Rivaroxaban had no advantage over aspirin, and increased bleeding risk in trial
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For the primary endpoint, the non-vitamin K antagonist oral anticoagulant (NOAC) had an annualized rate of first recurrence of ischemic or hemorrhagic stroke or systemic embolism of 5.1% compared with 4.8% for aspirin (HR 1.07; 95% CI 0.87-1.33, P=0.52).
Recurrent ischemic stroke occurred at an identical 4.7% per year in both groups, Robert Hart, MD, of the Population Health Research Institute in Hamilton, Ontario, and colleagues reported online in the New England Journal of Medicine in a study published simultaneously with presentation at the European Stroke Organisation Conference in Gothenburg, Sweden.
Rivaroxaban substantially increased major bleeding, though, at an annualized rate of 1.8% compared with 0.7% on aspirin (HR 2.72, 95% CI 1.68-4.39, P<0.001). Life-threatening or fatal bleeding (HR 2.34), symptomatic intracranial hemorrhage (HR 4.02), and clinically relevant nonmajor bleeding (HR 1.51) were also significantly worse with rivaroxaban.
The trial included 7,213 patients ages 50 and older with "embolic stroke of undetermined source" -- i.e., not associated with proximal arterial stenosis or a recognized cardioembolic source, such as atrial fibrillation or left ventricular thrombus, and that are not lacunar -- who were randomized to 15-mg immediate-release rivaroxaban or 100-mg aspirin enteric coated tablets along with placebo given both groups to maintain blinding.
All participants had at least 20 total hours of cardiac rhythm monitoring to rule out atrial fibrillation lasting 6 minutes or longer.
"Rivaroxaban, including the 15-mg daily dose that was used in the current trial, has been effective for the prevention of recurrent stroke in patients with atrial fibrillation," the researchers noted, "and the absence of an observed lower rate of recurrent ischemic stroke with rivaroxaban than with aspirin in the current trial suggests that undetected paroxysmal atrial fibrillation was not a major cause of recurrent stroke."
While 7% of the included patients had a patent foramen ovale, the outcome influence of including these patients "is uncertain," according to the researchers, noting that the trials showing a benefit to closure in cryptogenic stroke came out just when recruitment stopped in NAVIGATE ESUS.
The trial was stopped early for excess bleeding risk without an offsetting chance of stroke prevention efficacy after patients had been followed for a median 11 months and 74% of the planned efficacy events had occurred.
Using a 20 mg rather than 15 mg dose of rivaroxaban wouldn't likely have made any difference in the findings, Hart's group suggested. But they noted that ongoing randomized trials are comparing other NOACs with aspirin in secondary prevention after cryptogenic stroke, such as RE-SPECT ESUS with dabigatran (Pradaxa) and ATTICUS with apixaban (Eliquis).
Hart reported grants and personal fees from Bayer, outside of the NAVIGATE ESUS study.
New England Journal of MedicineSource Reference: Hart RG, et al "Rivaroxaban for stroke prevention after embolic stroke of undetermined source" N Engl J Med 2018; DOI: 10.1056/NEJMoa1802686.