New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source - NAVIGATE ESUS

Contribution To Literature:

The NAVIGATE ESUS trial showed that rivaroxaban 15 mg is not effective compared with low-dose aspirin in reducing recurrent strokes among patients with embolic stroke of undetermined source; it, however, increased major bleeding, including hemorrhagic strokes and symptomatic ICH.


The goal of the trial was to compare the safety and efficacy of rivaroxaban 15 mg compared with low-dose aspirin to reduce recurrent strokes among patients with recent embolic stroke of undetermined source.

Study Design

Patients were randomized in a 1:1 ratio to either rivaroxaban 15 daily (n = 3,609) or aspirin 100 mg daily (n = 3,604). Both arms also received a placebo.

  • Total number of enrollees: 7,213
  • Duration of follow-up: 11 months
  • Mean patient age: 67 years
  • Percentage female: 28%
  • Percentage with diabetes: 25%

Inclusion criteria:

  • Ischemic stroke on cerebral imaging within 7 days to 6 months
  • No obvious cause of stroke identified
  • Age ≥50 years. If age 50-59 years, patients had to have an additional vascular risk factor: diabetes, smoking, hypertension, heart failure, and/or previous ischemic stroke

Exclusion criteria:

  • Lacunar stroke
  • Extracranial vessel with >50% stenosis supplying the area of the ischemic stroke
  • Identified risk factors for cardioembolic stroke (atrial fibrillation, mechanical prosthetic cardiac valve, severe mitral stenosis, left ventricular thrombus)
  • Severely disabling stroke (modified Rankin scale score ≥4)
  • Indication for chronic anticoagulation or antiplatelet therapy
  • Estimated glomerular filtration rate <30 ml/min/1.73 m2

Other salient features/characteristics:

  • Prior cerebrovascular accident/transient ischemic attack: 18%
  • Patent foramen ovale: 7%
  • Median National Institutes of Health Stroke Scale score: 1

Principal Findings:

The trial was terminated early due to excess risk of bleeding with rivaroxaban without any benefit. The primary efficacy outcome, recurrent stroke or systemic embolism for rivaroxaban vs. aspirin, was 5.1%/year vs. 4.8%/year (hazard ratio [HR] 1.07, 95% confidence interval [CI] 0.87-1.33, p = 0.52). Any recurrent stroke: 5.1%/year vs. 4.7%/year.

The primary safety outcome, International Society of Thrombosis and Hemostasis (ISTH) major bleeding, was 1.8%/year for rivaroxaban vs. 0.7%/year for aspirin (HR 2.72, 95% CI 1.68-4.39, p < 0.001).

Secondary outcomes (for rivaroxaban vs. aspirin):

  • Myocardial infarction: 0.5%/year vs. 0.7%/year
  • Hemorrhagic stroke: 0.4%/year vs. 0.1%/year (HR 6.5, 95% CI 1.47-28.8)
  • Symptomatic intracranial hemorrhage (ICH): 0.6%/year vs. 0.1%/year (p = 0.003)
  • Life-threatening bleeding: 1%/year vs. 0.4%/year (p = 0.004)
  • All-cause mortality: 1.9%/year vs. 1.5%/year


The results of this important trial indicate that rivaroxaban 15 mg is not superior to low-dose aspirin in reducing recurrent strokes among patients with embolic stroke of undetermined source; it, however, increased major bleeding, including hemorrhagic strokes and symptomatic ICH. This strategy is thus inferior to aspirin.

Rivaroxaban is a direct-acting oral anticoagulant. In a dose of 15-20 mg, it has been shown to be effective for stroke prophylaxis among patients with atrial fibrillation. Recently, reduced-intensity rivaroxaban (2.5 mg BID with low-dose aspirin; 5 mg BID monotherapy) was shown to be effective for secondary prevention of atherosclerotic events including strokes compared with aspirin, albeit with a higher risk of bleeding. It is unclear if a similar strategy would have been beneficial here. Patients with embolic stroke of undetermined source represent a heterogeneous population, and may have atherosclerosis-mediated events rather than thrombus-mediated events. Trials with other direct oral anticoagulants in this patient population are ongoing.


Hart RG, Sharma M, Mundl H, et al., on behalf of the NAVIGATE ESUS Investigators. Rivaroxaban for Stroke Prevention After Embolic Stroke of Undetermined Source. N Engl J Med 2018;378:2191-2201.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Prevention, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Hypertension, Smoking

Keywords: Anticoagulants, Aspirin, Atherosclerosis, Atrial Fibrillation, Brain Ischemia, Diabetes Mellitus, Embolism, Heart Failure, Hemorrhage, Hemostasis, Hypertension, Intracranial Hemorrhages, Ischemic Attack, Transient, Myocardial Infarction, Primary Prevention, Risk Factors, Secondary Prevention, Smoking, Stroke, Thrombosis, Vascular Diseases

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