Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation, according to the EINSTEIN researchers, who published their results Dec. 4 in the New England Journal of Medicine.
Acute venous thromboembolism (VTE) (i.e., deep vein thrombosis [DVT] or pulmonary embolism) is a common disorder with an annual incidence of approximately one or two cases per 1,000 persons in the general population. According to the authors, short-term treatment is effective, with the risk of recurrent disease — the major complication — reduced from an estimated 25 percent to approximately 3 percent during the first six to 12 months of therapy. The risk of recurrence remains after treatment ends and can reach 5 to 10 percent during the first year.
In two dose-finding studies, researchers established the feasibility of single-agent therapy with rivaroxaban in patients with DVT. This led to the EINSTEIN program, consisting of three randomized trials of rivaroxaban: one for the treatment of acute DVT (the Acute DVT study), one for the treatment of acute pulmonary embolism (the Acute PE Study) and one for continued treatment in patients who have received treatment for acute DVT or pulmonary embolism (the Continued Treatment Study). In these findings, Harry R. Buller, MD, from the department of vascular medicine at the Academic Medical Center in Amsterdam, and colleagues are reporting the results of the first and third trials; the second trial is ongoing.
They conducted an open-label, randomized, event-driven, non-inferiority study that compared oral rivaroxaban alone (15 mg twice daily for three weeks, followed by 20 mg once daily) with subcutaneous enoxaparin (Lovenox, Sanofi-Aventis) followed by a vitamin K antagonist (either warfarin or acenocoumarol) for three, six or 12 months in patients with acute, symptomatic DVT.
In parallel, the researchers carried out a double-blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional six or 12 months in patients who had completed six to 12 months of treatment for VTE.
The primary efficacy outcome for both studies was recurrent VTE. The principal safety outcome was major bleeding or clinically relevant non-major bleeding in the initial-treatment study and major bleeding in the continued-treatment study.
The study of rivaroxaban for acute DVT included 3,449 patients: 1,731 given rivaroxaban and 1,718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had non-inferior efficacy with respect to the primary outcome (2.1 percent of events vs. 3 percent of events with enoxaparin–vitamin K antagonist). The principal safety outcome occurred in 8.1 percent of the patients in each group.
In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (1.3 percent vs. 7.1 percent with placebo). Four patients in the rivaroxaban group had nonfatal major bleeding (0.7 percent) versus none in the placebo group.
“A unique aspect of the Acute DVT Study is the use of rivaroxaban as a single agent, replacing both low-molecular-weight heparin and a vitamin K antagonist in the treatment of DVT,” Buller and colleagues wrote. “Accordingly, the great majority of patients in the rivaroxaban group either did not receive low-molecular-weight heparin or received a single dose. Nevertheless, efficacy during the first weeks of treatment was similar in the two study groups. A pre-specified indicator of net clinical benefit (symptomatic recurrent VTE plus major bleeding) favored rivaroxaban. Therefore, the rivaroxaban regimen may further facilitate the outpatient management of DVT.”
Bayer Schering Pharma and Ortho-McNeil Pharmaceuticals funded the study.