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EINSTEIN-CHOICE: Recurrent VTE lower with rivaroxaban vs. aspirin, without rise in bleeding
WASHINGTON — Patients with venous thromboembolism assigned 10 mg or 20 mg of rivaroxaban had lower risk for recurrence compared with those who used aspirin, with no difference in bleeding, according to new data from the EINSTEIN-CHOICE trial.
“Rivaroxaban 10 mg once daily provides an additional option for extended VTE treatment, one we did not have available to us before,” Phillip S. Wells, MD, from the department of medicine at University of Ottawa and the Ottawa Hospital Research Institute, Canada, said during a presentation.
Researchers assigned 3,396 patients with VTE (mean age, 58 years; 55% men) to receive rivaroxaban (Xarelto, Janssen Pharmaceuticals/Bayer) in a 10-mg or 20-mg dose, or 100 mg of aspirin. Patients received the study drugs for up to 12 months. All had completed 6 to 12 months of oral anticoagulation therapy without interruption for more than 7 days.
The primary analyses included 3,365 patients; 31 were excluded because they did not receive any study drug.
According to Wells, both doses of rivaroxaban were associated with lower risk for the primary efficacy endpoint of fatal or nonfatal recurrent VTE. The rate was 1.5% in the 20-mg rivaroxaban group, 1.2% in the 10-mg rivaroxaban group and 4.4% in the aspirin group (HR for rivaroxaban 20 mg vs. aspirin = 2.01; 95% CI, 0.5-8.04; HR for rivaroxaban 10 mg vs. aspirin = 1.64; 95% CI, 0.39-6.84).
The primary safety outcome of major bleeding occurred in 0.5% of the 20-mg rivaroxaban group, 0.4% of the 10-mg rivaroxaban group and 0.3% of the aspirin group (HR for rivaroxaban 20 mg vs. aspirin = 0.34; 95% CI, 0.2-0.59; HR for rivaroxaban 10 mg vs. aspirin = 0.26; 95% CI, 0.14-0.47).
“Similarly, if you look at major or clinically relevant nonmajor bleeding, and if you look at bleeding which required study drug interruption ... none of these changed the outcomes in any specific ways,” Wells said.
Moreover, there was no significant difference between the two rivaroxaban groups for efficacy and safety outcomes, but the study was not powered to differ between them, Wells said.
Adverse events occurred at a similar rate in all three groups.
“Both rivaroxaban 20 mg and rivaroxaban 10 mg are superior to aspirin for the primary [outcome] and all efficacy outcomes, and are associated with similar and very low rates of bleeding,” Wells said. He further noted that the number needed to treat to prevent one VTE event was 33 for rivaroxaban 20 mg and 30 for rivaroxaban 10 mg.
The study was simultaneously published in The New England Journal of Medicine. Given these results and those of AMPLIFY-EXT, which found that 2.5-mg and 5-mg doses of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) reduced risk for recurrent VTE compared with placebo without increased bleeding risk, direct oral anticoagulants are “attractive for long-term secondary prevention of [VTE], Mark A. Crowther, MD, MSc, FRCPC, department chair and professor of pathology and molecular medicine, McMaster University, Hamilton, Ontario, Canada, and Adam C. Cuker, MD, MS, assistant professor of medicine at the Hospital of the University of Pennsylvania and assistant professor of pathology and laboratory medicine at University of Pennsylvania Perelman School of Medicine, wrote in a related NEJM editorial.
“The emergence of rivaroxaban and other direct oral anticoagulant agents has altered the standard of care among patients with [VTE],” Crowther and Cuker wrote. “Clinicians who choose this strategy can be confident of excellent efficacy and low bleeding risk similar to that observed with aspirin or placebo.” – by Erik Swain
References:
Weitz JI, et al. Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 17-19, 2017; Washington, D.C.
Crowther MA, Cuker A. N Engl J Med. 2017;doi:10.1056/NEJMe1701628.
Weitz JI, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1700518.
Disclosure: The study was funded by Bayer. Crowther reports financial ties with Alexion, Bayer, Leo Pharma, OctaPharma, Pfizer, Portola and Shinogi. Cuker reports receiving grant support from Bayer/Janssen. Wells reports serving on an advisory board and receiving honoraria from Bayer, receiving research support and honoraria from Bristol-Myers Squibb/Pfizer, and receiving honoraria from Daiichi Sankyo.
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This is a very important study because it is another piece of the puzzle that helps us figure out how best to take care of patients with prior VTE who have received a short-term anticoagulant therapy. Most guidelines recommend a short duration of anticoagulation therapy, but now there is some suggestion that extended duration is of value, and there are many different options, including vitamin K antagonists, one of the direct oral anticoagulants and aspirin. There has been a lot of use of aspirin therapy because it was compared against placebo. But aspirin was never compared with a direct oral anticoagulant in this population.
There are important clinical implications of this trial. Rivaroxaban, likely at the lower dose of 10 mg per day, will become a very viable option for treating patients with VTE. This adds to information that this regimen is better than aspirin. Some clinicians have preferred to use aspirin in patients at high risk for bleeding, but this trial supports that there is no major increased risk for bleeding with rivaroxaban vs. aspirin, and there is more benefit regarding recurrence.
Despite the very robust benefit of rivaroxaban — the absolute risk reduction was 3% over 12 months, which is very impressive — we don’t have a great handle on the safety because there were very few major bleeds. Monitoring what happens in the real world will be very important.