1

2 Definition Definition Causes Causes Risk Factors Risk Factors Symptoms Symptoms Importance Importance Treatments Treatments Content Introduction Aims Methods Results Conclusions Collecting Articles Collecting Articles Research Question Research Question Query Query Inclusion / Exclusion criteria Inclusion / Exclusion criteria Data to extract from the articles Data to extract from the articles Variables for data extraction Variables for data extraction Study type Study type Follow-up Follow-up Participants Participants Treatments applied Treatments applied

Superficial Venous Thrombosis of the Lower Limbs Superficial venous thrombosis consists in the formation of a blood clot in a superficial vein. Most commonly, it affects the lower limbs. Under normal physiological conditions, there is a continuous formation of clots in the veins, but they disintegrate rapidly, not causing any harm. Definition Methods Aims Introduction Results Conclusions 3

Superficial Venous Thrombosis of the Lower Limbs  Varicose veins;  Hormone therapy;  Family history;  History of malignancy; Risk Factors Uncu H., 2009  Cigarette smoking;  Obesity;  Diabetes… Methods Aims Introduction Results Conclusions 4

Superficial Venous Thrombosis of the Lower Limbs Causes Methods Aims Introduction Results Conclusions 5

Symptoms Superficial Venous Thrombosis of the Lower Limbs Pain Redness of the skin with increase of temperature Induration Edema (swelling) Fever Methods Aims Introduction Results Conclusions 6

SVT Saphenofemoral junction Perforator veins Saphenopopliteal junction DVT (deep venous thrombosis) The thrombus can detach and clot the pulmonary artery Pulmonary Embolism Importance The thrombus can reach the deep venous system through: Methods Aims Introduction Results Conclusions 7

Superficial venous thrombosis rarely causes serious complications,BUT In some cases, SVT can evolve (Litzendorf and Satiani, 2011): 6-40% - Deep Venous Thrombosis (DVT); 2-13% - Pulmonary embolism. Superficial Venous Thrombosis of the Lower Limbs Importance - statistics Methods Aims Introduction Results Conclusions 8

Treatment temporal evolution Elastic compression bandages and anti-inflammatory creams Surgery (patients with serious pain) Medical therapy – Drugs* Superficial Venous Thrombosis of the Lower Limbs (Decousus H, Epinat M, Guillot K, 2003) Methods Aims Introduction Results Conclusions * There is still no consensus about using surgery as a possible treatment. Therefore, in some cases, it is still used. 9

Superficial Venous Thrombosis of the Lower Limbs Treatments Possible Treatments Symptomatic control Surgery (cut of the saphenofemoral junction) Drugs: - Warfarin; - Low Molecular Weight Heparin; - Nonsteroidal Anti-inflammatory Agent; - Xabans (Direct Xa factor inhibitor); - Fondaparinux (indirect Xa factor inhibitor) If SVT has a history longer than one week, medical therapy is considered to be more effective than surgical therapy (Bergqvist D, Brunkwell J, Jensen N, Persson NH 1990) Methods Aims Introduction Results Conclusions 10

Costs Compressions alone had the lowest costs Medical costs Treatments including LMWH had the highest costs Medical costs Lost of working days and/or inactivity was higher in the subjects treated only with stockings Social costs (Belcaro G. et al, 1999) Superficial Venous Thrombosis of the Lower Limbs Methods Aims Introduction Results Conclusions 11

Superficial Venous Thrombosis of the Lower Limbs Aims Methods Aims IntroductionResults Conclusions Discovering the possible treatments Evaluate their results and complications 12

Databases used: Pubmed Scopus ISI Web of Knowledge Superficial Venous Thrombosis of the Lower Limbs Collecting Articles Methods AimsIntroductionResults Conclusions 13

Superficial Venous Thrombosis of the Lower Limbs Research Question: Which are the results and complications of Superficial Venous Thrombosis’ treatments? Superficial Venous Thrombosis of the Lower Limbs Methods AimsIntroductionResults Conclusions 14

SVT of the Lower Limbs Results/ complications Treatment Our aim Aim to achieve with the queries Superficial Venous Thrombosis of the Lower Limbs Methods AimsIntroductionResults Conclusions 15

Venous Thrombosis – Entry Terms Thrombosis, Venous; Thromboses, Venous; Venous Thromboses; Phlebothrombosis; Phlebothromboses; Deep Vein Thrombosis; Deep Vein Thromboses; Thromboses, Deep Vein; Vein Thromboses, Deep Venous Thrombosis, Deep; Deep-Vein Thrombosis; Deep-Vein Thromboses; Thromboses, Deep-Vein; Thrombosis, Deep-Vein; Vein Thrombosis, Deep; Thrombosis, Deep Vein; Deep-Venous Thrombosis Deep-Venous Thromboses; Thromboses, Deep-Venous; Thrombosis, Deep-Venous; Deep Venous Thrombosis; Deep Venous Thromboses; Thromboses, Deep Venous; Thrombosis, Deep Venous; Venous Thromboses, Deep Query - Pubmed Methods AimsIntroductionResults Conclusions 16

Lower Extremity – Entry Terms Extremities, Lower; Lower Extremities; Lower Limb Limb, Lower; Limbs, Lower; Lower Limbs Membrum inferius; Extremity, Lower Query - Pubmed Therapeutics – Entry Terms Therapeutic Treatment Treatments Superficial Venous Thrombosis of the Lower Limbs Methods AimsIntroductionResults Conclusions 17

Query - Pubmed Pubmed Query - Main Topics Condition definition: (superficial venous thrombosis OR SVT) AND (lower extremity OR leg OR lower limb) Intervention: (Treatments OR therapeutics OR therapy) Analysis of: (results OR complications) Superficial Venous Thrombosis of the Lower Limbs Query applied on Pubmed (superficial venous thrombosis OR SVT) AND (lower extremity OR leg OR lower limb) AND (Treatments OR therapeutics OR therapy) AND (results OR complications) Methods AimsIntroductionResults Conclusions 18

Scopus Query - Main Topics Condition definition: (svt OR superficial venous thrombosis) AND (lower limbs OR lower extremity OR legs) Intervention: (Treatments or therapy or therapeutics) Analysis of: (results OR complications) Query - Scopus Superficial Venous Thrombosis of the Lower Limbs Query applied on Scopus TITLE-ABS-KEY (svt OR superficial venous thrombosis) AND (lower limbs OR lower extremity OR legs)) AND (Treatments or therapy or therapeutics) AND (results OR complications) AND DOCTYPE(ar) Methods AimsIntroductionResults Conclusions 19

Definition of the topic TOPICS (superficial venous thrombosis OR svt) (treatment OR therapy OR therapeutics ) (lower limb) NOT (varicose) NOT (artery) NOT (ulcers) Definition of the target group and thematic scope REFINED BY Languages=(ENGLISH) Document Type=(ARTICLE) Query - ISI Web of Knowledge Methods AimsIntroductionResults Conclusions 20

Query - ISI Web of Knowledge Superficial Venous Thrombosis of the Lower Limbs Query obtained and applied on ISI Web of Knowledge Topic=(superficial venous thrombosis OR svt) AND Topic=(treatment OR therapy OR therapeutics) AND Topic=(lower limb) NOT Topic=(varicose) NOT Topic=(artery) NOT Topic=(ulcers) Refined by: Languages=(ENGLISH) AND Document Type=(ARTICLE) Timespan= Methods AimsIntroductionResults Conclusions 21

Outcome Articles obtained: Superficial Venous Thrombosis of the Lower Limbs Deadline for the research of the articles: March 22, 2012 Methods AimsIntroductionResults Conclusions 22

Flowchart Methods AimsIntroductionResults Conclusions 23

First selection phase Methods AimsIntroductionResults Conclusions 24

Inclusionand exclusion criteria Inclusion and exclusion criteria Studies that fully describe the treatment applied in SVT; Studies describing the evolution of SVT according to the treatment applied. Articles without original data (ex: systematic review); Articles not written in English, Portuguese or Spanish; Articles whose full-text was not available. Articles describing only one clinical case. Inclusion CriteriaExclusion Criteria Methods AimsIntroductionResults Conclusions 25

By reading the abstracts a first selection of the articles was made. - Language - Study Type - Not relevant - Language - Study Type - Not relevant First selection phase Methods AimsIntroductionResults Conclusions 26

Flowchart Methods AimsIntroductionResults Conclusions 27

Second selection phase Methods AimsIntroductionResults Conclusions 28

Second selection phase 1 – Articles in doubt, during the first selection phase, due to their ambiguous abstracts. - Not available - Not relevant 1 - Repeated - Not available - Not relevant 1 - Repeated Methods AimsIntroductionResults Conclusions 29

Order of exclusion - summary Language Type of Study Relevance Availability 13% of the articles excluded 5% of the articles excluded 73% of the articles excluded 6% of the articles excluded Superficial Venous Thrombosis of the Lower Limbs For a total of 361 articles obtained Methods AimsIntroductionResults Conclusions 30

1 – High vs. low doses of low-molecular-weight heparin for the treatment of superficial vein thrombosis of the legs: a double-blind, randomized trial 2 – Superficial Thrombophlebitis ofthe Legs: A Randomized, Controlled, Follow-up Study 3 – Simultaneous occurrence of superficial and deep thrombophlebitis in the lower extremity 4 – High versus low doses of unfractionated heparin for the treatment of superficial thrombophlebitis of the leg. A prospective, controlled, randomized study 5 – A comparison of low-molecular-weight heparin and combined therapy of low-molecular-weight heparin with an anti-inflammatory agent in the treatment of superficial vein thrombosis List of the articles Methods AimsIntroductionResults Conclusions 31

6 – The use of liposomal heparin spray-gel in the treatment of superficial thrombophlebitis: a multicenter clinical investigation analysis; 7 – A Pilot Randomized Double-blind Comparison of a Low-Molecular-Weight Heparin, a Nonsteroidal Anti-inflammatory Agent, and Placebo in the Treatment of Superficial Vein Thrombosis; 8 – Prospective five-year study of ultrasound-guided foam sclerotherapy in the treatment of great saphenous vein reflux; 9 – Fondaparinux for the Treatment of Superficial-Vein Thrombosis in the Legs; 10 – A retrospective analysis of patients treated for superficial vein thrombosis; 11 – Fondaparinux for Isolated Superficial Vein Thrombosis of the Legs : A Cost-Effectiveness Analysis; List of the articles Methods AimsIntroductionResults Conclusions 32

Methods AimsIntroductionResults Conclusions 33

General table of the articles’ data Article nºFollow-up (in days) Nº of participantsTreatments LMWH* Surgery, LMWH*, elastic compression Heparin; Warfarin; surgery LMWH* LMWH* Lipossomal gel-spray heparin Heparin; placebo; tenoxicam Ultra-sound guided foam sclerotherapy Fondaparinux; Placebo LMWH*; vitamin k antagonists; nasodroparin Fondaprinux; Placebo * LMWH: Low Molecular Weight Heparin 34 Methods AimsIntroductionResults Conclusions

Variables for data extraction Superficial Venous Thrombosis of the Lower Limbs Methods AimsIntroductionResults Conclusions 35

Relative to the article extraction: Database Article number Year Study Type Variables Methods AimsIntroductionResults Conclusions Relative to article’s content: Nº of participants Nº of groups Follow-up Drop out Age Gender Treatments Efficacy Superficial Venous Thrombosis of the Lower Limbs 36

Data extraction to SPSS Superficial Venous Thrombosis of the Lower Limbs Methods AimsIntroductionResults Conclusions 37

Study Type Methods AimsIntroduction Results Conclusions Superficial Venous Thrombosis of the Lower Limbs 38

Follow-up (in days) Superficial Venous Thrombosis of the Lower Limbs Article nº Methods AimsIntroduction Results Conclusions 39

Participants Superficial Venous Thrombosis of the Lower Limbs Article nº Total of participants: Methods AimsIntroduction Results Conclusions 40

Different treatments applied Eleven articles analyzed: a total of patients received treatment, 1502 with placebo and with Fondaparinux. The remaining treatments used are in the chart below. Methods AimsIntroduction Results Conclusions 41

Heparin Data Superficial Venous Thrombosis of the Lower Limbs Methods AimsIntroduction Results Conclusions 42

Antithrombotic therapy vs placebo (1/2) Superficial Venous Thrombosis of the Lower Limbs Methods AimsIntroduction Results Conclusions Incidence of DVT by day 12 Placebo 4/111 - (3.6%) 40-mg enoxaparin* 1/109 - (0.9%) 1.5 mg/kg enoxaparin* 1/102 - (1.0%) Incidence of DVT and SVT by day 12 Placebo 34/111 - (30.6%) 40-mg enoxaparin* 9/109 - (8.3%) 1.5 mg/kg enoxaparin* 7/102 - (6.9%) Data obtained from article 7 * enoxaparin: a kind of heparin (in this case, different doses were used) 43

Antithrombotic therapy vs placebo (2/2) Methods AimsIntroduction Results Conclusions Incidence of pulmonary embolism or DVT Placebo 20/ (1.3%) Fondaparinux 3/ (0.2%) Incidence of delayed surgery by day 77 Placebo 52/ (3.5%) Fondaparinux 8/ (0.5%) Superficial Venous Thrombosis of the Lower Limbs Data obtained from article 9 44

Methods AimsIntroduction Results Conclusions Elastic compression vs anti-coagulants and surgery (1/2) Superficial Venous Thrombosis of the Lower Limbs Elastic compression only Thrombus extension at 3 months 32/78 - (41.0%) DVT at 3 months 6/78 - (7.7%) Thrombus extension at 6 months 13/78 - (16.7%) Total for complications 51/78 - (65.4%) Elastic compression + LMWH + Delayed surgery Thrombus extension at 3 months 4/76 - (5.3%) DVT at 3 months 0/76 - (0.0%) Thrombus extension at 6 months 1/76 - (1.3%) Total for complications 5/76 - (6.6%) Data obtained from article 2 45

Methods AimsIntroduction Results Conclusions Superficial Venous Thrombosis of the Lower Limbs Elastic compression + oral anti-coagulant Thrombus extension at 3 months 5/71 - (7.0%) DVT at 3 months 0/71 - (0.0%) Thrombus extension at 6 months 5/71 - (7.0%) Total for complications 10/71 - (14.0%) Elastic compression vs anti-coagulants and surgery (2/2) Data obtained from article 2 46

High vs low doses of LMWH Superficial Venous Thrombosis of the Lower Limbs Incidence of thromboembolic complications High dosesLow doses During treatment period 0/30 - (0%)4/30 - (13.3%) After drug discontinuation 1/30 - (3.3%)2/30 - (6.7%) Incidence of thrombus extension High dosesLow doses During treatment period 3/30 - (10.0%)7/30 - (23.3%) After drug discontinuation 0/30 - (0%) Methods AimsIntroduction Results Conclusions Data obtained from article 4 47

Prophylactic vs therapeutic doses of LMWH Methods AimsIntroduction Results Conclusions Prophylatic doses Nº of patients with complications During treatment period5/81 - (6.2%) After drug discontinuation2/81 - (2.5%) Therapeutic doses Nº of patients with complications During treatment period2/83 - (2.4%) After drug discontinuation4/83 - (4.8%) Superficial Venous Thrombosis of the Lower Limbs Data obtained from article 1 48

49 Lipohep spray-gel is an heparin gel that has recently appeared on the market. Its effect has been compared with subcutaneous injections of heparin (as showed above). Lipossomalgel-spray heparin vs heparin injections Lipossomal gel-spray heparin vs heparin injections Methods AimsIntroduction Results Conclusions Data obtained from article 6 N – Lipohep: 43 N – injections: 45

High doses of LMWH have better results than low doses. Conclusions (1/3) 50 Antithrombotic therapy is more effective than placebo and may avoid surgery; Elastic compression by itself seems not to be a good option of treatment. Although the group involving delayed surgery as treatment had better outcomes, anti-coagulants seem to be a good alternative to it; Methods AimsIntroduction Results Conclusions

51 There are no statistically significant differences between prophylactic and therapeutic doses of LMWH, after drug discontinuation. Methods AimsIntroduction Results Conclusions Conclusions (2/3) There are no statistically significant differences between the spray-gel and the injections, so as it represents an easier way of treatment Lipohep spray gel seems to be an alternative to be considered.

52 It also important to mention ultrasound-guided foam sclerotherapy (UGFS), a recent treatment in which study (article 8) no serious adverse outcomes were observed and it had 100% patient acceptance of success. However, as it is a recent finding, more studies need to be done in order to evaluate its effect in treating SVT. Unfortunately, we did not found any articles comparing fondaparinux and heparin, therefore we were not able to conclude which one was the best. Even so, there seems to exist a preference regarding heparin. AimsIntroductionResults Conclusions Methods Conclusions (3/3)

Heterogeneity of the articles included: each article presented unique points of view and different methodology; Unavailability of articles in the UP database (23 articles): we can't assure the inexistence of important information among those whose full-text wasn’t available; Articles describing very specific populations: clinical cases or articles describing SVT within very specific populations (cancer patients, etc.) were excluded. Study Limitations Superficial Venous Thrombosis of the Lower Limbs AimsIntroductionResults Conclusions Methods 53