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Endovascular Management of Acute Lower Limb Deep Vein Thrombosis: A Systematic Review and Meta-analysis
Accepted Manuscript Endovascular Management of Acute Lower Limb Deep Vein Thrombosis: A Systematic Review & Meta-Analysis Matthew Thomas, Andrew Hollingsworth, Reza Mofidi PII:
S0890-5096(19)30130-X
DOI:
https://doi.org/10.1016/j.avsg.2018.12.067
Reference:
AVSG 4242
To appear in:
Annals of Vascular Surgery
Received Date: 14 March 2018 Revised Date:
24 December 2018
Accepted Date: 25 December 2018
Please cite this article as: Thomas M, Hollingsworth A, Mofidi R, Endovascular Management of Acute Lower Limb Deep Vein Thrombosis: A Systematic Review & Meta-Analysis, Annals of Vascular Surgery (2019), doi: https://doi.org/10.1016/j.avsg.2018.12.067. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Endovascular Management of Acute Lower Limb Deep Vein Thrombosis: A Systematic Review & Meta-Analysis
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Matthew Thomasa, Andrew Hollingsworthb, Reza Mofidib
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Department of Vascular Surgery, Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7 7DN, United Kingdom b
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Corresponding Author:
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Department of Vascular Surgery, James Cook University Hospital, Marton Road, Middlesbrough, TS4 3BW, United Kingdom
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Tel: +44 191 2336161
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Email: [email protected]
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Keywords: Deep Vein Thrombosis – Thrombolysis – Post Thrombotic Syndrome – Anticoagulation
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Mr Matthew Thomas, Department of Vascular Surgery, Freeman Hospital, Newcastle-uponTyne, NE7 7DN, United Kingdom.
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Conflicts of Interest: None declared
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Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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ACCEPTED MANUSCRIPT ABSTRACT
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Background
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Deep vein thrombosis (DVT) is associated with significant complications, including the
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development of post-thrombotic syndrome (PTS). Traditional management is with oral
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anticoagulation, but the endovascular techniques of catheter-directed thrombolysis (CDT),
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pharmaco-mechanical thrombolysis and venous stenting are now increasingly used. This
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study aims to review the evidence for these endovascular techniques in the management of
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acute lower limb DVT, and their role in the reduction of complications such as PTS.
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Methods
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A systematic review and meta-analysis was carried out, with studies that compared CDT,
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pharmaco-mechanical thrombolysis and/or venous stenting with oral anticoagulation
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included. Primary outcome measure was the incidence of PTS; secondary outcome
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measures were the incidence of recurrent venous thromboembolism (VTE) and bleeding
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complications. Treatment effects were calculated as risk ratios (RR) with their 95%
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confidence interval (CI).
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Results
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Five studies met the final inclusion criteria. CDT reduced the incidence of PTS (RR 0.56, 95%
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CI 0.43 - 0.73), whereas pharmaco-mechanical thrombolysis had only a minor effect on the
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incidence of PTS that did not achieve statistical significance (RR 0.87, 95% CI 0.75 – 1.01).
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Recurrent VTE following CDT was reduced compared to oral anticoagulation (RR 0.62, 95%
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CI 0.34 – 1.13), whilst bleeding complications were more likely following CDT (RR 5.11, 95%
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CI 2.16 – 12.08).
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Conclusions
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ACCEPTED MANUSCRIPT CDT decreases the incidence of PTS when treating ileofemoral DVT, but pharmaco-
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mechanical thrombolysis does not. CDT also reduces the incidence of recurrent VTE, but
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leads to more bleeding complications when compared to oral anticoagulation. Further
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randomised controlled trials are needed to determine the role of endovascular
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management of DVT occurring below the ileofemoral level, and the role of venous stenting.
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ACCEPTED MANUSCRIPT 1.1 INTRODUCTION
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Lower limb deep venous thrombosis has an incidence of between 45 to 117 per 100,000
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person-years, whilst pulmonary embolism (PE) with or without an associated DVT has an
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incidence of between 28 to 79 per 100,000 person-years (1). These venous thromboemboli
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carry a high risk of mortality – at 1 month, the mortality rate from DVT is approximately 6%,
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and as high as 10% for PE, and within the first 12 months from diagnosis of VTE there is an
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attributed 5% all-cause mortality rate (2).
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As well as embolization to the lungs, complications of acute DVT include recurrence
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(affecting 30% of patients within 10 years of their origin presentation) (1), and the
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development of the post-thrombotic syndrome (PTS), which affects between 20 to 50% of
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patients with a DVT (3). The development of PTS is associated with a poor quality of life,
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with quality of life assessments poorer than those associated with other chronic health
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conditions such as osteoarthritis, diabetes or chronic lung disease (4).
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When standard anticoagulation is used alone, PTS has been shown to develop in between
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25 – 46% of patients within 2 years, and up to 90% at 5 years (5). Recent years have
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therefore seen the development of further VTE treatment techniques in order to try and
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reduce the risk of recurrence and of PTS. These include the endovascular procedures of
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catheter-directed thrombolysis (CDT), pharmaco-mechanical thrombolysis and venous
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stenting.
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CDT is the placement of a catheter within the deep venous thrombus followed by the
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infusion of a thrombolytic drug directly through the catheter to achieve thrombus
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dissolution. Pharmaco-mechanical thrombolysis combines the use of a thrombolytic infusion
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through a catheter within the thombus with a mechanical device that further fragments the
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thrombus. These devices can be rheolytic (creation of a high-pressure jet), rotational (use of
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a high-velocity rotating device) or ultrasound-enhanced.
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Current evidence on the effectiveness of endovascular management of lower limb DVT,
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including two Cochrane reviews, (6,7) mainly focuses on the treatment of proximal disease
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in the ileofemoral veins. The role of these techniques in the management of more distal
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DVT in the femoro-popliteal or infra-popliteal veins is less clear. Given the significant
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morbidity attached to the development of PTS, and the mortality associated with pulmonary
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embolization, the aim was to systematically review the best available evidence for the use
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of these endovascular techniques in the management of lower limb DVT at every anatomical
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level, in order to guide best practice.
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2.1 METHODS
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2.1.1 Search Strategy
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The systematic review and meta-analysis reported here follows the preferred reporting
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standards as defined by the Preferred Reporting Items for Systematic Reviews and Meta-
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Analyses (PRISMA) group (8). An electronic search of the following databases was carried
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out, up to 19th January 2018: BMJ Clinical Evidence; American College of Physicians Journal
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Club; Medline; CINAHL; EMBASE and the Cochrane Library. The search strategy used the
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following keywords: venous AND thrombosis AND (thrombolysis OR thrombectomy OR
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stent); venous AND thromboembolism AND (thrombolysis OR thrombectomy OR stent)
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“deep vein” AND thrombosis AND (thrombolysis OR thrombectomy OR stent) “deep vein”
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AND thromboembolism AND (thrombolysis OR thrombectomy OR stent).
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The search was carried out for articles written in the English language, with no time
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restrictions on the year of publication. All articles initially identified by the search strategy
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were screened first by title, with those deemed relevant then screened by abstract and
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finally via review of the full text of the study. The full reference lists of all retrieved full text
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articles were also screened to identify any further potentially relevant studies.
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2.1.2. Study Selection
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Randomised controlled trials and non-randomised comparative observational studies that
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directly compared the use of pharmaco-mechanical thrombolysis, catheter directed
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thrombolysis and/or venous stenting with anticoagulation, or with each other, in the
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treatment of acute lower limb DVT were identified. The therapeutic agent or agents in the
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CDT and pharmaco-mechanical studies included any agents specifically designed to achieve
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thrombolysis. The therapeutic agent or agents in the anticoagulation group included any
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agents designed to prevent thrombus formation, but not agents whose primary action was
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to achieve thrombolysis. Studies were included where they directly compared these
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endovascular techniques in the treatment of acute lower limb DVT, where treatment was
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commenced within 21 days of initial symptoms. The diagnosis of DVT must be confirmed by
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duplex ultrasound scanning, CT venography, MR venography or catheter venography, and
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not just by clinical suspicion alone. The specific anatomical level of DVT needed to be
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specified. The included studies must also have reported the incidence of PTS during their
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follow-up period.
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ACCEPTED MANUSCRIPT Studies were excluded where they detailed the use of open surgical thrombectomy, and
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where it was not possible to discern the precise anatomical level of the lower limb DVT.
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2.1.3 Data Extraction
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Data extraction was performed using a data extraction form. Data was collected on study
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design (whether randomised controlled trial, or comparative observational study), number
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of participants, method of confirming DVT diagnosis, details of the endovascular
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intervention, time from symptoms to intervention, and outcome measures. The primary
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outcome measure for this review was the incidence of post-thrombotic syndrome.
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Secondary outcome measures were the development of recurrent VTE, and the post-
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procedure complication of bleeding. Major bleeding was defined as bleeding that required a
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blood transfusion, surgical intervention, bleeding in to a critical site (eg intra-cranial) or
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bleeding with associated mortality. Minor bleeding was any bleeding episode other than
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that considered as major.
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2.1.4 Statistical Analysis
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Statistical analysis was performed with the use of the Review Manager statistical software
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package (RevMan, version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane
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Collaboration, 2014), with a comparison of the treatment effect calculated as risk ratios with
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their 95% confidence interval. Statistical heterogeneity between included studies was
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calculated using the Chi-squared test; the effect of this heterogeneity on the final meta-
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analysis (known as the “inconsistency” between the included studies) was also displayed as
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the I2 statistic. An I2 statistic of >50% was taken to represent significant inconsistency
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between studies.
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2.1.5 Risk of Bias and Quality of Included Studies
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ACCEPTED MANUSCRIPT A risk of bias assessment was carried out for each included study. For randomised controlled
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trials, this was carried out using the assessment criteria described in the Cochrane
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Handbook (9). For non-randomised comparative studies, the risk of bias assessment was
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carried out using the criteria described by the ROBINS-I tool (Risk of Bias In Non-randomised
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Studies of Interventions) (10). The overall quality of the evidence leading to the final meta-
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analysis results was judged using the “GRADE” (Grading of Recommendations Assessment,
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Development and Evaluation) classification system, with a judgement of either high,
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moderate, low or very low quality (11).
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2.1.6 Sub-group Analyses
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Sub-group analysis, where possible, was performed on those studies that detailed the
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separate treatment of ileofemoral DVT, femoro-popliteal DVT and infra-popliteal/distal DVT,
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with a sub-group comparison of catheter-directed thrombolysis, pharmaco-mechanical
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thrombolysis and venous stenting.
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3.1 RESULTS
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3.1.1 Literature Search
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FIve studies met the final inclusion criteria, with a total of 1022 participants (12 – 16). Figure
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1 shows a PRISMA flow chart of the electronic search process.
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3.1.2 Quality of Included Studies
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Tables 1 & 2 detail the characteristics of the included studies, and tables 3 & 4 show a risk of
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bias assessment. Using the “GRADE” assessment (Grading of Recommendations
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Assessment, Development and Evaluation), the quality of the evidence was judged as
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“moderate” for the above primary outcome measure for the effectiveness of CDT, and for
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outcomes measures, the quality of the evidence was also judged as “moderate”.
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3.1.3 Meta-Analysis
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Incidence of PTS
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The effect of CDT and of pharmaco-mechanical thrombolysis on the incidence of PTS is
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displayed in figure 2.
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Recurrent VTE
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The effect of CDT on the incidence of recurrent VTE is displayed in figure 3. Only one of the
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three pharmaco-mechanical thrombolysis studies reported the incidence of recurrent VTE;
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this was 12% in the pharmaco-mechanical thrombolysis group vs 8% in the control group (p
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=0.09) (16).
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Bleeding Complications
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The effect of CDT on the incidence of bleeding complications is displayed in figure 4. Only
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one of the three pharmaco-mechanical thrombolysis studies reported the incidence of
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bleeding complications; this was 5.7% in the pharmaco-mechanical group vs 3.7% in the
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control group for major bleeding (p = 0.23), and 14% vs 11% for any bleeding (p = 0.25).
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3.1.4 Sub-group Analyses
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All of the included studies reported the treatment of ileofemoral DVT. Vedantham et al
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included patients with DVT involving the femoral, common femoral or iliac veins with or
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without involvement of other ipsilateral veins, but did not perform any sub-group analyses
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to separate the effect of pharmaco-mechanical thrombolysis on different anatomical
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location. There were no studies that met the final inclusion criteria that specifically reported
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the effect of treatment of infra-popliteal/distal DVT. There were also no studies meeting the
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final inclusion criteria that specifically reported a comparison of the use of venous stenting
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(either as a single treatment modality or when used in combination with either CDT or
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pharmaco-mechanical thrombolysis) to anticoagulation in the management of acute lower
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limb DVT. The planned analysis of these sub-groups was therefore not possible.
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4.1 DISCUSSION
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Overall, the use of CDT reduces the risk of the development of PTS by 44% (risk ratio 0.56,
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95% CI 0.43 – 0.73) when used to treat acute ileofemoral DVT. The use of pharmaco-
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mechanical thrombolysis reduced the risk by only 13%, which did not achieve statistical
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significance (risk ratio 0.87, 95% CI 0.75 – 1.01). There was no significant statistical
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heterogeneity between the results of the two CDT studies with regards to the risk of PTS,
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but there was significant heterogeneity between the results of the three pharmaco-
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mechanical studies in terms of effect size. The factor adding the most weight to the
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heterogeneity in effect size is highly likely to stem from the much larger size and the
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randomised-controlled methodology of the study by Vedantham et al (16) when compared
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to the other two pharmaco-mechanical studies. There is further heterogeneity between the
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three studies in the use of chosen thrombolytic agent (urokinase vs alteplase), and in the
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duration of unfractionated or low molecular weight heparin before starting oral
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anticoagulation following thrombolytic therapy. One of the two much smaller studies is
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retrospective in nature, and both of the two smaller studies were assessed as having a
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higher overall risk of bias when compared to the randomised trial from Vedantham et al
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(16).
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CDT treatment reduces the risk of VTE recurrence by 38%. There was once again no
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significant statistical heterogeneity between the results of the two CDT studies with regards
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VTE recurrence is not significantly significant. CDT also significantly increases the risk of
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bleeding complications, with a 5-fold increase in risk (risk ratio 5.11, 95% CI). However,
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there was significant statistical heterogeneity between the two included CDT studies, with
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the study by Haig et al showing an extremely high risk ratio of 41.93 compared to Lee et al’s
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risk ratio of 1.54, with a wide confidence interval. The difference may be explained by the
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length of follow-up, as Haig et al report their results out to 5 years, whereas Lee et al (2013)
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report their bleeding events out to only 6 months.
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The findings of this systematic review of the effect of CDT on the risk of PTS support those of
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the Cochrane review by Watson et al (6), whose subgroup analysis found a risk ratio of 0.74
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(95% CI 0.55 – 1.00) for the risk of PTS following CDT to treat acute ileofemoral DVT. There
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was no data available to comment directly on the treatment of femoro-popliteal or infra-
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popliteal/distal DVT, nor on the use of venous stenting. At the time of the Cochrane review
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by Robertson et al in 2016 (7), they found no randomised controlled studies that examined
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the role of pharmaco-mechanical therapy in lower limb DVT. With the inclusion of the
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ATTRACT trial by Vedantham et al (16), the review presented here therefore extends the
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evidence available for endovascular treatment of lower limb DVT. This review found no data
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that directly compares CDT and pharmaco-mechanical thrombolysis.
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This review is limited by the inclusion of only a small number of studies, and further by their
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small number of participants – only a total of 229 patients were included in the two CDT
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studies. Further, only two of the five included studies was a randomised controlled trial,
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with the remaining three studies non-randomised comparative studies. The decision to
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include non-randomised studies was made deliberately, in order to capture the highest
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number of studies in to final the meta-analysis, but as described above, this has an impact
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on the quality of the evidence on which this systematic review & meta-analysis is based.
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Using the “GRADE” classification, the overall quality of evidence for the primary outcome
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measures in the meta-analysis was judged as “moderate” for the effects of CDT, and
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“moderate” for the effects of phamaco-mechanical thrombolysis. For the secondary
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outcome measures, the quality was judged as “moderate”. Although the outcomes for the
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primary and secondary outcome measures include the results of one well designed
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randomised trial with a low level of bias, the judgement to downgrade the quality of
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evidence was made based on the inclusion of the three non-randomised studies. These
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studies are very small, with some areas of their design that may have high risk of bias. For
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the secondary outcome measure of bleeding events, there is also a wide confidence interval
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around the risk ratio for the effect of the intervention.
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The original aim was to review the evidence for the use of endovascular techniques in lower
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limb DVT at different anatomical levels. There were no studies that met the final inclusion
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criteria that examined the effect of CDT or pharmaco-mechanical thrombolysis on DVT
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occurring below the femoral vein, with four out of the five included studies treating
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proximal combined ileo-femoral DVT. The fifth study, Vedantham et al (16), did include
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patients with thrombus within the femoral, common femoral and/or the iliac veins but in
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presenting their results they did not separate them in to those with an isolated femoral or
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common femoral vein DVT versus those with a combined ileo-femoral DVT. The conclusions
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drawn from this review therefore can only be applied to the management of a proximal ileo-
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femoral DVT.
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Ongoing research in the form of the “CAVA” trial should add to our understanding of the
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effectiveness of endovascular management of acute lower limb DVT. The Dutch CAVA trial
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(Catheter Versus Anticoagulation Alone for Acute Primary (Ileo)Femoral DVT;
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ClinicalTrials.gov Identifier NCT00970619) is currently recruiting to randomise patients with
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acute ileofemoral DVT to ultrasound enhanced CDT or to conventional anticoagulation, with
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an estimated date of completion in December 2018. The primary outcome measure will be
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the percentage of patients with PTS at 12 months following their acute event (17).
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5.1 CONCLUSIONS
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Based on the current best evidence reported here, endovascular management of acute
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lower limb DVT should therefore be reserved for those with ileofemoral DVT only, and
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should be performed with catheter-directed thrombolysis rather than pharmaco-mechanical
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thrombolysis. Further, large randomised controlled trials are needed to determine the
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efficacy of endovascular venous stenting in acute lower limb DVT, and in the management
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of DVT occurring below the ileofemoral level.
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6.1 ACKNOWLEDGEMENTS
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This systematic review and meta-analysis formed part of dissertation for a post-graduate
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Masters qualification from the University of Edinburgh & Royal College of Surgeons of
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Edinburgh, UK.
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7.1 FUNDING
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This research did not receive any specific grant from funding agencies in the public,
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commercial or not-for-profit sectors.
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8.1 REFERENCES 1. Heit, JA, Spencer, FA & White, RH (2016) The epidemiology of venous thromboembolism. Journal of Thrombosis & Thrombolysis, 41: 3-14. 2. Behravesh, S, Hoang, P, Nanda, A, Wallace, A, Sheth, RA, Deipolyi, A et al (2017)
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Pathogenesis of thromboembolism and endovascular management. Thrombosis,
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3. Kahn, SR, Comerota AJ, Cushman, M, Evans, NS, Ginsberg, JS, Goldenberg, NA et al
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(2014) The post-thrombotic syndrome: evidence-based prevention, diagnosis and
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treatment strategies: a scientific statement from the American Heart Association.
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Circulation, 130: 1636-1661.
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4. Kahn, SR, Shbaklo, H, Lamping, DL, Holcroft, CA, Shrier, I, Miron, MJ et al (2008) Determinants of health-related quality of life during the 2 years following deep vein
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thrombosis. Journal of Thrombosis & Haemostasis, 6: 1105-1112.
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thrombosis. Seminars in Thrombosis and Hemostasis, 39: 446-451.
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5. Oklu, R & Wicky, S (2013) Catheter-directed thrombolysis of deep venous
6. Watson, L, Broderick, C & Armon, MP (2016) Thrombolysis for acute deep vein thrombosis. Cochrane Database Systematic Reviews, 11: CD002783.
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7. Robertson, L, McBride, O & Burdess, A (2016) Pharmacomechanical thrombectomy
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for ileofemoral deep vein thrombosis. Cochrane Database Systematic Reviews, 11:
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CD011536.
8. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred
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Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement.
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PLoS Med 6(7): e1000097.
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9. Cochrane Collaboration (2011) Cochrane Handbook for Systematic Reviews of
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Interventions Version 5.1.0 [updated March 2011] Available at [http://handbook-5-
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1.cochrane.org/], last accessed 27th October 2017.
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10. Sterne, JAC, Hernan, MA, Reeves, BC, Savovic, J, Berkman ND, Viswanathan, M et al (2016) ROBINS-I: a tool for assessing risk of bias in non-randomized studies of
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interventions. British Medical Journal, 355: i4919.
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GRADE: an emerging consensus on rating quality of evidence and strength of
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recommendations. British Medical Journal, 336: 924.
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12. Lee, CY, Lai, ST, Shih, CC & Wu, TC (2013) Short-term results of catheter-directed
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intrathrombus thrombolysis versus anticoagulation in acute proximal deep vein
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thrombosis. Journal of the Chinese Medical Association, 76: 265-270. 13. Srinivas, BC, Patra, S, Nagesh, CM, Reddy, B & Manjunath (2014) Catheter-directed
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thrombolysis along with mechanical thromboaspiration versus anticoagulation alone
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in the management of lower limb deep venous thrombosis – a comparative study.
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14. Ezelsoy, M, Turunc, G & Bayram, M (2015) Early outcomes of pharmacomechanical
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thrombectomy in acute deep vein thrombosis patients. Heart Surgery Forum, 18: E222-225.
15. Haig, Y, Enden, T, Grotta, O, Klow, NE, Slagsvold, CE, Ghanima, W et al (2016) Post-
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thrombotic syndrome after catheter-directed thrombolysis for deep vein thrombosis
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(CaVenT): 5-year follow-up results of an open-label, randomised controlled trial.
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Lancet Haematology, 3: e64-71.
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16. Vedantham, S, Goldhaber, SZ, Julian, JA et al (2017) Pharmacomechanical catheter-
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directed thrombolysis for deep-vein thrombosis. New England Journal of Medicine,
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17. ClinicalTrials.gov (2017) DUTCH CAVA-trial: Catheter Versus Anticoagulation Alone for Acute Primary (Ileo)Femoral DVT (NL28394). Available at
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[https://clinicaltrials.gov/ct2/show/NCT00970619], last accessed 27th October 2017.
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TABLE & FIGURE LEGENDS
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Table 1. Characteristics of studies comparing CDT with anticoagulation alone. (UFH =
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unfractionated heparin; LMWH = low molecular weight heparin).
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Table 2. Characteristics of studies comparing pharmaco-mechanical thrombolysis with
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anticoagulation alone. (UFH = unfractionated heparin; LMWH = low molecular weight
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heparin).
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Table 3. Risk of bias assessment of included non-randomised, comparative studies.
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Table 4. Risk of bias assessment of included randomised controlled trials.
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Figure 1. PRISMA flow diagram of included studies.
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Figure 2. Forest plot showing the effect of CDT and pharmaco-mechanical thrombolysis on
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the incidence of post-thrombotic syndrome, including assessment of heterogeneity.
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Horizontal lines represent the 95% confidence interval (CI ), with the black diamond
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representing the pooled effect.
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Figure 3. Forest plot showing the effect of CDT on recurrence of venous thromboembolism,
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including assessment of heterogeneity. Horizontal lines represent the 95% confidence
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interval (CI), with the black diamond representing the pooled effect.
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Figure 4. Forest plot showing the effect of CDT on the development of bleeding
428
complications, including an assessment of heterogeneity. The black lines represent the 95%
429
confidence interval (CI), with the black diamond representing the pooled effect.
430
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ACCEPTED MANUSCRIPT Lee et al 2013
Haig et al 2016
Methods
Retrospective, non-ramdomised
Multi-centre, open label randomised control
comparative study
trial
53 participants:
209 participants enrolled:
27 in intervention group – mean age 62.4
Intervention group – 101 randomised; 6
years; 51.9% female
withdrew, 4 not eligible, 3 died, 1 lost to follow-
26 in control group – mean age 59.8 years;
up = 87 included at 5 year follow-up. Median
46.2% female
age 58, 34% female
Participants
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Study Reference
SC
Control group – 108 randomised; 9 withdrew, 9 died, 1 lost to follow-up = 89 included at 5 year
Intervention group - CDT with urokinase for
Intervention group – CDT with alteplase, plus
48 – 72 hours, plus unfractionated heparin
UFH, followed by oral anticoagulation with
(UFH); oral anticogulation with warfarin
warfarin for at least 6 months
overlapped with UFH until INR therapeutic,
Control group – LMWH plus Warfarin for at
and continued for at least 6 months
least 5 days, followed by continued oral
Control group - Low molecular weight
anticoagulation with warfarin for at least 6
heparin (LMWH) for 7-14 days, followed by
months
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follow-up. Median age 53, 40% female
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oral anticogulation with warfarin for at least 6 months
Safety: Bleeding events; pulmonary
Outcomes at 5 years – incidence of PTS; venous
embolism; death
patency; quality of life; recurrence of VTE;
Efficacy: Immediate ileo-femoral venous
bleeding complications
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Outcomes
patency; valvular competence; recanalization; thrombus propogation/resolution at 6 months; recurrent DVT at 3 months; incidence of PTS at 12 months
Table 1.
ACCEPTED MANUSCRIPT Srinivas et al 2014
Ezelsoy et al 2015
Vedantham et al 2017
Methods
Prospective. non-
Retrospective, non-
Multi-centre, open label
randomised comparative
randomised comparative
randomised controlled
study
study
trial
60 initial participants
50 participants:
692 patients enrolled:
Intervention group – 30
Intervention group – 25
Intervention group – 336
initial patients. 2 died, 1
Control group – 25
randomised; 257
failed to complete
Patients aged between
completed 2 year follow-
treatment, 2 lost to
20 -75 years included,
up; 79 followed-up for
follow up = 25 included
but mean age and
<2 years (10 withdrew, 7
in results. Mean age 39
male:female ratios not
died, 62 lost to follow-
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Study Reference
years, 48.1% female
quoted
years. 39% female.
patients. 2 died, 2 lost to
Control group – 355
follow-up = 26 included
randomised; 243
in results. Mean age 53
completed 2 year follow-
years, 42.9% female
up; 112 followed up for
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Control group – 30 initial
<2 years (18 withdrew, 8 died, 86 lost to follow
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Interventions
up). Median age 52
up). Median age 53. 38% female.
Intervention group -
Intervention group -
Intervention group –
Pharmaco-mechanical
insertion of inferior vena
Mechanical
thrombolysis, with
cava filter, mechanical
thrombectomy with
mechanical aspiration
thrombectomy with
rheolytic or rotational
first followed by CDT
rotational
thrombectomy device
with streptokinase, plus
thrombectomy device,
followed by CDT with
UFH, followed by oral
followed by CDT with
alteplase, plus UFH or
ACCEPTED MANUSCRIPT alteplase, plus UFH for 5
LMWH followed by oral
warfarin or nicoumalone
days followed by oral
anticoagulation with
for 6 months
anticaogulation with
warfarin for median 211
Control group - UFH for
warfarin for 3 months
days (treatment arm) vs
48 hours, followed by
Control group - LMWH
231 days (control arm);
UFH or LMWH for
for 5 days followed by
further 5 days, followed
oral anticaogulation with
until stable &
by oral anticoagulation
warfarin for at least 6
therapeutic INR
with warfarin or
months
achieved
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months
Venous recanalization
Incidence of PTS at 6
lysis; serious adverse
within 6 months;
months and 2 years;
events; minimal adverse
femoral venous
patient reported health-
events; venous patency
insufficiency; incidence
related quality of life;
at 6 months (defined as
of PTS
bleeding; recurrent
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Immediate thrombus
venous
thrombus); incidence of
thromboembolism;
PTS at 6 months
death
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>90% clearance of
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Table 2.
UFH or LMWH continued
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nicoumalone for 6
Outcomes
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anticoagulation with
ACCEPTED MANUSCRIPT
Study
Bias due to: Selection of
Classification
Deviation
Missing
Measurement
Reported
Participants
of
from
Data
of Outcomes
Results
Interventions
Intended Interventions
Lee et
High
High
Low
Low
Moderate
Low
Low
High
High
High
Low
Low
Srinivas et al 2014 (13) Ezelsoy
2015 (14)
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Table 3.
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et al
High
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(12)
Moderate
Moderate
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al 2013
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Confounding
Low
Low
Low
Low
Moderate
Low
ACCEPTED MANUSCRIPT Study
Bias due to: Allocation
Blinding of
Blinding
Blinding
Incomple
Selectiv
Oth
sequenc
Concealm
Participants/Perso
of
of
te
e
er
e
ent
nnel
Outcome
Outcome
Outcome
Reporti
Bias
generati
Assessme
Assessme
Data
ng
on
nt – Self-
nt –
reported
Objective
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Random
Outcome
Haig et al
Low
Low
Unclear
Low
Low
Low
Moderate
Vedanth am et al
Moderat e
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(2017)
Table 4.
Low
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s
Low
Low
Low
Low
High
Low
Low
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S0890-5096(19)30130-X
DOI:
https://doi.org/10.1016/j.avsg.2018.12.067
Reference:
AVSG 4242
To appear in:
Annals of Vascular Surgery
Received Date: 14 March 2018 Revised Date:
24 December 2018
Accepted Date: 25 December 2018
Please cite this article as: Thomas M, Hollingsworth A, Mofidi R, Endovascular Management of Acute Lower Limb Deep Vein Thrombosis: A Systematic Review & Meta-Analysis, Annals of Vascular Surgery (2019), doi: https://doi.org/10.1016/j.avsg.2018.12.067. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
TITLE PAGE
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Endovascular Management of Acute Lower Limb Deep Vein Thrombosis: A Systematic Review & Meta-Analysis
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Matthew Thomasa, Andrew Hollingsworthb, Reza Mofidib
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a
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Department of Vascular Surgery, Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7 7DN, United Kingdom b
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Corresponding Author:
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Department of Vascular Surgery, James Cook University Hospital, Marton Road, Middlesbrough, TS4 3BW, United Kingdom
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Tel: +44 191 2336161
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Email: [email protected]
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Keywords: Deep Vein Thrombosis – Thrombolysis – Post Thrombotic Syndrome – Anticoagulation
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Mr Matthew Thomas, Department of Vascular Surgery, Freeman Hospital, Newcastle-uponTyne, NE7 7DN, United Kingdom.
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Conflicts of Interest: None declared
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Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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ACCEPTED MANUSCRIPT ABSTRACT
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Background
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Deep vein thrombosis (DVT) is associated with significant complications, including the
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development of post-thrombotic syndrome (PTS). Traditional management is with oral
32
anticoagulation, but the endovascular techniques of catheter-directed thrombolysis (CDT),
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pharmaco-mechanical thrombolysis and venous stenting are now increasingly used. This
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study aims to review the evidence for these endovascular techniques in the management of
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acute lower limb DVT, and their role in the reduction of complications such as PTS.
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Methods
37
A systematic review and meta-analysis was carried out, with studies that compared CDT,
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pharmaco-mechanical thrombolysis and/or venous stenting with oral anticoagulation
39
included. Primary outcome measure was the incidence of PTS; secondary outcome
40
measures were the incidence of recurrent venous thromboembolism (VTE) and bleeding
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complications. Treatment effects were calculated as risk ratios (RR) with their 95%
42
confidence interval (CI).
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Results
44
Five studies met the final inclusion criteria. CDT reduced the incidence of PTS (RR 0.56, 95%
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CI 0.43 - 0.73), whereas pharmaco-mechanical thrombolysis had only a minor effect on the
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incidence of PTS that did not achieve statistical significance (RR 0.87, 95% CI 0.75 – 1.01).
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Recurrent VTE following CDT was reduced compared to oral anticoagulation (RR 0.62, 95%
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CI 0.34 – 1.13), whilst bleeding complications were more likely following CDT (RR 5.11, 95%
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CI 2.16 – 12.08).
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Conclusions
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ACCEPTED MANUSCRIPT CDT decreases the incidence of PTS when treating ileofemoral DVT, but pharmaco-
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mechanical thrombolysis does not. CDT also reduces the incidence of recurrent VTE, but
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leads to more bleeding complications when compared to oral anticoagulation. Further
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randomised controlled trials are needed to determine the role of endovascular
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management of DVT occurring below the ileofemoral level, and the role of venous stenting.
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ACCEPTED MANUSCRIPT 1.1 INTRODUCTION
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Lower limb deep venous thrombosis has an incidence of between 45 to 117 per 100,000
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person-years, whilst pulmonary embolism (PE) with or without an associated DVT has an
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incidence of between 28 to 79 per 100,000 person-years (1). These venous thromboemboli
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carry a high risk of mortality – at 1 month, the mortality rate from DVT is approximately 6%,
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and as high as 10% for PE, and within the first 12 months from diagnosis of VTE there is an
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attributed 5% all-cause mortality rate (2).
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As well as embolization to the lungs, complications of acute DVT include recurrence
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(affecting 30% of patients within 10 years of their origin presentation) (1), and the
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development of the post-thrombotic syndrome (PTS), which affects between 20 to 50% of
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patients with a DVT (3). The development of PTS is associated with a poor quality of life,
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with quality of life assessments poorer than those associated with other chronic health
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conditions such as osteoarthritis, diabetes or chronic lung disease (4).
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When standard anticoagulation is used alone, PTS has been shown to develop in between
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25 – 46% of patients within 2 years, and up to 90% at 5 years (5). Recent years have
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therefore seen the development of further VTE treatment techniques in order to try and
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reduce the risk of recurrence and of PTS. These include the endovascular procedures of
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catheter-directed thrombolysis (CDT), pharmaco-mechanical thrombolysis and venous
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stenting.
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CDT is the placement of a catheter within the deep venous thrombus followed by the
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infusion of a thrombolytic drug directly through the catheter to achieve thrombus
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dissolution. Pharmaco-mechanical thrombolysis combines the use of a thrombolytic infusion
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through a catheter within the thombus with a mechanical device that further fragments the
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thrombus. These devices can be rheolytic (creation of a high-pressure jet), rotational (use of
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a high-velocity rotating device) or ultrasound-enhanced.
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Current evidence on the effectiveness of endovascular management of lower limb DVT,
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including two Cochrane reviews, (6,7) mainly focuses on the treatment of proximal disease
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in the ileofemoral veins. The role of these techniques in the management of more distal
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DVT in the femoro-popliteal or infra-popliteal veins is less clear. Given the significant
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morbidity attached to the development of PTS, and the mortality associated with pulmonary
109
embolization, the aim was to systematically review the best available evidence for the use
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of these endovascular techniques in the management of lower limb DVT at every anatomical
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level, in order to guide best practice.
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2.1 METHODS
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2.1.1 Search Strategy
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The systematic review and meta-analysis reported here follows the preferred reporting
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standards as defined by the Preferred Reporting Items for Systematic Reviews and Meta-
117
Analyses (PRISMA) group (8). An electronic search of the following databases was carried
118
out, up to 19th January 2018: BMJ Clinical Evidence; American College of Physicians Journal
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Club; Medline; CINAHL; EMBASE and the Cochrane Library. The search strategy used the
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following keywords: venous AND thrombosis AND (thrombolysis OR thrombectomy OR
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stent); venous AND thromboembolism AND (thrombolysis OR thrombectomy OR stent)
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“deep vein” AND thrombosis AND (thrombolysis OR thrombectomy OR stent) “deep vein”
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AND thromboembolism AND (thrombolysis OR thrombectomy OR stent).
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The search was carried out for articles written in the English language, with no time
126
restrictions on the year of publication. All articles initially identified by the search strategy
127
were screened first by title, with those deemed relevant then screened by abstract and
128
finally via review of the full text of the study. The full reference lists of all retrieved full text
129
articles were also screened to identify any further potentially relevant studies.
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2.1.2. Study Selection
131
Randomised controlled trials and non-randomised comparative observational studies that
132
directly compared the use of pharmaco-mechanical thrombolysis, catheter directed
133
thrombolysis and/or venous stenting with anticoagulation, or with each other, in the
134
treatment of acute lower limb DVT were identified. The therapeutic agent or agents in the
135
CDT and pharmaco-mechanical studies included any agents specifically designed to achieve
136
thrombolysis. The therapeutic agent or agents in the anticoagulation group included any
137
agents designed to prevent thrombus formation, but not agents whose primary action was
138
to achieve thrombolysis. Studies were included where they directly compared these
139
endovascular techniques in the treatment of acute lower limb DVT, where treatment was
140
commenced within 21 days of initial symptoms. The diagnosis of DVT must be confirmed by
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duplex ultrasound scanning, CT venography, MR venography or catheter venography, and
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not just by clinical suspicion alone. The specific anatomical level of DVT needed to be
143
specified. The included studies must also have reported the incidence of PTS during their
144
follow-up period.
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ACCEPTED MANUSCRIPT Studies were excluded where they detailed the use of open surgical thrombectomy, and
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where it was not possible to discern the precise anatomical level of the lower limb DVT.
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2.1.3 Data Extraction
149
Data extraction was performed using a data extraction form. Data was collected on study
150
design (whether randomised controlled trial, or comparative observational study), number
151
of participants, method of confirming DVT diagnosis, details of the endovascular
152
intervention, time from symptoms to intervention, and outcome measures. The primary
153
outcome measure for this review was the incidence of post-thrombotic syndrome.
154
Secondary outcome measures were the development of recurrent VTE, and the post-
155
procedure complication of bleeding. Major bleeding was defined as bleeding that required a
156
blood transfusion, surgical intervention, bleeding in to a critical site (eg intra-cranial) or
157
bleeding with associated mortality. Minor bleeding was any bleeding episode other than
158
that considered as major.
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2.1.4 Statistical Analysis
160
Statistical analysis was performed with the use of the Review Manager statistical software
161
package (RevMan, version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane
162
Collaboration, 2014), with a comparison of the treatment effect calculated as risk ratios with
163
their 95% confidence interval. Statistical heterogeneity between included studies was
164
calculated using the Chi-squared test; the effect of this heterogeneity on the final meta-
165
analysis (known as the “inconsistency” between the included studies) was also displayed as
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the I2 statistic. An I2 statistic of >50% was taken to represent significant inconsistency
167
between studies.
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2.1.5 Risk of Bias and Quality of Included Studies
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ACCEPTED MANUSCRIPT A risk of bias assessment was carried out for each included study. For randomised controlled
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trials, this was carried out using the assessment criteria described in the Cochrane
171
Handbook (9). For non-randomised comparative studies, the risk of bias assessment was
172
carried out using the criteria described by the ROBINS-I tool (Risk of Bias In Non-randomised
173
Studies of Interventions) (10). The overall quality of the evidence leading to the final meta-
174
analysis results was judged using the “GRADE” (Grading of Recommendations Assessment,
175
Development and Evaluation) classification system, with a judgement of either high,
176
moderate, low or very low quality (11).
177
2.1.6 Sub-group Analyses
178
Sub-group analysis, where possible, was performed on those studies that detailed the
179
separate treatment of ileofemoral DVT, femoro-popliteal DVT and infra-popliteal/distal DVT,
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with a sub-group comparison of catheter-directed thrombolysis, pharmaco-mechanical
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thrombolysis and venous stenting.
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3.1 RESULTS
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3.1.1 Literature Search
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FIve studies met the final inclusion criteria, with a total of 1022 participants (12 – 16). Figure
186
1 shows a PRISMA flow chart of the electronic search process.
187
3.1.2 Quality of Included Studies
188
Tables 1 & 2 detail the characteristics of the included studies, and tables 3 & 4 show a risk of
189
bias assessment. Using the “GRADE” assessment (Grading of Recommendations
190
Assessment, Development and Evaluation), the quality of the evidence was judged as
191
“moderate” for the above primary outcome measure for the effectiveness of CDT, and for
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193
outcomes measures, the quality of the evidence was also judged as “moderate”.
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3.1.3 Meta-Analysis
195
Incidence of PTS
196
The effect of CDT and of pharmaco-mechanical thrombolysis on the incidence of PTS is
197
displayed in figure 2.
198
Recurrent VTE
199
The effect of CDT on the incidence of recurrent VTE is displayed in figure 3. Only one of the
200
three pharmaco-mechanical thrombolysis studies reported the incidence of recurrent VTE;
201
this was 12% in the pharmaco-mechanical thrombolysis group vs 8% in the control group (p
202
=0.09) (16).
203
Bleeding Complications
204
The effect of CDT on the incidence of bleeding complications is displayed in figure 4. Only
205
one of the three pharmaco-mechanical thrombolysis studies reported the incidence of
206
bleeding complications; this was 5.7% in the pharmaco-mechanical group vs 3.7% in the
207
control group for major bleeding (p = 0.23), and 14% vs 11% for any bleeding (p = 0.25).
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3.1.4 Sub-group Analyses
209
All of the included studies reported the treatment of ileofemoral DVT. Vedantham et al
210
included patients with DVT involving the femoral, common femoral or iliac veins with or
211
without involvement of other ipsilateral veins, but did not perform any sub-group analyses
212
to separate the effect of pharmaco-mechanical thrombolysis on different anatomical
213
location. There were no studies that met the final inclusion criteria that specifically reported
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the effect of treatment of infra-popliteal/distal DVT. There were also no studies meeting the
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final inclusion criteria that specifically reported a comparison of the use of venous stenting
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(either as a single treatment modality or when used in combination with either CDT or
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pharmaco-mechanical thrombolysis) to anticoagulation in the management of acute lower
218
limb DVT. The planned analysis of these sub-groups was therefore not possible.
219
4.1 DISCUSSION
221
Overall, the use of CDT reduces the risk of the development of PTS by 44% (risk ratio 0.56,
222
95% CI 0.43 – 0.73) when used to treat acute ileofemoral DVT. The use of pharmaco-
223
mechanical thrombolysis reduced the risk by only 13%, which did not achieve statistical
224
significance (risk ratio 0.87, 95% CI 0.75 – 1.01). There was no significant statistical
225
heterogeneity between the results of the two CDT studies with regards to the risk of PTS,
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but there was significant heterogeneity between the results of the three pharmaco-
227
mechanical studies in terms of effect size. The factor adding the most weight to the
228
heterogeneity in effect size is highly likely to stem from the much larger size and the
229
randomised-controlled methodology of the study by Vedantham et al (16) when compared
230
to the other two pharmaco-mechanical studies. There is further heterogeneity between the
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three studies in the use of chosen thrombolytic agent (urokinase vs alteplase), and in the
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duration of unfractionated or low molecular weight heparin before starting oral
233
anticoagulation following thrombolytic therapy. One of the two much smaller studies is
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retrospective in nature, and both of the two smaller studies were assessed as having a
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higher overall risk of bias when compared to the randomised trial from Vedantham et al
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(16).
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CDT treatment reduces the risk of VTE recurrence by 38%. There was once again no
239
significant statistical heterogeneity between the results of the two CDT studies with regards
ACCEPTED MANUSCRIPT to the risk of recurrent VTE. However, with a 95% CI of 0.34 to 1.13, this 38% reduction in
241
VTE recurrence is not significantly significant. CDT also significantly increases the risk of
242
bleeding complications, with a 5-fold increase in risk (risk ratio 5.11, 95% CI). However,
243
there was significant statistical heterogeneity between the two included CDT studies, with
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the study by Haig et al showing an extremely high risk ratio of 41.93 compared to Lee et al’s
245
risk ratio of 1.54, with a wide confidence interval. The difference may be explained by the
246
length of follow-up, as Haig et al report their results out to 5 years, whereas Lee et al (2013)
247
report their bleeding events out to only 6 months.
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The findings of this systematic review of the effect of CDT on the risk of PTS support those of
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the Cochrane review by Watson et al (6), whose subgroup analysis found a risk ratio of 0.74
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(95% CI 0.55 – 1.00) for the risk of PTS following CDT to treat acute ileofemoral DVT. There
252
was no data available to comment directly on the treatment of femoro-popliteal or infra-
253
popliteal/distal DVT, nor on the use of venous stenting. At the time of the Cochrane review
254
by Robertson et al in 2016 (7), they found no randomised controlled studies that examined
255
the role of pharmaco-mechanical therapy in lower limb DVT. With the inclusion of the
256
ATTRACT trial by Vedantham et al (16), the review presented here therefore extends the
257
evidence available for endovascular treatment of lower limb DVT. This review found no data
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that directly compares CDT and pharmaco-mechanical thrombolysis.
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This review is limited by the inclusion of only a small number of studies, and further by their
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small number of participants – only a total of 229 patients were included in the two CDT
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studies. Further, only two of the five included studies was a randomised controlled trial,
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with the remaining three studies non-randomised comparative studies. The decision to
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include non-randomised studies was made deliberately, in order to capture the highest
265
number of studies in to final the meta-analysis, but as described above, this has an impact
266
on the quality of the evidence on which this systematic review & meta-analysis is based.
267
Using the “GRADE” classification, the overall quality of evidence for the primary outcome
269
measures in the meta-analysis was judged as “moderate” for the effects of CDT, and
270
“moderate” for the effects of phamaco-mechanical thrombolysis. For the secondary
271
outcome measures, the quality was judged as “moderate”. Although the outcomes for the
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primary and secondary outcome measures include the results of one well designed
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randomised trial with a low level of bias, the judgement to downgrade the quality of
274
evidence was made based on the inclusion of the three non-randomised studies. These
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studies are very small, with some areas of their design that may have high risk of bias. For
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the secondary outcome measure of bleeding events, there is also a wide confidence interval
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around the risk ratio for the effect of the intervention.
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The original aim was to review the evidence for the use of endovascular techniques in lower
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limb DVT at different anatomical levels. There were no studies that met the final inclusion
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criteria that examined the effect of CDT or pharmaco-mechanical thrombolysis on DVT
282
occurring below the femoral vein, with four out of the five included studies treating
283
proximal combined ileo-femoral DVT. The fifth study, Vedantham et al (16), did include
284
patients with thrombus within the femoral, common femoral and/or the iliac veins but in
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presenting their results they did not separate them in to those with an isolated femoral or
286
common femoral vein DVT versus those with a combined ileo-femoral DVT. The conclusions
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drawn from this review therefore can only be applied to the management of a proximal ileo-
288
femoral DVT.
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Ongoing research in the form of the “CAVA” trial should add to our understanding of the
291
effectiveness of endovascular management of acute lower limb DVT. The Dutch CAVA trial
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(Catheter Versus Anticoagulation Alone for Acute Primary (Ileo)Femoral DVT;
293
ClinicalTrials.gov Identifier NCT00970619) is currently recruiting to randomise patients with
294
acute ileofemoral DVT to ultrasound enhanced CDT or to conventional anticoagulation, with
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an estimated date of completion in December 2018. The primary outcome measure will be
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the percentage of patients with PTS at 12 months following their acute event (17).
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5.1 CONCLUSIONS
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Based on the current best evidence reported here, endovascular management of acute
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lower limb DVT should therefore be reserved for those with ileofemoral DVT only, and
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should be performed with catheter-directed thrombolysis rather than pharmaco-mechanical
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thrombolysis. Further, large randomised controlled trials are needed to determine the
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efficacy of endovascular venous stenting in acute lower limb DVT, and in the management
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of DVT occurring below the ileofemoral level.
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6.1 ACKNOWLEDGEMENTS
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This systematic review and meta-analysis formed part of dissertation for a post-graduate
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Masters qualification from the University of Edinburgh & Royal College of Surgeons of
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Edinburgh, UK.
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7.1 FUNDING
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This research did not receive any specific grant from funding agencies in the public,
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commercial or not-for-profit sectors.
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8.1 REFERENCES 1. Heit, JA, Spencer, FA & White, RH (2016) The epidemiology of venous thromboembolism. Journal of Thrombosis & Thrombolysis, 41: 3-14. 2. Behravesh, S, Hoang, P, Nanda, A, Wallace, A, Sheth, RA, Deipolyi, A et al (2017)
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Pathogenesis of thromboembolism and endovascular management. Thrombosis,
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2017:3039713 Epub.
3. Kahn, SR, Comerota AJ, Cushman, M, Evans, NS, Ginsberg, JS, Goldenberg, NA et al
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(2014) The post-thrombotic syndrome: evidence-based prevention, diagnosis and
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treatment strategies: a scientific statement from the American Heart Association.
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Circulation, 130: 1636-1661.
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4. Kahn, SR, Shbaklo, H, Lamping, DL, Holcroft, CA, Shrier, I, Miron, MJ et al (2008) Determinants of health-related quality of life during the 2 years following deep vein
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thrombosis. Journal of Thrombosis & Haemostasis, 6: 1105-1112.
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thrombosis. Seminars in Thrombosis and Hemostasis, 39: 446-451.
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5. Oklu, R & Wicky, S (2013) Catheter-directed thrombolysis of deep venous
6. Watson, L, Broderick, C & Armon, MP (2016) Thrombolysis for acute deep vein thrombosis. Cochrane Database Systematic Reviews, 11: CD002783.
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7. Robertson, L, McBride, O & Burdess, A (2016) Pharmacomechanical thrombectomy
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for ileofemoral deep vein thrombosis. Cochrane Database Systematic Reviews, 11:
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CD011536.
8. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred
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Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement.
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PLoS Med 6(7): e1000097.
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9. Cochrane Collaboration (2011) Cochrane Handbook for Systematic Reviews of
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Interventions Version 5.1.0 [updated March 2011] Available at [http://handbook-5-
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1.cochrane.org/], last accessed 27th October 2017.
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10. Sterne, JAC, Hernan, MA, Reeves, BC, Savovic, J, Berkman ND, Viswanathan, M et al (2016) ROBINS-I: a tool for assessing risk of bias in non-randomized studies of
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interventions. British Medical Journal, 355: i4919.
11. Guyatt, GH, Oxman, AD, Vist, GE, Kunz, R, Falck-Ytter, Y, Alonso-Coello, P et al (2008)
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GRADE: an emerging consensus on rating quality of evidence and strength of
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recommendations. British Medical Journal, 336: 924.
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12. Lee, CY, Lai, ST, Shih, CC & Wu, TC (2013) Short-term results of catheter-directed
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intrathrombus thrombolysis versus anticoagulation in acute proximal deep vein
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thrombosis. Journal of the Chinese Medical Association, 76: 265-270. 13. Srinivas, BC, Patra, S, Nagesh, CM, Reddy, B & Manjunath (2014) Catheter-directed
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thrombolysis along with mechanical thromboaspiration versus anticoagulation alone
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in the management of lower limb deep venous thrombosis – a comparative study.
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International Journal of Angiology, 23: 247-254
375 376 377
14. Ezelsoy, M, Turunc, G & Bayram, M (2015) Early outcomes of pharmacomechanical
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thrombectomy in acute deep vein thrombosis patients. Heart Surgery Forum, 18: E222-225.
15. Haig, Y, Enden, T, Grotta, O, Klow, NE, Slagsvold, CE, Ghanima, W et al (2016) Post-
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thrombotic syndrome after catheter-directed thrombolysis for deep vein thrombosis
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(CaVenT): 5-year follow-up results of an open-label, randomised controlled trial.
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Lancet Haematology, 3: e64-71.
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16. Vedantham, S, Goldhaber, SZ, Julian, JA et al (2017) Pharmacomechanical catheter-
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directed thrombolysis for deep-vein thrombosis. New England Journal of Medicine,
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377: 2240-2252.
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17. ClinicalTrials.gov (2017) DUTCH CAVA-trial: Catheter Versus Anticoagulation Alone for Acute Primary (Ileo)Femoral DVT (NL28394). Available at
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[https://clinicaltrials.gov/ct2/show/NCT00970619], last accessed 27th October 2017.
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TABLE & FIGURE LEGENDS
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Table 1. Characteristics of studies comparing CDT with anticoagulation alone. (UFH =
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unfractionated heparin; LMWH = low molecular weight heparin).
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Table 2. Characteristics of studies comparing pharmaco-mechanical thrombolysis with
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anticoagulation alone. (UFH = unfractionated heparin; LMWH = low molecular weight
410
heparin).
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Table 3. Risk of bias assessment of included non-randomised, comparative studies.
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Table 4. Risk of bias assessment of included randomised controlled trials.
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Figure 1. PRISMA flow diagram of included studies.
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Figure 2. Forest plot showing the effect of CDT and pharmaco-mechanical thrombolysis on
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the incidence of post-thrombotic syndrome, including assessment of heterogeneity.
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Horizontal lines represent the 95% confidence interval (CI ), with the black diamond
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representing the pooled effect.
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Figure 3. Forest plot showing the effect of CDT on recurrence of venous thromboembolism,
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including assessment of heterogeneity. Horizontal lines represent the 95% confidence
425
interval (CI), with the black diamond representing the pooled effect.
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Figure 4. Forest plot showing the effect of CDT on the development of bleeding
428
complications, including an assessment of heterogeneity. The black lines represent the 95%
429
confidence interval (CI), with the black diamond representing the pooled effect.
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ACCEPTED MANUSCRIPT Lee et al 2013
Haig et al 2016
Methods
Retrospective, non-ramdomised
Multi-centre, open label randomised control
comparative study
trial
53 participants:
209 participants enrolled:
27 in intervention group – mean age 62.4
Intervention group – 101 randomised; 6
years; 51.9% female
withdrew, 4 not eligible, 3 died, 1 lost to follow-
26 in control group – mean age 59.8 years;
up = 87 included at 5 year follow-up. Median
46.2% female
age 58, 34% female
Participants
RI PT
Study Reference
SC
Control group – 108 randomised; 9 withdrew, 9 died, 1 lost to follow-up = 89 included at 5 year
Intervention group - CDT with urokinase for
Intervention group – CDT with alteplase, plus
48 – 72 hours, plus unfractionated heparin
UFH, followed by oral anticoagulation with
(UFH); oral anticogulation with warfarin
warfarin for at least 6 months
overlapped with UFH until INR therapeutic,
Control group – LMWH plus Warfarin for at
and continued for at least 6 months
least 5 days, followed by continued oral
Control group - Low molecular weight
anticoagulation with warfarin for at least 6
heparin (LMWH) for 7-14 days, followed by
months
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Interventions
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follow-up. Median age 53, 40% female
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oral anticogulation with warfarin for at least 6 months
Safety: Bleeding events; pulmonary
Outcomes at 5 years – incidence of PTS; venous
embolism; death
patency; quality of life; recurrence of VTE;
Efficacy: Immediate ileo-femoral venous
bleeding complications
AC C
Outcomes
patency; valvular competence; recanalization; thrombus propogation/resolution at 6 months; recurrent DVT at 3 months; incidence of PTS at 12 months
Table 1.
ACCEPTED MANUSCRIPT Srinivas et al 2014
Ezelsoy et al 2015
Vedantham et al 2017
Methods
Prospective. non-
Retrospective, non-
Multi-centre, open label
randomised comparative
randomised comparative
randomised controlled
study
study
trial
60 initial participants
50 participants:
692 patients enrolled:
Intervention group – 30
Intervention group – 25
Intervention group – 336
initial patients. 2 died, 1
Control group – 25
randomised; 257
failed to complete
Patients aged between
completed 2 year follow-
treatment, 2 lost to
20 -75 years included,
up; 79 followed-up for
follow up = 25 included
but mean age and
<2 years (10 withdrew, 7
in results. Mean age 39
male:female ratios not
died, 62 lost to follow-
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Participants
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Study Reference
years, 48.1% female
quoted
years. 39% female.
patients. 2 died, 2 lost to
Control group – 355
follow-up = 26 included
randomised; 243
in results. Mean age 53
completed 2 year follow-
years, 42.9% female
up; 112 followed up for
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Control group – 30 initial
<2 years (18 withdrew, 8 died, 86 lost to follow
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Interventions
up). Median age 52
up). Median age 53. 38% female.
Intervention group -
Intervention group -
Intervention group –
Pharmaco-mechanical
insertion of inferior vena
Mechanical
thrombolysis, with
cava filter, mechanical
thrombectomy with
mechanical aspiration
thrombectomy with
rheolytic or rotational
first followed by CDT
rotational
thrombectomy device
with streptokinase, plus
thrombectomy device,
followed by CDT with
UFH, followed by oral
followed by CDT with
alteplase, plus UFH or
ACCEPTED MANUSCRIPT alteplase, plus UFH for 5
LMWH followed by oral
warfarin or nicoumalone
days followed by oral
anticoagulation with
for 6 months
anticaogulation with
warfarin for median 211
Control group - UFH for
warfarin for 3 months
days (treatment arm) vs
48 hours, followed by
Control group - LMWH
231 days (control arm);
UFH or LMWH for
for 5 days followed by
further 5 days, followed
oral anticaogulation with
until stable &
by oral anticoagulation
warfarin for at least 6
therapeutic INR
with warfarin or
months
achieved
M AN U
months
Venous recanalization
Incidence of PTS at 6
lysis; serious adverse
within 6 months;
months and 2 years;
events; minimal adverse
femoral venous
patient reported health-
events; venous patency
insufficiency; incidence
related quality of life;
at 6 months (defined as
of PTS
bleeding; recurrent
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Immediate thrombus
venous
thrombus); incidence of
thromboembolism;
PTS at 6 months
death
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>90% clearance of
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Table 2.
UFH or LMWH continued
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nicoumalone for 6
Outcomes
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anticoagulation with
ACCEPTED MANUSCRIPT
Study
Bias due to: Selection of
Classification
Deviation
Missing
Measurement
Reported
Participants
of
from
Data
of Outcomes
Results
Interventions
Intended Interventions
Lee et
High
High
Low
Low
Moderate
Low
Low
High
High
High
Low
Low
Srinivas et al 2014 (13) Ezelsoy
2015 (14)
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Table 3.
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et al
High
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(12)
Moderate
Moderate
SC
al 2013
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Confounding
Low
Low
Low
Low
Moderate
Low
ACCEPTED MANUSCRIPT Study
Bias due to: Allocation
Blinding of
Blinding
Blinding
Incomple
Selectiv
Oth
sequenc
Concealm
Participants/Perso
of
of
te
e
er
e
ent
nnel
Outcome
Outcome
Outcome
Reporti
Bias
generati
Assessme
Assessme
Data
ng
on
nt – Self-
nt –
reported
Objective
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Random
Outcome
Haig et al
Low
Low
Unclear
Low
Low
Low
Moderate
Vedanth am et al
Moderat e
AC C
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(2017)
Table 4.
Low
M AN U
2016 (15)
SC
s
Low
Low
Low
Low
High
Low
Low
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