Vascular & Endovascular Review Volume 5 2022

Contents

Combined Treatment of the Anterior Accessory Saphenous Vein and the Great Saphenous Vein

Harold J Welch https://doi.org/10.15420/ver.2021.07

Aetiology and Therapeutic Options of Acute Subclavian Vein Thrombosis

Gergana Todorova Taneva, Jaime Muñoz Castellanos and Konstantinos P Donas https://doi.org/10.15420/ver.2021.20

Stent Grafting for Aortoiliac Occlusive Disease: Review of the VBX FLEX Study

Nolan Mann, Hosam El Sayed and Jean Panneton https://doi.org/10.15420/ver.2021.12

Acute Deep Vein Thrombosis Involving the Inferior Vena Cava: Interventional Perspectives

Adham Abou Ali, Othman A Malak, Karim Salem, George Alkhoury, Natalie Sridharan, Rabih A Chaer1 and Efthymios Avgerinos https://doi.org/10.15420/ver.2021.08

Treatment of Non-thrombotic Iliac Vein Stenosis: Where is the Evidence?

Maria Joh and Kush R Desai https://doi.org/10.15420/ver.2021.11

A Clinical Trial of Venous Stent Placement for Post-thrombotic Syndrome: Current Status and Pandemic-related Changes

Suresh Vedantham, Sameer Parpia and Susan R Kahn https://doi.org/10.15420/ver.2021.19

Does Current Evidence Support Carotid Artery Stenting for Asymptomatic Patients?

Mustafa Abbas and Trevor Cleveland https://doi.org/10.15420/ver.2020.18

The Role of Renal Artery Embolisation in the Management of Blunt Renal Injuries: A Review

Rosemary Denning Ho, Vivek Shrivastava, Amir Mokhtari and Raghuram Lakshminarayan https://doi.org/10.15420/ver.2022.01

The Importance of Early Thrombus Removal

Jason Cottrell and Mitchell Silver https://doi.org/10.15420/ver.2021.10

A Framework for Developing a Comprehensive Venous Practice

Ryan M Cobb and Deepak Sudheendra https://doi.org/10.15420/ver.2022.06

Editor-in-Chief

Stephen Black

Guy’s and St Thomas’ Hospital, London, UK

Deputy Editor

Kush R Desai

Division of Interventional Radiology, Northwestern University, Feinberg School of Medicine, Chicago, IL, US

Section Editors

Aortic Andrew Choong

National University of Singapore, Singapore

Venous Rick de Graaf

Clinical Centre of Friedrichshafen, Friedrichshafen, Germany

Complex Endovascular Procedures

Konstantinos P Donas

Asklepios Klinik Langen, Goethe University, Frankfurt, Germany

Vascular Medicine

Raghu Kolluri Ohio Health, Columbus, OH, US

Roger Barranco Pons

Bellvitge University Hospital, Barcelona, Spain

Lukla Biasi

Guy’s and St Thomas’ NHS Foundation Trust, London, UK

Elias Brountzos

Attikon University General Hospital, Athens, Greece

Andrew Bullen Wollongong Hospital, Wollongong, Australia

Alessandro Cannavale

Policlinico Umberto I, Rome, Italy

Patrick Chong Frimley Health NHS Foundation Trust, Surrey, UK

Fabrizio D’Abate

St George’s University Hospital, London, UK

Brian G DeRubertis

David Gefffen School of Medicine at UCLA, CA, US

Stephen Dubenec Royal Prince Alfred Hospital, Sydney, Australia

Mert Dumantepe

Istanbul University, Istanbul, Turkey

Steve Elias

Englewood Hospital, Englewood, NJ, US

Fernando Gallardo University Hospital Complex of Santiago de Compostela, Santiago de Compostela, Spain

Antonios Gasparis

Stony Brook University Medical Center, Stony Brook, NY, US

Andrew Holden

Auckland City Hospital, Auckland, New Zealand

Editorial Board

Emad Hussein

Peripheral Artery Disease

Michael Lichtenberg

Klinikum Arnsberg, Karolinen Hospital, Arnsberg, Germany

Case Reports

Ashish Patel King’s College London, UK

Update of New Literature

Athanasios Saratzis

Leicester University and NIHR Leicester Biomedical Research Centre, Leicester, UK

Ain Shams University Hospital, Cairo, Egypt

Houman Jalaie University Hospital RWTH, Aachen, Belgium

Michael Jenkins

Imperial College Healthcare NHS Trust, London, UK

Narayan Karunanithy

Guy’s and St Thomas’ NHS Foundation Trust, London, UK

Miltiadis E Krokidis

1st Department of Radiology, Areteion University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

Nicos Labropoulos

Stony Brook University Medical Center, Stony Brook, NY, US

Raghuram Lakshminarayan Hull University Teaching Hospitals NHS Trust, Hull, UK

Martin Maresch

Bahrain Defence Force Royal Medical Services Hospital, Bahrain

Ross Milner

University of Chicago Medical Center, Chicago, IL, US

Hayley Moore

Frimley Health NHS Foundation Trust, Surrey, UK

Erin Murphy

The RANE Center at St Dominic’s Memorial Hospital, Jackson, MS, US

Abdullah Omari St Vincent’s Clinic, Sydney, Australia

Gerry O’Sullivan

University College Hospital, Galway, Ireland

Premal Patel

Great Ormond Street Hospital, London, UK

Lakshmi Ratnam

St George’s University Hospital, London, UK

Maria Antonella Ruffino

AOU Citta della Salute e della Scienza, Turin, Italy

Prakash Saha

King’s College Hospital, London, UK

Morad Sallam

Guy’s and St Thomas’ NHS Foundation Trust, London, UK

Jan Sloves

Mount Sinai Beth Israel Medical Center, New York, NY, US

Michael C Stoner

University of Rochester Medical Center, Rochester, NY, US

Sherif Sultan

National University of Ireland, Galway, Ireland

Gustaf Tegler

Uppsala University, Uppsala, Sweden

Sarah Thomis

UZ Leuven, Leuven, Belgium

Gergana Todorova Taneva

Puerta de Hierro and Monteprincipe University Hospitals, Madrid, Spain

Marie-Josee Van Rijn

Erasmus University Medical Center, Rotterdam, the Netherlands

Ramon Varcoe

Prince of Wales Hospital, Sydney, Australia

Emma Wilton

Oxford University Hospitals NHS Foundation Trust, Oxford, UK

Editorial

Publishing Director Leiah Norcott | Managing Editor Agnieszka Topolska

Production Editors Aashni Shah, Bettina Vine | Senior Graphic Designer Lewis Allen

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Leadership

Chief Executive Officer David Ramsey

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Combined Treatment of the Anterior Accessory Saphenous Vein and the Great Saphenous Vein

Harold J Welch

The Vascular Care Group, Hyannis, MA, US

Abstract

The anterior accessory saphenous vein (AASV) is a common source of primary and recurrent lower extremity varicose veins. Reflux in the AASV can occur independently or simultaneously with great saphenous vein (GSV) reflux. A number of published reports describe recommendations and treatment of symptomatic refluxing AASVs, but descriptions of combined treatment are sparse. Treatment options for ablation of the AASV include both thermal and non-thermal techniques, and results are equivalent to ablation of the great and small saphenous veins. Although not commonly performed, concomitant ablation of the AASV and the GSV is effective and safe, and can be accomplished with minimal additional time. Concomitant treatment is an appropriate option that should be discussed with the patient.

Keywords

Anterior accessory saphenous vein, great saphenous vein, ablation, combined treatment

Disclosure: The author has no conflicts of interest to declare.

Received: 7 July 2021

Accepted: 25 October 2021 Citation: Vascular & Endovascular Review 2022;5:e01. DOI: https://doi.org/10.15420/ver.2021.07

Correspondence: Harold J Welch, The Vascular Care Group, 100 Camp St, Hyannis, MA 02601, US. E: hwelch@vascularcaregrp.com

Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The truncal vein on the anterior aspect of the thigh has several names and abbreviations and is a common source of both primary and recurrent lower extremity varicose veins. Treatment options are similar to that for the other superficial truncal veins and can sometimes be performed concomitantly.

Nomenclature and Anatomy

The anterior accessory saphenous vein (AASV) or, as it is formally known, the anterior accessory of the great saphenous vein, is a clinically important source of primary and recurrent varicose veins.1 The anatomy of the AASV was examined with ultrasound in a comprehensive paper by Cavezzi et al.2 Of course, there is significant variation in the venous anatomy of the lower limb, but the AASV typically lies within a fascial compartment and forms an ‘eye sign’ on ultrasound, similar to the great saphenous vein (GSV). It usually lies anterior and lateral to the GSV as it ascends the thigh. The terminus of the AASV is also variable, but most commonly it joins the GSV within 2 cm of the saphenofemoral junction (SFJ).2 The anterior thigh circumflex vein is a tributary of the AASV (although sometimes the GSV) and courses superomedial in the thigh.

The vein under discussion has several names and abbreviations. It has been called the anterior accessory GSV, the accessory saphenous vein and the AASV.3–5 This can lead to some confusion, and perhaps is one of the reasons why insurance companies often do not routinely cover treatment of this vein, given that it is seen by them as being only an ‘accessory’ to the GSV and therefore is downplayed as not important. One suggestion is to eliminate the ‘accessory’ designation, and name this the anterior saphenous vein. That designation is for the future and beyond the scope of this article. For the sake of consistency in this article, it will be referred to as the AASV.

Clinical Significance and Treatment

As known to venous practitioners, the AASV has important clinical implications. Due to anatomic variation the AASV can communicate with the GSV below the terminal valve, and if the terminal valve is incompetent, there can be direct reflux into the AASV. Additionally, the AASV can drain directly into the common femoral vein, which can also lead to reflux down the AASV.6,7

Schul et al. published a recent paper examining the importance of the AASV in clinical practice, using data from the American Vein and Lymphatic Society PRO Venous Registry.8 Patients in the study were divided into two groups: the primary group had no prior vein treatment, and the progressive group had a superficial venous intervention at some previous point. There were no demographic differences between the groups. The authors compared patients with reflux in the GSV and those with reflux in the AASV. They found that reflux in the AASV is common in patients with both primary and recurrent disease, has similar disease severity compared with GSV reflux, and has a higher incidence of superficial thrombophlebitis compared with the GSV.8 It therefore should be considered equivalent to the GSV and small saphenous vein (SSV) when considered for intervention and reimbursement.

Endovenous ablation, either by thermal techniques or ultrasound-guided foam sclerotherapy, of the AASV is generally not commonly performed. Treatment of the AASV ranges from 3.8% to 9.8% of truncal superficial veins ablated in several series.9,10

Theivacumar et al. examined endovenous laser ablation (EVLA) of the AASV in patients with isolated AASV reflux and a competent GSV and compared them with a group with EVLA of the GSV.3 They found that EVLA

Great Saphenous Vein and Anterior Accessory Saphenous Vein

documentation of both GSV and AASV reflux has been identified, the decision to treat sequentially or concomitantly must be made. If treatment of both at the same time has been determined to be optimal for the patient, then one can proceed accordingly. Both veins are mapped with duplex ultrasound prior to prepping the leg.

The author proceeds with ablation of the GSV first. Given that the tumescent anaesthesia for the first vein ablation may compromise access to the second vein, it is suggested to gain access to both veins with a micro puncture kit and 4 Fr sheath, and instil the planned second vein sheath with injectable saline (Figure 1). After ablating the first vein (usually the GSV), attention is turned toward the second vein. Ablating the AASV after the GSV should add no more than 10 minutes to the procedure. Compression after the ablations should follow the recently published guidelines.18

of the AASV would abolish SFJ reflux and had equivalent improvement according to Aberdeen varicose vein symptom severity score, and patient satisfaction when compared with EVLA of the GSV.3 Cavallini et al. published a report of nine incompetent AASVs treated with EVLA and found that the venous clinical severity score improved from a mean of 3.2 before intervention to a mean of 0 at 17 months.11

One of the most common causes of recurrent varicose veins after GSV ablation or stripping is new reflux in the AASV. This was shown by Bush et al., with 24% of recurrent varicose vein patients having new AASV reflux, and O’Donnell et al., who showed that new AASV reflux was the cause of recurrent varicose veins in 19% of patients, second only to GSV recanalisation (32%).12,13

One explanation for this could be provided by an elegant study by Uhl et al.14 They dissected 400 limbs in 200 fresh cadavers and found lymph nodes between the GSV and the origin of the AASV, and identified dilated lymph node venous networks in approximately 15% of dissected cadavers.14 Another study investigated AASV reflux over time after radiofrequency ablation of incompetent GSVs and found that reflux in the AASV increased from 2% at baseline to 32% at 4 years.15

Baccellieri et al. examined the role of anatomy of the AASV at the SFJ and junctional reflux as a risk for recurrent varicose veins. Patients in group A had junctional (SFJ) and GSV reflux on ultrasound, while group B patients had only GSV reflux. After undergoing radiofrequency ablation of the GSV, a higher rate of recurrent varicose veins at 3 years was found in group A patients, and a direct confluence of the AASV at the SFJ was found to be a negative predictor for recurrent varicose veins.16 Attempting to mitigate such anatomic factors in recurrences after GSV endovenous ablation, Spinedi et al. published a report using a radial emitting laser fibre positioned at the SFJ, and had only one case of endovenous heat-induced thrombosis (EHIT) class 2 (0.8%) and one EHIT class 3 (0.8%). Although no follow-up information concerning recurrence was obtained, they concluded that the procedure is feasible and safe.17

After thorough patient evaluation, including symptom and venous history, physical examination, and duplex ultrasound examination, if

Most published studies concerning ablation of the AASV describe sole treatment of the AASV, or group the results with ablation of the GSV and SSV. A case report of combined treatment has been published.19 The author’s experience with combined treatment of both GSV and AASV is similar to others, that is to say, not very extensive. Eleven patients were treated concomitantly with 1,470 nm laser (0.67% of ablations): five of those patients also had concomitant phlebectomy, one had phlebectomy at a later date, and five patients required no further treatment. The average length of the treated AASV was 12.7 cm (range, 7–26 cm), and there were no instances of EHIT or deep vein thrombosis in those patients.20

An interesting concept has been proposed to potentially treat a nonrefluxing AASV concomitantly with ablation of a refluxing GSV in order to decrease the recurrent varicose veins that would arise from a future incompetent AASV.16,21 However, the 2020 appropriate use criteria state that ablation of AASV with no reflux, but GSV with reflux (CEAP classes 2–6) is rarely appropriate and ablation for a vein with no reflux is never appropriate.22

Reimbursement

As all vein practitioners know, the AASV can be the source of primary varicose veins in the setting of a normal, competent GSV. A number of health insurance payers in the US will not approve treatment of an AASV unless the GSV has been previously treated. This creates difficulties for the patient and practitioner when the GSV is normal, usually requiring repeated appeals for treatment.23

In the US, typical reimbursement for CPT code 36475 (laser ablation 1st vein) ranges from US$970 (£716; Medicare) to US$1,700–$2,500 (£1,256–£1,847) from private payers, and CPT code 36476 (laser additional vein) from approximately US$200 (£148; Medicare) to approximately US$500 (£369; private payers). Blue Shield of California insists that all refluxing truncal veins be treated in one session.24 Therefore, sometimes it is mandatory that combined treatment be performed.

Conclusion

The American Venous and Lymphatic Society published guidelines for the treatment of refluxing accessory saphenous veins in 2017. The recommendation was that symptomatic refluxing accessory saphenous veins be treated with thermal ablation or ultrasound-guided foam sclerotherapy to reduce symptomatology, with a recommendation grade of 1C. It also stated that further studies concerning the management of isolated accessory vein reflux are not necessary.25

Figure 1: Vein Access in Concomitant Treatment of the

Example of the set-up used to access both veins in the combined treatment of the great saphenous vein and the anterior accessory saphenous vein.

The AASV is a common source of both primary and recurrent lower extremity varicose veins and has been shown to be clinically equivalent to the GSV in terms of symptoms and the relief of those symptoms after treatment. Combined treatment of the AASV and GSV is not often

1. Caggiati A, Bergan JJ, Gloviczki P, et al. Nomenclature of the veins of the lower limb: extensions, refinements, and clinical application. J Vasc Surg 2005;41:719–24. https://doi. org/10.1016/j.jvs.2005.01.018; PMID: 15874941.

2. Cavezzi A, Labropoulos N, Partsch H, et al. Duplex ultrasound investigation of the veins in chronic venous disease of the lower limbs: UIP consensus document. Part II. Anatomy. Eur J Vasc Endovasc Surg 2006;31:288–99. https:// doi.org/10.1016/j.ejvs.2005.07.020; PMID: 16230038.

3. Theivacumar NS, Darwood RJ, Gough MJ. Endovenous laser ablation (EVLA) of the anterior accessory great saphenous vein (AAGSV): abolition of the sapheno-femoral reflux with preservation of the great saphenous vein. Eur J Vasc Endovasc Surg 2009;37:477–81. https://doi.org/10.1016/J. EJVS.2008.11.035; PMID: 19201621.

4. Gibson K, Ferris B. Cyanoacrylate closure of incompetent great, small and accessory saphenous veins without the use of post-procedure compression: initial outcomes of a postmarket evaluation of the VenaSeal System (the WAVES study). Vascular 2017;25:149–56. https://doi. org/10.1177/1708538116651014; PMID: 27206470.

5. Chaar CI, Hirsh SA, Cwenar MT, et al. Expanding the role of endovenous laser therapy: results in large diameter saphenous, small saphenous, and anterior accessory veins. Ann Vasc Surg 2011;25:656–61. https://doi.org/10.1016/j. avsg.2011.02.031; PMID: 21724104.

6. Muhlberger D, Morandini L, Brenner E. Venous valves and major superficial tributary veins near the saphenofemoral junction. J Vasc Surg 2009;49:1562–9. https://doi. org/10.1016/j.jvs.2009.02.241; PMID: 19497520.

7. Chun MH, Han SH, Chung JW, et al. Anatomical observation on draining patterns of saphenous tributaries in Korean adults. J Korean Med Sci 1992;7:25–33. https://doi. org/10.3346/jkms.1992.7.1.25; PMID: 1418759.

8. Schul MW, Vayuvegula S, Keaton TJ. The clinical relevance of anterior accessory great saphenous vein reflux. J Vasc Surg Venous Lymphat Disord 2020;8:1014–20. https://doi. org/10.1016/j.jvsv.2020.02.010; PMID: 32205127.

9. Ravi R, Trayler EA, Barrett DA, Diethrich EB. Endovenous thermal ablation of superficial venous insufficiency of the lower extremity: single-center experience with 3000 limbs treated in a 7-year period. J Endovasc Ther 2009;16:500–5.

performed, but if concomitant reflux is identified in both the AASV and GSV on duplex ultrasound, the decision to perform staged or concomitant ablation of both truncal veins may be dictated by insurance companies, or warrants, at the very least, discussion between the provider and patient.

https://doi.org/10.1583/09-2750.1; PMID: 19702351.

10. Bradbury AS, Bate G, Pang K, et al. Ultrasound-guided foam sclerotherapy is a safe and clinically effective treatment for superficial venous reflux. J Vasc Surg 2010;52:939–45. https://doi.org/10.1016/j.jvs.2010.04.077; PMID: 20638224.

11. Cavallini A, Marcer D, Ferrari Ruffino S. Endovenous treatment of incompetent anterior accessory saphenous veins with a 1540 nm diode laser. Int Angiol 2015;34:243–9. PMID: 24945916.

12. Bush RG, Bush P, Flanagan J, et al. Factors associated with recurrence of varicose veins after thermal ablation: results of the Recurrent Veins after Thermal Ablation Study. ScientificWorldJournal 2014;2014:505843. https://doi. org/10.1155/2014505843; PMID: 24592172.

13. O’Donnell TF, Balk EM, Dermody M, et al. Recurrence of varicose veins after endovenous ablation of the great saphenous vein in randomized trials. J Vasc Surg Venous Lymphat Disord 2016;4:97–105. https://doi.org/10.1016/j. jvsv.2014.11.004; PMID: 26946904.

14. Uhl JF, Lo Vuolo M, Labropoulos N. Anatomy of the lymph node venous networks of the groin and their investigation by ultrasonography. Phlebology 2016;31:334–43. https://doi. org/10.1177/0268355515585039; PMID: 26060061.

15. Proebstle T, Mohler T. A longitudinal single-center cohort study on the prevalence and risk of accessory saphenous vein reflux after radiofrequency segmental thermal ablation of great saphenous veins. J Vasc Surg Venous Lymphat Disord 2105;3:265–9. https://doi.org/10.1016/j.jvsv.2014.10.001; PMID: 26992304.

16. Baccellieri D, Ardita V, Carta N, et al. Anterior accessory saphenous vein confluence anatomy at the saphenofemoral junction as risk factor for varicose veins recurrence after great saphenous vein radiofrequency thermal ablation. Int Angiol 2020;39:105–11. https://doi.org/10.23736/S03929590.20.04271-6; PMID: 32043339.

17. Spinedi L, Stricker H, Keo HH, et al. Feasibility and safety of flush endovenous laser ablation of the great saphenous vein up to the saphenofemoral junction. J Vasc Surg Venous Lymphat Disord 2020;8:1006–13. https://doi.org/10.1016/j. jvsv.2020.01.017; PMID: 32284310.

18. Lurie F, Lal BK, Antignani PL, et al. Compression therapy after invasive treatment of superficial veins of the lower

extremities: clinical practice guidelines of the American Venous Forum, Society for Vascular Surgery, American College of Phlebology, Society for Vascular Medicine, and International Union of Phlebology. J Vasc Surg Venous Lymphat Disord 2019;7:17–28. https://doi.org/10.1016/j. jvsv.2018.10.002; PMID: 30554745.

19. Basgu HS, Bitargil M, Ozisik K. Isolated insufficiency of the anterior accessory saphenous vein: should it be treated alone? Cardiovascular Surgery and Interventions 2015;2:36–9. https://doi.org/10.5606/e-cvsi.2015.362

20. Welch HJ. Combined treatment of GSV and AAGSV. Presented at: 2022 Venous Symposium (Virtual). 15 April 2022. http://www.venous-symposium.com/virtual-program/

21. Muller L, Alm J. Feasibility and potential significance of prophylactic ablation of the major ascending tributaries in endovenous laser ablation (EVLA) of the great saphenous vein: a case series. PLoS ONE 2021;16:e0245275. https://doi. org/10.1371/journal/pone.0245275; PMID: 33412566.

22. Masuda EM, Ozsvath K, Vossler J, et al. The 2020 appropriate use criteria for chronic lower extremity venous disease of the American Venous Forum, the Society for Vascular Surgery, the American Venous and Lymphatic Society, and the Society of Interventional Radiology. J Vasc Surg Venous Lymphat Disord 2020;8:505–25. https://doi. org/10.1016/j.jvsv.2020.02.001; PMID: 32139328.

23. Welch HJ, Schul MW, Monahan DL, Iafrati MD. Private payers’ varicose vein policies are inaccurate, disparate, and not evidence based, which mandates a proposal for a reasonable and responsible policy for the treatment of venous disease. J Vasc Surg Venous Lymphat Disord 2021;9:820–32. https://doi.org/10.1016/j.jvsv.2020.12.076; PMID: 33684590.

24. Blue Shield of California. Treatment of varicose veins/ venous insufficiency. Policy Statement. https://www. blueshieldca.com/bsca/bsc/public/common/ PortalComponents/provider/StreamDocumentServlet?fileNa me=PRV_TX_Varicose_Venous_Insufficiency.pdf (accessed 28 June 2021).

25. Gibson K, Khilnani N, Schul M, Meissner M. American College of Phlebology guidelines: treatment of refluxing accessory saphenous veins. Phlebology 2017;32:448–52. https://doi.org/10.1177/0268355516671624; PMID: 27738242.

Aetiology and Therapeutic Options of Acute Subclavian Vein Thrombosis

Gergana T Taneva , 1,2 Jaime Muñoz Castellanos2 and Konstantinos P Donas 2

1. Vascular Surgery Department, Puerta de Hierro and Montepríncipe University Hospitals, Madrid, Spain;

2. Vascular Surgery Department, Asklepios Klinik Langen, Frankfurt, Germany

Disclosure: GTT and KPD are on the Vascular & Endovascular Review editorial board; this did not influence acceptance. JMC has no conflicts of interest to declare.

Keywords: Subclavian vein thrombosis, Paget–Schroetter syndrome, pharmacomechanical thrombectomy, anticoagulation therapy, deep vein thrombosis treatment, thoracic outlet syndrome

Received: 2 November 2021 Accepted: 6 December 2021 Citation: Vascular & Endovascular Review 2022;5:e02. DOI: https://doi.org/10.15420/ver.2021.20

Correspondence: Gergana T Taneva, Department of Vascular and Endovascular Surgery, Asklepios Klinik Langen, University of Frankfurt, Röntgenstraße 20, 63225 Langen, Germany. E: dr.gtaneva@gmail.com

Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Dear Editor,

We read with interest the two largest registries with multiple studies on upper extremity deep vein thrombosis (UEDVT), namely RIETE and the Japanese COMMAND registries, and consider the importance of reflecting on this matter.1–4

UEDVT is a relatively rare phenomenon, accounting for up to 10% of all deep vein thrombosis (DVT).1–5 Its incidence increases in hospitalised patients, and is often related to central venous catheters.1–5 To better understand the mechanism of thrombus formation at this specific anatomical level, subclavian DVT has been categorised as primary and secondary.6

Primary subclavian DVT, also called effort-thrombosis, is common in young, healthy individuals who play sport or have occupational activities that require repetitive movements elevating the shoulders and arms. The neurovascular bundle is repetitively compressed between the first rib and anterior scalene muscle from below, and the clavicle, subclavius muscle and costocoracoid ligament from above, causing what is known as thoracic outlet syndrome (TOS).6 Due to the anatomical disposition, neurological symptoms are the most frequent symptoms described in more than 90% of cases.7 Venous TOS, also known as Paget–Schroetter syndrome, occurs less frequently, with no thrombus formation or subclavian vein thrombosis. Venous TOS prevails in the dominant arm, with an equal sex ratio, as described more recently.8 Arterial compression symptoms are even more rare.

Secondary thrombosis of the subclavian and axillary veins is a more frequent phenomenon often related to peripherally inserted central venous catheters, tunnelled catheters, subcutaneous ports and pacemaker wires.6 The ongoing presence of the catheter causes intimal venous wall irritation and inflammation, which can finally lead to thrombosis. Catheter-induced venous thrombosis is relatively frequent, occurring in 5% of central venous catheters with an estimated prevalence of two cases per 1,000 hospital admissions.9 Cancer, hypercoagulable states, congestive heart failure, mediastinal tumours, local surgery or trauma and nephrotic syndrome conditions can also cause secondary subclavian DVT. Several other factors have proved to increase the risk for

DVT. For example, the presence of pacemaker wires with ejection fraction <40% increases the incidence of venous thrombosis.10 Cancer patients have an eightfold higher risk of presenting UEDVT, whereas obese patients undergoing surgery have a 23-fold increased risk for UEDVT versus non-obese patients.6,11

A total of 9% of primary subclavian DVT and 33–60% of secondary subclavian DVT can be asymptomatic. The most common signs are arm swelling and heaviness, and, occasionally, cyanosis, pain and venous claudication. Dilated superficial collateral veins are often present over the shoulder in search of venous hypertension relief.6 Since clinical findings of UEDVT are non-specific and can be misleading, differential diagnosis spans through arm lymphoedema, muscle haematoma and external venous compression.6

Pulmonary embolism (PE) occurs in 12% of patients with primary subclavian DVT. However, the risk for PE rises in patients with catheter-induced subclavian DVT to 15–25% of the cases, with PE being the second most common cause of death in patients with cancer.9 Oncological patients also have more complications and reduced quality of life.2 Post-thrombotic syndrome presenting as persistent oedema and pain has been described in 7% of patients.1 The development of phlegmasia cerulea dolens is extremely rare in both groups, mostly being described in oncological patients and hypercoagulable states.1

The recognition of clinical signs and symptoms will be followed by definitive imaging studies.

Duplex ultrasound (DUS), a non-invasive, low-cost, and highly available method with high sensitivity (81–100%) and specificity (82–100%), is the most frequently used diagnostic modality and first step imaging method to confirm UEDVT.6 However, DUS examination is a subjective method with variable accuracy depending on the operator’s experience.

The gold standard is the performance of venography. Although, it is an invasive method requiring contrast medium use, radiation exposure and cannulation of a vein in the affected arm, which can sometimes be impossible due to arm swelling. Venography is only performed when DUS

seems equivocal. Magnetic resonance venography is a non-invasive alternative method correlating well with venography.9 Magnetic resonance venography presumes time delay and availability. Thus, in patients with high clinical suspicion where no other studies can be performed, the use of CT venography is indicated, especially if PE is suspected.

Anticoagulation alone, rest, and arm elevation in patients with primary subclavian DVT have been associated with high residual functional impairment, significant long-term morbidity and disability.6 Venous TOS patients are at significant risk for rethrombosis.12 Thus, thrombolytic therapy emerged as the preferred initial management of venous TOS, followed by surgical decompression. In secondary subclavian DVT, most patients improve with systemic anticoagulation for 3 months and catheter removal. In the case of axillo-subclavian DVT extension and severe symptoms, thrombolysis may be indicated.

Thrombolysis should be performed <14 days after the onset of the symptoms. Thrombolytic therapy can be catheter-directed with local infusion of thrombolytic agents for usually <48 hours, or employing thrombectomy devices. Through basilic vein DUS-guided puncture, a wire is advanced crossing the thrombus. Then, a multiperforated catheter is left to instil physician-specified fluids, usually urokinase.

Thrombectomy devices are more costly, but avoid the side-effects of continuous urokinase infusion, such as cerebral bleeding, while allowing rapid thrombus maceration and aspiration. Several devices are available on the market. The AngioJet PE system (Boston Scientific) functions on the principle of the Venturi effect. It is a rheolytic thrombectomy device that aspirates the generated thrombus fragments after local infusion of urokinase. High-pressure saline is infused through a distal catheter pore while simultaneously aspirated through an adjacent pore.6 The generated high-flow pressure not only fragments the thrombus, but also destroys blood cells producing haemolysis. Thus, a certain degree of haematuria or frank haematuria are relatively common after treatment with the AngioJet System. However, acute kidney failure has been described in several reports.13,14 Another thrombectomy device is the Indigo System (Penumbra). This device is advanced and retracted through the CAT catheter to the proximal edge of the thrombus to facilitate the clearing and aspiration. The Rotarex/Aspirex devices (Straub Medical) hold a rotational debulking catheter to fragmentate the cloth and aspirate it, generating negative pressure.

1. Muñoz FJ, Mismetti P, Poggio R, et al. Clinical outcome of patients with upper-extremity deep vein thrombosis: results from the RIETE registry. Chest 2008;133:143–8. https://doi. org/10.1378/chest.07-1432; PMID: 17925416.

2. Monreal M, Munoz FJ, Rosa V, et al. Upper extremity DVT in oncological patients: analysis of risk factors. Data from the RIETE registry. Exp Oncol 2006;28:245–7. PMID: 17080021.

3. Rosa-Salazar V, Trujillo-Santos J, Díaz Peromingo JA, et al. A prognostic score to identify low-risk outpatients with acute deep vein thrombosis in the upper extremity. J Thromb Haemost 2015;13:1274–8. https://doi.org/10.1111/jth.13008; PMID: 25980766.

4. Newton DH, Monreal Bosch M, Amendola M, et al. Analysis of noncatheter-associated upper extremity deep venous thrombosis from the RIETE registry. J Vasc Surg Venous Lymphat Disord 2017;5:18–24.e1. https://doi.org/10.1016/j. jvsv.2016.08.002; PMID: 27987605.

5. Woller SC, Stevens SM, Johnson SA, et al. Apixaban for Routine Management of upper extremity Deep Venous Thrombosis (ARM-DVT): methods of a prospective singlearm management study. Res Pract Thromb Haemost

Unsuccessful thrombolytic treatment is rare, being described in patients with rethrombosis and chronic DVT. Anticoagulation and measures to address pain, such as arm elevation, rest and compression, should be applied in these patients. Aggressive surgical treatment in these patients has shown variable results.6

When successful re-establishment of axillo-subclavian patency is achieved, positional venography with arm separation would diagnose patients with TOS compression. If there is a remaining venous stenosis, percutaneous balloon angioplasty with or without stenting can be performed. The results of subclavian stenting without thoracic outlet decompression are poor, with a 1-year primary patency of 35%, and a high compression, fracture and thrombosis risk for stents underneath the clavicle. Thus, stenting before surgical decompression in venous TOS plays no role.6 Some venous stenosis is resistant to dilatation due to intrinsic elastic recoil. Venous TOS patients would benefit from surgical decompression. In patients without extrinsic venous compression, 3–6 months of anticoagulation therapy is indicated.6

Some authors recommend immediate surgical decompression as early as 4 hours after thrombolysis to avoid vein rethrombosis.6 However, systemic anticoagulation treatment avoids rethrombosis risk while awaiting elective surgery to be performed no later than 1 month after thrombolysis. Surgical decompression involves resection of the cervical rib, if present, first rib, anterior scalene muscle and any other anatomical abnormalities as fibromuscular bands, and soft tissue defects. Mainly paraclavicular and transaxillary surgical approaches are favoured. The transaxillary approach allows visualisation of the first rib for resection, whereas the paraclavicular approach (supra- or infraclavicular) facilitates cervical rib, first rib and any other anatomical abnormalities resection.

Finally, UEDVT management depends on the aetiological process. In the presence of external compression, as in venous TOS, thrombolysis and surgical decompression are indicated. Secondary DVT is generally treated by systemic anticoagulation and catheter removal. Comfort measures are indicated for symptomatic patients. The risk of recurrence seems similar when comparing upper extremity and lower extremity DVT, whereas allcause mortality is significantly higher in the UEDVT group than the lower extremity DVT group (p=0.0338) according to the GARFIELD-VTE registry.4,15 This latter finding was likely due to the high prevalence of cancer in the UEDVT group.15

2019;3:340–8. https://doi.org/10.1002/rth2.12208; PMID: 31294320.

6. Cronenwett JL, Johnston KW. Rutherford’s Vascular Surgery Volume two. 7th ed. London: Saunders Elsevier, 2010.

7. Sanders RJ, Hammond SL, Rao NM. Diagnosis of thoracic outlet syndrome. J Vasc Surg 2007;46:601–4. https://doi. org/10.1016/j.jvs.2007.04.050; PMID: 17826254.

8. Hurlbert SN, Rutherford RB. Subclavian-axillary vein thrombosis. In: Rutherford RB (ed). Vascular Surgery Philadelphia, PA: WB Saunders, 2000, 1208–221.

9. Sajid MS, Ahmed N, Desai M, et al. Upper limb deep vein thrombosis: a literature review to streamline the protocol for management. Acta Haematol 2007;118:10–18. https://doi. org/10.1159/000101700; PMID: 17426392.

10. Malhotra S, Punia VPS. Upper extremity deep vein thrombosis. J Assoc Physicians India 2004;52:237–41. PMID: 15636316.

11. Blom JW, Doggen CJM, Osanto S, Rosendaal FR. Old and new risk factors for upper extremity deep venous thrombosis. J Thromb Haemost 2005;3:2471–8. https://doi. org/10.1111/j.1538-7836.2005.01625.x; PMID: 16241945.

12. Schneider DB, Dimuzio PJ, Martin ND, et al. Combination treatment of venous thoracic outlet syndrome: open surgical decompression and intraoperative angioplasty. J Vasc Surg 2004;40:599–603. https://doi.org/10.1016/j.jvs.2004.07.028;

PMID: 15472583.

13. Escobar GA, Burks D, Abate MR, et al. Risk of acute kidney injury after percutaneous pharmacomechanical thrombectomy using AngioJet in venous and arterial thrombosis. Ann Vasc Surg 2017;42:238–45. https://doi. org/10.1016/j.avsg.2016.12.018; PMID: 28412100.

14. Shen Y, Wang X, Jin SS, et al. Increased risk of acute kidney injury with percutaneous mechanical thrombectomy using AngioJet compared with catheter-directed thrombolysis. J Vasc Surg Venous Lymphat Disord 2019;7:29–37. https://doi. org/10.1016/j.jvsv.2018.06.016; PMID: 30442579.

15. Ageno W, Haas S, Weitz JI, et al. Upper extremity DVT versus lower extremity DVT: perspectives from the GARFIELD-VTE registry. Thromb Haemost 2019;119:1365–72. https://doi.org/10.1055/s-0039-1688828; PMID: 31183844.

Stent Grafting for Aortoiliac Occlusive Disease: Review of the VBX FLEX Study

Nolan Mann, Hosam El Sayed and Jean Panneton

Division of Vascular Surgery, Eastern Virginia Medical School, Norfolk, VA, US

Abstract

Endovascular treatment has become an accepted method in the treatment of aortoiliac occlusive disease. Bare metal stents have been used in the treatment of aortoiliac disease since the early 1990s. More recently, the use of covered stent grafts in the aortoiliac segment has shown clinical benefit in terms of patency, freedom from reintervention and quality of life. The VBX FLEX study evaluated the safety and efficacy of the Gore VBX stent graft for use in the aortoiliac segment. The early and mid-term data on the Gore VBX stent graft have shown it to be a safe device for use in the treatment of aortoiliac occlusive disease. This review examines the use of stents in aortoiliac occlusive disease with specific focus on the VBX FLEX Study.

Keywords

Aortoiliac occlusive disease, common iliac stent, covered stent, balloon expandable, VBX, VBX FLEX study

Disclosure: JP is a consultant for WL Gore and Getinge. All other authors have no conflicts of interest to declare.

Received: 7 September 2021 Accepted: 11 January 2022 Citation: Vascular & Endovascular Review 2022;5:e03. DOI: https://doi.org/10.15420/ver.2021.12

Correspondence: Jean M Panneton, EVMS Division of Vascular Surgery, Sentara Heart Hospital, 600 Gresham Drive, Suite 8620, Norfolk, VA 23507, US.

E: PannetJM@EVMS.edu

Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Peripheral artery disease (PAD) is a significant global health issue affecting more than 200 million people worldwide.1 Aortoiliac occlusive disease (AIOD) is implicated in approximately one-third of cases of PAD.2 Treatment of this segment has largely been guided by the Trans-Atlantic Inter-Society Consensus (TASC) II guidelines: endovascular treatment with stenting is recommended for less advanced AIOD, specifically TASC II A and B lesions, whereas surgery is recommended for more advanced lesions (TASC II C and D).3 The treatment of these advanced lesions has been challenged by recent practice guidelines and consensus recommendations that now generally advocate for an endovascularfirst strategy.4

Advances in endovascular techniques and technology have allowed the treatment of more extensive iliac lesions, and current endovascular treatment of AIOD often involves primary stenting unilaterally or the use of kissing iliac stents for disease involving the aortic bifurcation.

Evolution of Endovascular Treatment of the Iliac Segment

Endovascular treatment of the iliac segment was largely limited to angioplasty alone through the late 1980s and early 1990s. The first major experience from Palmaz et al. demonstrated both the safety and efficacy of balloon-expandable stent placement in the iliac segment.5–7 This landmark paper laid the foundation for the transition of treatment of the aortoiliac segment from primarily surgical to an endovascular approach.5

Selective Stenting Versus Primary Stenting

Many studies have followed the initial reports of Palmaz et al. and have reiterated favourable results of selective stent placement in lesions

refractory to angioplasty alone. The 1998 Dutch Iliac Stent trial was a randomised comparison of primary iliac stenting and selective iliac stenting in the case of residual stenosis after angioplasty in 279 patients.8 The investigators demonstrated equivalent iliac patency at 2 years between the two groups and greater cost efficiency in the selective stenting group. However, the majority of these lesions were TASC A and B, 43% of patients in the selective group required stenting for suboptimal outcome with angioplasty alone, and there was an increased complication rate in the selective stenting group (7% versus 4%).8

In a more recent study, AbuRahma et al. demonstrated superior clinical success with primary stenting over selective stenting in TASC C and D lesions.9 In that study, 110 consecutive patients with 149 iliac lesions underwent primary iliac stenting. These patients were compared to a cohort of 41 patients with 41 iliac lesions who had angioplasty followed by selective stenting if there was a suboptimal percutaneous transluminal angioplasty result. The study found that there was comparable initial and late clinical success in TASC A and B lesions.9 However, in TASC C and D lesions, primary stenting was superior to selective stenting with early clinical success of 93% versus 46% and late clinical success of 84% versus 46%.8 It was also noted that the selective stenting group had a significantly higher rate of perioperative complications than the group undergoing primary stenting (24% versus 2.7%).9 There were 10 complications in the selective stenting group, which included seven cases of early postintervention iliac artery thrombosis, one case of postintervention deep venous thrombosis, one episode of postoperative bleeding requiring surgery and one case of superficial cellulitis.9 In the primary stenting group there were three complications, all of which were minor postintervention haematomas.9

A large meta-analysis by Ye et al., in which 16 reports were reviewed with a total of 958 patients, showed a superior primary patency rate for primary stenting compared with selective stenting for TASC C and D aortoiliac lesions.10

The STAG trial randomised 112 patients to primary stenting (n=57) or angioplasty (n=55) for iliac artery occlusion.11 There was a significant difference in the technical success rate between the angioplasty and primary iliac stenting groups (84% versus 98%, respectively).11 In addition, there was a significant difference in the rate of major complications, which was 20% in the angioplasty group compared with 5% in the stenting group.11

Together, the data support the use of primary iliac stenting in the case of more advanced aortoiliac lesions, not only because of its superior technical success and superior early and late clinical outcomes, but also because of the significantly lower complication rates.

Covered Versus Uncovered Iliac Stents

The long-term efficacy of bare metal stents is generally accepted to be limited due to progressive narrowing of the luminal diameter as a result of neointimal hyperplasia. Conversely, covered stents are designed to exclude the diseased vessel wall and prevent in-stent restenosis from intimal hyperplasia, leading to improved long-term patency.

The COBEST trial was a prospective randomised controlled trial including 125 patients with 168 individual iliac artery lesions randomised to receive a covered balloon-expandable stent or a bare metal stent.12 The investigators found that patients treated with covered stents were more likely to remain free of restenosis at 18 months, with a hazard ratio of 0.35. In addition, they noted that this benefit was more significant when using covered stents for TASC C and D aortoiliac lesions.12 Sabri et al. reported similar findings when the placement of comparing bare metal and covered stents for aortic bifurcation disease.13

The COBEST investigators published 5-year durability data in 2016.14 These data indicated that covered stents offered significantly higher patency rates than bare-metal stents at 18, 24, 48 and 60 months (95.1%, 82.1%, 79.9% and 74.7% versus 73.9%, 70.9%, 63% and 62.5%, respectively).14 Patients who received a covered stent also required fewer target limb revascularisations than those who received a bare metal stent and enjoyed sustained improvement in the ankle–brachial index (ABI).14 However, as expected, this did not lead to a significant difference in major

amputation rate because most of the patients enrolled in the study were claudicants.14

Results of the ongoing double-blinded, randomised DISCOVER trial are awaited for comparison to the COBEST trial.15

Comparison of Covered Stents for Aortoiliac Segment

The COBEST trial was performed with the Advanta V12 covered stent (Atrium Medical), which is expanded polytetrafluoroethylene (ePTFE) encapsulated and mounted on a non-compliant balloon. This was the first covered balloon-expandable stent with an indication for use in the aortoiliac segment outside the US. There are currently three balloonexpandable covered stents available for the treatment of AIOD in the US: the LifeStream (BD/Bard Peripheral Vascular), the iCAST/Advanta V12 (Getinge) and the Gore VBX (WL Gore and Associates).

The BOLSTER trial evaluated the efficacy of the LifeStream stent.15 This is a balloon-expandable, ePTFE-encapsulated stainless steel stent. The trial results were promising, with primary patency of 89.1% at 9 months and overall improvement in quality of life.16

The iCARUS trial examined the iCAST stent in the aortoiliac segment.17 The iCAST has a similar design to the LifeStream stent, being an ePTFEencapsulated stainless steel stent. Early results were impressive, with a freedom from target lesion revascularisation (TLR) rate of 97.2% at 9 months and 86.6% at 3 years.17 A sustained clinical improvement was noted in the trial population at the 3-year mark. It is notable that there was a low percentage of TASC C and D lesions (5.8%) in that study.17

The most recent trial, the VBX FLEX study, was an industry-sponsored trial conducted at 26 sites in the US and one site in New Zealand to assess the safety and efficacy of the VBX stent graft for use in AIOD.18 The VBX stent graft is unique in that it is composed of independent stainless steel rings connected by graft material (Figure 1). It is the only peripheral stent graft without longitudinal struts. This allows for increased flexibility while maintaining shape and luminal diameter. The stent also has high radial strength, is resistant to foreshortening, has considerable ability to post dilate and can be accurately placed. The device’s deployment balloon also has an elastomer film that improves device sequestration while tracking, preventing inadvertent stent dislodgement. In addition, the luminal surface has covalent heparin bonding. The results of the initial study were published in 2017.18 The 3-year follow-up outcomes have recently been published.19

VBX FLEX Study Overview

The VBX FLEX study was an industry-sponsored prospective multicentre single-arm clinical trial conducted in the US (26 centres) and New Zealand (one centre) with the intention of evaluating the safety and efficacy of the Gore VBX stent graft for the treatment of iliac lesions.18 Patients with Rutherford Class 2–4 disease with at least one de novo or restenotic target lesion >50% were included. In addition, patients were required to have at least one sufficient (<50% stenosis) infrapopliteal run-off vessel that did not require treatment. Anatomical exclusion criteria included lesions that would require atherectomy to facilitate device delivery or coverage of the internal iliac artery. Between December 2013 and August 2015, 234 stent grafts were implanted in 134 patients (mean age 66 years; 79 men) across 213 lesions. After implantation of the VBX stent graft, patients underwent clinical evaluations that included duplex ultrasound, ABI measurements, Rutherford classification assessments and a walking

Figure 1: GORE VIABAHN VBX BalloonExpandable Endoprosthesis

For complete device information, including approved indications and safety instructions, see manufacturer’s instructions for use.21 Reproduced with permission from WL Gore and Associates.

impairment questionnaire at each follow-up visit at 1, 9, 12, 24 and 36 months.

The primary endpoint of the VBX FLEX study was major adverse events within 30 days, MI within 30 days, TLR within 9 months and amputation above the metatarsals in the treated leg within 9 months. Secondary endpoints were acute procedural success (<30% residual stenosis prior to procedure completion), 30-day clinical success (improvement of at least one Rutherford category at the first follow-up), primary, assisted primary and secondary patency rates at 1 year, freedom from TLR, freedom from clinically driven TLR (CD-TLR), freedom from target vessel revascularisation (TVR), freedom from clinically driven TVR, change in Rutherford category, ABI and functional status at up to 3 years.

VBX FLEX Study Results

Procedural Characteristics

Half the study population received bilateral iliac stents, many of which had aortic bifurcation disease requiring a kissing stent procedure (Figure 2); 15.4% of patients had stents placed in the external iliac artery alone.18 Total occlusions were found in 28 of 210 lesions (13.3%). There was 100% technical success with an overall median change in device length from predeployment to final implantation of −0.05 mm, indicating a high degree of resistance to foreshortening.

Early Results

The primary endpoints of the VBX FLEX study included a 97.7% rate of freedom from TLR within 9 months, a 2.3% major adverse events rate, no MIs, no device or procedure-related deaths and no major amputations within 9 months. The 9-month composite primary endpoint for the overall study population was 2.3% (three TLRs), which is well below the 17% performance goal. On subgroup analysis, those receiving kissing stents had a 9-month composite primary endpoint of 3.5% (two TLRs).

Secondary endpoint data reported a primary patency rate of 96.7% at 9 months for the entire cohort. Notably, the primary patency between TASC A/B versus C/D was not significantly different at 97.4% and 95.3%, respectively. Further, 4.6% of patients had an improvement in their Rutherford classification and mean ABI improved from 0.77 to 0.97 at 9 months, with associated improvements in walking impairment scores.

Mid-term Results

Three-year data from the VBX FLEX study demonstrated continued midterm benefit in the study population.19 Freedom from TLR on a per-lesion basis was 91.2% (18 TLRs) at 36 months. The freedom from CD-TLR estimate was 98.1% (four CD-TLRs) at 36 months. In addition, 94.6% of patients had an improvement in their Rutherford category at 9 months, and this benefit was sustained out to 3 years. The mean ± SD improvement in ABI was measured at 0.17 ± 0.26 at 3 years, with more than 85% of

1. Shu J, Santulli G. Update on peripheral artery disease: epidemiology and evidence-based facts. Atherosclerosis 2018;275:379–81. https://doi.org/10.1016/j. atherosclerosis.2018.05.033; PMID: 29843915.

2. Rueda CA, Nehler MR, Perry DJ, et al. Patterns of artery disease in 450 patients undergoing revascularization for critical limb ischemia: implications for clinical trial design. J Vasc Surg 2008;47:995–9. https://doi.org/10.1016/j. jvs.2007.11.055; PMID: 18372151.

3. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg 2007;45(Suppl S):S5–67. https://doi.org/10.1016/j.jvs.2006.12.037; PMID: 17223489.

4. Society for Vascular Surgery Lower Extremity Guidelines

Figure 2: Sample Case of Bilateral Common Iliac Lesions

patients noting improved health status and walking impairment scores out to 3 years.

On univariate analysis, TLR was associated with women compared with men (16.4% versus 2.5%, respectively; p=0.008), the number of treated segments (1.7% for one segment versus 13.3% for two to three segments; p=0.023) and the number of devices required (2.0%, 10.1% and 21.4% for one, two and three or more devices, respectively; p=0.013).

Study Conclusion

The short- and mid-term data from the VBX FLEX study demonstrate that the VBX stent graft is a safe and durable treatment for complex AIOD. There is enduring clinical improvement and a low rate of re-intervention at 3 years.

Conclusion

Endovascular stenting has become commonplace in the aortoiliac segment. The COBEST trial is the only randomised trial to compare covered and non-covered stents in the aortoiliac segment. That trial demonstrated that, in the treatment of TASC A and B lesions, covered and non-covered stents have equivalent efficacy; however, for more complex TASC C and D lesions, covered stents have better efficacy.12 The Gore VBX stent graft offers another tool for the endovascular management of AIOD. Its unique design offers increased flexibility, high radial strength, accuracy in deployment and resistance to foreshortening. When framing the VBX stent graft in the context of the two other devices approved in the US, namely the Bard LifeStream and Atrium iCAST covered stent grafts, they all offer very similar immediate technical success and patency rates at both the 9-month and 3-year marks.16–20 However, the VBX FLEX study population had a higher proportion of TASC C and D lesions, which indicates sustained high performance for treating more advanced disease.18 The iCAST stent graft is the only covered stent graft for which long-term outcomes data are available, with a documented primary patency of 74.7% at 5 years.20 It remains to be seen how the long-term durability of the VBX stent will compare.

Writing Group, Conte MS, Pomposelli FB, et al. Society for Vascular Surgery practice guidelines for atherosclerotic occlusive disease of the lower extremities: management of asymptomatic disease and claudication. J Vasc Surg 2015;61(3 Suppl):2S–41S. https://doi.org/10.1016/j. jvs.2014.12.009; PMID: 25638515.

5. Palmaz JC, Richter GM, Nöldge G, et al. Intraluminal Palmaz stent implantation. The first clinical case report on a balloon-expanded vascular prosthesis. Radiologe 1987;27:560–3 [in German]. PMID: 2964053.

6. Palmaz JC, Richter GM, Noeldge G, et al. Intraluminal stents in atherosclerotic iliac artery stenosis: preliminary report of a multicenter study. Radiology 1988;168:727–31. https://doi. org/10.1148/radiology.168.3.2970098; PMID: 2970098.

7. Palmaz JC, Garcia OJ, Schatz RA, et al. Placement of balloon-expandable intraluminal stents in iliac arteries: first 171 procedures. Radiology 1990;174:969–75. https://doi. org/10.1148/radiology.174.3.174-3-969; PMID: 2137638.

8. Tetteroo E, van der Graaf Y, Bosch JL, et al. Randomised comparison of primary stent placement versus primary angioplasty followed by selective stent placement in patients with iliac-artery occlusive disease. Lancet 1998;351:1153–9. https://doi.org/10.1016/S01406736(97)09508-1; PMID: 9643685.

9. AbuRahma AF, Hayes JD, Flaherty SK, et al. Primary iliac stenting versus transluminal angioplasty with selective stenting. J Vasc Surg 2007;46:965–70. https://doi. org/10.1016/j.jvs.2007.07.027; PMID: 17905559.

A: Bilateral common iliac lesions. B: After treatment with a bilateral kissing VBX stent graft.

10. Ye W, Liu CW, Ricco JB, et al. Early and late outcomes of percutaneous treatment of TransAtlantic Inter-Society Consensus class C and D aorto-iliac lesions. J Vasc Surg 2011;53:1728–37. https://doi.org/10.1016/j.jvs.2011.02.005; PMID: 21609804.

11. Goode SD, Cleveland TJ, Gaines PA. Randomized clinical trial of stents versus angioplasty for the treatment of iliac artery occlusions (STAG trial). Br J Surg 2013;100:1148–53. https://doi.org/10.1002/bjs.9197; PMID: 23842828.

12. Mwipatayi BP, Thomas S, Wong J, et al. A comparison of covered versus bare expandable stents for the treatment of aortoiliac occlusive disease. J Vasc Surg 2010;54:1561–70. https://doi.org/10.1016/j.jvs.2011.06.097; PMID: 21906903.

13. Sabri SS, Choudhri A, Orgera G, et al. Outcomes of covered kissing stent placement compared with bare metal stent placement in the treatment of atherosclerotic occlusive disease at the aortic bifurcation. J Vasc Interv Radiol 2010;21:995–1003. https://doi.org/10.1016/j.jvir.2010.02.032;

PMID: 20538478.

14. Mwipatayi BP, Sharma S, Daneshmand A, et al. Durability of the balloon-expandable covered versus bare-metal stents in the Covered versus Balloon Expandable Stent Trial (COBEST) for the treatment of aortoiliac occlusive disease. J Vasc Surg 2016;64:83–94.e1. https://doi.org/10.1016/j.jvs.2016.02.064; PMID: 27131926.

15. Bekken JA, Vos JA, Aarts RA, et al. DISCOVER: Dutch Iliac Stent trial: COVERed balloon-expandable versus uncovered balloon-expandable stents in the common iliac artery: study protocol for a randomized controlled trial. Trials 2012;13:215. https://doi.org/10.1186/1745-6215-13-215; PMID: 23164097.

16. Laird JR, Zeller T, Holden A, et al. Balloon-expandable vascular covered stent in the treatment of iliac artery occlusive disease: 9-month results from the BOLSTER multicenter study. J Vasc Interv Radiol 2019;30:836–44.e1. https://doi.org/10.1016/j.jvir.2018.12.031; PMID: 30956077.

17. Laird JR, Loja M, Zeller T, et al. iCAST balloon-expandable

covered stent for iliac artery lesions: 3-year results from the iCARUS multicenter study. J Vasc Interv Radiol 2019:30;822–9. e4. https://doi.org/10.1016/j.jvir.2018.12.707; PMID: 31031089.

18. Bismuth J, Gray BH, Holden A, et al. Pivotal study of a nextgeneration balloon-expandable stent-graft for treatment of iliac occlusive disease. J Endovasc Ther 2017;24:629–37. https://doi.org/10.1177/1526602817720463; PMID: 28697693.

19. Panneton JM, Bismuth J, Gray BH, et al. Three-year followup of patients with iliac occlusive disease treated with the Viabahn balloon-expandable endoprosthesis. J Endovasc Ther 2020;27:728–36. https://doi. org/10.1177/1526602820920569; PMID: 32329658.

20. Mwipatayi BP, Ouriel K, Anwari T, et al. A systematic review of covered balloon-expandable stents for treating aortoiliac occlusive disease. J Vasc Surg 2020;72:1473–86.e2. https:// doi.org/10.1016/j.jvs.2020.01.084; PMID: 32360678.

21. GORE. https://eifu.goremedical.com/ (accessed 23 August 2021).

Acute Deep Vein Thrombosis Involving the Inferior Vena Cava: Interventional Perspectives

Adham Abou Ali,1 Othman A Malak,1 Karim Salem , 1 George Alkhoury,1 Natalie Sridharan,1 Rabih A Chaer1 and Efthymios Avgerinos 1,2

1. Division of Vascular Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, US;

2. Clinic for Vascular and Endovascular Surgery, Athens Medical Center, Athens, Greece

Abstract

Extension of an iliofemoral thrombosis into the inferior vena cava (IVC), or from the IVC descending into the iliofemoral segments, can confer significant morbidity and mortality. Interventional management of acute deep vein thrombosis (DVT) has been controversial, but there is little doubt that certain subpopulations benefit, such as those with symptomatic IVC thrombosis. When considering an intervention, caval involvement introduces technical difficulties due to its larger diameter, high thrombus burden, bilateral limb clot extension and need for dual access. The frequent coexistence of an IVC filter increases the complexity even more. This review summarises the current indications and treatment modalities available for the management of acute DVT involving the vena cava.

Keywords

Inferior vena cava, deep vein thrombosis, thrombectomy, thrombolysis, post-thrombotic syndrome

Disclosure: EA is a consultant and member of the speakers bureau for Boston Scientific, Angiodynamics, BD Medical and INARI Medical. RAC is a consultant for Boston Scientific. All other authors have no conflicts of interest to declare.

Received: 02 August 2021

Accepted: 15 November 2021 Citation: Vascular & Endovascular Review 2022;5:e04. DOI: https://doi.org/10.15420/ver.2021.08

Correspondence: Efthymios Avgerinos, Division of Vascular Surgery, Heart and Vascular Institute, South Tower, Office 351.1, Presbyterian University Hospital, 200 Lothrop St, Pittsburgh, PA 15213, US. E: efavgerinos@gmail.com

Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Caval thrombus extension in the setting of acute iliofemoral deep vein thrombosis (DVT) occurs in around 15–20% of cases as a result of thrombus propagation.1 Other causes for caval thrombosis include in situ thrombosis secondary to congenital anomalies or traditional DVT risk factors such as malignancy or hypercoagulable states and, more recently, secondary to non-retrieved inferior vena cava (IVC) filters. The incidence of IVC filter-associated thrombosis is around 10%, although the published range varies widely between 2% and 30%.2,3 Extension of an iliofemoral thrombosis into the IVC, or from the IVC retrograde into the iliofemoral segments, can confer significant morbidity; the greater thrombus burden not only carries a higher pulmonary embolism risk but also has a significant effect on the development of a long-term post-thrombotic syndrome (PTS), frequently affecting both limbs.4 Mortality risk is also doubled compared with lower extremity DVT.5 As a result, the use of catheter interventions for proximal DVTs involving the cava has been appealing.6

The interventional treatment of lower extremity DVT has rapidly evolved over the past decade, and despite existing controversy there is little doubt of its benefits in carefully selected patients.7 Catheter-directed interventions for acute iliofemoral DVT aim at rapid thrombus removal, maintenance of venous valve function and ultimately the lowering of PTS rates and improvement of quality of life. When considering an intervention, caval involvement introduces technical difficulties due to its larger diameter, high thrombus burden, bilateral limb clot extension and need for dual access. The frequent coexistence of an IVC filter increases the

complexity even more. The purpose of this review is to summarise the current indications and treatment modalities available for the management of acute DVT with ascending (or descending) caval thrombosis.

Intervention for Acute Deep Vein Thrombosis Involving the Inferior Vena Cava

Catheter-directed interventions focus on early (and ideally) complete thrombus removal to rapidly improve symptomatology and reduce PTS incidence.7 Three major randomised controlled clinical trials and several institutional series have evaluated the utility of catheter-directed interventions compared with anticoagulation alone for the management of lower extremity DVT.8–10 The results have been conflicting, mainly due to improper patient inclusion or technical inappropriateness.11,12 Regardless of this, there is little doubt that certain subpopulations benefit, and the subpopulation with symptomatic IVC thrombosis is probably one of them. Although few studies have specifically addressed IVC involvement it seems that the more proximal and more extensive the thrombus, the higher the chance that the patient has severe symptoms and maximum benefit from an intervention. 13

A meta-analysis of the randomised trials published in the most recent European venous thrombosis guidelines reported that “early thrombus removal techniques are more effective than anticoagulation alone in preventing any PTS (RR 0.67; 95% CI [0.45–1.00]; p=0.05) and particularly moderate to severe PTS (RR 0.59; 95% CI [0.44–0.80]; p<0.001)” at the

Figure 1: Acute Iliofemoral or Caval DVT Treatment Algorithm

Iliofemoral or caval DVT <30 days

stenting after 8–24 hours. This technique can take up to 48 hours and multiple operating room trips to achieve complete thrombus resolution. The addition of ultrasound energy to CDT (EKOS, Boston Scientific) has not been translated into a clinically significant benefit over standard CDT.16 Technical success rates for CDT alone have ranged between 83% and 100%, with bleeding complications ranging between 4% and 9%.6,15–17

The associated bleeding risks, prolonged infusion time, and intensive care unit requirements have rendered thrombolytic techniques less appealing, especially since the advent of new-generation thrombectomy devices. Short-duration catheter thrombolysis, however, can soften thrombus and optimise subsequent aspiration thrombectomy. Particularly in extensive caval thrombosis, when there is no contraindication for lytics, it is the authors’ preference to prime thrombus with ~10 mg of tissue plasminogen activator (tPA; 2–4 mg on table followed by 1 mg/h for 6–8 hours). This will allow a less aggressive thromboaspiration and prevent blood loss (by aspiration) or even kidney injury when pharmacomechanical thrombectomy using AngioJet (Boston Scientific) is considered.18

In more recent practice, we would probably modify the suggested treatments towards an aspiration thrombectomy strategy first, selectively assisted by thrombolytics (e.g. extensive caval thrombosis). CDT = catheter-directed thrombolysis; DVT = deep vein thrombosis; PMT = pharmacomechanical thrombolysis. Source: Go et al. 2020.15 Reproduced with permission from Radcliffe Vascular.

expense of an increased risk of bleeding with interventional therapy (RR 5.68; 95% CI [1.27–25.33]; p=0.02).14 However, considering that current practice is gradually shifting towards non- (or minimal) thrombolytic techniques this risk–benefit ratio will probably improve further. The European guidelines advocate the consideration of early thrombus removal strategies for selected patients with symptomatic iliofemoral DVT. The choice of therapy is left to the discretion of the treating physician.14

Our current patient selection algorithm has been previously described.15 It is our practice to consider interventions for patients with iliofemoral DVT who have had symptoms for less than 30 days. Symptom severity and bleeding risks factor in the final decision on who and how to intervene (Figure 1).

Treatment Modalities

Anticoagulation is the standard treatment for DVT including caval thrombus extension. However, medical treatment alone in patients with complete iliocaval thrombosis involvement has been shown to be minimally effective. The interventional alternatives are summarised below (Figure 2).

Thrombolytic Techniques

Catheter-directed thrombolysis (CDT) involves the slow infusion of a plasminogen activator directly into the thrombus at a rate of 1 mg/h through a multi-sidehole infusion catheter. These catheters are the Unifuse (Angiodynamics), the Cragg-McNamara (Medtronic), and the Fountain (Merritt Inc.). The procedure is performed through a 5 Fr system via either a femoral or popliteal vein access; some interventionalists might opt for small saphenous or even proximal posterior tibial vein access. The patient is monitored in an intensive care unit throughout the infusion duration with complete blood counts and fibrinogen levels checked every 6 hours. The patient is eventually brought back for lysis termination and

On-table infusion of lytics inside the large mass of thrombus within the IVC can be more effective if done using small 3 ml syringes. This will enable a more efficient hand injection of the lytic solution (e.g. 4 mg tPA diluted in 20 ml heparinised saline).

A novel thrombolytic catheter is the Bashir Endovascular catheter (BEC, Thrombolex) that enables multichannel infusion in a basket configuration.19 Once deployed within the thrombus, the nitinol-reinforced basket at the tip of this catheter expands up to 45 mm, which can then be collapsed and redeployed to increase the surface area and binding sites for tPA within the thrombus. Its effectiveness is currently being trialled in the US.

Rheolysis – AngioJet

The rationale for pharmacomechanical thrombolysis (PMT) as a thrombus removal strategy has become more attractive given that PMT reduces the time required for thrombectomy to shorter and frequently single-session interventions.20 This reduces bleeding complications, intensive care unit stay and the associated costs.

PMT commonly involves a power pulse spray technique using the 8 Fr AngioJet Zelante catheter (Boston Scientific) that disperses thrombolytics forcefully along the thrombus (typically a 50–100 ml saline with 6–20 mg tPA solution). After allowing the thrombolytics to diffuse into the clot for 30 minutes, the AngioJet is switched to its rheolytic thrombectomy mode for clot removal. The unit/pump generates high-pressure pulsatile saline flow that exits the catheter tip through multiple retrograde-directed jets. These jets create a localised low-pressure zone (Bernoulli effect) for thrombus maceration and aspiration.

The technical success rate for PMT interventions for acute iliocaval thrombosis specifically ranges between 64% and 96%.20–22 One study that analysed 54 patients receiving PMT for IVC thrombosis noted a 64% primary technical success rate but a 100% stent-assisted success rate. The complication rate was 3.7%, with one patient requiring an intervention for a pulmonary embolism and another requiring a transfusion.21 In our institutional experience of 46 patients with caval thrombosis the technical success rate was 89.3% and the complication rate was 2.2%, with one access site haematoma requiring re-intervention. Compared with iliofemoral DVTs with no caval involvement, there were no differences in technical success, 30-day recurrence, or long-term patency rates in the

Sources: AngioJet image provided courtesy of Boston Scientific. ©2021 Boston Scientific Corporation or its affiliates. All rights reserved. Indigo system image provided courtesy of Penumbra, Inc. ClotTriever system image provided courtesy of Inari Medical, Inc. AngioVac image provided courtesy of AngioDynamics, Inc. and its affiliates.

caval involvement group. However, it was shown that IVC filter-associated caval thrombosis was less likely to respond to thrombolysis. Interestingly, caval extension of the DVT was associated with improved PTS outcomes compared with non-caval thrombosis.13

AngioJet use has been associated with acute kidney injury in around 20% of patients, although the vast majority of cases are transient.22 Our institutional experience confirms the high likelihood of acute kidney injury when the IVC is involved. It is our recommendation that in the presence of caval thrombosis a two-stage technique maybe a safer practice, starting with CDT (if no contraindications) to reduce thrombus burden, and finalising at a second stage with PMT.18 Physicians should otherwise be careful to monitor the duration of time spent and the volume removed.

Non-thrombolytic Techniques

Over the past 5 years, novel percutaneous venous thrombectomy systems have been on the rise and we have seen an enormous practice shift following the evolution of these technologies.23 The devices are becoming larger, more powerful and smarter (i.e. incorporating sensors to detect blood loss), and can minimise, if not eliminate, lytics and their associated risks. Given their size, their efficacy in caval thrombus clearance is enhanced. There are no comparative trials or long-term data with regards to the mechanical thrombectomy techniques summarised in the following section. Their use in the hands of expert operators at high-volume centres remains the safest way to obtain more evidence about their potential future role in the management of caval thrombosis.

ClotTriever and FlowTriever

The ClotTriever device uses a 13 Fr or 16 Fr system through which the ClotTriever catheter, consisting of a coring element and a braided nitinol collection bag, is inserted and then deployed in the IVC above the

thrombus. As the catheter is withdrawn, the thrombus is captured in the collection bag. Three to four passes of the device enable the largest amount of thrombus retrieval. The CLOUT registry is currently compiling a list of acute and chronic lower extremity DVT cases that use the ClotTriever catheter. Preliminary results indicate that more than three-quarters of patients have near-complete clot resolution, defined as >75% thrombus clearance. No device-related major adverse events or any major bleeding events were recorded.24 It is worth noticing that the presence of an IVC filter requires more complex interventional manoeuvres (e.g. internal jugular vein sheath access and ClotTriever wire snaring above the filter), which makes it cumbersome to use and should instead be avoided.

The FlowTriever system, typically used for caval thrombus, consists of a 16–24 Fr aspiration catheter. The aspiration catheter generates powerful suction via an attached vacuum-generating 60 ml custom-made syringe. Its large size makes it effective in removing large amounts of clot, but popliteal access can be challenging and potentially traumatic (Figure 3).

A retrospective review of 15 patients with caval thrombus treated with the ClotTriever and/or FlowTriever systems (used either separately or in combination) reported a technical success rate of 86.6% (13 of 15 patients) without the use of thrombolytics.25 There were no major bleeding events or any intensive care unit hospital stays; the median length of stay was 3 days.

The choice between the two devices is at the discretion of the operator; the ClotTriever’s ability to core out thrombus densely adherent to the vessel wall makes it a compelling option to remove the associated iliofemoral clot, whereas the FlowTriever’s large-bore catheter and powerful aspiration mechanism make it more suitable for extracting caval thrombus.

Figure 2: Available Systems for Pharmacomechanical or Purely Mechanical Caval Thrombectomy

Angio-Sac Collection System

AngioJet system: Zelante catheter

Indigo system: CAT8 and CAT12 catheters

ClotTriever system

Coring element

Collection bag

AngioVac System

AngioVac cannula

Figure 3: Persistent Right Leg Swelling and Failed Lyse Attempt Due to ‘Non-existent’ IVC in a 42-year-old Man

Indigo System CAT8 and Lightning 12

The Indigo CAT system consists of a catheter, a separator and a vacuum pump. The catheters are available in a variety of sizes from 3.4 Fr to 12 Fr. The CAT12 catheter is the most recent addition and is tailored towards large-bore vessels such as the IVC with or without the presence of a filter. The angled tip of these catheters in addition to the associated separator allows for thrombus fragmentation and clearing. The pump traditionally involved a manually controlled continuous suction.

The new Lightning 12 Intelligent Aspiration system has a dual pressure sensor that detects and differentiates thrombus from blood. Negative suction will be maintained as long as the catheter is in thrombus; once blood or continuous flow is detected, the suction becomes intermittent, thereby mitigating some of the blood loss associated with the earlier suction thrombectomy pumps. In a contemporary analysis of the CAT8 catheter a 60% technical success rate for iliofemoral DVTs was noted.26 The larger CAT12 system has recently gained approval for peripheral venous and pulmonary embolism treatment and is anticipated to offer significant advantages and efficiency over the smaller CAT8 (Figure 4).

AngioVac

The AngioVac (AngioDynamics) aspiration system comes with a 24 Fr suction cannula that is part of an extracorporeal veno-venous circuit that filters the blood and returns it via an 18 Fr reinfusion cannula at a separate access site. It is a very powerful device specifically designed to remove large clots in an en bloc fashion from large vasculature such as the IVC and/or the proximal iliac vessels, and it is otherwise too large to navigate in the femoropopliteal vessels.

The procedure needs to be done under general anaesthesia. The aspiration cannula should be typically introduced through a right internal jugular access to prevent proximal embolisation and pulmonary embolism. Once the cannula is placed across the thrombus, its self-expanding

funnel-tip is deployed, opening up to 48 Fr, the extracorporeal circulation is initiated and slowly increased to a maximum rate of 3 l/min; the catheter is repeatedly advanced and withdrawn. A recent report demonstrated its utility in patients with caval thrombosis (9 of 16 patients), with complete thrombus extraction in 81.3% of the patients.27

Angiodynamics recently launched the AlphaVac System, an off-circuit, multi-purpose mechanical aspiration thrombectomy device. The AlphaVac System incorporates a new mechanical aspiration handle, and the extracorporeal circuit function will remain as optional.

Other Devices

Several other thrombectomy catheters older or new are available in the market but are either not well investigated or are not suited for the IVC: the Arrow-Trerotola (Teleflex Inc.), the Clot Buster Amplatz Thrombectomy Device (Microvena Corp.), the Cleaner (Argon Medical Devices Inc.), the Aspirex (BD Medical), the JETi8 (Walk Vascular), the Quick Clear (Philips) and the ReVene Thrombectomy catheter (Vetex Medical).

Iliocaval Stenting

Residual thrombus, either from incomplete lysis or aspiration thrombectomy, is considered a chronic component, and if untreated it is associated with an early recurrence and a more severe PTS development.7,28 As a result, the liberal use of stents is favoured to cover residual thrombus and any uncovered external compression (e.g. May–Thurner syndrome).29 The 2- and 5-year stent patency rates (primarily for Wallstent [Boston Scientific]) range between 65% and 95%.29 Our own iliac vein stenting experience demonstrated 3-year primary and secondary patency rates of 75.2% and 82.2%, respectively.7 Iliocaval stenting patency rates have been reported to be even higher.29 The rates are otherwise favourable, provided that the appropriate technique has been used (e.g. correct sizing and the stent landing on healthy venous segments with appropriate inflow). The advent of dedicated venous stents is changing

A,B: KILT syndrome (kidney and IVC abnormalities with leg thrombosis); C,D: Venogram through popliteal access indicating extensive iliocaval thrombosis; the inferior vena cava (IVC) is hypoplastic, note the lumbar network. E: ClotTriever catheter thrombectomy; F: After three catheter passes the iliofemoral veins and hypoplastic vena cava are widely open with an area of iliac vein stenosis; G: The final result after venoplasty with a 14 mm balloon. The IVC was not stented because it was felt that the final result was the patient’s baseline venous circulation, including adequate collaterals, and the patient could do well on lifelong anticoagulation. Stenting would need to extend above the renal veins and might also compromise the contralateral side that was otherwise asymptomatic. One year later no subsequent events had occurred.

Figure 4: Acute Bilateral Leg Swelling and Back Pain Diagnosed with Iliocaval Thrombosis Related

to an IVC Filter Placed 10 years Previously in a 47-year-old Man

A: With the patient in the prone position, bilateral popliteal veins were accessed. The venogram confirms thrombosis into and above the inferior vena cava (IVC) filter. B: The Indigo CAT12 system. C: Aspiration thrombectomy with the CAT12 catheter throughout both iliofemoral segments and into the vena cava up to the filter. D: Significant improvement but with residual clot at the iliocaval segments and at the top of the filter. E: Placement of the kissing 14 mm VICI (Boston Scientific) stents; F,G: Residual thrombus above the filter, and continuation of CAT12 thrombectomy through jugular access; H: Filter retrieval. Source: B is reproduced with permission from Penumbra.

the landscape of venous interventions in terms of ease of use, length and radial force, however, long-term results are lacking (Table 1).

Although an isolated caval lesion may be easy to treat with a single large stent, it is not that frequent. Typically, the iliocaval bifurcation is involved and although multiple techniques have been described, the kissing stents technique seems to be popular, with very good long-term patency rates.30,31 When kissing stents are positioned they should be levelled at the same height within the IVC or else the one may be competing over the other.

For the few occasions in which an isolated caval stent, or extension above the renal veins, is required there are only two stainless steel stents available in the US and one more in Europe. The Wallstent (Boston Scientific) and the Z-stent (Cook) are available in large enough sizes (>20 mm) for IVC stenting (up to 24 mm and 35 mm, respectively). The Wallstent is strong and flexible but deployment is inaccurate due to foreshortening. The Z-stent offers a few advantages over the Wallstent due to its minimal foreshortening, greater radial force and its larger interstices, but it has large fixing spines and therefore carries a higher risk of caval perforation.32,33

The presence of a filter is highly debated with regard to whether it should be removed or over-stented. Few centres have documented expertise in safely removing chronically thrombosed filters, and a lot of complications related to attempted retrievals are probably underreported.34 Stent placement for chronically thrombosed IVC filters has previously been described by numerous authors, and although it has been shown to be technically feasible and safe in various series, large studies with longterm follow-up are lacking.35–38

It is our preference to attempt to remove the filter immediately after the thrombectomy (or in the same admission), but if excessive interventional manoeuvres are required, stenting across is a reasonable approach.

Intravascular Ultrasound

Intravascular ultrasound (Philips) enables the acquisition of detailed images in an axial plane relative to the catheter tip. Intravascular ultrasound has been shown in multiple studies to be superior for accurate lesion identification compared with plain venography.39

Specifically, for caval thrombosis, intravascular ultrasound can provide more accurate data on thrombus burden, IVC filter positioning and clot

Lightning 12

Penumbra ENGINE

E

F G H

Table 1: Venous Stents Currently Available for Use

Brand Design Sheath Size, Stent Diameter

Abre (Medtronic)*

BlueFLow (Plus Medica)

Z-Stent (Cook Medical)†

Zilver Vena (Cook Medical)*

Sinus (Optimed)

Sinus XL (Optimed)

Venovo (BD Medical)*‡

Vici (Boston Scientific)*§

Wallstent (Boston Scientific)*

Self-expanding nitinol, open cell

Self-expanding woven nitinol, closed cell

Self-expanding, stainless steel, large open cell

Self-expanding nitinol, open cell

Self-expanding nitinol, open cell

Self-expanding nitinol, closed cell

Self-expanding nitinol, open cell

Self-expanding nitinol, closed cell

Self-expanding, stainless steel, braided closed cell

9 Fr system, 10–20 mm

10 Fr system, 12–18 mm

12–14 Fr system, 15–35 mm

7 Fr system, 14–16 mm diameter

10 Fr system, 10–18 mm

10 Fr system, 16–34 mm

8–10 Fr delivery, 12–20 mm (flared ends)

9 Fr system, 12–16 mm

9–12 Fr system, 10–24 mm

*Food and Drug Administration approved. †Off-label use. ‡Temporary recall in 2021 for deploying mechanism malfunction. §Temporary recall in 2021 to investigate events of stent migration.

around it as well as the renal vein orifices and renal vein thrombosis. It is also essential to guide stent diameter, landing zones and to confirm a satisfactory final outcome. Despite that, one recent survey on iliocaval stent reconstruction reported that only 64.6% of operators used intravascular ultrasound to guide reconstruction, a testament to the persistent inconsistencies in venous thrombosis management.40

Prophylactic Inferior Vena Cava Filters

A theoretical risk factor for thrombolysis or aspiration thrombectomy is iatrogenic pulmonary embolism related to the instrumentation of extensive amounts of fresh thrombus. Although a small, randomised trial has indicated a higher rate of clinically significant pulmonary embolism in patients not receiving an IVC filter, there was no mortality difference and subsequent contemporary studies recommended highly selective IVC filtration.41 Pulmonary emboli can be unavoidable, but they are rarely clinically meaningful for otherwise low-risk patients, and placement of an IVC filter may introduce complexity and other potential risks.

In our experience, IVC filters are rarely used, irrespective of the type of catheter intervention. Patients who might benefit are those with clinically significant pulmonary embolism on presentation or known low cardiopulmonary reserve.42 If a filter is used, it should be placed prior to the intervention through the internal jugular vein or contralateral femoral vein,and retrieved at the end of the procedure or at any time before discharge, provided that anticoagulation is maintained.

1. Kahn SR, Shbaklo H, Lamping DL, et al. Determinants of health-related quality of life during the 2 years following deep vein thrombosis. J Thromb Haemost 2008;6:1105–12. https://doi.org/10.1111/j.1538-7836.2008.03002.x; PMID: 18466316.

2. Grewal S, Chamarthy MR, Kalva SP. Complications of inferior vena cava filters. Cardiovasc Diagn Ther 2016;6:632–41. https://doi.org/10.21037/cdt.2016.09.08; PMID: 28123983.

3. Milovanovic L, Kennedy SA, Midia M. Procedural and indwelling complications with inferior vena cava filters: frequency, etiology, and management. Semin Intervent Radiol 2015;32:34–41. https://doi.org/10.1055/s-0034-1396962; PMID: 25762846.

4. Kahn SR. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med 2008;149:698–707. https://doi. org/10.7326/0003-4819-149-10-200811180-00004;

PMID: 19017588.

5. Shah NG, Wible BC, Paulisin JA, et al. Management of inferior vena cava thrombosis with the FlowTriever and ClotTriever systems. J Vasc Surg Venous Lymphat Disord 2021;9:615–20. https://doi.org/10.1016/j.jvsv.2020.09.008; PMID: 33045392.

6. Alkhouli M, Zack CJ, Zhao H, et al. Comparative outcomes

Anticoagulation

All patients with a DVT diagnosis should retain their therapeutic anticoagulation in preparation for and during the procedure. Unfractionated or low-molecular-weight heparin can be used. Maintenance of therapeutic anticoagulation during ongoing thrombolysis varies with institutional policies.

In our practice, for DVT lysis we maintain small heparin doses through the sheath. The patient is fully heparinised in aspiration thrombectomy procedures. Postoperative anticoagulation, particularly when stents have been placed, should include low-molecular-weight heparin for 4–6 weeks and probably lifelong anticoagulation thereafter (given the extent of the caval thrombotic event and the reconstruction).

The role of antiplatelet agents is highly debated and practices vary.

Conclusion

Caval thrombus extension is an increasingly encountered pathology especially with the continued use of IVC filters. Treating iliocaval thrombosis with an interventional approach incorporating novel thrombectomy techniques and selective use of thrombolytics is gaining popularity as a means of immediate and long-term morbidity and PTS reduction. An appropriate technique for maximal thrombus elimination and liberal stenting between healthy segments are the cornerstone of a successful long-term outcome.

of catheter-directed thrombolysis plus anticoagulation versus anticoagulation alone in the treatment of inferior vena caval thrombosis. Circ Cardiovasc Interv 2015;8:e001882. https://doi.org/10.1161/ CIRCINTERVENTIONS.114.001882; PMID: 25663321.

7. Avgerinos ED, Saadeddin Z, Abou Ali AN, et al. Outcomes and predictors of failure of iliac vein stenting after catheterdirected thrombolysis for acute iliofemoral thrombosis. J Vasc Surg Venous Lymphat Disord 2019;7:153–61. https://doi. org/10.1016/j.jvsv.2018.08.014; PMID: 30660580.

8. Enden T, Haig Y, Kløw N-E, 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;379:31–8. https://doi.org/10.1016/S0140-6736(11)617534; PMID: 22172244.

9. Vedantham S, Goldhaber SZ, Julian JA, et al. Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis. N Engl J Med 2017;377:2240–52. https://doi.org/10.1056/NEJMoa1615066; PMID: 29211671.

10. Notten P, Ten Cate-Hoek AJ, Arnoldussen C, et al. Ultrasound-accelerated catheter-directed thrombolysis versus anticoagulation for the prevention of post-thrombotic syndrome (CAVA): a single-blind, multicentre, randomised

trial. Lancet Haematol 2020;7:40–9. https://doi.org/10.1016/ S2352-3026(19)30209-1; PMID: 31786086.

11. Avgerinos ED, Chaer RA. The ATTRACTiveness of catheterdirected thrombolysis. J Vasc Surg Venous Lymphat Disord 2018;6:303. https://doi.org/10.1016/j.jvsv.2018.02.002; PMID: 29661361.

12. Avgerinos ED, Jalaie H, Chaer RA. Catheter interventions: an unresolved clinical controversy. Lancet Haematol 2020;7:e189. https://doi.org/10.1016/S2352-3026(20)300028; PMID: 32109401.

13. Avgerinos ED, El-Shazly O, Jeyabalan G, et al. Impact of inferior vena cava thrombus extension on thrombolysis for acute iliofemoral thrombosis. J Vasc Surg Venous Lymphat Disord 2016;4:385–91. https://doi.org/10.1016/j. jvsv.2016.05.005; PMID: 27638990.

14. Kakkos SK, Gohel M, Baekgaard N, et al. European Society for Vascular Surgery (ESVS) 2021 clinical practice guidelines on the management of venous thrombosis. Eur J Vasc Endovasc Surg 2021;61:9–82. https://doi.org/10.1016/j. ejvs.2020.09.023; PMID: 33334670.

15. Go C, Chaer RA, Avgerinos ED. Catheter interventions for acute deep venous thrombosis: who, when and how. Vasc Endovasc Rev 2020;3:e07. https://doi.org/10.15420/ ver.2019.13

16. Engelberger RP, Stuck A, Spirk D, et al. Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis: 1-year follow-up data of a randomized-controlled trial. J Thromb Haemost 2017;15:1351–60. https://doi.org/10.1111/jth.13709; PMID: 28440041.

17. Comerota AJ, Kearon C, Gu CS, et al. Endovascular thrombus removal for acute iliofemoral deep vein thrombosis. Circulation 2019;139:1162–73. https://doi. org/10.1161/CIRCULATIONAHA.118.037425; PMID: 30586751.

18. Salem KM, Saadeddin Z, Malak OA, et al. Risk factors for acute kidney injury after pharmacomechanical thrombolysis for acute deep vein thrombosis. J Vasc Surg Venous Lymphat Disord 2021;9:868–73. https://doi.org/10.1016/j. jvsv.2020.11.005; PMID: 33186753.

19. Al-Otaibi M, Iftikhar O, Brailovsky Y, et al. Catheter-directed thrombolysis of iliocaval thrombosis in patients with COVID19 infection. JACC Case Rep 2020;2:2016–20. https://doi. org/10.1016/j.jaccas.2020.07.057; PMID: 32864630.

20. Go C, Saadeddin Z, Pandya Y, et al. Single- versus multiplestage catheter-directed thrombolysis for acute iliofemoral deep venous thrombosis does not have an impact on iliac vein stent length or patency rates. J Vasc Surg Venous Lymphat Disord 2019;7:781–8. https://doi.org/10.1016/j. jvsv.2019.05.010; PMID: 31495769.

21. Ye K, Qin J, Yin M, et al. Outcomes of pharmacomechanical catheter-directed thrombolysis for acute and subacute inferior vena cava thrombosis: a retrospective evaluation in a single institution. Eur J Vasc Endovasc Surg 2017;54:504–12. https://doi.org/10.1016/j.ejvs.2017.06.025; PMID: 28801136.

22. Morrow KL, Kim AH, Plato SA, et al. Increased risk of renal dysfunction with percutaneous mechanical thrombectomy compared with catheter-directed thrombolysis. J Vasc Surg 2017;65:1460–6. https://doi.org/10.1016/j.jvs.2016.09.047; PMID: 27876521.

23. Wang W, Sun R, Chen Y, Liu C. Meta-analysis and systematic review of percutaneous mechanical thrombectomy for lower extremity deep vein thrombosis. J Vasc Surg Venous Lymphat Disord 2018;6:788–800. https://doi.org/10.1016/j. jvsv.2018.08.002; PMID: 30336908.

24. Dexter DJ. First look at CLOUT registry reveals over 75% of DVT patients have near-complete clot resolution with

Interventions for IVC Thrombosis

ClotTriever. Venous News 17 November 2019. https:// venousnews.com/first-clout-registry-data-reveal-75-of-dvtpatients-resolve-75-of-clot-with-mechanical-thrombectomy (accessed 27 November 2019).

25. Shah NG, Wible BC, Paulisin JA. Management of inferior vena cava thrombosis with the FlowTriever and ClotTriever systems. J Vasc Surg Venous Lymphat Disord 2021;9:615–20. https://doi.org/10.1016/j.jvsv.2020.09.008; PMID: 33045392.

26. Lopez R, DeMartino R, Fleming M, et al. Aspiration thrombectomy for acute iliofemoral or central deep venous thrombosis. J Vasc Surg Venous Lymphat Disord 2019;7:162–8. https://doi.org/10.1016/j.jvsv.2018.09.015; PMID: 30639411.

27. Rajput FA, Du L, Woods M, Jacobson K. Percutaneous vacuum-assisted thrombectomy using AngioVac aspiration system. Cardiovasc Revasc Med 2020;21:489–93. https://doi. org/10.1016/j.carrev.2019.12.020; PMID: 31882331.

28. Haig Y, Enden T, Slagsvold CE, et al. Determinants of early and long-term efficacy of catheter-directed thrombolysis in proximal deep vein thrombosis. J Vasc Interv Radiol 2013;24:17–24. https://doi.org/10.1016/j.jvir.2012.09.023; PMID: 23176966.

29. Mahnken AH, Thomson K, de Haan M, et al. CIRSE standards of practice guidelines on iliocaval stenting. Cardiovasc Intervent Radiol 2014;37:889–97. https://doi. org/10.1007/s00270-014-0875-4; PMID: 24633533.

30. Neglén P, Darcey R, Olivier J. Bilateral stenting at the iliocaval confluence. J Vasc Surg 2010;51:1457–66. https:// doi.org/10.1016/j.jvs.2010.01.056; PMID: 20385465.

31. Neglén P. Stenting is the “method-of-choice” to treat iliofemoral venous outflow obstruction. J Endovasc Ther 2009;16:492–3. https://doi.org/10.1583/09-2719C.1; PMID: 19702344.

32. Funaki B. Inferior vena caval stenting. Semin Intervent Radiol 2004;21:347–9. https://doi.org/10.1055/s-2004-861570; PMID: 21331146.

33. Alkhouli M, Morad M, Narins CR, et al. Inferior vena cava thrombosis. JACC Cardiovasc Interv 2016;9:629–43. https:// doi.org/10.1016/j.jcin.2015.12.268; PMID: 26952909.

34. Desai KR, Xiao N, Karp J, et al. Single-session inferior vena cava filter removal, recanalization, and endovenous reconstruction for chronic iliocaval thrombosis. J Vasc Surg Venous Lymphat Disord 2019;7:176–83. https://doi.

org/10.1016/j.jvsv.2018.10.014; PMID: 30612972.

35. Chick JFB, Jo A, Meadows JM, et al. Endovascular iliocaval stent reconstruction for inferior vena cava filter-associated iliocaval thrombosis: approach, technical success, safety, and two-year outcomes in 120 patients. J Vasc Interv Radiol 2017;28:933–9. https://doi.org/10.1016/j.jvir.2017.04.017; PMID: 28527883.

36. Ye K, Lu X, Li W, et al. Outcomes of stent placement for chronic occlusion of a filter-bearing inferior vena cava in patients with severe post-thrombotic syndrome. Eur J Vasc Endovasc Surg 2016;52:839–46. https://doi.org/10.1016/j. ejvs.2016.08.050; PMID: 27751714.

37. Neglén P, Oglesbee M, Olivier J, et al. Stenting of chronically obstructed inferior vena cava filters. J Vasc Surg 2011;54:153–61. https://doi.org/10.1016/j.jvs.2010.11.117; PMID: 21316900.

38. Arabi M, Krishnamurthy V, Cwikiel W, et al. Endovascular treatment of thrombosed inferior vena cava filters: techniques and short-term outcomes. Indian J Radiol Imaging 2015;25:233–8. https://doi.org/10.4103/0971-3026.161436; PMID: 26288516.

39. Gagne PJ, Tahara RW, Fastabend CP, et al. Venography versus intravascular ultrasound for diagnosing and treating iliofemoral vein obstruction. J Vasc Surg Venous Lymphat Disord 2017;5:678–87. https://doi.org/10.1016/j. jvsv.2017.04.007; PMID: 28818221.

40. Hage AN, Srinivasa RN, Abramowitz SD, et al. Endovascular iliocaval stent reconstruction for iliocaval thrombosis: a multi-institutional international practice pattern survey. Ann Vasc Surg 2018;49:64–74. https://doi.org/10.1016/j. avsg.2018.01.076; PMID: 29486230.

41. Sharifi M, Bay C, Skrocki L. Role of IVC filters in endovenous therapy for deep venous thrombosis: the FILTER-PEVI (Filter Implantation to Lower Thromboembolic Risk in Percutaneous Endovenous Intervention) trial. Cardiovasc Intervent Radiol 2012;35:1408–13. https://doi.org/10.1007/ s00270-012-0342-z; PMID: 22271078.

42. Avgerinos ED, Hager ES, Jeyabaln G, et al. Inferior vena cava filter placement during thrombolysis for acute iliofemoral deep venous thrombosis. J Vasc Surg Venous Lymphat Disord 2014;2:274–81. https://doi.org/10.1016/j. jvsv.2013.12.006; PMID: 26993386.

Treatment of Non-thrombotic Iliac Vein Stenosis: Where is the Evidence?

Maria Joh and Kush R Desai

Department of Radiology, Division of Interventional Radiology, Northwestern University, Chicago, IL, US

Abstract

Non-thrombotic iliac vein lesions (NIVLs) refer to iliac vein lumen stenosis, usually secondary to extrinsic compression, without associated thrombosis. Clinical presentation varies; patients may be asymptomatic, have symptoms of lower extremity venous hypertension, or in women, may be associated with chronic pelvic pain. Given the significant variability in symptomatology, thorough history and physical examination are mandatory in excluding other causes of symptoms. Non-invasive imaging, such as venous duplex/insufficiency ultrasound examinations, and axial imaging aid in the diagnosis of a NIVL in the appropriate clinical context. Catheter venography and intravascular ultrasound remain the primary modalities for definitive diagnosis, treatment planning, and ultimately placement of self-expanding venous stents to resolve the causative iliofemoral venous obstruction. In appropriately selected patients, stent placement can lead to marked improvements in symptoms, heal stasis ulceration when present, and improve disease-specific and overall quality of life. Stents placed in patients with NIVL demonstrate high long-term primary patency. In this article, the authors discuss clinical presentation, diagnostic workup, endovascular interventions and outcomes of NIVL treatment.

Keywords

Iliac vein compression, May–Thurner syndrome, chronic venous insufficiency, venous stents

Disclosure: KRD reports speaker’s bureau/consulting for Cook Medical, Boston Scientific, Becton Dickinson/Bard, Medtronic, Penumbra, Tactile Medical; consultant for Philips, W.L. Gore, Tactile Medical, Shockwave Medical, Asahi Intecc; and is a Deputy Editor of Vascular & Endovascular Review, this did not influence peer review. MJ has no conflicts of interest to declare.

Received: 20 August 2021 Accepted: 11 January 2022 Citation: Vascular & Endovascular Review 2022;5:e05. DOI: https://doi.org/10.15420/ver.2021.11

Correspondence: Kush R Desai, Department of Radiology, Northwestern University, 676 N St Clair St, Suite 800, Chicago, IL 60611, US. E: kdesai007@northwestern.edu

Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

In 1908, McMurrich studied 107 cadavers and found 35 had adhesions in the iliac veins, the majority of which were on the left side.1 Subsequently in 1943, Ehrich and Krumbhaar found that 95 of 412 cadavers had obstructive lesions consisting of collagen and elastin in the left iliac veins.2 This was further characterised by May and Thurner in 1957 as ‘spurs’ in the left iliac veins that may predispose to venous thrombosis because of disruption of blood flow.3 This condition was referred to as ‘iliac vein compression’ by Cockett and Thomas in 1965.4,5 These initial studies did not attempt to differentiate between non-thrombotic iliac vein lesions (NIVLs) and thrombotic lesions. However, more recent evidence suggests that clinical outcome and recurrence rates may differ, necessitating distinction between the two lesion types.

NIVLs refer to iliac vein lumen stenosis, usually secondary to extrinsic compression, without associated thrombosis. Most commonly NIVLs are caused between arterial structures and the spine, and are associated with intrinsic vein stenosis characterised by wall fibrosis or intraluminal webs/ spurs. When there is compression of the left common iliac vein by the right common iliac artery, it is commonly referred to as May–Thurner syndrome or Cockett’s syndrome.6

Patients with NIVLs may develop symptoms of chronic venous insufficiency (CVI), although the true prevalence of NIVL-associated CVI is unknown. Symptoms of CVI can significantly decrease quality of life and increase healthcare costs.7,8 In patients with significant persistent symptoms

despite conservative management, endovascular stent placement has been used as a safe and effective treatment option for NIVLs.9 To achieve treatment success, patient selection is crucial to appropriately exclude patients experiencing symptoms because of other aetiologies.

In this article, we will discuss the clinical presentation, diagnostic workup and endovascular interventions of NIVLs, along with the outcomes of treatment.

Clinical Presentation

Clinical presentation of NIVL varies, ranging from asymptomatic patients to those with symptoms of CVI. Several studies have found that a significant portion of patients with NIVL may not have appreciable symptoms.10–12 One study retrospectively reviewed 50 abdominal/pelvic CT scans of patients presenting with abdominal pain to the emergency department; there were no lower extremity symptoms or prior deep venous thrombosis (DVT).11 Among these subjects, 33 (66%) had >25% diameter compression, which corresponds to approximately 50% area stenosis.11 In a more recent study, angiography of the iliac veins was performed prospectively in 20 healthy volunteers, among whom 19 had at least two angiographic findings consistent with significant iliac vein obstruction (including contrast translucency, lumen deformity, as well as axial, transpelvic or ascending lumbar collaterals). Sixteen of these subjects had no visible or palpable signs of venous disease (C0 by Clinical Etiology Anatomy Pathophysiology [CEAP] classification) and four of them

Figure 1: Proposed Algorithm for Diagnosis and Management of Non-thrombotic Iliac Vein Lesions

History and physical examination: Have non-venous causes of the patient’s symptoms been excluded?

Is there refractory or recalcitrant oedema, venous claudication or persistent stasis ulcer despite conservative management (e.g. compression stockings) and/or superficial venous therapy?

Non-invasive imaging studies: venous duplex ultrasound, CTV, MRV. Is there evidence of extrinsic compression?

Work up and treat nonvenous underlying cause

severe physical manifestation of venous disease, not taking into account functional limitaitons.16–18 At this time, there is no disease severity scoring metric that is specific to NIVL. Regardless of the classification system used, a baseline disease severity should be documented to allow assessment of clinical progression or improvement after treatment.

Continue conservative management

Consider other non-venous diagnosis of exclusion, such as lymphoedema

Catheter-based venography and IVUS ± stent placement

CTV = CT venography; IVUS = intravascular ultrasound; MRV = magnetic resonance venography.

were minimally symptomatic with telangiectasias/reticular veins (C1 by CEAP classification).12 Thus, the presence of a NIVL by imaging does not directly correlate to the presence of clinically symptomatic venous obstructive disease.

Symptomatic patients with NIVLs experience varying degrees of CVI symptoms in the lower extremities. These symptoms include – but are not limited to – lower extremity heaviness, discomfort, pain, oedema, varicose veins, telangiectasia or, in its most severe form, ulcers, in the affected lower extremity. Women with NIVLs may experience additional symptoms including chronic pelvic pain, dyspareunia, vulvar swelling/pressure, and superficial lower extremity pelvic-derived varicosities.

Given the wide range of presentation of NIVL, it has been hypothesised that NIVL is a permissive lesion, and factors such as vessel trauma or oedema are likely to precipitate further symptom manifestation.13 However, it remains unclear in which instances these lesions become clinically significant; a clinical conundrum, given a significant portion of the population has clinically silent compression that does not need treatment. Therefore, screening of asymptomatic patients currently remains impractical. Rather, these studies highlight the importance of appropriately selecting patients with symptoms directly attributable to iliac vein obstruction to maximise the potential benefits of endovascular treatment.

Approach to Diagnostic Workup

Diagnostic workup for a patient suspected to have a NIVL should begin with thorough history and physical examination to look for other aetiologies of the patient’s symptoms, including but not limited to medications (e.g. calcium channel blockers), congestive heart failure, lymphoedema, liver disease and endocrine dysfunction. Once other nonvascular aetiologies have been excluded and NIVL is suspected to be a major contributor to the patient’s symptoms, further evaluation for diagnosis and characterisation of NIVL may be pursued (Figure 1). Given that CVI more frequently affects women, female patients should routinely and specifically be assessed for chronic pelvic pain symptoms.14,15

The severity of symptoms can be scored using the revised Venous Clinical Severity Score (VCSS). This can be supplemented by the CEAP system, although this assessment lacks precision and simply reports the most

Imaging studies aid in diagnosis and treatment planning. Initial non-invasive workup should include a venous duplex ultrasound, which may directly visualise compression or obstruction of the iliac vein as well as exclude venous thrombosis and post-thrombotic changes. Venous insufficiency or reflux should be assessed with augmentation techniques. Ultrasound evaluation of the iliac vein may be limited by technical factors (including operator experience, body habitus, or overlying bowel gas) and may fail to directly visualise the pathology within the iliac vein. In these cases, indirect findings of a clinically significant iliac vein lesion may be utilised. These include pre-stenotic vein dilatation, absent respiratory phasicity, internal iliac vein flow reversal and poor response to augmentation.19–23 In addition to duplex ultrasound, axial imaging may aid in non-invasive diagnosis. CT or magnetic resonance venography (MRV) can identify extrinsic compression, as well as concurrent thrombosis or presence of collateral veins. Limitations of cross-sectional imaging includes variable sensitivity depending on the hydration status of the patient, ionizing radiation with the use of CT, and necessity for local expertise with MRV.24 Catheter-based venography and intravascular ultrasound (IVUS) are the primary interventional imaging modalities for diagnosis and treatment of NIVLs. With IVUS, high resolution circumferential sonographic imaging with high frequency probes leads to improved accuracy of diagnosing venous lesions, such as webs or spurs.24–28 Additionally, IVUS is critical to improved accuracy of luminal measurements for treatment planning and stent size selection, as well as assessment following stent placement.29,30

Endovascular Management

Asymptomatic patients with NIVLs discovered incidentally are not candidates for endovascular intervention. In these patients, counselling on risks of developing symptoms of CVI including DVT may be indicated, though has not been prospectively validated.31–34 Conservative management should always be pursued first in patients with symptoms of CVI, including regular use of compression stockings. Endovascular management should be considered in patients with moderate to severe symptoms and those who are refractory to conservative management. For patients with superficial venous pathology that is thought to be a significant contributing cause to their symptoms, superficial treatment should be considered prior to iliac vein stent placement.

The primary objective of intervention for an obstructive venous lesion is to establish adequate inflow and outflow. Studies have found that angioplasty without stent placement for NIVL is generally not sufficient because of lesion recoil, therefore stent placement is the primary endovascular treatment modality for NIVL.35 The interventional procedure involves a series of general technical steps. First, ultrasound-guided venous access is obtained below the level of disease, typically in the ipsilateral common femoral, cranial great saphenous, or femoral vein with placement of a vascular sheath. Initial venography is performed to assess the lesion and the degree of compression/obstruction, presence of pre-stenotic dilation and venous collaterals. IVUS is then used to further assess the obstructive venous lesion and obtain measurements to determine the size of the stent. The size of the stent is chosen based on the size of the adjacent normal segment (Figure 2). In our practice, we use a normal ipsilateral external iliac vein; care must be taken to not measure pre-stenotic dilation as a reference segment as this can lead to incorrect stent sizing. A self-

expanding stent is then deployed, extending into the external iliac vein, generally with a goal to extend the stent around the natural curve of the external iliac vein such that adequate stent anchoring in normal anatomy occurs, to minimise the risk of stent migration. Wallstent (Boston Scientific) is a type of elgiloy stent, which has now been approved for treatment of iliofemoral venous obstruction. Additionally, self-expanding nitinol stents such as VICI (Boston Scientific), Venovo (Becton Dickinson/Bard), Abre (Medtronic), and Zilver Vena (Cook Medical) have also been approved for this application in the United States. In Europe, Sinus Venous (Optimed) and BlueFlow (Plus Medica) are additional options.36

Historically, lesions with >50% area stenosis (corresponding to approximately 30% diameter stenosis) were considered candidates for stent placement.6,35,37 More recent evidence suggests otherwise. In the prospective, single-arm VIDIO trial, 68 patients were included with CEAP C4–6 who had a stent placement, 48 of whom had NIVL (20 had postthrombotic lesions).30 The study found no correlation between area of stenosis and outcome, and an area of receiver operating characteristic curve analysis demonstrated clinical improvement when a higher threshold of >61% diameter stenosis was used in NIVL.30 Based on this prospective trial, we suggest consideration of stent placement in patients with lesions that have >61% diameter stenosis relative to an average reference diameter in a normal venous segment (in our practice, this is frequently the external iliac vein). After placement of a stent, repeat venography and IVUS confirm appropriate stent position/apposition and the presence of unimpeded flow (Figure 3). Collaterals, if initially present, can be reassessed for resolution at this step, suggestive of a therapeutic outcome. Currently, there is no consensus on the use of anticoagulation or anti-platelet agents after stent placement.38 We do not routinely prescribe anticoagulation after NIVL stent placement.

In women with NIVL and coexistent ovarian vein reflux with symptoms of chronic pelvic pain, treatment should be directed according to the dominant symptomatic feature. For such patients who primarily present with pelvic pain and minimal lower extremity symptoms, we suggest ovarian vein embolisation prior to stent placement for NIVL. Patients who have a dominant feature of lower extremity symptoms, including venous claudication, we suggest consideration of initial stent placement. The patient should be reassessed at follow-up, with staged stent placement for NIVL or ovarian vein embolisation if symptoms are refractory or only minimally improved.

Outcomes and Complications

Stent placement has been shown to improve pain and swelling, ulcer healing and quality of life in NIVL patients.9,39,40 Oedema relief was reported in nearly 90% of the patients.41 Ulcer healing was reported in more than 80% patients, with one study reporting even better healing in patients with NIVL compared to post-thrombotic iliac vein lesions with 5-year healing rates of 87% and 66%, respectively.41,42

Multiple studies have reported excellent patency rates for endovascular treatment of NIVLs.9,43,44 A meta-analysis reported primary patency of 94.1% at 1 year and 88.9% at 3 years. Assisted primary-secondary patency rates were 100% at 3 years.45 In the recent prospective, multicentre trial VIRTUS, self-expanding nitinol stents were placed successfully in 170 symptomatic patients with >50% stenosis. At 1 year, the primary patency rate was 98.4% in the NIVL limb, compared with 79.8% in the post-thrombotic limb.36 In this study, which included patients with VCSS of ≥2 or CEAP ≥C3, 64% of patients (including both NIVL and post-thrombotic limbs) demonstrated at least a 3-point reduction in VCSS in 1 year, with 5-point average reduction

specifically in the NIVL limb.36 The majority (58%) of the patients (including both NIVL and post-thrombotic limbs) reported improvement in quality of life in 1 year with at least a 9-point reduction in the Chronic Venous Insufficiency Quality of Life Questionnaire-20, with 14-point average reduction specifically in the NIVL limb.36

The rate of development of in-stent restenotic material is lower in NIVL treatment compared with post-thrombotic lesion treatment. One study reported cumulative rate of material accumulation resulting in >50% stenosis to occur approximately in 1% of stents placed for NIVL lesions, compared to 10% for post-thrombotic lesions.9

The most common complication after endovascular treatment of NIVL is access-site-related complications including bleeding, haematomas or arteriovenous fistulas; the risk of the latter is further reduced by use of

Figure 2: Intravascular Ultrasound for the Treatment of Non-thrombotic Iliac Vein Lesions

Figure 3: Venographic Images from Nonthrombotic Iliac Vein Lesion Treatment

Intravascular ultrasound demonstrating (A) compression of the left common iliac vein resulting in subtotal luminal obliteration (red arrow) with adjacent patent right common iliac artery (green arrow) and (B) reference normal left external iliac vein used for stent sizing.

A: Initial venography demonstrating compression of the right common iliac vein (black arrows). B: Post-stent placement venography demonstrating satisfactory stent position with no residual compression. Intravascular ultrasound confirmed no residual compression (not shown).

ultrasound guidance.6,44 Another common complication includes, but is not limited to, back pain from stents, which is often self-limited.41 One specific complication of iliac vein stent placement is contralateral common iliac vein thrombosis from its exclusion in the case of stent extension into the inferior vena cava, though this is uncommon.46,47 Rare complications such as stent fracture, malposition, migration or erosion have also been reported.41

Future Directions

At this time, there is no consensus or guideline to suggest use of any specific stent for treatment of NIVL (for instance, those designed specifically for treatment of May–Thurner syndrome versus standard stents), although this would warrant further investigation. Additional areas for investigation include refinement of our understanding of what

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constellation of symptoms constitute a clinically relevant NIVL, identification of validated diagnostic criteria for NIVL given the presence of specific symptoms and procedural endpoints and outcomes measurements to demonstrate clinical improvement following treatment.

Conclusion

Appropriate initial patient selection is key to a successful outcome in the endovascular treatment of NIVL. Further studies are needed to determine which lesional or clinical features lead to a NIVL becoming clinically symptomatic, given that a significant number of NIVLs are clinically silent and do not merit treatment. Studies have demonstrated that stent placement is safe and effective with largely positive outcomes when performed at experienced centres in patients where it is clinically indicated.

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18. Vasquez MA, Rabe E, McLafferty RB, et al. Revision of the venous clinical severity score: venous outcomes consensus statement. J Vasc Surg 2010;52:1387–96. https://doi. org/10.1016/j.jvs.2010.06.161; PMID: 20875713.

19. Hui JZ, Goldman RE, Mabud TS, et al. Diagnostic performance of lower extremity Doppler ultrasound in detecting iliocaval obstruction. J Vasc Surg Venous Lymphat Disord 2020;8:821–30. https://doi.org/10.1016/j. jvsv.2019.12.074; PMID: 32107162.

20. Sloves J, Almeida JI. Venous duplex ultrasound protocol for iliocaval disease. J Vasc Surg Venous Lymphat Disord 2018;6:748–57. https://doi.org/10.1016/j.jvsv.2018.06.005; PMID: 30336903.

21. Jain AK, Soult MC, Resnick SA, et al. Detecting iliac vein thrombosis with current protocols of lower extremity venous duplex ultrasound. J Vasc Surg Venous Lymphat Disord 2018;6:724–9. https://doi.org/10.1016/j.jvsv.2018.06.010; PMID: 30336900.

22. Metzger PB, Rossi FH, Kambara AM, et al. Criteria for detecting significant chronic iliac venous obstructions with duplex ultrasound. J Vasc Surg Venous Lymphat Disord 2016;4:18–27. https://doi.org/10.1016/j.jvsv.2015.07.002; PMID: 26946891.

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24. Toh MR, Tang TY, Lim H, et al. Review of imaging and endovascular intervention of iliocaval venous compression syndrome. World J Radiol 2020;12:18–28. https://doi. org/10.4329/wjr.v12.i3.18; PMID: 32226586.

25. Forauer AR, Gemmete JJ, Dasika NL, et al. Intravascular ultrasound in the diagnosis and treatment of iliac vein compression (May-Thurner) syndrome. J Vasc Interv Radiol 2002;13:523–7. https://doi.org/10.1016/S1051-0443(07)615358; PMID: 11997362.

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27. Hurst DR, Forauer AR, Bloom JR, et al. Diagnosis and endovascular treatment of iliocaval compression syndrome. J Vasc Surg 2001;34:106–13. https://doi.org/10.1067/ mva.2001.114213; PMID: 11436082.

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29. Gagne PJ, Tahara RW, Fastabend CP, et al. Venography versus intravascular ultrasound for diagnosing and treating iliofemoral vein obstruction. J Vasc Surg Venous Lymphat Disord 2017;5:678–87. https://doi.org/10.1016/j. jvsv.2017.04.007; PMID: 28818221.

30. Gagne PJ, Gasparis A, Black S, et al. Analysis of threshold stenosis by multiplanar venogram and intravascular ultrasound examination for predicting clinical improvement after iliofemoral vein stenting in the VIDIO trial. J Vasc Surg Venous Lymphat Disord 2018;6:48–56.E1. https://doi. org/10.1016/j.jvsv.2017.07.009; PMID: 29033314.

31. Chen F, Den J, Yuan QW, et al. Compression of left common iliac vein is independently associated with left-sided deep vein thrombosis. J Vasc Surg Venous Lymphat Disord 2013;1:364–9. https://doi.org/10.1016/j.jvsv.2013.05.001; PMID: 26992757.

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org/10.1177/1358863X14560429; PMID: 25502563.

33. Chan KT, Tye GA, Popat RA, et al. Common iliac vein stenosis: a risk factor for oral contraceptive-induced deep vein thrombosis. Am J Obstet Gynecol 2011;205:537.e531–6. https://doi.org/10.1016/j.ajog.2011.06.100; PMID: 21893308.

34. Carr S, Chan K, Rosenberg J, et al. Correlation of the diameter of the left common iliac vein with the risk of lowerextremity deep venous thrombosis. J Vasc Interv Radiol 2012;23:1467–72. https://doi.org/10.1016/j.jvir.2012.07.030; PMID: 23101919.

35. Raju S. Treatment of iliac-caval outflow obstruction. Semin Vasc Surg 2015;28:47–53. https://doi.org/10.1053/j. semvascsurg.2015.07.001; PMID: 26358309.

36. Razavi MK, Black S, Gagne P, et al. Pivotal study of endovenous stent placement for symptomatic iliofemoral venous obstruction. Circ Cardiovasc Interv 2019;12:e008268. https://doi.org/10.1161/CIRCINTERVENTIONS.119.008268; PMID: 31833414.

37. Raju S, Tackett P, Jr., Neglen P. Reinterventions for nonocclusive iliofemoral venous stent malfunctions. J Vasc Surg 2009;49:511–8. https://doi.org/10.1016/j. jvs.2008.08.003; PMID: 18945579.

38. Tran MA, Lakhanpal P, Lakhanpal S, et al. Type of antithrombotic therapy for venous stenting in patients with nonthrombotic iliac vein lesions does not influence the development of in-stent restenosis. Phlebology 2020;35:805–13. https://doi.org/10.1177/0268355520941385; PMID: 32664804.

39. Raju S, Darcey R, Neglen P. Unexpected major role for venous stenting in deep reflux disease. J Vasc Surg 2010;51:401–88. https://doi.org/10.1016/j.jvs.2009.08.032; PMID: 20006920.

40. Liu Z, Gao N, Shen L, et al. Endovascular treatment for symptomatic iliac vein compression syndrome: a prospective consecutive series of 48 patients. Ann Vasc Surg 2014;28:695–704. https://doi.org/10.1016/j.avsg.2013.05.019; PMID: 24559785.

41. Ye K, Lu X, Li W, et al. Long-term outcomes of stent placement for symptomatic nonthrombotic iliac vein compression lesions in chronic venous disease. J Vasc Interv Radiol 2012;23:497–502. https://doi.org/10.1016/j. jvir.2011.12.021; PMID: 22342482.

42. Raju S, Kirk OK, Jones TL. Endovenous management of venous leg ulcers. J Vasc Surg Venous Lymphat Disord 2013;1:165–72. https://doi.org/10.1016/j.jvsv.2012.09.006; PMID: 26992338.

43. Raju S, Owen S, Jr., Neglen P. The clinical impact of iliac venous stents in the management of chronic venous insufficiency. J Vasc Surg 2002;35:8–15. https://doi. org/10.1067/mva.2002.121054; PMID: 11802127.

44. Razavi MK, Jaff MR, Miller LE. Safety and effectiveness of stent placement for iliofemoral venous outflow obstruction: systematic review and meta-analysis. Circ Cardiovasc Interv 2015;8:e002772. https://doi.org/10.1161/ CIRCINTERVENTIONS.115.002772; PMID: 26438686.

45. Wen-da W, Yu Z, Yue-Xin C. Stenting for chronic obstructive venous disease: a current comprehensive meta-analysis and systematic review. Phlebology 2016;31:376–89. https:// doi.org/10.1177/0268355515596474; PMID: 26205370.

46. Khairy SA, Neves RJ, Hartung O, O’Sullivan GJ. Factors associated with contralateral deep venous thrombosis after iliocaval venous stenting. Eur J Vasc Endovasc Surg 2017;54:745–51. https://doi.org/10.1016/j.ejvs.2017.07.011; PMID: 28886989.

47. Gloviczki P, Lawrence PF. Iliac vein stenting and contralateral deep vein thrombosis. J Vasc Surg Venous Lymphat Disord 2017;5:5–6. https://doi.org/10.1016/j. jvsv.2016.11.002; PMID: 27987610.

A Clinical Trial of Venous Stent Placement for Post-thrombotic Syndrome: Current Status and Pandemic-related Changes

Suresh Vedantham , 1 Sameer Parpia 2 and Susan R Kahn 3

1. Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, US;

2. Departments of Oncology, and Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada;

3. Faculty of Medicine and Health Sciences, McGill University, Montreal, Canada

Abstract

Patients with post-thrombotic syndrome (PTS) and iliac vein obstruction have lower extremity symptoms, activity limitation and impairment of health-related quality of life. Preliminary studies suggest that iliac vein stent placement, which eliminates venous outflow obstruction, may reduce the clinical severity of PTS. However, stent placement is associated with patient risk, inconvenience and cost. Therefore, the Chronic Venous Thrombosis – Relief with Adjunctive Catheter-directed Therapy (C-TRACT) trial was launched to rigorously assess the risk–benefit ratio of stent placement for the treatment of moderate or severe PTS. In the trial, patients in both treatment groups receive a high quality of multimodality PTS care that includes medical, compressive, and ulcer therapies. Due to the COVID-19 pandemic, the trial protocol and practices were modified to enhance the study feasibility while preserving its ability to answer its primary question. This review summarises the current status of the trial and the potential impact of the pandemic-related adaptations to future venous clinical practice and research.

Keywords

Deep vein thrombosis, post-thrombotic syndrome, stent, randomised trial

Disclosure: SV receives research support from Medi USA (in-kind donation of compression garments to C-TRACT study patients; no funds). SRK receives consulting fees from Alexion and may receive consulting fees from Sanofi (to her institution). SP has no conflicts of interest to declare.

Funding: The C-TRACT trial is sponsored by the National Heart, Lung, and Blood Institute (NHLBI) of the US National Institutes of Health (NIH) via grants UH3-HL138325 and U24-HL137835 (www.bloodclotstudy.wustl.edu). Study development was supported by additional NHLBI grants (U34-HL123831 and UG3-HL138325). Medi USA donates compression garments to study patients. SRK receives research support from the CanVECTOR Network and the Canadian Institutes of Health Research.

Acknowledgements: The authors thank the following additional investigators who contributed to the study: David J Cohen, Anthony J Comerota, Samuel Z Goldhaber, Jim Julian, Clive Kearon (deceased), Andrei Kindzelski, Elizabeth A Magnuson, Elaine Majerus, Daniel Marcus, William Marston, Mahmood K Razavi, Akhilesh Sista, Suman Wasan and Ido Weinberg. The authors also thank the investigators and research staff members at the study’s clinical centres, core laboratories and coordinating centres, and the patients who have generously volunteered to participate in the study.

Received: 27 October 2021

Accepted: 8 April 2022 Citation: Vascular & Endovascular Review 2022;5:e06. DOI: https://doi.org/10.15420/ver.2021.19

Correspondence: Suresh Vedantham, Mallinckrodt Institute of Radiology, 510 S Kingshighway Blvd, CB 8131-43-1220, St Louis, MO 63110, US. E: vedanthams@wustl.edu

Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

A substantial proportion of patients with proximal lower extremity deep vein thrombosis (DVT) develop post-thrombotic syndrome (PTS) within 2 years.1 These patients often experience severe leg swelling, chronic pain, venous claudication and stasis dermatitis, with some progressing to skin ulceration. As a result, PTS is associated with substantial impairment of health-related quality of life (QOL), direct medical costs and indirect costs to society.2,3

Conservative means of managing PTS do not restore normal venous physiology. In contrast, endovascular stent placement directly addresses the venous outflow obstruction and ambulatory hypertension that underlie the most severe PTS manifestations. Although stents have been used to treat PTS by endovascular specialists for many years, no multicentre randomised controlled trial (RCT) has been completed to show that they reduce clinically important PTS in a durable, safe and cost-effective manner.4 Due to the absence of such data, relatively few medical physicians routinely refer PTS patients for stent placement. In 2018, the Chronic Venous Thrombosis – Relief with Adjunctive Catheter-directed

Therapy (C-TRACT) trial was launched to rigorously evaluate iliac vein stent placement in patients with moderate or severe PTS.5 Although the results will not be available for a few years, this article summarises some ways in which this ongoing pivotal study can contribute to improving venous clinical practice and clinical trial implementation.

Study Rationale

There currently exists only a single published pilot RCT evaluating stent placement for chronic venous disease.6 In that double-blind, single-centre study performed in Brazil, 51 limbs with moderate–severe chronic venous disease and iliac vein obstruction were randomised to receive, or not receive, iliac vein stents. Patients in the non-stented arm underwent a sham procedure to maintain patient blinding, and patients in both arms received standard PTS therapy. Greater improvement in pain scores, Venous Clinical Severity Scale (VCSS) scores and QOL scores were seen over 6 months in the stented patients compared with the non-stented patients.6,7 However, PTS patients comprised only half the study sample and the study did not use dedicated venous stents that may offer greater

resistance to axial compression. Given that it was a pilot study in a single centre, that trial was not designed to provide precise estimates of treatment effects and harms that can be broadly generalised to other clinical practices.

The absence of a pivotal multicentre RCT evaluating iliac stent placement has created a number of problems. One the one hand, whereas many thousands of patients with previous DVT live with moderate or severe PTS, only a tiny fraction are referred to endovascular specialists for consultation. Many of them experience tragic life consequences and longterm disability, and are entirely unaware that their condition may be amenable to treatment. With the advent of direct oral anticoagulants, improved venous diagnostic capabilities and new endovascular treatment tools on top of the existing array of venoactive drugs and compression devices, there appears to be substantial potential to help these individuals. On the other hand, it is equally clear that patient selection for endovascular therapy may be excessively lax in some centres, and the experience to date with venous stent therapy also hints at potential drawbacks.

Although dedicated venous stents appear to enable more precise deployment and may resist axial compression better than older devices that were designed for non-venous indications, stent patency in PTS populations has been at approximately only 80% at 1-year follow-up and 70% at 3-year follow-up.8–10 In addition, maldeployment, migration and fracture of dedicated venous stents have been reported; and although the relative contributions of operator error and inexperience versus device limitations are unclear, these events have prompted two brands to be recalled from the marketplace.11,12

Overall, at this time, it is difficult to confidently forecast whether any individual patient will experience durable benefit from iliac vein stent placement and remain free of complications. This is of particular concern because many candidates for endovascular PTS therapy are relatively young, with long life expectancies. Given the absence of credible evidence of benefits, long-term complications and re-interventions after endovascular stent therapy can lead to patient dissatisfaction that negatively affects the patient–provider relationship and that poses risks for the provider as well. For these reasons, the successful completion of high-quality studies to rigorously quantify the risk–benefit ratio of venous stent placement is particularly urgent.

C-TRACT (NCT03250247) is a Phase III, multicentre, open-label, assessorblinded, parallel two-arm RCT that is sponsored by the National Heart, Lung, and Blood Institute (NHLBI), a part of the US National Institutes of Health (NIH). The study is being conducted under an investigational device exemption granted by the Food and Drug Administration (FDA).

Approximately 374 adult patients with moderate or severe PTS and iliac vein obstruction are being randomised to receive endovascular stent therapy + standard PTS therapy versus standard PTS therapy alone. The primary study hypothesis is that the use of endovascular stent therapy will reduce the severity of PTS at 6 months, assessed by a blinded examiner using the VCSS measure. Secondary outcomes assessed over 24 months include PTS severity, QOL, ulcer healing, safety, valve reflux and costeffectiveness. The study enrolled its first patient in July 2018 and is currently active in 30 US clinical centres.

Modelling Quality Venous Clinical Practice

High-quality data will benefit future care, but there is an equally pressing need for an immediate elevation of general clinical practice awareness

and standards around PTS care. Worldwide, and even within local clinical practices, PTS care is highly variable: few providers are well-educated on the nature of this condition or the various modes of therapy that can be used to help patients. Against this background, the C-TRACT trial can be a compelling vehicle to improve PTS care.

Because publicly funded studies require robust multidisciplinary expertise, community input and extensive peer review prior to funding, the resulting study protocols often provide excellent examples of expert consensus on best practices for disease management. This is certainly true of C-TRACT, which was developed via an organised multi-specialty process with active NHLBI support.5 In a number of areas, this study can be used to model the delivery of high-quality PTS care, including endovascular intervention.

Improving Patient Selection

The recent dramatic increase in the number of stent placements, endovascular operators and complications has prompted concern among venous experts and societies about current patient selection practices.13 C-TRACT restricts study inclusion to patients with sufficient life impact from PTS to justify a permanent device implant, and a strong potential to respond to stent recanalisation. Study patients must have PTS that is causing substantial limitation of daily activities or work capacity due to venous symptoms or a venous ulcer. Patients who do not have a VCSS score ≥8, a Villalta score ≥10, or an open venous ulcer are excluded.14

Study patients must also have ipsilateral iliac vein obstruction, as shown by occlusion or ≥50% stenosis on venogram, CT venogram, MRI venogram or intravascular ultrasound (IVUS); or a combination of reduced venous outflow fraction on air plethysmography and abnormal duplex ultrasound. Patients with poor inflow to the common femoral vein are excluded. Hence, patients with mild PTS, mild stenosis or a low likelihood of favourable stent patency are excluded from study participation and the risks of stent placement. Were these or similar criteria to be followed in clinical practice, the number of unnecessary or ineffective stent placements might be reduced.

Encouraging Quality Conservative Therapy

Traditional medical training can be criticised for a failure to view venous disease through a holistic lens. Indeed, many providers are trained to think about treating ‘chronic occlusions’ rather than ‘patients with a serious condition that is amenable to risk factor modification and multimodality therapies’. The C-TRACT trial plan instructs research teams to counsel patients in both treatment groups on lifestyle-related measures that they can take to reduce PTS severity. Compression therapy appropriate to the presence or non-presence of an open ulcer is routinely prescribed to study patients.

At each visit, the value of compression is reinforced and adjustments are made to address residual symptoms or intolerance. Anticoagulant therapy is reviewed and modified to follow published clinical practice guidelines for DVT care. The use of venoactive drugs that have been evaluated for chronic venous disease is encouraged, including pentoxyfilline for venous ulcers. Patients with ulcers are managed in specialised wound ulcer care facilities that adhere to published guidelines.15 Endovenous ablation is encouraged for patients in either arm who have saphenous reflux and a venous ulcer.16 In this way, C-TRACT proposes a conservative multimodality regimen that, if used in clinical practice, may enable some PTS patients to improve and be spared an irreversible stent implantation. Conversely, persistent disability after institution of the above organised program can strengthen the justification to consider endovascular options.

Advancing Best Practices for Endovascular Therapy

The C-TRACT endovascular therapy protocol embeds a number of good practices that can enhance safety and efficacy. The use of ultrasound guidance for venous access is required, as is the use of venography and IVUS to define the extent of the obstructive process.17,18 After crossing the obstruction, predilatation is required to optimise the potential for maximum stent expansion.

Self-expandable bare stents made of elgiloy or nitinol that are legally marketed in the United States (but not under recall) may be used, with the use of FDA-approved dedicated venous stents encouraged. Stents must be dilated to at least 12 mm (for the iliac vein, at least 14 mm is strongly encouraged). Post-stenting venogram and IVUS must be performed. Patients should receive anticoagulation and antiplatelet therapy daily for at least 6 months after the procedure, with low-molecular-weight heparin strongly recommended for the first 3 months if possible. General adoption of these practices to ensure optimal venous imaging, device selection and sizing, and follow-up care seems likely to enhance the likelihood of achieving durable stent patencies.

COVID-19 Pandemic: Adaptations and Opportunities

In-person follow-up visits of patients enrolled in the C-TRACT trial were initially planned for 2, 4, 6, 12, 18 and 24 months after randomisation. However, the onset of the COVID-19 pandemic in early 2020 resulted in near-complete cessation of in-person study activity for several months, with an incomplete and heterogeneous recovery thereafter. In March 2020, the C-TRACT investigators were provided written guidance on adapting the conduct of the study to the conditions imposed by the COVID-19 pandemic, which included allowance of remote visits when dictated by patient risk level and local requirements.

Coordinating centre staff applied enormous energy to actively engaging with study teams to guide them in implementing the study during the pandemic. Despite these efforts, it was observed that many participants were missing follow-up visits and that the complexities of arranging the visits were burdensome for study teams due to local COVID-19 restrictions on face-to-face visits and limitations on available staffing. Therefore, in January 2021 the protocol was amended to convert the 2-, 4-, 12-, 18- and 24-month visits into remote visits that could be performed with telemedicine tools.

Of note, although the study data capture at these time points is now conducted remotely, physicians are still encouraged to bring patients back for in-person clinical visits as needed to ensure quality PTS care, as is possible per local conditions and patient-specific risks: for example, to re-size compression therapy and maintain a high-quality relationship between the patient and the care team.

Importantly, to maintain the integrity of the study’s primary outcome assessment, the baseline and 6-month visits and VCSS assessments have been retained as required in-person visits, per the study’s original design. However, the Patient-Reported Villalta (PRV) scale has been substituted for the in-person VCSS and Villalta PTS Scale assessments that were required as secondary assessments at 12, 18 and 24 months, enabling remote data capture. The PRV, designed to permit patient self-assessment of the elements of the original Villalta PTS Scale, has been shown to have excellent agreement with the original scale when used with an accompanying visual aid (which is provided to study patients) to guide patients in self-assessing their visible PTS signs.19 The PRV has been

successfully used to enable remote assessment of PTS in a previous large clinical study.20 The study’s QOL questionnaires are now largely completed by participants at home and collected by mail.21,22

The C-TRACT investigators certainly did not foresee the possibility of being compelled to institute a mid-trial change in outcome assessment. However, the adaptations to the pandemic speak to new opportunities to revitalise the venous disease clinical trial enterprise. It has long been recognised that clinical trial conduct in the US can be inefficient and cumbersome, reducing the speed with which new therapies are translated into clinical practice; many of the same issues exist in other countries as well. The barriers are particularly high for investigator-initiated studies that evaluate complex (e.g. endovascular) interventions and that seek to compare treatment paradigms.

C-TRACT is already the largest RCT of its kind; however, despite starting more than 3 years earlier, the trial has enrolled less than one-third of its pre-planned patient sample. Of note, slow accrual was also observed with other major NIH endovascular trials (e.g. CORAL, ATTRACT, BEST-CLI).23,24 In this sense, it is hoped that an important silver lining of the pandemic will be the accelerated integration of innovative technology to support remote clinical trial conduct. In response to the pandemic, C-TRACT incorporated electronic informed consent, telemedicine visits and patient-reported remote clinical assessments. Beyond improving data capture, it is hoped that the reduction in the participant burden to only 2–3 required in-person visits will increase enthusiasm among patients (especially those who live distant from a clinical centre) to be enrolled and followed in the study.

It is hoped that venous clinical trials will routinely include such modes of efficient trial conduct, and that there will be robust efforts to scientifically validate new venous outcome assessment tools that can be remotely administered using smartphones, wearables and other mobile tools, as is done for other diseases.25 In addition to making trial participation easier for patients and less resource intensive for study teams, such tools have the potential to address a crucial current limitation of venous outcome assessment, namely, that despite the fact that PTS causes daily symptoms and life impact that fluctuates over time, patients are currently assessed only a few times during follow-up (e.g. every 6 months). The development and validation of remote venous assessment tools could enable a more complete capture of a patient’s daily experience with PTS. Their use should not be limited to research studies, but could be applied in clinical practice to enhance the follow-up of patient status and improve the overall patient experience by improving the degree and quality of communication with the patient care team.

Given the ongoing challenges to study enrolment, technology is also being applied to connect potential study candidates to C-TRACT Trial research teams. An institutional review board (IRB)-approved mobile app has been developed for the C-TRACT trial, and is available on the Apple and Google Play stores. This app is designed to enable rapid, Health Insurance Portability and Accountability Act (HIPAA)-compliant referral of a potential patient to the study by a busy provider. The provider answers three quick questions via check-box and enters a provider (e.g. nurse coordinator) contact telephone number, then the app sends a HIPAAcompliant message to the study’s clinical coordinating centre, whose staff then call the provided contact number to hear about the patient.

In addition, a number of barriers to study referral among endovascular providers have been recognised: first, within some surgical and interventional radiology practices the traditional culture is for a physician

to manage the patients referred to them, and the health system may reward providers with higher procedure volumes (these factors can deter physicians from referring patients even to providers within the same practice); second, referral to other (often competitive) local centres is often discouraged by division leaders and hospital systems, and there can also be insurance coverage barriers; and last, providers have different perceptions of the willingness of patients and caregivers to travel to more distant clinical sites for a clinical trial participation opportunity, which can reduce their inclination to refer patients. Hence, the C-TRACT investigators are now pursuing a social media campaign to directly target IRB-approved, study-related messaging to a target audience of DVT-interested laypersons (patients, family members and other caregivers). It is hoped that these technology-assisted strategies will pay major dividends in accelerating the pace of recruitment to this study, and that they can similarly support other studies and patient needs in clinical practice.

Conclusion

The C-TRACT trial will rigorously characterise the risk–benefit ratio of endovascular stent therapy for PTS. From a patient’s perspective, study enrolment enhances the likelihood of receiving high-quality expertendorsed PTS care and affords them the benefits of independent safety

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oversight, which is valuable given the nature of the endovascular procedure being evaluated. In addition, C-TRACT provides a useful model from which to improve the global standard for PTS care and drive innovation in the implementation of pivotal venous clinical trials.

Clinical Perspective

• Endovascular stent placement has shown strong potential to improve clinical outcomes in patients with severe limb symptoms and disability from post-thrombotic syndrome (PTS), but also poses risks and costs.

• Selection of PTS patients for venous stent placement in clinical practice can be improved through careful patient evaluation and diligent application of conservative therapies, as modelled by the National Institutes of Health-sponsored C-TRACT trial and other studies.

• The application of modern technology to aid the implementation of the C-TRACT trial during the COVID-19 pandemic highlights the potential for technology adjuncts to improve the PTS patient experience and expedite the completion of pivotal clinical trials.

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19. Utne KK, Ghanima W, Koyn S, et al. Development and validation of a tool for patient reporting of symptoms and signs of the post-thrombotic syndrome. Thromb Haemost 2016;115:361–7. https://doi.org/10.1160/th15-04-0318; PMID: 26422814.

20. Utne KK, Dahm A, Wik HS, et al. Rivaroxaban versus warfarin for prevention of post-thrombotic syndrome. Thromb Res 2018;163:6–11. https://doi.org/10.1016/j. thromres.2018.01.013; PMID: 29324334.

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22. Kahn SR, Lamping DL, Ducruet T, et al. The VEINES-QOL/ Sym questionnaire is a valid and reliable measure of quality of life and symptoms in patients with deep vein thrombosis. J Clin Epidemiol 2006;59:1049–56. https://doi.org/10.1016/j. jclinepi.2005.10.016; PMID: 16980144.

23. Cooper CJ, Murphy TP, Cutlip DE, et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N Engl J Med 2014;370:13–22. https://doi.org/10.1056/ NEJMoa1310753; PMID: 24245566.

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25. Mofsen AM, Rodebaugh TL, Nicol GE, et al. When all else fails, listen to the patient: a viewpoint on the use of ecological momentary assessment in clinical trials. JMIR Ment Health 2019;6:e11845. https://doi.org/10.2196/11845; PMID: 31066701.

Does Current Evidence Support Carotid Artery Stenting for Asymptomatic Patients?

Mustafa Abbas and Trevor Cleveland

Sheffield Vascular Institute, Northern General Hospital, Sheffield, UK

Abstract

Carotid interventions, carotid endarterectomy and carotid artery stenting (CAS) have proven to be effective treatments for the prevention of ischaemic stroke in recently symptomatic patients. Most studies were conducted before the development of strict statin guidance and the systematic use of antiplatelet drugs. The advances in medical treatments have raised questions regarding the benefit of carotid endarterectomy or CAS, especially for high-grade asymptomatic internal carotid artery stenosis. Reviewing the literature indicates that carotid artery stenosis of any degree is a relatively weak predictor of ipsilateral stroke, in the absence of recent symptoms referable to the carotid disease. This risk does not appear reduced by revascularisation by CAS if added to modern day best medical therapy. On-going trials are key to understanding if current techniques can provide an additional benefit.

Keywords

Carotid artery stenting, carotid endarterectomy, carotid artery stenosis, best medical therapy, asymptomatic carotid artery stenosis, internal carotid artery, coronary artery bypass grafting, transient ischaemic attack, MRI, embolic protection devices.

Disclosure: The authors have no conflicts of interest to declare.

Received: 2 August 2020 Accepted: 18 April 2022 Citation: Vascular & Endovascular Review 2022;5:e07. DOI: https://doi.org/10.15420/ver.2020.18

Correspondence: Mustafa Abbas, Sheffield Vascular Institute, Northern General Hospital, Herries Rd, Sheffield S5 7AU, UK. E: mustafaabbas1@doctors.org.uk

Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Stroke is the third most common cause of death in developed countries and the fourth in the UK.1,2 Approximately 600,000 first-ever strokes occur every year in the US and 100,000–150,000 in the UK where 12.5% die within 30 days.2,3 Carotid artery atherosclerosis can progress with debilitating or fatal stroke as the first presentation (in some cases brain events can be demonstrated using MRI but remain clinically silent and usually undetected). Approximately 7–34% of strokes are because of disease in the extracranial internal carotid artery (ICA).3,4

Carotid artery stenosis (CS) is usually classified as being mild (<50% left main stem [LMS] loss), moderate (50–69% LMS loss) or severe (≥70% LMS loss).5 While prevalence is relatively low in the general population, it increases with age, affecting up to 12.5% of men and 6.9% of women >70 years of age.6

Although certain ethnic subgroups are at highest risk, notably white and Native American people, the prevalence of significant asymptomatic carotid artery stenosis (ACS) is found to be increased in patients with peripheral artery disease (up to 39% of this group).7 People who have undergone coronary artery bypass grafting (CABG) have a 26.4% prevalence of moderate ACS and 8.6% have severe ACS.5 Individuals who have ACS experience a 3% yearly risk of having a stroke, which equates to a >50% increased relative risk compared with the general population.2

CS is most frequently the result of narrowing of the carotid artery LMS caused by atherosclerotic plaque formation within the artery wall. This may result in symptoms such as ipsilateral carotid territory ischaemic

stroke, transient ischaemic attack (TIA) or amaurosis fugax. ACS is considered in individuals who have CS without a history of the localising events or lack of the symptoms for at least 6 months.8 Modern noninvasive imaging modalities – most notably duplex ultrasound – are performed for a variety of reasons, which has resulted in asymptomatic stenosis being more frequently detected. This leads to the question of whether these people should be considered for treatment of their asymptomatic carotid stenosis by stenting, in addition to medical therapy.

Furthermore, there are some situations where stroke risk is considered to be high, in the presence of an ACS, such as when undergoing another intervention. The relationship between stroke and CABG is the area that has attracted the most attention.

Therapeutic options to treat the carotid stenosis include carotid endarterectomy (CEA) and medical therapy, carotid artery stenting (CAS) and medical therapy or medical therapy alone. There is strong evidence that CAS or CEA for symptomatic ICA stenosis of >70%, in addition to best medical therapy (BMT), is beneficial. The maximum benefit of intervention after an ipsilateral TIA or non-disabling stroke accrues if delivered in the first 2 weeks after an event.9 Nevertheless, the long-term prevention of stroke in asymptomatic patients remains ambiguous regarding whether either of CEA or CAS, in addition to BMT, is better than BMT alone. The available data to inform balancing the risks and benefits of the use of CAS in ACS, are considered below. Some of those data from trials not directly designed for the investigation of ACS and CAS, with many trials including both symptomatic and asymptomatic patients and both CEA and CAS.

Published Randomised Trials

The ACAS and ACST 1 trials were published in 1995 and 2004, respectively, and have remained the basis for most of the subsequent guidelines.10,11 However, the outcomes after BMT, CAS and CEA have significantly improved in the last 20 years and the data from these two trials, which have supported every practice guideline since 1995, may no longer be appropriate for use in 2022.4

In the ACAS trial, people with ACS ≥60% were investigated. Patients were randomised to receive either medical therapy in addition to CEA, or medical therapy with 325 mg aspirin daily along with coronary vascular disease risk modification. Based on a mean follow up of 2.7 years, it was estimated that the 5-year risk of stroke or death was 5.1% in the CEA with medical therapy group and 11% in the medical therapy alone group.5 On that basis, CEA in addition to medical therapy is often recommended, provided that the risk of the CEA is kept low. For CAS to be considered as an alternative to CEA, it needs to be delivered with at least similar rates of stroke. This has been shown to be the case in the ACST-2 trial where the complications of CAS and CEA are similar.12

In the ACST 1 trial, participants with asymptomatic CS ≥60% were randomised to BMT with or without concomitant CEA. After excluding perioperative strokes, CEA was associated with a 6.4% rate of carotid territory stroke compared to 11.8% in the BMT group at 5 years. The risk of perioperative stroke in ACST 1 was 2.8% (1.5% in ACAS) and – again – CAS needs to be similar or better to offer benefit.11

The CREST 1 study recruited 2,502 patients and used a primary endpoint of periprocedural stroke, MI, death or long-term rates of ipsilateral stroke. There was no difference in the estimated 4-year rates of the primary endpoint in CEA and carotid stenting treatment (in addition to medical therapy) for symptomatic and asymptomatic patients.13 During the periprocedural period, there was a higher risk of MI with CEA against a higher risk of all stroke with CAS. Also noted in this study was the effect of age on outcomes, whereby patients aged <70 years appeared to have lower complication rates with CAS while patients aged >70 years appeared to have higher complication rates with CAS compared to CEA.14 The authors found that the annual risks of stroke in asymptomatic patients including the periprocedural risk were 1.2% with CAS and 0.95% with CEA.7

This trial did not have a comparator group of medical therapy alone for patients with ACS. Similar results were shown in ACT-I.15 In this trial (primary endpoint of stroke, MI and death within 30 days of the procedure or ipsilateral stroke within a year and follow up to 5 years), there was no significant difference in asymptomatic patients after CEA or stenting and the procedural risk threshold was below 3%. This trial also did not have a medical therapy arm. However, it does support the concept that CEA and CAS offer a similar utility in stroke prevention following successful treatment.

The SPACE-2 trial aimed to compare BMT plus intervention (CAS or CEA) in patients with asymptomatic carotid stenosis with BMT alone. Unfortunately, the study was stopped prematurely after randomising 513 patients because of recruitment difficulties. One important reason why SPACE-2 had poor recruitment was the unwillingness of patients to accept BMT alone (they had already been prepared to undergo an intervention using either CAS or CEA), particularly when these patients would have received BMT in all three study arms anyway.

However, at termination of the trial, there was no superiority of CEA or CAS against the BMT in the primary prevention of ischaemic stroke in

patients with an asymptomatic carotid stenosis up to 1 year after treatment. As a result of the early termination of the trial, the sample size was too small for statistical confidence. It did indicate that there were no apparent differences the between the CAS or CEA in terms of safety during the first year after treatment. A 5-year follow-up is on-going.6

The findings of ACST-2, which compared CEA with CAS for long-term stroke prevention in patients with severe ACS on BMT, has recently been published. This study showed no significant difference in the risk of adverse, procedure-related events for CAS and CEA. For both treatments, 1% of patients had a disabling stroke or died within 30 days (15 in the CAS group and 18 in the CEA group) and 2% had a non-disabling stroke (48 in the CAS group and 29 in the CEA group). In addition, the number of strokes that occurred in the participants over the 5-year follow-up period was similar for CAS and CEA. Non-procedural fatal or disabling stroke occurred in 2.5% of patients in each group, and the rate of strokes was 5.3% in the CAS group, and 4.5% in the CEA group. Other complications including MI (fatal and non-fatal) were approximately similar (0.3% with CAS and 0.7% with CEA). BMT can also reduce stroke rates but – even when receiving it – patients with severe CAS might have a risk of approximately 1% per year of disabling stroke or death. Hence, in addition to BMT, carotid procedures are still considered appropriate for many patients.12 Summarised data from the studies described above are in Table 1

Review of Meta-analysis Data

A review of more recent meta-analyses shows that the short-term vascular endpoints at 30 days (i.e. stroke, MI or vascular death) are lower with BMT compared with any surgical or endovascular intervention. This is the result of the peri-operative risk associated with either intervention.

The long-term risk of stroke up to 10 years is lower with CEA than BMT, while there is no difference in the risk of death between the interventional treatment (CAS and CEA) and BMT.16,17 No studies are available to compare CAS with BMT alone, but long-term outcomes are considered to be probably no different between CEA and CAS.16 A systematic review and meta-analysis that included data from 56 studies on the evidence on treating and screening ACS, was conducted by the US Preventive Services Task Force.18 The authors compared carotid revascularisation (CEA and CAS) with medical therapy. The data analysis showed an absolute risk reduction of 5.5% for any non-perioperative stroke over approximately 5 years follow-up. However there was a 2.4% risk of perioperative (30 days) stroke or death after CEA and CAS. This study concluded that there is no overall benefit of CEA or CAS in ACS.18

The Role of Best Medical Therapy in Asymptomatic Carotid Artery Stenosis

Regardless of treatment type (CEA or CAS), the consensus of current guidelines is that intervening in ACS is indicated when the life expectancy of the patients is >5 years and the perioperative risk is <3% (class IIa; level of evidence A) and that CAS might be considered in highly selected patients (class IIb; level of evidence B).19 However, the question arises whether modern BMT confers as much benefit in ACS as does CAS, and if so, whether the peri-procedural risk is worth taking.

BMT includes lifestyle modifications promoting a healthy lifestyle, including smoking cessation, physical activity, a healthy diet and wellcontrolled blood pressure. These are the cornerstones for primary and secondary atherosclerotic prevention, including that of stroke. According to the European Society of Cardiology, smoking increases the risk of heart disease and stroke fivefold in people <50 years and doubles the risk in

Table 1: Summary of Trial Characteristics

201615 (65 centres)

364

1,089

Aspirin CAS: Aspirin + clopidogrel

of ≥60% on angiography, ≥70% on ultrasound, or ≥80% on CTA/MRA if the stenosis on ultrasonography was 50–69%

Patients aged ≤79 years with 70–99% ICA stenosis without symptoms during the previous 180 days. In the absence of substantial (>60%) contralateral carotid stenosis.

CAS: 2.2% p=0.51

SPACE-2 20166 (36 centres)

2009–2014 513

CEA: 203

CAS: 197

BMT: 113

CEA: Aspirin CAS: Aspirin + clopidogrel

BMT: Aspirin

Patients aged 50–85 years with a 70–99% ICA stenosis based on ultrasound without stroke/ TIA symptoms within the preceding 180 days

Not mentioned 30 days, 5 years On-going

ACST-2 202112

2008–2020

3,625

CEA: 1,814

CAS: 1,811 90–91% on antiplatelets; 8–9% on anticoagulation.

Asymptomatic ICA stenosis ≥70%

Not mentioned 30 days, annually for 5 years.

CEA: 4.5%

CAS: 5.3%

BMT = best medical therapy; CAS = carotid artery stenting; CEA = carotid endarterectomy; CTA = CT angiography; ICA = internal carotid artery; MRA = magnetic resonance angiography; NA = not applicable; TIA = transient ischaemic attack.

those >60 years. The lifestyle guidelines from the American Heart Association in 2013 advocated, alongside smoking cessation, a dietary pattern that encourages the intake of fruits, vegetables and whole grains with a decreased intake of sweets, red meat and saturated fat. Guidelines also encourage increased use of the Mediterranean diet, supplemented by nuts (walnuts, hazelnuts and almonds) or by extra virgin olive oil in order to reduce the stroke risk, along with increasing the intake of B vitamins to lower homocysteine levels.20

Somewhat surprisingly, data supporting the use of antiplatelet therapy for primary stroke prevention in ACS are limited. Based on limited studies, such as the Women’s Health Study and the Asymptomatic Cervical Bruit Study, the current guidelines include a class I recommendation for aspirin therapy in patients with ACS, but there are no data supporting dual antiplatelet therapy for ACS in the absence of other cardiovascular diseases.7

There is growing evidence that only a minority of patients receiving BMT for asymptomatic ICA stenosis will benefit from intervention given the significant improvement in the preventative management of cardiovascular diseases, particularly with the development and use of antiplatelets and lipid-lowering therapy, alongside improvements in lifestyle care. This is demonstrated by the ACAS trial, in which the 5-year risk for ipsilateral stroke in 1995 was 11% in those receiving BMT. This was halved to 5.3% by 2004 and to 3.6% by 2010 as shown in the ACST 1 trial. This corresponds to an overall relative risk reduction of approximately 70% over 15 years.

Patients with ACS also have a substantial frequency of associated coronary artery atherosclerosis: MI is about half as frequent as stroke, while the risk of cardiovascular death exceeds that of stroke. Aggressive medical management of ACS offers the additional benefit of prevention of coronary events.17

Spence et al. argued that the annual risk of ipsilateral stroke with modern BMT should be as low as 0.5% per year in ACS; based on trials, such as ACT 1 and CREST 1, outcomes for patients who have interventions trail behind BMT after taking peri-procedural risks into account.21,22 The outcomes of intervention are now comparable to medical therapy in terms of long-term stroke prevention. However, the periprocedural risks still exceed the risks of medical therapy alone.

Therefore, only ACS patients with a factor that renders them at higher risk of stroke would be likely to benefit from interventions such as CAS or CEA. It has been proposed that there may be subgroups who may benefit, which may be based on evidence of embolic activity using trans-cranial Doppler, MRI plaque morphology or plaque inflammation on PET CT.21

The recent systematic review and meta-analysis by Howard et al. indicates that the more severe degrees of ACS may benefit from intervention, but not those considered to have moderate ACS.23 The potential of benefit in these groups, who are considered to be at higher risk of stroke, has yet to be thoroughly investigated or the case proven.

Future Randomised Controlled Trials

There are a number of on-going trials that are attempting to answer some of the uncertainties in relation to the benefit (or not) of CAS or CEA in addition to BMT for ACS. The results of these trials are pivotal in understanding patient benefits and risks.

The CREST-2 trial (NCT02089217) has been designed to allow and facilitate decision making regarding the optimal management of highgrade ACS. It is comparing stroke prevention by BMT alone against revascularisation (CEA or CAS) with BMT in patients with a 70–99% ACS. The results of this trial will be available after recruitment completion, which was expected to be in December 2020. Follow-up will be required, and, as with many trials currently, there may be delays because of the COVID-19 pandemic.

In ECST-2 (NCT00883402), where CEA and CAS are being compared with BMT in patients with severe ACS. ACTRIS (NCT02841098) will compare CEA with BMT against BMT alone. CAS is not included in the trial, therefore further direct information of CAS in asymptomatic patients will not be available from this study.

When we have the benefit of the results of these trials it is hoped that there will be more clarity regarding management of patients with ACS –particularly with the use of new-designed stents – potentially increasing the safety and effectiveness of the CAS.

Of interest there is a new study, CREST-H, which is designed to investigate the decline of cognition due to a reduction in the cerebral blood flow secondary to high-grade carotid stenosis, which is otherwise ‘asymptomatic’ in terms of TIA or stroke. The trialists explore whether revascularisation of a haemodynamically significant carotid stenosis can alter the course of cognitive decline.24

Patients Undergoing CABG with Concomitant Asymptomatic Carotid Disease

Patients who fall into this group are considered to have a high risk of stroke at the time of their coronary artery surgery. There has been much debate in the literature as to the potential benefit that may be gained by having the carotid disease treated either before, or at the same time as, the coronary artery bypass. One of the major problems with offering CEA prior to CABG is that there is a higher risk of myocardial events at the time of CEA. However, if the CEA is performed simultaneously with the CABG, the stroke risk may remain high.25

Analysis of data including 2,813 patients from a prospective multicentre observational study showed that in patients with ACS who are undergoing isolated CABG, the risk of postoperative stroke is significant only when the stenosis is ≥90%, with an incidence of stroke in these patients of approximately 7.0%.26 As there is potential for differing levels of carotid disease on either the left or right side, the total burden of carotid artery disease was addressed by Naylor et al.27 This analysis of the data concluded that there was an increase in the CABG-related stroke rate as the total burden of carotid disease increased.

Because of the perceived reduced risk of cardiac events occurring when CAS is performed prior to CABG rather than CEA (which is supported by trials such as CREST), CAS has been proposed as a preferable method for

treating high-grade carotid disease prior to CABG. This was reviewed in 2017 by Paraskevas et al. who included 31 studies of 2,727 patients in whom 80% were neurologically asymptomatic with unilateral stenoses.28 This meta-analysis suggested that overall 30-day outcomes after CAS and CABG or after CEA and CABG are broadly similar. However, in patients with a history of TIA/stroke, staged or same-day CEA and CABG is considered to be the preferred option over CAS and CABG. For the majority of the patients who are asymptomatic, the risks following CABG and CAS are 7.9% for death/stroke and an 8.8% risk of death/stroke/MI. This exceeds the risk of death/stroke in patients who are undergoing isolated CABG (no prophylactic CAS/CEA), where, in the presence of a >50% carotid stenosis, the prevalence of stroke within 30 days of CABG was 7.4%, while death/stroke was 8.3%. The conclusion was that prophylactic CAS in asymptomatic patients does not add any additional benefits over isolated CABG in this group of patients. However, from the work of Naylor et al., it may still be the case that those with a higher burden of disease do indeed obtain benefit if their ACS is treated prior to CABG. However, Santarpino et al. argue the opposite, that asymptomatic, severe CS has a low prevalence and when left untreated is associated with a relatively low risk of stroke. This may argue that preoperative screening for ACS before CABG may not be justified.26

Conclusion

Carotid interventions have proven to be an effective treatment in preventing ischaemic stroke in symptomatic patients. However, the majority of studies for asymptomatic patients – and indeed recentlysymptomatic patients – were conducted before the advances in modern medical treatment with lipid-lowering therapy, antiplatelet treatment, antihypertensives and good diabetic control, together with lifestyle modifications such as smoking cessation, regular exercise and a wellbalanced diet. This change in BMT is likely responsible for the 33% relative risk reduction in the 5-year risk of any stroke noted in ACST (published in 2004) compared to the earlier ACAS trial (published in 1995), which has raised questions regarding the benefit of CEA or CAS in the context of asymptomatic ICA stenosis.29

This review of the literature indicates that CS of any degree is a relatively weak predictor of ipsilateral stroke, in the absence of recent symptoms referable to the carotid disease, and that this risk is not reduced by revascularisation if added to best medical therapy. It is possible that there are some subgroups who are at higher risk of stroke and the evidence in support of CAS prior to CABG, even in high level disease, remains controversial. Evidence from further randomised controlled trials will be key.

There are on-going trials currently recruiting patients. CREST-2 will test CEA and CAS for asymptomatic ICA stenosis versus BMT. In ECST-2, CEA and CAS are being compared with BMT in patients with severe ACS and ACTRIS compares CEA with BMT against BMT alone. The results of these trials are yet to be published, at which time they will hopefully further clarify the role of carotid interventions.

Current data do not support the routine treatment of asymptomatic carotid stenosis with CAS, outside the realms of research, and in the small group of patients at particularly high risk from their stenosis, such as patients undergoing CABG with bilateral high-grade stenosis or those with severe stenosis.

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10. Walker MD, Marler JR, Goldstein M, et al. Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA 1995;273:1421–8. https://doi.org/10.1001/ jama.1995.03520420037035; PMID: 7723155.

11. Halliday A, Mansfield A, Marro J, et al. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet 2004;363:1491–502. https://doi.org/10.1016/S01406736(04)16146-1; PMID: 15135594.

12. Halliday A, Bulbulia R, Bonati LH, et al. Second Asymptomatic Carotid Surgery Trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy. Lancet 2021;398:1065–73. https://doi. org/10.1016/S0140-6736(21)01910-3; PMID: 34469763.

13. Brott TG, Hobson RW, Howard G, et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010;363:11–23. https://doi.org/10.1056/ NEJMoa0912321; PMID: 20505173.

14. Brott TG, Howard G, Roubin GS, et al. Long-term results of stenting versus endarterectomy for carotid-artery stenosis. N Engl J Med 2016;374:1021–31. https://doi.org/10.1056/ NEJMoa1505215; PMID: 26890472.

15. Rosenfield K, Matsumura JS, Chaturvedi S, et al. Randomized trial of stent versus surgery for asymptomatic carotid stenosis. N Engl J Med 2016;374:1011–20. https://doi. org/10.1056/NEJMoa1515706; PMID: 26886419.

16. Barkat M, Roy I, Antoniou SA, et al. Systematic review and network meta-analysis of treatment strategies for asymptomatic carotid disease. Sci Rep 2018;8:4458. https:// doi.org/10.1038/s41598-018-22356-z; PMID: 29535395.

17. Galyfos G, Sachsamanis G, Anastasiadou C, et al. Carotid endarterectomy versus carotid stenting or best medical treatment in asymptomatic patients with significant carotid stenosis: a meta-analysis. Cardiovasc Revasc Med 2019;20:413–23. https://doi.org/10.1016/j.carrev.2018.07.003; PMID: 30057288.

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20. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129 (25 Suppl 2):S76–99. https://doi.

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23. Howard DPJ, Gaziano L, Rothwell PM, Oxford Vascular Study. Risk of stroke in relation to degree of asymptomatic carotid stenosis: a population-based cohort study, systematic review, and meta-analysis. Lancet Neurol 2021;20:193–202. https://doi.org/10.1016/S14744422(20)30484-1; PMID: 33609477.

24. Marshall RS, Lazar RM, Liebeskind DS, et al. Carotid revascularization and medical management for asymptomatic carotid stenosis – hemodynamics (CREST-H): study design and rationale. Int J Stroke 2018;13:985–91. https://doi.org/10.1177/1747493018790088; PMID: 30132751.

25. Garg A, Bansal AR, Singh D, et al. Combining carotid endarterectomy with off-pump coronary artery bypass graft surgery is safe and effective. Ann Indian Acad Neurol 2015;18:419–23. https://doi.org/10.4103/0972-2327.165457; PMID: 26713014.

26. Santarpino G, Nicolini F, De Feo M, et al. Prognostic impact of asymptomatic carotid artery stenosis in patients undergoing coronary artery bypass grafting. Eur J Vasc Endovasc Surg 2018;56:741–8. https://doi.org/10.1016/j. ejvs.2018.07.042; PMID: 30197287.

27. Naylor AR, Mehta Z, Rothwell PM, Bell PRF. Carotid artery disease and stroke during coronary artery bypass: a critical review of the literature. Eur J Vasc Endovasc Surg 2002;23:283–94. https://doi.org/10.1053/ejvs.2002.1609; PMID: 11991687.

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Complex Endovascular Procedures

The Role of Renal Artery Embolisation in the Management of Blunt Renal Injuries: A Review

Rosemary Denning Ho ,

1,2 Vivek Shrivastava,2 Amir Mokhtari3 and Raghuram Lakshminarayan 2

Abstract

Renal injuries are the most common urinary tract injury secondary to external abdominal trauma. They are caused by blunt, penetrating and iatrogenic mechanisms. Despite the high number of blunt renal injuries, little evidence is available to guide management, especially with the evolution of embolisation as a minimally invasive treatment. Consequently, clinical practice is driven by results of observational studies and anecdote. We have reviewed the current trends in practice when using renal artery embolisation in the management of blunt renal injuries. Three key principles are highlighted. First, high-grade blunt renal injuries can be successfully managed with embolisation. Second, embolisation should be considered when there is radiological evidence of active contrast extravasation, pseudoaneurysm or arteriovenous fistula. Third, embolisation can be used to manage blunt renal injuries in haemodynamically unstable patients. Beyond this, evidence regarding optimal technique, CT indications, clinical status, comorbidities and complications are inconclusive. We discuss the implications for clinical practice and how these findings should define the agenda for future clinical research.

Keywords

Interventional radiology, embolisation, renal, trauma

Disclosure: RL is on the editorial board for Vascular & Endovascular Review; this did not influence peer review. All other authors have no conflicts of interest to declare.

Received: 12 January 2022 Accepted: 10 June 2022 Citation: Vascular & Endovascular Review 2022;5:e08. DOI: https://doi.org/10.15420/ver.2022.01

Correspondence: Rosemary Denning Ho, Hull York Medical School, University of York, University Rd, York YO10 5DD, UK. E: rdh@doctors.org.uk

Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Renal injuries occur in approximately 1–5% of all patients with trauma and are the most common urinary tract injury secondary to external abdominal trauma.1 Renal trauma mainly arises from blunt, penetrating and iatrogenic mechanisms.2 3 Despite how common blunt renal injuries (BRIs) are, little evidence is available to guide management. Patients can undergo operative management or non-operative management and the use of expectant management, embolisation and surgery vary from institution to institution.

We aim to review the current trends concerning renal artery embolisation in the management of BRIs. We examine the evidence for indications for embolisation, outcomes of embolisation and its comparison to surgical and other non-operative adjunctive management, technical considerations, injury characteristics warranting embolisation and complications. Based on the evidence, we propose a treatment algorithm for the management of patients with BRI.

The Evidence

American Association for the Surgery of Trauma Grade

BRIs are usually identified using helical CT.4 Injuries are graded according to the American Association for the Surgery of Trauma (AAST) grading system. The AAST grading system was first described in 1989 and proposed to classify injury severity and guide management for a particular organ and was revised in 2018.5 The revised AAST grading for kidney

injuries is shown in Table 1. Severity is classified according to the depth of parenchymal injury and involvement of ureteric or renal vasculature.

Most BRIs are low-grade (AAST <2) and non-life-threatening.2,3 Renal artery embolisation (RAE) has been used to manage lower-grade BRIs (AAST ≤2), but since most of these injuries are minor and self-limiting, they can be managed conservatively as per the European Association of Urology (EAU) guidelines.6,7

For high-grade renal injuries (AAST ≥3), surgery has been traditionally preferred. There are no validated criteria to identify patients with BRIs requiring RAE by AAST grade. One study found that increasing AAST grade was an independent predictor for clinicians performing RAE in patients with BRIs (Grade 1: OR 0.4; Grade 2: OR 1.05; Grade 3: OR 1.49; Grade 4: OR 3.52; Grade 5: not reported).8 Other studies have grouped patients with both blunt and penetrating mechanisms of injury in their analyses, making it difficult to determine RAE success or failure as it is unclear whether blunt versus penetrating injuries could be confounders. These studies have shown that RAE is likely to be beneficial in patients with highgrade renal trauma (AAST >3).9–12

RAE in Grade V BRIs has been reported in the literature.6,9,13–23 However, the optimal strategy for Grade V kidney trauma remains uncertain as success rates have been variable and repeat embolisation may be necessary.6 9 15,17 22,24 More promising results show that when used in the

1. Hull York Medical School, University of Hull, University of York, York, UK; 2. Hull University Teaching Hospitals NHS Trust, Hull, UK;

3. Leeds Teaching Hospitals NHS Trust, Leeds, UK

Grade* CT Findings

I Subcapsular haematoma and/or parenchymal contusion without laceration

II Peri-renal haematoma confined to Gerota’s fascia

Renal parenchymal laceration ≤1 cm depth without urinary extravasation

III Renal parenchymal laceration >1 cm depth without collecting system rupture or urinary extravasation

Any injury in the presence of a vascular kidney injury or active bleeding contained within Gerota’s fascia

IV Parenchymal laceration extending into urinary collecting system with urinary extravasation

Renal pelvis laceration and/or complete ureteropelvic disruption

Segmental renal vein or artery injury

Active bleeding beyond Gerota’s fascia into retroperitoneum or peritoneum

Segmental or complete kidney infarction(s) due to vessel thrombosis without active bleeding

V Main renal artery or vein laceration or avulsion of hilum

Devascularised kidney with active bleeding

Shattered kidney with loss of identifiable parenchymal renal anatomy

Operative Criteria

Non-expanding subcapsular haematoma

Parenchymal contusion without laceration

Non-expanding peri-renal haematoma confined to Gerota’s fascia

Renal parenchymal laceration ≤1 cm depth without urinary extravasation

Renal parenchymal laceration >1 cm depth without collecting system rupture or urinary extravasation

Parenchymal laceration extending into urinary collecting system with urinary extravasation

Renal pelvis laceration and/or complete ureteropelvic disruption

Segmental renal vein or artery injury

Segmental or complete kidney infarction(s) due to vessel thrombosis without active bleeding

Main renal artery/vein laceration or avulsion of hilum

Devascularised kidney with active bleeding

Shattered kidney with loss of identifiable parenchymal renal anatomy

*Advance one grade for bilateral injuries up to Grade III. Source: Kozar et al. 2018.5 Reproduced with permission from Wolters Kluwer Health.

management of Grade V parenchymal and renovascular lesions, RAE can result in minimal complications and retains an excellent likelihood of preserving the maximal amount of functional renal parenchyma without the need for further intervention, even despite haemodynamic instability.16–18,22 Vascular injury with shattered kidneys in the presence of no suspicions of a pedicle injury using CT could be an indication for RAE.17,25

Grade V renal pedicle avulsion is usually managed with surgery as it is technically demanding, but advances in angioembolisation have likely shifted practice patterns.26 Renal pedicle avulsions may now be possible with RAE due to vasospasm and the use of various sizes of coils to scaffold and anchor the bleeding vessel.14 This discrepancy in findings for the use of RAE in Grade V injury could pertain to differences in injury mechanisms, techniques used by interventional radiologists or the lack of uniformity of Grade V renal injuries. Differences in the sample sizes of studies may also account for the variable success rates. Increasing the sample size in future studies will help combat this uncertainty.

CT Criteria

Retrospective studies have identified other findings from CTs in patients sustaining BRIs who were treated with RAE (Table 2). Active contrast extravasation, pseudoaneurysm and arteriovenous fistulae were the most reported indications. Of interest is a single-centre American study (n=84) showing that the presence of at least two high-risk criteria on CT (intravascular contrast extravasation, presence of medial laceration, perirenal haematoma rim distance >3.5 cm) predicted the need for intervention, including angioembolisation, in the management of Grade IV BRIs with haemodynamic instability.27 The findings from this and other

Pathologic Criteria

Subcapsular haematoma or parenchymal contusion without laceration

Peri-renal haematoma confined to Gerota’s fascia

Renal parenchymal laceration ≤1 cm depth without urinary extravasation

Renal parenchymal laceration >1 cm depth without collecting system rupture or urinary extravasation

Parenchymal laceration extending into urinary collecting system with urinary extravasation

Renal pelvis laceration and/or complete ureteropelvic disruption

Segmental renal vein or artery injury

Segmental or complete kidney infarction(s) due to vessel thrombosis without active bleeding

Main renal artery/vein laceration or avulsion of hilum

Devascularised kidney

Shattered kidney with loss of identifiable parenchymal renal anatomy

studies have been corroborated by a survey of clinicians regarding the management of BRI, which concluded that CT evidence of active arterial bleeding, pseudoaneurysm and/or arteriovenous fistula (AVF) and discontinuity of Gerota’s fascia may be associated with the need for RAE.28

Outcomes from Renal Artery Embolisation

Complete control of bleeding using embolisation for BRI was specified in eight studies after the first attempt, and in three studies after multiple attempts.11,16–19,21,29–32,33 Repeat embolisation was associated with inadequate haemostasis leading to persistent bleeding and higher renal injury grade.23–25

In some cases, there was an occasional need for nephrectomy and even exploratory laparotomy following failed embolisation, although these were in older studies.6 14,22 24 25,34–37 The most common indication for postembolisation surgery was a failure to control bleeding, regardless of whether embolisation was repeated or not.22,35,38 Other indications reported include pain, acute coronary syndrome and increased free fluid on CT.6,38 RAE during a hospital stay may also be more frequent in patients later requiring nephrectomy due to more severe renal injuries.9 Still, timely nephrectomy remains an important last resort despite advancements in RAE.

Adjunctive endoscopic procedures such as retrograde ureteric stent placement were used in patients with urosepsis, symptomatic ureteral clot obstruction or significant urine extravasation on subsequent CT (3–5 days post-procedure) in patients with high-grade blunt renal trauma.9 12,22,23,38 The effectiveness of adjunctive stenting is currently

Table 1: American Association for the Surgery of Trauma Renal Injury Scale.

Table 2: Studies with Other CT Evidence For Renal Artery Embolisation In Patients With Blunt Renal Injuries.

unknown, but this subgroup of patients may represent those who have more severe injuries and are therefore at higher risk of poor long-term functional renal outcomes. With the current evidence available, patients with radiological markers of urinomas or urinary extravasation, lower urinary tract symptoms or uroseptic features may therefore require more consistent or extended follow-up to rationalise the need for ureteric stenting.

Technical Considerations

Level of Embolisation

Embolisation of renal arteries leads to infarction downstream and eventual parenchymal death. Older direct catheterisation techniques often made sub-selecting smaller segmental branches impossible, leading to proximal embolisation and greater tissue loss.39,40 Therefore, as much renal parenchyma should be conserved by ‘selecting’ only the affected arteries at the most distal level to minimise loss of uninjured parenchyma. The preservation of renal parenchyma is an advantage of minimally invasive therapy compared to surgical intervention. Complete RAE of renal arteries was specified in only two studies, but the choice of renal artery total occlusion is usually reserved to achieve haemodynamic stability in polytrauma patients who are not fit for surgery due to associated injury or as an alternative to nephrectomy in cases not requiring surgical exploration.16,17

Newer selective and superselective methods allow for more directed localisation and catheterisation, as embolic material is deployed immediately proximal to the bleeding site using coaxial embolisation to preserve a greater proportion of nephrons, although most studies successfully controlled bleeding in a single session without further complications regardless of the level of embolisation (Table 3).29 Most tissue loss is therefore due to the original trauma itself.18 Neither superselective nor subselective embolisation are usually associated with a significant clinical reduction in renal function, but this depends on preprocedural renal function, comorbidities and volume of contrast media used for embolisation.29 31,39–42 Superselective techniques may also limit delayed procedure-related complications, such as infection and posttraumatic hypertension.33

For main renal artery injuries, endovascular stenting may present a feasible alternative to embolisation to achieve renal revascularisation.43–47 Main renal artery dissections and/or luminal stenosis may benefit from endovascular stenting and covered stenting may be considered for proximal arterial rupture.48–50 Clinical factors to consider would include the presence of concurrent injuries as patients with stents would need to be anticoagulated and the presence of bleeding at other sites may limit stenting as an alternative.43,44

Embolic Agent

Multiple embolic agents are available for transcatheter RAE including particulates, sclerosants, glue and coils.

Metallic Coils

Metallic coils are desirable because of their accuracy and radiopacity.15 They are made of steel, titanium or platinum. The size of the coil must be adjusted to carefully match the vessel diameter to avoid poor placement, which was reported in one older study where there were two cases of extensive parenchymal loss due to incorrectly measured coil size.35,39

Metallic coils can be used to treat renal haemorrhage, AVF, pseudoaneurysms and arterio-calyceal fistulas, and multiple coils can be used in the same procedure.10 17,18 Selective embolisation of subsegmental branches with microcoils has also been used to limit the amount of embolised parenchyma.18

There are three main concerns with metallic coils. First, usually more than one coil is needed for adequate occlusion, increasing the time and cost of the procedure.46–50 Second, coils may be unstable and dislodged.35 There are two methods reported to ensure stability of the coils. The first and more commonly used method is to release the proximal aspect of the coil outside of the leaking vessel or into a nearby side branch with the remainder of the coil deployed in the vessel. The second method is to slightly oversize the coil to the vessel, relying on the outward radial force of the coil to secure it to the vessel wall so that the larger outer coil or coils act as a scaffolding onto which smaller coils can be deployed to

Table 3: Level of Embolisation Used to Manage Patients with Blunt Renal Injuries and Need for Repeat Embolisation, Surgery or Complications

One patient receiving complete embolisation of the main renal artery developed hypertension. No other intermediate adverse effects were reported in all patients.

Uflacker et al. 198435 7

Dinkel et al. 200218 9

Brewer et al. 200917 9

Superselective embolisation (n=7) Bleeding was successfully terminated and no post-procedural complications in all patients

Superselective embolisation (n=9) In all patients, bleeding was successfully controlled in a single session

Total embolisation of the main renal artery (n=7) Selective embolisation (n=2)

All patients showed complete resolution of bleeding on follow-up imaging and all patients did not require further intervention

Burns et al. 201721 6 Selective embolisation (n=6) All patients did not require repeat embolisation or delayed nephrectomy, no treatment complications were reported

Lin et al. 201334 22

BRI = blunt renal injury; RAE = renal artery embolisation.

Superselective embolisation (n=22) Five patients required a repeat embolisation due to re-bleeding. Of these, one had subsequent nephrectomy

produce the occluding effect.17 Newer detachable coils provide precision and control leading to accurate embolisation.

Particulate Embolic Agents

Absorbable Gelatine Sponges

Absorbable gelatine sponge embolisation may be useful to occlude small arterial aneurysms but may be related to aneurysm wall rupture owing to increased intra-aneurysmal pressure during embolus injection and passage through the arteriovenous fistula.35 One case report has illustrated success when using Gelfoam for unselective renal artery embolisation in a haemodynamically unstable patient with delayed partial renal artery canalisation.51 The authors of this case report attribute this success partially to the rapid haemostasis resulting from the mechanics of Gelfoam and partially due to the patient having small vessel collateralisation to the inferior pole of the kidney. Absorbable gelatine sponge particles may be easily fragmented and inadvertently ablate normal renal parenchyma. The effectiveness of the embolisation is also limited by distal movement of the absorbable gelatine sponge pledgets.52

Polyvinyl Alcohol

Polyvinyl alcohol (PVA) is similar to absorbable gelatine sponges in its manipulation, indications and delivery.35 However, PVA is more difficult to pass through the catheter in large particles and is not reabsorbable. PVA should be avoided in AVF as they can pass into venous circulation, potentially resulting in unintentional pulmonary embolism.35

Vascular Plugs

Vascular plugs are versatile and are ideal for embolising high-flow medium-to-large-sized vessels. They are self-expanding and exert adequate radial force to prevent migration even in a high-flow vessel. Vascular plugs can therefore be considered for main renal artery occlusion.53

Liquid Embolic Agents

Cyanoacrylates, such as N-butyl cyanoacrylate (NBCA) glue or Onyx® have a low viscosity and can be easily injected through small or tortuous catheters.46,48–50 NBCA glue may also be used in patients with haemodynamic instability or in patients with underlying coagulopathies as they achieve haemostasis faster than other embolic agents, but this was not specified in any studies using RAE to manage BRI. 40–50

Injury Characteristics Mechanism of Injury

The most reported causes of injury were road traffic accidents involving cars, motorcycles or pedestrians.15–18,22 This was followed by falls and direct trauma.15–18

Presence of Concurrent Injuries

Blunt renal trauma can occur as an isolated injury or in a poly-trauma setting with injury to other non-urological organs. The most commonly reported concomitant injuries were to the abdominal viscera and thoracic structures, including the lungs, pleura or ribs, followed by pelvic fracture.17,18,22,54 Current European Association of Urology guidelines recommend renal exploration for high-grade renal trauma (AAST ≥3) and presence of concomitant intra-abdominal injuries as they can be managed in the same procedure. One study concluded that concomitant liver injury in combination with raised heart rate predicted the need for immediate intraoperative management in patients with high-grade BRI.7,55

Haemodynamic Status

RAE has a central role in the non-operative management of haemodynamically stable patients with blunt renal trauma.9–11,14 Persistent or delayed bleeding in a stable patient can be successfully managed with embolisation in most cases.2 15,54,56 Yet in patients with haemodynamic instability, defined as a systolic blood pressure of 90 mmHg or less, the role of embolisation is conflicting.15–17,22 Emergency laparotomy is traditionally favoured as these injuries are usually high grade and accompanied by other severe organ injuries which can also be managed during exploratory laparotomy.31,32 36

However, recent experience in Europe suggests that immediate angioembolisation by trained radiologists can be feasible regardless of patients’ haemodynamic status.9,38 Cases of isolated renal injury and haemodynamic instability can be safely managed with embolisation and in one study haemodynamic instability was not found to be a predictor of embolisation failure.9 10 In other studies, patients with haemodynamic instability were successfully controlled through embolisation and without the need for further surgical or radiological intervention.6,17,18,33

An exception may be during a peri-arrest situation, which is the period before or after a cardiac arrest. Clinically, the priority would be on

immediate management of airway, breathing and circulation before proceeding to intervention. Surgical versus minimally invasive management of patients with BRIs would depend on local factors such as logistics and in-house availability of services. We have created a treatment algorithm for the management of BRIs that covers this period (Figure 1)

Anatomic Level of Injury

Knowledge of renal artery anatomy is important to accurately select the injured renal artery and preserve renal function. The renal arteries arise from the abdominal artery at L1–L2. Most patients have one renal artery feeding into each kidney, with the left renal artery being shorter than the right. A minority of patients have variant renal artery anatomy, which is usually an accessory renal artery that usually arise from the aorta but can also arise from any artery between the diaphragm and pelvis.57 Knowledge of variant anatomy is important, as the actual site of contrast extravasation may be missed if arteriography is conducted on the main renal artery alone.

BRI can occur at any level of the renal vasculature. RAE was also used in patients with lesions at the level of the polar arteries, interlobar arteries, lobar branches, segmental branches and at the level of the main renal artery.15,17-18,21,27, 29-31,38,58

Complications

Post-embolisation Syndrome

Post-embolisation syndrome (PES) is the most common complication following RAE.42 Patients usually present with nausea, vomiting, fever and abdominal pain 1–3 days after embolisation.42 PES is usually self-limiting but prophylactic anti-inflammatories and anti-emetics may be given for symptomatic treatment.48 PES is more common when using liquid or particulate agents compared to coils, as they are more difficult to control under fluoroscopy.15 Only one study examined PES as a complication following embolisation for BRI and found that none of the patients experienced PES.18

Pain

Post-procedural pain usually lasts between 1–5 days.47 Patients may report post-procedural pain in the back or flank. The severity depends on the volume of parenchyma involved and is usually self-limiting.59 Patients should receive appropriate pre-, intra- and post-procedure analgesia.60

Arterial Hypertension

Transient increases in arterial blood pressure are a common postprocedural finding and can last for up to 24 hours, after which it resolves spontaneously and should not be a concern if complete occlusion is achieved.20 61 However, permanent hypertension may result from remnants of ischaemic (but not infarcted) tissue.47 One possible explanation could involve activation of the renin-angiotensin-aldosterone system secondary to either occlusion of the main renal artery, a branch from the main renal artery or AVF, or external compression of parenchyma by urine or blood.62

Renal Function

The risk factors for trauma-related renal impairment include pre-existing renal disease, age, having a single kidney and associated multi-organ failure.13 Blood clots may also lead to obstructive uropathy and after the resulting haematuria has resolved, renal function may return.42

Embolisation, particularly the less selective types, may also infarct healthy renal parenchyma and result in a decrease in renal function.56 One Chinese study found that RAE for Grade IV and V injuries led to worsened

Haemodynamically stable

Transfer to HDU/ICU

Repeat CT in 24–48h (sooner if unstable)

RAE if repeat CT shows active bleeding/ pseudoaneurysm

Blunt renal injury

Haemodynamically unstable

RAE if CT shows bleeding from a segmental artery or a pseudoaneurysm

Surgery if CT shows bleeding from main renal artery or vein

Peri-arrest

Open surgery

renal function after embolisation, but RAE was significantly more successful in preserving renal function compared to surgery.23 There was no difference in renal function at 6 months.23 Several other studies have found that renal function is not affected by RAE when serum creatinine was used as a crude indicator of renal function.18 23 35 In one study of 52 patients with high-grade renal trauma, RAE was not found to be a significant independent predictor of maximum serum creatinine rise compared to surgical management.35 Most patients in the study had BRIs, but those with penetrating trauma were also included in this study, which when taken into consideration with the small sample size, it is difficult to comment on whether the conclusions of the study are representative of the true effect.

The effects of iodinated contrast media on worsening renal function, particularly in hypotensive patients sustaining severe injuries, have been a cause for concern.38,63 The additional contrast needed does not increase the incidence of nephropathy regardless of renal injury grade, but patients should be adequately hydrated before embolisation.36,64

Haematuria

Haemorrhagic infarction may result in moderate haematuria following embolisation and usually resolves within 24–48 hours.20,37,47

Infection

Infection risk is low but there have been reported cases of post-RAE abscesses requiring percutaneous drainage.6,19,20,21 Interventional radiologists must be familiar with the patient’s past medical history, as reactivation of latent infections may also occur, evidenced by postprocedure CT scans showing air bubbles, although not all air bubbles are indicative of abscess formation.47 Some may correspond to normal aseptic infarction.48,49

Non-target Embolisation

Coil migration is a rare but serious complication of RAE. One study reported a dislodged microcoil into the lumbar artery in a patient due to

Figure 1: Proposed Treatment Algorithm for Blunt Renal Injuries at Hull Universities Teaching Hospitals Trust

HDU = high dependency unit; ICU = intensive care unit; RAE = renal artery embolisation.

catheter instability in an avulsed main renal artery, but no clinical consequences ensued.18 Endovascular snares can be used to retrieve migrated coils if that vessel cannot be safely killed.65 Advances in coil design, such as interlocking detachable coils and Guglielmi detachable coils allow for controlled deployment and easy retrieval if it is in an unfavourable position.18

Non-target embolisation of spinal arteries, lower extremity or bowel vessels can occur with particulate or liquid embolic agents. Adrenal artery non-target embolisation may lead to self-limiting transient hypertension or adrenal insufficiency and is treated conservatively.42 Correct catheter positioning, continuous monitoring during delivery of embolic agent and using occlusion balloon catheters can reduce the risk of non-target embolisation.60

Other Complications

Other complications that can arise with any endovascular procedure include access site haematoma, arterial thrombosis, arterial dissection, arterial rupture, distal site embolism, anaphylaxis, shock or volume overload.47

Discussion

BRIs are a common injury and although the use of embolisation to manage BRIs is becoming more widespread, the evidence base is still weak.

We examined the relevance of AAST grade on the outcomes for patients receiving embolisation. There is evidence to suggest that high-grade renal trauma (AAST ≥3) can be managed with embolisation. This is reflected in the present EAU guidelines which state that when RAE is included in the non-operative management pathways for patients with high-grade renal trauma, it can be successful in managing up to 94.9% of Grade III, 89% in Grade IV and 52% of Grade V injuries.9,10,25 Close examination of the patient’s CT to identify active contrast extravasation, pseudoaneurysm and arteriovenous fistulae may provide an accurate indication for the need for RAE.6 13 15 18 21 22 27 The patient’s CT should also be examined for polytrauma as concurrent intra-abdominal injuries may be managed intraoperatively.7 The patient’s clinical picture should also be considered, particularly their haemodynamic status. EAU guidelines suggest RAE in renal trauma patients who are haemodynamically stable, but there is some evidence to suggest that RAE is successful in patients with a systolic blood pressure <90 mmHg.7 In either case, the patient’s haemodynamic status should be considered with their overall clinical picture.6 9 10 17,18,33,38 More severe cases are usually accompanied by other severe organ injuries which may be managed concurrently during exploratory laparotomy. The risk of RAE failure should be balanced against the risk of secondary nephrectomy. The provision of 24-hour interventional radiology in major trauma centres may therefore play an integral role.

The choice of embolic agent for the management of BRI was also examined. Coils were the most commonly used embolic agent, probably because greater control can be achieved, particularly with microcoils under fluoroscopy, and the risk of post-embolisation syndrome that has been reported with particulate embolic agents due to reflux and nontarget tissue ablation.15,17,18 20-22,29,31 34,35,39,58 Absorbable gelatine sponges (Gelfoam) were the second most commonly used embolic agent followed by PVA.17,18 21,31,34,35 These materials can be used as stand-alone agents, but combinations of microcoils with gelatine sponges or PVA have also been documented.17,18 31 34 As a general rule, Gelfoam is preferred for smaller

pseudoaneurysms as it results in peripheral occlusion with minimal parenchymal loss, while coils in addition to Gelfoam are preferred for larger pseudoaneurysms.39 The choice of embolisation material depends on vascular anatomy, underlying pathology, size, flow pattern, material availability, experience and preference of the interventional radiologist.50 At our institution, microcoils are the most often used embolic agent and a combination of coils and gelatin sponges, such as coil/gel or foam/coil, are less commonly used to stop bleeding.

Finally, more common clinical complications are transient and self-limiting, such as post-embolisation syndrome, post-procedural pain, arterial hypertension, haematuria and renal impairment.18–20,22,23 35,47,50,59 Patients’ post-procedural status should be monitored appropriately so these complications can be managed. Appropriate monitoring will also alert clinicians to more serious complications such as intra-abdominal abscess formation, urosepsis, evidence suggestive of non-target embolisation or persistent bleeding which may warrant repeat embolisation or surgery.21,22,34,35,38,42

We have proposed a treatment algorithm in the management of patients with BRIs at a UK tertiary centre (Figure 1). In our unit, the management of BRIs depends on the haemodynamic stability of the patient and CT findings. Cases are discussed on a case-by-case basis with the on-call surgical team who are often on standby when RAE is performed on unstable patients. Our policy is for embolisation to be as superselective as possible. From our experience, the total procedure duration is approximately 20 minutes from common femoral needle access to successful embolisation, making RAE as quick or quicker than surgery depending on the complexity and number of vessels involved. Naturally for high-grade complex renal lesions with multiple segmental vessels involved procedure duration may increase and the benefits of RAE should be balanced against the benefits of surgical intervention. In the peri-arrest situation, the surgical teams are resident in hospital and so surgery is quicker. The interventional radiology team has a 30-minute call-out time.

This narrative review highlights institutional variation in practice and presents the available evidence surrounding the use of renal artery embolisation in the management of BRIs. While available evidence is promising for the use of RAE in the management of BRIs, this review article is limited in that only a few case series looked at renal artery embolisation in patients with BRIs.17,18,35 A formal meta-analysis was therefore not conducted because factors such as study design, mechanism of injury, definitions of clinical or technical success, study endpoints, reporting of complications, potential bias and the extent to which investigators controlled for confounding factors were too heterogeneous across the studies to enable comparison.

Conclusion

The evidence for renal artery embolisation in the management of renal trauma is so far promising, particularly with high-grade injuries and advances in embolisation techniques allowing for superselective methods and embolic agents on the order of microns. However, when considering patients with BRIs alone, most answers to the key clinical questions, such as optimal technique, CT indications, clinical status, comorbidities and complications are unknown. Retrospective reviews and case series do not provide robust evidence and sample size in these studies has been small. The question of operative versus non-operative management (including RAE) will remain unknown until the key clinical parameters as defined above, have been addressed by large, rigorous randomised controlled trials.

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The Importance of Early Thrombus Removal

Jason Cottrell 1 and Mitchell J Silver 2

Abstract

Historically, anticoagulation has been the primary treatment for acute lower extremity deep venous thrombosis (DVT) with or without thrombolysis. Despite large amounts of clinical research data supporting an ‘open vein hypothesis’, which favours early thrombus removal, clinicians have been hesitant to take this option due to a historically high risk of major bleeding and a few notable studies that failed to show any meaningful benefit. The ATTRACT trial failed to show the benefit of using pharmacomechanical catheter-directed thrombolysis (PCDT) for iliofemoral and femoropopliteal DVT but did result in more bleeding. However, the CaVent study before it revealed a significant reduction in post-thrombotic syndrome (PTS) for patients with iliofemoral and femoral DVT after long-term follow-up past 24 months that grew over time. Since these trials, there have been significant advancements in magnetic resonance and CT venography, intravascular ultrasound (IVUS), venous stenting and thrombectomy catheters meaning there is little to no need for adjunct thrombolytics. Results from ongoing research such as CLEAR-DVT reflect the advances in modern technology.

Keywords

Deep vein thrombosis, residual venous obstruction, post thrombotic syndrome

Disclosure: MJS has recieved consulting fees from Inari Medical, Boston Scientific, Gore Medical and Cook Medical and speaker fees from Bristol Myers Squibb, Pfizer, Astra Zeneca and Portola Pharmaceuticals; he is a stockholder for Contego Medical. JC has no conflicts of interest to declare.

Received: 13 August 2021 Accepted: 10 June 2022 Citation: Vascular & Endovascular Review 2022;5:e09. DOI: https://doi.org/10.15420/ver.2021.10

Correspondence: Mitchell J Silver, Center for Critical Limb Care and Endovascular Research, OhioHealth Heart and Vascular, Riverside Methodist Hospital, 3705 Olentangy River Rd, Columbus, OH 43214, US. E: Mitch.Silver@OhioHealth.com

Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The goals for treatment of acute deep venous thrombosis (DVT) have expanded as the understanding of the pathophysiology behind venous thromboembolism has evolved. There are four generally accepted goals for the treatment of lower extremity DVT. Those goals are to diminish the severity and duration of acute lower extremity symptoms, prevent pulmonary embolism, minimise the risk of recurrent venous thrombosis, and (prevent post-thrombotic syndrome (PTS). One argument against treating all DVT aggressively is the associated risk of major bleeding and common practice relies heavily on the use of thrombolytic agents, anticoagulation medications and procedures requiring endovascular access. Notwithstanding, the most recent multicentre randomised controlled trials (RCTs) regarding acute DVT intervention (ATTRACT, CaVenT, CAVA) all found weak effects from endovascular thrombus removal. Fortunately, the vascular community has witnessed a rapid refinement of endovascular devices and thrombotic therapy that reduce bleeding risk by requiring little to no adjunct thrombolysis. Such a monumental change calls into question the modern-day applicability of conclusions from previous foundational – and at times conflicting –vascular research that weighed the risks of bleeding against the benefits of acute intervention.

By the mechanism of action, conventional anticoagulation works to prevent further propagation of thrombus. Patients with acute DVT who are treated solely with anticoagulation, therefore rely on their innate fibrinolytic pathways to dissolve the clot if vein patency is to be re-

established. Such resolution can be slow and, in many cases, the entirety of the residual vein thrombosis (RVT) never completely dissipates.

DVT that is unsuccessfully treated can lead to venous reflux and venous hypertension that builds with time. The resultant venous hypertension then causes increased capillary bed pressures which cause inflammatory oedema and endothelial remodelling. When these physiological changes produce symptoms, PTS is diagnosed. PTS typically manifests as pain, swelling and skin changes of various degrees of severity from mild to severely debilitating. One survey of patients suffering from PTS reported quality of life measurements comparable to those reported by patients with chronic angina, heart failure and many cancers.1 Certain patient characteristics increase the risk of developing PTS (Table 1).

The prevention of PTS has been a focus of recent research, with conflicting evidence regarding its management. In the past, therapy centred around external venous compression; however, one RCT showed that DVT patients who wear elastic compression stockings daily after a proximal DVT showed no improvement in PTS.2 Furthermore, a meta-analysis of 674 reports suggested that the current body of evidence for compression therapy was limited and further studies of compression stockings to prevent PTS were needed.3

The purpose of this review is to outline the evolution in acute DVT management which now encompasses better patient selection, care

1. Division of Hospital Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, US; 2. Center for Critical Limb Care and Endovascular Research, OhioHealth Heart and Vascular, Riverside Methodist Hospital, Columbus, OH, US

Table 1: Patient Characteristics Associated with Increased Risk of Developing Post-thrombotic Syndrome Following Deep Vein Thrombosis

PTS Risk Factors

Proximal (iliofemoral) DVT

Presenting with symptomatic DVT at time of diagnosis

History of venous insufficiency or prior ipsilateral DVT

Residual thrombus months following diagnosis

Inadequate anticoagulation following diagnosis

Elderly age

Obesity

DVT = deep vein thrombosis; PTS = post-thrombotic syndrome.

more proximal, such as with IF-DVT, the recanalisation rates on a venous duplex at 6 months are less robust and have higher rates of RVT (Table 2).5 Hypothetically, if patients with IF-DVT received early interventions for thrombus removal and patients with more distal DVT were monitored on anticoagulation alone, RVT would be minimised and fewer patients would suffer moderate-to-severe PTS.

With this hypothesis in mind, a search for literature specifically assessing adverse outcomes associated with patients that had RVT after DVT identified seven peer-reviewed studies, comprising data from more than 3,000 patients. The data from those studies produced a pattern of three clinically relevant outcomes (Table 3). RVT after DVT was repeatedly associated with recurrent venous thromboembolism (VTE) (HR 2.2 and 2.4; OR 3.9 and 21.3).2,6–8 The presence of RVT after DVT was predictive of developing PTS (OR 2.17) and patients with RVT suffered more severe PTS symptoms (mean Villalta PTS severity score 7.1 versus 2.2).3,9,10 One recent study identified RVT as the single most powerful predictor of venous stent failure (HR 7.4).10 Beyond these seven studies, there are two others –CaVenT and ATTRACT – with seemingly contradictory conclusions that should be further analysed side by side.

CaVenT

The CaVenT study randomised 209 patients from 20 hospitals in Norway who presented with a first-time acute DVT that was either femoral or iliofemoral.11 The intention was to treat one arm of patients with catheterdirected thrombolysis (CDT) in addition to standard anticoagulation, treat the other arm with anticoagulation-based treatment alone and follow the clinical outcomes to see if thrombolysis reduced the risk of PTS. At 24 months, patients in the CDT arm experienced an absolute risk reduction for having PTS of 14.4% compared to conventional anticoagulation alone. Long-term follow-up results of the CaVenT trial showed this same absolute risk reduction increase to 28% after 5 years (42.5% versus 70.8%). Collecting such enduring data dropped the already low number needed to treat from seven to four.12 As qualification of PTS for these patients, 83.8% of cases in the CDT arm and 77.8% of the cases in the standard treatment arm were mild (Villalta score 5–9). Differences in quality of life (QOL) indices measured did not reach statistical significance.

pathways for earlier endovascular management and catheter thrombectomy technology that is more efficient and often requires minimal or no adjunctive thrombolytic medication.

Open Vein Hypothesis

It has long been hypothesised that rapid restoration of venous outflow by early thrombus removal can prevent valvular reflux and complications of PTS. The clinical importance of RVT as a determinant for the risk of developing PTS has borne out in clinical research for many years.4 Despite this knowledge, the burden of major bleeding risk has dissuaded many physicians from aggressively treating acute DVT as, until recently, systemic thrombolysis has been the only non-surgical option to achieve ‘open vein’ status.

The treatment of lower extremity DVT is typically stratified initially by the location as found on the presenting conventional duplex ultrasound. This stratification is commonly iliofemoral DVT (IF-DVT), femoropopliteal DVT and isolated calf DVT. The notion of ascending versus descending DVT is not part of this stricter anatomical imaging stratification. Skilled technicians can use modern point of care ultrasound to detect RVT with extremely high sensitivity and specificity and essentially no risk to the patient (Figure 1). Duplex ultrasound studies have found that conventional anticoagulation of distal infrapopliteal DVT is efficacious, but when the culprit anatomy is

Regarding the open vein hypothesis, the CaVenT study found that iliofemoral vein patency after 6 months was more often present in the CDT group and patency after 24 months correlated with residual thrombus burden after completing CDT treatment. Interestingly, regarding the effects on PTS itself, the end-of-procedure venogram result (i.e. the amount of residual thrombus) did not correlate with either 2-year PTS (binary) or with the continuous 2-year Villalta scores. The CaVenT study therefore, does suggest that maintenance of an open vein may best correlate with improved late clinical outcomes rather than early thrombus removal.

ATTRACT

The ATTRACT trial was an RCT designed to evaluate pharmacomechanical catheter-directed thrombolysis (PCDT) as a method for the prevention of PTS in patients with proximal DVT.13 The first arm underwent a PCDT protocol in addition to conventional anticoagulation. The control arm received conventional anticoagulation only. The protocol used three different catheter modalities and all patients in the intervention arm were given catheter-directed tissue plasminogen activator (tPA) as the thrombolytic agent. The primary efficacy outcome was the development of PTS, defined as a score of 5 or greater on the Villalta PTS scale or venous ulceration at any time from the 6-month post-randomisation

Figure 1: Ultrasound Imaging of a Left External Iliac Vein

Arrow points to chronic thrombotic material. The grey debris represents residual vein thrombosis (RVT) and the darkest portion represents the patent portion of the vein. The presence of significant RVT on follow-up imaging in this patient increases the risk of recurrent venous thromboembolism and developing post-thrombotic syndrome that is more severe than those of the average patient without RVT.

follow-up visit to the 24-month visit. Over 24 months, investigators were unable to detect any statistically significant relative risk reduction of PTS between the two trial arms. Of the patients, 47% that received PCDT and 48% of non-PCDT patients met the primary outcome (ARR <0.01; RRR 0.02, 95% CI [0.82–1.11]; p=0.56).

The ATTRACT study did find that PCDT reduced PTS severity and improved venous QOL in the subgroup of IF-DVT patients.14 For the IF-DVT subgroup, symptom severity scores were higher (worse), and venous disease-specific QOL scores were lower (worse) in patients with greater post-PCDT thrombus volume over 1 and 24 months, with the difference reaching statistical significance for the 24-month Villalta PTS severity score (p=0.0098).15

The ATTRACT investigators deserve congratulations on executing this important body of work. However, the field of venous intervention has gained considerable experience and improvement in technology since ATTRACT was initiated in 2009. Therefore, the nearly 50% rate of PTS –found not only in the ATTRACT trial but also in VETO, CaVenT, and CAVA –is not satisfactory.11,16,18 Clinicians and industry partners are actively working on procedural and technological advances.

Technological Advancements

There has been an ongoing effort to improve the efficacy of stand-alone CDT in reducing thrombus burden in acute IF-DVT. One such development is ultrasound-assisted catheter-directed thrombolysis (USAT), combining CDT with a catheter system that uses high-frequency, low-power ultrasound.18 According to in vitro studies, ultrasound causes reversible disaggregation of uncrosslinked fibrin fibres, which when combined with ultrasound pressure waves increases the thrombus penetration of thrombolytic drugs.19–21 Unfortunately, the clinical benefit of these USAT devices remains uncertain.

When CDT was compared with USAT for the treatment of patients with acute IF-DVT in the BERNUTIFUL trial, no statistically significant difference in PTS symptoms or thrombus load reduction was found between the two treatment groups.22 In addition, the CAVA trial, a multicentre RCT that compared USAT in addition to standard therapy against standard therapy alone in patients with acute IF-DVT found no benefits to USAT in terms of PTS or QOL at 1-year follow-up.17

Over the past few years, there have been substantial advances in catheterbased thrombectomy devices which allow for more efficient and faster treatment times as well as reducing or even eliminating a need for adjunctive thrombolytic medications. These newer thrombectomy devices are the focus of current studies and will hopefully be found to have a positive impact on reducing RVT which should decrease the incidence of PTS.

In addition, advances in the care pathway of the lower extremity DVT patient have led to more thoughtful pre-procedural planning. Advanced imaging such as MR venography (MRV) or CT venography (CTV) are noninvasive but provide vast amounts of data to contextualise DVTs. Their use prior to intervention can characterise the presence of extrinsic compression, better assess the overall thrombus burden, and identify important concomitant pathologies such as tumours or masses. Having those data before attempting endovascular intervention allows for a more tailored approach which helps drive efficiency and device selection.

The use of intravascular ultrasound (IVUS) to guide venous intervention is an especially important advancement as highlighted by the VIDIO trial which compared the diagnostic efficacy of multiplanar venography

Table 2: Recanalisation Rates via Colour Duplex Venous Ultrasound

combined with IVUS against venography alone for iliofemoral vein obstruction.23 Results demonstrated that the addition of IVUS improved predictive imaging accuracy and guided decision-making for the treatment of iliofemoral venous lesions. In fact, in this series, IVUS changed the treatment plan by the type of therapy in 60 of 100 patients and determined the need for venous stenting in 50 of 100 patients. The VIDIO trial concluded that without IVUS, iliofemoral vein occlusive disease would have been undertreated in the majority of patients studied.

There is a common thread from the CAVA and CaVenT studies and the IFDVT patients of the ATTRACT trial, which inspires hope for a future in which it is possible to predict which patients will benefit most from early thrombus removal and the patients at greatest risk of developing PTS could receive the most advanced therapies giving them the greatest chance of lasting vein patency without PTS symptoms.

CLEAR-DVT

In an effort to build on the findings from studies such as CaVenT and ATTRACT, the CLEAR-DVT study (NCT03901872) was designed to demonstrate that contemporary venous intervention in the right patient population would result in an open vein and dramatically decrease PTS in patients with acute IF-DVT.

The CLEAR-DVT investigators started with a small prospective pilot study with no control group as a proof of principle study in patients with acute IF-DVT. It was funded by Boston Scientific and sponsored by Guy’s and St Thomas’ Hospital in London, England. The results gathered by the CLEARDVT cohort pilot study would then be used to power and plan a formal RCT of modern venous intervention for patients with acute IF-DVT.

The phase 1 cohort of CLEAR-DVT was a prospective pilot study with no control group comprising 35 patients (39% male, 61% female; average age 48 years, range 22–73 years) with acute IF-DVT and symptom onset of 14 days or less. The average Villalta score prior to intervention was 10 (range 4–19). All patients underwent pharmacomechanical thrombolysis (PMT) in the form of the 8F Zelante AngioJet catheter using a dose of thrombolytic that was standard of care for each investigational site. The use of IVUS was mandated in all patients and venous stenting was performed for any patients with >50% cross-sectional area reduction. All patients received standardised post-procedural anticoagulation. Follow up of the first 23 patients at 6 months post procedure demonstrated an average Villalta score of 2; 96% of patients had no PTS at all (4% had mild PTS and none had a Villalta score >5). All patients will be followed for 1 year for the Villalta score as well as a 6-minute walk test, venous clinical severity score and QOL scores.

The importance of early complete thrombus removal was suggested by the findings in the clear-DVT pilot cohort that demonstrated a dramatic reduction in PTS in patients with acute IF-DVT undergoing IVUS-guided

Table 3: Literature Review of Residual Vein Thrombosis Associations with Adverse Outcomes

contemporary venous intervention (Table 4). Certainly, these findings need to be validated in a formal RCT of contemporary venous intervention using lytic- and non-lytic based therapies against best medical therapy.

Conclusion

The field of venous intervention is dynamic. We now have mechanical thrombectomy catheters that remove thrombus efficiently without the need for adjunctive thrombolytics. Such technology will certainly make venous intervention safer with less bleeding complications. These devices will likely be effective at reducing RVT as they are known to be able to clear all or most of the thrombus acutely in a single setting. Additionally, dedicated venous stents that are engineered and purposebuilt for vein anatomy will be an incredibly positive addition to our treatment options.

It is encouraging that the field of venous intervention has made major advances in selecting the right patient population to treat acute lower extremity DVT, how to perform a high-quality venous intervention with IVUS guidance, and now has catheter thrombectomy systems that reduce and even eliminate the need for thrombolysis in the majority of acute IFDVT patients. Altogether these innovations will hopefully provide momentum to continue evolving procedures that are even safer and more effective. In so doing, the treatable patient population will continue to

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Table 4: Patient Characteristics and Preliminary Data of CLEAR-DVT

expand by including more and more patients with contraindications to thrombolysis.

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The Importance of Early Thrombus Removal

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A Framework for Developing a Comprehensive Venous Practice

Ryan M Cobb 1 and Deepak Sudheendra 2

Abstract

Chronic venous disease (CVD) of the lower extremities is a complex process encompassing abnormalities related to venous drainage secondary to thrombotic and non-thrombotic pathologies. CVD can have an untold economic impact due to lost productivity and the costs of treating its sequela and underlying aetiologies. Building a comprehensive venous service for the treatment of CVD requires a multifaceted approach with longitudinal care, similar to those that have been developed for peripheral arterial disease and oncology.

Keywords

Chronic venous disease, deep vein thrombosis, lower limbs, multidisciplinary care, pelvic venous disease

Disclosure: DS has received consultancy and speaker fees from Boston Scientific in the past 36 months; RMC has no conflicts of interest to declare.

Received: 29 April 2022 Accepted: 07 September 2022 Citation: Vascular & Endovascular Review 2022;5:e10. DOI: https://doi.org/10.15420/ver.2022.06

Correspondence: Ryan M Cobb, Department of Radiology, Interventional Radiology Section, The Hospital of the University of Pennsylvania, 3400 Spruce St, 1 Silverstein, Philadelphia PA 19104, US. E: ryan.cobb@pennmedicine.upenn.edu

Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Chronic venous disease (CVD) of the lower extremities is a complex process encompassing abnormalities related to venous drainage secondary to thrombotic and non-thrombotic pathologies. It has been reported that about 50% of people have CVD. Even more staggering is the untold economic impact due to lost productivity and healthcare costs of treating its sequelae and underlying aetiologies.

The 2022 European Society of Vascular Surgery Clinical Practice Guidelines on the Management of Chronic Venous Disease of the Lower Limbs states that the first step towards improving the diagnosis, management and treatment of CVD involves developing a comprehensive multidisciplinary venous care team.1 This requires identifying patient referral pathways and healthcare professionals involved in each aspect of their care, from external channels to internal sources at one’s own institution. These patients require multidisciplinary and chronic follow-up owing to the complexity of CVD and its treatment. Those who treat CVD are the best advocates for their patients and they need to continue to foster awareness of the impact of this disease.

Reaching Your Audience

Patients have become more able to research and educate themselves about conditions and diseases and are more proactive regarding their health. Direct patient outreach using educational posts on social media and other web-based platforms (such as an institutional departmental information page or advertisement) are easily searchable. These provide publicity and an initial point of contact with patients. In addition, free or discounted vein screening clinics with point-of-care ultrasound provide a great opportunity for growth. If point-of-care vascular ultrasound is not available, ensure that there is a streamlined process to refer patients for a dedicated venous ultrasound. Meticulous selection of patients with clinical history, signs and/or symptoms of CVD is crucial, as ultrasound is

able to identify clinically insignificant venous abnormalities. Advertising these clinics in one’s institution via newsletters, posters or bulletins can help increase exposure to other healthcare employees, whether they be future patients or potential referrers.

Outreach to other healthcare professionals, such as primary care physicians, hospital doctors, obstetricians and gynaecologists (OB/GYN), haematologists, physical medicine and rehabilitation specialists and wound care specialists, via lectures, talks and ground rounds will start a dialogue and open new avenues for patient care. CVD is often absent from medical education – or it is only covered superficially. Directly contacting institutional and local healthcare leaders – such as residency programme directors, heads of department, specialty and medical society education chairs and private practice partners – and offering to present a lecture will continue to expand your audience and referral base.

Partnering with front-line specialties such as emergency medicine, family medicine, internal medicine and hospital medicine will continue to improve patient care. Often, the first presentation of CVD symptoms is in these settings – especially in patients with acute deep vein thrombosis (DVT). For example, creating a DVT algorithm for treatment and follow-up can streamline acute and longitudinal care. A minority of patients with acute DVT may develop moderate-to-severe post-thrombotic syndrome, which requires chronic follow-up. A treatment algorithm with close longitudinal follow-up will identify those patients early, offering them better outcomes with interventions when needed. Following these patients may also help diagnose additional underlying venous issues such as peripheral venous insufficiency.

Many practices that treat CVD also treat patients with peripheral arterial disease. Screening patients in one’s own practice for signs and symptoms

1. Department of Radiology, Interventional Radiology Section, The Hospital of the University of Pennsylvania, Philadelphia, PA, US; 2. 360 Vascular Institute, Dublin, OH, US.

of CVD is good clinical practice for providing comprehensive vascular care.

Outpatient Clinic, Imaging Support and Procedural Infrastructure

Establishing an outpatient clinic is integral to developing a thriving practice. The reasons for this are several and include:

• Developing a close doctor-patient relationship.

• Educating patients on diagnosis, management and treatment options.

• Providing confidence to referring providers that you are responsible and provide long-term follow-up to patients.

• To track your complications and short- and long-term outcomes, especially in the current era of value-based care, which ensures that healthcare provides value for money.

• To develop your reputation as a physician.

• To receive reimbursement for evaluation and management coding in the US healthcare system.

While dedicated clinics can be time-consuming and less financially rewarding than doing procedures, providing this longitudinal comprehensive care is what separates the proceduralist from the true clinician.

Complete evaluation includes partnering with radiology and vascular labs. Evaluation of CVD patients includes cross-sectional imaging to map underlying pathology before intervention. Dedicated vascular imagers who are familiar with venous disease and the multiple modalities that evaluate it, such as MR and CT venography, and ultrasound, are critical to classifying the underlying diagnosis. One of the lynchpins for vascular imaging are ultrasonographers trained in performing thorough reflux ultrasound of the lower extremity. Well-trained ultrasonographers and experienced imagers will not only streamline and standardise diagnosis and treatment pathways but will also be able to identify those patients who do not fit standardised criteria. While knowledge of the acquisition and interpretation of diagnostic imaging is crucial to ensure a proper treatment plan, the main driver of treatment should rely on the patient’s clinical history and physical examination.

Once the diagnosis has been established, dedicated treatment spaces should be used. Superficial venous disease can often be treated in an outpatient or office-based setting. These patients tend to be ambulatory and complications tend to be limited and infrequent. While these cases can be performed in the hospital, it is often less efficient and more costly to the patient. More complex venous disease will necessitate high-level

investigation with techniques and image interpretation of catheterdirected venography and intravascular ultrasound (IVUS) requiring resource-intense dedicated angiography suites with support staff and access to inpatient facilities, as complex CVD cases may require a hospital stay. Hospitals that care for complex vascular patients will have nurses and support staff familiar with post-procedural care and possible complications. Early identification of signs or symptoms associated with highly morbid complications, such as haemorrhage and re-thrombosis, can help mitigate potentially poor outcomes. Embarking on complex venous procedures should not be taken lightly. Appropriate levels of training and expertise, as well as an established infrastructure for the care of high-acuity patients, is necessary for positive outcomes and to avoid disastrous complications.

Continuity of Care

After patients have been identified as having CVD and appropriate treatment has been initiated, a multifaceted and multidisciplinary followup approach is crucial if you are to achieve positive patient outcomes. Outpatient clinic follow-up is as important, if not more important, than the initial clinic evaluation. Many of these patients have multiple comorbidities that contribute to their venous health and will inhibit their return to full functionality. Management of the complications associated with CVD, its risk factors, as well as the associated sequela of those risk factors requires collaboration with different specialties. Direct contact with haematology (specifically those with an interest in thrombosis), OB/GYN, diagnostic radiology, vascular surgery, cardiology, physical medicine and rehabilitation, physiotherapy/occupational therapy, wound care, lymphoedema specialists and social work can be beneficial. Much like cancer care, interdisciplinary relationships should form the cornerstone of care for patients with CVD.

Advocacy beyond the direct clinical space via involvement with institutional and national committees and international societies will drive change and build a better future for patients with CVD. As new therapies and techniques develop, dissemination of information is the most robust tool for patient advocacy.

Conclusion

Building a comprehensive CVD practice begins with education and the development of internal and external collaboration for holistic patient care. Longitudinal multidisciplinary outpatient management of these patients with appropriate imaging, procedural and peri-procedural infrastructure in place is critical for positive outcomes. CVD advocacy is a great starting point and is an ongoing mission with the goal of developing a comprehensive venous practice.

https://doi.org/10.1016/j.ejvs.2021.12.024; PMID: 35027279.

1. De Maeseneer MG, Kakkos SK, Aherne T, et al. Editor’s Choice – European Society for Vascular Surgery (ESVS) 2022 Clinical Practice Guidelines on the Management of Chronic Venous Disease of the Lower Limbs. Eur J Vasc Endovasc Surg 2022;63:184–267.