1. Rivaroxaban is non-inferior to standard therapy of enoxaparin and vitamin K antagonist in treating acute, symptomatic deep-vein thrombosis
2. The risk of major and clinically relevant nonmajor bleeding was not significantly different when comparing rivaroxaban with standard therapy
Original Date of Publication: December 23, 2010
Study Rundown: The EINSTEN-DVT trial demonstrated that rivaroxaban is non-inferior to standard therapy (i.e., enoxaparin and warfarin) in treating acute, symptomatic deep-vein thrombosis (DVT) and preventing the recurrence of symptomatic venous thromboembolism (VTE) (HR 0.68; 95% CI 0.44-1.04). Moreover, this study demonstrated that there was no significant increase in the risk of bleeding with rivaroxaban, when compared to standard therapy. The new oral anticoagulants have shown much promise in randomized controlled trials thus far, particularly in treating acute VTE, VTE prophylaxis, and stroke prophylaxis in atrial fibrillation. Compared with low molecular weight heparins and vitamin K antagonists (VKA), these new oral agents are much easier to administer and also far less cumbersome with regards to monitoring. Concerns remain, however, regarding the lack of effective reversal agents for these medications, as numerous studies have demonstrated increased risk of clinically relevant bleeding.
In summary, rivaroxaban has been shown to be non-inferior to standard therapy, consisting of enoxaparin and warfarin, in treating acute, symptomatic DVT. Given the lack of a reversal agent, however, physicians should exercise caution in selecting the appropriate patients for treatment with the new oral anticoagulants.
In-Depth [randomized, controlled study]: The EINSTEN-DVT trial, originally published in 2010 in NEJM, consisted of two studies carried out in parallel. The first was an open-label, non-inferiority study that compared the effects of rivaroxaban with standard therapy (i.e., subcutaneous enoxaparin followed by a VKA) in treating acute, symptomatic DVT (the Acute DVT study). In the rivaroxaban group, patients received 15 mg BID for three weeks, followed by 20 mg OD for the remainder of the treatment time (3, 6, or 12 months). Patients in the standard therapy group were managed with enoxaparin until international normalized ratios (INR) exceeded 2, and their VKA dose was titrated to an INR of 2-3. The second was a double-blind, superiority study that compared 6-12 months of treatment with rivaroxaban with placebo after patients had completed 6-12 months of treatment for venous thromboembolism (the Extension study). Patients in the rivaroxaban group received 20 mg OD.
In both studies, the primary outcome was the recurrence of symptomatic venous thromboembolism (i.e., DVT, non-fatal or fatal pulmonary embolism). Notably, patients were excluded from both studies if they had creatinine clearance <30 mL/min. or clinically significant liver disease (i.e., acute hepatitis, chronic active hepatitis, cirrhosis).
A total of 3,449 patients were randomized to as part of the Acute DVT study, while 1,197 were enrolled in the Extension study. In the Acute DVT study, there were no significant differences between the two groups in terms of the primary outcome (HR 0.68; 95% CI 0.44-1.04). Moreover, there were no significant differences in terms of major bleeding (HR 0.63; 95% CI 0.33-1.30). In the Extension study, the rivaroxaban group experienced significantly lower rates of the primary outcome, as compared to the placebo group (HR 0.18; 95% CI 0.09-0.39). Patients in the rivaroxaban group, however, did experience significantly higher rates of major and clinically relevant nonmajor bleeding (HR 5.19; 95% CI 2.3-11.7).
By Adrienne Cheung and Andrew Cheung, M.D.
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