Rivaroxaban (Xarelto) was noninferior to standard treatment (heparin and warfarin) in preventing recurrent VTE in patients with acute pulmonary embolism (PE), in the large EINSTEIN-PE randomized trial published in the April 5 New England Journal of Medicine. A once-daily oral factor Xa inhibitor that has already been demonstrated to be noninferior for treatment of acute deep venous thrombosis (DVT), rivaroxaban now looks poised to soon displace the standard dual treatments of heparin and warfarin for these conditions, collectively referred to as venous thromboembolism (VTE).
What They Did
The EINSTEIN-PE investigators, working on behalf of Bayer HealthCare and Janssen Pharmaceuticals, randomized 4,832 patients with acute symptomatic PE to receive either rivaroxaban (15 mg twice daily for 3 weeks then 20 mg once daily) or enoxaparin then warfarin. This was an open-label trial (non-blinded). Patients were followed for 12 months. Primary outcomes were symptomatic recurrent DVT or PE, as well as bleeding.
What They Found
There were 50 episodes of recurrent VTE in the rivaroxaban group (2.1%), and 44 in the standard-therapy group (1.8%) -- statistically equal. Bleeding rates were also statistically equal. Events broke down as follows:
- Recurrent confirmed PEs: 24 on rivaroxaban (2 fatal) vs 20 on warfarin (1 fatal)
- Recurrent DVTs: 18 on rivaroxaban vs 17 on warfarin
- Major bleeding (>2 g/dL hemoglobin drop): 26 rivaroxaban (1.1%) vs 52 for standard therapy (2.2%)
- Notably, there were 10 intracranial hemorrhages and 7 retroperitoneal hemorrhages noted in the heparin/warfarin arm, and only 1 of each in the rivaroxaban arm.
- Minor bleeding: ~10% for each arm.
- All cause mortality: 2.4 vs. 2.1%
- There were a few deaths in which pulmonary embolism was not diagnosed but could not be ruled out; including all of these as well as the documented PEs, 11 deaths potentially due to PE were in the rivaroxaban arm and 7 in the warfarin arm.
What It Means
Rivaroxaban (Xarelto) was discovered by Bayer, who markets it in 110 countries outside the U.S. for multiple indications including atrial fibrillation, VTE prevention after orthopedic surgery, and for treatment/prevention after DVT/PE. Janssen (a division of Johnson & Johnson) sells Xarelto in the U.S., where it has FDA indications for VTE prevention after hip or knee replacement surgery and for stroke prevention for non-valvular atrial fibrillation.
If the event rates from the EINSTEIN-PE trial are borne out in clinical practice, an FDA indication for acute pulmonary embolism could usher in a new era of increased convenience for patients, shorter hospital stays and increased outpatient treatment of PE, and possibly fewer complications from drug interactions and/or bleeding associated with warfarin. As with any new drug approved on the basis of clinical trials designed, controlled and reported by industry, postmarketing data will be essential to determine the real-world risks and benefits of rivaroxaban.
Bayer/Janssen's rivaroxaban will compete in the marketplace with Boehringer-Ingelheim's oral direct thrombin inhibitor dabigatran (Pradaxa) for these indications. As of now, rivaroxaban seems to have the advantage that in the event of bleeding, it is reversible by infusion of prothrombin complex; dabigatran appears not to be reversible, although hemodialysis can remove some of the circulating drug.
EINSTEIN-PE investigators. Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism. N Engl J Med 2012;366:1287-1297.