Long-term efficacy and safety of once-daily enoxaparin plus warfarin for the outpatient ambulatory treatment of lower-limb deep vein thrombosis in the TROMBOTEK trial

Abstract

Objective: The present study was designed to evaluate the long-term efficacy and safety of once-daily enoxaparin plus warfarin for the outpatient ambulatory treatment of lower-limb deep venous thrombosis (DVT).

Methods: A total of 246 patients, comprising 128 men (mean age, 54.28±16.48 years) and 118 women (mean age, 50.11±16.47 years) with symptomatic lower extremity DVT, were included in this open-label, single-arm, multicenter, phase IV clinical trial conducted at 14 centers in Turkey. All patients were administered subcutaneous enoxaparin (1.5 mg/kg, once-daily) until international normalized ratio (INR) levels reached to 2 to 3, followed by oral warfarin (5 mg/d) for at least 3 months and elastic compression stockings (30-40 mm Hg). Clinical signs (leg circumference), symptoms (edema, pain, tenderness), recanalization rates upon duplex ultrasound examination, laboratory findings (D-dimer and INR levels), and postthrombotic syndrome status with CEAP classification were the efficacy parameters evaluated every 3 months during 18 months of follow-up. Safety end points included minor and major bleeding as well as serious adverse events.

Results: Ambulatory treatment with enoxaparin plus warfarin significantly reduced physical symptoms, including tenderness, edema, pain (P<.001), and the circumference of the affected leg (P<.001). The leg circumference difference in almost all patients was <1.5 cm at the end of 18 months (P<.001). Recanalization rates for occluded iliofemoral vein were 76.1% at 3 months and 86.5% at 18 months (P<.001). An early and significant decrease obtained in D-dimer levels on day 10 continued to decline significantly until month 6 and remained unchanged afterwards (P<.001). Of four patients diagnosed with major bleeding during oral anticoagulant use, three recovered with conservative treatment (reduction in hemoglobin levels in 2 developed at visit 2 [day 10] and intracranial bleeding in 1 developed at visit 3 [day 30]), and one patient required a hysterectomy after menorrhagia developed at visit 7 (month 18). Two of the 65 (9.9%) adverse events documented were serious adverse events, but none of the serious adverse events leading to death were related to the study medications.

Conclusion: Ambulatory treatment with enoxaparin plus warfarin seems to be effective in symptomatic healing and in clinical improvement by reducing thrombus formation and organization at all levels of lower extremity venous system with DVT, without a significant major bleeding risk. Therefore, the results of our conventional conservative treatment are in line with 1A level evidence reported in the recent American College of Chest Physicians guideline.