article291

NAVIGATE ESUS

The New England Journal of Medicine. 2018.

Clinical Question:

Does rivaroxaban, an oral factor Xa inhibitor, reduce the risk of recurrent stroke compared to aspirin in patients with recent embolic strokes of undetermined source?

Bottom Line:

Rivaroxaban did not reduce the risk of recurrent stroke compared to aspirin in patients with recent embolic strokes of undetermined source and was associated with a higher risk of bleeding.

Major Points:

Guidelines:

Guidelines for secondary prevention of stroke in the context of embolic strokes of undetermined source would need to reflect the results of this trial.

Design:

Randomized, double-blind, event-driven, phase 3 trial at 459 centers in 31 countries.

Population:

Patients with recent ischemic stroke of undetermined source without arterial stenosis, cardioembolic source, or other determined causes. 7213 participants were enrolled.

Inclusion Criteria:
- Ischemic stroke without a clear source
- Absence of proximal arterial stenosis, known cardioembolic source, or lacune
- Stroke occurrence between 7 days and 6 months prior to screening

Exclusion Criteria:
- History of atrial fibrillation
- Severe stroke (modified Rankin score ≥4)
- Indication for anticoagulation or antiplatelet therapy beyond study parameters

Interventions:

- Rivaroxaban (15 mg daily)
- Aspirin (100 mg daily)

Outcomes:

Primary Efficacy Outcomes:
- Recurrence of ischemic or hemorrhagic stroke or systemic embolism
- Rivaroxaban group: 172 patients (5.1% annualized rate)
- Aspirin group: 160 patients (4.8% annualized rate)

Primary Safety Outcomes:
- Major bleeding events
- Rivaroxaban group: 62 patients (1.8% annualized rate)
- Aspirin group: 23 patients (0.7% annualized rate)

Criticisms:

- The trial was stopped early due to the lack of benefit and increased bleeding risk with rivaroxaban.
- A majority of the included patients had minor residual deficits at trial entry (median NIHSS score of 1).

Funding:

Bayer and Janssen Research and Development.