.
      Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis: 1-year follow-up data of a randomized-controlled trial.
      Despite these observations, there was no significant inconsistency measured across the studies. Furthermore, there was no inconsistency found in age, sex, and BMI distribution.
      The Villalta scoring system was used to define patients with PTS in all the trials. The limitations of this are the subjective nature of the scoring system and the fact that many of the criteria used are not exclusive to PTS. Therefore, the use of this scoring system may have excluded certain patients with PTS that did not fall into the categories defined by the scoring system, including those with very mild or clinically insignificant PTS.
      The results of this review should be interpreted with caution in view of the limitations outlined. The network meta-analysis excluded all articles that were not in the English language and those published prior to 2000, although this may not have had an impact on effect estimates.
      • Dobrescu A.I.
      • Nussbaumer S.B.
      • Klerings I.
      • Wagner G.
      • Persad E.
      • Sommer I.
      • et al.
      Restricting evidence syntheses of interventions to English-language publications is a viable methodological shortcut for most medical topics: a systematic review.
      Only RCTs published after 2000 were selected, in order to reflect contemporaneous clinical practices and increase the external validity of the results. In addition, the different anticoagulation and thrombolytic agents used in different trials were not considered in the analysis. For instance, the ATTRACT trial used rt-PA for the CDT group, whereas the CaVenT trial used UFH and thereafter alteplase. The different use of various agents may have had some impact on effect estimates; however, the available data did not allow for disentangling the network to perform subgroup analyses. Differences across studies were also seen in medical therapy alone. There may be a consideration to investigate the effects of the different thrombolytic agents and anticoagulation therapies on treatment outcomes in future studies. Another shortcoming was the inability to account for the variable rates of deep venous stent insertion at the end of the procedures, which would have affected PTS and vessel patency rates.
      In conclusion, there may be no significant reduction in the incidence of PTS across different treatment modalities in the management of iliofemoral DVT. USCDT may result in higher venous patency rates than CDT and medical therapy alone; however, translating this improved patency to improved patient quality of life has not been demonstrated.

      Conflict of interest statement and Funding

      None.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:
      • Supplementary Table S1

        Search syntax. Bibliographic search strategy (terms in capital letters and within inverted comas represent thesaurus terms). The search on PubMed was run in August 2020, and the searches of MEDLINE, Embase, and CINAHL were last run on 4 April 2020.

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      Linked Article

      • Management of Proximal DVT: Clinical Benefit of Endovenous Intervention Is Still in Question
        European Journal of Vascular and Endovascular SurgeryVol. 63Issue 2
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          A recent systematic review by Ashrafi et al. aimed to compare various techniques for treating proximal and iliofemoral deep vein thrombosis (DVT).1 Sixty per cent of lower extremity DVTs are proximal, defined as those involving the popliteal and/or more proximal veins, thereby contributing to feared complications such as pulmonary embolism and post-thrombotic syndrome (PTS). PTS refers to the constellation of pain, oedema, ulceration, and limited mobility caused by venous insufficiency following DVT.
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