1

A systematic review on the use of deep venous stenting for acute venous thrombosis of the lower limb

Mohamed A. H.Taha*1,2, Andrew Busuttil*1, Roshan Bootun*1, Alun H Davies*11 Academic Section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, Charing Cross Hospital, Fulham Palace Road, London, W6 8RF, United Kingdom2 Department of Vascular and Endovascular Surgery, Assiut University Hospitals, Egypt

Correspondence to: Professor Alun H. Davies, MA DM FRCS DSc FHEA FEBVS FACPh, Academic section of Vascular Surgery, Department of Surgery and Cancer, Imperial College London, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK;E-mail: a.h.davies@imperial.ac.uk

2

WHAT THIS PAPER ADDS

This review demonstrates that quality of evidence behind the use of deep venous stenting following thrombolysis for treatment of acute deep venous thrombotic events is weak. This review intended to influence clinical practice and to alert physicians to enhance further studies to confirm or to disregard the recommendations given in the present paper.

3

Abstract:

Objectives:The aim is to evaluate venous stent patency, the development of post thrombotic syndrome (PTS), recurrence, quality of life(QOL) and the optimal post-procedural anticoagulation regimen in the treatment of iliofemoral deep venous thrombosis (DVT).

Method and Results: EMBASE and Medline databases were interrogated to identify studies in which acute DVT patients were stented. Twenty-seven studies and 542 patients were identified. Primary, assisted primary and secondary patency rates 12 months after stent placement ranged from 74-95%,90-95% and 84-100% respectively. The observed PTS rate was 14.6%. The incidence of stent re-thrombosis was 8%. In 26% of studies, patients received additional antiplatelet therapy. QOL questionnaires employed in 11% of studies, demonstrating an improvement in the chronic venous insufficiency questionnaire (CIVIQ) (22.67±3.01 vs. 39.34±6.66).

Conclusion: Venous stenting appears to be an effective adjunct to early thrombus removal; however, further studies are needed to identify optimal anticoagulant regimen and effect on QOL.

Keywords: stent; venous thromboembolism; acute; endovascular treatment; May- Thurner syndrome

4

Background:Acute deep vein thrombosis (DVT) of the lower limbs occurs in about 1·0 person per 1000 population per year and is associated with substantial morbidity 1. The majority of symptomatic iliofemoral venous obstructions are secondary to an episode of DVT. It may be limited to the iliofemoral segment or contiguous from the calf to iliac veins 2.Although anticoagulation effectively prevents thrombus extension, pulmonary embolism, death, and recurrence, many patients develop venous dysfunction resulting in post-thrombotic syndrome (PTS) 3. PTS probably evolves from venous obstruction, venous incompetence caused by destruction of the venous valves in response to the acute thrombotic occlusion, or both 4. There has been a shift in the treatment focus for patients with iliofemoral DVT towards the use of early thrombus removal strategies such as endovenous thrombolysis (eg catheter directed thrombolysis CDT and percutaneous mechanical thrombectomy PMT) and/or thrombectomy with or without venous stents to lower the incidence of post thrombotic syndrome (PTS) 5. Patients with PTS have a significantly decreased quality of life 6 and the condition can result in a substantial psychological and economic burden 7. Acute venous stenting is predominantly used in patients with residual venous outflow obstruction of the iliac and common femoral veins after early thrombus removal with CDT or PMT 8. The indication for stent placement after thrombolysis in patients with acute deep venous thrombosis is the presence of residual stenosis, ideally diagnosedby multiplanar venography and the use of intra-vascular ultrasound (IVUS) at the end of the procedure. When venous stenosis is treated by venoplasty alone, it has a high rate of recurrence or complete resistance to balloon dilation 9.In patients receiving venous stents after a DVT, anticoagulation and possibly antiplatelet therapy may play an important role in preventing recurrent thrombosis and pulmonary embolism. So far, the choice of agent, dosing and duration of anticoagulant and possibly antiplatelet therapy is unclear for patients with venousstents. The conventional anticoagulants have been shown to reduce the risk of recurrent DVT dramatically. However, their role in preventing DVT in patients with venous stents remains unclear. Antiplatelet therapy has proven to be safe and efficacious in patients with arterial stents, but the effect in patients with venous stents, with or without prior DVT again remains uncertain.Moreover, the most recent American College of Chest Physician (ACCP) guidelines (2016) fail to discuss the possibility of stenting after thrombolysis in patients presenting with DVT 10. Likewise, the most recent guidelines, such as theNational Institute for Health and Care Excellence (NICE) 11 and the European Society of Cardiology (ESC ) 12, do not discuss the role of venous stenting as part of the treatment option for patients after DVT13 .The aim of this review is to collate evidence on the effect of venous stent placement on venous patency after acute iliofemoral DVT and the subsequent development of PTS, as well as trying to evaluate the impact of different antithrombotic agents on venous stent patency.

Methods:Study selection:Research question, inclusion and exclusion criteria of the studies were specified in advance. The population of this review consists of patients who underwent venous stenting after acute venous thrombosis (with symptoms less than 14 days), often in

5

combination with balloon venoplasty preceded by CDT and/or PMT or surgical thrombectomy as well. Only studies where the use of post-interventional antithrombotic therapy was addressed were included. Any study design with more than 5 stented participants was included.All studies which included patients who were stented for chronic obstruction or which did not report primary or secondary outcomes were excluded.Interrogation of MEDLINE and EMBASE databases using the OVIDsp (Ovid Technologies, Inc.) platform from 1946 up to mid-March of 2016 was undertaken using certain MeSH headings (Appendix 1). No publication date restrictions were imposed; however, the search was restricted to articles in English and Arabic. Further selection was made on title and abstract screening. The final selection of articles was made by two researchers independently (MT and AB) after reviewing the full text as perthe Preferred Reporting Standards for Systematic reviews and Meta-Analysis (PRISMA)14.

Quality assessment:The quality of the included full-text studies was assessed by using the Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE Working Group) guidelines. Studies were screened by two authors (MT and AB) and any discrepancies were adjudicated by a third author (AHD). Data extractionwas also performed by two authors independently (MT and AB) regarding the study outcomes.

Data analysis:Venous stent patency rates in all of the included studies were assessed togetherwith thrombosis recurrence, post-thrombotic manifestations, anti-coagulation used and the duration of therapy. The results were tabulated using Microsoft Excel (Version 1702, Redmond, USA). Statistical meta-analysis was performed using SPSS 20.0 software (IBM, USA) and RevMan5.3.5.

Results:

Inclusion and quality assessment:

The initial search strategy resulted in a total of 760 studies and, after applying exclusion criteria and screening title, abstract and full text, as per PRISMA guidelines, 27 studies were included in the qualitative synthesis and 3 articles used for quantitativesynthesis (Fig. 1). The studies consisted of 3 systematic reviews 13,15,16, 3 randomisedcontrolled trials (RCTs) 17–19 and 21 cohort studies (8 prospective 20–27, 12 retrospective studies 28–39,and 1 study including 2 patient series 40.Five studies 23,28,32,33,37were included in whom the whole population wasstented. In 19 studies between 16% 24 and 81.2% 19 of the population was stented. In all included studies, the patients underwent lysis, venoplasty, stenting, with or without surgical thrombectomy and were prescribed anticoagulation and/or antiplatelet agents. Duplex or conventional venography was used in 24 articles to assess the 12- month primary patency rates, assisted primary patency rates and secondary patency rates. Other reported outcomes were PTS, recurrent DVT, quality of life

6

(QoL) assessment methods as well as the type and duration of antithrombotic regimen used during post-operative

Figure 1 PRISMA flow diagram summarising the results of application of the search strategy at each step

period. Assessment of PTS was performed using various methods, namely, the Villalta scale, modified Villalta score and venous clinical severityscores (VCSS). The overall range of follow up periods were from 3 months 28 to 8 years40. Two studies were limited to short follow up periods of 3 and 6 months respectively 17,28. All the included studies reported data on anticoagulant therapy or antiplatelet therapy. Recurrence of deep vein thrombosis was reported as early recurrence (within 1 day to 1 month after the procedure) in 13 studies 18–

20,23,24,26,27,31,32,34,35,37,38 and as late (within 1-2 years) recurrence in 17 of included studies 17,18,20–23,25–30,32,35,37,40. The findings of the search are summarised in (Table 1).

Level of the evidence and grading:

The quality of evidence to support the use of deep venous stenting as part of treatment of acute lower limb venous thromboembolism is currently weak. The interpretation of results of the GRADE assessment are displayed in (Appendix 2. a, b & c) 41.Using the GRADE approach for four of the five defined outcomes, the quality of evidence was rated as ‘’ low’’ as it largely pooled from cohorts and case series, and for the quality of life, it was rated as ‘’high’’ since it was obtained from the available RCTs. (Table 2).

Table 2: Clinical outcomes and GRADE assessment for the stented patientsin all studies that includes known number of stented patients or the whole study population had stents.

Outcomes Relative effect

(95% CI)

No of events (studies) Quality of

the

evidence

(GRADE)Stent patency Not 327 patients stented

Low aestimable

%patent (90.8%)

Follow-up:3months-8yrs (16 studies;16-18,20-23,27,28,30-32,34,35,37,39)

PTS Not 23 patients stented

Low aestimable

Validated measures (CEAP,Villalta, (9.6%)modifiedVillalta, &VCSS )

(11 studies; 16,21,22,26-28,30,31,34,35,37)Follow-up: 6-68 months

7

Anti- thrombotictherapy(Anticoagulation+/- Antiplatelet)

Follow-up:1-96 months

Not estimable

542 Patients stented

(100%)

(24 Studies; 16-39)

Low a

Quality of life

CIVIQ-20, Wong Baker chronic pain method.

Follow-up: 3-30 months

Not estimable

135 patients stented

(24.9%)

(3 studies; 16-18)

High b

Late DVT recurrence

Incidence (%)

Follow-up: 3 -36 months

Not estimable

14 Patients stented

(7.2%)

(12 studies; 16-18,20-23,26-28,30,31)

Low a

a Studies at serious risk of selection, detection, performance, attrition and selective reporting biases (see quality assessment of studies section).b Studies at low risk of selection, detection, performance, attrition and selective reporting biases (see quality assessment of studies section).GRADE; Grading of Recommendations Assessment, Development and Evaluation DVT; Deep venous thrombosisPTS; Post-thrombotic syndromeCEAP; Clinical-Etiology-Anatomy-Pathophysiology CIVIQ; Chronic Venous Insufficiency Questionnaire VCSS; Venous Clinical Severity Score

Risk of Bias:The included studies were assessed for several key biases by MT and AB: selection bias, performance bias, detection bias, attrition bias, and selective reporting bias. Attrition bias was deemed a high risk if the follow-up rate was less than 80%, in the absence of systematic examination of those participants who were lost to follow-up. Bias was also evaluated at outcome level using the GRADE assessment of the evidence. Thebias risk assessment of included studies was presented and summarized in (Fig.2)

Figure 2 Summary of Risk of Bias for the included studies. Green symbols represent low risk and red represent high risk

Outcomes:

Patency rates: Long and short-term stent patency rates were assessed in all studies 17–40. Primary, assisted primary patency and secondary patency rates 12 months after stent placement ranged from 74% to 95%, 90% to 95%, and 84% to 100% 32, respectively, 33. High patency rates were reported in all patients in a number of studies 17,19,24,31,40. The overall stent patency rate of included studies was 87.8% (475/542) with follow up period of 12-19.7 months. The overall patency data are listed in (Table 1).

Recurrent DVT:

43

8

Twenty-six studies provided data regarding DVT recurrence with follow up duration ranging between 3 months and 68 months 17–38,40. The incidence of re-thrombosis in the whole study population for all included studies ranged from 2% 30 to 25% 25,27. The overall re-thrombosis rate was 8% (60/542) with mean follow up period of 19.7 months. As well, the incidence of ipsilateral re-thrombosis in studies in which the whole population were stented or with known number of stented patients, ranged from 3.7% 17 to 50% as early recurrence 27 and 20% as late recurrence 23. The DVT recurrence data are tabulated in (Table 1).

Post-thrombotic syndrome:

Post-thrombotic syndrome was assessed in 26/27 studies 17–32,34–40. In most of these studies, the Villalta–Prandoni scale, modified Villalta scale 42, the venous clinicalseverity score (VCSS) and the change of C in CEAP 44 classification were used. Thesescoring systems have been validated in different settings 45–47 and subsequently endorsed by the International Society on Thrombosis and Hemostasis (ISTH).In 18% of the studies (5/27), PTS was reported based on the whole patient cohort receiving venous stents 17,23,28,32,37;2 studies were in the contextof symptomatic iliac vein compression syndrome (IVCS) or May-Thurner syndrome (MTS) presenting with acute DVT 23,37. All PTS data are tabulated in (Table 1).

The use of post-interventional antithrombotic therapy and optimal duration:

In all included studies, patients received anticoagulant therapy in the form of either vitamin K antagonists, direct oral anticoagulant (Factor X inhibitors) or low molecular weight heparin (LMWH) for at least 3 months, with or without addition of antiplatelet therapy 17–40. The antithrombotic regimen was decided on either placement of venous stents in 3 studies 17,25,34 or the presence of a hypercoagulable state in 7 studies 20–22,30–

32,35or both in 1 study 39. The criteria used was not mentioned in the remaining 15 studies. In addition, antiplatelet therapy was not used as a solo therapy after venous stenting in any of our included studies. In 7 studies, patients received additional antiplatelet therapy after CDT and /or PMT and stent placement 17,21,31,34,35,37,39 (Table 3). Dual antiplatelet therapy (Aspirin + Clopedogril) were used in 2 studies 17,35and it was unclear in another study39.

Table 3: Effect of additional antiplatelet therapy on study outcomes in studies where all/known number of population were stented.

Study No of patients: acute stented/all acute patients (%)

Antiplatelet agent Patency%

DVT recurrence% PTS % Notes

Fiengo L. etal 2015 21

6/24 (25%) Clopedogril 75mg^

80%(2yrs)*

0%(2yrs)* 8%(2yrs)# * For the stented population only which constitute about 25%

# For the whole study population.

9

^Unclear durationSharifi M. etal 2012 17

27/183 (14%) Aspirin 75mg for 6 months+ Clopedogril 75 mgfor 2-4 wks

100% (6months)*

3.7%(20 months)* 6.4%(30months)*

*For the stented population only which constitute about 14%.

Bloom A.I. 6/11 (54%) Aspirin 75mg for 3100% 16%( median 0%( median 20 *For the stented population onlyetal 2014 31 months (10-39 20months )* months)* which constitute about 54%.

months)*

Stanley G.A. etal 2011 39

33/52 (63%) Unclear antiplatelet agent for long life

94%(3.8yrs)

Not assessed 32%(3.8yrs)^ *For the stented population only which constitute about 63%.

^the valve incompetence was assessed as indicator for PTS changes.

Avgerinos E.D. etal 2015 34

34/ 70 (48.5%) Aspirin 75mg^ 97%(12months)*

5.6%(immediate re-thrombosis)*

11.7%(12months)*

*For the stented population only which constitute about 48.5%.

^ Unclear durationHager E.S. etal 2013 35

51/70 (72.8%) Aspirin 75mg+ Plavix ^

91%(36months)*

12.5%(36months)*

51.8% (median 29.7months )*

* For the interventional population only which constitute about 72.8%.

^ duration decided by the haematologist

Xue G.-H. etal 2014 37

61/61 (100%) Aspirin 75 mg for at least 6 months

91.8%( 12months)

11.5%(1-27months)

11.5%(1-27months)

All stented patients study.

DVT; Deep venous thrombosis

PTS; Post-thrombotic syndrome

The duration of oral anticoagulant therapy ranged from 3 months to life. The findings of anticoagulation regimen used in patients receiving stents following early thrombus removal and the effect on venous stent patency is tabulated in (Table 1).

Quality of life assessment:

Quality of life was assessed in only 11% of included studies (3/27) using disease- specific quality of life according to the chronic venous insufficiency questionnaire (CIVIQ) which is a disease-specific instrument to measure the impact of chronic venous insufficiency (CVI) on patients’ lives48. Furthermore, quality of life assessed by telephone (subjective patient perception of improvement) or by using the Wong Baker chronic pain method in two other studies. Of the three studies assessedby CIVIQ, only one (3.7%) reported quality of life assessment between stenting and non- stenting groups. However, the remaining two studies assessed the quality of life between two different interventions (CDT and USAT; Ultrasound assisted catheter directed thrombolysis groups) or between PEVI (Percutanous endovenous

10

intervention) and control groups in which 81.2% 19 and 14.7% 17 of their population were stented respectively. In a study done by Engelberger RP etal, in which 39 of 48 patients (81.2%) were stented, disease-specific quality of life according toCIVIQ was similar in both study groups (28 ± 11.6 in the USAT, (19/24) group versus26.2 ± 7.5 in the CDT, (20/24) group (p=0.55) 19. On the other hand, it was assessed in another trial performed by Meng Q. Y. etal using chronic venous insufficiency questionnaire, in which the CIVIQ Score was significantly different betweenthe stenting and non-stenting groups (22.67±3.01 vs. 39.34±6.66, respectively) with P value <0.001 18.

Discussion:

After early thrombus removal for acute iliofemoral DVT, venous stenting is often performed in case of residual thrombi or obstructive lesions appearing to be resistant to venous angioplasty 30. Overall, the evidence supporting the use of venous stents after a DVT in the iliofemoral area for improved short-term and long- term patency appears reduced, in addition, with limited methodological quality. This review emphasizes that additional stenting should have its proper indications, and unfortunately the available literature does not add a lot, to help the clinician in decision making, as indications / criteria for stent placement have rarely been validated so far. The lack of comparator studies is evident with only 2 studies 17,25;(one RCT) 17 comparing percutanous endovenous intervention (PEVI) plus anticoagulation to anticoagulation alone. In these studies, the PEVI + anticoagulation group performed significantly better than the anticoagulation alone group in terms of patency 25, recurrent venous thromboembolism and development of PTS 17. Our search noted an overall patency rate of 87.8% witha low incidence of thrombosis recurrence (8%) over follow-up period of 12 to 19.7 months but with low level of evidence. Although this overall patency rate appears to confirm the efficacy of the procedure, these figures are affected by both the heterogeneity between studies due to the different proportion of stented patients in these studies and the low level of evidence as most of studies were case series. In addition, the overall venous stent patency did not show any significant variability in the consistency and thoroughness of patient characteristics and outcomes reporting among studies. This review shows an improved patency rate when patients were stented.

Because of the fact that only 3 papers, not truly RCTs involving stenting and non- stenting groups, a meta-analysis can be hardly drawn. Only one RCT was really randomised patients between stent and no stent, the one by Meng Q. Y. et al18, as after receiving CDT, the major branch of the distal iliac vein was completely patent in 155 patients with lower extremity DVT, and 74 of these patients with iliac vein residual stenosis of >50% were randomly divided into a control group (n = 29) and a test group (n = 45)." The two other RCT's randomised patients between two treatment procedures, but not between stent/no stent17,19.

In all included studies, self-expandable and/ or balloon expandable stents were used to maintain the patency within the treated venous segments following deep venous thrombolysis. Large numbers of the earlier studies made use of arterial stents, modified

11

for venous application, so there is a need for further research using venous specific stents which are now more commonly used in Europe.

Post-thrombotic symptoms were less prominent in patients with venous stents than in those without stents, with an overall incidence of 14.6%, but again, with a low level of evidence. Although it is ideally to included studies with follow up periods up to 2 years when included studies are being assessed for PTS rate as separate outcome, one study performed by Engelberger RP etal19 reported PTS rate with follow up period of 3 months.

Interestingly, the ATTRACT trial 49,51; multicentre randomized trial to evaluate CDT for the prevention of PTS in patients with proximal DVT, reported PTS incidence rate of 46% at 2 years which is much more consistent with our systematic review. This difference could be interpreted by the way that PTS had been investigated using only Villalta scale which has been sufficiently validated for this purpose. In a few cases, some patients were asymptomatic although their stents were occluded 23. This might emphasize the controversy about the guidance of venous stenting placement.

The importance of ensuring a true improvement in a patient's QOL and not just venous severity scores has recently been demonstrated in the setting of endovenous intervention, although the follow up period was short (3months) 19. In contrast, a study, performed by Meng Q. Y. etal showed that VCSS and CIVIQ Score were both significantly different between the test and control groups. Furthermore, the improvement of symptoms was more significant in the test group compared with the control group, suggesting that stenting in the iliac vein following thrombolysis can improve clinical efficacy. This study showed, that although postoperative CIVIQ score was lower, quality of life was improved in both groups, with significantly better scores with iliac vein stenting, possibly due to the improved patency of the blood vessels 18. Therefore, the link between stent patency, post-thrombotic symptoms and quality of life require further evaluation. On the other hand, the recently published ATTRACT trial 49,51 showed that there was no significant difference between the two treatment groups in the change of venous disease-specific quality of life (P=0.08) or general quality of life (P=0.37) from baseline to 24 months follow up. In our opinion, this no QoL difference may be attributed to that only 82/ 297patients (28%) had received stenting in the interventional group and this not the case when evaluating the change in QoL between stent and no stent groups. Thus, it can under-estimate the effect of stenting following acute venous thrombolysis.

From our point of view, there is now a growing body of evidence to support venous stenting in both the acute and chronic setting, and as more patients receive stents, the production of stenting registries will hopefully further contribute to the evidence. Post- thrombotic syndrome manifestations following ilio-femoral DVT are seen less frequently when catheter-directed thrombolysis in combination with adjunct therapy than with systemic or regional lysis therapy 16 alone is used.

There remains much debate as to whether the addition of antiplatelet agents and their duration results in any improvement in patency. However, there could be an additional effect of aspirin, in addition to warfarin treatment, for the reduction in the prevalence of PTS 17. It is noticed that prominent figures play in favour for adding antiplatelets as

12

cornerstone in the antithrombotic regimen after venous stenting and their significant impact on various outcomes (Table 3). However, the level of evidence supporting the optimal type and duration of antithrombotic regimen post stent placement isstill lacking and further work is needed.Based on the evidence presented in this review, no firm conclusions regarding the association between the duration of antithrombotic therapy and the study outcomes can be drawn. Although the extended anticoagulation regimen is generally determined by the underlying thrombotic risk factors and not guided by presence of venous stent placement, the optimal duration of anticoagulation following venous stenting in the setting of early thrombus removal has not been adequately studied, and no evidence- based recommendations can be provided.

There are therefore several areas for future research. Before the practice is more widely rolled out though, more randomised studies should be performed comparing the practice against conservative measures particularly between stenting and non-stenting groups, with longer term follow-up and outcome measures to include validated chronic venous disorder (CVD) measures and QOL scores 50. In addition, there is pressing need to raise a call to study parameters and determine optimal patient selection criteria when deciding to stent after acute thrombolysis; based on anatomic (venographic and IVUS) and hemodynamic (duplex and venographic) determinants.

Limitations:Most studies still have limited information especially regarding the long-term data. Post thrombotic syndrome and quality of life evaluation were assessed by three different methods, although these methods were all individually validate; they add heterogeneity and inconsistency to the results. In addition, CIVIQ is validated for venous insufficiency48 and not only for post-thrombotic status. Furthermore, PTS has been reported at 3 months follow up period in one study19 although it is ideal to report PTS outcome at 2 years follow up and this ultimately affects the level of evidence of PTS outcome. One of the limitations of this review is that post- procedural antithrombotic therapy is not assessed separately as a potential factor for short term and long-term failure or success of the stenting procedure. Another limitation of this review was the heterogeneity (based on the variations and narrative compatibility of all included studies) and the low level in the quality of most of included studies as only a portion of patients underwent stenting within these studies. Furthermore, the absence of data regarding hemodynamic values measured by IVUS or duplex and detailed stent procedure complications in all cited studies.

Conclusion:Venous stenting for acute DVT patients appears to be an effective strategy of treatment with better patency, lower re-thrombosis and post- thrombotic rates and improved quality of life of patients as well. Although the evidence for the use of venous stents in the context of acute venous thromboembolism is still lacking, it appears promising and should therefore be considered as a treatment option, when indicated while the evidence base is improved. Several bodies are not recognising stenting as part of treatment while managing acute iliofemoral DVT patients as stenting is a new topic and researchers should highlight how big groups have not identified this treatment modality. The review describes the scarcity of robust studies on the acute venous stenting with long-term data and it alerts the physicians to enhance further

13

studies to confirm or to disregard the recommendations given in the present paper.

Disclosure and conflict of interest: None.Funding:

Imperial College Healthcare NHS Trust, NIHR and the Egyptian Ministry of Higher Education (Newton Mosharafa Fund Programme).

Ethical approval:

This systematic review article does not need any ethical approval.

Appendix: Supplementary dataThe following are the supplementary data related to this article: Appendix 1

Appendix 2a, b &c

References:1. White RH. The Epidemiology of Venous Thromboembolic Disease Venous

Thromboembolism. Circulation 2003; 107: 1-4-8.2. Neglen P RS. Iliocaval Obstruction: Endovascular Treatment. In: Jack L. Cronenwett,

MD, Professor of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire and K. Wayne Johnston, MD, FRCSC, R. Fraser Elliott Chair in Vascular Surgery, Professor of Surgery, University of Toronto; Toronto General Hospital, C (ed) Rutherford’s Vascular Surgery. Saunders, an imprint of Elsevier Inc. 2014, 2014, pp. 955–970.

3. Enden T, Haig Y, Kløw NE, 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. Lancet 2012; 379: 31–38.

4. Kahn SR. The post-thrombotic syndrome: progress and pitfalls. Br J Haematol 2006; 134: 357–365.

5. Meissner MH, Gloviczki P, Comerota AJ, et al. Early thrombus removal strategies for acute deep venous thrombosis: Clinical Practice Guidelines of the Society for Vascular Surgery and the American Venous Forum. J Vasc Surg 2012; 55: 1449–1462.

6. Kahn SR, Hirsch A, Shrier I, et al. Effect of Postthrombotic Syndrome on Health-Related Quality of Life After Deep Venous Thrombosis. Arch Intern Med 2002; 162: 1144.

7. Bergqvist D, Jendteg S, Johansen L, et al. Cost of Long-Term Complications of Deep Venous Thrombosis of the Lower Extremities: An Analysis of a Defined Patient Population in Sweden. Ann Intern Med 1997; 126: 454.

8. Jenkins JS. Endovascular Therapies to Treat Iliofemoral Deep Venous Thrombosis. Prog Cardiovasc Dis 2011; 54: 70–76.

9. Nazarian GK, Austin WR, Wegryn SA, et al. Venous recanalization by metallic stents after failure of balloon angioplasty or surgery: four-year experience. Cardiovasc Intervent Radiol; 19: 227–33.

10. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST

14

guideline and expert panel report. Chest 2016; 149: 315–352.11. NICE | The National Institute for Health and Care

Excellencehttp://www.nice.org.uk/aboutnice/howwework/developingniceclini-calguidelines/clinicalguidelinedevelopmentmethods/theguidelinesmanual2007/the_guidelines_manual_2007.jsp( (accessed 16 November 2016).

12. Konstantinides S V., Torbicki A, Agnelli G, et al. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014; 35: 3033–3080.

13. Eijgenraam P, ten Cate H, ten Cate-Hoek AJ. Venous stenting after deep venous thrombosis and antithrombotic therapy: A systematic review. Rev Vasc Med 2014; 2: 88–97.

14. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ; 339.

15. Bækgaard N, Just S. Indications for stenting during thrombolysis. Rev Vasc Med 2013; 1: 76–80.

16. Alesh I, Kayali F, Stein PD. Catheter-directed thrombolysis (intrathrombus injection) in treatment of deep venous thrombosis: a systematic review. Catheter Cardiovasc Interv 2007; 70: 143–8.

17. Sharifi M, Bay C, Mehdipour M, et al. Thrombus Obliteration by Rapid Percutaneous Endovenous Intervention in Deep Venous Occlusion (TORPEDO) trial: midterm results. J Endovasc Ther an Off J Int Soc Endovasc Spec 2012; 19: 273–80.

18. Meng QY, Li XQ, Jiang K, et al. Stenting of iliac vein obstruction following catheter-directed thrombolysis in lower extremity deep vein thrombosis. Chin Med J (Engl) 2013; 126: 3519–3522.

19. Engelberger RP, Spirk D, Willenberg T. Ultrasound-Assisted Versus Conventional Catheter-Directed Thrombolysis for Acute Iliofemoral Deep Vein Thrombosis. J Vasc Surg 2015; 62: 518.

20. Bækgaard N, Broholm R, Just S, et al. Long-Term Results using Catheter-directed Thrombolysis in 103 Lower Limbs with Acute Iliofemoral Venous Thrombosis. Eur J Vasc Endovasc Surg 2010; 39: 112–117.

21. Fiengo L, Bucci F, Khalil E, et al. Original approach for thrombolytic therapy in patients with Ilio-femoral deep vein thrombosis : 2 years follow-up. Thromb J 2015; 13: 40.

22. Srinivas BC, Patra S, Reddy B, et al. Outcome of venous stenting following catheter directed thrombolysis for acute proximal lower limb venous thrombosis: a prospective study with venous Doppler follow-up at 1-year. Cardiovasc Interv Ther 2015; 30: 320–326.

23. Patel N, Stookey KR, Ketcham DB, et al. Endovascular Management of Acute Extensive Iliofemoral Deep Venous Thrombosis Caused by. J Vasc Interv Radiol 2000; 11: 1297–1302.

24. Manninen H, Juutilainen A, Kaukanen E, et al. Catheter-directed thrombolysis of proximal lower extremity deep vein thrombosis: A prospective trial with venographic and clinical follow-up. Eur J Radiol 2012; 81: 1197–1202.

25. AbuRahma AF, Perkins SE, Wulu JT, et al. Iliofemoral deep vein thrombosis: conventional therapy versus lysis and percutaneous transluminal angioplasty and stenting. Ann Surg 2001; 233: 752–60.

26. Lamont JP, Pearl GJ, Patetsios P, et al. Prospective evaluation of endoluminal venous stents in the treatment of the May-Thurner syndrome. Ann Vasc Surg 2002; 16: 61–64.

15

27. Goldenberg NA, Branchford B, Wang M, et al. Percutaneous mechanical and pharmacomechanical thrombolysis for occlusive deep vein thrombosis of the proximal limb in adolescent subjects: Findings from an institution-based prospective inception cohort study of pediatric venous thromboembolism. J Vasc Interv Radiol 2011; 22: 121–132.

28. Husmann MJ, Heller G, Kalka C, et al. Stenting of Common Iliac Vein Obstructions Combined with Regional Thrombolysis and Thrombectomy in Acute Deep Vein Thrombosis. Eur J Vasc Endovasc Surg 2007; 34: 87–91.

29. Kim J-Y, Choi D, Guk Ko Y, et al. Percutaneous treatment of deep vein thrombosis in May-Thurner syndrome. Cardiovasc Intervent Radiol 2006; 29: 571–5.

30. Sillesen H, Just S, Jørgensen M, et al. Catheter directed thrombolysis for treatment of Ilio-femoral deep venous thrombosis is durable, preserves venous valve function and may prevent chronic venous insufficiency. Eur J Vasc Endovasc Surg 2005; 30: 556–562.

31. Bloom AI, Farkas A, Kalish Y, et al. Pharmacomechanical Catheter-Directed Thrombolysis for Pregnancy-Related Iliofemoral Deep Vein Thrombosis. J Vasc Interv Radiol 2014; 26: 992–1000.

32. H??lper P, Kotelis D, Attigah N, et al. Longterm Results After Surgical Thrombectomy and Simultaneous Stenting for Symptomatic Iliofemoral Venous Thrombosis. Eur J Vasc Endovasc Surg 2010; 39: 349–355.

33. Kwak H-S, Han Y-M, Lee Y-S, et al. Stents in common iliac vein obstruction with acute ipsilateral deep venous thrombosis: early and late results. J Vasc Interv Radiol 2005; 16: 815–22.

34. Avgerinos ED, Hager ES, Naddaf A, et al. Outcomes and predictors of failure of thrombolysis for iliofemoral deep venous thrombosis. J Vasc Surg Venous Lymphat Disord 2015; 3: 35–41.

35. Hager ES, Yuo T, Tahara R, et al. Outcomes of endovascular intervention for May-Thurner syndrome. J Vasc Surg Venous Lymphat Disord 2013; 1: 270–275.

36. Herrera S, Comerota AJ, Thakur S, et al. Managing iliofemoral deep venous thrombosis of pregnancy with a strategy of thrombus removal is safe and avoids post-thrombotic morbidity. J Vasc Surg 2014; 59: 456–464.

37. Xue GH, Huang XZ, Ye M, et al. Catheter-directed thrombolysis and stenting in the treatment of iliac vein compression syndrome with acute iliofemoral deep vein thrombosis: Outcome and follow-up. Ann Vasc Surg 2014; 28: 957–963.

38. Lindow C, Mumme A, Asciutto G, et al. Long-term results after transfemoral venous thrombectomy for iliofemoral deep venous thrombosis. Eur J Vasc Endovasc Surg 2010; 40: 134–138.

39. G.A. S, E.H. M, M.M. P, et al. Midterm results of percutaneous treatment for acute and chronic deep venous thrombosis. J Vasc Surg 2011; 54: 1851.

40. Blättler W, Heller G, Largiadèr J, et al. Combined regional thrombolysis and surgical thrombectomy for treatment of iliofemoral vein thrombosis. J Vasc Surg 2004; 40: 620–625.

41. Schünemann HJ, Oxman AD, Vist GE, Higgins JPT, Deeks JJ, Glasziou P GG. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JPT, Green S (editors), Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011.http://handbook.cochrane.org/chapter_12/12_8_chapter_information.htm (2011).

42. S. Villalta, P. Bagatella, A. Piccioli, A.W. Lensing, M.H. Prins PP. Assessment of validity and reproducibility of a clinical scale for the post-thrombotic syndrome

16

(abstract) Haemostasis. 1994; 24: 158a.43. Rutherford RB, Padberg FT, Comerota AJ, et al. Venous severity scoring: An adjunct

to venous outcome assessment. J Vasc Surg 2000; 31: 1307–1312.44. Porter JM, Moneta GL. Reporting standards in venous disease: an update.

International Consensus Committee on Chronic Venous Disease. J Vasc Surg 1995; 21: 635–45.

45. Jayaraj A, Meissner MH. A Comparison of Villalta-Prandoni Scale and Venous Clinical Severity Score in the Assessment of Post Thrombotic Syndrome. Ann Vasc Surg 2014; 28: 313–317.

46. Galanaud JP, Holcroft CA, Rodger MA, et al. Comparison of the Villalta post-thrombotic syndrome score in the ipsilateral vs. Contralateral leg after a first unprovoked deep vein thrombosis. J Thromb Haemost 2012; 10: 1036–1042.

47. KAHN SR. Measurement properties of the Villalta scale to define and classify the severity of the post-thrombotic syndrome. J Thromb Haemost 2009; 7: 884–888.

48. Launois R, Reboul-Marty J, Henry B. Construction and validation of a quality of life questionnaire in chronic lower limb venous insufficiency (CIVIQ). Qual Life Res 1996; 5: 539–54.

49. Vedantham S, Goldhaber SZ, Kahn SR, et al. Rationale and design of the ATTRACT Study: A multicenter randomized trial to evaluate pharmacomechanical catheter-directed thrombolysis for the prevention of postthrombotic syndrome in patients with proximal deep vein thrombosis. Am Heart J 2013; 165: 523–530.e3.

50. Soosainathan A, Moore HM, Gohel MS, et al. Scoring systems for the post-thrombotic syndrome. J Vasc Surg 2013; 57: 254–261.

51. Vedantham S, Goldhaber SZ, Julian JA, et al. Pharmacomechanical Catheter-Directed Thrombolysis for Deep-Vein Thrombosis. N Engl J Med 2017; 377: 2240–2252.

17

Table 1: Summary of the included studies.

Study Study design

Age (rang e)

MTS(No. Of patients)

M/ F

Sample size : acute stented/all acute patients

acute stented patients / acute non stented patients

Stent type Venous Stent patency (No. Of patent patients)(%)

Concurrent endovascular/ surgical deep venous interventions

DVTrecurren ce %( follow up)

Type of Antithromb otic Regimen

Decision upon which antithrom botic regimen was chosen

PTS symptoms:% (follow up period)

Fiengo L. Prospecti 18- Not present. Not 6/24 SES 80%^ 1ry CDT 0%* Anticoagulat Thrombolp 8% *etal 2015 ve cohort 62 men (25%) (not mention) (2 yrs). ion hilia (2 yrs)21 yrs. tion 6/18 +Antiplatelet

ed.

Srinivas Prospecti 31-62 IVCS 3/5 5/8 SES (WALL 100%^ 1ry CDT + 0%* Anticoagulat Thrombop 20%*B.C etal ve cohort yrs. (2^ ). * (62.5%) & SMART) (Early) Mechanical (1 yr) ion hilia (1 yr)2015 22 study 5/0 60%^1ry thromboaspirati

(1 yr) on

Patel NH etal 200023

Prospecti ve cohort study

22-52yrs.

MTS (10*)

Not men tion.

10/10 (100%) 10/0

SES (WALL)

90%* 1ry100%*2ry (mean 15.2 months).

CDT 20%* (1month) 20%* (36months).

Anticoagulat ion

Not mention

0%*(36 months)

Manninen H etal 2012 24

Prospecti ve cohort study

15-82yrs.

Not present. 26/21*

9/56

(16.07%)

SES(WALL) 100%*(mean 3.5 yrs)

CDT 3.8%* (12months)

Anticoagulat ion.

Not mention

9%* (mean3.5 yrs)

18

9/47Baekgaard Prospecti 15- Not mention. 23/ 57 SES 82%* CDT 5.3* Anticoagulat Thrombop 9.9%*N. etal ve cohort 59yrs 78* limbs/103 (6 yrs) (1w). ion hilia (6 yrs)2010 20 study . limbs in 5.3%*

101 pts (3yrs).(55.3%)

57/ 46limbs in101 pts.

Ali F. Prospecti 23-74 Not mention. 21/ 10/51 SES or BES 83%# CDT # 17%# Anticoagulat Stent 22% #AbuRahm ve cohort yrs. 30* (19.6%) (12 months) (long ion placement (12 months)a etal study 10/41 term200125 follow

up)Lamont JP. etal 2002 26

Prospecti ve cohort study

23-72yrs.

MTS (15*)

3/12*

9/15 (60%)9/0

SES 93%* 1ry (6 months)100%* Assist 1ry

CDT &/or PMT&/or surgical thrombectomy

0%* (Early) 13.3%* (14-41

Anticoagulat ion

Not mention

6.6% *(14-41 months)

months).Goldenber g N.A.etal 201127

Prospecti ve cohort study

16yrs(M edian).

MTS (6^).

8/8*

6/16 (37.5%) 6/10

SES 75% #(14 months)

CDT, PPMT & PMT

50%^(7 days) 40%*(7 days)

Anticoagulat ion

Not mention

50%^(1-2yrs)

27%*(14months).

Meng Q. RCTs 22-70 Not mention. 31/ 45/74 SES; 86% ^ CDT 11%^ Anticoagulat Not The change in theY. etal yrs. 43* (60.8%) SMART. (1 yr) (24 ion mention C2013 18 months) in CEAP classific

ion pre- and post-45/ 29 procedure was

significantlydifferent betweenthe test and controgroups (1.61+/-

19

0.21 vs. 0.69+/-0.23)

Engelberg RCTs 50 +/- Not present. 10/ 39/48 SES 100%^ USAT # &CDT (4.2% Anticoagulat Not There was noer RP. etal 21 14 (81.2%) (3 months) #,95% ion. mention. difference in the2015 19 yrs !!! CI 0,1- severity of PTS

(Mea 21.1%) (mean Villalta39/9 (1 day) score, 3.0 +/- 3.9

13/11!^

0 %^(3months).

[range, 0-15] vs 1.+/- 1.9 [range,0-7]; P =0.21,respectively).

Sharifi M. etal2012 17

RCTs 61 +/-11.3yrs#( Mean

Not present. 51/91#.

27/183 (14%)

SES & BES 100%^(6 months)

PMT, CDT, UASCDT ormanual aspiration.

3.7 %^(20months)

Anticoagulat ion + Dual Antiplatelet

Stent placement

< 3%#(6 months)6.4%#(30 months).

) 27/156HusmannM.J. etal 2007 28

Retrospe ctive cohort study

16-64yrs.

Not mention. 2/9*

11/11 (100%)

11/0

SES; (WALL)

81%*1ry (22months). 91%*Assisted 1ry(22 months)

CDT & surgical thrombectomy

9%* (3months)

Anticoagulat ion

Not mention

9% *(3 & 6 months)

Kim J.-Y.etal 200629

Retrospe ctive cohort study

51yrs (Avar age)

MTS (21*).

8/13*

10/21 (47.6%) 10/1

SES; (WALL)

80 %^(27 months)

CDT 10%^23.8%* (6months)

Anticoagulat ion

Not mention

10% ^(6 months)

Sillesen H. Retrospe 15- Not mention. 7/3 30/45 SES; 100%* CDT 2%* Anticoagulat Thrombop <5% *etal 2005 ctive 57 8*. (66.6%) (WALL & (2yrs) (2 yrs) ion hilia (49 months)30 cohort yrs. 30/15 SMART)

study.

.Bloom A.I. etal 201431

Retrospe ctive cohort

21-35yrs.

MTS ( 3^ ).

0/6^.

6/11 (54%)6/3^^ .

SES 100%^ (10-39months)

PCDT 16%^(Early) 9%

Anticoagulat ion+Antiplatelet

Stent placement.

0% ^(median 20 months)

study *(median20months)

20

Ho¨lper P. Retrospe 16-63 Not present. 3/2 25/25 SES & BES) 74%*1ry , Surgical 26%* Anticoagulat Thrombop 16% *etal ctive yrs !) 2* (100%) 84%* 2ry, thrombectomy. (7 days) ion hilia (median 682010 32 cohort & 25/0 (median 68 0%* months)

study. 56-70 months) (Late)yrs !!.

Kwak HS. etal.2005 33

Retrospe ctive coh ort study

Medi an age

MTS( 16 *).

9/13*

22/22 (100%)

SES;(WALL)

95%* 1ry,100%*2ry (2yrs)

CDT 4.5 %*(3months)

Anticoagulat ion

Not mention

Not assessed

58 22/0yrs

Stanley Retrospe Mean MTS 44/ 33/52 SES 96%,92% and PMT or US- Not Anticoagulat Thrombop 32% *G.A. etal ctive age (34*). 36* (63%) 94%* CDT or both. mention. ion hilia & (3.8 yrs ).2011 39 cohort 45.8 (1,6 months +Antiplatelet stent

study yrs9r 33/19 . and 3.8 yrs placementange respectively)15-78yrs).

AvgerinosE.D. etal

Retrospe ctive

Rang e 18-

MTS (4*).

12/22^

34/ 70(48.5%)

SES;(WALL or

97%^(12 months)

CDT alone, PMT alone or

5.8%^(immedi

Anticoagulat ion +

Stent placement

11.7 % ^ (12 months)

2015 34 cohort 83 34/18 ^^. Protégé ) combined. ate). Antiplateletstudy. yrs

Hager E.S. etal2013 35

Retrospe ctive cohort study.

Medi an age 51.9(range 41.4-

MTS(All^)

21/30^

51/70 (72.8%)

51/19

SES & BES 91% *1ry,98%*2ry (36 months)

CDT or CDT+PMT

5.3%#(immedi ate)12.5%#

(36months)

Anticoagula nt +Dual antiplatelet

Thrombop hilia

51.8% # (median29.7 months)

63.6)groupI pts

Herrera S. etal2014 36

Retrospe ctive cohort study.

Medi an age 26yrs (rang e 19-35yr)

Not mention 0/8^ 8/13

(61.5%)

8/5

SES & stent graft

92.3%*(1.3 yrs)

CDT or PMT;surgical thrombectomy.

7.6%*(not mention)

Anticoagulat ion

Not mention

15%* (1.3yr)

21

Xue G.-H Retrospe Mean IVCS 25/ 61/61 SES 96.7%,95.1%, CDT 11.5%* Anticoagulat Not 11.5%*etal ctive 64 (61*) 36* (100%) 91.8%,90.2%, (1-27 ion mention (1-27 months)2014 37 cohort and 88.5%,and months) +Antiplatelet

study range 61/0 85.25%*32-90 (1,6yrs. months,1,2,3

&5yrsrespectively)

Lindow C. etal

Retrospe ctive

Mean 52

Not mention. 40/43*

22/83 (26.5%)

Not mention 75 % *(mean 60

Venous thrombectomy+/

11%*(Early)

Anticoagulat ion

Not mention

20% *(mean 5 yrs)

2010 38 cohort SD 22/61 months) - AVFstudy. 18

yearsBlattler W. etal 200440

Two cohort studies

23,25yrs (Medi

MTS (7* ).

Not men tion

6/33 (18.2%) 6/27

SES 100%^(1year) 88%*

CDT +/-surgical thrombectomy

0%* (12months)

Anticoagulat ion

Not mention

3 % *(12 months)

(prospect an for . (8 yrs ).ive and cohorretrospec t 1tive). &2

respectively).

SES Self-expandable stents

BES Balloon expandable stents

*For the whole study population.

^For stented patients only within the study who had symptoms less than 14 days.

# For interventional group of patients within the study.

^^ The excluded stented patients in these studies had symptoms more than 14 days.

MTS; May Turner Syndrome , IVCS; Iliac Vein Compression Syndrome.

! Females !! Males !!! Ultrasound assisted catheter directed thrombolysis ( USAT), !^ Catheter Directed Thrombolysis CDT.

PMT Percutanous mechanical thrombolysis