Treatment for superficial thrombophlebitis of the leg

  • Review
  • Intervention

Authors

  • Marcello Di Nisio,

    Corresponding author
    1. University "G. D'Annunzio" of Chieti-Pescara, Department of Medical, Oral and Biotechnological Sciences, Chieti, Italy
    2. Academic Medical Center, Department of Vascular Medicine, Amsterdam, Netherlands
    • Marcello Di Nisio, Department of Medical, Oral and Biotechnological Sciences, University "G. D'Annunzio" of Chieti-Pescara, via dei Vestini 31, Chieti, 66013, Italy. mdinisio@unich.it.

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  • Iris M Wichers,

    1. Healthcare Center Borgerstraat, Amsterdam, Netherlands
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  • Saskia Middeldorp

    1. Academic Medical Center, Department of Vascular Medicine, Amsterdam, Netherlands
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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 second 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 Trials Search Co-ordinator searched the Specialised Register (last searched November 2012) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 11). 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 participants 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.

Main results

We identified four additional trials (941 patients), so this update considered 30 studies involving 6462 participants with ST of the legs.Treatment ranged from fondaparinux, low molecular weight heparin (LMWH), unfractionated heparin (UFH), non-steroidal anti-inflammatory agents (NSAIDs), topical treatment, oral treatment, intramuscular treatment, and intravenous treatment to surgery. Only a minority of trials compared treatment with placebo rather than an alternative treatment, none evaluated the same treatment comparisons on the same study outcomes (which precluded meta-analysis), and many of the studies were small and of poor quality. In one large, placebo-controlled RCT of 3002 patients, subcutaneous fondaparinux was associated with a significant reduction in symptomatic VTE (RR 0.15; 95% CI 0.04 to 0.50), ST extension (RR 0.08; 95% CI 0.03 to 0.22), and ST recurrence (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. In a further placebo-controlled trial, both prophylactic and therapeutic doses of LMWH (RR 0.44; 95% CI 0.26 to 0.74 and RR 0.46; 95% CI 0.27 to 0.77, respectively) and NSAIDs (RR 0.46; 95% CI 0.27 to 0.78) 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 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 treatment, topical treatment, or surgery did not report VTE, ST progression, adverse events, or treatment side effects.

Authors' conclusions

Prophylactic dose fondaparinux given for 45 days appears to be a valid therapeutic option for ST of the legs. The evidence on oral treatments, topical treatment, or surgery is too limited and does not inform clinical practice about the effects of these treatments in terms of VTE and ST progression. Further research is needed to assess the role of the new oral direct thrombin and activated factor-X inhibitors, LMWH, and 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. 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 to prevent the extension of the clot into a deep vein, ST recurrence, or the development of more serious events caused by VTE.

This review included 30 randomised controlled trials involving 6462 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 half of the patients included in the review, showed that treatment with fondaparinux for 45 days was associated with a significant reduction in symptomatic VTE, ST 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.

Fondaparinux appears to be an adequate treatment option in patients with ST. Further research is needed to assess the role of low molecular weight heparin or NSAIDs and to demonstrate the efficacy, if any, of oral treatments, topical treatment, or surgery in terms of VTE and ST progression.

Background

Description of the condition

The term superficial thrombophlebitis (ST), also known as superficial venous thrombosis, refers to a pathological state characterized 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). Predisposing risk factors for ST and venous thromboembolism (VTE) are similar and include varicose veins, immobilization, trauma, postoperative states, pregnancy, puerperium (the period immediately following childbirth), active malignancy, auto-immune diseases, use of oral contraceptives 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 1990b). 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; 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 patients were referred for suspected DVT. In a recent cross-sectional and prospective epidemiologic cohort study, ST at diagnosis was associated with VTE in 25% of the cases (Decousus 2010). During a three-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.

Description of the intervention

There is no consensus on the optimal treatment of ST in clinical practice. Several therapies have been proposed in the literature, including surgical therapy (ligation or stripping of the affected 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 ligation (crossectomy) would be the emergency surgical treatment option. It is not clear 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.

Why it is important to do this review

While the estimates of VTE prevalence in patients with ST vary, management of ST should consider the prevention of this scaring complication beyond the mere resolution of local symptoms (Decousus 2010; 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 risks, such as (major) bleeding events with anticoagulants.

Objectives

To review 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 participants with a diagnosis of ST of the lower extremities based on signs and symptoms of ST (for example pain, tenderness, induration (hardening of the tissue), or erythema (reddening of the skin) in a superficial vein) and clinical signs (palpation), and objective diagnosis of the thrombus in the superficial vein by means of ultrasound scanning of the lower limbs 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 (for example NSAIDs or anticoagulants such as fondaparinux, low molecular weight heparin (LMWH)), and surgical intervention (for example 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 (including the combined 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 (for example pain);

  • signs (for example induration and erythema);

  • quality of life (assessed by means of disease-specific and non-specific questionnaires);

  • mortality;

  • side effects of treatment (for example, 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 patients with ST of the legs. There was no restriction on language.

Electronic searches

For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched November 2012) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 11), part of The Cochrane Library at www.thecochranelibrary.com. See Appendix 1 for details of the search strategy used to search CENTRAL. The Specialised Register is maintained by the TSC and is constructed from weekly electronic searches of MEDLINE, EMBASE, CINAHL, and AMED, and through handsearching relevant journals. The full list of the databases, journals, and conference proceedings which have been searched, as well as the search strategies used, are described in the Specialised Register section of the Cochrane Peripheral Vascular Diseases (PVD) Group module in The Cochrane Library (www.thecochranelibrary.com).

Searching other resources

We searched reference lists of relevant papers and conference proceedings of the International Society for Thrombosis and Hemostasis (2003 to 2011) and American Society of Haematology (2004 to 2011), 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 any disagreement was resolved through discussion or involvement of a third review author (SM). We independently reviewed the full text of identified articles, including those where there was disagreement in the initial title or abstract scanning, 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

We (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 review author (SM). For any study published twice, we extracted the data from the more complete study. Collected information included methodological quality, characteristics of patients, type of intervention and control, and outcomes.

Assessment of risk of bias in included studies

Two review authors independently assessed randomisation, blinding, and adequacy of analyses (Juni 2001). Disagreements were resolved 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 patients according to date of birth, were considered quasi-randomised.

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

Blinding of patients 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 patients were included in the analysis according to the intention-to-treat 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. We planned to use GRADE to describe the quality of the overall body of evidence (Guyatt 2008; Higgins 2011); however, due to the heterogeneity between the studies in terms of treatment comparisons and study outcomes the GRADE approach was considered not informative and therefore omitted from the review.

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 I2 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 relative risks (RR) for dichotomous variables and standardised mean differences (SMD) for all continuous variables. We determined the 95% confidence interval (CI) for each estimate. Where possible, we analysed the results by intention to treat, including every individual in the randomly assigned treatment group regardless of whether they completed the treatment or withdrew from the trial.

We evaluated 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 assessed asymmetry by 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.

The data analysis was performed in RevMan 5 (Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen).

Results

Description of studies

See Characteristics of included studies; Characteristics of excluded studies

Results of the search

For this update, six potentially relevant citations were obtained from the search of the PVD Group Specialised Register and from the CENTRAL search. Following screening of titles and abstracts (if available) full copies of five reports relating to five studies were obtained. Of these, four studies met the review inclusion criteria (Belcaro 2011; Cosmi 2012; Rathbun 2012; Winter 1986). One study could be retrieved only as an abstract and it is still awaiting classification (Bijuan 2003).

Included studies

Four additional studies were included in the updated review (Belcaro 2011; Cosmi 2012; Rathbun 2012; Winter 1986) and in total 30 studies involving 6462 participants were included in the review (Andreozzi 1996; Anonymous 1970; Archer 1977; Belcaro 1989; Belcaro 1990; Belcaro 1999; Belcaro 2011; Cosmi 2012; Decousus 2010a; De Sanctis 2001; Ferrari 1992; Gorski 2005; Holzgreve 1989; Incandela 2001; Katzenschlager 2003; Koshkin 2001; Kuhlwein 1985; Lozano 2003; Marchiori 2002; Marshall 2001; Messa 1997; Nocker 1991; Nusser 1991; Pinto 1992; Rathbun 2012; Stenox Group 2003; Titon 1994; Uncu 2009; Vesalio Group 2005; Winter 1986). One study is still ongoing (Rabe 2009). In nine studies data were reported for 50 patients or less, in eleven trials patients were between 50 to 100 patients, and in ten studies data were available for 100 patients or more.

Interventions and comparisons varied greatly among the studies. Nine trials included a topical treatment group (Belcaro 2011; De Sanctis 2001; Gorski 2005; Holzgreve 1989; Incandela 2001; Katzenschlager 2003; Nocker 1991; Pinto 1992; Winter 1986); three studies a surgical treatment group (Belcaro 1989; Belcaro 1999; Lozano 2003); 13 LMWH (Belcaro 1989; Belcaro 1990; Belcaro 1999; Cosmi 2012; Gorski 2005; Katzenschlager 2003; Lozano 2003; Marchiori 2002; Rathbun 2012; Stenox Group 2003; Titon 1994; Uncu 2009; Vesalio Group 2005); six NSAIDs (Anonymous 1970; Ferrari 1992; Nusser 1991;Rathbun 2012; Stenox Group 2003; Titon 1994); one fondaparinux (Decousus 2010a); and eight studies evaluated another oral (Archer 1977; Belcaro 1989; Belcaro 1999; Kuhlwein 1985; Koshkin 2001; Messa 1997), intramuscular (Andreozzi 1996), or intravenous (Marshall 2001) treatment.

Excluded studies

Overall 34 studies were excluded from the review. The reasons for exclusion are listed in the table Characteristics of excluded studies. Twenty 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; 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 patients without a diagnosis of ST of the legs (Bernicot 1980; Gandhi 1984; Resta 1967; van Cauwenberge 1972) and two studies included patients with DVT (Di Perri 1986; Rea 1981). In one study it was unclear whether the study was randomised or not (Giorgetti 1990). Five studies included patients with ST of the arm (Gouping 2003; Mehta 1975; Rozsos 1994; Stolle 1986; van der Knaap 1988) and in one study the evaluated outcomes were not among those considered in the present review (Ibanez-Bermudez 1996).

Risk of bias in included studies

Details of the methodological quality for each trial are reported in the table Characteristics of included studies. A risk of bias summary is presented in Figure 1.

Figure 1.

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

Allocation

The randomisation sequence was adequately generated in 11 studies (Belcaro 2011; Cosmi 2012; Decousus 2010a; Gorski 2005; Katzenschlager 2003; Marchiori 2002; Marshall 2001; Messa 1997; Rathbun 2012; Vesalio Group 2005; Winter 1986), not adequate in one (Uncu 2009), and unclear in the remaining 18 studies. Allocation was adequately concealed in six studies (Belcaro 2011; Cosmi 2012; Decousus 2010a; Marshall 2001; Rathbun 2012; Stenox Group 2003), and unclear in the remaining 24 studies.

Blinding

Twelve studies did not attempt to blind the assessment of the outcomes or did not report whether blinding was used or not, 10 studies had a double-blinded design (Cosmi 2012; Decousus 2010a; De Sanctis 2001; Incandela 2001; Marshall 2001; Nusser 1991; Pinto 1992; Rathbun 2012; Stenox Group 2003; Vesalio Group 2005), and in eight studies it was unclear whether blinding was attempted or not (Anonymous 1970; Archer 1977;Ferrari 1992; Koshkin 2001; Kuhlwein 1985; Marchiori 2002; Nocker 1991; Winter 1986).

Incomplete outcome data

Seven studies performed the analysis according to the intention-to-treat principle (Decousus 2010a; 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 patients randomised and subsequently excluded from the analysis ranged from 2% to 33% (Anonymous 1970; Archer 1977; Belcaro 1989; Belcaro 1999; Belcaro 2011; Cosmi 2012; Ferrari 1992; Gorski 2005; Holzgreve 1989; Katzenschlager 2003; Lozano 2003; Marshall 2001; Stenox Group 2003; Titon 1994).

Selective reporting

All studies were judged to be free of selective reporting except the studies of Anonymous 1970, Belcaro 2011, Lozano 2003, and Uncu 2009 which did not provide data on some of the specified outcomes and Winter 1986, which was reported as an abstract only and did not pre-specify outcomes.

Effects of interventions

None of the studies evaluated similar treatments on the same study outcomes. Treatment ranged from fondaparinux, LMWH, unfractionated heparin (UFH), NSAIDs, topical treatment, oral treatment, intramuscular treatment, and intravenous treatment to surgery.

Fondaparinux

The CALISTO study, a large double-blinded, placebo-controlled RCT, evaluated a prophylactic dose (2.5 mg sc once daily) of fondaparinux given for 45 days (Decousus 2010a). The primary efficacy outcome of this RCT (that is, the composite of death from any cause, symptomatic 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 to 0.26) with a number needed to treat (NNT) of 20. The incidence of each component of the primary efficacy outcome was significantly reduced in the fondaparinux group as compared with the placebo group except for the incidence of death, which did not differ significantly between the two groups (see Analysis 1.6). The risk of the composite of symptomatic DVT or PE was reduced by 85% with fondaparinux as compared with placebo (RR 0.15; 95% CI 0.04 to 0.50) with a NNT of 88. Fondaparinux was associated with lower rates of 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). By day 47, major bleeding had occurred in one patient (0.1%) in each group (RR 0.99; 95% CI 0.06 to 15.86; P = 1.00). The rate of clinically relevant non-major, minor, and total bleeding and arterial thromboembolic complications did not differ significantly between the two groups.

Low molecular weight heparin (LMWH) and unfractionated heparin (UFH)

Thirteen studies included a LMWH group (Belcaro 1989; Belcaro 1990; Belcaro 1999; Cosmi 2012; Gorski 2005; Katzenschlager 2003; Lozano 2003; Marchiori 2002; Rathbun 2012; Stenox Group 2003; Titon 1994; Uncu 2009; Vesalio Group 2005).

Although not statistically significant, the incidence of VTE tended to be lower with both prophylactic and therapeutic LMWH compared with placebo shortly after treatment (RR 0.25; 95% CI 0.03 to 2.24 and RR 0.26; 95% CI 0.03 to 2.33, respectively) but not at the end of the three-month follow-up (RR 1.22; 95% CI 0.38 to 3.89 and RR 0.85; 95% CI 0.23 to 3.06, respectively), suggesting a catch-up phenomenon (Stenox Group 2003). Prophylactic and therapeutic LMWH given for eight to 12 days significantly reduced ST extension or recurrence, or both, compared with placebo (RR 0.44; 95% CI 0.26 to 0.74 and RR 0.46; 95% CI 0.27 to 0.77, respectively). No episodes of major bleeding or heparin-induced thrombocytopenia (HIT) were observed in any treatment group (Stenox Group 2003).

Combined therapy with LMWH plus elastic compression stockings seemed to reduce the incidence of VTE and ST extension or recurrence, or both, compared with elastic stockings alone (RR 0.08; 95% CI 0.00 to 1.38 and RR 0.08; 95% CI 0.01 to 0.59, respectively), although the former difference was not statistically significant (Belcaro 1999). In this study no data were provided on safety outcomes.

Two studies (Gorski 2005; Katzenschlager 2003) randomised patients to topical treatment with heparin spray gel or LMWH. A non-significant decrease in DVT was found with LMWH (RR 0.30; 95% CI 0.03 to 2.70) while local symptoms were similarly relieved by both treatments at 21 days (Gorski 2005).

LMWH versus surgical treatment (saphenofemoral disconnection) was evaluated in one study (Lozano 2003). A comparable reduction of VTE events and a similar safety profile were observed in the two study groups. Surgery seemed to be associated with a lower risk of ST extension or recurrence, or both, although the differences were not statistically significant (RR 0.33; 95% CI 0.04 to 3.03).

LMWH was evaluated against NSAIDs in three studies (Rathbun 2012; Stenox Group 2003; Titon 1994). Fixed-dose LMWH and weight-adjusted LMWH seemed to produce a similar reduction in VTE (RR 0.93; 95% CI 0.24 to 3.63) and ST recurrence relative to NSAIDs (RR 1.01; 95% CI 0.58 to 1.78). In the study by Rathbun 2012 there was one case of ST progression into the posterior tibial veins and one symptomatic PE, both in the LMWH group. Rathbun 2012 was not pooled with the other two studies for the outcome VTE since the administration of therapeutic LMWH in any patient with thrombus progression during follow-up could have introduced significant confounding. In Stenox Group 2003, which used placebo as a control group, an indirect comparison between prophylactic LMWH and NSAIDs suggested a non-statistically significant reduction in VTE at the end of treatment (RR 0.45; 95% CI 0.04 to 4.89). No major bleeding events nor HIT occurred within the LMWH or NSAIDs groups. Rathbun 2012 reported two episodes of cutaneous rash with LMWH. In addition, a significant reduction in pain was reported in both the LMWH and NSAIDs groups without differences between the two groups.

One study compared LMWH alone versus LMWH combined with the anti-inflammatory agent acemetacin (Uncu 2009). There were no cases of VTE, extension of ST, nor major bleeding in either study group. Combined LMWH plus acemetacin was associated with a significant 10% reduction in pain (mean difference 0.90; 95% CI 0.18 to 1.62).

Two studies compared different regimens of LMWH head-to-head but without using a placebo or inactive control group (Cosmi 2012; Vesalio Group 2005). In Cosmi 2012 (the STEFLUX study), the incidence of symptomatic VTE at the end of treatment and at the three-month follow-up was not different in the 30-day intermediate dose LMWH and 30-day prophylactic dose LMWH groups (see Analysis 4.1; Analysis 4.2), and it was lower in the 30-day intermediate dose LMWH compared with the 10-day intermediate dose LMWH (0.46% versus 4.72%, RR 0.10; 95% CI 0.01 to 0.75; and 1.82% versus 5.19%, RR 0.35; 95% CI 0.11 to 1.09, respectively). At the three-month follow-up, symptomatic PE had occurred in none of the patients of the 30-day intermediate dose group and in one patient of both the 10-day intermediate and 30-day prophylactic dose LMWH groups. The incidence of symptomatic DVT did not differ between the three groups (see Analysis 4.4; Analysis 5.4; Analysis 6.4). ST extension at three months was significantly reduced by the 30-day intermediate dose LMWH in comparison to both the 30-day prophylactic (2.28% versus 8.29%, RR 0.28; 95% CI 0.10 to 0.73) and 10-day intermediate dose LMWH (10.38%, RR 0.22; 95% CI 0.08 to 0.57) while recurrence of ST was similar in the 30-day intermediate dose LMWH and the other two groups (see Analysis 4.6; Analysis 6.6). There were no cases of major bleeding nor HIT. The intensity of local symptoms evaluated by visual analogue scales was comparable in the 30-day intermediate, 10-day intermediate, and the 30-day prophylactic dose LMWH at the start of treatment (5.0, 5.1, 5.1; P = 0.97) as well as at the end of treatment (0.7, 0.6, 0.8; P = 0.10) and at three months (0.2, 0.3, 0.4; P = 0.47). Allergic reactions occurred in 0.4%, 1.4%, and 0%, respectively.

In the Vesalio Group 2005, one-month of weight-adjusted full therapeutic dose of LMWH or fixed prophylactic dose LMWH led to a similar reduction in ST extension or recurrence, or VTE (RR 1.20; 95% CI 0.42 to 3.40) over a three-month follow-up. In the prophylactic dose LMWH group most of the VTE events (77%) occurred while patients were still on treatment, whereas only 33% of patients on therapeutic dose LMWH developed VTE during LMWH administration. This advantage was lost after drug discontinuation with no difference at the end of the study period. No major bleeding nor HIT were observed during the study. Local symptoms and signs regressed faster with therapeutic dose LMWH although the difference was not statistically significant.

Subcutaneous (sc) UFH at prophylactic doses was used as the comparator treatment in two studies (Belcaro 1999; Marchiori 2002). Relative to elastic stockings alone, prophylactic sc UFH plus elastic stockings was associated with a non-statistically significant lower VTE rate (RR 0.08; 95% CI 0.00 to 1.47) and a 83% reduction in ST extension or recurrence (RR 0.17; 95% CI 0.04 to 0.72) (Belcaro 1999). 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) and a 27% (RR 0.73; 95% CI 0.34 to 1.55) reduced rate of ST extension or recurrence were observed among patients treated with high-dose UFH (Marchiori 2002). There were no episodes of major bleeding or HIT in either study group.

Subcutaneous calcium heparin was evaluated in two studies (Belcaro 1989; Belcaro 1990). The combination of elastic stockings plus calcium heparin did not significantly improve local symptoms and signs compared with elastic stockings alone. Treatment with calcium heparin was correlated with a faster reduction of the analogue score and the area at maximum temperature than with defibrotide, although the difference was not significant. There were no side effects.

Non-steroidal anti-inflammatory drugs (NSAIDs)

Six studies included a NSAID group (Anonymous 1970; Ferrari 1992; Nusser 1991; Rathbun 2012; Stenox Group 2003; Titon 1994). Of these, two compared NSAIDs with placebo (Anonymous 1970; Stenox Group 2003), three with LMWH (Rathbun 2012; Stenox Group 2003; Titon 1994), and two randomised patients to two different NSAIDs (Ferrari 1992; Nusser 1991). The trials comparing NSAIDs versus LMWH have been discussed previously (Rathbun 2012; Stenox Group 2003; Titon 1994).

NSAIDs significantly reduced the risk of ST extension or recurrence, or both, by 54% (RR 0.46; 95% CI 0.27 to 0.78) compared with placebo (Stenox Group 2003). However, there were no differences in the incidence of VTE or in the resolution of local symptoms and signs. While no major bleeding episodes were recorded in any of the NSAID or placebo groups, indomethacin carried a significantly higher rate of side effects compared with placebo (RR 2.60; 95% 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). Local 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) although this difference was not statistically significant (Ferrari 1992).

Topical treatment

Nine studies included a topical treatment group (Belcaro 2011; De Sanctis 2001; Gorski 2005; Holzgreve 1989; Incandela 2001; Katzenschlager 2003; Nocker 1991; Pinto 1992; Winter 1986). The comparison of heparin spray gel versus LMWH has been discussed earlier (Gorski 2005; Katzenschlager 2003).

Belcaro 2011 randomised patients to three doses of an heparin spray gel versus placebo for seven to 14 days. After one week, heparin spray gel was associated with a significant reduction in pain assessed by the visual analogue scale (VAS) (-93.13 versus -61.35; P < 0.0001), a lower erythema extension (-92% versus -26%; P < 0.012), and thrombus length (-40.81 versus -4.22; P < 0.0001). No adverse events or drug related reactions were reported by the authors.

One study randomised patients to receive topical methylthioadenosine or placebo (Pinto 1992). Methylthioadenosine was associated with a non-significant reduction in local signs and symptoms relative to placebo.

In a similar way, a significant improvement in the local symptomatology was observed with diclofenac gel (Nocker 1991) and essaven gel (De Sanctis 2001; Incandela 2001) compared with placebo.

Holzgreve 1989 and Winter 1986 compared two different types of gel. Holzgreve 1989 evaluated diclofenac gel versus etofenak gel and showed a comparable efficacy profile of the two topical medications. Winter 1986 compared diclofenac gel and heparin gel and found a better efficacy with the former.

None of the studies evaluating a topical treatment reported data on VTE or ST recurrence.

Surgery

Three studies included a surgical treatment (Belcaro 1989; Belcaro 1999; Lozano 2003). As described above, one study compared surgery (saphenofemoral disconnection) with LMWH (Lozano 2003). In the remaining two studies surgery combined with elastic stockings was compared with elastic stockings alone (Belcaro 1989; Belcaro 1999).

In the first trial, thrombectomy plus elastic stockings with or without venoruton led to an improvement of the local clinical signs and a greater reduction in the number of veins with ST compared with elastic compression bandages alone (Belcaro 1989). There were no cases of DVT in either study group. In the second trial, ligation of the vein plus elastic stockings was associated with a non-significant reduction in VTE events (RR 0.33; 95% CI 0.07 to 1.60) and ST recurrence and extension (RR 0.46; 95% CI 0.18 to 1.15) relative to the control treatment (Belcaro 1999).

Compared with elastic stockings alone, venous stripping plus elastic stockings decreased the risk of ST extension and recurrence (RR 0.09; 95% CI 0.01 to 0.64) and seemed to be associated with a lower, while non-significant incidence of VTE (RR 0.37; 95% CI 0.08 to 1.78) (Belcaro 1999).

Other

Eight studies evaluated an oral (Archer 1977; Belcaro 1989; Belcaro 1999; Koshkin 2001; Kuhlwein 1985; Messa 1997), intramuscular (Andreozzi 1996), or intravenous (Marshall 2001) treatment.

Compared with placebo, oral vasotonin was associated with a higher proportion of patients who were cured or improved (Kuhlwein 1985). The criteria to determine the response to study treatment were not described. Vasotonin seemed to be well tolerated, with one case of poor tolerability among patients treated with vasotonin (3%) versus five cases (13%) in the placebo arm (RR 0.20; 95% CI 0.02 to 1.63).

The combination of venoruton, thrombectomy, and elastic stockings versus elastic stockings alone has been discussed above (Belcaro 1989). In the same trial, venoruton combined with elastic stockings led to an improvement of local symptoms compared with elastic stockings alone.

One study evaluating oral heparansulphate versus oral sulodexide suggested a greater decrease in local pain, itching, and redness in patients receiving oral heparansulphate than in the group receiving sulodexide (Messa 1997).

Compared with placebo, oxyphenbutazone reduced local tenderness four-fold and halved the intensity of pain and erythema (Archer 1977).

Oral vitamin K antagonists in combination with elastic stockings were evaluated in one study, which suggested a non-significant reduction in VTE events (RR 0.08; 95% CI 0.00 to 1.47) and ST extension or recurrence (RR 0.42; 95% CI 0.16 to 1.13) with the use of vitamin K antagonists and elastic stockings relative to elastic stockings alone (Belcaro 1999).

Two studies addressed the use of enzyme therapy versus placebo (Koshkin 2001; Marshall 2001). Enzyme treatment seemed to improve local symptoms although the criteria to evaluate the response to study treatment were not reported.

The efficacy of three doses of desmin was assessed in one trial (Andreozzi 1996). A better control of local symptoms was obtained with higher doses of desmin without any increase in the risk of adverse events.

Discussion

A lot of controversy still exists around the optimal treatment of ST of the legs. The therapeutic approach for ST should aim at the resolution or improvement of the local symptoms but also, and even more importantly, at preventing the possible extension of the superficial vein thrombosis into the deep venous system (Wichers 2005).

This review summarised data from 6462 patients with ST of the legs. About half of the participants were included in the CALISTO study, which compared 45 days of fondaparinux versus placebo in a double-blinded fashion (Decousus 2010a). Fondaparinux reduced the incidence of symptomatic VTE by 85%, ST extension by 92%, and the recurrence of ST by 79%. A total of 88 patients would need to be treated with fondaparinux to prevent one PE or DVT. These benefits were achieved without increasing the risk of bleeding and they were maintained at the one-month follow-up after discontinuation of treatment.

Compared with placebo or topical treatments, both NSAIDs and LMWH could help preventing ST extension while effectively 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 worsening of ST. However, these conclusions need to be taken cautiously due to the methodological drawbacks, the low incidence of VTE, and the sample size of the available studies, which did not have enough power for a direct comparison between LMWH and NSAIDs. Thus, these data remain preliminary and further research 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 should be balanced against the associated side effects such as bleeding and gastric complications. None of the studies reported major bleeding episodes in patients randomised to LMWH. NSAIDs increased three-fold the risk of gastric pain compared with placebo. To date, no study has evaluated NSAIDs versus surgery whereas one trial directly compared LMWH with surgical treatment, showing a comparable efficacy and safety (Lozano 2003). Despite the methodological limitations of this study its results would suggest that a medical approach with LMWH would be as effective and safe as an invasive surgical treatment.

Cosmi 2012 and Vesalio Group 2005 compared different regimens of LMWH head-to-head. While symptomatic VTE occurred at a similar rate with prophylactic and higher (intermediate or therapeutic) dose LMWH, the latter seemed to be associated with a significant 70% reduction in ST progression (Cosmi 2012). Furthermore, the findings of Cosmi 2012 suggest that treatment with LMWH should be prolonged for at least 30 days to reduce the incidence of symptomatic VTE, compared to shorter usage of LMWH. It should be noted, however, that neither Cosmi 2012 nor Vesalio Group 2005 had a placebo or inactive control group and Cosmi 2012 was prematurely interrupted, which may have led to an overestimation of the differences between the groups.

Preliminary data suggest that high-dose UFH can be effective in the treatment of ST although this needs to be confirmed in larger studies (Marchiori 2002). While not directly evaluated against UFH, fondaparinux and LMWH may still be preferable due to the easier mode of administration and the more predictable response not requiring laboratory monitoring as for UFH.

Most of the studies comparing oral treatment, topical treatment, or surgery did not report VTE, ST progression, adverse events, or treatment side effects. In addition, the methodological quality of these studies was often poor, with major study design flaws such as an unclear method of allocation or randomisation, the lack of a placebo as control group, or an unacceptably high dropout rate. All these limitations weaken the clinical applicability of the results and cast doubts about the actual efficacy and safety of these treatments.

Summary of main results

Fondaparinux is associated with a significant lower incidence of VTE, ST extension, or ST recurrence relative to placebo with similar risk of bleeding. As compared to placebo, LMWH and NSAIDs appear to reduce the extension or recurrence of ST, or both, whereas the available data do not show any significant effect on VTE. The evidence on oral treatments, topical treatment, or surgery is too limited and does not inform clinical practice about the effects of these treatments in terms of VTE and ST progression.

Quality of the evidence

Our systematic approach to searching, study selection, and data extraction followed that of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The methodological quality of the included studies varied from low to high (See Figure 1). Poor reporting did not allow proper scoring of relevant study design features, such as sequence generation and allocation concealment, in the majority of included studies.

Potential biases in the review process

One limitation of this review is that, despite the relatively large number of comparisons found, only few studies compared the same treatment on the same study outcomes. The 'no difference' findings on a specific outcome may thus be the result of insufficient power of the analysis to show a difference between treatment groups as well as the absence of a true effect. For similar reasons, it was not possible to conduct subgroup analyses for the primary efficacy outcomes to evaluate the interaction of trial characteristics with treatment effects.

Agreements and disagreements with other studies or reviews

Since our previous systematic review on the prevention of VTE in patients with ST (Wichers 2005), the results of a large RCT on the efficacy of fondaparinux for the treatment of ST have become available (Decousus 2010a). The high methodological quality and the size of that study, which alone accounts for half of the overall review population, makes it a landmark investigation in the field.

Authors' conclusions

Implications for practice

Given the available evidence, prophylactic dose fondaparinux appears to be a valid treatment option in patients with ST. Fondaparinux should be given at a dose of 2.5 mg sc once daily for 45 days. 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, and parenteral treatments evaluated this far.

Implications for research

Several questions about the treatment of ST remain unsolved. Additional studies should evaluate the costs, effects on quality of life, and the cost-effectiveness of fondaparinux before recommending its routine use in the treatment of ST (Goldman 2010). Until 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 would be required to assess the actual role of NSAIDs and LMWH, and how these drugs compare with fondaparinux. Whether topical treatment might add some benefit if given in combination with fondaparinux remains unclear. Finally, adapting the treatment based on the location and the etiology of ST warrants further investigation.

Acknowledgements

We would like to thank the external peer referee Dr Benilde Cosmi for her comments and Mrs Carole Gibson for acting as the consumer on this review. We would also like to thank the Cochrane Consumer Network for their contribution to the Plain Language Summary. We would like to thank the personnel from the Cochrane Peripheral Vascular Diseases Review group, especially Marlene Stewart and Karen Welch for their invaluable assistance and advice.

Data and analyses

Download statistical data

Comparison 1. Fondaparinux versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Pulmonary embolism1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Deep vein thrombosis1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Deep vein thrombosis and pulmonary embolism1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
4 Extension of ST1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
5 Recurrence of ST1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
6 Mortality1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
7 Major bleeding1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
8 Clinically relevant non-major bleeding1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
9 Minor bleeding1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
10 Arterial thromboembolic complication1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
11 Any adverse event1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
12 Non-fatal serious adverse event1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 1.1.

Comparison 1 Fondaparinux versus placebo, Outcome 1 Pulmonary embolism.

Analysis 1.2.

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

Analysis 1.3.

Comparison 1 Fondaparinux versus placebo, Outcome 3 Deep vein thrombosis and pulmonary embolism.

Analysis 1.4.

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

Analysis 1.5.

Comparison 1 Fondaparinux versus placebo, Outcome 5 Recurrence of ST.

Analysis 1.6.

Comparison 1 Fondaparinux versus placebo, Outcome 6 Mortality.

Analysis 1.7.

Comparison 1 Fondaparinux versus placebo, Outcome 7 Major bleeding.

Analysis 1.8.

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

Analysis 1.9.

Comparison 1 Fondaparinux versus placebo, Outcome 9 Minor bleeding.

Analysis 1.10.

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

Analysis 1.11.

Comparison 1 Fondaparinux versus placebo, Outcome 11 Any adverse event.

Analysis 1.12.

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

Comparison 2. Prophylactic LMWH versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Venous thromboembolism end-of-treatment1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Venous thromboembolism 3-month follow up1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Extension and/or recurrence of ST1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
4 Major bleeding1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
5 Heparin-induced thrombocytopenia1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 2.1.

Comparison 2 Prophylactic LMWH versus placebo, Outcome 1 Venous thromboembolism end-of-treatment.

Analysis 2.2.

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

Analysis 2.3.

Comparison 2 Prophylactic LMWH versus placebo, Outcome 3 Extension and/or recurrence of ST.

Analysis 2.4.

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

Analysis 2.5.

Comparison 2 Prophylactic LMWH versus placebo, Outcome 5 Heparin-induced thrombocytopenia.

Comparison 3. Therapeutic LMWH versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Venous thromboembolism end-of-treatment1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Venous thromboembolism 3-month follow up1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Extension and/or recurrence of ST1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
4 Major bleeding1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
5 Heparin-induced thrombocytopenia1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 3.1.

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

Analysis 3.2.

Comparison 3 Therapeutic LMWH versus placebo, Outcome 2 Venous thromboembolism 3-month follow up.

Analysis 3.3.

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

Analysis 3.4.

Comparison 3 Therapeutic LMWH versus placebo, Outcome 4 Major bleeding.

Analysis 3.5.

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

Comparison 4. Thirty-day prophylactic LMWH versus 30-day intermediate LMWH
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Venous thromboembolism end-of-treatment1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Venous thromboembolism 3-month follow-up1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Symptomatic DVT end-of-treatment1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
4 Symptomatic DVT 3-month follow-up1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
5 Extension of ST 3-month follow-up1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
6 Recurrence of ST 3-month follow-up1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 4.1.

Comparison 4 Thirty-day prophylactic LMWH versus 30-day intermediate LMWH, Outcome 1 Venous thromboembolism end-of-treatment.

Analysis 4.2.

Comparison 4 Thirty-day prophylactic LMWH versus 30-day intermediate LMWH, Outcome 2 Venous thromboembolism 3-month follow-up.

Analysis 4.3.

Comparison 4 Thirty-day prophylactic LMWH versus 30-day intermediate LMWH, Outcome 3 Symptomatic DVT end-of-treatment.

Analysis 4.4.

Comparison 4 Thirty-day prophylactic LMWH versus 30-day intermediate LMWH, Outcome 4 Symptomatic DVT 3-month follow-up.

Analysis 4.5.

Comparison 4 Thirty-day prophylactic LMWH versus 30-day intermediate LMWH, Outcome 5 Extension of ST 3-month follow-up.

Analysis 4.6.

Comparison 4 Thirty-day prophylactic LMWH versus 30-day intermediate LMWH, Outcome 6 Recurrence of ST 3-month follow-up.

Comparison 5. Thirty-day prophylactic LMWH versus 10-day intermediate LMWH
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Venous thromboembolism end-of-treatment1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Venous thromboembolism 3-month follow-up1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Symptomatic DVT end-of-treatment1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
4 Symptomatic DVT 3-month follow-up1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
5 Extension of ST 3-month follow-up1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
6 Recurrence of ST 3-month follow-up1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 5.1.

Comparison 5 Thirty-day prophylactic LMWH versus 10-day intermediate LMWH, Outcome 1 Venous thromboembolism end-of-treatment.

Analysis 5.2.

Comparison 5 Thirty-day prophylactic LMWH versus 10-day intermediate LMWH, Outcome 2 Venous thromboembolism 3-month follow-up.

Analysis 5.3.

Comparison 5 Thirty-day prophylactic LMWH versus 10-day intermediate LMWH, Outcome 3 Symptomatic DVT end-of-treatment.

Analysis 5.4.

Comparison 5 Thirty-day prophylactic LMWH versus 10-day intermediate LMWH, Outcome 4 Symptomatic DVT 3-month follow-up.

Analysis 5.5.

Comparison 5 Thirty-day prophylactic LMWH versus 10-day intermediate LMWH, Outcome 5 Extension of ST 3-month follow-up.

Analysis 5.6.

Comparison 5 Thirty-day prophylactic LMWH versus 10-day intermediate LMWH, Outcome 6 Recurrence of ST 3-month follow-up.

Comparison 6. Thirty-day intermediate LMWH versus 10-day intermediate LMWH
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Venous thromboembolism end-of-treatment1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Venous thromboembolism 3-month follow-up1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Symptomatic DVT end-of-treatment1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
4 Symptomatic DVT 3-month follow-up1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
5 Extension of ST 3-month follow-up1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
6 Recurrence of ST 3-month follow-up1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 6.1.

Comparison 6 Thirty-day intermediate LMWH versus 10-day intermediate LMWH, Outcome 1 Venous thromboembolism end-of-treatment.

Analysis 6.2.

Comparison 6 Thirty-day intermediate LMWH versus 10-day intermediate LMWH, Outcome 2 Venous thromboembolism 3-month follow-up.

Analysis 6.3.

Comparison 6 Thirty-day intermediate LMWH versus 10-day intermediate LMWH, Outcome 3 Symptomatic DVT end-of-treatment.

Analysis 6.4.

Comparison 6 Thirty-day intermediate LMWH versus 10-day intermediate LMWH, Outcome 4 Symptomatic DVT 3-month follow-up.

Analysis 6.5.

Comparison 6 Thirty-day intermediate LMWH versus 10-day intermediate LMWH, Outcome 5 Extension of ST 3-month follow-up.

Analysis 6.6.

Comparison 6 Thirty-day intermediate LMWH versus 10-day intermediate LMWH, Outcome 6 Recurrence of ST 3-month follow-up.

Comparison 7. Fixed-dose LMWH versus weight-adjusted LMWH
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 ST or venous thromboembolism1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Venous thromboembolism2238Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.10, 2.72]
3 Superficial thrombophlebitis1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
4 Swelling disappearance1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
5 Tenderness disappearance1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
6 Pain disappearance1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
7 Pitting oedema disappearance1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
8 Collateral veins disappearance1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
9 Redness disappearance1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
10 Palpable cord disappearance1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
11 Major bleeding2238Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
12 Heparin-induced thrombocytopenia2238Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.07, 16.11]
Analysis 7.1.

Comparison 7 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 1 ST or venous thromboembolism.

Analysis 7.2.

Comparison 7 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 2 Venous thromboembolism.

Analysis 7.3.

Comparison 7 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 3 Superficial thrombophlebitis.

Analysis 7.4.

Comparison 7 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 4 Swelling disappearance.

Analysis 7.5.

Comparison 7 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 5 Tenderness disappearance.

Analysis 7.6.

Comparison 7 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 6 Pain disappearance.

Analysis 7.7.

Comparison 7 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 7 Pitting oedema disappearance.

Analysis 7.8.

Comparison 7 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 8 Collateral veins disappearance.

Analysis 7.9.

Comparison 7 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 9 Redness disappearance.

Analysis 7.10.

Comparison 7 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 10 Palpable cord disappearance.

Analysis 7.11.

Comparison 7 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 11 Major bleeding.

Analysis 7.12.

Comparison 7 Fixed-dose LMWH versus weight-adjusted LMWH, Outcome 12 Heparin-induced thrombocytopenia.

Comparison 8. Therapeutic LMWH versus saphenofemoral disconnection
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Venous thromboembolism1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Extension and/or recurrence of ST1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Major bleeding1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
4 Complications1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 8.1.

Comparison 8 Therapeutic LMWH versus saphenofemoral disconnection, Outcome 1 Venous thromboembolism.

Analysis 8.2.

Comparison 8 Therapeutic LMWH versus saphenofemoral disconnection, Outcome 2 Extension and/or recurrence of ST.

Analysis 8.3.

Comparison 8 Therapeutic LMWH versus saphenofemoral disconnection, Outcome 3 Major bleeding.

Analysis 8.4.

Comparison 8 Therapeutic LMWH versus saphenofemoral disconnection, Outcome 4 Complications.

Comparison 9. Fixed-dose LMWH versus NSAIDs
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Venous thromboembolism2278Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.24, 3.63]
2 Extension and/or recurrence of ST3331Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.58, 1.78]
3 Major bleeding3335Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4 Heparin-induced thrombocytopenia2278Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 9.1.

Comparison 9 Fixed-dose LMWH versus NSAIDs, Outcome 1 Venous thromboembolism.

Analysis 9.2.

Comparison 9 Fixed-dose LMWH versus NSAIDs, Outcome 2 Extension and/or recurrence of ST.

Analysis 9.3.

Comparison 9 Fixed-dose LMWH versus NSAIDs, Outcome 3 Major bleeding.

Analysis 9.4.

Comparison 9 Fixed-dose LMWH versus NSAIDs, Outcome 4 Heparin-induced thrombocytopenia.

Comparison 10. Weight-adjusted LMWH versus NSAIDs
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Venous thromboembolism1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Extension and/or recurrence of ST1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Major bleeding1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
4 Heparin-induced thrombocytopenia1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 10.1.

Comparison 10 Weight-adjusted LMWH versus NSAIDs, Outcome 1 Venous thromboembolism.

Analysis 10.2.

Comparison 10 Weight-adjusted LMWH versus NSAIDs, Outcome 2 Extension and/or recurrence of ST.

Analysis 10.3.

Comparison 10 Weight-adjusted LMWH versus NSAIDs, Outcome 3 Major bleeding.

Analysis 10.4.

Comparison 10 Weight-adjusted LMWH versus NSAIDs, Outcome 4 Heparin-induced thrombocytopenia.

Comparison 11. Prophylactic LMWH versus NSAIDs
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Venous thromboembolism end-of-treatment1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Venous thromboembolism 3-month follow up1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Extension and/or recurrence of ST1209Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.50, 1.84]
4 Major bleeding1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
5 Heparin-induced thrombocytopenia1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 11.1.

Comparison 11 Prophylactic LMWH versus NSAIDs, Outcome 1 Venous thromboembolism end-of-treatment.

Analysis 11.2.

Comparison 11 Prophylactic LMWH versus NSAIDs, Outcome 2 Venous thromboembolism 3-month follow up.

Analysis 11.3.

Comparison 11 Prophylactic LMWH versus NSAIDs, Outcome 3 Extension and/or recurrence of ST.

Analysis 11.4.

Comparison 11 Prophylactic LMWH versus NSAIDs, Outcome 4 Major bleeding.

Analysis 11.5.

Comparison 11 Prophylactic LMWH versus NSAIDs, Outcome 5 Heparin-induced thrombocytopenia.

Comparison 12. LMWH versus LMWH + acemetacin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Pulmonary embolism1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Deep vein thrombosis1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Extension of ST1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
4 Pain reduction1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
5 Hyperaemia reduction1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
6 Tenderness reduction1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
7 Palpable cord reduction1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
8 Mortality1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
9 Major bleeding1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
10 Minor bleeding1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
11 Adverse event1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 12.1.

Comparison 12 LMWH versus LMWH + acemetacin, Outcome 1 Pulmonary embolism.

Analysis 12.2.

Comparison 12 LMWH versus LMWH + acemetacin, Outcome 2 Deep vein thrombosis.

Analysis 12.3.

Comparison 12 LMWH versus LMWH + acemetacin, Outcome 3 Extension of ST.

Analysis 12.4.

Comparison 12 LMWH versus LMWH + acemetacin, Outcome 4 Pain reduction.

Analysis 12.5.

Comparison 12 LMWH versus LMWH + acemetacin, Outcome 5 Hyperaemia reduction.

Analysis 12.6.

Comparison 12 LMWH versus LMWH + acemetacin, Outcome 6 Tenderness reduction.

Analysis 12.7.

Comparison 12 LMWH versus LMWH + acemetacin, Outcome 7 Palpable cord reduction.

Analysis 12.8.

Comparison 12 LMWH versus LMWH + acemetacin, Outcome 8 Mortality.

Analysis 12.9.

Comparison 12 LMWH versus LMWH + acemetacin, Outcome 9 Major bleeding.

Analysis 12.10.

Comparison 12 LMWH versus LMWH + acemetacin, Outcome 10 Minor bleeding.

Analysis 12.11.

Comparison 12 LMWH versus LMWH + acemetacin, Outcome 11 Adverse event.

Comparison 13. Prophylactic LMWH + elastic compression stockings (ECS) versus elastic stockings alone
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Venous thromboembolism1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Extension and/or recurrence of ST1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 13.1.

Comparison 13 Prophylactic LMWH + elastic compression stockings (ECS) versus elastic stockings alone, Outcome 1 Venous thromboembolism.

Analysis 13.2.

Comparison 13 Prophylactic LMWH + elastic compression stockings (ECS) versus elastic stockings alone, Outcome 2 Extension and/or recurrence of ST.

Comparison 14. LMWH versus heparin spray gel
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Deep-venous thrombosis283Risk Ratio (M-H, Fixed, 95% CI)0.30 [0.03, 2.70]
2 Patients with thrombus at 21 days1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Allergic reaction or elevated sedimentation rate1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 14.1.

Comparison 14 LMWH versus heparin spray gel, Outcome 1 Deep-venous thrombosis.

Analysis 14.2.

Comparison 14 LMWH versus heparin spray gel, Outcome 2 Patients with thrombus at 21 days.

Analysis 14.3.

Comparison 14 LMWH versus heparin spray gel, Outcome 3 Allergic reaction or elevated sedimentation rate.

Comparison 15. High-dose UFH versus low-dose UFH
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of venous thromboembolism1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 ST recurrence or extension1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Major bleeding1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
4 Heparin-induced thrombocytopenia1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 15.1.

Comparison 15 High-dose UFH versus low-dose UFH, Outcome 1 Incidence of venous thromboembolism.

Analysis 15.2.

Comparison 15 High-dose UFH versus low-dose UFH, Outcome 2 ST recurrence or extension.

Analysis 15.3.

Comparison 15 High-dose UFH versus low-dose UFH, Outcome 3 Major bleeding.

Analysis 15.4.

Comparison 15 High-dose UFH versus low-dose UFH, Outcome 4 Heparin-induced thrombocytopenia.

Comparison 16. Calcium heparin + elastic compression bandage versus elastic compression bandage alone
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Deep venous thrombosis1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 16.1.

Comparison 16 Calcium heparin + elastic compression bandage versus elastic compression bandage alone, Outcome 1 Deep venous thrombosis.

Comparison 17. Heparin sc versus defibrotide
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Decrease in the analogue score1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2 Treatment side effects1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 17.1.

Comparison 17 Heparin sc versus defibrotide, Outcome 1 Decrease in the analogue score.

Analysis 17.2.

Comparison 17 Heparin sc versus defibrotide, Outcome 2 Treatment side effects.

Comparison 18. NSAIDs versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Venous thromboembolism1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Extension and/or recurrence of ST1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Major bleeding1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
4 Heparin-induced thrombocytopenia1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 18.1.

Comparison 18 NSAIDs versus placebo, Outcome 1 Venous thromboembolism.

Analysis 18.2.

Comparison 18 NSAIDs versus placebo, Outcome 2 Extension and/or recurrence of ST.

Analysis 18.3.

Comparison 18 NSAIDs versus placebo, Outcome 3 Major bleeding.

Analysis 18.4.

Comparison 18 NSAIDs versus placebo, Outcome 4 Heparin-induced thrombocytopenia.

Comparison 19. Indomethacin versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Side effects1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 19.1.

Comparison 19 Indomethacin versus placebo, Outcome 1 Side effects.

Comparison 20. Nimesulide versus diclofenac sodium
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Gastric pain1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 20.1.

Comparison 20 Nimesulide versus diclofenac sodium, Outcome 1 Gastric pain.

Comparison 21. Essaven gel versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Intolerance1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 21.1.

Comparison 21 Essaven gel versus placebo, Outcome 1 Intolerance.

Comparison 22. Thrombectomy + venoruton + elastic compression bandage versus elastic compression bandage alone
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Deep venous thrombosis1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 22.1.

Comparison 22 Thrombectomy + venoruton + elastic compression bandage versus elastic compression bandage alone, Outcome 1 Deep venous thrombosis.

Comparison 23. Thrombectomy + elastic compression bandage versus elastic compression bandage alone
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Deep venous thrombosis1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 23.1.

Comparison 23 Thrombectomy + elastic compression bandage versus elastic compression bandage alone, Outcome 1 Deep venous thrombosis.

Comparison 24. Ligation + elastic compression stockings versus elastic compression stockings alone
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Venous thromboembolism1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Extension and/or recurrence of ST1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 24.1.

Comparison 24 Ligation + elastic compression stockings versus elastic compression stockings alone, Outcome 1 Venous thromboembolism.

Analysis 24.2.

Comparison 24 Ligation + elastic compression stockings versus elastic compression stockings alone, Outcome 2 Extension and/or recurrence of ST.

Comparison 25. Prophylactic UFH + elastic compression stockings versus elastic compression stockings alone
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Venous thromboembolism1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Extension and/or recurrence of ST1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 25.1.

Comparison 25 Prophylactic UFH + elastic compression stockings versus elastic compression stockings alone, Outcome 1 Venous thromboembolism.

Analysis 25.2.

Comparison 25 Prophylactic UFH + elastic compression stockings versus elastic compression stockings alone, Outcome 2 Extension and/or recurrence of ST.

Comparison 26. Oral vasotonin versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Cured or substantially better1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Poor tolerability1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 26.1.

Comparison 26 Oral vasotonin versus placebo, Outcome 1 Cured or substantially better.

Analysis 26.2.

Comparison 26 Oral vasotonin versus placebo, Outcome 2 Poor tolerability.

Comparison 27. Elastic compression bandage + venoruton versus elastic compression bandage alone
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Deep venous thrombosis1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 27.1.

Comparison 27 Elastic compression bandage + venoruton versus elastic compression bandage alone, Outcome 1 Deep venous thrombosis.

Comparison 28. Oral heparan sulphate versus oral sulodexide
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Redness disappearance1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Pain disappearance1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3 Disappearance of itching1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
4 Oedema improvement1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
5 Trophism improvement1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 28.1.

Comparison 28 Oral heparan sulphate versus oral sulodexide, Outcome 1 Redness disappearance.

Analysis 28.2.

Comparison 28 Oral heparan sulphate versus oral sulodexide, Outcome 2 Pain disappearance.

Analysis 28.3.

Comparison 28 Oral heparan sulphate versus oral sulodexide, Outcome 3 Disappearance of itching.

Analysis 28.4.

Comparison 28 Oral heparan sulphate versus oral sulodexide, Outcome 4 Oedema improvement.

Analysis 28.5.

Comparison 28 Oral heparan sulphate versus oral sulodexide, Outcome 5 Trophism improvement.

Comparison 29. Oxyphenbutazone versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Tenderness improvement1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 29.1.

Comparison 29 Oxyphenbutazone versus placebo, Outcome 1 Tenderness improvement.

Comparison 30. VKA + elastic compression stockings versus elastic compression stockings alone
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Venous thromboembolism1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Extension and/or recurrence of ST1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 30.1.

Comparison 30 VKA + elastic compression stockings versus elastic compression stockings alone, Outcome 1 Venous thromboembolism.

Analysis 30.2.

Comparison 30 VKA + elastic compression stockings versus elastic compression stockings alone, Outcome 2 Extension and/or recurrence of ST.

Comparison 31. Stripping + elastic compression stockings versus elastic compression stockings alone
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Venous thromboembolism1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Extension and/or recurrence of ST1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 31.1.

Comparison 31 Stripping + elastic compression stockings versus elastic compression stockings alone, Outcome 1 Venous thromboembolism.

Analysis 31.2.

Comparison 31 Stripping + elastic compression stockings versus elastic compression stockings alone, Outcome 2 Extension and/or recurrence of ST.

Comparison 32. Enzyme therapy versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Pain reduction1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
2 Responders1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 32.1.

Comparison 32 Enzyme therapy versus placebo, Outcome 1 Pain reduction.

Analysis 32.2.

Comparison 32 Enzyme therapy versus placebo, Outcome 2 Responders.

Comparison 33. Desmin im 200 versus desmin 100
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Adverse events1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Adverse drug reactions1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 33.1.

Comparison 33 Desmin im 200 versus desmin 100, Outcome 1 Adverse events.

Analysis 33.2.

Comparison 33 Desmin im 200 versus desmin 100, Outcome 2 Adverse drug reactions.

Comparison 34. Desmin sc 2 x 100 versus desmin 100
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Adverse events1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
2 Adverse drug reactions1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
Analysis 34.1.

Comparison 34 Desmin sc 2 x 100 versus desmin 100, Outcome 1 Adverse events.

Analysis 34.2.

Comparison 34 Desmin sc 2 x 100 versus desmin 100, Outcome 2 Adverse drug reactions.

Appendices

Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Venous Thrombosis] this term only 915
#2 MeSH descriptor: [Thrombophlebitis] explode all trees 1088
#3 MeSH descriptor: [Phlebitis] this term only 144
#4 SVT:ti,ab,kw (Word variations have been searched) 105
#5 superficial near thrombo* 154
#6 *phlebit*:ti,ab,kw (Word variations have been searched) 1736
#7 #1 or #2 or #3 or #4 or #5 or #6 in Trials (Word variations have been searched) 2362

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.

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 randomisation, 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. 

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

DateEventDescription
15 October 2013AmendedAmendments made to the 'Risk of bias' tables and minor data errors corrected. Outcomes reordered to reflect clinical importance.

History

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

DateEventDescription
23 November 2012New citation required but conclusions have not changedReview updated. Four new trials included and one new trial excluded. Conclusions unchanged.
23 November 2012New search has been performedSearches re-run. Four new trials included and one new trial excluded. Conclusions unchanged.
30 November 2011Feedback has been incorporatedFeedback addressed.
30 November 2011New citation required and conclusions have changedReview updated. Conclusions changed.
30 November 2011New search has been performedReview updated, searches rerun. Two new trials included, one being a large RCT with fondaparinux.
27 October 2010Feedback has been incorporatedFeedback added
26 April 2010AmendedContact details updated
1 September 2008AmendedConverted to new review format.
19 February 2007New citation required and minor changesUpdated to correct error in citation. Searches re-run and no new trials found.

Contributions of authors

Marcello Di Nisio selected and assessed the quality of trials, extracted data, and wrote the review.
Iris 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.

Declarations of interest

Dr Middeldorp was a member of the Steering Committee of the CALISTO study, which was funded by GlaxoSmithKline (GSK) and which investigated the efficacy and safety of fondaparinux for superficial thrombophlebitis; funds were paid to Dr Middeldorp's institution. Dr Middeldorp's institution has also received funding from several pharmaceutical companies, including GSK, to support some of her other educational and research activities. 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.

Differences between protocol and review

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 to take into account possible sources of bias (for example open-label design, incomplete follow-up, high levels of exclusions unbalanced between the groups, or inadequate allocation concealment) were not possible. For most of the treatment comparisons, SMD could not be calculated for continuous variables since the standard deviations of the means were not reported.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Andreozzi 1996

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

Desmin (Dermatan sulphate) (100 mg bid sc)

Desmin (200 mg od im)

Desmin (100 mg od sc)

Study treatment was given for 30 days

OutcomesPain and functional inability; local oedema; palpable thrombophlebitic cord; fever; hyperemia and cutaneous hyperthermia; adverse events or adverse drug reactions
Notes

Funding: Alfa Wassermann S.p.A (Bologna, Italy) supplied Desmin

Disclosure of potential conflicts of interest: two authors from Alfa Wassermann S.p.A., Bologna, Italy

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation not reported
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
High riskOpen study "open and multicenter"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe number of patients analysed unclear. One patient discontinued treatment and was excluded from the baseline descriptive table
Selective reporting (reporting bias)Low riskAll outcomes reported in the methods section were addressed in the results or discussion section.

Anonymous 1970

MethodsPlacebo-controlled, double-blind RCT
ParticipantsPatients (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)

Placebo

Study treatment was given for 1 week

OutcomesErythema, 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)

Funding: not reported

Disclosure of potential conflicts of interest: not reported, no COI forms available

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation not reported. "..comparison between indomethacin and inactive placebo..the choice being determined by random selection"
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble-blind study. "double-blind comparison", however, It is not reported who was blinded and how blinding was attempted
Incomplete outcome data (attrition bias)
All outcomes
High riskNot clear how many patients of those initially included had full assessment of the study endpoints. From Table I in Anonymous 1970 it is clear that at least for one of the outcomes not all patients were evaluated at the longest follow-up
Selective reporting (reporting bias)High riskNo data are provided for some of the outcomes. Side effects are reported in the Results section but not mentioned in the methods section.

Archer 1977

MethodsMulticentre, double-blind RCT
ParticipantsNon-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)

Placebo (4 times daily)

Study treatment was given for 7 days

OutcomesPain, 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

Funding: not reported

Disclosure of potential conflicts of interest: not reported, no COI forms available

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation not reported. "Oxyphenbutazone..and matching placebo were allocated at random"
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo 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. It is not reported who was blinded and how blinding was attempted
Incomplete outcome data (attrition bias)
All outcomes
High risk1 patient (from the placebo group) was excluded post-randomisation (2%). Unclear if all the remaining patients were analysed
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Belcaro 1989

MethodsOpen RCT
ParticipantsPatients (n = 83) with ST without DVT on duplex ultrasonography; 36 males, 45 females; mean age 38.9 years (range 27 - 46). Not reported if patients were hospitalised or non-hospitalised
Interventions

Superficial thrombectomy plus ECB

Calcium heparin (0.5 mg bid sc) plus ECB

Venoruton (1000 mg tid) plus ECB

Venoruton (1000 mg tid) after superficial thrombectomy plus ECB

ECB alone

Non-surgical treatment was given for 8 weeks

OutcomesArea of maximum temperature; pain and tenderness (analogical score); DVT. Not specified 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

Funding: not reported

Disclosure of potential conflicts of interest: not reported, no COI forms available

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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation not reported. "patients were randomized in 5 groups of treatment"
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
High riskNo information provided about blinding, but it is likely an open study
Incomplete outcome data (attrition bias)
All outcomes
High riskNine patients were 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 riskAll pre-specified outcomes are reported

Belcaro 1990

MethodsSingle-centre RCT
ParticipantsPatients (n = 40) with ST confirmed by colour duplex ultrasonography; 13 males, 27 females; age range 46 to 48 years. Not reported if patients were hospitalised or non-hospitalised. Angiodynography was 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

OutcomesArea of maximum temperature, analogue score (redness, local tenderness, inflammation)
Notes

All patients got compression bandages

Funding: not reported

Disclosure of potential conflicts of interest: not reported, no COI forms available

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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation not reported: "Patients were randomized in two treatment groups"
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
High riskNo information provided about blinding, but it is likely an open study
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear if all included patients were evaluated for study outcomes
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Belcaro 1999

MethodsMulticentre, open RCT; 6-month follow-up
ParticipantsNon-hospitalised patients (n = 562) with ST, large varicose veins, and venous incompetence; 181 males, 263 females; mean age range across study groups 53 to 56 years. The diagnosis of ST was objectively confirmed by colour Doppler compression ultrasonography
Interventions

Surgery (ligation)

Surgery (complete stripping)

Low-dose sc heparin

LMWH

Coumadin

OutcomesDVT 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 and the dose of heparin or coumadin was not specified

Funding: not reported

Disclosure of potential conflicts of interest: not reported, no COI forms available

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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation not reported
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
High riskNo information provided about blinding, but it is likely an open study
Incomplete outcome data (attrition bias)
All outcomes
High risk118 patients lost to follow-up (21%)
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Belcaro 2011

MethodsSingle-centre, randomised, placebo-controlled study
ParticipantsNon-hospitalised patients (n = 120) with ST of the legs within 72 hours prior to study inclusion. ST was confirmed by colour-Doppler ultrasonography. Mean age was 46.3 years (11.51), 26 males, 94 females
Interventions

Heparin-spray gel (Viatromb 2.400 IU/g): 4.122 IU sodium heparin applied as 3 times 3 spray puffs
Heparin-spray gel (Viatromb 2.400 IU/g): 5496 IU sodium heparin applied as 3 times 4 spray puffs

Heparin-spray gel (Viatromb 2.400 IU/g): 6879 IU sodium heparin applied as 3 times 5 spray puffs

Placebo applied as 3 times 5 puffs

Study medication was applied for 7 to 14 days

OutcomesPain reduction (VAS scale and VRS), erythema extension, thrombus size, oedema reduction, adverse events, investigator's and subject's assessment of efficacy
Notes

Funding: The study was sponsored by CRO Opera S.r.L., Genoa, Italy.

Disclosure of potential conflicts of interest: the authors report to have no COI

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
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated: "The treatments were allocated according to a randomization list (randomization by blocks)."
Block allocation sequences were created at random by using numbers generated by a computer program".
Allocation concealment (selection bias)Low riskComputer-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 riskSingle blind: "observer blinded design"
Incomplete outcome data (attrition bias)
All outcomes
High risk14 of 150 (11.7%) dropped out, 68.3% completed treatment on day 7, 11.7% on day 14, and 8.3% had a treatment failure
Selective reporting (reporting bias)High riskData are not reported for all pre-specified outcomes. The outcome DVT is mentioned in the methods but not reported in the results or discussion

Cosmi 2012

MethodsSTEFLUX: Multicentre, randomised, double-blinded, placebo-controlled study
ParticipantsConsecutive outpatients (n = 664) with at least a 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 was 69 yrs (20-94); 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

Efficacy outcomes

Primary: composite of symptomatic and asymptomatic DVT, symptomatic PE and relapse and/or symptomatic or asymptomatic SVT recurrence in the first 33 days

Secondary: a) reduction in local symptoms during treatment, b) the combined efficacy end-point during a follow-up of 93 days after the start of treatment

Safety outcomes

Primary: major bleeding
Secondary: composite of minor bleeding, thrombocytopenia or any other adverse events (e.g. local allergic reactions)

Notes

Patients were instructed to wear graduated elastic stockings (knee-high or at the thigh) 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.

The study was prematurely interrupted according to predefined stopping rules.

Funding: the study was 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 say in study design; analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. Alfa Wassermann provided the study drug and placebo.

Disclosure of potential conflicts of interest: three authors including the lead author reported to have received consulting fees from Alfa Wasserman

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskCentral computer-generated randomisation sequence: "The randomization sequence was computer generated centrally in blocks of six"
Allocation concealment (selection bias)Low riskCentral 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 riskDouble blinded: "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 risk16 out 664 (2.4%) patients excluded from the analysis, 8 lost to follow-up
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

De Sanctis 2001

MethodsPlacebo-controlled RCT
ParticipantsPatients (n = 30) with ST confirmed by colour duplex ultrasonography and varicose veins; mean age 51 years; 17 males, 13 females. Not reported if patients were hospitalised and/or non-hospitalised
Interventions

Essaven gel (5 cm of gel)

Placebo (5 cm of gel)

Study treatment was given for 4 weeks

OutcomesAverage decrease in temperature; average symptomatic score (local pain, disability, swelling)
Notes

All patients received LMWH (Clexane 0.1ml/10kg of body weight od) for 4 weeks and elastic compression stockings

Funding: not reported

Disclosure of potential conflicts of interest: not reported, no COI forms available

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation not reported: "the randomization process was controlled by an external statistical controller according to GCP rules"
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind study: "Placebo comparable to Essaven gel was used", "operators were unaware of the contents of the tube"
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Decousus 2010a

MethodsCALISTO: Multicentre, randomised, double-blind, placebo-controlled study, intention-to-treat analysis
Participants

Hospitalised or non-hospitalised patients (n = 3002) 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.

Mean age 57.1 ± 13.3 yrs fondaparinux and 56.9 ± 13.6 yrs placebo. 1084 Males, 1918 females

Interventions

Fondaparinux (2.5 mg sc od)

Placebo

Study treatment was given for 45 days

Outcomes

Primary efficacy outcome:

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

Secondary efficacy outcomes: the composite primary efficacy outcome up to day 77 and the following outcomes up to day 47 and 77: each component of the primary efficacy outcome, the composite of symptomatic PE or DVT, and surgery for ST

Primary safety outcome: major bleeding

Secondary safety outcomes: clinically relevant non-major, minor, total (any) bleeding, arterial thromboembolic events, adverse events

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.

Funding: the study was funded by the GlaxoSmithKline which collected and analysed the data

Disclosure of potential conflicts of interest: all authors reported to have received grant support and supporting fees from GlaxoSmithKline

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer based: "computer-generated randomisation list"
Allocation concealment (selection bias)Low riskCentral allocation: "with the use of a central telephone system and a computer-generated randomization list, consecutive patients were randomly assigned.."
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind study. "Fondaparinux and placebo were packaged in identical boxes containing visually identical, prefilled 0.5-ml single-dose syringes". "All symptomatic outcomes were reviewed by the central adjudication committee, whose members were unaware of the patients’ group assignments"."The database of adjudicated outcomes was managed by an independent central adjudication committee"
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Efficacy analyses performed on data from the intention-to-treat data. Safety analyses were performed on data from the as-treated population. Overall, 18 patients in the fondaparinux group (1.2%) and 22 in the placebo group (1.5%) did not have a primary efficacy assessment. Overall, 1.8% of the randomised patients did not complete follow-up

Safety analysis "1499 patients in the fondaparinux group (99.8%) and 1488 in placebo group (99.2%) were included in the safety analyses."

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

Ferrari 1992

MethodsSingle centre, open RCT
ParticipantsPatients (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)

Diclofenac sodium (50 mg bid)

Study treatment was given for 10 days

OutcomesSpontaneous pain, hyperaemia, oedema, local hyperaemia, fever, tolerability
Notes

All patients received prophylaxis with heparin calcium

Funding: not reported

Disclosure of potential conflicts of interest: not reported, no COI forms available

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation not reported: "randomly allocated to oral treatment"
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote from the abstract: "Double-blind study". However, blinding is not mentioned in the methods, results or discussion sections. It is not reported who was blinded and how blinding was attempted
Incomplete outcome data (attrition bias)
All outcomes
High riskOverall, 3 patients were not analysed for efficacy outcomes (6%): 2 patients in the nimesulide group and 1 in the diclofenac
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Gorski 2005

MethodsMulticentre, open, RCT; 7 to 14 day follow-up
ParticipantsNon-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)

LMWH (enoxaparin 40 mg sc od)

Study treatment was given for 7 or 14 days

Outcomes

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

Secondary outcomes: patient and investigator assessment of efficacy of treatment

Notes

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

Funding: the study was sponsored by CSC Pharmaceuticals Handelsges, Austria

Disclosure of potential conflicts of interest: not reported, no COI forms available

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"patient randomization was performed according to a prespecified randomization list"
Allocation concealment (selection bias)Unclear risk

"each patient...was allocated to a treatment group according to the next free number on the randomization list".

It is not reported if allocation was done centrally

Blinding (performance bias and detection bias)
All outcomes
High riskOpen study: "treatment were administered in a open way, there was no blinding"
Incomplete outcome data (attrition bias)
All outcomes
High risk4 patients lost to follow-up (10%)
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Holzgreve 1989

MethodsRCT
ParticipantsPatients (n = 60) with ST of the legs; 17 males, 43 females; mean age 53,4 ±12 years. Not reported if patients were hospitalised or non-hospitalised nor if the diagnosis of ST was objectively confirmed by ultrasonography
Interventions

Etofenak gel

Diclofenac gel

OutcomesLength of superficial venous thrombosis (cm), pain, redness, palpable veins, oedema
Notes

All patients had compression therapy

Funding: not reported

Disclosure of potential conflicts of interest: not reported, no COI forms available

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation not reported
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
High riskSingle-blinded. The authors state it is a single-blinded study, and the patients received medication that was labelled as "trial medication". It is unclear from the paper whether the trial physician was blinded to the treatment, and since the outcome was symptom improvement, there is a high risk of detection bias by imperfect blinding.
Incomplete outcome data (attrition bias)
All outcomes
High risk20 patients lost to follow-up (33%)
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Incandela 2001

MethodsMulticentre, placebo-controlled RCT
ParticipantsPatients (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)

Placebo (5 cm of gel)

Study treatment was given for 8 weeks

OutcomesAnalog 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 for the study period

Funding: not reported

Disclosure of potential conflicts of interest: not reported, no COI forms available

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskUnclear method of random sequence generation: "randomisation process was controlled by an external statistical controller"
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blinded. "Placebo comparable to Essaven gel was used", "operators were unaware of the contents of the tube
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear if all patients included were analysed
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Katzenschlager 2003

MethodsMulticentre, open RCT
ParticipantsNon-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

LMWH (enoxaparin 40 mg sc) plus compressive stockings

Study treatment was given for 7 to 14 days

OutcomesMedian pain (VAS scale), median area of erythema, thrombus size
Notes

Patients received paracetamol (1000 mg/day) as pain rescue medication

Funding: not reported

Disclosure of potential conflicts of interest: not reported, no COI forms available

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"The assignment of patients to treatment was done accordingly to a randomisation list using a validated system"
Allocation concealment (selection bias)Unclear risk"Each valid subject...was assigned to the next number on the randomization list". Unclear if allocation was done centrally
Blinding (performance bias and detection bias)
All outcomes
High riskOpen study: "treatments were administered in a open randomised way"
Incomplete outcome data (attrition bias)
All outcomes
High risk3 patients, all in the heparin spray gel group, lost to follow-up (7%)
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Koshkin 2001

MethodsPlacebo-controlled, double-blinded RCT
ParticipantsPatients (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)

Placebo

Study treatment was given for 16 days

OutcomesPositive changes for a combined outcome including pain, redness, and oedema
Notes

Funding: not reported

Disclosure of potential conflicts of interest: not reported, no COI forms available

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation not reported
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble-blind study, however, it is not reported who was blinded and how blinding was obtained
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo information provided. Unclear if all included patients were evaluated for study outcomes
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Kuhlwein 1985

MethodsMulticentre, placebo-controlled RCT
ParticipantsPatients (n = 76) with ST, diagnosed on signs and symptoms only by general practitioners or internists. Not reported if some patients were hospitalised. No data on sex or age were reported.
Interventions

Vasotonin forte

Placebo

Study treatment was given for 3 weeks

OutcomesOverall score including pain, redness, swelling, movement improvement
Notes

Funding: not reported

Disclosure of potential conflicts of interest: not reported, no COI forms available

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation not reported
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble-blind study. The authors state in the abstract that the study was double-blinded and placebo-controlled. However, no details regarding the study medication or placebo are given in the text.
Incomplete outcome data (attrition bias)
All outcomes
Low riskIt appears that after 3 weeks there were no losses to follow-up
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Lozano 2003

MethodsOpen RCT
ParticipantsPatients (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
Interventions

LMWH (enoxaparin 1mg/kg bid for the first week, then 1 mg/kg for 3 weeks) on an outpatient basis

Saphenofemoral disconnection with a short hospital stay

OutcomesResolution of symptoms and signs, ST recurrence, VTE, complications from treatment, socioeconomic assessment. Not specified if VTE and ST recurrence were symptomatic or asymptomatic
Notes

In the immediate postoperative period, a compression bandages/elastic stocking was used and early walking recommended. Pain was controlled with oral acetaminophen (500 mg). Compressive bandage/elastic stockings were continued at home by all patients.

Funding: not reported

Disclosure of potential conflicts of interest: not reported, no COI forms available

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation not reported
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
High riskOpen study
Incomplete outcome data (attrition bias)
All outcomes
High risk3 patients, all in the saphenofemoral disconnection group, lost to follow-up (5%)
Selective reporting (reporting bias)High riskNo information provided on the resolution of signs and symptoms

Marchiori 2002

MethodsSingle-centre RCT
ParticipantsConsecutive 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)

UFH (5000 IU)

Study treatment was given for 4 weeks

Outcomes

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

Safety outcomes: major bleeding, heparin-induced thrombocytopenia, overall mortality

Notes

Systemic and/or local anti-inflammatory drugs were allowed

Funding: not reported

Disclosure of potential conflicts of interest: the authors report no COI

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-based: "List generated by a computer"
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
Unclear riskThe ultrasound assessment was performed by blinded investigators. However, it is not reported if patients and investigators evaluating all other events were blinded to study treatment
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Marshall 2001

MethodsMulticentre, placebo-controlled RCT
ParticipantsPatients (n = 159) with acute ST of the leg, diagnosed on symptoms and signs only; 40 males, 116 females; mean age 53.8 years. Not reported if patients were hospitalised or non-hospitalised
Interventions

Wobenzym (4 tablets tid)

Placebo

Study treatment was given for 12 to 16 days

OutcomesThe 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.

Funding: not stated

Disclosure of potential conflicts of interest: not reported, no COI forms available

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-based. Patients assigned to treatment with a list generated by a computer
Allocation concealment (selection bias)Low riskPatients assigned to treatment with a list generated by a computer. Concealment of allocation was present since randomisation took place with a computer program called "Random V.5" by Firma Wiedey GmbH Konstanz.
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind study. The study medication is described as "similarly looking study medication [placebo]",
Incomplete outcome data (attrition bias)
All outcomes
High risk1 withdrew consent post-randomisation; 10 patients lost to follow-up (6%)
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Messa 1997

MethodsSingle-centre, open RCT
ParticipantsPatients (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)

Sulodexide (250 LSU bid, orally)

Study treatment was given for 2 weeks

OutcomesRedness of the skin, pain, itching, oedema, trophism
Notes

Funding: not reported

Disclosure of potential conflicts of interest: not reported, no COI forms available

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskPatients assigned to treatment with a random list
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
High riskOpen study. "The study was performed in a open-label..design"
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Nocker 1991

MethodsPlacebo-controlled RCT
ParticipantsPatients (n = 20) with unilateral ST of the legs diagnosed on symptoms and signs only; 8 males, 12 females; mean age 59.7 ± 7.1 years in the intervention group; 54.6 ± 5.6 years in placebo group. Not reported if patients were hospitalised or non-hospitalised
Interventions

Diclofenac gel (1 g diclofenac/100 g gel) applied three times a day

Placebo applied three times a day

Study treatment was given for 3 weeks

OutcomesEfficacy 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
NotesHeparin gel was given to 10 patients, without randomisation.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation not reported
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble-blind study. The authors state that the study was double-blinded and placebo-controlled. However, no details regarding the study medication or placebo are given in the main text
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Nusser 1991

Methods RCT
ParticipantsPatients (n = 60) with ST diagnosed on symptoms and signs only; 25 males, 34 females with mean age of 53 ± 13 and 53 ± 16 years, respectively. Not reported if patients were hospitalised or non-hospitalised
Interventions

Oral acemetacin (60 mg tid)

Oral diclofenac (50 mg tid)

Study treatment was given until symptoms resolved for maximally 15 days

OutcomesArea of ST, pain, redness, palpable venous induration, oedema
Notes

All patients received compression stockings

Funding: not reported

Disclosure of potential conflicts of interest: not reported, no COI forms available

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation not reported
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind study. The study medication is described as "similarly looking study medication".
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear if all included patients were evaluated for study outcomes
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Pinto 1992

MethodsMulticentre, placebo-controlled RCT
ParticipantsPatients (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)

Placebo

Study treatment was given for 1 week

OutcomesOedema, erythema, pain, functional impairment, subcutaneous induration, tolerability, VAS score
Notes

No compression therapy was allowed during the study.

Patients with ST represent a subgroup of a larger RCT which included also patients with chronic venous insufficiency or second degree haemorrhoids.

Funding: not reported

Disclosure of potential conflicts of interest: not reported, no COI forms available

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation not reported
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind study. "indistinguishable placebo"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear if all included patients were evaluated for study outcomes
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Rathbun 2012

MethodsRandomised, controlled, double-blind, double-dummy trial
ParticipantsConsecutive inpatient and outpatients (n = 72) with ST of the lower (n = 57) or upper extremities confirmed by ultrasonography in the absence of a current intravenous catheter. ST involved the lower extremities in 27/37 of the patients in the dalteparin group and in 30/35 in the ibuprofen group. Mean age was 51 yrs (28 – 88) in dalteparin and 52 (19 – 85) in ibuprofen. 21 males, 51 females
Interventions

LMWH (dalteparin 200 IU/kg at presentation followed by a fixed dose of 10,000 units sc daily for additional 6 – 13 days) plus placebo given orally tid for 7 days

Ibuprofen 800 mg given orally three times daily for up to 14 days plus placebo injection od for 7 days

If symptoms of ST were not resolved at day 7–9, in the absence of thrombus extension, the patient received an additional 7 days of the blinded therapy. If symptoms of ST were resolved at day 7-9 in the absence of thrombus extension, study medication was stopped.
If at any time thrombus was found to extend either superficially or into the deep venous system, study treatment was discontinued and full therapeutic anticoagulation with iv heparin or low-molecular-weight heparin started

Outcomes

Efficacy outcomes

Primary: incidence of thrombus extension or new symptomatic VTE during the 14-day and 3-month follow-up period

Secondary: reduction in pain, evaluated through the 11-point Box Pain scale, from baseline to day 7 and 14-16 day follow-up

Safety outcomes

Incidence of major and minor bleeding

Notes

Compression stockings not routinely prescribed

Funding: grant from the National Center for Research Resources, National Institute of Health and Pfizer Inc. for provision of dalteparin, ibuprofen and nurse personnel salary support

Disclosure of potential conflicts of interest: the authors report no COI

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Balanced randomization blocks of four each consisting of equal numbers" for the 2 treatment groups
Allocation concealment (selection bias)Low risk"randomization..was performed by the investigational pharmacist within 24 h of presenting with a confirmed diagnosis.."
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blinded. "The patient, research assistant and principal investigator were blinded to the treatment group"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear if all included patients were evaluated for study outcomes
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Stenox Group 2003

MethodsSTENOX: Multicentre, placebo-controlled RCT with a 3-month follow-up, intention-to-treat analysis
ParticipantsHospitalised 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)

LMWH (enoxaparin 1.5 mg/kg sc od)

Oral tenoxicam (20 mg od)

Placebo

Study treatment was given for 8 to 12 days

Outcomes

Primary efficacy outcome: symptomatic PE and symptomatic and asymptomatic DVT at 12 days

Secondary efficacy 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 (97 days)

Safety outcomes: death, major and minor bleeding, thrombocytopenia, and any other adverse event

Notes

All patients used elastic bandages or support stockings from day 1 of therapy and continued for at least 15 days. Patients requiring anticoagulant therapy, ligation of the saphenofemoral junction or thrombectomy, anticoagulants or NSAIDs for more than 48 hours were excluded from the study.

The study was prematurely interrupted due to slow recruitment rate.

Funding: Laboratoires Aventis, Paris and Association Francaise de Formation Continue en Angiologie, Paris

Disclosure of potential conflicts of interest: the authors report no financial interests

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskUnclear method of sequence generation: "patients were centrally randomly assigned to receive.."
Allocation concealment (selection bias)Low riskCentral allocation
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind study: "study medications were packaged in boxes of identical appearance.", "all boxes had visually identical contents". "outcomes were reviewed blindly by an independent critical event committee"
Incomplete outcome data (attrition bias)
All outcomes
High risk9/436 patients lost to follow-up (2%)
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Titon 1994

MethodsMulticentre, open RCT
ParticipantsNon-hospitalised patients (n = 117) with ST confirmed by ultrasonography; 25 males, 92 females; age range 54 to 64 years. Mean ages vary between groups, particularly for the few men in the dose adjusted group of nadroparin who were much younger than the men in the other two groups.
Interventions

Naproxene (oral 500 mg od)

LMWH (nadroparin 0.6 ml /6150 anti-Xa IU od)

LMWH (nadroparin 61.5 anti-Xa IU/kg sc od)

Study treatment was given for 6 days

Outcomes

Primary efficacy: Recurrence and/or extension of ST, VTE after treatment (day 7) and after 8 weeks

Secondary efficacy outcomes: symptoms (pain and functional disability) and signs (erithema, oedema)

Safety outcomes: major and minor bleeding

Notes

All patients received elastic stockings for the first 7 days.

Funding: not reported

Disclosure of potential conflicts of interest: not reported, no COI forms available

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of random sequence generation not reported
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
High riskOpen study. "open trial".
Incomplete outcome data (attrition bias)
All outcomes
High riskAt day 7, no patients were lost to follow up. Four (3.4%) patients were not evaluated by ultrasonography. At 8 weeks, 8 (6.8%) patients were lost to follow-up and 25 (21%) patients were not evaluated by ultrasonography
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Uncu 2009

MethodsOpen RCT
ParticipantsPatients (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. Mean age: 48.6 (25 - 90) years in Ca-nadroparin and 44.9 (28-85) years in Ca-nadroparin and acemetacin. 27 males, 23 females
Interventions

LMWH (Ca-nadroparin 190 IU Axa/Kg od)

LMWH (Ca-nadroparin 190 IU Axa/Kg od) + acemetacin (60 mg oral bid)

Study treatment was given for 10 days

Outcomes

Primary outcomes

Spontaneous pain, erythema, local tenderness and palpable cord

Notes

Funding: not reported

Disclosure of potential conflicts of interest: not reported, no COI forms available

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskAlternation: "consecutive alternating method"
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
High riskNo information provided about blinding, but it is likely an open study
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe authors do not report they performed an ITT and it is not clear whether the study outcomes were evaluated in all included patients
Selective reporting (reporting bias)High riskAll pre-specified outcomes are reported. The outcomes symptomatic DVT, PE, ST extension, bleeding, death, and AE were reported in the results but not mentioned in the methods

Vesalio Group 2005

MethodsVESALIO: Multicentre, double-blind, double-dummy RCT, intention-to-treat analysis
ParticipantsHospitalised 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)

Fixed-dose LMWH (nadroparin 2850 anti-Xa IU)

Study treatment was given for 30 days

Outcomes

Primary efficacy outcome: asymptomatic and symptomatic extension of the ST, and/or VTE in a 3-month follow-up period.

Secondary efficacy outcomes: clinical signs and symptoms

Primary safety outcomes: major bleeding, heparin-induced thrombocytopenia

Notes

No aspirin use or NSAIDs use throughout the study

Study prematurely interrupted due to the slow recruitment rate

Funding: grant from Sanofi-Synthelabo, Sanofi Aventis Group, Milano and GlaxoSmithKline, Verona

Disclosure of potential conflicts of interest: the authors declared no COI

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer based: "each patient was assigned a unique sequential subject number, generated by a computer"
Allocation concealment (selection bias)Unclear riskSealed envelopes, not clear if opaque. "each center received a initial fixed amount of randomization numbers and corresponding sealed envelopes
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind study. "placebo identical in appearance to nadroparin". "all suspected outcome events were reviewed and classified by a Central Adjuducation Committee whose members were unaware of treatment assignment"
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskAll pre-specified outcomes are reported

Winter 1986

  1. a

    bid: twice daily
    cm: centimetre
    COI: conflict of interest
    CUS: compression ultrasound
    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
    VRS: visual rating scale

MethodsMulticentre, randomised trial
ParticipantsPatients with ST (n = 100). Not reported if patients were hospitalised or non-hospitalised nor if the diagnosis of ST was objectively confirmed by ultrasonography
Interventions

Diclofenac emulgel

Heparin gel

Study treatment was given 14 days

Outcomes

Pain (spontaneous and after pressure)

Redness

Palpable cord

NotesThis study is only reported as an abstract for a scientific meeting. No full paper available.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation list
Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information on study medication or outcome assessment is provided
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe authors do not report whether they performed an ITT analysis
Selective reporting (reporting bias)Unclear riskOutcomes were not specified, only a general outcome of "efficacy" was reported

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    DVT: deep vein thrombosis
    ST: superficial thrombophlebitis

Agus 1993Not possible to extract outcomes data separately for the two study-treatment groups.
Allegra 1981Mixed population. It was not possible to extract data separately for the ST.
Annoni 1991Mixed population. It was not possible to extract data separately for ST.
Argenteri 1983Mixed population including patients with deep venous thrombosis. It was not possible to extract data separately for ST.
Bagliani 1983Mixed population including also patients with DVT. It was not possible to extract data separately for ST.
Becherucci 2000Mixed 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 1990Mixed 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 1980Patients without a diagnosis of ST of the legs.
Bracale 1996Mixed population including also patients with DVT. It is not possible to extract data separately for the ST.
Bruni 1979Mixed 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 1989Mixed population including also patients with DVT and post-phlebitic syndrome. It is not possible to extract data separately for the ST.
Di Perri 1986Patients with DVT.
Gandhi 1984Patients without a diagnosis of ST of the legs.
Giorgetti 1990Single blind study of patients with varicophlebitis who received either Seaprose S or placebo. It is unclear whether the study was randomised or not.
Gouping 2003Patients with post-infusion ST of the arm.
Ibanez-Bermudez 1996The evaluated outcomes are not among those evaluated in the present review.
Luttichau 1989Mixed population. It was not possible to extract data separately for ST.
Mari 1982Mixed 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 1985Mixed population. It was not possible to extract data separately for ST.
Mauro 1992Mixed population including patients with DVT. It was not possible to extract data separately for ST.
Mehta 1975Patients with ST of the arm.
Paciaroni 1982Mixed population including patients with chronic venous insufficiency. It is not possible to extract data separately for ST.
Porters 1981Mixed 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 1980Mixed 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 1981Patients with DVT.
Resta 1967Patients without a diagnosis of ST of the legs.
Rozsos 1994Patients with ST of the arm.
Seccia 1989Mixed 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 1972Mixed 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 1969Mixed population including patients with DVT. It was not possible to extract data separately for ST.
Stolle 1986Patients with ST of the arm.
Tomamichel 1983Mixed population including patients with DVT. It was not possible to extract data separately for ST.
van Cauwenberge 1972Patients without a diagnosis of ST of the legs.
van der Knaap 1988Patients with ST of the arm.

Characteristics of studies awaiting assessment [ordered by study ID]

Bijuan 2003

  1. a

    ST; superficial thrombophlebitis

MethodsRandomised study
ParticipantsPatients (n = 64) with phlebitis but unclear if ST of the legs or upper extremities
Interventions

Aloe pigmentum

Wet packing with routine 50% magnesium sulphate

Outcomes

To investigate the clinical effects of aloe pigmentum on phlebitis

Colour Doppler was used to detect and compare inner diameter of blood vessels before and after treatment in the two groups

Notes 

Characteristics of ongoing studies [ordered by study ID]

Rabe 2009

Trial name or titleDAPS-dalteparin in patients with superficial leg vein phlebitis in addition to compression treatment - a placebo-controlled phase III study
MethodsRandomised, double-blind, multicentre, phase III trial
ParticipantsPatients (n = 276) with superficial leg vein phlebitis
InterventionsCompression 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 VAS and calculation of symptom scores (tension, heaviness, swelling).

Starting dateNot reported
Contact informationRabe E
Notes 

Ancillary