Treatment for superficial thrombophlebitis of the leg

Marcello Di Nisio; Iris M Wichers; Saskia Middeldorp

doi:10.1002/14651858.CD004982.pub6

. 2018 Feb 25;2018(2):CD004982. doi: 10.1002/14651858.CD004982.pub6

Treatment for superficial thrombophlebitis of the leg

Marcello Di Nisio ^1,^2,^✉, Iris M Wichers ³, Saskia Middeldorp ²

Editor: Cochrane Vascular Group

PMCID: PMC6953389 PMID: 29478266

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 the third update of a review first published in 2007.

Objectives

To assess the efficacy and safety of topical, medical, and surgical treatments for ST of the leg in improving local symptoms and decreasing thromboembolic complications.

Search methods

For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register (March 2017), CENTRAL (2017, Issue 2), and trials registries (March 2017). We handsearched the reference lists of relevant papers and conference proceedings.

Selection criteria

Randomised controlled trials (RCTs) evaluating topical, medical, and surgical treatments for ST of the legs that included people with a clinical diagnosis of ST of the legs or objective diagnosis of a thrombus in a 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. We assessed the quality of the evidence using the GRADE approach.

Main results

We identified three additional trials (613 participants), therefore this update considered 33 studies involving 7296 people with ST of the legs. Treatment included fondaparinux; rivaroxaban; low molecular weight heparin (LMWH); unfractionated heparin (UFH); non‐steroidal anti‐inflammatory drugs (NSAIDs); compression stockings; and topical, intramuscular, or intravenous treatment to surgical interventions such as thrombectomy or ligation. Only a minority of trials compared treatment with placebo rather than an alternative treatment and many studies were small and of poor quality. Pooling of the data was possible for few outcomes, and none were part of a placebo‐controlled trial. In one large, placebo‐controlled RCT of 3002 participants, subcutaneous fondaparinux was associated with a significant reduction in symptomatic VTE (risk ratio (RR) 0.15, 95% confidence interval (CI) 0.04 to 0.50; moderate‐quality evidence), ST extension (RR 0.08, 95% CI 0.03 to 0.22; moderate‐quality evidence), and ST recurrence (RR 0.21, 95% CI 0.08 to 0.54; moderate‐quality evidence) relative to placebo. Major bleeding was infrequent in both groups with very wide CIs around risk estimate (RR 0.99, 95% CI 0.06 to 15.86; moderate‐quality evidence). In one RCT on 472 high‐risk participants with ST, fondaparinux was associated with a non‐significant reduction of symptomatic VTE compared to rivaroxaban 10 mg (RR 0.33, 95% CI 0.03 to 3.18; low‐quality evidence). There were no major bleeding events in either group (low‐quality evidence). In another placebo‐controlled trial, both prophylactic and therapeutic doses of LMWH (prophylactic: RR 0.44, 95% CI 0.26 to 0.74; therapeutic: RR 0.46, 95% CI 0.27 to 0.77) and NSAIDs (RR 0.46, 95% CI 0.27 to 0.78) reduced the extension (low‐quality evidence) and recurrence of ST (low‐quality evidence) in comparison to placebo, with no significant effects on symptomatic VTE (low‐quality evidence) or major bleeding (low‐quality evidence). Overall, topical treatments improved local symptoms compared with placebo, but no data were provided on the effects on VTE and ST extension. Surgical treatment combined with elastic stockings was associated with a lower VTE rate and ST progression compared with elastic stockings alone. However, the majority of studies that compared different oral treatments, topical treatments, or surgery did not report VTE, ST progression, adverse events, or treatment adverse effects.

Authors' conclusions

Prophylactic dose fondaparinux given for 45 days appears to be a valid therapeutic option for ST of the legs for most people. The evidence on topical treatment or surgery is too limited and does not inform clinical practice about the effects of these treatments in terms of VTE. Further research is needed to assess the role of rivaroxaban and other direct oral factor‐X or thrombin inhibitors, LMWH, and NSAIDs; the optimal doses and duration of treatment in people at various risk of recurrence; 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

Background

Superficial thrombophlebitis (ST) is a relatively common inflammatory process associated with a blood clot (thrombus) that affects the superficial veins (veins that are close to the surface of the body). Symptoms and signs include local pain, itching, tenderness, reddening of the skin, and hardening of the surrounding tissue. There is some evidence to suggest a link between ST and venous thromboembolism (VTE; a condition where blood clots form (most often) in the deep veins of the leg and can travel in the circulation and lodge in the lungs). Treatment aims to relieve the local symptoms and to prevent the extension of the clot into a deep vein, ST recurrence, or the development of more serious events caused by VTE. This is the third update of a review first published in 2007. The evidence is current to March 2017.

Study characteristics and key results

This update included 33 randomised controlled trials (clinical trials where people are randomly put into one of two or more treatment groups) involving 7296 participants. Treatments included rivaroxaban (a medicine called a direct oral inhibitor of activated factor X), injections of medicines under the skin to prevent blood clotting (e.g. fondaparinux, low molecular weight heparin, or unfractionated heparin), elastic compression stockings, oral non‐steroidal anti‐inflammatory drugs (NSAIDs; a pain killer medicine), topical treatment (medicine applied to the skin), and surgery.

One large study, accounting for half of the participants included in the review, showed that treatment with fondaparinux for 45 days was associated with a significant reduction in symptomatic VTE (where symptoms indicate there is a VTE), ST extension (where the clot moves further up the leg), and recurrence of ST (where clots return) compared to placebo. Major bleeding was infrequent in both groups. In one study in people with ST at high risk of recurrent thromboembolic events, fondaparinux was associated with a non‐significant reduction of symptomatic VTE compared to rivaroxaban. There were no major bleeding events in either group. Both low molecular weight heparin and NSAIDs reduced the occurrence of extension or recurrence of ST with no effect on symptomatic VTE or major bleeding. 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.

Quality of the evidence

Overall, the quality of evidence was very low for most treatments due to poor study design, imprecision of results, lack of a placebo (non‐treated) group and only one study in some comparison. The quality of evidence was low to moderate for comparisons in two placebo‐controlled trials.

In conclusion, fondaparinux appears to be an adequate treatment for most people with ST. The optimal dose and duration of treatment need to be established in people at high risk as well as people at low risk for recurrent thrombotic events. Further research is needed to assess the role of rivaroxaban and other such medicines, or thrombin, low molecular weight heparin or NSAIDs and to demonstrate the effectiveness, if any, of topical treatment, or surgery in terms of VTE.

Summary of findings

Background

Description of the condition

The term superficial thrombophlebitis (ST), also known as superficial venous thrombosis, refers to a pathological state characterised by an inflammatory‐thrombotic process in a superficial vein. Distinctive clinical findings include pain and a reddened, warm, tender cord extending along the vein. The surrounding area may show signs of erythema (reddening of the skin) and oedema (swelling of the tissue). ST is a relatively common disease and, although its incidence has never been properly determined, it is estimated to be higher than that of deep vein thrombosis (DVT), which is about 1 per 1000 cases (De Weese 1991; Nordstrom 1992). In one community‐based study conducted in a population of 265,687 adults in France, the annual diagnosis rate of symptomatic, confirmed ST was 0.64% (95% confidence interval (CI) 0.55% to 0.74%) (Frappé 2014).

While the majority of ST occurs in varicose veins, additional predisposing risk factors similar to those for venous thromboembolism (VTE) include immobilisation, trauma, postoperative states, pregnancy, puerperium (the period immediately following childbirth), active malignancy, autoimmune diseases, use of oral contraceptive pills or hormonal replacement therapy, advanced age, obesity, and a history of previous VTE (Barrelier 1993; Bergqvist 1986; Chengelis 1996; de Moerloose 1998; Lutter 1991; Samlaska 1990a). Furthermore, the presence of inherited thrombophilia (a disorder where there is a tendency for thrombosis to occur, for example factor V Leiden, the prothrombin 20210A mutation, and deficiencies of the natural anticoagulant proteins C and S) in ST suggests a similar pathophysiology as VTE (de Moerloose 1998; Hanson 1998; Martinelli 1999; Samlaska 1990a; Samlaska 1990b). Traditionally, ST has been considered a relatively benign disease, but several studies have described an association between ST and VTE (Bergqvist 1986; Blumenberg 1998; Bounameaux 1997; Chengelis 1996; Jorgensen 1993; Krunes 1999; Lutter 1991; Quenet 2003; Unno 2002; Verlato 1999). In people with a diagnosis of ST, 6% to 44% have an associated (or develop) DVT, 20% to 33% have asymptomatic pulmonary embolism (PE), and 2% to 13% have symptomatic PE (Bergqvist 1986; Blumenberg 1998; Bounameaux 1997; Chengelis 1996; Frappé 2014; 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 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 probably due to the retrospective design of most studies, the small number of participants included, and the fact that ST was often diagnosed in vascular laboratories where people were referred for suspected DVT. In one cross‐sectional and prospective epidemiological cohort study, ST at diagnosis was associated with VTE in 25% of the cases (Decousus 2010a). During a three‐month follow‐up, 10% of people with ST developed thromboembolic complications despite 90% having received anticoagulant drugs, and about 98% had used elastic compression stockings. In one nationwide population‐based cohort study of 10,973 people with a first diagnosis of ST, the incidence of VTE in the first three months after ST diagnosis was 3.4%, which was estimated to be over 70 times higher compared to the general population without ST (Cannegieter 2015).

Description of the intervention

There is no consensus on the optimal treatment of ST in clinical practice as suggested by a survey in 2011 among practitioners mostly from North America showing a large variability in the management of ST (Dua 2014). Several therapies have been proposed in the literature, including surgery (ligation or stripping of the affected veins), elastic stockings, non‐steroidal anti‐inflammatory drugs (NSAIDs) that aim to reduce pain and inflammation, and several anticoagulant agents. It is unclear whether different locations of ST may influence the choice of treatment. The thrombus location in trunks of either the great saphenous vein (saphena magna) or small saphenous vein (saphena parva) may have the highest risk of extension into the deep vein system and thus could require an aggressive form of treatment, whereas other locations may be associated with a lower risk of extension and thus may warrant a less aggressive approach. Validated risk stratification tools based on ST location and patient characteristics are currently unavailable.

Why it is important to do this review

While the estimates of VTE prevalence in people with ST vary, management of ST should consider the prevention of this scaring complication beyond the mere resolution of local symptoms (Cannegieter 2015; Decousus 2010a; Wichers 2005). Conservative management, mainly focusing on the painful symptoms of disease, might therefore be insufficient. While provision of adequate treatment for ST may help prevent (fatal) VTE, the efficacy of the intervention needs to be balanced against the potential associated risks, such as (major) bleeding events with anticoagulants.

Objectives

To assess the efficacy and safety of topical, medical, and surgical treatments for ST of the leg in improving local symptoms and decreasing thromboembolic complications.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) evaluating topical, medical, and surgical treatments for ST of the legs.

Types of participants

Hospitalised and non‐hospitalised people with a diagnosis of ST of the lower extremities based on signs and symptoms of ST (e.g. pain, tenderness, induration (hardening of the tissue), or erythema (redness of the skin)) in a superficial vein, and objective diagnosis of the thrombus in the superficial vein by means of compression ultrasonography that excludes any concomitant DVT.

Types of interventions

Interventions included any treatment to relieve the symptoms and signs or to prevent complications of ST, such as topical treatments, compression stockings, compression bandages, leg elevation, medical treatments (e.g. NSAIDs, anticoagulants such as fondaparinux, low molecular weight heparin (LMWH) or the oral direct inhibitors of factor Xa or thrombin), and surgical intervention (e.g. ligation, vein stripping, crossectomy). Each treatment could be compared with another form of treatment, placebo, or no intervention. Combinations of therapies could be used.

Types of outcome measures

We included RCTs assessing any of the following outcome measures for any of the reviewed interventions.

Primary outcomes

Primary efficacy outcome:

symptomatic VTE (i.e. the combined of symptomatic PE and symptomatic DVT).

Primary safety outcome:

major bleeding.

The presence of PE or DVT had to be confirmed by an objective test, namely pulmonary angiography, ventilation/perfusion lung scan, or spiral computed tomography for PE; and ultrasonography, venography, or plethysmography for DVT.

Secondary outcomes

The secondary outcomes considered for the review were:

symptomatic PE;
symptomatic DVT or the progression of ST into DVT;
extension (symptomatic and asymptomatic) of ST;
recurrence (symptomatic and asymptomatic) of ST;
symptoms (e.g. pain);
signs (e.g. induration and erythema);
quality of life (assessed by means of disease‐specific and non‐specific questionnaires);
mortality;
adverse effects of treatment (e.g. minor bleeding, thrombocytopenia (reduced platelet count), allergic reactions, or surgery complications);
arterial thromboembolic events.

Search methods for identification of studies

We searched for RCTs comparing any treatment versus placebo or another treatment in people with ST of the legs. There was no restriction on language.

Electronic searches

For this update, the Cochrane Vascular Information Specialist (CIS) searched the following databases for relevant trials:

Cochrane Vascular Specialised Register (March 2017);
Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2) via the Cochrane Register of Studies Online.

See Appendix 1 for details of the search strategy used to search CENTRAL.

The Cochrane Vascular Specialised Register is maintained by the CIS and is constructed from weekly electronic searches of MEDLINE Ovid, Embase Ovid, CINAHL, and AMED, and through handsearching of relevant journals. The full list of the databases, journals, and conference proceedings that have been searched, as well as the search strategies used, are described in the Specialised Register section of the Cochrane Vascular module in the Cochrane Library (www.cochranelibrary.com).

The CIS searched the following trials registries for details of ongoing and unpublished studies in March 2017:

ClinicalTrials.gov (www.clinicaltrials.gov);
World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch);
ISRCTN Register (www.isrctn.com/).

See Appendix 2.

Searching other resources

We searched reference lists of relevant papers and conference proceedings of the International Society for Thrombosis and Hemostasis (2003 to 2016) and American Society of Hematology (2004 to 2014), and we attempted to contact known experts in the field.

Data collection and analysis

Selection of studies

Two authors (MDN and IMW) independently reviewed titles and abstracts identified from the database searches to determine whether the inclusion criteria were satisfied. Two authors (MDN and IMW) independently assessed trials for inclusion in the review, and resolved any disagreements through discussion or involvement of a third author (SM). We independently reviewed the full text of identified articles, including those where there was disagreement in the initial title or abstract scanning stage, to ensure that the inclusion criteria were met. We obtained hard copies of the full text of 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 were translated into English and assessed for inclusion. We documented reasons for excluding studies and resolved disagreements by consensus. One author (MDN) scanned conference proceedings, identified articles from other sources (experts or reference lists), and contacted trialists for further information if required.

Data extraction and management

Two authors (MDN and IMW) independently extracted the data from the included studies using an agreed format. We resolved any disagreements by consensus and, if necessary, by the involvement of the third author (SM). For any study published twice, we extracted the data from the more complete study. Collected information included methodological quality, characteristics of participants, type of intervention and control, and outcomes.

Assessment of risk of bias in included studies

Two authors independently assessed randomisation, blinding, and adequacy of analyses (Juni 2001). We resolved disagreements by consensus.

Two components of randomisation were assessed: generation of allocation sequences and concealment of allocation. Generation of allocation sequences was considered adequate if it resulted in an unpredictable allocation schedule. Mechanisms considered adequate included random‐number tables, computer‐generated random numbers, minimisation, coin tossing, shuffling cards, and drawing lots. Trials using an unpredictable allocation sequence were considered randomised. Trials using potentially predictable allocation mechanisms, such as alternation or the allocation of participants according to date of birth, were considered quasi‐randomised.

Concealment of allocation was considered adequate if participants and investigators responsible for participants selection were unable to predict, before allocation, which treatment was next. Methods considered adequate included central randomisation; pharmacy‐controlled randomisation using identical prenumbered containers; and sequentially numbered, sealed, opaque envelopes.

Blinding of participants and therapists was considered adequate if experimental and control preparations were explicitly described as indistinguishable or if a double‐dummy technique was used. Assessors were considered blinded if this was explicitly mentioned by the investigators.

Analyses were considered adequate if all randomised participants were included in the analysis according to the intention‐to‐treat (ITT) principle. The item 'free of selective reporting' was classified as at 'low 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 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 either the protocol or the methods section. The risk of bias item 'free of other bias' was not considered in this review. We assessed the reporting of primary outcomes and sample size calculations.

Data synthesis

Prior to obtaining the global effect estimators (a balanced mean of the effect in different trials), we planned to evaluate the heterogeneity of treatment effects between trials using the I² statistic (Higgins 2003), which describes the percentage of total variation across trials that is attributable to heterogeneity rather than chance. I² values of 25%, 50%, and 75% may be interpreted as low, moderate, and high between‐trial heterogeneity, although the interpretation of the I² statistic depends on the size and number of trials included (Rücker 2008). In the presence of no or low heterogeneity, we planned to use the fixed‐effect model (Mantel‐Haenszel method) and the random‐effects model to pool and analyse summary effect sizes. Where possible, we presented results as summary risk ratios (RR) or hazard ratios (HRs) for dichotomous variables and mean differences (MD) for all continuous variables. We determined the 95% CI for each estimate. The unit of analysis was the number of participants with the outcome of interest. Where possible, we analysed the results by ITT, including every individual in the randomly assigned treatment group regardless of whether they completed the treatment or withdrew from the trial.

We planned to evaluate publication bias and other biases related to small study size using funnel plots, plotting effect sizes on the vertical axis against their standard errors on the horizontal axis. We planned to assess asymmetry using the asymmetry coefficient: the difference in effect 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.

We used Review Manager 5 for data analysis (RevMan 2014).

'Summary of findings' tables

We presented the main findings of the review concerning the quality of evidence and the magnitude of treatment effects in the 'Summary of findings' tables, according to the GRADE principles described by Higgins 2011 and Guyatt 2008. We used GRADEproGDT software (GRADEproGDT 2015) to create the tables. We included the primary efficacy and safety outcomes of the review as well as the major secondary outcomes (i.e. extension and recurrence of ST, minor bleeding, adverse effects of treatment, and mortality). We focused on the active treatments fondaparinux, LMWH, and NSAIDs with placebo as comparator and at least one primary outcome comparison.

Results

Excluded studies

Two additional studies were excluded in this update (Ng 2010; Supe 2013) and one study which had previously been in the Studies awaiting classification section (Bijuan 2003) was also excluded making a total of 37 excluded studies. The reasons for exclusion are listed in the Characteristics of excluded studies table. Twenty‐one studies included a mixed population and it was not possible to extract data separately for ST (Allegra 1981; Annoni 1991; Argenteri 1983; Bagliani 1983; Becherucci 2000; Bergqvist 1990; Bracale 1996; Bruni 1979; Della Marchina 1989; Luttichau 1989; Mari 1982; Marsala 1985; Mauro 1992; Paciaroni 1982; Porters 1981; Pozza 1980; Seccia 1989; Seghezzi 1972; Seligman 1969; Stolle 1986; Tomamichel 1983). In one study it was not possible to extract outcome data separately for the two study treatment groups (Agus 1993). Four studies included people without a diagnosis of ST of the legs (Bernicot 1980; Gandhi 1984; Resta 1967; van Cauwenberge 1972), and two studies included people with DVT (Di Perri 1986; Rea 1981). In one study, it was unclear whether the study was randomised or not (Giorgetti 1990). Six studies included people with ST of the arm (Gouping 2003; Mehta 1975; Ng 2010; Rozsos 1994; Supe 2013; van der Knaap 1988), and in one study, the evaluated outcomes were not among those considered in the present review (Ibanez‐Bermudez 1996). For one study, we were unable to retrieve sufficient information to judge eligibility fully (Bijuan 2003).

Ongoing studies

One study is still ongoing (Rabe 2009). See Characteristics of ongoing studies table.

Risk of bias in included studies

Details of the methodological quality for each trial are reported in the Characteristics of included studies table. A risk of bias summary is presented in Figure 2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Thirteen studies adequately generated the randomisation sequence (Belcaro 2011; Beyer‐Westendorf 2017; Cosmi 2012; Decousus 2010b; Gorski 2005; Katzenschlager 2003; Marchiori 2002; Marshall 2001; Messa 1997; Rathbun 2012; Spirkoska 2015; Vesalio Group 2005; Winter 1986), one was not adequate (Uncu 2009), and the remaining 18 studies were unclear. Eighteen studies adequately concealed allocation (Belcaro 2011; Beyer‐Westendorf 2017; Cosmi 2012; Decousus 2010b; Marshall 2001; Rathbun 2012; Spirkoska 2015; Stenox Group 2003), and the remaining 25 studies were unclear.

Blinding

Ten studies had a double‐blinded design (Cosmi 2012; Decousus 2010b; De Sanctis 2001; Incandela 2001; Marshall 2001; Nusser 1991; Pinto 1992; Rathbun 2012; Stenox Group 2003; Vesalio Group 2005), and in nine studies it was unclear whether blinding was attempted (Anonymous 1970; Archer 1977; Ferrari 1992; Koshkin 2001; Kuhlwein 1985; Marchiori 2002; Nocker 1991; Spirkoska 2015; Winter 1986). The remaining 14 studies did not attempt to blind the assessment of the outcomes or did not report whether blinding was used.

Incomplete outcome data

Seven studies performed the analysis according to the ITT principle (Beyer‐Westendorf 2017; Decousus 2010b; De Sanctis 2001; Kuhlwein 1985; Marchiori 2002; Messa 1997; Nocker 1991; Vesalio Group 2005); in nine this was unclear, while in the remaining studies the percentage of participants randomised and subsequently excluded from the analysis ranged from 2% to 33% (Anonymous 1970; Archer 1977; Belcaro 1989; Belcaro 1999; Belcaro 2011; Boehler 2014; Cosmi 2012; Ferrari 1992; Gorski 2005; Holzgreve 1989; Katzenschlager 2003; Lozano 2003; Marshall 2001; Spirkoska 2015; Stenox Group 2003; Titon 1994). In Beyer‐Westendorf 2017 the primary analysis was originally planned as ITT analysis, but later modified into a per‐protocol analysis. Although 7.6% (36/471) participants randomised were excluded from the primary analysis authors report results also according to the ITT principle.

Selective reporting

Most studies were free of selective reporting except Anonymous 1970; Belcaro 2011; Lozano 2003; Spirkoska 2015; and Uncu 2009 (all high risk), which did not provide data on some of the specified outcomes and Winter 1986 (unclear risk), which was reported as an abstract only and did not prespecify outcomes.

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4

Summary of findings for the main comparison. Fondaparinux compared to placebo for superficial thrombophlebitis of the leg.

Fondaparinux compared to placebo for superficial thrombophlebitis of the leg
Patient or population: people with ST of the leg  Settings: hospitalised or non‐hospitalised  Intervention: fondaparinux  Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Fondaparinux
Symptomatic VTE  Ventilation‐perfusion scanning, helical computed tomography, pulmonary angiography, autopsy, ultrasonography, or venography  Follow‐up: 77 days	13 per 1000	2 per 1000  (1 to 7)	RR 0.15   (0.04 to 0.5)	3002  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
Major bleeding  Follow‐up: 77 days	1 per 1000	1 per 1000  (0 to 11)	RR 0.99   (0.06 to 15.86)	2987  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
Extension of ST  Ultrasonography  Follow‐up: 77 days	34 per 1000	3 per 1000  (1 to 7)	RR 0.08   (0.03 to 0.22)	3002  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
Recurrence of ST  Ultrasonography  Follow‐up: 77 days	16 per 1000	3 per 1000  (1 to 9)	RR 0.21   (0.08 to 0.54)	3002  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
Mortality  Follow‐up: 77 days	1 per 1000	1 per 1000  (0 to 15)	RR 2   (0.18 to 22)	3002  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
Minor bleeding  Follow‐up: 77 days	4 per 1000	6 per 1000  (2 to 17)	RR 1.49   (0.53 to 4.17)	2987  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
Adverse effects of treatment  Follow‐up: 77 days	33 per 1000	37 per 1000  (26 to 54)	RR 1.13   (0.78 to 1.65)	2987  (1 study)	⊕⊕⊕⊝  Moderate¹	‐
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; RR: risk ratio; ST: superficial thrombophlebitis; VTE: venous thromboembolism.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Prophylactic LMWH versus placebo for superficial thrombophlebitis of the leg
Patient or population: people with ST of the leg  Settings: hospitalised and non‐hospitalised  Intervention: prophylactic LMWH versus placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Prophylactic LMWH
Symptomatic VTE  Follow‐up: 97 days	45 per 1000	54 per 1000  (17 to 174)	RR 1.22   (0.38 to 3.89)	222  (1 study)	⊕⊕⊝⊝  Low^1,2	‐
Major bleeding  Follow‐up: 97 days	See comment	See comment	Not estimable	222  (1 study)	⊕⊕⊝⊝  Low^1,2	0 episodes of major bleeding
Extension or recurrence (or both) of ST  Follow‐up: 97 days	330 per 1000	145 per 1000  (86 to 244)	RR 0.44   (0.26 to 0.74)	222  (1 study)	⊕⊕⊝⊝  Low^1,2	‐
Mortality	See comment	See comment	See comment	‐	See comment	Data not available
Minor bleeding	See comment	See comment	See comment	‐	See comment	Data not available
Adverse effects of treatment	See comment	See comment	See comment	‐	See comment	Data not available
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; LMWH: low molecular weight heparin; RR: risk ratio; ST: superficial thrombophlebitis; VTE: venous thromboembolism.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Therapeutic LMWH versus placebo for superficial thrombophlebitis of the leg
Patient or population: people with ST of the leg  Settings: hospitalised and non‐hospitalised  Intervention: therapeutic LMWH versus placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	Therapeutic LMWH
Symptomatic VTE  Follow‐up: 97 days	45 per 1000	38 per 1000 (10 to 137)	RR 0.85   (0.23 to 3.06)	218  (1 study)	⊕⊕⊝⊝  Low^1,2	‐
Major bleeding  Follow‐up: 97 days	See comment	See comment	Not estimable	218  (1 study)	⊕⊕⊝⊝  Low^1,2	No episodes of major bleeding
Extension or recurrence (or both) of ST  Follow‐up: 97 days	330 per 1000	152 per 1000 (89 to 254)	RR 0.46   (0.27 to 0.77)	218  (1 study)	⊕⊕⊝⊝  Low^1,2	‐
Mortality	See comment	See comment	See comment	‐	See comment	Data not available
Minor bleeding	See comment	See comment	See comment	‐	See comment	Data not available
Adverse effects of treatment	See comment	See comment	See comment	‐	See comment	Data not available
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; LMWH: low molecular weight heparin; RR: risk ratio; ST: superficial thrombophlebitis; VTE: venous thromboembolism.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

NSAIDs versus placebo for superficial thrombophlebitis of the leg
Patient or population: people with superficial thrombophlebitis of the leg  Settings: hospitalised and non‐hospitalised  Intervention: NSAIDs versus placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	Placebo	NSAIDs
Symptomatic VTE  Follow‐up: 97 days	45 per 1000	41 per 1000  (11 to 146)	RR 0.91   (0.25 to 3.28)	211  (1 study)	⊕⊕⊝⊝  Low^1,2	‐
Major bleeding  Follow‐up: 97 days	See comment	See comment	Not estimable	211  (1 study)	⊕⊕⊝⊝  Low^1,2	0 episodes of major bleeding
Extension or recurrence (or both) of ST  Follow‐up: 97 days	330 per 1000	152 per 1000  (89 to 258)	RR 0.46   (0.27 to 0.78)	211  (1 study)	⊕⊕⊝⊝  Low^1,2	‐
Mortality	See comment	See comment	See comment	‐	See comment	Data not available
Minor bleeding	See comment	See comment	See comment	‐	See comment	Data not available
Adverse effects of treatment	See comment	See comment	See comment	‐	See comment	Data not available
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).  CI: confidence interval; NSAIDs: non‐steroidal anti‐inflammatory drugs; RR: risk ratio; ST: superficial thrombophlebitis; VTE: venous thromboembolism.
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Date	Event	Description
9 March 2017	New search has been performed	Searches re‐run. Three new trials included and three trials excluded. Ten additional publications to previously included studies.
9 March 2017	New citation required but conclusions have not changed	Searches re‐run. Three new trials included and three trials excluded. Ten additional publications to previously included studies. Review updated including the addition of Summary of Findings tables. Conclusions not changed.

Date	Event	Description
15 October 2013	Amended	Amendments made to the 'Risk of bias' tables and minor data errors corrected. Outcomes reordered to reflect clinical importance.
23 November 2012	New search has been performed	Searches re‐run. Four new trials included and one new trial excluded. Conclusions unchanged.
23 November 2012	New citation required but conclusions have not changed	Review updated. Four new trials included and one new trial excluded. Conclusions unchanged.
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.
30 November 2011	New citation required and conclusions have changed	Review updated. Conclusions changed.
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.

Search run on Thur 9 Mar 2017		Hits
#1	MESH DESCRIPTOR Thrombophlebitis EXPLODE ALL TREES	1046
#2	MESH DESCRIPTOR Phlebitis	145
#3	MESH DESCRIPTOR Venous Thrombosis EXPLODE ALL TREES WITH QUALIFIERS CO	197
#4	(superficial near thrombo*):TI,AB,KY	152
#5	(superficial near phleb*):TI,AB,KY	33
#6	SVT:TI,AB,KY	175
#7	phleb:TI,AB,KY	3102
#8	#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7	3452
#9	* NOT SR‐PVD:CC AND 12/12/2012 TO 28/02/2017:DL	349958
#10	#8 AND #9	707

Outcome or subgroup title	No. of studies	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 or pulmonary embolism	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Extension of superficial thrombophlebitis	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5 Recurrence of superficial thrombophlebitis	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 bleeding	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
9 Minor bleeding	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
10 Arterial thromboembolic complication	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
11 Adverse effects of treatment	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

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Venous thromboembolism end‐of‐treatment	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Venous thromboembolism 3‐month follow‐up	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Extension or recurrence (or both) of superficial thrombophlebitis	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Major bleeding	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
5 Heparin‐induced thrombocytopenia	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Symptomatic venous thromboembolism	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Symptomatic pulmonary embolism	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Superficial thrombophlebitis progression into deep vein thrombosis	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
4 Major bleeding	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Superficial thrombophlebitis or venous thromboembolism	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Venous thromboembolism	2	238	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.10, 2.72]
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	2	238	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
12 Heparin‐induced thrombocytopenia	2	238	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.07, 16.11]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Venous thromboembolism	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Extension or recurrence (or both) of superficial thrombophlebitis	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 Complications	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Venous thromboembolism	2	278	Risk Ratio (M‐H, Fixed, 95% CI)	0.93 [0.24, 3.63]
2 Extension or recurrence (or both) of superficial thrombophlebitis	3	331	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.58, 1.78]
3 Major bleeding	3	335	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Heparin‐induced thrombocytopenia	2	278	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Deep vein thrombosis	2	83	Risk Ratio (M‐H, Fixed, 95% CI)	0.30 [0.03, 2.70]
2 Participants with thrombus at 21 days	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
3 Allergic reaction or elevated sedimentation rate	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Incidence of venous thromboembolism	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
2 Extension or recurrence (or both) of superficial thrombophlebitis	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 thrombocytopenia	1	Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Decrease in the analogue score	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2 Adverse effects of treatment	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of 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

Outcome or subgroup title	No. of studies	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

Outcome or subgroup title	No. of studies	No. of 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

Outcome or subgroup title	No. of studies	No. of 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

Outcome or subgroup title	No. of studies	Statistical method	Effect size
1 Pain (VAS, cm) at 3 weeks	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
2 Skin erythema (cm²) at 3 weeks	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
3 SF‐36 physical score at 3 weeks	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected
4 SF‐36 mental score at 3 weeks	1	Mean Difference (IV, Fixed, 95% CI)	Totals not selected

PERMALINK

Treatment for superficial thrombophlebitis of the leg

Marcello Di Nisio

Iris M Wichers

Saskia Middeldorp

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Data synthesis

'Summary of findings' tables

Results

Description of studies

Results of the search

1.

Included studies

Excluded studies

Ongoing studies

Risk of bias in included studies

2.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Effects of interventions

Summary of findings for the main comparison. Fondaparinux compared to placebo for superficial thrombophlebitis of the leg.

Summary of findings 2. Prophylactic LMWH versus placebo for superficial thrombophlebitis of the leg.

Summary of findings 3. Therapeutic LMWH versus placebo for superficial thrombophlebitis of the leg.

Summary of findings 4. NSAIDs versus placebo for superficial thrombophlebitis of the leg.

Fondaparinux

1.1. Analysis.

1.6. Analysis.

2.2. Analysis.

2.3. Analysis.

2.5. Analysis.

2.6. Analysis.

2.8. Analysis.

2.10. Analysis.

2.11. Analysis.

Low molecular weight heparin and unfractionated heparin

3.2. Analysis.

4.2. Analysis.

14.4. Analysis.

14.5. Analysis.

14.6. Analysis.

14.7. Analysis.

5.1. Analysis.

5.2. Analysis.

7.1. Analysis.

7.2. Analysis.

5.4. Analysis.

6.4. Analysis.

7.4. Analysis.

5.6. Analysis.

Methods	Multicentre, open RCT.
Participants	56 participants with ST or varicophlebitis of lower limbs; 19 males, 36 females; mean age range 48‐52 years. Diagnosis of ST objectively confirmed by Doppler compression ultrasonography. Not reported if the included participants were hospitalised or non‐hospitalised.
Interventions	Desmin (Dermatan sulphate) (100 mg bid sc). Desmin (200 mg od im). Desmin (100 mg od sc). Study treatment given for 30 days.
Outcomes	Pain and functional inability, local oedema, palpable thrombophlebitic cord, fever, hyperaemia and cutaneous hyperthermia, adverse events or adverse drug reactions.
Notes	Funding: Alfa Wassermann S.p.A (Bologna, Italy) supplied desmin. Disclosure of potential COI: 2 authors from Alfa Wassermann S.p.A., Bologna, Italy.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation not reported.
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Blinding (performance bias and detection bias)   All outcomes	High risk	Open study "open and multicenter."
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Number of participants analysed unclear. 1 participant discontinued treatment and was excluded from baseline descriptive table.
Selective reporting (reporting bias)	Low risk	All outcomes reported in the methods section were addressed in the results or discussion section.

Methods	Placebo‐controlled, double‐blind RCT.
Participants	56 participants with ST of the calf (68%), thigh (16%), both (16%). Not reported if included participants were hospitalised or non‐hospitalised. Not reported if diagnosis of ST was objectively confirmed by ultrasonography.
Interventions	Indomethacin (50 mg tid). Placebo. Study treatment given for 1 week.
Outcomes	Erythema, spontaneous pain, tenderness, oedema.
Notes	Every participant received tetracyclines (250 mg 4 times daily), paracetamol when required, warm socks (5 participants in indomethacin group, 3 in placebo group). Funding: not reported. Disclosure of potential COI: not reported, no COI forms available.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation not reported. "..comparison between indomethacin and inactive placebo..the choice being determined by random selection."
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	Double‐blind study. "double‐blind comparison;" however, not reported who was blinded and how blinding was attempted.
Incomplete outcome data (attrition bias)   All outcomes	High risk	Not clear how many participants of those initially included had full assessment of the study endpoints. From Table 1 in Anonymous 1970, it was clear that ≥ 1 of the outcomes not all participants were evaluated at longest follow‐up.
Selective reporting (reporting bias)	High risk	No data provided for some of the outcomes. Adverse effects reported in the results section but not mentioned in the methods section.

Methods	Multicentre, double‐blind RCT.
Participants	54 non‐hospitalised participants 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). Placebo (4 times daily). Study treatment given for 7 days.
Outcomes	Pain, erythema, tenderness, length of indurated vein.
Notes	Paracetamol and firm bandaging allowed. Outcome tenderness assessed in 24/26 participants in the oxyphenbutazone group. Funding: not reported. Disclosure of potential COI: not reported, no COI forms available.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation not reported. "Oxyphenbutazone..and matching placebo were allocated at random."
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Blinding (performance bias and detection bias)   All outcomes	Unclear risk	No clear information provided about blinding. "...none was a satisfactory double‐blind controlled study...". "...it was felt that such a study should be undertaken.." It could be a double blinded study, however, blinding is not clearly mentioned in the methods, results or discussion sections. Not reported who was blinded and how blinding was attempted.
Incomplete outcome data (attrition bias)   All outcomes	High risk	1 participant (from the placebo group) excluded postrandomisation (2%). Unclear if all the remaining participants were analysed.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes are reported.

Methods	Open RCT.
Participants	83 participants with ST without DVT on duplex ultrasonography; 36 males, 45 females; mean age 38.9 years (range 27‐46 years). Not reported if participants were hospitalised or non‐hospitalised.
Interventions	ST + ECB. Heparin calcium (0.5 mg bid sc) + ECB. Venoruton (1000 mg tid) + ECB. Venoruton (1000 mg tid) after ST + ECB. ECB alone. Non‐surgical treatment given for 8 weeks.
Outcomes	Area of maximum temperature, pain and tenderness (analogical score), DVT. Not specified if DVTs were symptomatic or asymptomatic.
Notes	6/9 participants excluded postrandomisation underwent surgery of the superficial venous system. DVT verified at 6 weeks by strain‐gauge plethysmography. Funding: not reported. Disclosure of potential COI: not reported, no COI forms available. Gianni Belcaro erased from the UK medical register in June 2007 for "misconduct," which seems to have been that he included as coauthors on his papers people who were not involved in the research. The General Medical Council report did not suggest that data were falsified webcache.gmc‐uk.org/minutesfiles/3313.HTML.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation not reported. "patients were randomized in 5 groups of treatment."
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Blinding (performance bias and detection bias)   All outcomes	High risk	No information provided about blinding, but it was likely an open study.
Incomplete outcome data (attrition bias)   All outcomes	High risk	9 participants excluded after inclusion in the study (10%): "6 patients underwent surgery of the superficial venous system and 3 failed to follow the prescribed treatments."
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported.

Methods	Single‐centre RCT.
Participants	40 participants with ST confirmed by colour duplex ultrasonography; 13 males, 27 females; aged 46‐48 years. Not reported if participants were hospitalised or non‐hospitalised. Angiodynography used to exclude the presence of obstruction and DVT.
Interventions	Defibrotide (first week 400 mg bid; second and third weeks 400 mg od). Low‐dose heparin (5000 IU bid sc) for 3 weeks.
Outcomes	Area of maximum temperature, analogue score (redness, local tenderness, inflammation).
Notes	All participants received compression bandages. Funding: not reported. Disclosure of potential COI: not reported, no COI forms available. Gianni Belcaro erased from the UK medical register in June 2007 for "misconduct," which seems to have been that he included as coauthors on his papers people who were not involved in the research. The General Medical Council report did not suggest that data were falsified webcache.gmc‐uk.org/minutesfiles/3313.HTML.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation not reported. "Patients were randomized in two treatment groups."
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Blinding (performance bias and detection bias)   All outcomes	High risk	No information provided about blinding, but it was likely an open study.
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Unclear if all included participants were evaluated for study outcomes.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported.

Methods	Multicentre, open RCT; 6‐month follow‐up.
Participants	562 non‐hospitalised participants with ST, large varicose veins, and venous incompetence; 181 males, 263 females; mean age range across study groups 53‐56 years. Diagnosis of ST objectively confirmed by colour Doppler compression ultrasonography.
Interventions	Surgery (ligation). Surgery (complete stripping). Low‐dose sc heparin. LMWH. 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 participants received compression bandages. Duration of non‐surgical treatments unclear and dose of heparin or coumadin not specified. Funding: not reported. Disclosure of potential COI: not reported, no COI forms available. Gianni Belcaro erased from the UK medical register in June 2007 for "misconduct," which seems to have been that he included as coauthors on his papers people who were not involved in the research. The General Medical Council report did not suggest that data were falsified webcache.gmc‐uk.org/minutesfiles/3313.HTML.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation not reported.
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Blinding (performance bias and detection bias)   All outcomes	High risk	No information provided about blinding, but it was likely an open study.
Incomplete outcome data (attrition bias)   All outcomes	High risk	118 (21%) participants lost to follow‐up.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported.

Methods	Single‐centre, randomised, placebo‐controlled study.
Participants	120 non‐hospitalised participants with ST of the legs within 72 hours prior to study inclusion. ST confirmed by colour‐Doppler ultrasonography. Mean age 46.3 years (11.51), 26 males, 94 females.
Interventions	Heparin spray gel (Viatromb 2400 IU/g): 4122 IU sodium heparin applied as 3 times 3 spray puffs. Heparin spray gel (Viatromb 2400 IU/g): 5496 IU sodium heparin applied as 3 times 4 spray puffs. Heparin spray gel (Viatromb 2400 IU/g): 6879 IU sodium heparin applied as 3 times 5 spray puffs. Placebo applied as 3 times 5 puffs. Study medication applied for 7‐14 days.
Outcomes	Pain reduction (VAS scale and VRS), erythema extension, thrombus size, oedema reduction, adverse events, investigator's and participant's assessment of efficacy.
Notes	Funding: study sponsored by CRO Opera S.r.L., Genoa, Italy. Disclosure of potential COI: authors reported to have no COI. Gianni Belcaro erased from the UK medical register in June 2007 for "misconduct," which seems to have been that he included as coauthors on his papers people who were not involved in the research. The General Medical Council report did not suggest that data were falsified webcache.gmc‐uk.org/minutesfiles/3313.HTML.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated: "The treatments were allocated according to a randomization list (randomization by blocks)."  Block allocation sequences created at random by using numbers generated by a computer program.
Allocation concealment (selection bias)	Low risk	Computer‐generated randomisation sequence. "Each subject enrolled into the study received the respective lowest randomization number available."
Blinding (performance bias and detection bias)   All outcomes	High risk	Single blind: "observer blinded design."
Incomplete outcome data (attrition bias)   All outcomes	High risk	14/150 (11.7%) dropped out, 68.3% completed treatment on day 7, 11.7% on day 14, and 8.3% had treatment failure.
Selective reporting (reporting bias)	High risk	Data not reported for all prespecified outcomes. DVT mentioned in methods but not reported in results or discussion.

Methods	Open‐label, masked endpoint, randomised, non‐inferiority phase 3b trial.
Participants	472 participants aged ≥ 18 years with symptomatic ST (≥ 5 cm in a supragenual superficial‐vein segment) and ≥ 1 additional risk factor for thromboembolic complications (aged ≥ 65 years, male sex, previous VTE, cancer, autoimmune disease, thrombosis of non‐varicose veins).
Interventions	Rivaroxaban (10 mg oral od). Fondaparinux (2.5 mg sc od). Study treatment given for 45 days.
Outcomes	Primary efficacy outcome: composite of symptomatic DVT or PE, progression or recurrence of ST, and all‐cause mortality at 45 days. Secondary efficacy outcomes: composite primary efficacy outcome at 90 days, incidence of each component of the primary efficacy outcome at 45 and 90 days; major VTE (symptomatic PE, symptomatic proximal DVT, or VTE‐related death) at days 45 and 90; and surgery for ST within 45 and 90 days of initiation of study drug treatment. Primary safety outcome: major bleeding. Secondary safety outcomes: clinically relevant non‐major bleeding, and minor bleeding within 45 days of initiation of treatment with study drug, censored 2 days after the last dose of study drug.
Notes	Funding: GWT‐TUD and Bayer Vital.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Adequate method of randomisation. Quote: "Randomisation was done with a central block randomisation process, with a random block sequence of four numbers per block."
Allocation concealment (selection bias)	Low risk	Participants and investigators could not foresee treatment allocation. Quote: "The generation of the allocation sequence to assign all patients to the two treatment groups and the allocation were done at the sponsor’s site by the study manager, who had no role in the trial or in data collection or analysis."
Blinding (performance bias and detection bias)   All outcomes	High risk	Open‐label study with blinded outcome assessment. Quote: "An independent committee, whose members were unaware of study group assignment, adjudicated the qualifying diagnosis, the anatomical extent of the initial superficial‐vein thrombosis, and all suspected outcomes."
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Primary analysis originally planned as ITT, but modified into a per‐protocol analysis during study. 36/471 (7.6%) participants randomised were excluded from the primary analysis but the authors reported results also according to the ITT principle. Quote: "The original study protocol specified that the primary efficacy analysis would be done in the intention‐to‐treat population; however, the protocol was changed by the steering committee on June 15, 2016, to specify analysis in the per‐protocol population."
Selective reporting (reporting bias)	Low risk	All outcome described in the methods and protocol were presented in the results.

Methods	Prospective, single‐centre, open‐label, randomised study.
Participants	73 outpatients with isolated superficial vein thrombosis of the legs. Thrombus length ≥ 5 cm and confirmed by compression ultrasonography. Mean age 56.3 years (SD 13.2) in compression stockings group and 60.3 years (SD 14.8) in control group.
Interventions	Thigh‐length compression stockings, class II (23‐32 mmHg; Venotrain, Bauerfeind, Zeulenroda, Germany) for 3 weeks. No compression.
Outcomes	Primary outcome: reduction of spontaneous and induced pain as assessed by a VAS and Lowenberg test. Secondary outcomes: consumption of analgesics, thrombus length, skin erythema, D‐dimer, and quality of life through the SF‐36. Main safety outcomes: symptomatic or asymptomatic DVT and HIT.
Notes	All participants received LMWH at prophylactic dosage (enoxaparin 40 mg/day). NSAIDs (mefenamic acid, diclofenac, and dexibuprofen) were allowed.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of sequence generation not reported. "The randomization procedure was performed in a 1:1 ratio in blocks of 20 with closed envelopes."
Allocation concealment (selection bias)	Unclear risk	Unclear if envelopes were sealed and sequentially numbered. "The randomization procedure was performed in a 1:1 ratio in blocks of 20 with closed envelopes, with the investigators not being aware of the sequence within the envelopes."
Blinding (performance bias and detection bias)   All outcomes	High risk	Open study.
Incomplete outcome data (attrition bias)   All outcomes	High risk	7/80 (8.7%) participants initially enrolled were excluded from the analysis due to missing data during follow‐up.
Selective reporting (reporting bias)	Low risk	All outcomes described in methods section were reported in results section of the study publication.

Methods	STEFLUX: multicentre, randomised, double‐blind, placebo‐controlled study.
Participants	664 consecutive outpatients with ≥ 4 cm long ST of long or short saphenous veins or their collaterals confirmed by CUS. ST of the long saphenous or short saphenous vein within 3 cm to, respectively, the sapheno‐femoral or sapheno‐popliteal junction were excluded. Median age 69 years (range 20‐94 years); males 37% (246/664).
Interventions	Intermediate‐dose LMWH (parnaparin 8500 IU od) for 10 days followed by placebo for 20 days. Intermediate‐dose LMWH (parnaparin 8500 IU od for 10 days followed by 6400 IU od for 20 days). Prophylactic‐dose LMWH (parnaparin 4250 IU od) for 30 days.
Outcomes	Primary efficacy outcomes: composite of symptomatic and asymptomatic DVT, symptomatic PE and relapse, symptomatic or asymptomatic SVT recurrence, or a combination in first 33 days. Secondary efficacy outcomes: reduction in local symptoms during treatment, combined efficacy endpoint during a follow‐up of 93 days after the start of treatment. Primary safety outcomes: major bleeding. Secondary safety outcomes: composite of minor bleeding, thrombocytopenia or any other adverse events (e.g. local allergic reactions).
Notes	Participants were instructed to wear graduated elastic stockings (knee high or thigh length) with a compression of 20‐40 mmHg at the ankle, unless contraindicated. Oral or topical NSAIDs were permitted for only 4 days after study inclusion. Only paracetamol, naproxen, or ibuprofen were allowed. Study prematurely interrupted according to predefined stopping rules. Funding: study supported by the non‐proﬁt organisation Angioclot in the Department of Angiology and Blood Coagulation, S. Orsola Malpighi University Hospital through an unrestricted grant by Alfa Wassermann, Bologna, Italy which had no input into study design; analysis and interpretation of data; writing of the report; and decision to submit the article for publication. Alfa Wassermann provided the study drug and placebo. Disclosure of potential COI: 3 authors including the lead author reported to have received consulting fees from Alfa Wasserman.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Central computer‐generated randomisation sequence: "The randomization sequence was computer generated centrally in blocks of six."
Allocation concealment (selection bias)	Low risk	Central computer‐generated randomisation sequence: "The randomization sequence was computer generated centrally in blocks of six and centers were provided with consecutively numbered boxes of identically appearing preﬁlled syringes."
Blinding (performance bias and detection bias)   All outcomes	Low risk	Double blind. "Consecutive outpatients were randomly assigned to receive in a double‐blind fashion one of the following subcutaneous treatments." "All primary and secondary outcomes were evaluated by a central adjudication committee, whose members were not involved in patient recruitment."
Incomplete outcome data (attrition bias)   All outcomes	High risk	16/664 (2.4%) participants excluded from the analysis, 8 lost to follow‐up.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes reported.