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Editor-in-Chief Stephen Black

Guy’s and St Thomas’ Hospital, London

Section Editor – Aortic

Section Editor – Venous

Andrew Choong

Rick de Graaf

National University of Singapore, Singapore

Maastricht University Medical Centre, the Netherlands

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Michael Lichtenberg

Konstantinos P Donas

Klinikum Arnsberg, Karolinen Hospital, Germany

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Ashish Patel

Raghu Kolluri

King’s College London, UK

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Editorial Board Lukla Biasi

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

Elias Brountzos

University Hospital RWTH, Aachen, Belgium

Narayan Karunanithy

Attikon University General Hospital, Greece

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

Andrew Bullen

Miltiadis E Krokidis

Wollongong Hospital, Australia

University of Cambridge, Cambridge, UK

Patrick Chong

Nicos Labropoulos

Frimley Health NHS Foundation Trust, Surrey, UK

Brian G DeRubertis

David Gefffen School of Medicine at UCLA, CA, US

Mert Dumantepe

Istanbul University, Istanbul, Turkey

Steve Elias

Englewood Hospital, Englewood, NJ, US

Fernando Gallardo

University Hospital Complex of Santiago de Compostela, Spain

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

Maria Antonella Ruffino AOU Citta della Salute e della Scienza, Torino, Italy

Prakash Saha King’s College Hospital, London, UK

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

Michael C Stoner University of Rochester Medical Center, New York, US

Martin Maresch

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Sherif Sultan

Ross Milner

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Gustaf Tegler Sarah Thomis UZ Leuven, Leuven, Belgium

St Vincent’s Clinic, New South Wales, Australia

Gergana Todorova Taneva

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

Gerry O’Sullivan

University Ramón y Cajal, Madrid, Spain

University College Hospital, Ireland

Ramon Varcoe

Andrew Holden

Premal Patel

Prince of Wales Hospital, Sydney, Australia

Antonios Gasparis

Auckland City Hospital, New Zealand

Emad Hussein

Ain Shams University Hospital, Cairo, Egypt

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Great Ormond Street Hospital, London, UK

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St George’s University Hospital, London, UK

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Contents

Incisional Hernia Following Open Abdominal Aortic Aneurysm Repair: A Contemporary Review of Risk Factors and Prevention Thuy-My Nguyen, Saissan Rajendran, Kilian GM Brown, Prakash Saha and Raffi Qasabian DOI: https://doi.org/10.15420/ver.2019.01.R1

Restenosis After Tack Implantation is Associated with Less Complex Patterns of Restenosis Compared to Stent Implantation Raghu Kolluri, William A Gray, Ehrin Armstrong and Brian C Fowler DOI: https://doi.org/10.15420/ver.2019.03.R1

Thrombosis Following Endovenous Glue Ablation Raeed Deen and Andrew Bullen DOI: https://doi.org/10.15420/ver.2019.08

The Role of Wearable Technologies and Telemonitoring in Managing Vascular Disease Calvin Chan, Viknesh Sounderajah, Amish Acharya, Pasha Normahani, Colin Bicknell and Celia Riga DOI: https://doi.org/10.15420/ver.2019.11

BEST Endovascular Versus Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) Trial Raghu Motaganahalli, Matthew Menard, Matt Koopman and Alik Farber DOI: https://doi.org/10.15420/ver.2019.12

Stiff to Dilate and Risky to Cut Through: Iliac Radiation Arteritis Huthayfa Ghanem, Sadia Jaskani, Mohamed Alloush, Ibrahim Hanbal, Marzouk Albader, Hussein Safar, Jassim Al-Ali and Sami Asfar DOI: https://doi.org/10.15420/ver.2019.07

Catheter Interventions for Acute Deep Venous Thrombosis: Who, When and How Catherine Go, Rabih A Chaer and Efthymios D Avgerinos DOI: https://doi.org/10.15420/ver.2019.13

Background and Proposed Design for a Metformin Abdominal Aortic Aneurysm Suppression Trial Ronald L Dalman, Ying Lu, Kenneth W Mahaffey, Amanda J Chase, Jordan R Stern and Robert W Chang DOI: https://doi.org/10.15420/ver.2020.03

Anticoagulation in Peripheral Artery Disease: Are We There Yet? Alessandro Cannavale, Mariangela Santoni, Giuseppe Cannavale and Fabrizio Fanelli DOI: https://doi.org/10.15420/ver.2019.10

Antithrombotic Therapy after Venous Stent Placement Nicholas Xiao and Kush R Desai DOI: https://doi.org/10.15420/ver.2020.06

Use of the Orbital Atherectomy System in Isolated, Chronic Atherosclerotic Lesions of the Popliteal Artery Patricia Torres Lebruno, Konstantinos P Donas, Stefano Fazzini, Charlott Elise Köhler, Arne Schwindt and Giovanni Torsello DOI: https://doi.org/10.15420/ver.2020.08

Treatment of May–Thurner Syndrome in a Patient with an Iliac Artery Stent Raleene Gatmaitan, Keagan Werner-Gibbings, Tommaso Donati, Prakash Saha and Stephen Black DOI: https://doi.org/10.15420/ver.2020.10

Radial Access for Neurointerventions Roger Barranco Pons, Isabel Rodriguez Caamaño and Marta de Dios Lascuevas DOI: https://doi.org/10.15420/ver.2020.13

Conservative Management of a Splenic Artery Aneurysm in Pregnancy: A Case Report Raleene Gatmaitan, Keagan Werner-Gibbings, Morad Sallam, Rachel Bell and Panos Gkoutzios DOI: https://doi.org/10.15420/ver.2020.11

Post-thrombotic Syndrome: Preventative and Risk Reduction Strategies Following Deep Vein Thrombosis Adam M Gwozdz, Stephen A Black, Beverley J Hunt and Chung S Lim DOI: https://doi.org/10.15420/ver.2020.15

Ultrasound Detection of Extracranial Carotid Artery Aneurysms: A Case Report Fabrizio D’Abate and Cristiana Vitale DOI: https://doi.org/10.15420/ver.2020.09

Left Renal Vein Stenting in Nutcracker Syndrome: Outcomes and Implications Patrick Cherfan, Efthymios D Avgerinos and Rabih A Chaer DOI: https://doi.org/10.15420/ver.2020.12

Aortic

Incisional Hernia Following Open Abdominal Aortic Aneurysm Repair: A Contemporary Review of Risk Factors and Prevention Thuy-My Nguyen,1 Saissan Rajendran,1 Kilian GM Brown,2,3 Prakash Saha4 and Raffi Qasabian1 1. Department of Vascular Surgery, Royal Prince Alfred Hospital, Sydney, Australia; 2. Surgical Outcomes Research Centre (SOuRCe), Sydney, Australia; 3. The Institute of Academic Surgery at Royal Prince Alfred Hospital, Sydney, Australia; 4. Academic Department of Vascular Surgery, King’s College London, UK

Abstract While the endovascular approach has been the treatment of choice for abdominal aortic aneurysm (AAA) repair in the modern era, open AAA repair remains a treatment option and may have a resurgence after the recent release of draft guidelines from the National Institute for Health and Care Excellence (NICE). Incisional hernia is a common long-term complication of open AAA repair and causes significant patient morbidity. As the number of patients undergoing open AAA repair increases, it is imperative that vascular surgeons are aware of and aim to reduce the complications associated with open surgery. This review article summarises current evidence, highlighting the risk factors for incisional hernia and the modern surgical techniques that can prevent complications.

Keywords Abdominal aortic aneurysm, incisional hernia, laparotomy, National Institute for Health and Care Excellence Disclosure: The authors have no conflicts of interest to declare. Received: 23 June 2019 Accepted: 29 July 2019 Citation: Vascular & Endovascular Review 2020;3:e01 DOI: https://doi.org/10.15420/ver.2019.01.R1 Correspondence: Saissan Rajendran, Department of Vascular Surgery, Royal Prince Alfred Hospital, PO Box M157, Missenden Road, NSW 2050, Australia. E: saissanrajendran@hotmail.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 noncommercial purposes, provided the original work is cited correctly.

Abdominal aortic surgery has seen a significant shift over the past two decades, with increasing use of endovascular techniques compared with open surgery. In contemporary practice, an endovascular approach to aortic aneurysm repair is used in more than two-thirds of elective cases and now represents the treatment of choice in the emergency setting for ruptured aneurysms if anatomically suitable.1 Despite this, a draft National Institute for Health and Care Excellence (NICE) guideline for the diagnosis and management of abdominal aortic aneurysms, released in May 2018, has recommended open repair rather than endovascular aortic repair (EVAR) for unruptured infrarenal abdominal aortic aneurysms (AAA) on the basis of cost-effectiveness and long-term outcomes. It also recommended that EVAR should not be offered to patients with unruptured infrarenal AAAs who were not considered suitable for open AAA repair because of medical comorbidity. Open repair was also recommended as the choice for repair of ruptured aneurysm in men under 70 years of age or for people with complex aneurysms.2 Although these draft guidelines have generated controversy among the international vascular surgery community and are currently being debated, it is a strong possibility that they may be implemented in the UK. Therefore, this may increase the numbers of patients having an open AAA repair which will inevitably cause a rise in specific complications from this open procedure. One of the most common long-term complications of open AAA repair is incisional hernia. Rates for this complication are reported to

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be as high as 38% and it is symptomatic in more than 80% of patients.3,4 Symptoms include abdominal pain and discomfort and it can lead to life-threatening complications, including bowel strangulation, intestinal obstruction and/or perforation. In addition, patients with incisional hernias report significantly lower mean scores in physical functioning, cosmetic and body image scores when compared with patients without hernias.4 Repair of an incisional hernia is required in about 10% of patients.5,6 This article reviews the risk factors for incisional hernias in patients who undergo open repair AAA and it will consider the surgical techniques that vascular surgeons could consider at the time of surgery that could mitigate the risk of an incisional hernia after surgery.

Risk Factors and Pathophysiology AAA is an independent risk factor for incisional hernia after laparotomy. A systematic review in patients who underwent open AAA repair compared with patients undergoing laparotomy for aortoiliac occlusive disease (AOD) has reported an approximate threefold increase in risk for both inguinal and postoperative incisional hernia (OR 2.85; 95% CI [1.71–4.77]; p<0.0001 and OR 2.79; 95% CI [1.33–4.13]; p<0.0001, respectively).7 These findings were supported with data from the Danish Vascular Registry that showed AAA to be an independent risk factor for incisional hernia (HR 1.58; 95% CI [1.06–2.35]; p=0.024) when adjusted for age, American Society of Anesthesiologists (ASA) score and BMI >25 kg/m2. Although the cumulative risk of incisional hernia repair was the same in

Incisional Hernia Following Open Abdominal Aortic Aneurysm Repair AAA and AOD by 5 years, patients with AAA had a 1.6-fold higher cumulative risk of incisional hernia repair compared with those treated for AOD (p=0.08).6 These findings suggest that while early incisional hernias may be secondary to technical failures of wound closure or wound dehiscence, incisional hernias that develop in the longer term after open AAA repair may be associated with factors involved in aneurysmal degeneration. The precise mechanism for higher rates of incisional hernia in open AAA repair is likely to be multifactorial. These can be classified into patient-related risk factors and surgery-related factors and have been listed in Table 1.8,9 Obesity is a modifiable risk factor in the prevention of incisional hernias and is an independent risk factor for this complication (HR 1.74; 95% CI [1.21–2.46]; p=0.002).6 8,9 A prospective observational study has reported similar findings, with BMI ≥25 kg/m2 associated with increased risk of incisional hernia (HR 1.76; 95% CI [1.35–2.30]; p<0.001). In addition, for every 1 cm increase in thickness of subcutaneous fat there was an increased risk of developing an incisional hernia (HR 1.18; 95% CI [1.03–1.35]; p<0.017).8

Table 1: Risk Factors for Incisional Hernia After Laparotomy Patient-Related Factors • Increased age • Obesity (BMI >25 kg/m2) • Subcutaneous tissue depth at incision • Previous laparotomy • Previous incisional hernia • Pre-operative chemotherapy • Liver disease

Indication for Surgery • Surgery for AAA • Surgery for obesity • Emergency laparotomy

Surgical Factors • Midline incision • Surgical site infection • Intraoperative blood transfusions Source: Itatsu et al. 20148 and Fischer et al. 2016.9

Mechanism of Incisional Hernia Development Both AAAs and abdominal wall hernias share common pathophysiological mechanisms including increased collagen breakdown caused by a protease/antiprotease imbalance. Elastin interposed between the smooth muscle cells of the tunica media and longitudinally arranged collagen in the tunica adventitia allow the aorta its structural elastic properties and strength. Collagen is the primary structural element of the adventitia and helps prevent expansion of the arterial wall beyond physiological limits during systole.10 Elastin and collagen metabolism is regulated by the aortic wall’s extracellular matrix (ECM). Imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are thought to impair normal physiological aortic wall remodelling leading to aneurysm development. Several MMPs, including MMP2 and MMP9, have been implicated as the dominating proteolytic enzymes for inciting and propagating aneurysm development.11 This process is also implicated in the pathological formation of abdominal wall and inguinal hernias. Type 1 collagen is highly cross-linked and provides the abdominal fascia with its mechanical strength while type 3 collagen is less abundant, less crosslinked and offers less tensile strength to tissues. Type 3 collagen is eventually replaced with type 1 collagen during the stages of wound healing and remodelling. Similar to AAAs, the altered ratio of type 1 to type 3 collagen ratio may be a result of increased collagen metabolism caused by dysfunctional ECM activity. Studies of inguinal hernias have found an overexpression of degrading MMP2 and MMP9, as well as increased MMP1 and MMP13 activity in recurrent inguinal hernias.11.12

Prevention Incision Guidelines from the European Hernia Society on the closure of abdominal wall incisions recommend non-midline laparotomy incisions where possible.13 A systematic review comparing midline, transverse and paramedian incisions concluded that non-midline incisions were associated with a significantly lower rate of incisional hernias compared with those on the midline for both transverse (RR 1.77; 95% CI [1.09–2.87]) and paramedian incisions (RR 3.41; 95% CI [1.02–11.45]).14 This is in contrast to a previous study that showed no difference in the rate of incisional hernias between transverse abdominal incision compared with midline laparotomy incisions for

VASCULAR & ENDOVASCULAR REVIEW

elective infrarenal aortic reconstruction.15 However, this study included both AAA and AOD patients. In a randomised controlled trial (RCT) of patients undergoing midline versus transverse incision for open AAA repair, a significantly lower risk of incisional hernia was demonstrated if a transverse incision was used.16 Despite this, not all AAAs can be repaired with a transverse incision due to the difficulty in access for either proximal or distal control. If the anatomy is favourable, however, a transverse incision should be considered to reduce the risk of incisional hernias.

Suture Technique The European Hernia Society recommends using slowly absorbable suture material rather than non-absorbable sutures for continuous closure of midline abdominal wall incisions.13 These recommendations are based on results of systematic reviews.17,18,19 Although there is no difference in incisional hernia rate between the two suture types, there is an increased incidence of suture sinus formation and wound pain when non-absorbable sutures are used to close the midline fascia.18,19 The beneficial effect of a high suture length to wound length (SL:WL) ratio of at least 4:1 on reducing the incidence of incisional hernias in midline laparotomy wounds is well reported.20 In patients undergoing open AAA repair, the development of an incisional hernia is associated with a longer incision, longer operating time, and a SL:WL ratio of less than 4:1 at the time of index surgery.21 Laparotomy closure has been classically taught with ‘long stitches’ placed at least 10 mm away from the wound edge. Following contrary evidence from experimental studies, a short-stitch technique for midline laparotomy wound closure has more recently been proposed.22,23 The short-stitch technique consists of placing sutures 5–8 mm from the wound edge, 5 mm from suture to suture, including only the aponeurosis, which is thought to reduce trauma and complications of infection and excessive scarring. An RCT has suggested that there is a twofold risk of wound infection (OR 2.15; 95% CI [1.17–3.96]) and a fourfold risk of incisional hernia (OR 4.24; 95% CI [2.19–8.23]) when the long-stitch technique is used.23 These outcomes were affirmed by the Suture Techniques to reduce the Incidence of The inCisional Hernia (STITCH) trial, a multicentre RCT from the Netherlands.

Aortic Patients in the experimental group underwent laparotomy closure using the small-stitch technique and reported a 1-year incisional hernia rate of 13% (compared with 21% in patients closed with the large-stitch technique) (OR 0.52; CI [0.31–0.87]; p=0.0131). The smallbite technique was, however, associated with a higher SL:WL ratio (5.0 [SD 1.5] versus 4.3 [SD 1.4]; p<0.0001) and a longer closure time (14 [SD 6] minutes versus 10 [SD 4] minutes; p<0.0001).24 Although this technique is not specific to abdominal wound closure post AAA repair, the findings may still be applicable.

Prophylactic Mesh Repair Prophylactic mesh placement has been supported by the European Hernia Society which recommends prophylactic mesh augmentation for elective midline laparotomies in high-risk patients.13 A recent metaanalysis addressing the use of prophylactic non-absorbable mesh in midline closure of high-risk patients, which included patients undergoing laparotomy for AAA, suggested a significant reduction of the incisional hernia rate in the prophylactic mesh group with pooled odds ratio of 0.14 (95% CI [0.07–0.27]).25 A systematic review examining prophylactic mesh re-enforcement, specifically for patients undergoing open AAA repair via a midline laparotomy, has further demonstrated the benefit of this procedure. Interventions were heterogenous between the included trials with respect to the type of mesh used as well as mesh positioning relative to the fascia (i.e. sublay, onlay or within the rectus sheath).26 Metaanalysis demonstrated a significant reduction in the risk of incisional hernia after AAA repair when mesh reinforcement was used, compared with primary suture closure. There was no difference in re-operation rate and intraoperative or postoperative complication rates between the groups, and the pain scores were similar. A later trial, which included high-risk patients who underwent laparotomy for either AAA repair or had a BMI ≥27 kg/m2, found no difference in the rate of incisional hernia between onlay or sublay mesh positioning. There was, however, a higher frequency of seroma in the onlay mesh group (34 of 188) compared with primary suture (5 of 107; p=0.02) or sublay mesh reinforcement (13 of 185; p=0.02).27 In addition, there appears to be a significant increase in overall operative time (211 [SD 62] minutes versus 190 [SD 83] minutes, p<0.05) and time to close the abdominal wall (46 [SD 19] minutes versus 30 [SD 18] minutes; p<0.05) between the mesh and no mesh groups. Prophylactic mesh reinforcement of the abdominal wall after open AAA repair via midline laparotomy significantly reduces the risk of incisional hernia. Based on this data,

eck AW, Sedrakyan A, Mao J, et al. Variations in abdominal B aortic aneurysm care: a report from the international consortium of vascular registries clinical perspective. Circulation 2016;134:1948–58. https://doi.org/10.1161/ CIRCULATIONAHA.116.024870; PMID: 27784712. National Institute for Health and Care Excellence. Abdominal Aortic Aneurysm: Diagnosis and Management. Draft for consultation, May 2018. 2018. Available at: https://www.nice. org.uk/guidance/gid-cgwave0769/documents/short-versionof-draft-guideline (accessed 17 August 2019). Holland AJA, Castleden WM, Norman PE, Stacey MC. Incisional hernias are more common in aneurysmal arterial disease. Eur J Vasc Endovasc Surg 1996;12:196–200. https://doi.org/10.1016/ S1078-5884(96)80106-7; PMID: 8760982. van Ramshorst GH, Eker HH, Hop WC, et al. Impact of incisional hernia on health-related quality of life and body image: a perspective cohort study. Am J Surg 2012;204:144–50. https:// doi.org/10.1016/j.amjsurg.2012.01.012; PMID: 22579232. Lederle FA, Freischlag LA, Kyriakides TC, et al. Long-term comparison of endovascular and open repair of abdominal aortic aneurysm. N Eng J Med 2012;21:1988–97. https://doi. org/10.1056/NEJMoa1207481; PMID: 23171095. Henriksen NA, Helgstrand F, Vogt KC, et al. Risk factors for incisional hernia repair after aortic reconstructive surgery in

patients undergoing open AAA repair should be considered high risk, and prophylactic mesh placement at the time of laparotomy closure should be performed routinely, unless there are concerns about patient instability, where the benefits of a more rapid abdominal closure would outweigh the increased risk of incisional hernia.

Recommendations Based on current data, we recommend that vascular surgeons employ a transverse incision as a first line if suitable. Meticulous abdominal wall closure with a slowly-absorbable suture material and a long suture length to wound ratio of at least 4:1 should be carried out.21 The ‘short stitch’ technique of laparotomy closure, i.e. 5 mm deep, 5 mm a part, should be employed as it has demonstrated a significant reduction in the risk of developing an incisional hernia in patients undergoing elective laparotomy.24 This benefit may be even more significant in patients who undergo open AAA repair as they are at high risk of incisional hernia for many reasons. Contemporary data suggests that prophylactic implantation of mesh may reduce the incidence of incisional hernias in at-risk patients, although mesh repair does increase operative time. We suggested this approach be performed routinely in patients undergoing AAA repair, unless patient instability necessitates a more rapid abdominal closure. With current vascular training models having minimal general surgical exposure, surgeons will need to be taught the technical skills to perform mesh repair. Obesity is a consistent modifiable risk factor and weight loss should be encouraged during the surveillance period for AAA. Every centimetre reduction in thickness of abdominal subcutaneous fat will reduce the risk of incisional hernias. Weight loss will also profoundly reduces perioperative cardiovascular and anaesthetic complications.

Conclusion Incisional hernias represent a significant cause of long-term morbidity after open AAA repair, often requiring surgical repair under general anaesthesia in a relatively high-risk group. The recent NICE guideline draft has the potential to prompt an increase in the rate of open AAA repairs and vascular surgeons must ensure they meticulously apply contemporary laparotomy closure techniques to minimise postoperative incisional hernias. This is particularly important in an era of subspecialist training programmes where junior surgeons may have had limited exposure to general surgery.

a nationwide study. J Vasc Surg 2013;57:1524–30. https://doi. org/10.1016/j.jvs.2012.11.119; PMID: 23548175. Takagi H, Sugimoto M, Kato T, et al. Postoperative incision hernia in patients with abdominal aortic aneurysm and aortoiliac occlusive disease: a systematic review. Eur J Vasc Endovasc Surg 2007;33:177–181. https://doi.org/10.1016/j. ejvs.2006.07.009; PMID: 16934501. 8. Itatsu K, Yokoyama Y, Sugawara G, et al. Incidence of and risk factors for incisional hernia after abdominal sugery. Br J Surg 2014;140:1439–47. https://doi.org/10.1002/bjs.9600; PMID: 25123379. 9. Fischer J, Masta M, Mirzabeigi M, et al. A risk model and cost analysis of incisional hernia after elective abdominal surgery based upon 12,373 cases: the case of targeted prophylactic intervention. Ann Surg 2016;263:1010–7. https:// doi.org/10.1097/SLA.0000000000001394; PMID: 26465784. 10. Ross M, Pawlina W. Cardiovascular system. In: Paulina W. Histology: A Text and Atlas with Correlated Cell and Molecular Biology. 5th ed. Baltimore: Lippincott Williams & Wilkins, 2006; 364–86. 11. Antoniou GA, Georgiadis GS, Antoniou SA, et al. Abdominal aortic aneurysm and abdominal wall hernia as manifestation of a connective tissue disorder. J Vasc Surg 2011;54:1175–81. https://doi.org/10.1016/j.jvs.2011.02.065; PMID: 21820838. 7.

12. K linge U, Binnebösel M, Mertens PR. Are collagens the culprits in the development of incisional and inguinal hernia disease? Hernia 2006;10:471–7. https://doi.org/10.1007/ s10029-006-0145-8; PMID: 17024306. 13. Muysoms FE, Antoniou SA, Bury K, et al. European Hernia Society guidelines on the closure of abdominal wall incisions. Hernia 2015;19:1–24. https://doi.org/10.1007/s10029-014-13425; PMID: 25618025. 14. Birkenbach KA, Karanicolas PJ, Ammor JB, et al. Up and down or side to side? A systematic review and metaanalysis examining the impact of incision on outcomes after abdominal surgery. Am J Surg 2013;3:400–9. https://doi. org/10.1016/j.amjsurg.2012.11.008; PMID: 23570737. 15. Lord RSA, Crozier JA, Snell J, Meek AC. Transverse abdominal incisions compared with midline incisions for elective infrarenal aortic reconstruction: predisposition to incisional hernia in patients with increased intraoperative blood loss. J Vasc Surg 1994;20:27–33. https://doi.org/10.1016/07415214(94)90172-4; PMID: 8028086. 16. Fassiadis N, Roidl M, Hennig M, et al. Randomized clinical trial of vertical or transverse laparotomy for abdominal aortic aneurysm repair. Br J Surg 2005;92:1208–11. https://doi. org/10.1002/bjs.5140; PMID: 16175532. 17. Diener MK, Voss S, Jensen K, et al. Elective midline

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Incisional Hernia Following Open Abdominal Aortic Aneurysm Repair

18.

19.

20.

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laparotomy closure: the INLINE systematic review and metaanalysis. Ann Surg 2010;251:843–56. https://doi.org/10.1097/ SLA.0b013e3181d973e4; PMID: 20395846. van’t Riet M, Steyerberg EW, Nellensteyn J, et al. Metaanalysis of techniques for closure of midline abdominal incision. Br J Surg 2002;89:1350–6. https://doi.org/10.1046/ j.1365-2168.2002.02258.x; PMID: 12390373. Sajid MS, Parampalli U, Baig MK, McFall MR. A systematic review on the effectiveness of slowly-absorbable versus non-absorbable sutures for abdominal fascial closure following laparotomy. Int J Surg 2011;9:615–25. https://doi. org/10.1016/j.ijsu.2011.09.006; PMID: 22061310. Israelsson La, Jonsson T. Suture length to wound length ratio and healing of midline laparotomy incisions. Br J Surg 1993;80:1284–6. https://doi.org/10.1002/bjs.1800801020; PMID: 8242299. Israelsson LA. Incisional hernias in patients with aortic

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aneurysmal disease: the importance of suture technique. Eur J Vasc Endovasc Surg 1999;17:133–5. https://doi.org/10.1053/ ejvs.1998.0726; PMID: 10063408. Cengiz Y, Blomquist P, Israelsson LA. Small tissue bites and wound strength: an experimental study. Arch Surg 2001;136:272–5. https://doi.org/10.1001/archsurg.136.3.272; PMID: 11231844. Millbourn D, Cengiz Y, Israelsson LA. Effect of stitch length on wound complications after closure of midline incisions: a randomized controlled trial. Arch Surg 2009;144:1056–9. https://doi.org/10.1001/archsurg.2009.189; PMID: 19917943. Deerenberg EB, Hariaar JJ, Steyerberg EW, et al. Small bites verus large bites for closure of abdominal midline incisions (STITCH): a double-blind multicenter randomised controlled trial. Lancet 2015;386:1254–60. https://doi.org/10.1016/ S0140-6736(15)60459-7; PMID: 26188742. Payne R, Aldwinckle J, Ward S. Meta-analysis of randomised

trials comparing the use of prophylactic mesh to standard midline closure in the reduction of incisional herniae. Hernia 2017;21:843–53. https://doi.org/10.1007/s10029-017-1653-4; PMID: 28864937. 26. Indrakusuma R, Jalalzadeh H, van der Meij JE, Koelemay MJW. Prophylactic mesh reinforcement versus sutured closure to prevent incisional hernias after open abdominal aortic aneurysm repair via midline laparotomy: a systematic review and meta-analysis. Eur J Vasc Endovasc Surg 2018;56:120–8. https://doi.org/10.1016/j.ejvs.2018.03.021; PMID: 29685678. 27. Jairam AP, Timmermans L, Eker HH, et al. Prevention of incisional hernia with prophylactic only and sublay mesh reinforcement versus primary suture only in midline laparotomies (PRIMA): 2 year follow-up of a multicentre, double-blind, randomised controlled trial. Lancet 2017;10094:567–76. https://doi.org/10.1016/S01406736(17)31332-6; PMID: 28641875.

Peripheral Artery Disease

Restenosis After Tack Implantation is Associated with Less Complex Patterns of Restenosis Compared to Stent Implantation Raghu Kolluri,1 William A Gray,2 Ehrin Armstrong3 and Brian C Fowler4 1. Syntropic CoreLab, Columbus, OH, US; 2. Lankenau Heart Institute, Wynnewood, PA, US; 3. University of Colorado, Aurora, CO, US; 4. Syntropic CoreLab, Columbus, OH, US

Abstract In-stent restenosis is complex, difficult to treat and has led to a ‘leave less metal behind’ approach to femoropopliteal intervention. Postangioplasty dissection often requires scaffolding to maintain patency. The Tack Endovascular System provides minimal-metal dissection repair that preserves future treatment options. Tack implants are designed to minimise the inflammation and neointimal hyperplasia that lead to in-stent restenosis. An independent angiographic core laboratory evaluated the restenosis patterns in clinically driven target lesion revascularisation (CD-TLR) during the 12 months following the index procedure in the Tack Optimized Balloon Angioplasty (TOBA) II study and compared these results to those published for nitinol stent implantation. Of the 213 patients in TOBA II, 31 (14.6%) required a CD-TLR. Of these, 28 had angiograms that were evaluated by the core laboratory and 45.2%, 16.1%, and 29% were graded as Tosaka class I, II and III, respectively. There were no significant differences (p>0.05) in lesion length, degree of calcification or dissection class between the three groups. Tack restenotic lesion classification and analysis show a prevalence of both class I and shorter lesions relative to in-stent restenosis, which may be beneficial to long-term patient outcomes.

Keywords Angioplasty, dissection, peripheral artery disease, drug-coated balloon, femoropopliteal, stent, restenosis Disclosure: This study was funded by Intact Vascular. RK and BF are employees of Syntropic Core Laboratory. WG is the National Principal Investigator for TOBA II. EA is an investigator for TOBA II. Received: 1 August 2019 Accepted: 25 October 2019 Citation: Vascular & Endovascular Review 2020;3:e02. DOI: https://doi.org/10.15420/ver.2019.03.R1 Correspondence: Raghu Kolluri, 3535 Olentangy River Rd, Suite 514, Columbus, OH 43214, US. E: Raghu.Kolluri@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 noncommercial purposes, provided the original work is cited correctly.

Peripheral artery disease (PAD) affects more than 200 million people worldwide, and its prevalence is increasing due to numerous risk factors, including age and diabetes.1–3 Endovascular treatments, primarily percutaneous transluminal angioplasty (PTA), have become common first-line therapy for symptomatic PAD.4,5 However, mechanical dilatation of the vessel during PTA often results in vessel dissection.6–8 Left untreated, lesions with dissections have high 1-year restenosis rates of 40–60% and a threefold increase in 6-month target lesion revascularisation (TLR) compared to lesions without dissections.7,9–12 The most commonly employed treatment for dissections is stent placement. Stents improve procedural success and patency relative to PTA. However, stents exert a strong radial force on the vessel wall and the extensive nitinol surface area has the potential to promote inflammation, hyperplasia and in-stent restenosis at not insignificant rates.13–16

Tack Endovascular System The sub-optimal outcomes associated with the current treatments for dissection led to the development of the Tack Endovascular System (Intact Vascular). Tack implants are designed for focal dissection treatment. Tacks are shorter than stents (6 mm) and constructed with an open cell design, which limits the metal surface in contact with the luminal wall and exerts a lower chronic outward

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force when compared to stents. The Tack Endovascular System consists of a 6 Fr (2.0 mm) delivery catheter pre-loaded with six independent nitinol implants 6 mm in length (Figure 1). The implants are of a single-size and self-expanding and can treat a range of vessel diameters from 3.5–6.0 mm. The recently published single-arm Tack Optimized Balloon Angioplasty II (TOBA II) study evaluated 213 patients who developed dissections following PTA of the superficial femoral arteries (SFA) or proximal popliteal arteries (PPA) and were treated with Tacks. The primary patency and freedom from clinically driven TLR at 1 year were 79.3% and 86.5%, respectively. Clinically driven target lesion restenosis (CD-TLR) occurred in 31 patients (14.6%) in the first year post-index procedure.17 The incidence rates and extent of restenosis can vary due to the vessels treated, the treatment modality utilised and patient comorbidities.18 To better understand the severity and extent of restenosis in peripheral vessels and the effect on these patterns on successful treatment, Tosaka et al. evaluated 116 patients with in-stent restenosis (ISR) and proposed a three-level classification of severity, ranging from class I (focal lesions) to class III (total occlusion).19

Tack Implant Restenosis Patterns Aim

Figure 1: Tack Endovascular System

The objective of this investigation was to evaluate the restenosis patterns in patients who received Tacks as part of the TOBA II study and compare these results to the lesion characteristics published for nitinol stent implantation. Furthermore, the pattern of restenosis relative to the placement of Tack(s) was evaluated.

Methods The TOBA II study was a prospective, single-arm, multicentre clinical investigation to evaluate the safety and efficacy of the Tack Endovascular System for the repair of all post-PTA dissections (NCT02522884). It was conducted in compliance with the International Conference on Harmonization Good Clinical Practice, ISO 14155 and the Declaration of Helsinki and the ethics committees at the participating sites approved the study protocol. Study participants provided written informed consent before undergoing any study procedures. Patients included in this study were required to meet the following major inclusion criteria: Rutherford Category 2–4 claudication; atherosclerotic lesions (≥70% diameter stenosis) in the SFA, PPA or both; and lesion length ≥20 mm and ≤150 mm for lesions with 70–99% stenosis and ≤100 mm for occluded arteries. Patients were treated with balloon angioplasty or Lutonix (BD) drugcoated balloons, based on physician preference. Post-angioplasty, lesions with <30% residual diameter stenosis and at least one dissection of any severity were treated with the Tack Endovascular System. To treat the post-PTA dissections, Tacks were deployed singly or in multiples at the discretion of the treating physician. Angiographic evaluation of the index target lesions in TOBA II was conducted by an independent core laboratory (Yale Cardiovascular Research Group Angiographic Core Laboratory, New Haven, CT, US). This evaluated the per cent diameter stenosis, lesion length and degree of calcification of the index lesion. The core laboratory also provided post-treatment grades of dissections, using the National Heart Lung and Blood Institute classification system.20 For patients who had target lesion restenosis in the first year following the index procedure, the angiographic images were analysed and scored by an independent core laboratory (Syntropic CoreLab, Columbus, OH, US). The restenotic lesions were evaluated for per cent diameter occlusion and lesion length. They were classified using the methodology of Tosaka et al. as follows: class I – focal (<50 mm in length) lesions located within the stent body, at the stent edge, or a combination of both; class II – diffuse (>50 mm in length) including both stent body and stent edge lesions; and class III – total occlusion. As noted, the Tosaka classification system was developed to describe lesions in full-length stents. Unlike stents, Tacks, by design, do not cover the full length of treated lesions and multiple Tacks can be used to treat dissections. Due to this unique feature, the core lab also provided an analysis of the location of target lesion restenosis relative to Tack location(s) using the following qualitative analysis: • • • • •

proximal – lesion located proximal to an area that was Tacked; at – lesion located within a Tack; distal – lesion located distal to a Tacked area; between – lesion located between Tacks; and involving multiple – lesions located at multiple Tacks.

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The Tack Endovascular System (6 Fr) consists of six nitinol implants pre-loaded on a single delivery catheter for the repair of post-angioplasty dissections. Source: Intact Vascular. Published with permission from Intact Vascular.

Table 1: Characteristics of Restenotic Lesions in Patients Who Received Tacks Class I (n=14)

Class II (n=5)

Class III (n=9)

p-value

83.9 ± 17.0

87.8 ± 15.2

0.127

Baseline Lesion Characteristics Diameter stenosis (%)

71.0 ± 22.4

Target lesion length (mm) 104.5 ± 46.1 123.6 ± 48.0 117.5 ± 35.4 0.637 Calcification: None/mild Moderate Severe

5 (35.7%) 8 (57.1%) 1 (7.1%)

1 (20.0%) 4 (80.0%) 0 (0%)

6 (66.7%) 3 (33.3%) 0 (0%)

Dissection class: A B C D

2 (14.3%) 2 (14.3%) 3 (21.4%) 7 (50.0%)

2 (40.0%) 0 (0%) 1 (20.0%) 2 (40.0%)

1 (11.1%) 1 (11.1%) 4 (44.4%) 3 (33.3%)

0.387

0.797

Tack Treatment Characteristics Total Tacks used

4.9 ± 2.4

5.2 ± 2.9

5.1 ± 2.6

0.956

Target lesion length: Tack length ratio

29.1 ± 14.7

31.2 ± 17.7

30.7 ± 15.4

0.745

<0.001

Restenosis Lesion Characteristics % Diameter stenosis

63.2 ± 13.1

71.6 ± 4.6

100

Restenotic lesion length (mm)

27.1 ± 12.4

79.6 ± 20.8

118.4 ± 89.7 0.002

2 (14.3%) 4 (28.6%) 0 (0%) 8 (57.1%) 0 (0%)

1 (20.0%) 0 (0%) 0 (0%) 4 (80.0%) 0 (0%)

1 (11.1%) 0 (0%) 1 (11.1%) 1 (11.1%) 6 (66.7%)

Restenosis location relative to Tacks: Proximal At Distal Between Involving multiple

<0.001

Results expressed as mean ± SD or n (%). Statistical analysis: continuous variables (analysis of variance); categorical variables (Fisher’s exact test).

Statistical Analysis Continuous and categorical variables are expressed as mean ± SD and number (per cent of total), respectively. Analysis of variance was utilised to evaluate continuous variables. Fisher’s exact test was used to

Peripheral Artery Disease Table 2: Comparison of TOBA II and Tosaka et al. Cohorts Class I

Class II

Class III

p-value

occlusions (class III) involved multiple Tacks, while none of the class I or II lesions involved multiple Tacks. Figure 2 illustrates a class I restenosis from the TOBA II study.

Number (%) Tosaka cohort TOBA II

39 (29.3%) 14 (50.0%)

50 (37.6%) 5 (17.9%)

44 (33.1%) 9 (32.1%)

0.067

Comparison of TOBA II and Tosaka Cohorts

Lesion length (mm) Tosaka cohort TOBA II p-value

32.0 ± 17.3 27.1 ± 12.4 0.336

137.8 ± 53.6 197.5 ± 62.1 <0.001 79.6 ± 20.8 118.4 ± 89.7 0.001 0.020 0.002

Total stent/Tack length (mm) Tosaka cohort 143.6 ± 84.5 179.0 ± 78.7 185.0 ± 77.1 0.046 TOBA II 29.1 ± 14.7 31.2 ± 17.7 30.7 ± 15.4 0.953 p-value <0.001 <0.001 <0.001

Figure 2: Class I Restenosis from TOBA II

The Tosaka et al. and TOBA II cohorts are compared in Table 2. The Tosaka et al. study was a retrospective analysis of 133 limbs in 116 ptients with ISR.19 In comparing the two studies, the percentage of patients with each of the three restenosis classifications was not significantly different (p=0.067). There was a trend toward more limbs with class I restenosis (the least clinically severe category) in the TOBA II cohort (50.0% versus 29.3%). The class I mean lesion length was not significantly different (p=0.336) between the two cohorts. However, the class II and III mean lesion lengths in the stented cohort were significantly (p=0.020 and p<0.001, respectively) longer compared to the length of restenosis in the TOBA II cohort. Stent length was increased with severity of restenosis and the difference across the restenosis classifications was significantly (p=0.046) longer. In comparison, there was no significant difference (p=0.953) in total Tack length across the three restenosis classifications. Across all Tosaka classes, the total Tack length was significantly (p<0.001) shorter than the total stent length.

Discussion

Six Tacks (arrows) were deployed in the index procedure (A) with resolution of dissection (B). An angiogram for CD-TLR at 12 months (C) and magnified (D) shows a class I restenosis between the implants. CD-TLR = clinically driven target lesion revascularisation.

evaluate categorical variables. Unpaired t-tests were used to compare continuous variables between the Tosaka et al. and TOBA II cohorts. A p value of <0.05 was considered as statistically significant.

Results A total of 213 patients were enrolled in the TOBA II study, of whom 31 (14.6%) required a clinically driven revascularisation within the first year of the index procedure. Of these 31 patients, 28 had angiograms that were evaluable by the core laboratory, and 14 (45.2%), five (16.1%) and nine (29%) were graded as having Tosaka class I, II and III type lesions, respectively. Table 1 summarises the baseline lesion, Tack treatment and restenosis lesion characteristics by lesion classification. There were no significant differences (p>0.05) in lesion length, degree of calcification, or dissection class between the three groups. There was no significant difference in the total number of Tacks used to treat dissections, which were 4.9 ± 2.4, 5.2 ± 2.9 and 5.1 ± 2.6 in class I, II and III lesions, respectively. Similarly, there was no significant difference in the target lesion length:Tack length ratio. Evaluation of the restenotic lesions showed a significant difference (p=0.002) in lesion length between the restenosis classes: 27.1 ± 12.4 mm (class I); 79.6 ± 20.8 (class II); and 118.4 ± 89.7 mm (class III). Location of lesions relative to location of the Tack(s) was also significant. Across all three restenosis classifications, 18 patients (64.3%) had lesions that did not involve the Tacks (proximal, distal and between categories). Of note, 66.7% of the lesions with total

Tacks were developed to provide a minimal metal alternative to stents for the treatment of post-PTA dissections. Like stents, Tacks facilitate the apposition of dissection flaps to the luminal surface. However, they have a reduced surface area when compared to stents. Increased surface area and the more expansive metal scaffold of stents promote the development of neointimal hyperplasia and predispose to stent fracture, both of which can facilitate the development of restenosis in a target lesion.21–23 Histologically, Tacks have been shown to have a reduced hyperplastic response when compared to stents.24 The TOBA II clinical study, which evaluated Tacks for treatment of dissections following treatment of femoropopliteal disease, met its 1-year primary endpoints of primary patency (79.3%) and freedom from clinically driven TLR (86.5%). The 1-year restenosis rate in this cohort (14.6%) is favourable when compared to stents.17 A primary motivation for developing lesion scoring systems was to better understand the prognostic significance of angiographic patterns of restenosis to the outcomes following secondary revascularisation procedures. Tosaka et al. identified nearly equal numbers of class I, II and III lesions (29.3%, 37.6% and 33.1%) in their cohort. Of note, a single centre retrospective analysis of ISR by Armstrong et al. showed nearly similar proportions of ISR, with 37.3%, 29.3% and 33.3% in class I, II and III, respectively.25 The TOBA II cohort had a higher percentage (50.0%) of patients with less severe class I lesions than these two studies, but the percentage with class III lesions was 32.1%, similar to both Tosaka et al. and Armstrong et al. As in the Tosaka et al. analysis, there are key differences between class I/II and class III lesions. Class I/II lesions had nearly identical 3-year recurrent ISR rates of 49.9% and 53.3%, respectively, which were significantly better than class III lesions (84.8%). During 2 years of followup, Armstrong et al. showed significant (p=0.04) differences in the rates of repeat restenosis: 39% class I; 67% class II; and 72% class III.25

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Tack Implant Restenosis Patterns A key and statistically significant difference (p<0.001) between the TOBA II cohort and the Tosaka cohorts is the shorter lesion length of the class II and III lesions in TOBA II patients. The Armstrong study displayed similar lesion lengths to the Tosaka study. Lesion length was identified as a significant univariate predictor of recurrent ISR. Tacks allow for multiple potential options due to their minimalist approach of reduced metal burden compared with stents. These options could include repeat angioplasty, drug-coated balloon angioplasty, laser atherectomy, or other modalities. Future studies should investigate the optimal treatment strategies for in-Tack restenosis. One additional analysis that was unique to TOBA II was the localisation of restenosis relative to Tack placement. These data showed that only four out of 19 (21%) of class I/II lesions were within the body of the Tack. In class III lesions, 66.7% involved multiple Tacks. As with stent-treated lesions, class III lesions with Tacks were the longest lesion type. Unlike class III stent lesions where the restenosis essentially covered the majority of stent surface, Tacks only represented about 25% of the total lesion length in class III Tack lesions, which may be indicative of broad diffuse disease rather than the presence of Tacks. Overall, the 14.6%

Fowkes FGR, Rudan D, Rudan I, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013;382:1329–40. https://doi.org/10.1016/S01406736(13)61249-0; PMID: 23915883. Dua A, Lee CJ. Epidemiology of peripheral arterial disease and critical limb ischemia. Tech Vasc Interv Radiol 2016;19:91–5. https://doi.org/10.1053/j.tvir.2016.04.001; PMID: 27423989. Criqui MH, Aboyans V. Epidemiology of peripheral artery disease. Circ Res 2015;116:1509–26. https://doi.org/10.1161/ CIRCRESAHA.116.303849; PMID: 25908725. Rooke TW, Hirsch AT, Misra S, et al. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:1555–70. https://doi.org/10.1016/j.jacc.2013.01.004; PMID: 23473760. Aboyans V, Ricco JB, Bartelink MEL, et al. 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries. Eur Heart J 2018;39:763–816. https://doi.org/10.1093/eurheartj/ehx095; PMID: 28886620. Werk M, Albrecht T, Meyer DR, et al. Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: Evidence from the randomized PACIFIER trial. Circ Cardiovasc Interv 2012;5:831–40. https://doi.org/10.1161/ CIRCINTERVENTIONS.112.971630; PMID: 23192918. Tepe G, Zeller T, Schnorr B, et al. High-grade , non-flow-limiting dissections do not negatively impact long-term outcome after paclitaxel-coated balloon angioplasty: an additional analysis from the THUNDER study. J Endovasc Ther 2013;20:792–800. https://doi.org/10.1583/13-4392R.1; PMID: 24325695. Fujihara M, Takahara M, Sasaki S, et al. Angiographic dissection patterns and patency outcomes after balloon angioplasty for superficial femoral artery disease. J Endovasc Ther 2017;24:367–

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10.

11.

12.

13.

14.

15.

16.

restenosis rate in the TOBA II cohort is lower than the rate of restenosis than the 20–37% range reported for stents and is within the 3–20% range reported for non-stent technologies.13–16,18 There are a few limitations to this study. Although the sample size of the TOBA II cohort is small, it is still the largest cohort to date in which patients received standard treatment. It is important to note that the Tosaka classification was developed to describe re-stenosis in long stents. However, it is widely accepted longer lesions and occlusions are associated with inferior secondary patency rates compared to less severe lesions. As such, it is worth comparing the patterns of re-stenosis between these two groups. Conclusions on comparative prognostic data on recurrent restenosis rates between the two groups can be achieved only with an appropriately designed randomised controlled trial.

Conclusion This the first core lab-adjudicated observational data report on patterns of in-Tack stenosis. These data show that Tacks have a relatively low rate of target lesion restenosis at 1 year. Furthermore, Tack restenotic lesion analysis demonstrate a prevalence of both class I and shorter lesions.

75. https://doi.org/10.1177/1526602817698634; PMID: 28351208. orgren L, Hiatt WR, Dormandy JA, et al. Inter-society N consensus for the management of peripheral arterial disease (TASC II). Eur J Vasc Endovasc Surg 2007;33:S1–75. https://doi. org/10.1016/j.ejvs.2006.09.024; PMID: 17140820. Rocha-Singh KJ, Jaff MR, Crabtree TR, et al. Performance goals and endpoint assessments for clinical trials of femoropopliteal bare nitinol stents in patients with symptomatic peripheral arterial disease. Catheter Cardiovasc Interv 2007;69:910–9. https://doi.org/10.1002/ccd.21104; PMID: 17377972. Werk M, Langner S, Reinkensmeier B, et al. Inhibition of restenosis in femoropopliteal arteries. Paclitaxel-coated versus uncoated balloon: Femoral paclitaxel randomized pilot trial. Circulation 2008;118:1358–65. https://doi.org/10.1161/ CIRCULATIONAHA.107.735985; PMID: 18779447. Tepe G, Zeller T, Albrecht T, et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med 2008;358:689–99. https://doi.org/10.1056/NEJMoa0706356; PMID: 18272892. Schillinger M, Sabeti S, Loewe C, et al. Balloon Angioplasty versus implantation of nitinol stents in the superficial femoral artery. N Engl J Med 2006;354:1879–88. https://doi.org/10.1056/ NEJMoa051303; PMID: 16672699. Krankenberg H, Schlüter M, Steinkamp HJ, et al. Transluminal angioplasty in superficial femoral artery lesions up to 10 cm in length: the Femoral Artery Stenting Trial (FAST). Circulation 2007;116:285–92. https://doi.org/10.1161/ CIRCULATIONAHA.107.689141; PMID: 17592075. Bosiers M, Torsello G, Gissler HM, et al. Nitinol stent implantation in long superficial femoral artery lesions: 12-month results of the DURABILITY I study. J Endovasc Ther 2009;16:261–9. https://doi.org/10.1583/08-2676.1; PMID: 19642788. Laird JR, Katzen BT, Scheinert D, et al. Nitinol stent implantation versus balloon angioplasty for lesions in the superficial femoral artery and proximal popliteal artery: Twelve-month results from the RESILIENT randomized trial. Circ Cardiovasc Interv 2010;3:267–276. https://doi.org/10.1161/

CIRCINTERVENTIONS.109.903468; PMID: 20484101. 17. G ray W. TOBA II 12-month results: Tack optimized balloon angioplasty. Presented at: VIVA 2018, Las Vegas, NV, 5–8 November 2018. 18. Garcia LA, Rocha-Singh KJ, Krishnan P, et al. Angiographic classification of patterns of restenosis following femoropopliteal artery intervention: a proposed scoring system. Catheter Cardiovasc Interv 2017;90:639–646. https://doi. org/10.1002/ccd.27198; PMID: 28795488. 19. Tosaka A, Soga Y, Iida O, et al. Classification and clinical impact of restenosis after femoropopliteal stenting. J Am Coll Cardiol 2012;59:16–23. https://doi.org/10.1016/j.jacc.2011.09.036; PMID: 22192663. 20. Coronary artery angiographic changes after PTCA: In: Manual of Operations NHLBI PTCA Registry. Bethesda, MD: National Heart, Lung, and Blood Institute, 1985;6–9. 21. Ballyk PD. Intramural stress increases exponentially with stent diameter: a stress threshold for neointimal hyperplasia. J Vasc Interv Radiol 2006;17:1139–1145. https://doi.org/10.1097/01. RVI.0000228361.23849.7F; PMID: 16868167. 22. Freeman JW, Snowhill PB, Nosher JL. A link between stent radial forces and vascular wall remodeling: the discovery of an optimal stent radial force for minimal vessel restenosis. Connect Tissue Res 2010;51:314–26. https://doi. org/10.3109/03008200903329771; PMID: 20388019. 23. Zhao HQ, Nikanorov A, Virmani R, et al. Late stent expansion and neointimal proliferation of oversized nitinol stents in peripheral arteries. Cardiovasc Intervent Radiol 2009;32:720–6. https://doi.org/10.1007/s00270-009-9601-z; PMID: 19484292. 24. Schneider PA, Giasolli R, Ebner A, et al. Early experimental and clinical experience with a focal implant for lower extremity post-angioplasty dissection. JACC Cardiovasc Interv 2015;8:347– 54. https://doi.org/10.1016/j.jcin.2014.07.032; PMID: 25700758. 25. Armstrong EJ, Singh S, Singh GD, et al. Angiographic characteristics of femoropopliteal in-stent restenosis: Association with long-term outcomes after endovascular intervention. Catheter Cardiovasc Interv 2013;82:1168–74. https://doi.org/10.1002/ccd.24983; PMID: 23630047.

Case Reports

Thrombosis Following Endovenous Glue Ablation Raeed Deen and Andrew Bullen Circulation Health, Wollongong, NSW, Australia

Abstract Endovenous glue ablation for lower limb varicose veins is growing in popularity due to its safety and efficacy. Of significant concern is glue-associated thrombus extension into deep veins. We present a case of thrombus extending into the common femoral vein following endovenous glue ablation for varicose veins with the VenaSeal™ closure system (VCS; Medtronic). A 63-year-old man who presented with symptomatic varicose veins had incompetence of the saphenofemoral junction. He underwent endovenous glue ablation using VCS closure. At 1 month, improvement in varicosities was mirrored by duplex ultrasound confirmation of successful long saphenous vein ablation, but ultrasound indicated thrombus extending into the common femoral vein. This was managed by surveillance duplex and serial clinical observation, with spontaneous resolution at 12 months. With increasing use of VCS for varicose veins, it is likely that thrombotic complications of the deep veins will be encountered more frequently. It is time for formulation of guideline-based management of this complication.

Keywords Endovenous glue ablation, VenaSeal, varicose veins, thrombus with glue extension Disclosure: The authors have no conflicts of interest to declare. Received: 4 October 2019 Accepted: 15 December 2019 Citation: Vascular & Endovascular Review 2020;3:e03. DOI: https://doi.org/10.15420/ver.2019.08 Correspondence: Raeed Deen, Circulation Health, Suite 101/62 Harbour Street, Wollongong, NSW 2500, Australia. E: raeeddeen30@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 noncommercial purposes, provided the original work is cited correctly.

The treatment of varicose veins has become a rapidly evolving landscape with the expansion of endovenous therapies, which can be categorised into thermal tumescent (TT) and newer non-thermal nontumescent (NTNT) methods. TT endovenous techniques, such as radiofrequency and laser ablation, have been extensively studied and shown to be effective and safe.1 The newer NTNT techniques, such as glue and mechanochemical ablation, have been studied to a lesser degree. These techniques are growing in popularity due to the exclusion of tumescent anaesthesia and the absence of any risk of heat-related injuries to the skin and surrounding nerves.2 Despite this, a significant concern of endovenous glue ablation is the formation of thrombosis with glue extensions into the deep venous system. Progression of thrombus from the saphenofemoral junction (SFJ) to the common femoral vein is a rare complication following glue ablation.3 To date, there are no guidelines for management. There is a similar, well-researched complication, in TT techniques – endogenous heat-induced thrombosis (eHIT), for which classification systems and management guidelines exist.4,5 In the case of endovenous glue ablation, further concerns are raised in patients who are high risk, as to whether the risk of embolisation may be similar to that of eHIT. We report a case of endovenous glue ablation with the VenaSeal closure system (VCS; Medtronic) and subsequent thrombus formation extending into the femoral vein.

Case Report A 63-year-old man presented to the vascular clinic with extensive lower limb venous incompetency, associated varicosities and two prior

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episodes of superficial thrombophlebitis (STP) treated with anticoagulation by his primary care physician. He was otherwise fit and well, with a medical history significant for controlled hypertension. There was no history of smoking, malignancy, deep vein thrombosis, thrombophilia or other prothrombotic conditions. Examination revealed multiple varicosities in the bilateral medial thighs with palpable old superficial phleboliths, and reticular veins at the ankles with associated oedema. Pulses were present throughout the lower limbs. On initial presentation, the venous clinical severity score was 13. Duplex ultrasound of the left lower limb indicated a markedly incompetent long saphenous vein (LSV) and SFJ, primarily responsible for the lower leg varicosities. In addition, a short segment of STP was identified in an LSV medial thigh tributary, but no deep vein thrombosis. This was treated with therapeutic low molecular weight heparin and compression. Once the STP had resolved, endovenous glue ablation with the VCS was carried out. Following protocol, access was gained into the LSV at the mid-calf with ultrasound guidance. The VCS catheter tip was placed in the LSV, 5 cm distal to the SFJ, and VCS adhesive was delivered with simultaneous compression near the SFJ. The entire length of the LSV was treated with adhesive and simultaneous compression, up to the point of access at the mid-calf. The patient returned 1 month later for review. Apart from mild tenderness on the medial thigh lasting 48 hours after the procedure, he reported significant improvement in symptoms. The site of incision for LSV access had healed, and there was marked improvement in venous oedema with no superficial thrombosis palpable. The LSV and associated varicosities had resolved on examination, and the follow-up

Thrombosis Following Endovenous Glue Ablation venous clinical severity score was 3, a significant improvement. Postoperative venous duplex confirmed successful ablation of the LSV from calf to groin, but the scan additionally showed a tongue of partially occlusive material extending into the common femoral vein without acute deep venous thrombosis (Figure 1). This was managed with surveillance duplex and serial clinical observation at 1, 3, 6 and 9 months, with spontaneous resolution by 12-month follow-up.

Figure 1: Venous Duplex Ultrasound Image at the Groin Showing Mixed Echogenic Thrombus (within Markers) Extending into the Common Femoral Vein

Discussion Overall, the VCS has proven to be an effective and safe modality in the treatment of varicose veins.3 Thrombus with glue extension into the deep venous system has been reported as a rare and minor complication of the VCS. The aetiology has mainly been attributed to technique: that is, the distance of the glue-injecting catheter tip from the SFJ on initial delivery of the adhesive.3 The first safety study on humans reported thrombus extensions in 21% of patients when the catheter tip was placed 2 cm from the SFJ.6 Subsequent clinical trials positioned the catheter tip 5 cm from the SFJ, and no thrombus extensions were reported.7,8 However, despite this change in catheter tip positioning, as in the present case, thrombus extensions were still reported. Lam et al., in an expert review of six major studies of VCS (n=344), reported 10 patients with glue extension; an incidence of 0.03%.3 Those 10 cases all resolved with anticoagulant treatment, whereas the present patient was managed non-pharmacologically.3 In order to ensure successful occlusion of the LSV, VCS glue (an n-butyl2-cyanoacrylate-based adhesive) has been formulated to transform into a solid material upon exposure to body fluids or tissue.9 As such, VCS glue has prothrombotic properties, which may explain the increased risk of formation of thrombus extension. However, it is unclear if the volume of injected glue has an impact on this complication. A similar complication, eHIT, occurs in TT techniques.1,2 Initial studies described eHIT as a complication with low incidence rates, but subsequent clinical experience reported the actual incidence to be higher.4 As a result, eHIT was studied more extensively, with risk factors demonstrated in the literature, and classification systems created to guide management ranging from observation with serial ultrasound to anticoagulation.5 Similar to eHIT, the theoretical risk of a thrombus with glue extension in the deep venous system is the potential for embolus to the pulmonary system – a potentially fatal event. Currently, there is no clear evidence to guide clinicians in the management of thrombus with glue extension.

Rasmussen LH, Lawaetz M, Bjoern L, et al. Randomized clinical trial comparing endovenous laser ablation, radiofrequency ablation, foam sclerotherapy and surgical stripping for great saphenous varicose veins. Br J Surg 2011;98:1079–87. https://doi.org/10.1002/bjs.7555; PMID: 21725957. Bootun R, Lane TR, Davies AH. The advent of non-thermal, non-tumescent techniques for treatment of varicose veins. Phlebology 2016;31:5–14. https://doi. org/10.1177/0268355515593186; PMID: 26130051. Lam YL, De Maeseneer M, Lawson J, et al. Expert review on the VenaSeal® system for endovenous cyano-acrylate adhesive ablation of incompetent saphenous trunks in patients with varicose veins. Expert Rev Med Devices

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Furthermore, many of the safety studies involving the VCS excluded patients with a history of STP.6–8 Although active STP remains a relative contraindication to VCS, a history of STP is not a listed contraindication.9 More research is required to stratify those who are at risk of thrombus formation following endovenous glue ablation and to guide appropriate management before and after intervention. There may be a role for prophylactic anti-platelets or anti-coagulation when performing VCS on patients with a history of STP or a prothrombotic history. With the increasing prevalence of chronic venous disease and varicose veins, and the rapidly growing popularity of endovenous glue ablation, it is prudent for future studies to further investigate this minor but likely underreported and potentially fatal complication.

2017;14:755–62. https://doi.org/10.1080/17434440.2017.13780 93; PMID: 28892412. Kane K, Fisher T, Bennett M, et al. The incidence and outcome of endothermal heat-induced thrombosis after endovenous laser ablation. Ann Vasc Surg 2014 ;28:1744–50. https://doi. org/10.1016/j.avsg.2014.05.005; PMID: 24911803. 5. Dexter D, Kabnick L, Berland T, et al. Complications of endovenous lasers. Phlebology 2012;27(Suppl 1):40–5. https:// doi.org/10.1258/phleb.2012.012S18; PMID: 22312066. 6. Almeida JI, Javier JJ, Mackay E, et al. First human use of cyanoacrylate adhesive for treatment of saphenous vein incompetence. J Vasc Surg Venous Lymphat Disord 2013;1:174– 80. https://doi.org/10.1016/j.jvsv.2012.09.010; 4.

PMID: 26992340. 7. Proebstle TM, Alm J, Dimitri S, et al. The European multicenter cohort study on cyanoacrylate embolization of refluxing great saphenous veins. J Vasc Surg Venous Lymphat Disord 2015;3:2–7. https://doi.org/10.1016/j.jvsv.2014.09.001; PMID: 26993674. 8. Morrison N, Gibson K, McEnroe S, et al. Randomized trial comparing cyanoacrylate embolization and radiofrequency ablation for incompetent great saphenous veins (VeClose). J Vasc Surg 2015;61:985–94. https://doi.org/10.1016/j. jvs.2014.11.071; PMID: 25650040. 9. VenaSeal™ closure system. www.accessdata.fda.gov/cdrh_ docs/pdf14/P140018c.pdf (accessed 20 February 2020).

Peripheral Artery Disease

Abstract Wearable devices and telemonitoring are becoming increasingly widespread in the clinical environment and have many applications in the tracking and maintenance of patient wellbeing. Interventions incorporating these technologies have been used with some success in patients with vascular disorders. Wearable fitness monitors and telemonitoring have been used in the community to mobilise patients with peripheral vascular disease with good results. Additionally, wearable monitors and telemonitoring have been studied for blood pressure monitoring in patients with hypertension. Telemonitoring interventions incorporating electronic medication trays and ingestible sensors have also been found to increase drug adherence in hypertensive patients and ultimately improve health outcomes. However, wearable and telemonitoring interventions often face problems with patient adherence, digital literacy and infrastructure. Further work needs to address these challenges and validate the technology before widespread implementation can occur.

Keywords Peripheral vascular disease, wearable technology, personalised medicine, telemedicine, digital health Disclosure: The authors have no conflicts of interest to declare. Received: 18 November 2019 Accepted: 2 February 2020 Citation: Vascular & Endovascular Review 2020;3:e04. DOI: https://doi.org/10.15420/ver.2019.11 Correspondence: Viknesh Sounderajah, Department of Surgery and Cancer, Imperial College London, London W2 1NY, UK. E: vs1108@imperial.ac.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 noncommercial purposes, provided the original work is cited correctly.

Wearable technology refers to the broad category of compact electronic devices that can be incorporated into clothing or accessories.1 These devices are used in the clinical and non-clinical environment and they offer multiple applications that help maintain physiological and psychological wellbeing.2 Wearable technologies not only facilitate selftracking for the consumer but also allows for remote monitoring and analysis by a third party, such as a healthcare provider. The Internet of Things is a network of real-world objects that have the ability to communicate data and sense the status of each object and the surrounding environment.3 Through the combined use of wearable devices and Internet of Things technology, patients and healthcare providers may be able to track, monitor and analyse various clinically relevant measurements. This could lead to real-time monitoring of disease progression as well as treatment adherence. This concept feeds into the premise of telemonitoring, which is defined as the use of telecommunication devices to remotely monitor patients at a distance.4 Of note, telemonitoring is broadly synonymous with biotelemetry, which involves the transmission of health data from one location to another where the data can be interpreted and used to affect healthcare decision-making.4,5 Telemonitoring is useful in collecting biological, environmental or physiological data in a remote setting when direct observation is not possible.5 Common clinically pertinent measurements such as blood pressure (BP), blood glucose and lung function have been successfully tracked using telemonitoring technologies.6–10 The use of telemonitoring allows patients to be

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managed at home, thereby helping to overcome barriers concerning access to healthcare, such as travel, time and costs. These technological advancements may prove useful in the management of cardiovascular disease (CVD). CVD is a major global health burden and accounts for a significant proportion of hospital admissions, as well as up to one-third of all deaths globally.11 However, given the importance of conservative management and lifestyle modifications, wearable technology may be able to disrupt the way in which medical therapy and lifestyle modification advice is delivered to this patient cohort. Therefore, in this review, we aim to summarise the current applications of wearable and telemonitoring technologies in facilitating the management of CVD outside the hospital setting.

Current Wearable Technologies The broad definition of wearable technologies encompasses a variety of devices, such as head-mounted displays, clothing with smart technology, fitness trackers, smart watches and biosensors. Fitness trackers (activity monitors) allow the long-term daily monitoring of physical activity in a real-world setting and usually take the form of wrist bands, ankle bracelets or clip-ons. Fitness trackers use sensors (pedometers or accelerometers) to detect movement and are therefore able to measure physical activity. Electronic displays on devices allow quick and easy viewing of exercise progress and goals. Many devices are able to transfer data to computer or smartphone apps, allowing remote access to data.

Wearable Technologies and Telemonitoring for Vascular Disease Luley et al. used AiperMotion 440 (Aipermon) fitness trackers as part of an intervention to increase physical activity in patients with metabolic syndrome and found significant improvements in weight loss and markers of the metabolic syndrome.12 In a randomised controlled trial, Frederix et al. used triaxial accelerometers (Yorbody) to monitor physical activity and set daily step-count prescriptions for patients with coronary artery disease enrolled in hospital-based cardiac rehabilitation.13 This study found a significant improvement in lung function assessments and a trend towards fewer rehospitalisations in the intervention group. Kirk et al. conducted a meta-analysis examining the use of wearable devices to alter physical activity behaviour in adults with chronic cardiometabolic disease and found a positive impact on physical health.14 Smart watches have many of the same functions as smartphones, such as mobile applications, internet connectivity and GPS.15 Similar to fitness trackers, smart watches can also incorporate movement and exercise sensing functions, but their functionality is expanding. For example the Apple Watch (Apple) is currently being validated by clinical trials for detection of AF and other abnormal heart rhythms.16 Wearable biosensors are attached to the body for long continuous periods of time and have diagnostic and monitoring applications. The Wearable Biosensor (Philips Medical Systems) is a lightweight, wireless self-adhesive biosensor that can detect vital signs – ECG, respiratory rate, skin temperature – and movement data – posture, fall detection, step count. A study conducted by Braem et al. found that the use of this wearable device as a tool for screening activity levels in patients undergoing transcatheter aortic valve implantation was feasible, but noted some concerns regarding the reliability of the data collection.17 Continuous glucose monitoring can provide real-time blood glucose data otherwise unobtainable by conventional intermittent sampling. GlucoWatch (Cygnus) is a non-invasive wearable continuous glucose monitor that extracts and samples glucose through intact skin via reverse iontophoresis.18 A validation study by Tierney et al. found blood glucose readings from the device were clinically acceptable. However, a randomised trial by Chase et al. found no improvement in glycaemic control with the GlucoWatch, which was, in part, attributed to poor device adherence due to skin irritation.18,19

Peripheral Artery Disease Management Wearable devices with the ability to monitor movement may be particularly useful in the management of patients with peripheral artery disease (PAD). PAD is a debilitating condition that results in significant walking impairment and poor quality of life.20 Current recommended first-line management for PAD is supervised exercise therapy, with patient mobilisation crucial to prevent disease progression and reduce hospital admissions.21,22 Despite this, patients often face challenges in accessing therapy due to cost, travel and time constraints. This contributes to the low uptake and adherence with such programmes.23,24 Several studies have investigated the efficacy of home-based exercise programmes incorporating fitness trackers and telemonitoring as an alternative to supervised exercise (Table 1).25–33 Duscha et al. used wrist-worn commercially available fitness trackers (FitBit Charge, FitBit) to monitor daily physical activity and set exercise prescriptions based increasing patients’ step count each day.27 Patients wore fitness trackers continuously during waking hours and daily step count was synchronised with smartphones where it could be remotely viewed. This allowed investigators to not only monitor physical activity, but also

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offer personalised feedback via phone calls. Patients using the fitness tracker intervention were found to have significant improvement in claudication distance, maximum walking distance and steps walked per day, compared with baseline. Similarly, Normahani et al. incorporated the Nike+ FuelBand (Nike) fitness tracker as part of a home-based exercise intervention for patients with PAD.28 Instead of setting exercise prescriptions using step count, ‘fuel points’ were used, which measure overall activity and movement. Online accounts on the Nike+ website allowed activity data to be reviewed at follow-up visits and exercise prescriptions could be programmed into patient devices. The study found significant increases in walking ability and quality of life in patients using the device, compared with those attending a weekly 1-hour supervised exercise session over a 12-month period. In addition to using the AE120XL pedometer (Accusplit) to track daily physical activity and weekly phone consultations, Mays et al. incorporated an element of coaching into their study.30 This allowed them to identify local barriers and encourage exercise adherence. This involved an assessment of a patient’s local area using Google Street View to identify walking routes and community resources, such as benches on which to rest. Moreover, they identified potential barriers to walking, such as discontinuous pavements.30,34 This resulted in significant improvements in walking ability for the intervention group compared with baseline and usual care. The use of smartphone applications may also be beneficial for the remote monitoring and management of PAD. Ata et al. developed VascTrac, an Apple smartphone app that enabled remote collection of medical and physical activity data.35 VascTrac is able to record measures of daily physical activity (steps walked, distance walked, flights of stairs climbed and maximum continuous number of steps) using the built-in accelerometer in Apple smartphones. Patients were sent notifications through the app to perform twice-weekly 6-minute walk tests which allows tracking of changes in walking ability. Study results are yet to be published.

Blood Pressure Monitoring Hypertension is a well-known risk factor for CVD.21 Environmental factors can often limit the usefulness of conventional BP measurements because of phenomena such as white-coat, masked and nocturnal hypertension.36 Home measurement is a superior method of determining BP and wearable devices are well established for this purpose.37 Apart from traditional oscillometry-based BP measurement (involving an inflatable cuff), wearable devices also use other noninvasive methods of eliciting measures of BP such as tonometry, volume clamp, pulse wave velocity and pulse transit time (Table 2).38 The BPro (Healthstats) is a cuffless, wrist-bound BP measurement system that works via arterial applanation tonometry. The wrist monitor incorporates a small protruding force sensor that rests over the radial artery and captures the arterial pulse waveform.39 The device requires initial calibration to bronchial BP using a standard oscillometry-based BP monitor. In a validation study, the device was found to meet the accuracy criteria for systolic and diastolic BP in both European Society of Hypertension protocol and Association for the Advancement of Medical Instrumentation (AAMI) standards under stationary conditions.40 However, in a study comparing accuracy of the BPro against intraarterial BP measurement in post-operative patients, there were

Peripheral Artery Disease Table 1: Characteristics and Main Findings of Studies Incorporating Wearable Devices for Management of Peripheral Artery Disease Study

Study Study Design Duration

Study Wearable Size (n) Device

Patient Wearable Population Intervention

Additional Control Interventions

Main Findings

Dacha et al. RCT 201827

12 weeks

FitBit Charge

Exercise limited by IC, ABPI <0.9

Daily walking prescription, increasing every 4 weeks

Electronic PAD information, weekly tips, phone consultations

Physician advice, PAD book

Significant improvement in walking ability and VO2 max, increase in steps per day and exercise intensity

Endicott et al. 201925

6 months

FitBit One

Veterans, symptomatic IC

Daily walking prescription

Clinic consultations every 4 weeks

Significant increase in steps per day

Gardner et al. 201132

RCT

12 weeks

119

StepWatch3 (modus)

Symptomatic IC, ABPI <0.9

Walking three times per week, increasing duration biweekly

15 min consultation biweekly

3-month SET, physician advice

Significant improvement in walking ability, walking speed, QoL and VO2 max

Gardner et al. 201431

RCT

12 weeks

180

StepWatch3 (modus)

Symptomatic IC, ABPI <0.9

Walking three times per week, increasing duration evert 4 weeks

15 min consultation every 4 weeks

3-month SET, light resistance training

Significant improvement in walking ability, walking speed, QoL and VO2 max

Mays et al. 2015,30 201531

RCT

14 weeks

Accusplit AE120XL

Symptomatic Walking three IC, previous times endovascular per week therapy

Initial 2-week SET Physician (3× per week), advice weekly phone consultations

Significant improvement in walking ability.

McDermott RCT et al. 201826

9 months

200

FitBit Zip

ABPI <0.9

Exercise five times per week, increasing duration and intensity

Four initial SET sessions then weekly phone consultations

No intervention

No improvement in walking ability or QoL. Significant improvement in exercise frequency

Nicolaï et al. RCT 201033

12 months

304

Pam Personal Stage II PAD Activity Monitor

Walking feedback and encouragement

SET (60–90 mins per week), WAM scores used to give feedback on walking effort outside SET

SET (2–3× per week), physician advice

Significant improvement in walking ability and QoL. No difference compared with SET only

Normahani RCT et al. 201828

12 months

Nike+ FuelBand

Daily activity targets: ‘fuel points’

SET (1 hour/ 3-month SET week), clinic (1 hour per consultations at 3, week) 6 and 12 months

Significant improvement in walking ability and QoL

Tew et al. 201529

6 weeks

Yamax SW-200 Clinically Digiwalker diagnosed IC

Walking self-regulation, goal to reach >7,500 steps/day

Structured IC education (SEDRIC), phone consultation at 2 weeks

Significant improvement in walking ability and QoL. No change in steps/day

RCT

Symptomatic IC, stenosis on ultrasound

PAD information leaflet

ABPI = ankle–brachial pressure index; IC = intermittent claudication; NA = not available; PAD = peripheral artery disease; PS = prospective study; QoL = quality of life; RCT = randomised controlled trial; SEDRIC which is Structured EDucation for Rehabilitation in Intermittent Claudication; SET = supervised exercise therapy; WAM = wearable activity monitor.

Table 2: Characteristics and Validation Study Findings for Wearable Blood Pressure Monitoring Devices Measurements Provided

Method of Measurement

Required with validated oscillometry-based device

SBP, DBP, rAIx

Applanation tonometry

• Meets AAMI and ESH standards of accuracy compared with sphygmomanometer under stationary conditions.40 • Inaccurate agreement in SBP against intra-arterial measurement in post-operative patients; device affected by slight movement.41 • Fair agreement with a brachial cuff-based device under ambulatory conditions; volunteers instructed to hold still during measurements.39 • Inaccuracies in estimating rAIx.41

Required with validated oscillometry-based device

SBP, DBP

Pulse transit time

Acceptable DBP measurements when volunteers were static.45

Wearable Device

Calibration

BPro (MedTach)

Seismo-Watch

Level of Validation

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Wearable Technologies and Telemonitoring for Vascular Disease Table 2: Cont. Measurements Provided

Method of Measurement

Required with validated oscillometry-based device

SBP

Pulse transit time

Good reproducibility of results but weak correlation with cuff-based BP monitors. Device failed to produce measurements 30% of the time.47

Freescan (Maisense)

Required with validated oscillometry-based device

SBP, DBP

Pulse transit time

Produced valid SBP and DBP measurements that met AAMI accuracy standards. Required careful calibration.47

HeartGuide (Omron)

Not required

SBP, DBP, pulse rate, physical activity

Oscillometry

None

Wearable Device

Calibration

Checkme (Viatom)

Level of Validation

AAMI = Association for the Advancement of Medical Instrumentation; DBP = diastolic blood pressure; ESH = European Society of Hypertension; rAIx = radial augmentation index; SBP = systolic blood pressure.

significant inaccuracies according to AAMI standards in systolic and mean BP between the methods, which was attributed to patient movement.41 A 24-hour study comparing the BPro to conventional armbound oscillometry-based BP monitoring in 50 normotensive and prehypertensive volunteers found fair agreement between the two devices.39 However, during BP measurements the volunteers were asked to keep still and the BPro was unable to obtain almost 50% of the scheduled measurements.39 In addition to BP measurement, radial augmentation index (rAIx) can be calculated from radial wave pulse measurements from the BPro.42 The rAIx has been proposed as an estimate of central BP and a useful parameter of vascular function and ageing.43 Although there were discrepancies in rAIx measured by BPro versus a reference device, Vardoulis et al. developed and validated a novel wrist-bound tonometer that produced accurate rAIx readings compared with a reference handheld tonometer.42,44 The SeismoWatch is an example of a wrist-worn BP monitor that functions via pulse transit time.45 To obtain BP measurements, the watch face contains an accelerometer which is pressed for a short duration on the sternum to obtain a seismocardiogram and determine timing of left ventricular ejection. This is compared with a distal reading from a wrist-obtained photoplethysmogram to obtain the pulse transit time and, therefore, an estimate of BP.45 In a small feasibility study, the device was found to obtain acceptable mean and diastolic BP, but required subjects to perform measurements while static.45 Similarly, Ogink et al. investigated the feasibility of a cuffless BP monitor (Checkme Pro, Viatom) based on pulse transit time to measure systolic BP of hypertensive patients at home.46 The study found that the device produced reproducible BP readings and had good adherence due to its ease of use. However, the device was limited by its inability to measure diastolic BP and failure to measure BP 30% of the time. Boubouchairopoulou et al. validated a cuffless BP monitor (FreeScan, Maisense) that obtained readings via pulse transit time.47 In large successive feasibility and validation studies (a total of 313 patients were involved in the four feasibility studies), the device was found capable of obtaining systolic and diastolic BP readings when compared with a standard mercury sphygmomanometer. However, accurate readings required a device sensor upgrade and careful initial device calibration in a research setting. Further work is needed to investigate the validity of this prototype device in a clinical setting. The HeartGuide (Omron Corp) is a novel smartwatch with the ability to monitor BP.48 It uses the traditional oscillometry-based principle

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where the strap of the wrist-worn device acts as a BP cuff and allows BP measurement for up to 7 days on a single charge. It has additional abilities such as data synchronisation to an online account as well as step count and heart rate monitoring. However, this device is yet to be validated.

Best Medical Therapy Compliance Monitoring Non-adherence to medication in hypertensive patients is a contributing factor to poor BP control and is associated with higher risks of vascular events, hospitalisation and increased healthcare costs.49 Davidson et al. developed and validated a telemonitoring intervention involving electronic medication trays, Bluetooth-enabled BP monitors and SMS messaging.50 The electronic medication tray (Maya, MedMinder) reminded patients to take their dose at the prescribed time first with a blinking light, then a 30-minute chime and finally an automated phone call or SMS. Patients were reminded to use the Bluetooth-enabled BP monitor (UA-767PlusBT, A&D Engineering) via SMS, and readings were sent from the device to a provided smartphone and a remote data repository via cellular network. If BP measurements were above a predefined threshold, patients were instructed via phone to obtain additional measurements and their physician was alerted. Patients in the telemonitoring group had significant lower systolic and diastolic BP across the study’s duration and a significantly greater proportion achieved BP control. Frias et al. validated a system involving ingestible sensors and wearable sensor patches (Proteus Discover, Proteus Digital Health) for patients with uncontrolled hypertension and type 2 diabetes.51 The medications of patients in the intervention group were coencapsulated with ingestible sensors. Once swallowed, the ingestible sensor would activate and send a signal to the adhesive sensor patch. Data from the patch was then transmitted to an online data repository via a smartphone app. Data could be viewed by patients on the mobile app and remotely by their physicians. The mobile app also prompted patients to take their medications at the prescribed times. There were significant improvements in systolic BP and a larger proportion of patients achieved their BP goal in the intervention group. In terms of diabetes, however, there was no significant difference in HbA 1c or fasting plasma glucose between intervention and control groups. Physicians with access to the online data made approximately three times more medical decisions per participant and patients with uncontrolled hypertension in the intervention group were more likely to be given a medication adjustment or adherence counselling. However, a comparison of adherence to medication could not be assessed due to the intrinsic design of the study.

Peripheral Artery Disease Discussion The NHS Long Term Plan pushes for a digital transformation where digitally enabled care will become mainstream.52 As the NHS shifts towards a digital-first approach for patient consultations, there must be robust and validated methods for remote patient monitoring to aid analysis and decision-making by clinicians. Concurrently, wearable technologies are increasingly ubiquitous, with an estimated 722 million devices connected to the internet.48,49 These trends are set to continue, with shipments of wearable devices expected to almost double from 2019 to 2022, increasing from 226 million to 453.19 million.53 As these technologies become more widespread, clinicians have the responsibility to be early adopters, harnessing the potential they possess especially regarding their telemonitoring properties. However, before these technologies can be implemented clinically, a number of issues must first be addressed.

Compliance and the Digital Divide The digital divide is the difference between those who possess technological skills and those who do not.54 Cardiovascular diseases most commonly manifest in older patients, the cohort with the lowest rates of smartphone adoption and digital literacy.55 It has been suggested that older adults are reluctant to use mobile electronic devices due to factors such as lack of knowledge, disinterest or vision impairment.56 This potentially limits the use of wearable technology in this population. Poor adherence has also been demonstrated in other groups. Several studies included in this review mentioned limitations of technology due to know-how or non-use. Ogink et al. found that only 36% of participants correctly performed BP measurements with their cuffless monitor after instruction.46 However, the authors suggested that education using a set procedure or an instructional video may increase correct usage.46,57,58 Nicolaï et al. found that 30% of patients in the wearable intervention group did not use the prescribed fitness tracker for the duration of the study or at all.33 Similarly, Endicott et al. reported 43% non-use of fitness trackers by participants.25 Although adherence to the use of fitness trackers was very good (>80%) in a series of trials by Gardner et al., it was noted that participants were volunteers.31,32 This exposes the study to selection bias, where patients who were more comfortable with technology or were more motivated were more likely to participate.

that negatively affected telemonitoring.61 Suboptimal internet connectivity, especially in rural areas, affected data collection and patient adherence. There were hardware issues that needed to be diagnosed remotely and required replacement equipment, thereby reducing patient access and increasing costs. Software issues were identified that could affect large-scale implementations of telemonitoring. For successful wearable and telemonitoring interventions, there is a need for robust and reliable infrastructure. Larger-scale extended studies could be conducted to validate the large-scale extension of a wearable or telemonitoring intervention.

Cost The up-front cost of novel technology is often cited as prohibitive to widespread adoption. In fact, wearable and telemonitoring interventions may have cost benefits compared with conventional management. With regards to PAD management, a standard 3-month supervised exercise programme was estimated to cost about £235–£345 per patient in a 2013 study.62 In comparison, fitness trackers can cost as little as £21 per unit, although this can be considerably higher with more advanced devices. Furthermore, this cost can be offset by the reduction in travel expenses for the patient. These interventions additionally allow the individual tailoring of exercise requirements for each patient, which cannot be achieved with group supervised exercise. Similarly, telemonitoring hypertension interventions may be costefficient. Low adherence to antihypertensive therapy was estimated to cost US$3,574 per patient over a 3-year period.49 In a 2015 study, Davidson et al. estimated the cost of their telemonitoring intervention (electronic medication tray, SMS encouragement, Bluetooth BP monitor and associated support staff) to be US$65 per month for patients who owned a smartphone and US$128 per month for those who did not.50 Investigators noted that the average cost of an emergency department visit to be US$5,923 and the intervention group had a 57% reduction in visits compared with those receiving standard care, therefore giving a US$17,548 cost saving over a 6-month period. In addition, as telemonitoring can potentially identify patients with white-coat hypertension. It may avoid overtreatment and associated medication costs.7 There is a need, however, for further work to formally evaluate cost-effectiveness of wearable and telemonitoring interventions in cardiovascular patients.

Conclusion Further work is needed to determine digital literacy in vascular patients. This could be achieved through validated literacy questionnaires such as eHEALS for eHealth literacy or MDPQ-16 for mobile device proficiency.59,60 Thus, appropriate wearable and telemonitoring interventions may be used and adequate coaching given to participants.

Digital Infrastructure The expansion of wearable and telemonitoring interventions is limited by infrastructure. Hovey et al. investigated several practical aspects

Tehrani K, Michael A. Wearable technology and wearable devices: everything you need to know. Wearable Devices Magazine 2014. http://www.wearabledevices.com/what-is-awearable-device (accessed 10 March 2020). Iqbal MH, Aydin A, Brunckhorst O, et al. A review of wearable technology in medicine. J R Soc Med 2016;109:372–80. https:// doi.org/10.1177/0141076816663560; PMID: 27729595. Haghi M, Thurow K, Stoll R. Wearable devices in medical internet of things: Scientific research and commercially available devices. Healthc Inform Res 2017;23:4–15. https://doi. org/10.4258/hir.2017.23.1.4; PMID: 28261526.

Wearable technologies are becoming increasingly prevalent and there is some evidence that wearable and telemonitoring interventions may be beneficial for managing vascular patients and keeping them out of hospital. With healthcare moving towards a digital future, it is inevitable that wearable devices and telemonitoring will become increasingly widespread in the clinical environment. More work is needed to validate these technologies with regards to digital literacy of patients, costeffectiveness and supporting digital infrastructure before widespread implementation.

Meystre S. The current state of telemonitoring: A comment on the literature. Telemed J E Health 2005;11:63–9. https://doi. org/10.1089/tmj.2005.11.63; PMID: 15785222. Güler NF, Übeyli ED. Theory and applications of biotelemetry. J Med Syst 2002;26:159–78. https://doi. org/10.1023/A:1014862027454; PMID: 11993572. Artinian NT, Flack JM, Nordstrom CK, et al. Effects of nursemanaged telemonitoring on blood pressure at 12-month follow-up among urban African Americans. Nurs Res 2007;56:312–22. https://doi.org/10.1097/01. NNR.0000289501.45284.6e; PMID: 17846552.

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Peripheral Artery Disease

BEST Endovascular Versus Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) Trial Raghu Motaganahalli,1 Matthew Menard,2 Matt Koopman3 and Alik Farber4 1. Division of Vascular Surgery, Department of Surgery, Indiana University School of Medicine, Indiana University, Indianapolis, IN, US; 2. Division of Vascular Surgery, Department of Surgery, Brigham and Women’s Hospitals, Harvard Medical School, Boston, MA, US; 3. Division of Vascular Surgery, Department of Surgery, Portland VA Medical Center, Portland, OR, US; 4. Division of Vascular Surgery, Department of Surgery, Boston Medical Center, Boston, MA, US

Abstract The Best Endovascular versus Best Surgical Therapy in Patients with Critical Limb Ischemia trial (BEST-CLI) is an international, prospective, multicentre, multidisciplinary and pragmatic, open-label, superiority-based, comparative-effectiveness randomised controlled trial designed to address the knowledge gap in choosing the appropriate therapy for the treatment of critical limb ischaemia (CLI). This study compares the effectiveness of the best available surgical treatment with the best available endovascular treatment in adults with CLI who are eligible for both treatment options. The study has completed its enrolment phase and patients included in the study are currently being followed up to 50 months. Results of the study promise to provide us with answers to several questions regarding treatment options for patients with CLI, more recently referred to as chronic limb-threatening ischaemia.

Keywords Surgical revascularisation, endovascular revascularisation, peripheral artery disease, BEST-CLI trial, critical limb ischaemia, chronic limb-threatening ischaemia, amputation Disclosure: MM and AF are BEST-CLI trial Co-chairs, supported by NHLBI: 1U01HL107407-01A1. RM and MK are BEST-CLI investigators. For the purposes of this review, no author received any payment or other support from a commercial company. The BEST-CLI trial is funded by the NHLBI (National Heart, Lung, and Blood Institute) 1U01HL107407-01A1. No additional funding was required for the preparation of this manuscript. Received: 2 December 2019 Accepted: 8 March 2020 Citation: Vascular & Endovascular Review 2020;3:e05. DOI: https://doi.org/10.15420/ver.2019.12 Correspondence: Raghu Motaganahalli, Division of Vascular Surgery, Department of Surgery, Indiana University, Indianapolis, IN, US. E: rmotagan@iupui.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 noncommercial purposes, provided the original work is cited correctly.

Patients with chronic limb-threatening ischaemia (CLTI), also known as critical limb ischaemia, secondary to infrainguinal occlusive disease have multiple treatment options. The historic gold standard of lower extremity surgical revascularisation has recently been challenged by endovascular therapy. Generally associated with lower rates of significant life-threatening and limb-threatening complications than open surgical methods, endovascular lower extremity revascularisation offers an alternative strategy for treating complex CLTI patients. The rise of endovascular therapy has been driven, in part, by patient and physician preference, given the appeal of a less invasive option. Despite the intervention’s increasing popularity, the scientific evidence underpinning the shift toward endovascular treatment, and specifically the adoption of an endovascular-first strategy for all CLTI patients, is lacking; the preponderance of studies are retrospective and poorly controlled or are industry-sponsored trials supporting a particular technologic platform. Unlike in other surgical or interventional specialties, a diverse group of practitioners – including interventional cardiologists, interventional radiologists, vascular medicine specialists and vascular surgeons – provide treatment and care for patients with CLTI.1 Therefore, the treatment decision typically reflects the individual provider’s training, skill

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set and bias. Appropriately, treatment decisions are also influenced by patient factors, such as the presence or absence of an adequate conduit, the particular anatomical disease pattern and comorbidities. As noted in the Vascular Quality Initiative (VQI), there is wide variation among VQI participating sites with regard to the proportion of open surgical or endovascular surgery treatments offered for CLTI at a given institution.2 The evolution of endovascular therapy has not only affected the treatment paradigms of CLTI; the non-selective approach has also raised questions about the use of resources and the appropriateness of the intervention.3 Certainly, endovascular therapy may be an effective and more appropriate treatment in patients aged ≥75 years, who are poor candidates for open surgery.4 Questions over durability, the compromise of outflow arterial vessels associated with periprocedural embolisation, and the potential compromise of subsequent surgical revascularisation following endovascular failure remain unanswered.5 In the current era of precision medicine and patient-specific treatment options, there remains a paucity of unbiased information guiding the treatment of CLTI in patients who qualify for both open and endovascular treatment. The Best Endovascular versus Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) trial (NCT02060630) is a

BEST-CLI Trial comparative-effectiveness, prospective, multicentre, multidisciplinary, pragmatic, open-label, superiority-based randomised controlled trial that is designed to address knowledge gaps in choosing the appropriate therapy for CLTI. The trial includes a clinical coordinating centre with joint principal investigators Alik Farber, Matthew Menard and Kenneth Rosenfield, and a data coordinating centre located at Healthcore (known as New England Research Institutes before acquisition by Anthem/Healthcore). The National Heart, Lung, and Blood Institute (NHLBI) has been the sole sponsor of the trial to date. The study includes men and women aged ≥18 years considered eligible to receive either open surgical treatment or endovascular treatment. Patients are to be followed for at least 6 months and up to 50 months after treatment to primarily assess survival and major adverse limb events (MALE) in the treated limb and, secondarily, to determine clinical and cost-effectiveness outcomes after treatment. A number of secondary outcomes – time to reintervention of the index leg, number of reinterventions in the index leg, time to all-cause mortality, change in Vascular Quality of Life Questionnaire (VascuQoL) score, change in EuroQoL EQ-5D score, treatment-associated costs, major adverse cardiovascular events and proportion of subjects with at least one perioperative complication – will be compared within two cohorts of subjects: those with an available adequate single-segment great saphenous vein (SSGSV; cohort 1); and those with an alternative conduit (cohort 2). The null hypothesis for cohort 1 is that a bypass with a good SSGSV will outperform endovascular therapy; that for cohort 2 assumes that endovascular therapy will outperform bypass with a non-SSGSV conduit. The primary and secondary endpoints chosen are of day-today relevance to the practising vascular care providers. In addition to the above outcomes, BEST-CLI will shed light on emerging concerns of excessive mortality with the use of paclitaxel-associated balloons and stents. It will also prospectively validate the Society for Vascular Surgery’s Wound, Ischemia, and foot Infection (Wifi) scoring system in a way that has not previously been done. Similarly, it will provide a framework to consider the utility of the recently published Global Vascular Guidelines on CLTI.6,7 Subset analysis from the study will help define treatment paradigms for select subgroups of patients, including those with renal failure, diabetes or a history of smoking. The study began randomising patients in August 2014 and completed enrolment in October 2019, randomising 1,843 patients into either open surgical or endovascular treatment. Physicians enrolling patients into the study have gone through a credentialing process to ensure the best outcomes are achieved for the treatment arm each patient is randomised into. It has a fully pragmatic trial design, allowing each investigator to use an open surgical or endovascular strategy of their choice. As such, one of the most appealing aspects of the study is the degree to which the clinical outcomes should match real-world experience in patients who have therapeutic equipoise between open and endovascular options. The hope and expectation is that the resultant robust dataset will serve as a level I evidence base, which is currently lacking, on which to guide therapeutic decision-making for this challenging patient population.8 The study is designed to optimise a collaborative approach at each participating institution, emphasising a multidisciplinary, team-based approach that includes all specialists who typically treat CLTI at a given site. Through this approach, the BEST-CLI trial has, in many cases, provided a mechanism for drawing together all vascular community

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caregivers in a single CLI team. Instead of the traditional siloed approach, this team structure facilitates communication between participating specialists and fosters a collaborative environment where patients benefit from the expertise and technical skill sets of each of the diverse specialists working together. Specialists in vascular medicine, vascular surgery, endovascular therapy, diabetes, infectious disease, wound management and rehabilitation should be part of such a team. The team must be comprehensive enough to cover the needs of the patient from the standpoint of primary care, diabetes, diagnosis, revascularisation, wound care, infectious disease and ongoing surveillance.9 Over the course of the recruitment phase, the trial expanded beyond the US and Canada to include sites in Finland, Italy and New Zealand. More than 150 institutions contributed, with 78% of sites having some combination of multidisciplinary participation. Both rural and urban centres are involved, as are academic teaching institutions and private practice groups. Within the US, sites are balanced geographically, with 25% located in the east, 20% in the south, 22% in the Midwest and 26% in the west. Seven per cent of sites are in Canada, Europe or New Zealand.10 While it is not in the scope of this article to examine the causes of slow recruitment, not unexpectedly, there were multiple challenges to enrolling patients into the BEST-CLI trial. Beyond patient-related factors, such as the lack of perceived equipoise in a given patient, the biggest obstacle to randomisation was overcoming the strong treatment biases that many investigators have developed over time. To date, treatment perceptions remain a major obstacle for trials assessing revascularisation therapies in patients eligible for both treatments. Identification of a site champion who served as an inspiring role model and motivated practitioners was probably the biggest driver to successful enrolment at participating sites. In comparison to the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial, the BEST-CLI trial is more contemporary and more generalisable, given its pragmatic design. It has also enrolled a much larger number of patients and will be well powered for its primary endpoint of MALE-free survival. This aggregate measure best captures the therapeutic goals of treatment for CLI, which include preservation of a functional limb and avoidance of major interventions that significantly reduce quality of life. Accurately assessing limb-related morbidity and the need for reintervention are of paramount importance in a trial comparing revascularisation strategies, particularly in light of the remaining questions regarding treatment durability. The trial will comprehensively assess the role of best medical therapy in CLTI and provide a current-era benchmark report card with regard to metrics such as statin use, diabetes management and hypertension control. Additionally, BEST-CLI, in conjunction with the ongoing BASIL-2 trial, will provide additional information on the optimal treatment of patients with infra-popliteal disease.11 The combined datasets will also help us formulate and validate clinical risk-prediction models and understand both the quality of life and cost-effectiveness associated with different open surgical and endovascular treatment strategies to a degree not currently possible.12 Unlike BASIL-2, the BEST-CLI trial will also examine the role of other conduits when the optimal saphenous vein is not available, and allow Wifi to be prospectively validated for the first time. Before BEST-CLI, there has been no multidisciplinary, randomised controlled trial in patients with CLTI of this magnitude. BEST has brought

Peripheral Artery Disease together more than 1,000 physicians passionate about the treatment of CLTI and dedicated to better understand the optimal initial therapeutic strategy. The study will serve to provide the high-quality, level 1 evidence base that is sorely lacking, and that is critical for optimal and responsible therapeutic decision-making. Replacing individual

Menard MT, Farber A, Assman SF, et al. Design and rationale of the Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia (BEST-CLI) trial. J Am Heart Assoc 2016;5:e003219. https://doi.org/10.1161/ JAHA.116.003219; PMID: 27402237. Siracuse JJ, Menard MT, Eslami MH, et al. Comparison of open and endovascular treatment of patients with critical limb ischemia in the Vascular Quality Initiative. J Vasc Surg 2016;63:958–65.e1. https://doi.org/10.1016/j.jvs.2015.09.063; PMID: 26830690. Barshes NR, Chambers JD, Cohen J, Belkin M. Costeffectiveness in the contemporary management of critical limb ischemia with tissue loss. J Vasc Surg. 2012;56:1015–24.e1. https://doi.org/10.1016/j.jvs.2012.02.069; PMID: 22854267. Peters CML, de Vries J, Redeker S, et al. Cost-effectiveness of the treatments for critical limb ischemia in the elderly population. J Vasc Surg 70:530–8. https://doi.org/10.1016/j.

7. 8.

treatment bias with an evidence-based approach, informed by data on what matters most to patients and an accurate sense of the cost and cost-effectiveness of each treatment option, will provide a framework for us to begin to understand how best to care for this highly complex, growing and vulnerable group of patients.

jvs.2018.11.042; PMID: 30922757. Goodney PP, Beck AW, Nagle J, et al. National trends in lower extremity bypass surgery, endovascular interventions, and major amputations. J Vasc Surg 2009;50:54–60. https://doi. org/10.1016/j.jvs.2009.01.035; PMID: 19481407. Mills JL Sr. BEST-CLI trial on the homestretch. J Vasc Surg 2019;69:313–4. https://doi.org/10.1016/j.jvs.2018.08.156; PMID: 30683190. Siracuse J. Experiences with the BEST-CLI trial. Vascular Specialist 2019;15:8. Powell R, Menard M, Farber A, et al. Comparison of specialties participating in the BEST-CLI trial to specialists treating peripheral arterial disease nationally. J Vasc Surg 2019;69:1505–9. https://doi.org/10.1016/j.jvs.2018.08.188; PMID: 31010516. Farber A, Rosenfield K, Siami FS, et al. The BEST-CLI trial is nearing the finish line and promises to be worth the wait. J

Vasc Surg 2019;69:470–81.e2. https://doi.org/10.1016/j. jvs.2018.05.255; PMID: 30683195. 10. Villarreal MF, Siracuse JJ, Menard M, et al. Enrollment obstacles in a randomized controlled trial: a performance survey of enrollment in BEST-CLI Sites. Ann Vasc Surg 2020;62:406–411. https://doi.org/10.1016/j.avsg.2019.08.069; PMID: 31491479. 11. Popplewell MA, Davies H, Jarrett H, et al. Bypass versus angio plasty in severe ischaemia of the leg – 2 (BASIL-2) trial: study protocol for a randomised controlled trial. Trials 2016;17:11. https://doi.org/10.1186/s13063-015-1114-2; PMID: 26739146. 12. Bradbury AW, Adam DJ, Bell J, et al. Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: a survival prediction model to facilitate clinical decision making. J Vasc Surg 2010;51(5 Suppl):52S–68S. https://doi.org/10.1016/j. jvs.2010.01.077; PMID: 20435262.

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Clinical Review

Stiff to Dilate and Risky to Cut Through: Iliac Radiation Arteritis Huthayfa Ghanem,1 Sadia Jaskani,2 Mohamed Alloush,3 Ibrahim Hanbal,4 Marzouk Albader,3 Hussein Safar,3 Jassim Al-Ali3 and Sami Asfar5 1. Department of Vascular Surgery, Nottingham University Hospitals NHS Trust, Nottingham, UK; 2. Department of Surgery, Bedford Hospital NHS Trust, Bedford, UK; 3. Vascular Surgery Unit, Mubarak Al-Kabeer Hospital, Jabriya, Kuwait; 4. Vascular Surgery Unit, Al-Azhar Faculty of Medicine, Nasr City, Cairo, Egypt; 5. Vascular Surgery Unit, Kuwait University Health Sciences Center, Jabriya, Kuwait

Abstract Radiation arteritis is not an uncommon clinical situation, given that almost 50% of patients with cancer receive radiotherapy in the course of treatment. Radiation effects are non-specific, and late radiation tissue injury presentation can be very variable. However, radiation arteritis has some unique clinical and radiological features, with consequent special therapeutic considerations. Iliac radiation arteritis may be accompanied by radiation-associated iliac vein disease and small vessel disease. Therefore, diagnostic and therapeutic plans should be directed toward all possible late radiation effects as relevant. Despite the complexity of the disease process and diagnostic challenges, treatment can be very straightforward if adequately planned. Otherwise, limb loss and/or life-threatening complications can rapidly ensue. This article highlights the natural history of radiation arteritis, with a particular emphasis on the iliac segment, and discusses the risk potentials of this condition, given that limb loss may be multifactorial, not merely because of the iliac arterial flow interruption. The main lines of management are also briefly discussed.

Keywords Radiotherapy, iliac, arteritis, pelvic cancer, late radiation tissue injury, extra-anatomic bypass Disclosure: The authors have no conflicts of interest to declare. Received: 22 September 2019 Accepted: 18 November 2019 Citation: Vascular & Endovascular Review 2020;3:e06 DOI: https://doi.org/10.15420/ver.2019.07 Correspondence: Huthayfa Ghanem, Nottingham University Hospitals – Queens Medical Centre, Derby Rd, Lenton, Nottingham NG2 2UH, UK. E: avihoses@hotmail.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 noncommercial purposes, provided the original work is cited correctly.

Cancer survival rates have increased threefold in the last few decades because of advances in diagnosis and treatment. Radiotherapy has been used in multidisciplinary cancer control plans for a long time. The current radiotherapy protocols have significantly improved the prognosis of many cancers, with a consequent positive impact on patient longevity. Regrettably, this also means that the latent effects of radiation now have more chance to present themselves, with a corresponding decrease in quality of life.1–3

the form of endarteritis obliterans and telangiectasia are usually seen. Occasionally, ARS can be very severe and there will be no resolution; and in such cases the radiation injuries become chronic and indistinguishable from the delayed features, called ‘consequential effects’. CRS has been identified in survivors of Hiroshima and Nagasaki, Kyshtym, Chernobyl and the Fukushima nuclear disasters.

Radiation sickness or acute radiation syndrome (ARS) occurs due to a brief period of high-dose ionising radiation. ARS involves reactive oxygen species-mediated DNA damage, which manifests – in increasing severity, according to the dosage – as mucositis, bone marrow suppression, endothelial cell damage and neurological effects. ARS occurs at radiation rates higher than 0.1 Gy/h, may last for months and can be fatal. This acute phase occurs in 60–80% of patients treated with abdominal or pelvic radiotherapy and is considered a risk of treatment intolerance for which a modification may be necessary.4–6

Akleyev has described the manifestations of CRS and defined the latent period to be 1–5 years. The CRS formation period coincides in time with the exposure at the highest dose rate. The symptoms are non-specific and usually involve multiple organs, particularly with regard to haematopoiesis and the nervous system. The recovery period usually starts 3–12 months after the termination of exposure or following a considerable reduction in the exposure rate. Haematopoietic impact can be fully reversible, as can the functional neurologic impairment, but ostealgic syndrome and micro-organic disorders usually last longer. The period of late effects may follow the recovery period.4,5,7

Chronic radiation syndrome (CRS) can be defined as the whole body’s systemic response to chronic total body exposure. In its initial phase, it is considered as a ‘dysregulatory pathology’ because of the involvement of the regulatory systems. The exact mechanism of development of late radiation effects is only partially understood and vascular changes in

In DNA-damaged cells, sometimes the damage can be detected and repaired, but if not then apoptosis may be triggered. Alternatively, in the case of non-lethal DNA defects (i.e. novel mutations), subsequent divisions will pass these mutations on to the whole line and may predispose to carcinogenesis or teratogenesis. Secondary malignancies

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Clinical Review can occur a few decades after radiotherapy, within the irradiation field as well as remote from it.8 Apart from the increased risk for carcinogenesis, radiation-induced cardiovascular disease (RICVD) is a well-known sequel to radiation exposure. RICVD occurs both in patients with low cardiovascular risk and healthy vascular beds, and those with established atherosclerotic cardiovascular disease. It accelerates the process of atherogenesis. Both acute and chronic RICVD can present as pericarditis. In addition, both coronary artery disease and peripheral vascular disease may complicate the radiation exposure and present after many years.9 Chronic cellular exposure to elevated reactive oxygen species and sustained nuclear factor kappa B activation result in a chronic inflammatory state with the subsequent ineffective healing and remodelling. Additionally, vascular endothelial growth factor depletion will lead to disturbed angiogenesis. Impaired relaxation due to humoral and mechanical factors is another contributing cause that will lead to turbulence formation and, consequently, accentuation of the atherosclerotic process.10,11

Pathology of Radiation Arteritis The correlation between the pathological findings and radiation exposure was first noted by Gassman, a few years after the introduction of the X-ray.12 Morphologically, in the radiotherapy field, the diseased arterial segment is usually sharply demarcated, contracted and narrowed with a relative pallor compared with the unaffected segments. The intima appears diffusely thickened, faintly granular and roughened with delicate wrinkles. Multiple white fibrous minute plaques can be seen in the intima, especially in the posterior walls, and most commonly longitudinally oriented. In some cases, these plaques coalesce to form larger ones. In contrast to atherosclerotic plaques, the yellowish pigmentation and fatty streaks are far less frequent. The adventitia is fibrous and indurated. The length of the diseased segment is variable and proportional to the radiation field. As a result, vessel wall thickening, lumen progressive narrowing and occlusion, pseudoaneurysm formation, vessel rupture, thrombus formation and distal embolisation can occur.13,14 Microscopically, circumferential alteration to the internal elastic lamina can be observed. Focal beading and fragmentation of elastic layers are also detectable. Moreover, loss of the refractile quality of elastic lamellae leads to a granular and swollen appearance. Regeneration of the disrupted membranes occurs with acid mucopolysaccharide accumulation, in addition to the proliferation of plump fibroblasts and collagen deposition; hence, intimal thickening (focal or diffuse), elevation and plaque formation. Variable plaque growth sequences are suggested as the plaque composition has a poor correlation with age. Injury to vasa vasora, ischaemic necrosis, hyalinisation and thickening of the vessel wall with fibrin deposition can also be seen as well.13,14 Broadly speaking, the radiation arteritis lesions may be categorised, according to the time elapsed since exposure, into the following: early lesions (up to 5 years), with a predominance of mural thrombosis; intermediate lesions (5–10 years), where panmural fibrosis, occlusion and the relative paucity of collateralisation can be seen; and late lesions (mean, 26 years), including periarterial fibrosis and atherosclerosis.15

Radiologically, the diagnosis can be made in the following cases: detection of the typical lesion in the radiotherapy field; when the typical lesion is of a long, uniform sub-occlusive nature in the involved vessel; and for other forms of lesion such as tight stenosis, multiple stenoses and subtotal or total occlusion.16–18 There can also be relative sparing of the arteries outside the irradiation field. They do not show radiologic abnormalities except in patients with well-known atherosclerotic disease. Stenosis and thrombosis of the major abdominal and pelvic veins should always be looked after. Fibrosis and tight stenosis of the superior vena cava have been reported 5 years after the completion of bronchogenic carcinoma treatment and radiotherapy. Other nonvascular tissues may show radiation-related changes as well.

Clinical Considerations Pelvic radiation disease (PRD) may lead to radiation-induced damage to the nearby non-cancerous tissues in the gastrointestinal, genitourinary, dermatological, haematological and musculoskeletal systems. All major pelvic vessels are susceptible to chronic inflammatory changes, which eventually lead to stiffness, stenoses, fibrosis and accelerated atherosclerosis.19–21 These changes are as follows: • Microvascular changes, such as generalised capillary network failure, vasa vasora injury and vessel blockage by endothelial sloughing. • Arteritis, which may present as acute or critical limb ischaemia or as worsening claudication. • Radiation-associated venous stenosis of the iliac segment (with or without a history of venous thrombosis), which is a cause of chronic limb pain, swelling, discolouration or ulceration. Therefore, it is not uncommon to find multiple admissions to the accident and emergency department in the previous medical records of these patients, with a clinical picture suggestive of deep vein thrombosis (DVT) with negative venous duplex scans for DVT. In this condition, severe chronic venous insufficiency (CVI) due to radiation-associated iliac venous stenosis must be considered in the management plan. • Lymphovascular fibrosis with a proximal obliteration pattern lymphoedema. • Mixed involvements. In addition, the management process of radiation-induced peripheral vascular disease (RIPVD) is usually challenging in both diagnosis and treatment, due to the following considerations:2,9,14,19,21–26 • RIPVD is sometimes diagnosed a decade or more after radiation; this delayed occurrence makes it less likely to be considered as a diagnostic possibility. The complex nature of PRD and RIPVD, with multiple system involvements and wide-ranging symptoms, makes the diagnosis more challenging. Similarly, the multifactorial limb swelling and/or lymphoedema may add to the diagnostic and therapeutic challenges. • The difficulty of clinical examination and lower limb arterial pulse detection, due to skin induration and hardening, CVI, chronic limb swelling and lymphoedema. • Presentation can be altered by the accompanying lumbosacral radiculo-plexopathy, which is a possible consequence of radiotherapy, which may be manifested by a varying degrees of motor and sensory impairments. • There may be vasculitis and leucocytoclastic symptoms, due to chemotherapeutic agents, such as oxaliplatin. These may present as

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Understanding Iliac Radiation Arteritis

•

digital gangrene, livedoid reticulopathy and purpura. Clearly, the aggregation of the large vessel and small vessel disease features is more demanding in terms of making the appropriate diagnosis and planning the treatment strategy, with a less promising prognosis. There may be adjuvant and/or neoadjuvant cancer immunotherapy with angiogenesis inhibitors, such as bevacizumab and ponatinib, which are well-known causes of atherosclerosis and cardiovascular disease. Hypertension, ischaemic heart disease, aortic dissection and involvement of large- and medium-sized vessels are all reported in treated patients. Cancer recurrence and the associated paraneoplastic syndromes that accompany certain types of cancers may present with vasoocclusive digital and small vessel disease patterns. In this setting, it is exceedingly difficult to assign this very distal disease to a specific cause from this long list of possible aetiologies. This is particularly problematic if the cancer recurrence has not yet been diagnosed. There may be unduly delayed development of collateral circulation when compared with the classical atherosclerotic peripheral vascular disease, possibly due to radiation effects on the whole radiation field tissues, generalised capillary failure and extensive fibrosis, leading to faster progression of foot necrosis. The heralding phase of intermittent claudication and rest pain may be very faint clinically and its duration is usually much shorter than in the standard atherosclerotic disease, with a narrower window of time to prevent major tissue loss. With consideration of the previously mentioned factors, the distal foot circulation deterioration may be rapidly evolving and overwhelming. Multiple diagnostic and therapeutic procedures associated with primary cancer, such as abdominal and pelvic cancer resection, stomas, inguinal lymph node biopsy and groin vascular accesses, all add to the difficulties of management and decision-making. The pathological changes to the irradiated vessels may take very long to be radiologically and clinically significant and this is an ongoing process taking place within the irradiation field. Therefore, it is not uncommon to see early failure and/or new lesions in the vicinity after the initial revascularisation procedure. Hence, it is vital to consider treating the whole pathological segment or bypass it altogether. The chronic inflammatory changes in almost all tissue types in the radiation field, from the skin (radiation dermatitis or ulcer) through to the bone (osteonecrosis), and the associated radiation enteritis and proctitis, add much to the complexity of any planned surgical approach. Management is complicated by the older age of a considerable percentage of patients who have had radiation therapy for pelvic malignancy, and the associated greater likelihood of multiple comorbidities, poor functional status and impaired immune response, as well as arteriopathy in different territories. Peripheral vascular disease in this cohort of patients may be multi-level in nature, which will complicate the process of revascularisation. Medical nephropathy and obstructive uropathy are possible comorbidities in people receiving radiotherapy. Exposure to chemotherapy, radiation-induced renal artery stenosis, ureteral strictures and/or compression may be causative factors. The rates of postoperative anastomotic and septic complications and redo bypass are much higher for radiation arteritis than for other indications.

Magnitude of the Problem It must be emphasised that RIPVD – like any other radiation-related late sequel – is largely underestimated and the diagnosis can be missed

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very easily. It was once reported that the incidence of radiation enteritis is as common as Crohn’s ileitis.19 Information on RIPVD and iliac radiation arteritis incidence is lacking, but it is obvious that the incidence is increasing.9,19 Many cases of iliac radiation arteritis have been treated as standard peripheral vascular disease or as mixed arterial/venous leg ulcers. The history of previous radiotherapy to the pelvis may be totally missed or may not have been linked to the clinical situation. Consequently, unnecessary difficulties, unexpected operative challenges, and easily avoidable complications may be encountered as a result of the rush to explore the ‘radiotherapy groins’.16,17 More than 50% of patients with cancer receive radiotherapy. According to Bergonié and Tribondeau in 1906, a decade after the discovery of radiation, tissue radiosensitivity is directly proportional to the mitotic capability and potentials of proliferation, and inversely proportional to the degree of differentiation. Tissue radiosensitivity is stratified according to the Casarett or the Michalowski systems. Generally, genital glands, lymphatic, haemopoietic and foetal tissues are highly radiosensitive. Iliac radiation arteritis has been reported after radiotherapy for gynaecological (ovarian, cervical and endometrial) cancers, colorectal cancer, and lymphomas.27–30 In some reports, the diagnosis occurred 25 and 28 years after the radiotherapy, or even later.31 A very severe and rare form of radiation arteritis that involved the whole length of the infrarenal abdominal aorta, along with the visceral branches, as well as the bifurcation, was reported after the 31st birthday of a woman who had undergone nephrectomy and radiotherapy due to Wilms’ tumour at the age of 5 years.32 Cardiovascular complications were also noted in more than 10% of Hodgkin’s lymphoma patients followed for a median of 9 years after radiotherapy.33 The reported radiotherapy dose associated with arteritis is 20–80 Gy. Additionally, the specific radiation dose associated with iliofemoral radiation arthritis is 39.5–80 Gy. Both stenosis incidence and stenosis severity are proportional to the radiation dose and duration.17,34 Interestingly, colorectal cancer survival rates are higher in women, and there is no clear explanation. Moreover, the outcome of treatment for gynaecological malignancy is improving. Hence, it is not surprising that iliac radiation arteritis is more commonly diagnosed in women.35

Radiation Field and Delivery Methods Iliac vessels are vulnerable to radiation effects because of the treatment of the nodal clinical targets rather than of the primary itself. The nodal clinical target volume has been defined in some protocols as the area in a 7 mm margin around the major vascular structures in the pelvis. It is subdivided into five groups: common iliac; external iliac; internal iliac; obturator; and presacral. Planning CT has replaced X-ray markers as a prerequisite to proceed with radiotherapy. The new radiotherapy field protocols have been designed to reduce the damage to the surrounding tissues, but this reduction of radiotherapy dosage delivery to the surrounding pelvic tissues has increased the chance of missing the local pelvic microscopic disease.

Clinical Review Figure 1: Left Foot Digital Gangrene in Case 1

The following principles are vital when considering revascularisation. Urgent revascularisation is crucial, given that the clinical course and tissue loss are more dramatic when compared with the standard atherosclerotic disease. It is not uncommon for these patients to present with acute-on-chronic lower limb ischaemia. Restoration of adequate perfusion can be accomplished with an endovascular or surgical approach. The patient should be actively involved in the decision-making process after a clear and detailed discussion of the options and the challenges due to the nature of this disease, and this should include major amputation and mortality. Angioplasty of the iliac arterial segment is the recommended first choice. It can be straightforward and produces satisfactory revascularisation. Nevertheless, the complications are much more frequent than with interventions for atherosclerotic lesions. Obviously, angioplasty can be the only feasible option in the case of bilateral iliac disease, because the bypass options are more complex in such circumstances. Treatment of symptomatic iliac vein disease is an integral part of the management. To the best of our knowledge, however, no reports have yet discussed the outcome of placement of concomitant ipsilateral iliac arterial and venous stenting. Thus, if venoplasty and stenting are deemed necessary, crossover bypass seems a more logical option. The complications are: detachment of an existing thrombus and distal embolisation; inadequate dilatation, persistence of a waist or failure to deal with the lesion because of the unduly stiff affected segment; dissection; perforation and rupture; and puncture-site bleeding, which is much more difficult to deal with.

In lymphomas, the radiotherapy dose varies according to the type, grade and stage of the disease, which can be as high as 40 Gy/20 fractions. Femoral, iliac and paraaortic nodes are potential targets. Colorectal cancer treatment involves either short-course radiotherapy (SCRT) or long-course radiotherapy/chemoradiotherapy. SCRT is given at a dose of 5 Gy for 5 days or 1 week. Long-course radiotherapy/ chemoradiotherapy patients are given either 2 Gy per fraction for 5 weeks or 1.8 Gy per fraction for 5.5 weeks. Radiotherapy delivery is achieved by either of the following ways: anterior and posterior fields; or four-field box/brick, in which two lateral fields are also included. In the management of cervical or uterine malignancy, treatment is given 5 days/week, 200 cGy/day, with all fields treated daily. When managing urological malignancy such as prostate cancer, the organs at risk include bladder, rectum, intestine and femoral heads. The occurrence of radiation-induced iliac arteritis after radiotherapy for prostate cancer needs to be investigated, due to the lack of data currently available on this association.36–39

Therefore: it is advisable to avoid the affected groin as an angioaccess; preferably, contralateral femoral, radial, brachial or ipsilateral midthigh superficial femoral access can be tried instead; thrombolysis has also been considered in some protocols as an integral part of the intervention; covered stents may be used primarily or at least kept on standby; completion angiogram is mandatory not only to ensure satisfactory dilatation of the lesion or to rule out extravasation, but also to exclude distal embolism at the popliteal trifurcation or pedal arch; and the operator needs to be ready to do surgery for unsuccessful or complicated intervention if required. The simplest surgical revascularisation option is a short extra-anatomic bypass from the contralateral groin (common femoral artery; CFA) to the ipsilateral superficial femoral artery (SFA) in a healthy area just distal to the radiotherapy field effects. The advantages of this bypass are that it is technically less demanding; it is less time-consuming; the bypass is short; it has longer patency; and it totally excludes the affected groin. Anastomotic and septic complications, however, are more frequent due to local and systemic factors. Other – more complex – surgical revascularisation options may be necessary for bilateral or multilevel disease. Moreover, in unsuccessful and complicated angioplasty cases, surgical treatment can be far more demanding and less promising.16,17,19,26,29

Decision-Making Regarding Treatment Options Treatment of radiation arteritis of the iliac segment presenting with rest pain, tissue loss or acute limb ischaemia is broadly the same as for atherosclerotic/thrombo-embolic disease, although the challenges listed in the earlier section still need to be kept in mind.

Four Cases of Iliac Radiation Arteritis The following case reports are discussed in an attempt to highlight, as much as possible, the aetiological and clinical characteristics of iliac radiation arteritis.

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Understanding Iliac Radiation Arteritis Case 1

Figure 2: Imaging in Case 1

A 59-year-old female patient presented in 2011 with gangrene of all toes of the left foot, 14 years after pelvic irradiation for endometrial cancer. There was no clinical evidence of tumour recurrence and no other comorbidities or arteriopathy. The left foot was mildly swollen and all toes were gangrenous, with multiple blisters, mottled skin patches and minute ulcers (Figure 1). Ankle–brachial pressure index (ABPI) was 0.79 on the right side and 0.35 on the left side. Magnetic resonance angiography indicated a left common iliac artery (CIA) 3 cm stenosis with a mild narrowing of the internal iliac artery (IIA) ostium, plus non-significant changes in the right CIA. No other arterial segments were involved (Figures 2A and 2B). Endovascular treatment was suggested to this patient, given that the contralateral iliac arterial segment showed mild disease; hence, it was not considered as the best inflow to support an extra-anatomic crossover bypass. After adequate heparinisation, the left CIA lesion was successfully treated with a balloon-expandable stent (Figures 2C and 2D; Express LD Iliac 8 mm: 4 cm; pressure limit, 11 atm; Boston Scientific), which spared the IIA, but a high inflation pressure balloon angioplasty after stenting (16 atm, 3 min) was required to relieve a stiff waist. Dual antiplatelet therapy (DAPT) was started along with atorvastatin. A distal trans-metatarsal amputation was carried out and the wound healed soundly. ABPI improved to 0.92 on the left side. Regular ABPI checks showed no further reductions bilaterally.

A: MR angiography in case 1 showing severe narrowing of the left common iliac artery (CIA) with a uniform sub-occlusive lesion. B: Angiography of the same patient, confirming the left CIA lesion. C: Deployment of a balloon-expandable stent. D: Post-stenting run.

Case 2 A 55-year-old woman presented in 2016 with severe rest pain and dry right big toe gangrene of 10 days’ duration, 10 years after radiotherapy for Hodgkin’s lymphoma with a right inguinal lymph node biopsy. Over the 3 years before presentation, she had been admitted four times with severe right leg pain, swelling and bluish discolouration, and DVT was excluded each time on duplex scan (the most likely explanation was severe CVI due to iliac vein stenosis). Therefore, severe CVI was suggested, but none of these episodes were linked to the previous radiotherapy. Progressive lymphoedema had developed and the limb had attained a huge size. In addition, the patient had diabetes, hypertension, dyslipidaemia and ischaemic heart disease with coronary stenting. On examination, the whole right lower limb was massively enlarged, the groin was indurated with light brown discolouration and there was a skin blister in the groin, near a lymph gland biopsy scar. There were multiple skin blisters and venous/lymphatic skin changes in the distal leg, in addition to the big toe dry gangrene. ABPI measurement was not possible because of the skin condition and limb swelling, but pedal waveforms were monophasic on the right side and biphasic on the left side, and toe brachial pressure index (TBPI) was 0.3 on the right side and 0.4 on the left side. CT angiography (CTA) indicated bilateral mild tibial arterial multiple stenoses with short occluded segments in the tibio-peroneal trunks and a long atherosclerotic segment of stenoses and occlusions in the right SFA. The right CIA and external iliac artery were significantly narrowed with a sustained 7 cm segment of sub-occlusion, similar to a stretched thread, and very different from the SFA disease pattern. The right IIA was severely attenuated as well. The right common iliac vein (CIV) diameter was 6 mm and the diameter of the contralateral one was 8 mm. The diameter of the common femoral veins was 15 mm and 12 mm on the right and left sides, respectively.

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Due to the multiple comorbidities and the nature of the disease, the endovascular option was considered to be the best treatment in this case. The right iliac arterial segment was accessed from the contralateral groin, after an IV heparin bolus, and two stents were deployed (Express LD Iliac 8 mm: 6 cm and 4 cm; pressure limit, 9 atm; Boston Scientific) with a 2 cm overlap. The SFA disease was treated with a RANGER paclitaxel-coated PTA balloon catheter on an 0.018" platform (100 mm, 6 mm diameter, 10 atm). Again, a higher than recommended inflation pressure limit was mandatory to adequately stretch the stent (16 atm). TBPI improved on the right side to 0.52 and waveforms became biphasic on the right side. DAPT was given along with a statin. Skincare instructions and class I compression stockings were advised to limit venous and lymphatic disease progression. Again, no further treatment was offered for the iliac veins disease because of the multiple comorbidities and the complexity of venolymphatic insufficiency. Unfortunately, the patient was admitted to the intensive care unit 7 weeks after the intervention with septic shock due to severe necrotising fasciitis of the right lower limb. Above-the-knee amputation was unavoidable. Additionally, the right groin blister had worsened and developed into a classical radiation ulcer. It took almost 2 years for both wounds to heal.

Case 3 A 53-year-old woman presented in 2017 with progressively worsening severe rest pain and gangrene of the lateral three toes in her right foot, of 4 days duration. She had undergone endometrial cancer treatment with radiotherapy 9 years earlier. There was no history of angina, stroke or claudication. In addition, there was no clinical evidence of tumour recurrence. On examination, all peripheral pulses were palpable in all extremities apart from the right lower limb. The right foot was colder than the left

Clinical Review Figure 3: Schematic Diagram of Left Common Femoral Artery to Right Superficial Femoral Artery Cross-over Bypass in Case 3

Case 4 A 67-year-old woman presented in 2017 with a 2 week history of fifth right toe tip gangrene and increasingly worsening leg ulcer over the previous 3 months, most likely a mixed arterial and venous ulcer. She had received radiotherapy for Hodgkin’s lymphoma, 12 years earlier, in addition to right groin inguinal lymph node biopsy. She had a background history of stable angina, diabetes and right hip osteoarthritis with bilateral knee mild flexion deformity. The right foot had only a dry gangrenous patch on the fifth toe. Also, the leg had a deep 4 × 5 cm ulcer above the medial malleolus, in addition to the knee mild contracture and the groin scar. ABPI was 0.5 on the right and 0.93 on the left . CTA showed calcifications in different segments on both sides, but there were stenoses only on the right side; one tight stenotic segment in the distal 3 cm segment of the CIA; and atherosclerotic multiple stenoses in the SFA. Of note, the right CIV was narrower than the left CIV in cut sections distal to L5 (8 mm versus 13 mm in diameter, respectively), but not much information about the interior was obtainable from this arterial phase scan.

side and showed gangrene of the lateral three toes, along with skin mottling patches proximally, in addition to mild pitting oedema in the dorsal aspect of the foot with a sort of skin glistening. There was no cellulitis or deep collections. Her right groin was hard and indurated with a mahogany discolouration of the skin. ABPI was 0.3 on the right side and 1.1 on the left side. The clinical picture was a combination of acute and critical limb ischaemia; nonetheless, there was no motor impairment. Urgent CTA showed a 6 cm uniform near-total occlusion of the distal CIA and proximal external iliac artery and the involved segment looked like a stretched thread, the distal flow was attenuated and no collaterals were noted. There was no radiological evidence of thrombosis. Otherwise, the whole arterial tree proximally and on the contralateral side was essentially unremarkable. Urgent cross-over bypass was done given that there was no access to the out-of-hours interventional radiology service. Additionally, the disease morphology was considered as ideal for a short bypass, which was done with an inflow from the left CFA to the right SFA using a fluoropolymer-coated Dacron 6 mm graft to avoid dissection through the right groin (Figure 3). Postoperatively, the foot condition improved, with an ABPI of 0.89 on the right side and 1.12 on the left side. Local foot amputation of the lateral three toes was carried out. The wound healing process was uneventful. The same treatment and follow-up protocols as in the previous cases were adopted in this case.

This patient was treated in a similar way to the previous case, given that she declined angioplasty because she was very conscious about the risk of renal impairment and dialysis, but the distal anastomosis was done at the retrogenicular popliteal segment. ABPI improved postoperatively to 0.85 on the right side, the patient was maintained on DAPT and a statin and was advised to have regular ABPI measurement. Moreover, multi-layer compression bandaging was necessary for 3 months to achieve complete healing of the leg ulcer.

Conclusion The incidence of RIPVD is much higher than expected and can be easily missed. Hence, a high index of suspicion is the key to successful diagnosis. It should not be dealt with in a similar way to atherosclerotic arteriopathy. It seems that there is some female predilection to RIPVD. In the presence of new lower limb ischaemic features with a background of pelvic radiotherapy, particularly with better prognosis tumours, iliac radiation arteritis should be borne in mind. Similarly, the picture of DVT or CVI in this setting should warrant detailed investigations to uncover the underlying radiation-related iliac vein disease. Regardless of presentation, it is vital to consider other structures in the radiation field, for example major veins, lymphatics and pelvic viscera in imaging plans. In a high proportion of cases, radiation arteritis lesions can be easily differentiated from the atherosclerotic disease. However, this would be increasingly difficult in late lesions. The outcome of limb salvage (surgical and interventional) procedures can be very variable and adequate planning is necessary to reduce the risk of major amputation. Every effort should be made to avoid surgical manipulation of the radiation field. Follow-up after a successful procedure is needed in all cases, indefinitely, given that late radiation tissue injury is an ongoing process.1,2,13–17,29

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Understanding Iliac Radiation Arteritis 1.

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Morris KA, Haboubi NY. Pelvic radiation therapy: between delight and disaster. World J Gastrointest Surg 2015;7:279–88. https://doi.org/10.4240/wjgs.v7.i11.279; PMID: 26649150. Chun YS, Cherry KJ. Radiation arteritis. J Am Coll Surg 2003;196:482. https://doi.org/10.1016/S1072-7515(02)01802-1; PMID: 12648702. American Cancer Society. Cancer treatment and survivorship: facts and figures 2019-2021. https://www.cancer.org/content/ dam/cancer-org/research/cancer-facts-and-statistics/cancertreatment-and-survivorship-facts-and-figures/cancertreatment-and-survivorship-facts-and-figures-2019-2021.pdf (accessed 24 January 2020). Acosta R, Warrington SJ. Radiation Syndrome. Treasure Island, FL: StatPearls Publishing, 2019. PMID: 28722960. Brown KR, Rzucidlo E. Acute and chronic radiation injury. J Vasc Surg 2011;53(1 Suppl):15S–20. https://doi.org/10.1016/j. jvs.2010.06.175; PMID: 20843630. Donnelly EH, Nemhauser JB, Smith JM, et al. Acute radiation syndrome: assessment and management. South Med J 2010;103:541–6. https://doi.org/10.1097/ SMJ.0b013e3181ddd571; PMID: 20710137. Akleyev AV. Chronic Radiation Syndrome. Berlin: Springer-Verlag, 2014. Shuryak I, Brenner DJ, Ullrich RL. Radiation-induced carcinogenesis: mechanistically based differences between gamma-rays and neutrons, and interactions with DMBA. PloS One 2011;6:e28559. https://doi.org/10.1371/journal. pone.0028559; PMID: 22194850. Sylvester CB, Abe JI, Patel ZS, Grande-Allen KJ. Radiationinduced cardiovascular disease: mechanisms and importance of linear energy transfer. Front Cardiovasc Med 2018;5:5. https:// doi.org/10.3389/fcvm.2018.00005; PMID: 29445728. Halle M, Gabrielsen A, Paulsson-Berne G, et al. Sustained inflammation due to nuclear factor-kappa b activation in irradiated human arteries. J Am Coll Cardiol 2010;55:1228–35. https://doi.org/10.1016/j.jacc.2009.10.047; PMID: 20298930. Koukourakis MI. Radiation damage and radioprotectants: new concepts in the era of molecular medicine. Br J Radiol 2012;85:313–330. https://doi.org/10.1259/bjr/16386034; PMID: 22294702. Gassman A. The histoloy of X-ray ulcers. Fortschr Geb Rontgenstr 1899;2:199 [in German]. Lindsay S, Entenman C, Ellis EE, Geraci CL. Aortic arteriosclerosis in the dog after localized aortic irradiation with electrons. Circ Res 1962;10:61–7. https://doi. org/10.1161/01.res.10.1.61; PMID: 14465539. Weintraub NL, Jones WK, Manka D. Understanding radiationinduced vascular disease. J Am Coll Cardiol 2010; 55:1237–9. https://doi.org/10.1016/j.jacc.2009.11.053; PMID: 20298931. Andros G, Schneider PA, Harris RW. Radiation-induced arteritis. In: Stanley MD, Veith F, Wakefield TW, eds. Current Therapy in

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Vascular and Endovascular Surgery. 5th ed. Philadelphia, PA: Saunders, 2014. 16. Souza J, Cavalcante L, Bernardes M, et al. Acute limb ischemia secondary to radiation-induced arteritis: case report. J Vasc Bras 2013;12:243–6. https://doi.org/10.1590/jvb.2013.033. 17. Baerlocher MO, Rajan DK, Ing DJ, Rubin BB. Primary stenting of bilateral radiation-induced external iliac stenoses. J Vasc Surg 2004;40:1028–31. https://doi.org/10.1016/j.jvs.2004.08.031; PMID: 15557921. 18. Mesurolle B, Qanadli SD, Merad M, et al. Unusual radiologic findings in the thorax after radiation therapy. Radiographics 2000; 20:67–81. https://doi.org/10.1148/ radiographics.20.1.g00ja1167; PMID: 10682772. 19. Denham JW, Hauer-Jensen M. Radiation induced bowel injury: a neglected problem. Lancet 2013;382(9910):2046–7. https:// doi.org/10.1016/S0140-6736(13)61946-7; PMID: 24067489. 20. Chuang VP. Radiation-induced arteritis. Semin Roentgenol 1994;29:64–9. https://doi.org/10.1016/s0037-198x(05)80072-0; PMID: 8128269. 21. Himmel PD, Hassett JM. Radiation-induced chronic arterial injury. Semin Surg Oncol 1986;2:225–47. https://doi.org/10.1002/ ssu.2980020405; PMID: 3330279. 22. Dahele M, Davey P, Reingold S, Shun Wong C. Radiationinduced lumbo-sacral plexopathy (RILSP): an important enigma. Clin Oncol 2006;18:427–8. https://doi.org.10.1016/j. clon.2006.03.004; PMID: 16817337. 23. Quack H, Erpenbeck L, Wolff HA, et al. Oxaliplatin-induced leukocytoclastic vasculitis under adjuvant chemotherapy for colorectal cancer: two cases of a rare adverse event. Case Rep Oncol 2013;6:609–15. https://doi.org/10.1159/000357166; PMID: 24474925. 24. Cardio-oncology: Vascular and metabolic perspectives: a scientific statement from the American Heart Association. Circulation 2019;139:e579–602. https://doi.org/10.1161/ CIR.0000000000000641; PMID: 30786722. 25. Park HJ, Ranganathan P. Neoplastic and paraneoplastic vasculitis, vasculopathy, and hypercoagulability. Rheum Dis Clin North Am 2011;37:593–606. https://doi.org/10.1016/j. rdc.2011.09.002; PMID: 22075199. 26. Lee J, Shaw P. Endovascular management of TransAtlantic Inter-Society Consensus D iliac artery occlusion secondary to radiation arteritis. J Vasc Surg Cases Innov Tech 2018;4:109–11. https://doi.org/10.1016/j.jvscit.2018.01.003; PMID: 29942894. 27. Gelband H, Jha P, Sankaranarayanan R, Horton S (eds). Cancer: Disease Control Priorities. 3rd ed. Washington, DC: International Bank for Reconstruction and Development/The World Bank, 2015. https://doi.org/10.1596/978-1-4648-0349-9. PMID: 26913318. 28. Bergonié J, Tribondeau L. Interpreting some results of radiotherapy and an attempt to establish a rational technique. Comptes Rendus des Séances de l’Académie des Sciences

1906;143:983–5 [in French]. 29. Fujimura H, Kurose K.Experience of revascularization for iliac artery occlusion that occurred after radiation irradiation considered to be radiation arteritis. Jpn J Vasc Surg 2009;18:641–5 [in Japanese]. https://doi.org/10.11401/ jsvs.18.641. 30. Chang DS, Lasley FD, Das IJ, et al. Normal tissue radiation responses. In: Basic Radiotherapy Physics and Biology. Cham, Switzerland: Springer, 2014. https://doi.org/10.1007/978-3-31906841-1_26. 31. Mellière D, Desgranges P, Berrahal D, et al. [Radiation-induced aorto-ilio-femoral arterial arteritis. Mediocrity of the long-term results after conventional surgery]. J Mal Vasc 2000;25:332-335. PMID: 11148394. 32. Ghosh AK, Lundstrom CE, Edwards WD. Radiation arteritis following treatment for Wilms’ tumor: an unusual case of weight loss. Vasc Med 2002;7:19–23. https://doi. org/10.1191/1358863x02vm408cr; PMID: 12083729. 33. Moser EC, Noordijk EM, van Leeuwen FE, et al. Long-term risk of cardiovascular disease after treatment for aggressive nonHodgkin lymphoma. Blood 2006;107:2912–19. https://doi. org/10.1182/blood-2005-08-3392; PMID: 16339404. 34. Dorth JA, Patel PR, Broadwater G, Brizel DM. Incidence and risk factors of significant carotid artery stenosis in asymptomatic survivors of head and neck cancer after radiotherapy. Head Neck 2014;36:215–19. https://doi. org/10.1002/hed.23280; PMID: 23554082. 35. White A, Ironmonger L, Steele RJ, et al. A review of sex-related differences in colorectal cancer incidence, screening uptake, routes to diagnosis, cancer stage and survival in the UK. BMC Cancer 2018; 18: 906. https://doi.org/10.1186/s12885-0184786-7; PMID: 30236083. 36. Specht L, Yahalom J, Illidge T, et al. Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the International Lymphoma Radiation Oncology Group (ILROG). Int J Radiat Oncol Biol Phys 2014;89:854–62. https://doi. org.10.1016/j.ijrobp.2013.05.005; PMID: 23790512. 37. Zhang MX, Li XB, Guan BJ, et al. Dose escalation of preoperative short-course radiotherapy followed by neoadjuvant chemotherapy in locally advanced rectal cancer: protocol for an open-label, single-centre, phase I clinical trial. BMJ Open 2019;9:e025944. https://doi.org/10.1136/ bmjopen-2018-025944; PMID: 30904869. 38. Banerjee R, Kamrava M. Brachytherapy in the treatment of cervical cancer: a review. Int J Womens Health 2014;6:555–64. https://doi.org/10.2147/IJWH.S46247; PMID: 24920937. 39. Milecki P, Baczyk M, Skowronek J, et al. Benefit of whole pelvic radiotherapy combined with neoadjuvant androgen deprivation for the high-risk prostate cancer. J Biomed Biotechnol 2009;2009:625394. https://doi. org/10.1155/2009/625394; PMID: 19859572.

Venous

Catheter Interventions for Acute Deep Venous Thrombosis: Who, When and How Catherine Go, Rabih A Chaer and Efthymios D Avgerinos Division of Vascular Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, US

Abstract Deep venous thrombosis (DVT) is common and can be a source of morbidity by way of pulmonary embolism and post-thrombotic syndrome. Recent trials have demonstrated both early and late symptomatic benefit in venous thrombolysis and early recanalisation of the iliocaval system of selected patients. Based on the emerging evidence, national societies have published guidelines that recommend early thrombus removal in iliofemoral DVT in patients with low bleeding risk and good life expectancy. In light of these recommendations, endovenous thrombolysis and/or thrombectomy have become more popular among vein specialists. As more venous technology becomes available, surgeons and interventionalists should take pause and ensure their patient selection and treatment algorithms parallel that of existing and emerging evidence. This article summarises current evidence, technology, and the approach used at a high-volume academic centre in treating iliofemoral DVT.

Keywords Deep venous thrombosis, catheter-directed thrombolysis, intravascular ultrasound, pharmacomechanical thrombolysis, aspiration thrombectomy, venous stent Disclosure: EDA has received speaking honoraria from Gore Medical and Boston Scientific Corporation. All other authors have no conflicts of interest to declare. Received: 21 December 2019 Accepted: 13 April 2020 Citation: Vascular & Endovascular Review 2020;3:e07. DOI: https://doi.org/10.15420/ver.2019.13 Correspondence: Efthymios D Avgerinos, Heart and Vascular Institute, South Tower, Building 3, Office 351.1, Presbyterian University Hospital, 200 Lothrop St, Pittsburgh, PA 15213, US. E: avgerinose@upmc.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 noncommercial purposes, provided the original work is cited correctly.

Deep venous thrombosis (DVT) affects approximately one in 1,000 patients yearly, and 40–70% of these patients will develop postthrombotic syndrome (PTS) in their lifetime: a constellation of symptoms and signs of chronic venous insufficiency, including pain, swelling, varicose veins, and ulcerations.1,2 PTS is associated with profound morbidity and cost, which justifies the attention it has received in recent years in the form of randomised controlled trials (RCTs) on how to decrease its incidence.3–5 The pathophysiology of PTS is believed to be a culmination of outflow obstruction, valvular damage leading to reflux, and chronic inflammation secondary to thrombosis.6 The ‘open vein hypothesis’ endorses the relieving of the venous obstruction in order to improve flow and decrease the risk of reflux, thereby reducing the chance of developing PTS.7 Anticoagulation at this time remains the mainstay of treatment for DVT, with dose durations varying based on aetiology according to the American College of Chest Physicians (CHEST) guidelines.8 Prolonged anticoagulation, however, has not been shown to reduce the risk of PTS, and recanalisation of the iliac vein is rare after a DVT.9 Some view the results of the Extended Anticoagulation Treatment versus Standard Treatment for the Prevention of Recurrent Venous Thromboembolism (VTE) and Post-thrombotic Syndrome in Patients Being Treated for a First Episode of Unprovoked VTE (ExACT) study as evidence supporting the open vein hypothesis. That study was an RCT comparing standard and extended regimens of anticoagulation

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that demonstrated no differences in the risk of PTS or in quality of life (QOL).9 The landmark Catheter-directed Venous Thrombolysis (CaVenT) and Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-directed Thrombolysis (ATTRACT) trials were the first to show a benefit with catheter-based interventions in preventing or alleviating PTS in patients with first-time DVT. The former found an absolute risk reduction in the development of PTS of 14.4% at 2 years and 28% at 5 years, while the latter demonstrated lower incidence of moderate (Villalta score >9) and severe (Villalta score >15) PTS, faster pain relief, and improved QOL for patients with iliofemoral DVT.3,4 The most recent Catheter-directed Thrombolysis versus Anticoagulation (CAVA) trial, which randomised patients with iliofemoral DVT to ultrasound-assisted thrombolysis or anticoagulation, failed to show a benefit in preventing PTS development at 1 year follow-up.5 The conflicting results of the studies have raised criticism mainly with regard to incorrect patient inclusion or technical inappropriateness.10 We need to acknowledge, otherwise, that catheter-based interventions come at a cost. Although no difference in mortality has been shown, when compared with anticoagulation alone, catheter-directed thrombolysis (CDT) has been associated with higher rates of blood transfusion, pulmonary embolism, intracranial haemorrhage, and vena cava filter placement. In some countries, CDT is also associated with longer hospital stay and threefold higher hospital costs.11 Despite these disadvantages, current evidence helps us to better select our patients,

DVT Lysis: Who, When, and How experience keeps improving, and the popularity of endovenous treatment will continue to grow. With the advent of new devices, it is imperative for vascular surgeons and interventionalists to increase their familiarity with the techniques and to choose their patients wisely.

Patient Selection Algorithm The ATTRACT trial demonstrated no benefit of intervention for patients with femoropopliteal DVT.12 The CaVenT study demonstrated successful outcomes in patients with up to 21 days of symptoms, but we have noted an approximately 90% technical success rate in patients with symptoms for up to 30 days at our institution.3,13,14 It is thus our practice to consider intervention for patients with iliofemoral DVT and symptoms for less than 30 days. Symptom severity represents the next decision point with regard to who and how to intervene. For patients presenting with limbthreatening ischaemia (phlegmasia), emergency clot removal is selfexplanatory as the only option, while asymptomatic patients would not qualify for any intervention.15 The difficulty in decision-making is for those with mild–moderate pain and swelling. Patients with moderately severe symptoms are typically monitored on IV heparin infusion for 24–48 hours. If symptoms persist or worsen even with ambulation, intervention can be offered, provided the patient is ambulatory with acceptable life expectancy. A small subset of this group may opt for immediate clot removal (e.g. young, athletic patients) after a thorough discussion of expectations and risks. Among those who warrant intervention, bleeding risk is the final criterion that must be evaluated. Pharmacomechanical thrombolysis and/or catheter dripping of thrombolytics are generally reserved for patients with low bleeding risk. High bleeding risk patients (Table 1) should be treated with aspiration thrombectomy with minimal or no use of thrombolytics.16 Those with moderate bleeding risk are treated at the surgeon’s discretion with pharmacomechanical thrombectomy (PMT) and/or aspiration thrombectomy with sparing use of tissue plasminogen activator (tPA; Figure 1).

Table 1: Contraindications to the Use of Thrombolytics Absolute Contraindications Active bleeding Disseminated intravascular coagulation Recent (<3 months) stroke/transient ischemic attack Recent (<3 months) neurosurgery Recent (<3 months) intracranial trauma

Relative Contraindications Recent (<10 days) CPR/chest compressions Recent (<10 days) major surgery or trauma Recent (<10 days) delivery Recent (<3 months) major gastrointestinal bleed Serious allergy to tPA or contrast Severe thrombocytopenia Renal failure Infected thrombus Pregnancy/lactation CPR = cardiopulmonary resuscitation; tPA = tissue plasminogen activator.

Figure 1: Author Recommendations for Patient and Treatment Selection Iliofemoral or caval DVT <30 d

Assess symptoms Threatened limb

Optimising Outcomes Achieving optimal results requires far more than selecting the right patient and technique. A certain to do list needs to be followed to minimise failure. Herein we summarise our institution’s recommendations to prolong patency.

Thrombus Clearance Achieving thrombus clearance of >90% is of paramount importance. Mewissen et al. found in their review of 221 iliofemoral DVTs within the national venous registry a clinical success (>50% thrombus clearance) rate of 83%. Primary patency was significantly better in patients with >50% clot removal (85%) compared with those with significant residual disease (36%).14 In our investigation of 142 patients who underwent CDT/PMT and stenting, technical success was achieved in more than 90% of patients with a 1-year primary stent patency of 83.1%. The strongest predictor of stent thrombosis was incomplete lysis (<50% thrombus clearance), HR 7.41. Furthermore, incomplete lysis was also the strongest predictor of the development of PTS in 5 years.17

Stenting In the landmark trials, stenting of identifiable obstructive lesions after DVT lysis was performed in less than 50% of cases.3,4,14 However, stenting has evolved to become an essential component of acute DVT

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Moderate to severe pain/swelling

Minimal or no symptoms

Persistent symptoms on heparin drip >24–48 h

Anticoagulation only

Ambulatory Good life expectancy Plan for intervention: assess bleeding risk High

Moderate

Low

Aspiration thrombectomy

Aspiration thrombectomy or PMT

PMT and/or CDT

CDT = catheter-directed thrombolysis; DVT = deep venous thrombosis; PMT = pharmacomechanical thrombectomy.

intervention given that multiple studies have demonstrated improved patency with adjunctive stenting after thrombolysis. Mewissen et al. demonstrated 1-year primary patency of 74% with stenting compared with 53% without.14 Similarly, Meng et al. from China randomised 74 patients with >50% venous obstructive lesions discovered after thrombolysis to stenting versus no stent placement. The stented group benefitted from significantly greater primary patency rates (86% versus 55%) and improvements in symptomatology based on various clinical scales.18 Current guidelines recommend the use of self-expanding stents in iliocaval lesions that are uncovered by thrombus removal.15 Current convention defines 50% stenosis as the threshold for stenting. The Venogram Versus Intravascular Ultrasound for Diagnosing and Treating Iliofemoral Vein Obstruction (VIDIO) trial validated this threshold

Venous Table 2: Venous Stents Currently Available for Use Brand

Design

Tips and Tricks

Wallstent (Boston Scientific)

Self-expanding, stainless steel, braided closed cell

Maximum diameter 24 mm; significant foreshortening, inaccurate deployment, weak radial force at the ends

Venovo (Bard)

Self-expanding nitinol, open cell

8–10 Fr delivery, maximum diameter 20 mm, flared ends; VERNACULAR study (NCT02655887)

Vici (Boston Scientific)

Self-expanding nitinol, closed cell

9 Fr system up to 16 mm diameter; VIRTUS trial (NCT02112877)

Zilver Vena (Cook Medical)†

Self-expanding nitinol, open cell

7 Fr system, 14–16 mm diameter; VIVO trial (NCT01970007) enrolling

Abre (Medtronic)†

Self-expanding nitinol, open cell

9 Fr delivery, 10–20 mm diameter

†

Not yet Food and Drug Administration approved.

and reported 6-month clinical improvement with stenting of thrombotic lesions causing >54% area reduction.19 In a 2015 meta-analysis, 1-year stent primary patency was 87% for acute thromboses.20 Stenting rates have been steadily increasing since the early trials and continue to do so with the advent of novel dedicated venous stents. In the same metaanalysis, stenting in acute DVT ranged from 34% to 100%.20 In principle, optimal outcomes are achieved when the stent lands in healthy vein segments proximally and distally. Recent studies (including from our institution) have reported mixed results regarding duration of lysis treatment and stented vein length.21–23 In our experience, we found no difference in stented length between single PMT sessions and staged CDT/PMT interventions.21 Historically, longer stents have been associated with inferior patency, but no differences were found in these studies.21–24 Regarding extension to the infrainguinal level, there is little controversy regarding its necessity when disease extends to that level. However, patency and long-term outcomes will likely be inferior, mainly due to the extent of the disease and not because of stent complications (fractures are very rare). Neglen et al. demonstrated an association with worse secondary patency, with infrainguinal extension of stents mirroring the severity of the chronic disease.25 In our institution’s experience, stenting into the common femoral vein was not predictive of stent failure, at least, for our 3-year follow-up. It was predictive, however, of PTS development, which is also a sign of more extensive disease.21 Proximal extension of the stent into the vena cava has been recommended to guarantee complete coverage of the proximal iliac vein lesion/compression and to compensate for the reduced peripheral radial forces of the traditionally used Wallstent (Boston Scientific). Stent extension into the vena cava, however, jails the contralateral iliac vein, and there has been increasing concern regarding development of contralateral DVT. According to our own experience, we found no significant association between caval extension and contralateral DVT development, as recurrent DVT seems to occur irrespective of stent placement; still, we cannot ignore it is a precipitating factor.17 Khairy et al. published a 4% contralateral DVT rate for 376 patients (84% Wallstent) at two institutions, while a 2019 systematic review by DuarteGamas et al. reported an incidence ranging from 0 to 15.6% in 1,864 patients.26,27 Novel stents with their uniform radial force have reduced the need to extend far into the vena cava.

Dedicated venous stents have been available over the past few years in Europe and have recently been Food and Drug Administration approved and entered the US market (Table 2). Gone are the days when we resorted to using stents designed for the smaller and more dynamic arterial system. Arteries bear a different haemodynamic load compared to larger, low flow, externally compressed, or scarred veins. Large venous stents provide better inflow and outflow avenues. Raju et al. investigated the utility of iliac vein stent oversizing by 2 mm compared to the anatomic norms and confirmed larger flow channels on intravascular ultrasound (IVUS) and better clinical outcomes.28 It is thus our practice to use 16–18 mm stents in the common iliac vein, 14 mm stents in the external iliac vein, and 12–14 mm when extending distally to the common femoral vein.

Intravascular Ultrasound The utility of IVUS (Philips) cannot be overstated. In contemporary practice, IVUS is essential to identify obstructive venous lesions, guide stent diameters, landing zones and to confirm a satisfactory final outcome. The 2017 VIDIO trial compared measurements of venous anatomy in 100 patients using both multiplanar venography and IVUS.29 Use of IVUS led to the detection of clinically significant vein stenosis (>50% stenosis) in 81 patients versus 51 patients via venography. More importantly, the use of IVUS led to a change in treatment plan in 57 patients: 54 patients received stents for lesions not otherwise seen on venography and 3 patients had false positive findings on venography that were not seen on IVUS.29 Authors of the VIDIO trial concluded that IVUS was both more sensitive and more specific than venography for identifying and sizing iliac vein stenosis.29 Furthermore, a subsequent publication reported that clinical improvement could be predicted by the percent change in vein diameter before and after treatment.19 However, at this time, longterm patency with and without the use of IVUS has yet to be compared.

Catheter Techniques Here we aim to describe the main thrombectomy techniques/devices in the deep venous armamentarium.

Catheter-directed Thrombolysis CDT or lytic dripping is the standard baseline technique for delivering tPA into the thrombus, softening it. It can be achieved through a 5 Fr system with femoral or popliteal vein access. A multi-sidehole infusion catheter can be manoeuvred over a wire until it is embedded in the iliocaval thrombus. Through this catheter, a continuous infusion of 1 mg/h tPA is delivered. Simultaneously, 500 units/h of unfractionated heparin is infused through the sheath sideport. The patient’s neurologic function is evaluated every 2 hours, usually in the intensive care unit. Complete blood counts and coagulation levels (e.g. fibrinogen) are checked every 4–6 hours. The patient is brought back to the angiography suite for lysis check versus termination and stenting every 8–24 hours. Performed alone, this technique may take 24–48 hours to complete. Technical success rates with CDT alone range from 83% to 100%.3,4,12,24 Bleeding complications ranged from 4% to 9% which included haematomas or transfusion requirements.3,4,17 A 2016 Cochrane review, the CaVenT study and ATTRACT trial reported no incidences of stroke or intracerebral haemorrhage.3,4,30 Overall, in the right patient, CDT is effective and safe. However, due to the prolonged tPA infusion times and increased costs, the authors’ practice has gradually shifted to a single-stage, PMT-only approach with adjunctive CDT if thrombus clearance is unsatisfactory.

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DVT Lysis: Who, When, and How Ultrasound-assisted CDT Standard dripping can be enhanced with ultrasound, which has shown increased clot lysis in vitro.31 This is the theory behind the EkoSonic catheter (EKOS). The EKOS catheter is the multi-sidehole infusion catheter combined with a high-frequency ultrasound transducer to increase lytic penetration into the thrombus. The technique for ultrasound-assisted (UA) CDT is similar to standard dripping except for the need for normal saline coolant and the ultrasound tower. Patients are similarly monitored for neurologic changes and abrupt changes in their laboratory work. The recently published RCT comparing UACDT versus anticoagulation (CAVA trial) showed no difference in PTS development, PTS severity, or QOL at 1 year.5 Currently only one RCT has compared standard CDT and UACDT: the Ultrasound-enhanced Thrombolysis versus Standard Catheter-directed Thrombolysis for Iliofemoral Deep Vein Thrombosis (BERNUTIFUL) trial.32 Engelberger et al. randomised 48 patients to 20 mg tPA over 15 hours via UACDT versus CDT. At the end of 15 hours, both groups had significantly less thrombus burden compared with baseline but there were no significant differences seen between groups in clot clearance, hospital length of stay, or 3-month patency. No differences were found at 1 year as well, and the authors concluded that the addition of ultrasound energy to CDT had no impact on clinical outcomes.32,33

Rheolytic Thrombolysis In line with the Society for Vascular Surgery/American Venous Forum guidelines for early thrombus removal,15 our own institution’s practice is a ‘PMT-first’ approach followed by selective CDT with the goal of completing clot removal in one session. This is performed most often with the AngioJet catheter (Boston Scientific). The AngioJet catheter works in two phases. The first is the power-pulse mode in which 6–10 mg tPA in saline solution is forcefully sprayed into the thrombus. After 30 minutes to allow tPA to soften and partially dissolve the clot, the thrombectomy mode is activated. Using multiple directional saline jets, a pressure gradient is created that draws softened thrombus into the multiple inflow windows of the catheter and then into the collection bag. In 2015, Garcia et al. published the results of the Peripheral use of AngioJet Rheolytic Thrombectomy with a Variety of Catheter Lengths (PEARL) study, which describes outcomes after peripheral use of AngioJet thrombectomy in DVTs. Twelve-month patency was 83% with a 3.6% bleeding event rate, leading the authors to conclude that rheolytic PMT is a safe and effective potential alternative to CDT.34 The Zelante catheter (Boston Scientific) is the latest development of the AngioJet technology. This 8-Fr system utilises a singular, larger powerpulse, saline jet, and single inflow window, which allows the operator to control and focus on a specific area by rotating the catheter in order to effectively treat the vessel wall circumferentially. Clinical guidelines recommend a PMT-first approach over CDT based on similar efficacy and potentially better safety.15 Two meta-analyses from China demonstrated that PMT ± CDT is not inferior and may be superior to CDT alone.33,34 One study reported no difference in Villalta scores while the other stated that PMT achieves lower scores. Both studies concluded shorter hospital stays, lysis time and volume, with similar bleeding complication rates.35,36 One particular study by Lin et al. compared CDT (n=46) and AngioJet (n=52) and found no differences in technical success and symptom relief.37 The PMT group, however, underwent significantly fewer venograms, less lytic infusion time (76 minutes versus 18 hours), and shorter ICU stays (0.6 versus 2.4 days). Safety profiles were similar but with the CDT group requiring

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Figure 2: Treatment of Iliofemoral Deep Venous Thrombosis With the Indigo CAT 8 A

Wallstent 16 mm × 9 cm A: Extensive iliofemoral deep venous thrombosis and thrombocytopenia of unknown aetiology in a 29-year-old woman who presented with right leg pain and swelling. B: Due to bleeding risk, aspiration thrombectomy was performed with the Indigo CAT 8 in a single session without the use of tissue plasminogen activator. C: Post-aspiration venogram showed residual disease, which was stented successfully (D and E).

more blood transfusions.37 In our experience, AngioJet PMT in a single session was not associated with any significant differences in technical success, differences in stented length, or long-term patency.21 PMT alone was also associated with fewer trips to the operating room and no difference in clinical improvement when compared with CDT.13 Rheolytic PMT, however, is not infallible. AngioJet use is associated with acute kidney injury (AKI) in up to 20% of patients.38,39 In our own experience, >95% of these AKIs are transient and resolve in the first 30 days after the procedure, and can be eliminated by staging extensive iliocaval DVTs (starting with a few-hour lytic drip), thus lowering the thrombectomy volumes.40

Aspiration Aspiration techniques have been traditionally reserved for patients who would benefit from early thrombus removal but have a contraindication to receiving pharmacological thrombolysis. More recently, novel aspiration thrombectomy devices have entered the market and increased utilisation is seen, justified by the known risks and timeconsuming nature of thrombolytics. Safety and efficacy against thrombolytics/rheolysis and PTS development have yet to be described.

Syringe Aspiration Aspiration using a large-bore catheter and syringe is the simplest possible technique and can be selectively performed when small amounts of clot are present. A Turkish RCT compared a 9 Fr catheter/20 ml syringe aspiration system to anticoagulation. Technical success (unobstructed venous flow) was achieved in 90.4% of patients (n=19). At 1-, 3-, and 12-month follow-up, the aspiration group had significant improvement in clinical symptom scores. Although significantly higher than the anticoagulation control group, 1-year primary patency was only 57.1%.41

Penumbra Indigo The Indigo CAT 8 (Penumbra) is a single-use, powerful 8 Fr aspiration catheter that can aspirate up to 160 ml/s. It consists of three components: a suction catheter, a separator for fragmentation and cleaning, and the vacuum pump. Currently, no studies exist comparing the Indigo CAT with pharmacological techniques. One retrospective series of 10 patients had >70% thrombus clearance in a single session in six patients, while the remaining four required adjunctive percutaneous methods of clot removal. Long-term patency data were

Venous Figure 3: Treatment of Thrombus with the ClotTriever Device A

Inari FlowTriever and ClotTriever The FlowTriever and ClotTriever devices (Inari Medical) combine both aspiration and mechanical thrombectomy into one device without the need for pharmacological lysis. They are currently available in the US only. The FlowTriever consists of a 16–24 Fr aspiration sheath that is advanced up to the distal end of the thrombus, which is then drawn to the vacuum sheath. Thrombectomy can be assisted as needed with nitinol discs that engage the clot and pull into the FlowTriever sheath. The ClotTriever is a 13 or 16 Fr, mechanical thrombectomy system with a catheter coring element and collection bag that is deployed proximal to the thrombus and retracted into the sheath. Successful use of these devices is available as case reports and small series (Figure 3). The most recent series of 12 patients demonstrated 100% technical success, 92% clinical improvement, and 80% patency at early follow-up.44

Conclusion A: CT venogram showing thrombus in the left common femoral vein (white arrow) of a 64-year-old man who presented with left lower extremity pain and swelling with ambulation. B: ClotTriever device (black arrow) was used with (C) successful thrombus removal without the use of lytics.

not available. However, no bleeding complications were reported, and none of the patients required transfusion.42 Indigo CAT 8 may provide an alternative to thrombolysis infusion or PMT (Figure 2).

AngioVac The AngioVac (AngioDynamics) is a large veno-venous filtration system requiring drainage and reinfusion cannulas. The suction catheter requires 26 Fr venous access, one of the device’s limitations. Due to its large size, it is most frequently used for caval and iliac thromboses. Limited data on the AngioVac system exist. A meta-analysis found that patients undergoing AngioVac aspiration for thrombotic indications had successful recanalisation rates of approximately 80%.43

Roberston L, McBride O, Burdess A. Pharmacomechanical thrombectomy for iliofemoral deep vein thrombosis. Cochrane Database Syst Rev 2016;11:CDO11536. https://doi. org/10.1002/14651858.CDO011536.pub2; PMID: 27814432. Kahn SR. The post-thrombotic syndrome. Hematology Am Soc Hematol Educ Program 2016;2016:413–8. https://doi. org/10.1182/asheducation-2016.1.413; PMID: 27913509. Haig Y, Enden T, Grotta O, et al. Post-thrombotic syndrome after catheter-directed thrombolysis for deep vein thrombosis (CaVenT): 5-year follow-up results of an open-label, randomized controlled trial. Lancet Haematol 2016;3:e64–71. https://doi.org/10.1016/S2352-3026(15)00248-3; PMID: 2685365. 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. Notten P, Ten Cate-Hoek AJ, Arnoldussen CWKP, et al. Ultrasound-accelerated catheter-directed thrombolysis versus anticoagulation for the prevention of post-thrombotic syndrome (CAVA): a single-blind, multicenter, randomized trial. Lancet Haematol 2020;7:e40–9. https://doi.org/10.1016/S23523026(19)30209-1; PMID: 31786086. Baldwin MJ, Moore HM, Rudarakanchana N, et al. Postthrombotic syndrome: a clinic review. J Thromb Haemost 2013;11:795–805. https://doi.org/10.1111/jth.12180; PMID: 23433231. Nathan AS, Giri J. Reexamining the open-vein hypothesis for acute deep venous thrombosis. Circulation 2019;139:1174–6. https://doi.org/10.1161/CIRCULATIONAHA.118.037903; PMID: 30802168. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016;149:315–52. https://doi.org/10.1016/j.chest.2015.11.026; PMID: 26867832. Bradbury C, Fletcher K, Sun Y, et al. A randomized controlled trial of extended anticoagulation treatment versus standard treatment for the prevention of recurrent venous thromboembolism (VTE) and post-thrombotic syndrome in

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Multiple RCTs have found symptomatic benefit of early percutaneous DVT debulking in accordance with the open vein hypothesis. Multiple academic and clinical venous societies have incorporated percutaneous treatment recommendations into clinical guidelines for the treatment of DVT. Although anticoagulation and compression remain the mainstay of treatment, patients with moderate swelling and pain, low bleeding risk, and good life expectancy could potentially be treated with a combination of pharmacological and mechanical thrombectomy methods. These procedures are generally safe but do confer an increased risk of bleeding or AKI. Thus, patient and technique selection should be of utmost importance. Regardless of the treatment modality, physicians should strive for complete clot clearance, and residual disease should be assessed on IVUS and subsequently stented. With the increasing popularity of percutaneous thrombus removal, it is essential to familiarise oneself with the who, when, and how of venous thrombosis treatment to provide effective and durable symptom relief to our patients.

patients being treated for a first episode of unprovoked VTE (the ExACT study). Br J Haematol 2020;188:962–75. https://doi. org/10.1111/bjh.16275; PMID: 31713863. Avgerinos EA, 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. Bashir R, Zack CJ, Zhao H, et al. Comparative outcomes of catheter-directed thrombolysis plus anticoagulation vs anticoagulation alone to treat lower-extremity proximal deep vein thrombosis. JAMA Intern Med 2014;174:1494–501. https:// doi.org/10.1001/jamainternmed.2014.3415; PMID: 25047081. 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. Hager E, Yuo T, Avgerinos E, et al. Anatomic and functional outcomes of pharmacomechanical and catheter-directed thrombolysis of iliofemoral deep venous thrombosis. J Vasc Surg Venous Lymphat Disord 2014;2:246–52. https://doi. org/10.1016/j.jvsv.2014.02.003; PMID: 26993382. Mewissen MW, Seabrook GR, Meissner MH, et al. Catheterdirected thrombolysis for lower extremity deep venous thrombosis: report of a national multicenter registry. Radiology 1999;211:39–49. https://doi.org/10.1148/ radiology.211.1.r99ap4739; PMID: 10189452. Gianesini S, Obi A, Onida S, et al. Global guidelines trends and controversies in lower limb venous and lymphatic disease: narrative literature revision and experts’ opinions following the vWINter international meeting in Phlebology, Lymphology & Aesthetics 23–25 January 2019. Phlebology 2019;34(1 Suppl):4–66. https://doi.org/10.1177/0268355519870690; PMID: 31495256. Vedantham S, Sista AK, Klein SJ, et al. Quality improvement guidelines for the treatment of lower-extremity deep vein thrombosis with use of endovascular thrombus removal. J Vasc Interv Radiol 2014;25:1317–25. https://doi.org/10.1016/j. jvir.2014.04.019; PMID: 25000825. Avgerinos E, Saadeddin Z, Abou Ali AN, et al. Outcomes and

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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. Meng QY, Li XQ, Jiang K, et al. Stenting of iliac vein obstruction following catheter-directed thrombolysis in lower extremity deep vein thrombosis. Chin Med J (Engl) 2013;126:3519–22. PMID: 24034101. 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. https://doi.org/10.1016/j. jvsv.2017.07.009; PMID: 29033314. 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. 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. Dopheide JF, Sebastian T, Engelberger RP, et al. Early clinical outcomes of a novel rheolytic directional thrombectomy technique for patients with iliofemoral deep vein thrombosis. Vasa 2018;47:56–62. https://doi.org/10.1024/0301-1526/ a000666; PMID: 28980513. Liu G, Qin J, Cui C, et al. Comparison of direct iliofemoral stenting following AngioJet rheolytic thrombectomy vs staged stenting after AngioJet rheolytic thrombectomy plus catheterdirected thrombolysis in patients with acute deep vein thrombosis. J Endovasc Ther 2018;25:133–9. https://doi. org/10.1177/1526602817714570; PMID: 28618846. Park YJ, Choi JY, Min SK, et al. Restoration of patency in iliofemoral deep vein thrombosis with catheter-directed thrombolysis does not always prevent post-thrombotic

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DVT Lysis: Who, When, and How

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damage. Eur J Vasc Endovasc Surg 2008;36:725–30. https://doi. org/10.1016/j.ejvs.2008.08.020; PMID: 18851923. Neglen P, Tackett TP Jr, Raju S. Venous stenting across the inguinal ligament. J Vasc Surg 2008;48:1255–61. https://doi. org/10.1016/j.jvs.2008.06.035; PMID: 18771877. Khairy SA, Neves RJ, Hartung O, et al. 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. Duarte-Gamas L, Rocha-Neves JP, Pereira-Neves A, et al. Contralateral deep vein thrombosis after stenting across the iliocaval confluence in chronic venous disease: a systematic review. Phlebology 2020;35:221–30. https://doi. org/10.1177/0268355519889873; PMID: 31793374. Raju S, Knight A, Buck W, et al. Caliber-targeted reinterventional overdilation of iliac vein Wallstents. J Vasc Surg Venous Lymphat Disord 2019;7:184–94. https://doi.org/10.1016/j. jvsv.2018.06.015; PMID: 30771830. 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. Foegh P, Jensen LP, Klitfod L, et al. Editor’s choice: factors associated with long-term outcome in 191 patients with iliofemoral DVT treated with catheter-directed thrombolysis. Eur J Vasc Endovasc Surg 2017;53:419–24. https://doi. org/10.1016/j.ejvs.2016.12.023; PMID: 28132743. Blinc A, Francis CW, Trudnowski JL, Carstensen EL. Characterization of ultrasound-potentiated fibrinolysis in vitro. Blood 1993;81:2636–43; PMID: 8490172. Engelberger RP, Spirk D, Willenberg T, et al. Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute

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iliofemoral deep vein thrombosis. Circ Cardiovasc Interv 2015;8(1):e002027. https://doi.org/10.1161/ CIRCINTERVENTIONS.114.002027; PMID: 25593121. Engelberger RP, Stuck A, Spirk D, et al. Ultrasoundassisted 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. Garcia MJ, Lookstein R, Malhotra R, et al. Endovascular management of deep vein thrombosis with rheolytic thrombectomy: final report of the prospective multicenter PEARL (Peripheral use of AngioJet rheolytic thrombectomy with a variety of catheter lengths) registry. J Vasc Interv Radiol 2015;26:777–85. https://doi.org/10.1016/j.jvir.2015.01.036; PMID: 25824314. Wang W, Sun R, Chen Y, et al. 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. Tang T, Chen L, Chen J, et al. Pharmacomechanical thrombectomy versus catheter-directed thrombolysis for iliofemoral deep vein thrombosis: a meta-analysis of clinical trials. Clin Appl Thromb Hemost 2019;25:1076029618821190. https://doi.org/10.1177/1076029618821190; PMID: 30808224. Lin PH, Zhou W, Dardik A, et al. Catheter-direct thrombolysis versus pharmacomechanical thrombectomy for treatment of symptomatic lower extremity deep venous thrombosis. Am J Surg 2006;192:782–8. https://doi.org/10.1016/j. amjsurg.2006.08.045; PMID: 17161094. Morrow KL, Kim AH, Plato SA 2nd, et al. Increased risk of renal dysfunction with percutaneous mechanical thrombectomy

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compared with catheter-directed thrombolysis. J Vasc Surg 2017;65:1460–6. https://doi.org/10.1016/j.jvs.2016.09.047; PMID: 27876521. Escobar GA, Burk 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;42:238–245. https://doi. org/10.1016/j.avsg.2016.12.018; PMID: 28412100. Salem KM, Saadeddin Z, Go C, et al. Risk factors for acute kidney injury after pharmacomechanical thrombolysis for acute deep venous thrombosis. J Vasc Surg 2019;70:e18. https://doi.org/10.1016/j.jvs.2019.06.009. Cakir V, Gulcu A, Akay E, et al. Use of percutaneous aspiration thrombectomy vs. anticoagulation therapy to treat acute iliofemoral venous thrombosis: 1-year follow-up results of a randomized, clinical trial. Cardiovasc Intervent Radiol 2014;37:969–76. https://doi.org/10/1007/s00270-014-0925-y; PMID: 24934734. 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. Hameed I, Lau C, Khan FM, et al. AngioVac for extraction of venous thromboses and endocardial vegetations: a metaanalysis. J Card Surg 2019;34:170–80. https://doi.org/10.1111/ jocs.14009; PMID: 30843269. Benarroch-Gampel J, Pujari A, Aizpuru M, et al. Technical success and short-term outcomes after treatment of lower extremity deep vein thrombosis with the ClotTriever system: a preliminary experience. J Vasc Surg Venous Lymphat Disord 2020;8:174–81. https://doi.org/10.1016/j.jvsv.2019.10.024; PMID: 31843476.

Aortic

Background and Proposed Design for a Metformin Abdominal Aortic Aneurysm Suppression Trial Ronald L Dalman,1 Ying Lu,2 Kenneth W Mahaffey,3 Amanda J Chase,4 Jordan R Stern1 and Robert W Chang5 1. Department of Surgery, Division of Vascular and Endovascular Surgery, Stanford University School of Medicine, Stanford, California, US; 2. Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, California, US; 3. Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, US; 4. Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, US; 5. Department of Vascular Surgery, Kaiser Permanente San Francisco, California, US

Abstract Abdominal aortic aneurysm (AAA) may lead to rupture and death if left untreated. While endovascular or surgical repair is generally recommended for AAA greater than 5–5.5 cm, the vast majority of aneurysms detected by screening modalities are smaller than this threshold. Once discovered, there would be a significant potential benefit in suppressing the growth of these small aneurysms in order to obviate the need for repair and mitigate rupture risk. Patients with diabetes, in particular those taking the oral hypoglycaemic medication metformin, have been shown to have lower incidence, growth rate, and rupture risk of AAA. Metformin therefore represents a widely available, non-toxic, potential inhibitor of AAA growth, but thus far no prospective clinical studies have evaluated this. Here, we present the background, rationale, and design for a randomised, double-blind, placebo-controlled clinical trial of metformin for growth suppression in patients with small AAA.

Keywords Abdominal aortic aneurysm, metformin, diabetes, growth suppression, medical therapy Disclosure: The authors have no conflicts of interest to declare. Received: 15 January 2020 Accepted: 13 April 2020 Citation: Vascular & Endovascular Review 2020;3:e08. DOI: https://doi.org/10.15420/ver.2020.03 Correspondence: Ronald L Dalman, Stanford University School of Medicine, 300 Pasteur Drive, Alway Building Suite M-121, Stanford, CA 94305-5642, US. E: rld@stanford.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 noncommercial purposes, provided the original work is cited correctly.

History and Challenges of Abdominal Aortic Aneurysm Suppression Research Abdominal aortic aneurysm (AAA) is a common and lethal disease in the US, affecting more than 1 million men and women over 50 years old.1 The natural history, if left untreated, is one of progressive aneurysm enlargement, rupture and sudden death (Figure 1). Current management guidelines call for surgical repair of aneurysms ≥5.5 cm in diameter in men or ≥5.0 cm in women, based on evidence that population screening reduces AAA-related mortality by >40%.2 In the US, at-risk Medicare beneficiaries ≥65 years old undergo ultrasound screening for AAA disease. More than 90% of AAAs identified at screening, or as an incidental finding on cross-sectional abdominal imaging studies ordered for other reasons, are below the size thresholds recommended for surgical repair.1 Thus, most affected individuals are entered into surveillance programmes at the time of diagnosis to monitor disease progression, with 70% or more ultimately requiring surgery at a later time point.2

AAA Disease Progression can be Closely Monitored When excluding aortic conditions such as Marfan or Ehlers–Danlos syndromes, or mycotic or traumatic aortic aneurysms, the remainder of infrarenal aortic aneurysms are considered ‘atherosclerotic’, in that they share many of the same risk factors as the broader category of

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cardiovascular diseases (CVD). These atherosclerotic aneurysms are typically asymptomatic until the time of impending rupture, and typically enlarge at a predictable rate of 2–3 mm/year, depending on baseline diameter and associated risk factors.3 Importantly, current smoking increases the rate of enlargement by 35% compared with nonsmokers. Although the ultimate goal of AAA suppression is to prevent rupture and sudden death, larger aneurysms are surgically repaired and thus censored from further follow-up. Given that the aortic diameter/rupture risk relationship is reasonably well-established, maximum diameter is the primary clinical marker used to monitor disease progression.4

AAA Pathobiology is Coming into Focus Key pathological features associated with aneurysm enlargement include progressive medial elastin and smooth muscle cell depletion, mural leucocyte accumulation and angiogenesis, and laminar accumulation of luminal thrombus. Infiltrative mural leucocytes, including monocytes/ macrophages, neutrophils, mast cells, B-cells, and CD4 and CD8 T-cells promote aneurysmal aortic degeneration via production of extracellular matrix-degrading metalloproteinases and other proteases, proinflammatory cytokines and lipid mediators, angiogenic factors, and reactive oxygen species (ROS).5–14 We and others have demonstrated that interventions effective in limiting aortic macrophage accumulation, including hyperglycaemia and exercise-induced aortic hyperaemia, as

Metformin AAA Suppression Trial well as apelin, rapamycin, angiotensin II type 1 receptor blockers, inhibition of CXCL4-CCL5 dimerisation and hypoxia inducible factor inhibition, are particularly effective in suppressing experimental aneurysm progression, underscoring the significance of aortic mural inflammation in aneurysm pathobiology.15–22

Figure 1: Ruptured Abdominal Aortic Aneurysm

Limited Translation of Research Advances Into Effective Clinical Therapies Despite apparent progress in understanding the mechanisms fundamental to AAA pathobiology, as outlined above, and the fact that most AAAs are identified when they are small, allowing for years of surveillance and potential pharmacological intervention, no class of medication, including statins, angiotensin-converting enzyme inhibitors (ACEIs) or receptor blockers, beta-blockers, anti-proteolytic, antiinflammatory, anti-angiogenic, or immune modulating agents, has proven effective in limiting clinical AAA enlargement.4,23 The absence of an effective inhibitory strategy for early AAA disease greatly increases the likelihood that patients will ultimately need surgery, regardless of their overall health, advanced age, or comorbid conditions, with substantial attendant mortality and morbidity.4 Knowing that an AAA is present, but still below the threshold required for surgical repair, leads to significant decrements in the quality of life of ‘worried well’ patients at risk for disease progression and rupture.24,25

Need for Identification of Safe and Effective Alternatives to Surgical Repair Significant societal benefits will accrue from identifying an inexpensive, relatively non-toxic and easy to administer pharmacological agent effective in suppressing early AAA disease. More than 20 years ago, the National Heart, Lung and Blood Institute identified medical management of AAA disease as a significant unmet medical need, with substantial financial and intellectual support for this critical research area continuing since that time.26 The Society for Vascular Surgery, ranking the top 50 research priorities to improve health for patients with vascular disease, placed identification of a safe and effective medical agent to limit progression of AAA disease near the top of a list that included interventions to limit amputations, prevent strokes and improve the quality of life for patients requiring haemodialysis, among others.27 Despite progress in understanding aneurysm biology, and some reduction in AAA-related mortality in the past decade,28 AAA remains a leading cause of death in adult Americans and is still without effective therapeutic options short of major surgery. Many pharmacological strategies have been trialled, albeit none successfully to date (Table 1).23,29–31 Even in retrospective analyses, no agent otherwise known to be effective in the prevention of cardiovascular (CV)-related endpoints has been linked to reduced prevalence or progression of AAA disease.32 In the absence of effective medical therapies, care today often defaults to an excessive reliance on surgical intervention for small AAAs, a practice not supported by evidence.33 These interventions cost an estimated >US$1m for every AAA-related death prevented by surgical intervention.34 Two level I trials have clearly demonstrated that surgery for AAA <5.5 cm in diameter, even when performed percutaneously with endoluminal grafts, is not justified based on safety or cost considerations (Figure 2).35 However, no other effective treatment options have been identified, other than cessation of cigarette smoking for those who are still smoking. Thus, there is a compelling societal benefit associated with identifying a safe and effective medical inhibition therapy for AAA disease.

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Ruptured abdominal aortic aneurysm (centre) with extraluminal contrast extravasation into the right retroperitoneum.

Challenges Inherent in AAA Suppression Clinical Trials Multiple logistical and scientific hurdles challenge the organisation and conduct of medical trials for AAA suppression. Some are common to clinical research in general, such as ensuring adequate recruitment, retention and patient adherence. Other challenges, unique to AAA trials, are outlined in Table 2.23 Notably, these include slow AAA growth, especially in the smaller, more common AAA that can obscure intervention efficacy, as well as loss to follow-up due to surgical repair (for larger aneurysms) and controversies regarding optimal endpoint assessment. Perhaps the biggest challenge is uncertainty regarding the fundamental mechanisms of AAA disease initiation and progression. Most prior failed candidate mechanisms, including those outlined in Table 1, were imputed from the status of surgical specimens harvested at the time of operative repair: tissues typically atretic, relatively acellular, and of uncertain relevance to the initiating or sustaining conditions present earlier in the course of the disease, when drug therapy may be more effective. Additionally, problems with AAA experimental model systems limit their ability to provide independent, aetiological insight into the human condition. In humans, AAAs grow at a slow rate, approximately 2–3 mm per year, whereas induced model aneurysms dilate to rupture within days or weeks, implying that mechanisms of chronic aneurysm remodelling, for example, may not be well represented in experimental systems.36

Rationale for Trialling Metformin for AAA Disease Suppression Existing Evidence: Bedside to Bench Following decades of futility in translating aneurysm research into effective medical therapies, strategies are shifting to approaches identified through population science, rather than through animal modelling or pathological analysis of late-stage human tissue, to limit AAA disease progression. Unlike its influence on other peripheral CVD equivalents such as peripheral arterial or cerebrovascular disease, diabetes appears to reduce the burden of AAA disease, an observation that has intrigued investigators for more than 20 years.3 As first recognised in the US Department of Veterans Affairs Aneurysm Detection and Management (ADAM) trial, the concurrent diagnosis of

Aortic Table 1: Candidate Abdominal Aortic Aneurysm Suppression Agents and Targets that Failed in Published Clinical Trials Agent

Pathologic targets

Sample size

Follow-up (months)

Primary output/AAA growth rate (versus control)

Propranolol77

Hypertension, matrix remodelling

548

Unclear

2.2 mm versus 2.6 mm/year (NS) 42% patient dropouts due to adverse effects

Doxycycline78

MMPs and inflammation

286

4.1 mm versus 3.3 mm/1.5 year (NS)

Mast cell inhibitor

326

2.58 mm (10 mg), 2.34 mm (25 mg), 2.71 mm (40 mg) versus 2.04 mm/year (NS at any dose)

Perindopril80

Hypertension, inflammation, and matrix remodelling

152

1.77 mm versus 1.68 mm/year (NS)

Amlodipine80

Hypertension

151

1.81 mm versus 1.68 mm/year (NS)

Pemirolast

Ultrasound imaging was used for diameter measurements in all trials listed. AAA = abdominal aortic aneurysm; MMP = metalloproteinase; NS = not significant. Source: Golledge et al. 2017.23 Adapted with permission from Elsevier.

Figure 2: Endovascular Repair of a <5 cm Abdominal Aortic Aneurysm Before

After

progression under normoglycaemic conditions in mice, underscoring the translational potential for metformin therapy even in the absence of diabetes. That study was the first to recognise and report the inhibitory potential of metformin on AAA progression in both diabetic (human) and non-diabetic (experimental modelling) conditions.44 In a subsequent report, Taiwanese investigators confirmed a negative association between metformin prescriptions for diabetes management and the diagnosis of AAA in their national health system. These investigators reported that the observed negative relationship was not a class effect: for example, present for metformin but not all hypoglycaemic drugs.45 Golledge et al. reported a negative association between prescription records for metformin and AAA disease progression in three separate small diabetic AAA cohorts in Australia, with adjusted ORs for a reduced likelihood of median or greater AAA growth of 0.59 (95% CI [0.39–0.87]), 0.38 (95% CI [0.18–0.80]), and 0.13 (95% CI [0.03–0.61]), respectively (all with p<0.02).46

Example of endovascular repair of a <5 cm abdominal aortic aneurysm. This is a practice not supported by evidence in the absence of symptoms or clinical evolution. White arrow indicates maximum diameter, approximately 3 cm, assuming no significant mural thrombus present.

diabetes not only reduces the risk of developing an AAA, but also reduces the rate of AAA enlargement and risk of AAA-related death when an aneurysm is present.37,38 Available evidence supports the conclusion that this benefit is not simply due to reduced life expectancy due to diabetes-related complications in affected patients.39,40 Mechanisms suggested to explain the protective effect of diabetes in AAA disease include reduced activation of pro-inflammatory macrophages in the extracellular matrix,41 modification of the balance of aortic mural pro- and anti-proteolytic enzymes,15 or advanced glycation end product-mediated limitation of mural proteolysis.42 Hyperglycaemia alone clearly limits AAA progression in experimental models.16 An alternative explanation, however, may lie in the medications used to manage hyperglycaemia in the older, insulinresistant patient population also at risk for AAA disease.43 We examined the relationship of known aneurysm risk factors, comorbid conditions and diabetic and cardiovascular medications to the rate of aneurysm enlargement in AAA patients with diabetes identified from a clinical database of nearly 9 million patient visits to Stanford Health Care over a 10-year period.44 When entered into a logistic regression, after adjusting for known AAA risk factors, we found metformin therapy to be the variable most significantly associated with reduced aneurysm enlargement. In subsequent experimental modelling, we also found metformin to be effective in limiting AAA

Every retrospective study examining this question has reached the same conclusion: AAAs enlarge less rapidly in diabetic patients taking metformin versus those taking other hypoglycaemic agents (or those treated by dietary management alone), and diabetic patients taking metformin appear to be less likely to have concurrent AAA disease, accounting for all other relevant variables. Of the series reported to date, the negative association of metformin and AAA progression varies only in the size of the effect, ranging from 20 to 76% growth rate reduction compared with AAAs in diabetic patients not taking metformin, with the smallest effect size associated with the largest cohort (>10 000 patients).47 Importantly, this hypothesised inhibitory effect is significant even within a cohort of patients whose overall rate of AAA enlargement is significantly lower than that in patients without diabetes, with both clinical and experimental evidence suggesting that other features of diabetes, including hyperglycaemia,16 may also limit aneurysm enlargement. For the first time in the history of aneurysm research, population science has identified a candidate therapeutic agent of great promise. This bedside to bench approach represents an innovative and promising new strategy for limiting AAA disease progression.

Novel Agent for Cardiovascular Disease Management As noted above, comorbidities and concurrent medications present significant barriers to the conduct of meaningful AAA research. We recently participated in a multinational, multi-site trial of the angiotensin II receptor blocker (ARB), Study of the Effectiveness of Telmisartan in Slowing the Progression of Abdominal Aortic Aneurysms (TEDY;

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Metformin AAA Suppression Trial Table 2: Logistical Challenges for Abdominal Aortic Aneurysm Suppression Trials Problem

Implication

Slow AAA growth

Smaller AAA, although more common, tend to grow more Use CT to optimise precision/reproducibility. Recruit patients with slowly, obscuring intervention efficacy, particularly when changes are larger AAAs and increase follow-up duration if possible. Caveat: within the measurement error enrolling patients with larger AAA increases risk for adverse events

Solution

Loss of follow-up

Significant dropouts, particularly for studies with larger Balance smaller and larger AAAs within recruitment cohort. Smaller AAAs and longer follow-up. Participants with larger AAAs undergoing AAAs are less likely to be censored due to surgery but grow at a slower surgical repair are censored rate: e.g. require a larger sample size to confirm effectiveness

Variable AAA growth

Maximise retention and follow-up duration to avoid imputing growth Intermittent AAA growth (e.g. periods of active growth and data. quiescence) typically complicates growth predictions. Further complexity is introduced by variability in modifiable risk factors (e.g. smoking intensity) or concurrent medication regimens for other conditions

Frequent comorbidities

Patients may be excluded from participation in trials due to common comorbidities, such as organ dysfunction, conflicting concurrent medication regimens, or poor overall prognosis

Carefully select candidate interventions while taking into account both comorbidities and ultimate treatment feasibility

Endpoint (diameter) measurement variability

Variability in diameter measurement is due to sampling different locations, planes (coronal or sagittal), orientations (orthogonal and axial), or variable cursor placement (e.g. “outer wall to outer wall, leading edge to leading edge or inner wall to inner wall)

Use standardised, clinically relevant, and reproducible measurement methods providing maximal resolution

AAA = abdominal aortic aneurysm. Source: Golledge et al. 2017.23 Adapted with permission from Elsevier.

NCT01683084). The data supporting the use of telmisartan versus other ARBs in this application is compelling and previously summarised.20 The trial design itself was relatively straightforward, with well-defined endpoints and conservative sample size estimates.48 Yet TEDY struggled to reach sufficient power, largely because most eligible AAA patients were already on a regimen that included an ACEI or ARB, and to delete those medications from their overall regimen to facilitate trial enrolment would have been inappropriate and unethical. Similar problems have been encountered with alternative candidate agents such as statins and anti-platelet agents in prior AAA clinical trials.23 Essentially every drug used for CVD risk reduction is commonly prescribed in the setting of AAA disease, given that the latter is presumed to be a CVD equivalent, to reduce risk of all-cause mortality,42 making none of these drugs practical or realistic candidates for AAA suppression trials specifically.

intracellular concentrations of adenosine monophosphate, which in turn acts to lower blood glucose, enhance insulin sensitivity and favourably modify serum lipid profiles. In addition to indirect effects on vascular disease management (e.g. promoting weight loss and improved serum lipid profiles and endothelial function), metformin may limit the progression of AAA disease by inducing favourable effects on ROS production by infiltrative mural macrophages in atherosclerotic or aneurysmal vascular diseases, reduction of pro-inflammatory nuclear factor kappa activity, inhibition of the mammalian target of rapamycin pathway and autophagy, inhibition of mural angiogenesis (a key pathological feature of AAA disease), potential anti-inflammatory changes to the gastrointestinal microbiome, and upregulation of the silent information regulator 2 (SIRT) family of proteins or sirtulins, as partially demonstrated in Figure 3.19,22,53–60

There is intense interest in the ability of metformin to improve outcomes in cancer, cognitive disorders and cutaneous wound healing,as well as cardiovascular diseases.49–52 Indeed, people with type 2 diabetes (T2D) on metformin appear to have improved life expectancy compared with those managed with insulin or other insulin sensitiser agents.52

Metformin therapy clearly reduces the burden of CVD, as measured by major adverse cardiovascular events (MACE) in people with diabetes.61 To date, however, no level I evidence has been generated regarding CVD endpoints, including AAAs, in non-diabetic patients. Given that nearly 50% of the American population over the age of 65 is in the prediabetes stage (and is also most at risk for sudden death due to AAA disease), the latter cohort remains of great interest in any proposed trial of metformin in AAA disease suppression. Although MACE as an endpoint captures potential death from AAA rupture, VA CSP 2002 does not assess for the presence or progression of AAA disease in trial participants, and will not lend insight into the potential influence of metformin on aneurysm pathobiology or progression of early disease (small aneurysm enlargement).

These data, as well as the large burden of obesity, metabolic syndrome, and cardiovascular disease in the US veteran population, recently led the Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) to initiate a multicentre study to determine whether metformin therapy reduces the risk of major cardiovascular events (MACEs) in pre-diabetic patients (as determined by an HbA1c level from 5.7 to 6.5% in the absence of diabetes treatment) with established CVD (VA CSP 2002, NCT 02915198; Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular OuTcomes; VA-IMPACT). As of September 2019, this trial has enrolled more than 300 participants, with excellent adherence and drug tolerance reported to date. Despite widespread use, the precise mechanisms of action of metformin remain incompletely understood. In T2D, metformin, a weak inhibitor of the mitochondrial electron transport chain, increases

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The influence of metformin on cancer is somewhat more controversial, with meta-analyses citing both salutary and indeterminate effects, leading to the initiation of multiple clinical trials of metformin in antioncologic applications, in patients with and without diabetes.62,63 Ample experience in cancer-related applications provides assurance that metformin therapy is well-tolerated and does not promote hypoglycaemia in non-diabetic or pre-diabetic patients except under unusual and well-recognised circumstances.64,65

Aortic Figure 3: Potential Anti-abdominal Aortic Aneurysm Effects Attributable to Metformin Mechanisms of Action Indirect effects

Direct effects

Metformin

Insulin

Metformin

p53

IGF-1 and insulin receptors IRS-1 Body weight

ROS

PI3K

Inflammation

Insulin resistance Glucose levels Insulin levels

Other upstream kinases

AKT

LKB1

TSC2–TSC1

CaMKK2

Ragulator

RA GTPases

RHEB

mTORC1

AMPK

HIF-1-alpha

P Fatty acid synthesis

cMYC

DICER

ATM

p53

NF-κB

IL-6

Protein synthesis Cell growth Cell viability

Source: Pernicova and Korbonits 2014. Adapted with permission from Springer Nature. 60

In summary, given that no non-diabetic AAA patient is currently prescribed metformin outside the auspices of a clinical trial, this proposed trial design offers a highly innovative solution to enrolment hurdles that have hindered previous trials of broad classes of CVD risk reduction medications for AAA disease suppression.

Proposed Trial Design Considerations Distinguishing Impact of Metformin Versus Diabetes Alone in AAA Suppression The original metformin AAA inhibition hypothesis was leveraged on retrospective case–control studies encompassing a few hundred patients, as described above. To gain more substantial perspective, we queried the Department of Veterans Affairs VA Informatics and Computing Infrastructure to identify all diabetic veterans with AAA disease treated nationwide between 2003 and 2013. Records were included in the study cohort if the diagnosis of diabetes was made prior to or within 6 months after the diagnosis of AAA disease; and patients had received at least two abdominal imaging procedures documenting infrarenal aortic diameter (ultrasound, CT, and/or MRI) in a ≥1-year interval between the first and last imaging procedure. Patients were censored from further analysis after undergoing surgical AAA repair. Aortic diameter measurements were obtained from radiographic reports. The prescribed outpatient medical regimen at the time of AAA diagnosis (± 6 months) was obtained from pharmacy records. Patient comorbidities, smoking status, and other medication records were included from other VA online resources. Mixed effect modelling was used to fit the aneurysm growth rate (mm/year) to account for the inconsistent interval of radiographic dates and number of scans between individual patients. Using these methods, 13,834 diabetic AAA patients with 58,833 radiographic records were identified, with mean radiology imaging

follow-up of 4.2 ± 2.6 years (Figure 4). The average patient age at diagnosis was 70 ± 8 years. Forty per cent had metformin prescriptions at or around the time of AAA diagnosis. In the study cohort overall, the average annual AAA rate of enlargement was 1.3 ± 1.6 mm/year, which was approximately 50% of the annual growth rate for AAAs identified on population screening in the UK Small Aneurysm Trial (UK SAT) cohort, of whom <5% had diabetes.66 The unadjusted mean rate of AAA growth was 1.2 ± 1.9 mm/year for patients with a metformin prescription compared with 1.5 ± 2.2 mm/year for the remainder (p<0.001); prescription for metformin was associated with a 20% decrease in yearly growth rate. When adjusted for comorbidities, this effect remained significant: a 0.20 mm/year reduction with metformin (95% CI [0.26–0.14], p<0.001; Figure 5). A secondary analysis of 7,462 patients with initial AAA size 35–49 mm (the size range appropriate for a clinical trial testing medical therapy) showed a similar decrease in AAA growth from 1.7 ± 2.2 to 1.4 ± 2.0 mm/year.47 Factors associated with an increased AAA growth rate were baseline AAA size, metastatic solid tumours, current smoking, chronic obstructive pulmonary disease, and renal disease. Factors associated with decreased growth rates included prescription for ARBs or sulfonylureas and the presence of diabetes-related complications (Table 3). These findings validate and extend those previously published by us as well as by others, all using different methods to address essentially the same question. The association between diabetic complications and reduced AAA progression further supports the related hypothesis that increased chronic hyperglycaemia (reflected by diabetic complications) independently inhibits AAA progression, regardless of medical treatment provided, while refuting an alternative metformin explanation, for example that the association between metformin prescription and

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Metformin AAA Suppression Trial Figure 4: Veterans Affairs Veterans Informatics and Computing Infrastructure Abdominal Aortic Aneurysm Cohort VINCI Database: 2003–2013

General population

2.3

Diabetes w/o metformin

Diagnosis of AAA (ICD-9 441.4) n=274,903

Excluded No diabetes (ICD-9 250.x) n=174,049 Diabetes diagnosis >6 months after AAA diagnosis n=21,639

Diagnosis of diabetes prior to or up to 6 months after AAA diagnosis n=79,215 Patients with <2 radiographic studies n=54,426 ≥2 abdominal radiographic studies n=24,789/109,542 radiographic studies

Figure 5: Mean Abdominal Aortic Aneurysm Growth Rate for Respective Cohorts

22,812 studies: exact AAA diameter missing 11,073 studies: after AAA intervention 3,028 studies: AAA diameter <29 mm 13,796 studies: first and last scan <1 year apart

13,834 patients/58,833 radiographic studies Main cohort 7,462 patients 33,418 radiographic studies

Patients with initial AAA <35 mm n=5,411 Patients with initial AAA >50 mm n=961

Secondary cohort AAA = abdominal aortic aneurysm. Source: Itoga et al. 2019.47 Adapted with permission from Elsevier.

aneurysm suppression simply reflects the influence of more advanced diabetes. In practice, progressive insulin resistance and increased endorgan complications in T2D are managed with supplemental insulin rather than metformin in most cases, and no study to date has associated exogenous insulin therapy with AAA suppression. Recent observations also suggest that some AAA clinical benefits attributed to diabetes, metformin or both, such as reduced risk for surgical repair and rupture-related mortality, may be primarily attributable to metformin itself rather than to the underlying diabetic condition.67

Existing and Proposed Metformin Trials for AAA Suppression In 2018, a pilot prospective, randomised, double-blind clinical trial testing the safety and efficacy of metformin to suppress early AAA disease in non-diabetic patients was initiated in Austria (Metformin Therapy in Non-diabetic AAA Patients [MetAAA], NCT03507413). Participants in this trial receive 12 months of drug therapy, with CT aortography (CTA)-determined rate of AAA diameter change between participants taking metformin and placebo as the primary study endpoint. Participants are prescribed metformin XR in 500 mg increments, up to 2000 mg/day, in a dose-escalating scheme to maximise tolerance and retention. The MetAAA trial started in September 2018, and the estimated primary completion date is January 2022. In addition to clinical endpoints, MetAAA is comparing inflammatory cytokine profiles and markers of neutrophil activation in plasma between participants prescribed metformin and placebo. The proposed sample size is 170 participants (85 in each group) to achieve a power of 0.85. Early results suggest that

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Diabetes with metformin

1.5

1.2

Mean AAA growth rate (mm/year) for the respective cohorts.47 The question mark shows the potential maximum metformin effect on AAA progression when trialled in a non-diabetic cohort as proposed. General population is the UK Small Aneurysm Trial cohort.66

metformin appears to be well-tolerated in this small group of older, non-diabetic AAA patients at short-term follow-up (verbal report from the principal investigator). These investigators hope to use encouraging preliminary data from this pilot study, if and when available, to justify a much larger, pan-European consortium trial to more rigorously test the metformin hypotheses. As of September 2019, one additional metformin trial for AAA suppression has initiated enrolment in Europe (Metformin for Abdominal Aortic Aneurysm Growth Inhibition [MAAAGI], NCT04224051), along with an international trial being organised from Australia (verbal reports from the respective trialists). It remains to be seen whether any of these trials, proposed or running, will be able to effectively test the metformin hypothesis in an ethnically and racially diverse population burdened with high levels of obesity and sedentary lifestyles, characteristic of the middle-aged American population today. Despite the somewhat cynical assessment that interest in metformin across such a wide spectrum of applications equates it to the “aspirin of the 21st century”, there is a clear and compelling opportunity now to validate metformin as the first pharmaceutical agent to effectively suppress progression of aortic aneurysm disease by proceeding with a well-designed clinical trial in the US.68,69 In preliminary modelling, we estimate that a 30% reduction in mean rate of enlargement for small AAAs (≥3.5 cm) with relatively inexpensive pharmacotherapy would reduce surgical utilisation and surgical costs by >US$23,000 per AAA patient over a 5-year period, as well as reduce AAA-related deaths in all patients by 40/1,000, or 4%. Based on the accumulated clinical evidence outlined above, clinical trials are justified at this time to confirm or refute the ability of metformin to prevent disease progression in nondiabetic AAA patients.

Experimental Approach Two essential questions need to be answered to evaluate metformin’s suitability for this clinical application: is metformin therapy safe for, and well tolerated by, non-diabetic patients with AAA disease; and does metformin therapy suppress progression of small to intermediate-size AAAs in non-diabetic patients? The following proposed specific aims address these questions.

Specific Aim 1: Assess the Safety and Tolerance of Daily Metformin XR Therapy in Non-diabetic AAA Patients Although metformin is currently being trialled extensively for antioncologic applications in non-diabetic patients, limited level I safety and tolerance data have been generated for non-diabetic patients with cardiovascular disease generally, let alone those with AAA (see the

Aortic Table 3: Abdominal Aortic Aneurysm Enlargement Based on Baseline Characteristics Characteristic

Adjusted difference (mm/year)

95% CI

P-value

Baseline AAA diameter/10 mm

0.51

0.47–0.55

<0.001

Metastatic solid tumour

0.36

0.07–0.65

0.02

Current smoker

0.26

0.16–0.36

<0.001

Renal disease

0.10

0.01–0.019

0.021

COPD

0.11

0.04–0.17

0.001

Metformin

–0.20

−0.26 to −0.14

<0.001

ARB

–0.15

−0.25 to −0.06

0.001

Diabetes with complications

–0.12

−0.20 to −0.05

0.001

Sulfonylureas

–0.10

−0.15 to −0.04

0.002

AAA = abdominal aortic aneurysm; ARB = angiotensin receptor blocker; COPD = chronic obstructive pulmonary disease. Source: Itoga et al. 2019. Adapted with permission from Elsevier. 47

Existing and Proposed Metformin Trials section above). The most commonly reported side-effects in non-diabetic patients taking metformin are gastrointestinal in nature, infrequent and self-limited. Hypoglycaemia is rarely experienced by healthy non-diabetic individuals taking up to 2,000 mg/day metformin, and occurs most commonly in debilitated and malnourished individuals, especially in the elderly, or in those with adrenal, pituitary or hepatic insufficiency. Metabolic acidosis is the most serious adverse effect associated with metformin use, and although infrequent, occurs mostly in patients with chronic renal insufficiency. Thus, patients with an estimated glomerular filtration rate (eGFR) <45 ml/min/1.73 m2 should be excluded from trial participation at the outset, and individuals whose eGFR falls below 30 ml/min/1.73 m2 should cease study drug ingestion. A comprehensive review of known health risks related to chronic metformin ingestion, important to any such trial design, is beyond the scope of this article. The proposed trial (LIMIting AAA Progression with MeTformin; LIMIT) will recruit 480 participants, randomised 1:1 to metformin XR or placebo. For participants randomly assigned to metformin XR, daily dosage will begin at 500 mg/day and be titrated up in 500 mg increments/week to 2,000 mg/day over the first 4 weeks of the study (take one pill daily the first week, two daily the second week, etc.). Metformin tolerance will be assessed via quality of life surveys, laboratory monitoring, and analysis of participant adherence and retention metrics.

Specific Aim 2: Test the Ability of Metformin XR to Reduce the Rate of Enlargement of Existing Small to Intermediate AAAs by ≥30%, Compared with Placebo This will be a prospective, randomised, placebo-controlled, doubleblinded, stratified, Phase II superiority trial testing the ability of metformin to suppress progression of early AAA disease. In total, 480 non-diabetic participants with AAAs between 35 and 49 mm in diameter will be randomised 1:1 to metformin or placebo. A ≥30% reduction in the rate of annual AAA enlargement was chosen as a clinically significant translational target based on the review by Wang et al.70 Sample size calculations are conservatively based on a two-sample t-test at a two-sided 5% significance level. Two hundred evaluable participants in each arm are required in order to have an 85% power to reject the null hypothesis of no difference when there is a 0.69 mean difference between two arms. Table 4 demonstrates sample sizes for a range of reductions and power levels.

Table 4: Number of Participants per Arm for 80–90% Power and 25–35% Reduction in Abdominal Aortic Aneurysm Size Growth Rate SD (mm/year) Reduction (%)

µC−µT|H1

Power 80%

85%

90%

0.58

248

283

331

2.3

0.69

175

200

234

2.3

0.81

128

146

170

To allow for a 20% dropout from the trial, we anticipate recruiting 240 participants per arm for a total of 480 participants enrolled. The projected dropout rate is conservative and based partly on the results of the Non-invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT; NCT01756833), which required eight study visits over 24 months of study participation (versus five proposed for this trial), to determine if doxycycline will inhibit the increase of AAAs over a 24-month observation period.71 Dropout in the placebo arm of N-TA3CT was 19.5% (personal communication, Michael Terrin, N-TA3CT Co-PI, 27 February 2019). Notably, N-TA3CT was a multicentre trial, incorporating additional challenges in participant, staff, and centre retention and protocol adherence. At 480 participants, the current LIMIT trial design constitutes one of the most ambitious and comprehensive AAA growth inhibition trial proposed or conducted to date. Potential participants will be recruited from Stanford Health Care (SHC), the Veterans Affairs Palo Alto Health Care System (VAPAHCS), and the Kaiser Permanente Northern California Health Care System (KP) in the greater San Francisco Bay Area of northern California. From 2006 to 2012, our research group conducted a single site trial of supervised exercise training for AAA patients at Stanford (Abdominal Aortic Aneurysm – Simple Treatment or Prevention; AAA-STOP).72 In AAA-STOP, more than 1,000 eligible patients with AAAs similar to those required for this trial were identified and screened from existing patient lists from the same health systems (SHC, VAPAHCS and KP).73 Given the substantially reduced requirements for participation in the proposed trial compared with three times per week supervised exercise training at a single location in the San Francisco Bay Area, as was required in AAASTOP, we conservatively estimate that we can recruit 480 participants from the thousands of eligible patients in these combined registries. Identifying eligible trial candidates from registries of existing patients is by far the most efficient method of recruiting potential participants

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Metformin AAA Suppression Trial for AAA-related clinical trials. In our prior experience, given the dearth of available treatment options for patients with early AAA disease, affected and eligible individuals are particularly eager to help identify effective alternatives to eventual surgical repair. In the unlikely event that registry-based recruitment does not suffice to meet trial enrolment goals, region-wide institutional review board-approved advertising will also be instituted to attract trial participants, trial participation will be promoted at local medical meetings, public interest events and health fairs, and commercial organisations such as LifeLine Screening will be contacted to identify additional candidates within the region. The sex distribution of AAA disease is approximately 4:1 M:F. Enrolling subjects from all three systems will maximise our likelihood of obtaining a representative sample of sex distribution in our cohort (given that the VAPAHCS is predominately male). Given that the risk for AAA disease is age-related, and younger patients are likely to have syndromic aortic conditions that represent exclusions for study participation, eligibility is limited to individuals 55–90 years old. The upper age limit reflects the fact that participants need 2 years of follow-up to complete the trial. Given that AAA disease affects mature individuals of all races and ethnicities, we will intentionally recruit a broadly representative trial cohort to maximise translational value of the derived results. Fortunately, the San Francisco Bay Area, home to more than 9 million individuals, is one of the most ethnically and racially diverse regions of the continental US. One-third of adults living in California were born outside the US. Again, our experience with AAA-STOP demonstrates that due to the substantial connection between cigarette smoking and AAA disease (much stronger association than AAA disease and ethnic/ racial identity), we will be able to recruit from a broad and representative patient population, less skewed toward specific ethnic/racial identities than other areas of the US.74 According to ClinicalTrials.gov, no competing trials are enrolling patients with AAA of similar size in northern California at this time. The primary study endpoint will be the relative rate of increase in maximum orthogonal AAA diameter through 24 months, as determined on CTA, in treatment versus control participants. All comparisons will be performed against placebo treatment, with stratification by sex, baseline diameter, smoking status (active or not), and HbA1c status (<5.7% versus ≥5.7% to 6.5%). ANOVA will be used to test the treatment effect controlling for stratification variables. Rate of AAA enlargement will be evaluated on CT angiographic measurement of maximum aortic diameter at baseline and at 24 months, and reported as a per-year rate (mm/year). Ultrasound measurement at 6-month intervals may be added as a secondary endpoint, both to add fidelity to the rate of growth and to capture some data from those who do not complete the 24-month scan. All measurements will be obtained by a core lab at Stanford with specific expertise in aortic aneurysm endpoint determination. Both manual and automatic measurement methods will be used, with examiners blinded to study group assignment. Treatment consists of the highest tolerated dose of metformin XR (500– 2,000 mg/day) for 24 months. Metformin will be paid for from the study budget. This trial is designed and powered to confirm the suppressive efficacy of metformin in a non-diabetic AAA patient cohort, if indeed it exists, as a Phase II trial. Broader generalisability of the derived results, if proven effective, should be provided by a subsequent Phase III trial adequately powered to assess optimal dosing regimens.

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Maximum transverse aortic diameter (orthogonal when obtained from transverse abdominal CT) is the primary clinical standard to measure AAA disease progression, determine need for intervention, and correlate with clinical outcomes. Using this as the primary endpoint will insure the maximum translational relevance of the outcome. Reliance on outcome determination via serial CTA will also enable inclusion of exploratory endpoints including AAA volume, which although of uncertain clinical relevance in determining need for surgical intervention, may provide increased sensitivity in identifying an effect on aneurysm progression as noted in the Existing and Proposed Metformin Trials for AAA Suppression section. Also, highresolution cross-sectional CTA will allow for quantification of periaortic adipose tissue volume present in the retroperitoneum at baseline and following 24 months on study drug between active treatment and control participants. Recent observations suggest that increased circumferential peri-aortic adipose volume, as determined on CT, distinguishes AAA patients from those with aorto-occlusive disease or normal age-matched control aortic diameters,75 and genome-wide expression profiling of this adipose tissue, when harvested at surgery and compared between areas of maximal aortic enlargement and uninvolved proximal aorta, identifies an immunological signal consistent with underlying autoimmunity as a prominent influence in AAA pathogenesis.76 Given the known influence of metformin on weight loss and metabolic balance, an additional exploratory endpoint will include differential volume of peri-aortic adipose tissue in treatment versus control patients via CTA over the course of 24 months of study participation.

Rigor and Reproducibility As discussed above and in Tables 1 and 2, best-practice solutions to the methodological challenges inherent in AAA suppression trials informed the design, methods and analysis plan of this proposed clinical trial. Probably the most significant reproducibility consideration for this trial is its single-centre design, intentionally adopted to minimise the variability in eligibility assessment, data acquisition, participant follow-up, and study adherence inherent in multicentre constructs. Although recruiting from phenotypically well-characterised AAA cohorts compiled from three distinct regional healthcare systems to maximise enrolment, all trial activities take place at the Stanford Clinical and Translational Research Unit (CTRU) to ensure uniformity of data acquisition and participant engagement. Study eligibility is based on the confirmed presence of an AAA in the diameter range deemed appropriate for trial participation, excluding syndromic or traumatic aneurysms. To maximise the likelihood of progressive AAA enlargement in all participants, only patients with larger AAA (those between 3.5 and 4.9 cm in diameter) will be included. The selection of CTA-determined aortic diameter rate of change as the primary clinical endpoint will minimise imprecision and interpretation error. Comprehensive accounting of, and outcome stratification based on known confounding conditions and comorbidities in AAA disease will maximise accuracy and reproducibility of the determination of a metformin effect. Conservative assumptions and definitions have been applied to the target effect size and determination of significance to maximise rigor and reproducibility. Working within the auspices of the CTRU ensures rigid adherence to protocol and timelines. Real-world and diseasespecific assessment modalities, such as CTA and AAA-specific quality of life surveys, were incorporated wherever possible to maximise

Aortic translational impact of the acquired results. Even the selection of metformin as the candidate inhibitor was made, in addition to potential efficacy considerations, with reproducibility considerations in mind (see the Existing Evidence section above). Also, the broad outline of our study protocol has been shared with collaborative groups worldwide in an effort to allow data aggregation for maximum sample size and power should all currently proposed trials be completed (see the Existing and Proposed Metformin Trials section). In short, all aspects of trial design, methods, data analysis, and results reporting (including adaptation of rate of orthogonal AAA diameter

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enlargement, the primary determinant for risk of AAA rupture, as the primary study endpoint) were adopted with the goal of maximising the rigor and reproducibility of this proposed trial.

Conclusion After decades of research and hundreds of thousands of premature deaths from untreated or undertreated AAA disease or complications from surgical repair, this proposed trial provides the opportunity to validate metformin as the first inexpensive, non-toxic, and effective pharmacological agent to reduce the burden of AAA disease worldwide.

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https://doi.org/10.1016/j.cct.2016.03.008; PMID: 27018941. 72. Myers JN, White JJ, Narasimhan B, Dalman RL. Effects of exercise training in patients with abdominal aortic aneurysm: preliminary results from a randomized trial. J Cardiopulm Rehabil Prev 2010;30:374–83. https://doi.org/10.1097/ HCR.0b013e3181ebf2db; PMID: 20724934. 73. Myers J, McElrath M, Jaffe A, et al. A randomized trial of exercise training in abdominal aortic aneurysm disease. Med Sci Sports Exerc 2014;46:2–9. https://doi.org/10.1249/ MSS.0b013e3182a088b8; PMID: 23793234. 74. Kent KC, Zwolak RM, Egorova NN, et al. Analysis of risk factors for abdominal aortic aneurysm in a cohort of more than 3 million individuals. J Vasc Surg 2010;52:539–48 PMID: 20630687. https://doi.org/10.1016/j.jvs.2010.05.090; PMID: 20630687. 75. Dias-Neto M, Meekel JP, van Schaik TG, et al. High density of periaortic adipose tissue in abdominal aortic aneurysm. Eur J Vasc Endovasc Surg 2018;56:663–71. https://doi.org/10.1016/j. ejvs.2018.07.008; PMID: 30115505. 76. Piacentini L, Werba JP, Bono E, et al. Genome-wide expression profiling unveils autoimmune response signatures in the perivascular adipose tissue of abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol 2019;39:237–49. https://doi. org/10.1161/ATVBAHA.118.311803; PMID: 30567485. 77. Lindholt JS, Henneberg EW, Juul S, et al. Impaired results of a randomised double blinded clinical trial of propranolol versus placebo on the expansion rate of small abdominal aortic aneurysms. Int Angiol 1999;18:52–7. PMID: 10392481. 78. Meijer CA, Stijnen T, Wasser MN, et al. Doxycycline for stabilization of abdominal aortic aneurysms: a randomized trial. Ann Intern Med 2013;159:815–23. https://doi.org/10.7326/00034819-159-12-201312170-00007; PMID: 24490266. 79. Sillesen H, Eldrup N, Hultgren R, et al. Randomized clinical trial of mast cell inhibition in patients with a medium-sized abdominal aortic aneurysm. Br J Surg 2015;102:894–901. https://doi.org/10.1002/bjs.9824; PMID: 25963302. 80. Bicknell CD, Kiru G, Falaschetti E, et al. An evaluation of the effect of an angiotensin-converting enzyme inhibitor on the growth rate of small abdominal aortic aneurysms: a randomized placebo-controlled trial (AARDVARK). Eur Heart J 2016;37:3213– 21. https://doi.org/10.1093/eurheartj/ehw257; PMID: 27371719.

Peripheral Artery Disease

Anticoagulation in Peripheral Artery Disease: Are We There Yet? Alessandro Cannavale,1 Mariangela Santoni,1 Giuseppe Cannavale1 and Fabrizio Fanelli2 1. Department of Radiological Sciences, Policlinico Umberto I, Rome, Italy; 2. Department of Vascular and Interventional Radiology, Careggi University Hospital, University of Florence, Florence, Italy

Abstract Thromboembolism in patients with peripheral artery disease (PAD) represents a common cause of morbidity and mortality. In this article, the authors analyse the use of anticoagulants for patients with PAD. Anticoagulants have been used to reduce the risk of venous thromboembolism, but have recently been applied to the arterial circulation. Heparins were introduced to reduce short-term major adverse limb events in patients undergoing arterial revascularisation. Low molecular weight heparins have allowed easier management and carry a lower risk of bleeding than unfractioned heparin. Vitamin K anticoagulants have been tested in trials that included patients with PAD, showing an increased risk of bleeding when compared with aspirin alone, but longer patency rates for venous surgical bypass, although the evidence remains weak. Those anticoagulants are currently recommended only in patients with PAD who need anticoagulation for other diseases. Direct oral anticoagulants have only recently been investigated for use in patients with PAD. Promising results from low dose rivaroxaban plus aspirin have been recently outlined by a randomised controlled trial and supported by international guidelines.

Keywords Thrombosis, anticoagulation, peripheral artery disease, atherosclerosis, endovascular Disclosure: The authors have no conflicts of interest to declare. Received: 7 November 2019 Accepted: 31 July 2020 Citation: Vascular & Endovascular Review 2020;3:e09. DOI: https://doi.org/10.15420/ver.2019.10 Correspondence: Alessandro Cannavale, Department of Radiological Sciences, Vascular and Interventional Radiology Unit, Policlinico Umberto I, 166 Viale del Policlinico, Rome 00161, Italy. E: alessandro.cannavale@hotmail.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 noncommercial purposes, provided the original work is cited correctly.

The development of atherosclerotic disease is an evolving process that may present as chronic to subacute or acute.1 Arterial thrombosis – the formation of obstructive thrombus – may be part of the atherosclerotic process and may occur spontaneously due to abnormal balance of haemostasis/thrombosis and the fibrinolytic system or in response to vessel injury, for example during balloon angioplasty.1,2 Balance is maintained by the complex interactions among the coagulation cascade, platelets and the fibrinolytic system. Anticoagulants are effective in inhibiting the activity or synthesis of coagulation factors, hence preventing the formation of a fibrin clot. Anticoagulants have been approved for prevention and treatment of deep venous thrombosis/pulmonary embolism (DVT/PE) or AF since the 1940s and their use for people with peripheral artery disease (PAD) has been tested over the past decade. This review analyses the use of anticoagulants in patients with lower limb artery disease with claudication or critical limb ischaemia. Papers included in the literature search were selected using the keywords anticoagulant/anticoagulation, direct anticoagulant, thrombosis and peripheral artery disease, published from 2000 onwards. Studies investigating anticoagulants versus antiplatelets were included, otherwise studies focusing only on antiplatelets in PAD or anticoagulation which did not report PAD outcomes were excluded from this review.

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Old Anticoagulants Used for Peripheral Arterial Disease Up until the 1990s, two types of anticoagulants – heparins and vitamin K antagonists (VKAs) – were considered standard for antithrombotic therapy. Their limitations, including major bleeding, unpredictable pharmacodynamic responses and immunogenicity, sparked the development of low molecular weight heparin (LMWH) and heparin oligosaccharides, such as fondaparinux. Heparins and the common VKA warfarin both have multiple targets in the coagulation system.3 Heparin takes effect rapidly via IV infusion, while warfarin acts slowly via oral administration. Both drugs have a narrow therapeutic window and large variation in responses among patients. In rare cases they may cause serious complications, such as heparin-induced thrombocytopenia and coumarin-induced necrosis.3 Thus, clinical monitoring and dose adjustment are required during treatment.

Heparins The heparins used for the clinical management of PAD are unfractionated heparin (UFH) and LMWH and they are mainly used in a perioperative context. UFH is associated with immediate initial bioavailability, rapid clearance and is usually administered by continuous IV infusion. The platelet count should be monitored after the prolonged administration (>4 days) of heparin due to the risk of heparin-induced thrombocytopenia.4

Anticoagulation in Peripheral Artery Disease For decades, UFH has been the anticoagulant of choice for longer-term treatments. Due to its pharmacodynamic drawbacks, it has been replaced mainly by LMWH and also by fondaparinux. UFH is currently used with an IV bolus for periprocedural anticoagulation in endovascular and surgical procedures or in cases of acute limb ischaemia at higher doses in continuous infusion. In the latter situation, full anticoagulation should be initiated as soon as possible and continued until thrombolysis is started, as it has been shown that the risk of amputation is related to time to therapy.5 A commonly used intraoperative IV dose is 100–150 units/kg; intraarterial use, which although commonly used in practice, remains offlabel.5 Thompson et al. reported intraoperative UFH can protect against perioperative MI in abdominal aortic aneurysm surgery.6 Otherwise low LMWHs are not widely used intraoperatively because of their long duration of action that cannot be completely reversed with protamine. LMWHs, such as enoxaparin, dalteparin and tinzaparin, may be used either for short- and long-term therapy in patients with PAD undergoing endovascular or surgical interventions and is mainly administered subcutaneously. Therapeutic dosing (often dosed by weight) is maintained at 12-hour intervals, whereas prophylactic dosing is kept at 24-hour intervals. LMWH has a much higher bioavailability than UFH (>90% of the administered dose) and a more predictable dose response. However, the use of LMWH in patients with renal failure or morbid obesity is complicated by less predictable clearance kinetics.3,5 A study investigating the use of LMWH in patients undergoing endovascular interventions found that perioperative enoxaparin administered in low-risk and high-risk patients for reocclusion, is a safe and effective treatment in regard the risk of bleeding and short-term target lesion reocclusion with no reocclusion in low-risk patients (n=44) versus 3.6% in the high-risk group (n=140) at 180 days.7 A randomised controlled trial (RCT) of patients undergoing endovascular interventions for PAD (Fontaine stage IIb–IV) found that the use of enoxaparin as a single weight-adapted bolus of 0.5 mg per kg body weight is superior to UFH with regard to safety and efficacy. The primary composite endpoint of bleeding, occlusion or reintervention occurred in 10.5% of cases for UFH versus 2.5% for enoxaparin (p<0.05).8 In patients taking aspirin, the risk of bleeding was higher with UFH compared with enoxaparin. Otherwise in patients with uncomplicated claudication, a Cochrane review found that there is no definite role of heparin (UH and LMWH) in preventing atherothrombotic events.9

Warfarin and Other Coumarins Worldwide, warfarin is the most used drug for non-PAD antithrombotic therapy, but in Europe, acenocumarol and phenprocoumon are also prescribed.3 These have a shorter half-life than warfarin, which could be an advantage in cases of bleeding. Warfarin is currently approved for use in the treatment of AF and thrombosis prevention for people with coagulation disorders. A number of studies have also investigated the use of these oral anticoagulants in patients with PAD. A Cochrane systematic review found that oral anticoagulants may have a potential role in the treatment of patients with intermittent claudication (IC).7 Their antithrombotic action might influence the progression of disease and the acute complications of thrombosis superimposed on chronic atherosclerotic lesions. However, it concludes

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that a clear benefit of anticoagulants for IC cannot be established due to the low methodological quality of the available studies. Among trials and studies that tested oral anticoagulants in PAD, the Warfarin and Antiplatelet Vascular Evaluation (WAVE) and the Dutch By-pass Oral anticoagulants or Aspirin study (Dutch BOA) are the landmark trials, as they are the largest and best designed studies.10–12 The WAVE trial enrolled both claudicant and critically ischaemic patients, randomisation was warfarin or acenocoumarol plus antiplatelet therapy versus antiplatelet alone. In a cohort of 2,161 patients, anticoagulation or antiplatelet therapy compared with antiplatelet therapy alone did not reduce major adverse cardiovascular or cerebrovascular events (MACCE; 12.2% versus 13.3%, respectively; RR 0.92; 95% CI [0.73–1.16]) or a composite endpoint of MACCE and severe ischaemia of the peripheral or coronary arteries (15.9% versus 17.4%, respectively; RR 0.91; 95% CI [0.74–1.12]). Life-threatening bleeding was increased with anticoagulation (4.0% versus 1.2%; RR 3.41; 95% CI [1.84–6.35]). The Dutch BOA trial studied the benefit of phenprocoumon or acenocoumarol versus daily 80 mg aspirin in 1,546 patients with an infrainguinal venous bypass as a prespecified subgroup analysis with a mean follow-up of 21 months. The target international normalised ratio range was kept at 3.0–4.5 in patients on VKA therapy. Results showed not only that VKAs were superior to aspirin in the prevention of graft occlusion (HR 0.69; 95% CI [0.54–0.88]), but also increased the risk of major bleeding. Although it did not reach statistical significance, the rate of amputations appeared to be lower in patients receiving VKAs after a venous bypass (6.6% versus 9.3%; HR 0.72; 95% CI [0.5–1.01]), and the composite outcome of vascular death, MI, stroke or amputation (HR 0.89; 95% CI [0.75–1.06]) was also reduced. A re-analysis of the Dutch BOA trial found that aspirin alone instead of VKAs in patients with a high risk of bleeding would result in fewer non-fatal haemorrhages, but would increase ischaemic events and graft occlusions.13 A meta-analysis including eight trials comparing antiplatelet versus anticoagulation, confirmed that the addition of an anticoagulant to an antiplatelet drug leads to an increased patency rate of vein bypass at the cost of a higher incidence of bleeding complications.10 Contrary patients undergoing prosthetic bypass grafts benefitted more from antiplatelet monotherapy than anticoagulation. In the WAVE trial, patients with known risk factors, such as long-term use of non-steroidal anti-inflammatory drugs, previous gastrointestinal bleeding or recent stroke were excluded from participation to minimise the risk of bleeding.11 Despite this, nearly 30% of patients discontinued oral anticoagulation therapy during follow-up, many (126 of 319) because of bleeding episodes. On the basis of those results, international guidelines recommend the use of oral anticoagulants for PAD only if there is a concomitant condition, such as AF or mechanical aortic valve, that requires anticoagulation.14 This is because the evidence of the benefit of oral anticoagulants in reducing major adverse limb events or revascularisation in PAD is weak and a higher incidence of bleeding was found when compared with antiplatelet therapy.

Peripheral Artery Disease Direct Oral Anticoagulants Direct oral anticoagulants (DOACs) were introduced in 2008 and are used for multiple thromboembolic disorders as they have advantages over existing agents. They are also known as non-VKA OACs or novel oral anticoagulants and offer reliable levels of anticoagulation and lower rates of intracranial haemorrhage and life-threatening or fatal bleeding compared with VKAs. They are alternatives to LMWH in a perioperative setting for venous thromboembolism (VTE) prophylaxis and therapy, and to VKAs for longer-term therapy.3,10 DOACs have predictable pharmacokinetic/pharmacodynamic effects, which means that routine coagulation monitoring for titration and maintenance is not required. Most DOACs are direct inhibitors of Factor Xa or thrombi which are responsible for the coagulation cascade. The new antiplatelet agents ticagrelor and vorapaxar act directly on specific platelet receptors, such as P2Y12, inhibiting the platelets’ aggregation.15 Essentially acting on different pathways, all those agents reduce the risk of thrombus formation. Several studies and trials are investigating the effectiveness of these new anticoagulants in improving long-term outcomes in patients with PAD and reducing major adverse limb events.15 One of the earlier trials was the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial which assessed the efficacy of rivaroxaban ± aspirin versus aspirin alone.16 The trial enrolled 27,395 patients at 602 centres worldwide with stable atherosclerotic vascular disease (CAD, PAD or both), who were randomised to three arms (aspirin 100 mg daily versus rivaroxaban 5 mg twice daily versus aspirin 100 mg daily plus rivaroxaban 2.5 mg twice daily. In a sub-cohort of 7,470 patients affected by PAD (55.2% symptomatic limbs, 19.1% with low ankle-brachial index and the rest with carotid disease), rivaroxaban 2.5 mg twice daily plus aspirin compared with aspirin alone reduced MACCE (5.1% versus 6.9%; p=0.005), major adverse limb events (MALE; 0.9% versus 2.4%; p=0.004), MALE components of acute limb ischaemia (0.8% versus 1.4%; p=0.04), and major amputation (0.2% versus 0.7%; p=0.01). The combination of rivaroxaban plus aspirin increased bleeding compared with aspirin alone. Bleeding was mainly gastrointestinal (1.6% versus 0.7%; p=0.03) with few intracranial (0.2% versus 0.4%) or fatal haemorrhages (0.2% versus 0.1%). The authors concluded that rivaroxaban 2.5 mg twice daily administered with aspirin should be considered for the prevention of atherothrombotic events only in adult patients with CAD or symptomatic PAD at high risk of ischaemic events. Considering this study, the European Society of Cardiology (ESC) guidelines on diabetes and the European Society for Vascular Medicine (ESVM) guidelines recommend that low-dose rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily may be considered in patients with symptomatic lower extremity PAD but without a high risk of bleeding (recommendation Class IIb for ESC guidelines and Class IIa for ESVM guidelines, level of evidence B).17,18 The National Institute for Health and Care Excellence also released a similar recommendation for low-dose rivaroxaban twice daily in patients with CAD or PAD at high risk of ischaemic events, including acute limb ischaemia and amputation.19 The latest trial, Efficacy and Safety of Rivaroxaban in Reducing the Risk of Major Thrombotic Vascular Events in Subjects With Symptomatic Peripheral Artery Disease Undergoing Peripheral Revascularization Procedures of the Lower Extremities (VOYAGER PAD), confirmed the

positive results of rivaroxaban plus aspirin versus placebo plus aspirin in patients who have undergone revascularisation.20 In this trial, 6,564 patients were recruited and blindly randomised with 3,286 assigned to the rivaroxaban group and 3,278 assigned to the placebo group. Results showed acute limb ischaemia and limb loss for vascular causes were significantly lower in the rivaroxaban group at 28 months (acute limb ischaemia: 4.7% versus 6.9%; major amputation: 3.1% versus 3.5% for rivaroxaban versus placebo group, respectively; p<0.001). The unplanned index-limb revascularisation for recurrent limb ischaemia rate was also lower in the rivaroxaban group (17.8% versus 20%; p=0.03). Primary safety outcome thrombolysis in MI (TIMI), major bleeding incidence (fatal bleeding, intracranial haemorrhage, a decrease in haemoglobin level of ≥5 g/dl, or a decrease in haematocrit of ≥15%) was not different between the two groups. The secondary safety outcome of major bleeding, defined by International Society on Thrombosis and Haemostasis (ISTH), was significantly more frequent in the rivaroxaban group versus placebo (5.94% versus 4.06%; p=0.007). Another RCT – Edoxaban plus aspirin versus dual antiplatelet therapy in endovascular treatment of patients with peripheral artery disease (ePAD) – investigated the safety and efficacy of edoxaban to prevent loss of patency following endovascular treatment.21 This trial compared the use of edoxaban plus aspirin versus conventional treatment with dual antiplatelet therapy (clopidogrel and aspirin) in 275 symptomatic patients (29% who were claudicant). Lesions were mainly located in the superficial femoral artery and stents were used in about 54% of patients in each group. There were no major or life-threatening bleeding events in the edoxaban group while there were two major and two life-threatening bleeding events in the clopidogrel group. After 6 months of observation, there was a lower incidence of restenosis/reocclusion with edoxaban compared with clopidogrel, although this was not statistically significant (30.9% versus 34.7%; RR 0.89; 95% CI [0.59–1.34]; p=0.643). Although there is evidence of a real advantage of using edoxaban over clopidogrel, the authors concluded that larger and longer-term trials should confirm those findings.

Other Direct Anticoagulants Other direct anticoagulants can inhibit the thrombin directly rather than acting on Factor Xa and they are mainly dabigatran (univalent) and bivalirudin (BIV) which is bivalent and IV administration only. Dabigatran is a DOAC that is mainly used in the prevention of stroke/ embolism in patients with non-valvular AF, or VTE prevention in patients undergoing hip surgery.3 There is a paucity of evidence about the use of this DOAC for PAD with only an observational analysis by Lopes et al. finding dabigatran comparable to the other DOACs in terms of stroke/MI/all-cause mortality rates, being lower than warfarin.22 However, no specific results were focused on the long-term effect on peripheral artery atherosclerosis. In regard to BIV, RCTs for percutaneous coronary interventions have shown that BIV had a significant advantage of decreasing procedural bleeding over UFH due to its very short half-life.23 A contemporary systematic review has analysed the efficacy of BIV versus UFH in peripheral endovascular interventions excluding intracardiac procedures.24 Generally, patients who received BIV had significantly reduced risks of MACCE, net adverse clinical events, major and minor vascular complications, compared with the unfractionated UFH group. Patients who received BIV had a lower but non-

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Anticoagulation in Peripheral Artery Disease Table 1: The Main Characteristics of Anticoagulants and Their Use for Peripheral Artery Disease Anticoagulant Route Dose

Onset

Metabolism Half-life

Offset Parameter

Unfractionated heparin

IV (or SC)

60–100 IU/kg

Immediate (IV) Liver 20–60 min (SC)

Variable 4–6 h 23–168 min

Low molecular weight heparin (enoxaparin, dalteparin, tinzaparin)

Variable Prophylactic/ therapeutic

3–6 h

Kidney Liver

1.5–4.5 h

12–24 h aPTT

Protamine sulphate (poor effect)

Periprocedural

Vitamin K antagonist oral anticoagulants (warfarin, acenocumarol, phenprocoumon)

Oral

Variable (5–10 mg)

2–3 days

Liver

40 h

5 days

INR (target 2–3)

Vitamin K

After surgery bypass (Class I)* After percutaneous intervention (Class IIa)

Non-vitamin K antagonist oral anticoagulants

Oral

Variable

2–3 h

Kidney

12–24 h

24 h

Not currently available

Not currently available†

Low-dose rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily may be considered in patients with diabetes and symptomatic PAD

Bivalirudin

Bolus: 0.75 mg/kg Immediate Infusion: 1.75 mg/kg/h

aPTT and ACT

Perioperative

Kidney (20%) 25 min 1h and proteolytic (eGFR >60) cleavage (80%)

Reversal Agent

Use in PAD

aPTT Protamine Periprocedural (target 1.5-2.5) sulphate Acute limb ischaemia (1 mg per 100 U)

* In patients that need anticoagulation for other disease, such as AF. †Idarucizumab antidote for dabigatran – recombinant mFactor X – approved in US, but under review in EU. ACT = activated clotting time; aPTT = activated partial thromboplastin time; eGFR = estimated glomerular filtration rate; INR = international normalised ratio; PAD = peripheral artery disease; PTT = partial thromboplastin time; SC = subcutaneous.

significant odds of major bleeding (OR 0.72; 95% CI [0.47–1.11], minor bleeding (OR 0.74; 95% CI [0.55–1.00]) and transfusion. From the enrolled studies that reported postprocedural limb amputation, the difference between BIV and UFH was not significant, suggesting that the incidence of stent thrombosis may be similar between BIV and UFH. Given the equivocal results, the authors conclude that BIV may be chosen solely as an alternative procedural anticoagulant to UFH.

What’s Next? Large clinical studies are ongoing in the US and should provide meaningful information on treatments for people with PAD. The Best Endovascular Versus Best Surgical Therapy in Patients With Critical Limb Ischemia (BEST-CLI) trial, is an open-label RCT plans to enrol 2,100 patients at 120 centres in the US and Canada.25 A concurrent registry is planned and will capture real-world antithrombotic therapy in patients with critical limb ischaemia. Another study named DUAL Pathway Inhibition to Improve Endothelial Function in Peripheral Artery Disease (DUAL-PAD; NCT04218656), is still

Cannavale A, Santoni M, Gazzetti M, et al. Updated clinical and radiological classification of lower limb atherosclerotic disease. Ann Vasc Surg 2019;55:272–84. https://doi. org/10.1016/j.avsg.2018.06.011; PMID: 30114503. Hess CN, Norgren L, Ansel GM, et al. A structured review of antithrombotic therapy in peripheral artery disease with a focus on revascularization: A TASC (InterSociety Consensus for the Management of Peripheral Artery Disease) Initiative. Circulation 2017;135:2534–55. https:// doi.org/10.1161/CIRCULATIONAHA.117.024469; PMID: 28630267. Lin L, Zhao L, Gao N, et al. From multi-target anticoagulants to DOACs, and intrinsic coagulation factor inhibitors. Blood Rev 2019;Aug29:100615. https://doi.org/10.1016/j.

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recruiting and will provide information about endothelial function in patients on low-dose rivaroxaban plus aspirin (100 mg) versus aspirin (100 mg) alone.

Conclusion LMWH represents the leading drug for perioperative management of patients with PAD. Otherwise oral anticoagulation with warfarin/ cumarols is mostly used in patients who need this for AF or DVT and have symptomatic PAD. A certain benefit may be to maintain patency of lower-limb bypass grafts, considered at risk. In regard to DOACs, there is now level 1b evidence regarding the longterm benefit of low-dose rivaroxaban plus aspirin that is recommended by the most recent ESC guidelines for people with diabetes. Finally, the additional risk of bleeding over aspirin alone still remains. The appropriate anticoagulation regimen for patients with PAD should be decided by balancing ischaemic and bleeding risks for individual patients when selecting the type, dose and intensity of antithrombotic therapies (Table 1).

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Group study. Eur J Vasc Endovasc Surg 1996;12:86–90. https://doi. org/10.1016/S1078-5884(96)80281-4; PMID: 8696904. Brodmann M, Dorr A, Hafner F, et al. Safety and efficacy of periprocedural anticoagulation with enoxaparin in patients undergoing peripheral endovascular revascularization. Clin Appl Thromb Hemost 2014;20:530–5. https://doi.org/10. 1177/1076029613492877; PMID: 23785050. Duschek N, Vafaie M, Skrinjar E, et al. Comparison of enoxaparin and unfractionated heparin in endovascular interventions for the treatment of peripheral arterial occlusive disease: a randomized controlled trial. J Thromb Haemost 2011;9:2159–67. https://doi.org/10.1111/j.1538-7836.2011. 04501.x; PMID: 21910821. Cosmi B, Conti E, Coccheri S. Anticoagulants (heparin, low

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14.

molecular weight heparin and oral anticoagulants) for intermittent claudication. Cochrane Database Syst Rev 2014;7:CD001999. https://doi.org/10.1002/14651858. CD001999.pub2; PMID: 24801382. Ambler GK, Waldron CA, Contractor UB, et al. Umbrella review and meta-analysis of antiplatelet therapy for peripheral artery disease. Br J Surg 2020;107:20–32. https://doi.org/10.1002/ bjs.11384; PMID: 31808552. Anand S, Yusuf S, Xie C, et al. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med 2007;357:217–27. https://doi.org/10.1056/NEJMoa065959; PMID: 17634457. Dutch Bypass Oral anticoagulants or Aspirin (BOA) Study Group. Efficacy of oral anticoagulants compared with aspirin after infrainguinal bypass surgery (The Dutch Bypass Oral Anticoagulants or Aspirin Study): a randomised trial. Lancet 2000;355:346–51. https://doi.org/10.1016/S0140-6736(99)071998; PMID: 10665553. Ariesen MJ, Tangelder MJD, Lawson JA, et al. Risk of major haemorrhage in patients after infrainguinal venous bypass surgery: therapeutic consequences? The Dutch BOA (Bypass Oral Anticoagulants or Aspirin) Study. Eur J Vasc Endovasc Surg 2005;30:154e9. https://doi.org/10.1016/j.ejvs.2005.03.005; PMID: 15996602. Aboyans V, Ricco JB, Bartelink MEL, et al. 2017 ESC guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular

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Surgery (ESVS): Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries. Eur Heart J 2018;39:763–816. https://doi.org/10.1093/eurheartj/ehx095; PMID: 28886620. Amer MR, Chaturvedula ST, Joshi S, Ingrassia J. Antithrombotic therapy after revascularization in patients with peripheral arterial disease: what is here, what is next. Vasc Endovascular Surg 2019;53:325–36. https://doi.org/10.1177/ 1538574419836316; PMID: 30885060. Anand SS, Bosch J, Eikelboom JW, et al. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, doubleblind, placebo-controlled trial. Lancet 2018;391:219–29. https://doi.org/10.1016/S0140-6736(17)32409-1; PMID: 29132880. Cosentino F, Grant PJ, Aboyans V, et al. ESC Scientific Document Group. 2019 ESC Guidelines on diabetes, prediabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020;41:255–323. https://doi.org/10.1093/eurheartj/ehz486; PMID: 31497854. Frank U, Nikol S, Belch J, et al. ESVM guideline on peripheral arterial disease. Vasa 2019;48(Suppl 102):1–79. https://doi. org/10.1024/0301-1526/a000834; PMID: 31789115. National Institute for Health and Care Excellence. Rivaroxaban for preventing atherothrombotic events in people with coronary or peripheral artery disease. London: NICE, 2019. https://www. nice.org.uk/guidance/ta607 (accessed 12 August 2020).

20. Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med 2020;382:1994–2004. https://doi.org/10.1056/NEJMoa2000052; PMID: 32222135. 21. Moll F, Baumgartner I, Jaff M, et al. Edoxaban plus aspirin vs dual antiplatelet therapy in endovascular treatment of patients with peripheral artery disease: results of the ePAD Trial. J Endovasc Ther 2018;25:158–68. https://doi. org/10.1177/1526602818760488; PMID: 29552984. 22. Lopes RD, Steffel J, Di Fusco M, et al. Effectiveness and safety of anticoagulants in adults with non-valvular atrial fibrillation and concomitant coronary/peripheral artery disease. Am J Med 2018;131:1075–85.e4. https://doi.org/10.1016/j. amjmed.2018.05.007; PMID: 29807001. 23. Verheugt FW, Steinhubl SR, Hamon M, et al. Incidence, prognostic impact, and influence of antithrombotic therapy on access and nonaccess site bleeding in percutaneous coronary intervention. JACC Cardiovasc Interv 2011;4:191–7. https://doi. org/10.1016/j.jcin.2010.10.011; PMID: 21349458. 24. Hu Y, Liu AY, Zhang L, et al. A systematic review and metaanalysis of bivalirudin application in peripheral endovascular procedures. J Vasc Surg 2019;70:274–84.e5. https://doi. org/10.1016/j.jvs.2018.12.037; PMID: 31230646. 25. Farber A, Rosenfield K, Siami FS, et al. The BEST-CLI trial is nearing the finish line and promises to be worth the wait. J Vasc Surg 2019;69:470–481.e2. https://doi.org/10.1016/j. jvs.2018.05.255; PMID: 30683195.

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Venous

Antithrombotic Therapy after Venous Stent Placement Nicholas Xiao and Kush R Desai Department of Radiology, Northwestern University, Chicago, IL, US

Abstract Chronic deep venous disease (CVD) affects millions of Americans and can result in significant morbidity, such as debilitating lower extremity oedema, venous claudication, and in severe cases, venous ulcers. CVD can be caused by thrombotic and non-thrombotic disease processes, such as deep venous thrombosis and iliac compression syndrome. Recently, endovascular intervention with percutaneous transluminal angioplasty and venous stent placement has become the mainstay therapy for these patients, with several studies demonstrating its safety and efficacy. However, anticoagulation management following venous stent placement is largely unstudied, and there are no large randomised controlled trials or official guidelines establishing an optimal regimen. Most published studies are plagued with data heterogeneity and incomplete reporting. This is further complicated by rapidly evolving improvements in technique and dedicated devices in endovenous intervention. In this article, the authors discuss the current literature to date and offer an approach to anticoagulation and antiplatelet management following venous stent placement in CVD.

Keywords Anticoagulation, venous stent placement, in-stent restenosis, stent thrombosis, chronic deep venous disease, antithrombotic therapy Disclosure: KRD serves as a consultant for Cook Medical, Boston Scientific, Becton Dickinson/Bard, Philips, Medtronic, WL Gore, Walk Vascular and Tactile Medical. NX has no conflicts of interest to declare. Received: 9 March 2020 Accepted: 24 August 2020 Citation: Vascular & Endovascular Review 2020;3:e10. DOI: https://doi.org/10.15420/ver.2020.06 Correspondence: Kush R Desai, Department of Radiology, Northwestern University, 676 N St Clair, 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 noncommercial purposes, provided the original work is cited correctly.

Chronic deep venous disease (CVD) affects millions of patients and causes significant morbidity, including lower extremity oedema, venous claudication, and in severe cases, venous ulceration. Commonly, CVD is caused by either thrombotic aetiologies, such as deep venous thrombosis (DVT), or by non-thrombotic aetiologies, such as in iliac vein compression syndrome (May−Thurner syndrome). In CVD, the affected veins become markedly atretic, thus impairing appropriate venous drainage, despite the formation of collaterals (Figure 1). Recently, endovascular intervention with percutaneous transluminal angioplasty and venous stent placement has become a mainstay treatment for this disease entity, and has been shown to have high rates of technical and clinical success (Figure 2). A feared complication of venous stent placement is post-procedural in-stent restenosis and/or stent thrombosis. Previous studies have cited rates as high as 28% at 1 year and up to 62% at 5 years.1,2 An appropriate post-stent placement anticoagulation regimen is of utmost importance in the clinical management of these patients to maintain patency and provide durable symptom resolution. Several other factors are also essential for stent failure prevention, such as elimination of thrombus when treating acute DVT, appropriate stent landing and positioning into disease-free segments of the vein, and ensuring that inflow and outflow of the stent is optimised and sufficient. Despite increasing rates of venous stent placement, few studies have been performed to inform the optimal antithrombotic therapy

regimen, and no high-grade, evidence-based guidelines exist for the management of these patients. Most current practices reflect prior experiences in treating venous thromboembolism or are based on data produced from arterial stent placement. However, the pathophysiology underlying venous stent stenosis is distinct to its arterial counterpart, with animal models showing significantly different rates of intimal proliferation, hyperplasia and in-stent stenosis.3 These differences are likely related to markedly different flow dynamics, shear forces and vessel characteristics.4–6 In this article, we provide a review of the current data regarding anticoagulation therapy after venous stent placement and summarise currently practiced management.

Literature Review There are no prospective randomised controlled trials demonstrating increased efficacy or superiority of one antithrombotic management strategy over another after the placement of venous stents. The available evidence regarding anticoagulation in this context is limited by heterogeneity in study design, measured outcomes and disparate outcome time points. Furthermore, as the availability of venous-specific stents are a relatively recent development, no long-term data are available regarding technical and clinical outcomes using these devices. Nevertheless, several studies discussing venous stent placement and antithrombotic management are available, which may help guide management. These are summarised in Table 1.

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Venous Figure 1: Young Woman Presenting with Post-thrombotic Chronic Venous Disease

single-agent antiplatelet therapy is recommended (American College of Chest Physicians).

Systematic Reviews and Meta-Analyses A systematic review conducted by Eijgenraam et al. aimed specifically at assessing anticoagulation following venous stent placement, was unable to demonstrate superiority of any specific antithrombotic agent or regimen.10–12 However, their study had major limitations in methodology; specifically, it combined data from acute and chronic thromboses, and included data in which patients did not receive a stent. A meta-analysis of the data was also not performed.

A: Coronal computed tomography images demonstrate an acute thrombus involving the left external iliac vein (white arrow) and extending into the tibioperoneal veins (not shown). B: CT images obtained 2 months later reveal a markedly diminutive left external iliac vein (white arrowhead), consistent with post-thrombotic chronic venous disease.

Figure 2: Endovascular Therapy for Chronic Venous Disease Treatment

A: A wire was successfully advanced through the left femoral and left external iliac vein occlusions. Venography demonstrates complete occlusion of the left external and common iliac veins (white arrow) with multiple body wall and retroperitoneal collaterals. B: Successful endovascular placement of a venous stent through the occluded iliac segments. Post-stent placement venography demonstrates brisk flow through the native left femoral and iliac veins. C: Follow-up CT images demonstrate maintained patency of the venous stent.

Consensus of Common Anticoagulation Management At present, there are no consensus guidelines regarding the role of anticoagulation following venous stent placement. Despite this, a recent survey of vascular surgeons, interventional radiologists and haematologists showed a general consensus; anticoagulation is preferred the first 6–12 months post-stent, with lifelong anticoagulation for those with a history of multiple deep venous thromboses. No consensus could be reached on long-term anticoagulation.7 The current body of literature concerning anticoagulation and antiplatelet therapy following stent placement is nearly exclusively in the context of arterial stent placement.8,9 Much of the practice in the realm of venous stents are based off these data. However, as previously discussed, the pathophysiology underlying venous stent stenosis is distinct from arterial stenosis, as there are marked differences in vessel characteristics and flow haemodynamics. Consensus guidelines in coronary stent placement state that triple therapy (warfarin, dual antiplatelet therapy [DAPT]) is recommended (American Heart Association/American College of Cardiology), while in the context of peripheral arterial stent placement,

A meta-analysis by Razavi et al. assessed a total of 37 studies on 2,869 patients who underwent stent placement for iliofemoral venous outflow obstruction;12 however, the number of available studies was inadequate for the comparison of peri-procedural anticoagulation. Post-procedural anticoagulation in the analysed studies commonly entailed warfarin for 2–6 months with a target international normalised ratio of 2.0–3.0. In high-risk patients, anticoagulation was generally extended to 6–12 months. Antiplatelet medication regimens were variable, and lifelong antiplatelet medication was routinely proscribed in some studies. Primary and secondary patency rates with these protocols were 96% and 99% for non-thrombotics, 87% and 89% for acute thrombosis and 79% and 94% for post-thrombotics, respectively. Subgroup analysis was limited by heterogeneity of the abstracted data and underreporting, and no difference was reported between anticoagulation regimens. A systematic review by Padrnos et al. assessing antithrombotic use in thrombotic May-Thurner syndrome concluded that treatment with anticoagulation for a finite duration of 6 months after stent placement was reasonable, with or without antiplatelet therapy, in the absence of other risk factors. Data from the same study showed that, with the addition of antiplatelet therapy (aspirin and clopidogrel), there were cumulatively improved rates of stent patency and event-free outcomes at 12 months compared with treatment using anticoagulation alone (96% versus 80%).11

Use of Concomitant Anticoagulation/ Antiplatelet Therapy A retrospective study in 2018 examined the effectiveness of anticoagulation alone (warfarin, enoxaparin or a factor Xa inhibitor) versus the concomitant use of aspirin, clopidogrel or DAPT. The study showed higher stent patency (HR 0.28) in patients receiving concomitant antiplatelet and anticoagulation therapy versus anticoagulation therapy alone.13 A second retrospective study assessing triple therapy (anticoagulation with DAPT) versus DAPT alone showed lower rates of in-stent restenosis and stent thrombosis with the addition of anticoagulation, while also maintaining similar levels of major bleeding events.14 This was consistent with a systematic review, which analysed 14 studies on venous stent placement and showed that antiplatelet therapy alone did not change patency rates on follow-up.10

Selection of Anticoagulation and Antiplatelet Agents For specific anticoagulation agents, warfarin and enoxaparin remain the mainstays for anticoagulation therapy. With the advent of new agents and their integration into other management guidelines,

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Antithrombotic Therapy after Venous Stent Placement Table 1: Studies Investigating Anticoagulation and Venous Stent Placement Study

Type of Study

Number Studied

Conclusion

Milinis et al.7

Survey

N/A, 106 experts

Consensus among interventionalists for anticoagulation 6–12 months after venous stent placement; lifelong anticoagulation for multiple deep venous thromboses

Eijgenraam et al.10

Systematic review

819 patients, 14 studies

Antiplatelet therapy alone did not change patency rates on follow-up; no association between duration of anticoagulation therapy and outcomes

Razavi et al.12

Systematic review, meta-analysis

2,869 patients, 37 studies

Most studies used warfarin treatment for 2–6 months with a target INR of 2.0–3.0; extension to 6–12 months in high-risk patients. Patency rates were 99% for non-thrombotics, 89% for acute thrombosis and 79% for chronic post-thrombotics

Lin et al.14

Retrospective

241 patients

Lower rates of in-stent restenosis and stent thrombosis with triple therapy versus DAPT

Systematic review

61 patients, 5 studies

High stent patency rates at 12 months for patients with iliac vein compression

Padrnos et al.11 15

Prospective cohort

111 patients

No difference in patency between rivaroxaban and vitamin K antagonist

Langwieser et al.1

Case series

9 patients

100% stent patency on DOAC at 14 months

Endo et al.13

Retrospective

62 patients

Antiplatelet medication in addition to anticoagulation following stent placement significantly decreased the risk of stent malfunction (HR 0.28)

Sebastian et al.2

Prospective cohort

113 patients

No difference in patency between 3–12 months and >12 months of anticoagulation therapy

Sebastian et al.

DAPT = dual antiplatelet therapy; DOAC = direct oral anticoagulant; INR = international normalised ratio; N/A = not available.

alternate choices of agents have become more frequently utilised. Direct oral anticoagulants (DOACs) in particular have been increasing in use due to their relative ease of use and less need for monitoring. Data on DOAC use following venous stent placement is scant. One small case series of nine patients reported no in-stent restenosis or stent thrombosis at 14 months.1 A recent ongoing prospective cohort study from the Swiss Venous Stent registry compared rivaroxaban or vitamin K antagonists following early stent placement, and showed no significant difference between the two groups in patency or complications.15 Aspirin and clopidogrel are the current preferred antiplatelet agents following venous stent placement, with their use largely extrapolated from experience with arterial stent placement. Newer antiplatelet agents, such as P2Y12 inhibitors, are an interesting prospect, with some studies suggesting lower rates of arterial in-stent restenosis or thrombosis.16,17 While not technically an anticoagulant, cilostazol, a phosphodiesterase-3 inhibitor, has also been shown to affect peripheral arterial angiographic patency.18

Optimal Duration of Anticoagulation Therapy The optimal duration of anticoagulation therapy following stent placement is also unknown, with few studies addressing this issue. A recent study of 113 patients by Sebastian et al. showed that there was no difference between 3–12 months of post-stent placement anticoagulation and >12 months of anticoagulation, suggesting that discontinuing anticoagulation at 3–12 months is reasonable in this patient population.19

Thrombophilia Testing and Adjustment of Anticoagulation The role of thrombophilia and thrombophilia testing in the setting of venous stent placement has been inconsistently and incompletely reported in the literature.11 The limited number of studies that have examined stent outcomes in patients with underlying thrombophilia have drawn varied conclusions as to the risk of venous thrombosis. Several studies with under 15 patients have suggested that there may be a higher rate of venous occlusion in those with thrombophilia; however, a single study of 205 patients who underwent iliofemoral

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venous stent placement noted no difference in patency and re-intervention.20–22

Ongoing Studies Several large randomised controlled trials assessing outcomes in venous stents are underway, and their results are likely to greatly influence clinical practice. Most relevant to the topic of anticoagulation, especially concerning the need for both antiplatelet and anticoagulation therapy, is the open-label ARIVA (Aspirin® Plus Rivaroxaban Versus Rivaroxaban Alone for the Prevention of Venous Stent Thrombosis in Patients With PTS) trial, whose primary objective is to compare aspirin and rivaroxaban to rivaroxaban alone in patients with endovascular venous stents (NCT04128956). Early studies in a porcine venous stent model demonstrated a reduction in measured platelet deposition in animals that received a direct factor Xa inhibitor compared to those that received antiplatelet agents.23 In the currently enrolling Chronic Venous Thrombosis: Relief with Adjunctive Catheter-directed Therapy (C-TRACT) clinical trial, one of the largest trials investigating endovenous stent placement, patients are placed on anticoagulation and low-dose aspirin (81 mg) for the first 6 months in the absence of contraindications and low-molecular weight heparin at fully therapeutic doses for the first 3 months (Vedantham S, pers. comm., 2018). While C-TRACT focuses primarily on postthrombotic syndrome, outcomes regarding stent patency and persistent clinical symptom relief are likely to shed light on several important questions regarding perioperative anticoagulation.

Discussion Currently, there are no large prospective randomised controlled trials that clearly establish a superior efficacy of a particular anticoagulation regimen following endovenous stent placement. Many current management practices are derived from previous literature regarding arterial stent placement, and while some consensus is present among interventionalists, few data are available to inform practice. In this article, we present several studies that may help inform management. Meta-analyses, systematic reviews and all prospective trials to date have failed to show differences between anticoagulation

Venous Figure 3: Recommended Algorithm for Anticoagulation after Venous Stent Placement Venous stent placement

Thrombotic aetiology

Non-thrombotic aetiology

Contraindications to DOAC?

No anticoagulation or antiplatelet therapy

Yes Warfarin (international normalised ratio 2.0–3.0) for 6–12 months with daily aspirin (81 mg) or clopidogrel (75 mg)

DOAC for 6–12 months with daily aspirin (81 mg) or clopidogrel (75 mg)

Multiple deep vein thromboses or other indications for anticoagulation? No

No additional anticoagulation. Aspirin (81 mg) indefinitely

Yes Haematology consultation. Consider lifelong anticoagulation in addition to aspirin (81 mg) indefinitely

DOAC = direct oral anticoagulant.

agents. Most of the available studies suggest the need for postoperative anticoagulation, and a few select, smaller retrospective studies have shown that concomitant antiplatelet therapy may also reduce in-stent stenosis. There are also some early data suggesting the superiority of DOACs for short-term anticoagulation, and given their ease of use compared to vitamin K antagonists, they may be the preferred agent. Finally, multiple studies have concluded that anticoagulation in the 3–12 months after stent placement is likely sufficient in patients without additional risk factors or need for anticoagulation. Further complicating the issue is that the aetiology of CVD greatly influences stent patency, and therefore, the optimal anticoagulation regimen for each aetiology may be different. In cases of external compression, such as May–Thurner syndrome, where there is relatively maintained vessel wall architecture, data have shown that patency rates are exceedingly high (99%), and therefore anticoagulation may not be necessary.2,12 On the contrary, lower rates of patency in post-thrombotic stents likely relate to the near complete fibrous retraction of the native vessel, whereby the wall is composed nearly entirely of collagen and may also benefit more from one anticoagulation regimen over another. Large enough studies to power subgroup analyses will need to be undertaken to further clarify differences between these patients.

Thrombophilia among patients with venous stents has not been well studied, and the available data do not allow for any scientific conclusions to be drawn on whether thrombophilia should affect antithrombotic management or whether testing for thrombophilia is needed after venous stent placement. At our institution, testing for thrombophilia is left to the discretion of the haematologist, and we do not routinely recommend testing after venous stent placement. While no consensus guidelines exist, these data suggest the use of anticoagulation in the 3–12 months post-stent placement, along with a single-agent antiplatelet therapy (aspirin 81 mg or clopidogrel), in patients with thrombotic disease without indication for lifelong anticoagulation. At our centre, we prefer the use of a DOAC if no contraindications are present, otherwise warfarin is used (Figure 3). In patients with no history of multiple deep venous thromboses, there appears to be no data to suggest any benefit of extending therapy beyond 1 year. Therefore, we anticoagulate patients for 6–12 months, depending on the quality of venous inflow. Patients with multiple deep venous thromboses, other indications for anticoagulation or additional risk factors are referred for haematology consultation. In these patients, extension of anticoagulation, potentially lifetime, may be reasonable. Additionally, in cases of more complex reconstruction, for example, infra-inguinal stent placement and caval reconstruction, lifelong anticoagulation may also be considered. In patients presenting with CVD caused by non-thrombotic aetiologies, such as iliac compression syndrome, we do not routinely place patients on anticoagulation, as patency rates are exceedingly high (99%) in this cohort. At this time, data regarding newer anticoagulation and antiplatelet medications are scant, and their use in this setting is experimental. Several clinical trials involving venous stent placement are underway; their results are eagerly awaited and will likely change the current paradigm. Complicating the issue is that nearly all studies include patients in whom off-label stents were placed. With the advent of several new venous-specific devices and rapid advancements in techniques, ongoing studies will be needed to understand optimal post-procedural management in these patients.

Conclusion More research is needed to establish the optimal anticoagulation regimen following thrombotic and non-thrombotic venous stent placement, especially with the advent of venous-specific stents. Until these data are available, it is reasonable to place patients undergoing venous stent placement for thrombotic disease on anticoagulation in the 3–12 months post-stent placement, along with concomitant singleagent antiplatelet therapy (low-dose aspirin or clopidogrel). For patients with other indications for anticoagulation, haematology consultation may be considered, and lifetime anticoagulation may be reasonable. Patients presenting with non-thrombotic causes of CVD are likely to not need anticoagulation post-stent placement, as patency rates are exceedingly high in this cohort. At our centre, in the absence of other indications for anticoagulation, we place thrombotic CVD patients on a DOAC and a single antiplatelet agent (clopidogrel followed by low-dose aspirin) for the 6 months following stent placement, with low-dose aspirin to continue indefinitely thereafter.

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Antithrombotic Therapy after Venous Stent Placement 1.

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16. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57. https://doi.org/10.1056/ NEJMoa0904327; PMID: 19717846. 17. Schomig A. Ticagrelor--is there need for a new player in the antiplatelet-therapy field? N Engl J Med 2009;361:1108–11. https://doi.org/10.1056/NEJMe0906549; PMID: 19717845. 18. Iida O, Yokoi H, Soga Y, et al. Cilostazol reduces angiographic restenosis after endovascular therapy for femoropopliteal lesions in the Sufficient Treatment of Peripheral Intervention by Cilostazol study. Circulation 2013;127:2307–15. https://doi. org/10.1161/CIRCULATIONAHA.112.000711; PMID: 23652861. 19. Sebastian T, Engelberger RP, Spirk D, et al. Cessation of anticoagulation therapy following endovascular thrombus removal and stent placement for acute iliofemoral deep vein thrombosis. Vasa 2019;48:331–9. https://doi.org/10.1024/03011526/a000774; PMID: 30667348. 20. Tincknell LG, Gwozdz A, Jackson N, et al. Relevance of thrombophilia testing in patients undergoing iliofemoral venous stenting for post-thrombotic occlusion. J Vasc Surg Venous Lymphat Disord 2019;7:300–1. https://doi.org/10.1016/j. jvsv.2019.01.036. 21. Goldman RE, Arendt VA, Kothary N, et al. Endovascular management of May-Thurner syndrome in adolescents: a single-center experience. J Vasc Interv Radiol 2017;28:71–7. https://doi.org/10.1016/j.jvir.2016.09.005; PMID: 27818112. 22. Matsuda A, Yamada N, Ogihara Y, et al. Early and long-term outcomes of venous stent implantation for iliac venous stenosis after catheter-directed thrombolysis for acute deep vein thrombosis. Circ J 2014;78:1234–9. https://doi. org/10.1253/circj.CJ-13-1247; PMID: 24583973. 23. McBane RD II, Leadley RJ Jr, Baxi SM, et al. Iliac venous stenting: antithrombotic efficacy of PD0348292, an oral direct factor Xa inhibitor, compared with antiplatelet agents in pigs. Arterioscler Thromb Vasc Biol 2008;28:413–8. https://doi. org/10.1161/ATVBAHA.107.158691; PMID: 18096830.

Peripheral Artery Disease

Use of the Orbital Atherectomy System in Isolated, Chronic Atherosclerotic Lesions of the Popliteal Artery Patricia Torres Lebruno,1 Konstantinos P Donas,2 Stefano Fazzini,3 Charlott Elise Köhler,3 Arne Schwindt3 and Giovanni Torsello3 1. Department of Vascular and Endovascular Surgery, University Hospital Fundación Jiménez Díaz, Madrid, Spain; 2. Department of Vascular and Endovascular Surgery, Asklepios Clinic Langen, University of Frankfurt, Frankfurt, Germany; 3. Department of Vascular and Endovascular Surgery, St Franziskus Hospital, Münster, Germany

Abstract The treatment of isolated calcified lesions involving the popliteal artery are demanding and they often require stent placement to achieve acceptable luminal gain. This study evaluates the safety and performance of the orbital atherectomy system (Cardiovascular Systems Inc.) and percutaneous transluminal angioplasty with a drug-coated balloon (PTA-DCB) for the treatment of chronic atherosclerotic lesions within the popliteal artery segment. From November 2018 to November 2019, a series of six patients with Rutherford classification stage III peripheral arterial disease with isolated, focal, calcified occlusions of the popliteal artery were treated with orbital atherectomy followed by PTA-DCB. No embolic protection devices were used. The technical success rate was 100%, the primary patency rate was 100% at 7.0 (±4.2) months of follow-up. The Rutherford classification improved in all patients from stage III to stage II and the mean ankle brachial pressure index after the procedure was 0.97 (±0.08), with a preoperative mean ankle brachial pressure index of 0.69 (±0.21). In one instance, spasm was noted in a distal arterial bed and it was successfully treated with local nitroglycerine. No distal embolisation, perforation or aneurysmal degeneration was observed. During follow-up there were no deaths, major amputations or revascularisation of target lesions. The use of orbital atherectomy system in combination with PTA-DCB was found to be safe and effective in modifying focal, chronic, calcified plaques in the popliteal artery segment in these six cases.

Keywords Atherectomy, drug-coated balloon, angioplasty, occlusion, isolated, calcified, popliteal artery Disclosure: The authors have no conflicts of interest to declare. Received: 31 March 2020 Accepted: 7 September 2020 Citation: Vascular & Endovascular Review 2020;3:e11. DOI: https://doi.org/10.15420/ver.2020.08 Correspondence: Patricia Torres Lebruno, Department of Vascular and Endovascular Surgery, University Hospital Fundación Jiménez Díaz, Avda Reyes Católicos, 2, 28040, Madrid, Spain. E: patricia.torresl@quironsalud.es 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 noncommercial purposes, provided the original work is cited correctly.

Despite recent advances in endovascular therapies, the treatment of calcified popliteal artery lesions represents an ongoing challenge. Drugcoated balloons (DCBs), while effective in soft atherosclerotic lesions, are unable to expand completely in calcified lesions and the calcium presents a barrier to drug uptake. Calcium also remains a challenge to traditional and interwoven selfexpanding stents, resulting in stent malapposition and high rates of stent fracture.1–3 There are also biomechanical forces of external compression, torsion and elongation that occur with locomotion, which are unique to the popliteal segment. Atherectomy aims to reduce the complications of traditional angioplasty such as dissection, recoil and disruption of the elastic lamina, which can result in smooth muscle cell proliferation and restenosis. The Stealth 360 Peripheral Orbital Atherectomy System (OAS; Cardiovascular Systems, Inc.) modifies calcified plaques using a 10 micron diamondcoated crown.4 The system uses the principle of centrifugal force, producing 360° of contact with calcified lesions to create a smooth concentric lumen by differential sanding.

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The aim of this article is to assess the performance of the OAS in combination with percutaneous transluminal angioplasty with a DCB (PTA-DCB) on calcified popliteal artery lesions.

Method From November 2018 to November 2019, six cases of focal popliteal arterial disease, involving the second popliteal artery segment (P2) were treated with OAS in combination with PTA-DCB. The Stealth 360 Peripheral OAS was used in each case. Patients were included if they had Rutherford classification (RC) stage III peripheral arterial disease with isolated calcified occlusions (according to the Fanelli classification) involving the popliteal artery and having at least two patent runoff arteries.5 Patients were excluded if they had thrombotic lesions detected using CT angiography, or MRI or duplex ultrasound for those with chronic kidney disease, in-stent or bypass restenosis or occlusions, if they had been treated with other atherectomy systems or cutting balloon angioplasty and if they had additional atherosclerotic lesions of the superficial femoral artery or the infrapopliteal segment.

Orbital Atherectomy in Chronic Atherosclerotic Lesions of the Popliteal Artery Table 1: Demographics and Comorbidities Characteristics

Total n=6

Sex, n (%): – Male – Female

4 (66.7%) 2 (33.3%)

Age (years)

68.8 ± 8.5 (53–78)

Smoker, n (%)

5 (83.3%)

Hypertension, n (%)

5 (83.3%)

Diabetes, n (%)

1 (16.7%)

Hyperlipidaemia, n (%)

4 (66.7%)

Coronary artery disease, n (%)

3 (50.0%)

Chronic kidney disease,* n (%)

2 (33.3%)

Cerebrovascular disease, n (%)

0 (0.0%)

Rutherford classification (preoperative)

3.0 ± 0.0

Ankle brachial index (preoperative)

0.69 ± 0.21 (0.4–0.96)

Continuous data are presented as mean + standard deviation (range); categorical data are given as the n (%). *Estimated glomerular filtration rate <60 ml/min/1.73m2.

Table 2: Lesion Characteristics Lesion location, n (%): – Isolated P2 – P1 + P2

4 (66.7%) 2 (33.3%)

Mean lesion length (mm)

30.0 ± 16.5 (16.3–61.7)

Proximal vessel diameter (mm)

5.1 ± 0.5 (4.4–5.8)

Distal vessel diameter (mm)

4.9 ± 0.4 (4.6–5.6)

Runoff vessel*, n (%): –1 –2 –3

0 (0%) 1 (16.7%) 5 (83.3%)

Continuous data are presented as mean + standard deviation (range); categorical data are given as the n (%). *Distal number of patent vessels before the foot. P1 = first popliteal segment; P2 = second popliteal segment.

Due to the retrospective design of the study, no ethical approval was necessary. We developed the paper’s protocol in accordance with the Declaration of Helsinki and all patients gave informed consent.

Figure 1: Coral Reef Chronic Occlusion of the Second Segment of the Popliteal Artery

A: CT angiography reconstruction showing the calcified occlusion in the second popliteal segment (arrow) in a patient with three distal vessel runoffs; B: Endovessel reconstruction, sagital view; C: Diagnostic digital subtraction angiography.

Endpoints The primary endpoint was the primary patency rate at 6 months, defined as the freedom from haemodynamically significant stenosis (peak systolic velocity ratio ≥2.5) on duplex ultrasound at the target lesion and without target lesion revascularisation (TLR). The secondary endpoints were: the technical success, defined as the recanalisation of the occluded popliteal artery with residual angiographic stenosis <40% in absence of recoil, arterial dissection or perforation or distal embolisation without bailout stenting; the clinical success, defined as the improvement of the ankle brachial pressure index (ABPI) and one or more stages of RC at 6-month follow-up; 30-day morbidity, defined as the presence of any procedure-related complication at the puncture site, haematomas or pseudoaneurysms after the procedure or other clinical events; and the mortality rate at 6-month follow-up. Follow-up protocol included examination with ABPI and duplex ultrasound at 6 months postoperatively.

Results Patient Demographics and Lesion Characteristics Baseline characteristics of the patients and their lesions are described in Tables 1 and 2. The mean age was 68.8 years (53.0–78.0) and four of the patients were men. In all cases, the patients presented with RC stage III severe claudication and a mean preoperative ABPI of 0.69 ± 0.21 (0.40–0.96). The mean lesion length was 30 ± 16.5 mm (16.3–61.7) and five of the patients (83.3%) had three distal patent vessels.

Procedure All the patients had lesions in the P2 popliteal artery segment and two patients also had lesions in the first segment of the popliteal artery (P1). All patients were treated with a simple antiplatelet regimen of aspirin before the procedure. After revascularisation, heparin infusion was administrated for the first 24 hours (15 IU at 1.2 ml/h). Two months of dual antiplatelet therapy of 100 mg acetylsalicylic acid and 75 mg of clopidogrel were taken followed by lifelong monotherapy with acetylsalicylic acid. Under local anaesthesia, a diagnostic digital subtraction angiography of the affected limb was performed to identify the lesion and calcification. After catheterisation of the lesions, patients were treated with the OAS followed by PTA-DCB. We performed two passes per lesion with a 2 mm solid crown (the 1.5 mm, 1.75 mm solid crown, classic or micro crown were not available at our centre at the time) at 60, 90 and 120 rpm (a total of six passes per lesion) without the need for embolic protection. Thereafter, angioplasty was performed with a 5 mm diameter DCB with an average balloon inflation pressure of 8.7 ±1.6 atm for 3 minutes. A vascular closure device (Angioseal, St Jude Medical) was used for groin closure in all cases.

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Figure 1 illustrates an example of a patient presenting with a severely calcified chronic occlusion of the popliteal artery and is representative of the lesions treated in this series.

Procedural Results and Clinical Outcomes Table 3 shows details regarding devices used and the intraoperative variables. The most frequently used DCB catheter was the Passeo-18 Lux (Biotronik). No distal embolisation, arterial dissection or perforation, puncture site haematomas or pseudoaneurysms were observed. The technical success rate was 100%, with no need for bailout stent placement. Figure 2 demonstrates the angiographic results after the use of the OAS and PTA-DCB. In one case, spasm of the anterior tibial artery at ankle level was noted distally after treatment of a 28 mm lesion. The spasm was resolved without sequalae after local nitroglycerine administration (0.2 mg).

Peripheral Artery Disease Table 3: Procedural Data Mean fluoroscopy time (min)

18.5 ± 6.2 (11–29)

Mean contrast used per patient (ml)

126.3 ± 54.9 (61–215)

Balloon angioplasty, n (%): – Passeo-18 Lux (Biotronik) – In.Pact Admiral (Medtronic)

4 (66.7%) 2 (33.3%)

Mean maximum balloon inflation pressure (atm)

8.7 ± 1.6 (8–12)

Postoperative ankle brachial pressure index

0.97 ± 0.08 (0.8–1.0)

Postoperative Rutherford classification

2.0 ±0.0

Figure 2: Angiographic Results After the Use of the Orbital Atherectomy System (2.0 mm Solid Crown) and Angioplasty with a Drug-coated Balloon (PTA-DCB)

Continuous data are presented as mean + standard deviation (range); categorical data are given as the n (%).

The postoperative mean ABPI was 0.97 ± 0.08 (0.8–1.0). Mean follow-up was 7.0 ± 4.2 months (1–12 months). During this period, there were no deaths, major amputations or TLR. Primary patency rate of the popliteal arteries was 100%.

Safety One patient with history of MI and a triple coronary bypass more than 10 years before the procedure developed de novo AF in the first postoperative day and an asymptomatic elevation of ST interval in the ECG with new cardiac ischaemia proved in a myocardial scintigraphy. He was discharged after treatment adjustment by cardiology with control in 4 weeks to schedule coronary angiography.

Discussion To our knowledge, this is the first paper focusing on the performance of the OAS in combination with PTA-DCB for isolated popliteal artery occlusions. The technical success rate was 100%. We observed no incidents of distal embolisation, arterial dissection, perforation or aneurysmal degeneration. No filter devices were used during the procedure. An improvement of ABPI and symptoms were observed in all patients postoperatively. The primary patency rate was 100% at 6 months. Foley et al. reported the results of using the OAS to treat femoropopliteal disease. The treated cohort included 10 cases with lesions of the popliteal artery.6 However, due to the mixed population and presentation of the results for the entire femoropopliteal segment without specifying the performance of the technique in the popliteal segment, the study does not allow us to draw robust conclusions. Orbital atherectomy is based on two principles: the centrifugal force due to the orbital motion produces 360° of contact of the crown with the vessel wall and creates a smooth concentric lumen, allowing the radius of orbit to increase with speed while maintaining continuous blood flow during treatment; and differential sanding with 30 micron diamond coating that sands away arterial calcium from atherosclerotic tissue, producing the elastic healthy tissue flexion minimising the coated surface on healthy tissue and liberation of micro-particulates of 2 microns. There is a low risk of distal embolisation without the need of filter devices. Both principles can explain the lower risk per se of perforation and embolisation when using OAS compared with other atherectomy systems. In the COroNary CT Angiography Evaluation For Clinical Outcomes: An InteRnational Multicenter Registry (CONFIRM) series involving 3,135

A: After treatment with first speed (60 rpm); B: After third speed (120 rpm); C: Final result after adjunctive percutaneous transluminal angioplasty with a drug-coated balloon.

patients, low rates of dissections (11.3% overall, 1.8% flow-limiting), embolism (2.2%) and vessel perforation (0.7%) were obtained. The goal after using OAS is to modify the vessel compliance rather than luminal gain.7 The absence of any relevant dissection in our cases despite the severe calcification of the lesions confirms the smooth modification of the plaque by OAS increasing the adaptability of the DCB. This avoids deployment of additional stents in an area which is associated with stent fractures due to high mechanical stress, external compression and elongation.1,8 Other atherectomy systems have also shown promising results, but the majority of them focused on the treatment of femoropopliteal lesions in general.9 Our group reported on the directional atherectomy with antirestenotic therapy (DAART) versus DCB angioplasty for isolated popliteal lesions.10 In that study, 41 patients were treated with DAART, including the TurboHawk atherectomy catheter (Medtronic), the SilverHawk (Medtronic) peripheral plaque excision system and the HawkOne atherectomy device (Medtronic); and the Pantheris optical coherence tomography atherectomy catheter (Avinger) and 31 with DCB angioplasty only. The results showed a higher technical success rate (93% versus 84%, p=0.24) and primary patency rate at 6 months with DAART (95% versus 79%). However, 7% of the treated cases resulted in an aneurysmal degeneration and 5% had an injury of the popliteal artery. Compared with those atherectomy systems, OAS was not associated with aneurysmal degeneration or with injury of the popliteal artery. One other advantage is that due to the mode of action, use of filter devices is not necessary, especially when a good distal vessel runoff is present.

Study Limitations This is a single-centre report with a small number of patients and shortterm follow-up. Nevertheless, isolated calcified popliteal lesions remain a significant challenge to treat and OAS is a relatively new technique in Europe. There is no comparison arm in the present study.

Conclusion This is the first article focusing on the popliteal artery that evaluates the performance of PTA-DCB-assisted OAS. Short-term results are promising, with a low rate of major adverse events and no need for additional stent placement. OAS and PTA-DCB should be considered an alternative treatment option in selected cases, especially in younger patients, minimising the risk of additional deployment of stents. More data are needed to confirm these results.

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Orbital Atherectomy in Chronic Atherosclerotic Lesions of the Popliteal Artery 1.

Davaine JM, Quérat J, Guyomarch B, et al. Incidence and the clinical impact of stent fractures after primary stenting for TASC C and D femoropopliteal lesions at 1 year. Eur J Vasc Endovasc Surg 2013;46:201–12. https://doi.org/10.1016/j. ejvs.2013.05.010; PMID: 23773773. Iida O, Nanto S, Uematsu M, et al. Influence of stent fracture on the long-term patency in the femoro-popliteal artery: experience of 4 years. JACC Cardiovasc Interv 2009;2:665–71. https://doi.org/10.1016/j.jcin.2009.04.014; PMID: 19628191. Micari A, Nerla R, Vadalà G, et al. 2-year results of paclitaxelcoated balloons for long femoropopliteal artery disease: evidence from the SFA-long study. JACC Cardiovasc Interv 2017;10:728–34. https://doi.org/10.1016/j.jcin.2017.01.028; PMID: 28385412. Babaev A, Zavlunova S, Attubato MJ, et al. Orbital atherectomy plaque modification assessment of the femoropopliteal artery via intravascular ultrasound (TRUTH Study). Vasc Endovasc Surg

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2015;49:188–94. https://doi.org/10.1177/1538574415607361; PMID: 26490645. Fanelli F, Cannavale A, Gazzetti M, et al. Calcium burden assessment and impact on drug-eluting balloons in peripheral arterial disease. Cardiovasc Intervent Radiol 2014;37:898–907. https://doi.org/10.1007/s00270-014-0904-3; PMID: 24806955. Foley TR, Cotter RP, Kokkinidis DG, et al. Mid-term outcomes of orbital atherectomy combined with drug-coated balloon angioplasty for treatment of femoropopliteal disease. Catheter Cardiovasc Interv 2017;89:1078–85. https://doi.org/10.1002/ ccd.26984; PMID: 28295971. Das T, Mustapha J, Indes J, et al. Technique optimization of orbital atherectomy in calcified peripheral lesions of the lower extremities: the CONFIRM series, a prospective multicenter registry. Catheter Cardiovasc Interv 2014;83:115–22. https://doi. org/10.1002/ccd.25046; PMID: 23737432.

San Norberto EM, Flota CM, Fidalgo-Domingos L, et al. Realworld results of supera stent implantation for popliteal artery atherosclerotic lesions: 3-year outcome. Ann Vasc Surg 2020;62:397–405. https://doi.org/10.1016/j.avsg.2019.06.038; PMID: 31449958. 9. Schwindt AG, Bennet JG, Crowder WH, et al. Lower extremity revascularization using optical coherence tomography-guided directional atherectomy: final results of the evaluation of the Pantheris optical coherence tomography imaging atherectomy system for use in the peripheral vasculature (VISION) study. J Endovasc Ther 2017;24:355–66. https://doi. org/10.1177/1526602817701720; PMID: 28393673. 10. Stavroulakis K, Schwindt A, Torsello G, et al. Directional atherectomy with antirestenotic therapy vs drug-coated balloon angioplasty alone for isolated popliteal artery lesions. J Endovasc Ther 2017;24:181–8. https://doi.10.1177/1526602816683933; PMID: 28008792.

Venous

Treatment of May–Thurner Syndrome in a Patient with an Iliac Artery Stent Raleene Gatmaitan,1 Keagan Werner-Gibbings,1,2,3 Tommaso Donati,2,3 Prakash Saha2,3 and Stephen Black2,3 1. Department of Vascular Surgery, Nepean Hospital, Kingswood, NSW, Australia; 2. Department of Vascular Surgery, Guy’s Hospital, London, UK; 3. Department of Vascular Surgery, St Thomas’ Hospital, London, UK

Abstract May–Thurner syndrome (MTS) is caused by compression of the left iliac vein by the right iliac artery, leading to clinical manifestations of outflow obstruction in the lower limb and deep vein thrombosis. There have been increasing reports of iatrogenic MTS caused by medical implants. The authors report the case of a 60-year-old man who developed MTS after stenting of the right common iliac artery. Due to the debilitating nature of the patient’s symptoms of venous congestion in the left leg, he proceeded with endovascular venoplasty and venous stent insertion with concurrent intra-arterial balloon angioplasty of the existing right common iliac artery stent. Technical success and primary patency of arterial and venous stents were achieved. The patient remained asymptomatic at 6 weeks and 3 months follow-up and arterial and venous stents were found to be patent on duplex ultrasound. Surgical management of MTS may include thrombolysis, thrombectomy, venoplasty and stenting of the left common iliac vein. Care must be taken to preserve existing medical implants during treatment of MTS. The authors demonstrate that concurrent angioplasty of the right common iliac artery during treatment of the vein is an effective method of preventing arterial stent disruption during surgical management of MTS.

Keywords May–Thurner syndrome, venoplasty, stent, deep vein thrombosis, iatrogenic Disclosure: The authors have no conflicts of interest to declare. Received: 20 June 2020 Accepted: 23 September 2020 Citation: Vascular & Endovascular Review 2020;3:e12. DOI: https://doi.org/10.15420/ver.2020.10 Correspondence: Keagan Werner-Gibbings, Nepean Hospital, Derby St, Kingswood, NSW 2747, Australia. E: keagan.werner-gibbings@health.nsw.gov.au 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 noncommercial purposes, provided the original work is cited correctly.

May–Thurner syndrome (MTS) is a well-known condition where compression of the left iliac vein by the right iliac artery can lead to clinical manifestations of lower limb outflow obstruction and precipitate deep venous thrombosis (DVT). Endovascular intervention of the iliac arteries is a common procedure and is frequently done without any incidence of MTS. Although rare, it is important to recognise that the implantation of a device in the iliac arteries can precipitate iatrogenic MTS while also complicating the treatment of underlying venous pathology.1–4 With an increase in iliac artery interventions and the recognition of the contribution of iliac veins in lower limb pathology, clinicians need to be aware of the implications of treating venous disease. We present a case of the treatment of a long-standing iliac vein occlusion with an overlying stent in the iliac artery.

Case Report A 60-year-old man presented to our tertiary referral centre for review of post-thrombotic syndrome in his left lower limb. His medical history included type 1 diabetes with neuropathy, hypertension and coronary artery bypass surgery 4 years before this presentation. His presenting symptoms were of heaviness, pain and fatigue in his left leg with recurrent bouts of venous eczema. These symptoms had developed 6 years earlier after the patient developed DVT in the context of a right common iliac artery mycotic aneurysm. The patient presented to an external hospital, where the aneurysm was initially thought to be inflammatory in nature and he was given a course of steroid management. Infective symptoms and positive blood cultures led to a

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diagnosis of mycotic disease. Due to the patient’s emergent presentation, the aneurysm was treated with a covered stent (V12 8 × 32 mm, Atrium Medical) and a prolonged course of antibiotics. After no further degeneration was noted during follow-up, the decision was made to not perform further reconstructive surgery. However, the patient developed a left-sided iliofemoral DVT – presumed secondary to compression by the aneurysm – that was treated conservatively via anticoagulation with a vitamin K antagonist and compression stockings. As his symptoms were severely affecting his quality of life, the patient underwent diagnostic investigations to determine his eligibility for surgical management of his disease. A venous duplex ultrasound demonstrated patent though incompetent deep veins in the left leg with incompetence of the superficial system. A formal venogram with intravascular ultrasound (IVUS) showed an occluded left common iliac venous system. The left external iliac vein was reconstituted via the left internal iliac vein with acceptable inflow. Compression of the left iliac vein at the level of the right iliac stent was noted. A CT angiogram demonstrated effacement of the iliac vein deep to the patent iliac artery stent (Figure 1). It is likely that the initial precipitating event was the arterial aneurysm. However, after the aneurysm sac involuted, the stent was causing residual compression of the vein. This was confirmed with intraoperative IVUS findings. The patient’s case was discussed in a multidisciplinary venous forum consisting of vascular surgeons, interventional radiologists and

Treatment of May–Thurner Syndrome in a Patient with an Iliac Artery Stent Figure 1: CT Angiogram Demonstrating Compression of the Left Common Iliac Vein by the Right Common Iliac Artery

Figure 3: Concurrent Angioplasty of the Right Common Iliac Artery and Venoplasty of the Left Common Iliac Vein

Figure 2: Intravenous Ultrasound of Left Common Iliac Vein Before Venoplasty and Stent Insertion

Figure 4: Venogram of Left Common Iliac Vein Post Venoplasty and Stent Insertion

haematologists. The decision was to treat the iliac lesion with venoplasty and endovenous stenting. To ensure patency of the arterial stent while the venous system was being treated, it was suggested that an intraarterial balloon be inflated while venoplasty was performed with the high-pressure balloon.

patient was given 8,000 units of IV heparin. An 8 × 40 mm high pressure angioplasty ‘buddy’ balloon (Charger, Boston Scientific) was placed in the arterial stent, while a 14 × 40 mm high pressure balloon (Atlas Gold, Bard) was used across the IVUS-identified lesion. Both balloons were concurrently inflated to 18 atmospheres. Significant waisting of the venous balloon was noted as it was dilated underneath the arterial stent (Figure 3). The remainder of the iliac venous system was dilated with 14 mm venoplasty down to the landing zone proximal to the profunda vein confluence in the common femoral vein. A 14 × 140 mm closed cell venous stent (Vici, Boston Scientific) was deployed cranially across the compression point followed by a 14 × 120 mm open cell stent (Medtronic) caudally down to the common femoral vein. The stents were then post-dilated with the 14 mm high pressure balloon, again with arterial protection. Completion IVUS and venography demonstrated a widely patent vessel with brisk flow (Figures 4 and 5). Completion angiography of the iliac system showed a widely patent

The procedure took place in a hybrid operating room under general anaesthesia as per department practice for venous stenting procedures. General anaesthesia was used due to the prolonged operation and the significant pain induced by dilating a chronically occluded iliac vein with a large diameter balloon. Left femoral venous access was gained under ultrasound guidance and a 9 Fr sheath was placed in the venous system. The venous iliac lesion was crossed with a stiff glide wire (Terumo Medical Corp). IVUS and venography confirmed the previously noted anatomy (Figure 2). Once crossing of the lesion was confirmed, right-sided arterial access was gained, and a 6 Fr sheath inserted. The

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Venous Figure 5: Intravenous Ultrasound of Left Common Iliac Vein After Venoplasty and Stent Insertion

these cases has consisted of pharmacomechanical thrombolysis, diagnostic confirmation of the compression by angiography and IVUS, venous stenting and a period of postoperative anticoagulation. The reported outcomes have been acceptable with resolution of symptoms and acceptable stent patency. No previous case report has described protecting the arterial stent during high pressure venoplasty. The culprit for the DVT and subsequent post-thrombotic syndrome in this case was likely to be the original mycotic aneurysm (as opposed to the placement of the arterial stent) because the DVT arose before the stent placement. However, the presence of the stent meant that adjunctive manoeuvres were needed during the venous stenting to ensure there were no arterial sequelae. The high pressures required of venoplasty balloons to disrupt the fibrotic venous scarring are sufficient to cause structural failure in an arterial stent. We ensured arterial stent patency via simultaneous inflation of arterial and venous balloons to ensure there was no impingement on the arterial stent. Arterial access was gained only after the venous lesion had been crossed to reduce the risk of an unnecessary arterial puncture.

arterial stent. The patient was commenced on therapeutic low molecular weight heparin and calf compressors while in hospital. A venous and arterial duplex ultrasound a day after the procedure demonstrated patent stents. At 2-week, 6-week and 3-month follow-up visits, the patient’s symptoms were significantly improved and duplex ultrasonography confirmed arterial and venous stent patency.

Discussion Case reports have increasingly drawn attention to the role of medical implants as a possible causative mechanism for May–Thurner syndrome. Iliac artery stenting for occlusive disease has been shown previously to precipitate iliac vein compression and induce iatrogenic MTS, as has spinal fusion surgery and endovascular repair of aortic aneurysms.3–9 In cases of arterial stenting, reports describe episodes of acute DVT in the immediate post-stenting period. Compression of the vein by the newly implanted stent, along with other factors in the stenting process, such as immobility, peri-procedural cessation of anticoagulants and manual compression of the arterial puncture site, may contribute to DVT development. The management algorithm for

Jeniann AY, Hadley JB, Kuwayama DP. Atypical May–Thurner syndrome caused by endovascular aortic aneurysm repair. J Vasc Surg Cases Innov Tech 2020;6:397–400. https://doi. org/10.1016/j.jvscit.2020.06.0004; PMID: 32715178. Xu F, Tian Z, Huang X, et al. A case report of May–Thurner syndrome induced by anterior lumbar disc herniation: novel treatment with radiofrequency thermocoagulation. Medicine (Baltimore) 2019;98:e17706. https://doi.org/10.1097/ MD.0000000000017706. PMID: 31689801. Reddy D, Mikhael MM, Shapiro GS, et al. Extensive deep venous thrombosis resulting from anterior lumbar spine surgery in a patient with iliac vein compression syndrome: a case report and literature review. Global Spine J 2015;5:e22–7. https://doi.org/10.1055/s-0034-1396431; PMID: 26225289.

Venography and IVUS were employed in tandem to ensure accurate stent deployment. Contrast venography alone is poor at demonstrating lesions in the iliac veins, as antero-posterior compression and consequent vein effacement can demonstrate a seemingly patent vessel.10 IVUS is therefore integral in identifying the MTS compression point and ensuring the cranial extent of the stent is placed across this point without projecting excessively into the inferior vena cava. IVUS is especially advantageous in cases of iatrogenic MTS where the crossing point of the echogenic stent is easily identified.

Conclusion The use of iliac intervention for arterial disease is rapidly increasing.11 This factor, along with the burgeoning recognition of the role iliac vein compression plays in lower limb symptoms, will result in iatrogenic MTS being encountered more frequently. Clinicians need to be alert for the potential role that stents and other medical implants have in precipitating MTS and they must develop a strategy to ensure adequate treatment of the venous system without disrupting any arterial stents. In these cases, a ‘buddy’ balloon in the arterial stent – as shown in this case report – is a prudent way of ensuring that the risks of a disrupted arterial stent are reduced.

Pandit AS, Hayes M, Guiney-Borgelt S, et al. Iatrogenic May–Thurner syndrome after EVAR. Ann Vasc Surg 2014;28:e17–20. https://doi.org/10.1016/j.avsg.2013.07.019; PMID: 24559787. Rosen E, Groben L, George JC. Rare case of bilateral common iliac vein compression by arterial stents and calcification. Vascular Disease Management 2012;9:e172–4. Young L, Kwon J, Arosemena M, et al. Symptomatic compression of right iliac vein after right iliac artery stent placement. J Vasc Surg Venous Lymphat Disord 2017;5:735–8. https://doi.org/10.1016/j.jvsv.2016.10.082; PMID: 28818230. Chan HY, Choke ET, Tang TY, et al. A rare cause of May– Thurner syndrome postarterial intervention. Journal of Clinical Interventional Radiology 2019;3:180–4. https://doi. org/10.1055/s-0039-1693630.

Hermany PL, Badheka AO, Mena-Hurtado CI, et al. A unique case of May–Thurner syndrome: extrinsic compression of the common iliac vein after iliac artery stenting. JACC Cardiovasc Interv 2016;9:e39–41. https://doi.org/10.1016/j.jcin.2015.11.042; PMID: 26896887. 9. Rachaiah JM, Goyal V, Nagesh CM, et al. An interesting case of iatrogenic May–Thurner like syndrome. International Journal of Medical Research & Health Sciences 2016;5:83–6. 10. McLafferty RB. The role of intravascular ultrasound in venous thromboembolism. Semin Intervent Radiol 2012;29:10–5. https:// doi.org/10.1055/s-0032-1302446; PMID: 23450229. 11. Upchurch GR, Dimick JB, Wainess RM, et al. Diffusion of new technology in health care: the case of aorto-iliac occlusive disease. Surgery 2004;136:812–8. https://doi.org/10.1016/j. surg.2004.06.019; PMID: 15467666.

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Peripheral Artery Disease

Radial Access for Neurointerventions Roger Barranco Pons, Isabel Rodriguez Caamaño and Marta de Dios Lascuevas Department of Interventional Neuroradiology, Hospital Universitari de Bellvitge, Hospitalet de Llobregat, Barcelona, Spain

Abstract Transradial access (TRA) has become the standard approach for cardiac intervention, with a large body of evidence demonstrating a lower incidence of vascular complications, better patient experience and cost reduction. There has been increasing interest in using TRA both for diagnostic neuroangiography and for interventional neurovascular procedures. The aim of this article is to discuss the advantages and limitations of TRA for neurointerventions. General technical details, such as pre-procedure recommendations, prevention of spasm and occlusion, haemostasis protocols and distal TRA puncture, are also described, along with the specific technical details of TRA for aneurysm embolisation, stroke thrombectomy and other neurovascular interventions. TRA provides additional tools to the neurointerventionist and – with appropriate training – the whole spectrum of intervention procedures can be achieved using this approach.

Keywords Radial access, neurointerventions, stroke, brain aneurysm embolisation Disclosure: The authors have no conflicts of interest to declare. Received: 30 April 2020 Accepted: 24 August 2020 Citation: Vascular & Endovascular Review 2020;3:e13. DOI: https://doi.org/10.15420/ver.2020.13 Correspondence: Roger Barranco Pons, Hospital Universitari de Bellvitge, Feixa llarga s/n. 08907, Hospitalet de Llobregat, Barcelona, Spain. E: rbarranco@bellvitgehospital.cat 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 noncommercial purposes, provided the original work is cited correctly.

Transfemoral access (TFA) has been widely used in interventional neuroradiology and is the most frequently used vascular approach for catheterisation of the supraaortic and intracranial vessels. However, TFA can lead to potentially life-threatening complications, which has sparked interest in transradial access (TRA) as a safer access option. In a review of 19,826 consecutive patients undergoing diagnostic cerebral angiography using TFA, access-site haematoma was the most common complication overall (4.2%).1 Percutaneous radial access was described by Campeau in 1989 for coronary angiography in 100 patients.2 Since then, a growing body of evidence suggests that TRA is safer for patients and more cost-effective compared with TFA. Radial access reduces mortality and major adverse cardiovascular events and improves safety, with reductions in major bleeding and vascular complications across the whole spectrum of patients with coronary artery disease.3 The 2018 European Society of Cardiology/European Association for Cardio-Thoracic Surgery guidelines on myocardial revascularisation state that radial access is preferred for any percutaneous coronary intervention irrespective of clinical presentation, unless there are overriding procedural considerations.4 Matsumoto and colleagues described TRA for neurointervention procedures in 2000 and there are large series showing the safety and feasibility of transradial cerebral angiography.5–9 Furthermore, complex interventions for both ischaemic and haemorrhagic disease of the posterior and anterior circulation have been reported, highlighting the feasibility of this approach despite the use of femoral-designed devices.10–16 Adoption of TRA has been slow in the neuroendovascular field, although interest has increased in recent years.

In this review, we examine the advantages, limitations and technical details of neurovascular interventions using TRA. Specific technical details for neurointerventions in haemorrhagic and ischaemic disease are also described.

Advantages The vast experience of using TRA in cardiology has yielded considerable knowledge about its safety, although some specific conditions regarding neurointerventions need to be considered. Because of its recognised safety, TRA might be the first option in patients with severe femoral or aorto-iliac disease, obese patients with deep femoral arteries or patients with high haemorrhagic risk. Anticoagulants do not need to be withdrawn when using TRA in patients receiving these medications. Even though it is not well established that TRA is necessarily safer in patients with atherosclerotic disease involving the aortic arch for neuroendovascular procedures, it is known that in the thoracic region calcifications are more often formed in the aortic arch and descending rather than ascending aorta.17,18 For some TFA-challenging anatomies such as a bovine or type III aortic arch type, TRA might be a better option. TRA also has the advantage of offering direct access to the vertebrobasilar system. Other TRA access advantages include better tolerability and short haemostasis times allowing for very short hospital stays – both in diagnostic angiographies and scheduled interventions. From a financial perspective, there are savings in access complication costs, closure devices and hospital stay.19

Limitations, Crossovers and Complications Despite the feasibility and known advantages of TRA, there are access site and cerebrovascular-specific limitations to TRA. In the field of

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Peripheral Artery Disease cardiology, recent registries have shown that risk of access failure and conversion to TFA has a low conversion index (1.5%), due to operator experience, improved techniques and material.20,21 This contrasts with older trials, in which the failure index was 7.3% compared to 2% for TFA.22

puncture and to measure the diameter of the artery serves to correctly select and rule out radial procedures in patients in whom the radial inner diameter is <1.5 mm (Figure 1). It is important to note that when measuring the diameter of the artery there are factors that can influence the results (check that the patient is not cold and is calm).

There are data showing that experience performing approximately 30–50 TRA cerebral angiograms is needed to become comfortable with TRA. During the learning curve, there is a reduction in crossover rate and fluoroscopy times, with better success in catheterising all intended supra-aortic arteries.23,24 In a recent systematic review of 1,342 procedures of TRA for neurointerventions, the crossover rate to TFA was 4.77%. Among the crossover group, 10.93% crossed over because of the failure to obtain radial artery (RA) access and because of the inability to catheterise the target vessel in 89.06%.25

Several authors have analysed the diameter of the RA with ultrasound and correlated the risk of occlusion depending on the external diameter of the introducer used.21 They found no correlation of the radial diameter with BMI.22 A cannulation procedure can still be attempted with smaller radial diameters, but the chances of vasospasm and TFA conversion are higher, especially in young women.37 Administration of topical lidocaine and nitroglycerin or subcutaneously administered nitroglycerin prior to puncture has been shown prospectively to increase the diameter of the RA and facilitate TRA.34,38,39

The two most common complications associated with TRA are RA spasm and RA occlusion. RA spasm is noted in 15–30% of cases, but this can be reduced to 6–10% with intra-arterial administration of nitroglycerin and a calcium channel blocker.26,27 RA occlusions have been reported to occur at rates of 0.8–33% in different series, but this can be reduced significantly with precautions described in the following section.20,28 Furthermore, RA occlusion is clinically silent in the majority of cases, secondary to collateral circulation via the palmar arch. Apart from difficulty using the same RA for future access, the clinical implications of RA occlusion are very limited.29,30

In most patients, performing a diagnostic angiogram with a 5 Fr introducer will be possible. A cross-sectional inner RA diameter of approximately 1.5–2.0 mm is required for a 5 Fr sheath and diagnostic catheters. Some interventions can be done through a 6 Fr or 7 Fr thinwalled specific radial sheath, from which a 6 Fr (0.070 inner diameter [ID] system) or 7 Fr guiding catheter can be used. For a 6 Fr sheath, we recommend at least 1.9 mm of radial diameter. The Terumo slender 6 Fr and Prelude Ideal (Merit Medical) thin-walled specific radial sheaths have an outer diameter of 2.44 mm compared to other non-thin-walled radial sheaths (2.63−2.8 mm) and Terumo 6 Fr femoral sheaths (2.62 mm). Other interventions may require larger sheaths and intermediate catheters for support. In our institution, for cases in which large-bore sheaths (0.088 ID) are needed, this approach is used if the radial diameter is at least 2.3 mm.

Clinically relevant complications, such as hand ischaemia requiring amputation and compartment syndrome, have been reported, but are exceedingly rare.31 Minor complications, such as extended access site pain, haematoma and bruises, are other possibilities.32 There are some anatomic variations of the RA that operators should be aware of, such as high brachial artery bifurcation, radial or brachial artery loops, tortuosity of the RA and the presence of an accessory RA. For cerebrovascular angiography specifically, some challenging anatomies may cause difficulty in catheterisation of the vessels. These include the left vertebral artery, a proximal right common carotid artery (CCA) with an acute angle or a loop in the left CCA. Another anatomic variant, subclavia lusoria (reported to be present in 0.1–0.8% of cases) may present some catheterisation difficulties from a right TRA.33

Technical Details Pre-procedure Traditionally, assessment of the collateral circulation to the hand via Allen’s test and the Barbeau test (objective Allen’s test using pulse oximetry and plethysmography) has been used prior to TRA. However, significant controversy exists regarding the need for pre-procedural collateral circulation testing.34 Of note, the Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX (MATRIX) trial randomised more than 4,000 patients to TRA (regardless of the preprocedure collateral testing result) and found no post-procedure symptomatic hand ischaemia.35

Size Matters The RA – having a smaller calibre – has a series of limitations regarding the diameter of the materials used and, in some patients, this may preclude its use.36 In our experience, the use of ultrasound both for

Prevention of Spasm and Occlusion While essentially clinically silent, prevention of RA occlusion is important, especially with regard to consideration of further procedures. RA occlusion rates have been shown to increase with increasing sheath diameter, especially when the outer diameter of the sheath exceeds the inner diameter of the RA. The use of sheathless TRA has been described as allowing for larger ID guide catheters to be placed without an attendant increase in outer diameter from sheath placement.40 Administration of unfractionated heparin at therapeutic levels (50 IU/kg or 5,000 IU) has been shown prospectively to lead to a sixfold reduction in RA occlusion rates, with higher rates of administration (100 IU/kg) further decreasing the incidence of RA occlusion.41,42 However, the best route for heparin administration remains unclear, with no difference between intravenous and intra-arterial bolus administration through a sheath with regard to RA occlusion rates.41–43 The administration of intra-arterial antispasmodic medications has been shown prospectively in multiple trials to reduce RA spasm although without a clear consensus on the most effective combination and dose.44–46 A meta-analysis of 22 randomised trials found the lowest rates of RA spasm following intra-arterial administration of nitroglycerin 200 µg and verapamil 5 mg.47 We recommend preparation and administration of a cocktail in a 20 ml syringe with 200 µg nitroglycerin, 5 mg of verapamil and 4,000 IU heparin. Once the sheath is in place, we aspirate blood to fill the 20 ml cocktail syringe and inject it gently to minimise discomfort. Recalcitrant RA spasm can be managed with further administration of antispasmodic medications.

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Radial Access for Neurointerventions Figure 1: Radial Access, Step-by-step

A: Pre-intervention ultrasound radial inner diameter measurement after subcutaneous nitroglycerin injection (arrow); B: Ultrasound-guided puncture; C: Short sheath placement and antispasmodic cocktail injection; D: Long sheath with stylet placement up to subclavia; E: Stylet removal and catheter placement for catheterisation; F: Long sheath removal after inflation of a dedicated haemostatic device (example of distal transradial access).

Closure The use of a patent haemostasis technique significantly improves RA patency rates. Patent haemostasis has been shown to reduce rates of RA occlusion by 75% compared with conventional pressure application, either manually or with a compressive haemostatic band.48 Prophylactic ulnar artery compression, added to patent haemostasis, is reported to result in RA occlusion rates <1%.49 Although use of patent haemostasis is paramount in preventing RA occlusion, there is no consensus on the optimal protocol for deflation of the radial haemostatic band.48 If RA occlusion is encountered immediately post-operatively, ulnar compression, as well as administration of low-molecular-weight heparin can promote recanalisation.50

Distal Transradial Access Recently, distal transradial access (dTRA) has received more attention in the attempt to improve some of the limitations of conventional radial access.51 Recent series have reported both cerebral angiography and neurointerventions successfully performed through dTRA.52,53 In puncturing the RA in the anatomic snuffbox, distal to the origin of superficial palmar branch, in the case of occlusion there is a theoretically lower risk of compromising the superficial palmar arch and less risk of hand ischaemia. In addition, the forearm can be kept in mid-prone position right next to the body, which reduces discomfort because the position is more ergonomic. In interventions in which left RA is needed, it is very difficult to use the left conventional radial approach as most neuro suites are designed (e.g., the position of controls and the screen) to work on the right side of the patient. In these cases, left distal radial access is particularly useful to perform left vertebral artery procedures via the left forearm. The left forearm is kept partially flexed over the

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patient’s abdomen with the hand close to the left groin and then taped in place (Figure 2). The diameter of the distal RA, which can be smaller in the snuffbox compared with the conventional radial puncture site therefore predisposing to spasm, may result in higher conversion rates.54 We strictly recommend the use of ultrasound to measure, select, and puncture the distal RA at the snuffbox. Another advantage of puncturing the dTRA is that patency rates are reported to be very high and this permits short haemostatic protocols.55 In addition, in the case of artery occlusion, this normally happens at the level of the snuffbox. Therefore, the RA can still be punctured in the forearm.

Haemorrhagic Disease Because haemorrhagic disease can involve both acute ruptured disease or elective cases, we recommend first trying radial access in elective rather than acute cases. During this kind of intervention – in which larger diameter catheters and sheaths might be used – sedation and general anaesthesia also help to reduce the incidence of RA spasm by reducing both anxiety and sympathetic drive.56,57

Aneurysm Treatment A 6 Fr short sheath can be used to introduce a 0.070 ID system after spasmolytics are administered. The 0.070 ID system can either be a Simmons-2 guiding catheter Envoy (Codman Neuro) or any other guiding catheter using a long Simmons-2 catheter or using a wire exchange. In the event that simple coiling is used, a 6 Fr catheter such

Peripheral Artery Disease Figure 2: Left Distal Transradial Access for Flow Diverter Placement in a Basilar Aneurysm

A: Non-contrast CT shows Fisher IV subarachnoid haemorrhage with ventricular haemorrhagic contamination and incipient signs of acute hydrocephalus; B: CT angiography showing a dominant LVA; C: Transfemoral access angiography of LVA demonstrating wide-neck aneurysm at the left side of the mid-third basilar artery; D: Immediate post-balloon-assisted coiling embolisation angiography showing residual neck; E: 1 month after subarachnoid haemorrhage resolution, flow diverter placement is scheduled and left distal transradial access is decided upon. Image illustrates left distal transradial access assembly and working position. 6 Fr short sheath and 5 Fr intermediate catheter placed in the left vertebral artery; F and G: Native image and left vertebral artery angiography after flow diverter placement and slow filling of the aneurysm sac; H: Discharge of patient after overnight observation. Left anatomical snuffbox puncture site.

as Envoy DA may allow the use of a 0.058 intermediate catheter if needed (e.g. a 5 Fr Navien [Medtronic] or 5 Fr Sofia [Microvention]). Most aneurysm embolisation techniques can be performed through a 6 Fr guiding catheter, which allows two microcatheters in order to perform balloon-assisted coiling (BAC) and/or stent-assisted coiling (SAC). In more challenging cases where greater support is needed, larger sheaths and intermediate catheters may be required. For treatments in which a large-bore sheath (0.088 ID) is needed, we would recommend that the RA size be at least 2.3 mm in crosssectional diameter. To use them, we perform an exchange of the short sheath (after the injection of a spasmolystic) by placing a guidewire in the subclavia. The short sheath is removed, and a long sheath is then advanced into the RA over the wire. Similar to TFA, a small skin incision might be necessary prior to advancing the large-bore sheath. The stylet is then removed, and a Simmons-2 shaped catheter is navigated over a guidewire into the target internal carotid artery (ICA) and then the Simmons shape is reformed in the arch. Once the catheter is in the CCA, a guidewire is advanced into the ICA. The catheter can be advanced over the guidewire to the ICA, and then the long sheath is advanced over the Simmons catheter. Simmons catheters may not advance easily over the wire and tend to herniate in the arch. This problem can be solved with a stiffer 0.35 guidewire or by advancing the long sheath while the guidewire is in the ICA and the selected catheter is in the origin of the CCA. Our institutional experience is using catheters such as Shuttle (Cook Medical) and more recently Ballast (Balt). A largebore 6 Fr long sheath allows using a 6 Fr intermediate catheter, which can provide enough support to deploy flow diverters14 and offer better support for BAC or SAC (Figure 3).

In some embolisation cases where a double access is needed to control both carotids, both vertebral arteries, a posterior and anterior circulation artery, or to do a transcirculation approach, TRA can be also useful.58 Access can be through both RAs or combining TRA and TFA. In cases with ruptured aneurysms, we tend to administer the radial cocktail without heparin and give systemic heparin once the first coil is detached and BAC is performed. The decision as to when to give heparin depends more on the need for neurovascular intervention and safety rather than prevention of RA occlusion. In our experience, the use of radial access for elective aneurysm embolisation also allows early patient discharge after overnight observation.

Treatment of Arteriovenous Malformation and Arteriovenous Fistula Complex interventions such as arteriovenous malformation (AVM) and arteriovenous fistula (AVF) embolisation can also be done through TRA (Figure 4). In cases of a multiple feeder AVF or AVM, double access may be required. While one access can be the treating one, in other vessels diagnostic catheters may help to ensure all the feeders are closed. TRA can be used as the main treating access, as a control catheter access or as a multiple access from both radial arteries (for the left radial a left dTRA is recommended). Most embolisation techniques, such as single microcatheter, balloon assisted embolisation, pressure cooker technique with an Echelon-10 (Microvention), and detachable tip microcatheter can be applied through a 6 Fr guiding catheter and a 6 Fr radial sheath.59 When the pressure cooker technique with magic catheter is required, a 6 Fr long sheath or a 7 Fr guiding catheter through a 7 Fr radial sheath can be used.59

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Radial Access for Neurointerventions Figure 3: Right Transradial Access for a Pericallosal Aneurysm Treatment After Tansfemoral Access Failure

A: Previous failure of transfemoral access for common carotid tortuosity and transradial access. catheterisation; B: Non-ruptured and growing pericallosal aneurysm; C and D: Substracted and native images of post-treatment results using Silk Vista Baby stent (Balt) and coiling; E: Transradial access use of a 6 Fr long sheath, an intermediate support catheter and microcatheter; F and G: Retrieval of long sheath using a haemostatic band.

A specific potential drawback of TRA for this kind of intervention is the need to work with low blood pressure and not administer systemic heparin.

Ischaemic Disease Stroke Thrombectomy As is commonly recognised, stroke revascularisation has a crucial difference compared with other neurovascular procedures in that not wasting time is mandatory. In our experience, we have performed TRA thrombectomies once both the operator and the rest of the team have gained enough experience performing diagnostic angiographies and other interventions. Even with experience, the first TRA cases were done after TFA failure. With experience, cases can be selected to do TRA as a first approach in vertebro-basilar stroke, bovine arch and type III aortic arch. One potential advantage of TRA over TFA is that the smaller radial and brachial diameter acts as a support to the system when dealing with vascular tortuosity. Some authors have compared TRA and TFA performance in stroke thrombectomy in different challenging aortic anatomies,60 demonstrating its feasibility (Figure 5). Before proceeding with a TRA we first measure the RA inner diameter and rule the procedure out if the diameter is <2.3 mm in order to minimise the risk of RA spasm. The simplest means of performing the thrombectomy is with a stentriever while aspirating from a 6 Fr guiding catheter placed in the ICA through a 6 Fr specific radial sheath. Either a Simmons-2 shaped 6 Fr Envoy guiding catheter placed directly, or a 6 Fr

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guide catheter coaxially navigated into the target ICA over a 125 cm Simmons-2 shaped diagnostic catheter can be used. However, this technique means not using a distal aspiration catheter as a proximal occlusion balloon.10 For anterior circulation stroke, in the case of the Direct Aspiration First Pass Technique (ADAPT) or distal aspiration with retrievable stent assisted thrombectomy, a large 6 Fr sheath is required. As previously described, a 6 Fr large sheath can placed in the ICA, having enough support through the arch and allowing aspiration catheters up to 0.71 inches, such as Penumbra ACE 6 (Penumbra) Sofia 6 Fr+, React 071 (Medtronic), or AXS Vecta 71 (Stryker). Having a 6 Fr long sheath in place also allows treatment of tandem stroke, and, if required, carotid stents can be place through it. For operators who prefer using balloon occlusion aspiration, there are several options: • When the radial diameter is small, a 7 Fr radial thin-walled sheath allows a Cello 6+ balloon guide catheter (Medtronic). • Once a Simmons catheter is introduced into the 7 Fr sheath and used to navigate to the target ICA over an exchange guidewire, the catheter is removed and the Cello balloon guide catheter is advanced. One possible disadvantage of this technique is that as the balloon inner diameter is smaller there is a theoretically greater risk of catheter occlusion in cases with high thrombotic burden.

Peripheral Artery Disease Figure 4: Radial Transradial Access for Arteriovenous Fistula Embolisation

A: Non-enhanced CT showing right cerebellar hemisphere haemorrhage and subarachnoid haemorrhage in fourth ventricle; B: Coronal view of CT angiography showing vessel dilatation and aneurysm with suspicion of posterior circulation origin; C, D: Right transradial access angiography of both vertebral arteries without pathologic findings; E: Lateral angiography of left common carotid artery showing Cognard type IV arteriovenous fistula. Main feeder is ascending pharyngeal artery and secondary small feeder of occipital artery. Right transradial access placement of a 6 Fr long sheath in external carotid artery; F: Selective angiography of occipital artery. Failed attempt to embolise through transmastoidal branch using pressure cooker technique with detachable microcatheter and coil protection of distal occipital artery; G: Balloon microcatheter (arrow) inflated and placed in ascending pharyngeal artery during onyx embolisation and reaching the venous pouch (arrowhead); H: Post-embolisation angiography of left external carotid.

• When in the pre-procedural ultrasound radial diameter is at least 2.4 mm, an 8 Fr balloon guide catheter can be used. We recommend doing this sheathlessly, without an 8 Fr short sheath. Both Cello 8 Fr (Medtronic) and Merci 8 Fr (Stryker) have stylets, and can be placed as previously described with long sheaths, by wire exchange from a previously placed short sheath. Once the balloon tip is placed in the subclavian artery, the stylet can be removed and replaced by a Simmons-2 shaped catheter. The Flowgate 2 balloon (Stryker) package has a 6 Fr catheter instead of a stylet, which might be used as well making a prior skin incision almost mandatory. More data are needed regarding the safety of prophylactic heparin administration to prevent RA occlusion owing to the risk of haemorrhagic conversion after stroke. Most centres perform thrombectomy without systemic heparinisation, even though some heparin is infused through the saline perfusion of the catheters. In our experience, in those cases with bridging therapy and previous recombinant tissue plasminogen activator, we do not administer heparin to prevent RA occlusion. In other cases, once the procedure is finished without complications, we administer lower heparin doses (2,000 IU) just before retrieving the sheath from the RA.

Carotid Stenting Access site bleeding and vascular access complications are the most common adverse events after carotid artery stenting (CAS) with TFA. The need for transfusion may significantly increase the stroke risk as well.61 Complex aortic arch is a risk factor for technical failures, and type III aortic arch with friable atheromas is the most risky feature for CAS complications.62 The highest prevalence of atherosclerosis distribution is in the descending aorta (38.2%), followed by arch (27.6%) distal to the innominate artery, especially with increasing age.63 On the other hand, symptomatic stroke (14%) contralateral to the treated carotid stenosis indicates that aortic arch catheter manipulation is a cause of atheroembolic brain lesion.61,64 TRA may minimise catheter contact in the arch, particularly for right ICA and left bovine ICA. Transradial CAS can be successfully performed by experienced operators with a low complication rate in a large percentage of patients.65,66 From a technical point of view, in terms of the type of carotid stent and the required ID of the delivery system, a 6 Fr or 7 Fr guiding catheter may be used. When stents require a larger delivery system or better support is needed, a long 5 Fr or 6 Fr sheath may also be used. Either way, a distal protection filter system can also be used. If a proximal balloon occlusion technique is desired, it also can be done as described above.

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Radial Access for Neurointerventions Figure 5: Right Transradial Access for a Tandem Stroke Treatment

A: Transradial access catheterisation of common internal carotid. Guidewire support together with a 5 Fr Simmons catheter placed in the ostium of common carotid (arrow), allowing support for navigation of a 6 Fr long sheath (arrowhead); B: Right internal carotid proximal occlusion; C: Post-occlusion angiography from a coaxial 5 Fr guiding catheter and filter placement (arrow); D: Angiography post stent placement, balloon dilatation and filter retrieval; E: Intracranial run with a middle cerebral artery segment 1 (M1) occlusion (thrombolysis in cerebral infarction 0); F: 4.5 x 35 mm stentriever deployment (arrow) and M1 placement of a 6 Fr Sofia distal aspiration catheter (arrowhead); G: Post-first pass angiography with complete revascularisation (thrombolysis in cerebral infarction 3).

Conclusion TRA has become the standard approach for cardiac intervention due to the large body of evidence demonstrating the lower incidence of vascular complications, better patient experience and cost reduction. The neurovascular field can benefit from the available knowledge from

Kaufmann TJ, Huston 3rd J, Mandrekar J, et al. Complications of diagnostic cerebral angiography: evaluation of 19,826 consecutive patients. Radiology 2007;243:812–9. https://doi. org/10.1148/radiol.2433060536; PMID: 17517935. Campeau L. Percutaneous radial artery approach for coronary angiography. Cathet Cardiovasc Diagn 1989;16:3–7. https://doi. org/10.1002/ccd.1810160103; PMID: 2912567. Snelling BM, Sur S, Shah SS, et al. Transradial access: lessons learned from cardiology. J Neurointerv Surg 2018;10:487–92. https://doi.org/10.1136/neurintsurg-2017-013295; PMID: 28963366. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 2019;40:87–165. https://doi.org/10.1093/eurheartj/ehy394; PMID: 30165437. Matsumoto Y, Hokama M, Nagashima H, et al. Transradial

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the cardiology field. TRA provides additional tools for the neurointerventionalist and, with adequate training, the whole spectrum of intervention procedures can be carried out. The use of ultrasound is recommended to measure and puncture the RA, as well as to begin the learning curve through performing diagnostic angiography.

approach for selective cerebral angiography: technical note. Neurol Res 2000;22:605–8. https://doi.org/10.1080/01616412.20 00.11740727; PMID: 11045024. Park JH, Kim DY, Kim JW, et al. Efficacy of transradial cerebral angiography in the elderly. J Korean Neurosurg Soc 2013;53:213– 7. https://doi.org/10.3340/jkns.2013.53.4.213; PMID: 23826476. Brunet MC, Chen SH, Sur S, et al. Distal transradial access in the anatomical snuffbox for diagnostic cerebral angiography. J Neurointerv Surg 2019;11:710–3. https://doi.org/10.1136/ neurintsurg-2019-014718; PMID: 30814329. Snelling BM, Sur S, Shah SS, et al. Transradial cerebral angiography: techniques and outcomes. J Neurointerv Surg 2018;10:874–81. https://doi.org/10.1136/ neurintsurg-2017-013584; PMID: 29311120. Jo KW, Park SM, Kim SD, et al. Is transradial cerebral angiography feasible and safe? A single center’s experience.

J Korean Neurosurg Soc 2010;47:332–7. https://doi.org/10.3340/ jkns.2010.47.5.332; PMID: 20539791. 10. Sur S, Snelling B, Khandelwal P, Caplan JM. Transradial approach for mechanical thrombectomy in anterior circulation large-vessel occlusion. Neurosurg Focus 2017;42:1–4. https:// doi.org/10.3171/2017.1.FOCUS16525; PMID: 28366055. 11. Schönholz C, Nanda A, Rodriguez J, et al. Transradial approach to coil embolization of an intracranial aneurysm. J Endovasc Ther 2004;11:411–3. https://doi.org/10.1583/03-1192.1; PMID: 15298511. 12. Ruzsa Z, Nemes B, Pintér L, et al. A randomised comparison of transradial and transfemoral approach for carotid artery stenting: RADCAR (RADial access for CARotid artery stenting) study. EuroIntervention 2014;10:381–91. https://doi.org/10.4244/ EIJV10I3A64; PMID: 25042266. 13. Peitz GW, Kura B, Johnson JN, Grandhi R. Transradial approach

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Aneurysms

Conservative Management of a Splenic Artery Aneurysm in Pregnancy: A Case Report Raleene Gatmaitan,1 Keagan Werner-Gibbings,1,2,3 Morad Sallam,2,3 Rachel Bell2,3 and Panos Gkoutzios4 1. Nepean Hospital, Kingswood, NSW, Australia; 2. Department of Vascular Surgery, Guy’s Hospital, London, UK; 3. Department of Vascular Surgery, St Thomas’ Hospital, London, UK; 4. Department of Radiology, Guy’s Hospital, London, UK

Abstract Splenic artery aneurysms (SAA) are a rare and life-threatening pathology. Ruptured SAA has a mortality rate of up to 25%, with increased rates of rupture in pregnancy, pseudoaneurysm, liver transplantation, portal hypertension, symptomatic SAA and diameter >2 cm. Management of SAA in pregnant women is poorly described in the literature, making treatment of these patients difficult. Furthermore, careful consideration of complications for both the mother and the foetus need to be taken into account. This case report demonstrates that conservative management with monthly surveillance MRI can be used as viable treatment option of an asymptomatic 17 mm splenic artery aneurysm in a pregnant woman.

Keywords Splenic artery aneurysm, pregnancy, peripartum, conservative, surveillance, MRI Disclosure: The authors have no conflicts of interest to declare. Received: 2 June 2020 Accepted: 6 October 2020 Citation: Vascular & Endovascular Review 2020;3:e14. DOI: https://doi.org/10.15420/ver.2020.11 Correspondence: Keagan Werner-Gibbings, Nepean Hospital, Derby St, Kingswood, NSW 2747, Australia. E: keagan.werner-gibbings@health.nsw.gov.au 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 noncommercial purposes, provided the original work is cited correctly.

Splenic artery aneurysms (SAA) are the most frequently encountered of the visceral aneurysms, with incidence rates up to 1% reported in the normal population.1 The most devastating complication of SAA is rupture, an event conferring mortality rates of approximately 25%. SAA is an especially concerning pathology in pregnant patients. Haemodynamic fluctuation and reduced connective tissue tensile strength during pregnancy have been theorised to contribute to the increased risk of SAA rupture, which is especially prevalent in the third trimester.2,3 Furthermore, mortality due to rupture is higher in pregnancy with maternal mortality and foetal mortality rates of 20–75% and 15– 95%, respectively.4,5 The thresholds for intervening in SAA in the general population are relatively well defined: size >2 cm, symptomatic, rapid growth or liver transplantation.6 However, when an unruptured SAA is encountered in pregnancy the indications for intervention are more opaque, especially for small aneurysms. We present a case of a patient with a small splenic aneurysm that was managed conservatively over the course of her pregnancy. Informed written consent regarding case report and images has been provided by the patient.

Case Report A 39-year-old woman presented to the vascular surgery outpatient department of our tertiary referral hospital for review of a splenic artery aneurysm in the context of being 20 weeks pregnant. Her past medical history was notable only for hypothyroidism. She had been reviewed 2 years earlier by our vascular service, having been referred from the general surgical unit, where work-up for acalculous cholecystitis had demonstrated a 17 mm splenic artery aneurysm on magnetic resonance cholangiopancreatography. At that time, a multidisciplinary team meeting

consisting of vascular surgeons, general surgeons and interventional radiologists had concluded that conservative management was appropriate, due to the sub-threshold diameter and the tortuosity of the splenic artery making any spleen preserving endovascular intervention technically difficult. The patient was counselled at this time regarding the increased risks of rupture during pregnancy and the preference of the team to pre-emptively intervene on her SAA if future pregnancies were planned. She confirmed that she had no plans for any further children at that time. A 6-month follow-up scan and review confirmed stable sac size with no changes in morphology. Unfortunately, the patient was lost to follow-up at this stage. Her next contact with the service came after referral from her primary care clinician, having unexpectedly become pregnant. At the time of review, she was 20 weeks pregnant and progressing normally. She had no abdominal pain or discomfort. Her examination demonstrated no abnormality. A non-contrast MRI was performed at this time which demonstrated a consistently stable SAA (Figure 1). The patient was well engaged in her health choices. A thorough discussion was undertaken concerning risks and benefits of the possible treatment pathways: conservative, endovascular and open. Well counselled about the risks, the patient expressed a strong desire to pursue a course of conservative management for her aneurysm through the course of her pregnancy. Her decision was guided by concerns regarding contrast, radiation and anaesthesia, in addition to the risks of asplenism on the foetus. Her case was reviewed again by the multidisciplinary team. Comprehensive literature review provided minimal guidance on the

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Aneurysms Figure 1: MRI Surveillance Scan at Initial Consultation (20 Weeks Gestation)

Figure 2: MRI Surveillance Scan at 34 Weeks Gestation

case. Given the stable nature of the SAA and the patient’s wishes, a treatment plan of vigilant surveillance was enacted. Blood pressure control was optimised and the patient was referred to an obstetrician specialising in high-risk pregnancy. Serial monthly MRIs were undertaken, which demonstrated a stable SAA in both size and morphology (Figure 2). The patient’s pregnancy progressed without issue and her progress foetal ultrasound scans were reassuring. She delivered at 40 weeks with no perinatal complications. She has been booked for endovascular treatment of her SAA.

have addressed this issue, all with differing treatment strategies.9 Laparoscopic resection of the SAA has been successfully performed in these cases with few complications. However, great care must be made with regards to the gravid uterus in operative technique.2,5 Furthermore, a single case of embolisation of the splenic artery has been reported on a 13 mm SAA in the third trimester. Although technically successful, the patient went on to develop a splenic abscess three weeks later.10 Only one case report describes conservative management of a SAA found incidentally at 25 weeks gestation. The patient went on to deliver a healthy baby at 34 weeks with elective caesarean section and postpartum embolisation.11 This lack of published literature made the treatment of our patient, who firmly opted for a conservative approach, difficult. Our decision to opt for serial surveillance was made easier due to the presence of prepartum imaging, with which on-going comparison surveillance could be made. The availability of this baseline scan allowed assessment of size progression and morphological variation over the course of the pregnancy, factors which would have precipitated urgent treatment. This is a major advantage when compared to cases of SAA that have been identified when the patient was already pregnant. While consistency on serial imaging may have been comforting to infer SAA stability, there are no data to confirm that this is indicative of a reduced rupture risk. Our surveillance protocol was based on the premise that a stable SAA of size <20 mm was less likely to rupture than one in which changes were noted. The appropriateness of employing a size threshold as an indication for intervention is conjecture. A size of 20 mm is commonly used as the cut-off for treatment in the non-pregnant population. This absolute size indication may not hold for the pregnant cohort, where half of ruptured aneurysms have been reported as being below this diameter. Indeed, aneurysms as small as 5 mm have presented ruptured, prompting suggestions that intervention on SAA should occur in pregnancy at any size.4 We employed serial non-contrast MRI to monitor aneurysm size and morphology. MRI confers the obvious advantage over CT scanning of not employing radiation to obtain images and is safe in pregnancy. This is especially of benefit in this described case where repeated scans were necessary. MRI is also superior to ultrasound for imaging in these cases as it provides objective, topographical imaging and is less operator dependent. This is especially relevant in the latter stages of pregnancy, where the gravid uterus hampers adequate visualisation of the splenic artery anatomy. While guidelines have suggested gadolinium is likely to be safe in pregnancy, as minimal gadolinium crosses the placenta, we found non-contrast imaging was sufficient to visualise the SAA.12

Discussion A large body of evidence describes the natural history and management of SAA in the general population. SAA seems to be more prevalent in pregnancy, with half of all ruptures occurring in this population.7 When rupture during pregnancy occurs, it is most often in the third trimester (60%), with a lesser proportion occurring during the second trimester, at birth or puerperium.8 Commonly accepted practice dictates treatment of SAA at any size in those who anticipate becoming pregnant. However the bulk of evidence pertaining to the treatment of SAA in pregnancy describes cases that are ruptured on presentation. The appropriate management of patients with asymptomatic SAA who present already pregnant is poorly described; only isolated case reports

If intervention is decided upon, method and timing are important considerations. Endovascular repair is the treatment of choice for anatomically amenable SAA: those with simple morphology, not immediately adjacent to the splenic hilum. Endovascular techniques confer the attendant risks of ionising radiation on the developing foetus. Radiation exposure increases the likelihood of embryo nonimplantation, foetal abnormalities and childhood cancer.13 Methods to reduce radiation exposure to the foetus, such as targeted foetal shielding, low-dose fluoroscopy and minimal screening time, can assist in minimising risks.14 Furthermore, delaying the procedure as long as feasible can reduce the risk of side effects as evidence suggests risks from radiological procedures are greatest before 15 weeks of age. These risks taper as pregnancy progresses, such that the risks of

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Conservative Management of a Splenic Artery Aneurysm in Pregnancy intrauterine radiation after 26 weeks of gestation are similar to that of a newborn.15 This reduction in the radiation risk as the pregnancy progresses needs to be weighed against the increased risks of SAA rupture, the majority occurring in the late second or third trimester. Thus it seems that prompt treatment after 26 weeks of gestation is the ideal therapeutic window if endovascular intervention is to be undertaken. Laparoscopic treatment for SAA unable to be treated endovascularly takes the form of splenic artery ligation and splenectomy, necessitating post-operative coverage for encapsulated bacteria. Preservation of the spleen and its immune function should be considered for SAA requiring intervention far from the splenic hilum. Laparotomy with resection of the SAA and anastomosis of the proximal and distal splenic artery with successful preservation of the spleen in a non-pregnant woman has been described.16 If laparoscopic or open intervention is required, the timing of treatment needs to consider the risks to embryogenesis of

3. 4.

Stanley JC, Fry WJ. Pathogenesis and clinical significance of splenic artery aneurysms. Surgery 1974;76:907–9. PMID: 4428355. Samamé J, Kaul A, Garza U, et al. Laparoscopic aneurysm resection and splenectomy for splenic artery aneurysm in the third trimester of pregnancy. Surg Endosc 2013;27:2988– 91. https://doi.org/10.1007/s00464-013-2822-x; PMID: 23397504. Trastek VF, Pairolero PC, Joyce JW, et al. Splenic artery aneurysms. Surgery 1982;91:694–9. PMID: 7079972. Ha JF, Phillips M, Faulkner K. Splenic artery aneurysm rupture in pregnancy. Eur J Obstet Gynecol Reprod Biol 2009;146:133–7. https://doi.org/10.1016/j.ejogrb.2009.05.034; PMID: 19596508. Lang W, Strobel D, Beinder E, et al. Surgery of a splenic artery aneurysm during pregnancy. Eur J Obstet Gynecol Reprod Biol 2002;102:215–6. https://doi.org/10.1016/s03012115(01)00608-x; PMID: 11950496. Nanez L, Knowles M, Modrall JG, et al. Ruptured splenic artery aneurysms are exceedingly rare in pregnant women. J Vasc

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operating early, and technical difficulties with open and laparoscopic surgery posed by the gravid uterus in the third trimester. It is suggested that the second trimester is the most suitable for laparoscopic treatment.2 This case demonstrates that, adequately monitored, conservative management may be used as a treatment strategy in selected pregnant patients with known SAA. If a policy of conservative management is employed, multidisciplinary input is imperative. The patient requires adequate information to make informed decisions for her own welfare and that of her child. It is especially important to alert the patient to the symptoms that may manifest in the case of rupture and ensure there is a low threshold for attending urgent care. Early delivery has not yet been demonstrated to improve outcomes, but would seem prudent to minimise SAA rupture risk, as would aggressive management of hypertension. Serial surveillance with non-contrast MRI, where available, is appropriate.

Surg 2014;60:1520–3. https://doi.org/10.1016/j.jvs.2014.08.108; PMID: 25282697. Holdsworth RJ, Gunn A. Ruptured splenic artery aneurysm in pregnancy. A review. Br J Obstet Gynaecol 1992;99:595–7. https://doi.org/10.1111/j.1471-0528.1992.tb13828.x; PMID: 1525102. 8. Barrett JM, Van JH, Boehm FH. Pregnancy-related rupture of arterial aneurysms. Obstet Gynecol Surv 1982;37:557–66. https://doi.org/10.1097/00006254-198209000-00001; PMID: 6752786. 9. Sadat U, Dar O, Walsh S, Varty K. Splenic artery aneurysms in pregnancy–a systematic review. Int J Surg 2008;6:261–5. https://doi.org/10.1016/j.ijsu.2007.08.002; PMID: 17869597. 10. Parrish J, Maxwell C, Beecroft JR. Splenic artery aneurysm in pregnancy. J Obstet Gynaecol Can 2015;37:816–8. https://doi. org/10.1016/S1701-2163(15)30153-5; PMID: 26605452. 11. Wiener Y, Tomashev R, Neeman O, et al. Splenic artery aneurysms during pregnancy: an obstetric nightmare. Eur J Obstet Gynecol Reprod Biol 2019;237:121–5. https://doi. org/10.1016/j.ejogrb.2019.04.029; PMID: 31035119. 7.

12. Garcia-Bournissen F, Shrim A, Koren G. Safety of gadolinium during pregnancy. Can Fam Physician 2006;52:309–10. PMID: 16572573. 13. Wang PI, Chong ST, Kielar AZ, et al. Imaging of pregnant and lactating patients: part 1, evidence-based review and recommendations. AJR Am J Roentgenol 2012;198:778–84. https://doi.org/10.2214/AJR.11.7405; PMID: 22451541. 14. Thabet A, Kalva SP, Liu B, et al. Interventional radiology in pregnancy complications: indications, technique, and methods for minimizing radiation exposure. Radiographics 2012;32:255–74. https://doi.org/10.1148/rg.321115064; PMID: 22236906. 15. Centers for Disease Control and Prevention. Radiation and pregnancy: a fact sheet for the public. Washington DC: CDC, 2011. https://emergency.cdc.gov/radiation/pdf/prenatal.pdf (accessed 1 November 2020). 16. Aday U, Bozdag E, Gündeş E, et al. Spleen-preserving surgery in splenic artery aneurysm. Case Rep Surg 2017;2017:8716962. https://doi.org/10.1155/2017/8716962; PMID: 29527384.

Venous

Post-thrombotic Syndrome: Preventative and Risk Reduction Strategies Following Deep Vein Thrombosis Adam M Gwozdz,1 Stephen A Black,1 Beverley J Hunt2 and Chung S Lim3 1. Academic Department of Vascular Surgery, School of Cardiovascular Medicine and Sciences, Guy’s and St Thomas’ NHS Trust, King’s College London, London, UK; 2. Thrombosis and Haemostasis Centre, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 3. Department of Vascular Surgery, Royal Free London NHS Foundation Trust, London, UK

Abstract Venous disease is common in the general population, with chronic venous disorders affecting 50–85% of the western population and consuming 2–3% of healthcare funding. It, therefore, represents a significant socioeconomic, physical and psychological burden. Acute deep vein thrombosis, although a well-recognised cause of death through pulmonary embolism, can more commonly lead to post-thrombotic syndrome (PTS). This article summarises the pathophysiology and risk factor profile of PTS, and highlights various strategies that may reduce the risk of PTS, and the endovenous management of iliofemoral deep vein thrombosis. The authors summarise the advances in PTS risk reduction strategies and present the latest evidence for discussion.

Keywords Post-thrombotic syndrome, deep vein thrombosis, prevention, risk factor, anticoagulant, catheterisation, thrombolytic therapy Disclosure: SAB reports consulting and speakers fees for Cook, Bard, Gore, Veniti, Phillips-Volcano, Medtronic, Boston Scientific and Optimed. All other authors have no conflicts of interest to declare. Acknowledgements: The authors thank Miss Olivia Sharp, Dr Karen Breen, Dr Ander Cohen and Mr Prakash Saha for editorial assistance. Received: 8 June 2020 Accepted: 29 September 2020 Citation: Vascular & Endovascular Review 2020;3:e15. DOI: https://doi.org/10.15420/ver.2020.15 Correspondence: Adam M Gwozdz, Academic Department of Vascular Surgery, Guy’s and St Thomas’ NHS Foundation Trust, Westminster Bridge Rd, London SE1 7EH, UK. E: adam.gwozdz@kcl.ac.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 noncommercial purposes, provided the original work is cited correctly.

Deep vein thrombosis (DVT) is a common condition estimated to affect approximately 100,000 patients each year in the UK.1 DVT is a wellrecognised cause of death through pulmonary embolism (PE), and, rarely, limb loss through phlegmasia cerulea dolens. Most commonly, however, DVT can lead to post-thrombotic syndrome (PTS), which affects patients of all ages, and is characterised by leg pain, itchiness, heaviness, swelling, skin discolouration, and, in severe cases, venous ulceration (Figure 1).2 Severe PTS has major socioeconomic consequences, and even mild PTS can have adverse effects on quality of life (QOL).3,4 Traditionally, anti-coagulation alone was used to prevent the propagation of DVT and PE and allow natural thrombus resolution. However, PTS is increasingly recognised as an important and common debilitating long-term sequela of DVT, given that failure of natural thrombus resolution can lead to a chronically occlusive post-thrombotic limb. PTS can occur in up to approximately 50% of patients in the 2 years after DVT, and is resistant to conservative and early thrombus removal therapies.5,6 Therefore, every effort should be made to reduce the risk of PTS when managing patients with DVT. The aim of this review is to summarise the pathophysiology and risk factors of PTS, highlight various risk reducing strategies for the development of PTS, and discuss future perspectives.

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Diagnosis of Post-thrombotic Syndrome PTS is the most common long-term complication after DVT. PTS is primarily a clinical diagnosis based on the presence of typical symptoms and signs of chronic venous hypertension in a patient with a previous DVT, but no objective diagnostic test exists.7 A number of diagnostic and severity scales have been developed for PTS: the Villalta scale, the Ginsberg measure, the Brandjes scale, the Widmer classification, the Clinical–Etiological–Anatomical–Pathological (CEAP) classification and the Venous Clinical Severity Score (VCSS).8 However, the Villalta scale has been validated externally and endorsed by scientific societies.9 On the Villalta scale, PTS is defined as a score ≥5, or a venous ulcer present, in a leg with previous DVT.10 The Villalta score classifies patients as having or not having PTS, and rates its severity, based on the sum of five venous symptoms and six clinical signs. Mild refers to a Villalta score of 5–9, moderate if the score is 10–14, and severe when the score is ≥15, or if a venous ulcer is present, regardless of the Villalta scoring parameters.10

Pathogenesis of Post-thrombotic Syndrome DVT can cause venous outflow obstruction and persistent reflux secondary to vein wall and valvular damage, leading to venous pooling, with limited reversibility depending on the location and extent of thrombus.11–14 This causes changes in microvasculature of the leg,

Post-thrombotic Syndrome: Prevention and Risk Reduction leading to reduced perfusion of surrounding muscle, chronic inflammation, increased vascular permeability and scarring of the vessel wall.7 The presence of venous pooling indirectly affects distal deep veins and superficial collaterals causing dilation and incompetence. As a result, the calf muscle pump becomes ineffective and the ambulatory venous pressure fails to fall significantly with walking or exercise (as it does in the healthy state), which eventually leads to venous hypertension.15 Venous hypertension is thought to initiate chronic inflammatory cascades, which lead to features of PTS including venous claudication, ankle swelling, skin changes and even ulceration.16 However, PTS symptomatology varies over time.3 Figure 2 summarises the pathogenesis of PTS and potential risk reduction strategies.

Figure 1: Severe Post-thrombotic Syndrome

Risk Factors for Post-thrombotic Syndrome In clinical practice, it would be very useful to be able to predict the individual patient risk of developing PTS and its severity. As a result, prediction tools in the acute and sub-acute phase of DVT are being developed using baseline clinical and demographic characteristics.17–19 These baseline variables include age, BMI, sex, varicose veins, history of venous thrombosis, smoking status, provoked thrombosis and thrombus location. However, further validation is required before these risk scores are used in clinical practice. There are several key factors that increase the risk of developing PTS following DVT (Table 1).7,20–23 Identification of these risk factors, particularly modifiable ones, is important in strategic planning to minimise the risk of developing PTS; preventing DVT from occurring remains the most effective strategy.21 Therefore, it is important that individuals with increased risk of DVT are managed appropriately with the various prophylactic strategies available, such as anti-coagulation, compression hosiery, adequate mobilisation and lifestyle modifications. Strategies for the prevention of DVT are widely available in the literature, hence will not be covered in more detail in this review. Here, we focus on preventative and risk reduction strategies of PTS following DVT occurrence.

Preventative and Risk Reduction Strategies for Post-thrombotic Syndrome Lifestyle Modification Strategies and Compression Lifestyle Modifications There are no studies to support any specific lifestyle modification that may prevent or reduce the risk of PTS. However, in patients with moderate or severe pain initially, early ambulation compared with bed rest was related to remission of acute pain in the affected limb.24 Regular exercise training in patients with PTS was also demonstrated to reduce severity of PTS symptoms and signs.25 Other lifestyle modifications that are likely to improve calf muscle pump, such as weight loss if obese, and frequent leg elevation, relieve some of the symptoms and signs of PTS, and improve wellbeing following DVT. Therefore, all patients with DVT should be counselled on these lifestyle modifications.

Compression The graduated elastic compression stocking (GECS) has been central to PTS prevention for several decades and is thought to reduce both valvular reflux and venous hypertension.26–29 Although there have been several randomised controlled trials (RCTs) assessing the role of GECS in preventing PTS following DVT, all the studies were limited by their heterogeneity, including the interval between DVT diagnosis and compression, application, type, pressure, duration, co-intervention (in particular the type and duration of anticoagulation), first versus recurrent DVT, PTS diagnostic criteria, and length of follow-up.11,28–34

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Venous ulcers secondary to severe post-thrombotic syndrome.

Figure 2: Post-thrombotic Syndrome Pathogenesis and Risk Reduction Strategies Various prophylactic measures and risk factor management for venous thromboembolism Acute DVT

Risk factors and/or provocation

?Venous stenting

Adequate anticoagulation ?

May–Thurner lesions

Recurrent DVT

Adequate anticoagulation

Extension of venous thrombus Early thrombus removal procedures particularly in acute iliocaval DVT Inflammatory processes of the vein wall

Vein wall scarring

Valvular damage

Deep venous obstruction

Deep venous incompetence

Iliofemoral venous stenting Venous hypertension ?Compression/exercise Calf muscle pump failure

Superficial venous reflux ?Ablation of superficial reflux Inflammatory processes of skin and subcutaneous tissue

PTS

Black = pathogenesis; red = risk reduction strategies. DVT = deep vein thrombosis; PTS = post-thrombotic syndrome.

This heterogeneity complicates comparative analysis, but until recently, the overall evidence seemed to support GECS use for at least 2 years after DVT diagnosis to prevent future PTS.

Venous Table 1: Risk Factors and Risk Reduction Strategies for Post-thrombotic Syndrome Following Deep Vein Thrombosis Risk Factors for PTS

PTS Risk Reduction Strategies

Patient Characteristics High BMI Increased age Pre-existing chronic venous disease Specific biomarkers (e.g. D-dimer, tPA and factor VIII activity)

Generally non-modifiable other than weight loss, possibly some degree of lifestyle modifications, adequate anti-coagulation

DVT Characteristics Large thrombus burden Location (increased risk in iliofemoral compared with femoropopliteal DVT)

Early thrombus removal (catheter-directed thrombolysis, pharmacomechanical thrombectomy, deep venous stenting) from proximal deep veins and appropriate therapeutic anticoagulation

Treatment and Follow-up Recurrent ipsilateral DVT Residual thrombosis after treatment Presence of residual venous symptoms and signs 1 month after DVT Subtherapeutic anticoagulation

Close monitoring of therapeutic anticoagulation, appropriate selection of anticoagulant and target dose, patient compliance management, pro-thrombotic risk factor management

DVT = deep vein thrombosis; PTS = post-thrombotic syndrome; tPA = tissue plasminogen activator.

This long-held belief in GECS has been challenged by evidence from the Compression Stockings to Prevent the Post-Thrombotic Syndrome (SOX) trial; a placebo-controlled, multicentre RCT that showed no benefit of GECS in preventing PTS.34 In the RCT, cumulative incidence of PTS was 14.2% with GECS compared with 12.7% in the placebo group. However, the trial was criticised for the low GECS compliance, with only 55.6% of patients wearing the GECS for ≥3 days per week at 2 years. Two other studies with high GECS compliance demonstrated decreased PTS incidence, although it is unclear whether these studies included iliofemoral DVTs.30,31 This may suggest that GECS worn in a manner reflective of patient daily practice does not prevent PTS.35 As a result, there are some variations in the recommendation of the use of GECS following DVT among international and national guidelines. Overall, GECS may be used for symptom relief but the evidence of its role in preventing PTS is uncertain.36 In 2012, the National Institute for Health and Care Excellence (NICE) recommended offering below-knee GECS with ankle pressure >23 mmHg ≤3 weeks after the diagnosis of iliofemoral DVT. However, in 2015, following review of the SOX trial, NICE updated its guideline, and advised not to offer GECS following iliofemoral DVT for the prevention of PTS, but to use GECS only for symptomatic relief.37 More recently, the One versus Two Years of Elastic Compression Stockings for Prevention of Post-thrombotic Syndrome (OCTAVIA) study showed that stopping GECS after 1 year in patients with proximal DVT seemed to be non-inferior to continuing GECS for 2 years.38 In 2018, the Individualised versus Standard Duration of Elastic Compression Therapy for Prevention of Post-thrombotic Syndrome (IDEAL DVT) non-inferiority study showed that it was safe to shorten the duration of GECS on an individualised basis after proximal DVT for prevention of PTS.39 A further RCT, the multicentre Compression Hosiery to Avoid Post-thrombotic Syndrome (CHAPS) study (ISRCTN73041168) in the UK aims to address the effectiveness of GECS in preventing PTS in patients with DVT.40 Intermittent pneumatic compression (IPC) devices apply variable pressure cycles on the lower limb with inflatable compartments to emulate the calf muscle pump. Physiologically, IPC is thought to protect against venous thromboembolism (VTE) in a variety of ways: by reducing venous stasis, inducing flow-related venous endothelial alterations, improving lymphatic drainage and increasing endogenous fibrinolytic potential. A series of RCTs and meta-analyses have shown

that IPC use alone reduces DVT incidence by more than 60%, with further reduction when concurrent pharmacological prophylaxis is used.41 These data have been supported by a 2016 Cochrane review that confirmed that, based on moderate quality evidence, IPC plus pharmacological prophylactic measures decreased PE incidence when compared with anticoagulation alone and decreased the incidence of DVT compared with GECS alone.42 Therefore, the usage of IPC to prevent postoperative DVT, particularly in high-risk cases, should be considered as part of a multi-modal PTS prevention strategy.

Medical Strategies Anticoagulation The use of anticoagulation after first acute DVT has the largest, proven benefit in reducing the incidence of PTS when compared with no treatment. Systemic anticoagulation therapy following DVT prevents the propagation of existing thrombi, formation of new DVT, PE, and recurrent DVT, all of which are known risk factors for the development of PTS.43 However, anticoagulation cannot lyse acute thrombus; this depends on the patient’s endogenous fibrinolytic system.44 Current practice following acute DVT is use of low-molecular-weight heparin followed by bridging to dose-adjusted oral vitamin K antagonists (VKA), such as warfarin, until an international normalised ratio (INR) target of 2–3 is achieved, at which point warfarin only is continued; or the use of a direct oral anticoagulant (DOAC) from day 1 with or without bridging parenteral therapy.45 The time in therapeutic range is critical to the effectiveness; for example, in warfarin therapy monitored using INR, a subtherapeutic anticoagulation (defined as INR <2 for >20% of the time) was associated with a significant increase in PTS development.46 Recently it was found that treatment of DVT with rivaroxaban might be associated with a lower risk for PTS development.47–49 In 2020, in a study of patients with acute proximal DVT, the risk of PTS in the DOACtreated patients was reduced by 54% compared with patients treated with VKA (OR 0.46; 95% CI [0.33–0.63]).50 Although the authors advise interpreting the results with caution, they propose that patients treated with a DOAC, unlike those receiving VKAs, have progressively increased vein recanalisation over time. Overall, the anticoagulation strategy should be tailored to the individual, taking into account patient preference and compliance, comorbidities, polypharmacy, bleeding risk, DVT aetiology and risk of recurrence.51

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Post-thrombotic Syndrome: Prevention and Risk Reduction Other Drugs There is limited evidence to support venoactive drugs, such as rutosides (a herbal remedy used in chronic venous insufficiency to reduce swelling and skin changes), defibrotide (a single-stranded polydeoxyribonucleotide that has anti-thrombotic, anti-inflammatory and anti-ischaemic properties) and hidrosmin (a vasoprotective synthetic bioflavonoid) in preventing PTS following DVT, hence their use is not recommended at present.52,53 Sulodexide, a glycosaminoglycan consisting of unbranched polysaccharide chains with numerous biological effects including anti-thrombogenesis, anti-inflammatory effects, and endothelial protection, has recently been shown to potentially reduce recurrent VTE and PTS, although further clinical trials are needed to confirm its roles.54,55

Stategies for Early Thrombus Removal There are two main indications for early removal of thrombus in patients with acute DVT. First, removal of thrombus may be needed in patients with severe pain and swelling, especially when there is increased risk of limb-threatening ischaemia such as phlegmasia cerulea dolens, or worsening symptoms despite optimal medical and conservative treatment. Second, early removal of thrombus in patients with iliofemoral DVT may reduce the risk of PTS development, as a result of the reduction in inflammation and injury to the vein wall and valves that would otherwise be caused by residual thrombus. Several studies, including RCTs, reported that in selected patients, removal of acute thrombus resulted in better long-term outcomes compared with conservative measures alone in terms of reducing the risk of PTS.56–59 However, two recent multicentre RCTs have questioned the efficacy of early removal of thrombus to reduce PTS, although both studies were limited by various methodological flaws.6,60 Major guidance from NICE, and the American Venous Forum/Society for Vascular Surgery (AVF/SVS) recommend consideration of thrombus removal intervention in the 14 days after acute DVT; tissue plasminogen activator (tPA) has the greatest effect in experimental animal thrombi when fibrin content is greatest, between 7 and 10 days following induction.61

Surgical Thrombectomy Until the 1970s, the principal method of removal of thrombus in acute DVT was surgical thrombectomy.62 Surgical thrombectomy did not show long-term benefits until it was combined with arteriovenous fistula formation distal to the site of venous reconstruction in order to improve venous inflow.63,64 However, this was suitable only for a select group of patients, and thrombosis recurred early if residual thrombus remained after the procedure. Surgical thrombectomy is not routinely performed, largely due to the invasiveness of the procedure, and to the significant potential for morbidity compared with percutaneous interventions. However, occasionally it is still indicated, particularly in patients with acute DVT requiring rapid removal of thrombus to relieve a limb-threatening ischaemia.

an early observation from Meyerovitz et al. showed that systemic treatment with thrombolytic agent did not permit sufficient penetration into occluded thrombi, a challenge that catheter-directed thrombolysis (CDT) and pharmacomechanical thrombolysis (PMT) were developed to overcome.67

Catheter-directed Thrombolysis CDT was developed as a minimally invasive procedure with the aim of removing the bulk of the thrombus, leaving an ‘open vein’ with no obstruction to venous flow.68,69 In doing so, CDT has overcome many of the limitations of a systemic agent.70 The procedure involves ultrasound identification of a suitable vein for access (typically either popliteal, femoral or, more rarely, internal jugular vein) followed by introduction of a catheter into the deep venous system. This allows for targeted delivery of high concentrations of a fibrinolytic agent, such as tPA, directly into the occlusion site via a multi-sidehole catheter. In our practice, a 10 mg bolus of alteplase is infused throughout the thrombus followed by 1 mg/h for 5 hours. A check venogram will generally be carried out after 12–24 h to assess the degree of thrombus dissolution, and evaluate the need for repeat thrombolysis and adjunctive angioplasty or stenting (Figure 3).71,72 When considering CDT, patient preference, as well as bleeding risk and comorbidities must be taken into account. Location and extent of DVT is important, given that isolated calf DVT has a much lower risk of PTS compared with iliocaval extension.28,73 Early studies demonstrated a reduction in incidence of PTS following CDT.56,74,75 The Catheter-directed Venous Thrombolysis in Acute Iliofemoral Vein Thrombosis (CaVenT) study, a multicentre RCT of 209 patients comparing CDT with standard treatment alone (anticoagulation and compression), found significantly improved iliofemoral patency rates (65.9%) in patients treated with CDT (65.9% versus 47.4%, p=0.012).76 Additionally, after 2 and 5 years, there was a significant absolute risk reduction of 14.4% (41.1% in CDT versus 55.6% in control, 95% CI [0.2–27.9]; number needed to treat of 7, 95% CI [4–502]), and 28% (43% in CDT versus 71% in control, 95% CI [14– 42]; number needed to treat of 4, 95% CI [2–7]), respectively. Interestingly, QOL at 5 years as measured with the EuroQol-5 Dimension (EQ-5D) and the disease-specific VEnous INsufficiency Epidemiological and Economic Study (VEINES)–Quality of Life/ Symptoms (VEINES-QOL/Sym) questionnaires did not differ between treatment groups.77 CDT is recommended in the NICE and AVF/SVS guidelines for treatment of symptomatic iliofemoral DVT <14 days old, in patients with good functional capacity, life expectancy of more than 1 year and low risk of bleeding. However, potential limitations of CDT include time delay to lysis and hospital stay in a high dependency unit, with the associated economic implications, although this needs further research.66,78–80

Systemic Thrombolysis

Mechanical and Aspiration Thrombectomy

Systemic thrombolysis demonstrates superior clot lysis in acute DVT patients compared with conservative treatment alone.65 However, systemic thrombolysis (dose used varied; streptokinase the most common agent used, with and without heparin) was associated with a high rate of major bleeding complications such as intracranial haemorrhage and retroperitoneal haematoma.65 As such, systemic thrombolysis is not recommended in current practice.66 Furthermore,

Mechanical and aspiration thrombectomy provides an alternate minimally invasive method of thrombus removal in the case of contraindications to pharmacological thrombolysis. Potential contraindications to pharmacological thrombolysis, such as CDT, include recent major surgery, trauma, stroke, pregnancy and active or recent bleeding. As the name implies, this form of thrombectomy uses mechanical force generated through rotatory and rheolytic means to

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Venous Figure 3: Endovascular Therapy for Acute Iliac Vein Thrombosis

A: Angiogram of a patient with acute left iliac vein thrombosis (black arrow). Note the presence of collateral veins. B: Angiogram of the same patient 48 h after catheter-directed thrombolysis: most of the left iliac vein was patent with a very small amount of residual thrombus. There was a tight stenosis identified in the left common iliac vein (CIV; black arrowhead), indicating a May–Thurner lesion. C: Angioplasty was performed with a 14-mm diameter balloon (white arrow) to pre-dilate the May–Thurner prior to venous stent insertion. D: A 14-mm-diameter dedicated venous stent (white arrowhead) was deployed across the May–Thurner lesion in the left CIV following balloon angioplasty. E: Final check angiogram showing a patent iliac vein following successful thrombolysis, balloon angioplasty and venous stent insertion. Note the disappearance of collateral veins following successful recanalisation of the left iliac vein compared with A. CFV = common femoral vein; EIV = external iliac vein; FV = femoral vein.

break up the thrombus into smaller segments that can often then be aspirated. For example, a modern derivative of a Fogarty balloon is inserted distal to the thrombus and then retrieved with the thrombus.81,82 The rate of PE following surgical thrombectomy is <1%, which is comparable to the incidence in conservatively treated patients.83

Pharmacomechanical Thrombolysis Several types of pharmacomechanical catheter-directed therapy have been developed to improve the efficiency of thrombus clearance compared with CDT or mechanical thrombectomy alone. PMT consists of an endovascular device that is advanced into the thrombus, which performs a combination of maceration and/or aspiration to physically break down the thrombus. This increases the surface area of residual thrombus for both exogenous and endogenous thrombolytic processes, reducing both the dose of thrombolytic agent required and the duration of thrombolysis.84–86 Limited evidence thus far suggests PMT is safe and effective in reducing PTS.87 The Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-directed Thrombolysis (ATTRACT) trial set out to address the treatment effect of adding PMT (catheter mediated or device mediated, with or without venous stenting) compared with anticoagulation alone on the incidence of PTS, measured with the Villalta score, in patients with acute proximal DVT.6 In all, 692 patients with acute proximal DVT were randomised to receive either anticoagulation alone or anticoagulation plus PMT. The ATTRACT trial reported no significant between-group difference in the percentage of patients with PTS between 6 and 24 months (48% versus 47%, respectively, p=0.56). Importantly, a significant reduction in moderateto-severe PTS in patients receiving early thrombus removal therapy was observed (18% in the PMT group versus 24% of those in the anticoagulation alone group, p=0.04). Furthermore, when PTS was continuously assessed at 6, 12, 18 and 24 months after treatment, symptom severity scores at each follow-up were significantly lower in patients who had received PMT compared with anticoagulation alone (p<0.01).6 This suggests that although PMT did not prevent the onset of PTS, it resulted in significant symptom improvement. However, optimal timing of the intervention from the onset of DVT remains unclear.

A further post-hoc analysis of ATTRACT patients with iliofemoral DVT examined the effect of PMT.88 Although PMT did not influence the occurrence of PTS, it significantly reduced early leg symptoms, and, over 24 months, reduced PTS severity scores, and the proportion of patients who developed moderate-or-severe PTS. However, a limitation of this analysis was the substantial loss to follow-up that was unbalanced between the treatment groups (more missed PTS assessments in the non-PMT arm), which influenced the study’s estimates of treatment effects.6 More recently, the Dutch Catheter Versus Anticoagulation Alone for Acute Primary (Ilio)Femoral DVT (CAVA) trial with 184 participants randomised to ultrasoundaccelerated CDT versus standard care only (anticoagulation, kneehigh ECS and early ambulation) reported no significant difference in 1 year rates of PTS between the two groups (29% versus 35%).60 However, that study carried several limitations including a relatively small proportion of iliofemoral DVT patients and a low procedural technical success rate. In the AVF/SVS guidelines, early thrombus removal with PMT over CDT is recommended ≤14 days after acute iliofemoral DVT if resources and expertise allow, due to improved efficacy and the more favourable safety profile.66 According to recent NICE recommendations, percutaneous mechanical thrombectomy for acute DVT of the leg has well-recognised but infrequent complications; hence the procedure should be used only with special arrangements for clinical governance, consent, and audit or research.89

Adjuncts to Thrombus Removal Procedures Endovenous Balloon Angioplasty and Deep Venous Stenting This is a growth area as technologies are being developed to remove ‘old clot’ from patients with established PTS. Old clot, however, contains little residual thrombus but is replaced by fibrous tissue. 90 Endovenous balloon angioplasty and stenting of deep venous (particularly common femoral vein, iliac vein, and inferior vena cava) residual obstructive lesions after early thrombus removal procedures such as CDT and PMT are increasingly favoured.65,90 Venogram and/ or intravascular ultrasound (IVUS) is used to identify and measure the degree and extent of obstructive lesions prior to balloon angioplasty and stent insertion. Although endovenous balloon

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Post-thrombotic Syndrome: Prevention and Risk Reduction angioplasty and stenting may reduce the risk of recurrent DVT and PTS in some patients, there is as yet no high-quality evidence to support the routine use of such procedures. Further research is required to identify the group of patients who may benefit from such adjunct intervention, and the optimal time and degree of venous stenosis for endovenous balloon angioplasty and stenting, and its cost effectiveness. Due to the nature of the obstructive fibrotic and compressive lesions of the vein wall, balloon angioplasty alone is not sufficient, hence insertion of self-expandable stent is required to maintain the intended lumen diameter. Until recently, only stents designed for arterial pathology were used. However, several dedicated venous stents are currently available. These dedicated venous stents are made from nitinol (a metal alloy of nickel and titanium), with a size (diameter and length), strength, flexibility, and resistance to thrombosis tailored to the venous system and pathology, which differ from their arterial counterparts. 91 Patency rates of dedicated venous stents at 12 and 24 months are encouraging,92,93 but longerterm results are awaited. The abovementioned ATTRACT study, and CAVA trial both include venoplasty and/or stenting at the discretion of the operator following PMT in their management protocols.60 In a small prospective study looking specifically at venous stenting after CDT in extrinsic compression of iliac vein (e.g. May–Thurner or Cockett’s syndrome), the acute phase patency rate was 92.3%, and the mid-term patency rate was 90%.94 These non-occlusive, non-thrombotic lesions are significantly easier to treat compared with their thrombotic occlusive counterparts. May– Thurner or Cockett’s syndrome is most often characterised by extrinsic compression of the left common iliac vein by the overlying right common iliac artery, but compression may occur at multiple sites and commonly affects the left lower limb.

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Future Research and Perspectives Despite PTS being common and causing much physical, social and work-related morbidity, there has been little research interest in this area until recently. More research is required to understand, prevent and manage established PTS. Improving our understanding of the pathogenesis and natural history of DVT and PTS, including at the molecular level, will help in the identification and modification of the risk factors involved in DVT and PTS. Various potential molecular markers including d-dimer, factor VIII, soluble thrombomodulin, tPA and specific genetic and inflammatory markers are currently being investigated for their prognostic value in PTS.22,23,95,96 Developing objective and validated risk stratifications may help identify high-risk patients who may benefit from more aggressive measures to reduce the risk of PTS. Early removal of thrombus is associated with reduction of PTS risk in patients with acute iliofemoral DVT through effective recanalisation of the venous system, and reduction of venous wall and valve injury. There is also evidence from RCTs to support the role of early CDT in reducing the rate of PTS in patients with acute iliofemoral DVT. Further consensus and guidance are also needed in postoperative anticoagulation strategies to maintain long-term stent patency. Advances in imaging technology have provided opportunities to develop modalities that are able to characterise the thrombus. Saha et al. are currently researching the use of magnetic resonance in direct thrombus imaging in measuring the age of the thrombus, which may help with patient selection for endovenous therapies.61 Simple measures, including compression and regular exercise, still require further high-quality trials to clarify their roles in reducing the risk of PTS development. Advancements in endovascular technology, such as PMT and mechanical thrombectomy devices, and dedicated venous stents, have provided enormous research opportunities into the prevention and improved management of established PTS. Research on bioprosthetic venous valves is also potentially helpful in the prevention of PTS.

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development of post-thrombotic syndrome and serial ultrasound, D-dimer, and factor VIII activity after a first deep venous thrombosis. J Vasc Surg Venous Lymphat Disord 2016;4:28–35. https://doi.org/10.1016/j.jvsv.2015.07.008; PMID: 26946892. 96. Siudut J, Grela M, Wypasek E, et al. Reduced plasma fibrin clot permeability and susceptibility to lysis are associated with increased risk of postthrombotic syndrome. J Thromb Haemost 2016;14:784–93. https://doi.org/10.1111/jth.13264; PMID: 26786481.

Aneurysms

Ultrasound Detection of Extracranial Carotid Artery Aneurysms: A Case Report Fabrizio D’Abate1 and Cristiana Vitale2 1. Vascular Laboratory, Vascular Institute, St George’s University Hospital, London, UK; 2. IRCCS San Raffaele Pisana, Department of Cardiovascular and Respiratory Disease, Rome, Italy

Abstract The ultrasound definition of extracranial carotid artery aneurysms (ECCAs) is unclear. The threshold diameter to use for defining an extracranial carotid artery as aneurysmal is still debated. Similarly, the ultrasound method of choice for measuring the maximum diameter of ECCAs has not been agreed. In this paper we report the case of a patient with a fusiform aneurysm at the level of the carotid artery bifurcation and a large saccular aneurysm of the proximal internal carotid artery, and discuss the information essential to acquire when ECCAs are detected with ultrasound.

Keywords Carotid arteries, ultrasound, aneurysm, saccular Disclosure: The authors have no conflicts of interest to declare. Received: 15 April 2020 Accepted: 9 November 2020 Citation: Vascular & Endovascular Review 2020;3:e16. DOI: https://doi.org/10.15420/ver.2020.09 Correspondence: Fabrizio D’Abate, Vascular Laboratory, Vascular Institute, St George’s University Hospital, Blackshaw Rd, Tooting, London SW17 0QT, UK. E: fabrizio.dabate@hotmail.it 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 noncommercial purposes, provided the original work is cited correctly.

Extracranial carotid artery aneurysms (ECCAs) are very rare. Overall, ECCAs account for <1% of all arterial aneurysms and for approximately 4% of peripheral artery aneurysms.1,2 The most common aetiologies of ECCAs are atherosclerosis (in 40% of cases) and trauma.1,3 The carotid bulb and the proximal internal carotid artery are commonly affected, whereas ECCAs on the external carotid artery are rare.4 ECCAs can be divided in true and false aneurysms, with the latter being the most common;5 ECCAs can also be classified according to their shape as fusiform or saccular aneurysms.

No other comorbidities or cigarette smoking were reported. There was no history of any neurological symptoms or pain.

Many cases of ECCA will remain clinically silent, but in some cases patients will develop symptoms such as pain and/or cranial nerve damage, as well as symptoms related to the compression of adjacent structures.5 The early detection and treatment of ECCAs is of paramount importance, due to the risk of neurological symptoms and rupture. Despite ultrasound being the first-line imaging test used for the detection of ECCAs, there is no generally accepted consensus regarding criteria to define an ECCA.6

The ultrasound assessment started in B mode for each side at the level of the proximal common carotid artery (CCA) and proceeded upwards to the CCA bifurcation and subsequently to the internal (ICA) and external (ECA) carotid arteries. The B mode overview on the left side showed an abnormal enlargement of the CCA bifurcation and a further enlargement of the proximal ICA. The common carotid bifurcation enlargement involved both the anterior and posterior arterial walls of the CCA bifurcation, suggesting the presence of a fusiform aneurysmal dilatation. In contrast, the enlargement involving the ICA arose from the posterior wall of the vessel only, therefore suggesting either a saccular aneurysm or a pseudoaneurysm of the ICA (Figure 1).

Here, we report on a case of a fusiform aneurysm at the level of the carotid artery bifurcation and a large saccular aneurysm of the proximal internal carotid artery. A list of main points to consider when scanning ECCAs is also presented.

Case Presentation A 62-year-old woman presented with a 10-year history of an enlarging pulsatile left neck mass. She was fit and denied any history of trauma at the level of the neck or any neck surgery or therapy. The patient’s medical history included arterial hypertension and dyslipidaemia, currently being treated with angiotensin-converting enzyme inhibitors and statins.

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On physical examination, the pulsatile mass was non-painful and situated anterior to the left sternocleidomastoid muscle, with no extension to the angle of the mandible. A carotid colour Doppler ultrasound scan was performed with a medium frequency linear array (9–3 MHz) according to the standard protocol, using first a transverse and then a longitudinal view.

The anteroposterior (AP) and mediolateral (ML) diameters of the arteries were measured at both the level of the maximum enlargement and the level of the normal ICA diameter beyond the aneurysmal segment. The AP diameter of the CCA bifurcation measured 1.8 cm, whereas the AP and ML diameters of the proximal ICA aneurysm measured 2.65 and 3.4 cm, respectively. The AP diameter of the ipsilateral proximal CCA measured 0.77 cm, whereas the native ICA beyond the aneurysmal segment measured 0.4 cm (Figure 1). The

Ultrasound Detection of Extracranial Carotid Aneurysms Figure 1: B Mode Transverse Views of the Carotid Arteries

A: Transverse views of the common carotid artery. The anteroposterior (AP) diameter is approximately 0.77 cm. B: Internal carotid artery (ICA) transverse view at the level of the aneurysm. The aneurysm is considered saccular because the arterial blowout involves only the posterior wall of the ICA. The ICA measures 0.70 cm at this level (vertical double-headed arrow), whereas the ICA aneurysm has an AP diameter of 2.65 cm and a mediolateral diameter of 3.38 cm. C: Transverse view of the distal ICA where the AP diameter measures 0.4 cm. These diameters are used to calculate the aneurysm:ICA and aneurysm:common carotid artery ratios. AP = anteroposterior; ICA = internal carotid artery; ML = mediolateral.

lumen of the vessels was patent, with no evidence of intraluminal plaques on B mode, confirmed when colour Doppler flow was applied. The calibre of the ECA and CCA was normal throughout. CT angiography (CTA) was subsequently performed to confirm the presence of an ECCA and to determine whether the proximal ICA aneurysm was a true aneurysm or a pseudoaneurysm. The CTA confirmed the presence of a 3.1 cm × 2.8 cm × 2.3 cm saccular aneurysm arising from the left ICA, whereas the CCA bifurcation was defined as a fusiform aneurysmal dilatation that measured 2 cm × 1.7 cm × 2.1 cm (Figure 2). The CTA identified arterial calcifications within the walls of the ICA aneurysm, suggesting that the dilatation was a true aneurysm rather than a pseudoaneurysm. The patient underwent an elective open repair of the aneurysm with aneurysmectomy and an end-to-end arterial anastomosis between the CCA and ICA with 5–0 prolene. The patient was discharged on day 3 postoperatively, with no complications at follow-up. Histopathological examination of a surgical specimen determined the aneurysm to be atherosclerotic.

Discussion Although the natural history of ECCAs has not been well defined, their early detection is of importance before ischaemic neurological symptoms appear or the aneurysm ruptures.7,8 Due to its availability and non-invasive nature, ultrasound plays a key role in the detection and characterisation of ECCAs. However, some challenges remain with the ultrasound diagnosis of ECCAs, including unresolved methodological issues.6

Definition of Extracranial Carotid Artery Aneurysms An aneurysm is defined as a widening of an arterial or venous segment that results from a weakened blood vessel wall. An aneurysm can be present at different levels in the cardiovascular system, and its maximum diameter is often used to monitor its growth until a surgical threshold is reached and an intervention is warranted to prevent its rupture. The cut-off point to define a blood vessel as aneurysmal has been determined for several vascular territories, such as the abdominal aorta, where an AP diameter >3 cm is considered as the cut-off point for the presence of an abdominal aortic aneurysm. Cut-off values to

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define aneurysms have also been determined for the common iliac arteries and the popliteal arteries, but no such values have been determined for ECCAs. Hence, some authors have defined ECCAs as a localised increase in the calibre of the carotid artery of >50% compared with reference values or the expected vessel diameter.4,9 However, it is important to highlight that due to the scarcity of ultrasound data reporting the mean diameter of normal extracranial carotid arteries, this definition has intrinsic limitations. One study reported normal mean (±SD) diameters of 4.66 ± 0.78 and 6.10 ± 0.80 mm for the ICA and CCA, respectively, in women, and 5.11 ± 0.87 and 6.52 ± 0.98 mm, respectively, in men.10 Another study reported that the diameter of the CCA lumen ranged from 4.3 to 7.7 mm.11 However, considering that there are no significant differences in lumen diameter between the left and right carotid arteries and that ECCAs are usually unilateral, the contralateral normal side can be used as the reference value to determine the normal expected diameter of the vessel.12 This may prove to be particularly useful in the presence of a dilated or aneurysmal carotid bulb, which, by definition, is an already dilated segment. Another definition, proposed by De Jong et al., for ECCAs at the bifurcation level is the presence of bulb dilatation >200% of the diameter of the ICA or 150% of the diameter of the CCA, whereas, for ECCAs at the level of the distal extracranial ICAs, it is the presence of a dilatation >120% of the diameter of the normal ipsilateral ICA.13 In the present case report, the maximum AP diameter of the ICA aneurysm was 562% of the AP diameter of the non-aneurysmal ICA and 244% larger than the AP diameter of the non-aneurysmal CCA. According to the ECCA definition suggested by De Jong et al.,13 the AP diameter of the carotid bifurcation was 350% larger than the nonaneurysmal ipsilateral distal ICA AP diameter and 134% larger than the CCA AP diameter, thus suggesting the presence of a carotid bifurcation aneurysm.

Measurement of Extracranial Carotid Artery Aneurysm Diameter and Practical Ultrasound Considerations Depending on the ultrasound measurement technique used to evaluate the diameter at the level of abdominal aortic aneurysms, there are three methods that can be used to measure artery diameter: outer to outer, inner to inner or leading edge to leading edge (Figure 3). The diameters are

Aneurysms Figure 2: CT Angiography Performed to Confirm the Presence and Nature of Extracranial Carotid Arteries Aneurysms

Figure 3: Different Methods That Can be Used to Measure Aortic Diameter

Calliper placement for measurement of aortic diameter. ITI; LELE; OTO This image shows the three different methods that can be used to measure aortic diameter. In the OTO method, both callipers are placed on the outer layer of the artery walls; in the ITI method, both callipers are placed on the inner layer of the arterial walls; and in the LELE method, one calliper is placed on the outer layer and the second is placed on the inner layer of the arterial wall. ITI = inner to inner; LELE = leading edge to leading edge; OTO: outer to outer. Reproduced with permission from ABC Vascular.

In the present case report, all diameters were measured using the outer layer to outer layer method, because this is the method that is more likely to provide the largest diameter of the aneurysmal arterial segment. To date, there has been no recommendation as to whether the AP diameter and/or the ML diameter should be used to determine the size of the ECCA, and whether to use a longitudinal or transverse view. We suggest measuring both diameters at the level of the aneurysmal segment and to compare them to the non-aneurysmal diameters of the reference vessels.

CT angiography confirmed the presence of a 3.1 × 2.8 × 2.3 cm saccular aneurysm arising from the left internal carotid artery, whereas the common carotid bifurcation was defined as a fusiform aneurysmal dilatation and measured 2 × 1.7 × 2.1 cm. Arterial calcifications were noted within the internal carotid artery aneurysm walls. Arrow indicates the affected side.

usually measured using a B mode image and both transverse and longitudinal views can be used. The anterior and posterior arterial walls (AP diameter) or the medial and lateral arterial walls (ML diameter) are usually measured. The measurement of the ML diameter of a blood vessel is typically less precise than that of the AP diameter. This is due to poor lateral resolution of the medial and lateral wall boundaries, which are parallel to the ultrasound beam, thus producing poor images. Therefore, ML diameter measurements are more prone to error and less reproducible. If the ML diameter is the largest diameter of the aneurysm, a different angle of insonation should be used in an attempt to improve the lateral resolution of the wall boundaries.

We also suggest measuring the maximum diameter using a transverse view. However, in the case of a saccular aneurysm or in the presence of tortuous aneurysm, the longitudinal view can be of help in defining the maximum diameter. To obtain the maximum diameter of a vessel or aneurysm, the ultrasound beam must be perpendicular to its long axis; however, often in presence of a tortuous vessel, the ultrasound beam is horizontal to the actual vessel, therefore yielding a larger than actual vessel diameter. Confirming the diameter measurements obtained from the transverse view with the measurements obtained from the longitudinal view can improve the degree of confidence in the measurement recorded. Because a gold standard ultrasound method to measure the largest diameter of ECCAs is lacking, we also suggest that the operator should report the methodology used to determine the maximum diameter of the enlarged vessel.

Location of Extracranial Carotid Artery Aneurysms Depending on the location of the aneurysm, ECCAs can be classified into five types.4,8 Because the surgical options vary depending on this classification, it is important to describe the location of the ECCAs in the ultrasound report. When ultrasound views of the aneurysm are limited by patient body habitus of the depth of vessels, the use of a low-frequency curvilinear array (2–9 MHz) may improve the visualisation of the extension of the ECCAs and enable better depiction of the location of the aneurysm

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Ultrasound Detection of Extracranial Carotid Aneurysms Table 1: Summary of Practical Considerations Regarding the Use of Ultrasound to Detect Extracranial Carotid Artery Aneurysms 1. Despite the lack of an accepted definition of carotid aneurysm in the literature, comparing the size of the enlarged arterial segment to the expected diameter or reference values in the contralateral normal side seems an acceptable method as a preliminary standard for the definition of carotid aneurysm 2. ECCAs of the bifurcation can also be defined as a bulb dilatation >200% of the diameter of the ICA or 150% of the diameter of the CCA, and distal aneurysms of the extracranial ICAs can be defined as a dilatation >120% of the diameter of the normal ipsilateral ICA 3. Because there is no consensus as to which method (AP or ML diameter, transverse or longitudinal view) should be used to measure ECCA diameter, it is important to describe the methodology used and to be consistent with it if follow-up scans are performed 4. When an ECCA is detected on ultrasound, an attempt should be made to determine whether it is a pseudoaneurysm or a true aneurysm; the side and arteries involved, the shape of the aneurysm and its location should be always described 5. Ultrasound findings should be correlated with the clinical history and confirmed by CTA AP = anteroposterior; CCA = common carotid artery; CTA = CT angiography; ECCAs = extracranial carotid artery aneurysms; ICA = internal carotid artery; ML = mediolateral.

and its correlation with other anatomical structures. ECCAs represent 1% of all peripheral aneurysms. To date, there is no consensus as to whether patients with an ECCA should be screened for the presence of other aneurysms. Because patients with an aneurysm have a higher risk of having an aneurysm in a different location, it may be good practice to always search for peripheral aneurysms in patients with an ECCA.

Type and Shape of Extracranial Carotid Artery Aneurysms

image one could note the intima and media layers throughout the aneurysm, thus suggesting the presence of a true aneurysm. It is always important to correlate the ultrasound findings to the clinical history of the patient, because this could provide clues as to the nature of the enlargement. In the present case, there was no history of trauma or procedures to the neck region.

Differential Diagnoses

ECCAs can be divided in true aneurysms and pseudoaneurysms. True aneurysms, mostly caused by atherosclerosis, are localised enlargements of the artery diameter, with integrity of all three vascular layers, whereas pseudoaneurysms occur in presence of an interruption of the continuity of all three layers of the arterial wall. Most pseudoaneurysms develop as a complication of carotid endarterectomy or cervical trauma, such as blunt injury or penetrating trauma.5

There are other conditions that may mimic the presence of a carotid aneurysm. Coiling and/or kinking of the carotid arteries, dilatation of the internal jugular vein, bulb ectasia and carotid body tumour, lymph nodes, neck tumours and peritonsillar abscesses are the main differential diagnoses to be considered during an ultrasound assessment of ECCAs.

Conclusion A true aneurysm can be classified as either a fusiform aneurysm (the most common type, in which the whole cross-sectional area of an arterial segment is enlarged) or a saccular aneurysm (in which the dilatation affects only one side of the arterial segment). The main challenge with ultrasound is distinguishing a true saccular aneurysm from a pseudoaneurysm, especially when ECCAs are localised in the more distal regions of the ICA. As shown in this case report, despite the ultrasound being able to identify the presence of a proximal ICA dilatation, it was unclear whether this dilatation was a true saccular aneurysm or a pseudoaneurysm, because the dilatation was affecting only the posterior aspect of the ICA wall. The CTA suggested that this was a true saccular aneurysm based on the presence of arterial wall calcifications, which would suggest integrity of the arterial wall. In addition, using a high-definition B mode

El-Sabrout R, Cooley DA. Extracranial carotid artery aneurysms: Texas Heart Institute experience. J Vasc Surg 2000;31:702–12. https://doi.org/10.1067/mva.2000.104101; PMID: 10753278. McCollum CH, Wheeler WG, Noon GP, DeBakey ME. Aneurysms of the extracranial carotid artery. Twenty-one years’ experience. Am J Surg 1979;137:196–200. https://doi. org/10.1016/0002-9610(79)90144-2; PMID: 426176. Rosset E, Albertini JN, Magnan PE, et al. Surgical treatment of extracranial internal carotid artery aneurysms. J Vasc Surg 2000;31:713–23. https://doi.org/10.1067/mva.2000.104102; PMID: 10753279. Attigah N, Külkens S, Zausig N, et al. Surgical therapy of extracranial carotid artery aneurysms: long-term results over a 24-year period. Eur J Vasc Endovasc Surg 2009;37:127–33. https://doi.org/10.1016/j.ejvs.2008.10.020; PMID: 19046645. Longo GM, Kibbe MR. Aneurysms of the carotid artery. Semin

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Despite the lack of an accepted definition of aneurysm at the level of the carotid arteries in the literature, comparing the size of the enlarged arterial segment to the expected diameter or to reference values in the contralateral normal side seems an acceptable method to define a carotid aneurysm. When measuring an ECCA it is important to describe the methodology used and to use it consistently if followup scans are performed. Characteristics of the carotid aneurysm, such as the side and arteries involved, the shape of the aneurysm and its location, should be always described. An attempt to distinguish a pseudoaneurysm from a true aneurysm should be made when ECCAs are detected. Ultrasound findings should always be correlated to the patient’s clinical history and confirmed by CTA. The main points discussed in this case report are summarised in Table 1 and clearly show the need to develop a consensus regarding the methodology to use to assess ECCAs.

Vasc Surg 2005;18:178–83. https://doi.org/10.1053/j. semvascsurg.2005.09.002; PMID: 16360573. Welleweerd JC, den Ruijter HM, Nelissen BG, et al. Management of extracranial carotid artery aneurysm. Eur J Vasc Endovasc Surg 2015;50:141–7. https://doi.org/10.1016/j. ejvs.2015.05.002; PMID: 26116488. Bemelman M, Donker DN, Ackerstaff RG, Moll FL. Bilateral extracranial aneurysm of the internal carotid artery – a case report. Vasc Surg 2001; 35:225–8. https://doi.org/10.1177/ 153857440103500311; PMID: 11452350. Zhang Q, Duan ZQ, Xin SJ, et al. Management of extracranial artery aneurysms: 17 years’ experience. Eur J Vasc Endovasc Surg 1999;18:162–5. https://doi.org/10.1053/ejvs.1999.0876; PMID: 10426974. Rosset E, Albertini JN, Magnan PE, et al. Surgical treatment of extracranial internal carotid artery aneurysms. J Vasc Surg

2000;31:713–23. https://doi.org/10.1067/mva.2000.104102; PMID: 10753279. 10. Limbu YR, Gurung G, Malla R. Assessment of carotid artery dimensions by ultrasound in non-smoker healthy adults of both sexes. Nepal Med Coll J 2006;8:200–3. PMID: 17203830. 11. Krejza J, Arkuszewski M, Kasner SE, et al. Carotid artery diameter in men and women and the relation to body and neck size. Stroke 2006;37:1103–5. https://doi.org/10.1161/01. STR.0000206440.48756.f7; PMID: 16497983. 12. Williams MA, Nicolaides AN. Predicting the normal dimensions of the internal and external carotid arteries from the diameter of the common carotid. Eur J Vasc Surg 1987;1:91–6. https:// doi.org/10.1016/S0950-821X(87)80004-X; PMID: 3503020. 13. de Jong KP, Zondervan PE, van Urk H. Extracranial carotid artery aneurysms. Eur J Vasc Surg 1989;3:557–62. https://doi. org/10.1016/S0950-821x(89)80132-x; PMID: 2625165.

Complex Endovascular Procedures

Left Renal Vein Stenting in Nutcracker Syndrome: Outcomes and Implications Patrick Cherfan, Efthymios D Avgerinos and Rabih A Chaer Division of Vascular Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, US

Abstract Nutcracker syndrome refers to the symptomatic extrinsic compression of the left renal vein presenting most commonly as flank pain and haematuria. While surgery remains the first-line treatment, stenting is gaining more acceptance and there are now several published case series. This article highlights the outcomes of left renal vein stenting in the setting of nutcracker syndrome.

Keywords Nutcracker syndrome, endovascular, stenting, outcomes, left renal vein compression Disclosure: The authors have no conflicts of interest to declare. Received: 22 May 2020 Accepted: 9 November 2020 Citation: Vascular & Endovascular Review 2020;3:e17. DOI: https://doi.org/10.15420/ver.2020.12 Correspondence: Rabih A Chaer, Room 351.4, Division of Vascular Surgery, University of Pittsburgh Medical Center, 200 Lothrop St, South Tower, Pittsburgh, PA 15213–2582, US. E: chaerra@upmc.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 noncommercial purposes, provided the original work is cited correctly.

First described in 1937, the classic nutcracker syndrome (NCS) refers to the entrapment of the left renal vein (LRV) between the superior mesenteric artery (SMA) and the aorta.1 While the mainstay of treatment remains surgery, which is supported by good long-term outcomes, LRV stenting is an emerging alternative to open repair.2 The first successful case of LRV stenting was described by Neste et al. in 1996, and was performed in a patient who had a history of pancreatic cancer treated with a Whipple procedure, chemotherapy and radiation.3 Although patients with NCS are typically young and healthy, avoiding laparotomy and its associated complications makes stenting appealing, especially in patients with recurrent stenosis following renal vein transposition.4 With much of the natural course of this disease being unknown with no established prevalence, case series are a valuable addition to the relatively sparse published evidence for the procedure.5,6 The purpose of this article is to highlight the outcomes of LRV stenting as described in recent case series.

Overview LRV stenosis or NCS can have variable clinical presentations, with haematuria and flank pain being by far the most common presenting symptoms.7,8 A recent systematic review pointed towards an agreement among several investigators that an SMA branching angle of <35° is required in order to establish a diagnosis.9 However, the gold standard for diagnosis remains venography with a renocaval pullback pressure gradient of ≥3 mmHg.7 There is a subset of patients who have incidental findings of NCS or LRV stenosis on duplex/CT imaging; however, these people do not need intervention in the absence of clinical symptoms.10 Treatment should be tailored to the individual patient but non-surgical treatment should be attempted first for at least 6 months in all cases. In patients younger than 18 years, spontaneous remission is very common due to anatomic factors related to development and the distribution of

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body fat.7,11 Angiotensin-converting enzyme inhibitors and aspirin have also been used to improve orthostatic proteinuria and renal perfusion.12,13 Correction will be needed not only to ease persistent debilitating symptoms, but also to protect against possible complications, such as renal vein thrombosis, chronic glomerulopathy and compromised kidney function.8,14,15

Surgical Treatment Surgery remains the gold standard modality. A retrospective review of data from 36 patients who underwent several types of open surgery at the Mayo Clinic in the US demonstrated an overall resolution of symptoms exceeding 80%.2 The most commonly studied and performed surgery is LRV transposition. This is followed by gonadocaval bypass, SMA transposition, kidney auto transplantation and fibrous tissue resection at the aortomesenteric angle. Other much less commonly performed procedures are nephropexy, laparoscopic splenorenal venous bypass and external stenting of the LRV with a ringed polytetrafluoroethylene (PTFE) graft.7,16–18 However, surgery is not without complications and recurrent haematuria, LRV thrombosis and retroperitoneal haematoma have all been observed.16,19

Endovascular Treatment Endovascular treatment of LRV stenosis has gained favour since its introduction in 1996, due to the ease of the procedure compared to open surgery, and its lower morbidity secondary to its minimally invasive nature. This procedure can often be done under local anaesthesia and sedation. Despite its minimal invasiveness, LRV stenting lacks robust evidence mainly regarding its durability. For this reason, as with any other intervention, the decision to undergo stenting must be preceded by a thorough discussion with the patient about the risks, benefits and unknowns of LRV stenting. It is important to stress the fact that these procedures should be performed on symptomatic patients only and by experienced clinicians in endovascular suites that

Left Renal Vein Stenting in Nutcracker Syndrome Figure 1: CT Scan Showing Compression of the Left Renal Vein A

A 29-year-old woman presented with left lower quadrant pain. A: CT scan showing significant compression of the left renal vein (LRV) between the superior mesenteric artery and aorta; B: Intravascular ultrasound confirms tight stenosis of the LRV; C: A venogram after stenting with a 14 × 60 mm Wallstent; D: Intravascular ultrasound after stenting and balloon venoplasty shows a widely patent LRV.

have fixed imaging capability.5 Failures and complications, such as stent migration, can be frequent and can be accompanied by serious sequelae, especially if certain procedural rules are not followed.

Techniques There are no great differences in terms of technique among different institutions. In most procedures, the LRV is accessed through the right common femoral vein, with some physicians preferring to use the left common femoral vein or even the right internal jugular vein. While access site is determined by the physician’s preference, there is no reported difference in terms of complications.7,20,21 After selective catheterisation of the LRV, venography with the Valsalva manoeuvre should be performed to confirm the diagnosis. Intravascular ultrasound (IVUS) is also increasingly used to confirm a diagnosis through pullback imaging and to determine proper stent sizing.12 This has eliminated the need for the more traditional diagnostic pressure drop criterion of >3 mmHg across the stenotic lesion. Balloon venoplasty has no role in treatment due to the persistent external compression that leads to recompression upon deflating the balloon. Large self-expanding 4–6 cm stents that are 14–16 mm in diameter are typically appropriate. Smaller diameters are not recommended due to reported cases of stent migration.22 The Wallstent (Boston Scientific) has been the stent used in the majority of cases, but novel dedicated venous stents are entering the market and may become more popular for this procedure.23 Complications of LRV stenting treatment include stent thrombosis, migration, deformity, erosion, risk of reintervention and risk of conversion to open repair.22,24,25 A retrospective study from China that included 75 patients demonstrated a migration rate of 6.7%. Migration sites included the vena cava, right ventricle, right atrium and the left side of the renal vein. The main reason behind that was inappropriate stent sizing.2,10,22,24–26 The risk of stent migration can be minimised by oversizing the stent diameter. While partial protrusion of the stent into the inferior vena cava did not seem to cause complications, distal landing beyond the first branch of the LRV had been suggested to reduce stent migration but this is not to be encouraged due to the long-term disruption of smaller branches by the continuous radial force of the stent.6,27

Experiences from the University of Pittsburgh Medical Center The most recent large retrospective case series from the US was published by the University of Pittsburgh Medical Center featuring 18

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patients (17 women; mean age 38.1 ± 16.9 years) who underwent endovascular treatment.5 It demonstrated fewer perioperative complications when compared to previously published series. Among the 18 patients underwent stenting of the LRV, five had previously undergone a LRV transposition and had recurrent symptoms (or no improvement) within 7 ± 4.9 months. Failure was defined as symptom recurrence or no improvement along with imaging evidence of severe renal vein stenosis. The most common presenting symptoms were flank pain (n=15) and haematuria (n=10). Selective catheterisation of the LRV was performed through the right common femoral vein. Of the 18 patients, 13 (72.2%) noted improvement or resolution of symptoms at a follow-up of 41.4 ± 26.6 months. Of the five who did not have an improvement, three had previously undergone LRV bypass and two eventually needed renal autotransplantation. One of the remaining two women was later diagnosed with endometriosis, which can have a presentation similar to NCS. Haematuria resolved in 60%, which can be explained by the vascular changes resulting from chronic venous hypertension that cannot be reversed even with open surgery.5,16,19 Three underwent stent reintervention. The two-year primary and primary-assisted patency was 85.2% and 100% respectively. No stent migration occurred, which highlights the importance of accurate stent sizing. This might have been influenced by the use of an IVUS in 61% of cases. Patients were started on dual antiplatelet therapy for 1–3 months and switched indefinitely to 81 mg aspirin.5 Figure 1 demonstrates the pre- and post-stenting imaging of a patient who underwent LRV stenting.

Other Published Literature In a retrospective study including 61 patients in China with a median follow-up of 66 months, 59 patients noted improvement or resolution of symptoms within 6 months of LRV stenting. Postoperative complications included one stent migration to the hilar LRV, one stent migration into the right atrium, and one stent protrusion into the inferior vena cava. One perioperative complication of stent deployment in an LRV collateral was also reported.6 In another smaller Chinese case series, 30 patients underwent stenting of the LRV with a median follow-up of 36 months. Three months after stenting, complete resolution of haematuria and flank or abdominal pain was noted. No perioperative complications were recorded and two cases of stent prolapse into the inferior vena cava were found

Complex Endovascular Procedures Table 1: Case series of Left Renal Vein Stenting for Patients with Nutcracker Syndrome Source

Avgerinos et al. 18 20195

Sex Age Stent Type (M/W) (Years)

Outcome

Complications and Reintervention

Follow-up (Months)

1/17

72.2% resolved or improved symptoms

No perioperative complications

41.4*

60% resolved haematuria

Balloon venoplasty (n=2)

85.2% primary and 100% primary assisted patency on 2-year follow-up

Restenting with SMART (n=1)

Three out of five patients with stent migration developed symptom recurrence

5 cases of stent migration, 2 of them to the heart

Wallstent (n=2) SMART (n=1)

All noted significant improvement

No perioperative complications

100% patency throughout the reported follow-up period

Stent migration to the IVC with uneventful follow-up (n=2)

SMART

All noted significant improvement at 3 months

38.1*

Wallstent (Boston Scientific; n=4) Protégé EverFlex (Medtronic; n=9) SMART (Cordis; n=3)

Renal auto transplantation (n=2)

ev3 (Covidien; n=1) Zilver (Cook Medical; n=1) Wu et al. 201622

49/26

27†

Wallstent (n=7) SMART (n=68)

Policha et al. 201628

Wang et al. 201227

0/3

33.3*

55*

Reintervention with open surgery (n=3) 20*

Gonadal vein embolisation (n=2) 28/2

18.2*

100% patency throughout the reported follow-up period Chen et al. 20116

Hartung et al. 200520

45/16

26†

Wallstent (n=15)

Symptoms remained unchanged in 2 and recurred in 1

SMART (n=45)

0/5

34.7*

Palmaz (Johnson & Johnson; n=1)

100% patency on 6-year follow-up for the two patients with stent migration who underwent restenting

Wallstent

All noted significant improvement 100% patency on 1-month follow-up

No perioperative complications

36†

Stent migration to the IVC with uneventful follow-up (n=2) 1 perioperative complication from improper stent deployment requiring open repair

66†

Stent migration (n=2) Stent protrusion (n=1) 1 intraoperative stent migration managed by restenting

14.3*

Two patients had symptom recurrence 3 and 4 months later due to stent migration Chen et al. 200529

3/0

10*

Optimed (Optimed)

All noted significant improvement

No perioperative complications

36*

100% patency on 3-year follow-up

*Mean. †Median. IVC = inferior vena cava; M = man; W = woman.

during routine follow-up at 12 months with no symptom recurrence or reintervention.27 Table 1 summarises the findings of the largest and most recent published series assessing outcomes of LRV stenting.

Conclusion LRV stenting is a safe and effective treatment modality for treating NCS that is refractory to conservative management. The most common

1. 2.

Grant J. A Method of Anatomy: Descriptive and Deductive. Baltimore, MD: Williams and Wilkins, 1944. Erben Y, Gloviczki P, Kalra M, et al. Treatment of nutcracker syndrome with open and endovascular interventions. J Vasc Surg Venous Lymphat Disord 2015;3:389–96. https://doi. org/10.1016/j.jvsv.2015.04.003; PMID: 26992616. Neste MG, Narasimham DL, Belcher KK. Endovascular stent placement as a treatment for renal venous hypertension. J Vasc Interv Radiol 1996;7:859–61. https://doi.org/10.1016/ S1051-0443(96)70861-8; PMID: 8951753. Baril DT, Polanco P, Makaroun MS, et al. Endovascular management of recurrent stenosis following left renal vein transposition for the treatment of Nutcracker syndrome. J Vasc Surg 2011;53:1100–3. https://doi.org/10.1016/j.jvs.2010.10.112; PMID: 21215570. Avgerinos ED, Saadeddin Z, Humar R, et al. Outcomes of left renal vein stenting in patients with nutcracker syndrome. J Vasc Surg Venous Lymphat Disord 2019;7:853–9. https://doi.

reported complication is stent migration, and this risk could be eliminated with the accumulation of experience and expertise. LRV stenting should not be recommended as the gold standard as there is a lack of long-term data which would raise concerns about using the intervention in younger, otherwise healthy patients. The establishment of a registry is crucial to determine long-term outcomes of LRV stenting for patients with NCS.

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VASCULAR & ENDOVASCULAR REVIEW

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