Pathogenesis and etiology of recurrent varicose veins

Transcription

1 Pathogenesis and etiology of recurrent varicose veins Maresa Brake, MBBS, BSc, Chung S. Lim, MRCS, PhD, Amanda C. Shepherd, MRCS, MD, Joseph Shalhoub, MRCS, PhD, and Alun H. Davies, DM, FRCS, London, United Kingdom Background: Recurrent varicose veins (RVV) occur in 13% to 65% of patients following treatment, and remain a debilitating and costly problem. RVV were initially thought largely to be due to inadequate intervention, however, more recently neovascularization and other factors have been implicated. This review aims to provide an overview of the current understanding of the etiology and pathogenesis of RVV. Methods: A systematic search of the PubMed database was performed using the search terms including recurrent, varicose veins, and neovascularization. Results: Three types of RVV have been reported, namely residual veins, true RVV, and new varicose veins, although the definitions varied between studies. RVV are attributable to causes including inadequate treatment, disease progression, and neovascularization. Using duplex ultrasonography, neovascularization has been observed in 25% to 94% of RVV. These new vessels appear in various size, number, and tortuosity, and they reconnect previously treated diseased veins to the lower limb venous circulation. Histologically, these vessels appear primitive with incomplete vein wall formation, decreased elastic component, and lack of valves and accompanying nerves. Although the rate of RVV following open surgery and endovenous treatment appears similar, neovascularization seems less common following endothermal ablation. Other causes of RVV following endovenous treatment include recanalization and opening of collaterals. Conclusions: Recurrence remains poorly understood following treatment of varicose veins. Neovascularization is an established and common cause of RVV, although other factors may contribute. (J Vasc Surg 2013;57:860-8.) Open surgery remains the most common varicose vein intervention at present in the United Kingdom; approximately 24,000 operations are carried out annually. 1,2 Minimally invasive treatments including endovenous thermal ablation and ultrasound-guided foam sclerotherapy (UGFS) are becoming increasingly popular. 3 Despite advances in, and increased availability of, pre- and perioperative investigation such as duplex ultrasonography, recurrence rates following varicose veins treatment remain relatively high. 4 Recurrent varicose veins (RVV) have been reported to occur in 7% to 65% of patients following treatment 5-8 and remain a common, debilitating, complex, and costly problem. 9,10 Treatment for RVV is technically more difficult to perform 6 and patient satisfaction is poorer than after primary interventions. 11 Despite their frequent occurrence, the etiology and pathogenesis of RVV remain incompletely understood. RVV were initially thought to be largely due to inadequate surgery especially when procedures were often performed by junior surgeons, leaving remnants of diseased great From the Academic Section of Vascular Surgery, Department of Surgery and Cancer, Charing Cross Hospital, Imperial College London. Author conflict of interest: none. Reprint requests: Alun H. Davies, DM, FRCS, Academic Section of Vascular Surgery, Department of Surgery and Cancer, Charing Cross Hospital, Imperial College London, 4 East, Fulham Palace Road, London W6 8RF, UK ( a.h.davies@imperial.ac.uk). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest /$36.00 Copyright Ó 2013 by the Society for Vascular Surgery. saphenous vein (GSV) or tributaries that enlarged with time, or the development of varicosities in collateral veins. 12 More recently, other factors including neovascularization have been shown to contribute to RVV following surgery. 13,14 Furthermore, the factors leading to the development of RVV following endovenous ablation and sclerotherapy may be different from those after open surgery. The aim of this review was to provide an overview of the current understanding and ongoing debate regarding the etiology and pathogenesis of RVV. METHODS A systematic literature search of the PubMed database was performed for articles about the etiology and pathogenesis of RVV (Fig 1). Appropriate search terms were employed, including recurrent, varicose veins, and neovascularization. Only articles written in English were included. Results from animal studies were excluded. The search was expanded by scrutinizing the references of articles identified for further relevant papers. DEFINITIONS AND CLASSIFICATION OF RVV The definitions of RVV may vary. Three types of RVV have been described. 10 First, residual varicose veins are those which were already present in operated sites at 1-month follow-up, left as a result of tactical or technical error. Second are true RVV, which are absent at 1-month follow-up but subsequently appear either as a result of neovascularization or as a result of tactical or technical error. Third are new varicose veins, which were not present at 1-month follow-up but develop later in untreated areas due to disease progression. 860

2 Volume 57, Number 3 Brake et al 861 Number of articles identified by search strategy n=1439 Potentially relevant articles identified for title screening n=882 Potentially relevant articles identified for abstract screening n =89 Potentially relevant articles retrieved for more detailed evaluation n =46 Articles identified for inclusion in review n =26 Articles excluded Non-English n =496 Animal studies n =43 Duplicates n =18 Articles excluded based on title screen n =793 Articles excluded based on abstract screen n =43 Articles added from reference lists of articles reviewed n =5 Articles excluded No discussion of aetiology or pathogenesis of recurrent varicose veins n =25 Fig 1. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) diagram. RVV can also be classified into radiologic and clinical; importantly, radiologic recurrence does not necessarily translate into clinical recurrence. For example, in a prospective study of UGFS in the treatment of GSV reflux in 203 legs (146 patients), the 5-year clinical recurrence was reported to be 4%, whereas duplex ultrasound recurrence was 64%. 15 Certain positive ultrasound findings suggest an increased risk of development of clinical RVV and reoperation in future. In one study, patients with audible reflux in the groin on a hand-held Doppler 1 year after open surgery were found to have an increased risk of clinical recurrence after 2 years. 8 An international consensus meeting held on recurrent varices after surgery (REVAS) in Paris in 1998 agreed to adopt a clinical definition: the existence of varicose veins in a lower limb previously operated on for varicosities, with or without adjuvant therapies, which includes true recurrences, residual veins and new varices, as a result of disease progression The four major causes of RVV following treatment are shown in the Table. 10 Using the REVAS criteria, following open surgery RVV have been reported at rates ranging from 6.6% to 37% after 2 years and up to 51% after 5 years. 14 Most patients with RVV were symptomatic, with various clinical presentations. Most had uncomplicated varicose veins and swelling (70.9%), but the remainder had skin changes (29.1%). 18 There were multiple sources of reflux feeding the recurrence, though incompetence at the saphenofemoral junction (SFJ) was present in almost half of the patients. Ten percent had no apparent source of reflux; in 17%, it was of pelvic or abdominal origin. About 75% of legs had incompetent perforator veins. 18 Neovascularization (20%) was as frequent as technical failure (19%) and tactical error (10%), and a combined Table. Four major sources of recurrence following varicose vein surgery (adapted from Kostas et al, 2004) Causes Tactical error Technical error Disease progression Neovascularization Explanation The persistence of venous reflux in a saphenous trunk resulting from erroneous or inadequate preoperative evaluation and inappropriate surgery The persistence of venous reflux due to inadequate or incomplete surgical technique As a result of the natural history and evolution of the disease The presence of reflux in previously ligated saphenofemoral junctions cause by development of thin incompetent serpentine veins linked with a thigh varicosity presentation was found in 17%. In 35% of cases, the cause of reflux was uncertain. 18 When recurrence occurred at a different site, development of reflux in new sites was found in 32% of legs. 18 ETIOLOGY OF RVV Tactical and technical error RVV caused by tactical and technical error are attributable to inappropriate or inadequate treatment, respectively. Tactical and technical errors were historically reported to be the major cause of RVV, contributing up to 80% of recurrences although this is likely to be untrue and outdated. 6,19-24

3 862 Brake et al March 2013 Tactical error may arise from failure to identify the source of reflux or all the incompetent veins requiring treatment. 25 Expansion of collateral veins may also contribute to recurrent junctional incompetence ,26 The increasing use of duplex ultrasonography pre- and perioperatively during open surgery, endothermal ablation, and UGFS is likely to reduce the rate of tactical errors. 25 The risk of RVV may increase if the GSV is not stripped at all, or inadequately, although this remains controversial. 5 In a randomized trial of 100 patients (133 legs) who underwent SFJ ligation with or without GSV stripping, Jones et al demonstrated a clinical recurrence rate at 2 years of 43% after surgical ligation alone and 25% after ligation and stripping, although 89% of the patients remained satisfied. 5 Reoperation was required for 20 of 69 legs that underwent ligation only, compared with 7 of 64 legs that had additional GSV stripping (P ¼.012). 5 In endovenous treatment, ablation of the GSV to the ankle opposed to above-the-knee, appears to produce more favorable clinical results, with greater improvement in quality of life, and reduced recurrence. 27 However, treating below-knee GSV may also increase the rate of complications including paresthesia. 28 Therefore, further studies are needed to determine which patients will benefit from full length treatment of the GSV. In contrast to the above, there is recently some evidence to support that selective treatment of key points of venous reflux, and preservation of the saphenous vein may have a role to improve the efficacy of therapy and reduce risk of RVV. Examples of such treatment include the CHIVA (cure conservatrice et hémodynamique de l insuffisance veineuse en ambulatiore or ambulatory conservative hemodynamic management) and ASVAL (ablation sélective des varices sous anesthésie locale or ambulatory selective varicose vein ablation under local anesthesia of varicose veins) techniques. 14 In the CHIVA technique, following careful duplex mapping, the clinicians perform flush ligations at key points of venous reflux to decrease the hydrostatic pressure and preserve the superficial venous drainage in the saphenous veins and tributaries. There is some evidence from prospective studies including randomized trials that the CHIVA technique is efficacious with comparable, if not lower, rate of RVV Meanwhile, the ASVAL technique involves the treatment of the refluxing epifascial veins while preserving the saphenous vein in patients whom the clinicians judge that the reflux would progress in the anterograde fashion. 33 A retrospective study by Pittaluga and colleagues has reported good outcomes in patients with relatively less severe primary varicose veins. 33 At present, both techniques should only be carried out on selective patients by trained specialists. 14 Further larger randomized controlled trials are needed to confirm the efficacy and safety of these techniques. Inexperienced surgeons. Although there is no doubt inexperienced surgeons are more prone to tactical or technical errors, and therefore increased risk of RVV, the claim that this is the main cause of RVV has been disputed. Kostas 10 cited inadequate surgery as the least common etiology of recurrence (11%). A retrospective clinical follow-up study from Sweden 34 examined 100 legs from 89 patients who had primary SFJ ligation and stripping of the GSV, and re-examined them after 6 to 10 years with duplex imaging and varicography in some cases. There was no significant difference in the recurrence rates related to the surgeon s experience: surgical resident (52%), general surgeon (54%), and vascular surgeon (65%). Recanalization and collateralization. Endovenous ablation treatment and sclerotherapy cause obliteration of the refluxing axial veins through thermal (laser or radiofrequency) energy or chemical irritation. A major cause of RVV following endovenous ablation and sclerotherapy is recanalization of the diseased veins. Although recanalization is often reported as an outcome following endovenous treatment, studies have suggested that it does not necessarily result in clinical recurrence or symptomatic reflux. 28,35 The degree of damage to the vein wall required for long-term occlusion is also unknown. Recanalization can be reduced by improving the technical aspects of treatment. For example, delivering at least 70 joules per cm of laser energy to the vein wall reduces recanalization rates following thermal ablation with short wavelength laser (810 and 980 nm). 36 Similarly, in endovenous radiofrequency ablation, adequate pullback speed to ensure proper thermal dose delivery during the procedure has been shown to reduce the rates of recanalization of saphenous veins. 28 Recanalization is related to a number of factors, including the vein diameter in addition to the energy delivered. Similarly, in sclerotherapy, several technical factors including the use of foam rather than liquid sclerotherapy, and injecting a higher volume of foam in larger veins may reduce the rate of RVV. Disease progression This type of recurrence is attributable to the evolution or persistence of varicosities derived from incompetence in a remote or second saphenous system; usually the small saphenous vein (SSV) is affected following previous surgery to the GSV. 37 The affected veins are clinically not varicose at the time of treatment but later become refluxing as a result of the natural history of the disease. It is well known that primary varicose veins progress both in severity and distribution over time. 38,39 Disease progression is reported to account for 20% to 25% of recurrences Neovascularization Neovascularization refers to new blood vessel formation, which can occur in an abnormal tissue or position. 18 These new vessels arise in the granulation tissue along the track of previously stripped or ligated veins. 18,26 They form between the common femoral vein, the residual GSV stump, or its tributaries, and reconnect the incompetent veins to the superficial venous circulation of the leg. 26 These new blood vessels are found relatively frequently, even after correct functional ligation. Neovascularization has been reported to account for 8% to 60% of RVV 10,18,40-43 and is the most common cause of recurrence, together with the

4 Volume 57, Number 3 Brake et al 863 Fig 2. The factors involved in the pathogenesis of true recurrence of varicose veins. The postulated factors contributing to true varicose vein recurrence may broadly be divided into two groups: intraoperative factors (A) and postoperative factors (B). CFV, Common femoral vein; GSV, great saphenous vein; SFJ, saphenofemoral junction. development of varicose veins attributable to disease progression in many studies. 5,9,10,24,44,45 RVV secondary to neovascularization seem to be more common after open surgery than endovenous treatment or sclerotherapy. It contributed to 18% of the recurrences following open surgery compared with only 1% to 1.5% following endovenous treatment; yet, the overall rate of RVV was similar after both treatments after 2-year follow-up. 13,46 In a prospective 5-year study of radiofrequency ablation for GSV reflux, neovascularization was not detected in the follow-up. Endothermal ablation techniques seldom result in hematoma or spillage of endothelial cells as part of the procedure, which may be the origin of neovascularization. 47 Physiological and pathologic neovascularization. Neovascularization is thought to be pathologic angiogenesis. 48 Angiogenesis is the sprouting and expansion of new blood vessels from existing vessels. Various mediators are involved, including growth factors, matrix metalloproteinases and their tissue inhibitors, hypoxia-inducible factors, and angiopoietin. 49 Important growth factors that have been implicated in neovascularization include vascular endothelial growth factor, basic fibroblast growth factors, and platelet-derived growth factor. 49 Several factors including hypoxia, mechanical stress, and inflammation are known to stimulate angiogenesis, 49 which may be both physiological and pathologic. The mechanisms responsible for neovascularization in RVV remain unclear. It is thought that neovascularization first develops months or even years after the initial operation. 50 It may be induced by diffusible angiogenic factors 18 released from the surrounding tissues. Physical factors that have been implicated include the type of suture material used to ligate the GSV stump, exposure to free stump endothelium, 51 hemodynamic effects, 52 operative trauma, and thrombosis 53 (Fig 2). Several hypotheses have been postulated to explain the development of neovascularization following varicose vein surgery. First, neovascularization may be a physiological response to venous disconnection. Second, it may be a manifestation of the effect of altered venous hemodynamics in a system of susceptible veins. 24 Third, neovascularization may be part of the normal sequence of wound healing, originating from hypoxiainduced activation of endothelial cells distal to the stump ligature leading to the release of angiogenic factors. 54 Fourth, the track of the previously stripped vein may recanalize and endothelialize. Neovascularization may be associated with hematoma formation following the initial surgery, but this has not yet been assessed. 55 Imaging neovascularization. On venography and duplex ultrasonography, neovascularization appears as a complex network of tortuous vessels (Fig 3) reconnecting the proximal or distal cut ends of the GSV or one of its tributaries to the femoral vein. 24 The appearance is different from residual varicose veins (or non-varicose), 8 and neovascular veins are observed after 25% to 94% of RVV. 5,9,10,12,13,39,45,56 Duplex ultrasonography and venography are limited by their inability to differentiate true neovascularization from the dilatation of existing collateral veins as they appear similar. 8,40,42,57 New veins seen on clinical imaging may represent adaptive dilation of pre-existing venous channels in response to abnormal hemodynamic forces, rather than true neovascularization. 57 Histology and resin casting. The morphology of neovascularization has been studied using resin casts and histologic analysis including immunohistochemistry. In

5 864 Brake et al March 2013 Fig 3. Neovascularization (blue and red) around a previously ligated saphenofemoral junction of a patient with recurrent varicosities on color duplex ultrasonography. the 1980s, Glass conducted an early histologic study that found continuity of a ligated vein was restored by growth of new vessels in the surrounding tissue and vein wall. 18 Resin casts clearly illustrate the tortuosity and extent of the neovascularization as well as the variation in size of the veins (Fig 4). 41 The direction of the neovascularization channels from the stump is always outwards toward the subcutaneous tissue. 54 Some of these new vessels reconnect with the main venous tributaries and establish channels of sufficient caliber to become clinical recurrences. 54 Histologically, neovascular vessels appear primitive and immature, with incomplete vein wall formation, no valves, and a lack of clearly define tunica intima, media, and adventitia. The vessel wall appears asymmetrical and thinner than normal vein. Most of these vessels are either composed of squamous endothelium only or lined by few layers of vascular smooth muscle cells. No intimal thickening is observed and the vein wall lacks elastic fibers. In 80% no capillaries or vasa vasorum are detected in the vascular wall. Scar tissue is often seen around the vessel. 58 Blood vessels generally contain nerve fibrils, which express S100 protein, particularly S100A1 and S100B. Neovascularization in RVV is characterized by an incomplete vessel wall lacking intramural nerves on S100 staining, a feature similar to the immature neovessels seen in granulation tissue and tumor. 42 One study identified histologic evidence of neovascularization in 94% of RVV, all of which stained negative for S Other markers that have been used to identify neovascularization include Mib1, a monoclonal antibody that recognizes proliferating cells by binding to Ki Although many of the features observed in histologic studies support neovascularization as an important cause of RVV, other studies have disputed this. Using immunohistochemistry, El Wajeh et al found S100 positive nerve fibrils in the majority of dilated vascular channels from both their patients having redo varicose vein surgery and control groups. 57 They found little evidence of neovascularization Fig 4. Resin casts of recurrent refluxing saphenofemoral junction specimens. Following injection of resin from the saphenofemoral junction, a tortuous network of vessels is visualized. There is a variation in size and abundance of vessels when comparing both specimens (A and B). The direction of the neovascularization channels was noted to be outward from the stump toward the subcutaneous tissue. A, Several larger channels are accompanied by many much smaller channels running in a proximal to distal direction. B, This cast is dominated by three large-diameter tortuous channels, with a number of small channels present in continuity. Scale bars: (A) 5 mm; (B) 10 mm. (This image has been reproduced with permission from the Journal of Vascular Surgery.) 41 associated with RVV and concluded that the venous channels that develop at the previously ligated SFJ may represent an adaptive dilatation of pre-existing venous channels and vascular remodelling, in response to abnormal hemodynamic forces. 45 COMPARISON OF RVV BETWEEN TREATMENT MODALITIES A meta-analysis of endovenous treatments for varicose veins found that endovenous laser ablation demonstrated significantly better occlusion rate, although this may not necessarily translate into clinical recurrences, than stripping, UGFS, and radiofrequency ablation. 60 The 5-year vein occlusion rate for endovenous laser ablation (EVLA) was 95.4% compared with 79.9% with the original radiofrequency ablation (RFA) catheters, however, the latest radiofrequency devices deliver a higher energy and medium- and long-term outcome data for these new devices is awaited. 61 Stripping and UGFS have reported 5-year success rates of 75.7% and 73.5%, respectively. 60 The long-term results of all forms of treatment may depend on the rates of neovascularization. 13,60 However, despite apparent reductions in neovascularization and excellent occlusion rates,

6 Volume 57, Number 3 Brake et al 865 randomized clinical trials comparing EVLA and stripping have failed to show a significant advantage of laser at 2 years in terms of recurrence and quality of life outcomes. 25,62 Clinical trials comparing stripping and RFA have shown advantages in quality of life for RFA at 2 years. 46 Clinical studies comparing UGFS with surgery and thermal ablation suggest that foam sclerotherapy is less effective than surgery 60,63 and EVLA, 60 although longterm evidence from randomized controlled trials is scarce. The VEDICO trial (Foam-Sclerotherapy, Surgery, Sclerotherapy, and Combined Treatment for Varicose Veins: A 10-Year, Prospective, Randomized, Controlled, Trial) showed that low dose sclerotherapy was less effective than high dose; results were worse with highly diluted or undiluted 3% sclerosant compared with a 1.5% concentration. 63 Rates of RVV after 5 years were 44% for UGFS, rising to 56% after 10 years. Whereas short-term data after new endothermal techniques are plentiful, 56 long-term outcome data concerning recurrence and quality of life are currently awaited. A number of appropriately powered studies will report results in the next few years. 25,64,65 DISCUSSION There have been a number of recent advances in the treatment of varicose veins, including the increasing use of duplex ultrasonography, treatment by specialists, and new endovenous therapies. Yet, the recurrence rates after treatment remain a challenge, at least partly because of a lack of understanding of the pathogenesis and etiology of RVV. The definition of RVV often varies in studies. In some, residual veins are included as RVV whereas others consider them not strictly RVV. Understanding the mechanisms of recurrence is essential for the development of preventative and therapeutic strategies. SFJ reflux is caused by incompetence of one or more of the axial veins or tributaries arising from it. Therefore, during treatment of varicose veins, regardless of technique, all tributaries of the SFJ or proximal GSV with demonstrated reflux require obliteration to prevent recurrence. Most patients (85%) with SFJ incompetence only have GSV reflux. 66 Traditional teaching suggests all tributaries or axial veins arising from the SFJ should be ligated at open surgery, despite the lack of evidence that this reduces recurrence and neovascularization. Endovenous thermal ablation techniques obliterate axial vein reflux but do not specifically interrupt the proximal SFJ tributaries. Theivacumar and colleagues assessed 81 legs (70 patients) 12 months after EVLA of the GSV and found that none of the legs showed SFJ reflux, although one or more patent tributaries were visible in 48 (59%) patients. The authors concluded that persistent nonrefluxing GSV tributaries at the SFJ did not appear to have an adverse effect on clinical outcome 1 year after successful EVLA of the GSV. 66 However, in another study, several cases of new reflux in the anterior accessory vein were found 2 years after EVLA. 25 The observation time in randomized trials comparing RVV after endovenous treatment vs surgery is still relatively short, therefore, no firm conclusion can be drawn regarding differences in RVV and neovascularization. Meanwhile, the treatment of the competent GSV in patients with an isolated refluxing anterior accessory great saphenous vein (AAGSV), which may occur in 10% of patients with SFJ reflux, is also unclear. Theivacumar and colleagues studied 30 patients who underwent AAGSV laser ablation alone and 33 age/sex-matched controls undergoing GSV laser ablation. The authors concluded that GSV-sparing laser ablation of the AAGSV abolishes SFJ reflux associated with isolated SFJ/AAGSV reflux and improves symptom scores and patient satisfaction to a similar extent as GSV laser ablation, with no evidence of new GSV reflux or recurrent varicosities at 1-year follow-up. 67 Because of lack of long-term data, the optimal treatment of AAGSV remains unclear. Some clinicians advocate for primary ablation of the AAGSV even if it is competent at the initial treatment because of potentially relatively high incidence of late reflux in this vein. 25 However, some clinicians have suggested avoiding ablation of this vein at the initial operation 66,68 because it can be treated at a later stage should it become incompetent, resulting in the development of RVV. 25 Neovascularization is accepted by most vascular surgeons as an established cause of RVV, especially following open surgery. Despite this, several problems remain including the lack of a unifying definition which makes assessment and reporting difficult. It is difficult to be confident that all the neovascularization described in the literature was true neovascularization, which may explain some of the conflicting results reported by various studies. For example, one study considered all veins joining the GSV stump or junctional area as missed tributaries, 40 whereas other studies considered stump tributaries as substantial as 3 mm in diameter to be consistent with neovascularization. Another problem is that few studies have correlated imaging findings to histologic evidence, thereby making the interpretation of neovascularization more variable and less convincing. There is a lack of knowledge pertaining to the molecular biology of neovascularization despite the advancement in this area in other clinical contexts. Increasingly, research is being undertaken to develop effective strategies to prevent and treat RVV; neovascularization, therefore, is an important target. Various surgical techniques have been compared with elucidate which have more favorable outcomes, including lower rates of recurrence and neovascularization. 69 One important study compared the long-term clinical advantages of ligation of SFJ with and without GSV stripping during routine primary varicose vein surgery. 70 Although neovascularization was present in both groups, stripping reduced the need for reoperation by two-thirds at 5 years. 70 Another study compared traditional surgical treatment for varicose vein recurrence, which involved removing all sources of reflux from the deep venous network with the superficial venous network, with a less aggressive surgical approach focusing on treatment of the varicose reservoir and avoiding redo surgery at the groin. Postoperative complications

7 866 Brake et al March 2013 were 6.7% and 0.5%, respectively. After 3-year follow-up, traditional surgery had a recurrence rate of 9.2%, whereas recurrence in the second group was 7.1%. 33 The conservative approach to surgical varicose vein treatment, the CHIVA and ASVAL methods, show that selective surgical treatment may be a viable option. 29,33,69,71 Studies have shown that RVV occur more frequently following saphenous stripping than after CHIVA treatment. 29,71 One study showed that recurrence rates are halved at 10 years following CHIVA, with 35% recurrence after stripping and 18% recurrence after CHIVA. 29 Equally, ASVAL showed good results with regard to neovascularization, which was only seen in 0.9% of cases, and recurrence, which was present in 6.3%. 69 Other strategies to prevent neovascularization that have been described include the use of a synthetic physical barrier. These barriers include polytetrafluoroethylene and silicone patch saphenoplasty, which involves suturing a polytetrafluoroethylene and silicone patch, respectively, over the saphenous opening after flush saphenofemoral ligation. 56,72 This method has been deemed safe, 56 and a studies have reported an approximately 50% 48,72 reduction in neovascularization, although further studies are needed to confirm this before it can be used routinely. Studies comparing endovenous treatment and open surgery have already reported a reduction in neovascularization despite the overall RVV rate remaining similar in both treatment arms, likely attributable to recanalization and opening of collaterals. 3,6,73 It is unclear why collaterals do not open up after surgery as well as after endovenous therapies. One possible explanation for this is that there are still microchannels between the collaterals and the treated veins, whereas in open surgery, the connections between them are completely removed by either vein stripping or avulsion. Therefore, improving our understanding of RVV following endovenous therapies and refining the technology including optimizing the efficiency of energy delivery and targeting the right varicosities may have the potential to reduce the overall rate of RVV. In addition to applying and improving the currently established treatment of varicose veins, the application of pharmacologic agents that prevent neovascularization may have a role in the future. For example, the local application of inhibitors of angiogenesis during varicose vein treatment is an attractive putative approach to prevent or limit neovascularization. There are commercially available angiogenesis inhibitors such as bevacizumab, an antivascular endothelial growth factor biologic available for the treatment of cancer. 74 More selective angiogenesis inhibitors are also being developed to reduce the side effects and to improve the specificity of the treatment. CONCLUSIONS RVV remains a poorly understood pathology following treatment of varicose veins. Several etiologic factors including tactical and technical error, disease progression, and neovascularization contribute to the development of RVV. The factors contributing to the development may also vary with the type of varicose vein treatment. Additional molecular and clinical studies are required to understand the pathophysiology of RVV further in the development of more effective preventative and treatment strategies. AUTHOR CONTRIBUTIONS Conception and design: MB, CL, JS, AS, AD Analysis and interpretation: MB, CL, JS, AS, AD Data collection: MB, CL, JS, AS, AD Writing the article: MB, CL, JS, AS, AD Critical revision of the article: MB, CL, JS, AS, AD Final approval of the article: MB, CL, JS, AS, AD Statistical analysis: Not applicable Obtained funding: Not applicable Overall responsibility: MB, CL, JS, AS, AD REFERENCES 1. Lim CS, Davies AH. Pathogenesis of primary varicose veins. Br J Surg 2009;96: Lim CS, Gohel MS, Shepherd AC, Davies AH. Secondary care treatment of patients with varicose veins in National Health Service England: at least how it appeared on a National Health Service website. Phlebology 2010;25: Shepherd AC, Gohel MS, Hamish M, Lim CS, Davies AH. Endovenous treatments for varicose veins over-taking or over-rated? Phlebology 2010;25: Gohel MS, Davies AH. Choosing between varicose vein treatments: looking beyond occlusion rates. Phlebology 2008;23: Jones L, Braithwaite BD, Selwyn D, Cooke S, Earnshaw JJ. Neovascularisation is the principal cause of varicose vein recurrence: results of a randomised trial of stripping the long saphenous vein. Eur J Vasc Endovasc Surg 1996;12: Negus D. Recurrent varicose veins: a national problem. Br J Surg 1993;80: Fischer R, Chandler JG, De Maeseneer MG, Frings N, Lefebvre- Vilarbedo M, Earnshaw JJ, et al. The unresolved problem of recurrent saphenofemoral reflux. J Am Coll Surg 2002;195: Winterborn RJ, Foy C, Earnshaw JJ. Causes of varicose vein recurrence: late results of a randomized controlled trial of stripping the long saphenous vein. J Vasc Surg 2004;40: Allegra C, Antignani PL, Carlizza A. Recurrent varicose veins following surgical treatment: our experience with five years follow-up. Eur J Vasc Endovasc Surg 2007;33: Kostas T, Ioannou CV, Touloupakis E, Daskalaki E, Giannoukas AD, Tsetis D, et al. Recurrent varicose veins after surgery: a new appraisal of a common and complex problem in vascular surgery. Eur J Vasc Endovasc Surg 2004;27: Gandhi A, Froghi F, Shepherd AC, Shalhoub J, Lim CS, Gohel MS, et al. A study of patient satisfaction following endothermal ablation for varicose veins. Vasc Endovasc Surg 2010;44: Turton EP, Scott DJ, Richards SP, Weston MJ, Berridge DC, Kent PJ, et al. Duplex-derived evidence of reflux after varicose vein surgery: neoreflux or neovascularisation? Eur J Vasc Endovasc Surg 1999;17: Theivacumar NS, Darwood R, Gough MJ. Neovascularisation and recurrence 2 years after varicose vein treatment for sapheno-femoral and great saphenous vein reflux: a comparison of surgery and endovenous laser ablation. Eur J Vasc Endovasc Surg 2009;38: Gloviczki P, Comerota AJ, Dalsing MC, Eklof BG, Gillespie DL, Gloviczki ML, et al. The care of patients with varicose veins and associated chronic venous diseases: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. J Vasc Surg 2011;53(5 Suppl):2S-48S.

8 Volume 57, Number 3 Brake et al Chapman-Smith P, Browne A. Prospective five-year study of ultrasound-guided foam sclerotherapy in the treatment of great saphenous vein reflux. Phlebology 2009;24: Perrin MR, Guex JJ, Ruckley CV, depalma RG, Royle JP, Eklof B, et al. Recurrent varices after surgery (REVAS), a consensus document. REVAS group. Cardiovasc Surg 2000;8: Perrin M, Allaert FA. Intra- and inter-observer reproducibility of the Recurrent Varicose Veins after Surgery (REVAS) classification. Eur J Vasc Endovasc Surg 2006;32: Perrin MR, Labropoulos N, Leon LR Jr. Presentation of the patient with recurrent varices after surgery (REVAS). J Vasc Surg 2006;43: ; discussion: Lofgren EP, Lofgren KA. Recurrence of varicose veins after the stripping operation. Arch Surg 1971;102: Bradbury AW, Stonebridge PA, Callam MJ, Walker AJ, Allan PL, Beggs I, et al. Recurrent varicose veins: assessment of the saphenofemoral junction. Br J Surg 1994;81: Stonebridge PA, Chalmers N, Beggs I, Bradbury AW, Ruckley CV. Recurrent varicose veins: a varicographic analysis leading to a new practical classification. Br J Surg 1995;82: Zan S, Varetto G, Maselli M, Scovazzi P, Moniaci D, Lazzaro D. Recurrent varices after internal saphenectomy. Physiopathological hypothesis and clinical approach. Minerva Cardioangiol 2003;51:79-83, Tong Y, Royle J. Recurrent varicose veins after short saphenous vein surgery: a duplex ultrasound study. Cardiovasc Surg 1996;4: Jiang P, van Rij AM, Christie R, Hill G, Solomon C, Thomson I. Recurrent varicose veins: patterns of reflux and clinical severity. Cardiovasc Surg 1999;7: Rasmussen LH, Bjoern L, Lawaetz M, Lawaetz B, Blemings A, Eklof B. Randomised clinical trial comparing endovenous laser ablation with stripping of the great saphenous vein: clinical outcome and recurrence after 2 years. Eur J Vasc Endovasc Surg 2010;39: De Maeseneer MG. The role of postoperative neovascularisation in recurrence of varicose veins: from historical background to today s evidence. Acta Chir Belg 2004;104: Theivacumar NS, Darwood RJ, Dellegrammaticas D, Mavor AI, Gough MJ. The clinical significance of below-knee great saphenous vein reflux following endovenous laser ablation of above-knee great saphenous vein. Phlebology 2009;24: Merchant RF, Pichot O. Long-term outcomes of endovenous radiofrequency obliteration of saphenous reflux as a treatment for superficial venous insufficiency. J Vasc Surg 2005;42:502-9; discussion: Carandina S, Mari C, De Palma M, Marcellino MG, Cisno C, Legnaro A, et al. Varicose vein stripping vs haemodynamic correction (CHIVA): a long-term randomised trial. Eur J Vasc Endovasc Surg 2008;35: Escribano JM, Juan J, Bofill R, Maeso J, Rodriguez-Mori A, Matas M. Durability of reflux-elimination by a minimal invasive CHIVA procedure on patients with varicose veins. A 3-year prospective case study. Eur J Vasc Endovasc Surg 2003;25: Zamboni P, Cisno C, Marchetti F, Mazza P, Fogato L, Carandina S, et al. Minimally invasive surgical management of primary venous ulcers vs compression treatment: a randomized clinical trial. Eur J Vasc Endovasc Surg 2003;25: Maeso J, Juan J, Escribano J, Allegue NM, Di Matteo A, Gonzalez E, et al. Comparison of clinical outcome of stripping and CHIVA for treatment of varicose veins in the lower extremities. Ann Vasc Surg 2001;15: Pittaluga P, Chastanet S, Rea B, Barbe R. Midterm results of the surgical treatment of varices by phlebectomy with conservation of a refluxing saphenous vein. J Vasc Surg 2009;50: Blomgren L, Johansson G, Dahlberg AA, Noren A, Brundin C, Nordstrom E, et al. Recurrent varicose veins: incidence, risk factors and groin anatomy. Eur J Vasc Endovasc Surg 2004;27: Theivacumar NS, Dellagrammaticas D, Darwood RJ, Mavor AI, Gough MJ. Fate of the great saphenous vein following endovenous laser ablation: does re-canalisation mean recurrence? Eur J Vasc Endovasc Surg 2008;36: Theivacumar NS, Dellagrammaticas D, Beale RJ, Mavor AI, Gough MJ. Factors influencing the effectiveness of endovenous laser ablation (EVLA) in the treatment of great saphenous vein reflux. Eur J Vasc Endovasc Surg 2008;35: Darke SG. The morphology of recurrent varicose veins. Eur J Vasc Surg 1992;6: Rabe E, Pannier F, Ko A, Berboth G, Hoffmann B, Hertel S. Incidence of varicose veins, chronic venous insufficiency, and progression of the disease in the Bonn Vein Study II. J Vasc Surg 2010;51: Labropoulos N, Bhatti A, Leon L, Borge M, Rodriguez H, Kalman P. Neovascularization after great saphenous vein ablation. Eur J Vasc Endovasc Surg 2006;31: Egan B, Donnelly M, Bresnihan M, Tierney S, Feeley M. Neovascularization: an innocent bystander in recurrent varicose veins. J Vasc Surg 2006;44: ; discussion: van Rij AM, Jones GT, Hill GB, Jiang P. Neovascularization and recurrent varicose veins: more histologic and ultrasound evidence. J Vasc Surg 2004;40: Nyamekye I, Shephard NA, Davies B, Heather BP, Earnshaw JJ. Clinicopathological evidence that neovascularisation is a cause of recurrent varicose veins. Eur J Vasc Endovasc Surg 1998;15: Frings N, Nelle A, Tran P, Fischer R, Krug W. Reduction of neoreflux after correctly performed ligation of the saphenofemoral junction. A randomized trial. Eur J Vasc Endovasc Surg 2004;28: Khaira HS, Parnell A, CrowsonMC. Colour flow duplex in the assessment of recurrent varicose veins. Ann R Coll Surg Engl 1996;78: van Rij AM, Jiang P, Solomon C, Christie RA, Hill GB. Recurrence after varicose vein surgery: a prospective long-term clinical study with duplex ultrasound scanning and air plethysmography. J Vasc Surg 2003;38: Lurie F, Creton D, Eklof B, Kabnick LS, Kistner RL, Pichot O, et al. Prospective randomised study of endovenous radiofrequency obliteration (closure) versus ligation and vein stripping (EVOLVeS): two-year follow-up. Eur J Vasc Endovasc Surg 2005;29: Kianifard B, Holdstock JM, Whiteley MS. Radiofrequency ablation (VNUS closure) does not cause neo-vascularisation at the groin at one year: results of a case controlled study. Surgeon 2006;4: van Rij AM, Jones GT, Hill BG, Amer M, Thomson IA, Pettigrew RA, et al. Mechanical inhibition of angiogenesis at the saphenofemoral junction in the surgical treatment of varicose veins: early results of a blinded randomized controlled trial. Circulation 2008;118: Lim CS, Gohel MS, Shepherd AC, Paleolog E, Davies AH. Venous hypoxia: a poorly studied etiological factor of varicose veins. J Vasc Res 2011;48: Frings N, Tran VTP, Nelle A, Glowacki P. Unavoidable recurrence and neoreflux after correctly performed ligation of the saphenofemoral junction: neovascularisation? Phlebologie 1999;32: Frings N, Glowacki P, Nelle A, Van-Thanh-Phuong T. [Prospective study of avoiding neoangiogenesis after great saphenous vein crossectomy. Initial results]. Zentralbl Chir 2001;126: Chandler JG, Pichot O, Sessa C, Schuller-Petrovic S, Osse FJ, Bergan JJ. Defining the role of extended saphenofemoral junction ligation: a prospective comparative study. J Vasc Surg 2000;32: Creton D. A nondraining saphenous system is a factor of poor prognosis for long-term results in surgery of great saphenous vein recurrences. Dermatol Surg 2004;30:744-9; discussion: Witmer AN, van Blijswijk BC, Dai J, Hofman P, Partanen TA, Vrensen GF, et al. VEGFR-3 in adult angiogenesis. J Pathol 2001;195: Munasinghe A, Smith C, Kianifard B, Price BA, Holdstock JM, Whiteley MS. Strip-track revascularization after stripping of the great saphenous vein. Br J Surg 2007;94: Earnshaw JJ, Davies B, Harradine K, Heather BP. Preliminary results of PTFE patch saphenoplasty to prevent neovascularisation leading to recurrent varicose veins. Phlebology 1998;13: El Wajeh Y, Giannoukas AD, Gulliford CJ, Suvarna SK, Chan P. Saphenofemoral venous channels associated with recurrent varicose veins are not neovascular. Eur J Vasc Endovasc Surg 2004;28: Geier B, Olbrich S, Barbera L, Stucker M, Mumme A. Validity of the macroscopic identification of neovascularization at the saphenofemoral junction by the operating surgeon. J Vasc Surg 2005;41:64-8.

9 868 Brake et al March Stucker M, Netz K, Breuckmann F, Altmeyer P, Mumme A. Histomorphologic classification of recurrent saphenofemoral reflux. J Vasc Surg 2004;39:816-21; discussion: van den Bos R, Arends L, Kockaert M, Neumann M, Nijsten T. Endovenous therapies of lower extremity varicosities: a meta-analysis. J Vasc Surg 2009;49: Creton D, Pichot O, Sessa C, Proebstle TM. Radiofrequency-powered segmental thermal obliteration carried out with the ClosureFast procedure: results at 1 year. Ann Vasc Surg 2010;24: Christenson JT, Gueddi S, Gemayel G, Bounameaux H. Prospective randomized trial comparing endovenous laser ablation and surgery for treatment of primary great saphenous varicose veins with a 2-year follow-up. J Vasc Surg 2010;52: Belcaro G, Cesarone MR, Di Renzo A, Brandolini R, Coen L, Acerbi G, et al. Foam-sclerotherapy, surgery, sclerotherapy, and combined treatment for varicose veins: a 10-year, prospective, randomized, controlled, trial (VEDICO trial). Angiology 2003;54: Lee S, Jilani SM, Nikolova GV, Carpizo D, Iruela-Arispe ML. Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors. J Cell Biol 2005;169: Rasmussen LH, Lawaetz M, Bjoern L, Vennits B, Blemings A, Eklof B. Randomized clinical trial comparing endovenous laser ablation, radiofrequency ablation, foam sclerotherapy and surgical stripping for great saphenous varicose veins. Br J Surg 2011;98: Theivacumar NS, Dellagrammaticas D, Beale RJ, Mavor AI, Gough MJ. Fate and clinical significance of saphenofemoral junction tributaries following endovenous laser ablation of great saphenous vein. Br J Surg 2007;94: Theivacumar NS, Darwood RJ, Gough MJ. Endovenous laser ablation (EVLA) of the anterior accessory great saphenous vein (AAGSV): abolition of sapheno-femoral reflux with preservation of the great saphenous vein. Eur J Vasc Endovasc Surg 2009;37: Disselhoff BC, der Kinderen DJ, Kelder JC, Moll FL. Randomized clinical trial comparing endovenous laser with cryostripping for great saphenous varicose veins. Br J Surg 2008;95: Pittaluga P, Chastanet S, Guex JJ. Great saphenous vein stripping with preservation of sapheno-femoral confluence: hemodynamic and clinical results. J Vasc Surg 2008;47:1300-4; discussion: Dwerryhouse S, Davies B, Harradine K, Earnshaw JJ. Stripping the long saphenous vein reduces the rate of reoperation for recurrent varicose veins: five-year results of a randomized trial. J Vasc Surg 1999;29: Pares JO, Juan J, Tellez R, Mata A, Moreno C, Quer FX, et al. Varicose vein surgery: stripping versus the CHIVA method: a randomized controlled trial. Ann Surg 2010;251: De Maeseneer MG, Vandenbroeck CP, Van Schil PE. Silicone patch saphenoplasty to prevent repeat recurrence after surgery to treat recurrent saphenofemoral incompetence: long-term follow-up study. J Vasc Surg 2004;40: Winterborn RJ, Corbett CR. Treatment of varicose veins: the present and the future a questionnaire survey. Ann R Coll Surg Engl 2008;90: Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 1995;1: Submitted Mar 19, 2012; accepted Oct 22, 2012.