Factor Xa inhibitor shows lack of efficacy with increased bleeding in patients with embolic stroke of undetermined source

Introduction and methods

Embolic strokes of undetermined source are non-lacunar, and not caused by a proximal arterial stenosis, neither by a recognized cardioembolic source, such as atrial fibrillation (AF) of left ventricular thrombus, and they account for about 20% of all ischemic strokes [1-3]. Rivaroxaban, a direct factor Xa inhibitor, is indicated for the prevention of stroke in patients with AF, however, it is not known whether it is effective for the prevention of recurrent stroke in patients with embolic stroke of undetermined source.

In the NAVIGATE ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) study [4,5], the efficacy and safety of rivaroxaban for the prevention of recurrent stroke in patients with recent embolic stroke of undetermined source was evaluated.

In the randomized, phase 3 NAVIGATE ESUS trial, eligible patients were assigned to receive either rivaroxaban 15 mg plus placebo or aspirin 100 mg plus placebo in a 1:1 ratio. Patients were eligible for the study if they:

• had a history of classifying stroke between 7 days and 6 months before screening
• were older than 49 years when they suffered the classifying stroke
• were aged between 50-59 years at the time of stroke, they had to have at least one additional vascular risk factors: hypertension, diabetes, previous ischemic stroke, active tobacco smoking, heart failure

A classifying stroke had to fulfill the following criteria:

• non-lacunar
• not due to extracranial vessel atherosclerosis with a stenosis ≥50%
• no risk factors for a cardiac source of embolism (AF, left ventricular thrombus, mechanical prosthetic cardiac valve, or severe mitral stenosis)
• no other identifiable cause of stroke

The National Institutes of Health Stroke Scale (NIHSS) score was used to assess the stroke severity at baseline. The primary efficacy outcome was the time-to-event of first ischemic, hemorrhagic, or undefined recurrent stroke or systemic embolism. The primary safety outcome was major bleeding according to the International Society of Thrombosis and Hemostasis (ISTH) criteria.

Main results

• The study was discontinued prematurely due to excess bleeding and lack of an offsetting benefit regarding a reduction in stroke in the rivaroxaban group. Median follow-up until trial termination was 11 months (QR: 5-17 months).
• 7213 participants were included in the study, with a median time from the qualifying stroke to randomization of 37 days (IQ: 14-88), and with a median NIHSS score of 1 (IQ: 0-2).
• The primary efficacy outcome rate was 5.1%/year in the rivaroxaban group, and 4.8%/year in the aspirin group (HR: 1.07; 95%CI: 0.87-1.33; P = 0.52).
• Most events were ischemic strokes (95%), with similar rates in both groups (HR: 1.01; 95%CI: 0.81-1.26).
• In the rivaroxaban group, 13 hemorrhagic strokes were observed, compared with 2 in the aspirin group.
• The annualized rate of major bleeding was 1.8% in the rivaroxaban group, and 0.7% in the aspirin group (HR: 2.72; 95%CI: 1.68-4.39; P<0.001).

Conclusion

References

Find this article online at N Engl J Med