Abstract: We identified three additional trials (613 participants), therefore this update considered 33 studies involving 7296 people with ST of the legs. Treatment included fondaparinux; rivaroxaban; low molecular weight heparin (LMWH); unfractionated heparin (UFH); non-steroidal anti-inflammatory drugs (NSAIDs); compression stockings; and topical, intramuscular, or intravenous treatment to surgical interventions such as thrombectomy or ligation. Only a minority of trials compared treatment with placebo rather than an alternative treatment and many studies were small and of poor quality. Pooling of the data was possible for few outcomes, and none were part of a placebo-controlled trial. In one large, placebo-controlled RCT of 3002 participants, subcutaneous fondaparinux was associated with a significant reduction in symptomatic VTE (risk ratio (RR) 0.15, 95% confidence interval (CI) 0.04 to 0.50; moderate-quality evidence), ST extension (RR 0.08, 95% CI 0.03 to 0.22; moderate-quality evidence), and ST recurrence (RR 0.21, 95% CI 0.08 to 0.54; moderate-quality evidence) relative to placebo. Major bleeding was infrequent in both groups with very wide CIs around risk estimate (RR 0.99, 95% CI 0.06 to 15.86; moderate-quality evidence). In one RCT on 472 high-risk participants with ST, fondaparinux was associated with a non-significant reduction of symptomatic VTE compared to rivaroxaban 10 mg (RR 0.33, 95% CI 0.03 to 3.18; low-quality evidence). There were no major bleeding events in either group (low-quality evidence). In another placebo-controlled trial, both prophylactic and therapeutic doses of LMWH (prophylactic: RR 0.44, 95% CI 0.26 to 0.74; therapeutic: RR 0.46, 95% CI 0.27 to 0.77) and NSAIDs (RR 0.46, 95% CI 0.27 to 0.78) reduced the extension (low-quality evidence) and recurrence of ST (low-quality evidence) in comparison to placebo, with no significant effects on symptomatic VTE (low-quality evidence) or major bleeding (low-quality evidence). Overall, topical treatments improved local symptoms compared with placebo, but no data were provided on the effects on VTE and ST extension. Surgical treatment combined with elastic stockings was associated with a lower VTE rate and ST progression compared with elastic stockings alone. However, the majority of studies that compared different oral treatments, topical treatments, or surgery did not report VTE, ST progression, adverse events, or treatment adverse effects. Prophylactic dose fondaparinux given for 45 days appears to be a valid therapeutic option for ST of the legs for most people. The evidence on topical treatment or surgery is too limited and does not inform clinical practice about the effects of these treatments in terms of VTE. Further research is needed to assess the role of rivaroxaban and other direct oral factor-X or thrombin inhibitors, LMWH, and NSAIDs; the optimal doses and duration of treatment in people at various risk of recurrence; and whether a combination therapy may be more effective than single treatment. Adequately designed and conducted studies are required to clarify the role of topical and surgical treatments.

Plain-language summary: This update included 33 randomised controlled trials (clinical trials where people are randomly put into one of two or more treatment groups) involving 7296 participants. Treatments included rivaroxaban (a medicine called a direct oral inhibitor of activated factor X), injections of medicines under the skin to prevent blood clotting (e.g. fondaparinux, low molecular weight heparin, or unfractionated heparin), elastic compression stockings, oral non-steroidal anti-inflammatory drugs (NSAIDs; a pain killer medicine), topical treatment (medicine applied to the skin), and surgery. One large study, accounting for half of the participants included in the review, showed that treatment with fondaparinux for 45 days was associated with a significant reduction in symptomatic VTE (where symptoms indicate there is a VTE), ST extension (where the clot moves further up the leg), and recurrence of ST (where clots return) compared to placebo. Major bleeding was infrequent in both groups. In one study in people with ST at high risk of recurrent thromboembolic events, fondaparinux was associated with a non-significant reduction of symptomatic VTE compared to rivaroxaban. There were no major bleeding events in either group. Both low molecular weight heparin and NSAIDs reduced the occurrence of extension or recurrence of ST with no effect on symptomatic VTE or major bleeding. Topical treatments relieved local symptoms but the trials did not report on progression to VTE. Surgical treatment and wearing elastic stockings were associated with a lower rate of VTE and progression of the ST compared with elastic stockings alone. Overall, the quality of evidence was very low for most treatments due to poor study design, imprecision of results, lack of a placebo (non-treated) group and only one study in some comparison. The quality of evidence was low to moderate for comparisons in two placebo-controlled trials. In conclusion, fondaparinux appears to be an adequate treatment for most people with ST. The optimal dose and duration of treatment need to be established in people at high risk as well as people at low risk for recurrent thrombotic events. Further research is needed to assess the role of rivaroxaban and other such medicines, or thrombin, low molecular weight heparin or NSAIDs and to demonstrate the effectiveness, if any, of topical treatment, or surgery in terms of VTE.