March 26, 2012—The American College of Cardiology (ACC) announced that data from the EINSTEIN-PE trial demonstrated that the oral anticoagulant, rivaroxaban, outperformed standard therapy on important safety measures for initial and long-term treatment of pulmonary embolism (PE) and showed comparable efficacy. The findings were presented at the ACC’s annual scientific session in Chicago and were simultaneously published online ahead of print in The New England Journal of Medicine. Prof. Harry R. Buller, MD, PhD, chairs the program for the three EINSTEIN studies.
According to the ACC, EINSTEIN-PE is one of a series of large international phase III clinical trials evaluating rivaroxaban to treat venous thromboembolism (VTE) or prevent a recurrence in patients with acute PE or deep vein thrombosis (DVT). The ACC noted that the US Food and Drug Administration has approved rivaroxaban as the only oral anticoagulant for prevention of VTE in patients who have knee or hip replacement. Endovascular Today reported on the approval on July 1, 2011.
Bayer AG (Leverkusen, Germany) is the manufacturer and international marketer of rivaroxaban under the brand name Xarelto. In the United States, Xarelto is marketed under license from Bayer by Janssen Pharmaceuticals, Inc. (Titusville, NJ), a Johnson & Johnson company. The companies cosponsored the EINSTEIN program. Xarelto works by blocking the blood-clotting factor Xa to reduce the tendency of blood to form clots.
The EINSTEIN-PE trial compared rivaroxaban with standard therapy, which includes injection of the anticoagulant enoxaparin, followed by a vitamin K antagonist (VKA; either warfarin or acenocoumarol) chosen by each participating site. The investigators sought to demonstrate that the oral drug as a single agent is equivalent to the complicated two-drug standard therapy.
The ACC noted that in addition to the need to inject enoxaparin, the standard regimen is complicated by the need to monitor the VKA with blood tests to make sure the dose is adequate and safe. VKAs can interact with common drugs such as antibiotics, as well as with alcohol and some foods. The monitoring measure is international normalized ratio (INR).
“If you give standard treatment in the right way, it’s a perfectly effective drug with almost 90% reduction in recurrent thrombosis, but it has to be well controlled,” commented Prof. Buller. “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.”
As detailed by the ACC, the EINSTEIN-PE study was conducted at 263 sites in 38 countries. Investigators 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% in both groups also had DVT. Patients were treated for 3, 6, or 12 months (average, 7 months) as deemed appropriate by each clinician before randomization. The rivaroxaban group received 15 mg twice a day for 3 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 5 days and stopped when the INR ≥ 2.0 for 2 consecutive days, plus a VKA started within 48 hours after randomization with dose adjustment to maintain an INR of 2.0 to 3.0.
The investigators found that rivaroxaban’s efficacy was highly significant for non-inferiority with 2.1% recurrences (50 events) vs 1.8% (44 events) in the standard-therapy arm. On safety measures of bleeding, rivaroxaban did much better: for the principal safety measure of major or clinically relevant bleeding, 10.3% vs 11.4% for standard treatment; for major bleeding alone, 1.1% vs 2.2% for standard therapy. Rates for primary endpoints were similar in both study arms regardless of patient characteristics.
“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 Prof. Buller. “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 ACC stated that investigators will be doing a subgroup analysis of the 8,200 patients in the EINSTEIN-PE and EINSTEIN-DVT trials to try to identify a risk profile for patients who are likely to have bleeding problems on standard treatment or the new drug.
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