Vascular & Endovascular Review Volume 4 2021 by RadcliffeVascular

Volume 4 • 2021

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Vascular

Lifelong Learning for Vascular Professionals

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Volume 4 • 2021

Editor-in-Chief Stephen Black

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

Section Editors Section Editor – Aortic Andrew Choong

Section Editor – Peripheral Artery Disease Michael Lichtenberg

National University of Singapore, Singapore

Klinikum Arnsberg, Karolinen Hospital, Arnsberg, Germany

Section Editor – Venous Rick de Graaf

Section Editor – Case Reports Ashish Patel

Clinical Centre of Friedrichshafen, Friedrichshafen Germany

King’s College London, UK

Section Editor – Complex Endovascular Procedures Konstantinos P Donas

Asklepios Klinik Langen, Goethe University, Frankfurt, Germany

Section Editor – Vascular Medicine Raghu Kolluri

Section Editor – Update of New Literature Athanasios Saratzis

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

Ohio Health, Columbus, OH, US

Editorial Board Roger Barranco Pons Bellvitge University Hospital, Barcelona, Spain

Lukla Biasi

Emad Hussein

Ain Shams University Hospital, Cairo, Egypt

Houman Jalaie

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

University Hospital RWTH, Aachen, Belgium

Elias Brountzos

Imperial College Healthcare NHS Trust, London, UK

Attikon University General Hospital, Greece

Andrew Bullen Wollongong Hospital, Australia

Alessandro Cannavale Policlinico Umberto I, Rome, Italy

Patrick Chong Frimley Health NHS Foundation Trust, Surrey, UK

Fabrizio D’Abate St George’s University Hospital, London, UK

Brian G DeRubertis David Gefffen School of Medicine at UCLA, CA, US

Mert Dumantepe Istanbul University, Istanbul, Turkey

Steve Elias Englewood Hospital, Englewood, NJ, US

Fernando Gallardo University Hospital Complex of Santiago de Compostela, Spain

Antonios Gasparis

Michael Jenkins

Narayan Karunanithy

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

Miltiadis E Krokidis

University of Cambridge, Cambridge, UK

Nicos Labropoulos

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

Raghuram Lakshminarayan

Hull University Teaching Hospitals NHS Trust, Hull, UK

Martin Maresch

BDF Hospital, Bahrain

Ross Milner

University of Chicago Medical Center, Chicago, IL, US

Hayley Moore

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

Lakshmi Ratnam St George’s University Hospital, London, UK

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

Prakash Saha King’s College Hospital, London, UK

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

Michael C Stoner University of Rochester Medical Center, Rochester, NY, US

Sherif Sultan National University of Ireland, Ireland

Gustaf Tegler Uppsala University, Sweden

Sarah Thomis UZ Leuven, Leuven, Belgium

Gergana Todorova Taneva University Ramón y Cajal, Madrid, Spain

Marie-Josee Van Rijn

Erin Murphy

Erasmus University Medical Center, Rotterdam, the Netherlands

Abdullah Omari

Prince of Wales Hospital, Sydney, Australia

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

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

St Vincent’s Clinic, Sydney, Australia

Andrew Holden

Gerry O’Sullivan

Auckland City Hospital, New Zealand

Premal Patel Great Ormond Street Hospital, London, UK

University College Hospital, Ireland

Ramon Varcoe Emma Wilton Oxford University Hospitals NHS Foundation Trust, Oxford, UK

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Contents Endovascular Treatment of Giant Visceral Aneurysms: An Overview Davide Castiglione, Marcello Andrea Tipaldi, Michele Rossi and Miltiadis Krokidis DOI: https://doi.org/10.15420/ver.2020.07

Transradial Access: A Comprehensive Review

Shawn Hobby, Maxwell Stroebel, Ricardo Yamada, Thor Johnson, Andre Uflacker, Christopher Hannegan and Marcelo Guimaraes DOI: https://doi.org/10.15420/ver.2020.17

Paclitaxel- and Sirolimus-coated Balloons in Peripheral Artery Disease Treatment: Current Perspectives and Concerns

Masayuki Mori, Atsushi Sakamoto, Rika Kawakami, Yu Sato, Hiroyuki Jinnouchi, Kenji Kawai, Anne Cornelissen, Renu Virmani and Aloke V Finn DOI: https://doi.org/10.15420/ver.2020.16

Incidental Finding of an Asymptomatic Migrated Coil to the Right Ventricle Following Pelvic Vein Embolisation Luca Scott and Jack Cullen

DOI: https://doi.org/10.15420/ver.2020.22

Paclitaxel Exposure and Dosage of Drug-coated Devices for the Treatment of Femoropopliteal Peripheral Artery Disease Ceazón T Edwards, Peter A Schneider and Cindy Huynh DOI: https://doi.org/10.15420/ver.2020.14

Complex Endovascular Procedures

Endovascular Treatment of Giant Visceral Aneurysms: An Overview Davide Castiglione,1 Marcello Andrea Tipaldi,2 Michele Rossi2 and Miltiadis Krokidis

1. Department of Radiological Science, AOUP Paolo Giaccone, BiND, Università di Palermo, Palermo, Italy; 2. Department of Radiology, Sant’Andrea University Hospital La Sapienza, Rome, Italy; 3. 1st Department of Radiology, National and Kapodistrian University of Athens, Areteion Hospital, Athens, Greece

Abstract

Giant visceral aneurysms (or pseudoaneurysms) are aneurysmal lesions of the splanchnic vessels that are larger than 5 cm in diameter. As with other visceral aneurysms, treatment may be either surgical or endovascular. Both treatments face challenges given the anatomical complexity of such lesions. However, in the era of novel tools and techniques that have been developed in this field, an increasing number of giant visceral aneurysms can now be treated using endovascular approaches. The purpose of this article is to offer an overview of the most current techniques and trends in the endovascular treatment of giant visceral artery aneurysms.

Keywords

Visceral artery aneurysms, endovascular treatment, coils, covered stents, embolisation, surgery Disclosure: The authors have no conflicts of interest to declare. Received: 12 March 2020 Accepted: 9 November 2020 Citation: Vascular & Endovascular Review 2021;4:e01. DOI: https://doi.org/10.15420/ver.2020.07 Correspondence: Miltiadis Krokidis, School of Medicine, National and Kapodistrian University of Athens, 1st Department of Radiology, Areteion Hospital, 76 Vas Sophias Ave, 11528, Athens, Greece. E: mkrokidis@med.uoa.gr Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Visceral artery aneurysms (VAAs) are a quite rare but potentially lifethreatening vascular disorder involving predominantly the splenic and the common hepatic arteries and less frequently the coeliac, left gastric or branches of the superior mesenteric arteries. The incidence is between 1% and 2% in the general population and splenic artery aneurisms represent approximately two-thirds of them.1–4 VAAs are usually detected and treated when they reach a threshold diameter of 2 cm. Very rarely they may silently grow and reach a size larger than 5 cm. In such cases, they are referred to as ‘giant’ VAAs (GVAAs).5–7 GVAAs may be discovered as an incidental finding on a scan, or they may cause compression symptoms – mainly to the stomach – or present as a rupture.8–10 Because of the risk of rupture, surgical or endovascular treatment is required imminently when such lesions are discovered.

Management of Giant Visceral Artery Aneurysms

Surgical repair has historically been the treatment of choice for all visceral aneurysms.11,12 However, a less invasive endovascular approach has also been gradually adopted in a number of centres – in line with local expertise and available tools – and is now the first option in most centres.13–21 Both surgical and endovascular approaches present challenges in the treatment of these lesions and these are described in more detail in the following sections.

Surgery

Most commonly, GVAAs originate from the splenic artery. Giant aneurysms originating from the hepatic artery or the coeliac trunk are much less common and carry a higher element of complexity when surgical repair is attempted.6,22 For giant aneurysms of the splenic artery, aneurysmectomy with or without splenectomy is expected to be more feasible for lesions

located in the proximal or the distal third of the vessel.23,24 For giant splenic artery aneurysms located in the mid portion of the artery, therefore attached to the pancreas, simple ligation of the proximal and distal segments of the artery might be the preferred strategy. Aneurysm ligation without vascular reconstruction is also the preferred option in acute settings for haemodynamically unstable patients. For hepatic GVAAs, aneurysmectomy with vessel reconstruction is required for lesions that are located distally to the origin of the gastroduodenal artery whereas simple ligation may be performed for proximal lesions because of the presence of the collateral circuit.25 Coeliac giant aneurysms are extremely rare and most of them are diagnosed in post mortem examinations – in part because these lesions can also be infectious.26 Surgical approaches also include aneurysmorrhaphy and revascularisation with vein or prosthetic grafts. If the aneurysm includes trifurcation, complexity is significantly increased and mortality reaches 5%.27 Surgical access might be obtained with standard laparotomy – mainly for splenic giant aneurysms.28 This would comprise a left subcostal approach, dissection of the greater omentum with ligatures up to the omental sac followed by dissection and clamping of the two ends of the splenic artery and aneurysmectomy. For coeliac lesions, access might be more challenging. The coeliac trunk may not be accessible anteriorly because of the large size of the mass and a thoracoabdominal incision with retroperitoneal access to the vessels through the gastrocolic ligament might be required.24 Another similar approach might be performed with a chevron incision and rotation of the viscera medially.25 Sometimes control of the artery may be difficult to achieve and additional manoeuvres might be necessary such as medial rotation of the upper abdominal viscera to gain retroperitoneal access to the

Endovascular Treatment of Giant Visceral Aneurysms abdominal aorta. Laparoscopic approaches may also be used as an alternative given the lower morbidity, although there is very limited experience for the treatment of GVAAs.29,30 In cases where arterial reconstruction that would preserve flow towards the organs distally to the aneurysm is not possible, additional visceral resection may be required.31 Surgical options include splenectomy or even distal pancreatectomy when necessary.32,33 Multi-step procedures and combined treatment (both endovascular and surgical) may also be considered in complicated cases and successful use of this approach in the management of a patient with multiple GVAAs has been reported.34 Although data on the surgical management of GVAAs are limited, it is reasonable to assume that morbidity and mortality would increase proportionally for larger lesions. On the other hand – given the dramatic improvement in endovascular techniques and materials – endovascular approaches may also be feasible for challenging cases with unfavourable anatomy and complex sac morphology and are now considered as the first treatment option.

Endovascular Management

The endovascular approach is associated with early postoperative recovery and consequently shorter hospital stays. It represents a valid alternative in high-risk patients with multiple comorbidities and those with a history of abdominal surgery for whom intraperitoneal adhesions may be a concern. An essential prerequisite in planning endovascular treatment is the availability of good quality, high-resolution imaging. This should include dynamic CT scans and multi-planar reconstructions in order to assess vascular anatomy of the district and determine the most appropriate treatment strategy. When dealing with GVAAs, endovascular management may be more challenging and many operators are concerned about potential complications and long-term outcomes. Moreover, scientific literature is lacking in studies concerning the management of GVAAs and only a few case reports have been described.35–39 Spiliopoulos et al. advocated the efficacy of endovascular treatment in larger size aneurysms.40 They reported a high clinical and technical success rate dealing with VAAs with a mean diameter of 49.4 ± 21 mm and visceral artery pseudoaneurysms (VAPAs) with a mean diameter of 25.1 ± 14.6 mm. Procedural technical success was achieved in all cases. The target lesion re-intervention rate was 6.1% (2/33 cases) in the VAPA group and 14.2% (3/21) in the VAA group. A recent systematic review by Hamid et al. analysed 92 cases of giant splenic artery aneurysm.41 Endovascular treatment was considered successful in 89.7% of patients (35/39). The researchers compared endovascular and surgical treatments and noted a comparable efficiency in the reduction of aneurysm-related death and palliation of aneurysmrelated symptoms. The study also revealed a higher rate of post-procedure complications with endovascular treatment (p<0.05). However, this outcome may be subject to further interpretation. In fact, in the scenario of splenic artery GVAAs, embolisation of the feeding vessels is often strictly related to the possible onset of splenic infarcts and it can be considered as a minimum loss compared with the risk of splenectomy. So, the authors agreed that endovascular therapeutic techniques – even in the scenario of GVAAs – may be associated with a lower rate of major

complications.41

Considerations for Endovascular Techniques

Endovascular management of GVAAs is challenging and requires a combination of several techniques and materials from the interventional armamentarium, including coils, vascular plugs, liquid embolic agents and covered stents. Moreover, the procedure can be performed in a multistage fashion, in order to occlude the several efferent vessels progressively and reduce radiation exposure to the patient.42 The strategy may represent a risk due to the dynamic flow and pressure change inside the sac that may lead to a sudden rupture. Length of the neck, tortuosity of the arteries, the precise location of the aneurysm and angulation of the aneurysmal tract should be evaluated carefully prior to deciding the embolisation device and technique. It should also be taken into account that a combination of several treatment techniques might be necessary in most cases. The double inflow-outflow blockage technique is of paramount importance in order to diminish the risk of reperfusion. All the efferent vessels that originate from the sac – usually multiple in giant aneurysms – need to be embolised in order to obtain a complete exclusion of lesion. The outflow vessels should be addressed first. Selective micro-catheterisation of small arteries originating from huge sacs is a rather challenging task and, in some cases, partial embolisation of the aneurysmal sac helps in reducing the flow and visualising all the feeding vessels. In these cases, the use of liquid embolic agents is very useful as they may reach distal vessels.35 The endovascular coiling approach has been demonstrated to be effective even in very large aneurysms, and more than sufficiently fast and safe to use in the event of a ruptured visceral aneurysm and a sudden drop in blood pressure.36 The packing technique, to prevent the risk of endoleaks, due to the large space in the sac, may be performed using different embolic agents such as fragments of guidewire, long detachable coils (only recently available for peripheral interventions) or liquid agents in order to obtain a better thrombosis of the aneurysm. However, isolated sac packing has been reported to be associated with a high risk of coil compaction and recanalisation of the aneurysmatic sac.19 In fact, in partially thrombosed aneurysms, even sufficient packing does not preclude recanalisation of the aneurysm because factors other than compaction, such as thrombus resolution and migration of coils into the thrombus, cause the aneurysm to recanalise over time. Therefore, in giant-sized aneurysms, the presence or not of sac thrombus may be of paramount importance, as sufficient coil packing to prevent revascularisation would result in significant additional cost, time, and radiation exposure to the patient with equivocal overall benefit.35,36,42–44 In order to achieve a better post-coiling result, the use of the combination of liquid embolics, such as ethylene vinyl alcohol copolymer (Onyx), with coil has been reported with good results.37 The use of covered stents, although virtually appealing for preserving the vessel patency as reported in the literature, is not feasible in most cases for dealing with GVAAs because of the absence of an optimal landing zone, significant tortuosity and evidence of an infected sac.19,38 Even the use of some interesting techniques derived from the endovascular neurointervention experience has been applied in the case

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Endovascular Treatment of Giant Visceral Aneurysms Figure 1: Endovascular Treatment of a Giant Splenic Aneurysm A

A 74-year-old man was admitted to our hospital because of an incidental ultrasound finding of giant splenic artery aneurysm. He had a history of arrhythmia under β-blocker treatment, hiatal hernia, prostatic hypertrophy and no history of abdominal trauma, infection or surgery. The diagnosis of the lesion was confirmed by contrast-enhanced CT, which revealed a 63 × 55 mm partially thrombosed splenic artery aneurysm. (A) Angiographic approach followed, with deployment of a self expandable covered stent (Viabahn, Gore). A second covered stent was necessary to cover the whole length of the aneurysm but it was not possible to advance it due to significant vessel tortuosity therefore the aneurysm was only partially treated as shown by the reconstructed CT picture (B). Embolisation was performed the next day with occlusion of the proximal and distal ends with coils (C and D) and of the proximal neck of the aneurysm with a vascular plug (E) with good angiographic outcome (F). Some ischaemic areas were detected in the spleen in the follow-up CT; however, the patient remained asymptomatic (G).

of GVAAs. For example, Gjoreski et al. reported a case of GVAA of the hepatic artery successfully treated with dual-layer stents placement as a flow-diverting option.39 Figure 1 describes the management of a patient in our hospital after the incidental ultrasound discovery of a giant splenic artery aneurysm.

Conclusion

In summary, the management of GVAAs is a complex issue that has to be carried out in very experienced centres. Preliminary studies available in 1. Hossian A, Reis ED, Dave SP et al. Visceral artery aneurysms: experience in a tertiary-care center. Am Surg 2001;67:432–7. PMID: 11379643. 2. Pasha SF, Gloviczki P, Stanson AW et al. Splanchnic artery aneurysms. Mayo Clinic Proc 2007;82:472–9. https://doi. org/10.4065/82.4.472; PMID: 17418076. 3. Shanley CJ, Shah NL, Messina LM. Common splanchnic artery aneurysms. Ann Vasc Surg 1996;10:315–22. https://doi. org/10.1007/BF02001900; PMID: 8793003. 4. Chiesa R, Astore D, Guzzo G, et al. Visceral artery aneurysms. Ann Vasc Surg 2005;19:42–8. https://doi. org/10.1007/s10016-004-0150-2; PMID: 15714366. 5. Kim JH, Rha SE, Chun HJ et al. Giant aneurysm of the common hepatic artery: US and CT imaging findings. Abdom Imaging 2010;35: 212–4. https://doi.org/10.1007/s00261-0099501-3; PMID: 19283428. 6. Bachar GN, Belenky A, Lubovsky L, et al. Sonographic diagnosis of a giant aneurysm of the common hepatic artery. J Clin Ultrasound 2002;30:300–2. https://doi. org/10.1002/jcu.10077; PMID: 12116110. 7. Yadav S, Sharma P, Singh PK, et al. Giant splenic artery aneurysm: a rare but potentally catastrophic surgical challenge. Int J Surg Case Rep 2012;3:533–6. https://doi. org/10.1016/j.ijscr.2012.06.010; PMID: 22902799 . 8. Kemal Beksac and Derya Karakoc. Multiple giant splenic artery aneurysms causing sinistral (left-sided) portal hypertension. Case Rep Gastrointest Med 2016;2016:6278452. https://doi.org/10.1155/2016/6278452; PMID: 27110411. 9. Debnath J, George RA, Rao PP, Ghosh K. Splenic artery aneurysm--a rare cause for extrahepatic portal venous obstruction: a case report. Int J Surg 2007;5:351–2. https:// doi.org/10.1016/j.ijsu.2007.04.019; PMID: 17613289. 10. Elamurugan TP, Kumar SS, Muthukumarassamy R, Kate V. Splenic artery aneurysm presenting as extrahepatic portal vein obstruction: a case report. Case Rep Gastrointest Med 2011;2011:908529. https://doi.org/10.1155/2011/908529; PMID: 22606430. 11. Pulli R, Dorigo W, Troisi N et al. Surgical treatment of

the literature suggest that endovascular treatment is efficient and safe and may be considered as the first-line approach thanks to the low associated morbidity and mortality. However, when considering endovascular exclusion for GVAAs of the abdominal cavity, it is recommended that the patient is haemodynamically stable, there are no signs of aneurysm rupture, there is an experienced team of interventional radiologists and the surgical team is aware and on-board in case of complications or acute rupture. Further studies are necessary to assess the efficacy of this technique in the treatment of haemodynamically unstable patients due to the rupture of the sac.

visceral artery aneurysms: a 25-year experience. J Vasc Surg 2008;48:334–42. https://doi.org/10.1016/j.jvs.2008.03.043; PMID: 18644480. 12. Marone EM, Mascia D, Kahlberg A et al. Is open repair still the gold standard in visceral artery aneurysm management? Ann Vasc Surg 2011;25:936–46. https://doi.org/10.1016/j. avsg.2011.03.006; PMID: 21620671. 13. Tulsyan N, Kashyap VS, Greenberg RK, et al. The endovascular management of visceral artery aneurysms and pseudoaneurysms. J Vasc Surg 2007;45: 276–83. https://doi. org/10.1016/j.jvs.2006.10.049; PMID: 17264002. 14. Belli AM, Markose G, Morgan R. The role of interventional radiology in the management of abdominal visceral artery aneurysms. Cardiovasc Intervent Radiol 2012;35:234–43. https://doi.org/10.1007/s00270-011-0201-3; PMID: 21674280. 15. Shukla AJ, Eid R, Fish L, et al. Contemporary outcomes of intact and ruptured visceral artery aneurysms. J Vasc Surg 2015;61:1442–8. https://doi.org/10.1016/j.jvs.2015.01.005; PMID: 25752692. 16. Laganà D, Carrafiello G, Mangini M, et al. Multimodal approach to endovascular treatment of visceral artery aneurysms with stent-graft: technique and long term followup. Cardiovasc Intervent Radiol 2008;31:36–42. https://doi. org/10.1007/s00270-007-9167-6; PMID: 17922163. 17. Balderi A, Antonetti A, Ferro L, et al. Endovascular treatment of visceral artery aneurysms and pseudoaneurysms: our experience. Radiol Med 2012;117:815–30. https://doi. org/10.1007/s11547-011-0776-4; PMID: 22228131. 18. Loffroy R, Favelier S, Pottecher P, et al. Endovascular management of visceral artery aneurysms: when to watch, when to intervene? World J Radiol 2015;7:143–8. https://doi.org/10.4329/wjr.v7.i7.143; PMID: 26217453. 19. Cappucci M, Zarco F, Orgera G, et al. Endovascular treatment of visceral artery aneurysms and pseudoaneurysms with stent-graft: Analysis of immediate and long-term results. Cir Esp 2017;95:283–92. https://doi. org/10.1016/j.cireng.2017.04.022; PMID: 28583724. 20. Cochennec F, Riga CV, Allaire E et al. Contemporary

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management of splanchnic and renal artery aneurysms: results of endovascular compared with open surgery from two European vascular centers. J Vasc Endovasc Surg 2011;42:340–6. https://doi.org/10.1016/j.ejvs.2011.04.033; PMID: 21628100. 21. Kok HK, Asadi H, Sheehan M et al. Systematic review and single-center experience for endovascular management of visceral and renal artery aneurysms. J Vasc Interv Radiol 2016;27:1630–41. https://doi.org/10.1016/j.jvir.2016.07.030; PMID: 27692855. 22. Parmar H, Shah J, Shah B, et al. Imaging findings in a giant hepatic artery aneurysm. J Postgrad Med 2000;46;104–5. PMID: 11013477. 23. Akbulut S, Otan E. Management of giant splenic artery aneurysm. Medicine (Baltimore) 2015;94:e1016. https://doi. org/10.1097/MD.0000000000001016; PMID: 26166071. 24. Long CD, Bakshi KR, Kahn MB, Roberts AB. Giant splenic artery aneurysm. Ann Vasc Surg 1993;7:474–8. https://doi. org/10.1007/BF02002133; PMID: 8268094. 25. Pescarus R, Montreuil B, Bendavid Y. Giant splenic artery aneurysms: case report and review of the literature. J Vasc Surg 2005;42:344–7. https://doi.org/10.1016/j. jvs.2005.04.026; PMID: 16102637. 26. Graham LM, Stanley JC, Whitehouse WM Jr, et al. Celiac artery aneurysms: historic (1745–1949) versus contemporary (1950–1984) differences in etiology and clinical importance. J Vasc Surg 1985;2:757–64. https://doi.org/10.1016/07415214(85)90053-9; PMID: 3897591. 27. D’Ayala M, Deitch JS, deGraft-Johnson J, et al. Giant celiac artery aneurysm with associated visceral occlusive disease. Vascular 2004;12:390–3. https://doi.org/10.2310/ 6670.2004.00032; PMID: 15895764. 28. Rodrıguez-Caulo EA, Araji O, Miranda N, et al. Fusiform giant splenic artery aneurysm. Cir Esp 2014;92:215–6 [in Spanish]. https://doi.org/10.1016/j.ciresp.2012.01.013; PMID: 23219207. 29. Tiberio GA, Bonardelli S, Gheza F, et al. Prospective randomized comparison of open versus laparoscopic management of splenic artery aneurysms: a 10-year study.

Endovascular Treatment of Giant Visceral Aneurysms Surg Endosc 2012. https://doi.org/10.1007/s00464-012-2413-2; PMID: 22752279. 30. Barbaros U, Ozemir IA, Aksakal N, et al. Laparoscopic surgery of the splenic artery and vein aneurysm with spontaneous arteriovenous fistula. Surg Laparosc Endosc Percutan Tech 2013;23:e127–30. https://doi.org/10.1097/ SLE.0b013e31827775f2; PMID: 23752021. 31. O’Driscoll D, Olliff SP, Olliff JF. Hepatic artery aneurysm. Br J Radiol 1999;72:1018–1025. https://doi.org/10.1259/ bjr.72.862.10673957; PMID: 10673957. 32. Miao YD, Ye B. Intragastric rupture of splenic artery aneurysms: three case reports and literature review. Pak J Med Sci 2013;29: 656–9. https://doi.org/10.12669/ pjms.292.2992; PMID: 24353598. 33. Al-Habbal Y, Christophi C, Muralidharan V. Aneurysms of the splenic artery: a review. Surgeon 2010;8:223–31. https://doi. org/10.1016/j.surge.2009.11.011; PMID: 20569943. 34. Rehman ZU. Multiple giant splenic artery aneurysms with hypersplenism and portal hypertension: a case report. Ann Vasc Dis 2019;12:250–2. https://doi.org/10.3400/avd.cr.1900021; PMID: 31275486. 35. Rossi M, Virgilio E, Laurino F, et al. Giant hepatic artery aneurysm associated with immunoglobulin g4-related

disease successfully treated using a liquid embolic agent. Korean J Radiol 2015;16: 953–4. https://doi.org/10.3348/ kjr.2015.16.4.953; PMID: 26175600. 36. Nguyen AT, Jensen RJ, Lindegaard Pedersen B. Gigantic ruptured aneurysm of the gastroduodenal artery successfully treated by coiling. EJVES Short Rep 2019;45:10– 13. https://doi.org/10.1016/j.ejvssr.2019.08.001; PMID: 31646206. 37. Abdallah FF, Serracino-Inglott F, Ananthakrishnan G. Giant hepatic aneurysm presenting with hematemesis successfully treated with an endovascular technique. Vasc Endovasc Surg 2017;51:331–4. https://doi.org/10.1177/1538574417707145; PMID: 28478708. 38. Zhang W, Fu YF, Wei PL, et al. endovascular repair of celiac artery aneurysm with the use of stent grafts. J Vasc Interv Radiol 2016;27:514–8. https://doi.org/10.1016/j. jvir.2015.12.024; PMID: 26922007. 39. Gjoreski A, Risteski F, Damjanoski G. successful endovascular treatment of a giant hepatic artery aneurysm with dual layer stents placement as flow-diverting option: case report. Open Access Maced J Med Sci 2019;7:403–6. https://doi.org/10.3889/oamjms.2019.120; PMID: 30834011. 40. Spiliopoulos S, Sabharwal T, Karnabatidis D, et al.

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endovascular treatment of visceral aneurysms and pseudoaneurysms: long-term outcomes from a multicenter European study. Cardiovasc Intervent Radiol 2012;35:1315–25. https://doi.org/10.1007/s00270-011-0312-x; PMID: 22146976. 41. Hamid HKS, Suliman AEA, Piffaretti G, et al. A systematic review on clinical features and management of true giant splenic artery aneurysms. J Vasc Surg 2019;71:1036–45.e1. https://doi.org/10.1016/j.jvs.2019.09.026; PMID: 31727456. 42. Xiao N, Mansukhani N, Resnick S, Eskandari M. Giant celiac artery aneurysm. J Vasc Surg Cases Innov Tech 2019;5:447–51. https://doi.org/10.1016/j.jvscit.2019.05.003; PMID: 31660470. 43. Yasumoto T, Osuga K, Yamamoto H, et al. Long-term outcomes of coil packing for visceral aneurysms: correlation between packing density and incidence of coil compaction or recanalization. J Vasc Interv Radiol 2013;24:1798–1807. https://doi.org/10.1016/j.jvir.2013.04.030; PMID: 23810652. 44. Pitton MB, Dappa E, Jungmann F, et al. Visceral artery aneurysms: Incidence, management, and outcome analysis in a tertiary care center over one decade. Eur Radiol 2015;25:2004–14. https://doi.org/10.1007/s00330-015-35991; PMID: 25693662.

Transradial Access

Transradial Access: A Comprehensive Review Shawn Hobby, Maxwell Stroebel , Ricardo Yamada , Thor Johnson , Andre Uflacker , Christopher Hannegan and Marcelo Guimaraes Vascular and Interventional Radiology Division, Medical University of South Carolina, Charleston, SC, US

Abstract

Transradial access (TRA) via the left radial artery is an alternative to traditional transfemoral access for catheter-based procedures that is becoming increasingly more relevant in all types of arterial vascular interventions. First investigated in the realm of cardiology, TRA has been proven to provide many benefits (such as lower complication rates, lower cost, and improved patient comfort during and after the procedure) when compared with traditional femoral access while maintaining efficacy. This article provides an in-depth summary of the technical aspects of radial access while incorporating more recent data to explain patient preference for TRA, and the ways that TRA can improve peri-procedure workflow and compensation. It also describes potential complications, such as radial artery spasm, difficult anatomic variants and radial artery occlusion, and then gives techniques for mitigating and treating these complications. The article explains why TRA has become an important option for vascular and interventional radiology physicians, and why it is likely that this will continue to grow in relevance.

Keywords

Transradial, radial access, arterial access, alternative access, catheter-based access Disclosure: MG serves as a paid speaker for Terumo and serves on an advisory board for Medtronic. All other authors have no conflicts of interest to declare. Received: 13 August 2020 Accepted: 9 November 2020 Citation: Vascular & Endovascular Review 2021;4:e02. DOI: https://doi.org/10.15420/ver.2020.17 Correspondence: Maxwell Harris Stroebel, 7B Doughty St, Charleston, SC 29403, US. E: stroebel@musc.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Transradial artery access (TRA) has become a viable alternative to traditional transfemoral artery access (TFA) for many procedures performed by the interventionalist. Although this technique has been used for a number of years in the field of cardiology, the variety of intervention types and intervention locations were obstacles to the successful implementation of this technique within multiple fields of the vascular interventionalist, including vascular interventional radiology, interventional cardiology, vascular surgery and neurointervention. However, with the advent of a number of new devices specifically designed to optimise procedures from the radial approach, TRA for many common interventional procedures is now feasible and it is the preferred arterial access by patients compared to femoral.1–4 TRA techniques have specifically expanded into the areas of neurointervention and carotid and peripheral artery disease (PAD) interventions. At this time, all endovascular interventions (i.e. angioplasty, stenting, atherectomy and thrombectomy) are possible for viscera and coronary interventions and neurointervention. Most PAD interventions can be safely performed to the level of the superficial femoral artery (SFA) transradially; however, equipment size and length limit more peripheral work.1,5–8 Further research and device development supporting peripheral atherectomy and thrombectomy are underway in SFA interventions, given that TRA has been proven safe and feasible.9

intervention (PCI) studies demonstrated an improved safety profile of the TRA technique compared with TFA. The ACCESS, RIVAL, RIFLE-STEACS and MATRIX trials were randomised controlled studies comparing TRA with TFA for coronary intervention. These four trials involved more than 16,000 patients and demonstrated similar findings: that TRA leads to fewer bleeding-related complications, decreased all-cause mortality and fewer MIs when compared with TFA, without any difference in the incidence of stroke.8,10–13 In addition to decreased risk of major complications, there is a decreased risk of access-related complications when compared with femoral or brachial access.8 Access site complications are particularly relevant in the setting of anticoagulation and of thrombocytopenia. TRA has been shown to be a safe and feasible option with both thrombocytopenic and anticoagulated patients.13,14

Benefits of Transradial Artery Access

Additionally, TRA can be performed with the arm in abduction at 45–90° (Figure 1). In this configuration, the procedure table can be set up adjacent to the arm board as an extension of the patient table for convenient management of long devices. This positioning also increases the distance between the operator and the radiation source, with a

Before any new procedural technique can achieve mainstream implementation, there first needs to be proven benefit to the patient, the practitioner or the hospital system. As regards TRA, there is significant benefit in all three of these realms. Numerous percutaneous coronary

Because of the obesity epidemic in the US, there is an increasing number of patients with large panniculus, which obstructs access for TFA. Patient obesity necessitates creative patient positioning to expose the femoral crease; requires the interventionalist to access atypically deep femoral arteries; and poses increased risk of post-procedure access site bleeding and infection. Radial artery access obviates many of these challenges in obese patients, given that the wrist has minimal fat compared with the femoral artery.

Transradial Access Figure 1: Set-up Configuration for Transradial Artery Access

cases of high predicted bleeding risk.17 In VIR, two retrospective studies evaluated cost savings of TRA compared with TFA; both found significantly decreased costs, one of them indicating a saving of US$100 per procedure.18,19 There is, perhaps, an even greater opportunity for cost savings in VIR, given that many VIR procedures can be performed on an outpatient basis. Because TRA patients do not require mandatory bed rest, a radial lounge recovery environment should be considered at highvolume centres. In this environment, TRA patients may be seated in recliners with ambulation privileges. This would decrease the amount of space required to care for each patient and decrease the demands on the nursing staff. The time required to monitor a TRA patient (1–2 hours) is also significantly shorter than for a TFA patient (2–6 hours). TRA offers the potential to optimise space and human resource utilisation.

Placement of the left arm positioned in abduction at 45–90°, with the procedure table (grey rectangle) in line with the arm, and the radiation shield (orange bar; extending from top to bottom) between the radiation source and the operator (red square). This provides a threefold reduction in radiation exposure to the operator.

Learning Curve

Figure 2: Barbeau Test for Adequate Collateral Vascular Flow SpO2 +

+ Type A

Start radial artery compression

2 min SpO2

+ Type B

Start radial artery compression

+ 2 min SpO2 +

– Type C

Start radial artery compression

2 min SpO2

– Type D

Start radial artery compression

– 2 min

Waveforms A, B and C, positive test; waveform D, negative test (contraindication for transradial artery access). Source: Romagnoli et al. 2012.11 Reproduced with permission from Elsevier.

threefold reduction in overall operator radiation exposure.3,15 If the arm is placed along the torso, TRA will provide no benefit from the radiation safety standpoint.16 TRA has been associated with improved patient and recovery staff satisfaction during post-procedure care. Multiple studies have demonstrated patient preference for TRA over TFA due to earlier ambulation, decreased post-procedure pain, decreased recovery time and less stringent recovery restrictions.1–3 In competitive medical markets, in which the healthcare industry moves toward patient consumerism, the patient’s experience is paramount. If patients have a more favourable recovery period, they are more likely to advocate for TRA and for minimally invasive vascular and interventional radiology (VIR) procedures. The current economic pressure to reduce healthcare costs has elevated the importance of cost-effective treatments. Multiple publications have demonstrated conservative savings of US$250 per patient, which is in the realm of 10%. However, savings may be as high as US$1,621 per patient in

A study focused on the learning curve for interventionalists who are new to TRA demonstrated a threshold of only 20 cases to achieve equal procedure time, radiation dose and contrast use after implementation of TRA; and technical procedure success was equivalent for TRA and TFA regardless of TRA experience.20 Similar studies in PCI demonstrated a threshold for TRA experience of 30–50 cases; the difference is likely due to non-utilisation of ultrasound for access in the cardiology trials.21

Radial Access: Step by Step Pre-procedure Work-up for TRA

TRA work-up begins at the physical exam. A potentially limb-threatening complication of TRA is occlusion of the radial artery and ischaemia of the first and/or second fingers. However, in the appropriately triaged patient, digit ischaemia should never occur, even in the setting of radial artery occlusion (RAO), due to robust collateral circulation via a complete palmar arch vasculature. To assess for adequate collateral vascular flow, it is recommended to perform the Barbeau test. A pulse oximetry device, capable of displaying a plethysmographic venous waveform, is placed on the index or second finger. Initially the waveform should have normal amplitude. When manual compression is applied on the radial and ulnar arteries, the waveform should become flat. While compression is still applied to the radial artery, the pressure on the ulnar artery is released. The length of time to waveform return and the amplitude of the waveform determine the Barbeau waveform type: A, B or C (Figure 2). Barbeau type D refers to a waveform that does not return within a 2 minute window during compression of the radial artery.22 If the ulnar artery is the dominant feeding artery to the hand (larger diameter), then the Barbeau test should be performed in reverse on the ulnar artery using an equivalent technique. The Allen test is not recommended, due to the fact that the hand pigmentation in some patients might compromise visual evaluation of hand reperfusion. In addition to the Barbeau test, it is recommended to use B-mode ultrasound to assess patency and to measure the anteroposterior (AP) diameter of the radial artery, inner to inner wall, in order to assure the compatibility of the radial artery diameter with the outer diameter of the necessary introducer sheath. Ideally this should be done in clinic or in the pre-procedure area to allow time for planning, room set-up and selection of adequate supplies. In emergency cases, these exams can be quickly performed when the patient is on the angiography table given that both do not take more than 1 minute in total. Colour Doppler can also be used if desired, but the probe should be angled to 30–60° for proper flow assessment. If the vessel measures >1.6 mm, a lower profile introducer sheath such as the 5 Fr Slender sheath (Terumo) may be introduced. A regular 5 Fr

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Transradial Access introducer sheath needs a radial artery AP diameter of at least 1.8 mm. If a 6 Fr Slender sheath, regular 6 Fr or a regular 7 Fr introducer sheath is used, they will require a 2.4 mm, 2.6 mm and 3.1 mm radial artery AP diameter, respectively (Table 1). Caution should be used in patients with heavily calcified aortic arches, in those with a history of stroke and in the elderly. Theoretically, this population has increased stroke risk during TRA interventions. Meticulous technique is recommended to minimise neurological complications. Adequate TRA technique should include gentle catheter manoeuvres to minimise the risk of spasm and the use of fluoroscopy during the advancement of guidewire and catheter from the patient’s wrist until they reach the descending thoracic aorta. If the patient has an existing chest CT study, it should be reviewed prior to starting the procedure. Attention to these details will prevent inadvertent manoeuvres at the level of the aortic arch while obtaining access to the descending aorta. TRA interventions are possible in patients with a tortuous aortic arch (especially in type 3), but slow catheter manipulation will likely be necessary during abdominal aorta catheterisations.

Basic Technique for Successful Outcomes

Correct TRA technique begins with proper room set-up and patient positioning. The patient should be positioned supine with arm abducted at 45–90° on an arm board. The pulse oximetry detector is placed at the tip of the first or second fingers, ipsilateral to the wrist used for TRA. After sterilising the arm, a towel is placed on the arm board and another one is rolled and placed underneath the wrist to hyperextend it. Tape is used across the palm and the distal arm board to prevent inadvertent movement of the arm during the procedure. At the beginning of the procedure, the fluoroscopy table must be broken so that the image detector is collimated over the patient’s forearm. The sterile procedure table should be set up in line with the patient’s extended arm to allow for catheters and wires to rest on the work surface (Figure 1). Ideally, the radiologist should stand next to the patient’s thorax with both the ultrasound screen and fluoroscopy monitor near the patient’s head, across from the accessed arm. If this is not possible due to position of permanent room fixtures, the fluoroscopy or ultrasound screen can be placed on the opposite side of the patient’s torso. The radiation shield should be placed between the radiologist and the patient, just under the patient’s armpit. Decreased physician radiation exposure is a distinct advantage of the arm extended technique. The radiation protection tool that we typically use looks like a door on wheels. A good alternative is to position the ceiling-mounted shield above the angiography table skirt. With all equipment in place, begin access by identifying the skin entry site for the needle over the radial artery approximately 1–2 cm proximal of the wrist crease. Under ultrasound guidance, infuse 0.5–1 ml lidocaine without epinephrine at this location. In the case of a very shallow radial artery (minimal amount of soft tissues between the skin and the anterior radial artery wall), an extra amount of lidocaine may be needed to create additional space to facilitate the arterial puncture . A short 21 G needle is held at 30–45° (shallower than femoral access) from the skin to access the radial artery under direct ultrasound guidance. When possible, single wall puncture is preferred, to decrease the incidence of posterior wall haematoma and vessel spasm. Successful TRA will result in brisk backflow of blood from the needle hub and a 0.021 inch nitinol microwire is inserted (Seldinger technique). There

Table 1: Sheath Size by Radial Artery Diameter Introducer Sheath

Ideal Radial Artery Diameter (mm)

5 Fr slender radial

1.6

5 Fr regular radial

1.8

6 Fr slender radial

2.4

6 Fr regular radial

2.6

7 Fr regular radial

3.1

should be minimal friction advancing the wire. Fluoroscopy should be used whenever there is resistance to advancement of the wire. In the case of difficulties advancing the wire, verify on ultrasound whether the needle tip terminates in the centre of the vessel, without double wall penetration or anterior wall tenting due to incomplete wall penetration. Once the wire is advanced towards the elbow, thread a hydrophilic radial sheath over the wire. Typically, no skin nick is needed due to the sharpness of the insert tip and smooth tapering tip. Attach a 10 ml saline syringe to the sheath side port and aspirate to confirm intravascular position with easy blood return. Subsequently, flush the sheath with the TRA cocktail (200 µg nitroglycerine, 2.5 mg verapamil and 3,000–5,000 IU heparin) diluted to a volume of 5 ml aspirated blood. Saline flush the sheath to deliver the full medication amount to the vessel. To prevent the hydrophilic introducer sheath from moving during the procedure, it is highly recommended to place a transparent dressing (Opsite, Smith+Nephew) on the top of it (covering the head of the side arm of the sheath). Intra-arterial heparin should be given immediately following successful arterial access at a dosage of 50 units/kg with 1,000 unit boluses every 30 minutes for procedures that last longer than 1 hour. Alternatively, heparin can be given IV by the procedure nurse with assessment for re-administration every 30 minutes (our preference). For procedures lasting longer than 2 hours, make dosage adjustments based on ACT level (2–2.5-fold higher than the baseline). A prospective randomised clinical trial demonstrated radial artery spasm at the end of the procedure (after guidewire and catheter removal).3 Therefore, our institutional intra-arterial medication regimen includes completion of antispasmodic treatment (Table 2). Once TRA is successfully achieved, the radiologist can perform any of a large number of procedures from this location. Currently, TRA is primarily used for embolisation therapy, as well as in interventional oncology, visceral embolisation (splenic, renal, liver), gastrointestinal bleeding treatment, trauma, uterine fibroid embolisation and others. The length of the upper extremity arteries introduces challenges of device selection when operating on patients taller than 1.88 m. A 110 cm diagnostic catheter will often be sufficient for thoracic cases and upper abdomen procedures, while 125–130 cm systems will be needed for angiography of the inferior mesenteric artery, pelvic embolisations and selective lower extremity run-off. For superselective catheterisations, a 2.0–2.8 Fr 150 cm long microcatheter will provide access to virtually every location in the body. For trauma of the lower extremities (especially distal thigh and calf), femoral access is probably the best choice due to catheter length. Anatomic variants of the upper extremities increase the difficulty level by introducing increased tortuosity between the radial artery and aorta. To avoid spasm and upper extremity vascular injury, it is recommended to use a J-tip and hydrophilic wire. Radial artery kinks or loops typically will

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Transradial Access Table 2: Procedure-specific Medication Protocol During Transradial Access Based on >1,000 Cases Procedure

Medication to Prevent Spasm and Clot

Diagnostic arteriograms Interventional oncology Most embolisation procedures lasting <2 h

Beginning: • 3,000 IU heparin IV (systemic) • 200 µg nitroglycerine IA • Heparin 1,000 IU every 30 min End: • 200 µg nitroglycerine IA

Uterine fibroid embolisation Peripheral artery disease Complex embolisation therapy (>2 h, e.g. renal aneurysm embolisation)

Beginning: • 5,000 IU heparin IV (systemic) • 200 µg nitroglycerine IA • 2.5 mg verapamil IA • Heparin 1,000 IU every 30 min End: • 200 µg nitroglycerine IA

IA = intra-arterial.

The 5 Fr diagnostic catheter can then be advanced using the microcatheter and microwire as a guidewire. Increased resistance of the guidewire should be met with caution because this could indicate inadvertent catheterisation of the left internal mammary artery or that a right-sided aortic arch could be present with similar difficulty. When in doubt in any of these scenarios, perform contrast angiography to define the anatomy and rely on prior cross-sectional studies, which may be predictive of these challenges.

Access Closure

At completion of the procedure, remove the catheter over a wire to prevent vascular trauma to the aortic arch. Once the catheter is cleared from the introducer sheath, aspirate the sheath side port with a syringe to clear any blood clot that could have formed. Follow aspiration with a completion dose of intra-arterial anti-spasmodic cocktail of 200 µg nitroglycerine. Always make sure that the systolic pressure is above 100 mmHg. In the case of relative hypotension due to moderate sedation, consider the infusion of a bolus dose of saline to increase the blood pressure before the vasodilator is administered.

Patent Haemostasis

Figure 3: Radial Angiography

To prepare for sheath removal, place a 4 × 4 gauze under the sheath hub next to the skin entry site. Apply a radial artery compression device; the ideal device will allow adjustment to a pressure that achieves haemostasis at the arteriotomy without occluding the radial artery (patent haemostasis concept). The patency of the radial artery can be assessed manually by occluding the ulnar artery to perform a post-procedure reversed Barbeau test (occlude the ulnar artery to check if the radial artery is not excessively compressed by the balloon). Non-occlusive haemostasis decreases the incidence of RAO by 75% at 30 days.23 There should be a palpable pulse distal to the access site.

A: Normal vascular anatomy of the radial forearm on digital subtraction angiography. B: Example of extreme vessel tortuosity.

be reduced and straighten out after a hydrophilic wire is advanced through (Figure 3). In order to understand the forearm arterial anatomy, we recommend performing forearm angiography in every patient (5–6 ml iodine contrast) to anticipate these challenges, soon after the sheath is introduced in TRA. Navigating to the descending thoracic aorta can be challenging at times. Variations of aortic arch anatomy or aortic arch type 3 (elongated) might need special manoeuvres to overcome a difficult access. The simplest thing to do is to ask the patient to take a deep inspiration. Deep inspiration elongates the aorta and provides a better path for the guidewire. For more challenging anatomy, the whip manoeuvre may be used. The whip manoeuvre utilises a pigtail catheter positioned in the transverse arch with the open segment of the pigtail catheter facing the descending aorta. A 0.035 inch guidewire is advanced through the pigtail, which creates an exaggerated bend in the wire along the aortic arch and offers greater steerability to select the descending aorta. Alternatively, a microcatheter and microwire could be advanced coaxially through a 5 Fr diagnostic catheter to the descending aorta. Bending a long curve at the tip of the microcatheter may facilitate access to the descending aorta.

When the patient recovers in the post-procedure area, the patient should be monitored for bleeding at the access site. Monitor oxygen saturation of a digit distal to the access site, similarly to what was done in the procedure room. The pressure applied by the radial compression device can be systematically decreased per a standardised algorithm until the device can be removed. The patient should be monitored for an additional 30 minutes following removal of the device to ensure re-bleeding does not occur, at which point discharge is allowed. While in recovery, the patient will have less stringent positioning precautions compared with femoral access. The patient may be seated or semi-reclined with bathroom privileges. This small improvement in post-procedure care has a significant bearing on patient preference for radial access over femoral access.3

Radial Access Complications

The best way to minimise TRA complications is prevention. By implementing adequate pre-procedural patient selection and adhering to meticulous technique described above, many of these potential complications can be avoided. In the intra-procedure period, the two most common complications are radial artery spasm and RAO. While radial artery spasm is temporary, it accounts for up to 38% of the technical procedure failures.24 As a result of spasm, the patient may communicate new cramping pain in the arm; the interventionist may sense increased resistance when manipulating the catheter. Multiple medications have been shown to relax arteries undergoing spasm, although there is no consensus opinion on which medication is most beneficial. Spasmolytic pharmacological options include nitroglycerine,

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Transradial Access verapamil or diltiazem. Our institution uses 200 µg nitroglycerine given at the onset of spasm, as well as prophylactically at the beginning and end of the procedure. Moderate sedation medications have also been shown to prevent and treat spasm, while also improving patient comfort.13 Alternatives to pharmacological intervention include application of warm compresses and inflation of a blood pressure cuff to 40 mmHg over the region of spasm followed by rapid deflation. After the procedure, the most common complications are bruising and tenderness at the access site for 2–3 days. Radial artery anatomic variants occur in approximately 13.8% of patients and are predictive of intra-procedure spasm.25 Radial forearm digital subtraction angiography should be performed at the initiation of therapy to identify challenging vascular anatomy early. The 360° radial loops and extreme radial artery tortuosity (Figure 3) were most predictive of procedure failure and occurred in 2.3% and 2% of patients, respectively.25 Meticulous catheter technique while navigating known areas of tortuosity will decrease incidence of spasm. Post-procedure RAO is a potentially permanent complication. One metaanalysis suggests an incidence as high as 7.7% in the first 24 hours after the procedure.26 However, use of radial artery compression devices to provide non-occlusive haemostasis has decreased the incidence of RAO to less than 1%.27 Additionally, RAO is often clinically silent secondary to collateral flow. Early identification of RAO is an integral part of postprocedure care. A weak or absent pulse felt distal to the arteriotomy should initiate evaluation with Doppler ultrasound to confirm a diagnosis of RAO. Patients with confirmed RAO should receive systemic heparin. Non-invasive treatment manoeuvres include 20 minutes of compression to the ipsilateral ulnar artery to help re-establish flow via the palmar arch.28 Local intra-arterial tissue plasminogen activator at the site of occlusion or balloon angioplasty may be given. Patients with RAO should be admitted overnight for observation and the arm should be wrapped to keep it warm and to promote hyperaemia. A total of 3–6 months of anticoagulation may be warranted and the patient should be scheduled for follow up in 30 days with Doppler ultrasound. 1. Liu LB, Cedillo MA, Bishay V, et al. Patient experience and preference in transradial versus transfemoral access during transarterial radioembolization: a randomized single-center trial. J Vasc Interv Radiol 2019;30:414–20. https://doi. org/10.1016/j.jvir.2018.10.005; PMID: 30819485. 2. Iezzi R, Pompili M, Posa A, et al. Transradial versus transfemoral access for hepatic chemoembolization: intrapatient prospective single-center study. J Vasc Interv Radiol 2017;28:1234–9. https://doi.org/10.1016/j. jvir.2017.06.022; PMID: 28757286. 3. Yamada R, Bracewell S, Bassaco B, et al. Transradial versus transfemoral arterial access in liver cancer embolization: randomized trial to assess patient satisfaction. J Vasc Interv Radiol 2018;29:38–43. https://doi.org/10.1016/j. jvir.2017.08.024; PMID: 29150395. 4. Chen YY, Liu P, Wu YS, et al. Transradial vs transfemoral access in patients with hepatic malignancy and undergoing hepatic interventions: a systematic review and metaanalysis. Medicine (Baltimore) 2018;97:e13926. https://doi. org/10.1097/MD.0000000000013926; PMID: 30593212. 5. Sher A, Posham R, Vouyouka A, et al. Safety and feasibility of transradial infrainguinal peripheral arterial disease interventions. J Vasc Surg 2020;72:1237–46. https://doi. org/10.1016/j.jvs.2020.02.016; PMID: 32278576. 6. Joshi KC, Beer-Furlan A, Crowley RW, et al. Transradial approach for neurointerventions: a systematic review of the literature. J Neurointerv Surg 2020;12:886–92. https://doi. org/10.1136/neurintsurg-2019-015764; PMID: 32152185. 7. Ruzsa Z, Nemes B, Pinter L, et al. A randomised comparison of transradial and transfemoral approach for carotid artery

10.

11.

12.

One aspect of TRA that increases the technical challenge, is the need to traverse the aortic arch for treatment. Many providers presume that manipulating a catheter in the aortic arch increases the risk of embolic or ischemic stroke. However, the incidence of neurologic complication following cardiac catheterisation remained unchanged at 0.2%, while the percentage of TRA procedures increased dramatically; this suggests that access site does not affect the incidence of stroke.29 Regardless, attention to prior cross-sectional imaging of the chest or neck is an important part of pre-procedure TRA work-up. Screening for challenging anatomy and areas of significant atherosclerotic disease, particularly in patients aged over 70 years or with a history of prior stroke, may prevent this complication. Imaging findings may alert the physician to special equipment needs or, in rare circumstances, indicate when the femoral approach is preferable. Finally, there is a cluster of vascular complications that occurs in both TRA and TFA: post-procedural haematoma, access vessel rupture and access vessel pseudoaneurysm. Each of these complications occurs less frequently with TRA compared with TFA, and is more easily treated from TRA due to the easy exposure of the wrist.5 One exception is forearm compartment syndrome, which is encountered in only 0.4% of cases and is more likely to occur at the wrist than the groin in the setting of postprocedure haematoma.30

Staff Preparedness

An interventionalist is only as good as their surrounding staff. In implementing this new technique, consider including the nurses and radiological technologists in the education process. VIR staff are phenomenal resources for device selection and troubleshooting during challenging cases. Expert-led courses exist all around the world and the entire department could be included in this education from the beginning.

Conclusion

TRA is an emerging technique that can provide a safer and more convenient experience for the patient. Implementation of this new technique has unique advantages and pitfalls, but following best practice and using a meticulous technique can improve the quality of the service and increase patient satisfaction in endovascular interventions.

stenting: RADCAR (RADial access for CARotid artery stenting) study. EuroIntervention 2014;10:381–91. https://doi. org/10.4244/EIJV10I3A64; PMID: 25042266. Kiemeneij F, Laarman GJ, Odekerken D, et al. A randomized comparison of percutaneous transluminal coronary angioplasty by the radial, brachial and femoral approaches: the access study. J Am Coll Cardiol 1997;29:1269–75. https:// doi.org/10.1016/S0735-1097(97)00064-8; PMID: 9137223.. Hanna EB, Ababneh BA, Amin AN. Endovascular therapy of the superficial femoral artery via a stand-alone transradial access: a single-center experience. Vasc Endovascular Surg 2018;52:107–14. https://doi.org/10.1177/1538574417742239; PMID: 29179651. Mehta SR, Jolly SS, Cairns J, et al. Effects of radial versus femoral artery access in patients with acute coronary syndromes with or without ST-segment elevation. J Am Coll Cardiol 2012;60:2490–99. https://doi.org/10.1016/j. jacc.2012.07.050; PMID: 23103036. Romagnoli E, Biondi-Zoccai G, Sciahbasi A, et al. Radial versus femoral randomized investigation in ST-segment elevation acute coronary syndrome: the RIFLE-STEACS (Radial Versus Femoral Randomized Investigation in ST-Elevation Acute Coronary Syndrome) study. J Am Coll Cardiol 2012;60:2481–9. https://doi.org/10.1016/j. jacc.2012.06.017; PMID: 22858390. Valgimigli M, Gagnor A, Calabro P, et al. Radial versus femoral access in patients with acute coronary syndromes undergoing invasive management: a randomised multicentre trial. Lancet 2015;385:2465–76. https://doi. org/10.1016/S0140-6736(15)60292-6; PMID: 25791214.

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13. Mason PJ, Shah B, Tamis-Holland JE, et al. An update on radial artery access and best practices for transradial coronary angiography and intervention in acute coronary syndrome: a scientific statement from the American Heart Association. Circ Cardiovasc Interv 2018;11:e000035. https:// doi.org/10.1161/HCV.0000000000000035; PMID: 30354598. 14. Titano JJ, Biederman DM, Marinelli BS, et al. Safety and feasibility of transradial access for visceral interventions in patients with thrombocytopenia. Cardiovasc Intervent Radiol 2016;39:676–82. https://doi.org/10.1007/s00270-015-1264-3; PMID: 26696230. 15. Yamada R, Guimaraes M. Optimal room setup for transradial access. Endovascular Today 2018:17:41–7. 16. Liu LB, Cedillo MA, Bishay V, et al. Patient experience and preference in transradial versus transfemoral access during transarterial radioembolization: a randomized single-center trial. J Vasc Interv Radiol 2019;30:414–20. https://doi. org/10.1016/j.jvir.2018.10.005; PMID: 30819485. 17. Cooper CJ, El-Shiekh RA, Cohen DJ, et al. Effect of transradial access on quality of life and cost of cardiac catheterization: a randomized comparison. Am Heart J 1999;138:430–36. https://doi.org/10.1016/S00028703(99)70143-2; PMID: 10467191. 18. Wu T, Sun R, Huang Y, et al. Transradial arterial chemoembolization reduces complications and costs in patients with hepatocellular carcinoma. Indian J Cancer 2015;52(Suppl 2):e107–11 https://doi.org/10.4103/0019509X.172505; PMID: 26728666. 19. Kis B, Mills M, Hoffe SE. Hepatic radioembolization from transradial access: initial experience and comparison to

Transradial Access transfemoral access. Diagn Interv Radiol 2016;22:444–9. https://doi.org/10.5152/dir.2016.15571; PMID: 27353460. 20. Iezzi R, Posa A, Merlino B, et al. Operator learning curve for transradial liver cancer embolization: implications for the initiation of a transradial access program. Diagn Interv Radiol 2019;25:368–74. https://doi.org/10.5152/dir.2019.18437; PMID: 31348005. 21. Agostoni P, Biondi-Zoccai GG, de Benedictis ML, et al. Radial versus femoral approach for percutaneous coronary diagnostic and interventional procedures: systematic overview and meta-analysis of randomized trials. J Am Coll Cardiol 2004;44:349–56. https://doi.org/10.1016/j. jacc.2004.04.034; PMID: 15261930. 22. Barbeau GR, Arsenault F, Dugas L, et al. Evaluation of the ulnopalmar arterial arches with pulse oximetry and plethysmography: comparison with the Allen’s test in 1010 patients. Am Heart J 2004;147:489–93. https://doi. org/10.1016/j.ahj.2003.10.038; PMID: 14999199. 23. Pancholy S, Coppola J, Patel T, Roke-Thomas M. Prevention of Radial Artery Occlusion – Patent Hemostasis Evaluation

Trial (PROPHET study): a randomized comparison of traditional versus patency documented hemostasis after transradial catheterization. Catheter Cardiovasc Interv 2008;72:335–40. https://doi.org/10.1002/ccd.21639; PMID: 18726956. 24. Ball WT, Sharieff W, Jolly SS, et al. Characterization of operator learning curve for transradial coronary interventions. Circ Cardiovasc Interv 2011;4:336–41. https:// doi.org/10.1161/CIRCINTERVENTIONS.110.960864; PMID: 21813402. 25. Lo TS, Nolan J, Fountzopoulos E, et al. Radial artery anomaly and its influence on transradial coronary procedural outcome. Heart 2009;95:410–15. https://doi. org/10.1136/hrt.2008.150474; PMID: 18977799. 26. Rashid M, Kwok CS, Pancholy S, et al. Radial artery occlusion after transradial interventions: a systematic review and meta-analysis. J Am Heart Assoc 2016;5:e002686. https://doi.org/10.1161/JAHA.115.002686; PMID: 26811162. 27. Chugh SK, Chugh S, Chugh Y, Rao SV. Feasibility and utility of pre-procedure ultrasound imaging of the arm to facilitate

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transradial coronary diagnostic and interventional procedures (PRIMAFACIE-TRI). Catheter Cardiovasc Interv 2013;82:64–73. https://doi.org/10.1002/ccd.24585; PMID: 22887352. 28. Bernat I, Bertrand OF, Rokyta R, et al. Efficacy and safety of transient ulnar artery compression to recanalize acute radial artery occlusion after transradial catheterization. Am J Cardiol 2011;107:1698–1701. https://doi.org/10.1016/j. amjcard.2011.01.056; PMID: 21439528. 29. Posham R, Biederman DM, Patel RS, et al. Transradial approach for noncoronary interventions: a single-center review of safety and feasibility in the first 1,500 cases. J Vasc Interv Radiol 2016;27:159–66. https://doi.org/10.1016/j. jvir.2015.10.026; PMID: 26706186. 30. Tizon-Marcos H, Barbeau GR. Incidence of compartment syndrome of the arm in a large series of transradial approach for coronary procedures. J Interv Cardiol 2008;21:380–84. https://doi.org/10.1111/j.1540-8183. 2008.00361.x; PMID: 18537873.

Peripheral Artery Disease

Paclitaxel- and Sirolimus-coated Balloons in Peripheral Artery Disease Treatment: Current Perspectives and Concerns Masayuki Mori, Atsushi Sakamoto, Rika Kawakami, Yu Sato, Hiroyuki Jinnouchi, Kenji Kawai, Anne Cornelissen, Renu Virmani and Aloke V Finn CVPath Institute, Gaithersburg, MD, US

Abstract

Drug-coated balloons (DCBs) have become an established therapy for the treatment of above-the-knee peripheral artery disease. The paclitaxel DCB has shown clinical benefit in terms of patency and freedom from re-intervention in multiple randomised trials. However, a recent metaanalysis has suggested an association between mortality and the use of paclitaxel-coated devices. Sirolimus is another potential choice of antiproliferative agent for use in DCBs because of its wider therapeutic index and lower risk for dose-dependent toxicity. More recently, encapsulating sirolimus in micro-reservoirs or polymers has facilitated the development of effective sirolimus DCBs, some of which are available in Europe and Asia. In this review, the authors focus on paclitaxel and sirolimus DCB technologies from the standpoint of drug characteristics and clinical trials.

Keywords

Drug-coated balloon, peripheral artery disease, paclitaxel, sirolimus, percutaneous transluminal angioplasty Disclosure: RV has received honoraria from Abbott Vascular, Biosensors, Boston Scientific, Celonova, Cook Medical, Cordis, CSI, Lutonix Bard, Medtronic, OrbusNeich Medical, CeloNova, SINO Medical Technology, ReCore, Terumo Corporation, WL Gore and Spectranetics, and is a consultant for Abbott Vascular, Boston Scientific, Celonova, Cook Medical, Cordis, CSI, Edwards Lifescience, Lutonix Bard, Medtronic, OrbusNeich Medical, ReCore, Sinomedical Technology, Spectranetics, Surmodics, Terumo, WL Gore and Xeltis. AVF has received honoraria from Abbott Vascular, Biosensors, Boston Scientific, Celonova, Cook Medical, CSI, Lutonix Bard, Sinomed and Terumo, and is a consultant for Amgen, Abbott Vascular, Boston Scientific, Celonova, Cook Medical, Lutonix Bard and Sinomed. All other authors have no conflicts of interest to declare. Received: 9 July 2020 Accepted: 9 November 2020 Citation: Vascular & Endovascular Review 2021;4:e03. DOI: https://doi.org/10.15420/ver.2020.16 Correspondence: Aloke V Finn, CVPath Institute, 19 Firstfield Rd, Gaithersburg, MD 20878, US. E: afinn@cvpath.org Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Peripheral artery disease (PAD) in the lower extremities is the most prevalent cardiovascular disorder worldwide.1 PAD is mainly caused by atherosclerosis; other risk factors include diabetes, chronic kidney disease and smoking.2,3 Endovascular treatment for PAD is constantly being refined and is currently considered an indispensable therapeutic option in addition to exercise and pharmacotherapy. In recent years, treatment with drug-coated balloons (DCBs) has emerged as a novel approach for treating patients with PAD as well as coronary artery disease (CAD). The use of a DCB avoids implantation of a permanent metallic cage and may therefore prevent late complications related to foreign body reaction to the drug, polymer or metal in the vascular wall. Complications from such reactions include in-stent restenosis (ISR), neoatherosclerosis, and late stent thrombosis. Overall, DCBs have resulted in better clinical outcomes compared with conventional balloon angioplasty and bare metal stent implantation.4–6 Another advantage of DCBs is their flexibility. They allow for other options, including treatment for non-stented zones and repeat revascularisation of previously treated segments. According to the latest European Society of Cardiology guidelines, the use of drug-coated devices is recommended for ISR and short femoropopliteal lesions (i.e. <25 cm), as a Class B treatment option.7 Although drug-eluting stent (DES) technology has improved, the prevalence of both stent fractures (1.9% at 5-year follow-up in some

series) and 5-year target-lesion revascularisation (TLR) rate (17%) for treatment of above-the-knee PAD remains high and is inferior to the outcomes reported for CAD treatment.8,9 To overcome these drawbacks, DCB technologies may be a viable treatment option. In this review, we will describe the current status of both paclitaxel and sirolimus DCB technologies and summarise available clinical trial data for both above- and below-the-knee treatments, as well as discussing safety concerns that have arisen for paclitaxel-based technologies.

Paclitaxel-coated Balloons Paclitaxel

Paclitaxel is primarily used as an antiproliferative drug for DCBs because of its high-lipophilic characteristics, which allow for passive absorption through the cell membranes and a long-term effect inside the target vessel wall.10 Paclitaxel stabilises polymerised microtubules and prevents their disassembly, thereby suppressing mitotic division, proliferation and migration at the nanomolar level. These effects contribute to preventing neointimal smooth muscle cell overgrowth. Excipients can also facilitate dissolution of the paclitaxel and its transport into tissues. Without excipients, paclitaxel migration from the DCB into the tissues is limited, as shown in several preclinical studies.11 Despite

Paclitaxel- and Sirolimus-coated Balloons in PAD Treatment Table 1: Paclitaxel-coated Balloons Product

Company

Paclitaxel Dose (μg/mm2)

Excipient

Status

IN.PACT Admiral

Medtronic

3.5

Urea

CE mark (2009), FDA approved (2014)

Lutonix

CR Bard

2.0

Polysorbate/sorbitol

CE mark (2012), FDA approved (2014)

Stellarex

Philips

2.0

Polyethylene glycol

CE mark (2014), FDA approved (2019)

SeQuent Please

B. Braun

3.0

Resveratrol

CE mark (2009)

LEGFLOW

Cardionovum

3.0

Shelloic acid

CE mark (2011)

Ranger

Boston Scientific

2.0

Citrate ester

CE mark (2014)

Passeo-18 Lux

Biotronik

3.0

Butyryl-tri-hexyl citrate

CE mark (2016)

Luminor

iVascular

3.0

Organic ester

CE mark (2016)

SurVeil

SurModics

3.2

Proprietary photolink

CE mark (2020)

DCB = drug coated balloon; FDA = Food and Drug Administration.

Table 2: Comparison of Pivotal Clinical Trials of Paclitaxel-coated Balloons Study

Balloon Company Number Rutherford Lesion of Patients Class Length (Lesions) 2/3/4/5 (%) (mm)

IN.PACT SFA

De Novo Total

Severe Primary Evaluation Lesion (%) Occlusions Calcification Endpoint (%) (%)

Follow-up Duration

IN.PACT 2015/201820,21 Admiral

Medtronic

220 (221)

37.7/57.3/5.0/0 89.4 ± 48.9 95.0

25.8

8.1

Freedom from Duplex 1 and 3 years CD-TLR ultrasonography (PSVR ≤2.4)

LEVANT 2 201522

Lutonix

CR Bard

316 (322)

29.4/62.7/7.9/0 62.8 ± 41.8

76.6

20.6

10.4

Freedom from Duplex 1 year CD-TLR and ultrasonography restenosis (PSVR <2.5)

ILLUMENATE 201724

Stellarex

Philips

222 (254)

15.0/83.0/4.0/0 72.0 ± 52.0 92.0

19.0

13.0

Freedom from Duplex 1 year CD-TLR ultrasonography (PSVR ≤2.5)

RANGER SFA 20175

Ranger

Boston Scientific

71 (71)

46.2/53.8/0/0* 68.0 ± 46.0 74.0

34.3

35.7

Late lumen loss

Angiography

6 months

B. Braun

78 (87)

5.1/94.9/0/0

23.1

Late lumen loss

Angiography

6 months

CONSEQUENT SeQuent Please 201727

137.0 ± 122.0 NA

Continuous variables shown as mean ± SD. *Exact number is not available. The number was inferred from the figure. DCB = drug coated balloon; CD-TLR = clinically driven target lesion revascularisation; NA = not available; PSVR = peak systolic velocity ratio.

advancement of coating technology, transportation of paclitaxel into the target vascular tissues is still inefficient, resulting in a loss of at least 30% of loaded paclitaxel into the blood stream during treatment.12 Thus, at present, hydrophilic excipients are indispensable in the paclitaxel balloon for effective drug delivery.11,13 Paclitaxel coating is available in two forms: amorphous and crystalline. An optimal mix of amorphous and crystalline paclitaxel together with the right excipient is necessary for DCB efficacy. The balance of crystalline to amorphous forms affects the pharmacokinetic behaviour of the drug and thus affects neointimal formation and healing. In a preclinical study, DCBs were loaded with the crystalline or amorphous forms of drug in equal doses (3 µg/mm2) and deployed in pigs, after which arterial wall pharmacokinetic levels of the drug were examined.14 Although both formulations achieved similar arterial paclitaxel levels 1 hour after deployment, the crystalline forms retained higher drug concentrations at both 24-hour and 28-day follow-up. So far, more than nine paclitaxel balloons for PAD treatment have received the CE mark and three are approved by the Food and Drug Administration (FDA). The loaded paclitaxel dose and excipient of each device are listed in Table 1. In experimental models using different doses of paclitaxel delivered from stents, paclitaxel caused dose-dependent increases in tissue necrosis,

vascular wall haemorrhage and delayed healing with higher doses.15 Paclitaxel has been used for both drug delivery from DES used in the above-the-knee disease as well as in DCBs as discussed. Nonetheless question about potential toxicities from delivery remain, including the potential for aneurysm formation around paclitaxel-eluting stents. In one single-centre experience of 62 patients treated with the fluoropolymercased paclitaxel-eluting stent (Eluvia, Boston Scientific), five aneurysms were identified in the treated segment and thought to be attributable to paclitaxel.16 The IMPERIAL trial was a randomised single-blind non-inferiority study of Eluvia or Zilver PTX (Cook) for the treatment of patients with symptomatic lower limb ischaemia in the superficial femoral or proximal popliteal artery. Retrospective analysis of a subset of patients with duplex ultrasound images found six cases of aneurysm exclusively in the Eluvia group at 1 year.17 Case reports also have been published about the occurrence of aneurysms associated with paclitaxel-coated balloons.18,19 The possible mechanisms of intervention-related aneurysms might be associated with the high dose, high concentration and rapid onset of action of paclitaxel delivered from a drug-coated balloon. This and other safety concerns regarding paclitaxel-coated devices have limited enthusiasm for their use as treatments for vascular disease. We will discuss these safety concerns in the following sections in more detail.

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Paclitaxel- and Sirolimus-coated Balloons in PAD Treatment Table 3: Clinical Studies Evaluating Paclitaxel-coated Balloon Treatment for Critical Limb Ischaemia Study

Balloon

Number Rutherford Lesion of Patients Class Length (Lesions) 4/5/6 (%) (mm)

Phair et al. 202033

IN.PACT, Lutonix

32 (NA*)

XLPAD registry 202034 IN.PACT Global Study 201935

De Novo Total Severe Follow-up Freedom Primary Freedom Lesion (%) Occlusions Calcification Duration From Patency From Major (%) (%) TLR (%) (%) Amputation (%)

0/65.6/34.4

86.0 ± 39.4 100† (SFA), 69.0 ± 5.5 (POP)

12.5

1 year

85.7

58.1

71.1

IN.PACT 105 (NA*) Admiral, Lutonix

150.0 ± 123.3 86.7

59.1

31.2

1 year

83.8

88.6

IN.PACT Admiral

156 (194)

76.9/23.1/0

139.4 ± 105.5 74.2

41.2

11.3

1 year

86.3

98.6

Spanish Luminor Luminor Registry 202036

148 (180)

16.0/84.0/0

77.4 ± 50.3

53.9

56.7

1 year

92.1

87.7

84.7

91.1

Continuous variable shown as mean ± SD. *No available information regarding number of lesions. †Based on the history of past intervention. DCB = drug-coated balloon; TLR = target lesion revascularisation; NA = not available; SFA = superficial femoral artery; POP = popliteal.

Clinical Studies

The safety and efficacy of paclitaxel-coated balloons – including IN.PACT Admiral (Medtronic), Lutonix (CR Bard), Ranger (Boston Scientific), Stellarex (Philips) and SeQuent Please (B. Braun) – have been clinically evaluated in randomised controlled trials (RCTs) evaluating them against standard percutaneous transluminal angioplasty (PTA).20–28 However, differences in patient background, definition of endpoints, and follow-up duration among these RCTs make it difficult to differentiate the exact relative performances of DCBs (Table 2). For instance, the study endpoints of some trials were primary patency, defined as freedom from restenosis and clinically driven TLR (CD-TLR) assessed by duplex ultrasound peak systolic velocity ratio (i.e. ≤2.4, <2.5 or ≤2.5, the criteria differ for each RCT) at 1–3 years follow-up.20–22,25 In contrast, in two other RCTs regarding Ranger and SeQuent Please balloon, the primary endpoint was late lumen loss (LLL) assessed by angiography at 6 months.5,27 The studies concluded that paclitaxel DCB was both superior to standard PTA and had a better safety profile for the treatment of patients with PAD. One limitation these RCTs share is the relatively small number of patients enrolled (from 71 to 316). Additionally, although DCB treatment was shown to be superior to standard PTA in terms of study endpoint, DCB treatments need to be compared with each other to determine which device is safest and most effective. Further clinical trials are needed to directly compare the performance of different DCB devices. Critical limb ischaemia (CLI) is a clinical end-stage of PAD associated with poor outcomes, with 1- and 5-year mortality rates estimated to be 25% and 50%, respectively.29 Because CLI patients are susceptible to tissue inflammation, anatomical complexity and medical comorbidities, DCB usage can exacerbate their downstream tissue damage due to the risk of distal embolisation in patients with CLI. Several previous clinical case reports and preclinical studies have reported microvasculitis/panniculitis induced by paclitaxel embolisation after DCB treatment and subsequent poor outcomes.30–32 However, to date, the clinical studies evaluating paclitaxel DCB treatment for CLI patients are quite limited (Table 3). Phair et al. have evaluated the performance of paclitaxel DCB and DES in CLI patients.33 In that study, a total of 88 limbs were revascularised in 88 patients. The DES was used in 56 patients and DCB in 32 patients. Freedom from TLR was not different between patients treated with DES and DCB (90.6% versus 85.7%; p=0.518). However, primary patency and amputation-free survival in the DES group were significantly greater

versus the DCB group (80.4% versus 58.1%; p=0.0255 and 88.5% versus 71.1%; p=0.0443, respectively). The authors assumed that distal embolisation of paclitaxel induced by DCB treatment resulted in greater incidence of amputation and mortality compared to DES. The XLPAD registry demonstrated no significant differences between the DCB and the non-DCB (i.e. stenting and plain balloon angioplasty) group in terms of late outcomes at 1-year follow-up.34 In that registry, a total 327 patients underwent femoropopliteal endovascular intervention (105 DCB versus 222 non-DCB). Although a higher incidence of 12-month major amputation was observed in the DCB group (11% versus 4% in non-DCB; p=0.01), after adjusting for several risk factors the odds of major amputation were not statistically different between the two groups (OR 1.54; 95% CI [0.53–4.51]; p=0.43). Another two clinical studies suggested that treatment of PAD in CLI patients by DCB is safe and effective with respect to freedom from TLR and amputation-free survival.35,36 In addition, a network meta-analysis demonstrated that paclitaxel DCB has shown encouraging results in terms of primary patency for infrapopliteal lesions in CLI.37 Furthermore, paclitaxel DCB may be better than other treatments (standard PTA and DES) in terms of TLR. As mentioned above, theoretically paclitaxel DCB has the potential risk of distal embolisation, while the DES has almost no risk of such embolisation. Therefore, although some clinical trials have demonstrated that DCB devices are safe for the treatment of CLI, DES has an advantage regarding the risk of distal embolisation and subsequent worsening of CLI.32,38 Clinicians need to carefully consider the use of DCB in CLI patients. Further clinical trials are needed to understand the risks and benefits in using DCB devices to treat CLI, and improvements in DCB technologies are needed to reduce the risk of distal embolisation.

Safety Concerns Surrounding Paclitaxel Devices

Although several trials have already shown that paclitaxel-coated balloons reduce the rate of restenosis and TLR, a recent meta-analysis has demonstrated increased all-cause mortality at 2 and 4–5 years in patients who underwent paclitaxel-coated device treatment.39 According to this report, all-cause mortality at 1 year after treatment was equivalent between paclitaxel and control devices (i.e. DES and standard PTA) groups. However, the incidence of all-cause death appeared to be significantly greater in the paclitaxel device group after the 1-year follow-up (i.e. at 2 and 5 years). Indeed, there are critical limitations in this meta-analysis that deserve

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Paclitaxel- and Sirolimus-coated Balloons in PAD Treatment special attention. First, although a significant difference in mortality between paclitaxel and control device groups was evident at 2 and 4–5 years postprocedure, the number of patients involved in the analysis dropped sharply from 1 year (28 RCTs) at both the 2- (12 RCTs) and 5-year (three RCTs) time points. Second, the meta-analysis adopted the intention-to-treat principle without accounting for the rate of crossover to paclitaxel devices. Thus, the relationship between exposure and outcome could be confounded by significant crossover in PTA device of every RCT. Third, the study only demonstrated an association between paclitaxel drug exposure and total death. However, the exact causal mechanisms of death cannot be proven in this study design, which is a critical limitation.

The FDA reported a provisional warning on continuing DCB use in January 2019.46 Two updates were issued in March and August 2019, the latter after a public meeting of the Circulatory System Devices Panel. The FDA has stated that further observation is required and there is still no clear evidence of the mechanism by which paclitaxel could cause mortality.47 “For many patients, alternative treatment options to paclitaxel DCB and paclitaxel DES provide a more favourable benefit–risk profile based on currently available information. For individual patients judged to be at particularly high risk for restenosis and repeat femoropopliteal interventions, clinicians may determine that the benefits of using a paclitaxel-coated device outweigh the risk of the late mortality".48

More recently, Rocha-Singh et al. conducted a meta-analysis evaluating the safety of paclitaxel devices, further exploring the increased mortality association.40 A total of 2,185 patients across eight studies with a median follow-up of 4 years were included in this study. As a result, an increased mortality risk associated with the use of paclitaxel devices was observed, with absolute 4.6% increased mortality risk associated with paclitaxel device usage. However, a paclitaxel dose-dependent relationship with mortality was not proved. In long-term observation, loss of follow-up and withdrawal rate in both treatment arms were too high to ignore; inclusion of some of these missing data after further investigation further reduced the mortality risk.

Sirolimus-coated Balloons Sirolimus

On the other hand, observational studies in 2019 and 2020 demonstrated that the use of paclitaxel devices did not show any correlation with increased mortality.41–44 Secemsky et al. have reported a large Medicareand Medicaid-based analysis of the relationship between paclitaxel device usage and mortality.41 The authors compared mortality in 5,989 PAD patients treated with paclitaxel devices versus 10,571 PAD patients who received standard PTA (median follow-up duration was 389 days). Multivariate analysis did not show a causal relationship between paclitaxel device usage and mortality (adjusted HR 0.97; 95% CI [0.91–1.04]; p=0.43). In another study, Freisinger et al. evaluated clinical data involving 23,137 patients who underwent endovascular revascularisation.42 A multivariable Cox regression analysis showed paclitaxel DES was not associated with increased long-term mortality for over 11 years follow-up. Moreover, DCB was associated with decreased mortality for the first year past application and not correlated with long-term mortality in the years thereafter. Recently, a study from Germany has reported the long-term mortality after paclitaxel DCB versus standard PTA for femoropopliteal lesions in real-world clinical setting.43 A total 1,574 patients who underwent DCB (n=1065) or plain old balloon angioplasty (POBA; n=514) treatments were included. Mortality at median follow-up of 51 months was lower in the paclitaxel DCB group (16.9%) than the POBA group (27.8%) (p<0.001). Comorbidities, classic risk factors and disease severity were identified as predictors for death but treatment with a paclitaxel device was not. The biological nature of paclitaxel is well studied and recognised.45 It is used primarily for chemotherapy at 200 to 400 times the concentration compared to drug levels used in PAD endovascular treatment. Even if frequent DCB ballooning (i.e. more than one long balloon) is performed during one procedure, total paclitaxel doses cannot reach nearly the levels seen during systemic chemotherapy. Moreover, plasma pharmacokinetic levels of paclitaxel do not reach the level causing adverse effects as reported in cancer treatment. How a crystalline drug (i.e. paclitaxel) even if it embolized to non-target organs, such as the lungs, could be linked to a patient's death years later still needs to be elucidated.

Sirolimus, also known as rapamycin, is a macrolide compound that was initially discovered as an immunosuppressive agent. In the 1990s, seminal studies revealed the agent as a potent inhibitor of smooth muscle cell proliferation and migration, and only then did the potential of rapamycin for cardiovascular therapeutics emerge. Sirolimus inhibits mammalian target of rapamycin complex that promotes the translation of cyclin D1 mRNA, one of the cell cycle regulators.49 In animal studies, as discussed above, localised areas of inflammation and cell toxicity are observed for paclitaxel-containing devices. However, sirolimus is a cytostatic agent with the ability to inhibit cell division without creating vascular toxicity.50 In one animal study, no differences in histological endpoints, such as endothelialisation, were found with low- (64 µg/stent) or high-dose (196 µg/stent) sirolimus-eluting stents in the rabbit iliac model although neointimal suppression was better for the latter.51 Despite the beneficial therapeutic safety margin and anti-restenotic effects that have led to sirolimus becoming the preferred coating for coronary artery intervention, sirolimus and other -limus drugs present a challenge when used on balloons.52 Because tissue bioavailability – which affects both drug uptake and retention – is lower for sirolimus than paclitaxel, absorption enhancers are required to improve tissue uptake. A previous preclinical study showed that a balloon with novel phospholipidencapsulated sirolimus nanocarrier coating achieved efficient transfer of sirolimus to all layers of the vessel wall, with a high tissue concentration persisting for days after application.53 Moreover, recently reported clinical and preclinical studies have shown the efficiency and safety of sirolimus DCB treatment for the coronary artery.54,55 In conjunction with the safety concerns for paclitaxel mentioned above, there is a growing movement to develop effective sirolimus DCBs.

Clinical Studies

To date, there are three commercially available sirolimus DCB devices. These are Magic Touch PTA (Concept Medical), SELUTION (Med Alliance) and Virtue (Orchestra BioMed). The characteristics of each sirolimus DCB are listed in Table 4. The clinical trials of these devices will be conducted in the US. Magic Touch PTA, SELUTION and Virtue have been granted FDA breakthrough device designation.56–58 The novel sirolimus DCB has been tested in PAD treatment. The first-inman XTOSI study is a clinical registry to investigate the safety and efficacy of Magic Touch PTA in the treatment of femoropopliteal and below-theknee arterial lesions.59,60 The study endpoint was primary patency at 6 months determined by a duplex ultrasonography (criteria of restenosis: peak systolic velocity ratio ≤2.4). This registry includes 33 patients with relatively severe disease characteristics, i.e. >90% of patients had CLI (Rutherford category 5 or 6), and approximately 80% of patients had at

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Paclitaxel- and Sirolimus-coated Balloons in PAD Treatment Table 4: Sirolimus-coated Balloons Product

Company

Sirolimus dose Matrix/Carrier (μg/mm2)

Status

Magic Touch PTA Concept Medical

1.27

Phospholipid-based excipient (Nanolute technology)

CE mark (2019), FDA breakthrough device (2019)

SELUTION

MedAlliance

1.0

PLGA + phospholipid based micro reservoir (CAT)

CE mark (2020), FDA breakthrough device (2019)

Virtue

Orchestra BioMed 3 mg*

Porous balloon and biodegradable polyester-based polymer

FDA breakthrough device (2019)

*Sirolimus can be delivered via porous balloon without any balloon surface coating. CAT = cell adhesion technology; FDA = Food and Drug Administration; PLGA = poly lactic-co-glycolic acid.

least one total occluded lesion in below-the-knee arteries before angioplasty. Technical success rate was 100% in the initial treatment procedure. In this study, limb salvage was achieved in 975 of patients at 30 days. Primary patency and freedom from CD-TLR at 6 months were 82% and 91%, respectively. There was no evident distal embolisation or slow flow phenomena after application of sirolimus DCB in the below-the-knee lesions. Freedom from device- and procedure-related mortality was 100%. The results of the SELUTION first-in-human study, assessing the safety and efficacy in treatment of superficial femoral artery and popliteal artery, were also recently reported.50 The Cell Adherent Technology increases drug uptake into the arterial wall, prolongs exposure to the sirolimus, reduces dose loss to circulation, and minimises embolisation. In this trial, 50 patients with complex superficial femoral artery disease (30% total occlusions, 34% moderate or severe calcification, and target lesion length 64.3 mm) were treated with the SELUTION DCB. The primary endpoint of this study was angiographic LLL at 6 months. The study demonstrated that SELUTION achieved its 6-month LLL. The mean LLL was 0.29 ± 0.84 mm, which was significantly lower than the 1.04 mm objective performance criterion value for uncoated balloon angioplasty (p<0.001). Moreover, freedom from angiographic binary restenosis and duplex ultrasound primary patency at 6 months were 91.2% and 88.4%, respectively. The clinical improvement in Rutherford classification, ankle–brachial index, walking impairment, and quality-of-life at 6 months were improved and were significantly improved from 6 to 12 months follow-up (p<0.001, respectively). The 2-year results of the SELUTION study are currently under analysis. These findings will likely confirm the efficacy of sirolimuscoated balloon technology. In CLI treatment, the PRESTIGE below-the-knee clinical trial is on-going (NCT04071782). The objective of this trial is to evaluate the 6-month safety 1. Fowkes FG, 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/ S0140-6736(13)61249-0; PMID: 23915883. 2. Creager MA, Belkin M, Bluth EI, et al. 2012 ACCF/AHA/ACR/ SCAI/SIR/STS/SVM/SVN/SVS key data elements and definitions for peripheral atherosclerotic vascular disease. Circulation 2012;125:395–467. https://doi.org/10.1161/ CIR.0b013e31823299a1; PMID: 22144570. 3. O’Hare AM, Glidden DV, Fox CS, et al. High prevalence of peripheral arterial disease in persons with renal insufficiency: results from the National Health and Nutrition Examination survey 1999-2000. Circulation 2004;109:320–3. https://doi.org/10.1161/01.CIR.0000114519.75433.DD; PMID: 14732743. 4. Laird JR, Schneider PA, Tepe G, et al. Durability of treatment effect using a drug-coated balloon for femoropopliteal lesions: 24-month results of IN.PACT SFA. J Am Coll Cardiol 2015;66:2329–38. https://doi.org/10.1016/j.jacc.2015.09.063; PMID: 26476467. 5. Bausback Y, Willfort-Ehringer A, Sievert H, et al. Six-month results from the initial randomized study of the ranger paclitaxel-coated balloon in the femoropopliteal segment. J Endovasc Ther 2017;24:459–67. https://doi. org/10.1177/1526602817710770; PMID: 28558502.

and performance outcomes of SELUTION for the treatment of long tibial occlusive lesions in patients with CLI. In total, 22 patients have now been enrolled and clinical follow-up will be at 1, 3, 6 and 12 months. Sirolimus DCBs will offer a new approach to the endovascular treatment for PAD. Regarding coronary artery interventions, several trials have already shown the safety and efficacy for sirolimus DCB.61–63 A Nanolutè study (Magic Touch) has evaluated the long-term efficacy of sirolimus DCB for CAD. This study involved 408 patients (the sirolimus DCB was used for 183 patients with ISR, 185 with de novo small vessel lesion, and 40 with de novo large vessel lesion). Overall, the rate of major adverse cardiovascular events at 24 months was 4.2% (three cardiac deaths, 13 TLR, and one target vessel MI). The authors concluded that sirolimus DCB is a safe and feasible option for patients with ISR and for those with de novo lesions. Currently, the data obtained from preclinical and clinical studies are not enough to conclude the safety and efficacy of sirolimus DCBs and further studies are required to establish endovascular treatment using this approach.

Conclusion

DCBs have emerged as a newer treatment option for obstructive PAD and CAD and may offer some advantages compared with DES. Paclitaxel DCBs for the treatment of PAD have shown efficacy over plain PTA in several RCTs. However, a recent meta-analysis suggests an association between increased mortality and paclitaxel device usage, although a causal relationship is still being discussed. Alternatively, sirolimus DCB devices currently in development are attracting attention in the field of PAD and CAD treatment. Although it may be too early to conclude the safety and efficacy of sirolimus DCB over paclitaxel DCB, future DCB technologies will continue to improve and offer more promising treatment options with improved efficacy and safety.

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Associated with Increased Mortality. FDA, 7 August 2019. https://www.fda.gov/medical-devices/letters-health-careproviders/august-7-2019-update-treatment-peripheralarterial-disease-paclitaxel-coated-balloons-and-paclitaxel (accessed 11 February 2021). 49. Habib A, Karmali V, Polavarapu R, et al. Sirolimus-FKBP12.6 impairs endothelial barrier function through protein kinase C-α activation and disruption of the p120-vascular endothelial cadherin interaction. Arterioscler Thromb Vasc Biol 2013;33:2425–31. https://doi.org/10.1161/ATVBAHA. 113.301659; PMID: 23887639. 50. Zeller T, Brechtel K, Meyer DR, et al. Six-month outcomes from the first-in-human, single-arm SELUTION sustainedlimus-release drug-eluting balloon trial in femoropopliteal lesions. J Endovasc Ther 2020;27:683–90. https://doi. org/10.1177/1526602820941811; PMID: 32666871. 51. Klugherz BD, Llanos G, Lieuallen W, et al. Twenty-eight-day efficacy and phamacokinetics of the sirolimus-eluting stent. Coron Artery Dis 2002;13:183–8. https://doi.org/10.1097/ 00019501-200205000-00008; PMID: 12131023. 52. Wessely R, Schömig A, Kastrati A. Sirolimus and paclitaxel on polymer-based drug-eluting stents: similar but different. J Am Coll Cardiol 2006;47:708–14. https://doi.org/10.1016/j. jacc.2005.09.047; PMID: 16487832. 53. Lemos PA, Farooq V, Takimura CK, et al. Emerging technologies: polymer-free phospholipid encapsulated sirolimus nanocarriers for the controlled release of drug from a stent-plus-balloon or a stand-alone balloon catheter. EuroIntervention 2013;9:148–56. https://doi.org/10.4244/ EIJV9I1A21; PMID: 23685303. 54. Ali RM, Abdul Kader M, Wan Ahmad WA, et al. Treatment of coronary drug-eluting stent restenosis by a sirolimus- or paclitaxel-coated balloon. JACC Cardiovasc Interv 2019;12:558–66. https://doi.org/10.1016/j.jcin.2018.11.040; PMID: 30898253. 55. Cortese B, Di Palma G, Latini R. Magic Touch®: preliminary clinical evidence with a novel sirolimus drug coated balloon. Minerva Cardioangiol 2018;66:508–17. https://doi. org/10.23736/S0026-4725.18.04641-8; PMID: 29458247. 56. Concept Medical. Concept Medical granted “breakthrough device designation” by FDA for MagicTouch PTA sirolimus coated balloon. Concept Medical, 13 August 2019. https:// www.conceptmedical.com/press-release/concept-medicalgranted-breakthrough-device-designation-by-fda-formagictouch-pta-sirolimus-coated-balloon (accessed 27 November 2020). 57. MedAlliance. MedAlliance receives FDA breakthrough device designation status for sirolimus drug-eluting balloon to treat below-the-knee disease. MedAlliance, 25 September 2019. http://medalliance.com/2019/09/25/ medalliance-receives-fda-breakthrough-device-designationstatus-for-sirolimus-drug-eluting-balloon-to-treat-below-theknee-disease (accessed 27 November 2020). 58. Orchestra BioMed. Orchestra BioMed™ announces FDA breakthrough device designation for Virtue® sirolimuseluting balloon for treatment of below-the-knee peripheral artery disease. Orchestra BioMed, 17 September 2019. https://www.orchestrabiomed.com/news-events (accessed 27 November 2020). 59. Concept Medical. X-TOSI. 2020. https://www. conceptmedical.com/clinical-program/x-tosi (accessed 27 November 2020). 60. Crotti N. FDA grants breakthrough nod to concept medical for below-the-knee use of MagicTouch DCB. 13 August 2019. https://www.drugdeliverybusiness.com/fda-grantsbreakthrough-nod-to-concept-medical-for-below-the-kneeuse-of-magictouch-dcb (accessed 27 November 2020). 61. Verheye S, Vrolix M, Kumsars I, et al. The SABRE trial (Sirolimus Angioplasty Balloon for Coronary In-stent Restenosis): angiographic results and 1-year clinical outcomes. JACC Cardiovasc Interv 2017;10:2029–37. https:// doi.org/10.1016/j.jcin.2017.06.021; PMID: 28964764. 62. Cortese B, Pellegrini D, Latini RA, et al. Angiographic performance of a novel sirolimus-coated balloon in native coronary lesions: the FAtebenefratelli SIrolimus COated NATIVES prospective registry. J Cardiovasc Med (Hagerstown) 2019;20:471–6. https://doi.org/10.2459/ JCM.0000000000000806; PMID: 30994510. 63. El-Mokdad R, di Palma G, Cortese B. Long-term follow-up after sirolimus-coated balloon use for coronary artery disease. Final results of the Nanolutè study. Catheter Cardiovasc Interv 2020;96:e496–500. https://doi.org/10.1002/ ccd.28863; PMID: 32191384.

Venous

Incidental Finding of an Asymptomatic Migrated Coil to the Right Ventricle Following Pelvic Vein Embolisation Luca Scott

and Jack Cullen

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

Abstract

Pelvic vein embolisation (PVE) with metallic coils is an effective treatment for pelvic venous congestion. The migration of coils following the procedure has been well-reported; however, the most effective approach to management is still unclear. In the present case, the authors describe the delayed identification of a migrated coil to the right ventricle following an ovarian vein embolisation. The patient presented to the emergency department with chest pain and subsequent radiology identified a coil in the right ventricle. This was found to be present on previous radiology, but had not been reported on. The position of the coil had remained stable and therefore was deemed an unlikely cause for the chest pain. The coil was managed conservatively. This demonstrates how asymptomatic coil migration may go undetected and thus the migration rates in the literature may be underreported. Post-PVE screening to assess for migration could improve the accuracy of complication rates and prevent delayed complications associated with migrated coils.

Keywords

Pelvic vein embolisation, coil migration, venous congestion Disclosure: The authors have no conflicts of interest to declare. Informed consent: The patient provided informed consent on 25 August 2020 to write this case report. Acknowledgement: The authors thank Mr Stephen Black for his expertise and guidance on the scope of the article. Received: 16 November 2020 Accepted: 19 April 2021 Citation: Vascular & Endovascular Review 2021;4:e04. DOI: https://doi.org/10.15420/ver.2020.22 Correspondence: Luca Scott, Guy’s and St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, UK. E: lucascott@doctors.org.uk Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Case Report

A 54-year-old woman presented to the emergency department with sudden-onset right-sided pleuritic chest pain with associated shortness of breath. Her past medical history consisted of autoimmune thyroiditis, previous pancreatitis and a complex vascular history requiring several interventions. The patient’s chronic lower limb varicosities were treated with a long saphenous vein laser ablation and foam sclerotherapy. Her chronic pelvic pain associated with pelvic congestion syndrome had been managed with an ovarian iliac vein embolisation in 2014, which was repeated in 2019 due to persistent reflux through the original coils. On presentation the patient was tachycardic with a heart rate of 100 BPM, otherwise her observations were unremarkable. A chest X-ray and CT pulmonary angiogram (CTPA) were ordered to investigate primarily for a pulmonary embolism as well as for other differentials of her presentation, such as pneumothoraces and pneumonias. The chest X-ray (Figure 1) showed an 11 mm metallic ring opacity overlying the ventricles; this was at first queried as an artefact. Further examination of the patient revealed no overlying jewellery or clothing that could explain the radiological appearance. A lateral X-ray (Figure 2) confirmed the presence of the metallic ring in the right ventricle. A CTPA (Figures 3, 4 and 5) showed that there was no pulmonary embolus or right heart strain, and confirmed the presence of an 11 mm metallic

foreign body at the tip of the right ventricle, which was suspected to be a migrated pelvic vein embolisation (PVE) coil. On further investigation, the coil had been present on a previous CT of the abdomen and pelvis that had been requested for severe abdominal pain in 2016, but its presence had not been discussed in the radiologist’s report. The position of the coil had remained stable. The patient was referred to the cardiac surgeons, who performed a bedside echocardiogram and found that the coil had endothelialised into the cardiac septum. The foreign body was considered to be a low risk for thrombus, and therefore no intervention or anticoagulation was required. ECG showed a normal sinus rhythm, and blood tests including troponin were unremarkable. The chest pain was deemed to be musculoskeletal in nature given that no acute cause was identified. The patient was discharged and her case discussed in the vascular multidisciplinary meeting, which concluded that there was no interval change in appearance of the migrated coil, and therefore it was unlikely to be the cause of the patient’s symptoms. Similarly, an outpatient cardiology review concluded that the coil was both unlikely to be the cause of the patient’s symptoms or to result in future complications.

Discussion

Chronic pelvic pain is a complex condition that can be the result of gynaecological diseases, such as pelvic inflammatory disease,

Coil Migration to the Right Ventricle Following Pelvic Vein Embolisation Figure 1: Posteroanterior Chest X-ray Showing an 11 mm Opacity Over the Heart

Figure 3: Axial CT Pulmonary Angiogram Slice Showing the Stability of the Migrated Coil in the Tip of the Right Ventricle

15–30%.1–3 PVC can be managed conservatively with analgesia, through surgical ligation or alternatively with interventional PVE.

Figure 2: Lateral Chest X-ray Confirming the Position of the Metallic Ring in the Right Ventricle

PVE has been shown to be an effective treatment in women with chronic pelvic pain resulting from pelvic venous disorders.1,3 The embolic agents used can vary between coils, glue, vascular plugs, foam and liquid sclerosants, with some clinicians advocating the combined use of coils and sclerosing agents. Current clinical evidence is insufficient to compare the outcomes between the use of coils alone and in combination.1,4 Arterial percutaneous embolisation with coils was first used effectively in 1975, and in 1993 Edwards et al. documented the first use of coil embolisation in the management of PVC.5 PVE has been found to be efficacious in the management of PVC, with improvement in symptoms seen in 70–90% of patients.3,6 The complications associated with PVE include bleeding, venous perforation and coil migration. Coil migration can be an immediate or delayed complication. Common migration sites include the pulmonary vasculature and the heart. Several studies have investigated the effectiveness of PVE in pelvic congestion syndrome and identified the risks of coil displacement. Kwon et al. demonstrated an 82% reduction in pain in 67 patients, but a 3% risk of coil embolization.7 Similarly, Ratnam et al. found a 1.4% risk of coil migration in 218 patients undergoing PVE.1,8 A systematic review of the effectiveness PVE in 1,308 patients across 22 studies reported a substantial early improvement in pain in approximately 75% of patients and a coil migration risk of <2%.9

endometriosis and fibroids. Alternatively, referred pain, psychological factors and venous incompetence are known to also contribute. In up to 60% of patients no definitive aetiology for chronic pelvic pain is identified.1,2 Pelvic venous congestion (PVC) is a cause of persistent noncyclic chronic pelvic pain, typically as the result of ovarian vein incompetence resulting in pelvic varicosities. The pain is often exacerbated by standing and intercourse. Multiparous and premenopausal women are at greater risk of developing PVC and its prevalence is in the range of

Interestingly, in the present case, the migrated coil was an incidental finding in a symptomatic patient and may not have been discovered had the patient not presented to the emergency department with chest pain. The stable appearance and asymptomatic nature of the migrated coil in the 4 year interval between the CT of the abdomen and pelvis in 2016 and the CTPA in 2020 mean that the chest pain is unlikely to be related to the coil. This raises the possibility that asymptomatic migrated coils may go underreported following PVE. The current coil migration rates in the literature relate predominantly to symptomatic patients or to those presenting with complications in which investigations have noted a migrated coil. Thus, many patients who have had PVE may have migrated coils after the procedure, and the absence of associated symptoms mean that the migrated coils go undiscovered. Patients in

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Coil Migration to the Right Ventricle Following Pelvic Vein Embolisation this group could present at a later date with complications of coil migration, such as arrhythmias, thrombus, cardiac valve dysfunction or haemopericardium.2,3,10

Figure 4: Coronal Multiplanar Reconstruction of the CT Pulmonary Angiogram

To the best of our knowledge, the underreporting of coil migration rates has not previously been discussed in the literature. Post-PVE screening at 6 weeks could help to prevent future complications of undetected migrated coils and improve the accuracy of documented migration rates. If true, underreporting also highlights the preoperative issue of incorrect complication rates being discussed when obtaining patient consent. The heart and pulmonary vasculature are common sites of migration. Therefore, a plain film chest radiograph, given the associated minimal radiation exposure to the patient, may be a sufficient screening tool for this purpose. Coil migration following PVE has been well-reported in the literature, however, the management of displaced coils often differs between cases. In a similar respect to the present case; there are reports of coil migration to the right side of the heart both with and without methods of retrieval. Kyaw et al. outlined a case of coil migration to the right atrium immediately after a PVE procedure for pelvic congestion syndrome.10 Several unsuccessful percutaneous attempts were made at coil retrieval and thus their patient had to undergo an open thoracotomy in order for the coil to be removed from the damaged tricuspid valve.10 A further paper by Rastogi et al. discussed a case of coil migration following bilateral ovarian vein embolisation to the right ventricle.2 Their patient remained haemodynamically stable and asymptomatic throughout and it was decided that no further treatment was required.2

Figure 5: Sagittal Multiplanar Reconstruction of the CT Pulmonary Angiogram

In the present case, the patient had remained asymptomatic for several years after her PVE and the migrated coil was an incidental radiological finding. The endothelialised coil was believed to pose a low risk for thrombus and thus anticoagulation was not considered. Tonkin and Madden chose to anticoagulate in one of the three cases of coil migration they saw following PVE, advocating that anticoagulation should be considered only if there is an associated thrombus or an increased thrombotic risk due to position of the coil, for example within the valve apparatus.11 To prevent complications of PVE, the importance of characterising the vessels prior to embolisation is highlighted in the literature. The type of vessel (artery or vein), the volume of blood flow through the target vessel and the size of the coil can all affect the likelihood of migration. To optimise stability, it is recommended that the coil should be greater than the diameter of the embolised vein. Yamasaki et al. suggest a coil size 30–50% greater than the target vessel, with alternative literature advocating the use of an exact coil size 1–3 mm greater than the diameter of the vessel.8,12–14 To prevent coil migration, we are reliant on the frictional resistance of the vessel and the radial force exerted by the coil and thus it is important to note the variable calibre of target veins.8,12–14 Typically, 0.035–0.038 inch coils are used with diameters ranging between 5 and 20 mm and lengths of 7–14 cm, and the number of coils deployed varies between clinicians.1,4,7 To achieve permanent vessel occlusion the coils cause a mechanical obstruction, inducing thrombosis and eventual sclerosis of the target vessels.14 The choice of materials used to manufacture coils has progressed over time, primarily from stainless steel to platinum. Coils can be enlaced with fibres to increase their thrombogenic qualities, with materials such as PET and nylon enabling more rapid vessel

occlusion and the use of fewer coils.1,15,16 Further technological advances have resulted in bioactive coils. Platinum coils can be coated with a hydrogel polymer that facilitates an increase in the coil’s thickness of up to fourfold its size when it comes into contact with blood or a liquid. Expansion of coils can result in more reliable vessel occlusion in the absence of effective coagulation.17,18 In addition to the material used to produce a coil, the configuration and transformation of a material from a primary to a tertiary structure helps to determine other qualities of the coil, such as stiffness, length and diameter.19 Chest pain is one of the most common presenting complaints seen in the emergency department and it accounts for 25% of emergency medical admissions in England and Wales.20 The aetiology of chest pain can be characterised into cardiovascular causes (acute coronary syndromes,

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Coil Migration to the Right Ventricle Following Pelvic Vein Embolisation pulmonary emboli and aortic dissections), respiratory causes (pneumothoraces, pneumonia and pleurisy), musculoskeletal causes (costochondritis and chest wall injuries) and finally gastrointestinal causes (gastro-oesophageal reflux).20 In the present case, we suspect that the patient’s chest pain was musculoskeletal in nature. The absence of pulmonary emboli on CTPA, an ECG showing a normal sinus rhythm and unremarkable troponin and inflammatory markers helped to exclude many of the aforementioned life-threatening causes of chest pain. With regards to her chest pain specifically, the patient was discharged with safety-netting advice and simple analgesia.

Conclusion

PVE has been shown to be an effective treatment for PVC. Although rare, coil migration must be considered as a possible complication of the procedure. Several case reports including the present one have 1. Lopez AJ. Female pelvic vein embolization: indications, techniques, and outcomes. Cardiovasc Intervent Radiol 2015;38:806–20. https://doi.org/10.1007/s00270-015-1074-7; PMID: 25804635. 2. Rastogi N, Kabutey NK, Kim D. Unintended coil migration into the right ventricle during the right ovarian vein coil embolization. Vasc Endovasc Surg 2011;45:660–4. https://doi. org/10.1177/1538574411414924; PMID: 21757493. 3. Guerrero A, Theophanous RG. A case report of a migrated pelvic coil causing pulmonary infarct in an adult female. Clin Pract Cases Emerg Med 2020;4:436–9. https://doi.org/10.5811/ cpcem.2020.5.47463; PMID: 32926706. 4. Guirola JA, Sánchez-Ballestin M, Sierre S, et al. A randomized trial of endovascular embolization treatment in pelvic congestion syndrome: fibered platinum coils versus vascular plugs with 1-year clinical outcomes. J Vasc Interv Radiol 2018;29:45–53. https://doi.org/10.1016/j. jvir.2017.09.011; PMID: 29174618. 5. Edwards RD, Robertson IR, MacLean AB, Hemingway AP. Case report: pelvic pain syndrome – successful treatment of a case by ovarian vein embolization. Clin Radiol 1993;47:429–31. https://doi.org/10.1016/S00099260(05)81067-0; PMID: 8519153. 6. Laborda A, Medrano J, de Blas I, et al. Endovascular treatment of pelvic congestion syndrome: visual analog scale (VAS) long-term follow-up clinical evaluation in 202 patients. Cardiovasc Intervent Radiol 2013;36:1006–14. https:// doi.org/10.1007/s00270-013-0586-2; PMID: 23456353. 7. Kwon SH, Oh JH, Ko KR, et al. Transcatheter ovarian vein embolization using coils for the treatment of pelvic

10.

11. 12.

13.

14.

demonstrated the migration of coils into the heart and the pulmonary vasculature. The presence of symptoms as a result of the migration, the thrombotic risk posed by the coil and the potential for damage to the viscera will all influence decisions regarding the need for further management of a migrated coil. In the literature, conservative approaches, as well as interventional retrieval have both been successful in the management of migrated coils.2,3,10 The present case illustrates how a migrated coil can remain asymptomatic for several years, and suggests that there may be underreporting of migration rates in the literature and discussion of inaccurate complication rates when obtaining patient consent for PVE. Screening following PVE may be a useful tool to identify migrated coils, improve the accuracy of coil migration rates and prevent late complications associated with migrated coils.

congestion syndrome. Cardiovasc Intervent Radiol 2007;30:655–61. https://doi.org/10.1007/s00270-007-90407; PMID: 17468903. Ratnam LA, Marsh P, Holdstock JM, et al. Pelvic vein embolisation in the management of varicose veins. Cardiovasc Intervent Radiol 2008;31:1159–64. https://doi. org/10.1007/s00270-008-9402-9; PMID: 18756371. Daniels JP, Champaneria R, Shah L, et al. Effectiveness of embolization or sclerotherapy of pelvic veins for reducing chronic pelvic pain: a systematic review. J Vasc Interv Radiol 2016;27:1478–86. https://doi.org/10.1016/j.jvir.2016.04.016; PMID: 27397619. Kyaw H, Park W, Rodriguez C, et al. Coil embolization to the right side of the heart after elective hypogastric vein embolization requiring open-heart surgery. Cath Lab Digest 2018;26(9). https://www.cathlabdigest.com/article/CoilEmbolization-Right-Side-Heart-After-Elective-HypogastricVein-Embolization-Requiring (accessed 25 May 2021). Tonkin J, Madden B. From ovarian coils to pulmonary emboli. Am J Respir Crit Care Med 2018:197;A3700. Yamasaki W, Kakizawa H, Ishikawa M, et al. Migration to the pulmonary artery of nine metallic coils placed in the internal iliac vein for treatment of giant rectal varices. Acta Radiol Short Rep 2012;1:1–4. https://doi.org/10.1258/ arsr.2012.120024; PMID: 23986845. Nasser F, Cavalcante RN, Affonso BB, et al. Safety, efficacy, and prognostic factors in endovascular treatment of pelvic congestion syndrome. Int J Gynaecol Obstet 2014;125:65–8. https://doi.org/10.1016/j.ijgo.2013.10.008; PMID: 24486124. Knuttinen MG, Xie K, Jani A, et al. Pelvic venous

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insufficiency: imaging diagnosis, treatment approaches, and therapeutic issues. AJR Am J Roentgenol 2015;204:448–58. https://doi.org/10.2214/AJR.14.12709; PMID: 25615769. 15. Trerotola SO, Pressler GA, Premanandan C. Nylon fibered versus non-fibered embolization coils: comparison in a swine model. J Vasc Interv Radiol 2019;30:949–55. https:// doi.org/10.1016/j.jvir.2018.10.004; PMID: 30935867. 16. Liebig T, Henkes H, Fischer S, et al. Fibered electrolytically detachable platinum coils used for the endovascular treatment of intracranial aneurysms. Initial experiences and mid-term results in 474 aneurysms. Interv Neuroradiol 2004;10:5–26. https://doi.org/10.1177/159101990401000101; PMID: 20587260. 17. López-Benítez R, Hallscheidt P, Kratochwil C, et al. Protective embolization of the gastroduodenal artery with a one-HydroCoil technique in radioembolization procedures. Cardiovasc Intervent Radiol 2013;36:105–10. https://doi. org/10.1007/s00270-012-0361-9; PMID: 22414984. 18. Zander T, Medina S, Montes G, et al. Endoluminal occlusion devices: technology update. Med Devices (Auckl) 2014;7:425– 36. https://doi.org/10.2147/MDER.S49540; PMID: 25489252. 19. White JB, Ken CG, Cloft HJ, Kallmes DF. Coils in a nutshell: a review of coil physical properties. AJNR Am J Neuroradiol. 2008;29:1242–6. https://doi.org/10.3174/ajnr.A1067; PMID: 18417605. 20. Kendall J, Hancock I. Chest pain syndromes. London: Royal College of Emergency Medicine, 2019. https://www. rcemlearning.co.uk/reference/chest-pain-syndromes (accessed 20 May 2021).

Peripheral Artery Disease

Paclitaxel Exposure and Dosage of Drug-coated Devices for the Treatment of Femoropopliteal Peripheral Artery Disease Ceazón T Edwards , Peter A Schneider

and Cindy Huynh

Division of Vascular and Endovascular Surgery, University of California at San Francisco, San Francisco, CA, US

Abstract

The role of paclitaxel in the treatment of femoropopliteal peripheral arterial disease is currently ambiguous. A summary-level meta-analysis of randomised trials published in 2018 demonstrated that paclitaxel-coated devices were associated with an increased all-cause mortality in those who underwent treatment at 2 years and 5 years. Further evaluation has been undertaken to establish whether there is a specific dose response, mechanism or reproducible signal. At this time, there has been no confirmation of dose response, as was initially asserted by the summary-level meta-analysis. No mechanism of harm has been identified. Although an association with increased mortality has been confirmed by patient-level meta-analysis, the strength of the signal has been inconsistent. The information suggests there is only an association between paclitaxel-coated devices and increased all-cause mortality, not causation. The authors encourage additional studies designed to follow long-term results after treatment with paclitaxel-coated devices, using real patient data, before a conclusion can be made.

Keywords

Paclitaxel, femoropopliteal, femoral popliteal, drug-eluting stents, percutaneous transluminal angioplasty, mortality, peripheral arterial disease Disclosure: PAS has served as a consultant for Surmodics, Silk Road Medical, Medtronic, CSI, Profusa, Intact Vascular, Cagent, Illuminate, Intervene, Limflow, Devoro, PQ Bypass, Boston Scientific and Philips. All other authors have no conflicts of interest to declare. Received: 21 June 2020 Accepted: 17 February 2021 Citation: Vascular & Endovascular Review 2021;4:e05. DOI: https://doi.org/10.15420/ver.2020.14 Correspondence: Ceazón T Edwards, Division of Vascular and Endovascular Surgery, University of California San Francisco, 400 Parnassus Ave, A-581, San Francisco, CA 94143, US. E: ceazon.edwards@ucsf.edu Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

The treatment of peripheral artery disease (PAD), as related to lifestylelimiting claudication and chronic limb-threatening ischaemia, has changed drastically over the past 20 years with the advent of percutaneous intervention as an alternative to open surgery. More recently, the use of drug-coated devices (more specifically, paclitaxel-coated devices) has been shown to reduce the rate of restenosis, reintervention, the subsequent need for target limb revascularisation and lower extremity amputation rate in comparison with non-drug-coated devices.1 Paclitaxel is a common anti-neoplastic, anti-microtubular agent originally approved as a first-line treatment in several solid-organ carcinomas in the 1960s.2 Its biochemical and pharmacological properties are involved in the inhibition and prevention of cellular division. Similarly, as paclitaxel has also been used in drug-coated coronary devices in contemporary medicine, its properties have also been extrapolated in the treatment of PAD within the femoropopliteal segment due to the promise of anti-stenotic properties. First-generation paclitaxelcoated coronary devices in the early 2000s were associated with late stent thrombosis and have since been falling out of favour. In 2014, a meta-analysis of 76 different randomised controlled trials demonstrated that sirolimus-coated devices reduced both short- and long-term risks of target lesion revascularisation (TLR), restenosis, major adverse cardiac events and overall risk of MI in comparison with their paclitaxel counterparts.2,3 Although the REALITY trial and other randomised

studies showed the superiority of sirolimus over paclitaxel-coated devices in the treatment of coronary artery disease, the use of paclitaxel in the treatment of femoropopliteal PAD is promising.4,5 Although the potential cytotoxicity of paclitaxel in relation to systemic chemotherapy regimens has been well-delineated, additional concerns about its role in the treatment of peripheral arterial disease stem from a potential correlation to increased all-cause mortality, as was suggested in a 2018 study by Katsanos et al.6 More recently, the same group published a meta-analysis of randomised controlled trials involving the use of paclitaxel-coated balloons in the treatment of infrapopliteal peripheral arterial disease. That study emphasised a decreased amputation-free survival in those who underwent drug-coated balloon (DCB) angioplasty with high-dose devices (3.0–3.5 µg/mm2) in comparison with conventional balloon angioplasty, suggesting a cytotoxic dose-dependent harm signal.7 Conversely, the results of a 2019 meta-analysis by Schneider et al. did not show a significant difference in the 5-year mortality rates between those patients treated with percutaneous transluminal angioplasty (PTA) and paclitaxel DCB.8 In addition, of those patients treated with paclitaxel DCB, there was no dose-related increased mortality risk, and of those risk factors found to be predictors of increased mortality (which was largely related to the underlying disease process itself), exposure to paclitaxel was not found to be one of them.

Paclitaxel Exposure and Dosage of Drug-coated Devices for Femoropopliteal PAD Similarly, Secemsky et al. performed a multicentre retrospective cohort study using Medicare and Medicaid real-world data comparing drugcoated devices with standard non-drug-coated devices in the treatment of femoropopliteal PAD. Multivariate analysis suggested there was no difference in all-cause mortality between the two groups, which was consistent across patients with and without critical limb ischaemia and irrespective of the type of drug-coated device used (DCB or drug-eluting stent).9 More recently, Behrendt et al. also used real-world data to suggest increased long-term survival, amputation-free survival and decreased incidence of major cardiovascular events in those treated with drugcoated devices.10 It is easy to understand how the use of drug-coated devices in the treatment of femoropopliteal disease has become a topic of controversy, given the conflicting data. With this, the purpose of this review is to discuss the benefits and risks of exposure to paclitaxel, and to further understand the relationship between drug dose, exposure and its relationship to mortality.

Paclitaxel Mechanism of Action

Paclitaxel is a chemotherapeutic agent at high concentrations, acting to inhibit cell division and promote microtubule assembly, subsequently preventing microtubule breakdown and arresting the cell cycle in the G2/M phase.11 Paclitaxel also inhibits secretion of the extracellular matrix and proliferation of vascular smooth muscle cells and fibroblasts, as well as preventing migration of smooth muscle cells, fibroblasts and white blood cells.12 At lower concentrations, paclitaxel has been found to reduce restenosis, and continues to have a long-term inhibitory effect, even after short exposure time.13 Paclitaxel is lipophilic, allowing for rapid uptake into tissues at high concentrations within the intima of the artery, and low concentrations of the drug in the plasma. The delivery of the hydrophobic, lipophilic paclitaxel as the active component of drug-coated devices is facilitated by a hydrophobic delivery molecule, which allows for its absorption within the arterial wall over time. When investigated in PAD after treatment with paclitaxel-coated balloon (PCB), paclitaxel was undetectable in plasma by 24 hours with use of up to three balloons and no paclitaxel-related events occurred.14 The known side-effects of paclitaxel at chemotherapeutic concentrations include neutropenia, neuropathy, hypersensitivity and cardiovascular effects, such as hypotension, hypertension, bradycardia, myalgia, myelotoxicity, anaphylaxis and nausea. In clinical trials, the mean total treatment doses delivered by PCB and paclitaxel-eluting stent (PES) was from 1 mg or less up to 20 mg, depending on lesion size, number of lesions treated and type; in comparison, average doses of paclitaxel for a single chemotherapeutic treatment are approximately 230–300 mg, and a total dose of up to 1,200 mg for multiple treatments.8 The SNAPIST I trial examined paclitaxel administration along with baremetal stent (BMS) placement for the prevention of restenosis at doses of 10, 30, 70 and 100 mg/m2. Systemic side-effects, including moderate neutropenia, sensory neuropathy and alopecia, were noted with doses of 70 and 100 mg/m2, much higher than those delivered with PCB or PES; however, there has been no supported mechanism of possible paclitaxelmediated increase in mortality.15

Paclitaxel has been used in the treatment of PAD with both balloon angioplasty and stent placement in the femoropopliteal location. The advantages of balloon angioplasty include avoidance of permanent prosthesis placement, whereas stent placement may be challenging in locations with high mechanical force, as they must withstand compression, flexion leading to deformation, fracture and in-stent restenosis. There are currently five Food and Drug Administration (FDA)-approved paclitaxel-coated devices: three PCB and two PESs. The three PCBs include the Lutonix 035 DCB PTA catheter (BD/Bard), IN.PACT Admiral (Medtronic Vascular) and Stellarex (Philips). Several randomised clinical trials reported the benefit of PCB relative to traditional plain PTA. Tepe et al. compared the outcomes of 48 patients treated with PCB and 54 patients treated with plain PTA for superficial femoral and popliteal artery lesions, demonstrating a significant reduction in late lumen loss (0.4 ± 1.2 mm versus 1.7 ± 1.8 mm, p<0.001) and target lesion revascularisation (TLR; 4% versus 29%, p<0.001) at 6 months, and at 24 months.16 Rosenfield et al. found in a single-blinded, randomised study of 475 patients that Lutonix PCB had increased primary patency at 12 months compared with nondrug-coated PTA in femoropopliteal artery disease.17 Although these studies focused on focal lesions less than 10 cm, a post-hoc analysis in the IN.PACT 5-year analysis favoured PCB over PTA in longer lesions, total occlusions and in-stent restenosis.8 Ott et al. compared PCBs with PTA in 70 patients with symptomatic instent restenosis of the superficial femoral artery, with a mean lesion length of 13.9 ± 6.7 cm, and found significantly reduced rates of diameter stenosis (44 ± 33% versus 65 ± 33%, p=0.01) and binary restenosis when examined at 6–8 months, as well as reduced rates of TLR at 24 months.18 With this, DCBs appear to be effective and durable interventions superior to PTA for focal lesions at 5 years. In the ILLUMENATE Pivotal study (Stellarex DCB), the primary patency for DCB was 76.3% compared with 57.6% for PTA (p=0.003) when examined at 12 months, with TLR significantly decreased in the DCB group compared with the PTA group (7.9% versus 16.8%, respectively; p=0.023).19 More recently, in January 2019, Gray et al. performed a meta-analysis with real patient data to determine the safety of the Stellarex DCB in the treatment of femoropopliteal PAD, which revealed no difference in the all-cause mortality in those treated with DCB versus PTA over a 3-year timeframe (1.8 ± 0.7% versus 1.3 ± 0.9% at 1 year, 6.5 ± 1.2% versus 5.9 ± 1.9% at 2 years and 9.3 ± 1.5% versus 9.9 ± 2.4% at 3 years, p=0.86; Kaplan–Meier estimates).20 The two FDA-approved PESs include Eluvia (Boston Scientific) and Zilver PTX (Cook Medical). The Eluvia stent has a polymer coating designed to deliver paclitaxel over a longer period of time than the Zilver PTX, as well as low drug–dose density. The IMPERIAL trial compared the Eluvia PES with the Zilver PTX PES. At 1 year, the Eluvia stent demonstrated noninferiority to Zilver PTX. Primary patency rates were 86.8% in patients receiving the Eluvia and 81.5% in patients receiving the Zilver PTX (p<0.0001).21 Dake et al. randomised 474 patients in a prospective, multinational trial to PES or PTA. Patients who had initial PTA failure underwent randomisation to PES or BMS. PES was associated with higher 2-year event-free survival (86.6% versus 77.9%, p=0.02) and primary patency (74.8% versus 26.5%, p<0.01) compared with PTA, and also superior 2-year primary patency relative to the BMS group (83.4% versus 64.1%, p<0.01).22 At 5 years, there

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Paclitaxel Exposure and Dosage of Drug-coated Devices for Femoropopliteal PAD Table 1: Select Paclitaxel-eluting Devices Used in the Treatment of Femoropopliteal Peripheral Arterial Disease Device Name

Type

Nominal Dose

Dose Range

Study Name

Primary Endpoint

Follow-up Timeframe

Results

IN.PACT Admiral

DCB

3.5 μg/mm2

1.1–17.0 mg

IN.PACT SFA27

Primary patency at 1 year

5 years

DES: 82.2% versus PTA: 52.4% (p<0.001)

Zilver PTX

DES

3.0 μg/mm2

0.2–1.3 mg

ZILVER PTX22

Primary patency at 1 year

5 years (RCT) 3 years (Japan)

DES: 83.1% versus BMS: 32.8% (p<0.001)

Lutonix

DCB

2.0 μg/mm2

1.0–9.7 mg

LEVANT II17

Primary patency at 1 year

5 years

DCB: 65.2% versus PTA: 52.6% (p=0.02)

Stellarex

DCB

2.0 μg/mm2

1.1–4.7 mg

ILLUMENATE Pivotal19

Primary patency at 1 year

3 years

DCB: 76.3% versus PTA 57.6% (p<0.02)

ELUVIA

DES

0.167 μg/mm2

0.1–0.4 mg

IMPERIAL21

Primary patency at 1 year, % MAE; non-inferiority

12 months

ELUVIA: 86.8% versus Zilver PTX: 81.5% (p<0.0001)

BMS = bare metal stent; DCB = drug-coated balloon; DES = drug-eluting stent; MAE = major adverse events; PAD = peripheral arterial disease; PTA = percutaneous transluminal angioplasty; PTX = paclitaxel; RCT = randomised controlled trial; SFA = superficial femoral artery. Source: Schneider et al. 2021.28 Reproduced with permission from Elsevier.

were higher patency rates (66.4% versus 43.4%, p<0.01) and greater freedom from TLR in patients receiving PES compared with PTA (83.1% versus 67.6%, p<0.01). In addition, at 5 years there were higher primary patency rates of PES to the BMS group (72.4% versus 53%, p=0.03) and freedom from TLR (84.9% versus 71.6%, p=0.06).

Is the Mortality Increase Associated with Paclitaxel a Causal Relationship or an Association?

Given what we know about the pharmacological properties of paclitaxel and its use in paclitaxel-coated devices, it appears unclear whether increased mortality is simply an association or an actual causation. The 2018 meta-analysis by Katsanos et al. initially reported an increased risk of mortality in those patients who underwent treatment with paclitaxelcoated devices for femoropopliteal disease at 2 and 5 years using metaregression analysis; however, the methodology behind the dose–mortality calculations used is fundamentally flawed.6 Holden et al. stressed that for a drug to be associated with an adverse event, it must be dose related, be a consistent result among different patient populations, associated with a certain timeframe and there must be a ‘biological gradient’, as implied by the Bradford Hill criteria.23 In addition, it requires an associated clustering of deaths and/or adverse events, and a reproducible and predictable danger signal, which would insinuate a causal relationship. In the initial article, the proposed biological gradient was the paclitaxel dose response. As was described with the comparison among the 4,432 patients in 28 randomised controlled trials, there was no significant difference in allcause mortality between the paclitaxel arms and the control arm (2.3% crude risk of death in both arms) after 1 year. At 2 years, the all-cause mortality in the paclitaxel group was 7.2% versus 3.8% in the control group, and at 5 years, long-term analysis of all-cause mortality was 14.7% in the paclitaxel group versus 8.1% in the control group.6 Since this claim, there have been several other patient-level randomised trials that have tried to reproduce, but have failed to prove a dose–mortality relationship between paclitaxel dose and exposure over time. In several of the preclinical models, it was shown that the paclitaxel concentration within the tissues decreases over a 6-month timeframe to nearly undetectable levels. In addition, it would be expected that after initial drug exposure, the longer the patients are prospectively followed, the greater likelihood of there being mortality events in a direct causal relationship.

The aforementioned Katsanos study assumed that there is a continuous linear relationship over time between drug exposure and the severity of the adverse effect; however, several of the named studies used in the meta-analysis were small and not developed with the intent of long-term follow-up. Instead, these studies focused on 1-year patency, which is not enough time to assess long-term results. Not only were the majority of the follow-up intervals short, many of the pivotal randomised controlled trials had a high percentage of patients that were withdrawn from the study or lost to follow-up. With this information, and in an attempt to reproduce the findings in the initial Katsanos study, Ducasse et al. performed a systematic review and meta-analysis of DCB versus PTA for de novo femoropopliteal lesions, which included 13 different randomised controlled trials that did not show any significant difference in all-cause mortality between the two groups at 1, 2, 4 and 5 years after treatment.24 At 3 years, however, the study did show an increase in mortality, but these deaths were not adjudicated as device or procedure related. Similar to the Katsanos study, the deaths did not include patient-level data, given the endpoints were not highly powered or designed for long-term follow-up, as the design was to focus on primary patency at 6 and 12 months. More recently, the FDA released an updated report that focused on the long-term mortality results from three pre-market randomised, controlled trials involving the use of paclitaxel-eluting devices in the treatment of femoropopliteal disease: IN.PACT SFA I and II (Medtronic), Cook Zilver PTX and LEVANT 2 (BD/Bard).25 This update also reported an increase in the all-cause mortality in those patients who underwent treatment with paclitaxel-coated devices in comparison with the control group; however, the major flaw is that upon further review, there was no standardised calculation used among the three trials to calculate all-cause mortality, which is subject to bias (e.g. the intention to treat used by BD/Bard in the LEVENT 2 trial used a calculation that excluded pre-existing conditions), and significantly altered the way in which the data were presented and interpreted. As Holden et al. reported using a standardised proportion method for calculating 5-year mortality in these three groups, only the Zilver PTX DES was shown to have a statistically significant difference between the two arms (BMS or PTA) with all-cause mortality at 28.1% (p=0.008), which had the smallest amount of paclitaxel delivery (1.1 mg; Table 1). With these standardised results, a dose–response relationship was not able to be identified, which may imply an association and not a causation.25

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Paclitaxel Exposure and Dosage of Drug-coated Devices for Femoropopliteal PAD With regard to the IN.PACT SFA I (US), II (Europe) and Japan trials, it is important to note that follow-up visit attendance was lower in the DCB arm across all three locations at all time points, which again suggests bias, as patients in the PTA arm may have received more medical care and treatment than those patients in the DCB arm. In addition, the Zilver PTX, LEVANT 2 and IN.PACT SFA studies had anywhere from 20% to 86% of patients initially enrolled in the study lost to follow-up, to which the FDA responded by requesting the industry partners to resubmit updated follow-up patient numbers for their analysis. Updated patient-level meta-analysis from the Zilver PTX randomised controlled trial and Zilver PTX and B<S Japan post-market studies did not show an increase in long-term all-cause mortality.26 In the clinical trials that are still underway, it will be interesting to see how the COVID-19 pandemic affects data acquisition and patient follow-up.

Conclusion

Early results of the use of paclitaxel-coated devices in the treatment of femoropopliteal PAD are promising. A full and comprehensive study focused on the long-term risks and benefits of paclitaxel using real patient data remains to be ascertained. Without a consistent dose response, underlying pharmacokinetic mechanism and reproducible harm, it is difficult to infer that paclitaxel-coated devices are the cause of increased all-cause mortality. In addition, data amongst randomised controlled trials are not consistent between geographical areas, and the treatment practice of the DCB and PTA arms in each study appear to have been subject to treatment bias, which may account for the inconsistences 1. Katsanos K, Spiliopoulos S, Paraskevopoulos I, et al. Systematic review and meta-analysis of randomized controlled trials of paclitaxel-coated balloon angioplasty in the femoropopliteal arteries: role of paclitaxel dose and bioavailability. J Endovasc Ther 2016;23:356–70. https://doi. org/10.1177/1526602815626557; PMID: 26823485. 2. Mills JL, Conte MS, Murad MH. Critical review and evidence implications of paclitaxel drug-eluting balloons and stents in peripheral artery disease. J Vasc Surg 2019;70:3–7. https:// doi.org/10.1016/j.jvs.2019.05.002; PMID: 31230649. 3. Zhang X, Xie J, Li G, et al. Head-to-head comparison of sirolimus-eluting stents versus paclitaxel-eluting stents in patients undergoing percutaneous coronary intervention: a meta-analysis of 76 studies. PLoS One 2014;9:e97934. https://doi.org/10.1371/journal.pone.0097934; PMID: 24844284. 4. Morice MC, Colombo A, Meier B, et al. Sirolimus- vs paclitaxel-eluting stents in de novo coronary artery lesions: the REALITY trial: a randomized controlled trial. JAMA 2006;295:895–904. https://doi.org/10.1001/jama.295.8.895; PMID: 16493102. 5. Windecker S, Remondino A, Eberli FR, et al. Sirolimuseluting and paclitaxel-eluting stents for coronary revascularization. N Engl J Med 2005;353:653–62. https:// doi.org/10.1056/NEJMoa051175; PMID: 16105989. 6. Katsanos K, Spiliopoulos S, Kitrou P, et al. Risk of death following application of paclitaxel-coated balloons and stents in the femoropopliteal artery of the leg: a systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc 2018;7:e011245. https://doi.org/10.1161/ JAHA.118.011245; PMID: 30561254. 7. Katsanos K, Spiliopoulos S, Kitrou P, et al. Risk of death and amputation with use of paclitaxel-coated balloons in the infrapopliteal arteries for treatment of critical limb ischemia: a systematic review and meta-analysis of randomized controlled trials. J Vasc Interv Radiol 2020;31:202–12. https:// doi.org/10.1016/j.jvir.2019.11.015; PMID: 31954604. 8. Schneider PA, Laird JR, Doros G, et al. Mortality not correlated with paclitaxel exposure: an independent patientlevel meta-analysis of a drug-coated balloon. J Am Coll Cardiol 2019;73:2550–63. https://doi.org/10.1016/j. jacc.2019.01.013; PMID: 30690141. 9. Secemsky EA, Kundi H, Weinberg I, et al. Association of survival with femoropopliteal artery revascularization with drug-coated devices. JAMA Cardiol 2019;4:332–40. https:// doi.org/10.1001/jamacardio.2019.0325; PMID: 30747949. 10. Behrendt CA, Sedrakyan A, Peters F, et al. Editor’s choice –

observed. Again, with the information we currently have, there appears to be only an association between paclitaxel-coated devices and increased all-cause mortality, not a causation. Before we completely eliminate this promising treatment of recalcitrant peripheral arterial lesions in the lower extremity, we encourage additional studies specifically designed to follow long-term results, and for each clinician to weigh the risks and benefits with regard to each patient, and decide individually if this treatment will allow for the desired outcome; however, more information must be available to make a truly informed decision.

Clinical Perspective

• Paclitaxel is a well-established, potent, antineoplastic agent that

has been used in the treatment of femoropopliteal peripheral arterial disease due to its anti-stenotic properties. • A summary-level meta-analysis demonstrated an association between paclitaxel and increased all-cause mortality. • An association with increased mortality has been confirmed with patient-level meta-analysis; however, the strength of the signal has been highly variable and no specific mechanism of harm has been identified. • There exists only an association between paclitaxel-coated devices and increased all-cause mortality, not a causation, which warrants further investigation.

Long term survival after femoropopliteal artery revascularisation with paclitaxel coated devices: a propensity score matched cohort analysis. Eur J Vasc Endovasc Surg 2020;59:587–96. https://doi.org/10.1016/j. ejvs.2019.12.034; PMID: 31926836. 11. Horwitz SB. Mechanism of action of taxol. Trends Pharmacol Sci 1992;13:134–6. https://doi.org/10.1016/01656147(92)90048-B; PMID:1350385. 12. Ng VG, Mena C, Pietras C, et al. Local delivery of paclitaxel in the treatment of peripheral arterial disease. Eur J Clin Invest 2015;45:333–45. https://doi.org/10.1111/eci.12407; PMID: 25615282. 13. Axel DI, Kunert W, Göggelmann C, et al. Paclitaxel inhibits arterial smooth muscle cell proliferation and migration in vitro and in vivo using local drug delivery. Circulation 1997;96:636–45. https://doi.org/10.1161/01.CIR.96.2.636; PMID: 9244237. 14. Freyhardt P, Zeller T, Kröncke TJ, et al. Plasma levels following application of paclitaxel-coated balloon catheters in patients with stenotic or occluded femoropopliteal arteries. Rofo 2011;183:448–55. https://doi. org/10.1055/s-0029-1246028; PMID: 21274828. 15. Margolis J, McDonald J, Heuser R, et al. Systemic nanoparticle paclitaxel (nab-paclitaxel) for in-stent restenosis I (SNAPIST-I): a first-in-human safety and dosefinding study. Clin Cardiol 2007;30:165–70. https://doi. org/10.1002/clc.20066; PMID: 17443649. 16. 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. 17. Rosenfield K, Jaff MR, White CJ, et al. Trial of a paclitaxelcoated balloon for femoropopliteal artery disease. N Engl J Med 2015;373:145–53. https://doi.org/10.1056/ NEJMoa1406235; PMID: 26106946. 18. Ott I, Cassese S, Groha P, et al. ISAR-PEBIS (PaclitaxelEluting Balloon Versus Conventional Balloon Angioplasty for In-Stent Restenosis of Superficial Femoral Artery): a randomized trial. J Am Heart Assoc 2017;6:e006321. https://doi.org/10.1161/JAHA.117.006321; PMID: 28743787. 19. Krishnan P, Faries P, Niazi K, et al. Stellarex drug-coated balloon for treatment of femoropopliteal disease: twelvemonth outcomes from the randomized ILLUMENATE Pivotal and pharmacokinetic studies. Circulation 2017;136:1102–13. https://doi.org/10.1161/CIRCULATIONAHA.117.028893; PMID: 28729250. 20. Gray WA, Jaff MR, Parikh SA, et al. Mortality assessment of

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paclitaxel-coated balloons: patient-level meta-analysis of the ILLUMENATE clinical program at 3 years. Circulation 2019;140:1145–55. https://doi.org/10.1161/ CIRCULATIONAHA.119.040518; PMID: 31567024. 21. Gray WA, Keirse K, Soga Y, et al. A polymer-coated, paclitaxel-eluting stent (Eluvia) versus a polymer-free, paclitaxel-coated stent (Zilver PTX) for endovascular femoropopliteal intervention (IMPERIAL): a randomised, noninferiority trial. Lancet 2018;392:1541–51. https://doi. org/10.1016/S0140-6736(18)32262-1; PMID: 30262332. 22. Dake MD, Ansel GM, Jaff MR, et al. Sustained safety and effectiveness of paclitaxel-eluting stents for femoropopliteal lesions: 2-year follow-up from the Zilver PTX randomized and single-arm clinical studies. J Am Coll Cardiol 2013;61:2417–27. https://doi.org/10.1016/j.jacc.2013.03.034; PMID: 23583245. 23. Holden A, Varcoe RL, Jaff MR, et al. Paclitaxel and mortality: the dose argument is critical. J Endovasc Ther 2019;26:467– 70. https://doi.org/10.1177/1526602819857241; PMID: 31179816. 24. Ducasse E, Caradu C. Rigorous focus on paclitaxel-related mortality in femoropopliteal artery disease. J Vasc Surg 2020;71:216–9. https://doi.org/10.1016/j.jvs.2019.10.010; PMID: 31864645. 25. FDA. FDA Executive Summary: Circulatory System Devices Panel Meeting June 19 and 20, 2019. 2019. https://www.fda.gov/ media/127698/download (accessed 3 June 2020). 26. Dake MD, Ansel GM, Bosiers M, et al. Paclitaxel-coated Zilver PTX drug-eluting stent treatment does not result in increased long-term all-cause mortality compared to uncoated devices. Cardiovasc Intervent Radiol 2020;43:8–19. https://doi.org/10.1007/s00270-019-02324-4; PMID: 31502026. 27. Tepe G, Laird J, Schneider P, et al. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial. Circulation 2015;131:495–502. https://doi. org/10.1161/CIRCULATIONAHA.114.011004; PMID: 25472980. 28. Schneider PA, Varcoe RL, Secemsky E, et al. Update on paclitaxel for femoral-popliteal occlusive disease in the 15 months following a summary level meta-analysis demonstrated increased risk of late mortality and dose response to paclitaxel. J Vasc Surg 2021;73:311–22. https://doi.org/10.1016/j.jvs.2020.07.093; PMID: 32890719.