Phlebology Forum March-April 2013 by Phlebology Forum

Superficial vein ablation for the treatment of primary chronic venous ulcers: two perspectives PAGE 9

Fondaparinux for the treatment of superficial-vein thrombosis in the legs PAGE 15

From the Editor-in-Chief Dr. Nick Morrison

mar-apr â&#x20AC;&#x2DC;13

contents

Superficial vein ablation for the treatment of primary chronic venous ulcers: two perspectives Contributing Editor/Reviewer: Mehmet Kurtoglu, MD Pedro KomlĂłs, MD

Associate Editor: Sukiritharan Sinnathamby, MD, FACC, FSCAI, RVT

Diagnostic value of single complete compression ultrasonography in pregnant and postpartum women with suspected deep vein thrombosis: prospective study

Fondaparinux for the treatment of superficial-vein thrombosis in the legs

Contributing Editor/Reviewer: Nicos Labropoulos, MD

Contributing Editor/Reviewer: Armando Mansilha, MD, PhD, FEBVS

Associate Editor: Mark Forrestal, MD, FACPh

Associate Editor: Eric Mowatt-Larssen, MD, FACPh, RPhS

Determinants of early and long-term efficacy of catheterdirected thrombolysis in proximal deep vein thrombosis Contributing Editor/Reviewer: Akhilesh Sista, MD Associate Editor: Neil Khilnani, MD, FACPh

disclosure of interests

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Date Submitted

Disclosure

Stephanie Dentoni, MD

Recruitment & Retention (Chair)

6/25/12

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Mark Forrestal, MD, FACPh

ACP

6/25/12

New Star Lasers Cooltouch: Speaker, Trainer

Mitchel Goldman, MD, FACPh

Phlebology Forum Task Force

2/14/2013

American Society for Dermatologic Surgery, President-Elect; Merz Aesthetics/Kruesler, Consultant

Jean-Jerome Guex, MD, FACPh

ACP BOD, Communications, Standing Committee, Leadership Development, UIP 2013 Task Force, AMA HOD Task Force, International Affairs (Chair),

6/14/12

Kreussler: Speaker; Sigvaris: Speaker, Investigator, Consultant; Innotech: Principal Investigator; Pierre Fabre: Consultant; Boerighr Ingelheim: Consultant, Medical Writer; Servier: Investigator, Consultant, Speaker

Lowell Kabnick, MD, FACS, FACPh

UIP 2013 Task Force

7/17/12

Angiodynamics: Consultant, Shareholder, Patent; Vascular Insights: Scientific Advisory Board

Neil Khilnani, MD, FACPh

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7/24/12

Sapheon: Data Safety Board Member

Ted King, MD, FAAFP, FACPh

ACP BOD, Leadership Development, PES-QM Task Force, Public Education

6/14/12

BTG: Investigator; Merz: Speaker

Mark Meissner, MD

ACP BOD, Education Standing Committee

7/13/12

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Nick Morrison, MD, FACS, FACPh

UIP 2013 Task Force (Chair), Phlebology Forum Task Force (Chair), Annual Congress Planning Committee (Chair)

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Medi: Speakers Bureau; Merz: Speakers Bureau; Sapheon: Principle Investigator; VeinX: Scientific Advisory Board

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6/15/12

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Pauline RaymondMartimbeau, MD, FACPh

UIP 2013 Task Force

6/22/12

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From the

Editor-in-Chief Dear Readers

This issue of Phlebology Forum begins with two perspectives by international experts from Turkey (Kurtoglu) and Brazil (Koml贸s), both of whom have extensive experience with the treatment of venous ulcers. Treatment of superficial venous thrombosis continues to evolve as our understanding of the underlying pathophysiology expands. Follow up by duplex ultrasound of patients with pregnancy-associated deep vein thrombosis is discussed, and the timely critique of catheter-directed thrombolysis is included in this issue.

As a reminder, the deadline for abstract submission for inclusion in the XVII UIP World Congress in September in Boston (which supplants the ACP Annual Congress) is April 15, 2013. Now is the time to submit!

Nick Morrison, MD Editor-in-Chief Phlebology Forum

Superficial vein ablation for the treatment of primary chronic venous ulcers: two perspectives Author: Sufian S, Lakhanpal S, Marquez J. Phlebology. 2011 Oct;26(7):301-6. Review 1 Contributing Editor/Reviewer: Mehmet Kurtoglu, MD Review 2 Contributing Editor/Reviewer: Pedro Koml贸s, MD

Associate Editor for Both: Sukiritharan Sinnathamby, MD, FACC, FSCAI, RVT

KORTOGLU COMMENTARY Recently, Sufian et al reported a retrospective study of 18 patients (25 limbs) who underwent thermal ablation therapy for treatment of CEAP C6 primary chronic venous ulcers. Sixty-one percent (61%) of the studied patients were obese, 17% were overweight and 22% were of normal weight. The greatest diameter of the ulcers varied between 0.1 and 5 cm (70% 1-3 cm). A median of three (range 1-8) ablations were required. Treatment success was 96% (24 limbs) after 6-12 months of follow-up; while one ulcer failed healing and one ulcer reoccurred. The recurrence was managed with posterior tibial perforator ablation.

In 2006, Obermayer et al reported a retrospective study of 173 patients (239 limbs) encompassing 7 years of experience with CEAP C6 chronic venous ulcers treated with surgical interruption of superficial venous reflux followed by compression therapy. Forty-six percent (46%) of those patients

Currently, venous ulcers are not associated with a certain type of chronic venous insufficiency. To date, the mechanisms behind recurrence are not fully understood.

were obese, 35% were overweight, 18% were normal weight and 1% were underweight; in addition peripheral arterial disease co-existed in 22% of limbs. Ulcer sizes ranged from 0.25 to 500 cm2 (median 12 cm2); 13% had tendons, bones and joints involved and 49% had the fascia involved. The etiology was identified as primary reflux in 68% (118 limbs) and 32% (55 limbs) as secondary reflux. The median follow-up was 3 years (3 months â&#x20AC;&#x201C; 7 years). Initial ulcer healing was achieved in 87% (151 limbs). Increased age at the time of the operation was identified as the only significant risk factor related to healing time (p=0.0138). Recurrence occurred in 1.7% limbs at 6-months follow-up, which increased to 4.6% at 5-year follow-up. The mean time to recurrence was 70.4 months. As for recurrence, increased age at the time of the operation (p=0.0004) and presence of severe edema (p=0.0357) were identified as significant risk factors. Quality of life data, quantified by Nottingham Health Profile, was reported for 169 limbs, which showed a highly significant improvement between pre- and post-operative states (p<0.0001)1.

In 2004, Gohel et al reported a randomized study of 214 limbs, 112 treated with compression and 102 with compression plus surgery. At 5 year follow-up, addition of great saphenous vein stripping reduced the ulcer recurrence from 50% to

1 Obermayer A, GĂśstl K, Walli G, Benesch T.Chronic venous leg ulcers benefit from surgery: long-term results from 173 legs.J Vasc Surg. 2006 Sep;44(3):572-9.

25%. Furthermore, superficial venous surgery led to a significant hemodynamic improvement in limbs with reflux in superficial or deep segments as compared to compression stocking use only. This benefit was observed regardless of the pre-operative pattern of reflux2.

The rationale for interrupting reflux in the superficial venous system is to improve venous hemodynamics. This can be achieved either surgically or with endoablation (laser or radiofrequency). There are a number of defined risk factors related to recurrence: age at time of the operation, duration of ulcer, BMI etc.

In addition, a higher recurrence (5%) rate was reported at 5-years as compared to 6-months follow-up(1.7%). The main reason for recurrence and resistance to healing is deep venous system insufficiency (obstruction and/or reflux). Therefore, deep venous system must routinely be examined, especially in difficult cases. Iliac vein compression by iliac arteries (May-Thurner syndrome) should not be missed. Since Color Duplex investigation is not accurate for detection of the iliac veins; magnetic resonance, computerized venography or conventional venography should be employed. Although the study is limited by a small patient number, Raju and Neglen strongly suggest even intravenous ultrasonography (IVUS) to investigate iliac veins3. Thus, the current study by Sufian has limitations since the deep veins and iliacs were not investigated especially in the recurrent and intractable ulcers.

Currently, venous ulcers are not associated with a certain type of chronic venous insufficiency. To date, the mechanisms behind recurrence are not fully understood. Although the notion to improve hemodynamics by ablation is generally recommended, this does not always promote ulcer healing. Furthermore, certain ulcers do not recur despite deterioration in venous hemodynamics assessed by duplex findings during follow-up.

In the presence of many unsolved mysteries of venous ulcers, it is reasonable to target the superficial reflux. In this original article, the results of endoablation was compared indirectly with surgery, and similar outcomes were reported in short-term follow-up. Given the retrospective nature and low patient numbers, this study is not able to solve the mysteries of venous ulcers, however provides us a good reason to discuss this very important issue.

2. Gohel MS, Barwell JR, Earnshaw JJ, Heather BP, Mitchell DC, Whyman MR, Poskitt KR.Randomized clinical trial of compression plus surgery versus compression alone in chronic venous ulceration (ESCHAR study)--haemodynamic and anatomical changes.Br J Surg. 2005 Mar;92(3):291-7.

3. Lurie F, Kistner R, Perrin M, Raju S, Neglen P, Maleti O. Invasive treatment of deep venous disease. A UIP consensus.IntAngiol. 2010 Jun;29(3):199-204.

KOMLĂ&#x201C;S COMMENTARY The authors make a detailed review of the etiology of venous ulcers and conclude that, in 85% of the cases, they are caused by reflux in the superficial venous system. Among the various types of treatment possible, in addition to conservative compression therapy, the most frequently used are surgical ligation and stripping, ultrasound-guided foam, and endovenous ablation using EVLT (endovenous laser treatment) or RF (radiofrequency). The objective of this work is to describe the authorsâ&#x20AC;&#x2122; experience with the use of RF for axial vein ablation and EVLT for ablation of perforating veins, over a period of two years. The authors stress the advantages of the method proposed by them, especially in elderly or obese patients, or with significant co-morbidities.

All patients included in this study were diagnosed with chronic venous insufficiency, CEAP C6, and the ICAVAL (Intersocietal Commission for Accreditation of Vascular Laboratories) vascular laboratory criteria were adopted. The results of the treatment were followed by examinations in the second and third days to observe occlusion of the treated vein and to rule out a possible deep venous thrombosis. The observations were repeated after one month, three months and one year. The authors emphasize that the method of intravenous ablation of superficial veins, in

Clinical therapy, including the use of venous compression, offers initially good results, but it does not prevent the progression of the disease to more complex stages.

cases of venous ulcer, is less invasive, has fewer complications, is conducted on outpatient level with local anesthesia, with minimal postoperative pain and especially with early return to the usual activities.

The most advanced degree of trophic changes in the lower limbs in patients with chronic venous insufficiency is the formation of venous ulcers. Spontaneous venous ulcers tend to be located just above the malleolus, mainly internal, on perforating veins, where there is a high venous blood pressure. Isolated ulcers are more usually observed, but in cases of long evolution other ulcers may appear, leading to larger ulcers.

The overall changes that occur in the skin and subcutaneous tissue of the lower extremities resulting from long-term venous hypertension, due to valvular insufficiency and/or venous obstruction, are described as chronic venous insufficiency. A superficial venous insufficiency can be a part of the disease or be a cause for it. The ulcers caused by chronic venous insufficiency are classified as primary or secondary. Primary ulcers are due exclusively to the superficial venous insufficiency not associated with deep venous thrombosis (post thrombotic syndrome).

Chronic venous insufficiency is a frequent disease, representing a serious medical problem, both in developed as well as underdeveloped countries, with virtually zero mortality but with an important morbidity, affecting the quality of life and causing a great socio-economic impact. To solve this problem, many methods have been proposed, from the conventional clinical treatment to alternative invasive methods, represented in this work by traditional surgery, ultrasound-guided foam and methods of endovenous ablation.

Conservative, non-invasive therapy, including the use of venous compression, offers initially good results, but it does not prevent the progression of the disease to more complex stages. The traditional surgical methods, involving venous ablation and ligation of perforating vein, have been used with success for many decades, but can be difficult to use in cases of ulcerated lesions and skin hardening, besides the permanent risk of secondary infection. Even the subfascial endoscopic ligature of perforating veins, which reduced the postoperative complications of incisions and has been widely used for nearly two decades, was recently replaced by intravenous ablation methods with the use of EVLT or RF.

The authors point out, in a self-criticism, the small number of cases and the fact that this is a retrospective study. Another limitation was the lack of physiological tests for pathologies of the iliac venous system, venous reflux and efficiency of calf muscle pumps.

Although the authors worked with a predominantly older population, with mean age of 68 years, in Brazil the incidence of venous ulcer has been observed in patients with ages ranging from 18 to 70 years, causing more devastating social and economic consequences. Most of the patients in the present work were overweight or obese (14/18). Among our patients, although overweight or obesity favor the development of complications such as ochre (stasis) dermatitis, they are not necessarily involved in the generation of venous ulcers.

In a study published in 1991, Mayberry and collaborators showed that the clinical treatment of venous ulcers resulted in a recurrence rate of 29% after five years in patients who used elastic compression and 100% for those who did not. On the other hand, Raju et al. (2007) stressed in their study the low adherence to long-term compression treatment, with 63% drop out.

Even so, and considering other studies in this area, the two-year follow-up period in this study was short. Since this is a chronic and progressive disease a longer follow-up is necessary.

Finally, we agree with the authors that the treatment with intravenous ablation, in cases of active venous ulcer, is safe, technically feasible and can be conducted as an extra-hospital, outpatient level, under local anesthesia. The method results in more rapid healing of injuries and probably an earlier return to normal life, compared to traditional methods. However, a long-term study is needed to confirm these conclusions.

REFERENCES

1 Chiesa R, Marone EM, Limoni C, Volontè M, Petrini O. Chronic venous disorders: correlation between visible signs, symptoms, and presence of functional disease. J Vasc Surg 2007;46:322–30 2 Eklöf B, Rutherford RB, Bergan JJ, et al. Revision of the CEAP classification for chronic venous disorders: consensus statement. American Venous Forum International Ad Hoc Committee for Revision of the CEAP Classification. J Vasc Surg 2004;40:1248–52 3 Revision of the CEAP Classification. J Vasc Surg 2004;40:1248–52 Gillet JL, Donnet A, Lausecker M, Guedes JM, Guex JJ, Lehmann P. Pathophysiology of visual disturbances occurring after foam sclerotherapy. Phlebology 2010;25:261-6. 4

Kahn SR, M’lan CE, Lamping DL, et al. Relationship between clinical classification of chronic venous disease and patient-reported quality of life:Results from an international cohort study. J Vasc Surg 2004;39(4):318-28

5 Labropoulos N, Delis K, Nicolaides AN, Leon M, Ramaswami G. The role of the distribution and anatomic extent of reflux in the development of signs and symptoms in chronic venous insufficiency. J Vasc Surg 1996;23:504–10 6 Labropoulos N, Giannoukas AD, Delis K, et al. The impact of isolated lesser saphenous vein system incompetence on clinical signs and symptoms of chronic venous disease. J Vasc Surg 2000; 32:954–60. 7 Labropoulos N, Kokkosis AA, Spentzouris G, Gasparis AP, Tassiopoulos AK. The distribution and significance of varicosities in the saphenous trunks. J Vasc Surg 2010;51:96–103 8 Maffei FHA,Rollo HA. Trombose Venosa dos Membros Inferiores: incidência, patologia,patogenia, fisiopatologia e diagnóstico. In: Maffei FHA, Lastória S, Yoshida WB, Rollo HA. Doenças Vasculares Periféricas. 3ª ed. Rio de Janeiro, MEDSI,2002. p. 1363-86 9 Marsh P, Price BA, Holdstock J et al (2010) Deep vein thrombosis (DVT) after venous thermoablation techniques: rates of endovenous heat-induced thrombosis (EHIT) and classical DVT after radiofrequency and endovenous laser ablation in a single centre. Eur J Vasc Endovasc Surg 40:521–527 10 Marsh P, PriceBA, Holdstock J et al (2010) Deep Vein thrombosis(DVT) after venous thermoablation techniques : rates of endovenous heat-induced(EHIT) and classical DVT after radiofrequency and endovenous laser ablation in a single centre. Eur J Vasc Endovas Surg 40:521-527 11 MayberryJC, MonetaGL, Taylor LM Jr, et al. Fifteen-year results of ambulatory compression of chronic venous ulcer. Surgery 1991;109:575 12 Proebstle T, Gu D, Kargl A, Knop J. Endovenous laser treatment of the greater saphenous vein with a 940 nm diode laser: thrombotic occlusion after endoluminal thermal damage by laser generated steam bubbles. J Vasc Surg 2002;35:729–36. 13 Puggioni A, Kalra M, Carmo M, et al. Endovenous laser therapy and radiofrequency ablation of the great saphenous vein. Analysis of early efficacy and complications. J Vasc Surg 2005;42: 488–93. 14 Raju S, Hollis K, Neglen P. Use of compression stockings in chronic venous diseases: patient compliance and efficiency. Ann Vasc Surg 2007: 21:790-5 15 Ruckley CV, Evans CJ, Allan PL, et al. Chronic venous insufficiency: clinical and duplex correlations. The Edinburgh Vein Study of venous disorders in the general population. J Vasc Surg 2002;36:520–5. 16 Vasquez MA, Rabe E, McLafferty RB, et al. American Venous Forum Ad Hoc Outcomes Working Group. Revision of the venous clinical severity score: venous outcomes consensus statement: special

Diagnostic value of single complete compression ultrasonography in pregnant and postpartum women with suspected deep vein thrombosis: prospective study Author: Le Gal G, et al. BMJ 2012;344:e2635 Contributing Editor/Reviewer: Nicos Labropoulos, MD Associate Editor: Mark Forrestal, MD, FACPh

COMMENTARY This was a prospective outcome study in two tertiary care centers and 18 private practices specializing in vascular medicine in France and Switzerland. There were 226 females during pregnancy or up to 3 months after delivery that were seen in a period of 3 years. Of them 16 were excluded from the analysis due to previous pulmonary embolism (n=14) and deep vein thrombosis (DVT n=2). Clinical characteristics of the participating females were collected in detail. Imaging of the iliac and lower extremity veins was performed with ultrasound by vascular medicine physicians that had at least 10 years of experience in vascular ultrasound. All women without DVT were followed-up at the clinic or had a telephone interview. The median age was 33 years (interquartile range 28 to 37), 167 were pregnant and 47 postpartum. There were 22 (10.5%) women with DVT of which 18 (82%) were found in the left lower limb. The high prevalence in the left limb was not unexpected as compression on the left iliac veins is more common in general and it is increased during the pregnancy

One of the problems in the design is the lack of applying the pretest probability particularly as the majority of the women had low score.

as the uterus expands. This is often evident from the spontaneous contrast seen in the left common femoral vein due to the proximal compression in the absence of DVT. Furthermore DVT occurred most often during the third trimester and the postpartum period (9 and 8, for a total of 77.3%). Proximal DVT involving at least the popliteal vein was detected in 20 (90%). This finding was expected given that thrombi associated with pregnancy start proximally due to compression of the iliac veins and the injury (tissue factor release) associate with the delivery. The current study confirms the data from the systematic review by Chan WS et al. CMAJ 2010;182:657â&#x20AC;&#x201C;60. The pretest clinical probability correlated well with the presence of DVT (P<0.001). In the low probability group there were 2 events in 107 women (1.9%) in the intermediate group 7/85 (8.2%) and in the high group 13/18 (72.2%). The preclinical examination was not used in the management of the patients. In a previous study the LEFt score designed for pregnant women would make a pretest examination more targeted for managing VTE (Ref 18 in this paper). However that study as the current one had a low yield of DVT and both had low power as well. In 188 women where no DVT was detected another pathology was found in 26 (13.8%) with 21 having superficial vein thrombosis, popliteal cysts (n=2), muscle tear (n=1), tendonitis (n=1) and painful inguinal lymph nodes (n=1). During follow-up of these 188 women 10 received anticoagulation (superficial vein thrombosis 7, antibodies to phospholipid 2 and patent foramen ovale 1), one was lost to follow-up and were

excluded from further analysis. Of the remaining 177 women, 7 developed signs and symptoms of VTE of whom only 2 were found to have DVT. Therefore, the incidence of DVT at 3 months was 1.1% 95% CI 0.3 to 4%. These data are similar to other reports and demonstrate the low event rate in the first 90 days in patients who had no DVT on ultrasound. This was posed as the main significant finding in the study and its main contribution in the literature. However, what was not discussed of those 177 women how many did have the need to be examined? What was their presentation in the original ultrasound examination and what measures were taken to identify the importance and relevance of their symptoms? There was no mortality throughout the study period. As this was a management outcome study the strategy used was safe. Several limitations are found in this report. Although it is one of the largest published studies the event rate did not allow for concrete conclusions.

One of the problems in the design is the lack of applying the pretest probability particularly as the majority of the women had low score. This would have significantly increased the yield of DVT and made the management of the patients more cost effective and robust. Another issue was the inability to provide data on negative and positive predictive value. However, this would have been difficult to overcome as radiation avoidance is very important in this group of patients. Lastly, although the vascular physicians who performed the ultrasound had over 10 year experience the iliocaval segment could not be imaged in 88 (41.9%), common iliac veins in 8 (3.8%) all iliac veins in 9 (4.3%) and popliteal veins in 1 (0.5%). According to our experience this would indicate mediocre skill in the imaging of the inferior vena cava and iliac veins.

Overall this was a good study adding some relevant information in the management of pregnant women. Nevertheless, in order to get more concrete conclusions a much larger prospective study with a better design on decision making using also other parameters will take the management of this population to the next level.

Fondaparinux for the treatment of superficial-vein thrombosis in the legs Hervé Decousus, M.D., Paolo Prandoni, M.D., Ph.D., Patrick Mismetti, M.D., Ph.D., Rupert M. Bauersachs, M.D., Zoltán Boda, M.D., Benjamin Brenner, M.D., Silvy Laporte, Ph.D., Lajos Matyas, M.D., Saskia Middeldorp, M.D., Ph.D., German Sokurenko, M.D., and Alain Leizooicz, M.D. for the CALISTO Study Group New England Journal of Medicine 2010; 363:1222-1232 September 23, 2010 Contributing Editor/Reviewer: Armando Mansilha, MD, PhD, FEBVS Associate Editor: Eric Mowatt-Larssen, MD, FACPh, RPhS

ABSTRACT The authors conducted the “Comparison of Arixtra in Lower Limb Superficial Vein Thrombosis with Placebo” (CALISTO) trial to evaluate the efficacy and safety of fondaparinux, a specific factor Xa inhibitor, in reducing symptomatic venous thromboembolic complications or death from any cause in patients with acute, isolated superficial-vein thrombosis (SVT) of the legs. For the active treatment they used the prophylactic dose of 2.5 mg of fondaparinux once daily (considered prophylactic for DVT), administered for 45 days, followed by an observation period of 1 month, and compared with placebo.

The results showed an 85% relative reduction in the risk of symptomatic thromboembolic complications or death, without increasing the incidence of bleeding, in the group of patients treated with fondaparinux. Very high risk patients (e.g. with active cancer, recent history of venous thromboembolism, thrombus located within 3 cm of the saphenofemoral junction (SFJ) were not enrolled in this study. They chose a 45-day duration of treatment to avoid the â&#x20AC;&#x153;catch-upâ&#x20AC;? phenomenon observed with shorter (up to 30-day) courses of low-molecular-weight heparin, in previous studies. The feasibility of such treatment was confirmed by the high degree of patient adherence. It was associated with an improved quality of life.

COMMENTARY Recent studies of the epidemiology and treatment of SVT indicate that previous notions that this disease is a localized inflammatory condition need to be revised. SVT is associated with DVT and PE in a significant proportion of patients. Furthermore, some risk factors, such as malignancy, thrombophilic states and estrogen therapy, are shared by both superficial and deep venous thrombosis. This indicates that there is a common pathogenic mechanism for both phenomena1. As a result, treatment should not be just local and

patients with isolated, symptomatic SVT in the legs are at substantial risk for symptomatic thromboembolic complications.

symptomatic, but frequently requires administration of systemic anticoagulant drugs. Some randomized studies have been conducted, comparing systemic anticoagulant drugs with placebo, or comparing different doses and duration of anticoagulant drugs. The STENOX study2 was a placebo controlled pilot study in which enoxaparin, placebo or a tenoxicam (a non-steroidal antiinflammatory drug) were administered in patients with SVT for 2 weeks. In this study, the combined incidence of DVT and

1 Decousus H, Quere I, Presles E, Becker F, Barrellier M, Chanut M, Gillet J-L, Guenneguez H, Leandri C, Mismetti P, Pichot O, Leizorovicz A, for the POST (Prospective Observational Superficial Thrombophlebitis) Study Group. Superficial Venous Trombosis and Venous Thromboembolism. A large, prospective epidemiologic study. Ann Intern Med. 2010; 152:218-224. 2 The Superficial Thrombophlebitis Treated by Enoxaparin Study Group. A randomized double-blind comparison of low molecular-weight heparin, a nonsteroidal anti-inflammatory agent and placebo in the treatment of superficial-vein thrombosis. Arch Interrn Med 2003; 163:1657-1663.

extension of SVT by day 12 was significantly reduced in all active treatments groups, from 30.6% in the placebo group to 8.3% (enoxaparin 40 mg od), 6.9% (enoxaparin 1.5 mg/kg/od) and 14.9% (tenoxicam). A recent subgroup analysis of the CALISTO trial concluded that even thrombi whose proximal extent was greater than 3 cm from the SFJ could have their extension prevented by fondaparinux. This leads to significantly fewer hospitalizations and fewer surgical interventions3. The 2012 version of the American College of Chest Physician guidelines recommends the use of fondaparinux or LMWH for the treatment of symptomatic SVT of at least 5 cm in length (grade 2B recommendation). The British Council of Standards in Haematology, recently published, recommend therapeutic anticoagulation for SVT within 3 cm of the SFJ, while patients with SVT and risk factors for extension, recurrence and progression should be offered treatment with prophylactic doses of LMWH for 30 days or fondaparinux for 30-45 days (grade 1B recommendation). In a recent study (STEFLUX)4, patients with SVT were randomized into 3 groups, according to dose and time of administration of LMWH. The composite primary outcome of all DVT, symptomatic PE and new SVT was assessed at day 60. Patients receiving the intermediate dose of LMWH for 30 days had the best results: 1.8% of primary outcomes versus 15.6% in the first group (higher dose for 10 days) and 7.8% in the third group (lower dose for 30 days). In this study, prophylactic doses of LMWH were inferior to intermediate doses and duration of treatment was important. This study is important as it is possible to gather information from a cost-benefit perspective: fondaparinux is a more expensive anticoagulant for SVT than enoxaparin ($8.25 vs $3.75 per dose). A recent analysis of the CALISTO trial found that fondaparinux administered under the same conditions as in the study was not cost-effective. There was an incremental costeffectiveness ratio of $500,000 per QALY (quality-adjusted-life-year)5. In conclusion, patients with isolated, symptomatic SVT in the legs are at substantial risk for symptomatic thromboembolic complications. The treatment of these patients, based on the results of clinical trials, should include anticoagulation therapy, which appears to be both efficacious and safe. However, as patients without clinical risk factors are at lower risk to have concurrent or rapid progression to deep vein thrombosis, it seems rational to stratify the risk in an individual basis, to allow a tailored treatment. The precise doses of the various anticoagulant drugs available, and the ideal duration of therapy require further study. The best treatment of superficial vein thrombosis outside of the saphenous veins (saphenous vein tributary veins or localized varicose veins) has also not been studied specifically. Finally, formal cost-benefit analyses of the use of anticoagulants for SVT need to be performed.

3 Leizorovics A, Prandoni P and Decousus H. Fondaparinux reduces all types of symptomatic thromboembolic complications in patients with superficialvein thrombosis in the legs: data from the CALISTO study. Blood 2011, Abs 2310 4 Cosmi B, Filipini M. A randomized double-blind study of low-molecular weight heparin (parnaparin) for superficial vein thrombosis: STEFLUX (Superficial ThromboEmbolism and Fluxum). J Thromb Haemostasis 2012; 10:1026-1035 5 Blondon M, Righini M, Bounameaux H and Veenstra DL. Fondaparinux for isolated superficial vein thrombosis of the legs: a cost-effectiveness analysis. Chest 2012; 141:321-329

Determinants of early and long-term efficacy of catheter-directed thrombolysis in proximal deep vein thrombosis Haig Y, Endent T, Slagsvold CE, et al. J Vasc Interv Radiol 2013; 24:17-24 Contributing Editor/Reviewer: Akhilesh Sista, MD Associate Editor: Neil Khilnani, MD, FACPh

COMMENTARY We as interventional venous practitioners are at a nexus in the history of deep vein thrombosis (DVT) treatment, given the recent publication of the CaVenT study from Norway and the ongoing ATTRACT study in the United States, set to conclude in 2015. The data generated from these multi-center, randomized, controlled trials will essentially define the role catheter directed therapy (CDT) plays in preventing the post-thrombotic syndrome (PTS). Thus, it behooves us to carefully analyze the results of these trials to understand their limitations and which patients are most likely to benefit from intervention.

In the January 2013 issue of JVIR, Haig et al.1

while there was a 14% absolute

present a subgroup analysis of the landmark CaVenT study, published in last yearâ&#x20AC;&#x2122;s Lancet . 2

Specifically, they looked at the 92 patients in the CDT arm. The original publication generated as many questions as answers, and the JVIR article offered some insight into some of the questions

reduction in PTS incidence in the CDT group, many were left asking why less thrombus

raised. One of the more enigmatic conclusions from the original study was that the degree of thrombus burden at the end of lysis did not correlate with development of post-thrombotic syndrome. While there was a 14% absolute

in the deep veins could not be correlated with a lower incidence of this primary

reduction in PTS incidence in the CDT group, many were left asking why less thrombus in the deep veins could not be correlated with a lower incidence of this primary endpoint.

endpoint. The short answer is that CaVenT suffered from a relatively small sample size

The short answer is that CaVenT suffered from a relatively small sample size and possibly less aggressive stenting. Haig et al. retrospectively reviewed the post-treatment venograms and scored the degree of thrombus burden. Lower thrombus scores were significantly associated with improved 6 and 24-month patency. 6 and 24-month patency in turn were found to significantly correlate with a lower incidence of PTS. However, the group could not correlate a lower thrombus score at the end of treatment with a lower incidence of PTS. In essence, A (thrombus score) = B (patency),

1 Haig Y, Endent T, Slagsvold CE, et al. Determinants of early and long-term efficacy of catheter-directed thrombolysis in proximal deep vein thrombosis. J Vasc Interv Radiol 2013; 24:17-24 2 Enden T, Haig Y, Klow NE, et al. Improved functional outcome after additional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis: results of a randomized, controlled trial (the CaVenT study). Lancet 2013; 379: 31-38

and B (patency) = C (PTS), but A did not equal C. It is possible that a larger N would have revealed such an association. Furthermore, the authors acknowledge the low rate of angioplasty and stent placement in the study; it is possible that more liberal stenting would have resulted in improved pelvic venous flow, even better 6 and 24-month patency, and an even lower incidence of PTS. A retrospective analysis demonstrated a >80% incidence of a mechanical obstruction (most commonly May-Thurner) in the setting of iliofemoral DVT3. Given that 48 CDT patients had iliac or iliofemoral DVTs in CaVenT1, one would expect at least 20-30 of these to have an obstruction amenable to stenting. Yet only 16 patients received stents1.

Another widely cited difference between the Norwegian study and practice in the United States is the adjunctive use of mechanical tools, including balloon maceration, pharmacomechanical devices such as Angiojet and Trellis, and aspiration catheters. Such techniques may both result in shorter treatment times and improved patency, possibly reducing complications (although the major bleeding complications in CaVenT happened during the first 24 hours of infusion).

Overall the authors proved that CDT is safe. Most of their complications were access site bleeds, most commonly from calf and inguinal punctures, leading them to conclude that popliteal access was the safest route. Part of this conclusion stemmed from the need for multiple punctures for tibial vein access, and they emphasized the importance of an experienced practitioner skilled in ultrasound-guided access.

Several questions remain unanswered from the original CaVenT study. First, PTS was treated as a Boolean variable; the authors do not provide data on the severity of PTS. For example, it would be interesting to know how many patients later developed venous ulcers in each group. Second, the subgroup analysis did not report whether PTS or patency outcomes were different between iliofemoral and femoral DVTs.

In conclusion, Haig et al. provided confirmation of the â&#x20AC;&#x153;open-veinâ&#x20AC;? hypothesis, that by achieving venous patency, patients are at less risk for developing the post-thrombotic syndrome. They should be congratulated for providing some more insight into the treatment arm of this seminal study. They impressively treated patients on average 5 days after symptom onset. They confirmed the safety of performing CDT without the routine use of IVC filters, although it should be noted that they did not employ mechanical techniques. As suspected, they were still limited by the relatively low N, and hopefully the much larger ATTRACT trial will clarify some of the uncertain but important issues surrounding CDT in the treatment of acute lower extremity deep venous thrombosis.

3 Chung JW, Chang JY, Jung SI, et al. Acute iliofemoral deep vein thrombosis: evaluation of underlying anatomic abnormalities by spiral CT venography. J Vasc Interv Radiol 2004; 15:249-256

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Hosted by the American College of Phlebology in conjunction with the International Union of Phlebology, the UIP XVII World Meeting will bring together respected faculty, physicians and health care professionals from across the globe to showcase the most advanced research, technology and treatments in the field of vein care.

at uip2013.org

The program has been developed for practioners at all levels and includes: daily topical symposia from luminaries in the field of phlebology, formal nursing and ultrasound programs, paper & poster sessions, and discussions of controversial topics. Along with traditional didactic lecture formats, special emphasis has been placed on hands-on and simulation sessions to enhance the learning process. In addition, all plenary sessions will feature Spanish translation.

You will not want to miss this incomparable event with peers and exhibitors from all over the world.

World Meeting of the International Union of Phlebology /// September 8–13, 2013 Hynes Convention Center • Boston, Massachusetts • USA

510.346.6800 | www.uip2013.org | www.phlebology.org

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Note: This meeting will take the place of the 2013 ACP Annual Congress advancing vein care