Rivaroxaban (Xarelto(®)), an oral direct factor Xa inhibitor, is approved for the initial treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as the prevention of recurrent DVT and PE. It is administered at a fixed oral dose and does not require routine coagulation monitoring. In the EINSTEIN-DVT and EINSTEIN-PE trials, in over 8,000 patients with DVT and/or PE, a single-drug approach with rivaroxaban was shown to be noninferior to standard therapy consisting of subcutaneous enoxaparin sodium overlapping with and followed by an oral dose-adjusted vitamin K antagonist (enoxaparin-VKA) with regard to the incidence of symptomatic recurrent venous thromboembolism (VTE) after 3, 6 or 12 months of treatment. Rivaroxaban was generally well tolerated in patients with DVT or PE, with no significant between-group differences in clinically relevant bleeding between the rivaroxaban and enoxaparin-VKA groups. Notably, rivaroxaban was associated with a significantly lower rate of major bleeding compared with enoxaparin-VKA when EINSTEIN-DVT and EINSTEIN-PE data were pooled. Pharmacoeconomic analyses indicated that rivaroxaban may be a cost-effective alternative to enoxaparin-VKA for the treatment of DVT or PE and prevention of recurrent VTE.
NICE Guidelines
In all scenarios assessed for the 3-, 6- and 12-month treatment durations, rivaroxaban either continued to dominate or the ICER compared with LMWH and a vitamin K antagonist could be considered a cost-effective use of NHS resources. The Committee concluded that rivaroxaban was cost effective for treating pulmonary embolism for 3, 6 or 12 months.
NICE recommends rivaroxaban as a possible treatment for adults with pulmonary embolism and to prevent a further deep vein thrombosis or pulmonary embolism.
The primary efficacy outcome in EINSTEIN‑PE was symptomatic recurrent venous thromboembolism. The Committee noted that for the whole trial population, the rates of recurrent venous thromboembolism were not statistically significantly different in the rivaroxaban and LMWH with a vitamin K antagonist arms in the trial. The Committee concluded that rivaroxaban had acceptable clinical effectiveness compared with LMWH and a vitamin K antagonist.
EINSTEIN-PE
In a randomized, open-label, event-driven, noninferiority trial involving 4832 patients who had acute symptomatic pulmonary embolism with or without deep-vein thrombosis, they compared rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with standard therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding.
A total of 1173 patients (nearly 25%) in our study met our definition of extensive disease, and 608 (13%) had limited pulmonary embolism. Furthermore, nearly 25% had concomitant symptomatic deep-vein thrombosis. 64.7% of PE causes were unprovoked.
Rivaroxaban was noninferior to standard therapy (noninferiority margin, 2.0; P=0.003) for the primary efficacy outcome, with 50 events in the rivaroxaban group (2.1%) versus 44 events in the standard-therapy group (1.8%) (hazard ratio, 1.12; 95% confidence interval [CI], 0.75 to 1.68). The principal safety outcome occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard-therapy group (hazard ratio, 0.90; 95% CI, 0.76 to 1.07; P=0.23). Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P=0.003). Rates of other adverse events were similar in the two groups.
In this study involving patients with symptomatic pulmonary embolism, oral rivaroxaban alone provided protection from recurrent venous thromboembolism that was similar to the protection provided by standard therapy, with similar bleeding rates. During a mean study duration of approximately 9 months, there was a recurrence in 2.1% of patients in the rivaroxaban group and 1.8% of those in the standard-therapy group.
The INR in the therapeutic range 62.7% of the time and exceeding 3.0 only 15.5% of the time. These results compare favorably with the findings in other contemporary studies of venous thromboembolism. Adherence to the rivaroxaban regimen was high in 94% of patients. The number of patients who were lost to follow-up was negligible.
One potential limitation to this study is that, prior to randomization into the rivaroxaban or standard therapy groups, all patients received LMWH for varying amounts of time, though almost all patients received LMWH for less than 48 hours. While the authors argue that the administration of LMWH for such a brief period should not affect results, it is possible that receiving LMWH for up to 48 hours could have some impact. The other, and perhaps more significant, limitation of this study is that it was an open trial, meaning that neither patients nor researchers were blinded as to what treatment was being administered. However, while the criteria for diagnosing recurrence of venous thromboembolism were objective diagnostic findings, the open design may have had more of an impact on secondary outcomes.
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