Rivaroxaban was noninferior to standard treatment at preventing a recurrence of pulmonary embolism in an international open-label trial reported online in the New England Journal of Medicine and presented simultaneously at the annual meeting of the American College of Cardiology.
Rates of adverse bleeding events with rivaroxaban were similar to those with the more complex standard therapy of enoxaparin plus a vitamin K antagonist, a regimen that requires INR (international normalized ratio) monitoring, said Dr. Harry R. Buller of the department of vascular medicine at the University of Amsterdam and his associated in the EINSTEIN-PE clinical trial.
The study, sponsored by Bayer HealthCare and Janssen Pharmaceuticals, involved 4,832 adults with acute symptomatic pulmonary embolism (PE), with or without deep vein thrombosis (DVT), who were treated at 263 sites in 38 countries in 2007-2011. In all, 2,419 study subjects were randomly assigned to receive oral rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) and 2,413 to receive enoxaparin (1 mg/kg twice daily, which was discontinued when the INR reached 2.0 or greater for 2 consecutive days after at least 5 days of therapy) plus either warfarin or acenocoumarol at a dosage adjusted to maintain an INR of 2.0-3.0.
All study subjects were treated for durations of 3, 6, or 12 months, according to the wishes of their treating physicians and in keeping with current practice. The mean duration of treatment was approximately 9 months.
In the standard treatment group, the INR was in the therapeutic range 62.7% of the time. The INR was not measured in the rivaroxaban group, but adherence to therapy was high in 94.2% of patients.
The primary efficacy outcome was symptomatic recurrent venous thromboembolism, a composite of fatal and nonfatal PE or DVT. This occurred in 50 patients (2.1%) receiving rivaroxaban and 44 (1.8%) receiving standard therapy, which met the criterion for noninferiority, the investigators said (N. Engl. J. Med. 2012 March 26 [doi:10.1056/NEJMoa1113572]).
During the initial 3-week period of intensive rivaroxaban therapy, the primary efficacy outcome occurred in 18 patients (0.7%) of the rivaroxaban group and in 21 patients (0.9%) in the standard therapy group.
The efficacy results were similar in a per-protocol analysis and in an intention-to-treat analysis.
The primary safety outcome was clinically relevant bleeding, and it occurred in 249 subjects (10.3%) in the rivaroxaban group and in 274 (11.4%) in the standard treatment group. In particular, major bleeding events occurred in 26 patients (1.1%) taking rivaroxaban and 52 (2.2%) taking standard treatment.
During the initial 3-week period of intensive rivaroxaban therapy, bleeding rates were similar between the two study groups. Over the full course of treatment, "there were fewer episodes of intracranial bleeding or bleeding in critical areas in the rivaroxaban group than in the standard therapy group," Dr. Buller and his colleagues said.
With regard to other safety outcomes, the rates of acute coronary events were similar between the two study groups, at 0.6% with rivaroxaban and 0.9% with standard therapy. And abnormal findings on liver function tests were seen in 0.2% of both groups.
"The suggestion that rivaroxaban can be administered at the same dose in all patients without laboratory monitoring has raised concern," so the researchers performed multiple subgroup analyses to examine whether any particular patient group was at increased risk while taking the drug. They found that the rates of recurrent venous thromboembolism and of adverse bleeding events were similar between patients taking rivaroxaban and those on standard therapy regardless of age, sex, obesity status, level of renal function, and the extent of initial PE.
"We believe that our population is representative of the spectrum of patients who present with symptomatic PE," the investigators said, noting that nearly 25% of the study population had extensive PE and 13% had limited PE. Moreover, almost 25% also had concomitant DVT.
This study was supported by Bayer HealthCare and Janssen Pharmaceuticals. Dr. Buller reported ties to ICTOM/Bayer HealthCare, Sanofi-Aventis, Boehringer Ingelheim, Pfizer, GlaxoSmithKline, and Daiichi Sankyo, and his associates reported ties to numerous industry sources.