New Phase 3 study finds Xarelto to be superior to aspirin for long-term prevention of recurrent blood clots without observing any significant increase in major bleeding in patients with venous thromboembolism.
Janssen Pharmaceuticals, Inc. announced new Phase 3 results from EINSTEIN CHOICE showing patients with venous thromboembolism (VTE) taking Xarelto (rivaroxaban), who received either 10 mg or 20 mg once daily over an extended time period, had significantly fewer recurrent blood clots and similar rates of major bleeding compared to those taking aspirin 100 mg once daily. Specifically, Xarelto 10 mg reduced the risk of recurrent VTE by 74 percent and Xarelto 20 mg by 66 percent.
These findings were presented during a Joint American College of Cardiology/Journal of the American Medical Association “Late-Breaking Clinical Trials” session at the American College of Cardiology’s 66th Annual Scientific Session (ACC.17) and published simultaneously in The New England Journal of Medicine. EINSTEIN CHOICE is part of the EXPLORER clinical research program for Xarelto, a collaborative effort between Janssen and its development partner, Bayer.
VTE, which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), affects more than 900,000 Americans each year; one-third of these occurrences are fatali. As all people with VTE are at risk of having another occurrence, guidelines currently recommend anticoagulant therapy with a non-vitamin K antagonist oral anticoagulant (NOAC), like Xarelto, for three months or longerii.
Once anticoagulant therapy is stopped, up to 10 percent of people will experience a recurrence during the first year and up to 20 percent within three yearsiii. In people who decide to stop anticoagulant therapy, guidelines currently suggest using aspirin for long-term prevention of recurrent VTE rather than no aspirin at all.ii The EINSTEIN CHOICE study was designed to compare the efficacy and safety of Xarelto to aspirin for continued VTE management.
“How best to extend anticoagulant use beyond the initial treatment window has been a constant source of debate, with physicians carefully balancing patients’ risk of another VTE with the risk of anticoagulant-related bleeding,” said study investigator Philip S. Wells, M.D., Professor, Chair and Chief, Department of Medicine, University of Ottawa, and Senior Scientist, The Ottawa Hospital, Ontario, Canada. “With EINSTEIN CHOICE, for the first time we have clinical evidence confirming rivaroxaban is superior to aspirin in reducing recurrent VTE, with no significant impact on safety. These important results have the potential to trigger a paradigm shift in how physicians manage their patients and protect them from VTE recurrence over the long term.”
EINSTEIN CHOICE met its primary endpoint, finding both Xarelto doses (10 mg and 20 mg) to be superior to aspirin in preventing recurrent VTE. Researchers observed the following:
- The rate of recurrent VTE was 1.2 percent in the Xarelto 10 mg group (HR=0.26; 95% CI, 0.14 to 0.47; p<0.001) and 1.5 percent in the Xarelto 20 mg group (HR=0.34; 95% CI, 0.20 to 0.59; p<0.001) compared to 4.4 percent in the aspirin group. Fatal VTE occurred in 0 percent, 0.2 percent and 0.2 percent, respectively.
- Rates of major bleeding were comparable and low across all treatment groups at 0.4 percent for Xarelto 10 mg (HR=1.64; 95% CI, 0.39 to 6.84; p=0.50), 0.5 percent for Xarelto 20 mg (HR=2.01; 95% CI, 0.50 to 8.04; p=0.32) and 0.3 percent for aspirin. Rates of clinically relevant non-major bleeding also were similar between the groups at 2.0 percent, 2.7 percent and 1.8 percent, respectively.
Other efficacy outcomes were evaluated in the study. Researchers found 1.9 percent of the Xarelto 10 mg group (HR=0.33; 95% CI, 0.20 to 0.54; p<0.001) and 2.0 percent of the Xarelto 20 mg group (HR=0.35; 95% CI, 0.22 to 0.57; p<0.001) experienced either a recurrent VTE (primary efficacy endpoint), heart attack, ischemic stroke, systemic embolism or venous thrombosis in another location compared to 5.6 percent of the aspirin group.
Recurrent VTE or all-cause mortality occurred in 1.3 percent of the Xarelto10 mg group (HR=0.27; 95% CI, 0.15 to 0.47; p<0.001) and 2.1 percent of the Xarelto 20 mg group (HR=0.42; 95% CI, 0.26 to 0.68; p<0.001) compared to 4.9 percent of the aspirin group. When looking at pre-specified subgroups, researchers found results for the primary efficacy endpoint (recurrent VTE) and composite outcome of major and clinically relevant non-major bleeding to be consistent with the overall findings.
“In addition to confirming findings from previous studies examining the long-term use of Xarelto in VTE, EINSTEIN CHOICE provides valuable clinical insights on the superiority of Xarelto to aspirin as well as the potential extended use of a lower dose of Xarelto for continued venous protection,” said Paul Burton, M.D., Ph.D., FACC, Vice President, Medical Affairs, Janssen. “We look forward to discussing these important data with the U.S. Food and Drug Administration.”
EINSTEIN CHOICE was led by principal investigator Jeffrey Weitz, M.D., Professor of Medicine, Michael G. DeGroote School of Medicine, McMaster University, and Director of McMaster’s Thrombosis & Atherosclerosis Research Institute.
The Phase 3, global, randomized, double-blind, superiority study compared the efficacy and safety of two doses of Xarelto (a prophylactic dose of 10 mg once daily and a treatment dose of 20 mg once daily) with aspirin 100 mg once daily for the continued management of VTE in people with confirmed DVT or PE who were initially treated with anticoagulant therapy for six to 12 months.
Approximately 3,365 patients from 31 countries were included in the study analysis. People who required extended anticoagulation at therapeutic doses were not included, as the objective of the study was to investigate those patients for whom the treating physician was uncertain about the need for continuing anticoagulant therapy.
Patients were randomized in a 1:1:1 ratio, with one group receiving Xarelto 10 mg, another group receiving Xarelto 20 mg, and a third receiving aspirin 100 mg, all given once daily for up to 12 months. Sixty percent of patients completed the full 12 months of treatment. The primary efficacy endpoint was fatal or non-fatal recurrent VTE (a composite of recurrent VTE, VTE-related death and unexplained death for which PE could not be excluded).
The primary safety endpoint was major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH). Only the primary efficacy outcome comparisons of Xarelto 10 mg vs. aspirin and Xarelto 20 mg vs. aspirin were powered for significance. Comparison of the two Xarelto arms was not powered for significance.
(Source: Johnson & Johnson)
Filed Under: Drug Discovery