VER 1.1 by RadcliffeVascular

Vascular & Endovascular Review Volume 1 • Issue 1 • Autumn 2018

Volume 1 • Issue 1 • Autumn 2018

www.VERjournal.com

Drug-coated Balloons in the Femoropopliteal Region: Dream or Reality? Fabrizio Fanelli and Alessandro Cannavale

Computational Fluid Dynamics and Aortic Dissections: Panacea or Panic? Ian Wee, Chi Wei Ong, Nicholas Syn and Andrew Choong

Endovascular Treatment of Common Femoral Artery Atherosclerotic Disease Omar Jawaid and Ehrin Armstrong

An Ilio-iliac Arteriovenous Fistula Following Spontaneous Rupture of a Right Common Iliac Artery Aneurysm Yogeesan Sivakumaran, Manar Khashram and Paul Charles Haggart

ISSN: 2516–3299

B Estimated angulation of renal arteries prior to procedure

Transcarotid transcatheter aortic valve implantation

Human embryonic stem cells

Vascular

Lifelong Learning for Vascular Professionals

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Stellarex

Designed for performance in calcium Stellarex EnduraCoat technology was designed for long-term patency in severely calcified lesions. Only Stellarex has reported a two-year treatment drug dose. Stellarexâ&#x20AC;&#x201D;the clear DCB choice for your complex PAD patients. Two-year primary patency 1

67.8%

15.3%

52.5%

Stellarex

PTA

ILLUMENATE Pivotal

StellarexDCB.com

1. Mathews, J. NCVH, 2018. May 30, 2018. New Orleans, LA. ÂŠ2018 Koninklijke Philips N.V. All rights reserved. Some or all products manufactured by Spectranetics, a Philips company. Approved for external distribution. D044458-01 072018

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Volume 1 • Issue 1 • Autumn 2018

www.VERjournal.com

Editor-in-Chief Stephen Black Guy's and St Thomas’ Hospital, UK

Section Editor – Aortic

Section Editor – Venous

Andrew Choong

Rick de Graaf

National University of Singapore, Singapore

Maastricht University Medical Centre, the Netherlands

Section Editor – Peripheral Artery Disease

Section Editor – Update of New Literature

Michael Lichtenberg

Sebastian Debus

Klinikum Arnsberg, Karolinen Hospital, Germany

University Heart Center, Germany

Section Editor – Case Reports Ash Patel King's College London, UK

Patrick Chong Berkshire Independent Hospital, UK

Andrew Bullen Wollongong Hospital, Australia

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

Narayan Karunanithy Guy’s and St Thomas’ NHS Foundation Trust, UK

Prakash Saha King’s College Hospital, UK

Gerry O’Sullivan University College Hospital, Ireland

Elias Brountzos Attikon University General Hospital, Greece

Gustaf Tegler Uppsala University, Sweden

Martin Maresch BDF Hospital, Bahrain

Managing Editor Rosie Scott • Production Aashni Shah • Senior Designer Tatiana Losinska Sales & Marketing Executive William Cadden • Sales Director Rob Barclay Publishing Director Leiah Norcott • Commercial Director David Bradbury Chief Executive Officer David Ramsey • Chief Operating Officer Liam O’Neill •

Editorial Contact Rosie Scott rosie.scott@radcliffe-group.com Circulation & Commercial Contact David Ramsey david.ramsey@radcliffe-group.com •

Cover image medistock © stock.adobe.com

•

Cover design Tatiana Losinska

Vascular

Lifelong Learning for Vascular Professionals Published by Radcliffe Vascular. All information by Radcliffe Vascular and each of the contributors from various sources is as current and accurate as possible. However, due to human or mechanical errors, Radcliffe Vascular and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions, or for the results obtained from the use thereof. Published content is for information purposes only and is not a substitute for professional medical advice. Where views and opinions are expressed, they are those of the author(s) and do not necessarily reflect or represent the views and opinions of Radcliffe Vascular. Radcliffe Vascular, Unit F, First Floor, Bourne End Business Park, Cores End Road, Bourne End, Buckinghamshire, SL8 5AS. © 2018 All rights reserved ISSN: 2516–3299 eISSN: 2516–3302

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Established: September 2018 Frequency: Bi-annual Current issue: Autumn 2018

Aims and Scope • Vascular & Endovascular Review aims to assist time-pressured physicians to stay abreast of key advances and opinion in vascular and endovascular practice. • Vascular & Endovascular Review comprises balanced and comprehensive articles written by leading authorities, addressing the most pertinent developments in the field. • Vascular & Endovascular Review provides comprehensive updates on a range of salient issues to support physicians in continuously developing their knowledge and effectiveness in day-to-day clinical practice.

Structure and Format • Vascular & Endovascular Review is a bi-annual journal comprising review articles, expert opinion articles and guest editorials. • The structure and degree of coverage assigned to each category of the journal is the decision of the Editor-in-Chief, with the support of the Section Editors and Editorial Board. • Articles are fully referenced, providing a comprehensive review of existing knowledge and opinion. • Each edition of Vascular & Endovascular Review is available in full online at www.VERjournal.com

• Once the authors have amended a manuscript in accordance with the reviewers’ comments, the manuscript is assessed to ensure the revised version meets quality expectations. The manuscript is sent to the Editor-in-Chief for final approval prior to publication.

Submissions and Instructions to Authors • Contributors are identified by the Editor-in-Chief with the support of the Section Editors and Managing Editor, and guidance from the Editorial Board. • Following acceptance of an invitation, the author(s) and Managing Editor, in conjunction with the Editor-in-Chief and Section Editors, formalise the working title and scope of the article. • The ‘Instructions to Authors’ document and additional submission details are available at www.VERjournal.com • Leading authorities wishing to discuss potential submissions should contact the Managing Editor, Rosie Scott rosie.scott@radcliffe-group.com

Reprints All articles included in Vascular & Endovascular Review are available as reprints. Please contact the Publishing Director, Leiah Norcott leiah.norcott@radcliffecardiology.com

Editorial Expertise

Distribution and Readership

Vascular & Endovascular Review is supported by various levels of expertise: • Overall direction from an Editor-in-Chief, supported by Section Editors and an Editorial Board comprising leading authorities from a variety of related disciplines. • Invited contributors who are recognised authorities in their respective fields. • Peer review – conducted by experts appointed for their experience and knowledge of a specific topic. • An experienced team of Editors and Technical Editors.

Vascular & Endovascular Review is distributed bi-annually through controlled circulation to senior healthcare professionals in the field in Europe.

Peer Review

All manuscripts published in Vascular & Endovascular Review are available free-to-view at www.VERjournal.com. Also available at www.radcliffecardiology.com are manuscripts from other journals within Radcliffe Cardiology’s cardiovascular portfolio – including, Arrhythmia and Electrophysiology Review, Interventional Cardiology Review, Cardiac Failure Review, European Cardiology Review and US Cardiology Review. n

• On submission, all articles are assessed by the Editor-in-Chief to determine their suitability for inclusion. • The Managing Editor, following consultation with the Editor-in-Chief, Section Editors and/or a member of the Editorial Board, sends the manuscript to reviewers who are selected on the basis of their specialist knowledge in the relevant area. All peer review is conducted double-blind. • Following review, manuscripts are accepted without modification, accepted pending modification (in which case the manuscripts are returned to the author(s) to incorporate required changes), or rejected outright. The Editor-in-Chief reserves the right to accept or reject any proposed amendments.

Copyright and Permission Radcliffe Vascular is the sole owner of all articles and other materials that appear in Vascular & Endovascular Review unless otherwise stated. Permission to reproduce an article, either in full or in part, should be sought from the publication’s Managing Editor.

Online

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Contents

Foreword

Stephen Black Editor-in-Chief

Peripheral Artery Disease

Drug-coated Balloons in the Femoropopliteal Region: Dream or Reality? Fabrizio Fanelli and Alessandro Cannavale

Endovascular Treatment of Common Femoral Artery Atherosclerotic Disease

Stem Cell Therapy for Vascular Disorders

Omar Jawaid and Ehrin Armstrong

Emad A Hussein

Surgical Techniques

Lessons Learned After 366 Thermoablated Veins Alexandre Campos Moraes Amato, Ricardo Virgínio dos Santos, Daniel Augusto Benitti, Dumitriu Zunino Saucedo and Salvador José de Toledo Arruda Amato

Aorta

Computational Fluid Dynamics and Aortic Dissections: Panacea or Panic?

An Ilio-iliac Arteriovenous Fistula Following Spontaneous Rupture of a Right Common Iliac Artery Aneurysm

Ian Wee, Chi Wei Ong, Nicholas Syn and Andrew Choong

Yogeesan Sivakumaran, Manar Khashram and Paul Charles Haggart

Endovascular Rescue of Simultaneous Renal Stent Thrombosis: Case Report Fernando Gallardo Pedrajas, Rubén Rodriguez Carvajal, Alberto Martín-Palanca, Rocio Martin-Palanca Verdes, Teresa Hernández Carbonell and Rocio Lainez Rube

Carotid

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Carotid Access for Aortic Interventions: Genius or Madness? Ian Wee, Nicholas Syn and Andrew MTL Choong

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REACT.

REsponse Adapted Combination Therapy

Passeo-18 Lux and Pulsar-18: excellent 24-month clinical outcomes, proven individually1,2 and in combination.3,4*

Passeo-18 Lux Drug-Coated Balloon

Individually:

Passeo-18 Lux

Pulsar-18

91.7%

92.4%

Freedom from CD-TLR

Clinically proven5 For challenging patient groups Effective drug delivery6**

BIOLUX P-III

BIOFLEX PEACE

Pulsar-18 Self-Expanding Stent

In combination:

Passeo-18 Lux + Pulsar-18

Pulsar-18 + Passeo-18 Lux

Clinically proven7

86.1%3

88.0%4*

Thin struts

Freedom from TLR

BIOLUX 4EVER

Freedom from TLR

Low COF

DEBAS

Above presented numbers represent 24-month results.

1. Binkert C. BIOLUX P-III Real-world experience with a Paclitaxel-Coated Balloon for the treatment of atherosclerotic infrainguinal arteries: 24-month results of the BIOLUX P-III All Comers Registry in Superﬁcial Femoral Arteries. Presented at: CIRSE 2018. Lisbon, Portugal; 2. Lichtenberg M. BIOFLEX PEACE registry: 12 and 24 month results. Presented at: LINC 2018. Leipzig, Germany; 3. Deloose K. BIOLUX 4EVER: Combining Passeo-18 Lux DCB and Pulsar-18 BMS: 24-month results of full cohort. Presented at: LINC 2018. Leipzig, Germany; 4. Mwipatayi P. DEBAS First-in-man experience of self-expanding nitinol stents combined with drug-coated balloon in the treatment of femoropopliteal occlusive disease. Sage Journals. 2017; 0(0) 1-9, 24-month results; 5. Scheinert D, et al. Paclitaxel Releasing Balloon in femoropopliteal lesions using BTHC excipient: 12-month results from the BIOLUX P-I randomized trial. JEVT, 2015; 22(1): 14-21; 6. BIOTRONIK data on ﬁle; 7. Bosiers M. 4EVER study. J. Endovascular. Ther., 2013;20: 746-756. * The use of Passeo-18 Lux for post-dilatation is not within the indication for the product. ** Drug retention while in transit to the lesion and prolonged paclitaxel presence in the vessel wall. Freedom from TLR = Freedom from Target Lesion Revascularization; Freedom from CD-TLR = Freedom from Clinically Driven Target Lesion Revascularization. Passeo, Lux and Pulsar are trademarks or registered trademarks of BIOTRONIK AG.

Speciﬁcations are subject to modiﬁcation, revision and improvement.

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Foreword

Stephen Black Guy's and St Thomas’ Hospital, London

he treatment of vascular disease continues to advance at a rapid pace. Treatment has moved on from standard open procedures with a number of new technologies challenging old dogmas. In this context, it is vital for vascular practitioners to have ready access to information to help guide their thinking. New techniques require critical

appraisal to ensure that they are implemented appropriately, and practitioners need regular updates to help keep them informed. The constant struggle between what’s new and the gaps in evidence, as well as striving to maintain appropriate care, will always be paramount. Vascular & Endovascular Review (VER) aims to provide vascular interventionists – whether they be interventional radiologists, angiologists, vascular physicians, cardiologists or vascular surgeons – educational and informative material as a resource to keep their practice up to date. The journal provides a comprehensive update on a range of pertinent issues to support vascular interventionists to continuously develop their knowledge and effectiveness in day-to-day clinical practice. This first issue comprises a range of reviews and case studies focused on current topical issues in vascular and endovascular surgery. There are three articles on peripheral artery disease. Fabrizio Fanelli and Alessandro Cannavale discuss drug-coated balloons as an important innovation and established technique in the treatment of atherosclerotic disease of the femoropopliteal region. Emad Hussein looks at stem cell therapy for vascular disorders, and proposes that stem cell-based regeneration of the endothelium may be a promising approach for treating peripheral artery disease. In their review, Omar Jawaid and Ehrin Armstrong discuss the endovascular treatment of common femoral artery atherosclerotic disease, and summarise the current data regarding acute and long-term outcomes for endovascular treatment of common femoral artery disease. We also have an article by Wee et al. on carotid access for aortic interventions, as well as an article by Choong et al. on computation fluid dynamics and aortic dissections, in which the authors review the methodology, benefits as well as obstacles associated with computation flow dynamics in the field of vascular surgery. In their case report, Gallardo Pedrajas et al. discuss acute renal failure 4 months after endovascular aneurysm repair and bilateral renal arteries parallel stenting “chimney technique” (CH-EVAR), and compare renal artery geometry before and after CH-EVAR to find a possible cause of stent thrombosis. Amato et al. discuss advances in surgical techniques improving outcomes in varicose vein treatment. In their article, they determine whether the use of laser and different parameters influenced morbidity rates and learning curves for all technology improvements during the study period, and found that negatives outcomes diminished with the adoption of new strategies and skills, and Sivakumaran et al. provide a case report on an ilio-iliac arteriovenous fistula following spontaneous rupture of a right common iliac aneurysm. I am grateful to all those who have provided articles for this first edition and to the Board of Section Editors we have assembled for giving their time. The Editorial Team and Publisher hope you find this issue of VER valuable. n

DOI: 10.15420/ver.2018.1.1.FO

Access at: www.VERjournal.com

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ESVS 32nd Annual Meeting 25â&#x20AC;&#x201C;28 September 2018 Diversity Creates Knowledge Palau de Congressos Valencia, Spain

10/09/2018 21:08

Peripheral Artery Disease

Drug-coated Balloons in the Femoropopliteal Region: Dream or Reality? Fabrizio Fanelli 1 and Alessandro Cannavale 2 1. Careggi University Hospital, University of Florence, Florence, Italy; 2. Interventional Radiology Unit, North Bristol NHS Trust, Bristol, UK

Abstract Peripheral arterial disease is a severe pathology. Several methods have been tested in order to increase the patency rate and the quality of life. The superficial femoral artery is considered a very difficult region due to the continuous movement of the leg that modify the length and the morphology of this vessel. Since their introduction, drug-coated balloons have been correlated with an increased patency rate. Several studies have been performed and nowadays a level 1 evidence is available. Not all the lesions can be treated successfuly with drug-coated balloons. For example in case of heavely calcified lesions vessel preparation is required. This can be performed with atherectomy, scorig balloon, lithoplasty in order to debulk the lesion and increase the drug uptake.

Keywords Drug-coated balloon, drug-eluting stent, superficial femoral artery, peripheral arterial disease, angioplasty Disclosure: The authors have no disclosures to report. Received: 22 July 2018 Accepted: 1 September 2018 Citation: Vascular & Endovascular Review 2018;1(1):8–11. DOI: https://doi.org/10.15420/ver.2018.11.2 Correspondence: Fabrizio Fanelli, Vascular and Interventional Radiology Department, “Careggi” University Hospital, Largo A. Brambilla – Florence, Italy. E: fabrizio.fanelli@unifi.it

Peripheral arterial disease (PAD) is a severe and growing problem affecting the quality of life of over 200 million people worldwide.1 Endovascular treatment has been validated as first-line therapy for PAD. Several techniques and tools are available, supported by different levels and quantities of clinical evidence.2 Since their introduction in Europe in 2008, drug-coated balloons (DCBs) have increasingly been used for lower limb revascularisation. Following initial excellent results reported in the literature, many physicians started to use DCBs daily as a first-line therapy in the femoropopliteal region, supported by level 1 evidence.3,4 DCBs achieve high rates of primary patency (PP), compared with alternative therapies, with a limited use of provisional stents.

Clinical Studies DCBs act on the smooth muscle cells reducing intimal hyperplasia and the risk of restenosis. In recent years many clinical studies have been performed comparing DCBs with conventional percutaneous transluminal angioplasty (PTA). All of these studies have shown superiority of DCBs in late lumen loss (LLL) and in PP. More than 13 DCBs are available on the market in Europe, but not all of them have been evaluated with robust clinical studies.

1-year PP was 89.5 % in the Pivotal Trial of a Novel Paclitaxel-Coated Percutaneous Angioplasty Balloon (ILLUMENATE),10,11 82.2 % in the Randomized Trial of IN.PACT Admiral® Drug Coated Balloon vs Standard PTA for the Treatment of SFA and Proximal Popliteal Arterial Disease (INPACT SFA),12 73.5 % in the Moxy Drug Coated Balloon versus Standard Balloon Angioplasty for the Treatment of Femoropopliteal Arteries (LEVANT 2) study14,15 and 86.4 % in the Comparison of the Ranger™ Paclitaxel-coated PTA Balloon Catheter and Uncoated PTA Balloons in Femoropopliteal Arteries (RANGER SFA) trial.16 After 2 years of follow-up, PP was 80.3 % for the Stellarex™ DCB, 78.9 % for the IN.PACT® Admiral® DCB (Medtronic) and 58.6 % for the Lutonix® DCB (Bard). Initial analysis of these data underlines the concept of a prolonged effect of paclitaxel, confirmed by the difference in PP when compared with PTA after 2 years of follow-up. Three-year data are also available for the INPACT SFA trial, confirming the long-term efficacy of the DCB balloon versus PTA. A 3-year PP of 69.5 % (versus 45.1 % with PTA) and a clinically driven target lesion revascularisation (CD TLR) of 2.4 % at 1 year, 9.1 % at 2 years and 15.2 % at 3 years (versus a PTA CD TLR of 20.6 %, 28.3 % and 31.1 % at 1, 2 and 3 years, respectively; p<0.05) have been described.17 Table 1 summarises the main characteristics and outcomes of the most recent randomised controlled trials.

In the first milestone trial – Local Taxan With Short Time Contact for Reduction of Restenosis in Distal Arteries (THUNDER) – Tepe et al. reported a great advantage in the use of the prototype DCB over traditional angioplasty, in terms of LLL (0.7 ± 1.9 versus 1.5 ± 1.3 mm; p=0.5) and binary restenosis (BR) (17 % versus 54 %; p=0.04). The advantage of DCB has been maintained over more than 5 years.5,6

Real-world Data

More recently many other studies have confirmed similar results, not only after 12-month follow-up, but also after 24 and 36 months.7–15

In the IN.PACT Global Study,18 1,406 patients with Rutherford class from two to four were enrolled. Mean lesion length was 12.09 cm with 35 %

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Data coming from global registries are interesting and represent more of a real-world situation. Three studies have been conducted: the IN.PACT Global Study with the IN.PACT Admiral DCB.18 The Global SFA (superficial femoral artery) Registry with the Lutonix DCB19 and Ranger DCB Registry with the Ranger DCB (Boston Scientific).20

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Drug-coated Balloons in the Femoropopliteal Region Table 1. Summary of the Main Characteristics and Results from Drug-coated Balloon Randomised Controlled Trials Study name

Study type

Independent

Rutherford

Lesion complexity (lesion

Freedom from TLR

core-lab

class

length; TASC C/D; severe

at 12 months (DCB

Over 12 months (DCB

calcium)

versus PTA)

versus PTA) At 2 years: 90.9 % versus 71.7 % (p<0.05) At 3 years: 84.8 % versus 68.9 % (p<0.05)

surveillance INPACT SFA12

RCT

Yes

Class 2: 40 % Class 3: 50 % Class 4: 10 %

Lesion length: 89.4 ± 48.9 mm TASC C: N/R TASC D: N/R Severe calcium: N/R

97.6 % versus 79.4 % (p<0.05)

RANGER SFA16

RCT (FIH)

Yes

Class 2: 40 % Class 3: 50 % Class 4: 10 %

Lesion length: 68 ± 46 mm TASC C: 7 % TASC D: 0 % Severe calcium: 36 %

91.2 % versus 69.9 % (p<0.001)

ILLUMENATE FIH10

RCT (FIH)

Yes

Class 2: 12 % Class 3: 86 % Class 4: 2 %

Lesion length: 72 ± 47 mm TASC C: N/R TASC D: N/R Severe calcium: 13.8 %

90 % (DCB – predilation)

ILLUMENATE11

RCT PIVOTAL

Yes

Class 2: 31.5 % Class 3: 64.5 % Class 4: 4 %

Lesion length: 80 ± 45 mm TASC C: N/R TASC D: N/R Severe calcium: 43.9 %

93.6 % versus 87.3 % (p<0.025)

LEVANT 214

RCT

Yes

Class 2: 29.4 % Class 3: 62.7 % Class 4: 7.9 %

Lesion length: 62.8 ± 41 mm TASC C: 2.2 % TASC D: 0 % Severe calcium: 33 %

89.7 % versus 84.8 % (p=0.16)

BIOLUX P-19

RCT

Yes

Class Class Class Class

Lesion length: 51.4 ± 47.2 mm TASC C: N/R TASC D: N/R Severe calcium: 14.7 %

84.6 % versus 58.3 % (p=0.02)

1: 64.7 % 2: 11.8 % 3: 17.4 % 4: 5.9 %

At 2 years: 85.8 %

DCB = drug-coated balloon; FIR = first-in-human; N/R = not reported; PTA = percutaneous transluminal angioplasty; RCT = randomised controlled trial; SFA = superficial femoral artery; TASC = trans-atlantic inter-society consensus document; TLR = target lesion revascularisation.

total occlusion and 18 % in-stent restenosis (ISR). Freedom from CD TLR (primary endpoint) was 92.6 % at 360 days (evaluated by Kaplan-Meier analysis and adjudicated by an independent clinical event committee). In the Global SFA Registry, 691 patients with Rutherford class from two to six were enrolled. Mean lesion length was 101.2 mm with 31.2 % total occlusion. Freedom from TLR at 12 months was 93.6 % for the whole group of patients and 94.7 % for patients with total occlusion. Again, in this study results were evaluated with Kaplan–Meier analysis. Interim results at 24 months showed a freedom from TLR of 89.2 %.19 In the Ranger DCB All-comers Registry, patients with Rutherford class from one to six were enrolled. Mean lesion length was 129.0 mm and severe calcification was present in only 3 % of lesions. Freedom from TLR was 89.2 %, with significant improvement of the Rutherford class at 12 months.20 A study of the results of the Lutonix Global SFA Registry analysed long lesions (140–500 mm); of these 42.1% were chronic total occlusions (CTOs).21 Freedom from TLR in long lesions was similar to all lesions (93.0 % long lesions versus 93.6 % all lesions), as well as the 30-day safety (99.3 %). Long lesions (>15 cm in length) were also analysed in the IN.PACT Global Study.9 Of 157 lesions, with a mean length of 26.40 ± 8.61 cm, 60.4 % were CTO. 1-year PP was 91.1 % (360 days) and 80.7 % (390 days) and 1-year CD TLR was 6.0 % with 40.4 % provisional stenting.22 The IN.PACT Admiral DCB was also evaluated in a real-world registry of 260 patients with 288 lesions longer than 10 cm (mean lesion length of 24 cm).23 The patient population was complex with 65.3 % CTO,

VA S C U L A R & E N D O VA S C U L A R R E V I E W

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51.7 % de novo lesions, 11.1 % restenosis and 37.2 % ISR. Kaplan-Meier estimated PP was 79.2 ± 2.6 % at 1 year and 53.7 ± 3.4 % at 2 years. Freedom from TLR was 85.4 ± 2.1 % for the entire cohort at 1 year and 68.6 ± 3.0 % at 2 years. In the critical limb ischaemia group only, the amputation rate was 5.3 % at 1 year and 7.9 % at 2 years.23 Table 2 summarises the main characteristics and outcomes of the real-world registries. Although all DCBs use paclitaxel as the active drug, multiple technical differences exist between each DCB, such as drug dose (ranging from 2 μg/mm2 to 3.5 μg/mm2), formulation (crystalline versus amorphous), excipient type and coating technology. The ‘correct’ drug dose is under discussion. The drug dose on the balloon surface ranges from 2 μg/mm2 to 3.5 μg/mm2 but the optimal dose is not defined. It is queried whether drug dose should differ according to the patient’s condition (for instance, if they have diabetes or not) or according to the lesion morphologic characteristics (more or less calcific), the type of lesion (stenosis or occlusion) and the lesion length. Moreover, the actual drug dose that is released at the level of the target lesion cannot be precisely evaluated in vivo. This value depends on the lesion location, the time of exposure of the catheter to the blood flow, the lesion morphology, and so on. However, on the basis of the available results, drug dose seems not to be responsible for the performance of the DCB. Similar rates of PP have been reported for the IN.PACT and the Stellarex DCBs (PP at 2 years; 78.9 % versus 80.3 % for IN.PACT and Stellarex, respectively) despite the use of different drug doses (3.5 μg/mm2 versus 2.0 μg/mm2).10,11,17,18

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Peripheral Artery Disease Table 2. Summary of the Main Characteristics and Results from Drug-coated Balloon Registry and Sub-analysis Studies Study name

Study type

Independent core-lab surveillance

Rutherford class

Lesion complexity (lesion length; TASC C/D; severe calcium)

Freedom from TLR at 12 months (DCB)

Freedom from TLR Over 12 months (DCB versus PTA)

IN.PACT Global Study18

Multicentre prospective registry

Yes

Class Class Class Class

2: 31.1 % 3: 57.7 % 4: 8.6 % 5: 2.6 %

Lesion length: 120.9 ± 95.4 mm TASC C: N/R TASC D: N/R Severe calcium: 10.2 %

92.6 %

At 2 years: 83.3 %

IN.PACT Global Long Lesion Study22

Multicentre prospective registry

Yes

Class Class Class Class

2: 27.6 % 3: 61.9 % 4: 8.6 % 5: 1.9 %

Lesion length: 251.0 ± 78.9 mm TASC C: N/R TASC D: N/R Severe calcium: 13.3 %

96.0 %

Drug-Coated Balloons for Complex Femoropopliteal Lesions: 2-Year Results of a Real-World Registry23

Single centre registry (retrospective analysis)

Class Class Class Class Class

2: 3.8 % 3: 68.1 % 4: 11.5 % 5: 9.7 % 6: 5.2 %

Lesion length: 240 ± 10 mm TASC C: 21.5 % TASC D: 66 % Severe calcium: 14.2 %

85.4 %

At 2 years: 68.6 %

Global Lutonix SFA Registry19,21

Multicentre prospective registry

Class Class Class Class

2: 20.6 % 3: 66.9 % 4: 7.4 % 5: 1.5 %

Lesion length: 136.6 ± 89.7 mm TASC C: 13.2 % TASC D: 6.7 % Severe calcium: N/R

93.4 %

At 2 years: 89.3 %

Global Lutonix SFA Registry: Long Lesion21

Long lesions subanalysis (>140 mm)

Class Class Class Class

2: 16.4 % 3: 75.7 % 4: 5.0 % 5: 0.7 %

Lesion length: 242.5 ± 83.3 mm TASC C: N/R TASC D:N/R Severe calcium: N/R

93.2 %

At 2 years: 88.2 %

Ranger DCB registry20

Multicentre prospective registry (all comers)

Class Class Class Class Class

2: 18 % 3: 64 % 4: 8.0 % 5: 5.0 % 8: 1.0 %

Lesion length: 129 mm TASC C: 18 % TASC D: 30 % Severe calcium: 3 %

89 %

DCB = drug-coated balloon; N/R = not reported; PTA = percutaneous transluminal angioplasty; RCT = randomised controlled trial; SFA = superficial femoral artery; TASC = trans-atlantic inter-society consensus document; TLR = target lesion revascularisation.

Gongora et al. evaluated the arterial paclitaxel tissue concentration profiles over time for the IN.PACT Pacific, the Lutonix and the Ranger DCBs.24 Despite the different drug dose, all of the DCBs displayed similar levels of drug tissue concentration following inflation. However, after 24 hours, paclitaxel drug tissue concentration levels decreased to ~20 ng/mg for both IN.PACT and Ranger and to ~5 ng/mg for the Lutonix. At seven days, drug tissue concentration levels for IN.PACT and Ranger decreased to ~50 % and to ~1–2 ng/mg for Lutonix. IN.PACT and Ranger drug tissue concentration levels dropped to ~1–2 ng/mg after 30 days.

owkes FG, Rudan D, Rudan I et al. Comparison of global F estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013;382:1329–40. https://doi.org/10.1016/S01406736(13)61249-0; PMID: 23915883. Cortese B, Granada JF, Scheller B, et al. Drug-coated balloon treatment for lower extremity vascular disease intervention: an international positioning document. Eur Heart J 2016;37(14):1096–103. https://doi.org/10.1093/eurheartj/ ehv204; PMID: 26009594. Biondi-Zoccai G, Sangiorgi G, D’Ascenzo F, et al. Drug-eluting balloons for peripheral artery disease: a meta-analysis of 7 randomized clinical trials and 643 patients. Int J Cardiol 2013;168:570–1. https://doi.org/10.1016/j.ijcard.2013.01.247; PMID: 23462632. Werk M, Langner S, Reinkensmeier B, et al. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial. Circulation 2008;118:1358–65. https://doi.org/10.1161/ CIRCULATIONAHA.107.735985; PMID: 18779447. Tepe G, Zeller T, Albrecht T, et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med 2008;358:689–99. https://doi.org/10.1056/NEJMoa0706356; PMID: 18272892. Tepe G, Schnorr B, Albrecht T, et al. Angioplasty of femoral-

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DCBs represent an important innovation and established technique in the treatment of atherosclerotic disease of the femoropopliteal region. However, not all the DCBs are the same. Despite the use of the same drug, results are correlated with the technical characteristics of each balloon. Therefore, a ‘no class effect’ has been introduced and each DCB must stand on its own merit. This important concept should be kept in mind when choosing a DCB. We look forwards to further studies providing interesting and important data to confirm the safety and efficacy of this technology and help us to solve the still unanswered questions. n

popliteal arteries with drug coated balloons: 5-year follow-up of the Thunder trial. JACC Cardiovasc Interv 2015;8(1 Pt A): 102–8. https://doi.org/10.1016/j.jcin.2014.07.023; PMID: 25616822. 7. Werk M, Albrecht T, Meyer DR, et al. Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: evidence from the randomized PACIFIER trial. Circ Cardiovasc Interv 2012;5:831–40. https://doi.org/10.1161/ CIRCINTERVENTIONS.112.971630; PMID: 23192918. 8. Scheinert D, Duda S, Zeller T, et al. The LEVANT I (Lutonix Paclitaxel-Coated Balloon for the Prevention of Femoropopliteal Restenosis) Trial for Femoropopliteal Revascularization: First-in-Human Randomized Trial of Low-Dose Drug-Coated Balloon Versus Uncoated Balloon Angioplasty. JACC Cardiovasc Interv 2014;7:10–9. https://doi. org/10.1016/j.jcin.2013.05.022; PMID: 24456716. 9. Scheinert D, Schulte KL, Zeller T, et al. Novel paclitaxel releasing balloon in femoropopliteal lesions: 12-month evidence from the BIOLUX P-I randomized trial. J Endovasc Ther. 2015;22(1):14-21. 10. Schroeder H, Meyer DR, Lux B, et al. Two-year results of a low-dose drug-coated balloon for revascularization of the femoropopliteal artery: outcomes from the ILLUMENATE firstin-human study. Catheter Cardiovasc Interv 2015;86(2):278–86. https://doi.org/10.1002/ccd.25900; PMID: 25708850.

11. K rishnan 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(12):1102–13. https://doi.org/10.1161/CIRCULATIONAHA.117.028893; PMID: 28729250. 12. Tepe G, Laird J, Schneider PA, et al. Drug-Coated Balloon versus Standard Percutaneous Transluminal Angioplasty for the Treatment of Superficial Femoral and/or 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. 13. 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(21):2329–38. https://doi.org/10.1016/j.jacc.2015. 09.063; PMID: 26476467. 14. Rosenfield K, Jaff MR, White CJ, et al. Trial of a Paclitaxel coated balloon for femoropopliteal artery disease. N Engl J Med 2015;373(2):145–53. https://doi.org/10.1056/NEJMoa1406235; PMID: 26106946. 15. Jaff MR, Rosenfield K, Scheinert D, et al. Drug-coated balloons to improve femoropopliteal artery patency: rationale and design of the LEVANT 2 trial. Am Heart J 2015;169(4):479–85.

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Drug-coated Balloons in the Femoropopliteal Region https://doi.org/10.1016/j.ahj.2014.11.016; PMID: 25819854. 16. S teiner S, Willfort-Ehringer A, Sievert H, et al. 12-Month Results From the First-in-Human Randomized Study of the Ranger Paclitaxel-Coated Balloon for Femoropopliteal Treatment. JACC Cardiovasc Interv 2018;11(10):934–41. DOI: https://doi.org/10.1016/j.jcin.2018.01.276; PMID: 29730375. 17. Schneider PA, Laird JR, Tepe G, et al.; IN.PACT SFA Trial Investigators. DCB show superior 3-year outcomes vs. PTA: results from In.Pact SFA randomized trial. Circ Cardiovasc Interv. 2018;11(6):e006699. DOI: https://doi.org/10.1161/ CIRCINTERVENTIONS.118.006699. 18. Micari A, Brodmann M, Keirse K, et al. Drug-Coated Balloon Treatment of Femoropopliteal Lesions for Patients With Intermittent Claudication and Ischemic Rest Pain: 2-Year Results From the IN.PACT Global Study. JACC Cardiovasc Interv 2018;11(10):945–53. https://doi.org/10.1016/j.jcin.2018.02.019;

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PMID: 29798770. 19. S chmidt A, Piorkowski M, Görner H, et al. Drug-coated balloons for complex femoropopliteal lesions: 2-year results of a real-world registry. JACC Cardiovasc Interv. 2016;9(7):71524. https://doi.org/10.1016/j.jcin.2015.12.267; PMID: 27056311 20. Lichtenberg M, von Bilderling P, Ranft J, et al. Treatment of femoropopliteal atherosclerotic lesions using the ranger paclitaxel-coated balloon catheter: 12-month results from an all-comers registry. J Cardiovasc Surg (Torino) 2018;59(1):45–50. https://doi.org/10.23736/S0021-9509.17.10261-2; PMID: 28980462. 21. Thieme M, Von Bilderling P, Paetzel C, et al. The 24-Month Results of the Lutonix Global SFA Registry: Worldwide Experience With Lutonix Drug-Coated Balloon. JACC Cardiovasc Interv 2017;10(16):1682–90. https://doi.org/10.1016/j. jcin.2017.04.041; PMID: 28780030.

22. M icari A, Vadalà G, Castriota F, et al. 1-Year Results of Paclitaxel-Coated Balloons for Long Femoropopliteal Artery Disease: Evidence From the SFA-Long Study. JACC Cardiovasc Interv 2016;9(9):950–6. https://doi.org/10.1016/j. jcin.2016.02.014; PMID: 27151609. 23. Schmidt A, Piorkowski M, Görner H, et al. Drug-Coated Balloons for Complex Femoropopliteal Lesions: 2-Year Results of a Real-World Registry. JACC Cardiovasc Interv 2016;9(7):715–24. https://doi.org/10.1016/j.jcin.2015.12.267; PMID: 27056311. 24. Gongora CA, Shibuya M, Wessler JD, et al. Impact of Paclitaxel Dose on Tissue Pharmacokinetics and Vascular Healing: A Comparative Drug-Coated Balloon Study in the Familial Hypercholesterolemic Swine Model of Superficial Femoral In-Stent Restenosis. JACC Cardiovasc Interv 2015;8(8):1115–23. https://doi.org/10.1016/j.jcin. 2015.03.020; PMID: 26117470.

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Peripheral Artery Disease

Endovascular Treatment of Common Femoral Artery Atherosclerotic Disease Omar Jawaid and Ehrin Armstrong Rocky Mountain Regional VA Medical Center, Aurora, CO, USA

Abstract Common femoral artery atherosclerosis is a common cause of claudication and critical limb ischaemia. Surgical endarterectomy with or without patch angioplasty has been considered the gold standard for the treatment of common femoral peripheral artery disease. Endovascular intervention to the common femoral artery has gained popularity in recent years as devices and technical skills have advanced. A systematic review of the literature from 1987 to 2018 for endovascular treatment of common femoral artery disease was conducted. This article summarises the data on acute and long-term outcomes for endovascular treatment of common femoral artery disease.

Keywords Common femoral artery, peripheral artery disease, endovascular, stent, endarterectomy, outcomes Disclosure: Omar Jawaid has no disclosures to report. Ehrin Armstrong has served as a consultant for Abbott, Boston Scientific, Cardiovascular Systems, Spectranetics, and Medtronic. Received: 22 June 2018 Accepted: 31 August 2018 Citation: Vascular & Endovascular Review 2018;1(1):12–6. DOI: https://doi.org/10.15420/ver.2018.7.1 Correspondence: Ehrin Armstrong, Rocky Mountain Regional VA Medical Center Division of Cardiology, 1700 N Wheeling St, Aurora, CO 80045, USA. E: ehrin.armstrong@ucdenver.edu

Atherosclerosis of the common femoral artery (CFA) is a common cause of lifestyle-limiting claudication and, less commonly, a cause of critical limb ischaemia (CLI). Located in the femoral triangle, the CFA is the major artery supplying blood to the thigh. Prior to the inguinal ligament, the external iliac artery provides in-line flow to the CFA. After crossing the inguinal ligament, the external iliac artery becomes the CFA, which then branches into the profunda and superficial femoral artery (SFA). Surgical CFA endarterectomy (CFE), with or without patch angioplasty, has been considered the gold standard for revascularisation, based on excellent procedural success and outstanding long-term patency. Recent advances in endovascular therapies have made peripheral vascular interventions (PVI) more common for the treatment of peripheral artery disease (PAD), with the hope of reducing the need for surgical repair in selected patients. PVI is an attractive option for CFA stenosis for several reasons: PVI typically obviates the need for general anaesthesia, PVI is associated with fewer periprocedural complications and PVI requires shorter hospital stays.1–3 However, early studies of CFA PVI demonstrated inferior outcomes relative to CFE. CFA PVI endovascular procedures were plagued by early restenosis, reocclusion, and poor long-term outcomes.4 Despite these early setbacks, CFA PVI has become more common in recent years, owing to more options for endovascular therapies, operator familiarity, and an overall increased prevalence of PAD.2,5 CFA PVI with balloon angioplasty (BA), with or without adjunctive atherectomy and stent implantation, has been the subject of numerous studies. Given the emerging data in this field, the goal of this article is to summarise the current state-of-the-art techniques and their outcomes in the endovascular treatment of CFA atherosclerotic disease.

Access at: www.VERjournal.com

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Surgical Endarterectomy As a result of its superficial location, the CFA is easily accessible for surgery. A CFE can usually be completed in under a few hours, with an average hospital stay of 3–4 days.6 CFE can also be performed under local or general anaesthesia, although general anaesthesia is usually the preferred method to minimise patient discomfort.7 High rates of procedural success have been reported in the literature, approaching 95–100 %.6,7–10 CFE provides durable patency of the CFA, with a reported 5-year patency rate of 60–100 %.6–8,10 Although CFE is frequently performed, data are sparse on CFE outcomes. A periprocedural complication rate of approximately 6–10 % has been reported in published literature. 6,11 Moreover, these complications can necessitate a repeat operation during the same hospital stay in up to 10 % of patients. 6 The most common complications include infection, wound dehiscence and venous thromboembolism. However, more serious complications have also been noted including MI, cardiopulmonary arrest and stroke.11 In addition to these periprocedural complications, a 30-day mortality of 1.5 % has been reported.11 Careful patient selection is required to maximise the benefit of the procedure while minimising postprocedural complications.

Balloon Angioplasty Given the relatively high rates of infection and need for reoperation with CFE, an endovascular approach may be preferred for certain patient subgroups, especially patients with multiple comorbidities. However, the first reports of CFA PVI were discouraging. Early devices were ill-suited to the complex atherosclerotic plaque that is often present in CFA disease. In a study of 984 patients treated with percutaneous transluminal angioplasty, acute and long-term restenosis was common,

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Endovascular Treatment of Atherosclerotic Disease Table 1: Summary of the Outcomes of Common Femoral Artery Treated With Balloon Angioplasty Authors (year)

Study design

Country of study

Number of centers

Stent placement rate (indication)

Stent fracture rate (%)

Mean follow-up (months)

1-year patency (%)

1-year TLR rate

Male (%)

Silva et al. (2004)

Retrospective

Single centre

47 % (residual stenosis, dissection)

Not reported

5.0

Cotroneo et al. (2010)

Retrospective

Italy

Single centre

0.0 %

9.4

79.6

37.0

27.7

Bovini et al. (2011)

Retrospective

Germany

Single centre

321

36.9 % (residual stenosis, dissection)

Not reported

10.3

72.4

19.9

5.9

Paris et al. (2011)

Retrospective

Single centre

50 % (residual stenosis, dissection)

88.5

10.0

3.8

Maumann et al. (2011)

Retrospective

Switzerland

Single centre

26.9 % (residual stenosis)

Not reported

16.1

Not reported

23.4

5.1

Bovini et al. (2013)

Retrospective

Germany

Single centre

38.1 % (residual stenosis, dissection)

10.2

80.5

14.1

5.1

Dattilo et al. (2013)

Retrospective

Single centre

3 % (residual stenosis)

22.2

88.0

23.3

20.0

Davies et al. (2013)

Retrospective

Single centre

115

0.8 % (residual stenosis)

Not reported

23.0

16.0

de Blic et al. (2015)

Retrospective

France

Single centre

65.7 % (heavily calcified lesions, residual stenosis, dissection)

Not reported

88.0

16.0

17.1

Mehta et al. (2016)

Retrospective

Single centre

167

85.6 % (primary)

Not reported

25.8

77.2

10.7

14.9

Siracuse et al. (2016)

Retrospective

Single centre

1014

25 % (not reported)

Not reported

83.0

14.7

6.5

Bail-out indications include acute recoil, dissection, residual stenosis. Major adverse limb events include acute limb ischaemia, amputation or major surgical intervention. MALE = major adverse limb events; TLR = target lesion revascularisation.

with overall reported 1-month, 1-year, and 3-year success rates of 77.9 %, 58.5 % and 36.6 % in CFA stenosis.4 Patients with diabetes and those with more complex lesions, including multi-vessel PAD and occluded lesions, were reported to have even lower rates of success. In addition, stent placement in the CFA has historically been avoided because of concerns about fracture and difficult endovascular access at the site of stent placement, despite some observations that patency is improved with stent placement.30 Stenting of the CFA has generally been reserved as a bail-out intervention for complications including recoil, acute restenosis or dissection.12,13 These observations, along with guideline recommendations that cemented CFE as the gold standard, initially resulted in only a small minority of CFA endovascular interventions.14 However, in recent years, device innovations and operator expertise have sparked numerous investigations into CFA PVI. Studies examining CFA PVI have many limitations. CFA PVI investigations are often retrospective with relatively few patients included, indeed the largest cohort in CFA PVI studies is 1,014 patients.15 Several potential sources of bias exist as well; patients who undergo endovascular CFA PVI are often poor surgical candidates, have declined surgery or were offered PVI over surgery. These patients may have more complex atherosclerotic disease with higher rates of vascular and procedural complications. These studies should be considered hypothesisgenerating until higher quality randomised and controlled trials are performed. However, a growing body of evidence in recent years is

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beginning to demonstrate safety and efficacy in the endovascular treatment of CFA atherosclerosis. From 2004 to 2016, a total of 11 studies encompassing 1,990 patients treated with CFA PVI were identified in the literature. Table 1 summarises the key points of these studies. Major adverse limb events were defined as acute limb ischaemia, major amputation or major surgical intervention. Patients enrolled in these investigations ranged from poor surgical candidates to patients referred for PVI. These studies were analysed for procedural and patient-centred outcomes. The rates of claudication and CLI ranged from 44.4 % to 95.0 % and 5.0 % to 55.6 %, respectively. Procedural success (defined as <30 % residual stenosis) with BA was reported to be between 84 % and 100 %. Stent placement as a result of procedural complications ranged from 0 % to 50 %. Periprocedural complications including pseudoaneurysm, dissection, fistula formation, recoil and abrupt thrombosis occurred at a rate of 5.5 %–7.2 %, with most complications being self-limiting and requiring no additional interventions. However, up to 1 % of all patients required emergent surgery for bypass. One-year target lesion revascularisation (TLR) rates were reported to be between 5.0 % and 23.4 %, with up to 5.0 % of patients requiring surgical TLR.2,3,12,15–23 Longer-term outcomes are sparse, but three-year rates of freedom from TLR were reported at 57 %–86 %, with up to 12 % of patients requiring surgical intervention including bypass or amputation.3,24 Data on clinical improvement of claudication or CLI are sparse. As a surrogate measure, ankle–brachial indices (ABIs) increased between 0.23 and 0.30 points in selected studies at 1 year.12,16,19

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Peripheral Artery Disease Table 2: Outcomes of Stent Implantation in Common Femoral Artery Interventions Authors

Study design

(year)

Country

Number

of study

of centers

N (indication)

Stent

Mean

1-year in-stent

1-year

fracture

follow-up

restenosis (%)

TLR rate

Male (%)

rate (%)

(months)

Stricker et al. (2004)

Retrospective

Switzerland

Single centre

27 (primary)

3.7

18.5

7.4

11.1

Azéma et al. (2011)

Prospective

France

Single centre

36 (primary)

2.7

20.0

15.0

11.1

Bovini et al. (2011)

Retrospective

Germany

Single centre

133 (bail-out)

Not reported

10.3

20.0

13.1

Not reported

Paris et al. (2011)

Retrospective

Single centre

13 (operator preference)

15.3

7.7

Yamawaki et al. (2013)

Retrospective

Japan

Single centre

60 (operator preference)

Not reported

16.7

34.2

11.0

Linni et al. (2014)

Randomised, controlled

Austria

Single centre

40 (per protocol)

9.1

20.0

12.5

5.0

Thiney et al. (2015)

Prospective

France

Single centre

53 (primary)

4.0

6.0

Geiger et al. (2015)

Retrospective

Belgium

Dual centre

82 (primary)

Not reported

42.6

5.3

2.6

Not reported

Goueffic et al. (2017)

Randomised, controlled

France

Multicentre

56 (per protocol)

1.8

15.0

20.0

Not reported

Iwata et al. (2017)

Retrospective

Japan

Multicentre

125 (operator preference)

Not reported

27.1

Not reported

29.4

42.1

Nasr et al. (2017)

Retrospective

France

Single centre

40 (primary)

2.5

20.0

83.0 (3-year)

22.5

Drug-coated Balloon Angioplasty Because restenosis after standard BA is common, drug-coated balloons (DCB) may provide a means of increasing primary patency and freedom from TLR rates without the use of stents in CFA lesions.24 DCB treatment in the CFA provides an attractive alternative to conventional BA combined with stents. Two studies consisting of 56 patients have reported outcomes of DCB angioplasty to the CFA. The study population comprised patients with lifestyle-limiting claudication (53.8 %) and patients with CLI (46.2 %). At 1-year, TLR for all DCB treated lesions was 8.9%. Of those patients that required reintervention, surgical endarterectomy was performed in 3.5% of patients. Up to 12 % of patients treated with DCB required a major amputation. At 1-year, up to 55 % of patients treated with a DCB reported Rutherford category 1 symptoms. Bail-out stent placement was required in up to 10 % of patients.25,26 Most studies examined were single-centre, retrospective cohorts without randomisation or blinding, so there is a significant source of bias and self-selection. Although some of the reported data are encouraging, without high-quality clinical trials, these data should be interpreted as hypothesis-generating only. PVI of the CFA may be a viable alternative to surgery in the short term based on these studies but long-term data are lacking. PVI with conventional BA alone can offer a three-year TLR rate as low as 14.0 %, while DCB treated patients demonstrated a one-year TLR rate as low as 6.7 %; in both cases, TLR was most often a repeat endovascular procedure. Surgical revascularisation rates were reported to be up to 5 %. PVI periprocedural complication rates were significantly lower than with CFE, with most complications being self-limiting. More studies with larger cohorts and, ideally, randomisation or use of a pre-specified performance measure are needed to satisfactorily answer whether or not drugcoated balloon angioplasty of the CFA is an acceptable alternative to surgical endarterectomy.

VER_Armstrong_FINAL.indd 14

Stent Implantation for Common Femoral Artery Disease Concerns about vascular access, stent fracture, jailing of collateral vessels and acute stent thrombosis have all been raised as potential reasons to avoid stent implantation in the CFA. However, during PVI, the need for stents is sometimes unavoidable. As a result of suboptimal angiographic results, acute dissection, recoil or other complications of PVI, a stent usage rate of 36.9 % has been reported in a large singlecentre study.3 Successes noted in the femoropopliteal vasculature, as well as a newer generation of stents engineered to prevent stent fracture, may change practice patterns regarding CFA stenting.27–29 Stenting in the CFA is typically reserved for complications such as dissection, recoil or abrupt stenosis, so results must be viewed in the context of the indication for which stenting was employed. Universally, bare-metal stents have been studied. Studies examining a primary or secondary indication for stenting are summarised in Table 2.3,12,13,20,30–37 Only two randomised controlled trials of stenting in the CFA were found in the literature. These limitations should be considered when extrapolating outcomes from these patients. The first study to objectively research stent implantation in the CFA was performed in 25 patients in 2004.30 In a retrospective case series, these patients were followed for a mean of 30 months with a primary endpoint of primary patency. The indication for peripheral intervention was claudication (82%). Most stents were self-expanding and only one balloon expandable stent was used. Procedural success was 100 %. No stent thrombosis was noted at 30 days. At 1- and 3-year follow-up cumulative patency was 86 % and 83 %, respectively. Stent fracture was only observed in one patient, in which a balloon expanded stent was used. This case series called into question whether the accepted practice of avoiding stenting

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Endovascular Treatment of Atherosclerotic Disease in the CFA was warranted. The authors note that repeat PVI was required in two patients. Using fluoroscopy, the authors were able to access the stented vessel without damaging the stent. This suggests that stenting the CFA is both a safe and possibly viable method to maintain patency in the short and mid term.

unfounded with newer generation nitinol stents. Patency rates at 1- and 2-year intervals compare favourably to published rates of CFE as well as CFA PVI without stenting. Although randomised controlled data exist for CFA stenting, more studies with larger cohorts are needed to truly settle the question of optimal CFA revascularisation.

Two randomised controlled trials have subsequently been performed in CFA PVI with stenting. In 2014, a study using bioabsorbable stents versus CFE was performed.33 This study is unique because it is the first study in which CFA PVI was compared against CFE directly and in which a bioabsorbable stent was used rather than conventional stents. A total of 80 patients were randomised to either CFE or CFA PVI with bioabsorbable stent. Technical success was achieved in 97.5 % of PVI procedures, with 2.0 % of patients requiring surgical revascularisation for acute occlusion and 17.5 % of CFE patients experiencing a minor surgical site infection. At 1 year, primary and secondary patency rates for CFA PVI were 80 % and 84 %, respectively, while CFE reported 100 % 1-year primary and secondary patency rates. CFA PVI patients had a limb salvage rate of 88 % versus 90 % for CFE patients. The 1-year TLR rate was reported at 2.5 % in the PVI group and 7.5 % for CFEs. Notably, 15 % of bioabsorbable stents had a complication of acute occlusion requiring additional endovascular or surgical intervention.

Adjunctive Atherectomy

In 2017, a multicentre, prospective, randomised controlled trial of stenting in the CFA was performed.13 A total of 120 patients were randomised to either surgical revascularisation or PVI with stent placement. When possible, a self-expanding stent was placed. In the perioperative period 26.0 % of surgical patients had a complication; 63.0 % of these complications were delayed wound healing, although infection and haematoma were also noted. In contrast, the PVI group had a 12.5 % rate of complications. The rate of primary sustained clinical improvement (defined as claudication improved by 1 Rutherford class or resolution of chronic wounds and rest pain for CLI) was not significantly different between surgically revascularised patients and PVI patients; 76.1 % and 74.8 %, respectively. No significant difference was found in rates of TLR or primary patency at 24 months. At 24 months, only one stent fracture was identified, which did not require a repeat procedure. Conventional stenting compared favourably with CFE, while bioabsorbable stents were associated with a lower rate of success and a higher rate of TLR. It has been hypothesised that bioabsorbable stents lack the radial force necessary for displacement of highly calcified lesions, thus impairing implantation into the vessel intima. A conventional stent fracture rate of 2 % was in line with prior investigations, suggesting the concern over stent fracture may be

L ee M, Heikali D, Mustapha J, et al. Acute procedural outcomes of orbital atherectomy for the treatment of common femoral artery disease: Sub-analysis of the CONFIRM Registries. Vasc Med 2017;22(4):301–6. https://doi. org/10.1177/1358863X17708254; PMID: 28548625. Dattilo P, Tsai T, Rogers K, Casserly I. Acute and medium‐term outcomes of endovascular therapy of obstructive disease of diverse etiology of the common femoral artery. Catheter Cardiovasc Interv 2013;81(6):1013–22. https://doi.org/10.1002/ ccd.24475; PMID: 22581757. Bonvini R, Rastan A, Sixt S, et al. Endovascular treatment of common femoral artery disease: medium-term outcomes of 360 consecutive procedures. J Am Coll Cardiol 2011;58(8):792–8. https://doi.org/10.1016/j.jacc.2011.01.070; PMID: 21835313. Johnston K, Rae M, Hogg-Johnston S, et al. 5-year results of a prospective study of percutaneous transluminal angioplasty. Ann Surg 1987;206(4):403–13. https://doi. org/10.1097/00000658-198710000-00002; PMID: 2959214. Nasr B, Kaladji A, Vent P, et al. State-of-the-art treatment of common femoral artery disease. J Cardiovasc Surg (Torino)

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Atherosclerosis of the CFA is characterised by bulky, calcified plaques. Such plaques are less compliant, reducing the effectiveness of BA and increasing the risk of complications such as recoil and dissection. Debulking strategies including directional and orbital atherectomy, either as solitary therapy or combination therapy with BA and/or stenting, may provide more durable results than either therapy alone. In the literature, two studies were identified that examined atherectomy use in CFA disease totalling 333 patients. Each study enrolled patients consecutively at a single centre who were analysed in a retrospective manner. In patients with claudication, when combined with BA, adjunctive atherectomy treatment resulted in significantly higher rates of primary patency at 20 months (92.3 % compared with 72.7 % in BA alone). In patients with CLI, 16-month primary patency rates were 78.4 % in combined BA and atherectomy, compared with 68.4 % in BA alone.21 When atherectomy was used as sole therapy it was associated with a patency rate of 87.1 % versus 66.7 % with BA alone at a 4-year interval.37 Stent placement was reported to be 0 % in BA with atherectomy. Although current studies have a small sample size and may be subject to bias, atherectomy may provide an additional tool in PVI. Atherectomy has been used with good success in femoropopliteal disease, reducing the need for stent placement and improving TLR rates and patency outcomes.38,39 A tailored approached to CFA atherosclerosis involving debulking strategies when appropriate seems reasonable in the absence of high-quality clinical data that would otherwise guide decision making. CFE remains the gold standard for the treatment of symptomatic CFA atherosclerosis. However, CFE is not without risk and requires careful patient selection to avoid surgical complications. CFA PVI may offer short- and mid-term patency rates comparable with CFE, but long-term data are lacking to help guide clinical decision making. Moreover, adjunctive therapies involving stents and atherectomy may offer additive benefits in maintaining patency and preventing the need for TLR. A dearth of high-quality clinical data offers opportunities for further avenues of research into the treatment of CFA atherosclerosis. n

2015;56(2):309–16. PMID: 25644828. Ballotta E, Gruppo M, Mazzalai F, Da Giau G. Common femoral artery endarterectomy for occlusive disease: An 8-year single-center prospective study. Surgery 2010;147(2):268–74. https://doi.org/10.1016/j.surg.2009.08.004; PMID: 19828166. 7. Kang L, Patel V, Conrad M, et al. Common femoral artery occlusive disease: Contemporary results following surgical endarterectomy. J Vasc Surg 2008;48(4):872–7. https://doi. org/10.1016/j.jvs.2008.05.025; PMID: 18639427. 8. Kuma S, Tanaka K, Ohmine T, et al. Clinical Outcome of Surgical Endarterectomy for Common Femoral Artery Occlusive Disease. Circ J 2015;80(4):964–9. https://doi. org/10.1253/circj.CJ-15-1177; PMID: 26902450. 9. Nguyen B, Amdur R, Abugideiri M, et al. Postoperative complications after common femoral endarterectomy. J Vasc Surg 2015;61(6):1489–94. https://doi.org/10.1016/ j.jvs.2015.01.024; PMID: 25702917. 10. Chang R, Goodney P, Baek J, et al. Long-term results of combined common femoral endarterectomy and iliac stenting/stent grafting for occlusive disease. J Vasc Surg 6.

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2008;48(2): 362–7. https://doi.org/10.1016/j.jvs.2008.03. 042; PMID: 18572359. Siracuse J, Gill H, Schneider D, et al. Assessing the perioperative safety of common femoral endarterectomy in the endovascular era. Vasc Endovasc Surg 2014;48(1):27–33. https://doi.org/10.1177/1538574413508827; PMID: 24142958. Paris C, White C, Collins T, et al. Catheter-based therapy of common femoral artery atherosclerotic disease. Vasc Med 2011;16(2):109–12. https://doi. org/10.1177/1358863X11404280; PMID: 21511673. Gouëffic Y, Della Schiava N, Thaveau F, et al. Stenting or Surgery for De Novo Common Femoral Artery Stenosis. J Am Coll Cardiol 2017;10(13):1344–54. https://doi.org/10.1016/ j.jcin.2017.03.046; PMID: 28683941. Norgren L, Hiatt W, Dormandy J, et al. TASC II Working Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007;45:S5–67. https://doi. org/10.1016/j.jvs.2006.12.037; PMID: 17223489. Siracuse J, Van Orden K, Kalish J, et al. Vascular Quality Initiative. Endovascular treatment of the common

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femoral artery in the Vascular Quality Initiative. J Vasc Surg 2017;65(4):1039–46. https://doi.org/10.1016/j.jvs.2016.10.078; PMID: 28041804. Silva J, White C, Quintana H, et al. Percutaneous revascularization of the common femoral artery for limb ischemia. Catheter Cardiovasc Interv 2004;62(2):230–3. https://doi. org/10.1002/ccd.20035; PMID: 15170717. Cotroneo A, Iezzi R. The role of “cutting” balloon angioplasty for the treatment of short femoral bifurcation steno-obstructive disease. Cardiovasc Intervent Radiol 2010;33(5):921–8. https://doi. org/10.1007/s00270-010-9802-5; PMID: 20098989. Baumann F, Ruch M, Willenberg T, et al. Endovascular treatment of common femoral artery obstructions. J Vasc Surg 2011;53(4):1000–6. https://doi.org/10.1016/j.jvs.2010.10.076; PMID: 21215567. Bonvini R, Rastan A, Sixt S, et al. Angioplasty and provisional stent treatment of common femoral artery lesions. J Vasc Interv Radiol 2013;24(2):175–183. https://doi.org/10.1016/ j.jvir.2012.10.020; PMID: 23369554. Thiney P, Millon A, Boudjelit T, et al. Angioplasty of the common femoral artery and its bifurcation. Ann Vasc Surg 2015;29(5):960–7. https://doi.org/10.1016/j.avsg.2015.02. 001; PMID: 25765633. Mehta M, Zhou Y, Paty P, et al. Percutaneous common femoral artery interventions using angioplasty, atherectomy, and stenting. J Vasc Surg 2016;64(2):369–79. https://doi. org/10.1016/j.jvs.2016.03.418; PMID: 27763265. de Blic R, Deux J, Kobeiter H, et al. Initial Experience with Percutaneous Angioplasty of the Common Femoral Artery in De Novo Stenotic Lesions. Ann Vasc Surg 2015;29(8):1493–500. https://doi.org/10.1016/j.avsg.2015.05.002; PMID: 26151471. Davies R, Adair W, Bolia A, et al. Endovascular treatment of the common femoral artery for limb ischemia. Vasc Endovasc Surg 2013;47(8):639–44. https://doi. org/10.1177/1538574413500723; PMID: 24026878. Laird J, Schneider P, Tepe G, et al. Durability of Treatment

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Effect Using a Drug-Coated Balloon for Femoropopliteal Lesions: 24-Month Results of IN.PACT SFA. J Am Coll Cardiol 2015; 66(21):2329–38. https://doi.org/10.1016/ j.jacc.2015.09.063; PMID: 26476467. Cioppa A, Stabile E, Salemme L, et al. Combined use of directional atherectomy and drug-coated balloon for the endovascular treatment of common femoral artery disease: immediate and one-year outcomes. EuroIntervention 2017;12(14):1789–94. https://doi.org/10.4244/EIJ-D-15-00187; PMID: 28216476. Stavroulakis K, Schwindt A, Torsello G, et al. Directional Atherectomy With Antirestenotic Therapy vs Drug-Coated Balloon Angioplasty Alone for Common Femoral Artery Atherosclerotic Disease. J Endovasc Ther 2018;25(1):92–9. https://doi.org/10.1177/1526602817748319; PMID: 29251204. Dick P, Wallner H, Sabeti S, et al. Balloon angioplasty versus stenting with nitinol stents in intermediate length superficial femoral artery lesions. Catheter Cardiovasc Interv 2009;74(7):1090–5. https://doi.org/10.1002/ccd.22128; PMID: 19859954. Pastromas G, Katsanos K, Krokidis M, et al. Emerging stent and balloon technologies in the femoropopliteal arteries. Scientific World Journal 2014;2014:695402. https://doi. org/10.1155/2014/695402; PMID: 24672355. Bishu K, Armstrong E. Supera self-expanding stents for endovascular treatment of femoropopliteal disease: a review of the clinical evidence. Vasc Health Risk Manage 2015;11: 387–95. https://doi.org/10.2147/VHRM.S70229; PMID: 26203255. Stricker H, Jacomella V. Stent-assisted angioplasty at the level of the common femoral artery bifurcation: midterm outcomes. J Endovasc Ther 2004;11(3):281–6. https://doi. org/10.1583/03-1169.1; PMID: 15174914. Azéma L, Davaine J, Guyomarch B, et al. Endovascular repair of common femoral artery and concomitant arterial lesions. Eur J Vasc Endovasc Surg 2011;41(6):787–93. https://doi. org/10.1016/j.ejvs.2011.02.025; PMID: 21439857.

32. Y amawaki M, Hirano K, Nakano M, et al. Deployment of self-expandable stents for complex proximal superficial femoral artery lesions involving the femoral bifurcation with or without jailed deep femoral artery. Catheter Cardiovasc Interv 2013;81(6):1031–41. https://doi.org/10.1002/ccd.24502; PMID: 22639451. 33. Linni K, Ugurluoglu A, Hitzl W, et al. Bioabsorbable stent implantation vs. common femoral artery endarterectomy: early results of a randomized trial. J Endovasc Ther 2014;21(4): 493–502. https://doi.org/10.1583/14-4699R.1; PMID: 25101576. 34. Geiger M, Deloose K, Callaert J, Bosiers M. Is there already a place for endovascular treatment of the common femoral artery? J Cardiovasc Surg (Torino) 2015;56(1):23–9. PMID: 25366384. 35. Iwata Y, Ueshima D, Jujo K, et al. Crossover stenting across the deep femoral artery entry: a multicenter retrospective study. Cardiovasc Interv Ther 2017;[Epub ahead of print]. https:// doi.org/10.1007/s12928-017-0499-0; PMID: 29076053. 36. Nasr B, Kaladji A, Vent P, et al. Long-Term Outcomes of Common Femoral Artery Stenting. Ann Vasc Surg 2017;40: 10–18. https://doi.org/10.1016/j.avsg.2016.07.088; PMID: 27903480. 37. Guo J, Guo L, Tong Z, et al. Directional Atherectomy Is Associated with Better Long-Term Efficiency Compared with Angioplasty for Common Femoral Artery Occlusive Disease in Rutherford 2–4 Patients. Ann Vasc Surg 2017;Article In Press. https://doi.org/10.1016/j.avsg.2017.12.004; PMID: 29501593. 38. Feldman, D. Atherectomy for calcified femoropopliteal disease: Are we making progress? J Invasive Cardiol 2014;26(8):304–6. PMID: 25091094. 39. Dattilo R, Himmelstein S, Cuff R. The COMPLIANCE 360° Trial: a randomized, prospective, multicenter, pilot study comparing acute and long-term results of orbital atherectomy to balloon angioplasty for calcified femoropopliteal disease. J Invasive Cardiol 2014;26(8):355–60. PMID: 25091093.

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Peripheral Artery Disease

Stem Cell Therapy for Vascular Disorders Emad A Hussein Ain Shams University, Cairo, Egypt

Abstract Peripheral vascular disease results from narrowing of the peripheral arteries that supply oxygenated blood and nutrients to the legs and feet. This pathology causes symptoms such as intermittent claudication (pain with walking), painful ischaemic ulcerations, or even limbthreatening gangrene. It is generally believed that the vascular endothelium, a monolayer of endothelial cells (ECs) that lines the luminal surface of all blood and lymphatic vessels, plays a dominant role in vascular homeostasis and vascular regeneration. As a result, stem cell-based regeneration of the endothelium may be a promising approach for the treatment of PAD. Critical limb ischaemia (CLI) is an advanced form of peripheral artery disease which is responsible for about 100,000 amputations each year in the US. Trials to date have reported clinical improvement and reduced need for amputation in patients with CLI who receive autologous bone marrow or mobilised peripheral blood stem cells for stimulation of angiogenesis. There is no effective treatment for lower limb ischaemia caused by peripheral vascular disease and it is necessary to amputate the limb at the end stage. Therefore, the concept of effective therapeutic angiogenesis has become widely accepted during the past few years and it has emerged as a strategy to treat tissue ischaemia by promoting collateral growth using drug, gene or cell therapy. This article provides an overview of current therapeutic challenges for the treatment of critical limb ischaemia, the basic mechanisms of stem cell therapy, the most relevant clinical trials as well as future directions for translational research in this area.

Keywords Angiogenesis, limb ischaemia, peripheral vascular disease, stem cell, vascular Disclosure: The author has no disclosures to report. Received: 13 April 2018 Accepted: 2 September 2018 Citation: Vascular & Endovascular Review 2018;1(1):17–21. DOI: https://doi.org/10.15420/ver.2018.3.1. Correspondence: Emad A Hussein, Vascular Surgery Department, Ain Shams University, 1, Hussein Kamel Str, Heliopolis West 11351, Cairo, Egypt. E: emad.hussein52@hotmail.com

Cell Therapy for Peripheral Artery Disease Critical limb ischaemia (CLI) is an advanced form of peripheral artery disease, which is responsible for about 100,000 amputations per year in the US.1 A promising approach using cell therapy has recently been developed to treat intractable symptoms related to ischaemia in people with PAD in who have not responded successfully to conventional medical therapy and revascularisation. Credit goes to James Thompson at UW, Madison – who was the first to discover how to isolate and culture human embryonic stem cells (hES cells ) in 1998 (Figure 1).2

Background Peripheral vascular disease (PVD) is a growing health problem in Western societies. PVD presents itself with different degrees of severity; intermittent claudication (IC) is an early moderate manifestation and critical limb ischaemia (CLI) is a more chronic and severe problem typically involving tissue loss (Figures 2 and 3). Bypass surgery or balloon dilatation can be used, but many patients with moderateto-severe PVD cannot be helped by such interventions due to the presence of life-threatening comorbidities or the diffuse nature of underlying vascular disease.3 Furthermore, many patients with CLI do not respond to current treatments and require limb amputation.4 For patients with no other option, there is the possibility of using non-invasive, alternative revascularisation strategies that are being tested in the clinic as well as single angiogenic gene/protein and cellbased therapies. Unfortunately, the outcome of clinical trials using

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gene/protein-based therapy has been disappointing.5,6 The failure of this approach is likely to be caused by several factors, including an incomplete molecular understanding of the complex vascular growth process, the likely necessity for concurrent use of multiple angiogenic factors,7 and most of the references mentioned in the article have shown limitations and variable degrees of instability of currently used factors in treatment of no option patients suffering from CLI. Additionally, the dysfunctional endogenous vascular cells may fail to respond to these factors and administration of functional vascular cells may be needed. While transplantation with vascular stem cells may offer functional revascularisation and protection against tissue loss in patients with mild or severe forms of PVD, this therapy does not replace tissue that has already been lost. This has led to the hypothesis that treatment with multipotent stem cells that are able to generate blood vessels as well as replace lost target tissue may provide significantly more benefit for patients suffering from more severe forms of PVD, such as CLI. Several cell types, including bone marrow cells (BMCs), embryonic stem cells (ECs), mesenchymal stem cells (MSCs), skeletal myoblasts (SkMBs), umbilical cord or peripheral blood cells, adipose tissue-derived stem cells (ADSCs), and endothelial progenitor cells (EPCs), have been tested for their ability to restore blood supply and/or muscle function in ischaemic limbs.8–15 Despite encouraging results from pre-clinical and small uncontrolled clinical trials,16,17 many questions concerning stem cell-based therapy remain to be answered. The long-term efficacy and

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Peripheral Artery Disease Figure 1: Human Embryonic Stem Cells

of the transplanted cells,18 and we are unsure whether better results would be achieved with fully mature cells, with progenitors committed to a certain cell type, or with immature non-committed stem cells that have the capacity to differentiate into vascular and non-vascular tissue cells. Pre-clinical studies have suggested that in contrast to EPCs, terminally differentiated ECs do not improve revascularisation.10,19 The challenge of addressing these issues is further increased by the likelihood that results from studies with animal cells may not necessarily be extrapolated to those with human cells.

From Research to Practice

Figure 2: X-ray Showing Extensive Damage Caused by Peripheral Vascular Disease

The understanding of the mechanism of neovascularisation in adults has continued to evolve over the years. Previously, the process was thought to occur solely through angiogenesis (the sprouting of new vessels from pre-existing ones); but there has been a paradigm shift after the concept of vasculogenesis came to be redefined with the discovery of bone marrow-derived progenitor cells. Vasculogenesis is the de novo development of new vessels from endothelial cells with eventual transformation to mature endothelial cells, vascular smooth muscle cells and pericytes.20,21

Current Status and Clinical Trials The therapeutic use of progenitor cells poses certain unique questions for clinical trial design. In addition to the usual experimental variables that would be considered for a pharmaceutical agent, such as the dose of the drug, the patient population, and the end points, cardiovascular cell therapy studies must consider many additional variables, including the source of stem/progenitor cells, the method of obtaining cells, cell processing protocols, the selection of cell subtypes, the route of cell delivery, and whether a single dose or multiple dose regimen will be tested. In addition, as a biological therapy, extensive quality control measures must be in place to ensure safety and to evaluate the impact of cell phenotype on efficacy.

Figure 3: External Presentation of Peripheral Vascular Disease

safety of this approach has not been fully evaluated and some grafts may contain cells that are harmful to already-compromised tissue. It has not yet been determined whether cells that can also regenerate the ischaemic tissue aside from vascular restoration are superior to cells able to aid only in revascularisation and whether these cells are effective in both moderate and more severe forms of PVD. There is also little information as to the importance of the differentiation status

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Walter et al. report the results of the randomised, double-blind, placebo-controlled intraarterial progenitor cell transplantation of BM mononuclear cells (BM-MNCs) for induction of neovascularization in patients with peripheral arterial occlusive disease (PROVASA) study.22 In this study, 40 patients were randomised in a 1:1 fashion to intraarterial delivery of either BM-MNCs or placebo. The PROVASA study used an innovative randomised-start clinical trial design. After initial randomisation and treatment with either BM-MNCs or placebo, patients were followed for 3 months. At this point, placebo-treated patients crossed over to active treatment and active-treated patients received a second treatment of BM-MNCs. This unique protocol allowed the PROVASA investigators to determine whether repeated treatments of autologous cell therapy may be beneficial compared with a single treatment. This is important because randomised trials of cardiovascular cell therapy to date have primarily used a single administration of cells and there is evidence that a single administration may have a limited effect. The PROVASA study failed to meet its primary end point of a change in ankle brachial index (ABI) and the authors believe that change in ABI was a poor selection as a primary end point because they did not find a correlation between change in ABI and improvement in ulcer healing or improvement in rest pain. This same divergence between surrogate end points like ABI or transcutaneous oximetry and hard clinical end points has been noted in other CLI

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Stem Cell Therapy for Vascular Disorders Table 1: Summary of Published Data of the Most Relevant Clinical Trials on Mesenchymal Stem Cell-Based Therapy for Critical Limb Ischaemia Reference

Treatment

MSC recipients

Outcomes

• I ntramuscular administration of allogeneic UCBMSCs into proximal and around the necrotic lesions (1 × 106 cells per lesion) • Two patients received repeated UCB-MSCs about 1 year apart. • One patient received BM-MSCs 6 months before UCB-MSC administration.

4 patients with Buerger’s disease

• I ncreased collateral branches and vascularities in foot based on angiography • Resolution of rest pain as early as 5 hours after initial treatment • Complete healing of necrotic lesion within 120 days

Intramuscular and topical autologous BM-MSCs (>1 × 106 cells/cm2 of ulcer area)

9 patients with Buerger’s disease

Angiographically selected sites in soleus and gastrocnemius, popliteal fossa and ulcer area. Also around the diabetic foot ulcer.

3 patients with diabetic foot ulcers

At 12 weeks as compared with baseline: • Pain relief • Reduction in ulcer size • I ncreased pain-free walking distance: 38.33±17.86m to 284.44±212.12m (P<0.001)

Guiducci et al., 201032

Three intravenous administrations of autologous BM-MSCs: • Baseline: 0.9 × 106 cells/Kg cryopreserved cells at passage 1 • Month 1: 0.8 × 106 cells/Kg: culture-expanded at passage 2 • Month 2: 0.8 × 106 cells/Kg: culture-expanded at passage 2

1 patient with systemic sclerosis

At 2 months compared with baseline: • Reduction in skin necrosis • Formation of new vessel network and improved blood flow in both the upper and lower limbs based on angiography

Lu et al., 201133

Group A: Ipsilateral limb received a total of 9.3±1.1 × 108 BM-MSCs and contralateral limb received N/S (n=18)

Type 2 diabetes with foot ulcer, Fontaine IV (n=18)

At 24 weeks as compared with baseline (BM-MSCs versus BM-MNCs): • Improved in rest pain • Improved in pain-free walking time • Improved ABI • Improved TcO2 • Increased collateral vessels based on MRA • Improved ulcer healing rate • Reduced limb amputation

Diabetes, Fontaine IIbIV (n=10)

At 10±2 months as compared with baseline: • Improved ABI as early as 1 month after infusion • Improved walking time

Kim et al., 2006

Dash et al., 200931

Group B: Ipsilateral limb received a total of 9.6±1.1 × 108 BM-MNCs and contralateral limb received N/S (n=19) 20 intramuscular injections administered at the foot ulcer and surrounding areas (3 × 3cm intervals) Lasala et al., 201034

Ipsilateral limb received a total of 30 × 106 autologous BM-MSCs and 30 × 108 autologous BM-MNCs and contralateral limb received PBS and 5 % human serum albumin

At 6 months as compared with baseline: • I mproved quality of life (pain relief and physical functioning) • I mproved new collateral vessel formation based on digital subtraction angiography • I mproved limb perfusion based on 99mTc-TF perfusion scintigraphy

40 intramuscular injections administered at the most hypoperfused areas of the gastrocnemius (based on digital angiography)

Lasala et al., 201135

Group A: Ipsilateral limb received a total of 9 × 106 autologous BM-MSCs and 9 × 108 autologous BM-MNCs and contralateral limb received PBS + 5 % human serum albumin (n=12)

Diabetes, CLI Rutherford 4–6 (n=26)

At 4 months as compared with baseline: • Improved ABI (n=21) in the index leg • Improved pain-free walking time as early as 2 weeks • Improved quality of life (pain relief and improvement of physical functioning) • Improved limb perfusion • Complete healing of chronic ischaemic ulcers

Buerger’s disease, CLI Rutherford 2–4 to 3–6 (n=12)

At 6 months as compared with baseline: • Improved pain score • Improved claudication walking distance • Improved maximal walking distance (not statistically significant) • No change in ABI • Improved in temperature colour change using thermography • Improved in collateral vessel formation using digital subtraction angiography • Improved wound healing and clinical symptoms

Group B: Ipsilateral limb received a total of 18 × 106 autologous BM-MSCs and 18 × 108 autologous BM-MNCs and contralateral limb received PBS with 5 % human serum albumin (n=14) 40 intramuscular injections administered at the most hypoperfused areas of the gastrocnemius (based on digital angiography) Lee et al., 201236

Ipsilateral limb received a total of 3 × 108 autologous AT-MSCs 60 intramuscular injections to lower limb (5 × 106 AT-MSCs each)

Diabetic foot, CLI Rutherford 3–5 to 3–6 (n=3)

ABI = ankle–brachial index; AT-MSC = adipose tissue-derived mesenchymal stem cell; BM-MNC = bone marrow mononuclear cell; BM-MSC = bone marrow-derived mesenchymal stem cell; DM = diabetes mellitus; M/B = muscle-to-brain ratio; MRA = magnetic resonance angiography; MSC = mesenchymal stem cell; N/S = not significant; PBS = phosphate-buffered saline; TcO2 = total carbon dioxide; UCB-MSC = umbilical cord blood-derived mesenchymal stem cell.

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Peripheral Artery Disease studies and remains a major challenge in designing phase II studies for this condition.23 ºOther phase I/II human clinical trials have been conducted, based on the evidence from animal studies demonstrating positive outcomes of stem and progenitor cell therapy in models of ischaemia.24,25 The author’s pilot study using autologous bone marrow mononuclear cells to be directly injected in ischaemic calf muscles did not show consistent efficacy.26 Globally, stem cell therapies in peripheral atherosclerotic occlusive disease clinical trials during the past decade have shown wide discrepancies concerning stem cell source, mode of delivery and outcomes.27,28 This is equally true in similar trials addressing coronary ischaemia.29 Table 1 shows results of the most relevant published clinical trials of stem cell therapies for CLI resulting from various vascular disorders of the lower limb.30–36 It has been shown that adipose tissue-derived MSC (ATMSC) have similar characteristics to bone marrow stromal cells (BMSC). They can differentiate into endothelial cells and have a proangiogenic effect in the hind limb ischaemia model.37,38 In a small phase I pilot study for the determination of safety and effects of ATMSC transplantation in patients with CLI, Lee et al. could not exclude the possibility that the use of immunocompetent allogeneic cells exhibiting normal functions might provide better therapeutic efficacy for CLI treatment in patients with diabetes.39 It was demonstrated that multiple intramuscular ATMSC injections might be a safe alternative to achieve therapeutic angiogenesis in patients with CLI who are refractory to other treatment modalities.

Future Directions in Stem Cell Therapy for Critical Limb Ischaemia MSCs have been shown to be effective in multiple reports in pre-clinical models of CLI. In addition, there is a substantial amount

urphy MP, Wang H, Patel AN, et al. Allogeneic endometrial M regenerative cells: an “Off the shelf solution” for critical limb ischemia? J Transl Med 2008;6:45. DOI: https://doi.org/10.1186/1479-5876-6-45; PMID: 18713449. Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived from human blastocysts. Science 1998;282(5391):1145-7. DOI: https://doi.org/10.1126/ science.282.5391.1145; PMID: 9804556. Collinson DJ, Donnelly R. Therapeutic angiogenesis in peripheral arterial disease: can biotechnology produce an effective collateral circulation? Eur J Vasc Endovasc Surg 2004;28:9–23. DOI: https://doi.org/10.1016/j.ejvs.2004.03. 021; PMID: 15177227. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg 2007;45(Suppl):S5–S67. DOI: https://doi. org/10.1016/j.jvs.2006.12.037; PMID: 17223489. Makinen K, Manninen H, Hedman M, et al. Increased vascularity detected by digital subtraction angiography after VEGF gene transfer to human lower limb artery: a randomized, placebo-controlled, double-blinded phase II study. Mol Ther 2002;6:127–33. DOI: https://doi.org/10.1006/ mthe.2002.0638; PMID: 12095313. Rajagopalan S, Mohler ER, Lederman RJ, et al. Regional angiogenesis with vascular endothelial growth factor in peripheral arterial disease: a phase II randomized, doubleblind, controlled study of adenoviral delivery of vascular endothelial growth factor 121 in patients with disabling intermittent claudication. Circulation 2003;108:1933–8. DOI: https://doi.org/10.1161/01.CIR.0000093398.16124.29; PMID: 14504183. Jeon O, Kang SW, Lim HW, et al. Synergistic effect of sustained delivery of basic fibroblast growth factor and bone marrow mononuclear cell transplantation on angiogenesis in mouse ischemic limbs. Biomaterials 2006;27:1617–25. DOI: https://doi.org/10.1016/ j.biomaterials.2005.09.009; PMID: 16174524. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997;275:964–7. DOI: https://doi.org/10.1126/

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16.

of evidence on the safety of MSC administration in humans. So far, there has been no evidence of toxicity in terms of either aberrant differentiation or tumour genesis noted in human studies. Larger studies with longer follow-up will be required to confirm its safety. The published human data reviewed in this article have involved small numbers of patients with relatively short follow-up periods. Since CLI represents the most severe form of PAD, it may also reduce the likelihood of demonstrating efficacy given the severity of the disorder. Patients with CLI are the easiest group to obtain ethical approval for trials given that they have no alternative revascularization option. Once additional safety data are collected, it may be reasonable to progress to studies involving patients with intermittent claudication who represent the majority of patients with PAD and in whom therapeutic efficacy may be easier to demonstrate. This review did not focus on good manufacturing practice (GMP) in the production of cells or issues surrounding the need to scale up manufacture to generate a therapeutic product with predictable efficacy. The challenge remains to undertake clinical trials that progress from phase 1 to 3 while using cells manufactured under GMP conditions. The issue of whether to use autologous or allogeneic ‘off the shelf’ cells will also need to be addressed. In fact, after local injection of many kinds of stem cells in ischaemic areas of the lower limbs, as shown in the above-mentioned studies, a large proportion of the cell population either die or fail to mature into vascular endothelial cells. Porat et al. postulated that alternatively activated dendritic cells (DCs) can promote the generation of EPC-enriched stem cells within a 1-day culture.40 It is still unknown whether induced pluripotent cells (IPCs) are the most likely area toresearch. Isolation, purification as well as commercial preparation of some intracellular angiogenic factors such as vascular endothelial growth factor (VEGF) is another area of great interest that may add further insights to future research targeting nonreconstructible limb ischaemia. n

science.275.5302.964; PMID: 9020076. Ikenaga S, Hamano K, Nishida M, et al. Autologous bone marrow implantation induced angiogenesis and improved deteriorated exercise capacity in a rat ischemic hindlimb model. J Surg Res 2001;96:277–83. DOI: https://doi.org/10.1006/ jsre.2000.6080; PMID: 11266284. Kinnaird T, Stabile E, Burnett MS, et al. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation 2004;109:1543–9. DOI: https://doi.org/10.1161/01.CIR.0000124062.31102.57; PMID: 15023891. Kupatt C, Horstkotte J, Vlastos GA, et al. Embryonic endothelial progenitor cells expressing a broad range of proangiogenic and remodeling factors enhance vascularization and tissue recovery in acute and chronic ischemia. FASEB J 2005;19:1576–8. DOI: https://doi. org/10.1096/fj.04-3282fje; PMID: 16009705. Madeddu P. Emanueli C, Pelosi E, et al. Transplantation of low dose CD34+KDR+ cells promotes vascular and muscular regeneration in ischemic limbs. FASEB J 2004; 18:1737–9. DOI: https://doi.org/10.1096/fj.04-2192fje; PMID: 15345695. Nakagami H, Maeda K, Morishita R, et al. Novel autologous cell therapy in ischemic limb disease through growth factor secretion by cultured adipose tissue-derived stromal cells. Arterioscler Thromb Vasc Biol 2005;25:2542–7. DOI: https://doi. org/10.1161/01.ATV.0000190701.92007.6d; PMID: 16224047. Niagara MI, Haider HKH, Ye L, et al. Autologous skeletal myoblasts transduced with a new adenoviral bicistronic vector for treatment of hind limb ischemia. J Vasc Surg 2004;40:774–85. DOI: https://doi.org/10.1016/j.jvs.2004.07. 027; PMID: 15472608. Pesce M, Orlandi A, Iachininoto MG, et al. Myoendothelial differentiation of human umbilical cord blood-derived stem cells in ischemic limb tissues. Circ Res 2003;93:e51–62. DOI: https://doi.org/10.1161/01.RES.0000090624.04507.45; PMID: 12919944. Dimmeler S, Zeiher AM, Schneider MD. Unchain my heart: the scientific foundations of cardiac repair. J Clin Invest 2005;115:572–83. DOI: https://doi.org/10.1172/JCI200524283;

PMID: 15765139. 17. E mmerich J. Current state and perspective on medical treatment of critical leg ischemia: gene and cell therapy. Int J Low Extrem Wounds 2005;4:234–41. DOI: https://doi. org/10.1177/1534734605283538; PMID: 16286375. 18. Heng BC, Cao T, Haider HK, et al. Utilizing stem cells for myocardial repair – to differentiate or not to differentiate prior to transplantation. Scand Cardiovasc 2005;39:131–4. DOI: https://doi.org/10.1080/14017430510009023; PMID: 16146974. 19. Urbich C, Heeschen C, Aicher A, et al. Cathepsin L is required for endothelial progenitor cell-induced neovascularization. Nat Med 2005;11:206–13. DOI: https://doi.org/10.1038/nm1182; PMID: 15665831. 20. Rey S, Semenza GL. Hypoxia-inducible factor-1-dependent mechanism of vascularization and vascular remodelling. Cardiovasc Res 2010;86:236–42. DOI: https://doi.org/10.1093/ cvr/cvq045; PMID: 20164116. 21. Yamagushi J, Kusano KF, Masuo O, et al. Stromal cellderived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation 2003;107:1322–8. DOI: https://doi.org/10.1161/01. CIR.0000055313.77510.22; PMID: 12628955. 22. Walter DH, Krankenberg H, Balzer JO, et al. Intraarterial administration of bone marrow mononuclear cells in patients with critical limb ischemia: a randomized-start, placebo-controlled pilot trial (PROVASA). Circ Cardiovas Interv 2011;4:26–37. DOI: https://doi.org/10.1161/ CIRCINTERVENTIONS.110.958348; PMID: 21205939. 23. Tongers J, Roncalli JG, Losordo DW. Therapeutic angiogenesis for critical limb ischemia: microvascular therapies coming of age. Circulation 2008;118:9–16. DOI: https://doi.org/10.1161/ CIRCULATIONAHA.108.784371; PMID: 18591450. 24. Kawamoto A, Katayame M, Hande N, et al. Intramuscular transplantation of G-CSF-mobilized CD34 (4) cells in patients with critical limb ischemia: a phase I/II a multicenter, single-blinded, dose escalation clinical trial. Stem Cells 2009;27:2857–64. DOI: https://doi.org/10.1002/stem.207; PMID: 19711453. 25. Ouma GO, Zafrir B, Emile K, et al. Therapeutic angiogenesis in critical limb ischemia. Angiology 2013;64:466–80. DOI: https://

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Stem Cell Therapy for Vascular Disorders doi.org/10.1177/0003319712464514; PMID: 23129733. 26. H ussein E, Sabbour A, Wahba R. Treatment with autologous bone marrow mononuclear cells in patients with non reconstructible critical lower limb ischemia. Ain Shams J Surg 2011;4:435–8. 27. Gremmels H, Teraa M, Quax PH, et al. Neovascularization capacity of mesenchymal stromal cells from critical limb ischemia patients is equivalent to healthy controls. Mol Ther 2014;10:161. DOI: https://doi.org/10.1038/mt.2014.161; PMID: 25174586. 28. Trouson A, McDonald C. Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell 2015;17:11–22. DOI: https://doi.org/10.1016/j.stem.2015.06.007; PMID: 26140604. 29. Vogel R, Hussein EA, Mousa SA. Stem cells in the management of heart failure – what have we learned from clinical trials? Expert Rev Cardiovasc Ther 2015;13:75–83. 30. Kim SW, Han H, Chae GT, et al. Successful stem cell therapy using umbilical cord blood-derived multipotent stem cells for Buerger’s disease and ischemic limb disease animal model. Stem Cells 2006;24:1620–6. DOI: https://doi.org/10.1634/ stemcells.2005-0365; PMID: 16497946. 31. Dash NR, Dash SN, Routray P, et al. Targeting nonhealing ulcers of lower extremity in human through autologous bone

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marrow-derived mesenchymal stem cells. Rejuvenation Res 2009;12:359–66. DOI: https://doi.org/10.1089/rej.2009.0872; PMID: 19929258. Guiducci S, Porta F, Saccardi R, et al. Autologous mesenchymal stem cells foster revascularization of ischemic limbs in systemic sclerosis: a case report. Ann Intern Med 2010;153:650–4; DOI: https://doi.org/10.7326/0003-4819-15310-201011160-00007; PMID: 21079220. Lasala GP, Silva JA, Gardner PA, Minguell JJ. Combination stem cell therapy for the treatment of severe limb ischemia: safety and efficacy analysis. Angiology 2010;61:551–6. DOI: https://doi. org/10.1177/0003319710364213; PMID: 20498146. Lasala GP, Silva JA, Minguell JJ. Therapeutic angiogenesis in patients with severe limb ischemia by transplantation of a combination stem cell product. J Thorac Cardiovasc Surg 2012;144:377–82. DOI: https://doi.org/10.1016/j. jtcvs.2011.08.053; PMID: 22079876. Lu D, Chen B, Liang Z, et al. Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial. Diabetes Res Clin Pract 2011;92:26–36. DOI: https://doi. org/10.1016/j.diabres.2010.12.010; PMID: 21216483.

36. L ee HC, An SG, Lee HW, et al. Safety and effect of adipose tissue-derived stem cell implantation in patients with critical limb ischemia. Circ J 2012;76:1750–60. DOI: https://doi. org/10.1253/circj.CJ-11-1135; PMID: 22498564. 37. Kim SJ, Cho HH, Kim YJ, et al. Human adipose stromal cells expanded in human serum promote engraftment of human peripheral blood hematopoietic stem cells in NOD/SCID mice. Biochem Biophys Res Commun 2005;1:25–31. DOI: https://doi. org/10.1016/j.bbrc.2005.01.092; PMID: 15721268. 38. Lee RH, Kim B, Choi I, et al. Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue. Cell Physiol Biochem 2004;14:311–24. DOI: https://doi.org/10.1159/000080341; PMID:15319535. 39. Lee HC, An SG, Lee HW, et al. Safety and effect of adipose tissue-derived stem cell implantation in patients with critical limb ischemia – a pilot study. Circ J 2012;76:1750–60. DOI: https://doi.org/10.1253/circj.CJ-11-1135; PMID: 22498564. 40. Porat Y, Assa-Kunik E, Belkin M, et al. A novel potential therapy for vascular diseases: blood-derived stem/progenitor cells specifically activated by dendritic cells. Diabetes Metab Res Rev 2014;30:623–34; DOI: https://doi.org/10.1002/dmrr.2543; PMID: 24638886.

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Surgical Techniques

Lessons Learned After 366 Thermoablated Veins Alexandre Campos Moraes Amato 1,2 , Ricardo Virgínio dos Santos 1,2 , Daniel Augusto Benitti 3 , Dumitriu Zunino Saucedo 2 and Salvador José de Toledo Arruda Amato 2 1. Santo Amaro University (UNISA), São Paulo, Brazil; 2. Amato - Advanced Medical Institute, São Paulo, Brazil; 3. Valens Medical Center, Campinas, Brazil

Abstract In the past few years, advances in surgical techniques have improved outcomes in varicose veins treatment. The aim of this retrospective study was to determine whether the use of laser and different parameters influenced morbidity rates and the learning curve for all technology improvements during the period. From 2009 to 2018 we performed 366 vein procedures using endovenous laser technique for varicose veins. During this period, negative outcomes diminished with adoption of new strategies and skills. Laser wavelength, radial fibre, ultrasound guidance, anaesthetic intumescence, laser power and energy, and hospital setting were changed during the evaluation period. Laser technology requires many parameter adjustments, there is an understandable steeper learning curve at first. The use of new strategies and improved procedure steps allowed us to achieve a significant improvement in morbidity rates in the group of patients operated on using the 1,470 nm laser and in later quintiles.

Keywords Venous disease, endovenous laser therapy, endovenous ablation, saphenous vein, thermal ablation, varicose veins Disclosure: THe authors have nothing to disclose. Received: 1 September 2018 Accepted: 3 September 2018 Citation: Vascular & Endovascular Review 2018;1(1):22–6. DOI: https://doi.org/10.15420/ver.2018.13.1 Correspondence: Alexandre Campos Moraes Amato, Amato – Instituto de Medicina Avançada, Brazil Av Brasil, 2283, São Paulo, Brazil, Zip Code 01431-001. E: alexandre@amato.com.br; www.vascular.pro

Varicose veins are enlarged and tortuous veins that are often easily visible.1 They are part of the chronic venous insufficiency syndrome2 and are associated with complications such as oedema, skin pigmentation, lower-limb ulcers, thrombophlebitis and bleeding.3 The treatment of symptomatic varicose veins results in significant improvements in quality of life and has been shown to be cost effective.4,5 In recent years, the standard approach to treating saphenous vein insufficiency has been changing to the use of less-invasive techniques such as sclerotherapy, radiofrequency or endovenous laser ablation (EVLA) in suitable patients.6,7 Laser and radiofrequency ablation are currently well-established endovenous treatments.4 In the last decade, the use of EVLA has increased in popularity, with short- and mediumterm results comparable to, and in some reports superior to, traditional surgery.8 Furthermore, in the past decade, many small improvements in technical procedure have been shown to influence outcomes. While radiofrequency does not have many parameters for adjustment, EVLA technique has many intraoperative adjustments that can change outcomes.9 Compared with radiofrequency and other techniques, EVLA has more variables to be fine-tuned to achieve better results. Almost all studies that have been published on EVLA show high success rates (>90 %), independently of laser wavelength,10 but failed to assess evolution of procedural changes. In the last few years, advances in surgical techniques have improved outcomes in laser treatment. EVLA causes venous closure by inducing endothelial injury, which results in thrombosis, fibrosis and luminal occlusion,11 all of which can cause postoperative symptoms such as pain, inflammation, paresthesia, thrombophlebitis and thrombosis. Thermal damage to peripheral nerves is a known complication of EVLA of the small and great saphenous vein.12

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Currently, the method proposed by most of the published papers in this area uses tumescent ultrasound-guided peri-venous anaesthesia, because it is done in ambulatory care, which has the advantages of collapsing the treated vein during laser fire and protecting the adjacent tissue from burning. However, reaching this definition took a long time and numerous studies. When evaluating such outcomes in institutions that have only recently begun to systematically treat this condition, particular attention should be paid to the learning curve and to the constant updating of methods in accordance with the newest surgical strategies. In this study we offer an analysis of the cases we have treated, together with a description of the evolution of our therapeutic approach as our experience in the treatment of varicose veins and venous insufficiency has increased.

Objective We sought to evaluate the usage of laser for treatment of venous insufficiency using EVLA and fine-tuning of its parameters. The aims of this study were to compare efficacy, early postoperative morbidity rates and patient comfort associated with the use of two laser wavelengths and to define improvements in treatment strategy that enhanced outcomes, such as fibre types and use of tumescence or not in treatment of saphenous vein incompetence resulting in varicosities of the lower limb.

Methods We undertook a retrospective review of a service database to assess the efficacy of different wavelengths and protocols for EVLA for treatment of saphenous vein insufficiency and perforators.

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Lessons Learned After 366 Thermoablated Veins All consecutive patients with saphenous vein insufficiency treated by our staff during the revision period were considered for the study. Only those who formally agreed to undergo EVLA and signed informed consent were included in the study. Between 2009 and 2018, thermoablations using endovenous laser were performed in 366 veins from 245 patients by the same surgical team. The mean age was 48.2 years (range 18–82 years), and there were 66.9% (n=164) female participants. Inclusion criteria was patients undergoing laser ablation for great saphenous vein small saphenous vein (SSV) and perforators. Previous to February 2012, all venous ablations were performed using the 980 nm laser (group I). Subsequent to February 2012, ablations were performed using the 1,470 nm laser (group II). The primary outcome was the vein occlusion confirmed by ultrasound. Secondary outcomes included procedure-site complications, such as thrombophlebitis, ecchymosis/haematomas, paresthesia, long-term paresthesia, postoperative pain, inflammation, hyperchromia, occlusion rate and deep vein thrombosis.

Surgical Technique All group I EVLA procedures were performed using 980 nm wavelength diode laser (Synus Laser) in the continuous mode at 12 W of power with a linear endovenous energy density (LEED) of 80 J/cm (calculated postoperatively). Tumescent perivenous infusion of cold saline solution was initially not ultrasound guided. A bare-tip 600 mm laser fibre was inserted through the 4F sheath. The tip of the laser fibre was positioned 1–2 cm below the saphenofemoral junction without ultrasound guidance, but confirmed by direct visualisation of the red-aiming beam through the skin and being 5 cm below inguinal line. Laser energy was applied using the laser’s continuous mode and a constant pullback with the aim to achieve 80 J cm LEED. Catheter pullback at a rate of 2–3 cm/min was not monitored. First cases did not have ultrasound monitoring, but after the initial attempt it was clear that ultrasound guidance was required and was then included in the technique. Group II used 1,470 nm wavelength laser (Innova Touch Duo, Orlight Laser) in continuous mode at 5 W (later 7W) of power with 80 J/cm LEED. A 6F sheath was placed over the guidewire and a radial Saturn/Biolitec fibre was advanced under ultrasound guidance to the saphenofemoral junction, and then withdrawn to just distal to the orifice of the superficial epigastric vein. No tumescent infusion was performed at first, but partial and total tumescence was later included. The surgical technique for group II employed has been fully described elsewhere.3 Variables in EVLA treatment include laser wavelength, laser power, fibre pullback speed, fibre type, tumescence, inpatient/ outpatient facility and anaesthesia technique. The patients of the first 196 veins treated were exclusively given with spinal and general anaesthesia; they underwent the EVLA procedure under intravenous sedation with oxygen supplementation and spinal anaesthesia in hospital care at first. Procedures initiated by an ultrasound-guided percutaneous access at calf level with the patient in a reverse Trendelenburg position and a tourniquet to maximise vein diameter. After the first 196 cases, local anaesthesia with sedation was introduced. In both groups, after removing the fibre, closure of the vein was confirmed by ultrasound and deep veins were accessed for thrombosis evaluation. Concomitant phlebectomies were performed in both groups as needed and an eccentric compression bandage was applied

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over the course of the treated vein for 24 h in the first half of cases, and surgical 35 mmHg socking (Struva 35, Medi) in the second-half cases. Betamethasone injection was applied after the initial 20 cases. Patients then wore graduated compression stockings (20–30 mmHg, thigh-high) during the following 1 month during the day. Prophylactic low-molecular-weight heparin was not routinely used in either group, only for high-risk patients. Patients were advised to walk regularly during recovery from treatment and non-steroidal antiinflammatory drugs were prescribed for pain relief. At 3–7 days, postprocedural duplex ultrasound was performed to assess the status of vein occlusion and thrombosis. Saphenous veins were isolated to assess results of vein ablation, and deep veins were studied for presence of thrombosis.

Current Technique Venous access is usually obtained under ultrasound guidance by puncturing the vein with 16G or 18G needles or 6F sheath introducers at the distal point of reflux, often the medium third of calf.13 The next important step in the EVLA procedure is positioning the tip of the laser fibre 2–3 cm distally from the saphenofemoral junction (SFJ), using ultrasound guidance. In case of treatment of an SSV, the fibre tip is usually propagated towards the popliteal vein as long as the SSV still remains at the immediate subfascial level. Depending on the length of the treated vein, about 250–500 mL of tumescent local anaesthesia (TLA) is injected perivenously under ultrasound guidance. TLA usually contains 1 mg epinephrine, sodium bicarbonate, and 500–700 mg lidocaine or half lidocaine and half bupivacaine per 1000 mL saline solution. We introduced a mechanical infusion pump recently, which is highly recommended. TLA is warranted because it reduces pain, cools perivenous tissue and decreases the venous diameter.3,10 Moreover, it provides anaesthesia for several hours after the intervention and allows early discharge. A precooled TLA may enhance the analgesic effect14 and we also use external compression with ice. Before releasing laser energy, patient position is changed to Trendelenburg for diminishing even more vein diameter and avoiding bubble embolisation. During the release of laser energy, the laser fibre is pulled back centimetre by centimetre for achieving a 60–100 J/cm LEED, using a previously described method for precise LEED calculation,3,10 depending on its diameter and distance from nerves. Initial ablation requires higher energy. LEED consists of power x time/ distance, or W x s/cm. Measuring LEED, although imperfect, takes in four important variables of laser treatment: power, time, distance and, consequently, energy. As wavelength is fixed, this amounts to control over five of the variables in the procedure9. An endovenous fluence equivalent of at least 25 J/cm2 is recommended to achieve a sustained occlusion15 and it is calculated by dividing LEED by the vein circumference in cm.

Follow-up Patients were scheduled for clinical and ultrasound assessments at 7 and 30 days after EVLA. Ultrasound was used to confirm EVLA failures and occlusion rate during the follow-up period. Clinical failures were defined as the finding of measurable venous reflux in the treated segment, with or without recurrent varices, either clinically symptomatic or asymptomatic. All clinical and ultrasound examinations were carried out by medical doctors, in a standardised fashion. To assess the incidence of

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Surgical Techniques Table 1: Comparison of the Sociodemographic and Classification Data for the Two Groups of Participants Laser

Mean age (years)

Gender

CEAP

Female

Male

980

46.1

61.9 %

38.1 %

42.9 %

14.3 %

0 %

4.8 %

1,470

48.6

68.8 %

31.3 %

10.6 %

60.1 %

24.0 %

1.9 %

3.4 %

Gender chi-square, p=0.254 age chi-square, p=0.170. CEAP = Clinical, Aetiology, Anatomy, Pathophysiology.

Table 2: Outcomes by Laser Wavelength Group (Chi-square) Outcome

Paresthesia

Mean incidence (SD), %

P value

Group I (980 nm)

Group II (1470 nm)

17.9 (±3.3)

12.0 (±3.3)

0.328

2.3 (±1.7)

0.451

Long-term paresthesia Thrombophlebitis

3.6 (±1.2)

1.0 (±1.2)

0.222

Postoperative pain

32.1 (±2.6)

4.2 (±2.6)

<0.001

Inflammation

25.0 (±3.6)

1.9 (±3.6)

<0.001

2.9 (±1.7)

0.391

97.7 (±1.8)

0.001

1.3 (±1.2)

0.571

9.4 (±3.3)

<0.001

Hyperchromia/pigmentation Occlusion rate

85.7 (±1.8)

Deep vein thrombosis Ecchymosis

50 (±3.3)

SD = standard deviation.

clinical failures, both the side effects of EVLA (i.e. paresthesia, varicophlebitis, pigmentation, etc.) and the evolution of symptoms or signs affecting the patients before the procedure (i.e. heaviness, edema, skin changes, presence of visible varices, etc.) were systematically recorded at each follow-up visit, as applicable. Ultrasound assessments were performed by an experienced vascular physician, employing an Accuson X300 ultrasound machine (Siemens), equipped with 7.5- to 10.0-MHz linear probes. Testing was carried out in orthostatism, following a standardised protocol. First, the saphenous junction competence was assessed, defined as absence of venous reflux, or presence of venous reflux lasting for <1 second after Valsalva or augmentation (i.e. muscle squeezing) manoeuvres. Second, the saphenous trunk patency was assessed. If, despite EVLA, the trunk was still patent, then its diameter was recorded, and venous reflux, if present, evaluated with Valsalva and augmentation manoeuvres. Finally, varicose veins were evaluated to distinguish between residual or recurrent varicose veins, the latter defined as refluxing varices fed by an unsuccessfully treated venous segment.

(ANOVA) and Pearson correlation test. Multivariate statistical analysis of data was conducted using Excel (Microsoft) and Wizard 1.9.20 (Evan Miller) programs. Characteristics recorded as quantitative data were expressed as means, with standard deviations and ranges16 (p<0.05 was considered statistically significant).

Results Laser thermoablations were performed on a total of 366 veins among group I (n=28) and group II (n=312), and one case of a 1,940 nm laser. Patient demographics were similar between the two groups (Table 1). The incidences of postoperative pain, inflammation and ecchymosis were significantly greater in group I versus group II (p<0.001 for all). Whereas, the incidence of occlusion rate was significantly greater in group II (p=0.001). Incidences of paresthesia and symptomatic thrombophlebitis were non-significantly greater in group II. Long-term paresthesia, hypercromy and deep vein thrombosis were only noted group II (Table 2). Successful percutaneous access and endovenous placement of the laser fibre were achieved in all patients and were well tolerated. All patients in both groups were subdivided in quintiles and number of negative outcomes were added for each patient as points, this created a learning curve as shown in Figure 1B. The first quintile had 0.875±0.243 points in negative outcomes, the second quintile 0.622±0.194 points, the third quintile 0.458±0.189 and the fourth quintile 0.122±0.073 (Figure 1A). This represented a trend toward lower negative outcomes in later quintiles (Figure 1B). When grouped by CEAP classification, negative outcomes sum points are 0.733±0.379 for C2, 0.529±0.142 for C3, 0.509±0.214 for C4 and zero for C5 and C6 (Figure 2). Paresthesia incidence was lower after inclusion of intumescence anaesthesia (Figure 3): 40 % of cases in general anaesthesia, 6.2 % with local anaesthesia and sedation, 14.9 % in spinal anaesthesia and sedation, and no paresthesia in local anaesthesia with ice compression with or without sedation.

Statistical Analysis Descriptive statistics were calculated for all variables. Variables included in the analysis were age, gender, ‘C’ of CEAP (Clinical, Aetiology, Anatomy, Pathophysiology) classification and alreadymentioned outcomes. Quintiles were calculated by software. Data on the preoperative, intraoperative and follow-up periods were collected for all patients referred to our department with this pathology since 2009 and recorded in a secure database. After manual verification of the consistency of the data, descriptive and statistical analyses were conducted. Characteristics recorded as categorical data were expressed as absolute and proportional frequencies. Statistical analyses employed the t test, the chi-square test, analysis of variance

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Discussion Varicose vein variability has led to use of a classification system for chronic venous disorders (CEAP), as follows: C0 (no varicose veins), C1 (telangiectasias and reticular varicose veins up to 4 mm in diameter), C2 (trunk varicose veins), C3 (oedema relating to varicose veins), C4 (skin pigmentation), C5 (healed venous ulcer) and C6 (active venous ulcer).17,18 Worse outcomes were found in lower Cs, but with no statistical significance; this trend could probably occur due to less preoperative symptoms and higher aesthetical expectations in lower clinical classification, but it would require a different methodological approach to highlight this tendency.

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Lessons Learned After 366 Thermoablated Veins Figure 1: Learning Curve by Quintile Outcome sum by quintile (n) 4 ≤ quintile (n) ≤ 5

Total 70

0.122 ± 0.073

3 ≤ quintile (n) < 4

0.458 ± 0.189

0.622 ± 0.194

2 ≤ quintile (n) < 3

0.875 ± 0.243

1 ≤ quintile (n) < 2

Negative outcome sum

50 40 30 20 10 0

Quintile (n) Pearson negative correlation, p<0.001; ANOVA unequal means, p<0.001. ANOVA = analysis of variance.

Figure 2: Outcomes by CEAP Classification 0.733 ± 0.379

CEAP = 2

Figure 3: Best Outcomes Regarding Anaesthesia was Achieved with Local Intumescence and Ice Compression Anaesthesia General anaesthesia

CEAP = 3

0.529 ± 0.142 40 % Local + sedation

0.509 ± 0.214

CEAP = 4

6.2 % Local + sedation + ice

0±0

CEAP = 5

0% Local without sedation + ice

CEAP = 6

0±0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

Spinal + sedation

ANOVA, p=0.167. ANOVA = analysis of variance; CEAP = Clinical, Aetiology, Anatomy, Pathophysiology.

In our cohort, postoperative complications were rare and mild, confirming the good safety profile of EVLA. There was only one case of deep vein thrombosis, which caused a pulmonary embolisation (0.4 %; 95 % CI [0.1–2.3]); this patient subsequently developed thrombophilia. He was assisted in intensive care for 1 week and discharged with good health. Differences between 980 nm and 1,470 nm EVLA pain have already been noted19 and was clear with outcome differences noted in group I and II in our experience. This could be due to the learning curve or worse outcomes associated with 980 nm ablation. Despite the team’s learning curve, better outcome was also influenced by new technology adoption, and adaption to its usage. The first quintile had an outcome that did not suggest an outcome better than traditional stripping, which required many changes in strategy. It was

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14.9 % 0

1 – occurred paresthesia, 0 – no paresthesia (chi square, p=0.018).

marked by change from 980 nm to 1,470 nm and adoption of radial beam fibre, and initial usage of intraoperatory ultrasound guidance and steroids usage, which was associated with team technique and the first huge improvement in outcomes. To reduce inflammation, we also adopted the usage of long-term anti-inflammatory steroids. The second quintile was marked by a fine adjustment of laser parameters (power, energy and LEED) for the new wavelength adopted and development and usage of a LEED calculation method with the advent of centimetre-marked fibre;9 subsequently, second quintile cases also underwent manual tumescence with saline while first cases received no tumescence at all or partial tumescence. The third quintile was marked with fine-tuning laser parameters. The fourth

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Surgical Techniques quintile was marked with initial usage of manual local tumescent anaesthesia with sedation and perforating vein ablation treatment with laser. At this point, most of the cases were moved from general hospital to an ambulatory setting, and later were introduced to mechanical infusion pump infiltration device for easier and better infiltration. Continuous infiltration avoids vein puncture as saline extrusion push veins away from the needle and allows tumescence hydrodissection. Increasing ablation distance peripheral to the saphenofemoral junction may result in a diminished rate of endothermal heat-induced thrombosis.11

ampbell B. Varicose veins and their management. BMJ C 2006;333:287–92. DOI: 10.1136/bmj.333.7562.287; PMID: 16888305. Porter JM, Moneta GL. Reporting standards in venous disease: an update. International Consensus Committee on Chronic Venous Disease. J Vasc Surg 1995;21:635–45. PMID: 7707568. Amato ACM, Santos RV, Amato SJTA. Doença Venosa Crônica. In: Amato ACM. Cirurgia Vascular: O que você não pode ignorar. 1st Edition. São Paulo: Amato - Instituto de Medicina Avançada, 2017. ISBN 9781513624709. Shepherd AC, Ortega-Ortega M, Gohel MS, et al. Costeffectiveness of radiofrequency ablation versus laser for varicose veins. Int J Technol Assess Health Care 2016;31:289–96. DOI: 10.1017/S0266462315000537; PMID: 26715372. Oliveira RÁ, Mazzucca ACP, Pachito DV, et al. Evidence for varicose vein treatment: an overview of systematic reviews. Sao Paulo Med J 2018; pii: S1516-31802018005010101. DOI: 10.1590/1516-3180.2018.0003240418; PMID: 30020324. Spreafico G, Piccioli A, Bernardi E, et al. Six-year follow-up of endovenous laser ablation for great saphenous vein incompetence. J Vasc Surg Venous Lymphat Disord 2013;1:20–5. DOI: 10.1016/j.jvsv.2012.05.004; PMID: 26993888. Beale RJ, Gough MJ. Treatment options for primary varicose veins--a review. Eur J Vasc Endovasc Surg 2005;30:83–95. DOI:

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Adoption of new strategies and improvement of procedure steps requires a new adaption time.

Conclusions This study suggests that our current strategy and technique has a lower rate of negative outcomes, and that EVLA has a steep learning curve. Our current best results are due to 1,470 nm wavelength laser, radial fibre with centimetre markings, usage of steroids and fine-tuning LEED. Ongoing evaluation is required to validate these results and to affirm the long-term durability of this technique. n

10.1016/j.ejvs.2005.02.023; PMID: 15933989. van den Bos R, Arends L, Kockaert M, et al. Endovenous therapies of lower extremity varicosities: a meta-analysis. J Vasc Surg 2009;49:230–9. DOI: 10.1016/j.jvs.2008.06.030; PMID: 18692348. Amato ACM, Amato SJTA. EVLTraining®: aplicativo para treino do cálculo da densidade de energia endovenosa linear. J Vasc Bras 2016;15:134–7. DOI: 10.1590/1677-5449.000816; PMID: 29930578. Proebstle T, van den Bos R. Endovenous ablation of refluxing saphenous and perforating veins. Vasa 2017; 46:159–66. DOI: 10.1024/0301-1526/a000610; PMID: 28238282. Dexter D, Kabnick L, Berland T, et al. Complications of endovenous lasers. Phlebology 2012;27(Suppl 1):40–5. DOI: 10.1258/phleb.2012.012s18; PMID: 22312066. Kerver AL, van der Ham AC, Theeuwes HP, et al. The surgical anatomy of the small saphenous vein and adjacent nerves in relation to endovenous thermal ablation. J Vasc Surg 2012;56:181–8. DOI: 10.1016/j.jvs.2011.11.127; PMID: 22503186. Amato ACM, Amato SJ de TA. Termoablação com Laser de Safenas. In: Procedimentos Médicos: Técnica e Tática. Rio de Janeiro: Roca, 2016; 157–160.

14. D umantepe M, Uyar I. Comparing cold and warm tumescent anesthesia for pain perception during and after the endovenous laser ablation procedure with 1470 nm diode laser. Phlebology 2015;30:45–51. DOI: 10.1177/0268355513512827; PMID: 24243931. 15. Proebstle TM, Moehler T, Herdemann S. Reduced recanalization rates of the great saphenous vein after endovenous laser treatment with increased energy dosing: Definition of a threshold for the endovenous fluence equivalent. J Vasc Surg 2006;44:834–9. DOI: 10.1016/j. jvs.2006.05.052; PMID: 16945499. 16. Moraes IN, Amato ACM. Metodologia da pesquisa científica. São Paulo: Roca, 2007. 17. Gloviczki P, Gloviczki ML. Guidelines for the management of varicose veins. Phlebology 2012;27:2–9. DOI: 10.1258/ phleb.2012.012s28; PMID: 22312060. 18. Amato ACM. CEAP – Software para classificação venosa. https://software.amato.com.br/content/ceap-vcss 19. Doganci S, Demirkilic U. Comparison of 980 nm laser and bare-tip fibre with 1470 nm laser and radial fibre in the treatment of great saphenous vein varicosities: a prospective randomised clinical trial. Eur J Vasc Endovasc Surg 2010;40:254–9. DOI: 10.1016/j.ejvs.2010.04.006; PMID: 20547079.

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Aorta

Computational Fluid Dynamics and Aortic Dissections: Panacea or Panic? Ian Wee 1,2 , Chi Wei Ong 1,3 , Nicholas Syn 1,2 and Andrew Choong 1,4,5,6 1. SingVaSC, Singapore Vascular Surgical Collaborative; 2. Yong Loo Lin School of Medicine, National University of Singapore; 3. Department of Biomedical Engineering, National University of Singapore; 4. Cardiovascular Research Institute, National University of Singapore; 5. Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore; 6. Division of Vascular Surgery, National University Heart Centre, Singapore

Abstract This paper reviews the methodology, benefits and limitations associated with computational flow dynamics (CFD) in the field of vascular surgery. Combined with traditional imaging of the vasculature, CFD simulation enables accurate characterisation of real-time physiological and haemodynamic parameters such as wall shear stress. This enables vascular surgeons to understand haemodynamic changes in true and false lumens, and exit and re-entry tears. This crucial information may facilitate triaging decisions. Furthermore, CFD can be used to assess the impact of stent graft treatment, as it provides a haemodynamic account of what may cause procedure-related complications. Efforts to integrate conventional imaging, individual patient data and CFD are paramount to its success, given its potential to replace traditional registry-based, population-averaged data. Nonetheless, methodological limitations must be addressed before clinical implementation. This must be accompanied by further research with large sample sizes, to establish the association between haemodynamic patterns as observed by CFD and progression of aortic dissection.

Keywords Computational flow dynamics, aortic dissection, true lumen, false lumen, wall shear stress, endovascular aortic repair, blood flow dynamics Disclosure: The authors have nothing to disclose. Received: 2 May 2018 Accepted: 29 August 2018 Citation: Vascular & Endovascular Review 2018;1(1):27–9. DOI: https://doi.org/10.15420/ver.2018.8.2 Correspondence: Andrew MTL Choong, Department of Cardiac, Thoracic and Vascular Surgery, National University Heart Centre, Singapore, Level 9, NUHS Tower Block, 1E Kent Ridge Road, Singapore 119228. E: suramctl@nus.edu.sg

The traditional approach to investigation and management of aortic dissections has revolved around clinical examination, laboratory tests and a slew of imaging modalities including CT, chest X-ray, MRI, ultrasound and transoesophageal echocardiography.1 However, an inherent limitation of these techniques is that they do not consider the temporal dynamicity of aortic blood blow; they capture only a snapshot of the blood flow at single points in time. Recent research has highlighted the use of computational fluid dynamics (CFD) as a complementary tool to improve our limited understanding of the complex biomechanical behaviour of blood flow in both normal aortas and those with pathology. The potential application of CFD is widespread, spanning from technological development of new devices to routine clinical decision-making.2,3 The amalgamation of engineering and medical disciplines has allowed computer simulation to be used to solve numerical equations related to fluid flow. Since CFD’s inception in the 1950s by researchers from the Massachusetts Institute of Technology,4 several studies have attempted to employ CFD techniques to analyse blood flow in different aortic pathologies including aortic aneurysms,5–7 aortic dissections5,8–12 and differences before and after endovascular aortic repair (EVAR).13 A combination of technological advancements in computing software (ANSYS FLUENT,14 Open Foam,15 SIMVascular,16 ADINA,17 in-house

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coding18 and the falling cost of supercomputing have paved the way for the use of computing resources to solve mathematical equations in medicine. The Navier–Stokes equation, for instance, allows modelling of intravascular pressure and flow parameters. The use of appropriately framed model parameters gives a realistic picture of blood flow and pressure waveforms in real time, enabling the investigation of blood flow velocity in relation to pressure and density as well as a myriad of other stresses and forces, including ones that cannot be measured, such as wall shear stress (WSS). Haemodynamics is considered to play a paramount role in the development and progression of all types of aortic dissection aortic dissection but unfortunately remains poorly understood. Hitherto, no clinical consensus has been established as to whether medical, surgical or endovascular treatment is most appropriate for the management of aortic dissection. This has plausibly been attributed to the lack of an imaging criteria to determine the best treatment for individual patients. Therefore, there is burgeoning interest in the use of patient-specific CFD in clinical decision-making. This review aims to provide an overview of the benefits and challenges of CFD in the management of aortic dissections.

Haemodynamic Changes in True and False Lumens Imaging techniques such as CT angiography and MRI have allowed clinicians to accurately visualise the vasculature, which can then be reconstructed by employing various software packages such as

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Aorta Materialise Mimics (Materialise NV) and 3D Slicer (open source). When these are used with a suitable meshing algorithm, CFD software can be applied to the vascular geometry to run simulation tests, along with 4D flow MRI and other imaging modalities such as 2D PC-MRI to provide realistic boundary parameters.19 It is important to select the correct boundary condition for CFD models as this will improve CFD outcome as highlighted in the literature.20-22 As stated in a recent publication,23 it is important to consider the peripheral vascular network as a boundary condition, and model it through different elements of Windkessel Model. This will ensure a comprehensive analysis of blood flow dynamics, which should be useful in the future. CFD could be employed to investigate haemodynamic changes in both the true lumen (TL) and false lumen (FL), where geometrical changes as a result of the dissection may change the entire flow field significantly. This may provide clues on when to treat an uncomplicated type B dissection. It remains a challenge to identify patients who are at the greatest risk of developing aneurysmal changes and should be given priority for treatment. This could be attributed to the unique geometrical features of the true and false lumen in every patient, which means that changes in the haemodynamic field vary between individuals. Karmonik et al. demonstrated that occlusion of the exit tear can cause an increase in FL pressure, since the geometry is altered after the occlusion. In addition, several studies have showed FL dilation causes a reduction in pressure within the FL.24 However, some studies have demonstrated that pressure in the TL is generally higher than in the FL. Recent publications with state-of-the-art CFD models have shown that the pressure difference between the TL and the FL is strongly affected by the distensibility of the aortic wall,25, 26 which should be given consideration when modelling the pressure in aortic dissection. Cheng et al. showed that altered flow patterns in FL and TL may affect disease progression, and this is best explained by changes in wall shear stress (WSS). WSS exerted on the cell surface causes morphological deformation of the cells in the direction of blood flow, triggering rapid cytoskeletal remodelling and activating signalling cascades with the consequent acute release of nitric oxide and prostacylin followed by activation of transcription factors including NF-κB, c-fos, c-jun and SP-1.27 Low WSS is also associated with endothelial dysfunction, reduced nitric oxide production, increased oxidative stress, atheroma/ neointima formation and a propensity for vasoconstriction rather than vasodilatation.28 In contrast, high and moderate WSS is associated with good endothelial function, reduced expression of adhesion molecules, increased expression of endothelial nitric oxide synthase and reduction in oxidative stress.29,30 However, the threshold for low and high WSS appears controversial, and varies between studies. While Cheng et al. showed that WSS can go up to 17.98 Pa in the true lumen,31 Karmonik et al. showed that maximum WSS can decrease from 0.9 to 0.4Pa,32 and low WSS was determined to be less than 0.4 Pa. However, the authors believe that WSS can be geometry dependent, and might serve as an invaluable marker of vessel wall health, and thus, may help surgeons to prioritise patients for treatment.

progression of a dissected aorta.33 A high velocity profile located at the entry tear may result in high WSS. On the one hand, high time-averaged WSS (TAWSS) values have been found8,34 to increase the progression of the entry tear. Elevated WSS depends on the site of entry. On the other, a reduction in shear stress can minimise the propagation of dissection. However, because each patient has a unique anatomical structure, there is a large range of WSS values across various types of tears. For example, the TAWSS exceeded 5 Pa in a study by Alimohammadi et al.8 but twice this value was given (10 Pa) in a study by Karmonik et al.

Haemodynamic Differences Before and After Endovascular Aortic Repair Improvements in haemodynamic patterns within the aorta are expected after endovascular aortic aneurysm repair but this varies from patient to patient depending on the specific pathology and boundary conditions. Unfortunately, some patients develop thrombosis in the false lumen after EVAR, and this is postulated to be due to haemodynamic factors. Menichini et al., for instance,35 showed how turbulent flow in the aorta may promote thrombus formation in the FL, particularly following thoracic endovascular aneurysm repair (TEVAR). In addition, Wan Ab Naim et al. demonstrated that geometrical factors such as a re-entry tear and abdominal branches may cause the development of complete and incomplete FL thrombosis after stent graft repair.36 These studies show that haemodynamic changes should be monitored closely to assess the risk of thrombus formation in the FL. The use of computational flow dynamics may accurately provide crucial information about WSS and change in velocity patterns, allowing clinicians to assess the risk of thrombus formation in every patient.

Stent Design In addition, CFD offers a platform for stent design optimisation, with the primary aim of reducing the haemodynamic impact (reduced sscillatory shear index, renal replacement therapy and TAWSS) of the stent on the vessel. Simulation tests allow for assessment of the stent’s mechanical and hemodynamic parameters that influence its performance. Strut thickness, for instance, has been found to be an important factor in predicting a stent’s performance.37–39 A benefit of CFD is it makes it possible to accurately analyse the myriad of factors that cause potentially devastating stent-related complications, including malpositioning, neointimal hyperplasia and collapse.40,41 Vascular surgeons are then able to identify patients at high risk of such complications, and can decide to implement prophylactic interventions.

Clinical Integration of Computational Flow Dynamics

Haemodynamics of Exit and Re-entry Tears

CFD may prove to be an invaluable tool across the different stages of clinical management for patients who present with aortic dissection. However, much needs to be done to integrate CFD in virtual treatment planning and patient-specific risk prediction. Ideally, there should be smooth integration of a patients’ vasculature (cardiovascular imaging) with patients’ clinical data (baseline characteristics) before running a CFD simulation. However, once this has been attained, surgeons would have a comprehensive understanding of the condition they are dealing with, and can decide on the optimal treatment option.

Wan Ab Naim and colleagues showed that a re-entry tear can provide a return path for blood flow back to the TL during systole and an extra outflow path into the FL during diastole, which may alter the

Research wise, this may also represent a paradigm shift from populationbased data to digital patient representations,42,43 the former of which

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Panacea or Panic is severely limited because it requires large participant numbers and clinical trials to establish evidence. Instead, the combination of (Bayesian) machine-learning methods and CFD virtual data would enable continuous predictions of outcomes, thereby reducing the cost, time and resources associated with large-scale clinical trials. However, data are insufficient at present to establish a multidimensional database for machine-learning methods to be conducted appropriately.44

Limitations The benefits of CFD must be viewed in the context of known limitations. First, the sample sizes in published studies are small, given that most analyse a cohort of fewer than 30 patients. Ideally, a large cohort of patients should be recruited with long-term follow-up (1 year), to establish the association between progression of a dissected aorta and haemodynamic factors such as disturbed flow and elevated WSS. Secondly, the CFD technique itself is limited by its failure to consider biochemical interactions, although this is understandable because it

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rbel R, Aboyans V, Boileau C, et al. 2014 ESC Guidelines on E the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). Eur Heart J 2014;35(41):2873–926. https://doi.org/10.1093/eurheartj/ehu281. PMID: 25173340. Sun Z, Chaichana T. A systematic review of computational fluid dynamics in type B aortic dissection. Int J Cardiol 2016;210:28–31. https://doi.org/10.1016/j.ijcard.2016.02.099. PMID: 26922709. Numata S, Itatani K, Kanda K, et al. Blood flow analysis of the aortic arch using computational fluid dynamics. Eur J Cardiothorac Surg 2016;49(6):1578–85. https://doi.org/10.1093/ ejcts/ezv459. PMID: 26792932. Jones MR, Attizzani GF, Given CA 2nd, et al. Intravascular frequency-domain optical coherence tomography assessment of carotid artery disease in symptomatic and asymptomatic patients. JACC Cardiovasc Interv 2014;B(6):674–84. https://doi. org/10.1016/j.jcin.2014.01.163. PMID: 24947723. Karmonik C, Bismuth JX, Davies MG, Lumsden AB. Computational hemodynamics in the human aorta: a computational fluid dynamics study of three cases with patient-specific geometries and inflow rates. Technol Health Care 2008;16(5):343–54. PMID: 19126973. Chen CY, Anton R, Hung MY, et al. Effects of intraluminal thrombus on patient-specific abdominal aortic aneurysm hemodynamics via stereoscopic particle image velocity and computational fluid dynamics modeling. J Biomech Eng 2014;136(3):031001. https://doi.org/10.1115/1.4026160. PMID: 24316984;PMCID: PMC5101028. Tse KM, Chiu P, Lee HP, Ho P. Investigation of hemodynamics in the development of dissecting aneurysm within patientspecific dissecting aneurismal aortas using computational fluid dynamics (CFD) simulations. J Biomech. 2011;44(5):827–36. https:// doi.org/10.1016/j.jbiomech.2010.12.014. PMID: 21256491. Alimohammadi M, Sherwood JM, Karimpour M, et al. Aortic dissection simulation models for clinical support: fluidstructure interaction vs. rigid wall models. Biomed Eng Online 2015;14:34. https://doi.org/10.1186/s12938-015-0032-6. PMID: 25881252; PMCID: PMC4407424. Karmonik C, Muller-Eschner M, Partovi S, et al. Computational fluid dynamics investigation of chronic aortic dissection hemodynamics versus normal aorta. Vasc Endovascular Surg 2013;47(8):625–31. https://doi. org/10.1177/1538574413503561. PMID: 24048257. Karmonik C, Bismuth J, Shah DJ, et al. Computational study of haemodynamic effects of entry- and exit-tear coverage in a DeBakey type III aortic dissection: technical report. Eur J Vasc Endovasc Surg 2011;42(2):172–7. https://doi.org/10.1016/j. ejvs.2011.04.008. PMID: 21549622. Karmonik C, Partovi S, Muller-Eschner M, et al. Longitudinal computational fluid dynamics study of aneurysmal dilatation in a chronic DeBakey type III aortic dissection. J Vasc Surg 2012;56(1):260–3.e1. https://doi.org/10.1016/j.jvs.2012.02.064. PMID: 22579075. Cheng Z, Tan FP, Riga CV, Bicknell CD, Hamady MS, Gibbs RG, et al. Analysis of flow patterns in a patient-specific aortic dissection model. J Biomech Eng 2010;132(5):051007. https://doi. org/10.1115/1.4000964. PMID: 20459208. Karmonik C, Bismuth J, Davies MG, Shah DJ, Younes HK, Lumsden AB. A computational fluid dynamics study preand post-stent graft placement in an acute type B aortic dissection. Vasc Endovascular Surg 2011;45(2):157–64. https://doi. org/10.1177/1538574410389342. PMID: 21156714. Ong CW, Ho P, Leo HL. Effects of Microporous stent graft on the descending aortic aneurysm: a patient-specific computational fluid dynamics study. Artif Organs 2016;40(11):E230–e40. https://doi.org/10.1111/aor.12802. PMID: 28374412.

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was first used to model kinetics.45 Therefore, CFD should never be used in isolation and improvements are warranted in terms of setting the boundary conditions. Finally, CFD can never be entirely accurate in modelling the actual aortic environment, including pulsatile blood flow and vascular structure. Moreover, simulations may not be that specific to the individual patient given the continuous physiological fluctuations, which are affected by a host of factors such as lifestyle, medication or genetic predisposition. Integration of patient-specific data is lacking and should be addressed.

Conclusion The adoption of CFD modelling is a new era in vascular surgery. While potentially highly useful in the diagnosis, prediction and prognostication of aortic dissections, the application remains in its infancy. Addressing methodological and logistical challenges are paramount before implementation into clinical practice. n

15. K elly S, O’Rourke M. Fluid, solid and fluid-structure interaction simulations on patient-based abdominal aortic aneurysm models. Proc Inst Mech Eng H 2012;226(4):288–304. https://doi. org/10.1177/0954411911435592. PMID: 22611869. 16. Figueroa CA, Taylor CA, Yeh V, et al. Preliminary 3D computational analysis of the relationship between aortic displacement force and direction of endograft movement. J Vasc Surg 2010;51(6):1488–97. https://doi.org/10.1016/j. jvs.2010.01.058. PMID: 20488325; PMCID: PMC2874723. 17. Chandra S, Raut SS, Jana A, Biederman RW, Doyle M, Muluk SC, et al. Fluid-structure interaction modeling of abdominal aortic aneurysms: the impact of patient-specific inflow conditions and fluid/solid coupling. J Biomech Eng 2013;135(8):81001. https://doi.org/10.1115/1.4024275. PMID: 23719760; PMCID: PMC3705803. 18. Filipovic N, Milasinovic D, Zdravkovic N, et al. Impact of aortic repair based on flow field computer simulation within the thoracic aorta. Comput Methods Programs Biomed 2011;101(3):243–52. https://doi.org/10.1016/j.cmpb.2011.01.005. PMID: 21316789. 19. Stankovic Z AB, Garcia J, Jarvis KB, Markl M. 4D flow imaging with MRI. Cardiovasc Diagn Ther 2014;4:173–92. https://doi. org/10.3978/j.issn.2223-3652.2014.01.02. PMID: 24834414; PMCID: PMC3996243. 20. Madhavan S, Kemmerling EMC. The effect of inlet and outlet boundary conditions in image-based CFD modeling of aortic flow. Biomed Eng Online 2018;17(1):66. https://doi.org/10.1186/ s12938-018-0497-1. PMID: 29843730; PMCID: PMC5975715. 21. Moon JY, Suh DC, Lee YS, Kim YW, Lee JS. Considerations of Blood Properties, Outlet Boundary Conditions and Energy Loss Approaches in Computational Fluid Dynamics Modeling. Neurointervention 2014;9(1):1–8. https://doi.org/10.5469/ neuroint.2014.9.1.1. PMID: 24642855; PMC3955817. 22. Du T, Hu D, Cai D. Outflow boundary conditions for blood flow in arterial trees. PLoS ONE 2015;10(5):e0128597. https://doi. org/10.1371/journal.pone.0128597. PMID: 26000782; PMCID: PMC4441455. 23. Morris PD, Narracott A, von Tengg-Kobligk H, et al. Computational fluid dynamics modelling in cardiovascular medicine. Heart. 2015;102(1):18–28. https://doi.org/10.1136/ heartjnl-2015-308044. PMID: 26512019; PMCID: PMC4717410. 24. Karmonik C, Bismuth J, Shah D, et al. Computational study of haemodynamic effects of entry-and exit-tear coverage in a DeBakey type III aortic dissection: technical report. Eur J Vasc Endovasc Surg 2011;42(2):172–7. https://doi.org/10.1016/j. ejvs.2011.04.008. PMID: 21549622. 25. Bonfanti M, Balabani S, Greenwood JP, et al. Computational tools for clinical support: a multi-scale compliant model for haemodynamic simulations in an aortic dissection based on multi-modal imaging data. J R Soc Interface 2017;14(136). pii: 20170632. https://doi.org/10.1098/rsif.2017.0632. PMID: 29118115; PMCID: PMC5721167. 26. Rudenick PA, Segers P, Pineda V, et al. False lumen flow patterns and their relation with morphological and biomechanical characteristics of chronic aortic dissections. Computational model compared with magnetic resonance imaging measurements. PLoS ONE 2017;12(1):e0170888. https://doi.org/10.1371/journal.pone.0170888. PMID: 28125720; PMCID: PMC5270334. 27. Konner K, Nonnast-Daniel B, Ritz E. The arteriovenous fistula. J Am Soc Nephrol 2003;14(6):1669–80. PMID: 12761270. 28. Krishnamoorthy MK, Banerjee RK, Wang Y, Z et al. Hemodynamic wall shear stress profiles influence the magnitude and pattern of stenosis in a pig AV fistula. Kidney Int 2008;74(11):1410–9. https://doi.org/10.1038/ki.2008.379. PMID: 18818686. 29. Lehoux S, Castier Y, Tedgui A. Molecular mechanisms of the vascular responses to haemodynamic forces. J Intern Med 2006;259(4):381–92. https://doi.org/10.1111/j.13652796.2006.01624.x. PMID: 16594906.

30. H arrison DG, Widder J, Grumbach I, Chen W, Weber M, Searles C. Endothelial mechanotransduction, nitric oxide and vascular inflammation. J Intern Med 2006;259(4):351–63. https://doi. org/10.1111/j.1365-2796.2006.01621.x. PMID: 16594903. 31. Cheng Z, Tan FPP, Riga CV, et al. Analysis of flow patterns in a patient-specific aortic dissection model. J Biomech Eng 2010;132(5):051007. https://doi.org/10.1115/1.4000964. PMID: 20459208. 32. Karmonik C, Partovi S, Müller-Eschner M, et al. Longitudinal computational fluid dynamics study of aneurysmal dilatation in a chronic DeBakey type III aortic dissection. J Vasc Surg 2012;56(1):260–3.e1. https://doi.org/10.1016/j.jvs.2012.02.064. PMID: 22579075. 33. Wan Ab Naim WN, Ganesan PB, Sun Z, et al. The impact of the number of tears in patient-specific Stanford type B aortic dissecting aneurysm: CFD simulation. J Mech Med Biol 2014;14(02):1450017. https://doi.org/10.1142/ S0219519414500171. 34. Chen D, Müller-Eschner M, von Tengg-Kobligk H, Barber D, Böckler D, Hose R, et al. A patient-specific study of type–B aortic dissection: evaluation of true-false lumen blood exchange. Biomedical engineering online. 2013;12(1):65. https://doi.org/10.1186/1475-925X-12-65. PMID: 23829346; PMCID: PMC3734007. 35. Menichini C, Cheng Z, Gibbs RG, Xu XY. A computational model for false lumen thrombosis in type B aortic dissection following thoracic endovascular repair. J Biomech 2018;66:36–43. https:// doi.org/10.1016/j.jbiomech.2017.10.029. PMID: 29137728. 36. Wan Ab Naim WN, Ganesan PB, Sun Z, et al. Flow pattern analysis in Type B aortic dissection patients after stent‐ grafting repair: comparison between complete and incomplete false lumen thrombosis. Int J Numer Method Biomed Eng 2018;34(5):e2961. https://doi.org/10.1002/cnm.2961. 37. Gundert TJ, Marsden AL, Yang W, LaDisa JF, Jr. Optimization of cardiovascular stent design using computational fluid dynamics. J Biomech Eng 2012;134(1):011002. https://doi. org/10.1115/1.4005542. PMID: 22482657. 38. Murphy JB, Boyle FJ. A full-range, multi-variable, CFD-based methodology to identify abnormal near-wall hemodynamics in a stented coronary artery. Biorheology 2010;47(2):117–32. https://doi.org/10.3233/BIR-2010-0568. PMID: 20683155. 39. Martin D, Boyle F. Sequential structural and fluid dynamics analysis of balloon-expandable coronary stents: a multivariable statistical analysis. Cardiovasc Eng Technol 2015;6(3):314–28. https://doi.org/10.1007/s13239-015-0219-9. PMID: 26577363. 40. Keller BK AC, Hose DR, Gunn J, et al. Contribution of mechanical and fluid stresses to the magnitude of in-stent restenosis at the level of individual stent struts. Cardiovasc Eng Technol 2014;5:164–75. https://doi.org/10.1007/s13239-014-0181-y. 41. Pasta S, Cho JS, Dur O, et al. Computer modeling for the prediction of thoracic aortic stent graft collapse. J Vasc Surg 2013;57(5):1353–61. https://doi.org/10.1016/j.jvs.2012.09.063. PMID: 23313184. 42. Bonnici T, Tarassenko L, Clifton DA, Watkinson P. The digital patient. Clin Med (Lond) 2013;13(3):252–7. https://doi. org/10.7861/clinmedicine.13-3-252. PMID: 23760698. 43. Morris PD, Narracott A, von Tengg-Kobligk H, et al. Computational fluid dynamics modelling in cardiovascular medicine. Heart 2016;102(1):18–28. https://doi.org/10.1136/ heartjnl-2015-308044. PMID: 26512019; PMCID: PMC4717410. 44. Cheng Z, Riga C, Chan J, et al. Initial findings and potential applicability of computational simulation of the aorta in acute type B dissection. J Vasc Surg 2013;57(2 Suppl):35s–43s. https:// doi.org/10.1016/j.jvs.2012.07.061. PMID: 23336853. 45. Karmonik C, Partovi S, Davies MG, et al. Integration of the computational fluid dynamics technique with MRI in aortic dissections. Magn Reson Med 2013;69(5):1438–42. https://doi. org/10.1002/mrm.24376. PMID: 22700326.

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An Ilio-iliac Arteriovenous Fistula Following Spontaneous Rupture of a Right Common Iliac Artery Aneurysm Yogeesan Sivakumaran, Manar Khashram and Paul Charles Haggart Department of Vascular Surgery, Waikato District Health Board, Hamilton, New Zealand

Abstract The formation of an ilio-iliac arteriovenous fistula is a potentially lethal complication of common iliac artery aneurysm presentations. Whilst trauma predominantly accounts for the majority, spontaneous rupture of a common iliac artery aneurysm into an adjacent venous structure accounts for a small subset of patients. Urgent surgical intervention is warranted with the aim to restore arterial continuity and ideally, closure of the fistula. This case study describes the endovascular management of a spontaneous ilio-iliac arteriovenous fistula following rupture of a common iliac artery aneurysm into an adjacent vein.

Keywords Ilio-iliac arteriovenous fistula, common iliac artery aneurysm, endovascular repair, case study, intra-abdominal aneurysm, endoleak Disclosure: The authors declare no conflicts of interest. Received: 17 March 2018 Accepted: 1 August 2018 Citation: Vascular & Endovascular Review 2018;1(1):30–32. DOI: https://doi.org/10.15420/ver.2018.4.2 Correspondence: Dr Yogeesan Sivakumaran, Department of Vascular Surgery, Waikato District Health Board, Pembroke Street, Hamilton, New Zealand, 3204. E: yogeesan.sivakumaran@waikatodhb.health.nz

Isolated iliac artery aneurysms are an uncommon and usually asymptomatic pathology, accounting for 2 % of all intraabdominal aneurysms.1 The common iliac artery (CIA) is the most frequently involved, with a rate of rupture in untreated cases of approximately 75 %.2

Computed tomography angiogram revealed a saccular right CIAA, measuring 100 mm x 97 mm x 100 mm, with stranding around the aneurysm sac. An arteriovenous fistula (AVF) between the CIAA and the right common iliac vein (CIV) was demonstrated (Figure 1). The left CIA was ectatic, measuring 17 mm.

A potentially lethal complication of common iliac artery aneurysm (CIAA) rupture is the formation of a ilio-iliac arteriovenous fistula (IIAVF).3 While trauma accounts for the vast majority of presentations, spontaneous rupture into an adjacent vein is rare and occurs in fewer than 1 % of all CIAA presentations.3 Here we present a case of a spontaneous IIAVF following a rupture of CIAA.

The patient was transferred to a tertiary referral centre and proceeded urgently to theatre for an endovascular repair. Following standard Proglide (Abbott Vascular) deployment, a short 10F Radifocus introducer II sheath (Terumo Interventional Systems) was advanced through the left groin. A long 9 F Flexor Ansel guiding sheath (Cook Medical) was initially advanced through the right groin in an attempt to negotiate the right CIAA. This was unsuccessful, and a snare was introduced from the contralateral groin to achieve successful cannulation. A Zenith Low Profile 24 mm x 84 mm aortic endograft main body (Cook Medical) was advanced through the left groin and deployed. The contralateral gate was cannulated and two Zenith Spiral-Z Iliac Leg Grafts 13 mm x 107 mm and 13 mm x 74 mm (Cook Medical) were deployed sequentially to seal into right external iliac artery. A Zenith Spiral-Z Iliac Leg Grafts 24 mm x 56 mm (Cook Medical) was deployed to seal within the left CIA. The overlap zones were moulded with a CODA balloon (Cook Medical).

Case Report A 75-year-old man presented to a peripheral hospital with a 2-day history of lethargy, malaise, anorexia, increased work of breathing and an episode of loss of consciousness. His past medical history was significant for autobiographical memory deficiency but he denied a history of trauma or previous abdominal aortic aneurysm surgery. On examination, the patient’s blood pressure was 91/54 mmHg, heart rate was 103 BPM and respiratory rate was 25 with an oxygen saturation of 96 % on room air. His abdomen was soft and nontender with an evident pulsatile mass in the right iliac fossa with a thrill palpable into the right groin. A full complement of lower limb pulses was palpable with evident right-sided lower limb oedema. Electrocardiogram revealed inversion of T waves in the lateral chest leads. Bloods on presentation revealed acute renal failure (creatinine 283 μmol/l, urea 18 mmol/l) and evidence of myocardial injury (troponin-T 69 ng/L, B-type natriuretic peptide 199 pmol/l).

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The post-aortic endograft deployment angiogram revealed a Type 1b endoleak with flow into the right CIAA sac and persistent filling of the right CIV (Figure 2). A 10 mm x 57 mm BeGraft stent graft (Bentley) was used to bridge the right-sided iliac limbs. The completion angiogram revealed resolution of the Type 1b endoleak (Figure 2). On palpation of the abdomen intraoperatively, the previously demonstrated thrill had resolved. Proglide closure was performed for groin haemostasis. Initial aortoiliac arterial duplex ultrasound performed 3 days postoperatively revealed a Type 2 endoleak from the right internal

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Arteriovenous Fistula Figure 1: Coronal (A) and Axial (B) Computed Tomography Slice from the Patient’s Initial Computed Tomography Scan

Figure 2: Intra-operative Angiogram Following the Deployment of the Aortic Endograft

An isolated large saccular right CIA aneurysm (**) with evidence of an ilio-iliac arteriovenous fistula (*) with contrast is demonstrated within the right common iliac vein.

iliac artery (IIA) filling the residual right CIAA with outflow via the right CIV. Direct sac puncture and embolisation of branches of the right IIA was attempted with Amplatz plugs (Abbott Vascular) and Concerto coils (Covidien) but the aneurysmal sac was seen to be refilling (Figure 3). The decision was made not to stent the right CIV given the low resistance vascular bed, allowing the Type 2 endoleak to be decompressed via this route.

The initial run (A) revealed a Type 1b endoleak (**). This resolved (B) following relining of the right Spiral Z Iliac Leg Graft with a BeGraft stent graft.

Figure 3: Intra-operative Angiogram following the Attempted Right Internal Iliac Artery Embolization Procedure

The patient’s recovery was otherwise unremarkable, and he was discharged following a 10-day admission with normal renal function (creatinine 103 μmol/L, urea 5.6 mmol/L) and resolution of his presenting symptoms. On follow-up arterial duplex ultrasound at 6 and 12 months, a persisting Type 2 endoleak with decompression via the right CIV was found with no significant change in the residual aneurysm sac size (Figure 4). With no systemic consequences of the Type 2 endoleak, the patient continues to be managed conservatively and is enrolled in an ultrasound surveillance programme.

Discussion Isolated CIAAs account for 2 % of all intra-abdominal aneurysms. They are uncommon and often discovered incidentally due to symptoms resulting from compression to adjacent structures or at the time of rupture.1 Most spontaneous rupture of intra-abdominal aneurysms tends to occur into the intra- or retroperitoneal tissues. Rupture into an adjacent venous structure, as described in this case report, forms a very small subset of these patients.4,5 The spontaneous rupture of a CIAA into an adjacent venous structure creating an IIAVF accounts for fewer than 1 % of all ruptures in CIAAs.6 Trauma is usually the primary aetiology for presentation in intraabdominal arteriovenous fistula, with a variety of causes including gunshot wounds, stab wounds and seat belt trauma. Other causes such as malignancy, intervertebral disc surgery and other iatrogenic injuries have also been described.2,3,7 The development of an IIAVF results in an anomalous diversion of blood flow from a high-resistance arterial circuit to a low-resistance venous circuit, resulting in a decrease in total peripheral resistance and an increase in venous resistance, venous pressure and blood volume.8 This results in an elevated heart rate, with increased stroke volume, cardiac output and cardiac work overall manifesting as a triad of clinical findings:

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(A) and (B) revealed a high flow type 2 Endoleak. Following attempted embolisation (**) of the right internal iliac artery, filling of the aneurysm sac was still demonstrated (Image C).

• fulminant onset of high output cardiac failure; • pulsatile abdominal mass with accompanying bruit; and • unilateral lower limb ischaemia or venous engorgement.7–10 However, this triad of symptoms is present in only 20–50 % of reported cases, with their occurrence dependent on factors such as origin, size and location of the fistula, patient age and the presence of concomitant cardiac, liver and renal disease.6–8 On serum blood tests, leucocytosis is usually present but unlike free aneurysmal rupture, the haemoglobin level remains stable. Initial renal function tests indicate decreased effective circulatory volume, which is nearly always reversible following repair.3,11 IIAVFs are potentially life threatening and warrant urgent intervention with the primary goals of management being re-establishment of arterial continuity and ideally, closure of the fistula.10 Historically, IIAVFs were managed with open surgical repair, usually with a Dacron interposition graft and direct suturing of the fistula from inside the aortic lumen.8,9 However, this was often a technically challenging procedure, given the position of the CIAA within the pelvis. Furthermore, it was also associated with a perioperative mortality as high as 67 % due to the inevitable major blood loss associated with

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Aorta Figure 4: Surveillance Duplex Ultrasonography at 6 Months’ Post-Aortic Endograft Implantation Reveals an Unchanged Residual Right Common Iliac Artery Aneurysm Sac (A) and a Persisting Right Ilio-iliac Arteriovenous Fistula (B)

venous bleeding control, embolisation of aneurysmal debris through the arteriovenous fistula and also physiological stress secondary to the pre-existing hyperdynamic state with cardiac decompensation.1,9,12 Endovascular repair has become increasingly common, given it is less invasive and has a lower risk of major intra-procedural blood loss. Whether it can be carried out depends on favourable anatomy and the haemodynamic stability of the patient. Endovascular repair is associated with reduced in-hospital and 30-day mortality, as well as length of inpatient stay compared to open surgical repair.1,4 The predominant concern following endovascular repair is communication between the aneurysm sac and adjacent vein resulting in a persistent Type 2 endoleak.12

uck DB, Bensley RP, Darling J, et al. The effect of B endovascular treatment on isolated iliac artery aneurysm treatment and mortality. J Vasc Surg 2015;62(2):331–5. https:// doi.org/10.1016/j.jvs.2015.03.027. PMID: 25943454; PMCID: PMC4516629. Weimann S, Flora G. Primary arteriovenous fistula between the common iliac vessels secondary to aneurysmal disease. Surgery 1987;102(1):91–5. PMID: 3589981. Vallina EA, Perez MA, Pascual MF, et al. Iliac arteriovenous fistula secondary to iliac aneurysm rupture associated with pulmonary embolism and anuria. Ann Vasc Surg 2000;14(2): 170–3. https://doi.org/10.1007/s100169910029. PMID: 10742433. Park JK, Lee M, So A, Lee HY. Isolated common iliac aneurysm and spontaneous ilioiliac arteriovenous fistula in a patient with subsequent type II endoleak and successful endovascular management. J Vasc Interv Radiol 2015;26(5):757–60. https://doi.org/10.1016/j.jvir.2015.01.002. PMID: 25921458. Gregoric ID, Jacobs MJ, Reul GJ, Rochelle DG. Spontaneous common iliac arteriovenous fistula manifested by acute renal failure: a case report. J Vasc Surg 1991;14(1):92–7. https://doi.

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As demonstrated in this case study, we hypothesise that this persistent communication is unlikely to result in sac expansion because of the low-pressure venous outflow resistance following endovascular repair. Furthermore, given the low flow state present postoperatively, it is likely that the hyperdynamic effects of a highoutput fistula will not be clinically significant following restoration of normal cardiac status and renal function. While IIAVFs can be managed conservatively, long-term surveillance is recommended.13,14 The continued presence of an endoleak following endovascular repair potentially places the patient at risk of complications including systemic cardiac manifestations and aneurysm sac enlargement.13 Cardiac failure in particular, in the context of a persistent endoleak, occurs as a result of reduced systemic vascular resistance, with increased cardiac output eventually leading to ventricular remodelling.15 Venous stenting of the adjacent vein has been described to help exclude AVF but presents risks of graft collapse, thrombosis, migration and side branch occlusion.13.

Conclusion The formation of an IIAVF following a spontaneous CIAA rupture is a rare clinical phenomenon complicated by the heterogeneity of clinical presentation. Due to the lower mortality and lower rates of complication that have been observed compared to open surgical repair, endovascular repair of IIAVF following CIAA rupture should be seen as a safe and viable form of management. n

org/10.1016/0741-5214(91)90159-R. PMID: 2061962. Doi S, Motoyama Y, Ito H. Blood pressure shifts resulting from a concealed arteriovenous fistula associated with an iliac aneurysm: a case report. JA Clinical Rep 2016;2(1):33. https:// doi.org/10.1186/s40981-016-0057-2. PMID: 29492428; PMCID: PMC5814788. 7. Loos MJ, Scheer M, van der Vliet JA, Warle MC. Ruptured iliac artery aneurysm presenting as acute right heart failure and cardiac arrest. Ann Vasc Surg 2015;29(2):363.e5–7. https://doi. org/10.1016/j.avsg.2014.08.029. PMID: 25463337. 8. Davidovic L, Dragas M, Cvetkovic S, et al. Twenty years of experience in the treatment of spontaneous aorto-venous fistulas in a developing country. World J Surg 2011;35(8):1829-34. https://doi.org/10.1007/s00268-011-1128-1. PMID: 21533647. 9. Vandereyken F, Schwagten V, Hertoghs M, et al. Spontaneous ilio-iliac arteriovenous fistula due to an iliac artery aneurysm: a case-report. Acta Chir Belg 2012;112(2):164–6. https://doi.org/ 10.1080/00015458.2012.11680817. PMID: 22571082. 10. McAuley CE, Peitzman AB, deVries EJ, Silver MR, et al. The syndrome of spontaneous iliac arteriovenous fistula: a distinct clinical and pathophysiologic entity. Surgery 6.

1986;99(3):373–7. PMID: 3952659. 11. R ichards DD 3rd. Spontaneous fistula between a right common iliac artery aneurysm and iliac vein. JAMA 1984;251(9):1189–90. https://doi.org/10.1001/jama. 1984.03340330047022. PMID: 6694325. 12. Iijima M, Kawasaki M, Ishibashi Y. Successful surgical repair of an ilio-iliac arteriovenous fistula associated with a ruptured common iliac artery aneurysm. Int J Surg Case Rep 2015;13:55–7. https://doi.org/10.1016/j.ijscr.2015.06.008. PMID: 26117446; PMCID: PMC4529642. 13. van de Luijtgaarden KM, Bastos Goncalves F, Rouwet EV, et al. Conservative management of persistent aortocaval fistula after endovascular aortic repair. J Vasc Surg 2013;58(4):1080–3. https://doi.org/10.1016/j.jvs.2012.10.138. PMID: 23478500. 14. Antoniou GA, Koutsias S, Karathanos C, et al. Endovascular stent-graft repair of major abdominal arteriovenous fistula: a systematic review. J Endovasc Ther 2009;16(4):514–23. https:// doi.org/10.1583/09-2725.1. PMID: 19702345. 15. Mehta PA, Dubrey SW. High output heart failure. QJM 2009;102(4):235–41. https://doi.org/10.1093/qjmed/hcn147. PMID: 18990720.

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Endovascular Rescue of Simultaneous Renal Stent Thrombosis: Case Report Fernando Gallardo Pedrajas, 1 Rubén Rodriguez Carvajal, 1 Alberto Martín-Palanca, 2 Rocio Martin-Palanca Verdes, 2 Teresa Hernández Carbonell 1 and Rocio Lainez Rube 1 1. Department of Vascular Surgery, Hospital Quirónsalud Marbella, Spain; 2. Department of Interventional Radiology, Hospital El Angel, Malaga, Spain.

Abstract The chimney/periscope technique has been used to address complex aortic pathologies. This case report aims to report the outcomes of the endovascular management of the acute and simultaneous thrombosis of both renal covered stent grafts after bilateral renal arteries chimney technique for endovascular repair (CH-EVAR) of a juxtarenal abdominal aortic aneurysm. The cause of this early occlusion of stent grafts may be related to how procedures and devices combinations alter the native anatomy. The authors aimed to compare renal artery geometry before and after CH-EVAR to find a possible cause of stent thrombosis.

Keywords Chimney graft, complication, renal artery, target vessel, geometric analysis, renal failure. Disclosure: The authors have no conflicts of interest to declare. Received: 31 August 2018 Accepted: 2 September 2018 Citation: Vascular & Endovascular Review 2018;1(1):33–7. DOI: https//doi.org/10.15420/ver.2018.1.2 Correspondence: Fernando Gallardo Pedrajas, Malaga, Spain. E: fgallardo.vascular@gmail.com

Endovascular stent grafting, or endovascular aneurysm repair (EVAR), is a newer form of treatment for abdominal aortic aneurysm that is less invasive than open surgery. Endovascular stent grafting uses an endovascular stent graft to reinforce the wall of the aorta and to help keep the damaged area from rupturing. The chimney/periscope technique (CH-EVAR) has been used to address complex aortic pathologies. This case report shows the outcomes of the endovascular management of an acute and simultaneous thrombosis of both renal stent grafts used in the endovascular repair of a complex abdominal aortic aneurysm (AAA).

Case Report A 72-year-old man diagnosed with a 5.8 cm juxtarenal AAA was referred to our institution for consideration of complex endovascular repair. His medical history included active smoking, dyslipidaemia, hypertension and impaired renal function without a need for dialysis. He had been on various anti-hypertensives and statins without antiplatelet or anticoagulant therapy. The option of a complex endovascular repair was offered to the patient, due to his age and non-suitable anatomy for a standard infrarenal endovascular aneurysm repair (EVAR). He had refused open repair and showed a preference for an endovascular repair with an expected shorter length of stay and avoidance of other morbidities associated with surgery and general anaesthesia. The chimney technique has the potential to create a new sealing zone enough to treat patients with EVAR. The concept is to extend the sealing zone of a complex aneurysm neck, achieving the final goal of EVAR, i.e. the exclusion of the aneurysmal sac with the protection of essential aortic branches in the area of exclusion. In this case, CH-EVAR technique was chosen because of the favourable anatomy of both renal arteries, angulation downward >20°, with a

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predictable, easy and fast cannulation from an upper vascular access in the left humeral artery; and also because our team has experience with this technique. We considered the alternative of a fenestrated customised device (F-EVAR) with two branches for renal arteries, but we usually reserve this technique for cases with access to three or more visceral vessels. The risk of endovascular device failure, the need for lifelong surveillance with EVAR and possible additional interventions in future were outlined to the patient, and he rejected the open surgery option. The AAA anatomy evaluation was performed using orthogonal multiplanar, centre lumen line and volume rendering reconstructions. The proximal neck was not good for infrarenal EVAR (reverse tapered neck, <0.5 cm length) and there was also a proximal shaggy thoracic aorta, which carries a risk of distal embolisation complications during the procedure (Figure 1). The diameter of the right renal artery 2 cm from the origin was 5.6 mm, and the diameter of the left at 2 cm was 5.7 mm. The downward angle was 31° on the left renal artery and 35° on the right renal artery. The renal branch angle was defined relative to the plane orthogonal to the aorta (Figure 2). Planning and sizing of the case was performed using OsiriX (Pixmeo) and Horos (Horos Project)software by two experienced EVAR vascular surgeons and reviewed with Medtronic experts with the use of 3mensio (Pie Medical Imaging) software. The procedure was performed under loco-regional anaesthesia with percutaneous bilateral ultrasound-guided femoral access, using 18 Fr right sheath and 14 Fr left sheath (GORE, Gore Medical), and open left humeral brachial access for the introduction of two 6 Fr long (65 mm) sheaths (Flexor, Cook Medical; Figure 3). An oversizing of 30 % of the endograft is required, and thus our choice was the Endurant II bifurcated stent graft (ETBF 28-13c 124 EE; Medtronic) at the aortic neck and two 6 × 47 mm covered stent grafts

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Aorta Figure 1: Centre Lumen Line for Aortic Neck Evaluation

Figure 2: Estimated Angulation of (A) Right and (B) Left Renal Arteries Prior to Procedure

Figure 3: Brachial Access for Long Sheaths

The patient was discharged 4 days after the procedure, a longer stay due to a 48 hour fever associated with post-implantation syndrome, with long-term antiplatelet therapy (clopidogrel) recommended. Follow-up at 1 and 3 months with CT and ultrasound showed no endoleaks, aneurysms shrinking (diameter <5.5 cm), and both renal stent grafts were patent (Figure 6). Renal angulation downward was 46° left and 44° right after implantation relative to the plane orthogonal to the aorta stent graft. Four months after CH-EVAR, the patient was admitted to the emergency department of another centre. He had acute renal failure, with an emergent thoracic angio-CT showing aortic device patency but with changes at the suprarenal aorta thrombus and bilateral renal stent grafts occlusion, and a very poor distal right artery perfusion (Figure 7). He had haemodynamic instability and an emergent procedure was performed to try to rescue both renal arteries. Using a percutaneous approach from the left humeral artery, the right renal stent graft was successfully recanalised with a 0.035" hydrophilic Terumo guidewire after various attempts. A distal angiogram showed an acceptable distal perfusion of the right kidney with proximal total thrombosis of the stent. After intraluminal right renal covered stent recanalisation angioplasty with a 6 × 40 balloon was performed, observing a focal dissection just distal to the covered stent and also an area of possible kink at the medial part of the covered stent. A 7 × 60 Pulsar (Biotronik) self-expanding stent and a 7 × 38 Dynamic (Biotronik) balloon expandable stent were deployed for distal and proximal relining and correction of the previous stent kink. Recovery of the renal artery patency was immediately observed (Figure 8). Recovery of the left renal artery was not considered, due to the absence of any stump at the origin of the left renal chimney, the critical clinical situation of the patient and the long duration of the procedure (>180 minutes). After the procedure, patient received haemofiltration for 1 week in the critical care department. His renal function recovered to previous levels and he was discharged at 15 days without need of haemodialysis. Recent 12-month follow-up shows right renal artery patency, no endoleaks and no signs of stent failure. The patient has fully recovered his normal activity, but is still a smoker.

Discussion Juxtarenal aortic aneurysms are challenging cases for open surgery and there are still some controversies about adopting an endovascular approach as the first line of treatment. According to several articles in the literature, open surgery has remained the gold standard treatment for aortic pathologies, although endovascular techniques in the treatment of complex aortic pathologies have progressed greatly in recent times and are becoming a promising alternative in world reference centres.1-3

(BeGraft, Bentley) for both renal arteries. Contralateral limb stent graft (ETLW 16-10c 82 EE; Medtronic) was deployed through the left femoral access. Simultaneous ballooning of the Reliant balloon (Medtronic) and the two covered stent grafts was undertaken using a 'kissing balloon technique' (Figure 4). Control angiogram showed no endoleaks, patency of both renal arteries, and no signs of renal dissection or stent grafts kinking, but with changes in both renal angulations before and post procedure (Figure 5). Operation time was about 130 minutes, and 300 ml of half-strength contrast was used, along with 5,000 IU heparin and 30 IU protamine at the end of the procedure. Closure was achieved using the Abbott Perclose Proglide suture mediated closure system.

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It is predicted that the number of endovascular repair procedures continues to advance, based on patients’ preference for non-invasive procedures and the increasing numbers of eligible patients with anatomically complex AAAs as juxtarenals for EVAR. Well-informed patients tend to refuse procedures with high morbidity and general anaesthesia, and will usually choose the option of a minimally invasive approach, even bearing in mind the risks of endovascular device failure and the need for subsequent interventions and lifelong surveillance with EVAR. The chimney/periscope technique was introduced 15 years ago by Greenberg et al. as an adjunctive procedure to address challenging

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Endovascular Rescue anatomic situations for which open surgical interventions presented high physiological risks.4 The PERICLES registry, published in 2015, has analysed the collected worldwide experience of snorkel/chimney EVAR for complex AAA. This is the largest series in the CH-EVAR literature and demonstrates comparable outcomes to those in published reports of branched/fenestrated devices, where primary patency reported was 94 %. These results have supported CH-EVAR as a valid off-the-shelf and immediately available alternative in the treatment of complex abdominal EVAR and provide impetus for the standardisation of these techniques.5 Many groups agree that chimney/periscope techniques could be used to tackle complex aortic pathologies.6,7 Reasons include no need for customisation compared with fenestrated grafts and better applicability in emergent cases; in addition these techniques can also be used in selected complex procedures, such as management of juxtarenal aortic aneurysms.6,7 An interesting recent review by Ultee et al. examined patients undergoing complex EVAR.8 They examined perioperative outcomes, focusing on differences with complex open repair, but also with standard infrarenal EVAR with patients undergoing non-ruptured complex repair in the American College of Surgeons National Surgical Quality Improvement Program. Their study included 4,584 patients, 9.0 % undergoing complex EVAR, 8.6 % undergoing complex open repair and 82.4 % undergoing infrarenal EVAR. Their results show a perioperative mortality of 3.4 % after complex EVAR, 6.6 % after open repair and only 1.5 % after infrarenal EVAR. Open repair was identified as an independent predictor of 30-day mortality, renal function deterioration and any complications. They concluded that for patients undergoing repair for anatomically complex AAAs, complex EVAR had fewer complications than complex open repair, but carried a higher risk of adverse outcomes than infrarenal EVAR. Over the last few years increasing numbers of reports in the literature have demonstrated promising short and mid-term outcomes and high rates of technical success (≥95 %) after CH-EVAR for complex aortic pathologies.8-10 The selection of devices for CH-EVAR has been evaluated with different types of aortic and renal stent grafts. In our case we chose the Endurant II stent graft combined with a covered balloon stent graft (BeGraft) because it has been reported in the PERICLES registry that the combination of nitinol/polyester stent graft devices with balloon expandable covered stent during chimney endovascular aneurysm repair is associated with improved survival compared with other aortic endografts.11

Figure 4: Simultaneus Balloning of Aortic Stentgraft and Renal-covered Stents Using Kissing Balloon Technique

Figure 5: Intraoperative Angiogram Showing Position of Renal Arteries (A) Pre- and (B, C) Post-renal Stent Deployment

Figure 6: CT Post-procedure (1 month)

A variety of aortic stents grafts could be used as the main body, but only the Endurant II/IIs was CE mark approved for renal chimneys at the time of writing.12 The most frequently used stent design for the chimney technique is the covered balloon expandable stent, the use of the BeGraft monolayer balloon expandable stent graft provides some advantages, including a reduction in the size of the sheath and better conformability for vessel target. Despite the fact that all available stent designs (self-expanding, balloon expandable, non-covered and covered stents) have been applied in the chimney technique, at the present time the only on-label indication requires a covered balloon expandable stent. Our patient shows no events at 3-month follow-up, with patency of both renal stents and no signs of thrombus, intimal hyperplasia or any kink or morphological failure at the stents on CT or ultrasound. Studies by Pecoraro et al. reported that the primary patencies at

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(A) No proximal endoleak. (B) Renal stents patency.

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Aorta Figure 7: Bilateral Renal Stent (A, B) Occlusion with (C) Bifurcated Aortic Endoprotheses Patent A

Figure 8: Right Renal Stent Rescue and Relining A

(A) Right renal stent (BeGraft) rescue and relining distally with (B) a bare metal stent (PulsarBiotronik) and (C) proximally with balloon-expandable stent (Dinamic-Biotronik). (D) Final angiogram with patency of right renal and aortic bifurcated stentgraft. (D)

12, 24 and 36 months were 94 %, 94 %, and 93 %, respectively, and other groups also have showed target vessel patency of 92 % and a secondary patency of 96 %, similar to those reported previously.6,13 The acute renal failure after 4 months was probably the result of occlusion of both renal stents. Usai et al. reviewed the literature on pararenal EVAR to determine the frequency and clinical relevance of chimney graft occlusion.14 They identified 83 studies regarding chimneys/snorkels for pararenal pathologies. The mean time to chimney graft occlusion reported was 3.5 months, so the renal stent occlusions in our case is consistent with these results.14 Although most groups identify a similar low rate of chimney graft occlusions, it generally happens a few months after stent placement. In many cases, the involvement of the renal artery had no severe clinical consequences compared with occlusion of other visceral vessels as the superior mesenteric artery. However, as we saw in this case, when both renal arteries are affected it can lead to a critical and dramatic situation. More detailed information

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regarding occluded chimney grafts will be needed in future to help identify the causes. Different treatment strategies to solve stent occlusion after CH-EVAR have been reported, including open conversion, haemodialysis, placement of bare metal stents, placement of covered stents or conservative treatment.13,14 Our patient suffered acute bilateral renal thrombosis 4 months after the procedure, causing an acute renal failure with severe consequences that required critical care management. However, CT scans at 1 and 3 months did not demonstrate any sign of misplacement or significant kinking of the renal stents, with aneurysm sealing, no endoleaks and the size shrinking from 5.8 cm to 5.3 cm. The latter complication suggests that possibly our initial choice of BeGraft as the covered stent for renal arteries or some other technical details during CH-EVAR could have led to changes in the anatomy of the renal arteries. This might explain the late bilateral thrombosis, versus the more improbable option that the stents occlusion could be caused by a very selective distal embolisation of thrombus from the shaggy suprarenal aorta. Ullery et al. reported the impact of renal artery angulation after evaluating the imaging of 77 patients who underwent complex EVAR (24 fenestrated, 53 snorkel/chimney) and measuring the renal angulation on preoperative scans and post procedure.15 For patients undergoing fenestrated EVAR, mean renal artery angulation was lower (mean -28° ± 21°) from patients receiving snorkel/chimney grafts (mean -30° ± 19°). Renal artery cannulation during fenestrated EVAR was performed significantly faster in arteries with less downward (≥−30°) angulation, whereas cannulation in snorkel/chimneys was faster in arteries with greater downward (<−30°) angulation. It can be explained by the anatomic fact that downward angulation makes it easier for the brachial access that is usually performed for snorkel or chimneys procedure. However, their results also show that immediate renal function decline, procedural complications and postoperative issues were not associated with renal artery angulation. In our case, the angulation of both renal arteries was measured using a similar method to Ullery et al. We measured the difference between an orthogonal centre line axis inside the aorta and the renal arteries axis, with both renal arteries with a significant downward angulation (−35° the right and −31° the left). Also, in our case, the renal cannulation was performed quickly (<15 minutes) and without any incidents. The same group has also recently published other papers focused on dynamic geometric analysis of the anatomy of the renal arteries, quantifying the renal arteries geometry using a 3D model based on centre line extraction and computing the stent length, the branch angle, the end stent angle and the peak curvature within the stent.16 Although limited by having less experience, we agree with their initial assumption and paper conclusions about the fact that durability and patency of renal stent grafts after CH-EVAR may be related to how procedures and specific devices alter the native anatomy. The comparison of renal artery geometry in their review of 40 patients who underwent F-EVAR (n=21) or CH-EVAR (n=19) with a total of 72 renal artery stents shows that snorkels or chimneys had greater stented length compared to fenestrated renals, and this may be relevant as more artery covered more alteration of the original renal anatomy. With renal stent patencies of 97.2 % at mean

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Endovascular Rescue follow-up of more than 1 year they report clinical incidence of acute renal failure occurred in 12.5 % of patients, although none required dialysis, but they do not report any case of bilateral occlusion. The final conclusions are that chimneys during EVAR induced significantly greater angle change at the stent end and curvature change distal to the stent compared to F-EVAR, although no difference in patency was noted. Chimneys exhibited greater end-stent angle changes compared to the F-EVAR. After the re-evaluation of our case, we fit into their findings that these angle changes may exert differential effects on long-term renal artery patency, integrity and renal function following complex EVAR, and it could explain the bilateral thrombosis of the two renal arteries. In our case the original renal angulation downwards was remarkable and increased immediately after procedure, from 35° to 46° in the right and from 31° to 44° in the left, with a significant end-stent angulation increase, especially in the right renal. The fact that chimneys for renal branches angled downward opposite to F-renal branches that angled upward has been also analysed with statistically significant results in 29 patients, with chimneys renals exhibiting an increased end-stent angulation (12±15°).17 A left renal snorkel stent thrombosis due to severe kinking, observed on 4-month postoperative imaging, is reported in this paper. The authors concluded that only chimneys resulted in significant end-stent angulation increase and suggests that these anatomic alterations are primarily generated early as a consequence of the procedure itself and, although persistent, they show no evidence of continued significant change during the follow-up.

ao R, Lane TR, Franklin IJ, Davies AH. Open repair versus R fenestrated endovascular aneurysm repair of juxtarenal aneurysms. J Vasc Surg 2015;61:242–55. https://doi.org/ 10.1016/j.jvs.2014.08.068; PMID: 25240242. Schermerhorn ML, Buck DB, O’Malley AJ, et al. Long-term outcomes of abdominal aortic aneurysm in the medicare population. N Engl J Med 2015;373:328–38. https://doi. org/10.1056/NEJMoa1405778; PMID: 26200979. Patel R, Sweeting MJ, Powell JT, et al. Endovascular versus open repair of abdominal aortic aneurysm in 15-years’ followup of the UK endovascular aneurysm repair trial 1 (EVAR trial 1): A randomised controlled trial. Lancet 2016;388:2366–74. https://doi.org/10.1016/S0140-6736(16)31135-7; PMID: 27743617. Greenberg RK, Clair D, Srivastava S, et al. Should patients with challenging anatomy be offered endovascular aneurysm repair? J Vasc Surg 2003;38:990–6. https://doi.org/10.1016/ S0741-5214(03)00896-6; PMID: 14603205. Donas KP, Lee JT, Lachat M, et al. Collected world experience about the performance of the snorkel/chimney endovascular technique in the treatment of complex aortic pathologies: the PERICLES registry. Ann Surg 2015;262:546–53. https://doi. org/10.1097/SLA.0000000000001405; PMID: 26258324. Wu ZY, Chen ZG, Ma L,et al. Outcomes of chimney and/or periscope techniques in the endovascular management of complex aortic pathologies. Chin Med J 2017;130:2095–100.

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Conclusion To the authors’ knowledge, this is the first reported case of bilateral acute thrombosis of renal arteries after CH-EVAR solved with endovascular rescue of just one of the covered stents using a bare metal stent. Geometrical analysis shows how the combination of aortic stent grafts and covered renal stent grafts when performing chimneys procedures for complex endovascular repair induces changes in renal artery anatomy and how it could lead to and explain the early stent thrombosis. While the impact of these changes on stent graft durability and long-term patency has yet to be elucidated, such findings would support a theoretical caution for using chimneys with some specific covered stent grafts in extremely downward angulated renal arteries, even when it is a trend to select chimneys procedures with a homemade solution in these cases, due to the favourable position for cannulation of both renal arteries. Direct renal access, angioplasty and relining of the previous stent with self-expanding and balloon expandable stents seems to be a suitable procedure to rescue an acute stent thrombosis, also reducing the distal end-stent angulation that could lead to more complications in the future. Long-term complications including re-intervention rates after CH-EVAR are unknown and surveillance remains highly relevant. Future studies are warranted to further refine patient and anatomic selection for complex EVAR strategies and the application of geometric quantification techniques to longer term imaging studies would help to understand vessel anatomy’s changes following complex EVAR using different devices. n

https://doi.org/10.4103/0366-6999.213410; PMID: 28836554. Igari K, Kudo T, Toyofuku T, Inoue Y. The outcomes of endovascular aneurysm repair with the chimney technique for juxtarenal aortic aneurysms. Ann Thorac Cardiovasc Surg 2016;22:174–80. https://doi.org/10.5761/atcs.oa.16-00026; PMID: 26961481. 8. Ultee KHJ, Zettervall SL, Soden PA, et al. Perioperative outcome of endovascular repair for complex abdominal aortic aneurysms J Vasc Surg 2017;65:1567–75. https://doi. org/10.1016/j.jvs.2016.10.123; PMID: 28216344. 9. Pecoraro F, Veith FJ, Puippe G, et al. Mid- and longer-term follow up of chimney and/or periscope grafts and risk factors for failure. Eur J Vasc Endovasc Surg 2016;51:664–73. https://doi. org/10.1016/j.ejvs.2016.01.010; PMID: 26961762. 10. Xue Y, Sun L, Zheng J, et al. The chimney technique for preserving the left subclavian artery in thoracic endovascular aortic repair. Eur J Cardiothorac Surg 2015;47:623–9. https://doi. org/10.1093/ejcts/ezu266; PMID: 25009212. 11. Scali ST, Beck AW, Torsello G, et al. Identification of optimal device combinations for the chimney endovascular aneurysm repair technique within the PERICLES registry. J Vasc Surg 2018. https://doi.org/10.1016/j.jvs.2017.10.080; PMID: 29395423; epub ahead of press. 12. Medtronic. Medtronic’s Endurant™ II/IIs Stent Graft System Receives CE Mark for Use with ChEVAR Parallel Graft Technique. 6 December 2016. Available at: http:// 7.

13.

14.

15.

16.

17.

newsroom.medtronic.com/phoenix.zhtml?c=251324&p=irolnewsArticle&ID=2227788 (accessed 3 September 2018). Pecoraro F, Veith FJ, Puippe G, et al. Mid- and longer-term follow up of chimney and/or periscope grafts and risk factors for failure. Eur J Vasc Endovasc Surg 2016;51:664–73. https://doi. org/10.1016/j.ejvs.2016.01.010; PMID: 26961762. Usai MV, Torsello G, Donas KP. Current evidence regarding chimney graft occlusions in the endovascular treatment of pararenal aortic pathologies: a systematic review with pooled data analysis. J Endovasc Ther 2015;22:396–400. https://doi. org/10.1177/1526602815581161; PMID: 25878021. Ullery BW, Chandra V, Dalman RL, Lee JT. Impact of renal artery angulation on procedure efficiency during fenestrated and snorkel/chimney endovascular aneurysm repair. J Endovasc Ther 2015;22:594–602. https://doi. org/10.1177/1526602815590119; PMID: 26045462. Ullery BW, Suh GY, Lee JT, et al. Comparative geometric analysis of renal artery anatomy before and after fenestrated or snorkel/chimney endovascular aneurysm repair. J Vasc Surg 2016;63:922–9. https://doi.org/10.1016/j.jvs.2015.10.091; PMID: 26755068. Ullery BW, Suh GY, Kim JJ, et al. Dynamic geometric analysis of the renal arteries and aorta following complex endovascular aneurysm repair. Ann Vasc Surg 2017;43:85–95. https://doi. org/10.1016/j.avsg.2016.12.005; PMID: 28390918.

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Carotid

Carotid Access for Aortic Interventions: Genius or Madness? Ian Wee 1,2 , Nicholas Syn 1,2 and Andrew MTL Choong 1,3,4,5 1. SingVaSC, Singapore Vascular Surgical Collaborative; 2. Yong Loo Lin School of Medicine, National University of Singapore; 3. Cardiovascular Research Institute, National University of Singapore, Singapore; 4. Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore; 5. Division of Vascular Surgery, National University Heart Centre, Singapore

Abstract The endovascular-first approach remains is omnipresent ubiquitous amongst in the vascular community today. However, several key issues have ensued remain, one of which involves the choice of vessel site. Although the transfemoral route is the first-line approach has been established as first-line approach in endovascular interventions of the aorta (endovascular aortic repair [EVAR], thoracic endovascular aortic repair [TEVAR], and transcatheter aortic valve implantation [TAVI]), there remains a select some group of patients who are contraindicated for the aforementioned this as well as for alternatives vessel routes such as the transapical approach. The carotid artery, first used in aortic aneurysm repair, is potential alternative for these patients. Emerging evidence appears to support this relatively unpopular approach in EVAR, TEVAR and TAVI. Sporadic case reports and series have reported the transcarotid approach for EVAR and TEVAR, and collectively show relatively low rates of mortality and neurological complications. For TAVI, the carotid artery appears to be a safe and effective route of access compared to the transapical and even the transfemoral approach. However, technical aspects have not been ironed out; there are procedural variations, for example, in type of anaesthesia used, intraoperative neurological monitoring and choice of common carotid artery. The overall quality of evidence is poor, since the majority of it consists of case reports, and retrospective and prospective cohort studies. Although a randomised controlled trial (RCT) is needed to compare the transcarotid against the transfemoral approach, this is unlikely to take place because of ethical considerations. Therefore, the authors recommend future research to consider cohort studies with adequately powered sample sizes to establish any firm conclusions. However, as transcarotid procedures are performed infrequently, most institutions will have relatively small sample sizes. Therefore, it is recommended that collaborative efforts are undertaken to increase the overall sample size in the cohort analysis.

Keywords Transcarotid, carotid artery, endovascular aortic repair, thoracic endovascular repair, transcatheter aortic valve implantation, review Disclosure: All authors have no conflicts of interest to disclose. Received: 9 April 2018 Accepted: 1 September 2018 Citation: Vascular & Endovascular Review 2018;1(1):38–42. DOI: https://doi.org/10.15420/ver.2018.6.2 Correspondence: Andrew MTL Choong, Department of Cardiac, Thoracic and Vascular Surgery, National University Heart Centre, Singapore, Level 9, NUHS Tower Block, 1E Kent Ridge Road, Singapore 119228. E: suramctl@nus.edu.sg

Aortic intervention has attracted renewed interest since endovascular alternatives were introduced, which are distinct because of their minimally invasive nature. There is agreement today among the vascular community that an endovascular-first approach to aortic interventions should be taken, including endovascular aortic repair (EVAR), thoracic endovascular aortic repair (TEVAR) and transcatheter aortic valve implantation (TAVI). Substantial improvement in 30-day mortality has been reported in several pivotal randomised controlled trials1–4 investigating EVAR instead of open surgery for abdominal aortic aneurysm (AAA). However, a matched propensity score analysis demonstrated that this advantage diminished in the long term, specifically after 3 years.5 This was also reflected in the meta-analysis of a recent Cochrane review, which found EVAR conferred no intermediate- and longterm mortality benefits.6 Similar observations were noted in the INSTEAD trial, where TEVAR failed to demonstrate improved overall survival for patients with uncomplicated type B aortic dissection.7 Nonetheless, both TEVAR and EVAR remain robust tools in the surgeon’s armamentarium, especially for patients considered unfit for conventional surgery.

Access at: www.VERjournal.com

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Valve procedures have also witnessed a paradigm shift in the contemporary endovascular era. Patients with diseased valves traditionally underwent valve replacements during open surgery. However, open surgical repair started losing its traction ever since the inception of TAVI, which was pioneered by Cribier et al. in 2002.8 Since then, evidence has suggested that patients on the entire risk spectrum for valve degeneration benefit from TAVI, as demonstrated in a meta-analysis of patients at low and moderate risk,9 as well as in the PARTNER and PARTNER 1 trials that involved high-risk patients with aortic stenosis.10,11 However, these trials tend to include patients suitable for the conventional access routes, although some are contraindicated for these first-line options. The success of all three endovascular procedures conceivably depends on the technical difficulties of fitting a stent graft or aortic valve to the aorta. The femoral approach retains its ubiquitous appeal among vascular surgeons because of it is minimally invasive,12–14 and it has recently been agreed by the American College of Cardiology (ACC) expert consensus panel as the vessel of choice for TAVI procedures.15 However, an estimated 20 % of patients undergoing TAVI are not suitable for the transfemoral approach because the

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Endovascular Procedures condition of the vessel makes this unfeasible. Similar observations have been made in patients undergoing EVAR, where 13 % of patients were deemed unsuitable for the transfemoral access, as reported in the European Collaborators on Stent-Graft Techniques for Abdominal Aortic Aneurysm Repair (EUROSTAR) registry.16

Figure 1: Transcarotid Thoracic Endovascular Aortic Repair and Endovascular Aortic Repair

Despite the feasibility of alternate access techniques such as the transapical, transaortic and transaxillary17 routes, patients with previous coronary bypass artery grafts, respiratory pathology, porcelain aorta or inadequate vessel size would normally be excluded from these approaches. Therefore, some patients are precluded from open surgery and first-line as well as alternative vessel access routes. This quandary may have been resolved when May et al. pioneered the use of the carotid artery as an access option.18 Although it is regarded as last resort in the ACC guidelines15 as well as in modern practice,19 it offers a shorter and direct route to the aorta from the site of entry with improved movement stability and accuracy of catheter delivery.17,20 The following sections will examine the transcarotid approach with contemporary evidence, as an alternative or even potentially first-line access route for endovascular interventions of the aorta.

Transcarotid Endovascular Repair and Thoracic Endovascular Repair Procedural Technicalities Figure 1 depicts an EVAR and a TEVAR performed via the carotid artery. Because of the relative infancy of the transcarotid method, there are inconsistencies in how the procedure is carried out. For instance, a range of preoperative investigations can be used to identify disease-free carotid arteries, including angiography, CT angiograms, angiography, MRI and transcranial Doppler. Once systemic anticoagulation has been administered, a low anterior neck incision will be made to expose either of the common carotid arteries. Typically, vessel access can be obtained using a 19-F gauge needle, followed by advancing a guidewire under fluoroscopic control into the aorta. A 5F pigtail catheter with 1 cm measurement markers is used to administer contrast to conduct an aortogram. An oblique arteriotomy is performed in the proximal common carotid artery to facilitate advancement of the endograft caudally over a flexible guidewire into the aorta. Targeted measures can be employed to reduce the inadvertent risk of both proximal and distal attachment site migration, given presence of ‘windsock’ forces, particularly at the former. This includes augmenting the systemic blood pressure and administering adenosine to induce temporary asystole during deployment of the proximal attachment site. Finally, a balloon can be used to dilate both proximal and distal sites to achieve optimal fixation.20,21 Angiographies should be performed to ensure correct positioning before releasing the caudal and cranial trigger wires. In addition, surgical adjuncts should be considered to prevent complications. Clamping the distal common carotid artery may help to prevent catheter-associated embolisation.20,22,23 Carotid–carotid or carotid–carotid–subclavian bypasses can also be performed to increase intraoperative cerebral perfusion.24

axillary artery, traditional access routes were rejected in favour of the right common carotid artery. This first case was successful and had no significant complications, providing novel insights into an untried method. Similar indications were observed in a separate case report of a patient with extensive calcific occlusive disease, which precluded him from the iliofemoral approach. Although there is an inherent risk of stroke from cerebral emboli or hypoperfusion, intraoperative surveillance by duplex ultrasound scanning or CT imaging allows for detection and prompt neurointervention. The risk of cerebral ischaemia associated with common carotid clamping is alleviated by collateral flow through the external carotid vasculature. It is therefore imperative that both carotid arteries are disease free so the endograft can be accommodated and cerebral perfusion maintained.

Neurological Complications

Neurological complications – or any complications for that matter – could be more likely to occur in patients with thoracic arch pathologies, where unfavourable arch anatomies jeopardise the relative ease and safety of carotid access. This was highlighted in a case report by Heidenreich et al.,25 where a patient experienced multifocal infarct as a result of dislodged emboli during the process of traversing through a diseased aorta. Therefore, patients with unfavourable angulation of the left common carotid artery in relation to the aorta, aortic tortuosity or bovine anatomy25 should be identified with preoperative carotid duplex assessment.

There is, unsurprisingly, a lack of enthusiasm for the transcarotid approach in both EVAR and TEVAR, which is evident from the dearth of literature. The first reported case of transcarotid EVAR was in a patient who required a proximal Type 1 endoleak repair following a large AAA repair.18 As the patient had torturous iliac vessels and a small

A combination of the following factors could reduce the risk of neurological complications: anticoagulation therapy; multiple shorter devices instead of one longer device; and attaining an ideal angle of approach.

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Carotid Figure 2: Transcarotid Transcatheter Aortic Valve Implantation

While the carotid artery has an advantage in having a wider diameter than other vessels, this may cease to be an issue in the light of technological advancements where newer devices with smaller sheath sizes could be the solution to the problems associated with smaller vessels.

Mortality To date, the only case of mortality was reported by Faccenna et al.,26 where the patient experienced multi-organ failure stemming from acute pancreatitis. Because of the his past medical history of necrotising pancreatitis, the patient had a higher risk of organ ischaemia. In spite of that, it is erroneous to interpret the mortality rate for transcarotid EVAR and TEVAR at this present stage. Moreover, patients who undergo this procedure typically have numerous comorbidities, which is why they have been precluded from surgical or first-line vessel options. Publication bias in these studies could partially explain the relatively low and comparable mortality rate, as evident in the EVAR 2 trial where 30-day mortality rate was 7.3 %.2 In the light of this, the authors recommend future research that consider cohort studies with larger sample sizes to establish any firm conclusions.

Transcarotid Transcatheter Aortic Valve Implantation Procedural Technicalities Figure 2 depicts TAVI performed via the carotid artery. The transcarotid approach for transcatheter aortic valve implantation remains an alternative approach when all other vessel or open surgery options have been rejected. Nonetheless, its adoption has been growing, as evident from the FRANCE-TAVI registry, which reported a 3.4 % proportion of transcarotid access.31 Much remains to be improved in terms of intraoperative monitoring, given the poor adoption rate of transcranial Doppler or stump pressure monitoring.24,26,27 One other tool to consider in future cases is cerebral oximetry, which is used in routine practice to monitor neurological changes during TAVI procedures.28

Other Complications Apart from neurological complications, EVAR and TEVAR are often associated with delayed endoleaks; however, only two cases so far have been reported on this potentially calamitous complication.2,29 Although access site complications such as infection or haematoma are important site-specific issues, no studies so far have reported any occurrences of the aforementioned. Nonetheless, we recommend future studies to be consistent in reporting these clinically important complications.

Choice of Common Carotid Artery to Access Another contentious issue is deciding which common carotid artery to access. Advocates of the right common carotid artery say it confers a more favourable angle of approach to the aortic arch,18 particularly for right-handed surgeons.20 However, this appears to hold true for the left common carotid artery as well, since it offers a straighter and more direct route to the descending aorta.25 Ultimately, choice depends on the diameter of the carotid artery itself, which is known to provide a large diameter entry site, although vessels tend to be larger in men than women.30 Given this, it is more important to make a choice based on prioritising larger-sized arteries with minimal occlusive disease over vessel site per se for successful deployment of the device, and this decision should be made on a case-by-case basis.

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Before starting the procedure, it is essential to conduct a Doppler study and CT angiography of the carotid and vertebral vasculature to assess carotid patency, as well as of the Circle of Willis to evaluate the risk of cerebrovascular hypoperfusion. The procedure is often performed in a hybrid operating theatre involving a multidisciplinary team of a vascular surgeon, interventional cardiologist, cardiac surgeon, anesthesiologist and radiology technician. Under general anesthesia, a vertical 2–3 cm incision can be made one or two fingers above the left clavicle to expose common carotid artery. The common carotid artery is then carefully dissected to avoid damaging the vagus nerve. To ensure catheter and sheath stability during intravascular navigation, another small incision 1 cm above the first incision can be made. To prolong activated clotting time to 250 seconds and beyond, intravenous heparin should be administered. Next, a 0.035-inch J-tipped soft guidewire can be employed to guide the pigtail catheter, followed by changing it to a straight-tip guidewire to cross the aortic valve. When finally pushed in to the left ventricle, the straight guidewire can be switched to a stiff guidewire. Thereafter, the valve system (CoreValve Evolut R, Edwards Sapien valves) can be loaded into the delivery system (EnVeo R, Medtronic), and their orientation checked. Once the catheter has progressed through the carotid artery and aorta, and properly positioned, the valve can be deployed without rapid pacing. It is important to assess for periprosthetic regurgitation using aortography before removing the carotid sheath. Once the procedure has been completed, the arterial access site can be sutured in a transversal fashion using PROLENE® sutures, with short clamping both proximally and distally to the access site.32–34

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Endovascular Procedures Mortality Encouraging evidence for the transcarotid approach has emerged, and it has gradually been accepted as the alternate access route in patients who are contraindicated for the transfemoral route. This was discernible in a single centre where 137 TAVI procedures were conducted employing transfemoral, transapical and transcarotid approaches.19 The main finding was that in-hospital mortality rates between the transcarotid and transfemoral approaches were comparable. Furthermore, the former had a shorter procedural time and patients had a shorter overall length of stay in the intensive care unit. Because of these positive findings, the transcarotid approach has become be the choice of alternative access route for that centre.19 Similar findings were observed in a landmark study of 174 patients who underwent transcarotid TAVI in two French centres.35 Here, 30-day mortality was 7.4 %, which compares favourably with the transfemoral and transapical approaches demonstrated in recent meta-analyses.36,37 This was recently corroborated in a systematic review of real-world evidence, which reported a pooled mortality rate of 4.1 % across 16 studies.28

Risk of Neurological Complications The risk of neurological complications, including ischaemic stroke and transient ischaemic attacks (TIAs) are the Achilles’ heel of this approach. However, registry data has been reassuring, and shows that preoperative imaging is critical to preventing cerebrovascular events. For instance, the in-hospital stroke rate was reported to be only 2 % in the FRANCE TAVI registry.31 Surgical adjuncts remain contentious. Carotid bypass or shunting have been advocated to maintain intraoperative cerebral perfusion38,39 but these compromise procedural time and increase the risk of complications.19 Instead, comprehensive preoperative evaluation has been espoused as the strategy of choice to monitor cerebral perfusion, as evident from the French Transcarotid TAVI Registry.34 Furthermore, concerns about distal carotid clamping were assuaged when Kirker et al. demonstrated the absence of in-hospital neurological complications arising from the procedure. This, however, required scrupulous attention to reduce occlusion time coupled with intraoperative monitoring of cerebral oxygen saturation using cerebral oximetry.19 The success of these techniques was bolstered by another group, which performed transcarotid TAVI on five patients, none of whom experienced cerebrovascular complications.40 Cerebral oximetry has long been established as a useful adjunct in carotid endarterectomy,41 and is likely to remain as the cornerstone of neurological monitoring in transluminal procedures involving the carotid artery. Clinical monitoring of the neurological status during a transient carotid artery cross-clamping test (awake testing), is an effective and simple method that should not be disregarded. Azmoun et al. champion awake testing as the optimum approach, even though it is limited to procedures performed under local anaesthesia. Furthermore, a temporary carotid shunt can be performed to potentiate passive antegrade carotid perfusion if the patient becomes intolerant to the cross-clamping test.42 The risk of stroke should not be taken lightly in spite of the relatively low incidence.43–45 Clinical trials have shown that the use of a cerebral protection device in patients with severe aortic stenosis undergoing TAVI reduced the risk of ischaemic cerebral lesions; however, adequately powered studies are still warranted to evaluate the efficacy of protection devices on neurological and cognitive function after a TAVI procedure.46 Until such devices are commercially available, technical modifications can be employed to abate the risk of debris entry into the brain. One such technique

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involves clamping the distal carotid artery with back-bleeding after successful deployment of the valve.19

Choice of Anaesthesia Another unresolved issue involves the type of anaesthetic procedure. The use of general anaesthesia (GA) has risks of obstructive sleep apnoea, aspiration and hypotonic hypopharyngeal muscles, all of which are potentially fatal complications in a typical TAVI patient, most of whom are elderly.47 However, these do not explain the occurrence of perioperative stroke. In addition, GA prohibits real-time monitoring of neurological status, leading to prolonged cerebral hypoperfusion.41 The use of local anaesthesia (LA) permits awake testing during carotid cross-clamping, which is believed by some to be more robust for conducting neurological assessment.42 Furthermore, cross-clamping engenders an increase in systemic blood pressure and consequent cerebral perfusion.48 Despite the theoretical and hypothetical differences between GA and LA, the largest randomised controlled trial to date that compared LA with GA (the GALA trial) in carotid endarterectomy reported no significant differences in the risk of perioperative stroke.49 This was supported by a Cochrane review that included a meta-analysis of pooled data from 14 trials;50 however, 75 % of all patients in the review were part of the GALA trial.49

Paucity of Evidence to Date The benefits of transcarotid TAVI have been well encapsulated in a systematic review28 and in a recently updated version.51 Although the pooled data suggest that the carotid artery may be a viable alternative, the overall quality of data is poor because of the paucity of RCTs. Selection bias is inherent and inevitable, since most patients included were already precluded from open surgery, transfemoral or transapical TAVIs because of unfavourable baseline characteristics. Despite the unmet need for future research to conduct RCTs, we recognise it may never be possible to perform a proper RCT given ethical considerations.

Conclusion The emergence of encouraging results has led to the adoption of the transcarotid approach for aortic interventions as an alternative access route for patients who are contraindicated for the transfemoral approach. However, technical details remain to be ironed out, including those of choice of anaesthesia, whether to use the left or right carotid artery and approaches to neurological monitoring. Given a large and proper RCT comparing transcarotid against transfemoral approaches is unlikely to be conducted, the authors cannot draw any firm conclusions from the current pool of literature. While recent retrospective cohort studies have encouragingly shown similar levels of safety and efficacy between transcarotid and transfemoral TAVI approaches,52,53 this must be interpreted in the context of known limitations, such as selection and confounding biases. In this light of this, it is inconceivable for prospective guidelines to recommend the carotid artery as the vessel of choice. The authors recommend future research that will consider cohort studies with large sample sizes. As to whether carotid access for aortic interventions is a “genius” or “madness”, judicious selection of patients on a case-by-case basis remains the most appropriate answer to this question. Current evidence does not allow us to conclude otherwise. n

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37. L iu Z, He R, Wu C, Xia Y. Transfemoral versus transapical aortic implantation for aortic stenosis based on no significant difference in logistic EuroSCORE: a meta-analysis. Thoracic Cardiovasc Surg 2016;64(5):374–81. https://doi. org/10.1055/s-0035-1555606. PMID:26121378. 38. Thourani VH, Gunter RL, Neravetla S, et al. Use of transaortic, transapical, and transcarotid transcatheter aortic valve replacement in inoperable patients. Ann Thorac Surgery 2013;96(4):1349–57. https://doi.org/10.1016/j. athoracsur.2013.05.068. PMID:23972931. 39. Thourani VH, Li C, Devireddy C, et al. High-risk patients with inoperative aortic stenosis: use of transapical, transaortic, and transcarotid techniques. Ann Thorac Surgery 2015;99(3):817–23; discussion 23–5. https://doi.org/10.1016/j. athoracsur.2014.10.012. PMID:25596868. 40. Campelo-Parada F, Rodes-Cabau J, Dumont E, et al. A novel transcarotid approach for implantation of balloon-expandable or self-expandable transcatheter aortic valves. Can J Cardiol 2016;32(12):1575.e9–1575.e12. https://doi.org/10.1016/j. cjca.2016.03.015. PMID:27181189. 41. O’Neill BP. Transcarotid transcatheter aortic valve replacement: not just a pain in the neck. JACC Cardiovasc Interv 2016;9(20):2121–3. https://doi.org/10.1016/j. jcin.2016.09.022. PMID:27765305. 42. Azmoun A, Amabile N, Ramadan R, et al. Transcatheter aortic valve implantation through carotid artery access under local anaesthesia. Eur J Cardiothorac Surg. 2014;46(4):693–8; discussion 698. https://doi.org/10.1093/ejcts/ezt619. PMID:24431170. 43. Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363(17):1597–607. https://doi.org/10.1056/ NEJMoa1008232. PMID:20961243. 44. Van Mieghem NM, El Faquir N, Rahhab Z, et al. Incidence and predictors of debris embolizing to the brain during transcatheter aortic valve implantation. JACC Cardiovasc Interv 2015;8(5):718–24. https://doi.org/10.1016/j.jcin.2015.01.020. PMID:25946445. 45. Holmes DR Jr, Brennan JM, Rumsfeld JS, et al. Clinical outcomes at 1 year following transcatheter aortic valve replacement. JAMA 2015;313(10):1019–28. https://doi. org/10.1001/jama.2015.1474. PMID:25756438. 46. Haussig S, Mangner N, Dwyer MG, et al. Effect of a cerebral protection device on brain lesions following transcatheter aortic valve implantation in patients with severe aortic stenosis: the CLEAN-TAVI randomized clinical trial. JAMA 2016;316(6):592–601. https://doi.org/10.1001/ jama.2016.10302. PMID:27532914. 47. Mayr NP, Michel J, Bleiziffer S, et al. Sedation or general anesthesia for transcatheter aortic valve implantation (TAVI). J Thorac Dis 2015;7(9):1518–26. https://doi. org/10.3978/j.issn.2072-1439.2015.08.21. PMID:26543597; PMCID:PMC4598507. 48. McCleary AJ, Dearden NM, Dickson DH, et al. The differing effects of regional and general anaesthesia on cerebral metabolism during carotid endarterectomy. Eur J Vasc Endovasc Surg 1996;12(2):173–81. https://doi.org/10.1016/ S1078-5884(96)80103-1. PMID:8760979. 49. GALA Trial Collaborative Group, Lewis SC, Warlow CP, et al. General anaesthesia versus local anaesthesia for carotid surgery (GALA): a multicentre, randomised controlled trial. Lancet. 2008;372(9656):2132–42. https://doi.org/10.1016/ S0140-6736(08)61699-2. PMID:19041130. 50. Vaniyapong T, Chongruksut W, Rerkasem K. Local versus general anaesthesia for carotid endarterectomy. Cochrane Database Syst Rev. 2013;(12):Cd000126. https://doi. org/10.1002/14651858.CD000126.pub4. PMID:24353155. 51. Wee IJY, Stonier T, Harrison M, Choong A. Transcarotid transcatheter aortic valve implantation: a systematic review. J Cardiol. 2018;71(6):525–33. https://doi.org/10.1016/j. jjcc.2018.01.010. PMID:29499894. 52. Watanabe M, Takahashi S, Yamaoka H, et al. Comparison of transcarotid vs transfemoral transcatheter aortic valve implantation. Circulation J 2018.Circ J. 2018. https://doi. org/10.1253/circj.CJ-18-0530. PMID:30068794; epub ahead of press. 53. Kallinikou Z, Berger A, Ruchat P, et al. Transcutaneous aortic valve implantation using the carotid artery access: feasibility and clinical outcomes. Archives of cardiovascular diseases. 2017;110(6–7):389–94. https://doi.org/10.1016/j. acvd.2016.10.005. PMID:28433509.

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