Management of superficial vein thrombosis

Transcription

1 Journal of Thrombosis and Haemostasis, 13: DOI: /jth REVIEW ARTICLE Management of superficial vein thrombosis B. COSMI Department of Angiology & Blood Coagulation, S. Orsola-Malpighi University Hospital, Bologna, Italy To cite this article: Cosmi B. Management of superficial vein thrombosis. J Thromb Haemost 2015; 13: Summary. Superficial vein thrombosis (SVT) is less well studied than deep vein thrombosis (DVT), because it has been considered to be a minor, self-limiting disease that is easily diagnosed on clinical grounds and that requires only symptomatic relief. The most frequently involved sites of the superficial vein system are the lower limbs, especially the s, mostly in relation to varicosities. Lower-limb SVT shares the same risk factors as DVT; it can propagate into the deep veins, and have a complicated course with pulmonary embolism. Clinical diagnosis may not be accurate, and ultrasonography is currently indicated for both confirmation and evaluation of SVT extension. Treatment aims are symptom relief and prevention of venous thromboembolism (VTE) in relation to the thrombotic burden. SVT of the long within 3 cm of the saphenofemoral junction (SFJ) is considered to be equivalent to a DVT, and thus deserving of therapeutic anticoagulation. Less severe forms of lower-limb SVT not involving the SFJ have been included in randomized clinical trials of surgery, compression hosiery, non-steroidal anti-inflammatory drugs, unfractionated heparin, and low molecular weight heparins, with inconclusive results. The largest randomized clinical trial available, on 3004 patients with lower-limb SVT not involving the SFJ, showed that fondaparinux 2.5 mg once daily for 6 weeks is more effective than placebo in reducing the risk of the composite of death from any cause and symptomatic VTE (0.9% versus 5.9%). Further studies are needed to define the optimal management strategies for SVT of the lower limbs and other sites, such as the upper limbs. Keywords: anticoagulants; fondaparinux; heparin; ultrasonography; varicose vein; venous thromboembolism. Correspondence: Benilde Cosmi, Department of Angiology & Blood Coagulation, University Hospital S. Orsola-Malpighi, Via Albertoni, 15 Bologna, Italy. Tel.: ; fax: benilde.cosmi@unibo.it Received 5 February 2015 Manuscript handled by: F. R. Rosendaal Final decision: F. R. Rosendaal, 16 April 2015 Introduction Thrombosis of the superficial venous system has traditionally been considered to be a benign, self-limiting condition, distinct from thrombosis of the deep veins and requiring only clinical diagnosis and symptomatic relief [1]. As a result, it is less studied than thrombosis of the deep vein system, receiving much less attention in medical journals and textbooks. Superficial vein thrombosis (SVT) is currently the preferred term to indicate thrombosis of the superficial vein system; however, it encompasses many conditions indicated in the past, and even currently, such as the following: superficial phlebitis or superficial thrombophlebitis inflammation of superficial veins without or with thrombosis; infusion thrombophlebitis resulting from catheter insertion, venipuncture, or intravenous drug infusion; varicose vein thrombosis thrombosis involving dilated, tortuous veins, usually in subcutaneous tissue of the legs; suppurative (septic) thrombophlebitis; a misnomer superficial femoral vein thrombosis; and two eponyms, i.e. Mondor s disease thrombophlebitis involving the breast or the dorsal penile vein, and Trousseau s syndrome migratory thrombophlebitis associated with malignancy, particularly adenocarcinoma of the pancreas. These different terms are related to the different sites and etiologies of SVT. Lower-limb SVT is typically diagnosed in outpatients, and it has been estimated to be more frequent than deep vein thrombosis (DVT) in studies conducted in secondary and tertiary care [2]. The STEPH study [2] was conducted in primary care in a community of people in France, and found a yearly rate of lower-limb SVT of 0.64 per This is a lower incidence than that of venous thromboembolism (VTE), which is estimated to be 1 in 1000 per year [3]. In this study [2], the long saphenous vein was involved in 50 60% of cases, the short in 11 15%, and tributaries of long and short s in 30 40% (Fig. 1). Lower-limb SVT can extend into the deep veins, with the risk of development of pulmonary embolism (PE) (Fig. 1); in the STEPH study, concomitant DVT and PE were observed in 24.6% and 4.7% of patients, respectively [2]. Lowerlimb SVT shares common risk factors with DVT, including advanced age, obesity, active cancer, previous thromboembolic episodes, pregnancy, oral contraceptive use,

2 1176 B. Cosmi Superficial circumflex iliac vein Anterior circumflex of the thigh Anterior accessory of the thigh Deep femoral vein Femoral vein Superficial epigastric vein Saphenofemoral junction Superficial external pudendal vein Posterior circumflex of the thigh Great Mid thigh perforating vein superficial veins was considered to be adequate for SVT, without the need for any confirmatory objective testing. Thrombectomy and ligation of the thrombosed superficial vessels were state-of-the-art treatments. Modern studies on the diagnosis and management of VTE were initiated mostly by internists and hematologists only in the second half of the last century; however, SVT was not considered in these trials [1]. As a result, studies on SVT diagnosis and treatment are still scarce in comparison with the vast amount of methodologically sound literature available for the diagnosis and treatment of VTE. For the purpose of this review, the diagnosis and treatment of SVT of the lower and upper limbs, as well as of other sites, will be discussed. Popliteal vein Anterior accessory of the leg Anterior tibial vein Posterior tibial vein Perforating vein of the femoral canal Paratibial perforating vein Posterior accessory of the leg Posterior tibial perforating veins Medial marginal vein Fig. 1. Superficial and deep venous system of the lower limbs. From: Kundu [59]. hormone replacement therapy, recent surgery, and autoimmune diseases (particularly Behcet s and Buerger s diseases) [4 6]. However, unlike in DVT, varicose veins constitute the main risk factor for lower-limb SVT, as they are present in 80 90% of cases [2,5,6]. The overall 3-month mortality rate for SVT is < 1%, as opposed to approximately 5% in patients with DVT and 9 17% in patients with PE [7], because of the lower burden of comorbidities [5]. Thrombosis can also affect superficial veins in other parts of the body, such as the abdominal wall, thoracic wall, penis (Mondor s phlebitis), or neck, although rarely and mostly with a self-limiting course [8]. Superficial veins of upper limbs are frequently affected in hospitalized patients, with an estimated frequency of 25 35%, especially in association with short peripheral venous catheters or after peripheral vein infusions or venipuncture [9]. Unlike the signs and symptoms of lower-limb DVT, which can be asymptomatic and difficult to diagnose solely on clinical grounds, those of SVT are mostly attributable to inflammation of the vein walls and surrounding tissues, and can therefore be easily detected. For many years, clinical diagnosis based on the observation of red tender palpable cords of the skin along a segment of Diagnosis of SVT No diagnostic gold standards have been defined for SVT. The symptoms and signs of SVT are mostly attributable to its inflammatory components, such as pain, tenderness, swelling, warmth, and erythema, with a palpable cord along the course of a superficial vein. These clinical manifestations are straightforward, and objective testing may therefore not be considered to be mandatory for SVT diagnosis. Moreover, primary-care physicians, who frequently encounter SVT, may be reluctant to ask for additional testing, as clinical diagnosis may be considered to be sufficient for treatment choices. However, clinical characteristics may not be sufficient to confirm the diagnosis of SVT, as many other conditions, especially dermatologic conditions (Table 1), may mimic SVT [10]. Moreover, clinical assessment alone frequently underestimates the true extent of thrombosis, which may propagate from superficial into deep veins [11,12]. Data on the sensitivity and specificity of the clinical diagnosis of SVT are lacking, as is a scoring system based on those clinical features that make SVT more likely [13]. Ultrasonography is currently the objective test of choice for confirming the clinical suspicion of SVT, as the superficial veins can be easily explored [14]. The same principles of DVT diagnosis with compression ultrasonography (CUS) can be applied to SVT diagnosis, namely lack of compressibility of a superficial vein segment, and impairment of blood flow through the same venous Table 1 Dermatologic conditions in the differential diagnosis of superficial vein thrombosis Erysipelas Cellulitis Lymphangitis Chronic dermatitis Lyme disease Erythema nodosum Cutaneous manifestations of immunologic or rheumatologic disorders

3 Superficial vein thrombosis management 1177 segment [14]. Ultrasonography allows not only diagnostic confirmation of lower-limb or upper-limb SVT, but also evaluation of the true extent of SVT and exclusion of concomitant DVT. Lower-limb SVT carries a relevant risk of thromboembolic complications, as shown by two observational studies (POST and OPTIMEV) in which 23% of patients presenting with isolated lower-limb SVT also had DVT, with half being non-contiguous and 17% in the contralateral limb [15]. The analysis also attempted to examine which ultrasonographic risk factors make a DVT more likely. The involvement of the perforating veins or an SVT < 3 cm from the saphenofemoral junction (SFJ) was found to increase the risk significantly. Indeed, the proximity of SVT to the SFJ has long been accepted as a risk factor for the development of complications [13]. Unlike for DVT, no validated diagnostic algorithms are available for lower-limb SVT. Few studies on the diagnostic accuracy of D-dimer testing in this condition are available, with varying estimates of sensitivity and specificity, but with a high false-negative rate [16 18]. We have recently evaluated the diagnostic accuracy of D-dimer testing for suspected DVT and/or SVT of the upper limbs [19]. At the initial diagnostic work-up, SVT was found in 35 of 239 patients (14.6%), with a D-dimer sensitivity and specificity of 77% (95% confidence interval [CI] 59 89) and 60% (95% CI 52 67), respectively, and a negative predictive value of 93% (95% CI 86 97). Our study also confirmed that a negative D-dimer test result is also less reliable in patients with suspected upper-limb SVT, being falsely negative in > 20% of patients, possibly because of the low thrombotic burden of SVT. More recently, the ARMOUR study [20] evaluated an algorithm consisting of the sequential application of a clinical decision score (Constans score), D-dimer testing and ultrasonography for the diagnosis of upper-limb DVT and/or SVT in both inpatients and outpatients. Patients were first categorized as likely or unlikely to have thrombosis; in those with an unlikely score and normal D-dimer levels, DVT/SVT was excluded. All other patients had (repeated) CUS. The primary outcome was the 3-month incidence of symptomatic DVT and PE in patients with a normal diagnostic work-up. In 87 patients (21%), an unlikely score combined with normal D-dimer levels excluded DVT/SVT. SVT and DVT were diagnosed in 54 (13%) and 103 (25%) patients, respectively. No SVTs were diagnosed at the 3-month follow-up, and one only patient with a normal initial diagnostic work-up developed upper-limb DVT, giving an overall failure of rate of 0.4% (95% CI ). This study suggested that a diagnostic management strategy using the Constans clinical score, D-dimer testing and (repeated) ultrasonography can safely and effectively exclude both DVT and SVT of the upper limbs. However, the study was not powered to show the safety of the various substrategies used to exclude DVT and SVT. Owing to the scarcity of methodologically sound studies, the approach to SVT diagnosis in clinical routine is variable, and depending on local resources, and unlike for DVT diagnosis, the need for testing is unclear, and it may still be considered to be neither mandatory nor urgent. A survey [21] on diagnosis and management strategies for lower-limb SVT was conducted among attendees of the American Venous Forum meeting in 2011, with the majority (365/487; 75%) being classified as North American, and the rest representing the global community. Although the validity of the survey was limited by the specialists involved, who were typically surgeons and varicose vein specialists, it provided some insights into the variety of practitioners still involved in SVT management in different countries, including family practice physicians, dermatologists, internists, phlebologists, cardiologists, interventional radiologists, general surgeons, and vascular surgeons, resulting in further management variation. The key difference between the US and global community physicians was in the initial SVT diagnostic study: US physicians ordered fewer bilateral duplex ultrasonography scans and more unilateral duplex ultrasonography scans (49.6% versus 58.2%, and 39.7% versus 34.4%; P = 0.046), with 6% of both groups indicating no need for ultrasonography. However, concomitant contralateral DVT [2,6] can be detected in 17% of subjects with SVT, and this should make CUS of both lower limbs mandatory also for clinically suspected SVT. Recently Scott et al. [13] have proposed an algorithm for the management of clinically suspected lower-limb SVT (pain, erythema, warmth, and hardness along the course of the superficial vein) in which CUS is mandatory. The timing of CUS for the exclusion of SVT is not discussed by Scott et al. [13]; however, as for suspected DVT, it is reasonable to recommend urgent testing with ultrasonography within h for suspected SVT of the lower, and possibly the upper, limbs, and, if the clinical suspicion is high, to administer therapeutic doses of low molecular weight heparin (LMWH) while waiting for CUS [22] (Fig. 2; Table 2). However, these are experts opinions, and fur- DIAGNOSIS OF SVT (any site) Clinically suspected SVT (pain, erythema, warmth and hardness along the course of the superficial vein) Ultrasonography (CUS) within h (bilateral if lower limbs are involved) (if high clinical suspicion for lower-limb or upper-limb SVT: therapeutic doses of LMWH while waiting for ultrasonography to exclude concomitant DVT Fig. 2. Algorithm for the diagnosis of superficial vein thrombosis (SVT). CUS, compression ultrasonography; DVT, deep vein thrombosis; LMWH, low molecular weight heparin.

4 1178 B. Cosmi Table 2 Key points for diagnosis and treatment of superficial vein thrombosis Lower limbs are the most frequent sites of SVT, mostly related to varicose veins Ultrasonography within h is indicated for both confirmation and evaluation of SVT extension in any site and concomitant DVT for the lower and upper limbs Treatment aims are symptom relief and prevention of VTE in relation to the thrombotic burden SVT of the long within 3 cm of the SFJ is considered tobe equivalent to a DVT, and therapeutic anticoagulation is therefore indicated In the largest randomized trial in patients with SVT of the lower limbs of at least 4 5 cm in length and not involving the SFJ, fondaparinux 2.5 mg once daily for 6 weeks was more effective than placebo in reducing the risk of the composite of death from any cause and symptomatic VTE (0.9% versus 5.9%) The optimal treatment of SVT of other sites (upper limbs, neck, abdominal wall, thoracic wall, and penis) is not well established DVT, deep vein thrombosis; SFJ, saphenofemoral junction; SVT, superficial vein thrombosis; VTE, venous thromboembolism. ther management studies are required to test the validity of these approaches. Once a diagnosis of SVT has been confirmed and the etiology established, clinical monitoring of the patient is sufficient. There is no need to systematically repeat ultrasonography scans, unless there are new or worsening symptoms [23], as shown in a post hoc analysis of a prospective, multicenter, cohort study (POST), in which a repeated ultrasonography scan 8 5 days after the initial test detected a few asymptomatic thromboembolic events, but failed to identify patients at risk of thromboembolic events during follow-up. There are no studies on the diagnostic accuracy of D-dimer testing or ultrasonography for SVT of other sites, such as the abdominal wall, thoracic wall, or penis. For these, however, it is reasonable to propose ultrasonography with CUS as the test of choice to confirm suspected SVT. Management of lower-limb SVT No consensus has yet been reached regarding the optimal management of symptomatic isolated SVT (without concomitant DVT or PE). Disease severity varies according to the thrombotic burden, because of different risks of thromboembolic complications [11]. SVT with a small thrombus (empirically defined as less than 4 5 cm in length on ultrasonography) has been considered to be minor, benign, and self-limiting, requiring only symptom relief, whereas SVT with a significant thrombus burden (greater than 4 5 cm in length) would require more aggressive treatment, because of the higher risk of extension [24]. Randomized clinical trials have included patients with the most frequent locations of SVT, i.e. the long and short s, because of the higher risk of extension into the deep vein system through the saphenofemoral/saphenopopliteal junction [25,26]. In general, SVT of a long with the thrombus head within 3 cm of the SFJ has been traditionally excluded from interventional studies, as it is considered to be equivalent to a DVT with regard to its high risk of progression (10 70%) [10]. In the POST observational study, the distance between the head of the thrombus and the SFJ was < 3 cm in 20% of cases of SVT, and extension to perforating veins was observed in 13.8%, with concomitant DVT in 23% [6]. A cut-off value of 3 cm from the SFJ has been traditionally chosen for defining SVT extension, because most authors and consensus groups emphasize that extensions involving the SFJ, but also the perforating veins, are associated with an increased risk of thrombus propagation into the deep venous system and thus of PE [27 29]. However, few data are available on the natural history of patients presenting with an SVT extension, whether progressing to within < 3cmorto> 3 cm from the SFJ, and the optimal therapeutic strategy to manage this complication remains unclear. A post hoc analysis of the placebo arm of the double-blind randomized CALISTO study [30] of fondaparinux in SVT showed that, in 1500 patients, the risk of subsequent DVT or PE was similar whether symptomatic extension progressed to < 3cmor> 3 cm from the SFJ: 9.3% and 8.9%, respectively, with similar use of medical resources in both groups. Thus, the authors concluded that patients with SVT extension are at significant risk for thrombotic complications, and proximity to the SFJ in acute SVT of the long should not be used as an indicator of a higher risk of subsequent complications. A post hoc analysis of the STEFLUX [31] study of LMWH for SVT of at least 4 5 cm of the lower limbs has shown that, after treatment had been stopped, the composite of VTE and SVT recurrence or extension was associated with the absence of varicose veins and previous VTE and/or SVT and/or a family history of VTE. However, patients presumed to have the highest risk for complications were excluded from the initial CALISTO trial and from the STEFLUX study, such as those presenting with thrombus within 3 cm of the SFJ, those with cancer, and those with any condition favoring bleeding, whereas patients with recent SVT or DVT/PE were excluded only form the CALISTO trial. Optimal treatment approaches for these patient populations have yet to be determined [32]. A recent Cochrane review [25] on treatment of lowerlimb SVT led to inconclusive results, as randomized controlled trials were mostly small and of poor quality, with only a minority comparing treatment with placebo, and none evaluating the same treatment comparisons on the same study outcomes (which precluded meta-analysis). Treatment ranged from surgery to non-steroidal antiinflammatory drugs (NSAIDs), oral (vasotonin, heparan sulfate, sulodexide, oxyphenbutazone, vitamin K antago-

5 Superficial vein thrombosis management 1179 nists, and oxerutins), intramuscular (desmin) or intravenous (enzyme) treatment, and parenteral treatment with anticoagulants such as fondaparinux, LMWH, and unfractionated heparin (UFH). For the purpose of this review, only the roles of surgery, NSAIDs, graduated compression elastic stockings and anticoagulants will be considered. Surgery Surgery has traditionally been one option for treating isolated lower-limb SVT, not only for symptom relief but also for stopping thrombus progression into the deep venous system and reducing the PE incidence. Interventions range from ligation of the SFJ to ligation and stripping of the phlebitic veins. In the case of varicose veins, a local thrombectomy has been proposed, especially when the SVT is very painful [33], as well as stripping or sclerotherapy [34], but the optimal timing and benefit of these procedures in relation to SVT onset are not known. Indeed, they can induce hemostasis activation [35] and provoke massive PE [36]; as a result, performing these procedures during the acute phase of an SVT could be deleterious [37]. Moreover, in this situation, symptomatic PE has been described in up to 6% of patients [37]. Only three randomized clinical trials of surgical treatment [38 40] were included in the Cochrane review on lower-limb SVT treatment [24], comparing surgical saphenofemoral disconnection with LMWH (enoxaparin 1 mg kg 1 twice daily for the first week, then 1mgkg 1 for 3 weeks) [37] or surgery combined with elastic stockings versus elastic stockings alone, thrombectomy plus elastic stockings with or without rutosides, and ligation or stripping of the vein plus elastic stockings [38,39]. These studies had all major design flaws, such as an unclear method of allocation or randomization, lack of a placebo control, or an unacceptably high dropout rate. All of these limitations weaken the validity of these studies, and cast doubts on the actual efficacy and safety of surgical treatments of SVT. A qualitative review [41] of five retrospective and prospective studies and one randomized controlled trial of surgical treatment of SVT of the lower limb has suggested that heparin followed by oral anticoagulants is more effective than surgical treatment (SFJ ligation alone or with vein stripping with or without perforating vein ligation) in preventing DVT and PE in SVT of the great in the thigh. Surgical treatment was associated with a 2% risk of PE and extension into the deep venous system in 3.4% of cases. On the basis of these data, at present, surgery should not be considered for lower-limb SVT, in accordance with recent guidelines, which suggest only medical therapy [22,26]. Surgical excision, or exclusion of the vein, has been proposed for refractory or recurrent cases of lower-limb SVT, but no data are available on the surgical treatment of recurrent SVT. Elastic stockings and NSAIDs Elastic stockings in addition to NSAIDS, the latter as pills and /or topical cream, have traditionally and empirically been employed for symptomatic relief of the inflammatory components of SVT clinical manifestations. The duration of these treatments is variable, usually between 7 days and 14 days, although no data are available on the optimal degree of compression required or the duration of use for elastic stockings. Moreover, compression hosiery may be recommended for varicose veins [42]. In the placebo arm of the STENOX study [24], in which all patients with lower-limb SVT of at least 5 cm received elastic bandages or stockings, the placebo treatment group had a rate of DVT and/or PE and of symptomatic and asymptomatic recurrence or extension towards the SFJ of 17% from days 1 97, which was similar to that observed in any of the other active treatment arms, such as prophylactic enoxaparin or enoxaparin 1.5 mg kg 1. However, the study was prematurely stopped, and it was underpowered to detect differences among the treatment groups. Recently a single-center randomized controlled trial [43] showed no effect of compression stockings (23 32 mmhg at the ankle) for 3 weeks versus no compression on pain resolution, consumption of analgesics, thrombus regression or improvement in quality of life in 80 patients with isolated SVT of the legs of at least 5 cm. All patients received prophylactic LMWH, with NSAIDs being allowed. However, the study was underpowered to detect any significant difference in main outcomes, and had no blinded outcome assessment. The role of elastic stockings is therefore uncertain, and current guidelines do not mention elastic stockings for lower-limb SVT [22,26], although they are routinely prescribed, unless contraindicated. In the STENOX study [24], oral tenoxicam for 8 12 days was associated with lower rates of SVT extension and/or recurrence than placebo, and there was no association of NSAIDs with reductions in VTE rates. The guidelines of the British Committee for Standards in Haematology recommend that NSAIDs should be offered for 8 12 days, unless contraindicated, to those patients with SVT at low risk for complications (grade 1A) [26]; these could be those with thrombus less than 4 5 cmin length and without additional risk factors, such as cancer, previous SVT/VTE, or an absence of varicose veins, although no clear definition of such low-risk SVT is provided. Anticoagulants Antithrombotic agents have been proposed since the recognition of thromboembolic complications of SVT. The guidelines of the British Committee for Standards in Haematology recommend that confirmed SVTs within 3 cm

6 1180 B. Cosmi of the SFJ, which constitute the most severe spectrum of disease, should be considered for therapeutic anticoagulation (2B), although the optimal duration is uncertain [26]. For SVTs of intermediate severity, such as those with thrombus length of > 4 5 cm and not involving the SFJ, alternative treatments with variable doses and durations of UFH [44], LMWH and fondaparinux have been evaluated [24,45 48]. There was insufficient evidence to establish an association of LMWH with benefit or harm as compared with topical heparin gel, NSAIDs, or surgical therapy [44]. Randomized controlled trials with UFH or LMWH did not clearly demonstrate whether a prophylactic or therapeutic dose or a short or longer (from 10 days to 4 weeks) treatment duration were effective in reducing the risk of DVT and/or PE, mostly because of the lack of statistical power. Two studies compared different LMWH regimens head-to-head, but without using a placebo or an inactive control group [46,47]. The results suggested that 30-day intermediate doses or therapeutic doses of LMWH were associated with a trend for lower VTE event rates than shorter courses of intermediate doses or lower doses of LMWH, with no increases in major bleeding [44]. A synthetic heparin derivative, the pentasaccharide fondaparinux, was evaluated for SVT treatment in the doubleblind, randomized, placebo-controlled CALISTO study [48]. This is the largest trial conducted in SVT treatment, and it had the statistical power to show an effect on VTE complications. In 3004 subjects with SVT of the long of at least 5 cm, a prophylactic dose of fondaparinux (2.5 mg once daily) for 6 weeks was more effective than placebo, with a significant reduction in the composite endpoint of death from any cause and symptomatic events (PE/DVT or symptomatic extension to the SFJ or SVT recurrence) (0.9% in the fondaparinux group versus 5.9% in the placebo group) during a follow-up of up to 77 days. On the basis of this study, the American College of Chest Physicians (ACCP) guidelines suggest prophylactic-dose fondaparinux over prophylactic dose LMWH for lower-limb SVT (grade 2C) [22]. The guidelines of the British Committee for Standards in Haematology recommend prophylactic doses of LMWH for 30 days (currently an unlicensed indication) or fondaparinux 2.5 mg once daily for days in patients with SVT and risk factors for extension, recurrence, or progression (grade 1B) [26] (Table 2). Figure 3 shows proposed treatments for SVT of lower limbs, on the basis of thrombotic burden and also considering guidelines and experts opinions. A cost-effectiveness analysis has robustly shown that fondaparinux for 45 days does not appear to be costeffective when used in all patients with isolated SVT of the legs, when costs in US dollars are considered [49]. However, the results of cost-effectiveness studies depend on the overall cost of managing the disease, which includes not only the cost of the drug treatment assessed but also other expenditures, and may vary greatly from TREATMENT OF SVT OF THE LOWER LIMBS 1- Low-risk SVT * : thrombus length < 4 5 cm and > 3 cm from saphenofemoral/saphenopopliteal junction (topical or oral) NSAIDs for 8 12 days 2- Intermediate-risk SVT ** : thrombus length > 4 5 cm and > 3 cm from saphenofemoral/saphenopopliteal junction Fondaparinux 2.5 mg daily for 45 days or intermediate/therapeutic dose LMWH for 4 6 weeks 3-High risk SVT : thrombus < 3 cm from saphenofemoral junction (possibly also saphenopopliteal junction) Therapeutic anticoagulation as for DVT Vitamin K antagonists (possibly NOAC) for 3 months (if varicose veins, graduated compression elastic stockings in all cases, unless contraindicated) * Previous SVT/VTE and absence of varicose veins may indicate treatment as for intermediate-risk SVT. ** Previous SVT/VTE or a family history of SVT/VTE and absence of varicose veins may suggest a longer course (6 weeks) of intermediate/therapeutic-dose LMWH. Presence of active cancer may suggest long-term treatment, possibly with prophylacticdose LMWH, after the first month of intermediate/therapeutic-dose LMWH. Fig. 3. Algorithm for the treatment of superficial vein thrombosis (SVT) of the lower limbs. DVT, deep vein thrombosis; LMWH, low molecular weight heparin; NOAC, new oral anticoagulant; NSAID, non-steroidal anti-inflammatory drug; VTE, venous thromboembolism. one country to another, with the cost of fondaparinux possibly being further reduced once generics become available [5]. A 45-day course of treatment may be excessive in some patients, especially if the SVT is limited and they do not have drug payment coverage. Both the STE- NOX study [24] and the STEFLUX study [47] showed that 10 days of treatment of SVT of the lower limbs with a thrombus of 4 5 cm in length, with LMWH prophylactic doses, was associated with a higher risk of recurrence, especially in the first month. Shorter durations (e.g. 2 3 weeks) of either prophylactic LMWH or fondaparinux could be considered for low-risk SVT, although no data are available to support this approach. Better value for money could be obtained in subgroups of patients with a higher incidence of VTE after SVT, and longer durations of treatment should be further evaluated in future clinical studies. A post hoc analysis of the STE- FLUX [31] study has shown that the composite of symptomatic and asymptomatic DVT, PE and SVT recurrence or extension during treatment was associated with previous VTE and/or SVT and/or a family history of VTE (odds ratio [OR] 2.5; 95% CI ). After treatment had been stopped, only the absence of varicose veins (OR 2.5; 95% CI ) and previous VTE and/or SVT and/or a family history of VTE (OR: 1.9; 95% CI ) were significantly associated with outcomes. SVT patients with these factors may require higher-intensity and/or longer-duration anticoagulant treatment.

7 Superficial vein thrombosis management 1181 Currently, no data are available on the effectiveness of direct oral anticoagulants for SVT; however, studies are now being performed with rivaroxaban versus fondaparinux (ClinicalTrials.gov identifier NCT ). Thrombophilia and cancer screening in SVT Inherited thrombophilic alterations have a similar frequency in SVT patients and DVT patients [50]; however, there are no data to suggest that the presence of thrombophilia should alter the management of SVT, or influences the rates of SVT recurrence or progression. The UK guidelines [26] do not recommend routine investigation of patients with SVT for underlying thrombophilia, and existing guideline criteria for thrombophilia screening should be followed (1B). The association of SVT and cancer was described by Trousseau in 1865 as a recurrent and migratory pattern of inflammation of superficial veins, frequently in unusual sites such as the arm or chest [51]. Despite the long time since Trousseau syndrome was described, no data are available on the best treatment of such a condition, or the optimal screening for an occult malignancy after SVT. Van Dormaal et al. [52] followed up 250 patients with SVT diagnosed clinically by family physicians in any site and without ultrasonography at study entry. In only five of these 250 patients (2%; 95% CI 1 5) a new malignancy was diagnosed within 2 years after their SVT, as compared with 2% (95% CI 1 4) in a matched control group. In a retrospective investigation of a CALISTO study subgroup [53], in 737 consecutive patients with isolated lower-limb SVT not involving the SFJ, the risk of malignancies or arterial cardiovascular events was similar to that observed in 1438 matched controls followed up for an average period of 26 8 months. Malignancy was diagnosed in 3.5% and 3.9% of cases and controls, respectively, and arterial cardiovascular events occurred in 4.3% and 4.4%, respectively. This suggests that screening for cancer is not indicated after a single episode of isolated SVT not involving the SFJ. However, Sorensen et al. [54] evaluated 7663 patients with SVT, with DVT and with PE in the Danish National Registry, and found similar standardized incidence ratios of cancer in the first year of follow-up. However, the authors concluded that the practical consequences for screening seemed to be remote, as persons with venous thrombosis/embolism would have to be investigated for the 304 excess cancers to be found during the first year of follow-up. No randomized controlled trials are available on the best treatment for cancer-related lower-limb SVT. Regardless of the underlying mechanisms, the primary approach to treating Trousseau s syndrome is to eliminate the causative tumor, if possible. Although this is often not feasible, the recurring theme in the literature is that UFH or LMWH is the preferred treatment, as it can inhibit the binding of leukocyte and platelet selectins to their ligands and also a wide variety of inflammatory cytokines and chemokines, unlike vitamin K antagonists (e.g. warfarin) or direct thrombin inhibitors [51]. Indeed, UFH or LMWH should be continued indefinitely for patients with active cancer, and there are many reports of marked and even catastrophic acceleration of thrombosis on discontinuation of heparin in Trousseau s syndrome for even 1 day [51]. SVT in pregnancy Pregnant women have usually been excluded from studies of SVT treatment. However, pregnancy is a risk factor for both VTE and SVT, and also for the development of varicose veins during pregnancy. UFH and LMWH do not cross the placenta, and are the agents of choice, in addition to elastic stockings and topical NSAIDs, as oral extended NSAID use is discouraged in pregnancy after weeks of gestation. However, the optimal doses and duration of SVT treatment during pregnancy are uncertain. The Society of Obstetricians and Gynaecologists of Canada [55] recommendations are as follows; prophylactic-dose or intermediate-dose LMWH for 1 6 weeks is recommended for women with bilateral SVT, for very symptomatic women, and for SVT located 5 cm from the deep venous system (SFJ and saphenopopliteal junction) or affecting 5 cm of the vein (I-A). Observation alone is recommended in women with SVT at low risk for DVT and for those who do not require symptom control. Clinical follow-up of these women should occur within 7 10 days, with a repeat CUS within 1 week (I-A). Management of upper-limb SVT Peripheral vein infusion SVT occurs in 25 35% of hospitalized patients with peripheral intravenous catheters, and has both patient-related implications (e.g. sepsis) and economic consequences (e.g. extra nursing time). The duration of catheterization, catheter-related infection and catheter material are important risk factors for peripheral vein infusion thrombophlebitis, whereas patient-related risk factors are not well elucidated [56]. The best treatment options for peripheral infusion SVT are uncertain. The initial treatment for any form of SVT is to stop the infusion and remove the catheter. An anti-inflammatory cream or gel can be directly applied to the area. Antiinflammatory analgesics can be prescribed to treat both the inflammation and the pain associated with SVT [57]. No data are available on the use of antithrombotics in peripheral infusion SVT. Management of SVT in other sites No data are available for Mondor s disease (thoracic wall, abdominal wall or penile SVT) treatment. The

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