May 16, 2018
2 min read

NAVIGATE ESUS: Rivaroxaban fails to reduce recurrence in embolic stroke

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Rivaroxaban did not reduce the risk for recurrent stroke in patients with embolic stroke compared with aspirin, although it increased the risk for bleeding, according to data presented at the European Stroke Organization Conference.

The results were simultaneously published in The New England Journal of Medicine.

“The effect of the 15-mg daily dose of rivaroxaban on stroke prevention substantially overlaps the effect of the 20-mg daily dose,” Robert G. Hart, MD, professor in the division of neurology at McMaster University in Hamilton, Ontario and principal investigator of the stroke and cognition program at Population Health Research Institute in Hamilton, Ontario, and colleagues wrote. “The latter dose is approved in most countries for the prevention of stroke in patients with atrial fibrillation. Consequently, the use of the 15-mg dose of rivaroxaban in our trial was unlikely to account for the lack of benefit in stroke prevention.”

Patients with ischemic stroke

In the phase 3 NAVIGATE ESUS trial, researchers analyzed data from 7,213 patients (mean age, 67 years; 62% men) who had an ischemic stroke that was not lacunar and not linked to extracranial vessel atherosclerosis. Cardiac rhythm monitoring and echocardiography were performed to rule out other causes of stroke.

Patients were assigned 15 mg rivaroxaban (Xarelto, Janssen/Bayer) with placebo once per day (n = 3,609) or 100 mg aspirin with placebo once per day (n = 3,604). Follow-up was conducted at 1 month, 6 months, 12 months and every 6 months after that, when patients were assessed for safety and efficacy events, adverse events and adherence.

The primary efficacy outcome was first recurrent stroke or systemic embolism in a time-to-event analysis. The primary safety outcome was major bleeding at any site in the body.

At the recommendation of the data and safety monitoring committee, the trial was terminated on Oct. 5, 2017, due to an excess risk for bleeding in patients assigned rivaroxaban and the lack of benefit for the reduction of stroke risk. Due to the termination, follow-up was conducted for a median of 11 months.

Event rates

Recurrent stroke or systemic embolism occurred in 172 patients assigned rivaroxaban (5.1% annualized rate) vs. 160 patients assigned aspirin (4.8% annualized rate; HR = 1.07; 95% CI, 0.87-1.33).

Ischemic stroke was seen in 158 patients in the rivaroxaban group (4.7% annualized rate) and 156 patients in the aspirin group (4.7% annualized rate; HR = 1.01; 95% CI, 0.81-1.26).


More patients assigned rivaroxaban (n = 62; 1.8% annualized rate) had major bleeding compared with patients assigned aspirin (n = 23; 0.7% annualized rate; HR = 2.72; 95% CI, 1.68-4.39).

“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, 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,” Hart and colleagues wrote. – by Darlene Dobkowski


Hart RG, et al. Official Welcome and Large Clinical Trials. Presented at: European Stroke Organization Conference; May 16-18, 2018; Gothenburg, Sweden.

Hart RG, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1802686.

Disclosures: The study was funded by Bayer and Janssen Research and Development. Hart reports he received grants and personal fees from Bayer AG outside the submitted work. Please see the study for all other authors’ relevant financial disclosures.