Background
Venous thromboembolism (VTE) is a condition in which a blood clot forms in a vein, most commonly in the deep veins of the legs or pelvis. This is known as deep vein thrombosis, or DVT. The blood clot can dislodge and travel in the blood, particularly to the pulmonary arteries. This is known as pulmonary embolism, or PE. The term VTE includes both DVT and PE.
Distal DVT (also known as isolated distal DVT, calf DVT or below-the-knee DVT) occurs when the blood clot develops inside the leg veins (below the knee). The extension of the clot in proximal (above the knee) veins and the migration of a clot to the lungs (PE) are the most common complications. The best treatment of distal DVT is not clearly established. Distal DVT can either be treated with anticoagulation (medicines that help prevent blood clots), with or without additional use of compression stockings, or no medications can be given, and monitoring with repeat ultrasounds can be performed to see if the clots grow, which requires anticoagulation. The main side effect of anticoagulation medication is the increased risk of bleeding.
Study characteristics and key results
We identified eight randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) reporting on 1239 participants. Five of these trials randomised participants to anticoagulation for up to three months compared with no anticoagulation. Three trials compared anticoagulation treatment for different time periods.
Our review demonstrated that in participants with distal DVT compared with no anticoagulation or placebo (pretend treatment), anticoagulation reduced the risk of recurrence of VTE. There were similar results for the recurrence of DVT, while there was no clear effect on risk of PE. This benefit was seen at the expense of an increase in clinically relevant non-major bleeding, but not major bleeding.
In a direct comparison of treatment duration, anticoagulation for three months or more was superior to a shorter course lasting up to six weeks, showing a reduced risk of recurrence of VTE and DVT with no clear difference in major bleeding and clinically relevant non-major bleeding.
Reliability of the evidence
For the comparison anticoagulation versus no anticoagulation or placebo, the reliability of the evidence was high for recurrence of VTE, DVT, and clinically relevant non-major bleeding, and low for PE and major bleeding. For the comparison anticoagulation for three months or more versus six weeks, the reliability of the evidence was high for recurrence of VTE and DVT; and low for PE, major bleeding and clinically relevant non-major bleeding, The reliability of the evidence was downgraded because of variation (or imprecision) of the results due to small numbers of events.
Conclusion
Our review found a benefit for people with distal DVT treated with anticoagulation therapy with little or no clear difference in major bleeding events, although there was an increase in clinically relevant non-major bleeding when compared with no treatment or placebo. The small number of participants in this meta-analysis and strength of evidence suggests more research regarding the treatment of distal DVT is needed. Randomised controlled trials comparing different treatments and different treatment periods with placebo or compression therapy are required.
Our review found a benefit for people with distal DVT treated with anticoagulation therapy using VKA with little or no difference in major bleeding events although there was an increase in clinically relevant non-major bleeding when compared to no intervention or placebo. The small number of participants in this meta-analysis and strength of evidence prompts a call for more research regarding the treatment of distal DVT. RCTs comparing different treatments and different treatment periods with placebo or compression therapy, are required.
The treatment of distal (below the knee) deep vein thrombosis (DVT) is not clearly established. Distal DVT can either be treated with anticoagulation, or monitored with close follow-up to detect progression to the proximal veins (above the knee), which requires anticoagulation. Proponents of this monitoring strategy base their decision to withhold anticoagulation on the fact that progression is rare and most people can be spared from potential bleeding and other adverse effects of anticoagulation.
To assess the effects of different treatment interventions for people with distal (below the knee) deep vein thrombosis (DVT).
The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 12 February 2019. We also undertook reference checking to identify additional studies.
Randomised controlled trials (RCTs) for the treatment of distal DVT.
Two review authors independently selected trials and extracted data. We resolved disagreements by discussion. Primary outcomes of interest were recurrence of venous thromboembolism (VTE), DVT and major bleeding and follow up ranged from three months to two years. We performed fixed-effect model meta-analyses with risk ratio (RRs) and 95% confidence intervals (CIs). We assessed the certainty of the evidence using GRADE.
We identified eight RCTs reporting on 1239 participants. Five trials randomised participants to anticoagulation for up to three months versus no anticoagulation. Three trials compared anticoagulation treatment for different time periods.
Anticoagulant compared to no intervention or placebo for distal DVT treatment
Anticoagulation with a vitamin K antagonist (VKA) reduced the risk of recurrent VTE during follow-up compared with participants receiving no anticoagulation (RR 0.34, 95% CI 0.15 to 0.77; 5 studies, 496 participants; I2 = 3%; high-certainty evidence), and reduced the risk of recurrence of DVT (RR 0.25, 95% CI 0.10 to 0.67; 5 studies, 496 participants; I2 = 0%; high-certainty evidence). There was no clear effect on risk of pulmonary embolism (PE) (RR 0.81, 95% CI 0.18 to 3.59; 4 studies, 480 participants; I2 = 0%; low-certainty evidence). There was little to no difference in major bleeding with anticoagulation compared to placebo (RR 0.76, 95% CI 0.13 to 4.62; 4 studies, 480 participants; I2 = 26%; low-certainty evidence). There was an increase in clinically relevant non-major bleeding events in the group treated with anticoagulants (RR 3.34, 95% CI 1.07 to 10.46; 2 studies, 322 participants; I2 = 0%; high-certainty evidence). There was one death, not related to PE or major bleeding, in the anticoagulation group.
Anticoagulation for three months or more compared to anticoagulation for six weeks for distal DVT treatment
Three RCTs of 736 participants compared three or more months of anticoagulation with six weeks of anticoagulation. Anticoagulation with a VKA for three months or more reduced the incidence of recurrent VTE to 5.8% compared with 13.9% in participants treated for six weeks (RR 0.42, 95% CI 0.26 to 0.68; 3 studies, 736 participants; I2 = 50%; high-certainty evidence). The risk for recurrence of DVT was also reduced (RR 0.32, 95% CI 0.16 to 0.64; 2 studies, 389 participants; I2 = 48%; high-certainty evidence), but there was probably little or no difference in PE (RR 1.05, 95% CI 0.19 to 5.88; 2 studies, 389 participants; I2 = 0%; low-certainty evidence). There was no clear difference in major bleeding events (RR 3.42, 95% CI 0.36 to 32.35; 2 studies, 389 participants; I2 = 0%; low-certainty evidence) or clinically relevant non-major bleeding events (RR 1.76, 95% CI 0.90 to 3.42; 2 studies, 389 participants; I2 = 1%; low-certainty evidence) between three months or more of treatment and six weeks of treatment. There were no reports for overall mortality or PE and major bleeding-related deaths.