Rivaroxaban as effective as standard therapy for treating PE with lower risk of bleeding

April 5, 2012

Rivaroxaban, an oral blood thinner, is equally effective as standard therapy for the treatment of pulmonary embolism and may cause fewer bleeding complications, according to new data

Rivaroxaban, an oral blood thinner, is equally effective as standard therapy for the treatment of pulmonary embolism (PE) and may cause fewer bleeding complications, according to new data.

Standard therapy is the injection of the anticoagulant enoxaparin, followed by a vitamin K antagonist (VKA; either warfarin or acenocoumarol).

The data was presented March 26 at the American College of Cardiology’s 61st Annual Scientific Session and simultaneously published in the New England Journal of Medicine.

The EINSTEIN-PE study was a randomized, open-label trial comparing the efficacy and safety of rivaroxaban as a single-drug approach with standard therapy in patients with acute symptomatic PE with or without deep-vein thrombosis (DVT).

The trial was part of a larger program called EINSTEIN, which is a series of international phase 3 clinical trials looking at rivaroxaban to treat venous thromboembolism (VTE), the third most common cardiovascular disease, or to prevent a recurrence in patients with acute PE or DVT.

“For half a century, the standard therapy for most patients with pulmonary embolism has been the administration of heparin, overlapped and followed by a vitamin K antagonist,” stated Harry R. Buller, MD, PhD, professor of vascular medicine at the Academic Medical Center, Amsterdam, The Netherlands, and colleagues.

“This regimen is effective but complex. Recently developed oral anticoagulants that are directed against factor Xa or thrombin overcome some limitations of standard therapy, including the need for injection and for regular dose adjustments on the basis of laboratory monitoring,” the authors said.

The investigators enrolled 4,832 patients at 263 sites in 38 countries, with the following assignments:

2,419 patients received rivaroxaban 15 mg twice daily for the first 3 weeks followed by 20 mg once daily.

2,413 patients received enoxaparin 1.0 mg/kg of body weight twice daily followed by an adjusted dose of either warfarin or acenocoumarol (standard therapy) for 3, 6, or 12 months.

The monitoring measure was the international normalized ratio (INR), an expression of the time it takes blood to clot: the higher the INR number, the higher the risk of bleeding. INR was determined at least once a month. Enoxaparin was continued until a patient’s INR was 2.0 or more for 2 consecutive days and the patient had received at least 5 days of enoxaparin treatment. The dose of the vitamin K antagonist was adjusted to maintain an INR of 2.0 to 3.0.

Over a mean 9-month follow-up period, the authors noted a 2.1% recurrence rate in patients assigned to rivaroxaban compared with 1.8% for patients assigned to standard therapy. The primary safety outcome-major or clinically relevant nonmajor bleeding-occurred in 10.3% of patients assigned to rivaroxaban and 11.4% of patients assigned to standard therapy. Major bleeding was noted in 1.1% of patients assigned to rivaroxaban and 2.2% of those assigned to standard therapy.

“The suggestion that rivaroxaban can be administered at the same dose in all patients without laboratory monitoring has raised concern,” the authors noted. “Therefore, we performed multiple subgroup analyses for both efficacy and safety. Rates of recurrent venous thromboembolism and bleeding were similar in the two study groups regardless of age, sex, presence or absence of obesity, level of renal function, or extent of pulmonary embolism.”

The researchers said that the study supported the use of a fixed-dose regimen of rivaroxaban alone for the initial and long-term treatment of PE and may have a better benefit-risk profile than standard therapy.

According to a press release from Janssen Pharmaceuticals, the company plans to file a supplemental New Drug Application with FDA during the second quarter of this year.

The EINSTEIN-PE trial was sponsored by Bayer HealthCare and Janssen Pharmaceuticals.