Mechanochemical tumescentless endovenous ablation: final results of the initial clinical trial

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1 Table of Contents I. S Elias and J K Raines; Mechanochemical tumescentless endovenous ablation: final results of the initial clinical trail II. Ramon R.J.P. van Eekeren, MD, Doeke Boersma, MD, Steven Elias, MD, Suzanne Holewijn, PhD, Debbie A.B. Werson, Jean- Paul P.M. de Vries, MD, PhD, and Michel M.J.P. Reijnen, MD, PhD; Endovenous Mechanochemical Ablation of Great Saphenous Vein Incompetence Using the ClariVein Device: A Safety Study III. Jean- Paul P.M. de Vries, MD, PhD, Michel M.P.J. Reijnen, MD, PhD; Mechano- Chemical Tumescentless Endovenous Ablation (MOCA) of the ClariVein Catheter IV. Richard L. Mueller, MD, FACC, RVT, RPVI; ClariVein Mechanochemical Ablation V. Steve Elias, MD, FACS, FACPh; MechanoChemical Endovenous Ablation: Final Results of First Clinical Trial VI. Muath Bishawi, Angela Kokkosis, Mathew Fakoury, Antonios P. Gasparis, MD; The use of ClariVein for patients with lower extremity chronic venous disease: An observational multicenter study and short term results VII. Rick V. Bernstein M.D. FACS & Siran Dilovyan RDMSMOCA Treatment for Defiant venous ulcers of the lower extremities VIII. Dr. Sendhil Subramanian Treatment of Ulcers using ClariVein IX. Kate Stenson, ClariVein : A Novel Treatment for Varicose Veins X. Steve Elias MD, FACS, FACPh 2 Year Data SVS presentation XI. Diagrams XII. Steve Elias, MD, FACS, FACPh; SVS ClariVein Presentation Mechanochemical Ablation: MOCA 2 year Follow Up, Lessons Learned.

2 Original article Mechanochemical tumescentless endovenous ablation: final results of the initial clinical trial S Elias* and J K Raines *Columbia Vein Programmes, Columbia University, New York, NY; University of Miami, Homestead, FL, USA Abstract Objective: The purpose of this study was to assess the safety and efficacy of the ClariVein w system that employs mechanochemical ablation of the great saphenous vein (GSV). Method: Patients eligible for ablation of the GSV underwent micropuncture access with only local anaesthesia to insert a 4 or 5 Fr sheath. The ClariVein w catheter was placed through the sheath, the wire was extruded, and the distal tip of the wire positioned 2 cm from the saphenofemoral junction under ultrasound guidance. Catheter wire rotation was then activated for 2 3 seconds at approximately 3500 rpm. With the wire rotating, infusion of the sclerosant was started simultaneously with catheter pullback. The sclerosant used was 1.5% liquid sodium tetradecyl sulphate (Sotradecol #, Bioniche Pharma Group, Geneva, Switzerland). Results: Thirty GSVs in 29 patients were treated. All patients have reached six-month followup; the average number of postoperative days is 260. No adverse events have been reported. The Primary Closure Rate is 96.7%. Conclusion: Mechanochemical ablation appears to be safe and efficacious. The ClariVein w technique eliminates the need for tumescent anaesthesia. The great majority of incompetent GSVs can be treated with this technique. Keywords: chronic venous disease; endovenous techniques; ultrasound-guided sclerotherapy; varicose veins; venous insufficiency Introduction Over the last 10 years, numerous minimally invasive methods have been utilized to treat great and small saphenous vein incompetence. 1,2 Most of these techniques involve percutaneous access, local anaesthesia, some form of ablation, and short operative times with relatively good safety and efficacy. The endothermal technologies require the use of tumescent anaesthesia prior to energy delivery and a generator to produce either laser or radiofrequency energy. Results have improved and complications have decreased as these techniques and technologies have evolved. 3 In the modern era of Correspondence: Jeffrey K Raines PhD, Emeritus Professor of Surgery, University of Miami, 2101 SE 14 Circle, Homestead, FL 33035, USA. drjraines@yahoo.com Accepted 31 January 2011 endothermal ablation (after 2006), efficacy rates of long-term closure are reported at levels well above 97%. 4,5 However, these methods currently still require tumescent anaesthesia which can be a source of patient procedural discomfort; further, this portion of the procedure is the steepest part of the physician learning curve. Recent reports have evaluated ultrasound-guided foam sclerotherapy of the great saphenous vein (GSV). 6 While foam sclerotherapy does obviate the necessity for tumescent anaesthesia, efficacy rates are lower than endothermal ablation and reported complication rates are higher. 7,8 At present, it cannot be stated that foam sclerotherapy is as efficacious as endothermal ablation. A new mechanochemical device, (ClariVein w, Madison, CT, USA), was developed to minimize the negative aspects of both endothermal ablation and ultrasound-guided sclerotherapy (UGS) for the treatment of saphenous incompetence, while incorporating the benefits of each. The advantages DOI: /phleb Phlebology 2011:1 6

3 Original article S Elias and J K Raines. Mechanochemical ablation of incompetent great saphenous veins of this hybrid system are standard percutaneous access, endovenous treatment, local anaesthesia only (no tumescence anaesthesia) and a short procedure time. Since this system does not use thermal energy, the potential for nerve damage is minimized. The negative aspects eliminated by the hybrid procedure are: the need for tumescence anaesthesia required for endothermal ablation and lower efficacy rates for UGS. The mechanochemical method achieves venous occlusion utilizing a wire rotating within the lumen of the vein at 3500 rpm which abrades (i.e. injures) the intima to allow for better efficacy of the sclerosant. A liquid sclerosant (sodium tetradecyl sulphate) is concomitantly infused through an opening close to the distal end of the catheter near the rotating wire. These two modalities, mechanical and chemical, achieve venous occlusion results equal to endothermal methods. The entire device is for single use only and can be inserted through a 4 or 5 Fr sheath utilizing local insertion site anaesthesia only, without the need for tumescence anaesthesia. The system includes an infusion catheter, motor drive, stopcock and syringe (Figure 1). This report describes the initial human clinical trial in 30 limbs of mechanochemical ablation to treat GSV incompetence. Objectives The purpose of this study was to assess the safety and efficacy of the ClariVein w system which employs mechanochemical ablation of the GSV. Table 1 outlines the two primary objectives and Figure 1 Picture of the ClariVein w device the three secondary objectives of this study. Also given are the measures and measure definitions used to assess the objectives. Materials and methods ClariVein w is an infusion catheter system designed to introduce physician-specified medications intravenously with simultaneous mechanical agitation into a patient s peripheral vasculature. Infusion is through an opening at the distal end of the catheter. Fluid delivery is enhanced by the use of a rotating dispersion wire to mix the infused fluid in the target vein and onto the vessel wall, as well as, abrade the venous intima. The dispersion wire extends through the catheter lumen. It is connected to an interface Cartridge Unit for connection to the 9 V DC battery motorized Handle Unit on the Table 1 Primary and Secondary objectives Objective Objective definition Measures Measure definition Primary 1 Primary 2 Secondary 1 Secondary 2 Secondary 3 Determine overall safety of the ClariVein w procedure Define recannulation of treated veins following the ClariVein w procedure at six months Measures of pain associated with the ClariVein w procedure and during follow-up Listing of pain therapy during the ClariVein w procedure and medication required during follow-up Identify eccymosis secondary to the ClariVein w procedure Adverse events and serious adverse events. This includes all clinical complications Primary Closure Rate at six months Pain levels reported by the patient Monitoring of medication required for pain Degree of eccymosis as reported by the clinical staff using a simple scale Standard definitions of adverse events and serious advance events as defined by the FDA were used during the six-month postprocedure period Based on duplex ultrasound evaluation the closure of the treated vein is determined. Primary Closure Rate is calculated by dividing the number of closed veins at six months by the total veins treated (%). A continuous segment of 5 cm in length of treated vein is considered an open vein These data are gathered during the procedure and at all visits during the six-month postprocedure period Monitoring of medication, dose, and timing for pain during the procedure and during the six-month postprocedure period These data are gathered during the procedure and at all visits during the six-month postprocedure period. Possible answers ranged from No Eccymosis to Eccymosis over entire Length with Extension FDA, Federal Drug Administration 2 Phlebology 2011:1 6

4 S Elias and J K Raines. Mechanochemical ablation of incompetent great saphenous veins Original article proximal end, which controls wire rotation. The Handle Unit also provides a grip and syringe holder to facilitate physician-controlled infusion. After purging with saline to ensure a closed system and prior to drug infusion, the wire plus catheter sheath is inserted into the vein percutaneously. The catheter sheath is retracted to expose the wire tip, which is positioned 2 cm from the saphenofemoral junction. The catheter motor is turned ON and, with the wire rotating and sclerosant infusing, the catheter is pulled down the vein at a rate of approximately 1 2 mm per second. The wire that passes through the catheter is 304 V stainless steel; the configuration of the dispersion tip has been optimized for mechanochemical vein ablation. The wire is steerable and therefore will transverse most tortuous GSV segments. Protocol Assessment Patients underwent examination by a senior venous surgeon and ultrasound evaluation, and if deemed eligible for thermal ablation (laser or radiofrequency) of the GSV were considered for this Institutional Review Board (IRB) approved protocol. The assessment included evaluation of GSV reflux, Venous Clinical Severity Score (VCSS), 9 CEAP (clinical, aetiological, anatomical and pathophysiological elements) classification 10 and previous venous procedures. Reflux was determined at the saphenofemoral junction in the standing position using the Valsalva manoeuvre or manual distal compression with rapid release. Reflux as documented by ultrasound extending for 0.5 seconds or longer was considered significant. CEAP Class 1 patients were excluded. Other exclusion criteria were the same as those for endothermal ablation and included: acute deep vein thrombosis (DVT), immobility, anticoagulation and GSV diameters. 12 mm. ClariVein w procedure At the time of the procedure, patients were placed in the reversed Trendelenberg position on a procedure table. Repeat ultrasound examination was performed to confirm the important anatomic and haemodynamic parameters. This included imaging of the target vein for access, the saphenofemoral junction, perforators, tributaries, diameter and treatment length. With the patient in the reversed Trendelenburg position, micropuncture access was obtained. Only local anaesthesia was used to insert the 4 or 5 Fr sheath. The ClariVein w catheter was placed through the sheath, the wire was extruded and the distal tip of the wire positioned 2 cm from the saphenofemoral junction under ultrasound guidance. The patient was then rotated to a flat position for the remainder of the procedure. Catheter wire rotation was first activated for 2 3 seconds at the highest speed setting (approximately 3500 rpm). This creates venospasm which minimizes forward flow into the common femoral vein. With the wire continuing to rotate, infusion of the sclerosant was started simultaneously with catheter pullback. The sclerosant used was 1.5% liquid sodium tetradecyl sulphate (Sotradecol # ). For this study all treated veins received 12 cc of 1.5% sclerosant. The sclerosant volume was independent of vein diameter and treatment length. The pullback rate was between 1.0 and 2.0 mm/second. No other concomitant procedures were performed (i.e. microphlebectomy or perforator ablation) so as to have the evaluation of safety and efficacy wholly dependent on mechanochemical ablation. All entered subjects underwent a completed procedure. Postprocedure When the catheter had traversed the entire treatment length and had been removed, the surgical team checked for GSV occlusion and patency of the common femoral vein using ultrasound. A 4 and 6 compression bandage was applied to the treated limb from the foot to the groin. This remained in place for 24 hours. The patients then applied a mmhg thigh-high compression stocking continuously for the next 48 hours, except whilst showering. They then utilized the compression stocking only during the day for the next 10 days. Patient activity was not restricted. All forms of reasonable exercise were approved from the first postprocedure day. The patients were instructed to take only over-the-counter medication for discomfort. Follow-up Follow-up visits at one week, one month, three months and six months were performed. At each visit an ultrasound study and clinical exam was performed. Occlusion and vein wall changes were documented (Figures 2 and 3). Results Using the protocol described above, a single experienced venous surgeon treated 30 GSVs in 29 patients during the period 20 February 2009 and 17 July 2009 (+5 months). The average age of the Phlebology 2011:1 6 3

5 Original article S Elias and J K Raines. Mechanochemical ablation of incompetent great saphenous veins Figure 2 Ultrasound of closed GSV at one-week (no flow and no vein wall retraction). GSV, great saphenous vein patients was 54.3 years with a range of years. Sixty percent of the subjects were women. The ablation procedures were limited to the GSV. In all cases comprehensive lower-extremity venous duplex examinations were performed to determine venous insufficiency and indications for the procedure. GSV reflux was carefully measured in the standing position. In all cases GSV reflux time was.2 seconds with a range of 2 5 seconds. In 47% of the operated limbs, veins other than the GSV, Figure 3 Ultrasound of closed GSV at 12 months (no flow and complete vein wall retraction). GSV, great saphenous vein 4 Phlebology 2011:1 6

6 S Elias and J K Raines. Mechanochemical ablation of incompetent great saphenous veins Original article demonstrated a degree of reflux. This included the deep system, other superficial veins and perforating veins. The average VCSS score was 4.5 with a range of In all cases significant varicose veins were present. The six-point CEAP classification ranged from 2 4. In our series 77% were in Class 2 (varicose veins), 7% in Class 3 (varicose veins and oedema) and 16% in Class 4a (varicose veins with skin changes). In our series the average diameter of the treated GSV was 8.1 mm with a range of mm. The average treatment length was 37.5 cm with a range of cm. The total procedure time averaged 14 minutes. The average total time for the ablation portion of the procedure was nine minutes with a range of 6 17 minutes. The catheter was in the active treatment mode, including pullback for an average of five minutes and 15 seconds. The range was three minutes and 40 seconds to six minutes and 45 seconds (pullback rate 1 2 mm/second). For this series no other vein segments were treated and no secondary treatment was administered. During the procedure patients did not complain of pain. Three minor thigh eccymosis were observed at levels where the rotating wire may have caught on a valve cusp or vein wall. No DVT nerve or skin injury occurred. No patient complained of parathesia, hypothesia or motor dysfunction on clinical examination. To date, there are no patients lost to follow up. All patients have reached the six-month follow-up point. The average follow-up is 260 days with a range of days. At this point only one vein has recanalized. This was the first case in this series. While there is ultrasound evidence of recanalization, the treated vein is not refluxing. The recanalization occurred between the one-week and one-month visits. This corresponds to a Primary Closure Rate of 96.7% at 260 days. Thus, any vein with a successful outcome at one-month has remained occluded at the six-month follow-up visit. Discussion The first primary objective was to determine overall safety of the ClariVein w procedure. Most investigators have found that the vast majority of adverse events associated with superficial vein closure occur at the procedure or within the first 30 days after the procedure. An exception is recanalization of the treated segment. Our first primary objective was to assess safety of the procedure. A total of 30 veins were treated in 29 patients. No adverse events or serious adverse events were recorded. Our definition of adverse event included new events not seen before the index surgical procedure, a pre-existing event that recurred with increased intensity or increased frequency subsequent to the index procedure and events which were present at the time of study entrance which became exacerbated. Our definition of serious adverse events included death, life-threatening events, any event which is disabling or incapacitating, events requiring prolonged hospitalization, any cancer and clinical chemistry results that are considered a major clinical concern. With no adverse events our findings suggest that the ClariVein w procedure is safe based on up to six months of follow-up. Our second primary objective was to determine efficacy. The measure we elected to use was Primary Closure Rate based on ultrasound. In our series, 29 of 30 veins are closed corresponding to a Primary Closure Rate of 96.7% at a mean follow-up of 260 days. Since this rate is comparable to the best published results for endovenous laser (EVL) and radiofrequency at the same follow-up, our assessment suggests the procedure is efficacious based on six months of follow-up. The first and second secondary objective are associated with pain and required medication during the procedure and at follow-up. During the procedures (30 veins in 29 patients), no patient complained of pain and no medication in addition to the 1 cc injection at the cannulation site was requested. The third secondary objective is ecchymosis (bruising) secondary to the ClariVein w procedure. Again since tumescent anaesthesia is not required, bruising was not noted in our patients. Three patients did have minor upper-thigh ecchymosis perhaps due to the rotating wire catching on the side branch or valve cusp. A gentle tension is required for release; this may cause a small tear in the vein wall. Tumescent anaesthesia obviates the transfer of thermal energy to non-target tissues by creating a heat sink; further, it mechanically reduces the luminal diameter of the vein wall to better contact the indwelling items such as laser fibre or radiofrequency catheter. However, its placement requires multiple patient needle-sticks. Tumescent infusion is the steepest part of the learning curve for new practitioners. It is also the longest part of a short procedure; eliminating tumescent infusion is a desirable goal. Furthermore, thermal ablation (laser or radiofrequency) requires the acquisition of a generator and may be associated with a significant degree of postoperative pain and bruising. 3 It should be acknowledged that the closure rates Phlebology 2011:1 6 5

7 Original article S Elias and J K Raines. Mechanochemical ablation of incompetent great saphenous veins associated with thermal ablation are excellent, advances in radiofrequency catheters have reduced pain and bruising, and increased wavelengths in endovenous lasers have also reduced postoperative pain and bruising. The risk of thermal injury to nerve, muscle or skin is minimized. However, the generator cost and the requirement for tumescent anaesthesia remain negative issues for this technology. ClariVein w does not require a generator or the use of tumescent anaesthesia. The risk of thermal injury to nerve, skin or muscle is eliminated. The GSV can be treated over its full length if clinically indicated without concern for nerve injury. This can also be extrapolated to treatment of the small saphenous vein. The initial experience in patients described above using ClariVein w clearly has been valuable on several fronts. While only 30 GSVs were treated, the age and age range of the patients and their presenting profiles mimic studies using other endovenous modalities. Actually, this study had a higher percentage of men than the average superficial venous ablation trial. The patients in this study were clear candidates for GSV treatment; however, they did not have advanced disease. The average VCSS was 4.5% and 77% of subjects were in CEAP Class 2. The average GSV supine diameter at the saphenofemoral junction was 8.1 mm ( mm). This is the vein size published for many contemporary trials. Our average treatment length was 37.5 cm (24 47 cm) and is also consistent with current trial results. Conclusions Mechanochemical ablation appears to be safe and efficacious. The technique eliminates the need for tumescent anaesthesia, a goal that both radiofrequency and laser technologies are currently exploring. 11 The elimination of tumescent infusion decreases patient discomfort, shortens the physician learning curve and shortens procedure time by getting rid of the longest part of the relatively short procedure of endovenous ablation. The great majority of incompetent GSVs can be treated with this technique. Veins which may not be candidates for mechanochemical ablation include those with previous thrombophlebitis which have recanalized and are incompetent. A few of those were attempted after the clinical trial. The rotating wire was found to tangle on the synechiae and trabeculae of the recanalized vein which limits mechanical treatment. Follow-up in the initial 30 patients and subsequent patients will continue. In addition, a Clari- Vein w registry has been initiated. Those patients treated by properly-trained physicians will be entered. In conclusion, mechanochemical ablation utilizing the ClariVein w device has good safety and appears to have good efficacy; the method should be considered as another viable alternative for the management of saphenous incompetence. Declarations: This research was sponsored in part by Vascular Insights LLC. References 1 Merchant RF, DePalma RG, Kabnick LS. Endovascular obliteration of saphenous reflux: a multicenter study. J Vasc Surg 2002;35: Cavezzi A, Frullini A, Ricci S, Tessari L. Treatment of varicose veins by foam sclerotherapy: two clinical series. Phlebology 2002;17: Almeida JI, Kaufman J, Gockeritz O, et al. Radiofrequency endovenous closurefast versus laser ablation for the treatment of great saphenous reflux: a multicenter single-blinded randomized study (RECOVERY). J Vasc Interv Radiol 2009;20: Proebstle TM, Vago B, Alm J, et al. Treatment of the incompetent great saphenous vein by endovenous radiofrequency powered segmental thermal ablation: first clinical experience. J Vasc Surg 2008;47: Brar R, Nordon IM, Hinchliffe RJ, et al. Surgical management of varicose veins: meta-analysis. Vascular 2010;18: Blaise S, Bosson JL, Diamond JM. Ultrasound guided sclerotherapy of the great saphenous vein with 1% versus 3% polidocanol foam: a multicentre double-blind randomized trial with three-year follow-up. Eur J Vasc Surg 2010;39: Hamel Desnos C, Ouvry P, Benigni JP, et al. Comparison of 1% and 3% polidocanol foam in ultrasound guided sclerotherapy of the great saphenous vein: a randomized double blind trial with two year follow-up. The 3/1 study. Eur J Vasc Surg 2007;34: Ceulen RPM, Bullens-Goessens Y, Pi-Van de V, et al. Outcomes and side effects of duplex guided sclerotherapy in the treatment of great saphenous veins with 1% versus 3% polidocanol foam: Results of a randomized controlled trial with one year follow up. Dermatol Surg 2007;33: Rutherford RB, Padberg FT Jr, Comerota AJ, Kistner RL, Meissner MH, Moneta GL. Venous severity scoring: an adjunct to venous outcome assessment. J Vasc Surg 2000;31: Eklof B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification for chronic venous disorders: consensus statement. J Vasc Surg 2004;40: Elias S. Tumescentless endovenous ablation: where are we and where are we going? International Vein Congress (Oral Presentation, May 2010, Miami, FL, USA) 6 Phlebology 2011:1 6

8 328 J ENDOVASC THER 2011;18: CLINICAL INVESTIGATION Endovenous Mechanochemical Ablation of Great Saphenous Vein Incompetence Using the ClariVein Device: A Safety Study Ramon R.J.P. van Eekeren, MD 1 ; Doeke Boersma, MD 2 ; Steven Elias, MD 3 ; Suzanne Holewijn, PhD 1 ; Debbie A.B. Werson 2 ; Jean-Paul P.M. de Vries, MD, PhD 2 ; and Michel M.J.P. Reijnen, MD, PhD 1 1 Department of Surgery, Rijnstate Hospital, Arnhem, The Netherlands. 2 Department of Vascular Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands. 3 Division of Vascular Surgery Vein Programs, Columbia University, New York, New York, and Englewood Hospital, Englewood, New Jersey, USA. Purpose: 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 ecchymoses 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 (n52) 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 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. J Endovasc Ther. 2011;18: Key words: varicose veins, venous incompetence, great saphenous vein, endovenous therapy, mechanical endothelial damage, sclerosant, polidocanol, endovenous ablation 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 reflux. 1 During the past decade, therapy for varicose veins has changed considerably. Thermal Steven Elias was the principal investigator of the US clinical study sponsored by Vascular Insights LLC. The other authors have no commercial, proprietary, or financial interest in any products or companies described in this article. Address for correspondence and reprints: Michel M.P.J. Reijnen, MD, PhD, Department of Surgery, Rijnstate Hospital, Wagnerlaan 55, 6815 AD Arnhem, The Netherlands. mmpj.reijnen@gmail.com ß 2011 by the INTERNATIONAL SOCIETY OF ENDOVASCULAR SPECIALISTS Available at

9 J ENDOVASC THER 2011;18: ENDOVENOUS MECHANOCHEMICAL ABLATION OF VARICOSE VEINS 329 van Eekeren et al. endovenous modalities, including endovenous laser ablation and radiofrequency ablation, are highly effective for obliterating the See commentary page 335 incompetent great saphenous vein (GSV). 2 Occlusion rates of over 90% are consistently reported in clinical trials, with low complication rates. 3 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 Allaert 6 found occlusion rates of only 39.5% treating GSV incompetence with liquid sclerotherapy after 1 year of followup. Foam sclerotherapy may be more effective, with occlusion rates of.76% after 1 year. 6 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 rare. 7,8 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. Study Design METHODS A protocol was constructed to evaluate endovenous MOCA in combination with polidocanol using the ClariVein catheter (Vascular Insights, Madison, CT, USA) 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 class 9 and venous clinical severity score 10 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, C2 C6 varicose veins, written informed consent, and primary GSV incompetence. 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). Study Device The single-use, disposable ClariVein infusion catheter (Fig. 1A) 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 (Fig. 1A). 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. Intervention All procedures were performed under local anesthesia by a specialized team consisting of

10 330 ENDOVENOUS MECHANOCHEMICAL ABLATION OF VARICOSE VEINS van Eekeren et al. J ENDOVASC THER 2011;18: TABLE Baseline Characteristics and Operative Details for 25 Patients Undergoing Endovenous Mechanochemical Ablation in 30 Limbs Characteristics Men/women 7/18 Mean age, y Body mass index, kg/m VCSS CEAP classification C2 18 C3 9 C4 3 C5 C6 0 Operative details Procedures performed at each center (Arnhem/Nieuwegein) 9/21 Duration of procedure, min Vein diameter 2 cm below SFJ, mm Vein diameter at puncture site, mm Treated length, cm Continuous data are presented as means 6 standard deviation; categorical data are given as counts. VCSS: venous clinical severity score, CEAP: clinical, etiology, anatomy, and pathophysiology, SFJ: saphenofemoral junction. 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 Figure 1 (A) The ClariVein device consists of a 9V battery motorized handle unit (H) and cartridge unit (C) that contains the catheter with dispersion wire that extends though the catheter lumen (CL). The end of the wire has a dispersion tip (T) with a small ball attached that mechanically damages the endothelium. (B) Ultrasound guidance is used to position the dispersion tip (arrow) 2 cm below the saphenofemoral junction. (C) Duplex ultrasonography shows the saphenofemoral junction just after MOCA. The great saphenous vein is occluded.

11 J ENDOVASC THER 2011;18: ENDOVENOUS MECHANOCHEMICAL ABLATION OF VARICOSE VEINS 331 van Eekeren et al. junction (SFJ) under ultrasound guidance (Fig. 1B). 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 (Aetoxisklerol; 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 (Fig. 1C). 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 (30 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 6 standard deviation if distributed parametrically or as the median and interquartile range (IQR, 25 th to 75 th 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). RESULTS During procedures that averaged 20 minutes (Table), the mean length of GSV treated was 40 cm. A mean volume of 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 2 mm

12 332 ENDOVENOUS MECHANOCHEMICAL ABLATION OF VARICOSE VEINS van Eekeren et al. J ENDOVASC THER 2011;18: Figure 2 Visual analogue scale for pain within the first week after MOCA (n512). 7 days after MOCA (Fig. 2). 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 ) to 1.0 (IQR ) 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 ) to 2.0 (IQR ) 6 weeks after treatment. The venous clinical severity score worsened from 5 to 11 in 1 patient with a superficial phlebitis. 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 ultrasoundguided foam sclerotherapy, 79.9% for radiofrequency ablation, and 95.4% for endovenous laser ablation. 2 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 catheter 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 cord. 11,12 The first results of MOCA using the Clari- Vein catheter and sodium tetradecyl sulfate (Sotradecol) were recently published. 13 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

13 J ENDOVASC THER 2011;18: ENDOVENOUS MECHANOCHEMICAL ABLATION OF VARICOSE VEINS 333 van Eekeren et al. with incidences of 0% to 7.3% 7,8,16,17 and 2.6% to 7.9%, respectively. 17,18 Skin burns were reported in early endovenous laser ablation experience. 7,8 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. 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 well-tolerated 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. REFERENCES 1. Evans CJ, Fowkes FG, 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: Van den Bos R, Arends L, Kockaert M, et al. Endovenous therapy of lower extremity varicosities: a meta-analysis. J Vasc Surg. 2009;49: Ravi R, Trayler EA, Barrett DA, et al. Endovenous thermal ablation of superficial venous insufficiency of the lower extremity: singlecenter experience with 3000 limbs treated in a 7-year period. J Endovasc Ther. 2009;16: Min RJ, Khilnani N, Zimmet SE. Endovenous laser treatment of saphenous vein reflux: longterm results. J Vasc Interv Radiol. 2003;14: Darwood RJ, Theivacumar N, Dellagrammaticas D, et al. Randomized clinical trial comparing endovenous laser ablation with surgery for the treatment of primary great saphenous varicose veins. Br J Surg. 2008;95: Hamel-Desnos C, Allaert FA. Liquid versus foam sclerotherapy. Phlebology. 2009;24: Van den Bos RR, Neumann M, De Roos KP, et al. Endovenous laser ablation-induced complications: review of literature and new cases. Dermatol Surg. 2009;35:

14 334 ENDOVENOUS MECHANOCHEMICAL ABLATION OF VARICOSE VEINS van Eekeren et al. J ENDOVASC THER 2011;18: Sichlau MJ, Ryu RK. Cutaneous thermal injury after endovenous laser ablation of the great saphenous vein. J Vasc Interv Radiol. 2004;15: Kistner RL, Eklof B, Masuda EM. Diagnosis of chronic venous disease of the lower extremities: the CEAP classification. Mayo Clin Proc. 1996;71: Rutherford RB, Padberg FT, Comerota AJ, et al. Venous severity scoring: an adjunct to venous outcome assessment. J Vasc Surg. 2000;31: Mancini S, Lassueur F, Mariani F. Sclerosis of the great saphenous vein: an experimental study in humans of the sclerosing effect of iodo-iodide solution and polidodecane (histology and electron microscopy). Phlebology. 1991;44: Martin DE, Goldman MP. A comparison of sclerosing agents: clinical and histologic effects of intravascular sodium tetradecyl sulfate and chromate glycerin in the dorsal rabbit ear vein. J Dermatol Surg Oncol. 1990;16: Elias S, Raines JK. Mechanochemical tumescentless endovenous ablation: final results of the initial clinical trial. Phlebology. 2011; in press. 14. Uncu H. Sclerotherapy: a study comparing polidocanol in foam and liquid form. Phlebology. 2010;25: Gonzalez-Zeh R, Armisen R, Barahona S. Endovenous laser and echo-guided foam ablation in great saphenous vein reflux: one-year followup results. J Vasc Surg. 2008;48: Carradice D, Mazari FA, Mekako A, et al. Energy delivery during 810 nm endovenous laser ablation of varicose veins and post-procedural morbidity. Eur J Vasc Endovasc Surg. 2010;40: Gandhi A, Froghi F, Shepherd AC, et al. A study of patient satisfaction following endothermal ablation for varicose veins. Vasc Endovascular Surg. 2010;44: Zafarghandi MR, Akhlaghpour S, Mohammadi H, et al. 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: Shepherd AC, Gohel MS, Lim CS, et al. Pain following 980-nm endovenous laser ablation and segmental radiofrequency ablation for varicose veins: a prospective observational study. Vasc Endovascular Surg. 2010;44:

15 Mechano-Chemical Tumescentless Endovenous Ablation (MOCA TM ) of the GSV and SSV with the ClariVein Catheter Jean-Paul P.M. de Vries, MD, PhD Michel M.P.J. Reijnen, MD, PhD St.Antonius Hospital, Nieuwegein and Rijnstate Hospital, Arnhem, The Netherlands j.vries@antoniusziekenhuis.nl

16 Disclosures Consultant Le Maitre, Medtronic, Aptus Endovascular, and AngioCare

17 Trends in varicose treatment Sources: Millennium Research Group, Nov 2005 & MedTech Insight, Oct 7, 2005

18 Current endovenous techniques Catheter based -/- Need for tumescence (sedation) Heating / risk for thermal injury Per- and post-operative pain Hardware Energy source / generator

19 Mechano-Chemical Endovenous Ablation (MOCA TM ) Working mechanism Combination: Mechanical damage + Sclerotherapy Mechanic: rotating wire à intimal / cellular damage

20 Mechano-Chemical Endovenous Ablation (MOCA TM )

21 Mechano-Chemical Endovenous Ablation (MOCA TM ) Working mechanism Combination: Mechanic irritation + Sclerotherapy Mechanic: rotating wire à intimal/ cellular damage Sclerotherapy: penetrates cells + vessel wall à scar Obliteration

22 Mechano-Chemical Endovenous Ablation (MOCA TM ) Sclerosans is dispersed at end of the wire

23 Mechano-Chemical Endovenous Ablation (MOCA TM ) Working mechanism Combination: Mechanic irritation + Sclerotherapy Mechanic: rotating wire à intimal / cellular damage Sclerotherapy: penetrates cells + vessel wall à scar Obliteration MOCA TM isn t a form of foam sclerotherapy

24 Mechano-Chemical Endovenous Ablation (MOCA TM ) No tumescence Advantages No heating Quick procedure / comfortable for patient No hardware In-office procedure

25 MOCA TM : Access Technique Results Limitations Trials Conclusions Percutaneous ultrasound guided 18 gauge IV needle access 4 Fr. micropuncture sheath No further wires needed

26 MOCA TM : Clarivein Catheter Technique Results Limitations Trials Conclusions Small caliber (2.7 Fr) Soft, flexible Mechanical rotating tip wire included Angled tip, mimics Terumo wire

27 Clarivein Catheter Technique Results Limitations Trials Conclusions Flush device (lock the stopcock)

28 Clarivein Catheter Technique Results Limitations Trials Conclusions Working lengths: 45 and 65 cm

29 Motor unit Technique Results Limitations Trials Conclusions 3500 RPM

30 Connect motor unit & catheter Technique Results Limitations Trials Conclusions

31 Insert syringe with sclerosans Technique Results Limitations Trials Conclusions

32 Check position tip of the rotating wire Technique Results Limitations Trials Conclusions Don t bend the catheter

33 Tip device 0.5 cm below SFJ Technique Results Limitations Trials Conclusions

34 Start rotating first! Technique Results Limitations Trials Conclusions Patient supine position Start rotating to creat spasm Pull back device 1.0 cm Start injection sclerosans

35 Triple performance Technique Results Limitations Trials Conclusions Thumb: infuse sclerosans Index finger: power of the motor unit Both hands: pull back entire device (straight!)

36 Slowly pullback and inject Technique Results Limitations Trials Conclusions Pullback entire device 6-7 sec / 1 cm Inject sclerosans slowly during pullback Divide GSV into 2 3 segments before treatment Proximal 10 cm: 2% sclerosans Remaining GSV: 1.5% sclerosans

37 Resheath wire before taking out Technique Results Limitations Trials Conclusions White marker (5 cm left)

38 Post-treatment Technique Results Limitations Trials Conclusions Compression stockings first 24 hrs Compression stockings daytime 2 weeks Full activity

39 Results Courtesy Steve Elias, Mount Sinai and Englewood NJ Hospitals Technique Results Limitations Trials Conclusions 30 limbs (all GSV) C2 (24) C3 (2) C4 (4) Average age 55 years FU including duplex scan

40 Initital Results Courtesy Steve Elias, Mount Sinai and Englewood NJ Hospitals Technique Results Limitations Trials Conclusions Mean diameter GSVs: 8 mm (3 12) Mean length GSVs: 36 cm (20 45) GSV treatment time: 5 min (4 6) Treatment time: 14 min (11 17)

41 FU Results Courtesy Steve Elias, Mount Sinai and Englewood NJ Hospitals Technique Results Limitations Trials Conclusions Obliteration 1 month: 30/30 6 months: 29/30 12 months: 20/20 3 patients with ecchymoses (side branches?)

42 Results GSV St.Antonius Nieuwegein and Rijnstate Hospital series Technique Results Limitations Trials Conclusions Two different protocols: Safety study: Tip wire 2.5 cm below SFJ Entire GSV with 1.5% Registry study: Tip wire 0.5 cm below SFJ Proximal 10 cm with 2% Remaining GSV with 1.5%

43 Safety Study GSV St.Antonius Nieuwegein and Rijnstate Hospital series Technique Results Limitations Trials Conclusions 109 GSV s Median GSV diameter 7 mm (3 11) Median GSV length 41 cm (24 55) Median treatment time 16 min (13 21) Median VAS score 3 (1 8)

44 Safety Study GSV St.Antonius Nieuwegein and Rijnstate Hospital series Technique Results Limitations Trials Conclusions 6 wks duplex follow-up (all patients) 108/109 (99%) obliterated 6 patients (5%) open proximal segment (4 5 cm) GSV 1 patient (1%) not obliterated

45 Safety Study GSV St.Antonius Nieuwegein and Rijnstate Hospital series Technique Results Limitations Trials Conclusions 6 months duplex follow-up (n=42) 40/42 (95%) obliterated Patients with open proximal segment: no progression

46 Safety Study GSV St.Antonius Nieuwegein and Rijnstate Hospital series Technique Results Limitations Trials Conclusions No nerve injury No DVT No skin injury 28% small hematoma (tear of side branches) 17% local skin induration (side branch / access) 18% with discomfort > 1 week

47 Safety Study GSV St.Antonius Nieuwegein and Rijnstate Hospital series Technique Results Limitations Trials Conclusions Visual analogue scale for pain Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7

48 Registry Study GSV St.Antonius Nieuwegein and Rijnstate Hospital series Technique Results Limitations Trials Conclusions 113 GSV s 6 wks duplex follow-up: n=76 74/76 (97%) obliterated 4 patients (5%) with open proximal segment 2 not obliterated No major complications

49 SSV St.Antonius Nieuwegein and Rijnstate Hospital series Technique Results Limitations Trials Conclusions 37 SSV s 6 months duplex follow-up: n=27 26/27 (96%) obliterated No major complications

50 Pitfalls and limitations Technique Results Limitations Trials Conclusions Don t bend the wire during treatment: it might break Small veins (4 mm) à risk for obstruction device / perforation Increase pull back speed / lower RPM of motor unit Maximum dose of sclerosans (according to weight) Maximum diameter GSV = 12 mm Short-term follow-up

51 Trials and studies running Technique Results Limitations Trials Conclusions Animal studies (fine tuning technique) Dose finding Optimal pullback speed Bloodless (?) Histological analysis 2 years follow-up of safety and registry studies RCT comparing EVLT

52 MOCA TM : Conclusions Technique Results Limitations Trials Conclusions Fast and simple technique Very comfortable for patient (and physician) No tumescent, no heating In office procedure

53 MOCA TM : Conclusions Technique Results Limitations Trials Conclusions GSV: 6 wks 97% success (n=185) 6 mths 95% success (n=42) SSV: 6 mths 96% success (n=27) No major complications / no pain medication needed Longer-term data eagerly awaited

54 Mechano-Chemical Tumescentless Endovenous Ablation (MOCA TM ) of the GSV and SSV with the ClariVein Catheter Jean-Paul P.M. de Vries, MD, PhD Michel M.P.J. Reijnen, MD, PhD St.Antonius Hospital, Nieuwegein and Rijnstate Hospital, Arnhem, The Netherlands j.vries@antoniusziekenhuis.nl

55 MOCA TM : Conclusions GSV: 6 wks 97% success (n=185) 6 mths 95% success (n=42) SSV: 6 mths 96% success (n=27) Technique Results Limitations Trials Conclusions No major complications / no pain medication needed Longer-term data eagerly awaited

56 Start rotating first! Patient supine position Technique Results Limitations Trials Conclusions Start rotating to creat spasm Pull back device 1.0 cm Start injection sclerosans

57 Slowly pullback and inject Pullback entire device 6-7 sec / 1 cm Technique Results Limitations Trials Conclusions Inject sclerosans slowly during pullback Divide GSV into 2 3 segments before treatment Proximal 10 cm: 2% sclerosans Remaining GSV: 1.5% sclerosans

58 RICHARD L. MUELLER, MD, FACC, RVT, RPVI COSMETIC VEIN SOLUTIONS OF NY / SUTTON PLACE LASER VEIN + HAIR REMOVAL 401 EAST 55th STREET, NEW YORK, NY CLARIVEIN MECHANOCHEMICAL ABLATION ClariVein is an innovative, new, non thermal endovenous ablation technique. It is also known as MOCA (MechanOChemical Ablation) or Endomechanical Ablation. It is the first venous ablation technique to employ a dual-injury technique built into one catheter-based delivery device: endomechanical abrasion by the catheter s rotating wire tip (the mechanical component), and endovenous chemical ablation (EVCA) via instillation of sclerosant simultaneous to the spinning of the wire (the chemical component). ClariVein has numerous advantages over thermal endovenous ablation techniques, and over conventional endovenous chemical ablation, with a few potential disadvantages compared with thermal ablation. It is a solution to the main pitfalls of thermal ablation: need for tumescent anesthesia, risk of thermal injury, need for capital expenditure and maintenance of a complex energy source, and post procedural pain / phlebitis. ClariVein is an important emerging technique in endovenous therapy, and a welcome addition to the practitioner s toolbox. REGULATORY & DEVELOPMENT HISTORY ClariVein was developed around 2005 by Michael Tal, MD, a Yale University Interventional Radiologist, who describes getting the idea when confronted with a case of a patient with sciatic vein varices for whom he could not offer thermal ablation and in whom he was concerned about embolic complications from foam sclerotherapy. (1) In trying to find a solution, he thought of the washing machine analogy: hand washing and scrubbing will clean clothes fairly well, as will soaking in high concentrations of detergent, but a washing machine that combines mechanical agitation and detergent scrubbing, will clean clothes quickly and very well with a low concentration of detergent. Animal studies have not been published but were reportedly 100% effective. (2) Tal indicated in a slide presentation that in animal studies neither liquid sclerotherapy via the catheter, nor mechanical abrasion alone provided durable results, but the combination did. (1) Tal co-founded Vascular Insights, LLC (Madison, CT), which obtained 510(k) FDA clearance in May 2008 to market the ClariVein infusion catheter for the indication of infusion of physician-specified agents in the peripheral vasculature. This very broad and non specific indication does not specify an indication for vein closure, though it clearly does not preclude it. ClariVein obtained the CE mark in May 2010, allowing it to be marketed In Europe, with a specific indication as a vein occlusion catheter for the treatment of venous reflux disease. It is also approved in Canada. The pivotal first in man clinical trial was performed at Englewood Hospital, NJ by Steve Elias, MD, with results reported in 2009 and published in 2011 (3). Clinical use began in Europe and in the US in Currently, approximately 200 physicians are using the device in the US. Approximately 5,000

59 procedures have been performed to date (personal communication, John Marano, Vascular Insights, LLC). THE OCCLUSION / INFUSION CATHETER Figure 1. ClariVein assembled catheter and motor handle. Used by permission, Vascular Insights, LLC. The device (Figure 1) is composed of 2 sterile, single use components that are individually packaged and assembled at the treatment table: Cartridge Unit / Catheter catheter attached to a winged plastic cartridge that has a side port luer connection leading to the catheter lumen. The same lumen also contains the abrasion wire. A co-packaged 3 way stopcock is attached to the luer port, followed by attachment of the co-packaged 5 ml syringe used to flush with saline, then to be loaded with liquid sclerosant. Motor Unit / Handle - a plastic handpiece with an internal 9V battery that drives the motor, which has 4 speed settings (typically the maximum speed of 3500 rpm is used; this is the default speed; other speeds include 2,000, 2,500, & 3,000 rpm). The handpiece has a plastic clip for the syringe to be secured to, a motor trigger for the index finger to activate when the handle is gripped with one hand, while the thumb empties the syringe via its plunger.

60 Once the two units are assembled (after catheter positioning within the target vein), they cannot be disassembled. Since the catheter is steerable by its cartridge wing, it is important to position the catheter tip at the desired position within the target vein before attaching it to the motor unit. The catheter is very low profile and easy to handle; its outer diameter is 2.67 French, or 0.89 mm diameter (0.035 inches), the same diameter as a standard guidewire. It is currently available in 45 and 65 cm lengths, marked by cm increments; the rated length includes the 2 cm of extruded wire when it is unsheathed. The central lumen is both the infusion channel as well as the lumen containing the stainless steel abrasion wire (0.36 mm diameter, or inches). The wire can be in two positions: 1) sheathed, whereby only the the small ball at the tip of the wire extends distal to the catheter tip, or 2) unsheathed, whereby 2 cm of the wire extends distal to the catheter tip. When the wire is sheathed, as when it is introduced into and traverses the target vein, the most distal 1 cm of the catheter tip is bent/angled. When the wire is unsheathed, the distal 1 cm of the catheter tip is now straight, with 2 cm of extruded wire, of which the most distal 0.75 cm is angled. The center line of rotation of the wire tip is 6.5 mm diameter (0.258 inches), so for veins smaller than this diameter, the vessel wall is deformed and flexed by the rotating wire (Appendix A, movie 1). The small ball at the wire tip is designed to enhance echogenicity during ultrasound guided wire tip positioning. Wire unsheathing is accomplished by attaching the cartridge unit to the handle unit, pulling the cartridge wing into the handle and clicking to the first (distal to the trigger) lock position, then clicking the wing to the second (proximal) lock position. At this position, the wing is also pulled in slightly counterclockwise into position, while the syringe is clipped into its holder on the handle. When unsheathing, the wire tip remains stationary, while the catheter is pulled distally by 2 cm, exposing the angled wire tip. Resheathing is accomplished by pushing the cartridge wing out distally from second lock position back to the first lock position, after pushing out slightly clockwise. One important advantage of ClariVein is the catheter s steerability, due its bent tip and the cartridge wing. Moderately tortuous vein segments can be traversed, in contradistinction to catheters used for thermal ablation. Sclerosant longitudinal and radial delivery are ensured by the wire motion (Figure 2). The two assembled units are discarded at the end of the procedure, and cannot be resterilized or disassembled. OCCLUSION PROCEDURE Unlike thermal ablation, detergent sclerosant (liquid form) must be pre diluted prior to the procedure. Target vein access is similar to thermal ablation procedures: percutaneous and ultrasound guided at or distal to the most distal level of reflux in truncal or accessory veins. The only anesthesia needed for the procedure is a small amount of 1% lidocaine at the access site, intradermally or subcutaneously. Access is via a 4 or 5 F micro introducer placed over a guidewire, or via an 18 Gauge, 2 inch angiocath. A syringe is connected to the open end of the micro introducer or angiocath while preparing the ClariVein catheter. The catheter unit packaging is opened, the stopcock and 5 ml syringe is removed from packaging. The units should only be opened after it is certain that the procedure can proceed at each stage, due to the considerable cost of the disposable unit (close to $600 each). The stopcock is placed onto the luer lock and tightened; the sidearm must face laterally when attached. The company now makes available an optional one way check

61 valve luer adapter that be used as an alternative syringe interface. The catheter is flushed with saline (its internal volume is approx. 1 ml); sclerosant flush is not used as blood seeping into the catheter could thrombose the catheter when mixing with sclerosant. The stopcock is turned so that the closed position is facing the syringe (with a 30 degree tilt to ensure simultaneous closure of the side port), which is now replaced with a 5 ml sterile syringe containing liquid sclerosant (either sodium tetradecyl sulfate [STS] or polidocanol [POLI]). Any air bubbles in the syringe are carefully purged through the open side port, to avoid air embolism as well as inadvertent foaming of the sclerosant. The operator is careful not to allow any sclerosant into the catheter, which could thrombose if venous blood contacts sclerosant within the catheter prior to treatment. The catheter is packaged with the wire tip sheathed; the catheter is placed into the access device, without the need for any guidewire or exchanges. The angled catheter tip (while the wire is sheathed) along with the cartridge s wing allows for a high degree of steerability, making navigation of moderately tortuous veins possible, unlike with thermal ablation devices. Using ultrasound guidance, the catheter tip is placed at the desired location for the proximal ablation edge. It is important to visualize the ball at the end of the angled abrasion wire, as if it is not visualized, the wire tip may be significantly more proximally placed in the vessel than realized, risking DVT near the junctions (Figures 3 & 4). For Great Saphenous Vein (GSV) ablation, Vascular Insights advises placement of the wire tip 2 cm distal to the saphenofemoral junction (SFJ) or just distal to the inferior epigastric vein, whichever is more proximal. Other variations in proximal wire tip location exist: Dr. Steven Elias, who conducted the first in man clinical trial, advises wire tip placement 1 cm from the SFJ (personal communication), and Dr. Michel Reijnen and colleagues, who published the second clinical study, currently advocate placement 5 mm distal to the SFJ (4). For Small Saphenous Vein (SSV) ablation, Vascular Insights advises placement of the wire tip just distal to the fascial curve, within the initial portion of the straight segment of SSV within the saphenous sheath. If a gastrocnemius vein inserts into the SSV, wire tip should be placed 2 cm distal to that insertion. After placement at the desired location, the catheter cartridge is wedded to the handle unit, which is removed from its separate packaging. Prior to attachment, the trigger should be pulled briefly to test activate the battery; a small LED indicator on the handle turns green when the trigger is engaged. This test is important as once the catheter cartridge and the motor handle are attached, they cannot be disassembled. If the motor does not work after it has been wedded to the catheter, the catheter must be withdrawn from the leg and the entire combined unit must be discarded and replaced anew. The motor will not turn or become audible until the component are attached, which is achieved by sliding the cartridge wing into the slot groove in the handle unit. A click is felt at the first (distal to the trigger) stop position. This connects the two units irreversibly and engages the motor to the abrasion wire. The cartridge wing is then pulled back further into the handle groove. At the proximal end of the groove, the wing is turned slightly counterclockwise, clicking into the second (proximal) stop position. This step unsheathes the distal 2 cm of the angled abrasion wire. At the same time, the 5 ml syringe is snapped into the syringe clip and the unit has been fully assembled. Unsheathing of the wire is monitored by ultrasound to ensure wire tip position has not migrated and the vessel has not been perforated. The small echogenic ball at the tip of the wire as well as the angled distal 0.75 cm of the wire both enable visualization (Figures 5 & 6); again, the ball must be defined to avoid inadvertent proximal placement of the wire tip. A final ultrasound color Doppler (and

62 pulse wave [PW], if necessary) search for arteriovenous fistulae near the target vein should be made, though this should be sought at the diagnostic ultrasound forming the basis of the treatment plan. If an AVF is found near the target vein, the author advises aborting the procedure due to the risk of sclerosant movement into an artery, with risk of tissue loss or gangrene. Treatment can then commence: a right handed operator holds the handle with the right hand, and the catheter and access device hub near the skin with the left hand. The right index finger pulls the handle s motor trigger, while the right thumb delivers sclerosant by pressing on the syringe plunger. The stopcock is set to the off position at the open side port. The motor is activated, spinning the wire, which produces venospasm (Figures 7 & 8). For both GSV and SSV treatment involving the proximal portion of the vein, Vascular Insights advises 3 seconds of wire rotation and simultaneous pullback (for a distance of approx. 0.5 cm), to create venospasm at the proximal ablation edge, followed by continued spinning and pullback along with delivery of sclerosant. For more distal segments not near the junctions, or for accessory veins, wire rotation, pullback, and infusion can begin immediately without a period of mechanical treatment only. For the GSV, Dr. Elias rotates during pullback without injection for 1 cm (starting at 1 cm distal to the SFJ), then begins infusion at 2 cm distal to the SFJ. Dr. Reijnen et al start 0.5 cm distal to the SFJ, rotates without pullback for 3 seconds, then combines pullback, rotation, and infusion at approximately 1 cm distal to the SFJ (4). Wire rotation without pullback is technically difficult as the wire tends to snag on either the vein wall or a valve cusp, causing mild pain. Snagging requires that the motor be turned off, the wire resheathed by pushing the cartridge wing slightly clockwise, then toward the first (distal) lock position, the catheter gently tugged distally, the wire unsheathed, and treatment resumed. Alternatively, the resheathed wire can be pushed proximal to the point of snagging, the catheter rotated, then pulled distally, the wire unsheathed, and treatment resumed. Tissue is often noted to be adherent to the wire tip upon withdrawal, representing vein wall and or valve cusp avulsion. Such snagging is usually first detected by an audible change in the sound of the motor (more high pitched), patient pain, or resistance to pullback. Unless the wire snags, the patient typically feels nothing or usually a buzzing, scratching, or vibrating sensation in the leg that is not uncomfortable. Occasionally, mild pain is felt even in the absence of snagging. Manual compression is advised by the company over the length of treated vein whenever vein diameter is greater than 10 mm. It is noteworthy that given the 2 cm length of the abrasion wire distal to the tip of the catheter, the usual initial 0.5 cm pullback without injection, as well as the initial 1 ml of liquid delivered from the catheter being stored saline flush rather than sclerosant, the first several cm of vein is not treated by sclerosant, but solely by wire abrasion. Nonetheless, as with thermal ablation techniques, there is very frequently retrograde propagation of acute treatment related thrombus for several cm proximally. Wire tip positions are calculated with this net effect in mind. In the author s experience, it is not unusual to see the proximal ablation edge 1-3 cm proximal to the wire tip (3-5 cm proximal to the catheter tip). Furthermore, in terms of assessing the length of treated vein based on catheter length in the leg, treatment is stopped when 3-4 cm of catheter is left in the leg (see below). Given that target vein depths are typically 1-2 cm deep and access is angled, 2-3 cm of the 3-4 cm of catheter left in the leg are extravascular, leaving approximately 1 cm of catheter within the vein at the time of cessation of treatment. Treated vein length is the total catheter length minus catheter length measured outside the leg minus 2 cm of wire minus 4 cm of catheter in the leg when treatment is stopped.

63 The catheter is pulled back slowly (see next section for details on pullback rate), using gentle traction by the right hand pulling back while the left hand s index finger and thumb loosely secure the catheter at the access device s hub. A vibration is felt in the fingers holding the catheter, which undulates very slightly throughout its course. It is important to remember that the access device must be pulled back out of the vein and skin over the catheter well before the catheter and wire tips reach the tip of the access device (micro introducer sheaths are typically 9 cm long, angiocaths are inches long). If this is not done in timely fashion, the rotating wire will wind up treating the inside of the cannula and that vein segment will undoubtedly remain patent. The author prefers to pull the access cannula out of the leg and back over the free catheter prior to starting therapy, so as not to have to interrupt therapy later, and also to make pullback of the catheter easier with one hand. Alternatively, this can be performed when there is at least 12 cm of ClariVein catheter left in the leg. Treatment is monitored continuously by ultrasound, which reveals a whirling undulation of the abrasion wire appearing to be rotating at several cycles per second, far slower than the 3,500 rpm speed typically employed (Appendix A, movie 2). This is an optical illusion similar to the wagon train wheel explanation for why a movie of a rapidly spinning wheel seems to be occurring much slower and even in the opposite direction of rotation. Wire snagging, malfunction, or vessel perforation can be identified and the motor can be stopped if needed. If the wire is seen to approach a valve, wire rotation can be stopped, the wire can be pulled distal to the valve, and treatment resumed. If a tributary or perforator merits treatment, pullback can be slowed down while passing the ostium, in order to try to disperse sclerosant into these target branch veins. Sclerosant dispersal can be noted as an echogenic mobile haze within the undulating motion of the abrasion wire within the treated vein (Figure 9). A white mark is on the catheter 6 cm distal to the catheter tip (8 cm distal to the wire tip). This mark alerts the user to the limited catheter length remaining (the catheter s 1 cm black marks are not numbered) when the white mark is seen at skin level. When another 2 cm of catheter is pulled back, treatment is stopped (3 cm for a superficial vein, whereby there is a shorter length of subcutaneous, extravascular catheter between vein and skin). This limits sclerosant extravasation. Of note, pinkish liquid is often noted to be extruded at the skin near the end of treatment. This liquid is extravasated sclerosant mixed with blood pushed back distally by the vein spasm more proximally. The fact that no cases of skin ulceration or necrosis have been reported to date with ClariVein supports the recent realization that sclerosant extravasation itself is only rarely a cause of skin necrosis. If sclerosant volume is greater than 5 ml, treatment is interrupted to reload the syringe with more sclerosant. Since there is approximately 1 ml of sclerosant remaining in the catheter when the syringe is emptied, if treatment is nearly completed but sclerosant has run out, 1 ml of saline flush can be used for the final portion of treatment, which will deliver another 1 ml of sclerosant already in the catheter. When the motor trigger is disengaged and sclerosant infusion is stopped, ultrasound imaging of the vein is performed to assess the treated vein for closure. All modalities should be used, including gray scale assessment of vein compressibility and assurance of vessel spasm, as well as PW and color Doppler to assess for patency of the treated vein (Figures 10 & 11). This is performed before removing the catheter, as immediate retreatment without repeat access is possible. Often the vein is partially compressible, or becomes non compressible within several minutes of real time observation. Unlike thermal ablation, this partial compressibility is not a treatment failure. We have observed several cases where full non compressibility was not seen until the first follow up ultrasound 3-5

64 days after the procedure. In our experience, even there is partial compressibility of the vein, there is no flow by color or PW spectral Doppler interrogation. In contrast to thermal ablation, where immediate post treatment assessment of vein patency is hampered by tumescent anesthesia, there is no such imaging challenge with ClariVein. If the vein is found to be truly patent, immediate retreatment can be accomplished by passing the sheathed catheter tip proximally again, then retreating immediately. Flushing of sclerosant is not necessary in this case, as retreatment will be performed quickly. Maximal dose of sclerosant must be kept in mind, so retreatment of a large, long GSV may not be possible in all cases. If the vein is proven to be occluded, the wire tip is resheathed by unclipping the syringe, then slight clockwise twisting of the cartridge wing, then pushing the wing distally along the handle groove from second lock position back to the first. The wire is now protected from damage, and hence the vein near the access site. The catheter is now withdrawn from the skin. The wire should be unsheathed again in order to inspect it for tissue debris (innocuous) or damage to the wire or catheter. There have been no reports of wire breakage or retention within the body (Vascular Insights, personal communication). Manual pressure is applied at the access site. Unless a second vein segment is treated at the same treatment session, the entire ClariVein device is discarded and cannot be resterilized. Several minutes of foot dorsiflexion is performed by the patient. An immediate ultrasound is performed to assess for patency of the deep veins of the treated leg. We report the approximate length of treated vein as well as the volume, concentration, and type of sclerosant infused, along with sclerosant lot number and expiration date. The proximal and distal limits of the ablation zone and the location of the target vein are also reported. Actual volume of sclerosant delivered is total syringe volume administered minus approximately 1 ml remaining in the catheter when it is removed. In our practice, a simple dressing is placed at the access site, followed by application of thigh high class I compression stockings and immediate ambulation. Compression is continuous for 48 hours, then daytime only for the remainder of 2 weeks. All reasonable exercise is permitted beginning on the first postoperative day. Follow up ultrasound and clinical evaluations are within 3-5 days, one month, then every 3 months for the first year post procedure. Because currently the maximal length of the catheter is 65 cm, in some patients if a full length GSV ablation is planned, it may need to be performed with two separate access sites. The more tortuous segment should be treated first, as once the catheter and handle units are assembled, they cannot be disassembled. As the unattached catheter cartridge has maximal steerability, the more tortuous segment should be traversed with it before attachment to the handle and treatment of the two segments. In such a case, sclerosant within the catheter should be flushed out with saline after the first segment is treated, in order to prevent clotting within the catheter when it is placed within the second segment to be treated.

65 Figure 2. Cartoon demonstrating ClariVein catheter, abrasion wire, and wire rotation. Used by permission, Vascular Insights, LLC. Figure 3. Sheathed catheter, with angled tip and only the ball of the abrasion wire (see inplane in Figure 4) protruding from the catheter tip, within the GSV. Copyright 2012 Richard L. Mueller, MD, PC.

66 Figure 4. Sheathed catheter within the GSV (leftward arrow), with ball at tip of abrasion wire visible (downward arrow), placed just distal to a venous valve (upward arrow). Copyright 2012 Richard L. Mueller, MD, PC.

67 Figure 5. Image of unsheathed, angled abrasion wire protruding 2 cm from the tip of the ClariVein catheter (arrow) in the GSV, prior to wire rotation (same patient, different date). Copyright 2012 Richard L. Mueller, MD, PC. Figure 6. Unsheathed abrasion wire within GSV, with ball at wire tip better visualized and abutting the anterior vein wall. Copyright 2012 Richard L. Mueller, MD, PC.

68 Figure 7 & 8. Wire undulating in GSV during treatment. Vein spasm is evident. Copyright 2012 Richard L. Mueller, MD, PC.

69 Figure 9. Abrasion wire undulating during rotation in the GSV (up arrows), with the vein in spasm and sclerosant dispersion (heterogeneous appearance, including microbubbles [down arrow]) evident. Copyright 2012 Richard L. Mueller, MD, PC.

70 Figures 10 & 11. 2D and PW Doppler images of GSV immediately post procedure revealing no venous flow. In this case, the streaky gray scale hyperechogenicity is similar to thermal ablation, but there is often early hypoechogenicity. Copyright 2012 Richard L. Mueller, MD, PC. DOSING ISSUES (PULLBACK SPEED, SCLEROSANT DOSAGE & INFUSION RATE) & TECHNICAL DETAILS Pullback speed is constant for all vessels and all vessels sizes at 1.5 mm / second, or 6 7 (6.67) seconds per cm (3,4). We use a digital metronome to help time the pullback, with a backbeat set to chime every 7 seconds. Keep the catheter moving to avoid snagging of the wire, including when the wire is first activated for 3 seconds without rotation without injection. The catheter should never be bent at a tight or acute angle, or bent, in order to prevent kinking as well as wire damage/bending. Immediately after treatment, the patient should be asked or helped to perform several minutes of foot dorsiflexion in the treated leg in order to activate the calf muscle pump and flush sclerosant out of the deep system. The patient should be taken off the treatment table expeditiously in order to start walking for at least 10 minutes post procedure, as well as 10 minutes per hour for the remainder of the day, and minutes per day for 14 days. Standard post ablation compression should be employed, including continuous compression for the first 48 hours post treatment. For target veins where access is near tortuous segments or branching veins, if the micro introducer s guidewire consistently goes into the wrong channel, and another site cannot be tried, one can pass the short micro introducer cannula (or preferably, a much

71 shorter angiocath) into the wrong channel, then introduce the ClariVein catheter tip into the device, carefully pull it back under ultrasound control, and use the steerable tip of the ClariVein catheter to selectively enter the desired lumen as soon as the introducer is pulled back far enough. Other options include manual skin traction or pressure to help guide the wire, retrograde access, using an angled steerable (with torque device) Glidewire (Terumo Corporation, Tokyo, Japan), or straightening out the guidewires path with injection of saline via the catheter. Venospasm can be treated with injection of nitroglycerin 0.4 mg via the catheter. Traditional prepping of the entire leg and use of split drapes, as is done for thermal ablation where numerous tumescent anesthetic injections must be performed in sterile fashion, is redundant for ClariVein, whereby a single access skin puncture is the only site requiring sterile preparation. Liquid rather than foamed sclerosant is advised by the company, largely due to lack of FDA approval for foamed sclerosants, as well as excellent short term closure rates without resorting to foam, which has more side effects. Both the US and Dutch studies used liquid sclerosants (3,4). However, Dr. Karsten Hartmann of Germany has used 1% POLI foam in the proximal 5 cm of the GSV (3 ml volume), then 2% POLI liquid for the remainder of the vein in approximately 50 legs, with excellent results and no side effects (personal communication). A clinical trial is registered in the Netherlands comparing liquid POLI 2% and 3% as well as 1% foam (5). The company advises using STS 1.5% for GSV, 1% for SSV, and 2% POLI for GSV and SSV. The Elias pivotal study used STS 1.5% for GSV; other veins were not studied (3). The Dutch pivotal study used POLI 1.5% for GSV, and had a few cases of proximal GSV non closure, leading them to transition to using 2% POLI for the proximal third of the GSV (4). This is not surprising, as STS is 2-3 x more potent than POLI. An equivalent POLI concentration to STS is significant weaker sclerosant. Of note, unless one uses compounded drug, POLI is not available in the US at concentrations higher than 1%, nor is it FDA approved for vessels larger than reticular veins. Sclerosant dosage and infusion rate are obtained from a unique interactive MOCA dosing chart supplied by Vascular Insights, LLC. One inputs the vein treatment length, vein diameter, and patient weight into an Excel spreadsheet (Microsoft Corporation, Redmond, WA), and the spreadsheet calculates and displays sclerosant volume and infusion rate in ml/min. Weight only affects the maximal sclerosant volume and the infusion rate for GSV treatment with polidocanol. Rather than accessing this chart online and inputting values for each treatment when mixing sclerosant, we have created our own table of infusion rates and volumes for the GSV and SSV at various vein diameters and vein lengths for quick reference. I also converted the spreadsheet infusion rate of ml/min into the more practical ml/cm of catheter pullback, using the pullback rate for conversion. Linking infusion rates to catheter pullback unifies timing of the simultaneous tasks of the two hands during the procedure: catheter pullback and sclerosant infusion. The maximum volume of STS is given as 10 ml for the GSV and 4 ml for the SSV (8 10 ml for a large Giacomini / SSV vein complex is advised by the company), whereas the maximum volume of POLI is weight dependent of GSV and 4 ml for the SSV. Minimum volumes for small, short vein segments is 0.2 ml. An approximate rule of thumb is 1 ml of STS per mm diameter full GSV treatment. Of note, the dose of STS for the GSV in the Elias study was 12 ml for all patients by protocol, regardless of vein length, diameter, or patient size, with no significant complications. Regarding infusion rates, the smallest marked increments on the 5 ml syringe are 0.2 ml; infusion rates range from 0.04 to 0.38

72 ml/cm. Bilateral long truncal vein ablations are not advised, given the dose limitations of sclerosant. Foam sclerotherapy treatment of short segment recanalizations are advised, when clinically indicated (many recanalized segments do not reflux and may have no clinical relevance). Longer recanalized segments can be treated with thermal ablation. As noted, the company provides an optional one way luer duckbill checkvalve as an alternate interface to the 3 way stopcock between the catheter cartridges luer port and the sclerosant syringe. This checkvalve has less slippage but the author notes more resistance to flow. Smaller syringes than the standard 5 ml syringe can be used in order to provide more precise control and more even flow of sclerosant flow, by increasing infection pressure, if desired. However, the risk of venoarteriolar reflex mediated necrosis with higher injection pressures should be noted (6). Low resistance syringes such as reusable sterilized 5 ml glass syringes, or Epilor (BD, Franklin Lakes, NJ) 7 ml or similar disposable plastic LOR (loss of resistance) anesthesia syringes with special low resistance plungers can be used to provide smoother flow of sclerosant. Borosilicate glass syringe barrels have a very low coefficient of friction with their plungers and can be autoclaved. Typical disposable plastic syringes yield a stepwise infusion of sclerosant due to their high plunger resistance. However, this stepwise instillation has not compromised occlusion rates in the author s experience and in many ways makes the simultaneous infusion of sclerosant and catheter pullback easier. Rather than having two hands perform separate tasks at separate rates, the catheter pullback takes the lead, and a small aliquot of sclerosant can easily be injected after each cm of catheter pullback. Attention to meticulous ultrasound technique is essential, including pre procedure planning, as well as intra procedural guidance. In addition to standard ablation guidance steps of guiding access, catheter passage, and positioning, ultrasound is key to monitoring for any potential abrasion wire malfunction, snagging, or vessel perforation, as well as for identifying the occasional visible arteriovenous fistula in the region of the target vein. Unlike thermal ablation, where such an AVF would not likely worsen, ClariVein is contraindicated in the author s opinion, given the risk of backwash of sclerosant into the AVF, though one can reasonably argue that tissue ischemia and gangrene risk would be low given the pressure gradient the sclerosant would have to traverse. We have had one case where ClariVein treatment of the SSV was aborted in favor of EVLT, which proceeded uneventfully, when a small AVF was noted just prior to vessel treatment, connecting to the SSV at the location where the wire tip was positioned. While catheter assisted sclerotherapy using ultrasound guidance is considered by many to be the safest form of sclerotherapy due to the high confidence level of intravenous injection, rare catastrophic complications such as amputation related to injection near or into an AVF have been documented (7). This mandates meticulous attention to ultrasound assessment (including use of color Doppler and PW Doppler if needed) of any potential arteriovenous connections near the treated vein. Excessive injection pressure should be avoided, at least in the SSV, due to the potential for tissue ischemia or necrosis due to inciting veno-arteriolar reflex (6). The maximum treated vein diameter reported to date is 19 mm (8). The company advises manual ultrasound probe compression for veins larger than 10 mm diameter. The abrasion wire will still provide at least partial endothelial contact in veins larger than its centerline of rotation, due to drift and wobble of the wire caused by its rapid rotation. Manual compression will enhance circumferential wire endothelial contact. Larger veins can also theoretically be treated with application of tumescent anesthesia or saline prior to

73 treatment to enhance results. Extremely superficial veins, including those in patients with HIV lipodystrophy, may occasionally require tumescent anesthesia. If pain occurs in superficial veins, especially at the knee area, motor speed can be reduced to 3,000 rpm. We have not experienced any mechanical catheter/handle failures that have compromised any treatments. Though they are clearly theoretically possible, their potential for having to abort a case is far lower than with thermal ablation using complex energy generator sources. Given the disposable nature of the equipment, it seems the worst case scenario would involve replacing a catheter or handle intra procedure. We have encountered cases of detachment of handle and catheter after they have been locked into the second position, but this has not compromised procedural success. We have also had cases of a very high pitched, screaming noise emanating from the catheter, with shuddering of the wire on ultrasound, and eventual loss of motor function. However, the procedure was successful and necessitated only exchange of the handle, which detached from the catheter due to loss of washer function at their interface. One strategy is to stop the motor, resheathe the wire, then unsheathe again to try to stabilize the washer function and eliminate the vibration. Even if this fails to correct the problem, treatment can continue. We have had a case where the target SSV was nearly adjacent to a large gastrocnemius vein as well as the popliteal vein. Because of the 6.5 mm diameter or rotation of the wire tip, visible stretching of the smaller GSV was noted on ultrasound, along with deformation of the anterior wall of the gastrocnemius vein, then the popliteal vein. No thrombus was detected in either deep vein post procedure. In our experience, the minimal length of target vein appropriate for ClariVein is approximately 6 cm, somewhat longer than the minimum 3-4 cm segment that can be treated with EVLA spot welding. This minimum vein length is modeled based on the wire occupying 2 cm of vein length, approximately 1 cm of catheter left in the vein at time of termination of motor and pullback, and a minimal length of 3 cm of treated vein occupied by catheter. This presumes immediate instillation of sclerosant, so in such a case of a short target vein, the author advises slow instillation of 1 ml of sclerosant (to displace the 1 ml of saline stored in the catheter) prior to activation of the wire, followed by standard protocol. We have successfully treated vein diameters as small as 2 mm. While one advantage of ClariVein is lack of need for tumescent anesthesia, it may be employed for the rare patient with marked pain sensitivity with wire rotation, which we have seen once in a patient with GSV so superficial it was a visible skin bulge. For those familiar with thermal ablation techniques, the learning curve for ClariVein is short, as most steps are similar. The hardest part of the ClariVein learning curve is the manual and multitasking challenge of a simultaneous catheter pullback, motor activation, and sclerosant injection, with differential speeds of pullback and infusion. ADVANTAGES / DISADVANTAGES OF CLARIVEIN VS. THERMAL ABLATION Advantages of ClariVein over Thermal Ablation include: Minimal to no pain during the procedure Minimal to no pain after the procedure Minimal to no bruising after the procedure

74 No need for tumescent anesthesia No risk of direct heat injury to nearby nerves, skin, arteries, or deep veins Can therefore be advantageous in anatomic areas with higher risk of nerve, skin, or artery / vein damage (calf, popliteal fossa, SSV near gastrocnemius veins or arterial branches, very superficial veins, sciatic vein) Can be used in moderately tortuous veins (steerable catheter) No risk of creating arteriovenous fistula No risk of sheared off / retained laser fiber or catheter Often can simultaneously treat one or more side branches / varicose veins, due to collateral trickling of sclerosant into side branches / varicose veins Avoids the incremental side effects of Foam Sclerosants (uses liquid sclerosant) Faster procedure (14 minutes in Elias clinical trial, 9 minutes for the ablation portion) Disposable technology, not dependent on energy generator; No maintenance, QC checks, or equipment downtime; No large capital expenditure Minimal risk of having to abort a procedure (disposable equipment, without energy generator) No need for guidewires, dilator, or catheter exchanges No obscuration of ultrasound vascular structures by tumescent anesthesia Less extensive prep required (single skin puncture, no tumescent anesthesia) Minimal utilization of lidocaine in an era of lidocaine shortages Advantages of ClariVein over Chemical Ablation (EVCA) include: Significantly higher truncal vein occlusion rates (approximately 75% for foam sclerosants [55-80% after 1-3 years of follow up (9); 77% long term in a meta-analysis (10); 77% at 3 years in another meta-analysis [11]], with generally accepted higher side effect profile than for liquid sclerosant. Long term (6 months 10 years, typically 1 year) occlusion rates are only approximately 40% for liquid sclerosants [10]) Disadvantages of ClariVein compared with Thermal Ablation include: No long term (beyond 2 years) date regarding durability of closure, or peer review published data beyond 6 months of follow up Risks inherent in the sclerosant used

75 Cannot be used for retreatment of ClariVein recanalization or in veins with prior Superficial Venous Thrombosis (wire can snag on synechiae) Contraindications of ClariVein : All standard contraindications of the detergent sclerosant used Severe vein tortuosity precluding passage of the catheter Vein too small to cannulate Acute thromboembolic disease Deep venous occlusion PUBLISHED CLINICAL STUDIES The two pivotal studies published to date, as well as updated follow up, as noted by personal communication with the investigators as well as based on their presentations at venous symposia: Elias S & Raines J. Mechanochemical tumescentless endovenous ablation: final results of the initial clinical trial. Phlebology 2012;27:67-72 (published online 07/29/11) (3) 30 limbs treated at one center (Englewood Hospital, NJ), mean VCSS (venous clinical severity score) 4.5, CEAP class 2-4 (80% class 2). GSV treated only, all with 12 ml of 1.5% STS, vein diameters mm. Wire tip was 2 cm distal to the saphenofemoral junction (SFJ), with stationary rotation for 2-3 seconds, followed by 1-2 mm/sec pullback and injection, 1 day of compression bandage, and 12 days of compression stockings. 97% total occlusion of the treated vein segments was noted at 6 mo. (mean follow up 260 days). This compares very favorably to occlusion rates after EVLA (94% at 3 years [11] in one meta-analysis; 96% at mid term follow up in another [12]), and are superior numerically to occlusion rates after RF ablation (84% at 3 years [11]). The only recanalized vein was in the initial patient (occurring between the 1 week and 1 month follow up), without reflux; this patient was later retreated with RF ablation (personal communication, Dr. S. Elias). Mean total procedure time 14 minutes, 9 minutes ablation time, 5 minutes active treatment mode. No pain during the procedure in any patient. 3 ecchymoses, no other side effects; no major/dangerous side effects. Any vein occluded at 1 month remained occluded throughout follow up. Follow up since then: At 1 year: 100% occlusion (22/22) (8) At 2 years: 96% occlusion (personal communication, Dr. S. Elias; to be presented at Society for Vascular Surgery Annual Meeting, June 2012, National Harbor, MD)

76 Van Eekeren R, Boersma D, Elias S, et al. Endovenous mechanochemical ablation of great saphenous vein incompetence using the ClariVein device: A safety study. J Endovasc Ther 2011;18: (4) Pilot safety study at 2 centers (Rijnstate & St. Antonius Hospitals; Dutch study #1): Initial technical success was 100% in 30 limbs GSV (4-12 mm diameter; mean 6 mm near the SFJ). CEAP 2-4 patients (72% CEAP 2). Liquid polidocanol 1.5% was used; mean dosage was 6.8 ml, and was based on vein diameter (1 ml / mm). Wire tip was 2 cm distal to the SFJ, with stationary rotation for a few seconds, followed by infusion and pullback rate of 2 mm/sec. Average procedure duration was 20 minutes; compression was used for 24 hours continuously, then daytime for remainder of 2 weeks. There were no major adverse events; 30% had mild ecchymoses at entry site, and 13% had phlebitis. At 6 week followup: 87% complete occlusion occurred, and 97% partial + complete occlusion. 1 patient had complete recanalization (and was successfully retreated); 3 had > 4 cm length partial recanalization (2 in the proximal and 1 in the distal GSV). 88% patient satisfaction was recorded, in addition to significant improvement in VCSS (3.0 to 1.0), even in those with partial recanalization. Pain was 2-9 / 100 analog scale within the first week. Efficacy / Pivotal study (Dutch study #2 [13]): 97 patients, including GSV, SSV, and accessory GSV. 100% initial occlusion. 6 wk follow up = 97 % occlusion (3 patients had > 4 cm length partial recanalized proximal GSV segments). There were no major adverse events; 27% had minor hematoma, 22% had induration, and 13% had pain for > 1 week. Registry study (Dutch study #3 [14]): 100 GSV limbs 6 week follow up = 94% occlusion (2 open GSV, 2 proximal recanalizations) 6 month follow up = 91% occlusion (1 open GSV, 1 proximal recanalization) 6% hematoma, 6% induration; no major complications The Elias and Dutch study #1 are the only 2 English language published series regarding ClariVein. THE AUTHOR S EXPERIENCE Over 20 vessels treated between December 2011 and March 2012, including GSV, SSV, Giacomini Vein, GSV accessory Vein, as well as several Klippel Trenaunay Veins in one patient. One patient had treatment of his entire SSV as well as a thigh extension leading to a very long Giacomini vein that spanned the entire thigh. Several patients have had target several vessels treated, each at a separate session. 4 patients have been treated while on anticoagulation, with 3 on warfarin with target INR One patient on uninterrupted Pradaxa. We have treated veins as small as 2 mm diameter. 100% short term total occlusion of all treated segments has been noted, with no nerve damage, hyperpigmentation, induration, or palpable cord. No partial or complete recanalization has occurred, nor any immediate treatment failures.

77 One patient with one week of moderate pain near the access site, most likely due to difficult access / multiple needle passes. One patient with GSV treatment developed an ipsilateral immediate SSV SVT. This has persisted at 7 week follow up. An accessory GSV SVVT was noted 11 days post procedure, and persisted 5 weeks later. Both were attributed to passage of sclerosant into intersaphenous and tributary veins, which at times is advantageous (see below) and at times is deleterious, depending on whether the downstream vein is normal or refluxing. An ipsilateral intramuscular calf sinusoid focal DVT was noted 18 days post procedure, and resolved 13 days later without sequelae. Mild pain was present with each of these thrombotic events. The patient had a history of spontaneous DVT in the past, as well as placement of an IVC filter, and was non compliant with advice to remain on warfarin periprocedurally for an EVLA performed prior to ClariVein. He was persistently subtherapeutic on renewed warfarin thereafter, and non compliant with therapeutic dose enoxaparin prescribed at time of ClariVein, as well as with INR monitoring. He remains minimally symptomatic after 7 weeks. One patient with GSV treatment developed ipsilateral distal calf GSV SVT, distal to the treated segment, without symptoms, which resolved on aspirin 5 weeks later. He then was found to have an ipsilateral SSV SVT 3 days after treatment of the other GSV, persistent after 4 weeks. He was found to have a mildly reduced plasminogen level, but the hematology consultant recommended no future prophylaxis for venous treatments. Interestingly, he developed an immediate ipsilateral accessory SSV SVT at subsequent calf phlebectomy, though it is quite possible the SSV was manipulated at time of vein resection. Two patients with wire tip placed just distal to the fascial curve of the SSV had proximal propagation of acute thrombus flush with the Popliteal Vein; one has had no change after one month of follow up, while the other s proximal ablation edge receded more distally; neither progressed to DVT. One patient had two episodes of chest pain and dyspnea after treatment, within several weeks. While endothelin mediated side effects could not be completely excluded, the episodes were deemed more likely due to anxiety based on their temporal occurrence. One patient reported moderate pain during the procedure and requested tumescent anesthesia when the contralateral leg was treated, with excellent result. He has HIV medication induced lipodystrophy and is very thin, with extremely superficial GSV s on the skin surface. No cord or hyperpigmentation occurred. One patient had a planned ClariVein procedure cancelled due to failed access and resultant thrombosed SSV. The following week access was obtained, but the procedure was cancelled again when a small, previously unidentified AV fistula was found connecting to the SSV at the wire tip location. The patient returned soon after for successful EVLA of this vessel. One patient was noted to have a faint arterialized signal in the retracted proximal calf GSV vein wall / lumen. No true AV fistula was detected. Arterialized flow in the vein wall has been noted after EVLA. One patient with two large GSV accessory tributaries (both refluxing and additional ablation targets) had closure of both tributaries noted 3 days after GSV occlusion. Patients previously treated with EVLA who then are treated with ClariVein uniformly request ClariVein in the future if needed.

78 SUMMARY It is evident that ClariVein is an exciting incremental addition to the phlebologist s toolbox, with enormous potential to be a first line treatment. It addresses several of the deficiencies of thermal ablation. Given the very high procedural success of thermal ablation, next generation game changing technologies of venous ablation and treatment of chronic reflux disease will center not around higher efficacy rates, but on reducing side effects and enhancing procedural ease. Additional studies, including randomized clinical trials, dose ranging, and pathologic mechanistic studies, are needed, along with longer periods of follow up to ensure the durability of results and lack of an unacceptable morbidity rate when a large number of patient-years of follow up are monitored. As with all new ablation technologies, the main barrier to more extensive use is the lack of long term occlusion and clinical outcomes data. However, in the author s opinion, the evidence of vein wall retraction documented by ultrasound over time (3) as well as a very high occlusion rate at 2 years makes the likelihood of a high rate of late recanalization unlikely. As with all therapies, careful patient selection and informed explanation of therapeutic options to patients is paramount. ClariVein fills several therapeutic gaps, boosting its role in the treatment of several clinical scenarios. REFERENCES (1) tal+clarivein+answer+to+all+problems?&hl=en&gl=us&pid=bl&srcid=adgeeshrq0sg 2sYfuRJ5kNHnH- LxhsXdnyh4KQyDk5dpaVtmtz6sjgT0kTGh8CyLRuCcNtjKKWk2DwwtXI12GfW6RQxE Hu4twccylaNXOHFJzbvyZsbWTceDHmTZCqyJJ4MkPqe59YQj&sig=AHIEtbR0x8ZH_s JuW3dM_ZUdwODYit2JVA accessed 3/2/12. (2) accessed 3/2/12. (3) Elias S & Raines J. Mechanochemical tumescentless endovenous ablation: final results of the initial clinical trial. Phlebology 2012;27:67-72 (published online 07/29/11). (4) van Eekeren R, Boersma E, Elias S, et al. Endovenous Mechanochemical Ablation of Great Saphenous Vein Incompetence Using the ClariVein Device: A Safety Study. J Endovasc Ther 2011;18: (5) The ClariVein device using liquid Polidocanol and foam for the treatment of great saphenous vein incompetence : A dose finding study. Netherlands Trial Register # NTR accessed 1/13/12. (6) Tran D & Parsi K. Veno-arteriolar reflex vasospasm of small saphenous artery complicating sclerotherapy of the small saphenous vein. Aust NZ J Phleb 2007;10:29-32.

79 (7) Grommes J, Franzen EL, Binnebosel M, et al. Inadvertent arterial injection using catheter-assisted sclerotherapy resulting in amputation. Dermatol Surg 2010;36:1-3. (8) Elias S. Mechanochemical endovenous ablation: final results of first clinical trial. Presented at American College of Phlebology Annual Meeting, November (9) Rabe E & Pannier F. Sclerotherapy of varicose veins with polidocanol based on the guidelines of the German Society of Phlebology. Dermatol Surg 2010;36: (10) Hamel-Desnos C & Allaert FA. Liquid versus foam sclerotherapy. Phlebology 2009;24: (11) Van Den Bos RR, Arends L, Kockaert M, et al. Endovenous therapies of lower extremities: A meta-analysis. J Vasc Surg 2009;49: (12) Van Den Bos RR, Kockaert MA, Neumann HAM, et al. Technical review of endovenous laser therapy for varicose veins. Eur J Vasc Endovasc Surg 2008; 35: (13) Reijnen MM & de Vries JP. Safety and feasibility of mechano-chemical ablation of varicose veins: Initial results. accessed 12/27/11. (14) Reijnen MM & de Vries JP. Mechano-chemical ablation of varicose veins: Initial results presented at ESVS meeting, Athens accessed 12/27/11.

80 Steve Elias MD FACS FACPh Director, Division Vascular Surgery Vein Programs Columbia University NY Englewood Hospital NJ Assistant Professor of Surgery Columbia University

81

82 Combination endovenous mechanical and sclerotherapy Endovenous wire > rotates > intima damage Sclerosant liquid > penetrates > scar End result venous occlusion

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84

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86 RF/Laser MOCA A - Access P - Position E Exsanguinate T Treat APET A Access simpler P Position - same E - No Tumescence T Treat faster APT

87 Percutaneous ultrasound guided 4 fr. micropunture sheath 18 gauge IV access No further wires or larger sheath exchange

88

89

90 Pullback 1.o 1.5 mm. per second Inject during pullback Sodium tetradecyl sulfate 1.5% (or equivalent sclerosant see Europeans) Injection rate determined by vein length (12cc of 1.5% STD)

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97 Compression X 48hrs Compression 2 weeks Full activity (exercise, lifting etc.)

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100 30 limbs GSV only C2 24 C3 2 C4 4 Avg. 55 years Treat GSV only (no treatment VV or IPV) 6 month follow up to complete trial No tumescence or sedation

101 GSV size 8.1 mm. GSV length treated 36 cm. GSV treatment time 5 min. Overall treatment time - 14 min

102 All GSV closed except 1 st patient competent 1 month 30 3 month 29/30 6 month 29/30 12 month 27/27

103 Subcutaneous ecchymoses 3 pts. Side branch tear? No DVT No nerve injury No skin injury

104 Polidocanol 30 GSV in 25 patients M:F = 7:18 GSV diameter 6.1 ±2.1 mm GSV length 40.0±6.6 cm Treatment time 20±4.8 min Van Eekeren et al. Mechano-chemical endovenous ablation of great saphenous vein incompetence using the ClariVein TM device: a safety study. J Endovasc Ther, in press.

105 No nerve injury No DVT No skin injury No neurological or vision disturbances 9 (30%) minor haematoma 4 (13%) induration Van Eekeren et al. Mechano-chemical endovenous ablation of great saphenous vein incompetence using the ClariVein TM device: a safety study. J Endovasc Ther, in press.

106 Results: safety study Rijnstate, Arnhem and St.Antonius, Nieuwegein series 10 8 Visual analogue scale for pain Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Van Eekeren et al. Mechano-chemical endovenous ablation of great saphenous vein incompetence using the ClariVein TM device: a safety study. J Endovasc Ther, in press.

107 6 weeks follow- up (n = 30) 29/30 (97%) obliterated 1 recanalisation 3 patients proximal open segment (>4 cm) GSV Technical succes 87% Fine tuning of technique VCSS: 3.0 (IQR ) to 1.0 (IQR ) Improvement also in group with open proximal segment Van Eekeren et al. Mechano-chemical endovenous ablation of great saphenous vein incompetence using the ClariVein TM device: a safety study. J Endovasc Ther, in press.

108 224 GSV s C2 (13%) C3 (67%) C4 (20%) Median GSV diameter 7 mm (3 11) Median GSV length 41 cm (24 55) Median treatment time 16 min (13 22) Median VAS pain score 3 (1 8)

109 6 wks duplex follow- up (185 patients) 182/185 (98%) obliterated 10 patients (6%) open proximal segment (4 5 cm) GSV

110 6 months duplex follow- up (n=42) 40/42 (95%) obliterated Patients with open proximal segment: no progression

111 No major complications (DVT, nerve injury, PE, skin injury) 28% small hematoma (tear of side branches) 17% local skin induration (side branch / access) 18% with discomfort > 1 week

112 37 SSV s 6 months duplex follow- up: n=27 26/27 (96%) obliterated No major complications

113 Minimal risk nerve, skin, DVT, discomfort Fast and simple less steps Treat lower (ankle, calf, SSV) or residual GSV Some branch VV/ IPV treated at same time No tumescence or sedation No thermal injury risk No energy source - generator

114 Recanalized post thrombotic GSV/SSV Large veins > 12 mm. not in trial (19mm since) Anticoagulated pts. 6 done all closed 3 mos. Adjunctive phlebectomy do this first after access

115 Volume determined by vein diameter Using lower volumes now SSV 3-4 cc of 1.5 STD Lower strength of STD (1%) 12 pts. at 3 mos GSV - position 1 cm from SFJ rotate 1 cm then infuse SSV - position 1 cm below fascial curve rotate 1 cm then infuse Perforators 1 cc of 1.5% STD

116 Another very good option Simpler Faster Capital cost less Tumescentless already there - everyone else is trying - Cyanoacrylate/Varisolve Foam rescue small segments recanalize Most GSV or SSV

117 The use of Clarivein for patients with lower extremity chronic venous disease: An observational multicenter study and short term results Muath Bishawi, Angela Kokkosis, Mathew Fakhoury, Antonios P Gasparis SUNY at Stony Brook, Department of Surgery, Division of Vascular Surgery Background Methods Results Results There are several endovenous This was an observational multicenter Vessel Vessel P There were 419 patients,70%females, methods to ablate incompetent study on the immediate efficacy of Closed Open value with a mean age of 60±14 years. GSV superficial veins in the lower extremity Clarivein in selected patients with n = 406 n = 13 was treated in the vast majority of the all of which require tumescent lower extremity CVD. Demographic Age 60 ± ± patients (86.2%), followed by SSV anesthesia. This study was designed information, clinical and procedural Vessel Length 36 ± ± (8.4%). The median diameter for vein to evaluate the short term results of mechanic-pharmacological ablation data were collected prospectively on a standardized form that was distributed Vessel Diameter SFJ 7 ± 3 7 ± treated was 7 mm. The injected volume ranged from 1ml to 13ml with (Clarivein) of superficial veins of the to all centers. The distribution and Total Case Time 22 ± ± a mean of 7.3±3ml. Sotradecol was lower extremities without tumescent extent of venous reflux was used in 91% of patients, and anesthesia in patients with chronic venous disease (CVD). Methods ClariVein is a percutaneous, 2 2/3 documented with duplex ultrasound and the closure rate of the treated veins was determined with the same method. Results Treatment Volume 7 ± 3 9 ± Female % 70% 76% Side Treated (right side) 51% 46% Polidocanol in 9%. In the patients treated with Sotradecol,77% received a concentration of 1.5%, and 19% received a concentration of 1.0%.In the patients treated with Polidicanol, Vessel Treated Fr (0.035") infusion catheter that 3% concentration was used. contains a rotating wire driven by a GSV 86% 100% Short term follow up (2-7 days) was motor activated from a DC battery- SSV 9% 0% done to acquire occlusion rate. Out of powered handle. The system provides Other 5% 0% 419 patients with follow up data, 406 even, controlled irrigation of a (97%) were occluded. Occlusion rate treatment site for a physician-specified was 97.4% for GSV, and 100% for procedure with a physician-specified SSV. therapeutic fluid. Discussion/Conclusion Mechanic-pharmacological treatment of the superficial veins has the advantage of endovenous ablation without tumescent anesthesia, making it a pain-free procedure. High occlusion rates can be achieved using this device in the short-term. Studies to look at longer-term efficacy for this technique are warranted. TEMPLATE DESIGN

118 16th European Vascular Course March 11-13, 2012 Maastricht, The Netherlands RICK V. BERNSTEIN M.D. FACS & SIRAN DILOVYAN RDMS ADVANCED VEIN TREATMENT CENTER HENDERSON, NEVADA, USA

119 DEFIANT VENOUS ULCERS Ø SOME ULCERS AND SOME PATIENTS (MULTIFACTORIAL) DEFY MANY CURRENT TREATMENTS AND REFUSE TO HEAL Ø MY PATIENTS WANT THE MISERABLE LIFE OF VENOUS ULCERS TO END-PREFERABLY WITH THEM HAVING TO DO AS LITTLE AS POSSIBLE!!!!!!

120 Ø Ø Ø Ø Ø Ø Ø Ø Ø Ø VARIOUS TYPES OF TREATMENT FOR VENOUS STASIS ULCERS OF THE LOWER EXTREMITY ANTI-BIOTICS DRESSINGS LEG ELEVATION COMPRESSION UNNA BOOTS INJECTION SCLERO THERAPY WOUND CARE CLINICS EVLT VNUS CLOSURE FAST VNUS RFS ALL HAVE PROPONENTS AND LIMITATIONS

121 CLARIVEIN IN MY PRACTICE MECHANICO-CHEMICAL (CLARIVEIN) TREATMENT FOR DEFIANT ULCER HAS GREAT MERIT: Ø Ø Ø Ø Ø NON-THERMAL VEIN ABLATION SYSTEM NO TUMESCENT ANESTHESIA MINISCULE PAIN NONE/MINIMAL BRUISING NO RISK OF NERVE INJURY Ø Ø Ø Excellent results by combining mechanical agitation and proven chemical sclerosants High patient comfort level and acceptance with zero staining observed Removes the need for catheter / guide wire exchanges, therefore reducing costs and steps

122 CLARIVEIN Ø The patented ClariVein system combines two unique methods of action: Ø 1. Mechanical injury of the vessel endothelium (inside of the vein) by a rotating catheter tip (3500RPM). Ø 2. A sclerosant chemical sprayed from the tip of the catheter as it is withdrawn to ensure maximum effect.

123 CLARIVEIN CLARIVEIN SPECIFICALLY CAN ALLOW TREATMENT OF INCOMPETENT TRUNCAL AND PERFORATOR VEINS INCLUDING THOSE DIRECTLY UNDER AND WITHIN ACTIVE ULCERS, WHOSE SIZE AND LOCATION MAY MAKE USING TUMESCENT ANESTHESIA UNWISE OR INAPPROPRIATE.

124 STERILE SETUP FOR CLARIVEIN

125 CLARIVEIN PATIENT

126 LOWER EXTREMITY VENOUS ULCERS

127 ULCER CASE 1 Ø 70 YEAR OLD MALE Ø OCCUPATION: MACHINE OPERATOR Ø SYMPTOMS: Ø LOWER EXTREMITY PAIN, BURNING, SWELLING, HEAVINESS, TIREDNESS Ø LEFT LOWER EXTREMITY ULCER PRESENT FOR AT LEAST 2 YEARS ; CONSTANT CARE(2 YEARS) FROM WOUND CARE CLINICS WITH NO RESOLUTION, BUT A MISERABLE LIFESYLE

128 DX. OF LEFT LOWER EXTREMITY ULTRASOUND Ø LEFT LOWER EXTREMITY Ø NEGATIVE DVT Ø POSITIVE FOR PATHOLOGIC REFLUX: PATHOLOGIC REFLUX IN AASV(DOMINANT) WITH THIGH & CALF PERFORATOR W/PATHOLOGIC REFLUX AND VARICOSE VEINS Ø POSITIVE FOR PATHOLOGIC REFLUX : SSV WITH PERFORATOR

129 ULCER BEFORE CLARIVEIN

130 ULTRASOUND POST OPS 2 DAY POST OP: NEGATIVE DVT AASV OCCLUDED FROM PROXIMAL-DISTAL CALF W/OCCLUDED MID CALF PERFORATOR AND OCCLUDED VARICOSE VEINS AT THE SITE OF ULCER

131 ULCER AFTER CLARIVEIN 10 WEEK POST 6 WEEK POST

132 ULCER 12 WEEKS AFTER CLARIVEIN BEFORE AFTER

133 ULCER CASE 2 Ø 51 YEAR OLD MALE ON DISABILITY DUE TO DEFIANT VENOUS ULCER Ø SYMPTOMS: Ø LOWER EXTREMITY PAIN, BURNING, SWELLING, HEAVINESS, TIREDNESS Ø RIGHT LOWER EXTREMITY ULCER HAS HAD 2 PRIOR EVLT ABLATIONS OF THE GSV ABOVE THE KNEE

134 DX. OF BILATERAL LOWER EXTREMITY ULTRASOUND Ø RIGHT LOWER EXTREMITY Ø NEGATIVE DVT Ø POSITIVE FOR PATHOLOGIC REFLUX: RIGHT GSV FROM DISTAL THIGH- DISTAL CALF W/DISTAL CALF PERFORATOR AND ANTERIOR VARICOSE VEINS VARYING IN SIZE FROM 4-6MM Ø ULCER EXTENDS FROM MID CALF- ANKLE WITH POSTERIOR CALF EXTENSION, THEREFORE MAKING IT DIFFICULT TO DIFFERENTIATE BETWEEN SSV AND VARICOSITIES WITH ULTRASOUND

135 ULCER BEFORE CLARIVEIN

136 CLARIVEIN IN ACTION

137

138 CLARIVEIN IN ACTION Clarivein Cath Tip Clarivein Catheter Tip

139 ULTRASOUND POST OPS 2 DAY POST OP: NEGATIVE DVT GSV OCCLUDED FROM PROXIMAL CALF-DISTAL CALF ALONG W/MID CALF PERF 2 WEEK POST OP: SAME RESULTS AS 2 DAY POST OP WITH AN ADDITIONAL OCCLUDED DISTAL CALF PERF 1 MONTH POST OP: SAME RESULTS AS 2 WEEK POST OP ALSO ULTRASOUND GUIDED FOAM SCLERO DONE: 4CC OF 1.5% POLIDOCONAL INJECTED INTO MEDIAL DISTAL CALF AND POSTERIOR CALF VARICOSE VEIN 2 MONTH POST OP: NEGATIVE DVT, GSV AND PERFORATORS REMAIN OCCLUDED ALONG WITH OCCLUDED MEDIAL AND POSTERIOR CALF VARICOSE VEINS

140 ULTRASOUND POST OPS 2 MONTH POST OP ULTRASOUND OF RIGHT GSV: Compression image proving occluded GSV

141 9 WEEK POST ULCER AFTER CLARIVEIN POSTERIOR CALF EXTENSION

142 BEFORE AFTER 16 WEEKS AFTER CLARIVEIN

143 IN CONCLUSION. Clarivein treatment for lower extremity venous ulcers should be included in the complete phlebologist s armamentarium particulary if the ulcer has causative incompetent vein etiology (truncal and/or perforator), especially if there are contraindications to tumescent anesthesia and to avoid nerve injury.

144 Treatment of Venous Ulcers Using ClariVein Pictures provided by Dr. Sendhil Subramanian Georgia Vascular InsAtute Jonesboro, GA Treatment dates July 2011 through December 2011

145 8 Year Ulcer PaAent Pre Procedure

146 1 Month Post Procedure

147 2 Months Post Procedure

148 2 Year Ulcer PaAent Pre Procedure

149 1 Month Post Procedure

150 1 Year Ulcer PaAent

151 10 Month Post Procedure

152 Treating Varicose Veins In the NHS setting, we are only able to treat patients who meet these criteria therefore, we are treating the more severe cases. To use the Clinical/Aetiological/Anatomical/Pathophysiological classification all of our patients undergoing intervention have C4 disease at least. Treatment Options Those patients who don t meet the Primary Care Trust criteria for intervention are treated conservatively with compression hosiery. Those who do meet the criteria have venous duplex ultrasound scans according to the findings, are offered either endovenous laser treatment or ClariVein treatment. ClariVein Treatment An endovenous mechanochemical treatment invented by Dr Michael Tal in the US. Its use has been pioneered by Professor Steve Elias at Columbia, he is speaking next door. The wire is inserted via a 4-5 Fr micropuncture access system; it rotates within the vein lumen at 3500 rpm, causing abrasion of the intima. The mechanical component affords greater efficacy to the sclerosant, which is infused simultaneously through an opening at the distal end of the catheter, as it is mixed within the target vein and onto the vessel wall. The sclerosant we use is sodium tetradecyl sulphate. I ve got a diagram of the device on the next slide. Diagram Slide This slide shows the ClariVein device with a cartoon representation of its mechanism of action. It is a single- use device. Local anaesthetic is only used at the site of insertion and tumescent anaesthesia is not required. Our patients have not described any pain during the procedure most describe the sensation as being akin to an electric toothbrush on the inside of the leg. The Veins Our series thus far consists of 78 patients, almost 2 thirds are women. The treated veins have largely been great saphenous veins. The majority of veins have been cannulated below the knee. All of the patients in this series have been treated by the same surgeon. Mean Values Here are some data pertaining to the vein characteristics themselves.

153 I ve split the data into 2 groups; those treated with 1.5% STD and those treated with 1.0%. It s important to bear in mind that this study is an audit, not a trial. When we started using this technique, we used 1.5% STD, as developed by Dr Tal and Prof Elias. Subsequently, the manufacturers asked us to use 1.0% STD once we noticed that there was a smaller percentage of complete occlusions, we immediately changed back to the 1.5% solution. Results Our patients have post- procedure scans at 3, 6 and 12 months. The first thing to notice, as I alluded to earlier, is that the results with 1.5% STD are superior to those with 1.0%. We ve noted that in all but 1 case, if complete occlusion was observed at the initial duplex ultrasound, recanalisation was not subsequently observed. All of the scans are performed by the same sonographer, who is blinded to the concentration of the sclerosant. Conclusions Our audit shows that the ClariVein technique is safe and effective in treating superficial venous incompetence. Our results from Lewisham are comparable to those achieved by our colleagues in New York and the Netherlands. The initial results for this method are broadly comparable to those for EVLT at the same stage.

154 ClariVein : A Novel Treatment for Varicose Veins Kate Stenson University Hospital Lewisham, London, UK 16 September 2011

155 Treating Varicose Veins Very strict guidelines from Primary Care Trusts. Funding in place to treat varicose veins causing: o Ulcers. o Bleeding. o Recurrent thrombophlebitis. o Severe skin changes. CEAP classification all patients have C4 veins at least.

156 Treatment Options Conservative measures. Sclerotherapy. Open techniques: o Ligation & stripping. Endovascular techniques: o Endovenous laser treatment (EVLT). o Radiofrequency ablation. o VNUS.

157 ClariVein Treatment Endovascular technique. Developed & pioneered in the USA. Methods of action: 1. Mechanical agitation of the endothelium. 2. Instillation of a sclerosant.

158

159 The Veins 78 patients: o 30 male o 48 female Anatomy: o 65 GSV 2 recurrent o 11 SSV o 2 ASV Cannulation site: o 50 below-knee 11 SSV 39 GSV o 28 above-knee 2 ASV 26 GSV

160 Mean Values 1.0% STD 1.5% STD Overall Age (years) Length of treated segment (cm) SFJ diameter (mm) Mid- vein diameter (mm) Volume of STD used (ml)

161 Results 3- month scan 6- month scan 1.5% STD (n=50) 46 complete occlusions (92.00%) 27 complete occlusions (96.43%) 4 partial occlusions (8.00%) 1 partial occlusion (3.57%) 1.0% STD (n=28) 22 complete occlusions (78.57%) 13 complete occlusions (68.52%) 6 partial occlusions (21.43%) 6 partial occlusions (31.58%)

162 Conclusions A safe and effective technique. Early results are broadly equivalent to: o Those of our colleagues in the US and the Netherlands. o Early results for EVLT. For more information, plus a video of the ClariVein technique in action, visit

163 EMBARGOED RELEASE, JUNE 8, 2012, 8:00 AM Contact: Sue Crosson-Knutson, Initial Human Trial Results for Mechanochemical Ablation Catheter Revealed Catheter was efficacious at two year without the need of turmescent anesthesia WASHINGTON D.C. In its first human trial, the mechanochemical ablation (MOCA) catheter was efficacious at two years as current endothermal techniques, but without the need of tumescent anesthesia. In addition, MOCA was more effective than results of foam sclerotherapy of the great saphenous vein (GSV) and is another alternative modality for most incompetent GSV s and small saphenous veins (SSV s). Detailed results were presented today at the 66 th Vascular Annual Meeting presented by the Society for Vascular Surgery. According to author Steve Elias MD, FACS, FACPh, Director of the Division of Vascular Surgery Vein Programs of Columbia University NY, MOCA utilizes a liquid sclerosant (sodium tetradecyl sulfate or aethoxysclerol) and a mechanical rotating wire to accomplish occlusion of incompetent GSV or SSV. The procedure is performed with local anesthesia at the access site only. It can be characterized as mechanically enhanced sclerotherapy performed in an office setting. Thirty GSV s in 29 patients underwent micropuncture access with local anesthesia only. Through a 5 Fr.(1.7mm) micropuncture sheath the MOCA catheter was passed to a position 2 cm from the saphenofemoral junction. Catheter wire rotation was begun for three seconds at 3500 rpm. With the wire rotating, infusion of sclerosant (1.5 percent sodium tetradecyl sulfate) and catheter pullback (1.5 mm/sec) was begun simultaneously. A total of 12 cc of sclerosant was used for each GSV. At one year 29 of 30 GSV were successfully treated. Primary closure rate 96.7 percent. At two years 24 patients were examined and all 24 remain closed. No deep venous thrombosis, nerve or skin injury occurred. Average total procedure time was 14 minutes and catheter treatment time was five minutes. The MOCA technique has been modified as the technique has evolved; lower volumes are now used based on diameter and length of vein treated. Catheter placement is begun closer to the saphenofemoral junction (1 cm.), wire rotation starts and sclerosant is infused 2 cm from the SFJ. # # #

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