Treatment for superficial thrombophlebitis of the leg

Paolo Balzaretti,

S.C. Medicina e Chirurgia d’Accettazione e Urgenza
A.O. “Ordine Mauriziano”, Torino

What we already know about this topic

Superficial thrombophlebitis (ST) is a common condition, with a prevalence of about 0,64% per year (1). In the last decades, many different therapeutic strategies have been proposed but only recently data from large trials are available for decision making. Main focuses of the treatment should be the prevention of evolution to deep vein thrombosis (DVT) and pulmonary embolism (PE) and the reduction of pain, that is frequently associated.
The review we will summarize evaluates the efficacy and safety of the topical, medical and surgical treatments for ST tested in randomized clinical trials.

The Cochrane review (2)

Title: Treatment for superficial thrombophlebitis of the leg.
Authors: Di Nisio M, Wichers IM, Middeldorp S.
Bibliographic citation: Cochrane Database Syst Rev 2018; 2:CD004982.
Objective: to assess the efficacy and safety of topical, medical, and surgical treatments for ST of the leg in improving local symptoms and decreasing thromboembolic complications.
Included studies: randomized controlled trials evaluating topical, medical and surgical treatments for ST of the legs.
Primary outcome: 1) symptomatic VTE (i.e. combined of symptomatic pulmonary embolism and symptomatic deep vein thrombosis, 2) major bleeding.
Main secondary outcomes: 1) symptomatic isolated pulmonary embolism, 2) isolated symptomatic deep vein thrombosis, 3) extension of ST, 4) recurrence, 5) symptoms, 6) quality of life (assessed using a validated questionnaire), 7) mortality, 8) adverse effects (minor bleeding, thrombocytopenia, allergic reactions, surgical complications).
Number of included studies: 33 studies.
Quality of included studies: most of studies has unclear risk of bias regarding generation of randomization sequence and allocation concealment. Only ten studies have a double blinding design.
Number of patients: 7296.

Results:

Fondaparinux vs. placebo

Outcome	No. of studies / No. of patients	Relative effect (95% C.I.)	Quality of evidence
Symptomatic VTE	1 / 3002	0,15 (0,04 – 0,5)	Moderate
Major bleeding	1 / 2987	0,99 (0,06 – 15,86)	Moderate
Extension of ST	1 / 3002	0,08 (0,03 – 0,22)	Moderate
Recurrence of ST	1 / 3002	0,21 (0,0 – 0,54)	Moderate

Table 1. Efficacy and safety of fondaparinux vs. placebo. Relative effects below 1 favour fondaparinux

Prophylactic Low Molecular Weight Heparin (LMWH) vs. placebo

Outcome	No. of studies / No. of patients	Odds Ratio (95% C.I.)	Quality of evidence
Symptomatic VTE	1 / 222	1,22 (0,38 – 3,89)	Low
Extension or recurrence of ST	1 / 222	0,44 (0,26 – 0,74)	Low

Table 2. Efficacy and safety of prophylactic LMWH vs. placebo. Relative effects below 1 favour prophylactic LMWH. Major bleedings not assessable because no such events occurred

Therapeutic LMWH vs. placebo

Outcome	No. of studies / No. of patients	Odds Ratio (95% C.I.)	Quality of evidence
Symptomatic VTE	1 / 218	0,85 (0,23 – 3,06)	Low
Extension or recurrence of ST	1 / 218	0,46 (0,27 – 0,77)	Low

Table 3. Efficacy and safety of therapeutic LMWH vs. placebo. Relative effects below 1 favour therapeutic LMWH. Major bleedings not assessable because no such events occurred

Fondaparinux vs. rivaroxaban

Outcome	No. of studies / No. of patients	Relative effect (95% C.I.)	Quality of evidence
Symptomatic VTE	1 / 472	0,33 (0,03 – 3,18)
Recurrence of ST	1 / 472	0,75(0,17 – 3,31)
Serious adverse events	1 / 472	0,46(0,18 – 1,19)

Table 4. Efficacy and safety of fondaparinux vs. placebo. Relative effects below 1 favour fondaparinux. Extension of ST and major bleeding not assessable because no such events occurred

Non steroideal anti-inflammatory drugs (NSAID)

Outcome	No. of studies / No. of patients	Odds Ratio (95% C.I.)	Quality of evidence
Symptomatic VTE	1 / 211	0,91 (0,25 – 3,28)	Low
Extension or recurrence of ST	1 / 211	0,46 (0,27 – 0,78)	Low

Table 5. Efficacy and safety of NSAID vs. placebo. Relative effects below 1 favour NSAID

Comment and conclusions

The results of this systematic review confirm the recommendations of the latest guidelines on the subject. Both the American College of Chest Physicians and British Committee for Standards in Haematology (BCSH) documents suggest anti-coagulation for ST of the legs longer than 5 cm with fondaparinux o prophylactic dose LMWH (3,4).

In this systematic review, fondaparinux (2,5 mg daily for 45 days) appeared to be efficacious in reducing the incidence of MTVE during the follow up (RR 0,15 [95% C.I. 0,04 – 0,5]), the extension and the recurrence of SVT based on data from the CALISTO trial; quality of evidence was downgraded to moderate because of low number of events.

While for the strategy based on therapeutic dose of LMWH no clinical efficacy was demonstrated, when prophylactic dose was used a reduced incidence of extension or recurrence of ST was reported. In both cases, no major bleedings were recorded, probably because the sample size was not large enough to detect them. Consequently, the ACCP guidelines suggest the use of fondaparinux over prophylactic dose LMWH for treatment of SVT (3).

No conclusions can be drawn for NSAID, topical or surgical options due the small sample dimensions of the published trials and their low methodological quality.

For the whole of the included studies there is a high risk of bias; for this reason, quality of evidence is defined as low for most of interventions. Statistical analyses for publication bias were not performed because most studies did not evaluate the same treatment comparisons on the same study outcomes.

Anti-coagulation is now fully considered part of the treatment of SVT and the results of this meta-analysis, although based upon the data of the unique original trials, confirm this approach. In the future, it would be interesting to understand which anti-coagulation regimen is more useful and safe with a direct comparison of fondaparinux with LMWH.

Note:

SVT which extends to within 3 cm of the sapheno-femoral junction should be treated like DVT because the risks of progression are similar.

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