wenz iD - Doeke boersma

Mechanochemical endovenous ablation and new frontiers in venous intervention Doeke Boersma

Mechanochemical endovenous ablation and new frontiers in venous intervention Thesis, Utrecht University, The Netherlands Copyright Š by Doeke Boersma - 2016 Cover: Olieverf schilderij z.t., – Collectie Bauke Boersma Layout: wenz iD || Wendy Schoneveld Printing: Uitgeverij BOXpress || proefschriftmaken.nl ISBN: 9789462955356 Disclosures: The author declares that he has no competing interests. He is or was speaker for Deep Vein Medical Inc., FlebologiQ and Vascular Insights LLC. Studies described in chapter 6 and 7 were supported by an unrestricted research grant from Vascular Insights LLC. The study described in chapter 10 was supported by an unrestricted research grant from Deep Vein Medical Inc. Publication of this thesis was financially supported by: AngioCare, FlebologiQ, BioVentures Investors, Deep Vein Medical Inc., Vascular Insights LLC, Jeroen Bosch Academie & Maatschap Chirurgie Jeroen Bosch Ziekenhuis, BO Medical Technologies, Chirurgisch Fonds UMC Utrecht, Chemische Fabrik Kreussler & Co., ChipSoft

Mechanochemical endovenous ablation and new frontiers in venous intervention Mechano-chemische endoveneuze ablatie en nieuwe ontwikkelingen in veneuze interventies (met een samenvatting in het Nederlands)

Proefschrift ter verkrijging van de graad doctor aan de Universiteit van Utrecht op gezag van de rector magnificus, prof. dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op donderdag 19 januari 2017 des middags te 2.30 uur door

Doeke Boersma geboren op 23 april 1983 te Utrecht

Promotores: Prof. dr. F.L. Moll

Prof. dr. G.J. de Borst Copromotor: Dr. M.M.P.J. Reijnen

Financial support by the Dutch Heart Foundation for publication of this thesis is gratefully acknowledged.

There's nothing like it.

It gets in your blood and you can't get rid of it Sir Peter Blake, schipper Steinlager 2 Whitbread 1989-1990.

Voor Jet, Bauke en Feis

CONTENTS

OVERVIEW CHAPTER 1

Mechanochemical ablation of varicose truncal veins: An update on a non-tumescence technique

10

“Advances in Phlebology and Venous Surgery", Editor Prof. M. Whiteley 2016

CLINICAL ASPECTS CHAPTER 2

Treatment modalities for small saphenous vein insufficiency: Systematic review and meta-analysis

26

J Endovasc Ther. 2016 ;23:199-211

CHAPTER 3

Mechanochemical endovenous ablation of great saphenous vein incompetence using the ClariVein device: A safety study

48

J Endovasc Ther. 2011;18:328-334

CHAPTER 4

Mechanochemical endovenous ablation of small saphenous vein insufficiency using the ClariVein device: One-year results of a prospective series

58

Eur J Vasc Endovasc Surg. 2013;45:299-303

CHAPTER 5

Postoperative pain and early quality of life after radiofrequency ablation and mechanochemical endovenous ablation of incompetent great saphenous veins

68

J Vasc Surg. 2013;57:445-450

CHAPTER 6

Mechanochemical endovenous ablation versus radiofrequency ablation in the treatment of primary small saphenous vein insufficiency (MESSI trial): Study protocol for a randomized controlled trial Trials. 2014;15:421

82

HISTOPATHOLOGICAL ASPECTS CHAPTER 7

Macroscopic and histologic analysis of vessel wall reaction after mechanochemical endovenous ablation using the ClariVein OC device in an animal model

98

Accepted for publication in Eur J Vasc Endovasc Surg 2016

NEW FRONTIERS IN VENOUS INTERVENTIONS CHAPTER 8

Endovenous laser ablation of insufficient perforating veins: Energy is key to success

116

Vascular. 2016;24:144-149

CHAPTER 9

Proof-of-concept study of the VeinScrew: A new percutaneous venous closure device

128

Vascular 2016 [ePub ahead of print]

CHAPTER 10

Proof-of-concept study of the SailValve: A new self-expandable deep venous valve system

138

Accepted for publication in J Endovasc Ther 2016

DISCUSSION AND ADDENDA CHAPTER 11

General discussion

152

CHAPTER 12

Nederlandse samenvatting

160

CHAPTER 13

Review Committee Dankwoord List of publications and presentations Curriculum Vitae List of abbreviations

166 167 170 175 176

Overview

Chapter 1

Mechanochemical ablation of varicose veins: An update on a non-tumescence technique Chapter in "Advances in Phlebology and Venous Surgery", edited by Marc Whiteley 2016 Table 2 is derived from our manuscript "Mechanochemical endovenous ablation of saphenous veins using the ClariVein OC: a systematic review" as currently submitted.

Doeke Boersma, Ramon R.J.P. van Eekeren, Michel M.P.J. Reijnen, Jean-Paul P.M. de Vries

CHAPTER 1

INTRODUCTION Venous insufficiency of the lower extremities is a common condition and related to various symptoms, including venous ulcers. The effect of venous insufficiency on patients’ healthrelated quality of life is substantial and comparable with other chronic diseases such as arthritis, diabetes, and cardiovascular disease1. Superficial venous reflux, to a greater or lesser extent, will develop in approximately 40% of women and 20% of men during their lifetime2. These problems are mostly associated with insufficiency of great saphenous veins (GSVs); however, insufficiency of the small saphenous vein (SSV) is responsible for complaints in 15% of patients with varicose veins3. Until the 1990s, high ligation combined with surgical stripping was the gold standard in the treatment of GSV insufficiency, whereas standard of care in (surgical) treatment of SSV insufficiency was lacking.

The introduction of minimally invasive therapies has revolutionized the treatment of varicose veins. Chemical ablation, in which foam or liquid sclerotherapy is administered, is a widely used technique for truncal and reticular veins. Endothermal catheter modalities, including endovenous laser ablation (EVLA) and radiofrequency ablation (RFA), have become preferred techniques due to excellent success rates in both GSV and SSV4,5. In these techniques, the insufficient vein is ablated by heating the venous wall, but heat-related complications, such as prolonged pain, skin burns, and nerve injury, may occur despite tumescent anesthesia4-7.

Mechanochemical endovenous ablation (MOCA), using the ClariVein catheter (Vascular Insights, Madison, CT, USA), is a recently introduced treatment with a unique working mechanism. MOCA combines mechanical injury to the venous endothelium with simultaneous delivery and dispersion of sclerosant. Because no heat is generated during MOCA therapy, tumescent anaesthesia is no longer needed and thermal injury cannot occur.

ClariVein The concept of mechanochemical endovenous ablation and the ClariVein device were developed in 2005 by the interventional radiologist Michael Tal. During his work, he was confronted by patients with varicosities in which thermal ablation and foam sclerotherapy were both contraindicated. In animal experiments, Tal observed that the combination of mechanical injury with liquid sclerotherapy had superior results compared with both components individually. The best occlusion rate in these experiments was seen with the current design, which consists of an angle dispersion wire with a ball-shaped end. Selected data from these animal experiments were published in 20158. The ClariVein system is a single-use, disposable, two-component device: the catheter unit and the motor unit. The two components are distributed together in a sealed and sterilized package. The sclerosant is infused through the catheter unit, which consists of a 2.67F (0.89-mm diameter) catheter available in a length of 45 or 65 cm. A stainless steel wire is fitted within the lumen of the catheter. This dispersion wire has an angled tip with a small ball fitted to the end. When the components are disconnected, the catheter covers the angled tip. The catheter and

12

Introduction

wire are connected to a plastic base with a 3-way Luer-Lock port (Figure 1).

The 9-volt battery-powered motor unit is a white plastic handpiece. Once the two parts are connected, the wire tip protrudes from the catheter, and the motor can rotate the dispersion wire in various speeds, ranging from 2000 to 3500 rotations per minute (rpm).

A plastic holding clip is used to connect a 5-mL syringe to the Luer-Lock port. This syringe is used for flushing the system and infusing the sclerosing agent. When the device is connected, the hand piece allows steering the device, activating the motor by compressing the trigger with the index finger, and controlling simultaneous infusion of sclerosant with the thumb on the syringe.

1A

1B

H C T CL

FIGURE 1A ClariVein device consists of motor unit (H) and infusion catheter (C). Once the two are connected the dispersion tip (T) protrudes from the end of the infusion catheter (CL). B During positioning the dispersion tip is sheathed by the infusion catheter.

Treatment Preparation In the current (study) protocols, no preoperative analgesics, anticoagulants, or antibiotics are administered. The liquid sclerosant is prepared in the chosen concentration.

The ClariVein catheter is taken from the sterile package. The side port to the 3-way valve is capped with a stopcock, and the system is flushed with sterile saline. The valve is closed by turning the handle 45ยบ to avoid that blood will leak and clot in between the catheter and the metal wire during insertion of the device into the vein. Flushing the system with sclerosant is not advised due to the risk of clotting inside the catheter. The battery of the motor unit is checked. A small light-emitting diode is activated when the trigger is pulled.

The switch is set to the maximum speed of 3500 rpm. The motor will not start until both units are connected.

Access and placement The procedure to obtain percutaneous access to the varicose vein is similar to other endovenous techniques. Duplex ultrasound examination is used to plan the point of access

13

1

CHAPTER 1

distal to the insufficient part of the vein. A major advantage of the MOCA technique is that only local anesthesia is needed at the point of access. The patient is positioned supine with a cushion under the knee to enhance access to the medial part of the thigh when the GSV is insufficient or is positioned facedown when the SSV is treated. Ultrasound guidance is used to puncture the vein with an 18 gauge needle. A 4F sheath is introduced over a short guidewire.

The ClariVein catheter can be introduced via the sheath, without any additional guidewire.

The tip of the catheter is placed with ultrasound guidance at the planned location. Owing to the small calibre of the ClariVein device and the slightly angled tip of the sheath tip, it is easy to steer and position. A small plastic wing is attached to the base of the catheter unit to optimize rotatory steerability. When the catheter is placed in the proximal GSV or SSV, the wire tip is unsheathed by connecting the catheter and motor unit. To optimize safety, it is very important to visualize the ball shaped tip of the wire at the planned position (Figure 2). When the ball at the tip cannot be visualized, it should be assumed that the tip is placed too proximal, which risks injury to the deep venous system and deep venous thrombosis (DVT).

In the early experience, the tip was placed 2 cm distally from the saphenofemoral junction (SFJ). With growing experience, the distance in between tip and the SFJ has been shortened or just distal to the orifice of the superficial epigastric vein. In the more recent Dutch studies, the tip was positioned only 0.5 cm distal to the SFJ. For SSV ablation, the manufacturer advises positioning the tip distal to the fascial curve or 2 cm distal to insertion of the gastrocnemius vein.

Procedure Adequate placement of the tip is rechecked after the catheter and motor-unit are connected and the 5 mL syringe filled with sclerosant is attached. The motor is activated by pulling the trigger. The rotating tip will induce spasm to the proximal part of the vein. To obtain spasm, the motor is activated for 5-10 seconds without movement or infusion of sclerosant.

The spasm is considered important to prevent leakage of sclerosant into the deep veins.

The activated device is then pulled back 1 cm every 7 seconds. The sclerosant is administered simultaneously (Figure 3). Even though no tumescent anaesthesia is injected, pain has hardly been reported during the procedure, and some patients describe a tickling sensation. Directly after the procedure, the patient is asked to flex and extend the foot to let the calf muscle pump clear any sclerosant from the deep venous system. As with other endovenous ablation techniques, patients are recommended to walk immediately after the completion of MOCA. Patients are discharged with class 2 compression stockings (30-40 mm Hg) and advised to wear these continuously during the first 24 hours and during the daytime for the following 1-2 weeks.

Follow-up is planned 4 to 6 weeks after treatment to determine clinical success and to objectify anatomic success duplex ultrasound assessment is indicated. At this point, additional phlebectomies of sclerotherapy can be planned. In patients not included in clinical studies, the need for further follow-up after successful treatment can be debated.

14

Introduction

1

FIGURE 2 Ultrasound image shows the ball-shaped wire tip is positioned in the proximal great saphenous vein.

FIGURE 3 (a) The ClariVein device is placed in the planned position in the target vein. By connecting the catheter and the motor unit, the dispersion tip is unsheathed. The syringe filled with sclerosant is attached. (b) After induction of vasospasm solely by mechanical action, the activated device is pulled back and simultaneous infusion of sclerosant is controlled by operating the attached syringe. Acknowledgement: Figure 3 is reproduced with permission from Vascular Insights, LCC

Sclerotherapy Two types of sclerosant are used in clinical studies. In the studies from the United Kingdom, United States of America, and Australia, sodium tetradecyl sulfate (STS) (trademarks: Sotradecol, Bioniche Pharma Group, Geneva, Switzerland or Fibrovein, STD Pharmaceuticals, Hereford, UK) was infused in a 1.5% or 2% concentration. In the Dutch studies, polidocanol (trademark: Aetoxysklerol, Kreussler Pharma, Wiesbaden, Germany) was used in different concentrations. In an initial safety study, 1.5% polidocanol was administered. In an attempt to optimize technical success, the proximal part of the vein was treated with 2% polidocanol and the rest of the vein with a concentration of 1.5%.

The amount of used sclerosant is determined by the diameter and length of treated veins. A dosing table published by the manufacturer is available as a guideline (Table 1).

15

CHAPTER 1

It is important not to exceed the maximum allowed daily dosage, due to the possible side effects of the sclerosant.

TABLE 1 Dosing table for STS and polidocanol for non-US physicians. Acknowledgement: Table 1 is reproduced with permission from Vascular Insights, LCC

Patient selection The current studies give no explicit guideline for patient selection. The majority of patients included have long-segment varicose GSVs and SSVs with diameters ranging from 3 to 12 mm. No series of MOCA in larger diameters have been published so far. The mechanical effect on larger veins may be diminished by the 6.5 mm radius of the dispersion wire. As in other endovenous techniques, severe tortuosity may be considered an exclusion criterion. In general, a vein considered adequate for any other endovenous therapy is also accessible for MOCA. Although all published data consist of long-segment GSV and SSV, our experience is that MOCA is a technically feasible and effective

16

Introduction

treatment of short, anterolateral, and even perforating branches. In addition, Mueller et al9 published tips and tricks on treating miscellaneous varicosities.

Patients with allergies or any other contraindication to the sclerosant, history of ipsilateral deep venous thrombosis, coagulation disorders, or severe peripheral arterial disease are considered unsuitable for MOCA. There is no sufficient data on teratogenic effects of STS or polidocanol and therefore MOCA is discouraged during pregnancy.

RESULTS Clinical data: Since Food and Drug Administration approval in the United States in 2008 and ConformitĂŠ EuropĂŠene marking in Europe in 2010, several clinical studies have been conducted and published. Table 2 provides a complete overview of all published clinical data on MOCA10-22.

Safety studies: The first two studies focussed on feasibility and safety of the MOCA treatment and ClariVein device. The first to present and later publish their data were Elias et al. They treated 29 patients with GSV insufficiency in 30 limbs using the ClariVein catheter and Sotradecol 1.5%. The primary objectives were to determine overall safety of MOCA and the primary closure rate at 6 months. No major complications, defined as DVT, nerve injury or skin burn, were seen, and minor ecchymosis occurred in 10%. The anatomic success rate was 97% (29/30) at 6 months. Clinical success was not described.11 After introduction of the ClariVein device in Europe in 2010, a collaborative venous study group in the Netherlands were the first to publish a prospective observational study included 30 consecutive GSVs in 25 patients. Polidocanol was used in a 1.5% concentration. The main objectives were to evaluate technical feasibility and safety. Clinical and anatomic success were evaluated at 6 weeks of follow-up. To measure clinical success, the Venous Clinical Severity Score (VCSS) was assessed before treatment and after 6 weeks.

MOCA was technically feasible in all patients. Anatomical success was achieved in 26/30 limbs. Full recanalisation occurred in 1 limb. No major complications occurred. Local ecchymosis and hematoma at the puncture site were seen in up to 30%. Clinical success was illustrated by a significant decrease in VCSS from 3.0 (interquartile range, 2.0-4.75) to 1.0 (interquartile range, 0.25-3.0; P < .001)10.

Clinical cohorts and trails: Including the two safety studies described above, 13 clinical papers 10 cohorts were published from The Netherlands (5), United Kingdom (2), USA (2) and Australia (1). All study results are depicted in Table 2. Three patient cohorts were described in 2 serial publications, the data on these cohort were extracted from both publications and combined. Pooling of data led to a total 1521 veins treated with MOCA and analysed. In 5 cohorts polidocanol, in 4 STS, and in 1 both sclerosant were used in different concentrations.

17

1

18

P

30 30 0

POL 1.5%

100

Study design

Population Total GSV SSV

Sclerosant

Technical success, %

none

Major complications

none

n/a

n/a

n/a

n/a

29/30 (97)

29/30 (97)

100

STS 1.5%

30 30 0

P

USA

Elias 201211

57 51 6

n/a

Australia

Vun 201513

none

3 " 1*

n/a

n/a

44/47 (94)

n/a

50/50 (100)

100

n/a

n/a

n/a

n/a

n/a

n/a

52/57 (91)

n/a

POL 2% / 1.5% STS 1.5%

50 0 50

P

Netherlands

Boersma 201312

none

9,5 " 3*

n/a

60/65 (92)

75/79 (95)

84/89 (94)

126/126 (100)

100

STS or POL

126 126 0

P

USA

53 53 0

RCT

6 " 3*

n/a

n/a

n/a

n/a

46/53 (87)

n/a

2 PE / 2 DVT / none 1 paraesthesia

n/a

n/a

n/a

n/a

n/a

457/506 (90)ł

98

Microfoam

n/a

n/a

n/a

n/a

7/23 (30)

n/a

POL 1% microfoam

23 23 0

RCT

1 DVT

5 " 2*

n/a

n/a

n/a

54/62 (87)

64/69 (93)

n/a

STS 2.0%

83 77 6

RCT

none

n/a

n/a

n/a

n/a

n/a

382/393 (97)

100

STS 2.0%

393 333 60

P

UK

Bootun / Lane Tang 2014/2016†18,19 201620

Netherlands Netherlands UK

Liquid

Lam 201617

POL 2% / 1.5% POL 2 or 3%

570 438 132

n/a

Netherlands

Bishawi / Kim Deijen 2014/2016†14,15 201616

none

4 " 1*

42/48(87)

64/71(90)

90/102 (88)

96/103 (93)

n/a

99

POL 2% / 1.5%

106 106 0

P

Netherlands

Eekeren/ Witte 2014/201621,22

P, prospective cohort; RCT, randomized controlled trial; GSV, great saphenous vein; SSV, short saphenous vein; n/a not available; VCSS, Venous Clinical Severity Score; DVT, deep venous trombosis; PE pulmonary embolism. †two publications on same patient population; ł median follow up of 54 days (range 12 - 266 days) / anatomical success 92% in GSV / 87% in SSV; łłmedian follow up of 36 months (range 12.5 – 46.3 days) ;*statistically significant

3 " 1*

VCSS

Clinical success

n/a

3 years

n/a

1 year

n/a

n/a

6 months

2 years

26/30 (87)

up to 8 weeks

Anatomic success, n (%)

Netherlands

Country

Eekeren 201110

TABLE 2 Overview of results MOCA in published clinical studies

CHAPTER 1

Introduction

Technical success is 99%. Anatomical success is 93, 92, 91 and 87% after respectively 6 months, 1 year, 2 and 3 years. Although these results suggest long-lasting anatomical success rate around 90%, it should be appreciated that the number of cases with followup over 1 year is limited and lost-to-follow-up is significant.

The first and only study solely focussing on MOCA in SSV was published in 2012 and included 50 consecutive patients with primary long-segment SSV insufficiency. The first 15 patients were treated with polidocanol 1.5%. In the following 35 patients, 2% polidocanol was used to treat the proximal 10 to 15 cm and 1.5% was used to treat the remainder of the vein. Initial occlusion and anatomic success at 6 weeks were obtained in all 50 patients.

At the 1-year follow-up, the overall anatomic success was 94%, comprising 87% in the 1.5% group and 97% in 2% group (NS)12. Deijen et al. included within their very large cohort of 570 veins a total of 132 SSVs. Within this subgroup, they report an anatomical success rate of 85% and 80.5% after respectively 6 weeks and 3 months (although lost-to-followup was not mentioned)16.

Clinical success and pain scores were comparable with results from GSV studies.

The pooled data underline that MOCA is a safe treatment modality. Major complications are extremely rare. Deep venous thrombosis is seen in 0.3% and pulmonary embolism in 0.2%. Only 1 (<0.1%) case of transient paraesthesia is reported in a pooled cohort of 1464 treated veins. This is a clinically important message, especially in treating SSVs and GSVs below the knee5.

Pain studies In 2012, Van Eekeren et al published a prospective observational study in the Journal of Vascular Surgery on pain and health-related quality of life (HR-QoL) after MOCA compared with RFA. The study included 68 patients with unilateral GSV insufficiency, of which 34 were treated with MOCA and the other half with RFA (VNUS ClosureFast, VNUS Medical Technologies, Sunnyvale, CA, USA). Pain scores in the MOCA group during the 2 weeks after treatment were significantly lower in MOCA compared with RFA (Figure 4). Pain scores during treatment and complications were not significantly different between the groups in this study. Clinical symptoms (VCSS) and HR-QoL improved in both groups (NS)23.

Bootun et al. reported on intraprocedural painscores in a larger RCT, randomizing 119 legs between MOCA (60) and RFA (59) using Venefit (Covidien, San Jose, CA, USA). The mean VAS painscore during treatment was significantly lower in MOCA (2.6Âą2.2) compared to RFA (4.4Âą2.7) (P .001 ). Maximum procedural painscores were also significantly lower in MOCA. In line with the study above, the clinical and HR-QoL improved in both groups (NS)18.

Experimental data The working mechanism of MOCA is becoming more and more elucidate, due to the following experimental studies.

In 2015 Tal et al partially disclosed the data on the initial animal experiments by the manufacturing company. These results are very valuable, because they described the tissue reaction in a standardized model up to 12 weeks after MOCA. Duplex ultrasound showed

19

1

CHAPTER 1

occlusion in MOCA treated veins. All veins in the control groups (ClariVein without sclerosant or solely liquid sclerotherapy) remained fully patent. After MOCA, microscopy showed complete occlusion, wall thickening with endothelial injury and extensive fibrotic changes of the vein8.

A more recent large animal study, including 18 goats was conducted, focusing on tissue reaction after MOCA, mechanical injury and liquid sclerotherapy in both the acute and follow up setting. This acute experiments proof the hypothesis that MOCA improves the potency of liquid sclerosant by inducing (limited) endothelial injury combined with a distinct vasocontrictive effect. The endothelial injury might lead to easier penetration of the vein wall and vasoconstriction increase the effect of sclerosant by decreasing dilution of sclerosans and prolonging exposure of it to the vein wall. In the follow up experiments only showed occlusion in MOCA treated veins by organized thrombus formation and fibrotic changes. All veins in the control groups remains patent24.

FIGURE 4 Mean postoperative pain scores on a 0- to 100-mm visual analogue scale (VAS) during 14 days after mechanochemical ablation (MOCA) and radiofrequency ablation (RFA)23.

20

Introduction

Van Eekeren et al. are unique in describing histology of a human vein explanted 1 year after successful MOCA treatment. This vein was completely obliterated and histologically examined. In line with two animal studies described above, the microscopy revealed total disappearance of the endothelium with fibrotic neo-intima proliferation. The damage extended well into the media layer26.

21

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CHAPTER 1

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Boersma D, Kornmann VN, Eekeren RR, Tromp E, Unlu C, Reijnen MM, De Vries JP. Treatment modalities for small saphenous vein insufficiency: Systematic review and meta-analysis. J Endovasc Ther 2016; 23: 199-211.

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Van Eekeren RRJP, Boersma D, Elias S, Holewijn S, Werson DAB, De Vries JPPM, Reijnen MMJP. Endovenous mechanochemical Ablation of great saphenous vein incompetence using the ClariVein device: a safety study.

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Boersma D, Van Eekeren RRJP, Werson DAB, Reijnen MMJP, De Vries JPPM. Mechanochemical endovenous ablation of small saphenous vein insufficiency using the ClariVein® device: One-year results of a prospective series. Eur J Vasc Endovasc Surg 2013;45:299-303 Vun SV, Rashid ST, Blst NC, Spark JI. Lower pain and faster treatment with mechano-chemical endovenous ablation using ClariVein. Phlebology 2015;30:688-692.

Bishawi M, Bernstein R, Boter M, Draughn D, Gould CF, Hamilton C, Koziarski J. Mechano-chemical ablation in patients with chronic venous disease: a prospective multicenter report.Phlebology 2014; 29: 397–400.

Kim PS, Bishawi M, Draughn D, Boter M, Gould CF, Koziarski J, Bernstein R, Hamilton C. Mechanochemical ablation for symptomatic great saphenous vein reflux: a two-year follow up. Phlebology 2016 ePub ahead of print.

Deijen CL, Schreve MA, Bosma J, De Nie AJ, Leijdekkers VJ, Van den Akker PJ, Vahl A. Clarivein mechanochemical ablation of the great and small saphenous vein: early treatment outcomes of two hospitals.

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Lam YL, Toonder IM, Wittens CHA. ClariVein mechano-chemical ablation an interim analysis of a randomized controlled trial dose-finding study. Phlebology 2016;31:170-176.

Bootun R, Lane T, Dharmarajah B, Lim CS, Najem M, Renton S, Sritharan K, Davies AH. Intra-procedural pain score in a randomised controlled trial comparing mechanochemical ablation to radiofrequency ablation: the Multicentre Venefit versus ClariVein for varicose veins trial. Phlebology 2016;31:61-65 Lane T, Bootun R, Dharmarajah B, Lim CS, Najem M, Renton S, Sritharan K, Davies AH. A multi-centre randomised controlled trial comparingradiofrequency and mechanical occlusion chemically assited ablation of varicose veins - final results of the Venefit versus ClariVein for varicose veins trial. Phlebology 2016 ePub ahead of print.

Tang TY, Kam JW, Gaunt ME. ClariVein - Early results of a large single centre series of mechanochemical endovenous ablation for varicose veins. Phlebology 2016 ePub ahead of print.

Van Eekeren RRJP, Boersma D, Holewijn S, Werson DAB, De Vries JPPM, Reijnen MMJP. Mechanochemical endovenous ablation for the treatment of great saphenous vein insufficiency. J Vasc Surg: Venous and Lym Dis 2014;2:282-288 Witte ME, Holewijn S, Van Eekeren RR, De Vries JP, Zeebregts CJ, Reijnen MMPJ Reijnen. Mid-term outcome of mechanochemical endovenous ablation for the treatment of great saphenous vein insuffiency. J Endovasc Ther. 2016 ePub ahead of print Van Eekeren RRJP, Boersma D, Konijn V, De Vries JPPM, Reijnen MMJP. Postoperative pain and early quality of life after radiofrequency ablation and mechanochemical endovenous ablation of incompetent great saphenous veins. J Vasc Surg 2013;57:445-450

Introduction

24. Boersma D, Van Haelst STW, Van Eekeren RRJP, Vink A, Reijnen MMJP, De Vries JPPM, De Borst GJ. Macroscopic and histologic analysis of vessel wall reaction after mechanochemical endovenous ablation using the ClariVein OC device in an animal model. Accepted Eur J Vasc Endovasc 2016 25. van Eekeren RR, Hillebrands JL, van der Sloot K, de Vries JP, Zeebregts CJ, Reijnen MM. Histological observations one year after mechanochemical endovenous ablation of the great saphenous vein. J Endovasc Ther. 2014;21(3):429-433 26. McAree B, Ikponmwosa A, Brockbank K, Abbott C, Homer-Vanniasinkam S, Gough MJ. Comparative stability of sodium tetradecylsulphate (STD) and polidocanol foam: impact on vein damage in an in-vitro model. Eur J Vasc Endovasc Surg 2012;43:721â&#x20AC;&#x201C; 725.

23

1

Clinical aspects

Chapter 2

Treatment modalities for small saphenous vein insufficiency: Systematic review and meta-analysis J Endovasc Ther. 2016 ;23(1):199-211

Doeke Boersma, Verena N.N. Kornmann, Ramon R.J.P. van Eekeren, Ellen Tromp, Çagdas Ünlü, Michel M.J.P. Reijnen, Jean-Paul P.M. de Vries.

CHAPTER 2

ABSTRACT Purpose To investigate and compare the anatomical success rates and complications of the treatment modalities for small saphenous vein (SSV) incompetence.

Methods A systematic literature search was performed in PubMed, EMBASE, and the Cochrane Library on the following therapies for incompetence of SSVs: surgery, endovenous laser ablation (EVLA), radiofrequency ablation (RFA), ultrasound guided foam sclerotherapy (UGFS), steam ablation, mechanochemical endovenous ablation, and cyanoacrylate glue ablation. Methodical quality of the included studies was evaluated using the MINORS score.

The primary outcome was anatomical success, defined as closure of the treated vein on follow-up duplex ultrasound imaging. Secondary outcomes were technical success and complications.

Results The search identified 1157 manuscripts, of which 49 were included (5 randomized controlled trials; 44 cohort studies). The pooled anatomical success rate of surgery in these patients was 58.0% (95% confidence interval [CI], 40.9%-75.0%), 98.5% (97.7%-99.2%) for EVLA, 97.1% (94.3%-99.9%) for RFA , and 63.6% (47.1%-80.1%) for UGFS. One study reported results of mechanochemical endovenous ablation, with an anatomical success rate of 94%.

Neurologic complications were most frequently reported after surgery (mean, 19.6%) and thermal ablation (EVLA: mean, 4.8%; RFA: mean, 9.7%). Deep venous thrombosis is a rare complication. All studies were of moderate or good quality using the MINORS scoring scale.

Conclusion Endovenous thermal ablation (EVLA/ RFA) should be preferred to surgery and foam sclerotherapy in the treatment of SSV incompetence. Although data on non-thermal techniques in SSV is still sparse, the potential benefits, especially the reduced risk of nerve injury, might be of considerable clinical importance .

28

Meta-analysis on treatment of SSV

INTRODUCTION Chronic venous insufficiency (CVI) of the lower limbs is a common disorder: the Bonn Vein Study demonstrated a prevalence of superficial vein reflux of 21% in the adult population, which increased linearly with age1. Some clinical signs of CVI are present in approximately 10% of all adults2. CVI has been associated with decreased general and disease-specific quality of life3,4. Although superficial venous disease has frequently been associated with great saphenous vein (GSV) incompetence, small saphenous vein (SSV) reflux is responsible for approximately 15% of all varicose vein disease5. In addition, saphenopopliteal and SSV incompetence may result in complaints of equal severity compared with GSV incompetence5.

For more than a century, surgical high ligation, with or without stripping or compression therapy, was the only treatment option of truncal venous incompetence6. In contrast with the surgical treatment of GSV incompetence, there was no uniformity in the surgical treatment of SSVs among vascular surgeons. SSV surgery is considered more challenging and is associated with higher recurrence and complication rates7. The close anatomical location of the sural nerve to the SSV poses increased risks of nerve injury. Owing to anatomical variations, the proximal SSV/ saphenopopliteal junction (SPJ) is not adequately identified in 22% of patients, even after preoperative ultrasound localization8. There is a higher rate of recurrence in limited surgical exploration, whereas the risk of complications increases with the extent of exploration9.

The treatment of varicose veins has been revolutionized in recent decades by the introduction of minimally invasive endovenous ablation techniques. Many clinical studies of endothermal ablation in the GSV have shown excellent results; however, less is known about the optimal therapy for SSV incompetence10.

This systematic review and meta-analysis summarizes and compares the outcomes and major complications of the available treatment modalities for incompetent SSVs, including surgery, endovenous laser ablation (EVLA), radiofrequency ablation (RFA), ultrasound-guided foam sclerotherapy (UGFS), steam ablation and the more recently introduced mechanochemical ablation (MOCA) and cyanoacrylate glue ablation.

MATERIALS AND METHODS A structured literature search was performed using the guidelines outlined in the Cochrane Handbook for Systematic Interventions (version 5.1.0) and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)11,12.

Search strategy Three different biomedical bibliographic databases (PubMed, EMBASE, and the Cochrane Library) were used to perform a systematic search for all English literature. Search terms were all differently spelled text words or abbreviations on (“vein incompetence”, “varicose vein”, “small saphenous vein”, “venous reflux”) and (“stripping”, “saphenopopliteal

29

2

CHAPTER 2

ligation”, “saphenopopliteal disconnection”, “endovenous laser”, “endovenous ablation”, “foam sclerotherapy”, “radiofrequency ablation”, “mechanochemical ablation”, “steam”, “VNUS”, “ClariVein”, “Sapheon”, “cyanoacrylate glue”) and (“outcome”, “results”, “success rate”, “failure rate”, “complications”, “obliteration”, “occlusion”, “recurrence”, “recanalization”, “reflux”, “pain”, “return to normal activities or work”, “haematoma”, “paresthesia”, “nerve injury”, “wound infection”, “deep vein thrombosis”, “thromboembolism”) in the title, abstract, and medical subject heading (MeSH). We also searched the new specialty journal currently not indexed in the databases, the Journal of Vascular Surgery: Venous and Lymphatic Disorders. Search was performed in July 1st, 2015.

Validity assessment Two authors (D.B., V.K.) independently assessed the methodological quality of the articles using the Cochrane collaboration checklist and MINORS (Methological index for nonrandomized studies) quality score13. The Oxford Centre for Evidence-Based Medicine levels of evidence was noted for each included study14. Disagreement was resolved by discussion and consensus.

Inclusion and exclusion criteria Types of studies All manuscripts that included patients treated for SSV incompetence and with the primary outcome were eligible for inclusion in this review. Exclusion criteria were an unavailable full text (in 5 different Dutch university medical libraries), case reports, studies with 5 treated legs or less, studies on GSV incompetence, and recurrent SSV incompetence.

Studies describing cohorts with not solely SSV incompetence were only included if the data for patients with SSV incompetence could be specifically extracted from the study results. If more than one study reported the same patient cohort, only the most recent and complete manuscript was included in this review. Finally, the same criteria were used to screen all cross-references for potentially relevant studies not identified by the initial literature search.

Types of participants Included were patients with SSV incompetence who were treated with surgical stripping, SPJ ligation/disconnection, EVLA, RFA, foam sclerotherapy, MOCA, steam ablation, and cyanoacrylate glue ablation.

Types of outcome measures The primary outcome was anatomical success, defined as closure and absence of reflux on duplex ultrasound (DUS) imaging15. All of the included studies used DUS imaging to evaluate patients. Secondary outcomes were initial technical success and major complications.

30

Meta-analysis on treatment of SSV

Data extraction Two independent reviewers (D.B., V.K.) extracted data from the manuscripts by using a predetermined standardized extraction form. When studies included patients with treatment of both GSV and SSV, only the data of patients with SSV were extracted. Data were collected for all of the aforementioned treatment modalities.

Definition Outcome measures for success were described as “closure”, “occlusion”, “obliteration”, or “ablation.” Secondly, some studies described failure instead. Terms such as “recurrence”, “reflux”, “recanalization”, “patent”, or “open” were used. Failure rates were deducted from 100%, to standardize the primary outcome. Initial technical success, defined as the absence of technical failure, was the ability to complete the procedure as planned and the absence of recurrent reflux in target veins as demonstrated with DUS scanning15.

Two major complications were scored: deep venous thrombosis and nerve injury. Nerve injury was reported differently throughout the manuscripts as (sural) nerve injury, numbness, or paresthesia. The different terms describing persisting or transient nerve injury were pooled and defined as paresthesia in our review. Other (minor) complications (e.g. superficial phlebitis, haematoma, superficial infection and skin staining), postinterventional pain, clinical success, and satisfaction were poorly described and were excluded from analyses.

Data analysis Data were extracted from the studies and pooled into a database for each treatment modality. Outcomes were separately described. The number of legs per study at the start of the study was noted. For follow-up, the mean duration of follow-up per study was used.

Loss to follow-up was not included in the calculation of the anatomical success rates.

A meta-analysis was performed for the primary outcome of anatomical success. To provide a reliable outcome and to gain sufficient homogeneity of the pooled data, only 3 or more studies, with MINORS scoring scale of at least 8 and a minimum follow-up of 6 months were used for pooled analyses. Rates were pooled using a random-effects model. The presence of heterogeneity among the studies was determined by using a forest plot and by performing a χ2 heterogeneity test. The I2 index was calculated. Differences between treatments were assessed by Mann-Whitney-U test. All probability values are two-tailed and p < 0.05 was used as level of significance.

The secondary outcomes, technical success and major complications, were calculated for each treatment modality and were corrected for the number of treated legs for each treatment modality (weighted means).

Data were analyzed using SPSS 21.0 statistical software or MetaAnalyst 3.1 software.

31

2

CHAPTER 2

RESULTS The literature search included 1157 abstracts (Figure 1), of which 1013 were excluded for the following reasons: not written in English, review, study protocol, case reports, solely GSV, duplicate studies, and other study aim or subject (i.e., hemodynamic assessment, different analgesics, skin condition, anomalies). We analyzed 144 full text articles and excluded 95 articles (Figure 1). Finally, 49 manuscripts were included in the present systematic review. Data from the included studies were pooled and divided over the different treatment modalities: surgery (n = 9), EVLA (n = 28), RFA (n = 9), foam sclerotherapy (n = 6), and other therapies (n = 1). Two studies described two patient cohorts (surgery and EVLA)17,19. One study described three patient cohorts (surgery, EVLA and foam sclerotherapy)18. Characteristics of all studies are described in Tables 1-4. All studies were of moderate to good quality using the MINORS scoring scale (Table 6 A-B, Appendix A).

1. Surgery Nine manuscripts described surgical treatment of 798 SSVs (Table 1)8,17-24. One study included 679 legs, of which only 52 underwent follow-up with DUS imaging24. Only these 52 legs were included in the analysis of anatomical and technical success. Uniformity was lacking among the chosen surgical procedures, which and included ligation and/or disconnection of the SPJ, with or without stripping. The anatomical success rates were 24% to 94% with a mean follow-up of 17.3 months. Two studies randomized between surgery and EVLA, and both showed inferior anatomical success rates for surgery17,19. One study randomized between surgery, EVLA and foam, and showed inferior anatomical success rates compared with EVLA, but comparable results with foam sclerotherapy18. Allegra et al22 reported longterm anatomical success in 70% of 132 SSVs after 5 years of follow-up. Paresthesia occurred in up to 31% (mean 19.6%) and deep vein thrombosis (DVT) in 0.7%. Data were inconclusive to show superiority of one of the surgical treatment modalities.

2. Endovenous laser ablation EVLA was described in 2950 SSVs reported in 28 manuscripts (Table 2)17-19,25-49. Most of the included studies were individual cohort studies. Two RCTs randomized between EVLA and surgery17,19 and one study between EVLA, surgery and foam18. Another study randomized patients between cannulation of the SSV at the malleolar level versus cannulation at midcalf level32. Studies were heterogeneous regarding energy deliverance.

Wavelengths differed between and even within the 28 studies: 810 nm (n =14), 940 nm (n = 3), 980 nm (n = 8), 1320 nm (n = 1), and 1470 nm (n = 7). One study did not clearly describe the wavelength of the laser. Moreover, pulsed and continuous modes were both used, and there was no uniform amount of Joules per centimeter (range, 15-300 J/cm).

Mean follow-up was 12.5 months (range, 2 weeks - 48 months) for all studies. In almost all studies, patients underwent additional therapies. Mean technical success was almost 100% (range, 95%-100%). DVT was seen in 0.8% of all patients, and postprocedural paresthesia was described in 4.8%.

32

Meta-analysis on treatment of SSV

Potentially relevant articles identified from PubMed, Medline, EMBASE, Cochrane, and cross-references (n = 1157) Excluded after removing duplicates and screening title/abstract (n =1013)

Studies that met inclusion criteria based on title and abstract (n = 144)

Studies included in this systematic review (n = 49)

2

Excluded after reviewing full-text articles (n =95) • No extractable data (n = 39) • Incomplete or missing data (n = 17) • Our primary aim was not reported (n = 9) • Combined therapies (n = 4) • No small saphenous veins (n = 16) • Small cohort (n = 4) • Overlapping study cohorts (n = 6)

Surgery (n = 9)a,b Endovenous laser ablation (n = 28)a,b Radiofrequency ablation (n = 9) Foam sclerotherapy (n = 6)b Other therapies (n = 1)

FIGURE 1 Flow chart of the search strategy. a Two studies described surgery vs endovenous laser ablation. bOne study described surgery vs endovenous laser ablation vs foam sclerotherapy.

3. Radiofrequency ablation Nine manuscripts reported the results of RFA in 386 legs (Table 3)50-58. Three studies only included patients with SSV incompetence52,53,57. The studies reported an initial technical success rate of 100%. The anatomical success after a mean follow-up of 14.3 months ranged from 82% to 100%. Five studies reported results of the ClosureFast device (VNUS, San Jose, CA, USA/Covidien, Mansfield, MA, USA)54-57. One study analyzed the use of a double heat cycle during RFA with the ClosureFast device50. One study used the ClosurePlus catheter in the initial stages of the study but changed to ClosureFast in the latter stages52.

Studies by Doerler and Boon used the bipolar Celon device (Olympus, Hamburg, Germany)51,58. Complications were poorly reported: 5 study described a mean DVT rate of 1.2%, ranging from 0 to 8%. Paresthesia was seen in 9.7% (mean). Park et al described paresthesia in 26% of patients. RFA in some patients in this cohort was performed by proximal ligation and retrograde ablation52.

33

CHAPTER 2

Reference

Year

Country

Period

Design

Level of evidence

MINORS

Sample size (legs)

Anesthesia

TABLE 1A General characteristics – Surgery

Nandhra et al. 17

2015

UK

2005-2010

RCT

1b

22

53

GA

Brittenden et al. 18

2015

UK

2008-2012

RCT

1b

23

37

GA, RA

Roopram et al. 19

2013

The Netherlands

NR

RCT

1b

22

57

GA or SA

Ikponmwosa et al. 20

2010

UK

NR

P

2b

11

90

GA

O’Hare et al.

21

2008

UK

2002-2005

P

2b

13

234

GA or SA

Allegra et al. 22

2007

Italy

1989-2001

P

2b

13

132

GA + TA

Dumas et al. 23

2007

The Netherlands

2001-2004

RCT

1b

18

84

GA or SA

Whiteley et al. 24

2006

UK

NR

NR

NR

7

52*

GA

Rashid et al. 8

2002

UK

1998-2001

R

2b

10

59

GA

Data of patients with SSV incompetence; NR, not reported; RCT, randomized controlled trial; R, retrospective; P, prospective; Level of evidence: 1b - individual randomized controlled trial, 2b - individual cohort study; SA, spinal anesthesia; GA, general anesthesia; TA, tumescent anesthesia; RA, regional anesthesia. *Only 52 of 679 legs underwent follow-up DUS.

Complications

Follow-up

Nandhra et al. 17

Phlebectomy, stripping

24 months Recurrence 66%

100% DVT NR / Paresthesia 6.8%*

Brittenden et al. 18

Phlebectomy

6 months

NR

DVT 0% / Paresthesia NR

Roopram et al. 19

NR

1.5 months Occlusion

NR

DVT 0% / Paresthesia 31.0%

97%

DVT 0% / Paresthesia 9%

Recurrence 56% 67%

Recurrence 62%

Technical success

Additional therapy

Anatomical success

Reference

Definition of outcome

TABLE 1B Results – Surgery

Ikponmwosa et al. 20 NR

2 months

O’Hare et al. 21

NR

12 months Recurrence 40%

NR

DVT 0% / Paresthesia 23%

Allegra et al. 22

NR

60 months Recurrence 70%

NR

DVT NR / Paresthesia NR

Dumas et al. 23

Sclerotherapy/ Surgery GSV

3.8 months Recurrence 24%

NR

DVT 2% / Paresthesia 27%

Whiteley et al. 24

Surgery GSV NR and/or perforators

Rashid et al. 8

Surgery GSV

Recurrence 94%** 100% DVT 2% / Paresthesia 11%***

1.5 months Recurrence 39%

59%

DVT 3% / Paresthesia NR

Data of patients with SSV incompetence; NR, not reported; *paresthesia occurs in 26% at 6 weeks; at 24 months paraesthesia persists in 7%. **minor revascularization of treated track in 3 of 52 legs. ***percentages reflect to the total group of 679 legs after SSV surgery.

34

Meta-analysis on treatment of SSV

Brittenden et al.

Country

Period

Design

Level of evidence

MINORS

Sample size (legs)

Anesthesia

Nandhra et al. 17

Year

Reference

TABLE 2A General characteristics â&#x20AC;&#x201C; Endovenous laser ablation

2015

UK

2005-2010

RCT

1b

22

53

TA

2

2015

UK

2008-2012

RCT

1b

23

14

LA, TA

Aktas et al. 25

2015

Turkey

2013-2014

P

2b

14

52

TA

Park et al.

18

2014

Korea

2011-2013

R

2b

10

103

TA

Spreafico et al. 27

2014

Italy

2008-2012

P

2b

14

62

TA

Moul et al. 28

2014

USA

2007-2011

R

2b

10

105

TA

Murli et al.

26

2013

Malaysia

2010-2011

R

2b

13

57

GA, SA

Von Hodenberg et al. 30

2013

Germany

2008-2009

P

2b

13

41

TA

Roopram et al.

29

2013

The Netherlands

NR

RCT

1b

22

118

TA

Ozkan et al. 31

2012

Turkey

NR

P

2b

11

28

TA

Doganci et al. 32

2011

Turkey

2009-2010

RCT

1b

19

68

TA

19

Desmyttere et al.

2010

France

2003-2006

P

2b

12

147

TA

Janne dâ&#x20AC;&#x2122;Othee et al. 34

2010

USA

NR

R

2b

12

67

TA

Ravi et al.

2009

USA

2002-2009

R

2b

11

269

LA

2009

Netherlands

2006-2008

P

2b

12

169

GA, TA

33

35

Huisman et al. 36 Konthothanassis et al.

2009

Italy, France

2003- 2007

NR

NR

9

229

TA

Nwaejike et al. 38

2009

UK

2004-2009

P

2b

13

66

LA

Myers et al. 39

2009

Australia

2002-2007

P

2b

12

96

TA

Pannier et al.

37

2009

Latvia, Netherlands

2006-2007

P

2b

12

26

TA

Hamel et al. 41

2009

France, Switzerland

NR

R

2b

8

309

TA

Elmore et al.

40

2008

USA

2001-2006

R

2b

9

32

TA

Trip-Hoving et al. 43

2008

Netherlands

2007

R

2b

12

52

TA

Jung et al. 44

2008

Korea

2003-2006

R

2b

10

41

TA

Park et al.

2008

Korea

2003-2006

P

2b

12

390

TA

2007

USA

NR

P

2b

12

210

TA

42

45

Gibson et al. 46 Theivacumar et al.

2007

UK

2004-2006

P

2b

10

68

TA

Perkowski et al. 48

2004

USA

2002-2003

NR

NR

9

37

TA

Proebstle et al. 49

2003

Germany

NR

P

2b

11

41

TA

47

Data of patients with SSV incompetence; NR, not reported; RCT, randomized controlled trial; R, retrospective; P, prospective; Level of evidence: 1b - individual randomized controlled trial, 2b - individual cohort study; SA, spinal anesthesia; GA, general anesthesia; LA, local anesthesia; TA, tumescent anesthesia.

35

36

Phlebectomy, foam

Retreatment EVLA

Sclerotherapy

Phlebectomy, sclerotherapy

Phlebectomy, sclerotherapy

Phlebectomy, sclerotherapy

Sclerotherapy

NR

Retreatment EVLA, sclerotherapy

None

Phlebectomy

Sclerotherapy

Phlebectomy, sclerotherapy

Phlebectomy, sclerotherapy

Phlebectomy, sclerotherapy, surgery perforators 36 months

Phlebectomy, sclerotherapy

Sclerotherapy

Phlebectomy

Phlebectomy, sclerotherapy

Sclerotherapy

NR

Phlebectomy, sclerotherapy

Phlebectomy, sclerotherapy

EVLA GSV, phlebectomy, Sclerotherapy, perforator surgery

Sclerotherapy

Phlebectomy

None

Brittenden et al. 18

Aktas et al. 25

Park et al. 26

Spreafico et al. 27

Moul et al. 28

Murli et al. 29

Von Hodenberg et al. 30

Roopram et al. 19

Ozkan et al. 31

Doganci et al. 32

Desmyttere et al. 33

Janne d’Othee et al. 34

Ravi et al. 35

Huisman et al. 36

Konthothanassis et al. 37

Nwaejike et al. 38

Myers et al. 39

Pannier et al. 40

Hamel et al. 41

Elmore et al. 42

Trip-Hoving et al. 43

Jung et al. 44

Park et al. 45

Gibson et al. 46

Theivacumar et al. 47

Perkowski et al. 48

Proebstle et al. 49

Recurrence

Occlusion

Occlusion

Occlusion

Occlusion

Occlusion

Occlusion

Occlusion

Occlusion

Occlusion

Occlusion

Occlusion

Recurrence

Occlusion

Occlusion

Recurrence

Occlusion

Recurrence

Recurrence

Occlusion

Occlusion

Recurrence

Occlusion

Recurrence

Recurrence

Recurrence

Recurrence

Recurrence

Definition of outcome

Data of patients with SSV incompetence; NR, not reported; DVT, deep venous thrombosis.

6 months

12 months

6 months

4 months

9 months

3 months

6 months

15 months

6 months

11 months

48 months

1,5 months

3 months

2 wks

8 months

36 months

6 months

6 months

1.5 months

12 months

24 months

24 months

12 months

12 months

12 months

6 months

24 months

Phlebectomy, stripping, sclerotherapy

Nandhra et al. 17

Follow-up

Additional therapy

Reference

TABLE 2B Results – Endovenous laser ablation

100%

100%

100%

96%

94%

93%

100%

96%

100%

100%

95%

100%

99%

98%

93%

99%

97%

100%

96%

91%

100%

98%

100%

100%

98%

100%

100%

81%

Anatomical success

95%

100%

100%

100%

100%

NR

100%

NR

99%

100%

99%

100%

100%

NR

NR

100%

100%

100%

100%

NR

100%

NR

100%

100%

100%

NR

NR

100%

Technical success

DVT 3% / Paresthesia 11%

DVT 0% / Paresthesia 0%

DVT 0% / Paresthesia 4%

DVT 5.7% / Paresthesia 1.6%

DVT 0% / Paresthesia 2%

DVT 0% / Paresthesia 12%

DVT 2% / Paresthesia 6%

DVT 0% / Paresthesia 9.4%

DVT 0.3% / Paresthesia 1%

DVT 0% / Paresthesia 9.5%

DVT 2.1% / Paresthesia 1%

DVT 0% / Paresthesia 0%

DVT 1.3% / Paresthesia 2.2%

DVT 0% / Paresthesia 1.3%

DVT 0% / Paresthesia NR

DVT 0% / Paresthesia 3%

DVT NR / Paresthesia 40%

DVT 0% / Paresthesia 10.3%

DVT 0% / Paresthesia 0%

DVT 0.9% / Paresthesia 6.7%

DVT 0% / Paresthesia 0%

DVT NR / Paresthesia NR

DVT 0% / Paresthesia 0%

DVT 0% / Paresthesia NR

DVT 0% / Paresthesia NR

DVT 0% / Paresthesia NR

DVT 0% Paresthesia NR

DVT NR / Paresthesia 2.4%

Complications

CHAPTER 2

Slovenia, Austria

2015

2015

2014

2013

2013

2012

2012

2012

2010

Schuller-Petrović et al. 50

Doerler et al. 51

Park et al. 52

Harlander-Locke et al. 53

Choi et al. 54

Gabriel et al. 55

Bisang et al. 56

Monahan et al. 57

Boon et al. 58

2007-2009

2007-2008

2007-2009

2005-2011

2009-2011

2008-2012

2007-2012

2009-2011

2007-2011

Period

P

R

R

R

R

NR

NR

R

R

Design

2b

2b

2b

2b

2b

NR

NR

2b

2b

Level of evidence

11

12

10

12

12

10

10

10

9

MINORS

76

27

16

12

41

80

46

21

67

Sample size (legs)

SA or GA ± TA

TA

TA

NR

GA, SA or TA

GA, LA

TA

TA

TA

Anesthesia

36 months

Phlebectomy, sclerotherapy

NR

High ligation

Phlebectomy

Phlebectomy

None

NR

Phlebectomy/ RFA GSV

Phlebectomy, Crossectomy, sclerotherapy

Schuller-Petrović et al. 50

Doerler et al. 51

Park et al. 52

Harlander-Locke et al. 53

Choi et al. 54

Gabriel et al. 55

Bisang et al. 56

Monahan et al. 57

Boon et al. 58

Occlusion

Occlusion

Occlusion

Occlusion

Occlusion

Occlusion

Recurrence

Occlusion

Recurrence

100%

96%

100%

100%

95%

99%

89%

82%

100%

Definition of outcome Anatomical success

Data of patients with SSV incompetence; NR, not reported; DVT, deep venous thrombosis.

3 weeks

3 months

12 months

72 hours

14 months

6 months

27 months

22 months

Follow-up

Additional therapy

Reference

TABLE 3B Results – Radiofrequency ablation

100%

100%

100%

100%

100%

NR

NR

NR

100%

Technical success

DVT NR / Paresthesia 1.3%

DVT 8% / Paresthesia NR

DVT 0% / Paresthesia NR

DVT 0% / Paresthesia 0%

DVT NR / Paresthesia NR

DVT 0% / Paresthesia NR

DVT 0% / Paresthesia 26.1%

DVT NR / Paresthesia 9.5%

DVT NR / Paresthesia NR

Complications

Data of patients with SSV incompetence; NR, not reported; R, retrospective; P, prospective; Level of evidence: 2b - individual cohort study; SA, spinal anesthesia; GA, general anesthesia; LA, local anesthesia; TA, tumescent anesthesia.

The Netherlands

USA

Switzerland

USA

Korea

USA

Korea

Germany

Country

Year

Reference

TABLE 3A General characteristics – Radiofrequency ablation

Meta-analysis on treatment of SSV

2

37

38 NR

NR

2005-2007

2004-2007

2006-2010

2008-2012

Period

NR

NR

NR

P

P

RCT

Design

NR

NR

NR

2b

2b

1b

Level of evidence

10

11

10

14

13

23

MINORS

283

23

12

92

49

35

Sample size (legs)

NR

NR

NR

NR

LA

NR

Anesthesia

1.5 months 11 months

Retreatment UGFS

Retreatment UGFS

Retreatment UGFS

O’Hare et al. 61

Darke et al. 62

6 months

Occlusion

Occlusion

Occlusion

Occlusion

Occlusion

Recurrence

Definition of outcome

Data of patients with SSV incompetence; NR, not reported; DVT, deep venous thrombosis.

Coleridge Smith et al.

63

12 months

GSV Sclerotherapy

60

Darvall et al.

12 months

Retreatment UGFS

Asciutto et al. 59

6 months

Retreatment UGFS

Brittenden et al. 18

Follow-up

Additional therapy

Reference

TABLE 4B Results – Foam sclerotherapy

82%

96%

20%

91%

58%

57%

Anatomical success

100%

100%

NR

100%

100%

NR

Technical success

DVT NR / Paresthesia NR

DVT NR / Paresthesia NR

DVT 0% / Paresthesia NR

DVT 1% / Paresthesia 0%

DVT NR / Paresthesia NR

DVT NR / Paresthesia NR

Complications

Data of patients with SSV incompetence; NR, not reported; P, prospective; Level of evidence: 2b - individual cohort study; SA, spinal anesthesia; GA, general anesthesia; LA, local anesthesia; TA, tumescent anesthesia.

UK

UK

2006

2006

Coleridge Smith et al. 63

Darke et al.

2008

O’Hare et al. 61

62

UK

2009

UK

Sweden

2012

Darvall et al. 60

Asciutto et al.

UK

2015

59

Brittenden et al. 18

Country

Year

Reference

TABLE 4A General characteristics – Foam sclerotherapy

CHAPTER 2

Meta-analysis on treatment of SSV

TABLE 5 Summary Mean follow-up (months)

Number of treated legs

DVT

Paresthesia

Surgery 8,17-24

9

17.3

798

89.4% (n=4)

0.7% (n=7)

19.6 % (n=9)

Endovenous laser ablation 17-19,25-49

28

12.5

2950

99.7% (n= 20)

0.8% (n= 24)

4.8% (n=22)

Radiofrequency ablation 50-58

9

14.3

386

100% (n=6)

1.2% (n=5)

9.7% (n=3)

Foam sclerotherapy

6

10.4

494

100% (n=4)

0.9% (n=2)

0% (n=1)

1

12

50

100% (n=1)

0% (n=1)

0% (n=1)

Other therapies 64

18,59-63

Mean technical success

Number of studies

Treatment

2

Mean complication rate

Data of patients with SSV incompetence. n; number of studies

4. Ultrasound-guided foam sclerotherapy Six manuscripts reported the results of UGFS in 494 SSVs (Table 4)18,59-63. The Tessari method was mostly used to produce foam. A 1:4 liquid-to-air ratio was used in 2 studies59,60, and the remaining 4 groups used a 1:3 ratio18,61-63. Two research groups used 1% or 3% concentrations of polidocanol 59,62.= Sodium tetradecyl sulphate (1 or 3%) was used in 3 studies18,60,61. One study described treatment of foam sclerotherapy with polidocanol (1%) and with sodium tetradecyl sulphate (1% or 3%)63. The mean anatomical success rate ranged from 20% to 96%. Five studies allowed retreatment with foam sclerotherapy. Only 2 studies described postprocedural complications. DVT was noted in just 1 patient. Major complications after SSV treatment were not recorded in the remaining 4 studies.

5. Other therapies One study described the result of MOCA in patients with SSV incompetence62. In this recent prospective study, 50 patients were treated with the ClariVein catheter (Vascular Insights, Madison, CT, USA) along with polidocanol under local anesthesia. Initial technical success was 100%, and a 94% anatomical success rate was determined after a follow-up of 12 months. The absence of major complications, DVT and especially nerve injury, could be considered an important finding. MINOR quality score was 13. No manuscripts focused on treatment of SSV incompetence with the VenaSealTM Sapheon Closure System.

Pooled data Data on the primary outcome, anatomical success, was pooled. The pooled anatomical success rates of 98.5% in EVLA (95% confidence interval [CI], 97.7%-99.2%) and 97.1% (94.3%-99.9%) in RFA were significantly higher than of surgery and UGFS, respectively, 58.0% (40.9%-75.0%)and 63.6% (47.1%-80.1%) (p<0.001). The pooled data of EVLA and RFA were associated with moderate heterogeneity (I2 = 54% and I2 = 50%). Pooled data for surgery and UGFS showed considerable heterogeneity (I2 = 92% and I2 = 94%; Figure 2A-D).

39

CHAPTER 2

A

B

C

D

FIGURE 2A-D Forest plots of pooled data on anatomical success. 2A: Surgery; 2B: EVLA; 2C: RFA; 2D: UGFS. The solid squares denote the mean difference, the horizontal lines represent the 95% confidence intervals, the diamonds denotes the weighted mean differences

40

Meta-analysis on treatment of SSV

DISCUSSION This systematic review and meta-analysis shows that EVLA and RFA techniques to treat SSV incompetence will lead to higher anatomical success rates compared with surgery and UGFS. Pooled anatomical success rates for EVLA and RFA are high: 98.5% (97.7%-99.2%) and 97.1% (94.3%-99.9%), respectively, derived from data with moderate heterogeneity.

There is abundant literature on the treatment of GSV incompetence; however, large comparative trials for the treatment of SSV are lacking so far. Only 3 RCTs, randomizing between two or three different treatment modalities, could be included in this review17-19.

The available SSV literature remains heterogeneous regarding techniques and treatment protocols. In the manuscripts regarding UGFS, different types and concentrations of sclerosant as well as liquid-to-air ratios were described65,66. In the EVLA studies, 5 different laser wavelengths were used, and in some studies, subgroups of patients were treated with different wavelengths34,37,41. Although anatomical success of the various laser wavelengths seems similar, there may be differences in adverse effects67,68. Another important drawback is the mixture of additional treatments as well as renewed SSV treatments during the primary procedure or as a staged procedure (i.e., phlebectomy and sclerotherapy after EVLA, repeated UGFS after initial foam sclerotherapy, etcetera). To be able to adequately extract and compare data, we used the terms “anatomical” and “technical success” to reduce bias and to draw conclusions10,15,16.

Follow-up can be considered the major drawback in SSV research of most of the included studies. Within the current meta-analysis, the pooled data only included studies with followup periods longer than 6 months to provide a homogenous and reliable outcome. Moreover, approximately two-thirds of the included studies had substantial loss to follow-up of patients or failed to report on loss to follow-up, thereby inducing potential bias regarding the calculation of success rates during follow-up.

A considerable part of the studies included in the present review were of moderate methodological quality. Statistical power calculations were not performed in any of the prospective cohort studies. Another drawback of the available studies was the study design: almost half of the studies were retrospective analyses or the design was not reported.

The interpretation of this systematic review might have been hampered by publication bias. In addition, selective reporting can never be excluded.

A possible explanation for the low anatomical success of the surgical results may be due to more complex anatomy and anatomical variations of the proximal SSV and the SPJ69.

Rashid et al showed that even despite preoperative DUS identification, SPJ ligation was technically successful in only 59% of patients; moreover, one-third of these patients showed superficial venous residual flow8.

The risk of neurological damage is a clinically important downside of surgical treatment and thermal ablation. Paresthesia is seen in 19.6% of patients after surgery vs 9.7% after RFA and 4.8% after ELVA. An important advantage of non-thermal techniques is that no paresthesia was described. The incidence of paresthesia may be underreported due to mild or transient complaints and because no specific neurologic examination was performed

41

2

CHAPTER 2

routinely. Even in cases with recurrent varicosis after SPJ disconnection, EVLA remains a good option in terms of technical success and low occurrence of paresthesia70.

DVT only occurred rarely (0% to 1.2%), but remains a dreaded complication after venous intervention. DVT rates seem comparable after both surgical and endovenous therapy.

Patient-reported outcome measures could not be reviewed due to the variety in the reporting results or missing data. As recently reported by Brittenden et al71, clinical outcome and patient-reported disease-specific quality of life scores were similar after EVLA or surgery (of both GSV and SSV), despite the expected differences in anatomical success.

Similar results were shown in a recent randomized clinical trial in SSV: EVLA of the SSV was associated with a superior success rate, fewer complications, and earlier return to work compared with surgery but no significant differences in quality of life measures19.

A recently started randomized trial comparing nonthermal ablation (MOCA) and endothermal ablation (RFA) in SSVs might give further information on patient-reported clinical success72.

To date the innovative non thermal techniques is very limited. Only 1 study covered new treatments and included MOCA. Although 1 study limits the ability to draw firm conclusions, this new technique shows excellent 1-year results and some important advantages: no paresthesia, less postoperative pain compared with RFA and ELVA, and earlier return to work73,74. No data on cyanoacrylate glue ablation in SSV is available, nevertheless this tumescentless and non thermal techniques should considered promising, due to their results in GSV and reduced risk of nerve injury75.

Innovation for surgery and even for UGFS seems to plateau, but the techniques for EVLA and RFA are updated continuously. Therefore, it might be expected that future results will evolve even more favourably for the endovenous techniques.

CONCLUSION Endovenous thermal ablation (both EVLA and RFA) should be preferred to surgery and foam sclerotherapy in the treatment of SSV incompetence. Surgical treatment and UGFS should be reserved for patients in whom thermal ablation is technically not possible (e.g., extreme tortuosity, intraluminal thrombus, or short segment neovascularization). Although the evidence on non-thermal techniques in the treatment of SSV incompetence is still sparse, the potential benefits, especially the reduced risk of nerve injury, might be of considerable clinical importance .

42

Meta-analysis on treatment of SSV

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Meta-analysis on treatment of SSV

52. Park JY, Galimzahn A, Park HS, et al. Midterm results of radiofrequency ablation for incompetent small saphenous vein in terms of recanalization and sural neuritis. Dermatol Surg. 2014; 40(4): 383-389 53. Harlander-Locke M, Jimenez JC, Lawrence PF, et al. Management of endovenous heat-induced thrombus using a classification system and treatment algorithm following segmental thermal ablation of the small saphenous vein. J Vasc Surg 2013;58:427-432 54. Choi JH, Park HC, Joh JH. The occlusion rate and patterns of saphenous vein after radiofrequency ablation. J Korean Surg Soc. 2013; 84: 107-113.

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66. Parsi K, Exner T, Connor DE, et al. The lytic effects of detergent sclerosants on erythrocytes, platelets, endothelial cells and microparticles are attenuated by albumin and other plasma components in vitro. Eur J Vasc Endovasc Surg. 2008;36(2):216-23.

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68. Proebstle TM, Moehler T, Gül D, et al. Endovenous treatment of the great saphenous vein using a 1,320 nm Nd:YAG laser causes fewer side effects than using a 940 nm diode laser. Dermatol Surg. 2005;31(12):1678-83; discussion 1683-4 69. O’Donnell TF, Iafrati MD. The small saphenous vein and other ‘neglected’ veins of the popliteal fossa: a review.

Phlebology 2007; 22: 148-155.

70. Van Groenendael L, Flinkenflogel L, Van der Vliet JA, et al. Conventional surgery and endovenous laser ablation of recurrent varicose veins of the small saphenous vein: a retrospective clinical comparison and assessment of patient satisfaction. Phlebology 2010; 25: 151-157.

71. Brittenden J, Cotton SC, Elders A, et al. A randomized trial comparing treatments for varicose veins. N Engl J Med 2014;371:1218-27.

72. Boersma D, Van Eekeren RRJP, Kelder JC, et al. Mechanochemical endovenous ablation versus radiofrequency ablation in the treatment of primary small saphenous vein insufficiency (MESSI trial):study protocol for a randomized controlled trial. Trials 2014,15:421.

73. Vun SV, Rashid ST, Blest NC, et al. Lower pain and faster treatment with mechanico-chemical endovenous ablation using ClariVein. Phlebology 2014; Oct 8 (Epub ahead of print) 74. Eekeren RR, Boersma D, Konijn V, et al. Post-operative pain and early quality of life after radiofrequency ablation and mechanochemical endovenous ablation of incompetent great saphenous veins. J Vasc Surg 2013, 57: 445-450 75. Morrison N, Gibson K, McEnroe S, et al. Randomized trial comparing cyanoacrylate embolization and radiofrequency ablation for imcompetent great saphenous veins (VeClose). J Vasc Surg 2015;61:985-994

45

2

46

0

2

2

2

2

2

2

2

2

2

2

22

Inclusion of consecutive patients

Prospective collection of data

Endpoints appropriate to the aim of the study

Unbiased assessment of the study endpoint

Follow-up period appropriate to the aim of the study

Loss to follow up less than 5%

Prospective calculation of the study size

An adequate control group

Contemporary groups

Baseline equivalence of groups

Adequate statistical analyses

Total

23

2

2

2

2

2

1

2

2

2

2

2

2

2

14

n/a

n/a

n/a

n/a

0

2

2

2

2

2

2

2

3

10

n/a

n/a

n/a

n/a

0

1

2

2

2

1

0

2

4

14

n/a

n/a

n/a

n/a

0

2

2

2

2

2

2

2

5

10

n/a

n/a

n/a

n/a

0

1

2

2

2

1

0

2

6

13

n/a

n/a

n/a

n/a

0

2

2

2

2

1

2

2

7

13

n/a

n/a

n/a

n/a

0

1

2

2

2

2

2

2

8

22

2

2

2

2

2

1

1

2

2

2

2

2

9

11

n/a

n/a

n/a

n/a

0

0

1

2

2

2

2

2

10

19

2

2

2

1

2

1

1

2

2

2

0

2

11

12

n/a

n/a

n/a

n/a

0

1

2

2

2

2

1

2

12

12

n/a

n/a

n/a

n/a

0

2

1

2

2

1

2

2

13

11

n/a

n/a

n/a

n/a

0

1

1

2

2

1

2

2

14

12

n/a

n/a

n/a

n/a

0

1

1

2

2

2

2

2

15

9

n/a

n/a

n/a

n/a

0

1

2

2

2

0

0

2

16

13

n/a

n/a

n/a

n/a

0

2

1

2

2

2

2

2

17

12

n/a

n/a

n/a

n/a

0

2

2

2

2

2

0

2

18

12

n/a

n/a

n/a

n/a

0

1

1

2

2

2

2

2

19

8

n/a

n/a

n/a

n/a

0

0

1

2

2

1

0

2

20

9

n/a

n/a

n/a

n/a

0

0

2

2

2

1

0

2

21

12

n/a

n/a

n/a

n/a

0

2

1

2

2

1

2

2

22

10

n/a

n/a

n/a

n/a

0

0

1

2

2

1

2

2

23

12

n/a

n/a

n/a

n/a

0

1

1

2

2

2

2

2

24

12

n/a

n/a

n/a

n/a

0

1

1

2

2

2

2

2

25

10

n/a

n/a

n/a

n/a

0

1

1

2

2

2

0

2

26

9

n/a

n/a

n/a

n/a

0

1

2

2

2

0

0

2

27

11

n/a

n/a

n/a

n/a

0

2

1

2

2

2

0

2

28

1 Nandhra et al 17; 2 Brittenden et al 18; 3 Aktas et al 25; 4 Park et al 26; 5 Spreafico et al 27; 6 Moul et al 28; 7 Murli et al 29; 8 Von Hodenberg et al 30; 9 Roopram et al 19; 10 Ozkan et al 31;11 Doganci et al 32; 12 Desmyttere et al 33; 13 Janne dâ&#x20AC;&#x2122;Othee et al 34; 14 Ravi et al 35; 15 Huisman et al 36; 16 Konthothanassis et al 37; 17 Nwaejike et al 38; 18 Myers et al 39; 19 Pannier et al 40; 20 Hamel et al 41; 21 Elmore et al 42; 22 Trip-Hoving et al 43; 23 Jung et al 44; 24 Park et al 45; 25 Gibson et al 46; 26 Theivacumar et al 47; 27 Perkowski et al 48; 28 Proebstle et al 49.

2

A clearly stated aim

1

TABLE 6A MINORS score â&#x20AC;&#x201C; Endovenous laser ablation

CHAPTER 2

APPENDIX A Quality assessment (MINORS score)

0

2

2

2

2

2

2

2

2

2

2

22

Inclusion of consecutive patients

Prospective collection of data

Endpoints appropriate to the aim of the study

Unbiased assessment of the study endpoint

Follow-up period appropriate to the aim of the study

Loss to follow up less than 5%

Prospective calculation of the study size

An adequate control group

Contemporary groups

Baseline equivalence of groups

Adequate statistical analyses

Total

23

2

2

2

2

2

1

2

2

2

2

2

2

30

22

2

2

2

2

2

1

1

2

2

2

2

2

31

11

n/a

n/a

n/a

n/a

0

0

1

2

2

2

2

2

32

13

n/a

n/a

n/a

n/a

0

1

2

2

2

2

2

2

33

Surgery

13

n/a

n/a

n/a

n/a

0

1

2

2

2

2

2

2

34

18

2

2

2

1

2

0

1

2

2

2

0

2

35

7

n/a

n/a

n/a

n/a

0

1

0

2

2

0

0

2

36

19

10

n/a

n/a

n/a

n/a

0

2

1

2

2

1

0

2

37

9

n/a

n/a

n/a

n/a

0

1

2

2

2

0

0

2

38

10

n/a

n/a

n/a

n/a

0

1

2

2

2

1

0

2

39

10

n/a

n/a

n/a

n/a

0

2

2

2

2

0

0

2

40

10

n/a

n/a

n/a

n/a

0

0

2

2

2

0

2

2

41

12

n/a

n/a

n/a

n/a

0

1

2

2

2

1

2

2

42

12

n/a

n/a

n/a

n/a

0

2

1

2

2

1

2

2

43

10

n/a

n/a

n/a

n/a

0

1

2

2

2

1

0

2

44

Radiofrequency ablation

12

n/a

n/a

n/a

n/a

0

2

1

2

2

1

2

2

45

11

n/a

n/a

n/a

n/a

0

2

1

2

2

2

0

2

46

23

2

2

2

2

2

1

2

2

2

2

2

2

47

22

13

n/a

n/a

n/a

n/a

0

1

2

2

2

2

2

2

48

14

n/a

n/a

n/a

n/a

0

2

2

2

2

2

2

2

49

10

n/a

n/a

n/a

n/a

0

1

1

2

2

0

2

2

50

11

n/a

n/a

n/a

n/a

0

2

1

2

2

0

2

2

51

Foam sclerotherapy

10

n/a

n/a

n/a

n/a

0

1

2

2

2

0

2

2

52

13

n/a

n/a

n/a

n/a

0

1

2

2

2

2

2

2

53

O*

17

18

20

21

23

Surgery: 29 Nandhra et al ; 30 Brittenden et al ; 31 Roopram et al ; 32 Ikponmwosa et al ; 33 O’Hare et al ; 34 Allegra et al ; 35 Dumas et al ; 36 Whiteley et al 24; 37 Rashid et al 8. Radiofrequency ablation: 38 Schuller-Petrović et al 50; 39 Doerler et al 51 ; 40 Park et al 52; 41 Harlander et al 53; 42 Choi et al 54; 43 Gabriel et al 55; 44 Bisang et al 56; 45 Monahan et al 57; 46 Boon et al 58. Foam sclerotherapy: 47 Brittenden et al 18; 48 Asciutto et al 59; 49 Darvall et al 60; 50 O’Hare et al 61; 51 Darke et al 62; 52 Coleridge Smith et al 63. O*, other: 53 Boersma et al 64.

2

A clearly stated aim

29

TABLE 6B MINORS score – Surgery, Radiofrequency ablation, Foam sclerotherapy, Other

Meta-analysis on treatment of SSV

47

2

Chapter 3

Mechanochemical endovenous ablation of great saphenous vein incompetence using the ClariVein device: A safety study J Endovasc Ther 2011;18:328-334

Ramon R.J.P. van Eekeren, Doeke Boersma, Steve Elias, Suzanne Holewijn, Deborah A.B. Werson, Jean-Paul P.M. de Vries, Michel M.P.J. Reijnen

CHAPTER 3

ABSTRACT Background To evaluate the feasibility and safety of endovenous mechanochemical ablation (MOCA) for the treatment of great saphenous vein (GSV) incompetence.

Methods The newly developed ClariVein device uses a technique that combines mechanical endothelial damage using a rotating wire with the infusion of a liquid sclerosant. Heating of the vein and tumescent anesthesia are not required; only local anesthesia is utilized at the insertion site. In a pilot study, 30 limbs in 25 patients (18 women; mean age 52 years) with GSV incompetence were treated with MOCA using polidocanol at 2 centers. Initial technical success, complications, patient satisfaction, and classification by venous clinical severity score (VCSS) were assessed 6 weeks after the treatment.

Results Initial technical success of MOCA was 100%. There were no major adverse events. Minor complications consisted of 9 local ecchymosis at the puncture site and superficial phlebitis that resolved within a week in 4 limbs. Duplex ultrasonography at 6 weeks showed 26 (87%) of 30 veins were completely occluded; 3 veins showed partial recanalization in the proximal (n = 2) and distal GSV. One patient had full segment recanalization and was successfully retreated. The VCSS significantly improved at 6 weeks (P < 0.001). Patient satisfaction was high, with a median satisfaction of 8.8 on a 0 â&#x20AC;&#x201C; 10 scale.

Conclusion This study showed that endovenous MOCA, using polidocanol, is feasible and safe in the treatment of GSV incompetence. Larger studies with a prolonged follow-up are indicated to prove the efficacy of this technique in terms of obliteration rates.

50

Safety study on MOCA in GSV

INTRODUCTION Varicose veins cause symptoms varying from minor leg discomfort to chronic disabling venous ulceration. In a random sample of 1566 men and women aged between 18 and 64 years, the Edinburgh Vein Study showed that 40% of the men and 32% of the women had varicose veins originating from saphenous vein reflux1. During the past decade, therapy for varicose veins has changed considerably. Thermal endovenous modalities, including endovenous laser ablation and radiofrequency ablation, are highly effective for obliterating the incompetent great saphenous vein (GSV)2. Occlusion rates of over 90% are consistently reported in clinical trials, with low complication rates3-5. Novel treatment modalities focus mainly on reducing surgical trauma, minimizing periprocedural and postprocedural pain, and improving cosmetic outcome.

Liquid sclerotherapy is an effective and minimally invasive procedure to treat reticular varicose veins and spider veins. However, disappointing results have been published using liquid sclerotherapy for the treatment of GSV incompetence. In a recent meta-analysis, Hamel-Desnos and Allaert6 found occlusion rates of only 39.5% treating GSV incompetence with liquid sclerotherapy after 1 year of follow-up. Foam sclerotherapy may be more effective, with occlusion rates of >76% after 1 year6.

Currently, tumescent anesthesia is required for all types of endothermal ablation, but thermal-related complications, such as prolonged pain, skin burn, and neuralgia, are described in the literature, although they are very rare7,8. A new approach has recently been developed to induce occlusion by endovenous mechanical damage to the endothelial cells combined with infusion of a liquid sclerosant. This endovenous mechanochemical ablation (MOCA) technique does not require tumescent anesthesia, will not heat the vein or its surroundings, and is performed without an exogenous energy source. The present study evaluated the applicability and safety of MOCA in combination with polidocanol in an initial trial.

METHODS Study design A protocol was constructed to evaluate endovenous MOCA in combination with polidocanol using the ClariVein catheter (Vascular Insights LLC, Madison, CT, US) at 2 Dutch hospitals.

Ethical approval for the study was granted by the Committee on Research Involving Human Subjects at Arnhem-Nijmegen, The Netherlands (reference 2009/071). Data were gathered prospectively in a computerized database.

Candidates for the study underwent color duplex ultrasonography by a certified vascular technologist. The CEAP class9 and venous clinical severity score10 were assigned by a skilled vascular surgeon. Reflux was defined as retrograde flow of >0.5 seconds after calf compression measured in an upright position. Eligibility criteria were age over 18 years, C2â&#x20AC;&#x201C;C6 varicose veins, written informed consent, and primary GSV incompetence.

51

3

CHAPTER 3

Exclusion criteria included pregnancy and lactation, allergy or contraindication to the sclerosant, previous surgical treatment of varicose veins, history of deep venous thrombosis, the use of anticoagulants, severe tortuosity of the GSV, or GSV diameter >4 mm or >12 mm measured in the supine position.

Based on these criteria, 25 consecutive patients (18 women; mean age 52 years) with primary GSV incompetence in 30 limbs were enrolled in the study. Five patients had bilateral GSV insufficiency. Most treated limbs were classified as C2 using the CEAP classification (Table 1).

TABLE 1 Baseline characteristics and operative details for 25 patients undergoing endovenous mechanochemical ablation in 30 limbs Characteristics Men/women Mean age ,years Body mass index, kg/m2 VCSS CEAP classification C2 C3 C4 C5–C6

7/18 52.1 ± 14.0 26.9 ± 4.6 3.3 ± 1.6 18 9 3 0

Operative details Procedures performed at each center

9/21

Arnhem/Nieuwegein Duration of procedure, min

20 ± 4.8

Vein diameter 2 cm below SFJ, mm

6.1 ± 2.1

Vein diameter at puncture site, mm

4.8 ± 1.25

Treated length, cm

40 ± 6.6

Continuous data are presented as means ± standard deviation; categorical data are given as counts; VCSS = venous clinical severity score; CEAP = clinical, etiology, anatomy, and pathophysiology; SFJ = saphenofemoral junction

Study device The single-use, disposable ClariVein infusion catheter contains a rotating dispersion wire that extends through its lumen; at the end of the wire is an angled tip that protrudes 2 cm.

A small ball attached to the tip enhances ultrasonographic visibility and mechanically damages the endothelial layer as it rotates and disperses sclerosant into the bloodstream and onto the vessel wall. The catheter is connected to a 9V battery–motorized handle unit that controls wire rotation; a 5-mL syringe mounted on the handle delivers sclerosant. The catheter is inserted through a 4-F to 6-F micropuncture set positioned percutaneously via an 18-G intravenous access performed under ultrasound guidance.

52

Safety study on MOCA in GSV

Intervention All procedures were performed under local anesthesia by a specialized team consisting of a vascular surgeon and vascular practitioner at each center. No tumescent anesthesia, sedation, or antibiotics were given. The patient was positioned supine with a cushion under the knee to enhance access to the medial part of the thigh. Under ultrasound guidance, the GSV was accessed with an 18-G needle. Over a short guidewire, a 4-F microsheath was introduced and the guidewire was removed. The ClariVein catheter was positioned through the microsheath with the tip of the device 2 cm distal of the saphenofemoral junction (SFJ) under ultrasound guidance. The ClariVein catheter was then connected to the motorized handle unit, which unsheathed the distal end of the dispersion wire to expose the dispersion tip.

After the proper position of the dispersion tip was verified (the ball on the dispersion tip 2 cm distal of the SFJ), the wire was activated for a few seconds to induce spasm of the proximal vein. Then, the activated catheter with rotating tip was steadily withdrawn at 2 mm/s while simultaneously infusing a 1.5% polidocanol solution (Aethoxysklerol; Kreussler Pharma, Wiesbaden, Germany). The amount of liquid sclerosant was determined by the diameter of the varicose vein near the SFJ. During all procedures, the total dose of administered polidocanol was well below the maximum allowed dose. No concomitant phlebectomies were done.

Duplex ultrasonography was performed after the procedure to measure the length of the obliterated GSV and to confirm the patency of the deep venous system. The time taken to complete the procedure and length of the treated vein were noted. Patients were advised to walk for 20 minutes immediately after completion of the procedure. Patients were discharged with class 2 compression stockings (30â&#x20AC;&#x201C;40 mm Hg) and advised to wear them for 24 hours continuously for 2 weeks.

Outcomes and follow-up protocol The primary outcome measures were immediate occlusion, determined by duplex ultrasonography, and postprocedural complications. Secondary outcomes included patient satisfaction and postprocedural pain. Patients were asked to record the level of pain during treatment on a 100-mm visual analog scale. Following treatment, patients were asked to complete a diary card for 7 days to record the level of pain using the same scale. After 6 weeks, patients determined their satisfaction with the treatment using a 10-point scale.

All patients were examined at 7 days and 6 weeks by a vascular surgeon; a duplex ultrasound evaluation was performed at the 6-week follow-up.

Statistical analysis Variables are presented as means Âą standard deviation if distributed parametrically or as the median and interquartile range (IQR, 25th to 75th percentiles) if nonparametrically distributed. Improvement in clinical condition measured using the venous clinical severity score was analyzed using the Wilcoxon signed rank test; P < 0.05 was considered significant. Statistical analysis was performed using SPSS software (version 15.0; SPSS Inc, Chicago, IL, USA).

53

3

CHAPTER 3

RESULTS During procedures that averaged 20 minutes (Table 1), the mean length of GSV treated was 40 cm. A mean volume of 6.8 ± 1.3 mL of polidocanol (15 mg/mL) was used. All treated veins showed occlusion on ultrasonography directly after MOCA. No major adverse events were observed. There was no deep venous thrombosis, nerve injury, skin necrosis, infection, or hyperpigmentation. Minor complications included localized ecchymosis at the puncture site in 9 patients and transient superficial phlebitis of distal tributaries in 4 patients.

At 6 weeks, no additional complications were observed clinically or detected with duplex ultrasonography. The GSV was completely obliterated in 26 (87%) of 30 veins, starting 2 cm distal from the SFJ. Two patients had partial recanalization of the proximal GSV 15 and 18 cm, respectively, from the SFJ; another patient had partial recanalization of the distal GSV. One total recanalization of the GSV was successfully treated in a redo procedure at 7 weeks after initial treatment. The mean vein diameter 2 cm below the SFJ in the 4 veins with recanalization was comparable with the completely obliterated veins (6.3 vs. 6.1 mm).

Patient satisfaction and outcome During the procedure, the median maximal pain score was 4 (IQR 3–6) on a 10-point scale.

The mean maximal pain measured on the first postprocedural day was 9 mm on a 100-mm scale. The score decreased to a mean of 2mm 7 days after MOCA (Figure 1). All 4 patients with superficial phlebitis had prolonged pain for 1 week.

After 6 weeks, median patient satisfaction of the treatment was 8.5 (IQR 8–9) on a 10-point scale. The median venous clinical severity score decreased significantly from 3.0 (IQR 2.0–4.75) to 1.0 (IQR 0.25–3.0) 6 weeks after treatment (P < 0.001). In the 3 patients with partial recanalization, the venous clinical severity score had decreased from 4.5 (IQR 3.5– 5.5) to 2.0 (IQR 1.5–2.3) 6 weeks after treatment. The venous clinical severity score worsened from 5 to 11 in 1 patient with a superficial phlebitis.

FIGURE 1 Visual analogue scale for pain within the first week after MOCA (n=12)

54

Safety study on MOCA in GSV

DISCUSSION Thermal endovenous modalities are highly effective for obliterating incompetent GSVs. A recent meta-analysis of the most common endovenous therapies in treating varicose veins showed 5-year success rates of 75.7% for surgical stripping, 73.5% for ultrasound-guided foam sclerotherapy, 79.9% for radiofrequency ablation, and 95.4% for endovenous laser ablation2. Though the surgical method of saphenofemoral ligation with stripping is still considered the gold standard, these results support the increasing popularity of endovenous therapy.

Endovenous mechanochemical ablation is a new technique in the endovenous toolbox. Its mechanism of action is a combination of mechanical damage of the endothelium and scarring of the vein due to a liquid sclerosant. Animal experiments performed under the supervision of M.G. Tal of the Yale University School of Medicine have shown that the combination of mechanical damage with the chemical effect is crucial. Treatment with either the ClariVein catheter or with sotradecol alone was not successful, while the combination of both produced permanent vein occlusion (unpublished data, personal communication). The ClariVein catheterâ&#x20AC;&#x2122;s rotating tip causes spasm in the vein and mechanical damage to the endothelium, which increases the efficacy of the sclerosant that is dispersed over the endothelial layer. After successful treatment, the vein is obliterated and transformed into a fibrous cord11,12.

The first results of MOCA using the ClariVein catheter and sodium tetradecyl sulfate (sotradecol) were recently published13. In that study, mechanochemical ablation of 30 GSV in 29 patients resulted in occlusion rates of 97% after 260 days. The only complication was thigh ecchymosis in 3 patients; no deep venous thrombosis, skin necrosis, or nerve injury occurred. Because sotradecol is not approved in The Netherlands, we used polidocanol in our study, but our early outcomes were similar. Complete occlusion at 6 weeks was 87%.

Only 3 patients had partial recanalization of the proximal or distal GSV, and 1 total recanalization was successfully retreated. A few patients had localized ecchymosis at the puncture site, which was probably caused by leakage of the sclerosant during pullback of the device. We also saw transient superficial phlebitis in 13% (4 limbs), which is higher than the current literature on endothermal modalities but lower than the incidences following the use of foam or liquid sclerotherapy (18% to 42%)14,15.

Most current minimally invasive endovenous modalities rely on conduction of heat to obliterate varicose veins, which has several disadvantages. Thermal ablative procedures require tumescent anesthesia to buffer the heat and prevent damage to the surrounding tissues, but tumescent anesthesia prolongs the procedural time. Moreover, nerve damage and prolonged pain are known, but rare, complications of endovenous laser ablation with incidences of 0% to 7.3%7,8,16,17 and 2.6% to 7.9%, respectively17,18. Skin burns were reported in early endovenous laser ablation experience7,8.

MOCA is performed without tumescent anesthesia and requires only one injection with local anesthesia at the puncture site. There is no hardware to buy and maintain, and the technique can be performed on an outpatient basis, thereby further reducing procedure costs.

55

3

CHAPTER 3

However, studies are indicated to assess the cost-effectiveness of this technique. In our experience, MOCA is also probably faster than other endovenous techniques.

Patient satisfaction following MOCA is high, and the venous clinical severity score improved in all patients, except one with superficial phlebitis. Postprocedural pain scores were very low. Shepherd et al.19 described median postprocedural pain scores of 26 mm 3 days after endovenous laser; after radiofrequency ablation, the score was 15 mm at 3 days, while in our series, the pain score at day 3 was 5 mm. Randomized studies are required to prove reduced postoperative pain following MOCA compared to other techniques.

After 6 weeks, duplex ultrasonography showed recanalization in 4 treated veins in 30 limbs (3 partial and 1 complete). Thus, the anatomical success appears to be lower compared to thermal ablative techniques. Various factors may have contributed to this observation. First, the tip of the rotating wire was positioned 2 cm below the SFJ, which means that the tip of the catheter itself was located 4 cm distal to the SFJ and injection of the sclerosant also started 4 cm below the SFJ. Although the sclerosant was dispersed by the rotating wire, it might be possible that the first part of the target segment was treated only mechanically.

These first results led us to treat the next series of patients by positioning the tip of the rotating wire 0.5 cm distal to the SFJ to prevent early recanalization of the proximal segment. Moreover, the concentration of sclerosant may have been insufficient; it has now been increased to 2% polidocanol for the proximal third, while the remaining vein is still treated with 1.5% polidocanol.

Finally, because all new techniques involve a learning curve to optimize results, this technique should be adopted when experience increases. Nevertheless, larger series with prolonged follow-up and randomized trials are clearly indicated, especially because most of the recanalizations with other techniques will occur during the first year after treatment.

CONCLUSION The endovenous MOCA technique with the ClariVein device appears to be a safe and welltolerated procedure, without the need for tumescent anesthesia and heating of the vein.

Early results are promising, although studies with long-term follow-up and investigations evaluating the efficacy of different concentrations of sclerosant are indicated to define the role of MOCA.

56

Safety study on MOCA in GSV

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Gandhi A, Froghi F, Shepherd AC, Shalhoub J, Lim CS, Gohel MS, Davies AH. A study of patient satisfaction following endothermal ablation for varicose veins. Vasc Endovascular Surg. 2010;44:274–278.

Zafarghandi MR, Akhlaghpour S, Mohammadi H, Abbasi A. Endovenous laser ablation in patients with varicose great saphenous vein incompetence and incompetent saphenofemoral junction: an ambulatory single center experience. Vasc Endovascular Surg. 2009;43:178–184.

Shepherd AC, Gohel MS, Lim CS, Hamish M, Davies AH. Pain following 980-nm endovenous laser ablation and segmental radiofrequency ablation for varicose veins: a prospective observational study. Vasc Endovascular Surg. 2010;44:212–216.

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Mechanochemical endovenous ablation of small saphenous vein insufficiency using the ClariVein device: One-year results of a prospective series Eur J Vasc Endovasc Surg. 2013;45:299-30

Doeke Boersma, Ramon R.J.P. van Eekeren, Deborah A.B. Werson, Rutger I.F. van der Waal, Michel M.J.P. Reijnen, Jean-Paul P.M. de Vries

CHAPTER 4

ABSTRACT Objective This study evaluated the feasibility, safety, and 1-year results of mechanochemical endovenous ablation (MOCA) of small saphenous vein (SSV) insufficiency.

Design Prospective cohort study.

Materials and Methods Fifty consecutive patients were treated for primary SSV insufficiency with MOCA using the ClariVein device and polidocanol. Initial technical success, complications, patient satisfaction, and visual analogue scale pain score (VAS) were assessed. Anatomic and clinical success was assessed at 6 weeks and at 1 year.

Results Initial technical success of MOCA was 100%. At the 6-week assessment, all treated veins were occluded. The 1-year follow-up duplex showed anatomic success in 94% (95% confidence interval, 0.87-1). VCSS decreased significantly from 3.0 (interquartile range [IQR] 2-5) before treatment to 1.0 (IQR 1-3, P < 0.001) at 6 weeks and to 1.0 (IQR 1-2, P < 0.001) at 1 year. Median procedural VAS score for pain was 2 (IQR 2-4). No major complications were observed, especially no nerve injury.

Conclusion Mechanochemical endovenous ablation (MOCA) is a safe, feasible, and efficacious technique for treatment of SSV insufficiency. One year follow-up shows a 94% anatomic success rate and no major complications.

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MOCA in SSV

INTRODUCTION Varicose veins are a common medical wit overall prevalence between 20% and 60%.1 The effect of venous insufficiency on health-related quality of life is substantial and comparable with other chronic diseases such as arthritis, diabetes, and cardiovascular disease.2 These problems are mostly associated with insufficiency of great saphenous veins (GSVs); however, insufficiency of the small saphenous vein (SSV) is responsible in 15% of patients with varicose veins3.

Until the 1990s, high ligation, with or without surgical stripping, was the preferred option for venous insufficiency, although there was no standard in surgical treatment of SSV insufficiency. The introduction of minimally invasive endothermal catheter modalities, including endovenous laser ablation (EVLA) and radiofrequency ablation (RFA), has revolutionized the treatment of varicose veins. These have become the preferred techniques, with high success rates4,5.

Most endovenous ablation techniques are based on heating of the vein wall and therefore require the instillation of tumescent anaesthesia. Despite tumescent, thermal-associated complications, such as prolonged pain and skin burn, have been described. The risk of sural nerve injury is a major concern in surgical stripping and endovenous thermal ablation of the SSV6-8. The main focus of improving therapy is currently aimed at reducing pain during and after treatment, as well as reducing heat-related trauma.

The recently introduced mechanochemical endovenous ablation (MOCA) technique using the ClariVein catheter (Vascular Insights, Madison, CT, USA) is unique: mechanical injury to the venous endothelium is combined with simultaneous catheter-guided infusion of a liquid sclerosant. No heat is generated and therefore, tumescent is not required. Recent studies have proven that MOCA is a feasible and safe treatment of GSV insufficiency9,10.

We aimed to evaluate the initial results and 1-year follow up of MOCA using the ClariVein catheter in combination with polidocanol in SSV insufficiency.

MATERIALS AND METHODS The study included all patients with symptomatic, primary SSV insufficiency treated in the St. Antonius Hospital, Nieuwegein, and the Rijnstate Hospital, Arnhem, The Netherlands, from June 2010 to April 2011. Physical examination was performed by a vascular surgeon or vascular physician assistant before treatment, and the CEAP classification and Venous Clinical Severity Score (VCSS) were assessed. All patients underwent duplex ultrasonography (DUS) of the deep and superficial veins of the affected leg. SSV insufficiency was defined as a retrograde flow >0.5 seconds after calf compression while standing.

Inclusion criteria were age >18 years, duplex-confirmed SSV incompetence at saphenopopliteal junction, long-segment SSV insufficiency (>10 cm), SSV diameter between 2.5 and 11 mm, C2-6 EP AS4 PR, and written informed consent. Exclusion criteria were previous surgical treatment of the SSV, history of ipsilateral deep vein thrombosis (DVT), ipsilateral

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GSV or deep venous insufficiency, peripheral arterial occlusive disease, or use of anticoagulants. Patients with allergy, pregnancy or lactation, or other contraindications for the use of polidocanol were excluded.

Ethical approval for research was granted.

Intervention All interventions were performed with the ClariVein device, combined with polidocanol (Aethoxysklerol, KreusslerPharma, Wiesbaden, Germany), by a vascular surgeon or physician assistant on an outpatient basis. All physicians had previously performed more than 10 MOCA procedures using the ClariVein in the GSV. No analgesia or antibiotics were administered before treatment.

The MOCA technique has been previously described9. Briefly, the ClariVein device is a disposable 2.6F single-lumen catheter for infusing liquid sclerosant. A metal wire, fitted distally with a small ball, runs through the catheter. It is hypothesised that rotation of the wire (3000 rpm) induces intimal injury and disperses the liquid sclerosant.

The entire length of the first 15 SSVs was treated with 1.5% polidocanol. In the later 35 cases, the proximal SSV (10-15 cm) was treated with 2 mL polidocanol 2% and the remainder with polidocanol 1.5%. The protocol was altered because preliminary results in GSVs showed improved occlusion rates with the latter regimen. The total amount of used liquid sclerosant is noted in Table 1. In none of the patients the allowed daily dose of 2 mg/ kg/day is exceeded. No concomitant phlebectomies were performed.

DUS was performed to confirm occlusion of treated vein. Patients wore compression stockings (30-40 mm Hg) continuously for the first 24 hours and during the daytime for the next 2 weeks. Patients were allowed to perform their daily activities immediately. No standard analgesics were prescribed.

Outcomes and follow-up protocol The primary outcome measures were (1) technical success, defined as the ability to perform procedure as planned and achieve immediate occlusion after the procedure, and (2) anatomic success, defined as occlusion of treated vein. A recanalized SSV or treatment failure was defined as an open segment of more than 10 cm11. Secondary outcomes included complications, treatment time, patient satisfaction, and procedural pain.

The treatment time (from start of procedure to applying compression stocking) and length of the treated vein were noted. Patients were asked to record the level of pain during treatment on a visual analogue scale (VAS) from 0 cm (no pain) to 10 cm (worst imaginable pain). All patients were scheduled for a follow-up assessment at 6 weeks and 1 year by a vascular surgeon, including physical examination, determination of VCSS, and DUS. After 6 weeks, patients were asked to quantify their satisfaction of the treatment in a 10-point score. In case of residual varicosities sclerotherapy was offered. Any postprocedural complications were noted. All data were gathered prospectively and stored in computerized database.

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MOCA in SSV

TABLE 1 Patient demographics and treatment characteristics.

Number of patients†

50 (100%)

Bilateral SSV insufficiency

none

Age* (years)

53 (25 - 84)

Male†

18 (36%)

Female

32 (64%)

Weight* (kg)

76 (48 - 135)

†

15 (30%)

Dosage of polidocanol 1.5%† Dosage of polidocanol 2.0 mL 2%/1.5%

35 (70%)

C2 Varicose veins†

26 (52%)

C3 Oedema†

14 (28%)

†

C4 Skin changes†

8 (16%)

C5 Healed ulcer

1 (2%)

C6 Active ulcer†

1 (2%)

SSV diameter* (mm)

4.8 (3 - 10)

Length of treated SSV* (cm)

23 (10 - 35)

Total dosage of polidocanol‡ (mg)

72 (±19)

Duration of treatment (min)§

20 (11 - 40)

†

4

Number (percentage of total) *Mean value (range). ‡Mean value (SD). §Median value (interquartile range). SSV, small saphenous vein. †

Statistical analysis Variables are presented as mean with standard deviation (SD) or range for parametric continuous outcomes, as median with interquartile range (IQR) for nonparametric continuous outcomes, and as frequencies and percentages for categoric variables. KaplanMeier survival analysis was used to assess anatomic success rate. The log-rank test was used to compare anatomic success between the initial protocol using 1.5% polidocanol and the latter protocol using the higher dosage. Change in VCSS was analyzed with the Wilcoxon signed rank test. Statistical analyses were performed using SPSS 19.0 software (SPSS Inc, Chicago, IL, USA). A value of P < 0.05 was considered significant.

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RESULTS The study included 50 consecutive patients who met the eligibility criteria. Patient characteristics are described in Table 1. At 1 year, 3 patients (6%) were lost to follow-up: 1 was free of complaints and refused follow-up, and the other 2 did not respond to repeated invitations for the follow-up assessment.

Occlusion rates The technical success rate was 100%: all treated SSVs were occluded on DUS directly after MOCA. At 6 weeks, all treated veins (50 of 50) remained occluded. In 9 patients (18%) residual varicosities were treated by sclerotherapy to optimize cosmetic outcome.

At 1 year, 44 of 47 SSVs were occluded, for an anatomic success of 94% (95% confidence interval [CI], 0.87-1). Patients who were lost to follow-up were censored at 6 weeks after treatment. At the 1-year follow-up, recanalisation occurred in 2 of the 15 patients treated with low-dose polidocanol (anatomic success, 87%; 95%CI, 0.71-1) and in 1 of 32 patients who received the elevated dose of polidocanol (anatomic success, 97%; 95%CI, 0.91-1).

The difference between these subgroups was not significant (P=0.187).

Pain, patient satisfaction and duration of treatment The median VAS pain score during treatment was 2 cm (IQR 2-4 cm). The median duration of treatment was 20 minutes (IQR 15-24 minutes). After 6 weeks, median patient satisfaction of the treatment was 8 (IQR 8-9).

Venous Clinical Severity Score At the 6-week follow-up, median VCSS had decreased significantly from 3 (IQR 2-5) preMOCA to 1 (IQR 1-3; P < 0.001). At 1 year after treatment, VCSS remained significantly decreased compared with preprocedural scores (1 [IQR 1-2], P < 0.001).

Complications No major complications were observed. Importantly, there were no signs of any nerve injury, and no DVT, skin necrosis, infection, or hyperpigmentation was recorded. Minor complications included localized ecchymosis (12%), induration around the access site (12%), and transient superficial thrombophlebitis of the treated vein (14%). Pain lasted longer than 1 week in 5 patients (10%), all caused by superficial thrombophlebitis. After 6 weeks and 1 year, no additional complications were seen.

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MOCA in SSV

DISCUSSION This study is the first describing results of MOCA in treating SSV insufficiency. Technical success was 100%, and after 6 weeks of follow-up, no recanalization was noticed. At the 1-year follow-up, anatomic success persisted in 44 of 47 patients (94%). An important observation was the difference in anatomic success between the initial group treated with 1.5% polidocanol and the later group treated with 2% polidocanol in the proximal section.

Although this difference is not significant, probably because of the small number of patients, an elevated dosage of liquid sclerosant may be a key in optimizing occlusion rates in MOCA. The treatment of superficial venous insufficiency has changed dramatically in the last decade. Ligation, with or without surgical stripping, of insufficient saphenous veins has mostly been replaced by thermal endovenous catheter therapies, due to their superior efficacy and less invasive character12. Results of EVLA for SSV insufficiency have repeatedly been described, with short-term occlusion rates ranging from 91% to 100%7-6,13,14. RFA in treatment of varicosity of the SSV has only been described in a small series, but shows excellent results15.

Ultrasound-guided foam sclerotherapy (UGFS) is another widely used minimally invasive technique to ablate varicose veins. Success rates of UGFS in SSV are 82% after a mean follow-up of 11 months. Although liquid sclerotherapy is effective in treating reticular and spider veins, it should not be used to treat insufficiency of saphenous veins, due to inferior occlusion rates of 17% to 60% at 1 year4,11,16,17.

Two studies describing the safety and the initial results of MOCA were recently published.

Elias et al. showed an occlusion rate in GSV of 96.7% after MOCA using sodium tetradecyl sulfate (Sotradecol) after average follow-up of 260 days. MOCA combining Clarivein with polidocanol showed occlusion in 97% of treated GSV at 6 weeks after treatment, and partial recanalisation was described in 10%. No major complications occurred, and minor complains were acceptable in amount and severity9,10.

All modalities in the treatment of varicose veins have specific complications. Ecchymosis and postprocedural pain seem inherent to heat-based therapies. In GSV MOCA is associated with significantly less post-operative pain compared with RFA18. More importantly, in SSV treatment, the anatomic proximity of the sural nerve poses an additional risk. In published data, transient sural nerve injury caused by ELVA varies between 1.3% and 11%6,11,14,19.

In redo SSV surgery, the incidence of numbness 1 year after treatment is as high as 28%20.

In general, major complications, such as skin burns, DVT, and pulmonary embolism after EVLA seldom occur (<1%). Transient thrombophlebitis occurred in 14% of patients, comparable with foam sclerotherapy and RFA11. MOCA of the SSV has been proven to be safe: no major complications, including no sural nerve injuries, occurred. MOCA eliminates the need for tumescent anaesthesia, which can be desirable, because it is time-consuming and requires multiple injections.

Clinical results after endovenous ablation, in general, are excellent. In our study group, a significant decrease in VCSS was measured at 6 weeks and at 1 year of follow-up compared with preprocedural scores. Patient satisfaction was high.

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One of the limitations of this study is that the maximum diameter of treated SSVs was 11 mm. The technical and clinical success of MOCA in larger-diameter varicose veins is still unknown. Pain scores during MOCA were very low. Postprocedural pain scores were not measured. Further controlled studies are required to compare pain with other techniques in SSV ablation. Patients on oral anticoagulants were excluded; thus, we can not provide data on the effect of anticoagulant therapy on MOCA. In contrast to endothermal therapy, anticoagulants might influence clot formation and lead to increased recanalisation.

CONCLUSION Mechanochemical endovenous ablation using the ClariVein device and polidocanol appears to be a safe, feasible, and efficacious technique in the treatment of SSV insufficiency. Early and 1-year follow-up results are promising, with a 94% occlusion rate, no major complications, and low pain scores.

Acknowledgements The authors thank J.C. Kelder for his help with statistical analyses.

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Callam MJ. Epidemiology of varicose veins.Br J Surg. 1994;81:167-173.

Andreozzi GM, Cordova RM, Scomparin A, Martini R, D’Eri A, Andreozzi F; Quality of Life Working Group on Vascular Medicine of SIAPAV. Quality of life in chronic venous insufficiency.An Italian pilot study of the Triveneto Region. Int Angiol 2005;24:272-277.

Almgren B, Eriksson E. Valvular incompetence in superficial, deep and perforator veins of limbs with varicose veins. Acta Chirurg Scand 1990;156:69–74.

Van den Bos R, Arends L, Kockaert M, Neumann M, Nijsten T. Endovenous therapy of lower extremity varicosities: a meta-analysis. J Vasc Surg. 2009;49:230-239.

Darwood RJ, Theivacumar N, Dellagrammaticas D, Mavor AI, Gough MJ. Randomized clinical trial comparing endovenous laser ablation with surgery for the treatment of primary great saphenous varicose veins. Br J Surg.

2008;95:294-301.

Theivacumar NS, Beale RJ, Mavor AID, Gough MJ. Initial experience in endovenous laser ablation (EVLA) of varicose veins due to small saphenous vein reflux. Eur J Vasc Endovasc Surg 2007;33:614-618.

Van den Bos RR, Neumann M, De Roos KP, NijstenT. Endovenous laser ablation-induced complications: review of literature and new cases. Dermatol Surg. 2009;35:1206-1214.

Sichlau MJ, Ryu RK. Cutaneous thermal injury after endovenous laser ablation of the great saphenous vein. J Vasc Interv Radiol. 2004;15:865-867.

Van Eekeren RRJP, Boersma D, Elias S, Holewijn S, Werson DAB, De Vries JPPM, Reijnen MMJP. EndovenousMechanochemical Ablation of great saphenous vein incompetence using the ClariVein device: a safety study. J Endovasc Ther. 2011;18:328-334 Elias S, Raines JK. Mechanochemicaltumescentlessendovenous ablation: final results of the initial clinical trial.

Phlebology. 2012;27:67-72.

Rasmussen LH, Lawaetz M, Bjoern L, Vennits B, Blemings A, Eklof B. Randomized clinical trial comparing endovenous laser ablation, radiofrequency ablation, foam sclerotherapy and surgical stripping for great saphenous varicose veins. Br J Surg 2011;98:1079-1087 Tellings SS, Ceulen RPM, Sommer A. Surgery and endovenous techniques for the treatment of small saphenous varicose veins: a review of the literature. Phlebology 2011;26:179-184 Ravi R, Rodriguez-Lopez JA, Trayler EA Barret DA, Ramaiah V, Diethrich EB. Endovenous ablation of incompetent saphenous veins: a large single-center experience. J Endovasc Ther 2006;13:244-248 Gibson KD, Ferris BL, Polissar N, Neradilek B, Pepper D. Endovenous laser treatment of the small saphenous vein: efficacy and complications. J Vasc Surg 2007;45:795-803.

Bisang U, Meier TO, Enzler M, Thalhammer C, Hussman M, Amann-Vesti BR. Results of endovenous ClosureFast treatment for varicose veins in an outpatient setting. Phlebology 2012 Apr;27(3):118-123 Coleridge Smith P. Chronic venous disease treated by ultrasound guided foam sclerotherapy. Eur J Vasc Endovasc Surg 2006;31:577-583 Hamel-Desnos C, Allaert FA. Liquid versus foam sclerotherapy. Phlebology. 2009;24:240-6.

Van Eekeren RRJP, Boersma D, Konijn V, De Vries JPPM, Reijnen MMJP. Postoperative pain and early quality of life after radiofrequency ablation and mechanochemical endovenous ablation of incompetent great saphenous veins. J Vasc Surg 2013;57:445-450 Park SJ, Yim SB, Cha DW, Kim SC, Lee SH. Endovenous laser treatment of the small saphenous vein with a 980-nm diode laser: early results. Dermatol Surg 2008;34:517-24.

O’Hare JL, Vandenbreock CP, Whitman B et al. A prospective evaluation of the outcome after small saphenous varicose vein surgery wtih one-year follow-up. J Vasc Surg. 2008; 48:669-673

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Postoperative pain and early quality of life after radiofrequency ablation and mechanochemical endovenous ablation of incompetent great saphenous veins J Vasc Surg 2013;57:445-450

Ramon R.J.P. van Eekeren, Doeke Boersma, Vincent Konijn, Jean-Paul P.M. de Vries, Michel M.P.J. Reijnen

CHAPTER 5

ABSTRACT Objective Thermal ablative techniques of varicose veins carry a risk of heat-related complications, including postoperative pain. Mechanochemical endovenous ablation (MOCA) might avoid these complications and reduce postoperative pain because of the absence of thermal energy. This study evaluated postoperative pain and quality of life after radiofrequency ablation (RFA) and MOCA for great saphenous vein (GSV) incompetence.

Methods Sixty-eight patients with unilateral GSV incompetence were treated with either RFA or MOCA in this prospective observational study. Patients monitored their pain for the first 14 postoperative days on a 100-mm visual analog scale (VAS). They also completed the general (RAND 36-Item Short-Form Health Survey) and disease-specific (Aberdeen Varicose Vein Questionnaire) quality of life questionnaires before and 6 weeks after treatment.

Results Patients treated with MOCA reported significantly less postoperative pain than patients treated with RFA during the first 14 days after treatment (4.8 ± 9.7 mm versus 18.6 ± 17.0 mm; P < 0.001) (mean VAS over 14 days). The lower postoperative pain score was associated with a significantly earlier return to normal activities (1.2 ± 1.8 versus 2.4 ± 2.8 days; P = 0.02) and work resumption (3.3 ± 4.7 versus 5.6 ± 5.8 days, respectively; P = 0.02). At 6 weeks, patients in both groups perceived an improved change in health status and an improved disease-specific quality of life.

Conclusion MOCA is associated with significantly less postoperative pain, faster recovery, and earlier work resumption compared with RFA in the treatment of GSV incompetence. MOCA and RFA are both related to a rapid improvement in quality of life.

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Postoperative pain and quality of life after MOCA

INTRODUCTION Varicose veins are a common medical problem with overall prevalence of 20% to 60%1.

Chronic venous insufficiency may have a major effect on patientsâ&#x20AC;&#x2122; health-related quality of life in advanced stages of disease, leading to significant costs in total health care resources2,3. With occlusion rates over 90%, as reported for endovenous laser ablation (EVLA) and radiofrequency ablation (RFA) in prospective trials, more emphasis is placed on secondary outcome measures, such as postoperative pain, complications, quality of life, and return to normal activities4-6. Randomized studies have reported significantly lower postoperative pain after RFA compared with EVLA7,8. These studies, however, may have been biased by the choice of wavelengths and a difference in the fibers used.

Mechanochemical endovenous ablation (MOCA) is a recently introduced treatment that combines mechanical damage of the venous intimal layer with the dispersion of a liquid sclerosant. The use of tumescent anesthesia is not necessary because no heat is used.

The first studies of this technique have shown that MOCA is a safe and feasible method for treating great saphenous vein (GSV) incompetence with promising short-term results9,10.

Because heat is not used as the mechanism of action, the risk of heat-related complications, including postoperative pain is considered to be lower. The present study assessed the postoperative pain and quality of life in patients treated with RFA or MOCA.

METHODS Patients The study included 68 consecutive patients, treated between January and December 2011 with RFA or MOCA. All were diagnosed with unilateral symptomatic GSV incompetence, and were treated in the Rijnstate Hospital, Arnhem, The Netherlands. Patients treated with MOCA were also included in a prospective registry study (NCT01459263 at clinical.trials. gov). The regional medical ethics committee approved the study. Patients were included after signing the informed consent form in this prospective observational trial. Patients, who did not want to be treated with MOCA, were routinely offered treatment with RFA. All patients had primary GSV incompetence, as demonstrated by duplex imaging, performed by two certified vascular practitioners. Reflux was defined as a retrograde flow of â&#x2030;Ľ0.5 seconds after calf compression measured with the patient upright.

Eligibility criteria were age over 18 years, C2 to C6 varicose veins and primary GSV incompetence. Exclusion criteria included pregnancy and lactation, the use of anticoagulants, previous surgical treatment of varicose veins or history of deep venous thrombosis. Allergy to Polidocanol was a contra-indication for MOCA. Treatment Both treatments were performed under local anesthesia by a specialized team consisting of a vascular surgeon and vascular practitioner. Patients were treated as outpatients in daily

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care. No sedation or antibiotics were given.

MOCA was performed using the ClariVein catheter (Vascular Insights LLC, Madison, CT, USA), as previously described9. Briefly, a Seldinger technique was used to introduce a 4F introducer sheath into the GSV, and the ClariVein catheter was positioned with the tip of the dispersion wire 0.5 cm distal of the saphenofemoral junction (SFJ) under ultrasound guidance. After the tip was properly positioned, the wire was activated for a few seconds to induce spasm of the proximal vein. Then, the activated catheter with rotating tip was steadily withdrawn at 1 cm every 7 seconds, simultaneously dispersing liquid Polidocanol (Aethoxysklerol; Kreussler Pharma, Wiesbaden, Germany) to the damaged vein wall. The proximal 10 to 15 cm was treated with 2 mL polidocanol 2% and the remaining vein with polidocanol 1.5%. The total amount of liquid sclerosant used was determined by the diameter of the varicose vein near the SFJ and length of GSV. In patients treated with RFA, a 6F introducer sheath was inserted in the GSV under ultrasound guidance using a Seldinger technique. Then, the VNUS ClosureFAST catheter (VNUS Medical Technologies, Sunnyvale, Cal, USA) was introduced with the tip of the catheter located 2 cm below the SFJ. Subsequently, tumescent anesthesia was applied using normal saline containing 1% lidocaine with epinephrine. After proper positioning of the catheter tip was confirmed, the GSV was ablated in 7 cm segments during a 20-second treatment cycle. The temperature was maintained at 120° during withdrawal of the catheter by using a feedback system at the heating source.

After the procedures, patients were discharged with instructions to wear a compression stocking (30-40 mm Hg) for 2 weeks. Patients were instructed to use analgesics only when they experienced postoperative pain. No standard analgesics were prescribed. No concomitant phlebectomies or sclerotherapy were performed. Treatment time was defined as duration of the treatment starting with puncturing the vein and ending with removal of the catheter.

Assessment Patients were examined during the outpatient visit by a vascular surgeon, who recorded their CEAP classification11 and Venous Clinical Severity Score (VCSS)12. Before the procedure, patients were asked to complete the Dutch versions of the RAND-36-Item Short- Form Health Survey (RAND-36)13 and the Aberdeen Varicose Vein Questionnaire (AVVQ)14, to observe the general and disease-specific quality of life, respectively. The Dutch version of RAND-36 covers health status in eight dimensions: physical functioning, social functioning, role limitations due to physical health problems and emotional problems, general mental health, vitality, bodily pain, and general health perceptions. Also included is one item that provides an indication of perceived changes in health. A high score indicates good health status.

At the end of the procedure patients marked their pain perception on a 100-mm visual analog scale (VAS). Procedural pain was defined as the amount of pain patients experienced during the procedure. Afterward patients were instructed to complete a 14-day diary card to record the level of pain on a 100-mm VAS. On the diary card, patients were also asked

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Postoperative pain and quality of life after MOCA

to provide information about returning to normal activities and the amount of analgesics used was recorded. The dosage of medication was not listed. At the 6-week follow-up, RAND-36 and AVVQ were completed again, and a vascular surgeon assessed the VCSS. Statistical analysis The primary end point of this study was postoperative pain. A sample size calculation was performed based on the assumption that MOCA would reduce postoperative pain during the first 3 days by 50% compared with RFA. To describe a significant difference, 34 patients were necessary in each group.

Intergroup analysis was done using the Student t-test or Mann-Whitney U test for continuous data and the χ2 or Fisher exact test for categoric data. Variables are presented as means ± standard deviation (SD) if distributed parametrically, or as median with interquartile range (IQR, 25th to 75th percentiles) if distributed nonparametrically. Two sided significance was set at P < 0.05. The primary end point was analyzed using the Mann-Whitney U test. Analysis of pain was performed using repeated measurements design. Differences in scores of the AVVQ, RAND-36, and VCSS before and at 6 weeks after treatment were tested using the Wilcoxon signed-rank test, for single group analysis.

The Mann-Whitney U test was used to test differences in change between both groups.

Statistical analyses were performed using SPSS 15.0 software (SPSS Inc, Chicago, Ill, USA). A statistician supervised all analyses.

RESULTS During the study period, 68 patients (25 men, 43 women) were treated, 34 in each group, and all completed their 6-week follow-up assessment. Patients were a mean age of 58 ± 17 years. Patient characteristics are summarized in Table 1. There were no significant differences between the groups regarding demographic data, CEAP classification, preoperative VCSS, and initial AVVQ. The treated GSV was significantly wider at the SFJ in the RFA group than in the MOCA group (P = 0.03). Treatment time was significantly shorter in the MOCA group (P = 0.02). No major complications occurred in either group, and there was no difference in the incidence of minor complications between the two groups (Table 2).

After 6 weeks, the median VCSS significantly decreased in both groups, from 3.0 (IQR, 2.75 - 5.25) to 1.0 (IQR, 1.0 - 2.0) in the MOCA group (P < 0.001) and from 4.0 (IQR, 3.0 - 7.0) to 3.0 (IQR, 1.25 - 3.75) in the RFA group (P < 0.001). VCSS improvement was similar between groups (P = 0.21). Although the VCSS improved in most patients, VCSS deteriorated in five patients at 6 weeks after treatment; one in the MOCA group and four in the RFA group (Figure 1). There were three patients with reported postoperative pain after 2 weeks, one patient with a thrombophlebitis, and one patient with induration. The median deterioration in VCSS was 1.0 (IQR, 1.0 - 2.0).

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TABLE 1 Patient characteristics and technical data MOCA n = 34

RFA n = 34

P value

57.2 ± 15.2

58.0 ± 17.8

0.85a

Male

12 (35%)

13 (38%)

Female

Age, years Sex

0.80b

22 (65%)

21 (62%)

Unilateral

34

34

BMI

25.6 ± 3.9

26.6 ±4.1

C1

1 (3%)

0 (0%)

C2

16 (47%)

9 (26%)

C3

8 (23.5%)

10 (30%)

C4

8 (23.5%)

14 (41%)

C5-6

1 (3%)

1 (3%)

AVVQ

7.1 (5.3-9.2)

9.5 (4.5-16.4)

0.17c

VCSS

3.0 (2.75-5.25)

4.0 (3.0-7.0)

0.09c

GSV diameter, mm

5.7 ± 1.6

6.8 ± 2.4

0.03a

Length of vein ablated, cm

45.3 ± 9.7

46.8 ± 10.1

0.54a

Time of procedure, minutes

13.0 (10.0-15.0)

14.5 (12.0-17.3)

0.02c

Pain during treatment, 0-100 mm VAS

22 ± 16

27 ± 15

0.16a

Number RFA cycles

-

7.7 ± 1.4

Amount of Polidocanol, mg

118 ± 22

-

0.33a

CEAP classification 0.31b

Student’s t-test; b c2 test; c Mann Whitney U­-test; AVVQ = Aberdeen Varicose Vein Questionnaire; BMI = Body Mass Index; CEAP = Clinical Etiological Anatomical Pathophysiological classification; GSV = great saphenous vein; MOCA = mechanochemical endovenous ablation; RFA = radiofrequency ablation; VAS = visual analogue scale; VCSS = Venous Clinical Severity Score a

Postprocedural pain The mean procedural pain during treatment was 22 ± 16 mm for MOCA and 27 ± 15 mm for RFA (P = 0.16) on the 0 to 100-mm VAS. The progress of postoperative pain is shown in Figure 2. At each postoperative day, the difference between groups was statistically significant. Patients receiving MOCA reported less pain over the first 3 days, with mean pain of 6.2 ± 9.2 mm for MOCA and 20.5 ± 25.5 mm for RFA (P = 0.004). The mean postoperative pain per day during the first 14 days after treatment was 4.8 ± 9.7mmin the MOCA group and 18.6 ± 17.0 mm in the RFA group (P < .001). Thrombophlebitis and induration were associated with more postoperative pain in both groups.

Information about the number of days, in which patients used analgesics (mostly paracetamol or ibuprofen), was available in 60 patients (88%). Patients in the MOCA group used postoperative analgesics for a mean of 0.5 ± 1.5 days compared with 2.8 ± 4.2 days in had significantly less days, in which postoperative analgesics were used than in the RFA group, which was a significant difference (P = 0.008).

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Postoperative pain and quality of life after MOCA

TABLE 2 Complications in the first 6 weeks after MOCA and RFA MOCA n = 34

RFA n = 34

P value

Deep venous thrombosis

0

0

Pulmonary embolism

0

0

Skin burn

0

0

Hematoma

2 (6%)

4 (12%)

Paresthesia

0

0

Thrombophlebitis

0

2 (6%)

0.49a

Induration

4 (12%)

8 (24%)

0.20b

3 (9%)

3 (9%)

1.0a

Major complications

Minor complications

Hyperpigmentation a

Fisher exact test;

b Ď&#x2021;2

0.67a

5

test

FIGURE 1 Assessment of the Venous Clinical Severity Score (VCSS) 6 weeks after treatment with mechanochemical endovenous ablation (MOCA) and radiofrequency ablation (RFA)

Quality of life Six weeks after treatment, the AVVQ improved significantly in both groups, from 7.1 (IQR, 5.3 - 9.2) to 5.0 (IQR, 3.0 - 8.5) in the MOCA group (P = 0.006) and from 9.5 (IQR, 4.5 - 16.4) to 4.5 (IQR, 1.5 - 11.2) in the RFA group (P = .002). The difference in AVVQ change between the groups was not statistically significant (P = 0 .17).

Comparison of RAND-36 scores before and at 6 weeks after treatment with MOCA and RFA showed that health status significantly improved in two dimensions for MOCA (physical functioning and role limitations physical). For RFA there was an improvement in bodily pain after 6 weeks. No deterioration in quality of life was observed. Patients in both groups perceived an improved change in health status (Table 3).

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TABLE 3 Median (IQR) health status scores for patients before and 6 weeks after treatment with MOCA and RFA (RAND-36) Preoperative status

6 weeks

P valuea

P value intergroupb

Physical functioning MOCA RFA

87.5 (71.3-100) 80 (57.5-95)

95 (80-100) 80 (57.5-95)

0.02 0.83

0.21

Social functioning MOCA RFA

93.8 (78.1-100) 87.5 (62.5-100)

100 (75-100) 87.5 (75-100)

0.77 0.56

0.72

Role - Physical MOCA RFA

100 (50-100) 75 (0-100)

100 (100-100) 75 (25-100)

0.046 0.875

0.48

Role - Emotional MOCA RFA

100 (100-100) 100 (66.7-100)

100 (100-100) 100 (83.3-100)

0.10 0.68

0.46

Mental health MOCA RFA

84 (70-92) 76 (64-90)

84 (68-92) 80 (66-90)

0.49 0.88

0.37

Vitality MOCA RFA

70 (45-85) 65 (47.5-80)

75 (60-85) 65 (55-77.5)

0.14 0.66

0.42

Bodily pain MOCA RFA

84.7 (67.3-100) 67.3 (39.7-79.6)

89.8 (67.4-100) 69.4 (51-89.7)

0.30 0.025

0.34

Health perception MOCA RFA

70 (55-90) 65 (50-75)

75 (60-95) 70 (52.5-80)

0.30 0.52

0.89

Health change MOCA RFA

50 (50-50) 50 (25-50)

50 (50-75) 50 (50-75)

0.015 0.035

0.69

Wilcoxon Signed Ranks Test; b Mann Whitney U­-test MOCA = mechanochemical endovenous ablation; RFA = radiofrequency ablation a

Return to normal activities The time to return to normal activities was 1.0 day (IQR, 0 - 1.0) in the MOCA group and 1.0 day (IQR, 1.0 - 3.0) in the RFA group, which was significantly longer (P = 0.01). The median time to work resumption for employees was significantly shorter in the MOCA group than in the RFA group (P = 0.02), respectively, 1.0 days (IQR, 1.0 - 3.75) versus 2.0 days (IQR, 2.0 - 7.0).

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Postoperative pain and quality of life after MOCA

5

FIGURE 2 Mean postoperative pain scores on a 0- to 100-mm visual analogue scale (VAS) during 14 days after mechanochemical ablation (MOCA) and radiofrequency ablation (RFA).

DISCUSSION This study has demonstrated that postoperative pain is significantly lower after MOCA compared with RFA, corresponding to a 74% reduction in pain for the first 14 postoperative days. MOCA was also associated with a significantly faster return to normal activities and work resumption.

Whereas occlusion rates over 90% are constantly reported after endovenous treatment, secondary outcome measures of treatment, such as postoperative pain, return to normal activities and health-related quality of life become more important to determine the optimal endovenous treatment for patients with varicose veins15,16. Several studies have analyzed postoperative pain after thermal endovenous ablation, foam sclerotherapy, and surgical stripping. Rasmussen et al. reported significantly less postoperative pain in patients treated with RFA (1.21) and foam sclerotherapy (1.60) than those treated with EVLA (2.58) and surgical stripping (2.25)16. The observed pain was presented as mean pain during the first 10 days on a 0 to 10 cm VAS. Other randomized studies also confirmed the superiority of

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RFA over EVLA in postoperative pain7,8,17. The postoperative pain in patients treated with RFA in this study is consistent with those reports. However, results of postoperative pain are difficult to compare, while outcomes of postoperative pain have been valued in various ways. Most reports on postoperative pain after varicose vein treatment use a VAS to evaluate postoperative pain, but a validation study of different pain rating scales has never been performed for this specific subject. Evidence supports the reliability and validity of most pain intensity scales18. The authors advocate a uniform use of outcome measures for postoperative pain.

The postoperative pain in patients treated with MOCA was consistent with our previous report. In a safety study, we found that the mean postoperative pain on the first day was 9 mm on a 0 to 100mm VAS9. The score decreased to a mean of 2 mm, 7 days after MOCA. The main objective of this study was to evaluate postoperative pain and early quality of life, not to observe anatomical success. However, larger comparative studies are needed to assess the longterm efficacy of MOCA. Elias et al. reported a 96.7% occlusion rate at 260 days in patients treated with MOCA10. The observed differences in postoperative pain in the present study may be explained by the different mechanisms of action. Heating the vein and its surrounding tissue with RFA causes endothelial denudation, collagen denaturation, and vein closure at temperatures of 120°C 19.

Perforation of veins and heating of surrounding perivenous tissue is thought to be associated with (prolonged) postoperative pain.

MOCA combines mechanical damage to the endothelium of the vein wall with the infusion of a sclerosant. The liquid sclerosant produces irreversible damage to the venous endothelium. The cellular membranes of the endothelium are damaged, creating denudation of the endothelium and endofibrosis. Finally, this causes venous obliteration and thrombus development20. Damage of the endothelium depends on the concentration of sclerosant.

The purpose of the mechanical damage is fourfold: (1) promoting the coagulation activation by minimal mechanical damage to the endothelium, (2) inducing a vasospasm that reduces the diameter of the vein, (3) increasing the action of sclerosant by an increase in surface, and (4) ensuring an even distribution of the sclerosant at the endothelium. A recent study showed that adding mechanical balloon catheter injury to standard foam sclerotherapy increased endothelial cell loss21. No (in vivo) histologic studies on MOCA are to date, but the authors hypothesize that the rotating wire also increases endothelial cell loss. Moreover, endothelial cell loss and damage to the media are significantly greater with sodium tetradecyl sulfate compared with polidocanol22. In this study polidocanol was used as single sclerosant registered in The Netherlands.

Although the VAS was threefold lower in the MOCA group, the procedural pain was not significantly different between the groups. This may have been caused by the small sample size, because the study was powered a reduction of 50% in the postoperative course.

Previous studies have not assessed procedural pain as an outcome measure. Adding tumescence anesthesia to a standard treatment, however, does not seem to contribute to a clinically relevant increase in procedural pain. In addition, tumescence anesthesia is time-consuming, as reflected by the significantly longer treatment time with RFA. In the

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Postoperative pain and quality of life after MOCA

present study, tumescence anesthesia was widely applied before the RFA treatment was initiated. Because insufficient tumescent anesthesia may contribute to increased pain, the adequacy was assessed by duplex ultrasound imaging and by controlling the temperature of the catheter on the monitor. Patients treated with MOCA needed significantly less time to return to normal activities, and the time to resume work was also significantly shorter.

The observation that patients treated with MOCA resume their work 1 day earlier than patients treated with RFA might have a significant effect on the total health care burden of varicose vein treatment. This observation urges the initiation of further randomized studies to confirm the observation.

As assessed by the RAND-36 results, the health status of patients was improved 6 weeks after MOCA in the dimensions of physical functioning and role limitations physical. This suggests that these patients perceived fewer problems with their daily physical activities, also related toward employment. Both groups, however, had a significant improvement in perceived health change. In addition, the disease-specific quality of life improved in both groups, without differences between groups. These results regarding quality of life are in line with existing reports. However, differences in quality of life are usually observed 1 year after treatment16.

The present trial had some limitations. First, the study has a small population, although the expected 50% reduction in postoperative pain was achieved. Second, the study did not document other variables that can be associated with postoperative pain, such as depth of the vein from skin level, amount of tumescence fluid, quality of tumescence anesthesia, and incidence of perforation of the treated vein. The quality of tumescence anesthesia, in particular, is a complex parameter to observe, whereas we presume this parameter is the most important factor of pain after endothermal ablation. Finally, as with all nonrandomized studies, results are more susceptible to selection and measurement biases.

CONCLUSION MOCA is associated with significantly less postoperative pain and a faster recovery and work resumption, compared with RFA in the treatment of great saphenous incompetence.

These observations should be confirmed in a randomized controlled trial. Outcomes of postoperative pain after endovenous ablative techniques for varicose veins may be helpful for clinicians in the decision making for optimal treatment.

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REFERENCES 1.

2.

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16.

17.

18.

19.

20.

21.

22.

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Callam MJ. Epidemiology of varicose veins. Br J Surg 1994;81:167-173.

Andreozzi GM, Cordova RM, Scomparin A, Martini R, D’Eri A, Andreozzi F. Quality of life in chronic venous insufficiency. An Italian pilot study of the Triveneto region. Int Angiol 2005;24:272-277.

Kurz X, Lamping DL, Kahn SR, Baccaglini U, Zuccarelli F, Spreafico G, Abenhaim L. Do varicose veins affect quality of life? Results of an international population-based study. J Vasc Surg 2001;34:641-648.

Ravi R, Trayler EA, Barrett DA, Diethrich EB. Endovenous thermal ablation of superficial venous insufficiency of the lower extremity: single center experience with 3000 limbs treated in a 7-year period. J Endovasc Ther 2009;16:500-505.

Min RJ, Khilnani N, Zimmet SE. Endovenous laser treatment of saphenous vein reflux: long-term results. J Vasc Interv Radiol 2003;14:991-996.

Darwood RJ, Theivacumar N, Dellagrammaticas D, Mavor AI, Gough MJ. Randomized clinical trial comparing endovenous laser ablation with surgery for the treatment of primary great saphenous varicose veins. Br J Surg 2008;95:294-301.

Goode SD, Chowdhury A, Crockett M, Beech A, Simpson R, Richards T, Braithwaite BD. Laser and radiofrequency ablation study (LARA study): a randomized study comparing radiofrequency ablation and endovenous laser ablation (810 nm). Eur J Vasc Endovasc Surg 2010;40:246-253.

Shepherd AC, Gohel MS, Lim CS, Hamish M, Davies AH. Pain following 980-nm endovenous laser ablation and segmental radiofrequency ablation for varicose veins: a prospective observational study. Vasc Endovascular Surg 2010;44:212-216.

Van Eekeren RR, Boersma D, Elias S, Holewijn S, Werson DA, De Vries JP, Reijnen MM. Endovenous mechanochemical ablation of great saphenous vein incompetence using the ClariVein device: a safety study.

J Endovasc Ther 2011;18:328-334.

Elias S, Raines JK. Mechanochemical tumescent-less endovenous ablation: final results of the initial clinical trial. Phlebology 2012;27:67-72.

Kistner RL, Eklof B, Masuda EM. Diagnosis of chronic venous disease of the lower extremities: the “CEAP” classification. Mayo Clin Proc 1996;71:338-345.

Rutherford RB, Padberg FT, Comerota AJ, Kistner RL, Meissner MH, Moneta GL. Venous severity scoring: an adjunct to venous outcome assessment. J Vasc Surg 2000;31:1307-1312.

Bowling A. Measuring health. A review of quality of life measurement scales. Buckingham: Open University Press; 1991.

Klem TM, Sybrandy JE, Wittens CH, Essink Bot ML. Reliability and validity of the Dutch translated Aberdeen varicose vein questionnaire. Eur J Vasc Endovasc Surg 2009;37:232-238.

Van den Bos R, Arends L, Kockaert M, Neumann M, Nijsten T. Endovenous therapies of lower extremity varicosities: a meta-analysis. J Vasc Surg 2009;49:230-239.

Rasmussen LH, Lawaetz M, Bjoern L, Vennits B, Blemings A, Eklof B. Randomized clinical trial comparing endovenous laser ablation, radiofrequency ablation, foam sclerotherapy and surgical stripping for great saphenous varicose veins. Br J Surg 2011;98:1079-1087.

Nordon IM, Hinchliffe RJ, Brar R, Moxey P, Black SA, Thompson MM, Loftus IM. A prospective double-blind randomized controlled trial of radiofrequency versus laser treatment of great saphenous vein in patients with varicose veins. Ann Surg 2011;254:876-887.

Ferreira-Valente MA, Pais-Ribeiro JL, Jensen MP. Validity of four pain intensity rating scales. Pain 2011;152:23992404.

Weiss RA. Comparison of endovenous radiofrequency ablation versus 810 nm diode laser occlusion of large veins in an animal model. Dermatol Surg 2002;28:56-61.

Kern P. Sclerotherapy of varicose leg vein legs. Technique, indications and complications. Int Angiol 2002;21:4045.

Ikponmwosa A, Abbott C, Graham A, Homer-Vanniasinkam S, Gough MJ. The impact of different concentrations of sodium tetradecyl sulphate and initial balloon denudation on endothelial cell loss and tunica media injury in a model of foam sclerotherapy. Eur J Vasc Endovasc Surg 2010;39:366-371.

McAree B, Ikponmwosa A, Brockbank K, Abbott C, Homer- Vanniasinkam S, Gough MJ. Comparative stability of sodium tetradecyl sulphate (STD) and polidocanol foam: impact on vein damage in an in vitro model. Eur J Vasc Endovasc Surg 2012;43:721-725.

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Chapter 6

Mechanochemical endovenous ablation versus radiofrequency ablation in the treatment of primary small saphenous vein insufficiency (MESSI trial): Study protocol for a randomized controlled trial Trials. 2014;15:421

Doeke Boersma, Ramon R.J.P. van Eekeren, J.C. (Hans) Kelder, Debora A.B. Werson, Suzanne Holewijn, Michiel A. Schreve, Michel M.P.J. Reijnen, Jean-Paul P.M. de Vries

CHAPTER 6

ABSTRACT Background Minimally invasive endothermal techniques, for example, radiofrequency ablation (RFA), have revolutionized the treatment of insufficient truncal veins and are associated with an excellent outcome. The use of thermal energy requires the instillation of tumescent anesthesia around the vein. Mechanochemical endovenous ablation (MOCA) combines mechanical endothelial damage, using a rotating wire, with simultaneous infusion of a liquid sclerosans. Tumescent anesthesia is not required as no heat is used. Prospective studies using MOCA in both great and small saphenous veins showed good anatomical and clinical results with fast postoperative recovery.

Methods/Design The MESSI trial (Mechanochemical Endovenous ablation versus radiofrequency ablation in the treatment of primary Small Saphenous vein Insufficiency) is a multicenter randomized controlled trial in which a total of 160 patients will be randomized (1:1) to MOCA or RFA. Consecutive patients with primary small saphenous vein incompetence, who meet the eligibility criteria, will be invited to participate in this trial. The primary endpoint is anatomic success, defined as occlusion of the treated veins objectified with duplex ultrasonography at 1 year follow-up. Secondary endpoints are post-procedural pain, initial technical success, clinical success, complications and the duration of the procedure. Initial technical success is defined as the ability to position the device adequately, treat the veins as planned and occlude the treated vein directly after the procedure has been proven by duplex ultrasonography. Clinical success is defined as an objective improvement of clinical outcome after treatment, measured with the Venous Clinical Severity Score (VCSS). Power analyses are conducted for anatomical success and post-procedural pain.

Both groups will be evaluated on an intention-to-treat principle.

Discussion The hypothesis of the MESSI trial is that the anatomic success rate of MOCA is not inferior to RFA. The second hypothesis is that post-procedural pain is significantly less after MOCA compared to RFA. Trial registration Trial registration: NTR4613 Date of trial registration: 28 May 2014.

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MESSI trial: MOCA vs RFA in SSV

BACKGROUND Varicose veins are common and symptoms range from cosmetic complaints to venous ulcers. The incidence increases with age and women are more affected than men. The majority of venous associated complaints are due to great saphenous vein (GSV) insufficiency; however, in 15% of patients, small saphenous vein (SSV) insufficiency is the main cause1, 2, 3.

During the last decade, minimally invasive endothermal catheter modalities took over the role of surgical therapy in the treatment of small saphenous insufficiency. Surgery has been associated with high recurrence rates (25 to 60%), nerve injuries, and significant postoperative complications 4, 5, 6, 7, 8, 9, 10. Success rates after endothermal catheter techniques, for example, endovenous laser ablation (EVLA) and radiofrequency ablation (RFA), are excellent. At 1 year follow-up, the anatomical success rate of RFA is 88%10.

RFA is associated with fewer procedure-related symptoms, superior cosmetic results and earlier resumptions of daily activity compared to traditional surgical procedures11, 12.

However, to perform endothermal techniques, tumescent anesthesia is essential.

Furthermore, heat-induced nerve injury and post-procedural pain is inherent to endothermal ablation and can become chronic. Nerve injuries after endothermal ablation of SSV are seen in up to 11%13.

Mechanochemical endovenous ablation (MOCA), using the ClariVein system (Vascular Insights LLC, Madison, CT, USA) was introduced in Europe in 2010. Mechanical injury to the endothelium by a rotating wire at the tip of a catheter is combined with an infusion of liquid sclerosans, without the use of tumescent anesthesia. In Europe, the ClariVein device was registered on April 26, 2010, CE 558723.

Recently, the authors published the first results of MOCA in SSV. Occlusion rates in 50 patients were 100% at 6 weeks follow-up and up to 97% at 1 year. In this cohort of SSVs, no major complications, including nerve injury, were seen. Minor complications, such as localized ecchymoses and superficial thrombophlebitis were seen in 12 to 14%. The Venous Clinical Severity Score (VCSS), an objective measure for varicose vein-specific symptoms, improved significantly from 3 (IQR 2 to 5) before treatment to 1 (IQR 1 to 3, P <0.001) at 6 weeks follow-up. Clinical results were retained at 1 year after treatment (VCSS 1, IQR 1 to 2, P <0.001). Patients were satisfied after treatment14. Several other studies reported promising data on feasibility, safety, anatomical and clinical success regarding MOCA treatment in GSV insufficiency, without major complications15, 16, 17.

METHOD AND DESIGN Study design The multicenter randomized clinical MESSI trial is designed to compare MOCA and RFA in the treatment of SSV insufficiency. Patients with primary SSV insufficiency, meeting eligibility criteria, will be included at the outpatient clinics of the participating hospitals after

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giving written informed consent. The procedures are performed or supervised by dedicated vascular surgeons, who have performed over 20 procedures of both treatment modalities.

The following Dutch vascular centers are participating in the MESSI trial: St. Antonius Hospital Nieuwegein, Rijnstate Hospital Arnhem and Rode Kruis Hospital Beverwijk.

Study objectives The aim of the study is to show that MOCA has no inferior anatomical success compared to RFA at 1 year follow-up. The secondary aim is to evaluate post-procedural pain, which is hypothesized to be significantly less after MOCA. Sample size calculation Power analysis is calculated for anatomical success at 1 year follow-up after endovenous treatment of the SSV. The calculation is based on the hypothesis that MOCA will have no inferior occlusion rates at 1 year after treatment compared to RFA. The meta-analysis by Van de Bos et al. showed anatomical success rates of 88% after RFA10. Our recent study on MOCA in SSV showed an occlusion rate of 97% in the group treated according to our current study protocol17. A Chi-square test with a one-sided 0.05 significance has a power of 80% to observe no difference between both groups, when each group consists of 74 patients (non-inferiority principle, range 2%). The study population of both groups will consist of 148 patients. Corrected for 7.5% lost to follow-up, the total study population will consist of 160 patients.

Pain is an important secondary outcome parameter. A sample size calculation is also performed for this endpoint based on the hypothesis that MOCA will have lower postprocedural pain scores, as measured by a 100-point pain score, during the first two weeks after surgery. To evaluate a 30 percent reduction in post-procedural pain, 58 patients per group are needed (alpha 5%, power 80%). This analysis will be performed after inclusion and randomization of at least 58 patients in each group.

Primary endpoints The primary endpoint is anatomic success after treatment of SSV insufficiency with MOCA or RFA at 1 year follow-up. Anatomic success is defined as occlusion of the treated vein and proven with duplex ultrasonography.

Secondary endpoints Post-procedural pain is evaluated using a 100-millimeter visual analog scale (VAS) during the first 2 weeks after treatment. The other secondary endpoints are initial technical success, clinical success, pain during treatment, complications and duration of the procedure. Initial technical success is defined as the ability to position the device adequately, treat the veins as planned and occlude the treated vein directly after the procedure proven by duplex ultrasonography. Clinical success is measured using the Venous Clinical Severity Score (VCSS). Complications related to the endovenous treatment, that occur within 30 days after treatment, are divided between major complications (deep venous thrombosis,

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MESSI trial: MOCA vs RFA in SSV

pulmonary embolism, nerve injury, skin burn), minor complications (ecchymosis, superficial thrombophlebitis, hyperpigmentation, wound infection, prolonged pain >1 week) and sclerosans-related complications. Additionally, all endpoints will be evaluated at 2 and 5 years post-treatment.

Ethical considerations A patient, who meets the inclusion criteria, will be fully informed about the trial and provided with a patient information and informed consent form. Patients willing to participate in the study are included after signing the informed consent form. This study is conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The study protocol has been approved by the medical ethical committee in Nieuwegein, (VCMO NL42781.100.13) and the local institutional board of each participating center (LHC Rijnstate Arnhem/Commissie Lokale Uitvoerbaarheid RKZ Beverwijk).

Safety and quality control Data safety monitoring board The Data Safety Monitoring Board (DSMB) is composed of three independent physicians: two vascular surgeons and one dermatologist. The DSMB will review safety and provide recommendations regarding the conduct of the study to the steering committee and to the accredited medical ethical committee (VCMO Nieuwegein) that approved the study protocol. An interim safety analysis will be performed after treatment and at the 4-week follow-up of the first 80 patients.

Adverse and severe adverse events Adverse events (AE) are defined as any undesirable experience occurring to a participant during the study, whether or not considered related to the investigational device. This definition includes events occurring during hospital stay and up to 30 days of follow-up.

Underlying disease that was present at the time of enrollment is not reported as an AE, but any increase in the severity of the underlying disease will be reported as an AE. All AEs will be monitored from the time of enrollment through the 30-day follow-up visit.

Adverse events will be recorded on the case record forms. A description of the event, including the start date, end date, action taken, and the outcome will be provided.

A severe adverse event is any event leading to death, deep venous thrombosis, and neurological complications.

Data on AEs will be reported to the DSMB and to the accredited medical ethical committee via ‘Toetsingonline’ on the website of the Central Committee on Research involving Human Subjects (CCMO, http://www.ccmo.nl).

Inclusion criteria Inclusion criteria are: unilateral primary SSV insufficiency; C2 to C5 varicose veins; diameter of the SSV at the saphenopopliteal junction ≥3 or ≤12 millimeter; age between 18 and 80 years and written informed consent.

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Exclusion criteria Exclusion criteria are: C6 varicose veins; previous surgery or endovenous treatment for insufficient SSV of the ipsilateral leg; oral anticoagulants; pregnancy or lactation; previous deep venous thrombosis; immobilization; contraindication or known allergy for sclerosans; coagulation disorders or an increased risk of thromboembolism; severe renal insufficiency (eGFR <30 ml/min) and/or severe liver insufficiency (leading to coagulation disorders).

Recruitment A total of 160 patients with primary SSV insufficiency will be included in the MESSI trial after signing informed consent (Figure 1). Before treatment begins, a vascular surgeon or dedicated physician assistant will perform a physical examination. The Clinical Etiology Anatomy Pathophysiology (CEAP) score18 and VCSS19 are determined. Insufficiency of the SSV is defined by duplex ultrasound as a retrograde flow >0.5 seconds after calf compression while standing20.

After randomization, the SSV is obliterated in an outpatient setting according to the following: study arm 1: radiofrequency ablation (RFA) or study arm 2: mechanochemical endovenous ablation (MOCA).

All patients with primary SSV incompetence will be asked to participate

Eligibility criteria & Informed consent

Randomization N = 160

Group 1 Radiofrequency ablation

Group 2 Mechanochemical endovenous ablation

FIGURE 1 Flow chart. A total of 160 patients will be randomized to radiofrequency ablation (N = 80) or mechanochemical endovenous ablation (N = 80). SSV: small saphenous vein.

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MESSI trial: MOCA vs RFA in SSV

Randomization Patients will be randomized directly after inclusion by the treating vascular surgeon or physician assistant to one of the treatment arms, using a validated web-based randomization tool (Research Manager, NOVA Business Software, Zwolle, The Netherlands). The 1:1 randomization is performed by blocks of ten with stratification for participating centers.

Treatment details Radiofrequency ablation (RFA) During RFA, radiofrequency energy is used to heat the vein wall of the SSV. The catheter is inserted into the vein and direct energy is delivered to the endothelium with collapsing and sealing of the vein as effect. During the MESSI study, all participating centers are using the VNUS ClosureFAST catheter (VNUS Medical Technologies, San Jose, California, USA).

The VNUS ClosureFAST catheter contains a 7-cm long heating element at the end of the catheter, used for segmental ablation. Every 7-cm segment is treated during a 20-second treatment cycle in which a temperature of 120 degrees is maintained. Only the most proximal segment is treated during the two cycles21.

The insufficient SSV is punctured distally under ultrasound-guidance and a guide wire is inserted. An introducer sheath is placed over the guide wire. Subsequently, the RFA catheter is introduced and positioned approximately 2 cm distal to the saphenopopliteal junction using ultrasound guidance. Then, tumescent anesthesia is delivered along the entire SSV to be treated. The target vein is compressed circumferentially and positioned at least 1 cm below the skin, due to the tumescence.

Mechanochemical endovenous ablation The MOCA technique has been previously described15. Briefly, the ClariVein device is a disposable 2.6 F single-lumen catheter for infusing liquid sclerosans. A metal wire, fitted distally with a small ball, runs through the catheter. The motorized handle unit rotates this wire at 3,000 rpm. The purpose of this wire is to create intimal injury, to induce vasospasm and disperse the liquid sclerosans.

The ClariVein catheter is introduced into the distal SSV through a 4 F micropuncture sheath.

The tip of the dispersion wire is positioned 1 cm distal to the saphenopopliteal junction (SPJ). To induce spasm of the proximal SSV, the rotating wire is activated for 10 seconds.

Then, the activated catheter with rotating tip is steadily withdrawn at the rate of 1 cm every 7 seconds, simultaneously dispersing liquid polidocanol (Aethoxysklerol, KreusslerPharma, Wiesbaden, Germany). In the proximal 10 cm of the SSV 2 mL 3% polidocanol is used, the remaindering insufficient SSV is treated with 1.5% polidocanol. The total amount of used liquid sclerosans will be documented and will not exceed the allowed daily dose of 2 mg/kg/day.

Both treatments After treatment, both the deep venous system and the treated SSV are scanned by duplex ultrasound.

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A compression stocking (20 to 30 mmHg) will be applied for 24 hours continuously and for 2 weeks during the daytime. Patients are asked to resume normal activities immediately after the procedure. No concomitant phlebectomy or sclerotherapy are performed during the first 4 weeks of follow-up. Concomitant treatment after 4 weeks is reported in trial results.

Follow-up After 4 weeks, 1 year, 2 years and 5 years, patients are seen at the outpatient clinic to determine the anatomical and clinical success (Table 1). Ultrasound duplex imaging, VCSS, CEAP score and health status is measured at all aforementioned time points. Ultrasound duplex imaging is done according to a standardized protocol for all participating hospitals.

Post-procedural pain is evaluated using a linear VAS score of 0 to 100 mm during the 2 weeks after treatment. After 4 weeks follow-up, any small branch varicosities may be treated when indicated.

Health status measurement Health status will be measured according to the following:1.Short Form-36 (SF-36) is a multidimensional measurement of general health. It yields eight domains of functional health and well-being scores. 2. Aberdeen Varicose Vein Questionnaire22 (AVVQ) is a validated disease-specific health status measurement for chronic venous insufficiency (patient reported outcome). Both the SF-36 and AVVQ questionnaires are completed preprocedural and after 4 weeks, 1 year, 2 years and 5 years of follow-up.

Data collection and management All data will be collected at each participating treating center by case report forms (CRFs).

Photocopies of the CRFs will be sent to the coordinating investigator (DB). The data will be entered in a validated data management system (Research Manager, NOVA Business Software, Zwolle, The Netherlands) and controlled by an independent monitor. The participating centers will be informed about the current status of recruitment and adverse events via a newsletter every month. Additionally, there will be regular contact between the principle investigator and the local investigators from the participating centers.

Statistical analyses The study results will be evaluated based on intention-to-treat analysis. Data concerning the 1, 2, and 5 years follow-up will be analyzed for both study groups on an intention-totreat manner by student t-test (normal distribution) or Mann Whitney U-test (skewed distribution). To test for normality, the Kolmogorov-Smirnov test will be used. The Chisquare test will be used for binomial data. All probability values are two-tailed. P <0.05 will be considered significant. Obliteration rates will be presented as Kaplan Meier curves, including censoring in case of loss to follow-up.

An interim analysis will be performed after treatment and at 4 weeks follow-up for the first 80 patients to monitor the progression of the study. Final analysis will be performed after follow-up of the last patient included in this study is completed.

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Table 1 Follow up schedule.

Study period 4 wk

1 yr

2 yr

5 yr

Outpatient visit

Screening X

X

X

X

X

Physical examination

X

X

X

X

X

Informed consent

X

Inclusion criteria

X

Randomization

X

CEAP/VCSS

X

X

X

X

X

Ultrasound

X

X

X

X

X

Pain score

Procedure

X

X

AVVQ

X

X

X

X

X

SF-36

X

X

X

X

X

AVVQ: Aberdeen Varicose Vein Questionnaire; CEAP: Clinical Etiology Anatomy Pathophysiology classification; SF-36: Short Form 36-Item Health Survey; VCSS: Venous Clinical Severity Score.

Publication of data Data will be published after all patients had a follow-up period of 1 year, regardless of the outcome of the study. Separate publication of data on pain, initial technical success and short-term follow-up can be published earlier. Long-term results will be published after 2 or 5 years follow-up. Co-authorship will be assigned according to the â&#x20AC;&#x2DC;Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journalsâ&#x20AC;&#x2122; of the International Committee of Medical Journal Editors23.

Definitions Anatomical success is defined as occlusion of the treated SSV segment, measured with duplex ultrasonography. Clinical success is defined as the objective improvement of clinical outcome after treatment, measured with the Venous Clinical Severity Score (VCSS).

Initial technical success is defined as the safe placement of the device at the predefined distance from the SPJ, treatment of the SSV without technical problems and occlusion of the treated SSV directly after treatment.

Failure of treatment Failure of treatment is defined as follows: 1. Type 1 (non-occlusion): the treated vein failed to occlude initially and never occluded during the follow-up.

2. Type 2 (recanalisation): the treated vein occluded directly after treatment, but recanalized, partially (>10 cm) or completely, at a later time point during follow-up.

a. Type 2a: recanalization of the entire treated segment of the vein.

b. Type 2b: partial recanalization (open segment >10 cm)24.

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Complications Post-procedural complications (complications occurring within 30 days after treatment) are defined as follow: 1. Major complication: deep venous thrombosis, pulmonary embolism, skin burn, or nerve injury.

2. Minor complication: ecchymosis, superficial phlebitis, hyperpigmentation, induration, wound infection of the puncture site, or prolonged pain >1 week.

3. Sclerosans-related complications.

Duration of procedure includes the time of the procedure, starting from puncture of the vein to the extracting of the catheter, skin-to-skin contact.

DISCUSSION The introduction of minimal invasive endovenous ablation techniques has revolutionized the treatment of saphenous vein insufficiency. Different endothermal techniques have been introduced and tested in many prospective and randomized studies. Although most research is performed in GSVs, limited data on SSV is available. The results of endothermal techniques have proven to be excellent with a long-term anatomical success rate over 90%; therefore, the aim for future studies, especially in SSV, is diminishing heat-related complications, for example, pain and nerve injury, without compromising anatomical and clinical success. Until now the gold standard for the treatment of SSV insufficiency remains unclear.

This trial is designed to compare the anatomical success at 1 year after MOCA with RFA. A secondary aim is to investigate whether MOCA is associated with a significant reduction in post-procedural pain. A major point of discussion is the choice for RFA above EVLA techniques. Although the meta-analysis of Van de Bos et al. showed the superiority of endothermal ablation (EVLA) in terms of anatomical success at 1 to 5 years follow-up10, the more recent RCT of Rasmussen et al. has proven that the results of RFA using the ClosureFast device are at least similar to EVLT. In this randomized trial, RFA was associated with significantly less post-procedural pain compared to EVLA24. Furthermore, an important consideration in choosing ClosureFast is the uniformity of this technique, while in the case of ELVA, discussion about different tip designs and wavelengths might occur.

It has been proven that minimally invasive techniques will lead to a lower incidence of nerve injury in the SSV compared to conventional surgery (11% versus 28%). However, sural nerve injury is still considered a major and potentially underreported complication25, 26 . Due to the fact that no heat and tumescent is used in MOCA, nerve injury after SSV ablation might become a redundant complication.

In conclusion, the MESSI trial is a multicenter randomized controlled trial that aims to show a similar anatomical success of MOCA compared to RFA. Additionally, we hypothesize that this is accompanied by comparable clinical success and a reduction in post-procedural pain after MOCA compared with RFA.

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TRIAL STATUS The MESSI trial started including second quarter of 2014 in Rode Kruis Hospital Beverwijk.

The inclusion of patients in this study was seized, due to long-lasting uncertainties surrounding the reimbursement of endovenous therapies, in particular MOCA, and the exclusion of C2 varicosities from reimbursement of treatment. All participating physicians and patients were informed. The included patients were all treated successfully and were enrolled in standard follow up care.

6

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REFERENCES 1.

Andreozzi GM, Cordova RM, Scomparin A, Martini R, D’Eri A, Andreozzi F; Quality of Life Working Group on Vascular Medicine of SIAPAV. Quality of life in chronic venous insufficiency.An Italian pilot study of the Triveneto Region. Int Angiol 2005;24:272-277.

2. Callam MJ. Epidemiology of varicose veins.Br J Surg. 1994;81:167-173.

3. Almgren B, Eriksson E. Valvular incompetence in superficial, deep and perforator veins of limbs with varicose veins. Acta Chirurg Scand 1990;156:69–74.

4. Engelhorn CA, Engelhorn AL, Cassou MF, Salles-Cunha SX. Patterns of saphenous reflux in women with primary varicose veins. J Vasc Surg. 2005;41:645-651 5. Samuel N, Carradice D, Wallace T, Mekako A, Hatfield J, Chetter I. Randomized clinical trial of endovenous laser ablation versus conventional surgery for small saphenous varicose veins. Ann.Surg 2013;257(3):419-426 6. Ikponmwosa et al. Outcome following saphenopopliteal surgery: a prospective observational study. Phlebology 2010;25(4):174-178.

7. O’Hare, Vandenbroeck CP, Whitman B, Campbell B, Heather BP, Earnshaw JJ. A prospective evaluation of the outcome after small saphenous varicose vein surgery with one-year follow-up. J.Vasc.Surg 2008;48(3):669-673.

8. Allegra C, Antignani PL, Carlizza A. Recurrent varicose veins following surgical treatment: our experience with five years follow-up. Eur.J.Vasc.Endovasc.Surg 2007;33(6):751-756.

9. Trip-Hoving M, Verheul J, Van Sterkenburg SMM, De Vries WR, Reijnen MMPJ.Endovenous laser ablation of the small saphenous vein; short-term results and patient satisfaction. Photomed Laser Surg. 2009;27:655-658.

10. Van den Bos R, Arends L, Kockaert M, Neumann M, Nijsten T. Endovenous therapy of lower extremity varicosities: a meta-analysis. J Vasc Surg. 2009;49:230-239.

11. Shepherd AC, Gohel MS, Brown LC, Metcalfe MJ, Hamish M, Davies AH. Randomized clinic trial of VNUS ClosureFAST radiofrequency ablation versus laser for varicose veins. Br J Surg 2010;97:810-818.

12. Proebstle TM, Gul D, Kargl A, Knop J. Endovenous laser treatment of the lesser saphenous vein with a 940-nm diode laser: early results. Dermatol Surg 2003;29:357–361.

13. Creton D, Pichot O, Sessa C, Proebstle TM. Radiofrequency-powered segmental thermal obliteration carried out with the ClosureFast procedure: results at 1 year. Ann Vasc Surg 2010;24(3):360-366.

14. Boersma D, Van Eekeren RRJP, Werson DAB, De Vries JPPM, Reijnen MMJP. Mechanochemical endovenous ablation of small saphenous vein insufficiency using the ClariVein® device: One-year results of a prospective series. EJVES 2013;45(3): 299-303 15. Elias S, Raines JK.Mechanochemical tumescentless endovenous ablation: final results of the initial clinical trial.

Phlebology. 2012;27:67-72.

16. Van Eekeren RRJP, Boersma D, Elias S, Holewijn S, Werson DAB, De Vries JPPM, Reijnen MMJP. Mechanochemical endovenous ablation of great saphenous vein incompetence using the ClariVein® device: a safety study. J Endovasc Ther. 2011;18:328-334 17. Bishawi M, Bernstein R, Boter M, Draugh D, Gould C, Hamilton C, Koziarski J. Mechanochemical ablation in patients with chronic venous disease: a prospective multicenter report. Phlebology. 2014;29:397-400 18. Kistner RL, Eklof B, Masuda EM. Diagnosis of chronic venous disease of the lower extremities: the “CEAP” classification. Mayo Clin Proc 1996;71:338-345.

19. Rutherford RB, Padberg FT, Comerota AJ, Kistner RL, Meissner MH, Moneta GL. Venous severity scoring: an adjunct to venous outcome assessment. J Vasc Surg 2000;31:1307-1312.

20. Labropoulos N, Tiongson J, Pryor L Tassiopoulos AK, Kang SS, Mansour MA, Baker WH. Definition of venous reflux in lower extremity veins. J Vasc Endovasc Surg 2003;38:793-798 21. Proebstle TM, Vago B, Alm J, Gockeritz O, Lebard C, Pichot O. Treatment of the incompetent great saphenous vein by endovenous radiofrequency powered segmental thermal ablation: first clinical experience. J Vasc Surg 2008;47:151-156 22. Klem TM, Sybrandy JE, Wittens CH, Essink Bot ML. Reliability and validity of the Dutch translated Aberdeen Varicose Vein Questionnaire. Eur J Vasc Endovasc Surg 2009;37:232-238.

23. Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals . International Committee of Medical Journal Editors. Updated December 2013. http://www.icmje.org 24. Rasmussen LH, Lawaetz M, Bjoern L, Vennits B, Blemings A, Eklof B. Randomized clinical trial of endovenous laser ablation, radiofrequency ablation, foam sclerotherapy and surgical stripping for great saphenous varicose veins. Br J Surg 2011;98:1079-1087.

25. O’Hare JL, Vandenbroeck CP, Whitman B et al. A prospective evaluation of the outcome after small saphenous varicose vein surgery wtih one-year follow-up. J Vasc Surg. 2008; 48:669-673 26. Huisman LC, Bruins RMG, Van den Berg M, Hissink RJ. Endovenous laser ablation of the small saphenous vein: prospective analysis of 150 patients, a cohort study. Eur J Vasc Endovasc Surg 2009;38,:199-202.

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6

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Histopathological aspects

Chapter 7

Macroscopic and histologic analysis of vessel wall reaction after mechanochemical endovenous ablation using the ClariVein OC device in an animal model Accepted for publication in Eur J Vasc Endovasc Surg 2016

Doeke Boersma, Steven T.W. van Haelst, Ramon R.J.P. van Eekeren, Aryan Vink, Michel M.J.P. Reijnen, Jean-Paul P.M. de Vries, Gert Jan De Borst.

CHAPTER 7

ABSTRACT Introduction Mechanochemical endovenous ablation (MOCA) has been developed as a tumescentless technique to ablate saphenous veins and to avoid heat-induced complications, and postprocedural pain. The mechanism of action of MOCA is poorly understood. Our experiments were conducted to determine the effect of MOCA on vein wall injury and sclerosis in an animal model.

Methods A total of 36 lateral saphenous veins (LSVs) were treated in 18 goats according to human protocol. Veins from 9 goats were evaluated 45 minutes after the procedure while in the remaining 9 goats, the treated veins were evaluated 6 weeks later. All treated veins were divided equally over 3 treatment groups: MOCA, mechanical ablation without the sclerosant, and liquid sclerotherapy alone. The histologic effects of treatment on the vein wall were systematically evaluated.

Results The average diameter of the LSV was 4.0 Âą 0.5 mm. Technical success was achieved in all but 1 LSV (35/36, 97.2%), with a median procedure time of 14 minutes (range, 9-22 minutes). In the acute group, histologic examination showed that mechanical ablation (alone or MOCA) induced severe injury to the endothelium in 82% but no damage to other layers of the vein wall. Mechanical ablation led to vasoconstriction. After 6 weeks of followup, 4 of 6 MOCA-treated veins were occluded. The occluded segments consisted mainly of fibrotic lesions probably evolved from organized thrombus. No occlusions were observed after sclerotherapy or mechanical treatment alone.

Conclusion MOCA is associated with an increased occlusion rate compared to its separated components of mechanical ablation or sclerotherapy. The occlusion consists of cellular fibrotic material likely to be evolved from organized thrombus with fibrotic alterations to the surrounding media and adventitia. This study underlines the hypothesis that the additive use of MOCA increases the effectiveness of sclerosants alone by inducing endothelium damage and probably vasoconstriction.

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Macroscopic and histologic analysis after MOCA

INTRODUCTION Varicose veins of the lower limbs are a common diagnosis with a prevalence of up to 21% in the adult population associated with physical impairment and decreased general and disease-specific quality of life1-3. Without treatment venous pathology has a tendency to progress over time4.

For more than a century, surgical high ligation, with or without stripping or compression therapy, was the only available treatment option of superficial venous insufficiency. The introduction of minimally invasive ablation techniques in recent decades has revolutionized the treatment of varicose veins. As a result, endovenous laser or radiofrequency ablation became the new standard of care due to excellent occlusion rates in both the great and small saphenous vein (GSV/SSV)5,6. However, the need for tumescent anesthesia, the risk of heatinduced nerve injury, especially in the SSV and below-the-knee GSV, and postprocedural pain are considered disadvantages to both of these endothermal techniques. To eliminate these cons, a growing attention for nonthermal techniques has developed in recent years.

Mechanochemical endovenous ablation (MOCA) is a nonthermal technique that combines endovenous mechanical injury to the vein wall with simultaneous infusion of a liquid sclerosant. Even though MOCA has proven to be safe for the treatment of GSV and SSV insufficiency, with increasing data available on long-term results, the precise working mechanism and effect on the vein wall remain unknown. To date, experimental histologic studies on MOCA are sparse7-9. The goal of this study was to elucidate the mechanism of action of MOCA by analyzing its separate componentsâ&#x20AC;&#x2122; effect on the vessel wall histology in 18 goats.

MATERIALS AND METHODS Study design The study included 18 female dairy goats. Half of the goats (9 goats/18 veins) were enrolled into an acute experiment to assess direct effects of the MOCA treatment and its separate components. The remaining 9 animals (18 veins) were treated within the 6-week follow-up protocol. The following experimental groups (6 treated veins each) were formed: 1. Acute experiment: mechanochemical ablation (ClariVein + 2% Aethoxysklerol) 2. Acute experiment: liquid sclerotherapy (2% Aethoxysklerol) 3. Acute experiment: mechanoablation (ClariVein without Aethoxysklerol) 4. Follow-up experiment: mechanochemical ablation (ClariVein + 2% Aethoxysklerol) 5. Follow-up experiment: liquid sclerotherapy (2% Aethoxysklerol) 6. Follow-up experiment: mechanoablation (ClariVein without Aethoxysklerol) The experiments were approved by the Committee on Animal Experiments (DEC), Utrecht, The Netherlands (Protocol No.: 2012.II.12.185). All procedures were performed by an

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endovascular specialist with extensive experience with MOCA (over 50 procedures) and were conducted in accordance with good laboratory practice and international guidelines in animal research, under guidance of licensed biotechnicians at the animal laboratory of the Experimental Cardiology Department, University Medical Centre Utrecht, The Netherlands.

Total 18 goats / 36 hindlegs

Acute

Follow up

9 goats / 18 legs

9 goats / 18 legs

MOCA 6 legs

MOCA 6 legs

Mechanical 5 legs *

Mechanical 6 legs

Sclerotherapy 6 legs

Sclerotherapy 6 legs

* No successful cannulation in 1 vein due to small caliber vein

Animals After a pilot study was conducted to prove the feasibility of the study protocol, we included a total of 18 female dairy goats that were allocated to the different experimental groups.

The sample size of the study groups is in line with previous international publications in this field7,10. The fully grown animals were obtained from a local qualified supplier. All animals were given normal chow without supplements, and water was freely available.

The animals were housed in pairs, except for preprocedure and postprocedure days, when isolation was maintained to protect the animals.

Experimental Procedures All animals were treated under general anaesthesia and oxygenated with a mechanical respirator. The animal was placed lateral supine on the operating table. The hind legs were

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Macroscopic and histologic analysis after MOCA

FIGURE 1 (a) anatomy of the hind leg of a goat, arrow: LSV. (b) level of puncture. (c) placement of sheath.

shaved, the skin was disinfected with iodine, and sterile draping was applied. A small transverse skin incision at the level of the ankle was made to visualize the distal lateral saphenous vein (LSV) and to place a introducer sheath (Figure 1). The LSV of the goat was chosen because of similarity to the human saphenous vein regarding diameter and length.

The 2.67F ClariVein occlusion catheter (OC) [Vascular Insights LLC, Madison, CT, USA] was introduced via a 5F introducer sheath, and the tip was positioned at approximately 25 cm from insertion into the vein.

The goats were equally divided into the 6 groups, as stated above, and once the allocation was determined, changing the procedure was no longer possible. In groups 1 and 4, the treatment was in line with current treatment in humans11. In short, the ClariVein OC was used at maximum rotations per minute (3500 rpm), and after activation for 7 seconds proximally without infusion or withdrawal, the device was pulled back 1 cm every 7 seconds. Aethoxysklerol 2% (Kreussler Pharma, Wiesbaden, Germany) was administered simultaneously through the ClariVein OC. The dosage and infusion rate were chosen according to the dosing table made available by the manufacturer.

In groups 2 and 5, the treatment consisted of solely liquid sclerotherapy. The sclerosant was delivered over 25 cm using a ClariVein catheter, without activation of the motor, with a similar dosage and infusion rate as in MOCA. In the remaining groups 3 and 6, the treatment consisted of the mechanically induced damage without additional sclerosant.

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Venous explantation In the acute experiments, a pressure bandage was applied at the puncture site to control bleeding. The treated LSV was harvested between 30 and 45 minutes after the procedure was finished. The veins were surgically exposed over the total length of treatment.

The exposed vein was studied macroscopically for occlusion or any complication (perforation, rupture, or vein wall hematoma). Proximally and distally the vein was ligated with Vicryl 3-0 (Johnson & Johnson, New Brunswick, NJ, USA) suture. Long ends of the suture were used for identification of the proximal end. Large side branches were ligated with a similar suture or with a titanium clip. The veins were fixed in formaldehyde solution 4% for 48 hours before further histologic processing. After the veins were harvested, the animals in the acute experiment were killed directly with a lethal overdose of potassium.

In goats randomized to the follow-up experiments, the puncture site was closed with a Prolene 6-0 (Johnson & Johnson) suture. The skin was closed with Monocryl 3-0 (Johnson & Johnson). After monitored recovery, the animals were placed in group housing for 6 weeks. All follow-up animals were administered Augmentin (10 mg/kg intravenous; GlaxoSmithKline, London, UK) before treatment and Depomycine (1 mL/kg intramuscular; Intervet, Boxmeer, The Netherlands) at the end of the procedure. No anticoagulants or platelet aggregation inhibitors were administered.

At 6 weeks of follow-up, general anesthesia was initiated similar to the first procedure.

The hind legs were studied for ecchymosis, wound infection, and discolouration. After inspection, the treated veins were explanted, as described above, studied macroscopically, and stored in 4% formalin. Thereafter, the animals were killed with intravenous potassium.

Experimental outcomes The acute group was designed to assess the aspect and severity of the damage inflicted by the treatment. Macroscopically, the vein was inspected for perforations and surrounding hematoma. Microscopically, the degree of intimal damage and injury to other layers of the vein wall was evaluated. The vein wall thickness was measured to quantify vasoconstriction.

In the 6-week follow-up group, the veins were macroscopically and microscopically studied to assess venous occlusion (anatomic success). Microscopically, the veins were further analysed to describe the histology and components of the occluded segments.

Histological analysis The treated LSVs were fixed in formalin 4%. All veins were segmented into 5-mm pieces every 2 cm starting at 1 cm from the proximal end (1 cm, 3 cm, 5 cm, etc.) and processed into standard paraffin blocks. Slides were made of 4-Âľm-thick sections and stained with hematoxylin and eosin for general observations and with Elastin van Gieson for microscopic evaluation and assessment of fibrosis. Alpha smooth muscle actin (Îą-SMA) immunostains were used to assess vein medial damage, and quantatively scored with the use of cellSens (Olympus Lifesciences, Tokyo, Japan) in all sections.

In the acute experiments, the intimal layer and the entire vein wall were assessed for damage. To visualize the endothelial cells, von Willebrand factor and ERG (ETS related

104

Macroscopic and histologic analysis after MOCA

gene) immunostains were performed. The percentage of the circumference with injured or absent endothelium was measured and categorized as mild (<10% damage), moderate (20% to 50%), and severe (>50%)8. The section of each vein with the highest degree of injury was scored, in which the circumference of endothelium was measured and divided by the total circumference of the lumen of the vein. To score the injury, this percentage was deducted from 100%.To measure possible venous constriction, a ratio between diameter and vein wall thickness was calculated. The mean of the vein wall thickness measured on each quadrant of the vein was divided by the radius of the vein. Total occlusion or remaining lumen area and area of intimal hyperplasia and the aspect of the vein wall were assessed at 6 weeks. Additional α-smooth muscle actin immunostain and Perl’s iron stain were performed to further study the components of intimal lesions in selected slides.

Statistical analysis Final analysis was performed on the 9 acute goats (18 veins) and 9 goats with 6 weeks of follow-up (18 veins) separately. Mean data are presented with the ± standard deviation.

We used median and range to present numeric data. We used Chi-square tests to compare categorical variables and Kruskal - Wallis tests were used to compared continuous variables.

SPSS 21.0 software (IBM Corp, Armonk, NY) was used for all analyses.

RESULTS Procedure The goats were an average weight of 59 ± 7 kg. The average diameter of the LSV at the level of introduction was 4.0 ± 0.5 mm. The median skin-to-skin treatment duration was 14 minutes (range, 9-22 minutes). Cannulating and treating the LSV according to plan was feasible in all but 1 hind leg (technical success rate, 97.2%). The unsuccessful procedure was in a vein with the smallest diameter of all (2 mm) and was planned for mechanoablation without sclerosant in an acute experiment (group 3). After reviewing this case, no replacement for the vein was deemed necessary. In all remaining acute experiments, harvesting the vein was feasible within the designated time of 30 to 45 minutes after treatment. No other perioperative problems or complications were noted. No complications were observed during the follow-up, especially no signs of deep venous thrombosis or wound infection.

A pilot study of 2 animals was first conducted to evaluate the feasibility of the study protocol. This pilot study revealed no technical difficulties and showed that MOCA treatment could be executed as planned. Because the initial protocol was feasible and no changes were made to surgical procedures, the samples of these 2 animals were included in the analysis of group 1.

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Macroscopic evaluation All treated veins in the acute experiments were surgically exposed. No hematoma or perforation of the vein wall was observed (Figure 2a). All veins were compressible and filled with blood. No thrombus or occlusion was observed. The diameter varied between and within the veins (range 1,5 to 9mm).

The wounds in all follow-up animals healed without signs of infection or local hematoma.

Hyperpigmentation of the overlying skin was seen in the 3 hindlegs ( 1 after MOCA and 2 after liquid sclerotherapy), The most distinct cases were present in a leg treated with liquid sclerotherapy (Figure 2b). No ecchymosis over the treated trajectory was noted.

All veins treated with liquid sclerotherapy or mechanoablation (groups 5 and 6) were patent and compressible over the entire length. No macroscopic signs of perforation or total vein destruction were present. Of 6 veins treated with MOCA (group 4), 4 were macroscopically occluded, were fibroticly though, non-compressible, and no efflux of blood was seen (Figure 2c). Some of the smaller side branches of this part of the LSV were macroscopically occluded over the first millimeters. A major side branch was present in all animals a few centimeters above the puncture zone. Distal to this major side branch, all LSVs were patent.

The remaining 2 veins treated with MOCA (group 4) showed no macroscopic changes.

The veins were patent and compressible over the entire length.

FIGURE 2 (a) exposed LSV after acute experiment without hematoma or perforation. (b) hyperpigmentation after MOCA. (c) thickened, fibrotic LSV with full occlusion after MOCA.

Histological evaluation In the acute experiments, no histologic evidence of damage beyond the endothelium layer of the vessel wall was found in any of the treatment groups. In 82% (9 of 11) of the veins treated with MOCA and mechanical action (groups 1 and 3), at least one segment showed severe endothelial injury compared to 17% (1 of 6) in the veins treated with sclerotherapy (group 2). The endothelial damage differed greatly within the veins: segments with (nearly) total endothelium abrasion and segments with totally intact endothelium were seen within single veins (Figure 3). Veins with intact venous valves were seen in all acute groups.

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Macroscopic and histologic analysis after MOCA

Quantitative measurement of α-SMA staining in the media showed no (significant) differences between the treatment groups (p = 0.654). In the groups treated with mechanical ablation or MOCA, the vein wall thickness and the vein wall–to–vein radius ratio was increased compared with Aethoxysklerol, indicating venous constriction. The absolute measurements are reported in Table 1.

7

FIGURE 3 Histology of acute experiment: (a and b) mechanical treatment. (a) Venous constriction with reduction of the lumen. Elastica van Gieson stain. (b) Endothelial damage with loss of endothelial cells. Endothelial cells are stained red and indicated with arrow. ERG immunostain. (c and d) Aethoxysklerol treatment. (c) No venous constriction with preservation of the lumen. Elastica van Gieson stain. (d) No loss of endothelial cells. ERG immunostain.

In the follow-up experiments, we only observed occlusion in veins treated with MOCA, of which total occlusion was observed in 4 of 6 veins (Table 2). The veins with total occlusion showed a cellular fibrotic lesion with α-SMA–positive myofibroblasts and microvessels.

The observed fibrosis extended in the medial and adventitial layers, but showed no signs of earlier perforation of the vein wall. Abundant iron pigment was observed within the lesions, suggesting that these have evolved from organized thrombus (Figure 4).

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One segment in 1 of these veins showed a 50% stenosis, showing intimal hyperplasia consisting of loose connective tissue with myofibroblasts, a few deposits of iron pigment, and the presence of neovascularization. The media layer of this section showed no fibrotic alterations. Elastica van Gieson staining showed an increase of fibrosis in the media/ adventitia of totally occluded veins, which was not present in the nonoccluded veins. The 2 remaining MOCA-treated veins were open, with limited intimal hyperplasia of no more than 20% of the luminal area. Quantitative measurement showed a (significant) decrease in α-SMA positive area in the media of MOCA treated veins as compared to mechanical or aetoxysklerol treated veins (p = 0.001) (Figure 5). The open segments within the MOCA group showed higher percentages of α-SMA areas as compared to occluded segments in the MOCA group(p < 0.001).

TABLE 1 Histological aspects of veins in the acute experiments Acute experiment

MOCA (n = 6)

Mechanical (n = 5)

Sclerotherapy (n = 6)

Minor / moderate (<50%)

2 (33.3%)

0 (0%)

5 (83.3%)

Severe (>50%)

4 (66.7%)

5 (100%)

1 (16.7%)

Wall thickness, µm

376 (127-426)

277 (206-383)

170 (85-379)

Vein diameter, mm

2.5 (1.8-4.9)

2.9 (1.4-4.0)

4.0 (1.8-7.7)

Wall-to-radius ratio

0.31 (0.05-0.44)

0.25 (0.10-0.40)

0.10 (0.03-0.42)

αSMA‡

80 (67-88)

80 (51-92)

79 (62-87)

Maximal endothelial damage ERG*

Categoric data are reported as number, and continuous data are reported as mean ± standard deviation or median (range). *Segment with highest percentage of endothelial damage scored. ‡percentage of total media area (range).

As also reported in the macroscopic evaluation, only the segments proximal to the large side branch were occluded. In line with the macroscopic data, no occlusions were seen in groups 5 and 6. In 1 of 6 veins treated with Aethoxysklerol, limited intimal thickening was noted of up to 20% of the vein lumen. The remaining 5 veins were fully open. The occlusion rate in veins treated with MOCA was higher than in the other 2 treatment groups (p = 0.036). We observed no histologic signs of damage or fibrosis to other layers of the vein walls in the nonoccluded veins, including the 2 nonoccluded veins treated with MOCA.

FIGURE 4 Histology of total occlusion after mechanochemical endovenous ablation: a and b) Hematoxylin and eosin stain showing cellular fibrotic lesion ingrowth of microvessels and presence of iron pigment. b and c) Elastica van Gieson stain confirming the presence connective tissue in the lesion (purple). d and e) Perl’s iron stain shows abundant presence of iron pigment, suggesting an organized thrombus. g and h) α-Smooth muscle actin stain (red) shows the smooth muscle cells in the media and the myofibroblasts in the occlusive lesion. u

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Macroscopic and histologic analysis after MOCA

7

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Figure 5 Quantitative measurement of α-SMA positive area in the media. a) no difference between groups in acute experiment (groups 1-3). b) significant decrease in MOCA treated veins as compared to mechanical or aetoxysklerol treated veins (p = 0.001)

TABLE 2 Histological aspects of veins in the follow-up experiments Follow-up 6 weeks

MOCA (n = 6)

Mechanical (n = 6)

Aethoxysklerol 2% (n = 6)

Occlusion

4 (66.7%)

0 (0%)

0 (0%)

Open*

2 (33.3%)

6 (100%)

6 (100%)

Vessel diameter, mm

3.2 (1.7-4.8)

4.0 (2.0-5.5)

4.7; 3.3-6.0)

Lumen diameter, mm

1.1 (0-4.4)

3.6 (1.7-5.1)

4.5; 1.7-5.8)

Lumen area, mm

1.2 (0-11.9)

6.7 (2.3-15.2)

14.9; 0.8-18.6)

Intimal hyperplasia

5 (83.3)

0 (0)

2 (33.3)

Intimal hyperplasia area, mm

1.1 (0.0-5.9)

0.0 (0.0-0.1)

0.01 (0.0-0.7)

αSMA‡

64 (29-88)

80 (66-94)

80 (67-90)

Aspect lumen

2

2

Categoric data are presented as number (%) and continuous variables as median (range). *Limited intimal hyperplasia up to 20% may be present. ‡percentage of total media area (range).

The ClariVein OC got stuck in 2 veins several times during treatment, and debris was tangled around the tip of the device. One vein was in group 4 (MOCA) and was totally occluded at 6 weeks of follow-up, the other vein was in group 6 (mechanical only) and was fully patent at 6 weeks, with no signs of vein wall damage on histologic examination.

DISCUSSION The present study shows the effects of MOCA and its separate components in an acute and follow-up animal experiment. The experiments revealed that the mechanical action inflicts damage to the endothelium without signs of injury to the other layers of the vein

110

Macroscopic and histologic analysis after MOCA

wall. We observed a significant narrowing of the veins after MOCA or mechanical ablation compared with sclerotherapy. After 6 weeks of follow-up, the results of MOCA were superior to mechanical ablation only and sclerotherapy: we observed occlusion in 4 of 6 veins treated with MOCA compared with no occlusions in the veins treated with mechanical action or Aethoxysklerol separate.

The results of our study confirm the hypothesis that the ClariVein leads to venous occlusion by inflicting mechanical injury to the endothelial barrier, permiting the liquid sclerosans to induce an increased chemical reaction to the deeper layers of the vein wall. In the acute experiment severe endothelium injury was seen in 82% (9 of 11) of veins treated with MOCA or solely mechanical action, significantly more than after sclerotherapy. In line with results of an earlier small ex vivo study8, there was a large spread in degree of injury within a single vein. This is an interesting finding to discuss, because this could be the cause for occurrence of partial recanalization, which is relatively frequently seen in humans studies and is usually without clinical consequences11,14,16. Increasing endothelium injury might be the key in further optimizing treatment results. Decreasing the speed of pull-back of the ClariVein might lead to more injury by prolonged exposure to the mechanical action and, thus, potentially induce more vasoconstriction. Evaluation of techniques to increase endothelium damage and its effect on anatomic success could be relevant subjects for future studies.

Another important finding from this study is the observation that veins were significantly constricted after MOCA and solely mechanical treatment than after sclerotherapy alone.

This might be induced by direct contact of the â&#x20AC;&#x153;stirring wireâ&#x20AC;? to the vessel wall or by shear stress of whirling intraluminal fluid. This narrowing might be a contributor to the overall effect in MOCA by further increasing the effect of sclerosant on the vein wall.

Vasoconstriction will result in the sclerosant reaching a higher concentration in the vein as a result of a decreased amount of intraluminal blood and, possibly, stasis. Furthermore, vasoconstriction will theoretically limit the washout of liquid sclerosant and thereby lead to prolonged exposure. As recently published, prolonging the exposure to liquid sclerosant leads to increased chemically induced injury to the vein wall17 In contrast to histological studies with endovenous laser ablation in which acute and total destruction of venous wall is seen10, our results suggest that all occlusions seemed to originate from organized thrombus with fibrotic alterations to the surrounding media and adventitia. This might also give insight in the reason for recanalisation of initially MOCA occluded veins, especially when neovascularisation arises within these occlusive lesion.

This phenomenon is seen in almost all clinical cohort studies published to date.

Compared with the anatomic success of 88.2% to 96.7% occlusion rates in human cohort studies11-16, the occlusion rate in this animal study is less than expected. This leads to the discussion whether the current model is adequate to evaluated the working mechanism of MOCA. Even when the potential factors of influence on the anatomical success rate are evaluated the reason remains without clear explanation. The procedure was performed exactly as the standard procedure in clinical practice. To avoid bias due to experience, the procedures were performed by a dedicated team with vast experience in MOCA.

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Furthermore, the concentration and dosage of Aethoxysklerol was determined according to the human dosingtable.

Furthermore, the goat as the model to induce and study venous damage may be questioned.

The main reason this animal model was chosen is that previous experiments in endothermal ablation10 and MOCA7 used goats and the size of the LSV was another major reason: with an average diameter of 4 Âą 0.5 mm, the veins are within the lower range of varicose veins included in humans studies11. In contrast to the current study the occlusion rate in the study form Tal et al. was 100%. There two important differences compared with that study: 1. sodium tetradecyl sulfate 1.5% was used instead of Aethoxysklerol (polidocanol) 2% and 2. compression stockings were applied. Although sodium tetradecyl sulfate (trademarks: Sotradecol or Fibrovein) has been shown to be a more potent sclerosant than polidocanol in a in-vitro experiment18, no differences in anatomical success were observed in men.

Similar to our study, Tal et al. described no occlusion in the treatment with only mechanical ablation or sclerotherapy7. Finally, it is important to appreciate that the results from the discussed study described only selected data of a larger experiment (11 of 18 goats)7.

Only one aspect differs between this study or the clinical setting and our experiments: the MOCA procedure is directly followed by the use of compression stockings for at least the first 24 hours11,14,16. We were unable to apply stockings during follow-up for practical reasons and animal welfare. Compression therapy might be a beneficial addition measure in MOCA. Finally, even though this study gives an important insight into the tissue reaction to MOCA and its separate components, we could not retrieve significant data on end points to draw indisputable conclusions owing to the small sample size.

CONCLUSION MOCA is associated with an increased occlusion rate compared to its separated components of mechanical ablation or sclerotherapy. However, MOCA in the animal model resulted in occlusion in only two-thirds of the animals. The occlusion consists of cellular fibrotic material likely to be evolved from organized thrombus with fibrotic alterations to the surrounding media and adventitia. This study underlines the hypothesis that the additive use of MOCA increases the effectiveness of sclerosants alone by inducing endothelium damage and probably vasoconstriction.

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18.

Wittens C, Davies AH, Bækgaard N, Broholm R, Cavezzi A, Chastanet S, et al. Management of Chronic Venous Disease: Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS). Eur J Vasc endovasc Surg 2015;49(6):678-737 Carradice D, Mazari FA, Samuel N, Allgar V, Hatfield J, Chetter IC. Modelling the effect of venous disease on quality of life. Br J Surg 2011; 98(8): 1089-1098.

Andreozzi GM, Cordova RM, Scomparin A, Martini R, D’Eri, Andreozzi F, Quality of Life Working Group on Vascular Medicine of SIAPAV. Quality of life in chronic venous insufficiency. An Italian pilot study of the Triveneto Region. Int Angiol 2005; 24: 272-277.

Pannier F, Rabe E. Progression in venous pathology. Phlebology. 2015;30:95-97.

Van den Bos R, Arends L, Kockaert M, Neumann M, Nijsten T. Endovenous therapy of lower extremity varicosities: a meta-analysis. J Vasc Surg 2009; 49: 230-239.

Boersma D, Kornmann VN, Eekeren RR, Tromp E, Unlu C, Reijnen MM et al. Treatment modalities for small saphenous vein insufficiency: Systematic review and meta-analysis. J Endovasc Ther 2016; 23: 199-211.

Tal MG, Dos Santos SJ, Marano JP, Whiteley MS. Histological findings after mechanochemical ablation in a caprine model with use of the ClariVein. J Vasc Surg Venous Lymphat Disord 2015; 3:81-85 Kendler M, Averbeck M, Simon JC, Ziemer M. Histology of saphenous veins after treatment with the ClariVein device – an ex-vivo experiment. JDDG. 2013;348-352 van Eekeren RR, Hillebrands JL, van der Sloot K, de Vries JP, Zeebregts CJ, Reijnen MM. Histological observations one year after mechanochemical endovenous ablation of the great saphenous vein. J Endovasc Ther. 2014 Jun;21(3):429-433 Vuylsteke M, Van Dorpe J, Roelens J, De Bo T, Mordon S, Fourneau I. Intraluminal fibre-tip centring can improve endovenous laser ablation: a histological study. Eur J Vasc Endovasc Surg 2010;40:110-116 Boersma D,van Eekeren RR,Werson DA,van der Waal RI,Reijnen MM, de Vries JP. Mechanochemical endovenous ablation of small saphenous vein insufficiency using theClariVein(®) device: one-year results of a prospective series. Eur J Vasc Endovasc Surg. 2013 Mar;45(3):299-303.

Elias S, Raines JK. Mechanochemical tumescentless endovenous ablation: final results of the initial clinical trial. Phelbology 2012;27:67-72 Lam YL, Toonder IM, Wittens CH. Clarivein® mechano-chemical ablation an interim analysis of a randomized controlled trial dose-finding study. Phlebology. 2016 Apr;31(3):170-176 Deijen CL, Schreve MA, Bosma J, de Nie AJ, Leijdekkers VJ, van den Akker PJ, Vahl A. Clarivein mechanochemical ablation of the great and small saphenous vein: Early treatment outcomes of two hospitals.

Phlebology. 2016 Apr;31(3):192-197.

Tang TY, Kam JW, Gaunt ME. ClariVein® - Early results from a large single-centre series of mechanochemical endovenous ablation for varicose veins. Phlebology. 2016 Feb 22. [Epub ahead of print] van Eekeren RR, Boersma D, Holewijn S, Werson DA, de Vries JP, Reijnen MM. Mechanochemical endovenous ablation for the treatment of great saphenous vein insufficiency. J Vasc Surg Venous Lymphat Disord. 2014 Jul;2(3):282-288.

Whiteley MS, Dos Santos SJ, Fernandez-Hart TJ, Lee CT, Li JM. Media Damage Following Detergent Sclerotherapy Appears to be Secondary to the Induction of Inflammation and Apoptosis: An Immunohistochemical Study Elucidating Previous Histological Observations. Eur J Vasc Endovasc Surg. 2016 Mar;51(3):421-428.

McAreeB, Ikponmwosa A, Brockbank K, Abbott C, Homer-Vanniasinkam S, Gough MJ. Comparative stability of sodium tetradecylsulphate (STD) and polidocanol foam: impact on vein damage in an in-vitro model. Eur J Vasc Endovasc Surg 2012;43:721–725.

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Chapter 8

Endovenous laser ablation of insufficient perforating veins: Energy is key to success Vascular. 2016;24:144-149

Doeke Boersma, Daan L.J. Smulders, Olaf J. Bakker, Ronald F.F. van den Haak, Bart A.N. Verhoeven, Olivier H.J. Koning

CHAPTER 8

ABSTRACT Objective To evaluate the feasibility and anatomical success of endovenous laser ablation (EVLA) of incompetent perforating veins (IPV).

Methods All 135 consecutive patients with IPV treated with ELVA (intention-to-treat) from January 2008 to December 2013 were included. Up to the end of 2011, an 810-nm laserset (14 W) was used, afterwards, a 1470-nm laserset (6 W) was introduced. Duplex ultrasound was performed at 6 weeksâ&#x20AC;&#x2122; follow-up to assess anatomical success.

Results Overall anatomical success at 6 weeksâ&#x20AC;&#x2122; follow-up was 56%. Anatomical success was 63% after treatment with 810 nm and 45% with 1470 nm (p = 0.035). This difference in the success rate seems associated with the significantly higher amount of energy delivered in the 810 nm cohort (560 J) versus 1470 nm (186 J). Regardless of the type of laser, anatomical success was significantly higher after treatment with more than 400 J (66%) compared with 0 to 200 J (40%, p = 0.009) and 200 to 400 J (43%, p = 0.029). Complications were limited to 2 cases of transient paresthesia.

Conclusion EVLA of IPVs is a safe and feasible technique that can be considered a valuable alternative to open vascular surgery, especially in severe venous disease. An increased amount of energy delivered to the IPV is highly important in achieving anatomical success.

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Laser ablation of perforator veins

INTRODUCTION Varicose veins are among the top 10 most common problems for which patients consult their general practitioners. Epidemiologic studies show that some degree of varicose veins will develop in approximately 40% of women and in 20% of men1,2. The incidence increases with age and is associated with several risk factors including prolonged standing, pregnancy, and female gender. Clinical symptoms vary from cosmetic issues to therapy-resistant venous ulcers. Chronic venous leg ulceration will occur in approximately 1% of the general population. Venous insufficiency has a substantial effect, mostly associated with insufficiency of the great saphenous veins (GSVs), on patientsâ&#x20AC;&#x2122; health-related quality of life3.

Insufficient perforating veins (IPVs) are frequently observed in patients with chronic venous insufficiency. Although the effect of IPVs on hemodynamics remains controversial, there is some evidence for the potential role for IPVs in the pathogenesis of advanced venous disease4,5. An increasing number and diameter of calf IPVs are associated with deteriorating CEAP (Clinical, Etiology, Anatomy, and Pathophysiology) grade6. Treatment of IPVs in severe chronic venous insufficiency can result in improved rates of ulcer healing and lower recurrence7.

Over the years, several treatment options for IPVs have been advocated. Surgical ligation or disconnection is considered the gold standard. However, the revolution of minimally invasive therapies for saphenous insufficiency also led to innovation in the treatment of IPVs. Subfascial endoscopic perforator surgery, ultrasound-guided foam sclerotherapy, and endothermal ablation, such as radiofrequency ablation and endovenous laser ablation (EVLA), were introduced. Although EVLA is widely used and well proven in insufficient GSVs, laser ablation of IPVs was only described in small series8-13. This prospective singlecenter study was designed to evaluate the feasibility, safety, and anatomical success of EVLA as a minimally invasive therapy for IPVs.

METHODS Study design This prospective study included all consecutive patients treated with EVLA for IPV during a 5-year period from January 2009 to December 2013. All patients underwent standardized clinical and physical examination and duplex ultrasonography (DUS) of the affected lower limb. Complete venous mapping of the saphenous veins, deep system of the calf and thigh, and perforating veins was performed. Insufficiency was defined as a retrograde flow >500 milliseconds after calf compression while standing14. The C of the CEAP classification was used to score the clinical severity of each affected limb15.

In patients with combined long-segment saphenous insufficiency and concurrent IPV, the truncal insufficiency was treated first. In case of persistent complaints after adequate ablation of the superficial trunk or isolated perforator insufficiency, ELVA of the IPVs was offered. All patients gave informed consent for prospective follow-up.

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Intervention All interventions were performed by 1 of 3 vascular surgeons with the assistance of a vascular laboratory technician. Before treatment, the IPVs were identified by DUS with the patient upright and marked on the skin. An elastic tourniquet was applied to maintain venous congestion, and the patient was placed supine. The importance of adequate ultrasound guidance during the entire procedure must be underlined. An experienced ultrasonographer is critical for the initial puncture of the IPV, advancement, and the correct positioning of the laser tip within the IPV lumen at a level below the fascia, without protruding into the deep venous system.

In the period 2009 to December 2011, IPVs were treated with a 810-nm laser generator and a bare tip laserset (Angiodynamics, Queensbury, NY, USA). From December 2011 onwards, a 1470-nm laser generator with 400-Âľm perforator laserset (Angiodynamics, Queensbury, NY, USA) was used. The laserkit were changed following company recommendation. After adequate intraluminal access to the IPV with the puncture set, there were 2 options: direct insertion of the laser tip through the needle or placement of a sheath over a guidewire before insertion of the laser tip. Tumescent anesthesia was injected around the target vein before ablation. No sedatives were administered. According to instructions for use, the 810-nm laser delivered 14 Watts. The 1470-nm laser tip delivered 6 Watts. The procedure was performed under ultrasound guidance to confirm position and to guide laser fiber pull back. If necessary, ELVA of multiple IPVs was performed.

Patients were advised to wear 23 mm Hg compression stockings continuously for the first 48 hours and during the daytime for the next 5 days. Patients were allowed to perform their daily activities immediately. No anticoagulants were prescribed. Over-the-counter analgesics were advised if necessary.

Outcomes and follow-up protocol The primary outcome measure was anatomical success, defined as occlusion of the treated perforating vein on follow-up DUS at 6 weeks. Initial technical success was defined as ability to cannulate the IPV, place the laser tip as planned, and ablate without technical problems. Treatment failure was defined as a nonoccluded or recanalized IPV with persistent flow on DUS. The other important outcome was the occurrence of major complications, including deep venous thrombosis (DVT), skin burns, or nerve injury.

All patients were invited for a follow-up assessment by a vascular surgeon at 6 weeks. This assessment included an interview, a physical examination, and DUS by a vascular laboratory technician. Any complications immediately after the procedure and during the follow-up were noted. All data were gathered prospectively and stored in a computerized database.

Statistical analysis Variables are presented as mean with standard deviation (SD) or range for parametric continuous outcomes, as a median with interquartile range (IQR) for nonparametric continuous outcomes, and as frequencies and percentages for categoric variables. KaplanMeier survival analysis was used to assess the anatomical success rate. Statistical analyses

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Laser ablation of perforator veins

were performed using SPSS 19.0 software (SPSS Inc., Chicago, IL, USA). A value of p < 0.05 was considered significant.

RESULTS The study included 135 consecutive patients treated for IPVs. These patients underwent treatment for 184 IPVs in 142 lower limbs in 135 sessions. Patient characteristics and CEAP of all limbs were described in Table 1. The 810-nm laser was used to treat 98 IPVs in 69 lower limbs of 63 patients. The 1470-nm laser was used in 86 IPVs in 73 lower limbs of 72 patients. The median energy deliverance per treated IPV was 560 J (IQR, 407–640 J) in the 810-nm cohort and 186 J (IQR, 160–240 J) in the 1470-nm cohort (p < 0.001).

TABLE 1 Patient demographics and treatment characteristics Variables

No. (%) or mean (range)

Patients

135

Limbs

142

IPVs

184

Age (years)

60 (28-87)

Female

83 (61)

8

CEAP C2 Varicose veins

48 (34)

C3 Oedema

36 (25)

C4 Skin changes

34 (24)

C5 Healed ulcer

7 (5)

C6 Active ulcer

17 (12)

Laser treatment used 810 nm (14 W) Patients

63

Limbs

69

IPV

98

1470 nm (6 W) Patients

72

Limbs

73

IPV

86

Initial technical success A total of 184 IPVs were treated during 135 procedures. In 3 cases we failed to cannulate the IPV, and the treatment was aborted. The overall initial technical success was 98%. There were no significant differences in initial technical success between the different lasers.

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810-nm 63 pt; 98 IPVs Total: 135 pt; 184 IPVs 1470-nm 72 pt; 86 IPVs

Technical success: 132 pt; 181 IPVs

Technical failure: 3 pt; 3 IPVs

Lost to follow up: 8 pt; 10 IPVs

810-nm: 61 pt; 94 IPVs Follow up: 124 pt; 171 IPVs 1470-nm 63 pt; 77 IPVs

FIGURE 1 Flow diagram

Anatomical success DUS and clinical consultation was obtained in 131 limbs of 124 patients during a median follow-up of 46 days (IQR, 42â&#x20AC;&#x201C;58 days) (Figure 1). Three patients were excluded from follow-up due to initial technical failure. A total of 8 patients were lost to follow-up: 5 indicated they were freed of complaints and refused follow-up, 2 did not respond to repeated invitations for the follow-up assessment, and 1 died of an unrelated cause.

In the entire group of 124 patients, 131 limbs, and 171 IPVs with completed follow-up, DUS showed an overall anatomical success rate of 56%. The anatomical success of treatment with the 810-nm laser (61 patients, 67 limbs, 94 IPVs; median energy delivery, 560 J) was 63%. After treatment with the 1470-nm laser (63 patients, 64 limbs, 77 IPVs; median energy delivery, 186 J) the anatomical success was 45%. The difference in anatomical success between these 2 groups was significant (p = 0.035).

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Laser ablation of perforator veins

Regardless of the type of laser used, cohorts were compiled according to the amount of energy delivered. The cohorts were formed with 200-J intervals: 0 to 200 J, 200 to 400 J, and more than 400 J. The anatomical success in these groups was respectively 40%, 43%, and 66%. The anatomical success rate after treatment with more than 400 J seems to plateau. Univariate logistic regression analysis showed a significantly higher anatomical success after treatment with more than 400 J compared with, respectively, 0 to 200 J (p = 0.009) and 200 to 400J (p = 0.029). The difference in anatomical success among the 3 vascular surgeons was not significant. There was no significant difference in anatomical success between the different CEAP groups.

After failure of the primary intervention, 15 patients, 15 limbs, and 17 IPVs were treated a second time with EVLA of the persistent IPV. In this group, 10 patients with 11 IPVs underwent follow-up DUS. The anatomical success after the second treatment was 55%, which was similar to primary treatment. No significant differences between the different lasers were seen in this group.

The 3 patients (3 limbs, 3 IPVs) in whom the initial procedure was unsuccessful underwent retreatment with EVLA. In only 1 patient did retreatment lead to initial technical success and anatomical success at follow-up DUS. In the remaining 2 patients, cannulation of the IPV was not technically feasible due to difficult angle.

Complications No DVT or skin burns were seen. Transient paresthesia of the sural or saphenous nerve was observed in 2 patients, 1 in each laser wavelength group. Minor complications, including pain and ecchymosis, were common but did not require additional treatment.

DISCUSSION The most remarkable finding of this study is the significantly higher anatomical success after treatment with increased energy deliverance. This explains the difference we found in the anatomical success rate of the 2 different lasers used in this study. Because there is no evidence that the laser wavelength has any effect on the outcome16, the significant difference in anatomical success seems to be caused by the higher energy deliverance in the cohort treated with the 810-nm laser. Previous studies have shown that linear endovenous energy density values up to 400 J/cm in IPV ablation seem associated with improved results8,13. Further increasing linear endovenous energy density in the ablation of IPV with their characteristic high pressure gradient and short ablation tract can be advocated.

These finding led to changes in treatment strategy in our clinic using increased energy.

In contrast to this cohort, several studies of IPV ablation describe concomitant ablation of the GSV or small saphenous vein (SSV) in up to 100% of treated patients; this seems associated with higher anatomical success11,13. Short-term follow-up occlusion rates after ELVA of IPVs in recent literature range from 72.2% to 100%. Table 2 summarizes the results of previous publications. Radiofrequency ablation therapy of IPVs shows comparable

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anatomical success17,18. Endovenous embolization of varicosities using cyanoacrylate adhesive is a novel technique that has been described in several feasibility papers. The first data on this new technique in IPVs were recently published and showed anatomical success in 76% after 3 months of follow-up19.

Owing to their specific anatomy, a percutaneous approach of perforating veins can be challenging, and especially, cannulation of small diameter veins is associated with a significant learning curve9,12. Although several studies mentioned technical feasibility, only Park et al.11 quantify technical success in 76.5%. All procedures in our study were performed by 1 of 3 experienced vascular surgeons, which might have contributed to the technical success in 98% of IPVs. EVLA has been repeatedly shown to be a safe procedure. Especially in GSV ablation, the data on safety are abundant. In both insufficient perforating veins and SSVs, the treating physician should be well aware of anatomical proximity of nerves in the lower leg. Despite careful administration of tumescent anesthesia, transient paresthesia was seen in 2 patients. In our series no cases of skinburn/-necrosis occurred, which is especially of great importance in treating C5 and C6 patients. DVT remains a feared complication after venous

IPV (n)

Energy delivery

Watts

Follow-up

Anatomical success

940 nm

12a

Pulsed

5-30

1 day

100%

1320 nm

28a

Pulsed

5-10

1 day

100%

Hissink (2010)

810 nm

58

Continuous

14

3 months

78%

Paresthesia: 3.6% DVT: 0%

Corcos10 (2011)

808 nm

534c

Continuous

6-10

3 months - 6 years

72.2%

Paresthesia: 3.3% DVT: 0%

Park11 (2012)

980 nm

26d

Continuous

10

1 week 96.1% 1 - 12 months 100%

Paresthesia: 4% DVT: 0%

Dumantepe12 (2012)

1470 nm

24

Continuous

10

1 year

86.9%

Paresthesia: 15% DVT: 0%

Zerweck13 (2014)

1470 nm

69e

Continuous

8

1 week 1 month

94.2% 95.6%

Paresthesia: 1.8% DVT: 0%

Boersmag (2014)

810 nm

94

Continuous

14

6 weeks

62.8%

Paresthesia: 1.6% DVT: 0%

1470 nm

77

Continuous

6

6 weeks

45.5%

Paresthesia: 1.6% DVT: 0%

Proebstle8 (2007)

9

b

Major complications f

Wavelength

TABLE 2 Overview on reported series of endovenous laser ablation in insufficient perforating veins.

Paresthesia: 16% DVT: 0%

combined ablation of perforators and GSV / SSV in 75%; bcombined ablation of perforators and GSV / SSV in 64%; ccombined ablation of perforators with multiple techniques / not quantified; dcombined ablation of perforators and GSV / SSV in 100%; ecombined ablation of perforators and GSV / SSV in 100%; fpercentage of complications per patient; gcurrent study a

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Laser ablation of perforator veins

ablation or surgery. Neither in previous publications nor in our series did DVTs occur8-13.

Minor complications, such as local bruising, pain, induration, and superficial phlebitis, are common.

The indication for treatment of isolated perforator insufficiency remains up to discussion, especially in C2 and C3 varicosities14. In our opinion the indications to treat IPVs might be stretched due to minimizing surgical trauma, possibility of repetitive treatment and improvement of anatomical success. The clinical success and potential quality-of-life improvement after IPV ablation needs further investigation.

Important limitations of series on ELVA of IPVs are the small cohorts and the simultaneous treatment of saphenous veins. For example, Zerweck et al.13 describe in their series that concomitant ablation of the GSV or SSV is performed in all patients with IPVs treated by EVLA. The major limitation to our study is the length of follow-up of only 6 weeks.

CONCLUSION EVLA of IPVs is a safe and feasible technique that can be considered a valuable alternative to open vascular surgery, especially in severe venous disease. An increased amount of energy delivered to the IPV is highly important in achieving anatomical success.

8

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Carradice D, Mazari FAK, Samuel N, et al. Modelling the effect of venous disease on quality of life. Br J Surg 2011;98(8): 1089-1098 O’Donnell TF. The role of perforators in chronic venous insufficiency. Phlebology 2010;25(1):3-10 Labropoulos N, Mansour MA, Kang SS, et al. New insights into perforator vein incompetence. Eur J Vasc Endovasc Surg 1999;18:228-234.

Stuart WP, Adam DJ, Allan PL, et al. The relationship between the number, competence, and diameter of medial calf perforating veins and the clinical status in healthy subjects and patients with lower-limb venous disease.

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Rueda CA, Bittenbinder EN, Buckley CJ, et al. The management of chronic venous insufficiency with ulceration: The role of minimally invasive perforator interruption. Ann Vasc Surg 2013;27: 89-95 Proebstle TM, Herdemann S. Early results and feasibility of incompetent perforator vein ablation by endovenous laser treatment. Dermatol Surg 2007;33(2):162-168.

Hissink RJ, Bruins RMG, Erkens R, et al. Innovative treatments in chronic venous insufficiency: endovenous laser ablation of perforating veins: a prospective short-term analysis of 58 cases. Eur J Vasc Endovasc Surg 2010;40:403-406.

Corcos L, Pontello D, De Anna D, et al. Endovenous 808-nm diode laser occlusion of perforating veins and varicose collaterals: a prospective study of 482 limbs. Dermatol Surg 2011;37(10):1486-1498.

Park SW, Hwang JJ, Yun IJ, et al. Randomized clinical trial comparing two methods for endovenous laser ablation of incompetent perforator veins in thigh and great saphenous vein without evidence of saphenofemoral reflux. Dermatol Surg 2012;38(4):640-646.

Dumantepe M, Tarhan A, Yurdakul I, et al. Endovenous laser ablation of incompetent perforating veins with 1470 nm, 400 µm radial fiber. Photomed Laser Surg 2012;30(11):672-677.

Zerweck C, Von Hodenberg E, Knittel M, et al. Endovenous laser ablation of varicose perforating veins with the 1470-nm diode laser using the radial fibre slim. Phlebology 2014;29(1):30-36.

O’Donnell TF, Passman MA, Marston WA, et al. Management of venous leg ulcers: Clinical practice guidelines of the Society for Vascular Surgery® and the American Venous Forum. J Vasc Surg 2014;60:3S-59S Kistner RL, Eklof B, Masuda EM. Diagnosis of chronic venous disease of the lower extremities: the “CEAP” classification. Mayo Clin Proc 1996;71:338-345.

Malskat WSJ, Poluektova AA, Van der Geld CWM, et al. Endovenous laset ablation (ELVA): a review of mechanisms, modeling outcome, and issues for debate. Lasers Med Sci 2014;29:393-403 Van den Bos RR, Wentel T, Neumann MH, et al. Treatment of incompetent perforating veins using the radiofrequency ablation stylet: a pilot study. Phlebology 2009;24(5):208-212 Hingorani AP, Ascher E, Marks N, et al. Predictive factors of success following radio-frequency stylet (RFS) ablation of incompetent perforating veins (IPV). J Vasc Surg 2009;50(4):844-848.

Toonder IM, Lam YL, Lawson J, et al. Cyanoacrylate adhesive perforator embolization (CAPE) of incompetent perforating veins of the leg, a feasibility study. Phlebology 2014;29:49-54.

Laser ablation of perforator veins

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Proof-of-concept study of the VeinScrew: A new percutaneous venous closure device Vascular 2016: ePub ahead of print

Doeke Boersma, Gert Jan de Borst, Frans L. Moll

CHAPTER 9

ABSTRACT Objective This study evaluated the concept of percutaneous closure of insufficient veins using the VeinScrew principle.

Methods The VeinScrew is designed to place a spring-shaped implant that contracts and clamps around the vein. The ability of the device to occlude adequately was tested in a bench model experiment. The feasibility of accurate placement and adequate venous occlusion was evaluated in an animal experiment and in a human cadaveric experiment.

Results The VeinScrew implant occluded up to a pressure of 135mmHg. In vivo studies confirmed that deployment was challenging but technically feasible, and subsequent phlebography showed closure of the vein. The cadaveric study showed that percutaneous placement of the evolved VeinScrew around the GSV was feasible and accurate.

Conclusion The current studies show the feasibility of the VeinScrew concept. Future developments and translational studies are necessary to determine the potential of this technique as a new option in the phlebologistâ&#x20AC;&#x2122;s toolbox.

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INTRODUCTION Complaints of varicose veins are among the top 10 most common problems for which patients consult their general practitioners. Some degree of varicose veins will develop in approximately 40% of women and in 20% of men1,2. Clinical symptoms may vary from mere cosmetic issues to therapy-resistant venous ulcers. Chronic venous leg ulceration will occur in approximately 1% of the general population.

The treatment of insufficiency of great and small saphenous veins (GSV/SSVs) has been revolutionized within the last decade. Surgical ligation, with or without stripping, the former gold standard, has largely been replaced by endothermal techniques due to their superior occlusion rates3,4. In certain patients, however, the endovenous thermal ablation is contraindicated or technically unfeasible; for example, because of (partial) thrombosis, proximal recanalization, or severe tortuosity of the target vein. Until now these patients have required surgical treatment.

The VeinScrew concept is based on the short-segment occlusion of the insufficient veins by the percutaneous placement of a closure implant around the target veins.

METHODS The concept The VeinScrew is designed as an alternative to groin exploration and venous ligation by facilitating percutaneous closure of the proximal saphenous vein without the need for endovenous cannulation.

The VeinScrew procedure The VeinScrew device (Figure 1a) consists of a spiralling hollow needle fixed to an operating handle. A spring-shaped implant is loaded within the needle. For adequate positioning, the central guiding needle is inserted perpendicularly through the target vein (Figure 2a).

Ultrasound guidance ensures adequate positioning. The VeinScrew is placed over the guide needle and progressed percutaneously turning the tip of helical needle beyond the vein (Figure 2b). After reaching adequate depth, the implant can be released by returning the handle counterclockwise while keeping the back of the handle in place. With these steps, an internal plunger will push the implant out of the needle (Figure 2c). The implant contracts (like a key ring) and clamps around the vein (Figure 2d), leading to venous occlusion. The VeinScrew concept has been developed in cooperation with IMDS R&D, Roden, The Netherlands.

The implant The implant is a stainless steel spring (16.3 mm) of 2.5 windings with a pitch close to zero (Figure 1b). The implant is placed within the helical needle under tension, and upon release, will contract in axial direction. The force needed to open the spring 2 mm is 6 Newton and

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to open it 4 mm is 10 Newton. One end of the implant is ground to the exact angle and shape of the bevel of the needle to minimize resistance while the needle is being positioned.

FIGURE 1 (a) VeinScrew prototype 2 with central guiding needle and implant, (b) Implant.

FIGURE 2 (aâ&#x20AC;&#x201C;d) VeinScrew procedure in a cadaveric model.

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Proof of concept To evaluate the VeinScrew concept, three major issues had to be addressed: 1. Does the implant clamp the vessel sufficiently to prevent flow?

2. Is it feasible to place the implant onto the target vein and occlude it?

3. Is it feasible to deploy the VeinScrew percutaneously around a human proximal GSV? To evaluate the ability to occlude a vessel, a bench model was designed to quantify the pressure of the implant on the target vessel. In this model, an implant was placed around a 10 mm latex tube filled with water (Figure 3). Increasing pressure was gradually applied through the tube passed the implant. A similar experiment was performed with a latex tube embedded in gelatin, mimicking subcutaneous tissue.

To study the feasibility of percutaneous deployment around the target vein and occlusion on phlebography, an acute animal experiment was conducted at the animal experimental facilities of the Radboud University, Nijmegen, The Netherlands. The VeinScrew procedure was performed on the internal jugular vein in an adult porcine model. This experiment used a first-generation VeinScrew prototype (without the guiding needle). The experiment was approved by the Committee for Animal Experimental Research (RUDEC) Nijmegen, The Netherlands.

To investigate technical feasibility of the VeinScrew procedure with accurate placement of the implant on a human proximal GSV, the VeinScrew procedure was performed in a preserved female cadaver in a human cadaver at the anatomical theatre of the Department of Anatomy and Embryology of the University Medical Centre Utrecht. Owing to the absence of venous flow, duplex ultrasound guidance was not possible; therefore, the vein was visualized via a medial approach. This experiment used a second-generation VeinScrew prototype (with central guiding needle).

RESULTS Bench model The implant was placed onto a latex tube with a diameter of 10 mm and fully occluded the tube. In the model without gelatin embedding, water passed the spring at 125 mm Hg water pressure. The model with gelatin embedding withstood water pressure of 135 mm Hg. Animal model The in vivo studies in the porcine model showed that accurate percutaneous positioning was challenging. The tough skin of the pig led to bending of the helical needle rotating inwards. In a repeated experiment, placement of an implant onto the target vein was achieved. Subsequent phlebography showed total closure of the vein (Figure 4 a-b).

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The results of this experiment led to two important improvements in the VeinScrew design: 1. A central guiding needle was added to the design to avoid a false route of the helical needle caused by tissue resistance and to improve accuracy of positioning.

2. The tip of the helical needle and the end of the implant, which occluded the needle, was ground to a lancet point to further minimize resistance.

FIGURE 3 Bench model experiment (occlusion of the latex tube by the VeinScrew implant).

Cadaveric model The guide needle was placed perpendicularly through the GSV (Figure 2a). The VeinScrew was placed over the guiding needle. Via a 2 mm stab incision, the VeinScrew was driven inwards just over 1 winding beyond the GSV (Figure 2b). Although the tissue had the characteristic toughness of a preserved cadaver, no bending of the needle was observed.

Once the screw was in position encircling the vein, the ring was successfully deployed, completely closing off the vein (Figure 2c-d).

DISCUSSION The aim of this study was to evaluate the concept of the VeinScrew in treating proximal truncal insufficiency. The in vitro study and animal experiment showed that the springshaped implant was able to fully occlude a target vein but that adequate positioning was challenging. A central guiding needle was subsequently added to the prototype, which resolved the positioning difficulties, as shown in the cadaveric experiment.

Within the era after the endovenous revolution in varicose vein treatment, we are well aware that the potential role of the VeinScrew concept is limited. Endovenous laser ablation, radiofrequency ablation, and newer nonthermal techniques have proven their superiority

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FIGURE 4 (a) Ultrasound-guided percutaneous VeinScrew ablation. (b) Venous occlusion on phlebography. Note: second implant visible without venous occlusion, due to inaccurate placement. CSI: catheter sheath introducer.

to surgical ligation in treatment of SSV and GSV, with anatomical success rates approaching 100%3,4. Even in recurrent insufficiency, endovenous treatment should be considered5.

Nonetheless, endovenous therapy remains less suitable or even unfeasible in certain patients, such as in the case of extreme tortuosity, short-segment reflux, or insufficient neovascularization after a previous venous treatment, in which surgical exploration and proximal ligation would be unavoidable. In these cases, the VeinScrew concept could be valuable. Minimizing surgical trauma is important, especially in redo surgery, and the ultrasound-guided percutaneous approach could lead to easier identification and make tedious groin re-exploration redundant.

The idea of percutaneous closure of insufficient veins is not new: during the early 1990s, Van Cleef et al6 developed the V-Clip (research discontinued), and recently, Farber7 published the first data on the V-Block (preclinical animal research). The major differences between these devices and the VeinScrew concept are: (1) The V-Clip and V-Block are both placed with catheter guidance, and therefore, venous cannulation is obligatory, and (2) the devices are intended as â&#x20AC;&#x153;endovenous scaffoldingâ&#x20AC;? for subsequent sclerotherapy.

In the patient category described above, we believe that puncture perpendicularly across

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the vein is less challenging compared with venous cannulation. Although not within the scope of this study, the perpendicular approach to the target vein could be helpful, especially in ablation of insufficient perforator veins. A significant learning curve is associated with cannulation for endovenous perforator ablation because of the specific anatomy8,9. In our opinion, a puncture right-angled across perforators would be an easier alternative.

Future developments to the VeinScrew design will be essential. Manufacturing multiple sizes of the implants with matching pinch is needed to deliver more tailor-made options.

An important point for discussion is whether the implant will be felt as â&#x20AC;&#x153;a coin in the pocketâ&#x20AC;? and will lead to irritation; therefore, the development of a bioabsorbable implant could be of great value. Whilst placing the implant some bleeding from puncturing the veins would inevitable, although it could be expected that upon release the contraction of the implant would lead to mechanical compression and tamponade of the bleed. Further research will be necessary to evaluated this issue, especially in thin-walled varicosities.

The current study describes the development of a device based on a new concept that can be valuable in selected cases. The experiments give some insight to the working mechanism, feasibility of placement, and the evolution of the prototype. It is critical to appreciate the limitations of this study: improvements to the prototype design and the implant materials are essential before future studies can evaluate the potential of the VeinScrew concept.

CONCLUSION The current studies show the feasibility of the VeinScrew concept. Future developments regarding sizing, new bioabsorbable materials, and translational studies are necessary to determine the potential as a new option in the phlebologistâ&#x20AC;&#x2122;s toolbox.

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REFERENCES 1.

2.

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7.

8.

9.

Callam MJ. Epidemiology of varicose veins. Br J Surg 1994;81:167-173.

Evans CJ, Fowkes FGR, Ruckley CV, et al. Prevalence of varicose veins and chronic venous insufficiency in men and women in the general population: Edinburgh Vein Study. J Epidemiol Community Health 1999;53:149153.

Van den Bos R, Arends L, Kockaert M, et al. Endovenous therapy of lower extremity varicosities: a meta-analysis.

J Vasc Surg. 2009;49:230-239.

Boersma D, Kornmann VNN, Eekeren RRJ, et al. Treatment modalities for small saphenous vein insufficiency: systematic review and meta-analysis. J Endovasc Ther. 2016;23:199-211.

Van Groenendael L, Flinkenflogel L, Van der Vliet JA, et al. Conventional surgery and endovenous laser ablation of recurrent varicose veins of the small saphenous vein: a retrospective clinical comparison and assessment of patient satisfaction. Phlebology. 2010;25:151–157.

Van Cleef JF, Sintes P, Chleir F, et al. Dix ans d’experience du clip endo-saphene: les bonnes pratiques.

Phlebologie 2003; 56: 173–177.

Farber A, Belenky A, Malikova M, et al. The evaluation of a novel technique to treat saphenous vein incompetence: preclinical animal study to examine safety and efficacy of a new vein occlusion device.

Phlebology 2014; 29: 16–24.

Hissink RJ, Bruins RMG, Erkens R, et al. Innovative treatments in chronic venous insufficiency: endovenous laser ablation of perforating veins: a prospective short term analysis of 58 cases. Eur J Vasc Endovasc Surg 2010; 40: 403–406.

Boersma D, Smulder DJL, Bakker OJ, et al. Endovenous laser ablation of insufficient perforating veins: Energy is key to success. Vascular 2016;24:144-149.

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Chapter 10

Proof-of-concept study of the SailValve: A new self-expandable deep venous valve system Accepted for publication in J Endovasc Ther 2016

Doeke Boersma, Aryan Vink, Frans L. Moll, Gert Jan de Borst

CHAPTER 10

ABSTRACT Purpose Clinical application of endovascular valve replacement has been hampered by thrombosis and valve dysfunction in previous animal models. Our aim was to evaluate the SailValve, a new self-expandable deep venous valve concept, based on a single polytetrafluoroethylene cusp going up and down in the bloodstream as a sail. The valve acts as flow regulator, allowing for minimal reflux to reduce thrombogenicity.

Methods Five pigs were divided into three groups: A, acute pilot experiment (n = 1); B, 2 weeks of follow-up (n = 2); and C, 4 weeks of follow-up (n = 2). In all animals, valves were placed bilaterally in the iliac vein via femoral access. Patency and valve function were evaluated directly after placement in all groups and after follow-up in groups B and C by ascending and descending phlebography. For reasons of clinical relevance, a regimen of clopidogrel and aspirin was administered. Histologic analysis was performed according to a predefined protocol by an independent pathologist.

Results Deployment was technically feasible in all 10 iliac veins, and all were patent directly after placement. No perioperative or postoperative complications occurred. Ascending phlebographies in groups B and C confirmed the patency of all valves after 2 and 4 weeks, respectively. No macroscopic thrombosis was noted on histology. Descending phlebographies showed that five of eight were sufficient. Limited reflux was seen in one valve (group B), and the function in the remaining two valves (group C) was insufficient because of malpositioning. Histology in groups B and C revealed a progressive inflammatory reaction to the valves.

Conclusion The current animal study shows the potential of the SailValve concept with sufficient valve function, after adequate positioning, and no (thrombogenic) occlusions after short-term follow-up. Future research is essential to optimize valve material and long-term patency.

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INTRODUCTION In patients with chronic venous insufficiency (CVI), venous valve incompetence causes reflux and distal venous hypertension. CVI is a common disorder with a wide spectrum of complaints, ranging from mild edema to hard-to-treat venous ulcers, and is associated with a substantial effect on patientsâ&#x20AC;&#x2122; health-related quality of life1. Valve incompetence may be primary (congenital) or secondary. Secondary valve incompetence is especially associated with deep venous thrombosis (DVT). Although recanalization after DVT might occur, the thrombus can lead to irreversible damage to the native valves or even totally destroy them.

The best treatment for insufficient superficial veins is (endovenous) ablation2,3, however, the treatment of chronic deep venous insufficiency (CDVI) is less straight forward.

Repair or replacement of deep valves is conceptually the best treatment of CVDI. Although during the last 50 years several surgical venous valve repair or transplantation techniques have been reported4-12, none of the techniques became standard care, and to date, nearly all of these patients are still being sentenced to long-term conservative treatment with a compression stocking for symptom relief. Because of related morbidity with open surgical valve reconstruction, a well-functioning and easy-to-place stent-mounted venous valve should be considered the Holy Grail. A new stent valve has been designed to overcome complications caused by thrombosis and other device malfunctions reported in previous experiments. This study reports the proof of concept of the SailValve (Deep Vein Medical Inc., Canton, MA, USA) in an animal model and the short-term patency and competence.

MATERIALS AND METHODS Goal The study was designed to (1) evaluate feasibility of placement of the SailValve venous valve system (SVVS) and (2) describe the short-term patency and competence.

Study design The study included five pigs. An acute pilot study of 1 animal was conducted to show the feasibility of the study protocol (group A). Another four animals were enrolled in a follow-up experiment consisting of 2 weeks of follow-up (group B; n = 2) or 4 weeks of follow-up (group C; n = 2). The experiments were approved by the Committee on Animal Experiments (DEC), Utrecht, The Netherlands (Protocol No. AVD115002016336) and the Central Committee on Animal Experiments (CCD), The Hague, The Netherlands. All procedures were conducted in accordance with good laboratory practice and international guidelines in animal research under the guidance of licensed biotechnicians at the animal laboratory of the Department of Experimental Cardiology, University Medical Centre Utrecht.

All procedures were performed in a state-of-the-art hybrid endovascular operating room.

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Animals After the pilot study, we allocated four female pigs to the two experimental groups. The sample size of the study groups is in line with previous international publications in this field11,12. The animals weighed 60 to 80 kg and were obtained from a local qualified supplier.

All animals were given normal chow without supplements, and water was freely available.

The animals were housed in pairs, except for preprocedure and postprocedure days, when isolation was maintained to protect the animals. Entertainment toys were provided, and a normal 12-hour day/night cycle was used.

Materials The SVVS was developed and produced by Deep Vein Medical (Boston, MA, USA). The SVVS is designed as a valve leaflet attached to a nitinol stent frame, which acts as scaffold for the valve and fixes the implant to vein wall to avoid migration. The stent frame consists of two stent rings without barbs interconnected by two X-shaped nitinol cross braces (Figure 1A and B). After deployment, the stent rings self-expend to 10 mm. This diameter is chosen to ensure oversizing of 5% to 25% in the iliac veins of the animal model.

The valve leaflet is made of industrial-grade expanded polytetrafluoroethylene (ePTFE) and is bonded sutureless to the interconnecting brace by patented new welding process. In this experimental setting, the valves were not coated with heparin or an immune modulator.

The cusp of the SVVS forms a â&#x20AC;&#x153;sailâ&#x20AC;? that moves up and down in the bloodstream without completely opening or closing (flow regulator principle). The SVVS is designed to allow limited reflux (in a benchmodel under 5%) to simulate natural valves and thereby improve the patency of the valve, without compromising the clinical results.

At this experimental phase, the valve was mounted on the well-proven delivery system of the Greenfield cava filter (12F/60-cm shaft) with a hydrophilic coating (Boston Scientific, Natick, MA, USA).

Procedure Animals were positioned supine under general anesthesia with intravenous thiopentone, sufentanil, and cisatracurium, followed by endotracheal intubation and mechanical ventilation. The hind legs and lower abdomen were disinfected with iodine and sterile draping was applied. Duplex ultrasound (Philips Medical, Best, The Netherlands) imaging was used to measure iliac vein diameters. The superficial femoral veins and arteries on both sides were exposed surgically. A 6F sheath was placed in the femoral vein under direct vision.

Ascending phlebography was performed to evaluate venous patency before placement and to identify any native valve. On this baseline phlebography the venous diameter was measured after calibration. The phlebography was used to determine the desired position of the valve. The SVVS was placed through a 12F sheath at the designated position within the iliac vein and clear from the transition to the inferior vena cava. A completion phlebography and color-coded duplex ultrasound (DUS) imaging was performed to score for positioning and patency. After sheath removal, the puncture site was closed with a 6-0

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Figure 1. SailValve. A and B, The SailValve stent frame consists of two stent rings without barbs interconnected by two X-shaped cross brace. The valve leaflet is bonded sutureless to this cross brace. Size: 10 Ă&#x2014; 30 mm. C, Sections were made on four levels through the stent indicated by the dotted lines.

Prolene suture (Johnson & Johnson, Brunswick, NJ, USA). The procedure was repeated at the contralateral site and the skin closed with 3-0 Monocryl (Johnson & Johnson).

In the acute pilot experiment (group A), termination with potassium overdose was performed directly after the procedure while the pig was still under general anesthesia.

The iliac veins with the SVVS in situ were harvested.

The remaining animals were placed, after monitored recovery, in group housing for 2 or 4 weeks according to protocol. Inspection of the animal welfare was conducted multiple times a day with extra attention to clinical signs of DVT or pulmonary embolism.

At 2 or 4 weeks of follow-up, patency and reflux were evaluated during a second procedure under general anesthesia. Afterward, the iliac veins with the SVVS in place were harvested for macroscopic and microscopic evaluation. A suture was placed to mark the side of the vena cava. The animals were euthanized afterward, as described above.

Medical therapy All animals were administered on clopidogrel (75 mg) and calcium carbasalate (80 mg) once daily starting before treatment and continuing until euthanasia. During the valve placement procedure, heparin (100 IE/kg) was given intravenously. When general anaesthesia exceeded 2 hours after the first dose of heparin, another 50 IE/kg was administered. All follow-up animals were administered amoxicillin/clavulanic acid (12.5 mg/kg) intravenously before the initial treatment and in a similar oral dose during the first 2 days postoperatively.

Experimental outcomes The pilot study was designed to test the feasibility of accurate positioning via femoral access.

In all follow-up experiments, an ascending phlebography via femoral access and DUS imaging were performed to evaluated patency and the flow-regulating effect of the SailValve. Via jugular access, a 4F angiography catheter was positioned just above the SailValve, and descending phlebography was made to document reflux. Phlebographies with fluoroscopy were repeated in multiple angles to differentiate reflux and normal filling of side branches.

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The explanted iliac veins were macroscopically inspected for perforations or surrounding hematoma. The positioning in relation to side branches and distance to the vena cava was studied and described.

Histologic assessment The SailValve was fixed in 4% formalin directly after harvesting. The valve with a segment of vein was processed and embedded in methyl methacrylate and Lucidol. After air removal using vacuum, 215 µL N,N-dimethyl-p-toluidine was added to each glass container. The containers were preserved at -20°C in ethanol for 4 days. Of each specimen, four 35-µm sections were prepared using a diamond circular saw and stained with hematoxylin and eosin. Sections were made on four levels through the stent, as depicted in Figure 1 C. The histology was studied and reported by an independent experienced vascular pathologist.

RESULTS Procedures and Follow-up The experiments were conducted from January to April 2016. The five pigs had a median weight of 71.2 kg (range, 70.5-74.5). In all animals, the superficial femoral vein could be surgically exposed and cannulated. The iliac veins could be visualized and measured by DUS in all but one animal. The mean vein diameter was 8.7 ± 0.3 mm; therefore, the desired oversizing of 5% to 25% was achieved. Positioning of the SVVSs was technically feasibility in all animals, and phlebography directly after placement showed patency in all.

The average treatment duration from puncturing to closing the femoral vein was 43 ± 7 minutes for placement on both sides. For placement of one SVVS, 16.2 ± 4 mL of iodine contrast (Visipaque 270 mg I/mL; GE Healthcare, Little Calfont, UK) was used. The total amount of blood loss never exceeded 50 mL per animal. No perioperative problems or complications were noted. During the follow-up, no complications were observed, especially no clinical signs of wound infection, bleeding, DVT, or pulmonary embolisms. The logbooks showed that all animals were administered clopidogrel and calcium carbasalate in the correct dosages during the complete follow-up period.

After 2 and 4 weeks, respectively, a follow-up procedure was planned. The median weight had increased to 74.5 kg (range 73-80 kg). DUS imaging showed flow in the superficial femoral and iliac veins without signs of thrombus. High-resolution imaging in multiple directions showed no stent fractures or dislodgment. From the femoral veins, patency of all SVVSs was confirmed by ascending phlebography (Figure 2A. Via the jugular access, a flush catheter was placed just above the valves and blow back phlebographies were made.

Characteristics of all individual animals are shown in table 1. The valves in five of eight SVVSs were completely sufficient (Figure 2B). In one valve only limited reflux was seen on high-flow descending phlebogram. The remaining two SVVSs, in retrospection, had been positioned at the level of native valve of large side branch. This had led to mismatch in sizing of the cranial stent ring and reflux around the SVVS.

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Figure 2 A, Ascending phlebography after 4 weeks of follow-up shows that both SailValves (*) are patent and contrast passes quickly. B, Descending phlebography confirms that the SailValve (â&#x20AC;Ą) is fully sufficient and that no contrast passes the valve even at high flow.

All treated iliac veins were surgically exposed via laparotomy. The vein showed some dilation at the level of the SVVS caused by oversizing. All valves were positioned in the iliac vein with distance of 2-5cm from the vena cava. All valves overstented at least one (minor) side branch. The two SVVSs with major reflux were placed with the proximal stent ring at the level of a major side branch. No hematomas within the vein wall or perforations were observed. The segments of iliac vein with the SailValve in situ could be explanted without damaging the specimen. Macroscopically the valves showed a smooth lining of the valve leaflet at 2 weeks follow up. After 4 weeks there was a suggestion of thickening and increasing stiffness.

Histologic evaluation The histology in the acute pilot experiment (group A) showed no perforation or damage caused by overstretching or hemorrhage of the vessel wall and full deployment of the stent (Figure 3A and 3B). Similar results were seen in the follow-up groups B and C. In none of the specimens, both after acute and follow-up experiments, was occlusive thrombosis of the valves noted.

In the 2-week follow-up group B, a fibro-inflammatory reaction was observed around the sail leaflet consisting of loose connective tissue with infiltration of lymphocytes and macrophages and foreign body giant cells directly around the leaflet (Figure 3C).

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Figure 3 Histology of veins with SailValve. A and B, acute experiment. A, Good deployment of the stent and the SailValve, without thrombus formation or damage to the vessel wall. B, Detail of stent strut. C and D, 2 weeks of follow-up. C, A fibro-inflammatory tissue reaction was observed around the SailValve. D, Detail of stent strut with small neointimal layer. E and F, 4 weeks of follow-up. E, More advanced fibro-inflammatory reaction around the SailValve. F, After 4 weeks, all stent struts were covered with a neointimal layer. Size: A, C, and E, bar = 2 mm. B, D, and F, bar = 200 Âľm.

Remnants of erythrocytes with ingrowth of fibroblasts and microvessels were observed in both cases, suggesting that this reaction is part of organized thrombus formation directly on the SailValve leaflet. In group C, the fibro-inflammatory reaction around the sail leaflet was more advanced after 4 weeks of follow-up (Figure 3E). Iron pigment was observed around microvessels as a sign of local hemorrhage. The stent struts in groups B and C were covered with a layer of neointima (Figure 3D and 3F).

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TABLE 1 Animal

Pig 1

Pig 2

Pig 3

Pig 4

Pig 5

Side

Diameter iliac vein (mm)

Valve placement

Follow up

Patency

Sufficiency

20

n/a

n/a

n/a

12

n/a

n/a

n/a

20

2 weeks

Yes

Yes

20

2 weeks

Yes

Yes

18

2 weeks

Yes

Yes

18

2 weeks

Yes

Yes

12

4 weeks

Yes

Yesc

12

4 weeks

Yes

Yes

12

4 weeks

Yes

No

18

4 weeks

Yes

No

Feasible

Duration IV contrast (min)a (ml)b 50

R

9,2

Yes

L

9

Yes

R

9

Yes

L

8,5

Yes

R

8,5

Yes

L

8,5

Yes

R

8,2

Yes

L

8,6

Yes

R

8,8

Yes

L

8,4

Yes

43

35

38

49

R,right; L, left; aDuration of treatment for both sides from first puncture to closing the femoral veins. Due to experimental design duration could not be measured per side; b Visipaque 270 mg I/mL; c Limited reflux was seen on high-flow descending phlebogram;

DISCUSSION The present study reports the feasibility of placement of the SailValve in a porcine model and its short-term patency and functioning. The experiments showed that endovenous placement and deployment was feasible in all animals. After 2 or 4 weeks of follow-up, the SailValves were patent and competent in six of eight legs. Two valves with malpositioning showed reflux in the presence of a large side branch. No major complications were observed, and no bleeding complications were noted.

Thrombosis is the most feared complication after venous valve repairs, transplantation, or prosthesis placement. Previous stent-mounted venous valves aimed to imitate the anatomy of native valve by using a bicuspid concept13-17. With these designs, the valves are prone to thrombosis at 2 critical points during the valve cycle: (1) when closing, the two cusps are forced together by the venous pressure, and (2) once opened, the valves will touch the vein wall and might stick18. Furthermore, a recent study on thrombin formation and hemodynamics describes that an important area for thrombin formation is within the opened valve cusp19. To address these problems, the SailValve has a different design: the valve leaflet floats up and down in the bloodstream, as a spinnaker sail in the wind. The valve thereby acts as a flow regulator, without full contact with the vein wall.

In addition, this device is designed to allow a limited amount of reflux and thereby mimics native valves, which are allowed up to half a second of reflux without being graded incompetent. We hypothesize that this limited reflux might be a key in improving patency by bringing down the duration of stasis around the valve. In a previous bench model test, the SVVSs allowed very limited (well under 5%) reversed flow, even under relative high

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pressures. The fact that all valves remained patent, even under a mild anticoagulant therapy, might underline this.

The optimal leaflet material is still a matter of fierce debate. Previous devices were made from Dacron, small intestine submucosa, glutaraldehyde-fixed xenografts, cryopreserved homografts, or PTFE. These different materials have all been subject to specific pros and cons, especially in the area of thrombosis, as described previously11,12. The SailValve used in this experiment was a prototype fitted with industrial grade ePTFE with polyurethane impregnation on the borders for sutureless welding to the stent frame. The histology revealed this material was subject to ongoing and severe fibro-inflammatory reaction over time. Despite aiming to show feasibility and proof of concept, the tissue reaction is a crucial finding, because occlusion could be expected if this reaction is extrapolated. Pavcnik et al12,20. already showed that this thickening of the valve plays an important role in suboptimal functioning of the valve: the inflammatory thickening will lead to more rigid leaflet and thereby impairing the flow regulator function. Although no intravenous ultrasounds were performed in this study, the fact that insufficiency is only seen in the 4 weeks follow up group (with progressed thickening) and not in the 2 weeks group could be underlines this hypothesis. Future experiments will emphasize on this major problem and currently, new prototypes are engineered to minimize tissue reaction by improving the quality of the ePTFE, further reducing the area impregnated with polyurethane and/or coating of the valve with heparin or an immune modulator.

An open approach to the femoral veins was preferred to percutaneous placement because of the potential difficulties with passing the sheaths over the very tough pig skin and the relatively small size of the healthy femoral veins. With further development and reducing the caliber of the delivery system, a full percutaneous approach will likely be possible, especially in CDVI patients with large-sized veins.

Although deployment of the SailValves was feasible in all pigs, the stent was unintentionally placed at the level of a native valve in two pigs, leading to incompetence. This resulted from technical difficulties in identifying these side braches caused by challenging DUS visualization of the iliac veins in a supine pig and performing only antegrade phlebographies.

These positioning failures are not likely to occur in (future) placement in humans. The target vein in humans will be the femoral vein just below the saphenous junction, leading to excellent DUS access and no large side braches as are present in the iliacs.

Both on macroscopic and histologic evaluation, no rupture of the vein, perforation of the stent, or scarring of the vein wall were observed in this stent design. No migration of SVVSs or stent fracture was seen. This underlines that the current stent with the wide range of oversizing is adequate regarding fixation without the need of barbs or extensive strain on the vessel wall that could lead to fibrosis or perforation14,15,21.

CONCLUSION The current animal study shows the potential of the SailValve concept, with sufficient valve function after adequate positioning and no (thrombogenic) occlusions after short-term follow-up. Future research is essential to optimize valve material and long-term patency.

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SailValve: Proof-of-concept study

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2.

3.

4.

5.

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7.

8.

9.

10.

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16.

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19.

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21.

Andreozzi GM, Cordova RM, Scomparin A, et al. Quality of Life Working Group on Vascular Medicine of SIAPAV. Quality of life in chronic venous insufficiency. An Italian pilot study of the Triveneto Region. Int Angiol 2005;24:272-277.

Van den Bos R, Arends L, Kockaert M, et al. Endovenous therapy of lower extremity varicosities: a meta-analysis.

J Vasc Surg 2009;49:230-239.

Boersma D, Kornmann VN, Eekeren RR, et al. Treatment modalities for small saphenous vein insufficiency: Systematic review and meta-analysis. J Endovasc Ther 2016; 23: 199-211.

Kistner R. Surgical repair of a venous valve. Straub Clin Proc. 1968;34:41–43.

Taheri SA, Elias SM, Yacobucci GN, et al. Indications and results of vein valve transplant. J Cardiovasc Surg (Torino). 1986;27:163–168.

Raju S, Fredericks R. Valve reconstruction procedures for nonobstructive venous insufficiency: rationale, techniques, and results in 107 procedures with two- to eight-year follow-up. J Vasc Surg. 1988;7:301–310.

Raju S, Hardy JD. Technical options in venous valve reconstruction. Am J Surg. 1997;173:301–307.

Plagnol P, Ciostek P, Grimaud JP, et al. Autogenous valve reconstruction technique for postthrombotic reflux.

Ann Vasc Surg. 1999;13: 339–342.

Maleti O. Venous valvular reconstruction in post-thrombotic syndrome. A new technique. J Mal Vasc.

2002;27:218–221.

Opie JC, Izdebski T, Payne DN, et al. Monocusp novel common femoral vein monocusp surgery uncorrectable chronic venous insufficiency with aplastic/dysplastic valves. Phlebology. 2008;23:158–171.

De Borst GJ, Moll FL. Percutaneous venous valve designs for treatment of deep venous insufficiency. J Endovasc Ther 2012;19:291-303 Pavcnik D, Uchida B, Kaufman J et al. Percutaneous management of chronic deep venous reflux: review of experimental work and early clinical experience with bioprosthetic valve. Vasc Med 2008;13:75-84.

Gomez-Jorge J, Venbrux AC, Magee C. Percutaneous deployment of a valved bovine jugular vein in the swine venous system: a potential treatment for venous insufficiency. J Vasc Interv Radiol. 2000;11:931–936.

Pavcnik D, Uchida B, Timmermans HA, et al. Percutaneous bioprosthetic valve: a long term study in sheep. J Vasc Surg. 2002;35:598–602.

De Borst GJ, Teijink JA, Patterson M, et al. A percutaneous approach to deep venous valve insufficiency with a new self-expanding venous frame valve. J Endovasc Ther. 2003;10: 341–349.

Pavcnik D, Kaufman J, Uchida B, et al. Second generation percutaneous bioprosthetic valve: a short term study in sheep. J Vasc Surg. 2004; 40:1223–1227.

Pavcnik D, Yin Q, Uchida B, et al. Percutaneous autologous venous valve transplantation : short-term feasibility study in an ovine model. J Vasc Surg. 2007;46:338–345.

Brountzos E, Pavcnik D, Timmermans HA, et al. Remodeling of the suspended small intestinal submucosa venous valve: an experimental study in sheep to assess the host cells’ origin. J Vasc Interv Radiol. 2003;14:349– 356.

Dydek EV, Chaikof EL. Simulated thrombin responses in venous valves. J Vasc Surg: Venous and Lym Dis 2016;4:329-335 Pavcnik D. Update on venous valve replacement: long term clinical results. Vascular 2006;14:104 Dalsing MC, Sawchuk AP, Lalka SG, et al. An early experience with endovascular venous valve transplantation (letter). J Vasc Surg. 1996;24:903–904.

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Discussion and addenda

Chapter 11

General discussion

CHAPTER 11

The general discussion contains modified passages from the bookchapter “ Mechanochemical ablation of varicose veins – an update on a non-tumescence technique” published in the textbook “Advances in Phlebology and Venous Surgery” edited by Mark Whiteley in 2016, as well as data and figures from the manuscript “Mechanochemical endovenous ablation of saphenous veins using the ClariVein OC: a systematic review” as currently submitted.

Mechanochemical endovenous ablation Mechanochemical endovenous ablation (MOCA) has proven to be a safe and effective treatment for insufficient GSV and SSV. Initial technical success was 99%, and at shortterm follow-up, the anatomical success was 94%. Mid-term results range from 87 to 96% and anatomical success rate after 2 to 3 years stabilize at 87 to 91% (Table 1 and 2). These anatomical success rates almost approach the results described for endothermal ablation1,2.

Perhaps even more important are the observed good clinical success rates of MOCA. In all of the 8 studies (6 cohorts), describing the clinical symptoms of varicose disease before and after treatment, a significant decrease in venous clinical severity score (VCSS) was measured3-11. In addition, studies repeatedly showed that MOCA treatment led to a significant improvement in HR-QoL (without significant difference compared to RFA)8-12.

A clinically relevant advantage of MOCA is that only local anesthesia at the puncture site is necessary instead of tumescent anesthesia or even spinal or general anesthesia2.

Administering tumescent anesthesia is not only a painful burden to the patients, due to multiple injections, but it is also time-consuming, leading to a shorter duration of treatment in MOCA compared with endothermal ablation techniques12. The patient-reported pain during the procedure and in the weeks after treatment is significantly less in the MOCA compared to RFA8,9,12.

In the quest for optimizing the anatomical success rate, this thesis provides two important leads. First, as reported in chapter 4, an interesting difference in anatomical success rate was observed between the two groups in the SSV study: the first group was treated with 1.5% polidocanol, and the second was treated with 2% polidocanol in the proximal section. The anatomical success rate was 97% after 2% polidocanol, compared to 87% in the first group treated with 1.5% polidocanol. The difference was not significant (p = 0.187), probably due to the small number of patients, but an elevated dosage of liquid sclerosant might be the key in further optimizing anatomic occlusion rates in MOCA4. Several studies afterwards used increased concentrations of polidocanol. A large dose-finding RCT, currently enrolling patients, compares MOCA with either 2 or 3% liquid polidocanol to 1% polidocanol microfoam. An interim analysis revealed that results after MOCA with (off label) use of microfoam were abominable (only 30% anatomical success) and inclusion in this treatment arm was seized7.

Until the final results of this RCT are published, there will be no definitive answer on the question whether increased polidocanol concentration leads to improved results. Furthermore, it is up for discussion what the optimal type of sclerosant in MOCA therapy is: although STS has been shown to be a more potent sclerosant than polidocanol (in-vitro)13, currently there has not yet been a study comparing MOCA with the different agents. Randomized controlled

154

100

none

Major complications

126 126 0

57 51 6

50

0

50

100

none

n/a

n/a

n/a

n/a 60/65 (92) n/a

n/a

n/a n/a

n/a

3 " 1* none

none

9,5 " 3*

75/79 (95)

n/a

2 PE / 2 DVT / 1 paraesthesia

n/a

n/a

n/a

n/a

n/a

98

457/506 (90)‡

84/89 (94)

Microfoam

0

53

53

RCT

0

23

23

RCT

Netherlands Netherlands

Liquid

Lam 2016 none

6 " 3*

n/a

n/a

n/a

n/a

46/53 (87)

n/a

n/a

n/a

n/a

n/a

7/23 (30)

n/a

POL 2% / 1.5% POL 2 or 3% POL 1% microfoam

n/a

100

132

438

570

n/a

Netherlands

Deijen 2016

52/57 (91) 126/126 (100)

n/a

n/a

n/a

44/47 (94)

29/30 (97) n/a

29/30 (97) 50/50 (100)

100

STS 1.5% POL 2% / 1.5% STS 1.5% STS or POL

0

30

30

P

n/a

P

USA

Australia

Boersma 2013 Netherlands

Bootun / Lane 2014/2016† 1 DVT

5 " 2*

n/a

n/a

n/a

54/62 (87)

64/69 (93)

n/a

STS 2.0%

6

77

83

RCT

UK

Tang 2016 none

n/a

n/a

n/a

n/a

n/a

382/393 (97)

100

STS 2.0%

60

333

393

P

UK

none

4 " 1*

42/48(87)

64/71(90)

90/102 (88)

96/103 (93)

n/a

99

POL 2% / 1.5%

0

106

106

P

Netherlands

Eekeren/ Witte 2014/2016

P, prospective cohort; RCT, randomized controlled trial; GSV, great saphenous vein; SSV, short saphenous vein; n/a not available; VCSS, Venous Clinical Severity Score; DVT, deep venous thrombosis; PE pulmonary embolism. †two publications on same patient population; ‡median follow up of 54 days (range 12 - 266 days) / anatomical success 92% in GSV / 87% in SSV; ‡‡ median follow up of 36 months (range 12.5 – 46.3 days) ;*statistically significant

3 " 1*

VCSS

Clinical success

n/a

3 years

n/a

1 year

n/a

n/a

6 months

2 years

26/30 (87)

up to 8 weeks

Anatomical success, n (%)

POL 1.5%

0

SSV

Technical success, %

30

GSV

Sclerosant

30

Total

P

P

Population

Study design

Eekeren 2011

Netherlands USA

Elias 2012

Country

Bishawi / Kim 2014/2016†

Vun 2015

TABLE 1 Overview of results MOCA in published clinical studies

General discussion

11

155

CHAPTER 11

trials studing multiple sclerosing agents might be difficult to conduct because in some countries, STS and polidocanol are not both registered for this indication.

The second important lead results from the animal experimental studies as described in chapter 7. Mechanical ablation (with or without sclerosans) induced significantly more endothelium damage compared to sclerotherapy alone. However, there was a large spread in the amount of endothelium injury over the length of the vein, ranging from near complete endothelial destruction to completely intact endothelium within one single vein. This might be one of the reasons for partial occlusion, which is relatively frequently seen in humans, but is usually without clinical consequences4,10,14. On the other hand increasing endothelium injury might be a factor in further optimizing treatment results, for example decreasing the speed of pull-back of the ClariVein OC might lead to more injury by prolonged exposure to the mechanical action. Another reason for partial recanalisation might be that in MOCA, the venous occlusions are likely to evolve from organized thrombus. As shown in chapter 7, these occlusions might be prone for ingrowth of neo-vasculature, which might ultimately cause the segment of the vein to recanalize.

TABLE 2 Pooled data from clinical studies / trials Number of studies

10

Number of included veins Total

1521

GSV

1267

SSV

254

Mean technical success†

99% (1305 / 7)

Mean anatomical success†‡‡ Short term < 8wk

94% (1314 / 9)

Mid term 6 months

93% (284 / 4)

1 year

92% (228 / 3)

Long term 2 years

91% (136 / 2)

3 years

87% ( 48 / 1)

Mean major complication rate‡ Paraesthesia

<0.1%

(1 / 1464 / 9)

DVT

0.2 % (3 / 1464 / 9)

Pulmonary embolism

0.1 % (2 / 1464 / 9)

†,Percentage (number of veins / number of studies); ‡‡, Results from MOCA combined with 1% microfoam were not included; ‡,Percentage (absolute number of complications / number of veins / number of studies)

156

General discussion

All treatment modalities of varicose veins have their specific complications. Especially in SSV treatment, the anatomic proximity of the sural nerve poses an additional risk.

Endothermal ablation of SSVs lead to paresthesia in 4.8% (EVLA) to 9.7% (RFA)2. Pooled data showed that the risk of (transient) paresthesia after MOCA is less than 0.1%. Other major complications, such as DVT and pulmonary embolism, also occur only rarely (0.1 – 0.2%) (Table 2).

With the constantly increasing amount of studies published on the results of MOCA therapy in GSV and SSV insufficiency, it could be stated that MOCA is a good alternative of endothermal ablation. Especially, due to fact that no tumescent is necessary and the significantly lower painscores compared to endothermal ablation, MOCA should be considered an important treatment option. Nevertheless, there are some limitations. At first: all published data are cohort studies or RCTs not powered for anatomical success.

Unfortunately, the randomized controlled trial for SSV varicosities has been stopped after inclusion of only a small number of patients15, and the RCT comparing MOCA and RFA in GSV stopped inclusion prematurely16. Unfortunately, there are currently no adequately powered RCTs initiated, aiming to evaluate the anatomical success of MOCA in comparison to endothermal ablation. Secondly, the data regarding long-term anatomical success rates is limited and subject to a large number of patients lost-to-follow up.

New frontiers in venous interventions The series on laser ablation of insufficient perforator veins (IPVs) showed that this procedure is feasible and without major complications. The anatomical success rate seems significantly influenced by the amount of energy delivered to the target vein. Current literature gives no insight in the indication for minimally invasive IPV ablation and the clinical success. On the one hand, the treatment of solely the insufficient perforator veins without simultaneous ablation of the saphenous trunk seems associated with decreased anatomical success rates (as described in the majority of previous studies)17-20. On the other hand, the indication of perforator ablation should be up for discussion in those cases, where the IPV “leaks” to ablated GSV or SSV, which might only lead to prolonged procedures and an increased burden for the patient. Nonetheless, our study has some other and maybe even more important findings. It reveals that in this day and age every vascular specialist should be critical to their outcomes when implementing a new technique. Furthermore, we should be well aware of the potential implications of (company advised) changes to the devices or generator settings. Especially in cases beyond the standard procedures, it might influence the procedural outcomes.

The study in chapter 10 is the only one emphasizing on the deep venous system. As DVT has severe and long-lasting impact on life of its “victims”, the fight against DVT should be multidisciplinary: from prevention and modifying risk factors, optimizing anticoagulants, to exploring early and aggressive (endovascular) therapy. In this fight, at least for the near future, the development of a well-functioning and non-thrombogenic deep venous valve prosthesis is considered a Holy Grail. Previous venous valve concepts imitated the bicuspid design of the natural venous valves, unfortunately these concepts turned out to be

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susceptible for thrombotic occlusions21. In each cycle of opening and closing of the valve, two critical points prone for thrombosis exist: (1) when closing, the two cusps are forced together by the venous pressure, and (2) once opened, the valves will touch the vein wall and might stick22. To address these problems, the SailValve has a different design: the valve leaflet floats up and down in the bloodstream, like a spinnaker sail in the wind. The valve thereby acts as a flow regulator, without ever getting in full contact with the vein wall.

Unique in this design is that it allows limited venous reflux. In our hypothesis, limited reflux might play an important role in minimizing the risk for thrombotic occlusion.

Finding the optimal material for the valve leaflet will pose the greatest challenges in future development of the SailValve. Many different materials (both autologous, allograft or xenografts and prosthetic materials) were used in previous studies, all with their specific pros and cons. Current animal studies aim on minimizing inflammatory reaction by using high grade polytetrafluoroethylene, with additional processing to diminish inflammatory respons. On-going developments on 3-dimensional bioprinting might add additional options in the quest for the perfect venous valve prosthesis23.

158

General discussion

REFERENCES 1.

Van den Bos RR, Neumann M, De Roos KP, NijstenT. Endovenous laser ablation-induced complications: review of literature and new cases. Dermatol Surg 2009;35:1206-1214.

2. Boersma D, Kornmann VN, Eekeren RR, Tromp E, Unlu C, Reijnen MM, De Vries JP. Treatment modalities for small saphenous vein insufficiency: Systematic review and meta-analysis. J Endovasc Ther 2016; 23: 199-211.

3. Van Eekeren RRJP, Boersma D, Elias S, Holewijn S, Werson DAB, De Vries JPPM, Reijnen MMJP. Endovenous mechanochemical Ablation of great saphenous vein incompetence using the ClariVein device: a safety study.

J Endovasc Ther 2011;18:328-334 4. Boersma D, Van Eekeren RRJP, Werson DAB, Reijnen MMJP, De Vries JPPM. Mechanochemical endovenous ablation of small saphenous vein insufficiency using the ClariVein® device: One-year results of a prospective series. Eur J Vasc Endovasc Surg 2013;45:299-303 5. Bishawi M, Bernstein R, Boter M, Draughn D, Gould CF, Hamilton C, Koziarski J. Mechano-chemical ablation in patients with chronic venous disease: a prospective multicenter report.Phlebology 2014; 29: 397–400.

6. Kim PS, Bishawi M, Draughn D, Boter M, Gould CF, Koziarski J, Bernstein R, Hamilton C. Mechanochemical ablation for symptomatic great saphenous vein reflux: a two-year follow up. Phlebology 2016 ePub ahead of print.

7. Lam YL, Toonder IM, Wittens CHA. ClariVein mechano-chemical ablation an interim analysis of a randomized controlled trial dose-finding study. Phlebology 2016;31:170-176.

8. Bootun R, Lane T, Dharmarajah B, Lim CS, Najem M, Renton S, Sritharan K, Davies AH. Intra-procedural pain score in a randomised controlled trial comparing mechanochemical ablation to radiofrequency ablation: the Multicentre Venefit versus ClariVein for varicose veins trial. Phlebology 2016;31:61-65 9. Lane T, Bootun R, Dharmarajah B, Lim CS, Najem M, Renton S, Sritharan K, Davies AH. A multi-centre randomised controlled trial comparingradiofrequency and mechanical occlusion chemically assited ablation of varicose veins - final results of the Venefit versus ClariVein for varicose veins trial. Phlebology 2016 ePub ahead of print.

10. Van Eekeren RRJP, Boersma D, Holewijn S, Werson DAB, De Vries JPPM, Reijnen MMJP. Mechanochemical endovenous ablation for the treatment of great saphenous vein insufficiency. J Vasc Surg: Venous and Lym Dis 2014;2:282-288 11. Witte ME, Holewijn S, Van Eekeren RR, De Vries JP, Zeebregts CJ, Reijnen MMPJ Reijnen. Mid-term outcome of mechanochemical endovenous ablation for the treatment of great saphenous vein insuffiency. J EndoVasc Ther. 2016 ePub ahead of print 12. Van Eekeren RRJP, Boersma D, Konijn V, De Vries JPPM, Reijnen MMJP. Postoperative pain and early quality of life after radiofrequency ablation and mechanochemical endovenous ablation of incompetent great saphenous veins. J Vasc Surg 2013;57:445-450 13. McAree B, Ikponmwosa A, Brockbank K, Abbott C, Homer-Vanniasinkam S, Gough MJ. Comparative stability of sodium tetradecylsulphate (STD) and polidocanol foam: impact on vein damage in an in-vitro model. Eur J Vasc Endovasc Surg 2012;43:721– 725.

14. Deijen CL, Schreve MA, Bosma J, De Nie AJ, Leijdekkers VJ, Van den Akker PJ, Vahl A. Clarivein mechanochemical ablation of the great and small saphenous vein: early treatment outcomes of two hospitals.

Phlebology 2016;31:192-197.

15. Boersma D, Van Eekeren RRJP, Kelder JC, Werson DAB, Holewijn S,Schreve MA, Reijnen MMPJ, De Vries JPPM. Mechanochemical endovenous ablation versus radiofrequency ablation in the treatment of primary small saphenous vein insufficiency (MESSI trial): study protocol for a randomized controlled trial. Trials.

2014;15:421 16. Van Eekeren RRJP, Boersma D, Holewijn S, Vahl A, De Vries JPPM, Zeebregts CJ, Reijnen MMPJ. Mechanochemical endovenous Ablation versus RADiOfrequeNcy Ablation in the treatment of primary great saphenous vein incompetence (MARADONA): study protocol for a randomized controlled trial. Trials. 2014;15:121 17. Zerweck C, Von Hodenberg E, Knittel M, et al. Endovenous laser ablation of varicose perforating veins with the 1470-nm diode laser using the radial fibre slim. Phlebology 2014;29(1):30-36.

18. Park SW, Hwang JJ, Yun IJ, et al. Randomized clinical trial comparing two methods for endovenous laser ablation of incompetent perforator veins in thigh and great saphenous vein without evidence of saphenofemoral reflux. Dermatol Surg 2012;38(4):640-646.

19. Hissink RJ, Bruins RMG, Erkens R, et al. Innovative treatments in chronic venous insufficiency: endovenous laser ablation of perforating veins: a prospective short-term analysis of 58 cases. Eur J Vasc Endovasc Surg 2010;40:403-406.

20. Proebstle TM, Herdemann S. Early results and feasibility of incompetent perforator vein ablation by endovenous laser treatment. Dermatol Surg 2007;33(2):162-168.

21. De Borst GJ, Moll FL. Percutaneous venous valve designs for treatment of deep venous insufficiency. J Endovasc Ther 2012;19:291-303 22. Brountzos E, Pavcnik D, Timmermans HA, et al. Remodeling of the suspended small intestinal submucosa venous valve: an experimental study in sheep to assess the host cells’ origin. J Vasc Interv Radiol. 2003;14:349–356.

23. Murphy SV, Atala A. 3D bioprinting of tissues and organs. Nature Biotechnol. 2014; 32:773-785.

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Chapter 12

Nederlandse samenvatting

CHAPTER 12

Zoals de titel al doet vermoeden bestaat dit proefschrift uit twee delen. Het eerste deel richt zich op zowel klinische als experimentele aspecten van de mechano-chemische endoveneuze ablatie (MOCA) voor de behandeling van spataderlijden. Het tweede deel beschrijft een drietal innovaties ten aanzien van de behandeling van het oppervlakkige, het diepe veneuze systeem en de verbindende takken tussen beiden: de perforanten.

Het eerste hoofdstuk van dit proefschrift bevat een algemene overzicht over MOCA met behulp van de ClariVein catheter. In het kort wordt oppervlakkig veneuslijden, de (jonge) geschiedenis van de ClariVein en de werkwijze van de MOCA behandeling beschreven.

Vervolgens wordt een compleet overzicht van alle beschikbare studies over MOCA gegeven: de initiële veiligheidsstudies en cohorten, de studies over pijn en kwaliteit van leven en tenslotte de resultaten van experimenteel onderzoek.

Hoofdstuk 2 bevat een uitgebreide systematische literatuur overzicht en meta-analyse van alle beschikbare data omtrent de behandeling van de vena saphena parva (VSP; de oppervlakkige kuitvene). Deze review toont dat de behandeling van de VSP bij voorkeur door middel van endothermale technieken (verhitting van de vene door middel van laser of radiofrequente ablatie) moet worden verricht. De klassieke chirurgische behandeling en behandeling middels foam (= etsend schuim) sclerotherapie hebben significant grotere kans op terugkeren van veneus lekken. Men moet rekening houden met een kans van 5% tot haast 20% op (tijdelijke) zenuwuitval na endothermale techniek of chirurgisch behandelen. Ondanks de belangrijke theoretische voordelen, zijn er helaas onvoldoende gegevens om harde uitspraken te doen over de positie van MOCA in behandeling van de VSP. Onze onderzoeksgroep had een pioniersrol in de toepassing van MOCA. Dit leidde tot de morele en wetenschappelijke verplichting om de veiligheid en resultaten van de eerste groepen patiënten te beschrijven. In hoofdstuk 3 worden de resultaten beschreven van de eerste 30 behandelingen in de vena saphena magna (VSM) en in hoofdstuk 4 de eerste 50 behandelingen in de VSP. Deze studies tonen aan de behandeling goed toepasbaar en veilig is. Het anatomisch succes (het dichtmaken van de vene) bleek ruim boven de 90%, maar toonde wel de kans op deels en soms zelfs volledig rekanaliseren over de loop der tijd. De pijnklachten van de behandeling waren beperkt en er was een significante afname van spatader-gerelateerde klachten na behandeling bij de onderzochte patiënten.

Een belangrijk voordeel van de MOCA techniek is dat er geen hitte gebruikt wordt om de spatader te sluiten. Hierdoor is slechts enige lokale verdoving bij de insteek nodig in plaats van verdoving rond om de gehele vene (tumescent anesthesie), welke wordt aangebracht door middel van meerdere prikken. Hoofdstuk 5 is een studie waarin onderzocht wordt of de patiënten meer of minder pijn ervaren bij MOCA in vergelijking met radiofrequente ablatie. Er bleek geen verschil te zijn in pijn gedurende de behandeling. Echter was er wel significant minder pijn, in de 2 weken na de MOCA behandeling, een sneller herstel en snellere terugkeer naar werk, vergeleken met de radiofrequente ablatie therapie.

Om een definitief antwoord te kunnen geven over de positie van MOCA in de behandeling

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van oppervlakkige veneuze insufficiëntie werden twee gerandomiseerde studies ontworpen.

De MARADONA studie voor de VSM en zijn “kleinere broertje” de MESSI trial voor de VSP. Hoofdstuk 6 bevat het protocol voor de MESSI studie. Helaas zijn beide studies voortijdig gestaakt door veranderende regels van verzekeraars en langdurende onduidelijkheid rondom de vergoeding van de MOCA behandeling. De MESSI studie werd zelfs al gestopt na een 8-tal succesvolle behandelingen.

Hoofdstuk 7 beschrijft een experimenteel onderzoek naar het effect van MOCA op de vaatwand, zowel in het eerste uur na de behandeling als na enkele weken. Hierbij werd gebruikt gemaakt van een diermodel: de oppervlakkige ader in de achterpoot van de geit, die qua diameter en lengte erg lijkt op de vena saphena van de mens. Het effect van de mechanische component van de behandeling leidde tot schade aan de binnenste laag van de ader en zorgde voor verkramping/vernauwing van het vat. Waarschijnlijk zijn deze twee zaken essentieel voor de werking van de chemische component van MOCA en daarmee het succes van de therapie. De resultaten na 6 weken gaven meer inzicht in het mechanisme van occlusie in de ader.

Zoals boven beschreven beslaat het tweede deel van het proefschrift drie studies naar innovatieve opties voor de behandeling van oppervlakkige, perforerende en diepe aders.

Ondanks de grote hoeveelheid aan klinische studies over de behandeling met de endoveneuze laser, is er slechts beperkt literatuur beschikbaar omtrent de behandeling van perforerende venen met laser therapie. In hoofdstuk 8 worden de resultaten van de perforantes “laseren” beschreven vanuit het Jeroen Bosch Ziekenhuis. Dit is de eerste studie, die alleen kijkt naar behandeling van perforantes zonder ablatie van oppervlakkige venen. De resultaten van deze behandeling zijn niet optimaal, maar gelukkig ook niet geassocieerd met grote complicatie risico’s. Er worden tips gegeven om resultaat te verbeteren.

Omdat niet elke spatader geschikt is voor behandeling met een endoveneuze techniek, was ons doel het ontwikkelen van een concept om een ader te kunnen afsluiten zonder open operatie. Hoofdstuk 9 beschrijft onze ontdekkingstocht naar het potentieel van de VeinScrew door middel van experimenten in het lab, op een menselijk kadaver en in een dierproef. Op moment van de verdediging van dit proefschrift zijn er geen nieuwe ontwikkelingen ten aanzien van de VeinScrew.

Tenslotte wordt in hoofdstuk 10 gekeken naar een nieuw concept voor een diep veneuze kunstklep. Diep veneus kleplijden komt voor bij mensen die vanaf de geboorte deze kleppen missen, maar met name na het optreden van een diep veneuze trombose (trombosebeen) blijkt de functie van de kleppen in de diepe ader vaak onherstelbaar aangedaan. Het grootste obstakel in proeven met eerdere ontwerpen van veneuze kunstkleppen was dat deze vaak afgesloten raakte door een stolsel. Deze studie toonde dat er op de nieuwe klep geen afsluitend stolsel ontstond na enkele weken in de achterpoot van een varken. Ondanks dat er nog belangrijke stappen moeten worden gezet ten aanzien van het materiaal van de klep, lijkt het concept zeer veel belovend. Ten tijde van de verdediging wordt er aan nieuwe dierexperimenten gewerkt alvorens een eerste implantatie in de mens mogelijk zal zijn.

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Review Committee Dankwoord List of Publications and Presentations Curriculum Vitae List of abbreviations

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REVIEW COMMITTEE (alphabetically ordered) Prof. dr. R.L.A.W. Bleys Department of Anatomy, University Medical Center Utrecht, Utrecht.

Prof. dr. W.P.T.M. Mali Department of Radiology, University Medical Center Utrecht, Utrecht.

Prof. dr. F.L.J. Visseren Department of Vascular Medicine, University Medical Center Utrecht, Utrecht.

Prof. dr. M.R. Vriens Department of Surgical Oncology, University Medical Center Utrecht, Utrecht.

Prof. dr. C.H.A. Wittens Department of Vascular Surgery, Maastricht University Medical Centre+, Maastricht Department of Vascular Surgery, University Hospital Aachen, Aachen, Germany.

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DANKWOORD Dit proefschrift is tot stand gekomen met hulp en ondersteuning van velen, waarvoor veel dank. Een aantal van hen wil ik in het bijzonder danken.

Prof. dr. F.L. Moll, beste Frans, Ik wil u in het bijzonder danken voor de hulp en steun bij het tweede deel van mijn proefschrift. Ik heb erg genoten en veel geleerd van onze overleggen. Onze “Willy Wortel”-experimenten in dierenlab en snijzaal hebben gezorgd voor veel plezier in het afmaken van mijn promotie. Om de één of andere reden leidt samen nadenken altijd weer tot nieuwe plannen.

Prof. dr. G.J. de Borst, beste Gert Jan, Afgelopen twee jaar hebben we veel samengewerkt aan dierproeven met de ClariVein en later de SailValve. Elke dag in het GDL heb ik ervaren als een feest. Daarnaast ben je, samen met Frans, de motor geweest achter het afmaken van dit proefschrift. Ik waardeer jullie positieve en opbouwende werkwijze enorm. Dank voor het vertrouwen.

Dr. M.M.P.J. Reijnen, beste Michel, Ik wil je hartelijk danken voor de kansen die je me geboden hebt, de trouwe steun bij het promotietraject en hulp bij opzet van de verschillende studies.

Dr. J.P.P.M. de Vries, beste Jean-Paul, Ik wil je oprecht danken voor de geboden kansen.

De leden van de promotiecommissie, Prof. dr. R.L.A.W. Bleys, Prof. dr. W.P.Th.M. Mali, Prof. dr. F.L.J. Visseren, Prof. dr. M.R. Vriens, Prof. dr. C.H.A. Wittens, Hartelijk dank voor de beoordeling van mijn proefschrift.

Dr. R.R.J.P van Eekeren, beste Ramon, Jouw promotie in april 2015 was een goede extra stimulans om extra gas te geven naar de eindstreep. Onze samenwerking heeft geleid tot velen 1-2-tjes. Vond t een voorrecht met het VSP-stuk in jouw boekje te staan en ben blij dat je ook in mijn proefschrift staat. Dank voor je hulp.

Dr. S. Holewijn en Mw. D. Werson, beste Suzan en Debbie, Heel veel dank voor de fijne samenwerking en tomeloze inzet voor de verschillende ClariVein studies.

John en Anita Visscher, Jullie waren en zijn de steun en toeverlaat voor de hele ClariVein karavaan. Een goed voorbeeld hoe de industrie en wetenschap hand-in-hand kunnen gaan.

Drs. S.T.W. van Haelst, beste Steven, De juiste man op het juiste moment! Altijd stand-by voor een handje hulp op het GDL en uiteindelijk toch als mede-auteur betrokken bij de geitenstudie. Ben blij dat ik zo ook nog in jouw boekje beland.

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Dr. A Vink, beste Aryan, Elke roep om hulp werd steevast met een vergadervoorstel beantwoord. Op vele vrijdagochtenden heb je Steven en mij geholpen met de interpretatie van de coupes uit de dierstudies. Ik ben ook verheugd dat je deel van het SailValve team uitmaakt. Dank voor je trouwe hulp.

Dr. I.E. Hoefer, beste Imo, Dank voor je hulp bij het opzetten en organiseren van de dierexperimenten.

Behalve de bovengenoemden zijn er veel meer mede-auteurs, die een belangrijke bijdrage hebben geleverd aan dit proefschrift. Dank voor jullie inzet en meedenken.

Dames en heren van dierenlab Experimentele Cardiologie, Evelyn, Marlijn, Joyce, Tinus, Grace en Martijn, dank voor jullie ondersteuning bij ClariVein en Sailvalve experimenten.

Elke dag op het lab was een feestdag! En daarom ook regelmatig gebak ....

Chirurgen en arts-assistenten Heelkunde UMCU en in het bijzonder ook WKZ. Dank voor 18 maanden academische opleiding. De geboden kansen tot individualiseren van de opleiding en de ruimte voor wetenschap zijn uniek en jullie hebben een belangrijke rol in de ontwikkeling tot compleet chirurg.

Chirurgen en collega arts-assistenten Jeroen Bosch Ziekenhuis. Wat een geweldige tent!

Alles ingericht om een steengoede opleiding neer te zetten: vol positieve ondersteuning en vol vertrouwen worden we opgeleid. Het is heerlijk om terug te zijn.

Dr. B.A.N. Verhoeven en dr. K. Bosscha, beste Bart en Koop, Gedurende de promotie zijn er altijd periodes van tegenwind. In deze periodes zijn jullie zeer waardevol geweest. Ik wil jullie danken voor jullie meedenken, adviezen, steun en vertrouwen.

Dr. O.H.J. Koning, beste Olivier, het me een grote eer en genoegen dat je niet alleen als mede-auteur, maar ook als opponent betrokken bent bij mijn promotie.

Drs. M.N. Niekel, beste Maarten, Ruim 5 jaar geleden mijn getuige en nu paranimf. Als beste studievrienden begonnen, doorlopen we simultaan ook alle fases van de opleiding en veel belangrijker het leven. Mooi dat je erbij bent!

Dr. H.J.A.A. van Geffen, beste Erwin, Het is een hele eer dat jij mijn paranimf bent! Naast mijn opleider in de trauma en longchirurgie, heeft onze gemeenschappelijke interesse in het goede (Bourgondische) leven geleid tot een waardevolle vriendschap.

Lieve Annemiek, Ik ben heel blij dat je aanwezig bent op waarschijnlijk je eerste verdediging/ promotie. Albert Jan en jij hebben in de afgelopen vele jaren altijd voor ons klaargestaan

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en ons ondersteunt in al onze dromen. De afwezigheid van Albert Jan is bij gelegenheden als deze extra verdrietig.

Lieve papa en mama, Zonder jullie was ik nooit zover gekomen. Fijn dat jullie ook in de moeilijke tijden altijd voor ons klaarstonden. Dank voor jullie steun en liefdevolle opvoeding.

Marijke, Liesbeth en Yvette, ik ben dol op m’n zusjes! Emma en Siem, wat is het een cadeautje om jullie bij de club te hebben! Familie boven alles!

Als laatst de allerbelangrijksten: Lieve Bauke en Feis, allerliefste kleine aapies! Wat is het heerlijk om jullie vader te mogen zijn. Ik kijk er naar uit om de uren achter de laptop te verruilen voor zeilen, zwemmen, ravotten op de hei en eindeloos duplo-en.

Allerliefste Jet, Wat hebben we ‘t goed, hè?

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LIST OF PUBLICATIONS Mechanochemical endovenous ablation of saphenous veins using the ClariVein: a systematic review. Witte ME, Zeebregts CJ, De Borst GJ, Reijnen MMPJ, Boersma D. Submitted to Phlebology 2016 Proof-of-concept of the SailValve new self-expandable deep venous valve system in a porcine model. Boersma D, Vink A, Moll FL, De Borst GJ. Accepted for publication in J Endovasc Ther. 2016 Macroscopic and histologic analysis of vessel wall reaction after mechanochemical endovenous ablation using the ClariVein OC device in an animal model. Boersma D, Van Haelst STW, Van Eekeren RRJP, Vink A, Reijnen MMJP, de Vries JPPM, De Borst GJ. Accepted for publication Eur J Vasc Endovasc Surg 2016 Mechanochemical ablation (MOCA™) of varicose truncal veins - an innovative technique combining physical and chemical ablation to avoid tumescence. Boersma D, Van Eekeren RRJP, Werson DAB, Reijnen MMPJ, De Vries JPPM. Bookchapter “Advances in Phlebology and Venous Surgery 2016, Editor Prof. M. Whiteley.

Use of a multi-instrument access device in abdominoperineal resections, Van der Linden YT, Boersma D, Prins HA, Bosscha K, Lips DJ. J Min Access Surg 2016 ;12:248-253 “The vein is screwed” - A proof-of-concept study of the VeinScrew: A new percutaneous venous closure device.Boersma D, De Borst GJ, Moll FL. Vascular 2016 [ePub ahead of print] Treatment Modalities for Small Saphenous Vein Insufficiency: Systematic Review and Meta-analysis. Boersma D, Kornmann VN, van Eekeren RR, Tromp E, Ünlü Ç, Reijnen MM, de Vries JP. J Endovasc Ther. 2016;23:199-211.

The significance of regional hemoglobin oxygen saturation values and limb-to-arm ratios of near-infrared spectroscopy to detect critical limb ischemia. Boezeman RP, Boersma D, Wille J, Kelder JC, Visscher MI, Waanders FG, Moll FL, De Vries JP. Vascular 2016;24(5):492-500 Endovenous laser ablation of insufficient perforating veins: Energy is key to success.

Boersma D, Smulders DL, Bakker OJ, van den Haak RF, Verhoeven BA, Koning OH. Vascular 2016;24:144-149 Single-port laparoscopic appendectomy in children: single center experience in 50 patients.

Van der Linden YT, Boersma D, van Poll D, Lips DJ, Prins HA. Acta Chir Belg 2015;115:118122

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Update of endovenous treatment modalities for insufficient saphenous veins - a review of literature. Van Eekeren RRJP, Boersma D, De Vries JPPM, Zeebregts CJ, Reijnen MMJP. Semin Vasc Surgery 2014;27:118-136 Persistent endoleak after endovascular aneurysm repair for acute Q-fever-infected aortocaval fistula. Prinsen JH, Boersma D, van Loenhout R, van Schaik PM, Verhoeven BA. Vascular. 2015;23:645-647 Mechanochemical endovenous ablation versus radiofrequency ablation in the treatment of primary small saphenous vein insufficiency (MESSI trial): study protocol for a randomized controlled trial. Boersma D, van Eekeren RRJP, Kelder HJ, Werson DAB, Holewijn S, Schreve MA, Reijnen MMPJ, de Vries JPPM. Trials. 2014;15:421.

Mechanochemical endovenous ablation for the treatment of great saphenous vein insufficiency. Van Eekeren RRJP, Boersma D, Holewijn S, Werson DAB, De Vries JPPM, Reijnen MMJP. J. Vasc Surg: Venous and Lymphatic Disorders 2014;2:282â&#x20AC;&#x201C;288.

Mechanochemical endovenous Ablation versus RADiOfrequeNcy Ablation in the treatment of primary great saphenous vein incompetence (MARADONA): study protocol for a randomized controlled trial. Van Eekeren RR, Boersma D, Holewijn S, Vahl A, de Vries JP, Zeebregts CJ, Reijnen MM. Trials. 2014;15:121.

Reply to letter to the editor by Koza et al. Kooiman J, le Haen PA, Gezgin G, de Vries JP, Boersma D, Brulez HF, Sijpkens YW, van der Molen AJ, Cannegieter SC, Hamming JF, Huisman MV. Am Heart J. 2013;166:e43.

Contrast induced acute kidney injury after intravenous and intra-arterial contrast administration: risk assessment and clinical outcomes. Kooiman J, Le Haen PAA, Gezgin G, De Vries JPPM, Boersma D, Brulez HFH, Sijpkens YWJ, Van der Molen AJ, Cannegieter SC, Hamming JF, Huisman MV. Am Heart J. 2013;165:793-799 Laparoscopic pyloromyotomy, the tail of the learning curve. Oomen M, Bakx R, Peeters B, Boersma D, Wijnen M, Heij H. Surg Endosc. 2013;27:3705-3709.

Mechanochemical endovenous ablation of small saphenous vein insufficiency using the ClariVein(ÂŽ) device: one-year results of a prospective series. Boersma D, Van Eekeren RRJP, Werson DAB, van der Waal RI, Reijnen MMPJ, De Vries JPPM. Eur J Vasc Endovasc Surg. 2013;45:299-303 Postoperative pain and early quality of life after radiofrequency ablation and mechanochemical endovenous ablation of incompetent great saphenous veins. Van Eekeren RRJP, Boersma D, Konijn V, de Vries JPPM, Reijnen MMPJ. J Vasc Surg. 2013;57:445-450.

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Congenital bronchopulmonary foregut malformation in a neonate, a case report. Boersma D, Koot BG; Van Rijn RR, Van der Steeg AFW. J. Ped Surgery. 2012;47:e59-62 Endovascular retrieval of a dislodged femoral arterial closure device with Alligator forceps.

Boersma D, Van Strijen MJL, Kloppenburg GTL, Van den Heuvel D, De Vries JPPM. J. Vasc Surg. 2012;55:1150-1152 Fenestrated endograft repair of suprarenal aortic patch aneurysm in a patient with Marfan syndrome. Boersma D, Kloppenburg GTL, Vos JA, Van den Heuvel D, De Vries JPPM. Vasc and Endovasc Ther. 2012;46:66-69 Superior Mesenteric Artery Stent Fracture Leading to Recurrent Mesenteric Ischemia.

Schellekens JF, Vos JA, Van den Heuvel D, Boersma D, De Vries JPPM. Vasc and Endovasc Ther 2011;45: 654-659 Volvulus as a complication of chronic intestinal pseudo-obstruction syndrome. De Betue CT, Boersma D, Oomen MW, Benninga MA, De Jong JR. Eur. J. Pediatrics. 2011;170: 1591-1595 Mechano-chemische endoveneuze ablatie (ClariVeintm): een nieuwe endoveneuze techniek zonder tumiscentie-anaesthesie bij de behandeling van varicosis. Van Eekeren RRJP, Boersma D, De Vries JPPM, Reijnen MMPJ. Ned Tijdschrift Geneeskd. 2011; 155:14911493 Mechano-chemical endovenous ablation of great saphenous vein incompetence using the ClariVeintm device: A safety study.

Van Eekeren RRJP, Boersma D, Elias S, Holewijn S, Werson DAB, De Vries JPPM, Reijnen MMPJ. J Endovasc Ther. 2011;18:328-334 Surgical Snapshot: Varicosity of the round ligament. Boersma D, Kornmann VNN, Boerma D. Br J Surg. 2011;98:1266/1283 Inspanningsgerelateerde armvenetrombose: een beknopt klinisch overzicht. Van den Heuvel PM, Van der Waal RIF, Boersma D, Wille J, Vos JA, Koene HR. NTvDV. 2011;21:246-249 Anorectale malformatie met perineale fistel: gemakkelijk te missen? Boersma D, De Jong JR. Tijdschr Kindergeneeskd. 2010;78:247-248. â&#x20AC;&#x153;Gezienâ&#x20AC;?: Anorectale malformatie. Boersma D, Wilde JCH. Medisch contact 2010; 13: 514

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LIST OF PRESENTATIONS (selection) Macroscopic and histological scoring of mechanochemical endovenous ablation using the Clarivein device in an animal model. Annual Meeting European Society of Vascular Surgery 2016, Copenhagen, Denmark.

The vein is screwed. A proof of concept study of the VeinScrew. Annual Meeting Society of Vascular Surgery 2016, Washington DC, USA. The vein is screwed. The Veinscrew: a proof of concept study. Innovation Showcase / Charing Cross Meeting 2015, London, UK The Veinscrew: a new concept. Vascular Rounds 2015; UMC Utrecht Mechano-chemical endovenous ablation in great and small saphenous vein incompetence using ClariVein: experience and evidence. Up to Date in Phlebology 2014, Abano Terme, Italy Mechano-chemical endovenous ablation of great saphenous vein insufficiency using the ClariVein™ catheter: Multicentre Registry study. World Meeting UIP 2013, Boston, USA Mechano-chemische ablatie van VSM en VSP. Resultaten tot nu & lopende trials. Dutch College of Phlebology 2013, Utrecht.

Mechano-chemical endovenous ablation in small saphenous vein insufficiency using ClariVein; One year results. Annual Meeting DGP 2012, Lübeck, Germany. Prize: “Medi GmbH Young Scientist Stipendium” MARADONA & MESSI studies: randomized controlled studies. Society of Vascular Surgery 2012, Washington DC, USA. Prize:“Research principles Scholarship”.

Mechano-chemical endovenous ablation in great and small saphenous vein incompetence using ClariVein; Initial results of an innovative tumescentless technique. Annual Meeting Society of Vascular Surgery 2011, Chicago, USA Introduction to mechano-chemical endovenous ablation in great saphenous vein incompetence using ClariVein (invited speaker), Annual Meeting DGP 2011, Berlin, Germany. Prize: “Kreussler Travel Award for Best Abstract” Mechano-chemische endoveneuze ablatie van veneuze staminsufficiëntie met de ClariVein catheter; eerste resultaten van een innovatieve techniek. Chirurgendagen 2011, Veldhoven ClariVein catheter, een introductie. Vascular Rounds 2011; UMC Utrecht

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174

Curriculum vitae

CURRICULUM VITAE Doeke Boersma was born on April 23th, 1983 in Utrecht. He grew up in a loving family with 2 younger sisters. He graduated from the Utrechts Stedelijk Gymnasium and studied medicine at the University of Amsterdam. After graduating cum laude from medical school in 2009, he began working as a resident in pediatric surgery at the Emma Kinderziekenhuis, Amsterdam. From 2010 to 2012 he worked as a resident in general surgery at the St. Antonius Ziekenhuis, Nieuwegein. During this period, he commenced the PhD research program leading to this thesis. In 2012 Doeke started his formal surgical training in the Jeroen Bosch Ziekenhuis in Den Bosch and the University Medical Center in Utrecht.

Currently he is finishing his training with special interest in traumatology, surgery in children, and lung surgery.

Doeke is married to Jet Boersma-Otten and they are living in Bussum with their two sons, Bauke (2015) and Feis (2016)

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LIST OF ABBREVIATIONS AVVQ Aberdeen Varicose Vein Questionnaire α-SMA α-Smooth muscle actin BMI Body mass index CEAP Clinical Etiology Anatomy Pathophysiology CCD Centrale commissie dierexperimenteel onderzoek CCMO Centrale Commissie Mensgebonden Onderzoek CI Confidence interval CRF Case report forms CDVI Chronic deep venous insufficiency CVI Chronic venous insufficiency DEC Dier experimenten Commissie DSMB Data Safety Monitoring Board DUS Duplex ultrasound DVT Deep venous trombosis eGFR Estimated Glomerular filtration rate ePTFE (expanded) polytetrafluoroethylene ERG ETS related gene immunostain EvG Elastica van Gieson EVLA Endovenous laser ablation F French GSV Great saphenous vein H&E Hematoxylin & Eosin (HR-)QoL (Health related) Quality of life IPV Insufficient perforator vein IQR Interquartile range LSV Lateral saphenous vein (in goats) MARADONA Mechanochemical endovenous Ablation versus RADiOfrequeNcy Ablation MESSI Mechanochemical Endovenous ablation versus radiofrequency ablation in the treatment of primary Small Saphenous vein Insufficiency MeSH Medical subject heading METC Medisch ethische toetsingscommissie MINORS Methological index for non-randomized studies MOCA Mechanochemical endovenous ablation NS Non significant NTR Nederlands trial register OC Occlusion catheter RCT Randomized Clinical Trial R&D Research and development RFA Radiofrequency ablation RFITT Radiofrequency induced thermotherapy

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List of abbrevations

RUDEC (S)AE SD SF-36 SFJ SPJ SSV STS SVVS UGFS VAS VCMO VCSS

Radboud University dierexperimenten commissie (Serious) adverse event Standard deviation Short form 36 Saphenofemoral junction Saphenopopliteal junction Small saphenous vein Sodium tetradecyl sulphate SailValve venous valve system Ultrasound-guided foam sclerotherapy Visual analoge scale Verenigde Commissies Mensgebonden Onderzoek Venous Clinical Severity Score

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Mechanochemical endovenous ablation and new frontiers in venous intervention Š Doeke Boersma, 2016