Anticoagulation for Distal Lower Extremity Deep Venous Thromboses

Kirkilesis G, Kakkos SK, Bicknell C, Salim S, Kakavia K. Treatment of distal deep vein thrombosis. Cochrane Database Syst Rev. 2020;4:CD013422.

Study Population: 8 trials comprising 1,239 participants

Recurrent VTE (recurrent distal DVT, progression of DVT to proximal veins, or pulmonary embolism), post thrombotic syndrome

Major bleeding

Deep venous thrombosis (DVT) has an incidence of 45 to 117 per 100,000 person-years.1 Distal DVT, defined as a venous thrombosis isolated to the calf veins, comprises one-third to one-half of all DVTs.2 However, the treatment of distal DVTs is more controversial with significant variations in practice with regard to decisions on anticoagulation.3

This systematic review and meta-analysis discussed here included five randomized controlled trials (n = 503 patients) comparing anticoagulation with no intervention or placebo for the treatment of distal DVTs, as well as three randomized controlled trials (n = 736 patients) comparing anticoagulation for six weeks versus 12 weeks or more.4 The trials included adults over 18 years of age with a distal DVT identified on ultrasound or venography. The primary outcomes were recurrence of VTE (defined as DVT recurrence in the calf veins, progression of DVT to proximal veins, and pulmonary embolism [PE]) and major bleeding (defined as a 2 g/dL decrease in hemoglobin, transfusion of ≥ 2 units of red cells, bleeding in a critical site, or bleeding contributing to death). Secondary outcomes included recurrence of DVT, PE, clinically relevant non-major bleeding (defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, unscheduled contact with a physician, interruption or discontinuation of study treatment, or associated with any other discomfort such as pain or impairment of activities of daily life), overall mortality, mortality related to PE or major bleeding, post-thrombotic syndrome, and resolution of symptoms.

According to the meta-analysis, the recurrence of VTE was lower in patients who were anticoagulated (5 studies; 503 participants; Relative risk [RR]: 0.34; 95% confidence interval [CI], 0.15 to 0.77; absolute risk difference [ARD]: 6%; NNT: 17; high-certainty evidence). The risk of DVT was also significantly lower in anticoagulated (5 studies; 503 participants; RR 0.25; 95% CI, 0.10 to 0.67; ARD: 6%; NNT: 17; high-certainty evidence). There was also an increased risk of clinically relevant non-major bleeding (2 studies; 329 participants; RR: 3.34; 95% CI, 1.07 to 10.46; ARD: 5%; NNH: 20; high-certainty evidence). There was no significant difference in risk of PE, post-thrombotic syndrome, major bleeding, or mortality between the groups (all low-certainty evidence).

This systematic review and meta-analysis has several important limitations. First, the overall sample size was low, and it is possible that a significant difference in PE or major bleeding may have been identified with a larger sample size. Additionally, there were differences in the treatment periods, with some studies treating patients with anticoagulation for 3 months while others treated for 6 weeks. All studies used vitamin K antagonists (following an initial course of heparin), so it is unclear if similar findings would be present with direct oral anticoagulants (DOACs). There was also significant heterogeneity between patient populations, including whether the DVTs were provoked or unprovoked. Moreover, most studies excluded patients with cancer-associated or recurrent distal DVTs, so it is unclear how the findings of this meta-analysis would apply to this population. The primary outcome included recurrence of distal DVT, progression of DVT to proximal veins, and PE. However, recurrence of a distal DVT is a less clinically significant outcome than the latter two outcomes. Two studies were partially funded by pharmaceutical companies. Due to the open-label design in most of the trials, participants were not blinded to their treatment allocation. Furthermore, the risk of post-thrombophlebitis syndrome, a major complication of distal lower extremity DVT, was only assessed in one of the five trials. Therefore, the impact of anticoagulation on reducing the risk of post-thrombotic syndrome is inconclusive. Finally, while this study focused on anticoagulation, the CHEST guidelines recommend serial imaging for two weeks in patients that have a distal DVT without severe symptoms or risk factors for extension, while reserving anticoagulation only for those with more severe disease or a high risk of extension.5 Therefore, it is important to engage in shared decision-making with patients to individualize the decision based on an individual’s risk of recurrence versus risk of bleeding.

Based on the existing data, anticoagulation was associated with a reduced rate of recurrent VTE with no significant increase in the risk of major bleeding compared to placebo or no intervention. However, given the limitations of the specific studies and need to individualize patient-oriented risks and benefits, we have assigned a color recommendation of Yellow (unclear if benefits) to this intervention. Further study is needed with larger sample sizes, patients taking DOACs for treatment of distal DVT, and other populations including those with cancer-associated or recurrent distal DVTs.

The original manuscript was published in Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.

September 1, 2020