Treatment for Superficial Thrombophlebitis of The

Treatment for superﬁcial thrombophlebitis of the leg (Review)

Di Nisio M, Wichers IM, Middeldorp S

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2012, Issue 3 http://www.thecochranelibrary.com

HEADER...... 1 ABSTRACT ...... 1 PLAINLANGUAGESUMMARY ...... 2 BACKGROUND ...... 2 OBJECTIVES ...... 3 METHODS ...... 3 RESULTS...... 5 Figure1...... 7 Figure2...... 8 DISCUSSION ...... 11 AUTHORS’CONCLUSIONS ...... 12 ACKNOWLEDGEMENTS ...... 12 REFERENCES ...... 12 CHARACTERISTICSOFSTUDIES ...... 17 DATAANDANALYSES...... 42 Analysis 1.1. Comparison 1 Fondaparinux versus placebo, Outcome 1 Pulmonary embolism...... 51 Analysis 1.2. Comparison 1 Fondaparinux versus placebo, Outcome 2 Deep vein thrombosis...... 51 Analysis 1.3. Comparison 1 Fondaparinux versus placebo, Outcome 3 Deep vein thrombosis and pulmonary embolism. 52 Analysis 1.4. Comparison 1 Fondaparinux versus placebo, Outcome 4 Extension of ST...... 52 Analysis 1.5. Comparison 1 Fondaparinux versus placebo, Outcome 5 Recurrence of ST...... 53 Analysis 1.6. Comparison 1 Fondaparinux versus placebo, Outcome 6 Mortality...... 53 Analysis 1.7. Comparison 1 Fondaparinux versus placebo, Outcome 7 Major bleeding...... 54 Analysis 1.8. Comparison 1 Fondaparinux versus placebo, Outcome 8 Clinically relevant non-major bleeding. . . . 54 Analysis 1.9. Comparison 1 Fondaparinux versus placebo, Outcome 9 Minor bleeding...... 55 Analysis 1.10. Comparison 1 Fondaparinux versus placebo, Outcome 10 Arterial thromboembolic complication. . . 55 Analysis 1.11. Comparison 1 Fondaparinux versus placebo, Outcome 11 Any adverse event...... 56 Analysis 1.12. Comparison 1 Fondaparinux versus placebo, Outcome 12 Non-fatal serious adverse event. . . . . 56 Analysis 2.1. Comparison 2 Prophylactic LMWH versus placebo, Outcome 1 Venous thromboembolism end-of- treatment...... 57 Analysis 2.2. Comparison 2 Prophylactic LMWH versus placebo, Outcome 2 Venous thromboembolism 3-month follow up...... 57 Analysis 2.3. Comparison 2 Prophylactic LMWH versus placebo, Outcome 3 Extension and/or recurrence of ST. . 58 Analysis 2.4. Comparison 2 Prophylactic LMWH versus placebo, Outcome 4 Major bleeding...... 58 Analysis 2.5. Comparison 2 Prophylactic LMWH versus placebo, Outcome 5 Heparin-induced thrombocytopenia. . 59 Analysis 3.1. Comparison 3 Therapeutic LMWH versus placebo, Outcome 1 Venous thromboembolism end-of- treatment...... 59 Analysis 3.2. Comparison 3 Therapeutic LMWH versus placebo, Outcome 2 Venous thromboembolism 3-month follow up...... 60 Analysis 3.3. Comparison 3 Therapeutic LMWH versus placebo, Outcome 3 Extension and/or recurrence of ST. . . 60 Analysis 3.4. Comparison 3 Therapeutic LMWH versus placebo, Outcome 4 Major bleeding...... 61 Analysis 3.5. Comparison 3 Therapeutic LMWH versus placebo, Outcome 5 Heparin-induced thrombocytopenia. . 61 Analysis 4.1. Comparison 4 Prophylactic LMWH + elastic compression stockings (ECS) versus elastic stockings alone, Outcome 1 Venous thromboembolism...... 62 Analysis 4.2. Comparison 4 Prophylactic LMWH + elastic compression stockings (ECS) versus elastic stockings alone, Outcome 2 Extension and/or recurrence of ST...... 62 Analysis 5.1. Comparison 5 LMWH versus heparin spray gel, Outcome 1 Deep-venous thrombosis...... 63 Analysis 5.2. Comparison 5 LMWH versus heparin spray gel, Outcome 2 Patients with thrombus at 21 days. . . . 63 Analysis 5.3. Comparison 5 LMWH versus heparin spray gel, Outcome 3 Allergic reaction or elevated sedimentation rate...... 64 Analysis 6.1. Comparison 6 Therapeutic LMWH versus saphenofemoral disconnection, Outcome 1 Venous thromboembolism...... 64

Treatment for superﬁcial thrombophlebitis of the leg (Review) i Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 6.2. Comparison 6 Therapeutic LMWH versus saphenofemoral disconnection, Outcome 2 Extension and/or recurrenceofST...... 65 Analysis 6.3. Comparison 6 Therapeutic LMWH versus saphenofemoral disconnection, Outcome 3 Major bleeding. 65 Analysis 6.4. Comparison 6 Therapeutic LMWH versus saphenofemoral disconnection, Outcome 4 Complications. 66 Analysis 7.1. Comparison 7 Fixed-dose LMWH versus NSAIDs, Outcome 1 Venous thromboembolism. . . . . 66 Analysis 7.2. Comparison 7 Fixed-dose LMWH versus NSAIDs, Outcome 2 Extension and/or treatment of ST. . . 67 Analysis 7.3. Comparison 7 Fixed-dose LMWH versus NSAIDs, Outcome 3 Major bleeding...... 67 Analysis 7.4. Comparison 7 Fixed-dose LMWH versus NSAIDs, Outcome 4 Heparin-induced thrombocytopenia. . 68 Analysis 8.1. Comparison 8 Weight-adjusted LMWH versus NSAIDs, Outcome 1 Venous thromboembolism. . . 68 Analysis 8.2. Comparison 8 Weight-adjusted LMWH versus NSAIDs, Outcome 2 Extension and/or recurrence of ST. 69 Analysis 8.3. Comparison 8 Weight-adjusted LMWH versus NSAIDs, Outcome 3 Major bleeding...... 69 Analysis 8.4. Comparison 8 Weight-adjusted LMWH versus NSAIDs, Outcome 4 Heparin-induced thrombocytopenia. 70 Analysis 9.1. Comparison 9 Prophylactic LMWH versus NSAIDs, Outcome 1 Venous thromboembolism end-of- treatment...... 70 Analysis 9.2. Comparison 9 Prophylactic LMWH versus NSAIDs, Outcome 2 Venous thromboembolism 3-month follow up...... 71 Analysis 9.3. Comparison 9 Prophylactic LMWH versus NSAIDs, Outcome 3 Major bleeding...... 71 Analysis 9.4. Comparison 9 Prophylactic LMWH versus NSAIDs, Outcome 4 Heparin-induced thrombocytopenia. 72 Analysis 10.1. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 1 Pulmonary embolism...... 72 Analysis 10.2. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 2 Deep vein thrombosis. . . . . 73 Analysis 10.3. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 3 Extension of ST...... 73 Analysis 10.4. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 4 Pain reduction...... 74 Analysis 10.5. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 5 Hyperaemia reduction. . . . . 74 Analysis 10.6. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 6 Tenderness reduction...... 75 Analysis 10.7. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 7 Palpable cord reduction. . . . . 75 Analysis 10.8. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 8 Mortality...... 76 Analysis 10.9. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 9 Major bleeding...... 76 Analysis 10.10. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 10 Minor bleeding...... 77 Analysis 10.11. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 11 Adverse event...... 77 Analysis 11.1. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 1 ST or venous thromboembolism...... 78 Analysis 11.2. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 2 Venous thromboembolism...... 78 Analysis 11.3. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 3 Superﬁcial thrombophlebitis...... 79 Analysis 11.4. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 4 Swelling disappearance. 79 Analysis 11.5. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 5 Tenderness disappearance. 80 Analysis 11.6. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 6 Pain disappearance. 80 Analysis 11.7. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 7 Pitting oedema disappearance...... 81 Analysis 11.8. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 8 Collateral veins disappearance...... 81 Analysis 11.9. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 9 Redness disappearance. 82 Analysis 11.10. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 10 Palpable cord disappearance...... 82 Analysis 11.11. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 11 Major bleeding. . 83 Analysis 11.12. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 12 Heparin-induced thrombocytopenia...... 83 Analysis 12.1. Comparison 12 Prophylactic UFH + elastic compression stockings versus elastic compression stockings alone, Outcome 1 Venous thromboembolism...... 84 Analysis 12.2. Comparison 12 Prophylactic UFH + elastic compression stockings versus elastic compression stockings alone, Outcome 2 Extension and/or recurrence of ST...... 84 Analysis 13.1. Comparison 13 High-dose UFH versus low-dose UFH, Outcome 1 Incidence of venous thromboembolism. 85

Treatment for superficial thrombophlebitis of the leg (Review) ii Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 13.2. Comparison 13 High-dose UFH versus low-dose UFH, Outcome 2 ST recurrence or extension. . . 85 Analysis 13.3. Comparison 13 High-dose UFH versus low-dose UFH, Outcome 3 Major bleeding...... 86 Analysis 13.4. Comparison 13 High-dose UFH versus low-dose UFH, Outcome 4 Heparin-induced thrombocytopenia. 86 Analysis 14.1. Comparison 14 Calcium heparin + elastic compression bandage versus elastic compression bandage alone, Outcome 1 Deep venous thrombosis...... 87 Analysis 15.1. Comparison 15 Heparin sc versus defibrotide, Outcome 1 Decrease in the analogue score. . . . . 87 Analysis 15.2. Comparison 15 Heparin sc versus defibrotide, Outcome 2 Treatment side effects...... 88 Analysis 16.1. Comparison 16 NSAIDs versus placebo, Outcome 1 Venous thromboembolism...... 88 Analysis 16.2. Comparison 16 NSAIDs versus placebo, Outcome 2 Extension and/or recurrence of ST...... 89 Analysis 16.3. Comparison 16 NSAIDs versus placebo, Outcome 3 Major bleeding...... 89 Analysis 16.4. Comparison 16 NSAIDs versus placebo, Outcome 4 Heparin-induced thrombocytopenia. . . . . 90 Analysis 17.1. Comparison 17 Indomethacin versus placebo, Outcome 1 Side effects...... 90 Analysis 18.1. Comparison 18 Nimesulide versus diclofenac sodium, Outcome 1 Gastric pain...... 91 Analysis 19.1. Comparison 19 Essaven gel versus placebo, Outcome 1 Intolerance...... 91 Analysis 20.1. Comparison 20 Thrombectomy + venoruton + elastic compression bandage versus elastic compression bandage alone, Outcome 1 Deep venous thrombosis...... 92 Analysis 21.1. Comparison 21 Thrombectomy + elastic compression bandage versus elastic compression bandage alone, Outcome 1 Deep venous thrombosis...... 92 Analysis 22.1. Comparison 22 Ligation + elastic compression stockings versus elastic compression stockings alone, Outcome 1Venousthromboembolism...... 93 Analysis 22.2. Comparison 22 Ligation + elastic compression stockings versus elastic compression stockings alone, Outcome 2Extensionand/orrecurrenceofST...... 93 Analysis 23.1. Comparison 23 Stripping + elastic compression stockings versus elastic compression stockings alone, Outcome 1 Venous thromboembolism...... 94 Analysis 23.2. Comparison 23 Stripping + elastic compression stockings versus elastic compression stockings alone, Outcome 2 Extension and/or recurrence of ST...... 94 Analysis 24.1. Comparison 24 Oral vasotonin versus placebo, Outcome 1 Cured or substantially better...... 95 Analysis 24.2. Comparison 24 Oral vasotonin versus placebo, Outcome 2 Poor tolerability...... 95 Analysis 25.1. Comparison 25 Elastic compression bandage + venoruton versus elastic compression bandage alone, Outcome 1 Deep venous thrombosis...... 96 Analysis 26.1. Comparison 26 Oral heparan sulphate versus oral sulodexide, Outcome 1 Redness disappearance. . . 96 Analysis 26.2. Comparison 26 Oral heparan sulphate versus oral sulodexide, Outcome 2 Pain disappearance. . . . 97 Analysis 26.3. Comparison 26 Oral heparan sulphate versus oral sulodexide, Outcome 3 Disappearance of itching. . 97 Analysis 26.4. Comparison 26 Oral heparan sulphate versus oral sulodexide, Outcome 4 Oedema improvement. . . 98 Analysis 26.5. Comparison 26 Oral heparan sulphate versus oral sulodexide, Outcome 5 Trophism improvement. . 98 Analysis 27.1. Comparison 27 Oxyphenbutazone versus placebo, Outcome 1 Tenderness improvement...... 99 Analysis 28.1. Comparison 28 VKA + elastic compression stockings versus elastic compression stockings alone, Outcome 1 Venousthromboembolism...... 99 Analysis 28.2. Comparison 28 VKA + elastic compression stockings versus elastic compression stockings alone, Outcome 2 Extensionand/orrecurrenceofST...... 100 Analysis 29.1. Comparison 29 Enzyme therapy versus placebo, Outcome 1 Pain reduction...... 100 Analysis 29.2. Comparison 29 Enzyme therapy versus placebo, Outcome 2 Responders...... 101 Analysis 30.1. Comparison 30 Desmin im 200 versus desmin 100, Outcome 1 Adverse events...... 101 Analysis 30.2. Comparison 30 Desmin im 200 versus desmin 100, Outcome 2 Adverse drug reactions...... 102 Analysis 31.1. Comparison 31 Desmin sc 2x100 versus desmin 100, Outcome 1 Adverse events...... 102 Analysis 31.2. Comparison 31 Desmin sc 2x100 versus desmin 100, Outcome 2 Adverse drug reactions...... 103 APPENDICES ...... 103 FEEDBACK...... 103 WHAT’SNEW...... 105 HISTORY...... 105 CONTRIBUTIONSOFAUTHORS ...... 105 DECLARATIONSOFINTEREST ...... 106 SOURCESOFSUPPORT ...... 106

Treatment for superﬁcial thrombophlebitis of the leg (Review) iii Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. DIFFERENCES BETWEEN PROTOCOL AND REVIEW ...... 106 INDEXTERMS ...... 106

Treatment for superﬁcial thrombophlebitis of the leg (Review) iv Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. [Intervention Review] Treatment for superﬁcial thrombophlebitis of the leg

Marcello Di Nisio1, Iris M Wichers2, Saskia Middeldorp3

1Department of Medicine and Aging; Centre for Aging Sciences (Ce.S.I.), Internal Medicine Unit, “University G. D’Annunzio” Foundation, Chieti, Italy. 2Healthcare Center Borgerstraat, Amsterdam, Netherlands. 3Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands

Contact address: Marcello Di Nisio, Department of Medicine and Aging; Centre for Aging Sciences (Ce.S.I.), Internal Medicine Unit, “University G. D’Annunzio” Foundation, via dei Vestini 31, Chieti, 66013, Italy. [email protected].

Editorial group: Cochrane Peripheral Vascular Diseases Group. Publication status and date: New search for studies and content updated (conclusions changed), comment added to review, published in Issue 3, 2012. Review content assessed as up-to-date: 29 November 2011.

Citation: Di Nisio M, Wichers IM, Middeldorp S. Treatment for superﬁcial thrombophlebitis of the leg. Cochrane Database of Systematic Reviews 2012, Issue 3. Art. No.: CD004982. DOI: 10.1002/14651858.CD004982.pub4.

ABSTRACT Background The optimal treatment of superficial thrombophlebitis (ST) of the legs remains poorly defined. While improving or relieving the local painful symptoms, treatment should aim at preventing venous thromboembolism (VTE), which might complicate the natural history of ST. This is an update of a review first published in 2007. Objectives To assess the efficacy and safety of topical, medical, and surgical treatments in patients presenting with ST of the legs. Search methods For this update the Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (last searched 29 November 2011) and CENTRAL (2011, Issue 4). We handsearched reference lists of relevant papers and conference proceedings. Selection criteria Randomised controlled trials (RCTs) evaluating topical, medical, and surgical treatments for ST of the leg that included participants with a clinical diagnosis of ST of the legs or objective diagnosis of a thrombus in the superficial vein. Data collection and analysis Two authors assessed the trials for inclusion in the review, extracted the data, and assessed the quality of the studies. Data were independently extracted from the included studies and any disagreements resolved by consensus. Main results Twenty-six studies involving 5521 participants with ST of the legs were included in this review. The methodological quality of most of the trials was poor. Treatment ranged from fondaparinux, low molecular weight heparin (LMWH), unfractionated heparin (UFH), nonsteroidal anti-inflammatory agents (NSAIDs), topical treatment, oral treatment, intramuscular treatment, and intravenous treatment to surgery. In a placebo-controlled RCT of about 3000 patients, fondaparinux was associated with a significant reduction in symptomatic VTE (RR 0.15; 95% CI 0.04 to 0.50), extension (RR 0.08; 95% CI 0.03 to 0.22), and recurrence of ST (RR 0.21; 95% CI 0.08 to 0.54) with comparable rates of major bleeding (RR 0.99; 95% CI 0.06 to 15.86) relative to placebo. Both prophylactic and therapeutic

Treatment for superﬁcial thrombophlebitis of the leg (Review) 1 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. doses of LMWH (RR 0.40; 95% CI 0.22 to 0.72 and RR 0.42; 95% CI 0.23 to 0.75, respectively) and NSAIDs (RR 0.41; 95% CI 0.23 to 0.75) reduced the extension and recurrence of ST in comparison to placebo, with no signiﬁcant effects on symptomatic VTE nor major bleeding. Overall, topical treatments improved local symptoms. However, no data were provided on the effects of these treatments on VTE and ST extension. Surgical treatment combined with elastic stockings in ST was associated with a lower VTE rate and ST progression compared with elastic stockings alone.

Authors’ conclusions

Prophylactic dose fondaparinux given for six weeks appears to be a valid therapeutic option for ST of the legs. Further research is needed to assess the role of new oral direct thrombin and activated factor-X inhibitors, LMWH, NSAIDs; the optimal doses and duration of treatment; and whether a combination therapy may be more effective than single treatment. Adequately designed and conducted studies are required to clarify the role of topical and surgical treatments.

PLAIN LANGUAGE SUMMARY

Treatment for superﬁcial thrombophlebitis of the leg

Superficial thrombophlebitis (ST) is a relatively common inflammatory process associated with a blood clot (thrombus) that affects the superficial veins in the legs. Symptoms and signs include local pain, itching, tenderness, reddening of the skin and hardening of the surrounding tissue. There is some evidence to suggest an association between ST and venous thromboembolism (VTE). Treatment aims to relieve the local symptoms and prevent extension of the clot into a deep vein or recurrence and the development of more serious events caused by VTE. This review included 26 randomised controlled trials involving 5521 participants. Treatment ranged from subcutaneous injections of fondaparinux to low molecular weight heparin, unfractionated heparin, oral non-steroidal anti-inflammatory drugs (NSAIDs), topical treatment, and surgery. One large study, accounting for over half of the patients included in the review, showed that treatment with fondaparinux over six weeks was associated with a significant reduction in symptomatic VTE, extension and recurrence of ST with no increase in bleeding relative to placebo. Both low molecular weight heparin and NSAIDs reduced the incidence of extension or recurrence of ST without any significant effect on symptomatic VTE. Topical treatments relieved local symptoms but the trials did not report on progression to VTE. Surgical treatment and wearing elastic stockings were associated with a lower rate of VTE and progression of the ST compared with elastic stockings alone. The methodological quality of most of the trials was poor.

BACKGROUND operative states, pregnancy, puerperium (the period immediately following childbirth), active malignancies, auto-immune diseases, Description of the condition use of oral contraceptives or hormonal replacement therapy, ad- vanced age, obesity, and a history of previous VTE (Barrelier 1993; The term superficial thrombophlebitis (ST) (also known as super- Bergqvist 1986; Chengelis 1996; de Moerloose 1998; Lutter 1991; ficial venous thrombosis) refers to a pathological state characterized Samlaska 1990b). Furthermore, the presence of inherited throm- by an inflammatory-thrombotic process in a superficial vein. Dis- bophilia (a disorder where there is a tendency for thrombosis to tinctive clinical findings include pain and a reddened, warm, ten- occur, for example factor V Leiden, the prothrombin 20210A der cord extending along the vein. The surrounding area may show mutation, and deficiencies of the natural anticoagulant proteins signs of erythema (reddening of the skin) and oedema (swelling C and S) in ST suggests a similar pathophysiology as VTE (de of the tissue). ST is a relatively common disease and although its Moerloose 1998; Hanson 1998; Martinelli 1999; Samlaska 1990a; incidence has never been properly determined it is estimated to be Samlaska 1990b). Traditionally, ST has been considered a rela- higher than that of deep vein thrombosis (DVT), which is about tively benign disease, but several studies have described an associ- 1 per 1000 cases (De Weese 1991; Nordstrom 1992). Predispos- ation between ST and VTE (Bergqvist 1986; Blumenberg 1998; ing risk factors for ST and venous thromboembolism (VTE) are Bounameaux 1997; Chengelis 1996; Jorgensen 1993; Krunes similar and include varicose veins, immobilization, trauma, post-

Treatment for superficial thrombophlebitis of the leg (Review) 2 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 1999; Lutter 1991; Quenet 2003; Unno 2002; Verlato 1999). In OBJECTIVES people with a diagnosis of ST, 6% to 44% have an associated (or To review the efficacy and safety of topical, medical, and surgical develop) DVT, 20% to 33% have asymptomatic pulmonary em- treatments for ST of the leg in improving local symptoms and bolism (PE), and 2% to 13% have symptomatic PE (Bergqvist decreasing thromboembolic complications. 1986; Blumenberg 1998; Bounameaux 1997; Chengelis 1996; Jorgensen 1993; Krunes 1999; Lutter 1991; Plate 1985; Quenet 2003; Skillman 1990; Unno 2002; Verlato 1999). ST located in the saphenous main trunk seems to have the strongest association METHODS with VTE (Bergqvist 1986; Blumenberg 1998; Chengelis 1996; Jorgensen 1993; Lutter 1991; Quenet 2003; Unno 2002; Verlato 1999). The variations in estimates reported in the literature are Criteria for considering studies for this review probably due to the retrospective character of most studies, the small number of participants included, and the fact that ST was often diagnosed in vascular laboratories where patients were re- Types of studies ferred for suspected DVT. In a recent cross-sectional and prospective epidemiologic cohort study, ST at diagnosis was associated Randomised controlled trials (RCTs) evaluating topical, medical, with VTE in 25% of the cases (Decousus 2010). During a three- and surgical treatments for ST of the legs. month follow-up, 10% of the patients with ST developed thromboembolic complications despite 90% having received anticoagulant drugs and about 98% had used elastic compression stockings. Types of participants Hospitalised and non-hospitalised participants with a diagnosis of ST of the lower extremities based on signs and symptoms of ST (that is, pain, tenderness, induration (hardening of the tissue), Description of the intervention or erythema (reddening of the skin) in a superficial vein) and There is no consensus on the optimal treatment of ST in clinical clinical (palpation) and objective diagnosis of the thrombus in practice. Several therapies have been proposed in the literature, the superficial vein by means of ultrasound scanning of the lower including surgical therapy (ligation or stripping of the affected limbs that excludes any concomitant DVT. veins), elastic stockings, non-steroidal anti-inflammatory drugs (NSAIDs) which aim to reduce pain and inflammation, and several anticoagulant agents. For great saphenous ST,high saphenous Types of interventions ligation (crossectomy) would be the emergency surgical treatment Interventions included any treatment to relieve the symptoms and option. It is not clear whether different locations of ST may influ- signs, or to prevent complications, of ST such as topical treat- ence the choice of treatment. The thrombus location in trunks of ments, compression stockings, compression bandages, leg eleva- either the great saphenous vein (saphena magna) or small saphe- tion, medical treatments (for example, NSAIDs or anticoagulants nous vein (saphena parva) may have the highest risk of extension such as fondaparinux, low molecular weight heparin (LMWH)), into the deep vein system and thus could require an aggressive surgical intervention (for example, ligation, vein stripping, crossec- form of treatment, whereas other locations may be associated with tomy). Each treatment could be compared with another form of a lower risk of extension and thus may warrant a less aggressive treatment, placebo, or no intervention. Combinations of therapies approach. could be used.

Types of outcome measures Why it is important to do this review We included RCTs assessing any of the following outcome mea- While the estimates of VTE prevalence in patients with ST vary, sures for any of the reviewed interventions. management of ST should consider the prevention of this scar- ring complication beyond the mere resolution of local symptoms (Decousus 2010; Wichers 2005). Conservative manage- Primary outcomes ment, mainly focusing on the painful symptoms of disease, might 1. Incidence of complications including: therefore be insufﬁcient. While provision of adequate treatment • symptomatic PE; for ST may help prevent (fatal) VTE, the efﬁcacy of the interven- • symptomatic DVT or the progression of ST into DVT; tion needs to be balanced against the risks, such as (major) bleed- • (symptomatic and asymptomatic) extension of ST; ing events with anticoagulants. • (symptomatic and asymptomatic) recurrence of ST.

Treatment for superficial thrombophlebitis of the leg (Review) 3 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. The presence of PE or DVT had to be confirmed by an objective Two authors (MDN and IMW) independently reviewed titles test, namely pulmonary angiography, ventilation/perfusion lung and abstracts identified from the database searches to determine scan, or spiral computed tomography for PE; and ultrasonography, whether the inclusion criteria were satisfied. Decisions regarding venography, or plethysmography for DVT. inclusion were made separately and their results compared. We resolved any disagreement through discussion. We independently 2. Symptoms (for example, pain). reviewed the full text of identified articles, including those where 3. Signs (for example, induration and erythema). there was disagreement in the initial title or abstract scanning, 4. Quality of life (assessed by means of disease-specific and non- to ensure that the inclusion criteria were met. We obtained hard specific questionnaires). copies of the full text of possible trials for studies that fulfilled the selection criteria. We were not blinded to the journal, institution, or results of the study. Titles and abstracts of non-English articles Secondary outcomes were translated into English and assessed for inclusion. We docu- 1. Mortality; side effects of treatment (for example, bleeding, mented reasons for excluding studies and resolved differences by thrombocytopenia (reduced platelet count), allergic reactions, or consensus on whether trials met the inclusion criteria. One author surgery complications); arterial thromboembolic events. (MDN) scanned conference proceedings and identified articles from other sources (experts or reference lists) and contacted trial- ists for further information if required. Two authors (MDN and Search methods for identification of studies IMW) independently assessed trials for inclusion in the review. We searched for randomised controlled trials (RCTs) comparing any treatment versus placebo or another treatment in patients with Data extraction and management ST of the legs. There was no restriction on language. We (MDN and IMW) independently extracted the data from the included studies using an agreed format. We resolved any dis- Electronic searches agreements by consensus and, if necessary, by the involvement of For this update, the Cochrane Peripheral Vascular Diseases Group the third review author (SM). For any study published twice, we searched their Specialised Register (last searched 29 November extracted the data from the more complete study. Collected in- 2011) and the Cochrane Central Register of Controlled Trials formation included methodological quality, characteristics of pa- (CENTRAL) (2011, Issue 4), which is part of The Cochrane Li- tients participating in the study, characteristics of the intervention brary at www.thecochranelibrary.com. See Appendix 1 for details and control groups, and outcome characteristics of each group of of the search strategy used to search CENTRAL. The Specialised participants. Register is maintained by the Trials Search Co-ordinator and is constructed from weekly electronic searches of MEDLINE, EM- BASE, CINAHL and AMED; and through handsearching rele- Assessment of risk of bias in included studies vant journals. The full list of the databases, journals, and confer- Two review authors independently assessed randomisation, blind- ence proceedings which have been searched, as well as the search ing, and adequacy of analyses (Juni 2001). Disagreements were strategies used, are described in the Specialised Register section of resolved by consensus. the Cochrane Peripheral Vascular Diseases Group module in The Two components of randomisation were assessed: generation of Cochrane Library (www.thecochranelibrary.com). allocation sequences and concealment of allocation. Generation of allocation sequences was considered adequate if it resulted in Searching other resources an unpredictable allocation schedule. Mechanisms considered adequate included random-number tables, computer-generated ran- We searched reference lists of relevant papers and conference dom numbers, minimisation, coin tossing, shuffling cards, and proceedings of the International Society for Thrombosis and drawing lots. Trials using an unpredictable allocation sequence Hemostasis (2003 to 2009) and American Society of Haematol- were considered randomised. Trials using potentially predictable ogy (2004 to 2011); and we attempted to contact known experts allocation mechanisms, such as alternation or the allocation of in the field. patients according to date of birth, were considered quasi-randomised. Concealment of allocation was considered adequate if patients and Data collection and analysis investigators responsible for patient selection were unable to pre- dict, before allocation, which treatment was next. Methods considered adequate included central randomisation; pharmacy-con- Selection of studies trolled randomisation using identical pre-numbered containers;

Treatment for superficial thrombophlebitis of the leg (Review) 4 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. and sequentially numbered, sealed, opaque envelopes. Blinding RESULTS of patients and therapists was considered adequate if experimental and control preparations were explicitly described as indistin- guishable or if a double-dummy technique was used. Assessors Description of studies were considered blinded if this was explicitly mentioned by the investigators. See: Characteristics of included studies; Characteristics of excluded Analyses were considered adequate if all randomised patients were studies; Characteristics of ongoing studies. included in the analysis according to the intention-to-treat prin- See Characteristics of included studies; Characteristics of excluded ciple. The item ’free of selective reporting’ was classified as at low studies risk of bias if we had both the protocol and the full report of a given study, where the full report presented results for all outcomes Results of the search listed in the protocol. We classified a study as at high risk of bias if a report did not present data on all outcomes reported in eitherthe For this update, 87 citations potentially relevant citations were protocol or the methods section. The risk of bias item ’free of other obtained from the search of the Specialised Register and 1778 from bias’ was not considered in this review. We assessed the reporting the CENTRAL search. Following screening of titles and abstracts of primary outcomes and sample size calculations. We planned to (if available) full copies of 61 reports relating to 60 studies were use GRADE to describe the quality of the overall body of evidence obtained. Of these, two studies met the review inclusion criteria (Guyatt 2008; Higgins 2008); however, due to the heterogeneity (Decousus 2010a; Uncu 2009). Two studies were still ongoing between the studies in terms of treatment comparisons and study (NCT00362947; Rabe 2009). outcomes the GRADE approach was considered not informative and therefore omitted from the review. Included studies Two additional studies were included in the updated review (Decousus 2010a; Uncu 2009) and in total 26 studies involving 5521 participants were included in the review (Andreozzi 1996; Data synthesis Anonymous 1970; Archer 1977; Belcaro 1989; Belcaro 1990; Prior to obtaining the global effect estimators (a balanced mean Belcaro 1999; Decousus 2010a; De Sanctis 2001; Ferrari 1992; of the effect in different trials), we planned to evaluate the het- Gorski 2005; Holzgreve 1989; Incandela 2001; Katzenschlager erogeneity of treatment effects between trials using the I2 statis- 2003; Koshkin 2001; Kuhlwein 1985; Lozano 2003; Marchiori tic (Higgins 2003), which describes the percentage of total varia- 2002; Marshall 2001; Messa 1997; Nocker 1991; Nusser 1991; tion across trials that is attributable to heterogeneity rather than Pinto 1992; Stenox Group 2003; Titon 1994; Uncu 2009; Vesalio chance. I2 values of 25%, 50%, and 75% may be interpreted as Group 2005). In eight studies data were reported for less than 50 low, moderate, and high between-trial heterogeneity, although the patients, in 11 trials for 50 to 100 patients, and in seven studies interpretation of I2 depends on the size and number of trials in- data were available for more than 100 patients. cluded (Rücker 2008). In the presence of no or low heterogene- Interventions and comparisons varied greatly among the studies. ity, we planned to use the fixed-effect model (Mantel-Haenszel Seven trials included a topical treatment group (De Sanctis 2001; method) and random-effects model to pool and analyse summary Gorski 2005; Holzgreve 1989; Incandela 2001; Katzenschlager effect sizes. Where possible, we presented results as summary rel- 2003; Nocker 1991; Pinto 1992); three studies a surgical treat- ative risks (RR) for dichotomous variables and standardised mean ment group (Belcaro 1989; Belcaro 1999; Lozano 2003); 11 differences (SMD) for all continuous variables. We determined LMWH (Belcaro 1989; Belcaro 1990; Belcaro 1999; Gorski 2005; the 95% confidence interval (CI) for each estimate. Where possi- Katzenschlager 2003; Lozano 2003; Marchiori 2002; Stenox ble, we analysed the results by intention to treat, including every Group 2003; Titon 1994; Uncu 2009; Vesalio Group 2005); five individual in the randomly assigned treatment group regardless of NSAIDs (Anonymous 1970; Ferrari 1992; Nusser 1991; Stenox whether they completed the treatment or withdrew from the trial. Group 2003; Titon 1994); one fondaparinux (Decousus 2010a); We evaluated publication bias and other biases related to small and eight studies evaluated an oral (Archer 1977; Belcaro 1989; study size using funnel plots, plotting effect sizes on the vertical Belcaro 1999; Kuhlwein 1985; Koshkin 2001; Messa 1997), intra- axis against their standard errors on the horizontal axis. We assessed muscular (Andreozzi 1996), or intravenous (Marshall 2001) treat- asymmetry by the asymmetry coefficient: the difference in effect ment. size per unit increase in standard error (Sterne 2001), which is mainly a surrogate for sample size. Symmetry would be expected in the absence of any bias related to small study size. Excluded studies The data analysis was performed in RevMan 5 (Nordic Cochrane Overall 33 studies were excluded from the review. The reasons Centre, The Cochrane Collaboration, Copenhagen). for exclusion are listed in the table Characteristics of excluded

Treatment for superﬁcial thrombophlebitis of the leg (Review) 5 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. studies. Twenty studies included a mixed population and it was not the study was randomised or not (Giorgetti 1990). Four studies possible to extract data separately for ST (Allegra 1981; Annoni included patients with ST of the arm (Gouping 2003; Mehta 1991; Argenteri 1983; Bagliani 1983; Becherucci 2000; Bergqvist 1975; Rozsos 1994; van der Knaap 1988) and in one study the 1990; Bracale 1996; Bruni 1979; Della Marchina 1989; Luttichau evaluated outcomes were not among those included in the present 1989; Mari 1982; Marsala 1985; Mauro 1992; Paciaroni 1982; review (Ibanez-Bermudez 1996). Porters 1981; Pozza 1980; Seccia 1989; Seghezzi 1972; Seligman 1969; Tomamichel 1983). In one study it was not possible to extract outcome data separately for the two study-treatment groups Risk of bias in included studies (Agus 1993). Four studies included patients without a diagnosis of ST of the legs (Bernicot 1980; Gandhi 1984; Resta 1967; van Details of the methodological quality for each trial are reported in Cauwenberge 1972) and two studies included patients with DVT the table Characteristics of included studies. A risk of bias sum- (Di Perri 1986; Rea 1981). In one study it was unclear whether mary is presented in Figure 1.

Treatment for superﬁcial thrombophlebitis of the leg (Review) 6 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 1. Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.

Treatment for superficial thrombophlebitis of the leg (Review) 7 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Allocation (Anonymous 1970), which did not provide data on some of the Allocation was adequately concealed in seven studies included specified outcomes. in the meta-analysis (Decousus 2010a; Katzenschlager 2003; Marchiori 2002; Marshall 2001; Messa 1997; Stenox Group 2003; Effects of interventions Vesalio Group 2005), was not adequate in one (Uncu 2009), and unclear in the remaining 18 studies. None of the studies evaluated similar treatments on the same study outcomes. Treatment ranged from fondaparinux, LMWH, unfractionated heparin (UFH), NSAIDs, topical treatment, oral Blinding treatment, intramuscular treatment, and intravenous treatment to surgery. Eleven studies did not attempt to blind the assessment of the outcomes or did not report whether blinding was used or not, 14 studies had a double-blinded design (Anonymous 1970; Archer Fondaparinux 1977; Decousus 2010a; De Sanctis 2001; Ferrari 1992; Incandela One large double-blinded, placebo-controlled RCT evaluated pro- 2001; Koshkin 2001; Kuhlwein 1985; Marshall 2001; Nocker phylactic dose (2.5 mg sc od) fondaparinux given for 45 days 1991; Nusser 1991; Pinto 1992; Stenox Group 2003; Vesalio (Decousus 2010a). The primary efficacy outcome of this RCT Group 2005), and one used a single-blinded outcome evaluation (that is, the composite of death from any cause, symptomatic (Holzgreve 1989). PE, symptomatic DVT, or symptomatic extension to the saphenofemoral junction or symptomatic recurrence of ST up to day 47) was reduced by 85% by fondaparinux (RR 0.15; 95% CI 0.08 Incomplete outcome data to 0.26) with a number needed to treat (NNT) of 20. The in- Eight studies performed the analysis according to the intention- cidence of each component of the primary efficacy outcome was to-treat principle (De Sanctis 2001; Decousus 2010a; Incandela significantly reduced in the fondaparinux group as compared with 2001; Marchiori 2002; Messa 1997; Nocker 1991; Uncu 2009; the placebo group except for the incidence of death, which did not Vesalio Group 2005); in seven this was unclear, while in the differ significantly between the two groups (see Analysis 1.6). The remaining studies the percentage of patients randomised and risk of the composite of symptomatic DVT or PE was reduced by subsequently excluded from the analysis ranged from 2% to 85% with fondaparinux as compared with placebo (RR 0.15; 95% 33% (Archer 1977; Belcaro 1989; Belcaro 1999; Ferrari 1992; CI 0.04 to 0.50) with a NNT of 88 (Figure 2). Fondaparinux was Gorski 2005; Holzgreve 1989; Katzenschlager 2003; Lozano associated with lower rates of extension (RR 0.08; 95% CI 0.03 2003; Marshall 2001; Stenox Group 2003; Titon 1994). to 0.22) and recurrence of ST (RR 0.21; 95% CI 0.08 to 0.54). By day 47, major bleeding had occurred in one patient (0.1%) in each group (P = 1.00) (RR 0.99; 95% CI 0.06 to 15.86). The rates Selective reporting of clinically relevant non-major, minor, and total bleeding and ar- All studies were judged to be free of selective reporting except terial thromboembolic complications did not differ significantly the studies of Lozano et al (Lozano 2003) and Anonymous between the two groups.

Figure 2. Forest plot of comparison: 1 Fondaparinux versus placebo, outcome: 1.3 Deep vein thrombosis and pulmonary embolism.

Treatment for superficial thrombophlebitis of the leg (Review) 8 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. One study compared LMWH alone versus LMWH combined Low molecular weight heparin (LMWH) and with the anti-inflammatory agent acemetacin (Uncu 2009). There unfractionated heparin (UFH) were no cases of VTE, extension of ST,nor major bleeding in either study group. Combined LMWH plus acemetacin was associated Eleven studies included a LMWH group (Belcaro 1989; Belcaro with a significant 10% reduction in pain (mean difference (MD) 1990; Belcaro 1999; Gorski 2005; Katzenschlager 2003; Lozano 0.90; 95% CI 0.18 to 1.62). 2003; Marchiori 2002; Stenox Group 2003; Titon 1994; Uncu The Vesalio Study Group compared two regimens of LMWH 2009; Vesalio Group 2005). with each other (Vesalio Group 2005). In a head-to-head compar- Although the differences were not statistically significant, the in- ison, one-month therapeutic or prophylactic dose LMWH led to cidence of VTE tended to be lower both with prophylactic and a similar reduction in ST extension or recurrence, or both, and therapeutic LMWH shortly after treatment (RR 0.25; 95% CI VTE events (RR 1.20; 95% CI 0.42 to 3.40) over a three-month 0.03 to 2.24 and RR 0.26; 95% CI 0.03 to 2.33) but not at the end follow-up. In the prophylactic dose LMWH group most of the of the three-month follow-up period (RR 1.22; 95% CI 0.38 to VTE events (77%) occurred while patients were still on treatment, 3.89 and RR 0.85; 95% CI 0.23 to 3.06, respectively), suggesting whereas only 33% of patients on therapeutic dose LMWH de- a catch-up phenomenon (Stenox Group 2003). Both prophylactic veloped VTE during LMWH administration. This advantage was and therapeutic LMWH given for 8 to 12 days were associated lost after drug discontinuation with no difference at the end of the with a significantly lower incidence of ST extension and/or recur- study period. No major bleeding or heparin-induced thrombocy- rence compared with placebo (RR 0.40; 95% CI 0.22 to 0.72 and topenia events were observed during the study. Local symptoms RR 0.42; 95% CI 0.23 to 0.75, respectively). No episodes of major and signs regressed faster with therapeutic dose LMWH although bleeding or heparin-induced thrombocytopenia were observed in the difference was not statistically significant. any treatment group (Stenox Group 2003). Prophylactic dose, subcutaneous (sc) unfractionated heparin Combined therapy with LMWH plus elastic compression stock- (UFH) was used as the comparator treatment in two studies ings seemed to reduce the incidence of VTE and ST extension or (Belcaro 1999; Marchiori 2002). Relative to elastic stockings recurrence, or both, compared with elastic stockings alone (RR alone, prophylactic sc UFH plus elastic stockings was associated 0.08; 95% CI 0.00 to 1.38 and RR 0.08; 95% CI 0.01 to 0.59), with a non-statistically significant lower VTE rate (RR 0.08; 95% although the former difference was not statistically significant CI 0.00 to 1.47) and an 83% reduction in ST extension or recur- (Belcaro 1999). In this study no data were provided on safety out- rence, or both (RR 0.17; 95% CI 0.04 to 0.72) (Belcaro 1999). comes. One study compared high- versus low-dose sc UFH. A non-significant 83% reduction in VTE (RR 0.17; 95% CI 0.02 to 1.30) Two studies (Gorski 2005; Katzenschlager 2003) randomised pa- and a 27% (RR 0.73; 95% CI 0.34 to 1.55) reduced rate of ST ex- tients to topical treatment with heparin spray gel or LMWH. A tension or recurrence, were observed among patients treated with non-significant decrease in DVT was found with LMWH (RR high-dose UFH (Marchiori 2002). There were no episodes of ma- 0.30; 95% CI 0.03 to 2.70), while local symptoms were similarly jor bleeding or heparin-induced thrombocytopenia in either study relieved by both treatments at 21 days (Gorski 2005). group. LMWH versus surgical treatment (saphenofemoral disconnec- Subcutaneous calcium heparin was evaluated in two studies tion) was evaluated in one study (Lozano 2003). A comparable (Belcaro 1989; Belcaro 1990). The combination of elastic stock- reduction of VTE events and a similar safety profile were observed ings plus calcium heparin did not significantly improve the local in the two study groups. Surgery seemed to be associated with a symptoms and signs compared with elastic stockings alone. Treat- lower risk of ST extension or recurrence, or both (RR 0.33; 95% ment with calcium heparin was correlated with a faster reduc- CI 0.04 to 3.03) although the differences were not statistically tion of the analogue score and the area at maximum temperature significant. than with defibrotide, although the difference was not significant. Therapeutic dose LMWH was evaluated versus NSAIDs in two There were no side effects. studies (Stenox Group 2003; Titon 1994). Fixed-dose LMWH and dose-adjusted LMWH seemed to produce a similar reduction in VTE and ST recurrence relative to NSAIDs. Both these studies Non-steroidal anti-inflammatories (NSAIDs) were, however, not properly sized for a direct comparison between LMWH and NSAIDs. No major bleeding episodes or cases of Five studies included an NSAID group (Anonymous 1970; Ferrari heparin-induced thrombocytopenia occurred within either study 1992; Nusser 1991; Stenox Group 2003; Titon 1994). Of these, group. In one of these studies, which used placebo as a control two compared NSAIDs with placebo (Anonymous 1970; Stenox group, an indirect comparison between prophylactic LMWH and Group 2003), two with LMWH (Stenox Group 2003; Titon NSAIDs suggested a non-statistically significant reduction in VTE 1994), and two randomised patients to two different NSAIDs at the end of treatment (RR 0.45; 95% CI 0.04 to 4.89) (Stenox (Ferrari 1992; Nusser 1991). The trials that evaluated NSAID Group 2003). versus LMWH have been previously presented (Stenox Group

Treatment for superficial thrombophlebitis of the leg (Review) 9 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 2003; Titon 1994). reduction in VTE events (RR 0.33; 95% CI 0.07 to 1.60) and ST NSAIDs significantly reduced the risk of ST extension and/or recurrence and extension (RR 0.46; 95% CI 0.18 to 1.15) relative recurrence by 59% (RR 0.41; 95% CI 0.23 to 0.75) compared with to control treatment (Belcaro 1999). placebo (Stenox Group 2003). However, there were no differences Compared with elastic stockings alone, venous stripping plus elas- in the incidence of VTE or in the resolution of local symptoms tic stockings decreased the risk of ST extension and recurrence and signs. While no major bleeding episodes were recorded in any rate (RR 0.09; 95% CI 0.01 to 0.64) and seemed to be associated NSAID or placebo groups, indomethacin carried a significantly with a lower, non-significant incidence of VTE (RR 0.37; 95% higher rate of side effects compared with placebo (RR 2.60; 95% CI 0.08 to 1.78) (Belcaro 1999). CI 0.95 to 7.08) (Anonymous 1970). In one study, oral acemetacin led to a better resolution of the local clinical picture than diclofenac (Nusser 1991). Another trial compared nimesulide with diclofenac sodium (Ferrari 1992). Lo- Other cal symptoms were similarly improved by both treatments. In the group of patients randomised to nimesulide, a lower incidence of gastric pain episodes was evident (RR 0.25; 95% CI 0.03 to 2.08) Eight studies evaluated an oral (Archer 1977; Belcaro 1989; (Ferrari 1992) although this difference was not statistically signif- Belcaro 1999; Koshkin 2001; Kuhlwein 1985; Messa 1997), intra- icant. muscular (Andreozzi 1996), or intravenous (Marshall 2001) treatment. Topical treatment Compared with placebo, oral vasotonin was associated with a higher proportion of patients who were cured or improved Seven studies included a topical treatment group (De Sanctis 2001; (Kuhlwein 1985). The criteria to determine the response to study Gorski 2005; Holzgreve 1989; Incandela 2001; Katzenschlager treatment were not described. Vasotonin seemed to be well tol- 2003; Nocker 1991; Pinto 1992). The comparison of heparin erated with one case of poor tolerability among patients treated spray gel versus LMWH has been discussed earlier (Gorski 2005; with vasotonin (3%) versus five cases (13%) in the placebo arm Katzenschlager 2003). (RR 0.20; 95% CI 0.02 to 1.63). One study randomised patients to receive topical methylth- The combination of venoruton, thrombectomy, and elastic stock- ioadenosine or placebo (Pinto 1992). Methylthioadenosine was as- ings versus elastic stockings alone has been discussed above sociated with a non-significant reduction in local signs and symp- (Belcaro 1989). In the same trial, venoruton combined with elas- toms relative to placebo. tic stockings led to an improvement of local symptoms compared In a similar way, a significant improvement in the local symptoma- with elastic stockings alone. tology was observed with diclofenac gel (Nocker 1991) or essaven One study evaluating oral heparansulphate versus oral sulodexide gel (De Sanctis 2001; Incandela 2001) compared with placebo. suggested a greater decrease in local pain, itching, and redness in Only one study evaluated two different gels, diclofenac gel and patients receiving oral heparansulphate than in the group receiving etofenak gel (Holzgreve 1989), and showed a comparable efficacy sulodexide (Messa 1997). profile of the two topical medications. None of these studies eval- Compared with placebo, oxyphenbutazone reduced local tender- uating a topical treatment reported data on VTE or ST extension ness four-fold and halved the intensity of pain and erythema or recurrence. (Archer 1977). Oral vitamin-K antagonists in combination with elastic stockings were evaluated in one study. The findings of this study suggested a Surgery non-significant reduction in VTE events (RR 0.08; 95% CI 0.00 Three studies included a surgical treatment (Belcaro 1989; Belcaro to 1.47) and ST extension and/or recurrence (RR 0.42; 95% CI 1999; Lozano 2003). As described above, one study compared 0.16 to 1.13) with the use of vitamin-K antagonists relative to the surgery (saphenofemoral disconnection) with LMWH (Lozano control group treated with elastic stockings alone (Belcaro 1999). 2003). In the remaining two studies surgery combined with elastic Two studies addressed the use of enzyme therapy versus placebo stockings was compared with elastic stockings alone (Belcaro 1989; (Koshkin 2001; Marshall 2001). Enzyme treatment seemed to im- Belcaro 1999). prove local symptoms although the criteria to evaluate the response In the first trial, thrombectomy plus elastic stockings with or with- to study treatment were not reported. out venoruton led to an improvement of the local clinical signs and The efficacy of three doses of desmin was assessed in one trial a greater reduction in the number of veins with ST compared with (Andreozzi 1996). A better control of local symptoms was obtained elastic compression bandage alone (Belcaro 1989). There were no with higher doses of desmin, without any increase in the risk of cases of DVT in either study group. In the second trial, ligation of adverse events. the vein plus elastic stockings was associated with a non-significant

A lot of controversy still exists around the optimal treatment of Most of the studies comparing oral treatment, topical treatment, ST of the legs. The therapeutic approach for ST should aim at or surgery did not report VTE, ST progression, adverse events or the resolution or improvement of the local symptoms but also, treatment side effects. In addition, the methodological quality of and even more importantly, at preventing the possible extension of these studies was often poor, with major study design flaws such superficial vein thrombosis into the deep venous system (Wichers as an unclear method of allocation or randomisation, the lack 2005). of a placebo as control group, or an unacceptably high drop-out rate. All these limitations weaken the clinical applicability of the This review summarised data from over 5500 patients with ST of results and cast doubts over the actual efficacy and safety of these the legs. Sixty per cent of this study population was included inthe treatment strategies. CALISTO study which compared in a double-blinded fashion 45 days of fondaparinux versus placebo (Decousus 2010a). Fonda- Summary of main results parinux reduced the incidence of symptomatic VTE by 85%, the Fondaparinux is associated with a significant lower incidence of incidence of ST extension by 92%, and the recurrence of ST by VTE, ST extension or ST recurrence relative to placebo with 79%. A total of 88 patients would need to be treated with fonda- similar risk of bleeding. As compared to placebo, LMWH and parinux to prevent one PE or DVT. These benefits were achieved NSAIDs appear to reduce the extension or recurrence of ST, or without increasing the risk of bleeding and they were maintained both, whereas the available data do not show any significant effect at the one-month follow-up after discontinuation of treatment. on VTE. The evidence on oral treatments, topical treatment, or Compared with placebo or topical treatments, both NSAIDs and surgery is too limited and does not inform clinical practice about LMWH could help in preventing ST extension while effectively the effects of these treatment in terms of VTE and ST progression. controlling local symptoms (Stenox Group 2003; Titon 1994). When compared with each other, LMWH and NSAIDs seemed to be associated with a similar reduction in the incidence of VTE and Quality of the evidence worsening of ST.However, the conclusions of one of the two stud- Our systematic approach to searching, study selection, and data ies that evaluated LMWH and NSAIDs are hampered by several extraction followed that of the Cochrane Handbook for Systematic methodological drawbacks and the low incidence of VTE with the Reviews of Interventions (Higgins 2003). The methodological qual- small sample size (Titon 1994). The second study used placebo as ity of the included studies varied from low to high (See Figure the control and was not primarily designed nor properly sized for a 1). Poor reporting did not allow proper scoring of relevant study direct comparison between LMWH and NSAIDs (Stenox Group design features such as sequence generation and allocation con- 2003). Thus, these data remain preliminary and further research cealment in the majority of included studies. is required to determine which treatment works better in terms of VTE prevention, and whether a combination may be more effective. Moreover, the benefits of LMWH and NSAIDs have to be Potential biases in the review process balanced against the associated risk of bleeding and gastric com- One limitation of this review is that, despite the relatively large plications. None of the studies evaluating LMWH reported ma- number of comparisons found, none of the studies evaluated the jor bleeding episodes in patients randomised to LMWH. NSAID same treatment comparisons on the same study outcomes. The treatment increased three-fold the risk of gastric pain compared ’no difference’ findings on a specific outcome may thus be the with placebo. To date, no study has evaluated NSAIDs versus result of data that are underpowered to show any difference be- surgery, whereas one trial directly compared LMWH with sur- tween treatment groups as well as the absence of a true effect. For gical treatment, showing a comparable efficacy and safety of the similar reasons, it was not possible to conduct subgroup analyses two study treatments (Lozano 2003). Despite the methodological for the primary efficacy outcomes to evaluate the interaction of limitations of this study its results would suggest that a medical trial characteristics with treatment effects. approach with LMWH would be as effective and safe as invasive surgical treatment. Agreements and disagreements with other Preliminary data suggest that high-dose UFH can be effective in studies or reviews the treatment of ST although this needs to be confirmed in larger studies (Marchiori 2002). No direct comparisons of UFH versus Since our previous systematic review on the prevention of VTE in fondaparinux, LMWH or NSAIDs have been evaluated. In prin- patients with ST (Wichers 2005), the results of a large RCT on ciple, the use of fondaparinux or LMWH may be preferable due the efficacy of fondaparinux for the treatment of ST have become to the easier mode of administration and the more predictable available (Decousus 2010a). The high methodological quality and response, which does not require laboratory monitoring as with the size of that study, which alone accounts for more than half of

Treatment for superficial thrombophlebitis of the leg (Review) 11 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. the overall review population, makes it a landmark investigation life, and the cost-effectiveness of fondaparinux before recommend- in the field. ing its routine use in the treatment of ST (Goldman 2010). Un- til such trials are available, fondaparinux may be recommended for the more severe cases of ST, as evaluated in the CALISTO study (Decousus 2010a). Large and adequately designed RCTs are needed to assess the actual role of NSAIDs and LMWH and AUTHORS’ CONCLUSIONS to ascertain whether these drugs are actually comparable to fondaparinux. Whether topical treatment might add some benefit if Implications for practice given in combination with fondaparinux remains unclear. Finally, Given the available evidence, prophylactic dose fondaparinux ap- adapting the treatment based on the location and the etiology of pears to be a valid treatment option in patients with ST. Fonda- ST warrants further investigation. parinux should be given subcutaneously at a dose of 2.5 mg once daily for about six weeks. Final recommendations cannot be drawn for LMWH, UFH, or NSAIDs. Data are still too preliminary to draw firm conclusions on the role of surgery and the topical, oral, ACKNOWLEDGEMENTS and parenteral treatments evaluated this far. We would like to thank the external peer referee Dr Benilde Cosmi for her comments and Mrs Carole Gibson for acting as the con- Implications for research sumer on this review. We would also like to thank the Cochrane Several questions about the treatment of ST remain unsolved. Consumer Network for their contribution to the Plain Language Additional studies should evaluate the costs, effects on quality of Summary.

REFERENCES

References to studies included in this review De Sanctis 2001 {published data only} De Sanctis MT, Cesarone MR, Incandela L, Belcaro Andreozzi 1996 {published data only} G, Griffin M. Treatment of superficial vein thrombosis Andreozzi GM, Signorelli S, Di Pino L, Martini R, with standardized application of Essaven gel -- a placebo- Marchitelli E, Pinto A, et al.Tolerability and clinical controlled, randomized study. Angiology 2001;52(Suppl 3): efficacy of desmin in the treatment of superficial S57–62. varicothrombophlebitis. Angiology 1996;47(9):887–94. Decousus 2010a {published data only} Anonymous 1970 {published data only} Decousus H, Prandoni P,Mismetti P,Bauersachs RM, Boda Anonymous. Indomethacin in superficial thrombophlebitis. Z, Brenner B, et al. CALISTO Study Group. Fondaparinux The Practitioner 1970;205(227):369–72. for the treatment of superficial-vein thrombosis in the legs. Archer 1977 {published data only} New England Journal of Medicine 2010;363(13):1222–32. Archer DS, Fowler PD. Comparison of oxyphenbutazone Ferrari 1992 {published data only} and placebo in the treatment of superficial thrombophlebitis: Ferrari E, Pratesi C, Scaricabarozzi I, Trezzani R. A clinical an object lesson in clinical trial design. The Practitioner study of efficacy and tolerability of nimesulide compared 1977;218:712–75. with diclofenac sodium in the treatment of acute superficial Belcaro 1989 {published data only} thrombophlebitis [Studio clinico sull’efficacia terapeutica Belcaro G, Errichi BM, Laurora G, Cesarone MR, Candiani e la tollerabilità della nimesulide in confronto a diclofenac C. Treatment of acute superficial thrombosis and follow-up sodio nel trattamento delle tromboflebiti acute superficiali]. by computerized thermography. VASA 1989;18(3):227–34. Minerva Cardioangiologica 1992;40(11):455–60. Belcaro 1990 {published data only} Gorski 2005 {published data only} Belcaro G. Evolution of superficial vein thrombosis treated Gorski G, Szopinski P, Michalak J, Marianowska A, with defibrotide: comparison with low dose subcutaneous Borkowski M, Geremek M, et al.Liposomal heparin spray: heparin. International Journal of Tissue Reactions 1990;12 a new formula in adjunctive treatment of superficial venous (5):319–24. thrombosis. Angiology 2005;56(1):9–17. Belcaro 1999 {published data only} Holzgreve 1989 {published data only} Belcaro G, Nicolaides AN, Errichi BM, Cesarone MR, De Holzgreve A, Kleine W, Stegmann W. Local treatment Sanctis MT, Incandela L, et al.Superficial thrombophlebitis of superficial thrombophlebitis with nonsteroidal of the legs: a randomized, controlled, follow-up study. antiinflammatory agents. Zeitschrift fur Allgemeinmedizin Angiology 1999;50(7):523–9. 1989;65(27):663–7.

Treatment for superficial thrombophlebitis of the leg (Review) 12 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Incandela 2001 {published data only} [Lokaltherapie bei oberflachlicher thrombophlebitis. Incandela L, De Sanctis MT, Cesarone MR, Ricci A, Wirksamkeit eines diclofenac–natrium–gels im vergleich zu Errichi BM, Dugal M, et al.Treatment of superficial vein placebo– und heparin–gel]. Zeitschrift fur Allgemeinmedizin thrombosis: clinical evaluation of essaven gel--a placebo- 1991;67:2214–22. controlled, 8-week, randomized study. Angiology 2001;52 Nusser 1991 {published data only} Suppl 3:69–72. Nusser C-J, Schare W, Bernard I. The treatment of Katzenschlager 2003 {published data only} superficial thrombophlebitis with nonsteroidal antiphlogistic Katzenschlager R, Ugurluoglu A, Minar E, Hirschl agents [Therapie superfizieller thrombophlebitiden mit M. Liposomal heparin-spraygel in comparison with nichtsteroidalen antiphlogistika]. 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Drug treatment of superficial of a low-molecular-weight heparin, a nonsteroidal anti- thrombophlebitides [Medikamentose behandlung inflammatory agent, and placebo in the treatment of oberflachlicher thrombophlebitiden]. Therapiewoche 1985; superficial vein thrombosis. Archives of Internal Medicine 35(36):4067–70. 2003;163(14):1657–63. Lozano 2003 {published data only} Titon 1994 {published data only} Lozano FS, Almazan A. Low-molecular-weight heparin Titon JP,Auger D, Grange P,Hecquet JP,Remond A, Ulliac versus saphenofemoral disconnection for the treatment P, Vaissie JJ. Therapeutic management of superficial venous of above-knee greater saphenous thrombophlebitis: a thrombosis with calcium nadroparin. Dosage testing and prospective study. Vascular and Endovascular Surgery 2003; comparison with an non-steroidal anti-inflammatory agent 37(6):415–20. [Traitement curatif des thromboses veineuses superficielles Marchiori 2002 {published data only} par nadroparine calcique. Recherche posologique et Marchiori A, Verlato F, Sabbion P, Camporese G, Rosso F, comparaison à un anti–inflammatoire non stéroidien]. Mosena L, et al.High versus low doses of unfractionated Annales de Cardiologie et d’Angeiologie 1994;43(3):160–6. heparin for the treatment of superficial thrombophlebitis Uncu 2009 {published data only} of the leg. A prospective, controlled, randomized study. Uncu H. A comparison of low-molecular-weight heparin Haematologica 2002;87(5):523–7. and combined therapy of low-molecular-weight heparin Marshall 2001 {published data only} with an anti-inflammatory agent in the treatment of Marshall M, Kleine M-W. Efficacy and tolerability of an oral superficial vein thrombosis. Phlebology 2009;24(2):56–60. enzyme therapy in the treatment of painful acute superficial Vesalio Group 2005 {published data only} thrombophlebitis [Wirksamkeit und vertraglichkeit einer Prandoni P. High versus low doses of low-molecular-weight oralen enzymtherapie bei der schmerzhaften akuten heparin for the treatment of superficial vein thrombosis thrombophlebitis superficialis]. Phlebologie 2001;30(2): of the legs. A double-blind, randomized trial. http:// 36–43. www.blackwellpublishing.com/isth2005/abstract.asp?id= Messa 1997 {published data only} 46005. 2005; Vol. 3. Messa G, La Placa G, Puccetti L, Di Perri T. Prandoni P, Tormene D, Pesavento R. Vesalio Investigators Heparansulphate. Effectiveness and tolerability of heparan Group. High vs. low doses of low-molecular-weight heparin sulphate in the treatment of superficial thrombophlebitis. for the treatment of superficial vein thrombosis of the legs: Controlled clinical study vs sulodexide [Efficacia e a double-blind, randomized trial. Journal of Thrombosis and tollerabilità dell’eparansolfato nel trattamento della Haemostasis 2005;3(6):1152–7. tromboflebite superficiale. Studio clinico controllato References to studies excluded from this review vs sulodexide]. Minerva Cardioangiologica 1997;45(4): 147–53. Agus 1993 {published data only} Nocker 1991 {published data only} Agus GB, de Angelis R, Mondani P, Moia R. Double-blind Nocker W, Diebschlag W, Lehmacher W. The efficacy comparison of nimesulide and diclofenac in the treatment of a diclofenac gel compared with placebo and heparin of superficial thrombophlebitis witht telethermographic gel in the local treatment of superficial thrombophlebitis assessment. Drugs 1993;46 Suppl 1:200–3.

Treatment for superficial thrombophlebitis of the leg (Review) 13 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Allegra 1981 {published data only} un preparato a base di tripsina/chimotripsina e tetraciclina Allegra C, Pollari G, Criscuolo A, Bonifacio M, Tabassi D. cloridrato nelle flebiti acute]. Gazzetta Medica Italiana Centella asiatica extract in venous disorders of the lower 1979;138(11):567–70. limbs. Comparative clinical-instrumental trial against a Della Marchina 1989 {published data only} placebo [L’estratto di centella asiatica nelle flebopatie degli Della Marchina M, Renzi G, Palazzini E. Treatment arti inferiori. Ricerca clinico–strumentale comparativa con of phlebopathies with low molecular weight heparin as un placebo]. Clinica Terapeutica 1981;99:507–13. compared to heparin calcium. Riforma Medica 1989;104 Annoni 1991 {published data only} (4):99–104. Annoni F, De Stefano A, Pabisch S, Floresta M, Magnani Di Perri 1986 {published data only} P, Lietti F, et al.Efficacy and safety of topical treatment Di Perri T, Vittoria A, Messa GL, Cappelli R. Defibrotide with heparan sulfate in superficial phlebitis. A double- therapy for thrombophlebitis -- controlled clinical trial. blind placebo-controlled trial. Acta Therapeutica 1991;17: Haemostasis 1986;16 Suppl 1:42–7. 263–72. Gandhi 1984 {published data only} Argenteri 1983 {published data only} Gandhi DB, Palmar JR, Lewis B, Schraibman IG. Clinical Argenteri A, Vittori F, Longoni A. Flurbiprofen and comparison of elastic supports for venous diseases of the thrombophlebitis of lower limbs: a controlled clinical lower limbs. Postgraduate Medical Journal 1984;60:349–52. trial [Terapia antiinfiammatoria delle tromboflebiti degli Giorgetti 1990 {published data only} arti inferiori con flurbiprofen: studio clinico controllato]. Giorgetti PL, Bortolani EM, Morbidelli A, Vandone PL, Giornale Italiano di Angiologia 1983;3:203–8. Ghilardi G, Mattioli A, et al.Use of a new anti-inflammatory Bagliani 1983 {published data only} drug in the treatment of varicophlebitis of the lower Bagliani A, La Rosa A, Sarchi C. A new anti-inflammatory limbs [L’uso di un nuovo farmaco antiinflammatorio nel drug, suprofen, in the treatment of thrombophlebitis trattamento delle varicoflebiti degli arti inferiori]. Minerva [Un nuovo farmaco antiinfiammatorio, il suprofen, nel Chirurgica 1990;45(12):883–6. trattamento delle tromboflebiti]. Giornale Italiano di Gouping 2003 {published data only} Angiologia 1983;3:57–64. Gouping Z, Wan-Er T, Xue-Ling W, Min-Qian X, Kun F, Turale S, et al.Notoginseny cream in the treatment of Becherucci 2000 {published data only} phlebitis. Journal of Infusion Nursing 2003;26(1):49–54. Becherucci A, Bagilet D, Marenghini J, Diab M, Biancardi H. Effect of topical and oral diclofenac on superficial Ibanez-Bermudez 1996 {published data only} thrombophlebitis caused by intravenous infusion [Efecto del Ibanez-Bermudez S, Perez Martinez F, Llamas del Castillo diclofenaco topico y oral sobre la tromboflebitis superficial MD, Sevilla Jiménez JC, Gonzalez Gonzalez EM. inducida por infusion intravenosa]. Medicina Clinica 2000; Randomized double-blind clinical study on the efficacy 114(10):371–3. of topical sodium heparin versus sodium polysulphate pentosan [Estudio clinico randomizado y doble ciego sobre Bergqvist 1990 {published data only} la eficacia de heparina sodica topica frente a pentosan Bergqvist D, Brunkwall J, Jensen N, Persson NH. Treatment polisulfato sodico en patologias venosas superficiales]. of superficial thrombophlebitis. A comparative trial between Farmacia e Clinica 1996;13(2):110–5. placebo, hirudoid cream and piroxicam gel. Annales Chirurgiae et Gynaecologiae 1990;79(2):92–6. Luttichau 1989 {published data only} Luttichau U, Palazzini E. Antithrombotic therapy in Bernicot 1980 {published data only} phlebopathies of lower limbs: a controlled study of low Bernicot J. The value of Eucatex in venous pathology in the molecular weight heparin versus heparin calcium. Rivista young woman [Interet d’eucatex dans la pathologie veineuse Europea Per Le Scienze Mediche e Farmacologiche 1989;11 de la jeune femme]. Quest Medical 1980;33(5):221–2. (4):351–8. Bracale 1996 {published data only} Mari 1982 {published data only} Bracale G, Selvetella L. Controlled clinical trial comparing Mari F, Cerreta G, Nardi V, Dialti L. Piroxicam as seaprose S to serratio-peptidase in venous inflammatory antiinflammatory therapy in thrombophlebitis: clinical disease. Efficacy and safety [Studio clinico sull’efficacia e la experience [Il piroxicam nella terapia antiflogistica delle tollerabilità del seaprose S nelle flebopatie infiammatorie. tromboflebiti. Nostra esperienza clinica]. Gazzetta Medica Studio controllato verso serratio–peptidasi]. Minerva Italiana 1982;141(5):243–5. Cardioangiologica 1996;44(10):515–24. Marsala 1985 {published data only} Bruni 1979 {published data only} Marsala F. A controlled double-blind cross-over study of a Bruni M, Quarti Trevano GM, Lochis D, Baresi A, calcium heparin preparation [Studio controllato in doppio Soletti L. Double-blind assessment of the clinical and cieco cross–over su un preparato a base di calcio–eparina]. pharmacological results of administration of a preparation Clinica Terapeutica 1985;113(6):473–7. with trypsin/chymotrypsin and tetracycline hydrochloride Mauro 1992 {published data only} base in cases of acute phlebitis [Analisi in doppio cieco dei Mauro M, Ferraro G, Palmieri G. Profibrinolytic and risultati clinici e farmacologici dopom somministrazione di antithrombotic effects of sulodexide oral administration: a

Treatment for superficial thrombophlebitis of the leg (Review) 14 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. double-blind, cross-over, placebo-controlled study. Current oxyphenbutazone. Clinical Trials Journal 1983;20(3): Therapeutic Research, Clinical & Experimental 1992;51(3): 148–57. 342–50. van Cauwenberge 1972 {published data only} Mehta 1975 {published data only} van Cauwenberge H. Double-blind study of the efficacy Mehta PP, Sagar S, Kakkar VV. Treatment of superficial of a soluble rutoside derivative in the treatment of thrombophlebitis: a randomized double-blind trial of venous disease [Etude n double aveugle de l’efficacité de heparinoid cream. BMJ 1975;3(5984):614–6. l’O–(beta–hydroxyéthyl)–rutosides dans le traitement Paciaroni 1982 {published data only} des affections veineuses]. Archives Internationales de Paciaroni E, Marini M. Topical therapy for phlebophaties. Pharmacodynamie et de Therapie 1972;196:122–8. Results of a controlled clinical study [Sulla terapia topica van der Knaap 1988 {published data only} delle flebopatie. Risultati di uno studio clinico controllato]. van der Knaap JH, den Ottolander GJH, van Heerde LR. Policlinico Sezione Medica 1982;89(3):255–64. Research into efficacy of heparinoid cream [Onderzoek Porters 1981 {published data only} naar de effectiviteit van heparinodezalf]. Pharmaceutisch Porters J, Roekaerts F, Reyntjens A. R 41 468, a specific Weekblad 1988;123:973–5. serotonin antagonist, relieves symptoms of acute superficial References to ongoing studies thrombophlebitis. Current Therapeutic Research, Clinical & Experimental 1981;30(4):499–506. NCT00362947 {published data only} Pozza 1980 {published data only} Palareti G, Cosmi B. Different doses and duration of low Pozza E, Menghi R, Pansini GC, Duatti A, Carnovali M. molecular weight heparin (parnaparin) in superficial vein Clinical trial with BPH 689 for the treatment of superficial thrombosis. clinicaltrials.gov/ct2/show/NCT00362947 phlebitis [Impiego clinico del BPH 689 nel trattamento (accessed 9 November 2011). delle flebiti superficiali]. Acta Chirurgica Italiana 1980;36 Rabe 2009 {published data only} (2):157–66. Rabe E. DAPS-dalteparin in patients with superficial Rea 1981 {published data only} leg vein phlebitis in addition to compression treatment Rea WJ, Peters DW, Smiley RE, Edgar R, Greenberg - a placebo-controlled phase-III study. XVIth World M, Fenyves E. Recurrent environmentally triggered Meeting of the Union Internationale de Phlébologie (UIP) thrombophlebitis: a five-year follow-up. Annals of Allergy Principality of Monaco. August 31–September 4, 2009. 1981;47(5):338–44. Additional references Resta 1967 {published data only} Resta V. Clinical comparative experiment on 2 ointments of Barrelier 1993 different extractive heparinoid concentrations (double blind Barrelier MT. Superficial venous thrombosis of the legs. test). Arzneimittel-Forschung 1967;17(8):1078–82. Phlebologie 1993;46(4):633–9. Rozsos 1994 {unpublished data only} Bergqvist 1986 Rozsos I, Kollar L, Scholz ME. The topical treatment Bergqvist D, Jaroszewski H. Deep venous thrombosis in of infusion thrombophlebitis with pentosan polysulfate patients with superficial thrombophlebitis of the leg. British sodium ointment. A randomised double-blind study. Medical Journal 1986;292(6521):658–9. Annals of Hematology 1994;68 (Suppl 1):A92. Blumenberg 1998 Seccia 1989 {published data only} Blumenberg RM, Barton E, Gelfand ML, Skudder P, Seccia M, Bortolotti P,Bellomini MG, Buccianti P,Chiarugi Brennan J. Occult deep venous thrombosis complicating M, Cavina E. Use of defibrotide in the treatment of superficial thrombophlebitis. Journal of Vascular Surgery acute superficial thrombophlebitis of the legs [Impiego 1998;27(2):338–43. del defibrotide nel trattamento delle tromboflebiti acute Bounameaux 1997 superficiali degli arti]. Minerva Chirurgica 1989;44(9): Bounameaux H, Reber-Wasem MA. Superficial 1379–84. thrombophlebitis and deep venous thrombosis. A Seghezzi 1972 {published data only} controversial association. Archives of Internal Medicine Seghezzi R, Borri P, Chierichetti S, Ferrari P. Controlled 1997;157(16):1822–4. clinical trial of 4-prenyl-1,2-diphenyl-3,5-pyrazolidinedione Chengelis 1996 (DA2370) and oxyphenbutazone in thrombophlebitis. Chengelis DL, Bendick PJ, Glover JL, Brown OW, Ranval Arzneimittel-Forschung 1972;22(1):272–4. TJ. Progression of superficial venous thrombosis to deep Seligman 1969 {published data only} vein thrombosis. Journal of Vascular Surgery 1996;24(5): Seligman B. Oral bromelains as adjuncts in the treatment of 745–9. acute thrombophlebitis. Angiology 1969;20(1):22–6. de Moerloose 1998 Tomamichel 1983 {published data only} de Moerloose P, Wutschert R, Heinzmann M, Perneger Tomamichel M, Reiner M. Treatment of thrombophlebitis T, Reber G, Bounameaux H. Superficial vein thrombosis and superficial phlebitis. A comparison of nimesulide and of lower limbs: influence of factor V Leiden, Factor II

Treatment for superficial thrombophlebitis of the leg (Review) 15 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. G20210A and overweight. Thrombosis and Haemostasis thrombosis. Thrombosis and Haemostasis 1999;82(4): 1998;80(2):239–41. 1215–17. De Weese 1991 Nordstrom 1992 De Weese MS. Nonoperative treatment of acute superficial Nordstrom M, Lindblad B, Bergqvist D, Kjellstrom T. A thrombophlebitis and deep femoral venous thrombosis. In: prospective study of the incidence of deep-vein thrombosis Ernst C B, Stanley J C editor(s). Current Therapy in Vascular within a defined urban population. Journal of Internal Surgery. 2nd Edition. Philadelphia: B C Decker, 1991. Medicine 1992;232(2):155–60. Decousus 2010 Plate 1985 Decousus H, Quéré I, Presles E, Becker F, Barrellier M, Plate G, Eklof B, Jensen R, Ohlin P. Deep venous Chanut M, et al. POST (Prospective Observational thrombosis, pulmonary embolism and acute surgery Superficial Thrombophlebitis) Study Group. Superficial in thrombophlebitis of the long saphenous vein. Acta venous thrombosis and venous thromboembolism. Annals Chirurgia Scandinavica 1985;151(3):241–4. of Internal Medicine 2010;152(4):218–24. Quenet 2003 Goldman 2010 Quenet S, Laporte S, Decousus H, Leizorovicz A, Epinat Goldman L, Ginsberg J. Superficial phlebitis and phase M, Mismetti P. STENOX Group. Factors predictive of 3.5 trials. New England Journal of Medicine 2010;363(13): venous thrombotic complications in patients with isolated 1278–80. superficial vein thrombosis. Journal of Vascular Surgery Guyatt 2008 2003;38(5):944–9. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Rücker 2008 Alonso-Coello P, et al. GRADE Working Group. GRADE: Rücker G, Schwarzer G, Carpenter JR, Schumacher M. an emerging consensus on rating quality of evidence and Undue reliance on I2 in assessing heterogeneity may strength of recommendations. BMJ 2008;336:924–6. mislead. BMC Medical Research Methodology 2008;8:79. Hanson 1998 Samlaska 1990a Hanson JN, Ascher E, De Pippo P, Lorensen E, Scheinman Samlaska CP, James WD. Superficial thrombophlebitis I. M, Yorkovich W, et al.Saphenous vein thrombophlebitis Primary hypercoagulable states. Journal of the American (SVT): a deceptively benign disease. Journal of Vascular Academy of Dermatology 1990;22(6 Pt 1):975–89. Surgery 1998;27(4):677–80. Samlaska 1990b Higgins 2003 Samlaska CP, James WD. Superficial thrombophlebitis II. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Secondary hypercoagulable states. Journal of the American Measuring inconsistency in meta-analyses. BMJ 2003;327 Academy of Dermatology 1990;23(1):1–18. (7414):557–60. Skillman 1990 Higgins 2008 Skillman JJ, Kent KC, Porter DH, Kim D. Simultaneous Higgins JPT, Green S, editors. Cochrane Handbook for occurrence of superficial and deep thrombophlebitis in the Systematic Reviews of Interventions. Chichester: John Wiley lower extremity. Journal of Vascular Surgery 1990;11(6): & Sons, 2008. 818–23. Jorgensen 1993 Sterne 2001 Jorgensen JO, Hanel KC, Morgan AM, Hunt JM. The Sterne JA, Egger M. Funnel plots for detecting bias in meta- incidence of deep venous thrombosis in patients with analysis: guidelines on choice of axis. Journal of Clinical superficial thrombophlebitis of the lower limbs. Journal of Epidemiology 2001;54(10):1046–55. Vascular Surgery 1993;18(1):70–3. Unno 2002 Juni 2001 Unno N, Mitsuoka H, Uchiyama T, Yamamoto N, Saito Juni P, Altman DG, Egger M. Systematic reviews in health T, Ishimaru K, Kaneko H, Nakamura S. Superficial care: Assessing the quality of controlled clinical trials. BMJ thrombophlebitis of the lower limbs in patients with 2001;323(7303):42–6. varicose veins. Surgery Today 2002;32(5):397–401. Krunes 1999 Verlato 1999 Krunes U, Lindner F, Lindner R, Gnutzmann J. Verlato F, Zucchetta P, Prandoni P, Camporese G, Is the physical diagnosis of below-knee superficial Marzola MC, Salmistraro G, et al.An expectedly high thrombophlebitis reliable?. Phlebologie 1999;28(3):93–6. rate of pulmonary embolism in patients with superficial Lutter 1991 thrombophlebitis of the thigh. Journal of Vascular Surgery Lutter KS, Kerr TM, Roedersheimer LR, Lohr JM, 1999;30(6):1113–5. Sampson MG. Superficial thrombophlebitis diagnosed by Wichers 2005 duplex scanning. Surgery 1991;110(1):42–6. Wichers IM, Di Nisio M, Buller HR, Middeldorp S. Martinelli 1999 Treatment of superficial vein thrombosis to prevent deep Martinelli I, Cattaneo M, Taioli E, De Stefano V, Chiusolo vein thrombosis and pulmonary embolism: a systematic P, Mannucci PM. Genetic risk factors for superficial vein review. Haematologica 2005;90(5):672–7.

Di Nisio 2007 Di Nisio M, Middeldorp S, Wichers IM. Treatment for superﬁcial thrombophlebitis of the leg. Cochrane Database of Systematic Reviews 2007, Issue 1. [DOI: 10.1002/ 14651858.CD004982.pub2] ∗ Indicates the major publication for the study

Characteristics of included studies [ordered by study ID]

Andreozzi 1996

Methods Multicentre, open RCT

Participants Patients (n = 56) with ST or varicophlebitis of the lower limbs; 19 males, 36 females; age range 48 to 52 years. The diagnosis of ST was objectively conﬁrmed by Doppler ultrasonography with compression. Not reported if included patients were hospitalised and/or non-hospitalised

Interventions Dermatan sulphate (Desmin) (100 mg bid sc) versus Desmin (200 mg od Im) versus Desmin (100 mg od sc) for 30 days

Outcomes Pain and functional inability; local oedema; palpable thrombophlebitic cord; fever; hy- peremia and cutaneous hyperthermia

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information provided bias)

Allocation concealment (selection bias) Unclear risk No information provided

Blinding (performance bias and detection High risk Open study bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk No information provided on the number of patients on whom All outcomes the outcomes were ﬁnally evaluated

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Anonymous 1970

Methods Placebo-controlled, double-blinded RCT

Participants Patients (n = 56) with ST of the calf (68%), thigh (16%), both (16%). Not reported if included patients were hospitalised and/or non-hospitalised. Not reported if the diagnosis of ST was objectively conﬁrmed by ultrasonography

Interventions Indomethacin (50 mg 3 tid) versus placebo for 1 week

Outcomes Erythema, spontaneous pain, tenderness, oedema

Notes Every patient received tetracyclines (250 mg 4 times/day), paracetamol when required, warm socks (5 patients in the indomethacin group, 3 in the placebo)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information provided bias)

Allocation concealment (selection bias) Unclear risk No information provided

Blinding (performance bias and detection Low risk Double-blind study bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk Not clear how many patients of those ini- All outcomes tially included had full assessment of the study endpoints

Selective reporting (reporting bias) Unclear risk No data are provided for some of the outcomes

Archer 1977

Methods Multicentre, double-blind RCT

Participants Non-hospitalised patients (n = 54) with ST; 18 males, 36 females; mean age 55 years. Not reported if the diagnosis of ST was objectively conﬁrmed by ultrasonography

Interventions Oxyphenbutazone (Tandacote) (100 mg 4 times daily) versus placebo (4 times daily) for 7 days

Outcomes Pain, erythema, tenderness, length of indurated vein

Notes Paracetamol and ﬁrm bandaging allowed. Outcome tenderness assessed in 24 out of 26 patients in the oxyphenbutazone group

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information provided bias)

Allocation concealment (selection bias) Unclear risk No information provided

Blinding (performance bias and detection Low risk Double-blind study bias) All outcomes

Incomplete outcome data (attrition bias) High risk 1 patient excluded post-randomisation (2%). Un- All outcomes clear if all included patients were evaluated for study outcomes

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Belcaro 1989

Methods Open RCT

Participants Patients (n = 83) with ST without DVT on duplex ultrasonography; 36 males, 45 females; mean age 38.9 years. Not reported if patients were hospitalised or non-hospitalised

Interventions Superﬁcial thrombectomy plus ECB versus calcium heparin (0.5 mg bid sc) plus ECB versus venoruton (1000 mg tid) plus ECB versus venoruton (1000 mg tid) after superﬁcial thrombectomy plus ECB versus ECB alone. Non-surgical treatment was given for 8 weeks

Outcomes Area of maximum temperature; pain and tenderness (analogical score); DVT. Not spec- iﬁed if DVTs were symptomatic or asymptomatic

Notes 6 of the 9 patients excluded post-randomisation underwent surgery of the superficial venous system. DVT was verified at 6 weeks by strain-gauge plethysmography Gianni Belcaro was erased from the UK medical register in June 2007 for “misconduct”, which seems to have been that he included as co-authors on his papers people who were not involved in the research. The GMC report did not suggest that data were falsified http://webcache.gmc-uk.org/minutesfiles/3313.HTML.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information provided bias)

Allocation concealment (selection bias) Unclear risk No information provided

Blinding (performance bias and detection High risk Open study bias) All outcomes

Incomplete outcome data (attrition bias) High risk Nine patients excluded post-randomisation (10%) All outcomes

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Belcaro 1990

Methods RCT

Participants Patients (n = 40) with ST conﬁrmed by colour duplex scanning; 18 males, 27 females; age range 46 to 48 years. Not reported if patients were hospitalised or non-hospitalised

Interventions Deﬁbrotide ﬁrst week: 400 mg bid; second and third weeks: 400 mg od versus low-dose heparin 5000 IU bid sc for 3 weeks

Outcomes Area of maximum temperature, analogue score (redness, local tenderness, inﬂammation)

Notes All patients got compression bandages Gianni Belcaro was erased from the UK medical register in June 2007 for “misconduct”, which seems to have been that he included as co-authors on his papers people who were not involved in the research. The GMC report did not suggest that data were falsiﬁed http://webcache.gmc-uk.org/minutesﬁles/3313.HTML.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information provided bias)

Allocation concealment (selection bias) Unclear risk No information provided

Blinding (performance bias and detection Unclear risk No information provided bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk Unclear if all included patients were evaluated for study out- All outcomes comes

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Methods Multicentre, open RCT; 6-month follow-up

Participants Non-hospitalised patients (n = 562) with ST and large varicose veins; 181 males, 263 females; mean age 54 years. The diagnosis of ST was objectively conﬁrmed by colour Doppler ultrasonography with compression

Interventions Surgery (ligation) versus surgery (complete stripping) versus low-dose sc heparin versus LMWH versus coumadin

Outcomes DVT and extension of ST after treatment and after 3 and 6 months. Not speciﬁed if DVT and extension of ST were symptomatic or asymptomatic

Notes All patients got compression bandages. The duration of the non-surgical treatments is unclear Gianni Belcaro was erased from the UK medical register in June 2007 for “misconduct”, which seems to have been that he included as co-authors on his papers people who were not involved in the research. The GMC report did not suggest that data were falsiﬁed http://webcache.gmc-uk.org/minutesﬁles/3313.HTML.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information provided bias)

Allocation concealment (selection bias) Unclear risk No information provided

Blinding (performance bias and detection High risk Open study bias) All outcomes

Incomplete outcome data (attrition bias) High risk 118 patients lost to follow up (21%) All outcomes

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

De Sanctis 2001

Methods Placebo-controlled RCT; no patients lost to follow up

Participants Patients (n = 30) with ST conﬁrmed by colour duplex ultrasonography and varicose veins; mean age 51 years. Not reported if patients were hospitalised and/or non-hospitalised patients

Interventions Essaven gel (5 cm of gel) versus placebo (5 cm of gel) for 4 weeks

Outcomes Average decrease in temperature; average symptomatic score (local pain, disability, swelling)

Notes All patients received clopidogrel (0.1ml/10kg of body weight od) and elastic compression stockings

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information provided bias)

Allocation concealment (selection bias) Unclear risk Sealed envelopes, not clear if opaque and sequentially numbered

Blinding (performance bias and detection Low risk Double-blind study bias) All outcomes

Incomplete outcome data (attrition bias) Low risk No missing outcome data All outcomes

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Decousus 2010a

Methods Multicentre, randomised, double-blind, placebo-controlled study

Participants Hospitalised or non-hospitalised patients 18 years of age or older, with acute, symptomatic lower limb superﬁcial-vein thrombosis at least 5 cm long, as conﬁrmed by standardised compression ultrasonography

Interventions Fondaparinux (2.5 mg sc od) versus or placebo for 45 days

Outcomes Primary efﬁcacy outcome: a composite of death from any cause or symptomatic PE, symptomatic DVT, or symptomatic extension to the saphenofemoral junction or symptomatic recurrence of superﬁcial-vein thrombosis at day 47. Main safety outcome: major bleeding

Notes In the fondaparinux group, 83.0% of patients received graduated compression stockings, 41.5% topical NSAIDs, 3.9% topical anticoagulant drugs, 2.1% oral NSAIDs or COX-2 inhibitors, 1.1% oral or parenteral anticoagulant drugs, 21.4% aspirin or other antiplatelet agents. The corresponding values in the placebo group were similar (83.1%, 41.8%, 3.3%, 3.7%, 6.4%, and 22.6%) except for anticoagulant drugs and oral NSAIDs which were prescribed more frequently than in the fondaparinux group

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Central telephone system and computer- bias) generated randomisation list

Allocation concealment (selection bias) Low risk Central allocation

Blinding (performance bias and detection Low risk Double-blind study bias) All outcomes

Incomplete outcome data (attrition bias) Low risk Efﬁcacy analyses performed on data from All outcomes the intention-to-treat data. Safety analyses were performed on data from the as- treated population. Overall, 1.8% of the randomised patients did not complete follow-up

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Ferrari 1992

Methods Single centre, open RCT

Participants Patients (n = 50) with acute ST; 22 males, 28 females; median age 52 years. Not reported if patients were hospitalised or non-hospitalised nor if the diagnosis of ST was objectively conﬁrmed by ultrasonography

Interventions Nimesulide 100 mg bid versus diclofenac sodium 50 mg bid for 10 days

Outcomes Spontaneous pain, hyperaemia, oedema

Notes All patients received heparin calcium

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information provided bias)

Allocation concealment (selection bias) Unclear risk No information provided

Blinding (performance bias and detection Low risk Double-blind study bias) All outcomes

Incomplete outcome data (attrition bias) High risk 3 patients lost to follow up (6%) All outcomes

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Gorski 2005

Methods Multicentre, open, RCT; 7 to 14 day follow-up

Participants Non-hospitalised patients (n = 46) with symptomatic ST conﬁrmed by duplex ultrasonography with ﬁrst symptoms not earlier than 72 hours before inclusion; 15 males, 31 females; mean age 52.5 years

Interventions Topical liposomal heparin spray gel (4 puffs of 458 IU tid) versus LMWH (enoxaparin 40 mg sc od)

Outcomes DVT, pain scoring, erythema, safety, tolerance. Not speciﬁed if DVTs were symptomatic or asymptomatic

Notes Paracetamol up to 1000 mg/day and compression therapy permitted and documented

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information provided bias)

Allocation concealment (selection bias) Unclear risk No information provided

Blinding (performance bias and detection High risk Open study bias) All outcomes

Incomplete outcome data (attrition bias) High risk 4 patients lost to follow-up (10%) All outcomes

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Methods RCT

Participants Patients (n = 60) with ST of the legs; 17 males, 13 females; mean age 53 years. Not reported if patients were hospitalised or non-hospitalised

Interventions Etofenak gel versus diclofenac gel

Outcomes Length of superﬁcial venous thrombosis (cm), pain, redness, palpable veins, oedema

Notes All patients had compression therapy

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information provided bias)

Allocation concealment (selection bias) Unclear risk No information provided

Blinding (performance bias and detection High risk Single-blinded bias) All outcomes

Incomplete outcome data (attrition bias) High risk 20 patients lost to follow up (33%) All outcomes

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Incandela 2001

Methods Multicentre, placebo-controlled RCT

Participants Patients (n = 30) with ST conﬁrmed by colour duplex ultrasonography and varices; 14 males, 16 females; mean age 54 years. Not reported if patients were hospitalised or non- hospitalised

Interventions Essaven gel (5 cm of gel) versus placebo (5 cm of gel) for 8 weeks

Outcomes Analog clinical/symptomatic score including pain, tenderness, disability, local swelling, erythema, presence of thrombosis

Notes All patients received LMWH (Enoxaparin 0.1ml/10kg of body weight od) for the initial 4 weeks of the study and elastic compression stockings

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk The authors stated that the randomisation pro- bias) cess was controlled by an external statistical controller, not better speciﬁed

Allocation concealment (selection bias) Unclear risk Sealed envelopes, not clear if opaque and sequentially numbered

Blinding (performance bias and detection Low risk Double-blinded bias) All outcomes

Incomplete outcome data (attrition bias) Low risk No missing outcome data All outcomes

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Katzenschlager 2003

Methods Multicentre, open RCT

Participants Non-hospitalised patients (n = 42) with ST diagnosed by duplex ultrasonography with signs and symptoms lasting less than 72 hours; 11 males, 31 females; mean age 52 years

Interventions Topical liposomal heparin spray gel (Lipohep 2400 IU/g, 4 spray puffs tid) plus compressive stockings versus LMWH (enoxaparin 40 mg sc) plus compressive stockings for 7 to 14 days

Outcomes Median pain (VAS scale), median area of erythema, thrombus size

Notes Patients received paracetamol as pain remedy

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Assignment of patients to treatment done with a randomisa- bias) tion list

Allocation concealment (selection bias) Unclear risk No information provided

Blinding (performance bias and detection High risk Open study bias) All outcomes

Incomplete outcome data (attrition bias) High risk 3 patients lost to follow up (7%) All outcomes

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Koshkin 2001

Methods Placebo-controlled, double-blinded RCT

Participants Patients (n = 119) with acute ST conﬁrmed by duplex ultrasonography; mean age 54.5 years. Not reported if patients were hospitalised and/or non-hospitalised patients

Interventions Systemic enzyme therapy (Wobenzym) (10 tablets 3 tid) versus placebo for 16 days

Outcomes Positive changes for a combined outcome including pain, redness, and oedema

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information provided bias)

Allocation concealment (selection bias) Unclear risk No information provided

Blinding (performance bias and detection Low risk Double-blind study bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk No information provided. Unclear if all in- All outcomes cluded patients were evaluated for study outcomes

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Kuhlwein 1985

Methods Multicentre, placebo-controlled RCT

Participants Patients (n = 76) with ST,diagnosed on signs and symptoms only by general practitioners or internists. Not reported if some patients were hospitalised

Interventions Vasotonin forte versus placebo for 3 weeks

Outcomes Overall score including pain, redness, swelling, movement improvement

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information provided bias)

Allocation concealment (selection bias) Unclear risk No information provided

Blinding (performance bias and detection Low risk Double-blind study bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk Unclear if all included patients were evaluated All outcomes for study outcomes

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Lozano 2003

Methods Open RCT

Participants Patients (n = 60) with saphenous proximal thrombophlebitis conﬁrmed by Doppler ultrasonography; 22 males, 38 females; mean age 59 years. Not reported if patients were hospitalised or non-hospitalised patients

Interventions LMWH (enoxaparin 1mg/kg bid for the ﬁrst week, then 1 mg/kg for 3 weeks) versus saphenofemoral disconnection

Outcomes Resolution of symptoms and signs, ST recurrence, VTE, complications from treatment. Not speciﬁed if VTE and ST recurrence were symptomatic or asymptomatic

Notes In the immediate postoperative period, a compression bandage/elastic stocking was used and early walking recommended. Pain was controlled with oral acetaminophen (500 mg)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information provided bias)

Allocation concealment (selection bias) Unclear risk No information provided

Blinding (performance bias and detection High risk Open study bias) All outcomes

Incomplete outcome data (attrition bias) High risk 3 patients lost to follow up (5%) All outcomes

Selective reporting (reporting bias) Unclear risk No information provided on the resolution of signs and symptoms

Marchiori 2002

Methods Single centre RCT

Participants Patients (n = 60) with ST of the great saphenous vein conﬁrmed by ultrasonography; 26 males, 34 females; mean age 62 years. Not reported if patients were hospitalised or non- hospitalised

Interventions UFH (12500 IU sc for one week then 10000 IU) versus UFH (5000 IU) for 4 weeks

Outcomes (Asymptomatic and symptomatic) recurrence and/or extension of ST and VTE after treatment and at 3 and 6 months

Notes Systemic and/or local anti-inﬂammatory drugs were allowed

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk List generated by a computer bias)

Allocation concealment (selection bias) Unclear risk No information provided

Blinding (performance bias and detection Low risk Outcome assessment performed by blinded investigators bias) All outcomes

Incomplete outcome data (attrition bias) Low risk No missing outcome data All outcomes

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Methods Multicentre, placebo-controlled RCT

Participants Patients (n = 159) with acute ST of the leg, diagnosed on symptoms and signs only. Whether patients were hospitalised was not mentioned; 40 males, 116 females; mean age 53.8 years

Interventions Wobenzym (4 tablets tid) versus placebo for 12 to 16 days

Outcomes The reduction of pain until day 7 which had to amount to at least 4 points on the Visual Rating Analogue Scale (VRAS) at baseline

Notes LMWH was allowed and administered to 4 patients. Paracetamol (maximal 2g/day) plus compression stockings were given to all patients. Nine patients had already been treated with other medications, not better speciﬁed, which were stopped before the administration of study treatment. Four patients had received LMWH before inclusion and continued LMWH throughout the study

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Patients assigned to treatment with a list gener- bias) ated by a computer

Allocation concealment (selection bias) Low risk Patients assigned to treatment with a list generated by a computer

Blinding (performance bias and detection Low risk Double-blind study bias) All outcomes

Incomplete outcome data (attrition bias) High risk 1 exclusion post-randomisation; 10 patients All outcomes lost to follow-up (6%)

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Messa 1997

Methods Single-centre, open RCT

Participants Patients (n = 30) with ST; 7 males, 23 females; age range 32 to 72 years. Not reported if patients were hospitalised or non-hospitalised nor if the diagnosis of ST was objectively conﬁrmed by ultrasonography

Interventions Heparansulphate (100 mg 3 tid orally) versus sulodexide (250 LSU bid, orally) for 2 weeks

Outcomes Redness of the skin, pain, itching, oedema, trophism

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Patients assigned to treatment with a random list bias)

Allocation concealment (selection bias) High risk Allocation based on a list of random numbers in an open design

Blinding (performance bias and detection High risk Open study bias) All outcomes

Incomplete outcome data (attrition bias) Low risk No missing outcome data All outcomes

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Nocker 1991

Methods Placebo-controlled RCT

Participants Patients (n = 20) with unilateral ST of the legs diagnosed on symptoms and signs only. Whether patients were hospitalised was not mentioned; 8 males, 12 females; mean age 55 years

Interventions Diclofenac gel (1 g diclofenac/100 g gel) versus placebo for 3 weeks

Outcomes Efﬁcacy was measured by the volume change relative to baseline (difference between the affected and unaffected leg) and the reduction in pain described by a Visual Analogue Scale); tolerability

Notes Heparin gel was given without randomisation

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information provided bias)

Allocation concealment (selection bias) Unclear risk No information provided

Blinding (performance bias and detection Low risk Double-blind study bias) All outcomes

Incomplete outcome data (attrition bias) Low risk No missing outcome data All outcomes

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Nusser 1991

Methods RCT

Participants Patients (n = 60) with ST diagnosed on symptoms and signs only. Whether patients were hospitalised was not mentioned; 25 males, 35 females; mean age 53 years

Interventions Oral acemetacin (60 mg tid) versus diclofenac (50 mg tid) for maximally 15 days

Outcomes Area of ST, pain, redness, palpable venous induration, oedema

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information provided bias)

Allocation concealment (selection bias) Unclear risk No information provided

Blinding (performance bias and detection Low risk Double-blind study bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk Unclear if all included patients were evaluated for study out- All outcomes comes

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Pinto 1992

Methods Multicentre, placebo-controlled RCT

Participants Patients (n = 68) with ST; mean age 42 years. Not reported if patients were hospitalised or non-hospitalised nor if the diagnosis of ST was objectively conﬁrmed by ultrasonography

Interventions Topical 5’-methylthioadenosine 0.5% (0.1 ml/cm skin tid) versus placebo for 1 week

Outcomes Oedema, erythema, pain, functional impairment, subcutaneous induration, tolerability, VAS score

Notes No compression therapy was allowed during the study

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information provided bias)

Allocation concealment (selection bias) Unclear risk No information provided

Blinding (performance bias and detection Low risk Double-blind study bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk Unclear if all included patients were evaluated All outcomes for study outcomes

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Stenox Group 2003

Methods Multicentre, placebo-controlled RCT with a 3-month follow-up

Participants Hospitalised or non-hospitalised patients (n = 427) with ST of at least 5 cm on ultrasonography examination; 156 males, 271 females; mean age 62 years

Interventions LMWH (enoxaparin 40 mg sc od) versus enoxaparin (1.5 mg/kg sc od) versus oral tenoxicam (20 mg od) versus placebo for 8 to 12 days

Outcomes Symptomatic and asymptomatic recurrence and/or extension of ST at 12 days and 3 months; symptomatic PE and symptomatic and asymptomatic DVT at 12 days and 3 months

Notes All patients got elastic bandages or support stockings. Patients requiring anticoagulant therapy, ligation of the saphenofemoral junction or thrombectomy, anticoagulants or NSAIDs for more than 48 hours were excluded from the study

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Insufﬁcient information about the se- bias) quence generation process

Allocation concealment (selection bias) Low risk Central allocation

Blinding (performance bias and detection Low risk Double-blind study bias) All outcomes

Incomplete outcome data (attrition bias) High risk 9 patients lost to follow-up (2%) All outcomes

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Titon 1994

Methods Multicentre, open RCT

Participants Non-hospitalised patients (n = 117) with ST conﬁrmed by ultrasonography; 25 males, 92 females; age range 54 to 64 years

Interventions Naproxene (oral 500 mg od) versus LMWH (nadroparin 0.6 ml sc for 6150 IU anti-Xa od) versus LMWH (nadroparin 61.5 IU anti-Xa/kg od)

Outcomes Recurrence and/or extension of ST, VTE after treatment and after 2 months

Notes All patients got elastic stockings in the ﬁrst week

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk No information provided bias)

Allocation concealment (selection bias) Unclear risk No information provided

Blinding (performance bias and detection High risk Open study bias) All outcomes

Incomplete outcome data (attrition bias) High risk 25 (11%) patients were not evaluated for DVT by means of All outcomes Doppler ultrasonography

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Methods Open RCT

Participants Patients (n = 50) with ST of the greater saphenous vein of at least 5 cm in length on duplex ultrasonography. Not reported if patients were hospitalised or non-hospitalised

Interventions LMWH (Ca-nadroparin 190 IU Axa/Kg qd) versus LMWH (Ca-nadroparin 190 IU Axa/Kg qd) + acemetacin (60 mg oral bid) for 10 days

Outcomes Primary outcomes: spontaneous pain, erythema, local tenderness and palpable cord Secondary outcomes: symptomatic DVT, PE, or ST extension; bleeding, death, AE

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection High risk Alternation bias)

Allocation concealment (selection bias) High risk Alternation

Blinding (performance bias and detection High risk Open study bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk The authors do not report they performed an ITT and it is not All outcomes clear whether the study outcomes were evaluated on all included patients

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported

Vesalio Group 2005

Methods Multicentre, double-blinded RCT with a 3-month follow-up

Participants Hospitalised or non-hospitalised patients (n = 164) with ST of the great saphenous vein with the thrombosis extending up to 3 cm from the saphenus-femoral junction; 60 males, 104 females; mean age 63 years. The diagnosis of ST was objectively conﬁrmed by compression ultrasonography

Interventions Weight adjusted LMWH (nadroparin full dose for 10 days followed by half dose for 20 additional days) versus ﬁxed-dose LMWH (nadroparin 2850 anti-Xa IU) for 30 days

Outcomes Composite of symptomatic extension of the ST, symptomatic DVT, (non) fatal PE in a 3-month follow-up period. Major bleeding, heparin-induced thrombocytopenia

Notes No aspirin use or NSAIDs use throughout the study

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Sequence produced by a computer random bias) number generator

Allocation concealment (selection bias) Unclear risk Sealed envelopes, not clear if opaque

Blinding (performance bias and detection Low risk Double-blind study bias) All outcomes

Incomplete outcome data (attrition bias) Low risk No missing outcome data All outcomes

Selective reporting (reporting bias) Low risk All pre-speciﬁed outcomes are reported bid: twice daily cm: centimetre DVT: deep vein thrombosis ECB: elastic compression bandage HIT: heparin-induced thrombocytopenia Im: intramuscularly IU: international units LMWH: low molecular weight heparin mg: milligram od: once daily PE: pulmonary embolism RCT: randomised controlled trial sc: subcutaneously ST: superﬁcial thrombophlebitis tid: three times daily UFH: unfractionated heparin VAS: visual analogue scale VRAS: visual rating analogue scale

Characteristics of excluded studies [ordered by study ID]

Agus 1993 Not possible to extract outcomes data separately for the two study-treatment groups

Allegra 1981 Mixed population. It was not possible to extract data separately for the ST

Annoni 1991 Mixed population. It was not possible to extract data separately for ST

Argenteri 1983 Mixed population including patients with deep venous thrombosis. It was not possible to extract data separately for ST

Bagliani 1983 Mixed population including also patients with DVT. It was not possible to extract data separately for ST

Becherucci 2000 Mixed population including patients with acute ST of the upper limb. It was not possible to extract data separately for ST of the lower limbs

Bergqvist 1990 Mixed population including patients with acute ST of the upper limb. It was not possible to extract data separately for ST of the lower limbs

Bernicot 1980 Patients without a diagnosis of ST of the legs.

Bracale 1996 Mixed population including also patients with DVT. It is not possible to extract data separately for the ST

Bruni 1979 Mixed population including also patients with acute ST of the upper limb. It is not possible to extract data separately for the ST of the lower limbs

Della Marchina 1989 Mixed population including also patients with DVT and post-phlebitic syndrome. It is not possible to extract data separately for the ST

Di Perri 1986 Patients with DVT.

Gandhi 1984 Patients without a diagnosis of ST of the legs.

Giorgetti 1990 Single blind study of patients with varicophlebitis who received either Seaprose S or placebo. It is unclear whether the study was randomised or not

Gouping 2003 Patients with post-infusion ST of the arm

Ibanez-Bermudez 1996 The evaluated outcomes are not among those evaluated in the present review

Luttichau 1989 Mixed population. It was not possible to extract data separately for ST

Mari 1982 Mixed population including patients with acute ST of the upper limb. It was not possible to extract data separately for ST of the lower limbs

Marsala 1985 Mixed population. It was not possible to extract data separately for ST

Mauro 1992 Mixed population including patients with DVT. It was not possible to extract data separately for ST

Mehta 1975 Patients with ST of the arm.

Paciaroni 1982 Mixed population including patients with chronic venous insufﬁciency. It is not possible to extract data separately for ST

Porters 1981 Mixed population including patients with acute ST of the upper limb. It was not possible to extract data separately for ST of the lower limbs

Pozza 1980 Mixed population including patients with acute ST of the upper limb. It was not possible to extract data separately for ST of the lower limbs

Rea 1981 Patients with DVT.

Resta 1967 Patients without a diagnosis of ST of the legs.

Rozsos 1994 Patients with ST of the arm.

Seccia 1989 Mixed population including patients with acute ST of the upper limb. It was not possible to extract data separately for the ST of the lower limbs

Seghezzi 1972 Mixed population including patients with DVT and recurrent post-phlebitic syndromes. It was not possible to extract data separately for ST of the lower limbs

Seligman 1969 Mixed population including patients with DVT. It was not possible to extract data separately for ST

Tomamichel 1983 Mixed population including patients with DVT. It was not possible to extract data separately for ST van Cauwenberge 1972 Patients without a diagnosis of ST of the legs. van der Knaap 1988 Patients with ST of the arm.

Characteristics of ongoing studies [ordered by study ID]

NCT00362947

Trial name or title Different doses and duration of low molecular weight heparin (parnaparin) in superﬁcial vein thrombosis

Methods Study type: Interventional Allocation: Randomised Intervention model: Parallel assignment Masking: Double-blind

Participants Age: 18 years or older Gender: both Inclusion criteria: • Weight > 50 kg and less than 110 kg

• SVT of the grand saphenous vein for at least 4 cm • SVT of the small saphenous vein for at least 4 cm • Collateral SVT of the large saphenous vein of the thigh for at least 4cm Exclusion criteria: • SVT of the grand saphenous vein reaching the saphenofemoral cross (within 3 cm) • SVT of the small saphenous vein reaching the saphenopopliteal cross • Documented proximal or distal DVT or pulmonary embolism • SVT secondary to sclerotherapy • Pregnancy and puerperium • uncontrolled arterial hypertension (systolic pressure > 180 mmHg and diastolic pressure > 110 mmHg) • Active peptic ulcer • Bacterial endocarditis • Stroke in the previous 3 months • Haemorrhagic diathesis • Thrombocytopenia (platelets < 100,000/ µL) • Hypersensitivity to heparin or history of thrombocytopenia induced by heparin • Creatinine > 2 mg% (> 180 µmol/L) • Heparin therapy (any dose) or anticoagulant therapy for longer than the previous 72 hours • In-hospital development of SVT • Previous saphenectomy by any method • Surgery in the previous 30 days • Serious liver disease • Use of dextran, mannitol, thrombolytic treatment, chronic use of NSAID and cortisone-based drugs. • Active cancer or under chemotherapy or radiotherapy • Thrombectomy of superﬁcial vein involved • Refusal to give informed consent

Interventions Patients will be randomised into double-blind groups to receive (syringes will be identical in appearance) in consecutively numbered boxes: A - Parnaparin, dose of 8,500 IU aXa taken subcutaneously once a day for 10 days B - Parnaparin, dose of 8,500 IU aXa per day for 10 days followed by parnaparin 6,400 IU aXa per day for the subsequent three weeks C - Parnaparin, dose of 4,250 IU aXa per day for 30 days Elastic compression treatment will be recommended with special stocking and/or elastic bandaging with compression to the ankles of 20 - 40 mmHg, where not contraindicated

Outcomes Primary outcome measures: • Primary effectiveness objectives • Combined endpoint of symptomatic and asymptomatic DVT, relapse and/or local extension of SVT and symptomatic PE at 30 days • Major bleeding Secondary outcome measures: • Secondary effectiveness objectives • 1 - Evaluation of venous thromboembolic events with follow-up 3 months after the start of treatment • 2 - Reduction in local symptoms (subjective and objective evaluation) • Safety • Composite outcome of: minor haemorrhages, thrombocytopenia or any other adverse event (e.g. local allergic reactions)

Starting date August 2006

Contact information Study chair: Gualtiero Palareti, MD, + 39 051 6362482, [email protected] Pricipal investigator: Benilde Cosmi, MD PhD, + 39 051 6362301, [email protected]

Notes

Rabe 2009

Trial name or title DAPS-dalteparin in patients with superﬁcial leg vein phlebitis in addition to compression treatment - a placebo-controlled phase III study

Methods Randomised, double-blind, multicentre, phase III trial

Participants Patients (n = 276) with superﬁcial leg vein phlebitis

Interventions Compression stockings (30 mmHg) for 3 months and either dalteparin 10 000 IU (group A) or placebo (group B) for 14 days

Outcomes Primary end point: progression of the thrombotic process during the treatment period as conﬁrmed by ultrasound. Sonographic assessment was planned in all patients on days 1, 7, 14, and 90 Secondary end points: pain assessment by visual analogue scale (VAS) and calculation of symptom scores (tension, heaviness, swelling)

Starting date Not reported

Contact information Rabe E

Notes

Comparison 1. Fondaparinux versus placebo

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Pulmonary embolism 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 2 Deep vein thrombosis 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 3 Deep vein thrombosis and 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected pulmonary embolism 4 Extension of ST 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 5 Recurrence of ST 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 6 Mortality 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 7 Major bleeding 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 8 Clinically relevant non-major 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected bleeding 9 Minor bleeding 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 10 Arterial thromboembolic 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected complication 11 Any adverse event 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 12 Non-fatal serious adverse event 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

Comparison 2. Prophylactic LMWH versus placebo

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Venous thromboembolism 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected end-of-treatment 2 Venous thromboembolism 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 3-month follow up 3 Extension and/or recurrence of 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected ST 4 Major bleeding 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 5 Heparin-induced 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected thrombocytopenia

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

Comparison 4. Prophylactic LMWH + elastic compression stockings (ECS) versus elastic stockings alone

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Venous thromboembolism 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 2 Extension and/or recurrence of 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected ST

Comparison 5. LMWH versus heparin spray gel

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Deep-venous thrombosis 2 83 Risk Ratio (M-H, Fixed, 95% CI) 0.30 [0.03, 2.70] 2 Patients with thrombus at 21 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected days 3 Allergic reaction or elevated 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected sedimentation rate

Treatment for superﬁcial thrombophlebitis of the leg (Review) 43 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Comparison 6. Therapeutic LMWH versus saphenofemoral disconnection

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Venous thromboembolism 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 2 Extension and/or recurrence of 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected ST 3 Major bleeding 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 4 Complications 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

Comparison 7. Fixed-dose LMWH versus NSAIDs

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Venous thromboembolism 2 274 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.24, 3.63] 2 Extension and/or treatment of 2 274 Risk Ratio (M-H, Fixed, 95% CI) 1.16 [0.57, 2.33] ST 3 Major bleeding 2 274 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0] 4 Heparin-induced 2 274 Risk Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0] thrombocytopenia

Comparison 8. Weight-adjusted LMWH versus NSAIDs

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Venous thromboembolism 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 2 Extension and/or recurrence of 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected ST 3 Major bleeding 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 4 Heparin-induced 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected thrombocytopenia

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Venous thromboembolism 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected end-of-treatment 2 Venous thromboembolism 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 3-month follow up 3 Major bleeding 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 4 Heparin-induced 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected thrombocytopenia

Comparison 10. LMWH versus LMWH + acemetacin

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Pulmonary embolism 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 2 Deep vein thrombosis 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 3 Extension of ST 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 4 Pain reduction 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected 5 Hyperaemia reduction 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected 6 Tenderness reduction 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected 7 Palpable cord reduction 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected 8 Mortality 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 9 Major bleeding 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 10 Minor bleeding 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 11 Adverse event 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

Comparison 11. Fixed-dose LMWH versus weight-adjusted LMWH

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 ST or venous thromboembolism 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 2 Venous thromboembolism 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 3 Superﬁcial thrombophlebitis 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 4 Swelling disappearance 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 5 Tenderness disappearance 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 6 Pain disappearance 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 7 Pitting oedema disappearance 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 8 Collateral veins disappearance 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 9 Redness disappearance 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 10 Palpable cord disappearance 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 11 Major bleeding 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

Treatment for superﬁcial thrombophlebitis of the leg (Review) 45 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 12 Heparin-induced 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected thrombocytopenia

Comparison 12. Prophylactic UFH + elastic compression stockings versus elastic compression stockings alone

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Venous thromboembolism 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 2 Extension and/or recurrence of 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected ST

Comparison 13. High-dose UFH versus low-dose UFH

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Incidence of venous 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected thromboembolism 2 ST recurrence or extension 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 3 Major bleeding 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 4 Heparin-induced 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected thrombocytopenia

Comparison 14. Calcium heparin + elastic compression bandage versus elastic compression bandage alone

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Deep venous thrombosis 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

Comparison 15. Heparin sc versus deﬁbrotide

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Decrease in the analogue score 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected 2 Treatment side effects 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Venous thromboembolism 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 2 Extension and/or recurrence of 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected ST 3 Major bleeding 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 4 Heparin-induced 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected thrombocytopenia

Comparison 17. Indomethacin versus placebo

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Side effects 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

Comparison 18. Nimesulide versus diclofenac sodium

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Gastric pain 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

Comparison 19. Essaven gel versus placebo

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Intolerance 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

Treatment for superﬁcial thrombophlebitis of the leg (Review) 47 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Comparison 20. Thrombectomy + venoruton + elastic compression bandage versus elastic compression bandage alone

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Deep venous thrombosis 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

Comparison 21. Thrombectomy + elastic compression bandage versus elastic compression bandage alone

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Deep venous thrombosis 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

Comparison 22. Ligation + elastic compression stockings versus elastic compression stockings alone

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Venous thromboembolism 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 2 Extension and/or recurrence of 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected ST

Comparison 23. Stripping + elastic compression stockings versus elastic compression stockings alone

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Venous thromboembolism 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 2 Extension and/or recurrence of 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected ST

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Cured or substantially better 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 2 Poor tolerability 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

Comparison 25. Elastic compression bandage + venoruton versus elastic compression bandage alone

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Deep venous thrombosis 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

Comparison 26. Oral heparan sulphate versus oral sulodexide

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Redness disappearance 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 2 Pain disappearance 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 3 Disappearance of itching 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 4 Oedema improvement 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 5 Trophism improvement 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

Comparison 27. Oxyphenbutazone versus placebo

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Tenderness improvement 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

Treatment for superﬁcial thrombophlebitis of the leg (Review) 49 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Comparison 28. VKA + elastic compression stockings versus elastic compression stockings alone

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Venous thromboembolism 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 2 Extension and/or recurrence of 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected ST

Comparison 29. Enzyme therapy versus placebo

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Pain reduction 1 Mean Difference (IV, Fixed, 95% CI) Totals not selected 2 Responders 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

Comparison 30. Desmin im 200 versus desmin 100

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Adverse events 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 2 Adverse drug reactions 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

Comparison 31. Desmin sc 2x100 versus desmin 100

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Adverse events 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected 2 Adverse drug reactions 1 Risk Ratio (M-H, Fixed, 95% CI) Totals not selected

Treatment for superﬁcial thrombophlebitis of the leg (Review) 50 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.1. Comparison 1 Fondaparinux versus placebo, Outcome 1 Pulmonary embolism.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 1 Fondaparinux versus placebo

Outcome: 1 Pulmonary embolism

Studyorsubgroup Fondaparinux Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Decousus 2010a 0/1502 5/1500 0.09 [ 0.01, 1.64 ]

0.01 0.1 1 10 100 Favours Fondaparinux Favours Placebo

Analysis 1.2. Comparison 1 Fondaparinux versus placebo, Outcome 2 Deep vein thrombosis.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 1 Fondaparinux versus placebo

Outcome: 2 Deep vein thrombosis

Studyorsubgroup Fondaparinux Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Decousus 2010a 3/1502 18/1500 0.17 [ 0.05, 0.56 ]

0.01 0.1 1 10 100 Favours Fondaparinux Favours Placebo

Treatment for superﬁcial thrombophlebitis of the leg (Review) 51 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.3. Comparison 1 Fondaparinux versus placebo, Outcome 3 Deep vein thrombosis and pulmonary embolism.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 1 Fondaparinux versus placebo

Outcome: 3 Deep vein thrombosis and pulmonary embolism

Studyorsubgroup Fondaparinux Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Decousus 2010a 3/1502 20/1500 0.15 [ 0.04, 0.50 ]

0.01 0.1 1 10 100 Favours Fondaparinux Favours Placebo

Analysis 1.4. Comparison 1 Fondaparinux versus placebo, Outcome 4 Extension of ST.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 1 Fondaparinux versus placebo

Outcome: 4 Extension of ST

Studyorsubgroup Fondaparinux Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Decousus 2010a 4/1502 51/1500 0.08 [ 0.03, 0.22 ]

0.01 0.1 1 10 100 Favours Fondaparinux Favours Placebo

Treatment for superﬁcial thrombophlebitis of the leg (Review) 52 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.5. Comparison 1 Fondaparinux versus placebo, Outcome 5 Recurrence of ST.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 1 Fondaparinux versus placebo

Outcome: 5 Recurrence of ST

Studyorsubgroup Fondaparinux Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Decousus 2010a 5/1502 24/1500 0.21 [ 0.08, 0.54 ]

0.01 0.1 1 10 100 Favours Fondaparinux Favours Placebo

Analysis 1.6. Comparison 1 Fondaparinux versus placebo, Outcome 6 Mortality.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 1 Fondaparinux versus placebo

Outcome: 6 Mortality

Studyorsubgroup Fondaparinux Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Decousus 2010a 2/1502 1/1500 2.00 [ 0.18, 22.00 ]

0.01 0.1 1 10 100 Favours fondaparinux Favours placebo

Treatment for superﬁcial thrombophlebitis of the leg (Review) 53 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.7. Comparison 1 Fondaparinux versus placebo, Outcome 7 Major bleeding.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 1 Fondaparinux versus placebo

Outcome: 7 Major bleeding

Studyorsubgroup Fondaparinux Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Decousus 2010a 1/1499 1/1488 0.99 [ 0.06, 15.86 ]

0.01 0.1 1 10 100 Favours Fondaparinux Favours Placebo

Analysis 1.8. Comparison 1 Fondaparinux versus placebo, Outcome 8 Clinically relevant non-major bleeding.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 1 Fondaparinux versus placebo

Outcome: 8 Clinically relevant non-major bleeding

Studyorsubgroup Fondaparinux Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Decousus 2010a 5/1499 8/1488 0.62 [ 0.20, 1.89 ]

0.01 0.1 1 10 100 Favours Fondaparinux Favours Placebo

Treatment for superﬁcial thrombophlebitis of the leg (Review) 54 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.9. Comparison 1 Fondaparinux versus placebo, Outcome 9 Minor bleeding.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 1 Fondaparinux versus placebo

Outcome: 9 Minor bleeding

Studyorsubgroup Fondaparinux Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Decousus 2010a 9/1499 6/1488 1.49 [ 0.53, 4.17 ]

0.01 0.1 1 10 100 Favours Fondaparinux Favours Placebo

Analysis 1.10. Comparison 1 Fondaparinux versus placebo, Outcome 10 Arterial thromboembolic complication.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 1 Fondaparinux versus placebo

Outcome: 10 Arterial thromboembolic complication

Studyorsubgroup Fondaparinux Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Decousus 2010a 0/1502 3/1500 0.14 [ 0.01, 2.76 ]

0.01 0.1 1 10 100 Favours Fondaparinux Favours Placebo

Treatment for superﬁcial thrombophlebitis of the leg (Review) 55 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.11. Comparison 1 Fondaparinux versus placebo, Outcome 11 Any adverse event.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 1 Fondaparinux versus placebo

Outcome: 11 Any adverse event

Studyorsubgroup Fondaparinux Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Decousus 2010a 195/1499 199/1488 0.97 [ 0.81, 1.17 ]

0.01 0.1 1 10 100 Favours Fondaparinux Favours Placebo

Analysis 1.12. Comparison 1 Fondaparinux versus placebo, Outcome 12 Non-fatal serious adverse event.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 1 Fondaparinux versus placebo

Outcome: 12 Non-fatal serious adverse event

Studyorsubgroup Fondaparinux Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Decousus 2010a 10/1499 16/1488 0.62 [ 0.28, 1.36 ]

0.01 0.1 1 10 100 Favours Fondaparinux Favours Placebo

Treatment for superﬁcial thrombophlebitis of the leg (Review) 56 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.1. Comparison 2 Prophylactic LMWH versus placebo, Outcome 1 Venous thromboembolism end-of-treatment.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 2 Prophylactic LMWH versus placebo

Outcome: 1 Venous thromboembolism end-of-treatment

Studyorsubgroup ProphylacticLMWH Placebo RiskRatio Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 1/110 4/112 0.25 [ 0.03, 2.24 ]

0.01 0.1 1 10 100 Favours LMWH Favours Placebo

Analysis 2.2. Comparison 2 Prophylactic LMWH versus placebo, Outcome 2 Venous thromboembolism 3- month follow up.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 2 Prophylactic LMWH versus placebo

Outcome: 2 Venous thromboembolism 3-month follow up

Studyorsubgroup PhrophylacticLMWH Placebo RiskRatio Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 6/110 5/112 1.22 [ 0.38, 3.89 ]

0.1 0.2 0.5 1 2 5 10 Favours LMWH Favours Placebo

Treatment for superﬁcial thrombophlebitis of the leg (Review) 57 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.3. Comparison 2 Prophylactic LMWH versus placebo, Outcome 3 Extension and/or recurrence of ST.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 2 Prophylactic LMWH versus placebo

Outcome: 3 Extension and/or recurrence of ST

Studyorsubgroup ProphylacticLMWH Placebo RiskRatio Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 13/110 33/112 0.40 [ 0.22, 0.72 ]

0.1 0.2 0.5 1 2 5 10 Favours Prophylactic LMWH Favours Placebo

Analysis 2.4. Comparison 2 Prophylactic LMWH versus placebo, Outcome 4 Major bleeding.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 2 Prophylactic LMWH versus placebo

Outcome: 4 Major bleeding

Studyorsubgroup ProphylacticLMWH Placebo RiskRatio Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 0/110 0/112 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours Prophylactic LMWH Favours Placebo

Treatment for superﬁcial thrombophlebitis of the leg (Review) 58 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.5. Comparison 2 Prophylactic LMWH versus placebo, Outcome 5 Heparin-induced thrombocytopenia.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 2 Prophylactic LMWH versus placebo

Outcome: 5 Heparin-induced thrombocytopenia

Studyorsubgroup ProphylacticLMWH Placebo RiskRatio Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 0/110 0/112 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours Prophylactic LMWH Favours Placebo

Analysis 3.1. Comparison 3 Therapeutic LMWH versus placebo, Outcome 1 Venous thromboembolism end-of-treatment.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 3 Therapeutic LMWH versus placebo

Outcome: 1 Venous thromboembolism end-of-treatment

Studyorsubgroup TherapeuticLMWH Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 1/106 4/112 0.26 [ 0.03, 2.33 ]

0.01 0.1 1 10 100 Favours LMWH Favours Placebo

Treatment for superﬁcial thrombophlebitis of the leg (Review) 59 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 3.2. Comparison 3 Therapeutic LMWH versus placebo, Outcome 2 Venous thromboembolism 3- month follow up.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 3 Therapeutic LMWH versus placebo

Outcome: 2 Venous thromboembolism 3-month follow up

Studyorsubgroup TherapeuticLMWH Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 4/106 5/112 0.85 [ 0.23, 3.06 ]

0.1 0.2 0.5 1 2 5 10 Favours Therapeutic LMWH Favours Placebo

Analysis 3.3. Comparison 3 Therapeutic LMWH versus placebo, Outcome 3 Extension and/or recurrence of ST.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 3 Therapeutic LMWH versus placebo

Outcome: 3 Extension and/or recurrence of ST

Studyorsubgroup TherapeuticLMWH Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 13/106 33/112 0.42 [ 0.23, 0.75 ]

0.1 0.2 0.5 1 2 5 10 Favours Therapeutuc LMWH Favours Placebo

Treatment for superﬁcial thrombophlebitis of the leg (Review) 60 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 3.4. Comparison 3 Therapeutic LMWH versus placebo, Outcome 4 Major bleeding.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 3 Therapeutic LMWH versus placebo

Outcome: 4 Major bleeding

Studyorsubgroup TherapeuticLMWH Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 0/106 0/112 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours Therapeutic LMWH Favours Placebo

Analysis 3.5. Comparison 3 Therapeutic LMWH versus placebo, Outcome 5 Heparin-induced thrombocytopenia.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 3 Therapeutic LMWH versus placebo

Outcome: 5 Heparin-induced thrombocytopenia

Studyorsubgroup TherapeuticLMWH Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 0/106 0/112 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours Therapeutic LMWH Favours Placebo

Treatment for superﬁcial thrombophlebitis of the leg (Review) 61 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 4.1. Comparison 4 Prophylactic LMWH + elastic compression stockings (ECS) versus elastic stockings alone, Outcome 1 Venous thromboembolism.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 4 Prophylactic LMWH + elastic compression stockings (ECS) versus elastic stockings alone

Outcome: 1 Venous thromboembolism

Studyorsubgroup ECS+LMWH ECS RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Belcaro 1999 (1) 0/76 6/78 0.08 [ 0.00, 1.38 ]

0.001 0.01 0.1 1 10 100 1000 Favours ECS+LMWH Favours ECS (1) ECS: elastic compression stockings

Analysis 4.2. Comparison 4 Prophylactic LMWH + elastic compression stockings (ECS) versus elastic stockings alone, Outcome 2 Extension and/or recurrence of ST.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 4 Prophylactic LMWH + elastic compression stockings (ECS) versus elastic stockings alone

Outcome: 2 Extension and/or recurrence of ST

Studyorsubgroup ECS+LMWH ECS RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Belcaro 1999 1/76 13/78 0.08 [ 0.01, 0.59 ]

0.001 0.01 0.1 1 10 100 1000 Favours ECS+LMWH Favours ECS

Treatment for superﬁcial thrombophlebitis of the leg (Review) 62 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 5.1. Comparison 5 LMWH versus heparin spray gel, Outcome 1 Deep-venous thrombosis.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 5 LMWH versus heparin spray gel

Outcome: 1 Deep-venous thrombosis

Studyorsubgroup LMWH Heparinspraygel RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Gorski 2005 1/23 3/21 0.30 [ 0.03, 2.70 ]

Katzenschlager 2003 0/21 0/18 0.0 [ 0.0, 0.0 ] Total (95% CI) 44 39 0.30 [ 0.03, 2.70 ] Total events: 1 (LMWH), 3 (Heparin spraygel) Heterogeneity: Chi2 = 0.0, df = 0 (P = 1.00); I2 =0.0% Test for overall effect: Z = 1.07 (P = 0.29) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours LMWH Favours Heparin spraygel

Analysis 5.2. Comparison 5 LMWH versus heparin spray gel, Outcome 2 Patients with thrombus at 21 days.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 5 LMWH versus heparin spray gel

Outcome: 2 Patients with thrombus at 21 days

Studyorsubgroup LMWH Heparinspraygel RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Gorski 2005 14/23 11/21 1.16 [ 0.69, 1.96 ]

0.1 0.2 0.5 1 2 5 10 Favours LMWH Favours Heparin spraygel

Treatment for superﬁcial thrombophlebitis of the leg (Review) 63 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 5.3. Comparison 5 LMWH versus heparin spray gel, Outcome 3 Allergic reaction or elevated sedimentation rate.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 5 LMWH versus heparin spray gel

Outcome: 3 Allergic reaction or elevated sedimentation rate

Studyorsubgroup LMWH Heparinspraygel RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Gorski 2005 2/23 0/21 4.58 [ 0.23, 90.30 ]

0.001 0.01 0.1 1 10 100 1000 Favours LMWH Favours Heparin spraygel

Analysis 6.1. Comparison 6 Therapeutic LMWH versus saphenofemoral disconnection, Outcome 1 Venous thromboembolism.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 6 Therapeutic LMWH versus saphenofemoral disconnection

Outcome: 1 Venous thromboembolism

Studyorsubgroup TherapeuticLMWH Surgery RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Lozano 2003 0/30 2/30 0.20 [ 0.01, 4.00 ]

0.001 0.01 0.1 1 10 100 1000 Favours LMWH Favours surgery

Treatment for superﬁcial thrombophlebitis of the leg (Review) 64 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 6.2. Comparison 6 Therapeutic LMWH versus saphenofemoral disconnection, Outcome 2 Extension and/or recurrence of ST.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 6 Therapeutic LMWH versus saphenofemoral disconnection

Outcome: 2 Extension and/or recurrence of ST

Studyorsubgroup LMWH Surgery RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Lozano 2003 3/30 1/30 3.00 [ 0.33, 27.23 ]

0.01 0.1 1 10 100 Favours LMWH Favours surgery

Analysis 6.3. Comparison 6 Therapeutic LMWH versus saphenofemoral disconnection, Outcome 3 Major bleeding.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 6 Therapeutic LMWH versus saphenofemoral disconnection

Outcome: 3 Major bleeding

Studyorsubgroup LMWH Surgery RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Lozano 2003 0/30 0/30 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours LMWH Favours surgery

Treatment for superﬁcial thrombophlebitis of the leg (Review) 65 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 6.4. Comparison 6 Therapeutic LMWH versus saphenofemoral disconnection, Outcome 4 Complications.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 6 Therapeutic LMWH versus saphenofemoral disconnection

Outcome: 4 Complications

Studyorsubgroup LMWH Surgery RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Lozano 2003 2/30 2/30 1.00 [ 0.15, 6.64 ]

0.1 0.2 0.5 1 2 5 10 Favours LMWH Favours surgery

Analysis 7.1. Comparison 7 Fixed-dose LMWH versus NSAIDs, Outcome 1 Venous thromboembolism.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 7 Fixed-dose LMWH versus NSAIDs

Outcome: 1 Venous thromboembolism

Studyorsubgroup FixeddoseLMWH NSAIDS RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 4/106 4/99 0.93 [ 0.24, 3.63 ]

Titon 1994 0/36 0/33 0.0 [ 0.0, 0.0 ] Total (95% CI) 142 132 0.93 [ 0.24, 3.63 ] Total events: 4 (Fixed dose LMWH), 4 (NSAIDS) Heterogeneity: Chi2 = 0.0, df = 0 (P = 1.00); I2 =0.0% Test for overall effect: Z = 0.10 (P = 0.92) Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10 Favours ﬁxed LMWH Favours NSAIDS

Treatment for superﬁcial thrombophlebitis of the leg (Review) 66 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 7.2. Comparison 7 Fixed-dose LMWH versus NSAIDs, Outcome 2 Extension and/or treatment of ST.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 7 Fixed-dose LMWH versus NSAIDs

Outcome: 2 Extension and/or treatment of ST

Studyorsubgroup FixeddoseLMWH NSAIDS RiskRatio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 13/106 12/99 96.0 % 1.01 [ 0.49, 2.11 ]

Titon 1994 2/36 0/33 4.0 % 4.59 [ 0.23, 92.33 ] Total (95% CI) 142 132 100.0 % 1.16 [ 0.57, 2.33 ] Total events: 15 (Fixed dose LMWH), 12 (NSAIDS) Heterogeneity: Chi2 = 0.94, df = 1 (P = 0.33); I2 =0.0% Test for overall effect: Z = 0.40 (P = 0.69) Test for subgroup differences: Not applicable

0.001 0.01 0.1 1 10 100 1000 Favours ﬁxed LMWH Favours NSAIDS

Analysis 7.3. Comparison 7 Fixed-dose LMWH versus NSAIDs, Outcome 3 Major bleeding.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 7 Fixed-dose LMWH versus NSAIDs

Outcome: 3 Major bleeding

Studyorsubgroup FixeddoseLMWH NSAIDS RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 0/106 0/99 0.0 [ 0.0, 0.0 ]

Titon 1994 0/36 0/33 0.0 [ 0.0, 0.0 ] Total (95% CI) 142 132 0.0 [ 0.0, 0.0 ] Total events: 0 (Fixed dose LMWH), 0 (NSAIDS) Heterogeneity: Chi2 = 0.0, df = 0 (P<0.00001); I2 =0.0% Test for overall effect: Z = 0.0 (P < 0.00001) Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10 Favours ﬁxed LMWH Favours NSAIDS

Treatment for superﬁcial thrombophlebitis of the leg (Review) 67 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 7.4. Comparison 7 Fixed-dose LMWH versus NSAIDs, Outcome 4 Heparin-induced thrombocytopenia.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 7 Fixed-dose LMWH versus NSAIDs

Outcome: 4 Heparin-induced thrombocytopenia

Studyorsubgroup FixeddoseLMWH NSAIDS RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 0/106 0/99 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours ﬁxed LMWH Favours NSAIDS

Analysis 8.1. Comparison 8 Weight-adjusted LMWH versus NSAIDs, Outcome 1 Venous thromboembolism.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 8 Weight-adjusted LMWH versus NSAIDs

Outcome: 1 Venous thromboembolism

Studyorsubgroup LMWH NSAIDS RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Titon 1994 0/35 0/33 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours LMWH Favours NSAIDS

Treatment for superﬁcial thrombophlebitis of the leg (Review) 68 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 8.2. Comparison 8 Weight-adjusted LMWH versus NSAIDs, Outcome 2 Extension and/or recurrence of ST.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 8 Weight-adjusted LMWH versus NSAIDs

Outcome: 2 Extension and/or recurrence of ST

Studyorsubgroup LMWH NSAIDS RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Titon 1994 0/35 0/33 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours NSAIDS Favours Adjust LMWH

Analysis 8.3. Comparison 8 Weight-adjusted LMWH versus NSAIDs, Outcome 3 Major bleeding.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 8 Weight-adjusted LMWH versus NSAIDs

Outcome: 3 Major bleeding

Studyorsubgroup LMWH NSAIDS RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Titon 1994 0/35 0/33 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours LMWH Favours NSAIDS

Treatment for superﬁcial thrombophlebitis of the leg (Review) 69 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 8.4. Comparison 8 Weight-adjusted LMWH versus NSAIDs, Outcome 4 Heparin-induced thrombocytopenia.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 8 Weight-adjusted LMWH versus NSAIDs

Outcome: 4 Heparin-induced thrombocytopenia

Studyorsubgroup LMWH NSAIDS RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Titon 1994 0/35 0/33 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours LMWH Favours NSAIDS

Analysis 9.1. Comparison 9 Prophylactic LMWH versus NSAIDs, Outcome 1 Venous thromboembolism end-of-treatment.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 9 Prophylactic LMWH versus NSAIDs

Outcome: 1 Venous thromboembolism end-of-treatment

Studyorsubgroup ProphylacticLMWH NSAIDs RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 1/110 2/99 0.45 [ 0.04, 4.89 ]

0.01 0.1 1 10 100 Favours LMWH Favours NSAIDs

Treatment for superﬁcial thrombophlebitis of the leg (Review) 70 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 9.2. Comparison 9 Prophylactic LMWH versus NSAIDs, Outcome 2 Venous thromboembolism 3- month follow up.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 9 Prophylactic LMWH versus NSAIDs

Outcome: 2 Venous thromboembolism 3-month follow up

Studyorsubgroup ProphylacticLMWH NSAIDs RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 6/110 4/99 1.35 [ 0.39, 4.64 ]

0.1 0.2 0.5 1 2 5 10 Favours LMWH Favours NSAIDs

Analysis 9.3. Comparison 9 Prophylactic LMWH versus NSAIDs, Outcome 3 Major bleeding.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 9 Prophylactic LMWH versus NSAIDs

Outcome: 3 Major bleeding

Studyorsubgroup ProphylacticLMWH NSAIDs RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 0/110 0/99 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours LMWH Favours NSAIDs

Treatment for superﬁcial thrombophlebitis of the leg (Review) 71 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 9.4. Comparison 9 Prophylactic LMWH versus NSAIDs, Outcome 4 Heparin-induced thrombocytopenia.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 9 Prophylactic LMWH versus NSAIDs

Outcome: 4 Heparin-induced thrombocytopenia

Studyorsubgroup ProphylacticLMWH NSAIDs RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 0/110 0/99 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours LMWH Favours NSAIDs

Analysis 10.1. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 1 Pulmonary embolism.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 10 LMWH versus LMWH + acemetacin

Outcome: 1 Pulmonary embolism

Studyorsubgroup LMWH LMWH+acemetacine RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Uncu 2009 0/25 0/25 0.0 [ 0.0, 0.0 ]

0.01 0.1 1 10 100 Favours LMWH Favours LMWH+acemetacine

Treatment for superﬁcial thrombophlebitis of the leg (Review) 72 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 10.2. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 2 Deep vein thrombosis.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 10 LMWH versus LMWH + acemetacin

Outcome: 2 Deep vein thrombosis

Studyorsubgroup LMWH LMWH+acemetacine RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Uncu 2009 0/25 0/25 0.0 [ 0.0, 0.0 ]

0.01 0.1 1 10 100 Favours LMWH Favours LMWH+acemetacine

Analysis 10.3. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 3 Extension of ST.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 10 LMWH versus LMWH + acemetacin

Outcome: 3 Extension of ST

Studyorsubgroup LMWH LMWH+acemetacine RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Uncu 2009 0/25 0/25 0.0 [ 0.0, 0.0 ]

0.01 0.1 1 10 100 Favours LMWH Favours LMWH+acemetacine

Treatment for superﬁcial thrombophlebitis of the leg (Review) 73 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 10.4. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 4 Pain reduction.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 10 LMWH versus LMWH + acemetacin

Outcome: 4 Pain reduction

Mean Mean Studyorsubgroup LMWH LMWH+acemetacin Difference Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Uncu 2009 25 5.9 (1.2) 25 5 (1.4) 0.90 [ 0.18, 1.62 ]

-100 -50 0 50 100 Favours LMWH+acemetacin Favours LMWH

Analysis 10.5. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 5 Hyperaemia reduction.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 10 LMWH versus LMWH + acemetacin

Outcome: 5 Hyperaemia reduction

Mean Mean Studyorsubgroup LMWH LMWH+acemetacin Difference Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Uncu 2009 25 4.4 (1.9) 25 4 (1.7) 0.40 [ -0.60, 1.40 ]

-100 -50 0 50 100 Favours LMWH+acemetacin Favours LMWH

Treatment for superﬁcial thrombophlebitis of the leg (Review) 74 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 10.6. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 6 Tenderness reduction.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 10 LMWH versus LMWH + acemetacin

Outcome: 6 Tenderness reduction

Mean Mean Studyorsubgroup LMWH LMWH+acemetacin Difference Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Uncu 2009 25 5.3 (2.2) 25 4.2 (1.8) 1.10 [ -0.01, 2.21 ]

-100 -50 0 50 100 Favours LMWH+acemetacin Favours LMWH

Analysis 10.7. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 7 Palpable cord reduction.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 10 LMWH versus LMWH + acemetacin

Outcome: 7 Palpable cord reduction

Mean Mean Studyorsubgroup LMWH LMWH+acemetacin Difference Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Uncu 2009 25 3.3 (3.4) 25 2.2 (1.5) 1.10 [ -0.36, 2.56 ]

-100 -50 0 50 100 Favours LMWH+acemetacin Favours LMWH

Treatment for superﬁcial thrombophlebitis of the leg (Review) 75 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 10.8. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 8 Mortality.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 10 LMWH versus LMWH + acemetacin

Outcome: 8 Mortality

Studyorsubgroup LMWH LMWH+acemetacin RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Uncu 2009 0/25 0/25 0.0 [ 0.0, 0.0 ]

0.01 0.1 1 10 100 Favours LMWH Favours LMWH+acemetacin

Analysis 10.9. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 9 Major bleeding.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 10 LMWH versus LMWH + acemetacin

Outcome: 9 Major bleeding

Studyorsubgroup LMWH LMWH+acemetacin RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Uncu 2009 0/25 0/25 0.0 [ 0.0, 0.0 ]

0.01 0.1 1 10 100 Favours LMWH Favours LMWH+acemetacin

Treatment for superﬁcial thrombophlebitis of the leg (Review) 76 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 10.10. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 10 Minor bleeding.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 10 LMWH versus LMWH + acemetacin

Outcome: 10 Minor bleeding

Studyorsubgroup LMWH LMWH+acemetacin RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Uncu 2009 0/25 1/25 0.33 [ 0.01, 7.81 ]

0.01 0.1 1 10 100 Favours LMWH Favours LMWH+acemetacine

Analysis 10.11. Comparison 10 LMWH versus LMWH + acemetacin, Outcome 11 Adverse event.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 10 LMWH versus LMWH + acemetacin

Outcome: 11 Adverse event

Studyorsubgroup LMWH LMWH+acemetacin RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Uncu 2009 0/25 0/25 0.0 [ 0.0, 0.0 ]

0.01 0.1 1 10 100 Favours LMWH Favours LMWH+acemetacin

Treatment for superﬁcial thrombophlebitis of the leg (Review) 77 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 11.1. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 1 ST or venous thromboembolism.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 11 Fixed-dose LMWH versus weight-adjusted LMWH

Outcome: 1 ST or venous thromboembolism

Weight- adjusted Studyorsubgroup Fixed-doseLMWH LMWH RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Vesalio Group 2005 7/81 6/83 1.20 [ 0.42, 3.40 ]

0.1 0.2 0.5 1 2 5 10 Favours Fixed-dose Favours Weight-adjusted

Analysis 11.2. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 2 Venous thromboembolism.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 11 Fixed-dose LMWH versus weight-adjusted LMWH

Outcome: 2 Venous thromboembolism

Weight- adjusted Studyorsubgroup Fixed-doseLMWH LMWH RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Vesalio Group 2005 2/81 4/83 0.51 [ 0.10, 2.72 ]

0.01 0.1 1 10 100 Favours Fixed-dose Favours Weight-adjusted

Treatment for superﬁcial thrombophlebitis of the leg (Review) 78 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 11.3. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 3 Superﬁcial thrombophlebitis.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 11 Fixed-dose LMWH versus weight-adjusted LMWH

Outcome: 3 Superﬁcial thrombophlebitis

Weight- adjusted Studyorsubgroup Fixed-doseLMWH LMWH RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Vesalio Group 2005 5/81 2/83 2.56 [ 0.51, 12.83 ]

0.01 0.1 1 10 100 Favours Fixed-dose Favours Weight-adjusted

Analysis 11.4. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 4 Swelling disappearance.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 11 Fixed-dose LMWH versus weight-adjusted LMWH

Outcome: 4 Swelling disappearance

Weight- adjusted Studyorsubgroup Fixed-doseLMWH LMWH RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Vesalio Group 2005 16/19 12/17 1.19 [ 0.83, 1.72 ]

0.01 0.1 1 10 100 Favours Weight-adjusted Favours Fixed-dose

Treatment for superﬁcial thrombophlebitis of the leg (Review) 79 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 11.5. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 5 Tenderness disappearance.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 11 Fixed-dose LMWH versus weight-adjusted LMWH

Outcome: 5 Tenderness disappearance

Weight- adjusted Studyorsubgroup Fixed-doseLMWH LMWH RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Vesalio Group 2005 7/10 13/19 1.02 [ 0.62, 1.70 ]

0.1 0.2 0.5 1 2 5 10 Favours Weight-adjusted Favours Fixed-dose

Analysis 11.6. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 6 Pain disappearance.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 11 Fixed-dose LMWH versus weight-adjusted LMWH

Outcome: 6 Pain disappearance

Weight- adjusted Studyorsubgroup Fixed-doseLMWH LMWH RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Vesalio Group 2005 52/60 59/62 0.91 [ 0.81, 1.02 ]

0.01 0.1 1 10 100 Favours Weight-adjusted Favours Fixed-dose

Treatment for superﬁcial thrombophlebitis of the leg (Review) 80 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 11.7. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 7 Pitting oedema disappearance.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 11 Fixed-dose LMWH versus weight-adjusted LMWH

Outcome: 7 Pitting oedema disappearance

Weight- adjusted Studyorsubgroup Fixed-doseLMWH LMWH RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Vesalio Group 2005 7/9 16/17 0.83 [ 0.57, 1.20 ]

0.01 0.1 1 10 100 Favours Weight-adjusted Favours Fixed-dose

Analysis 11.8. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 8 Collateral veins disappearance.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 11 Fixed-dose LMWH versus weight-adjusted LMWH

Outcome: 8 Collateral veins disappearance

Weight- adjusted Studyorsubgroup Fixed-doseLMWH LMWH RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Vesalio Group 2005 7/13 9/16 0.96 [ 0.49, 1.86 ]

0.1 0.2 0.5 1 2 5 10 Favours Weight-adjusted Favours Fixed-dose

Treatment for superﬁcial thrombophlebitis of the leg (Review) 81 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 11.9. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 9 Redness disappearance.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 11 Fixed-dose LMWH versus weight-adjusted LMWH

Outcome: 9 Redness disappearance

Weight- adjusted Studyorsubgroup Fixed-doseLMWH LMWH RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Vesalio Group 2005 59/76 60/76 0.98 [ 0.83, 1.16 ]

0.1 0.2 0.5 1 2 5 10 Favours Weight-adjusted Favours Fixed-dose

Analysis 11.10. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 10 Palpable cord disappearance.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 11 Fixed-dose LMWH versus weight-adjusted LMWH

Outcome: 10 Palpable cord disappearance

Weight- adjusted Studyorsubgroup Fixed-doseLMWH LMWH RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Vesalio Group 2005 26/73 37/74 0.71 [ 0.49, 1.05 ]

0.1 0.2 0.5 1 2 5 10 Favours Weight-adjusted Favours Fixed-dose

Treatment for superﬁcial thrombophlebitis of the leg (Review) 82 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 11.11. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 11 Major bleeding.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 11 Fixed-dose LMWH versus weight-adjusted LMWH

Outcome: 11 Major bleeding

Weight- adjusted Studyorsubgroup Fixed-doseLMWH LMWH RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Vesalio Group 2005 0/81 0/83 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours Fixed-dose Favours Weight-adjusted

Analysis 11.12. Comparison 11 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 12 Heparin- induced thrombocytopenia.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 11 Fixed-dose LMWH versus weight-adjusted LMWH

Outcome: 12 Heparin-induced thrombocytopenia

Weight- adjusted Studyorsubgroup Fixed-doseLMWH LMWH RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Vesalio Group 2005 1/81 1/83 1.02 [ 0.07, 16.11 ]

0.01 0.1 1 10 100 Favours Fixed-dose Favours Weight-adjusted

Treatment for superﬁcial thrombophlebitis of the leg (Review) 83 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 12.1. Comparison 12 Prophylactic UFH + elastic compression stockings versus elastic compression stockings alone, Outcome 1 Venous thromboembolism.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 12 Prophylactic UFH + elastic compression stockings versus elastic compression stockings alone

Outcome: 1 Venous thromboembolism

ECS+prophylactic Study or subgroup UFH ECS RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Belcaro 1999 0/71 6/78 0.08 [ 0.00, 1.47 ]

0.001 0.01 0.1 1 10 100 1000 Favours ECS+UFH Favours ECS

Analysis 12.2. Comparison 12 Prophylactic UFH + elastic compression stockings versus elastic compression stockings alone, Outcome 2 Extension and/or recurrence of ST.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 12 Prophylactic UFH + elastic compression stockings versus elastic compression stockings alone

Outcome: 2 Extension and/or recurrence of ST

Studyorsubgroup ECS+UFH ECS RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Belcaro 1999 2/71 13/78 0.17 [ 0.04, 0.72 ]

0.01 0.1 1 10 100 Favours ECS+UFH Favours ECS

Treatment for superﬁcial thrombophlebitis of the leg (Review) 84 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 13.1. Comparison 13 High-dose UFH versus low-dose UFH, Outcome 1 Incidence of venous thromboembolism.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 13 High-dose UFH versus low-dose UFH

Outcome: 1 Incidence of venous thromboembolism

Studyorsubgroup High-doseUFH Low-doseUFH RiskRatio Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Marchiori 2002 1/30 6/30 0.17 [ 0.02, 1.30 ]

0.01 0.1 1 10 100 Favours High-dose UFH Favours Low-dose UFH

Analysis 13.2. Comparison 13 High-dose UFH versus low-dose UFH, Outcome 2 ST recurrence or extension.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 13 High-dose UFH versus low-dose UFH

Outcome: 2 ST recurrence or extension

Studyorsubgroup High-doseUFH Low-doseUFH RiskRatio Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Marchiori 2002 8/30 11/30 0.73 [ 0.34, 1.55 ]

0.1 0.2 0.5 1 2 5 10 Favours High-dose UFH Favours Low-dose UFH

Treatment for superﬁcial thrombophlebitis of the leg (Review) 85 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 13.3. Comparison 13 High-dose UFH versus low-dose UFH, Outcome 3 Major bleeding.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 13 High-dose UFH versus low-dose UFH

Outcome: 3 Major bleeding

Studyorsubgroup High-doseUFH Low-doseUFH RiskRatio Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Marchiori 2002 0/30 0/30 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours High-dose UFH Favours Low-dose UFH

Analysis 13.4. Comparison 13 High-dose UFH versus low-dose UFH, Outcome 4 Heparin-induced thrombocytopenia.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 13 High-dose UFH versus low-dose UFH

Outcome: 4 Heparin-induced thrombocytopenia

Studyorsubgroup High-doseUFH Low-doseUFH RiskRatio Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Marchiori 2002 0/30 0/30 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours High-dose UFH Favours Low-dose UFH

Treatment for superﬁcial thrombophlebitis of the leg (Review) 86 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 14.1. Comparison 14 Calcium heparin + elastic compression bandage versus elastic compression bandage alone, Outcome 1 Deep venous thrombosis.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 14 Calcium heparin + elastic compression bandage versus elastic compression bandage alone

Outcome: 1 Deep venous thrombosis

Studyorsubgroup ECB+calciumheparin ECB RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Belcaro 1989 0/19 0/15 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours ECB+heparin Favours ECB

Analysis 15.1. Comparison 15 Heparin sc versus deﬁbrotide, Outcome 1 Decrease in the analogue score.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 15 Heparin sc versus deﬁbrotide

Outcome: 1 Decrease in the analogue score

Mean Mean Studyorsubgroup Heparinsc Deﬁbrotide Difference Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Belcaro 1990 20 6 (2) 20 3 (2) 3.00 [ 1.76, 4.24 ]

-10 -5 0 5 10 Favours Heparin sc Favours Deﬁbrotide

Treatment for superﬁcial thrombophlebitis of the leg (Review) 87 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 15.2. Comparison 15 Heparin sc versus deﬁbrotide, Outcome 2 Treatment side effects.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 15 Heparin sc versus deﬁbrotide

Outcome: 2 Treatment side effects

Studyorsubgroup Heparinsc Deﬁbrotide RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Belcaro 1990 0/20 0/20 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours Heparin sc Favours Deﬁbrotide

Analysis 16.1. Comparison 16 NSAIDs versus placebo, Outcome 1 Venous thromboembolism.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 16 NSAIDs versus placebo

Outcome: 1 Venous thromboembolism

Studyorsubgroup NSAIDS Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 4/99 5/112 0.91 [ 0.25, 3.28 ]

0.1 0.2 0.5 1 2 5 10 Favours NSAIDS Favours Placebo

Treatment for superﬁcial thrombophlebitis of the leg (Review) 88 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 16.2. Comparison 16 NSAIDs versus placebo, Outcome 2 Extension and/or recurrence of ST.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 16 NSAIDs versus placebo

Outcome: 2 Extension and/or recurrence of ST

Studyorsubgroup NSAIDS Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 12/99 33/112 0.41 [ 0.23, 0.75 ]

0.1 0.2 0.5 1 2 5 10 Favours NSAIDS Favours Placebo

Analysis 16.3. Comparison 16 NSAIDs versus placebo, Outcome 3 Major bleeding.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 16 NSAIDs versus placebo

Outcome: 3 Major bleeding

Studyorsubgroup NSAIDS Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 0/99 0/112 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours NSAIDS Favours Placebo

Treatment for superﬁcial thrombophlebitis of the leg (Review) 89 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 16.4. Comparison 16 NSAIDs versus placebo, Outcome 4 Heparin-induced thrombocytopenia.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 16 NSAIDs versus placebo

Outcome: 4 Heparin-induced thrombocytopenia

Studyorsubgroup NSAIDS Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Stenox Group 2003 0/99 0/112 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours NSAIDS Favours Placebo

Analysis 17.1. Comparison 17 Indomethacin versus placebo, Outcome 1 Side effects.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 17 Indomethacin versus placebo

Outcome: 1 Side effects

Studyorsubgroup Indomethacin Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Anonymous 1970 12/30 4/26 2.60 [ 0.95, 7.08 ]

0.01 0.1 1 10 100 Favours Indomethacin Favours Placebo

Treatment for superﬁcial thrombophlebitis of the leg (Review) 90 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 18.1. Comparison 18 Nimesulide versus diclofenac sodium, Outcome 1 Gastric pain.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 18 Nimesulide versus diclofenac sodium

Outcome: 1 Gastric pain

Studyorsubgroup Nimesulide Diclofenac RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Ferrari 1992 1/25 4/25 0.25 [ 0.03, 2.08 ]

0.01 0.1 1 10 100 Favours Nimesulide Favours Diclofenac

Analysis 19.1. Comparison 19 Essaven gel versus placebo, Outcome 1 Intolerance.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 19 Essaven gel versus placebo

Outcome: 1 Intolerance

Studyorsubgroup Essavengel Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Incandela 2001 0/16 0/14 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours Essaven gel Favours Placebo

Treatment for superﬁcial thrombophlebitis of the leg (Review) 91 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 20.1. Comparison 20 Thrombectomy + venoruton + elastic compression bandage versus elastic compression bandage alone, Outcome 1 Deep venous thrombosis.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 20 Thrombectomy + venoruton + elastic compression bandage versus elastic compression bandage alone

Outcome: 1 Deep venous thrombosis

Studyorsubgroup ECB+thromb+venoruton ECB RiskRatio Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Belcaro 1989 0/17 0/15 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours ECB+thr+veno Favours ECB

Analysis 21.1. Comparison 21 Thrombectomy + elastic compression bandage versus elastic compression bandage alone, Outcome 1 Deep venous thrombosis.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 21 Thrombectomy + elastic compression bandage versus elastic compression bandage alone

Outcome: 1 Deep venous thrombosis

Studyorsubgroup ECB+thrombectomy ECB RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Belcaro 1989 0/14 0/15 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours ECB+thrombec Favours ECB

Treatment for superﬁcial thrombophlebitis of the leg (Review) 92 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 22.1. Comparison 22 Ligation + elastic compression stockings versus elastic compression stockings alone, Outcome 1 Venous thromboembolism.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 22 Ligation + elastic compression stockings versus elastic compression stockings alone

Outcome: 1 Venous thromboembolism

Studyorsubgroup ECS+ligation ECS RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Belcaro 1999 2/78 6/78 0.33 [ 0.07, 1.60 ]

0.01 0.1 1 10 100 Favours ECS+ligation Favours ECS

Analysis 22.2. Comparison 22 Ligation + elastic compression stockings versus elastic compression stockings alone, Outcome 2 Extension and/or recurrence of ST.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 22 Ligation + elastic compression stockings versus elastic compression stockings alone

Outcome: 2 Extension and/or recurrence of ST

Studyorsubgroup ECS+ligation ECS RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Belcaro 1999 6/78 13/78 0.46 [ 0.18, 1.15 ]

0.1 0.2 0.5 1 2 5 10 Favours ECS+ligation Favours ECS

Treatment for superﬁcial thrombophlebitis of the leg (Review) 93 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 23.1. Comparison 23 Stripping + elastic compression stockings versus elastic compression stockings alone, Outcome 1 Venous thromboembolism.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 23 Stripping + elastic compression stockings versus elastic compression stockings alone

Outcome: 1 Venous thromboembolism

Studyorsubgroup ECS+stripping ECS RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Belcaro 1999 2/70 6/78 0.37 [ 0.08, 1.78 ]

0.01 0.1 1 10 100 Favours ECS+strippin Favours ECS

Analysis 23.2. Comparison 23 Stripping + elastic compression stockings versus elastic compression stockings alone, Outcome 2 Extension and/or recurrence of ST.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 23 Stripping + elastic compression stockings versus elastic compression stockings alone

Outcome: 2 Extension and/or recurrence of ST

Studyorsubgroup ECS+stripping ECS RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Belcaro 1999 1/70 13/78 0.09 [ 0.01, 0.64 ]

0.001 0.01 0.1 1 10 100 1000 Favours ECS+strippin Favours ECS

Treatment for superﬁcial thrombophlebitis of the leg (Review) 94 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 24.1. Comparison 24 Oral vasotonin versus placebo, Outcome 1 Cured or substantially better.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 24 Oral vasotonin versus placebo

Outcome: 1 Cured or substantially better

Studyorsubgroup Vasotonin Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Kuhlwein 1985 34/38 19/38 1.79 [ 1.28, 2.50 ]

0.001 0.01 0.1 1 10 100 1000 Favours Vasotonin Favours Placebo

Analysis 24.2. Comparison 24 Oral vasotonin versus placebo, Outcome 2 Poor tolerability.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 24 Oral vasotonin versus placebo

Outcome: 2 Poor tolerability

Studyorsubgroup Vasotonin Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Kuhlwein 1985 1/38 5/38 0.20 [ 0.02, 1.63 ]

0.01 0.1 1 10 100 Favours Vasotonin Favours Placebo

Treatment for superﬁcial thrombophlebitis of the leg (Review) 95 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 25.1. Comparison 25 Elastic compression bandage + venoruton versus elastic compression bandage alone, Outcome 1 Deep venous thrombosis.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 25 Elastic compression bandage + venoruton versus elastic compression bandage alone

Outcome: 1 Deep venous thrombosis

Studyorsubgroup ECB+venoruton ECB RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Belcaro 1989 0/18 0/15 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours ECB+venoruton Favours ECB

Analysis 26.1. Comparison 26 Oral heparan sulphate versus oral sulodexide, Outcome 1 Redness disappearance.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 26 Oral heparan sulphate versus oral sulodexide

Outcome: 1 Redness disappearance

Studyorsubgroup Heparansulphate Sulodexide RiskRatio Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Messa 1997 14/15 10/15 1.40 [ 0.95, 2.05 ]

0.01 0.1 1 10 100 Favours Sulodexide Favours Heparan sulphate

Treatment for superﬁcial thrombophlebitis of the leg (Review) 96 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 26.2. Comparison 26 Oral heparan sulphate versus oral sulodexide, Outcome 2 Pain disappearance.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 26 Oral heparan sulphate versus oral sulodexide

Outcome: 2 Pain disappearance

Studyorsubgroup Heparansulphate Sulodexide RiskRatio Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Messa 1997 12/15 10/15 1.20 [ 0.77, 1.86 ]

0.01 0.1 1 10 100 Favours Sulodexide Favours Heparan sulphate

Analysis 26.3. Comparison 26 Oral heparan sulphate versus oral sulodexide, Outcome 3 Disappearance of itching.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 26 Oral heparan sulphate versus oral sulodexide

Outcome: 3 Disappearance of itching

Studyorsubgroup Heparansulphate Sulodexide RiskRatio Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Messa 1997 3/3 1/2 1.75 [ 0.53, 5.76 ]

0.001 0.01 0.1 1 10 100 1000 Favours Sulodexide Favours Heparan sulphate

Treatment for superﬁcial thrombophlebitis of the leg (Review) 97 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 26.4. Comparison 26 Oral heparan sulphate versus oral sulodexide, Outcome 4 Oedema improvement.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 26 Oral heparan sulphate versus oral sulodexide

Outcome: 4 Oedema improvement

Studyorsubgroup Heparansulphate Sulodexide RiskRatio Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Messa 1997 2/4 3/9 1.50 [ 0.39, 5.77 ]

0.01 0.1 1 10 100 Favours Sulodexide Favours Heparan sulphate

Analysis 26.5. Comparison 26 Oral heparan sulphate versus oral sulodexide, Outcome 5 Trophism improvement.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 26 Oral heparan sulphate versus oral sulodexide

Outcome: 5 Trophism improvement

Studyorsubgroup Heparansulphate Sulodexide RiskRatio Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Messa 1997 0/3 0/3 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours Heparan sulphate Favours Sulodexide

Treatment for superﬁcial thrombophlebitis of the leg (Review) 98 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 27.1. Comparison 27 Oxyphenbutazone versus placebo, Outcome 1 Tenderness improvement.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 27 Oxyphenbutazone versus placebo

Outcome: 1 Tenderness improvement

Studyorsubgroup Oxyphenbutazone Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Archer 1977 19/24 13/27 1.64 [ 1.06, 2.56 ]

0.01 0.1 1 10 100 Favours Oxyphenbutazone Favours Placebo

Analysis 28.1. Comparison 28 VKA + elastic compression stockings versus elastic compression stockings alone, Outcome 1 Venous thromboembolism.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 28 VKA + elastic compression stockings versus elastic compression stockings alone

Outcome: 1 Venous thromboembolism

Studyorsubgroup ECS+VKA ECS RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Belcaro 1999 0/71 6/78 0.08 [ 0.00, 1.47 ]

0.001 0.01 0.1 1 10 100 1000 Favours ECS+VKA Favours ECS

Treatment for superﬁcial thrombophlebitis of the leg (Review) 99 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 28.2. Comparison 28 VKA + elastic compression stockings versus elastic compression stockings alone, Outcome 2 Extension and/or recurrence of ST.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 28 VKA + elastic compression stockings versus elastic compression stockings alone

Outcome: 2 Extension and/or recurrence of ST

Studyorsubgroup ECS+VKA ECS RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Belcaro 1999 5/71 13/78 0.42 [ 0.16, 1.13 ]

0.1 0.2 0.5 1 2 5 10 Favours ECS+VKA Favours ECS

Analysis 29.1. Comparison 29 Enzyme therapy versus placebo, Outcome 1 Pain reduction.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 29 Enzyme therapy versus placebo

Outcome: 1 Pain reduction

Mean Mean Studyorsubgroup Enzymetherapy Placebo Difference Difference N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Marshall 2001 74 3.6 (2.1) 74 2.6 (2.37) 1.00 [ 0.28, 1.72 ]

-10 -5 0 5 10 Favours Placebo Favours Enzyme therapy

Treatment for superﬁcial thrombophlebitis of the leg (Review) 100 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 29.2. Comparison 29 Enzyme therapy versus placebo, Outcome 2 Responders.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 29 Enzyme therapy versus placebo

Outcome: 2 Responders

Studyorsubgroup Enzymetherapy Placebo RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Marshall 2001 57/74 43/74 1.33 [ 1.05, 1.67 ]

0.1 0.2 0.5 1 2 5 10 Favours Placebo Favours Enzyme therapy

Analysis 30.1. Comparison 30 Desmin im 200 versus desmin 100, Outcome 1 Adverse events.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 30 Desmin im 200 versus desmin 100

Outcome: 1 Adverse events

Studyorsubgroup Desminim200 Desmin100 RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Andreozzi 1996 0/20 3/17 0.12 [ 0.01, 2.22 ]

0.001 0.01 0.1 1 10 100 1000 Favours Desmin 200 Favours Desmin 100

Treatment for superﬁcial thrombophlebitis of the leg (Review) 101 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 30.2. Comparison 30 Desmin im 200 versus desmin 100, Outcome 2 Adverse drug reactions.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 30 Desmin im 200 versus desmin 100

Outcome: 2 Adverse drug reactions

Studyorsubgroup Desminim200 Desmin100 RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Andreozzi 1996 0/20 0/17 0.0 [ 0.0, 0.0 ]

0.1 0.2 0.5 1 2 5 10 Favours Desmin 200 Favours Desmin 100

Analysis 31.1. Comparison 31 Desmin sc 2x100 versus desmin 100, Outcome 1 Adverse events.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 31 Desmin sc 2x100 versus desmin 100

Outcome: 1 Adverse events

Studyorsubgroup Desminsc2x100 Desmin100 RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Andreozzi 1996 1/18 3/17 0.31 [ 0.04, 2.74 ]

0.01 0.1 1 10 100 Favours Desmin 200 Favours Desmin 100

Treatment for superﬁcial thrombophlebitis of the leg (Review) 102 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 31.2. Comparison 31 Desmin sc 2x100 versus desmin 100, Outcome 2 Adverse drug reactions.

Review: Treatment for superﬁcial thrombophlebitis of the leg

Comparison: 31 Desmin sc 2x100 versus desmin 100

Outcome: 2 Adverse drug reactions

Studyorsubgroup Desminsc2x100 Desmin100 RiskRatio RiskRatio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Andreozzi 1996 1/18 0/17 2.84 [ 0.12, 65.34 ]

0.01 0.1 1 10 100 Favours Desmin 200 Favours Desmin 100

APPENDICES Appendix 1. CENTRAL search strategy #1 MeSH descriptor Thrombophlebitis explode all trees1088 #2 MeSH descriptor Venous Thrombosis explode all trees with qualiﬁer: CO149 #3 MeSH descriptor Phlebitis, this term only143 #4 *phlebit*1897 #5 superﬁcial near thrombo*136 #6 (#1 OR #2 OR #3 OR #4 OR #5)1778

FEEDBACK

Comment on data analysis, 12 February 2009

Summary There are some analyses that are difficult to interpret and generate more statistics than data. This type of analysis is recommended in the Cochrane manual, but I am sure there must be a better way. See “Comparison 23. Exhirud ointment versus placebo”. This has one study. One outcome “efficacy” was split into 4 categories, and there were thus 4 analyses for ’excellent/good/some/no efficacy’. (Analysis 23.2)

Reply We fully agree with these comments, however, we felt that reporting these analysis in the dedicated section seemed the only way to inform the reader about these outcomes while avoiding to increase the confusion of the Results section caused by the already long list of comparisons as well as the endless list of studies cited after any statement. We welcome any advice.

Treatment for superﬁcial thrombophlebitis of the leg (Review) 103 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Contributors Feedback: Michael Power, Guideline author Reply: Marcello Di Nisio, Iris M Wichers, Saskia Middeldorp

Comment on Belcaro papers, 13 February 2009

Summary This review includes a number of papers by Gianni Belcaro who was erased from the UK medical register in June 2007. This was for “misconduct”, which seems to have been that he included as co-authors on his papers people who were not involved in the research. The GMC report does not suggest that data was falsiﬁed. http://webcache.gmc-uk.org/minutesﬁles/3313.HTML Should you mention in the systematic reviews that the data may be suspect in Belcaro’s papers?

Reply We understand and share the suspicion on the reliability of the data. However, it does not seem that the reason for misconduct would influence the quality of the data which, in any case, the GMC report suggested not to be falsified. Therefore we do not think that this misconduct should be explicitly mentioned in the text. Moreover, the data from the studies of Belcaro do not affect the main conclusions of the review. Finally the significant methodological limitations of these studies are underlined in the text.

Contributors Feedback: Michael Power, Guideline author Reply: Marcello Di Nisio, Iris M Wichers, Saskia Middeldorp

Best therapeutic options for ST of the legs, 27 October 2010

Summary The authors concluded that ’low molecular weight heparin and NSAIDs appear as the current best therapeutic options for ST of the legs.’ This statement does not fully capture the data presented in the review.

In their discussion section the authors note several serious limitations in the studies presented in the review. These include unclear methods of allocation or randomization, lack of a placebo group as control, high drop out rates, and poor reporting of serious adverse events. In addition, study data could not be pooled due to a high level of heterogeneity and thus data remains underpowered to show any difference in VTE between treatment groups.

In the implications for practice section the authors concede that “the data are still too preliminary to make any recommendation”. Yet the authors proceed to state that one month of therapy with LMWH may be appropriate to prevent VTE events as well the extension and/or recurrence of ST. Given these drawbacks coupled with the fact that individual trials fail to show signiﬁcant differences between treatment groups, a ﬁnal conclusion should not be drawn regarding therapeutic options.

Perhaps the question that should be asked is not what the best treatment for ST is, but rather whether or not ST requires treatment at all. The authors note that ST is estimated to be more common than DVT and go on to say that ST is associated with DVT in 6 to 44% of patients, but this does nothing to answer the question of how prevalent ST is in the general population. Given that limited data is available on the prevalence of ST and its clinically relevant outcomes, it is not clear to us whether or not treatment of ST is required to improve patient outcomes.

Treatment for superﬁcial thrombophlebitis of the leg (Review) 104 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Reply We agree with these comments and have modiﬁed the text accordingly. Since our previous review, the CALISTO study has been published (Decousus 2010a). The results of this large and methodologically robust RCT provide good answers to some of the reviewer’s concerns.

Contributors Feedback: Michelle Co, BScPharm; Hayley Coe, BScPharm; Sarah West, BSc, BScPharm; Aaron Tejani BScPharm, PharmD Reply: Marcello Di Nisio, Iris M Wichers, Saskia Middeldorp

WHAT’S NEW Last assessed as up-to-date: 29 November 2011.

Date Event Description

30 November 2011 New citation required and conclusions have changed Review updated. Conclusions changed.

30 November 2011 Feedback has been incorporated Feedback addressed.

30 November 2011 New search has been performed Review updated, searches rerun. Two new trials included, one being a large RCT with fondaparinux

HISTORY Protocol ﬁrst published: Issue 4, 2004 Review ﬁrst published: Issue 1, 2007

Date Event Description

27 October 2010 Feedback has been incorporated Feedback added

26 April 2010 Amended Contact details updated

1 September 2008 Amended Converted to new review format.

19 February 2007 New citation required and minor changes Updated to correct error in citation. Searches re-run and no new trials found

Treatment for superﬁcial thrombophlebitis of the leg (Review) 105 Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. CONTRIBUTIONSOFAUTHORS Marcello Di Nisio selected and assessed the quality of trials, extracted data and wrote the review. Iris M Wichers selected and assessed the quality of trials, extracted data and commented on the review. Saskia Middeldorp supervised the development of the review in all of its phases.

DECLARATIONSOFINTEREST Dr Middeldorp served as a member of the Steering Committee of the Calisto study, which investigated the efficacy and safety of fondaparinux for superficial thrombophlebitis. The first version of this review was written before the Calisto study was designed.

SOURCES OF SUPPORT

Internal sources • No sources of support supplied

External sources • Chief Scientist Ofﬁce, Scottish Government Health Directorates, The Scottish Government, UK. The PVD Group editorial base is supported by the Chief Scientist Ofﬁce.

DIFFERENCESBETWEENPROTOCOLANDREVIEW We planned to evaluate the heterogeneity of treatment effects between trials using the Chi2 test and the I2 statistic. However, despite the relatively broad number of comparisons found, no test of heterogeneity was performed since none of the studies evaluated the same treatment comparisons on the same study outcomes. For the same reason, subgroup analysis and sensitivity analysis were not possible. We had planned to perform a sensitivity analyses to explore the robustness of our results. We aimed to examine the effect of excluding lower quality studies (open-label studies and studies with incomplete follow-up) from the analysis. If possible, we planned to repeat the analysis taking into account factors that could have introduced bias, such as high levels of exclusions which were unbalanced between the groups, or inadequate allocation concealment. For most of the treatment comparisons, SMD could not be calculated for continuous variables since the standard deviations (SD) of the means were not provided by the studies.

INDEX TERMS

Medical Subject Headings (MeSH) Anti-Inﬂammatory Agents, Non-Steroidal [therapeutic use]; Anticoagulants [therapeutic use]; Heparin, Low-Molecular-Weight [therapeutic use]; Randomized Controlled Trials as Topic; Thromboembolism [prevention & control]; Thrombophlebitis [drug therapy; ∗ surgery; therapy]