Rivaroxaban found safe and effective in pulmonary embolism

By Dr. Ananya Mandal, MDMar 27 2012

Rivaroxaban has been found to be effective in the prevention of venous thromboembolism (VTE) after orthopedic surgery, for the prevention of stroke in AF (Atrial fibrillation) patients, and as additional therapy to conventional antiplatelet therapy in ACS (Acute coronary syndrome) patients.

In a new study presented at the American College of Cardiology meeting in Chicago and published simultaneously in the New England Journal of Medicine there is evidence that rivaroxaban is equally effective as standard therapy for the treatment of pulmonary embolism and may cause fewer bleeding complications.

The study called EINSTEIN-PE was a randomized, open-label, non-inferiority study comparing rivaroxaban to conventional therapy with enoxaparin and a vitamin K antagonist in 4,833 patients with pulmonary embolism. Rivaroxaban met the predefined margin for noninferiority to conventional treatment with respect to both clinical efficacy and safety.

The study, conducted at 263 sites in 38 countries, randomly assigned 2,419 patients to the rivaroxaban arm and 2,414 to standard treatment. All enrolled patients had a primary diagnosis of PE, and 25 percent in both groups also had DVT. Patients were treated for three, six or 12 months (average, seven) as deemed appropriate by each clinician before randomization. The rivaroxaban group received 15 mg twice a day for three weeks followed by 20 mg once a day. In the standard-therapy arm, the regimen was enoxaparin at 1.0 mg per kg of body weight twice daily, continued at least five days and stopped when the INR was 2.0 or more for two consecutive days, plus a VKA started within 48 hours after randomization with dose adjustment to maintain an INR of 2.0 to 3.0.

Primary efficacy endpoint was first symptomatic recurrent VTE. The endpoint was seen in 2.1%  for rivaroxaban patients versus 1.8% for standard therapy. Principal safety outcome (major or clinically relevant bleeding) was seen in 10.3% versus 11.4% in rivaroxaban compared to standard therapy. Major bleeding was significantly lower in the rivaroxaban group (1.1% versus 2.2%). Net clinical benefit (VTE plus major bleeding) was seen in 3.4% versus 4%.

“Physicians want to know about major bleeding, the most important safety outcome, and rivaroxaban was highly significantly superior. This was our most astonishing finding,” said EINSTEIN chair Harry Buller in an ACC press release. “Rivaroxaban is just as good as standard treatment for PE – these data are pretty convincing – and this is an oral-only approach, which makes it very simple. The subcutaneous injections can be hazardous as well.”

The EINSTEIN investigators concluded that, in conjunction with the earlier EINSTEIN trial in DVT, the EINSTEIN PE trial supports “the use of rivaroxaban as a single oral agent for patients with venous thromboembolism.”

Pulmonary embolism (PE) and deep vein thrombosis (DVT), a blot clot generally occurring in the legs, constitute the two categories of a condition called venous thromboembolism (VTE). VTE is the third most common cardiovascular disease, and PE is the third most common cause of hospital-related death.

EINSTEIN-PE is one of a series of large international phase III clinical trials of the anti-coagulant rivaroxaban to treat VTE or prevent a recurrence in patients with acute PE or DVT. The Food and Drug Administration has approved rivaroxaban as the only oral anti-coagulant for prevention of VTE in patients who have knee or hip replacement, procedures that carry clotting risks.

“If you give standard treatment in the right way, it’s a perfectly effective drug with almost 90 percent reduction in recurrent thrombosis, but it has to be well controlled,” said Harry R. Buller, professor of vascular medicine at the Academic Medical Center, Amsterdam, The Netherlands, who chairs the program for the three EINSTEIN studies. “The reason people look for alternatives is that it’s a nightmare to give. Rivaroxaban makes things easier for everybody – patients and physicians. Our major aim was to show that it’s at least as good as standard care.”

Researchers also will be doing a subgroup analysis of the 8,200 patients in the EINSTEIN-PE and EINSTEIN-DVT trials to see if they can identify a risk profile for patients who are likely to have bleeding problems on standard treatment or the new drug.

The trial was sponsored by Bayer HealthCare and Janssen Pharmaceuticals. Dr. Buller is reimbursed for patients who participate in the study, travel costs and administrative time, and those funds go to the hospital.