Best Evidence Analyses and Commentary

Rivaroxaban: Expanded Indication
Edward McLean, PharmD Candidate

In November 2012, the FDA expanded the approved use of the factor Xa inhibitor, rivaroxaban to include treatment of deep vein thrombosis (DVT), treatment of pulmonary embolisms (PE), and risk reduction of recurrent DVT and PE after acute treatment.1 Prior to this action, rivaroxaban gained FDA approval in 2011 for two indications: DVT / PE prophylaxis in post-surgical patients undergoing knee / hip procedures and the treatment of patients with atrial fibrillation. Rivaroxaban can be given orally, provides standardized dosing, and requires less invasive monitoring compared to alternative agents. The expanded use approval was based on results of three separate clinical trials that evaluated the safety and efficacy of rivaroxaban in an international patient population of 9,478 patients.

The Oral Rivaroxaban for Symptomatic Venous Thromboembolism (EINSTEIN-DVT) study was an open-label, randomized, event driven, non-inferiority trial published in the New England Journal of Medicine in 2010.2 Initially, the investigators compared safety and efficacy of once daily dosed rivaroxaban with subcutaneous enoxaparin and subsequent Vitamin K Antagonists (VKA) for the treatment of acute, symptomatic DVT for 3, 6, and 12 months in a patient population of 3,449. The primary efficacy endpoint was recurrent DVT events and the primary safety endpoint was major or clinically relevant non-major bleeding events. The results demonstrated non-inferiority of rivaroxaban to standard treatment causing recurrent events in 2.1% of the patient population vs. 3.0% in the control group, (hazard ratio, 0.68; 95% CI, 0.44 to 1.04; P<0.001). The primary safety outcome occurred in 8.1% of the patient population in both groups.

The EINSTEIN-DVT Continued Treatment Trial evaluated the use of rivaroxaban for an additional 6 to 12 months in a patient population which had completed a treatment course for an acute DVT / PE.2 The study was a double-blind, randomized, event-driven superiority clinical trial evaluating the safety and efficacy of rivaroxaban vs. placebo in a study population of 1,196 patients. The primary efficacy and safety endpoints were the same as the initial EINSTEIN-DVT Trial. The study concluded that rivaroxaban demonstrated superior efficacy, with thromboembolic event rate of 1.3% vs. 7.1%, (hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001). However, bleeding events occurred in 0.7% of the rivaroxaban treatment group vs. 0.0% for the placebo group.

The Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism (EINSTEIN-PE) study was a randomized, open-label, event driven, non-inferiority trial published in The New England Journal of Medicine in 2012. 3 Similar to the EINSTEIN-DVT trial, the investigators compared once daily dosed rivaroxaban with the standard treatment of enoxaparin and subsequent VKA for the treatment of acute symptomatic pulmonary embolism for 3, 6, and 12 months. Patient population for the study was 4,832, and the primary endpoints were recurrent events (efficacy) and major or clinically relevant non-major bleeding events (safety). The results demonstrated non-inferiority of rivaroxaban to standard treatment, with recurrent events occurring in 2.1% vs. 1.8%, (HR = 1.12; 95% CI, 0.75 to 1.68;
P = 0.003). Additionally, there was no difference in primary safety endpoints which occurred in 10.3 % of the rivaroxaban treatment group vs. 11.4% in the standard of care group (P = 0.23). Major bleeding occurred in 1.1% of the rivaroxaban group vs. 2.2% in the standard of care group (HR = 0.49; 95% CI, 0.31 to 0.79; P = 0.003).

Rivaroxaban offers an alternative option for clinicians to utilize in the treatment and prophylaxis of thromboembolic events. It should be noted that non-blinded, non-inferiority, comparative efficacy studies are not designed to demonstrate superiority. Use should be dictated by patient specific variables and clinicians should be mindful of the lack of adequate reversal agents for this particular medication.

1. "News & Events." FDA Expands Use of Xarelto to Treat, Reduce Recurrence of Blood Clots. Food and Drug Administration, 2 Nov. 2012. Web. 22 Nov. 2012. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm326654.htm.

2. Bauersachs R, Berkowitz DS, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363:2499-2510

3. Buller HR, Prins MH, Lensing AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287-1297


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