Residual Thrombosis on Ultrasonography to Guide the Duration of Anticoagulation in Patients With Deep Venous Thrombosis: A Randomized Trial

Abstract

Conclusion: Rates of recurrent venous thromboembolism (VTE) in adults with proximal deep venous thrombosis (DVT) can be reduced by tailoring the duration of anticoagulation on the basis of ultrasound findings. Summary: Patients with DVT are known to have an increased risk for recurrent VTE after anticoagulation (JAMA 2005;294:706-15). Anticoagulation is generally prescribed for 3 months for patients with reversible risk factors and for a minimum of 6 months for those patients with permanent risk factors or venous thrombosis (Chest 2008;133:454-5s). An association has been suggested between residual thrombosis present by ultrasound imaging at the time warfarin therapy is discontinued and an increased risk of subsequent recurrent VTE (Ann Intern Med 2002;137:955-60). The authors performed a randomized trial to evaluate the efficacy of tailoring the duration of anticoagulation based on recanalization or persistence of residual venous thrombosis as determined by ultrasound imaging. Patients with the first episode of proximal DVT who completed 3 months of anticoagulation were assigned to receive fixed-duration anticoagulation or flexible ultrasound-guided anticoagulation. This was a randomized, multicenter, open-label trial with independent and blinded assessments of study outcomes. Patients were recruited between January 1999 and July 2003, and the study ended when the last recruited patient had 3 years of follow-up. The study was conducted at nine centers in Italy. In patients assigned to the fixed-duration of anticoagulation, those with unprovoked DVT received 3 additional months of treatment for a total of 6 months, and anticoagulation was discontinued after 3 months in those with secondary DVT. Patients assigned to a flexible-duration of anticoagulation underwent ultrasound imaging after 3 months of anticoagulation. If the veins had recanalized, anticoagulation was discontinued. If the veins had not recanalized, patients were invited to undergo further ultrasound imaging after 3 and 9 months if they had a secondary DVT and to undergo further examinations after 3, 6, 9, 15, and 20 months if they had had an unprovoked DVT. Anticoagulation was discontinued when the veins had recanalized. Patients were monitored for symptomatic recurrent VTE and major bleeding episodes. Of 538 consecutive patients who underwent a 3-month period of anticoagulation, 530 completed the trial. Overall, recurrent VTE developed in 46 of 268 patients (17.2%) allocated to fixed-duration anticoagulation and 32 of the 270 (11.9%) allocated to flexible-duration anticoagulation (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.39-0.99). If patients had unprovoked DVT, the adjusted HR was 0.61 (95% CI, 0.36-1.02). In those with secondary DVT, the HR ratio was 0.81 (95% CI, 0.32-2.06). Major bleeding occurred in 0.7% of patients in the fixed-duration group and in 1.5% in the flexible-duration group (P = .67). Comment: Tailoring the duration of oral anticoagulant therapy based on follow-up ultrasound studies reduced the risk of recurrent VTE by 35% compared with a fixed-duration administration of warfarin therapy. The data also suggest the greatest benefit of flexible-duration warfarin therapy is in those with unprovoked DVT. The major problem in extrapolating these data to clinical practice is the authors' criteria for determining recanalization of a thrombosed vein. Ultrasound criteria for quantifying residual venous thrombosis are not widely used. Their criteria for a recanalized vein were that a vein was <2 mm in diameter with probe compression or <3 mm in diameter on two consecutive examinations. These criteria differ substantially from other criteria used to determine the presence of residual thrombosis after VTE (J Thromb Haemost 2006;4:1919-24). Additional studies will be needed to determine if the authors' approach and, in particular, their method of determining recanalization of a thrombosed vein is medically sound, safe, and cost-effective in routine clinical practice.