Oral Xa Drug Matches Warfarin in Afib
By Crystal Phend, Senior Staff Writer, MedPage Today
August 10, 2011
This randomized controlled trial compared rivaroxaban, an oral factor Xa inhibitor, to warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation.
Rivaroxaban was non-inferior to warfarin for the prevention of stroke or systemic embolization in both the per-protocol and intention-to-treat analysis. Rivaroxaban was not superior to warfain in the intention-to-treat analysis.
There was no difference in major bleeding between warfarin and rivaroxaban.
Review
The oral factor Xa inhibitor rivaroxaban (Xarelto) is at least as good as warfarin for stroke prevention in atrial fibrillation, with a similar rate of major bleeding and greater ease of use.
In the per protocol analysis, stroke or systemic embolism occurred at a rate of 1.7% per year with rivaroxaban compared with 2.2% per year with warfarin, Manesh R. Patel, MD, of Duke University Medical Center in Durham, N.C., and colleagues reported in the pivotal ROCKET-AF trial.
Rivaroxaban was non-inferior to warfarin for the prevention of stroke or systemic embolization in both the per-protocol (P<0.001) and intention-to-treat analyses (P<0.001), according to the study published online in the New England Journal of Medicine.
In the as-treated safety analysis, in which subjects must have received at least one dose of a study drug and included events which occurred while receiving the assigned drug or within two days after discontinuation, rivaroxaban was superior to warfarin (P=0.01). Rivaroxaban was not superior in the intention-to-treat analysis (P=0.12).
"For sure it's at least as good as warfarin," Patel told MedPage Today. "It's a once-a-day therapy without monitoring ... so there are some clear potential advantages here."
Safety may be another attractive point, he noted in the interview.
Although overall bleeding events didn't differ significantly for the two treatments (annual rate 14.9% rivaroxaban versus 14.5% warfarin, P=0.44), intracranial hemorrhage fell to 0.5% with rivaroxaban compared with 0.7% on warfarin (P=0.02).
Fatal bleeds also dropped to 0.2% and 0.5%, respectively (P=0.003), for a trend to fewer deaths overall in the as-treated safety population (1.9% versus 2.2% per year, P=0.07).
Bleeding from GI sites, bleeding that reduced hemoglobin levels, and bleeding that required transfusion, however, were all significantly more common with rivaroxaban, the researchers noted.
A significant increased risk of major bleeding from a gastrointestinal site occurred in the rivaroxaban arm (3.2% versus 2.2%, P<0.001).
These findings matched those reported at the American Heart Association meeting last November that led drugmaker Johnson & Johnson to apply to the FDA in January for an indication in stroke prevention in atrial fibrillation for rivaroxaban.
The drug won FDA approval last month for a separate indication -- prevention of deep vein thrombosis in patients undergoing knee or hip replacement surgery, adding to a rapidly changing landscape in anticoagulation choices.
Another new agent, the direct thrombin inhibitor dabigatran (Pradaxa) was approved for stroke prevention in atrial fibrillation last October based on the RE-LY study results showing noninferiority to warfarin at a low dose and superiority at a high dose. The higher dose, 150 mg twice daily, was approved by the FDA for use in atrial fibrillation.
Oral alternatives to warfarin for atrial fibrillation have arrived, Gregory J. del Zoppo, MD, of the University of Washington in Seattle, and Misha Eliasziw, PhD, of the University of Calgary, Alberta, announced in an editorial accompanying the NEJM paper.
"Their simplicity of use is attractive," del Zoppo and Eliasziw wrote, "and they appear to have an efficacy similar to that of warfarin, with the proviso that comparisons seem to depend on how easily the patient can be treated with warfarin."
Rivaroxaban and dabigatran don't require the blood tests, special diet, or alcohol restrictions necessary with warfarin.
Among the 14,264 ROCKET-AF patients, those randomized to warfarin were in the therapeutic INR range only 55% of the time on average, which Patel acknowledged was lower than in other anticoagulant trials.
In RE-LY, time in therapeutic range in the warfarin arm averaged 64%.
While less than optimal, the difficulty with management in ROCKET-AF "may be a reflection of what life is like in community practice," noted stroke expert Ralph Sacco, MD, of the University of Miami and AHA immediate past president.
Patel pointed to the trial's population as the oldest enrolled, with more high-risk patients, higher levels of comorbidity, and a geographic diversity across 45 countries, including some that used lower INR targets and others with poor INR management.
But, the group noted, "The efficacy of rivaroxaban, as compared with warfarin, was as favorable in centers with the best INR control as in those with poorer control."
ROCKET-AF and RE-LY both found no reduction in overall major and nonmajor clinically relevant bleeding over warfarin but lower intracranial bleeding risk.
One reason may be that both rivaroxaban and dabigatran impact a single hemostatic target whereas warfarin hits multiple targets, the editorialists suggested.
Neither trial addressed the lack of antidotes to these drugs that would be needed to reverse their anticoagulant effects in the case of life-threatening hemorrhage or surgery, del Zoppo and Eliasziw warned.
"All these issues need to be taken into account in clinical decision making," they concluded in the editorial.
Sacco agreed that physicians, patients, and professional organizations will have a job ahead of them sorting out the nuances of trial design, statistics, and pros and cons of the various anticoagulants on the horizon for stroke prevention in atrial fibrillation.
"Any new medication to help reduce stroke risk among those with atrial fibrillation would be helpful," he told MedPage Today. "What may happen, which I think would be a good thing, is there may be multiple options."
The study was funded by Johnson & Johnson and Bayer.
Patel reported having received money to his institution from Johnson & Johnson in the form of research grants and travel and trial activities, serving on an advisory board to Genzyme, and consulting for Ortho McNeil Jansen and Bayer Healthcare regarding rivaroxaban.
del Zoppo reported having no conflicts of interest to disclose.
Eliasziw reported having received funds from the National Institute of Neurological Disorders and Stroke for serving on the data safety monitoring board of the Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial.