In this issue of Blood, Leizorovicz et al show that progression of superficial venous thrombosis of the lower extremity is associated with a significant risk of deep vein thrombosis and pulmonary embolism regardless of proximity to the saphenofemoral venous junction.1 

Our approach to the evaluation and treatment of superficial venous thrombosis (SVT) has evolved over the past few decades. Until recently, it was generally believed that the course of SVT was benign and appropriately treated with local measures and/or antiinflammatory medications. However, we now know that up to 29% of patients presenting with acute SVT of the lower extremity have associated deep vein thrombosis (DVT) or symptomatic pulmonary embolism (PE).2,3  These findings have changed practice recommendations for patients presenting with acute SVT.4 

Given the thrombotic complications in patients with SVT, clinical trials to evaluate treatment approaches have been conducted. Three randomized trials separately evaluated 2 low-molecular-weight heparins (LMWHs) and fondaparinux compared with placebo or ibuprofen.5-7  While the dosing intensity and duration of treatment varied, patients randomized to the LMWHs or fondaparinux treatment arms in each study had a decrease in thrombus extension, and longer treatment (30 or 42 days) was associated with a significant decrease in DVT, PE, and/or thrombus extension compared with the control populations.

In the Comparison of Arixtra in lower LImb Superficial vein Thrombosis with placebO (CALISTO) trial, 3002 patients with acute SVT (≥5 cm by ultrasound) of the lower extremity were randomized in a double-blind fashion to receive fondaparinux (2.5 mg/day) or placebo injection for 45 days.5  In the treatment arm there was an 85% reduction in the composite endpoint of symptomatic PE, DVT, recurrent SVT, or extension of SVT to within 3 cm of the saphenofemoral junction (SFJ). In the placebo arm, 5 patients developed PEs and 18 developed DVT compared with no PEs and 3 DVT in the treatment arm. However, the cost effectiveness of this treatment approach has been questioned, with a cost of $500 000 per quality-adjusted life year gained compared with no treatment.8 

Our ability to define a higher-risk population could result in a more targeted and thus cost-effective approach to treatment of acute SVT. To that end, Leizorovicz et al used data on the 1500 patients randomized to placebo treatment in the CALISTO trial to further evaluate patients with SVT extension. In the placebo group subsequent thrombotic complications occurred more frequently if the involved veins were above the knee, if the subject had experienced venous thrombosis previously, or if the thrombus extended to within 10 cm of the SFJ. Symptomatic extension occurred in 7.3% of the placebo group (109/1500) compared to 1.1% of the fondaparinux-treated group (17/1502). Ninety-two percent of patients with extension had initial SVT involving the greater saphenous vein. Thus, extension into the SFJ, an accepted risk factor for deep venous propagation of SVT, would seem a likely risk factor for further complications.

In the report published in this issue of Blood, Leizorovicz et al performed a post hoc analysis of data from patients in the placebo arm of the CALISTO trial who experienced SVT extension by day 77, whether ≤3 cm or >3 cm from the SFJ. Surprisingly, there was no difference between the groups in incidence of subsequent DVT or PE, which occurred in approximately 9% of each group. There was also no difference in overall use of medical resources between the 2 groups.

Thus, patients with SVT extension are at significant risk of thrombotic complications, and proximity to the SFJ in patients with acute SVT of the greater saphenous vein should not be used as an indicator of greater risk of subsequent complications. Patients presumed to be at highest risk of complications were excluded from the initial CALISTO trial, including patients presenting with thrombus within 3 cm of the SFJ; those with cancer, recent SVT, or DVT/PE; and those with any condition favoring bleeding. Optimal treatment approaches for these patient populations, as well as for patients with upper extremity SVT, have yet to be determined.

Conflict-of-interest disclosure: The author's spouse holds stock in GlaxoSmithKline.

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