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Rivaroxaban vs a Vitamin K antagonist (EINSTEIN-DVT trial)
Non-inferior to standard treatment (enoxaparin/VKA) for acute DVT treatment and superior to placebo for extended secondary prophylaxis

Michael Gulseth, Pharm.D and Sara Fowler, Pharm.D., Sanford University of South Dakota Medical Center
July, 2011

A new, potentially paradigm shifting trial, has been published on the treatment of acute deep vein thrombosis (DVT).1 EINSTEIN-DVT is an open-label, randomized, noninferiority trial reporting the use of rivaroxaban for the treatment of acute DVT compared to standard treatment of a subcutaneous enoxaparin and vitamin K antagonist (VKA) using warfarin or acenocoumarol. Therapy was continued for 3, 6, or 12 months depending on the desired length of therapy for each patient. The dose of rivaroxaban studied in the trial was 15 mg orally twice a day for 3 weeks, followed by 20 mg once daily. The primary efficacy outcome was recurrent venous thromboembolism and the primary safety outcome was major bleeding or clinically relevant nonmajor bleeding.

For the primary efficacy analysis in the acute DVT trial (n=1731 for rivaroxaban and n=1718 for enoxaparin/VKA), the incidence of recurrent VTE was 2.1% for the rivaroxaban group and 3% for the warfarin group. Rivaroxaban met the trial’s non-inferiority criteria. The composite rate of major bleeding and clinically relevant non-major bleeding was 8.1% in both groups. Major bleeding rates were also similar.

It is certainly possible that this trial could have contained some unintentional bias as it was open label in design. Further, due to the challenge of quickly enrolling patients with acute DVT in a trial, a significant number of patients were enrolled into the study after they had already received doses of a parenteral anticoagulant (over 73% for rivaroxaban patients) although efficacy was not notably different for rivaroxaban patient who initially received parenteral anticoagulation compared to those who did not.2 Another drawback of the trial was that of the patients on enoxaparin/VKA treatment, only 81% had an INR that was greater than 2 when the enoxaparin was discontinued. Finally, assuring the dosing of rivaroxaban is done correctly in “real life” practice may also be challenging. Many of these patients, for example, may spend a short time in the hospital and it will be critical that the correct doses for the correct time periods are clearly spelled out at discharge. This may be less of a challenge if the DVT is completely treated in the ambulatory setting assuming the company develops some type of dosing aid for patients. Regardless, assuring the correct dosing at the correct times will be a key patient education issue.

This article also contains a treatment extension study looking at the efficacy and safety of using rivaroxaban (at a dose of 20 mg daily) for continued prophylaxis, after an initial treatment phase of 6-12 months, compared to placebo. The patients were followed for an additional 6-12 months. The Extension study was a randomized, double-blind, superiority trial. The primary efficacy outcome was recurrent venous thromboembolism and the primary safety outcome was major bleeding. For the primary efficacy analysis (n=602 for rivaroxaban and n=594 for placebo), the incidence of recurrent VTE and related mortality was 1.3% for the rivaroxaban group and 7.1% for the placebo group (p<0.001). The major bleeding rate was 0.7% in the rivaroxaban compared to 0% in the placebo group (p<0.001). Rivaroxaban was shown to have superior efficacy and similar bleeding rates, but a comparison to warfarin may have been more appropriate and helpful for determining proper long term prophylaxis therapy as warfarin has documented similar efficacy when compared to placebo.3,4

EINSTEIN-PE will evaluate the use of rivaroxaban compared to standard therapy for pulmonary embolisms (PE) and is expected to be published in the near future. These trials, as a whole, could lead to a strategy that eliminates the need for initial parenteral anticoagulation for some DVT/PE patients.

References

  1. Investigators TE. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. Dec 23 2010;363(26):2499-2510.

  2. Investigators TE. Supplement to: Oral rivaroxaban for symptomatic venous thromboembolism. http://www.nejm.org.ezproxy.usd.edu/doi/suppl/
    10.1056/NEJMoa1007903/suppl_file/nejmoa1007903_appendix.pdf
    . Accessed February 26, 2011.

  3. Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. Apr 10 2003;348(15):1425-1434.

  4. Kearon C, Ginsberg JS, Kovacs MJ, et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med. Aug 14 2003;349(7):631-639.
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