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.
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.
1- Stubbs M.J.
- Mouyis M.
- Thomas M.
Deep vein thrombosis.
In the acute phase, pulmonary embolism is the most serious complication.
2- 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.
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.
1- Stubbs M.J.
- Mouyis M.
- Thomas M.
Deep vein thrombosis.
Post-thrombotic syndrome (PTS) is a frequent complication affecting up to 60% of patients after DVT.
3- Kahn S.R.
- Shrier I.
- Julian J.A.
- Ducruet T.
- Arsenault L.
- Miron M.J.
- et al.
Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis.
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- Lindmarker P.
- Holmström M.
- Lärfars G.
- Carlsson A.
- Nicol P.
- et al.
Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months.
PTS develops from venous obstruction and insufficiency caused by the inflammatory response to the acute thrombus.
5The post-thrombotic syndrome: progress and pitfalls.
This results in venous hypertension, which leads to tissue oedema, subcutaneous fibrosis, and subsequent ulceration.
6Post-thrombotic syndrome: prevalence, prognostication and need for progress.
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- Hussein M.K.
- Szendro G.
- Christopoulos D.
- Vasdekis S.
- Clarke H.
The relation of venous ulceration with ambulatory venous pressure measurements.
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- et al.
The significance of calf muscle pump function in venous ulceration.
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- Comerota A.J.
- Katz M.L.
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Hemodynamic deterioration in chronic venous disease.
PTS negatively affects the quality of life and imposes substantial costs on healthcare systems.
10- Kumar R.
- Rodriguez V.
- Matsumoto J.M.
- Khan S.P.
- Weaver A.L.
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- et al.
Health-related quality of life in children and young adults with post-thrombotic syndrome: results from a cross-sectional study.
,11- Sarici I.S.
- Yanar F.
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- Ucar A.
- Poyanli A.
- Cakir S.
- et al.
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,
12- 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.
along with the use of compression therapy to help prevent PTS in the long term.
13- 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).
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,
3- Kahn S.R.
- Shrier I.
- Julian J.A.
- Ducruet T.
- Arsenault L.
- Miron M.J.
- et al.
Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis.
with more than half of these patients developing the syndrome.
14- 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.
As a result, patients with proximal DVT may benefit from invasive interventional treatment.
3- Kahn S.R.
- Shrier I.
- Julian J.A.
- Ducruet T.
- Arsenault L.
- Miron M.J.
- et al.
Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis.
,15- Tick L.W.
- Doggen C.J.
- Rosendaal F.R.
- Faber W.R.
- Bousema M.T.
- Mackaay A.J.
- et al.
Predictors of the post-thrombotic syndrome with non-invasive venous examinations in patients 6 weeks after a first episode of deep vein thrombosis.
,16- Strijkers R.H.
- Arnoldussen C.W.
- 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.
14- 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.
,17Treatment 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.
12- 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.
A recent Cochrane review compared thrombolytic clot removal strategies with anticoagulation against anticoagulation alone for the management of acute lower limb DVT.
18- Broderick C.
- 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.
18- 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.
19- Lichtenberg M.K.W.
- Stahlhoff S.
- Młyńczak K.
- Golicki D.
- 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.
20- Tang T.
- 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,
21- Kakkos S.K.
- Gohel M.
- Baekgaard N.
- Bauersachs R.
- Bellmunt-Montoya S.
- 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.
22- Liberati A.
- Altman D.G.
- Tetzlaff J.
- Mulrow C.
- Gøtzsche P.C.
- Ioannidis J.P.
- et al.
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.
23- 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.
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.
24- Sterne J.A.C.
- Savović J.
- Page M.J.
- Elbers R.G.
- 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).
25- 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.
26- 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.
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,
28- 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.
,31The ATTRACT trial: rationale for early intervention for iliofemoral DVT.
, 32- 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.
, 33- 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.
, 34- 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.
, 35- 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.
, 36- 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.
, 37- 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.
13- 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).
,14- 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.
,28- 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.
,30- 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,
2- 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.
12- 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.
,27Early 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.
39- 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.
40- 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.
40- 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.
41Percutaneous 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.
42- Sharifi M.
- Mehdipour M.
- Bay C.
- Smith G.
- Sharifi J.
Endovenous therapy for deep venous thrombosis: the TORPEDO trial.
,43- 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.
27Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis. A randomised clinical trial.
,28- 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.),
2- 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.
,12- 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.
27Early 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.
27Early results of thrombolysis vs anticoagulation in iliofemoral venous thrombosis. A randomised clinical trial.
,31The 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.36- 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.
,37- 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.
44- 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.
Article info
Publication history
Published online: January 24, 2022
Accepted:
October 31,
2021
Received:
May 9,
2021
Copyright
© 2021 European Society for Vascular Surgery. Published by Elsevier B.V.