NAVIGATE ESUS

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Hart RG, et al.. "Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source". The New England Journal of Medicine. 2018. (378):2191-2201.
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Clinical Question

Is Rivaroxaban superior to ASA for the prevention of recurrent strokes in patients following an initial embolic stroke of unknown source (ESUS)?

Bottom Line

Rivaroxaban is not superior to ASA for prevention of secondary strokes in patients following ESUS but had increased bleeding compared to ASA.

Major Points

Guidelines

AHA/ASA 2014 Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: [1]

  • For patients who have experienced an acute ischemic stroke or TIA with no other apparent cause, prolonged rhythm monitoring (≈30 days) for AF is reasonable within 6 months of the index event.

Design

  • Open-label, multicenter, randomized control trial
  • N=7213
    • ASA, n=3604
    • Rivaroxaban, n=3609
  • Setting: 454 centers in multiple continents
  • Enrollment: December 2014-Feb 2018
  • Mean follow-up: 15 months
  • Analysis: Intention to Treat
  • Primary outcome: Time from randomization to first occurrence of any of the components of the composite outcome (Ischemic stroke, hemorrhagic stroke, undefined stroke, TIA with positive neuroimaging, systemic embolism) and first major hemorrhage

Population

Inclusion Criteria

Recent ESUS 7days to 6 months prior to enrollment defined as recent ischemic stroke (including TIA) with visualized infarct by brain imaging that is not lacunar, and absence of:

  • Cervical carotid atherosclerotic stenosis> 50% (on doppler or CT angiography)
  • Atrial fibrillation after ≥ 24-hour cardiac rhythm monitoring
  • Intra-cardiac thrombus (after assessment with transesophageal or transthoracic echocardiography)
  • Other specific cause of stroke (for example, arteritis, dissection, migraine/vasospasm, drug abuse)

Exclusion Criteria

  • Severely disabling stroke (modified Rankin score ≥4)
  • Indication for chronic anticoagulation or antiplatelet therapy
  • Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2
  • Ongoing regular use of conventional nonsteroidal antiinflammatory drugs
  • Major bleeding within the previous 6 months
  • Previous nontraumatic intracranial hemorrhage

Baseline Characteristics

Given for Rivaroxaban group

Interventions

Outcomes

Comparisons are ASA vs.

Primary Outcomes

; Detection of atrial fibrillation with duration ≥30 sec within 90 day:

16.1% vs. 3.2% (number needed to screen 8; 95% CI 5.7-12.5; P<0.001)

Secondary Outcomes

; Detection of atrial fibrillation with duration ≥2.5 min:

9.9% vs. 2.5% (number needed to screen 14; 95% CI 8.8-29.4; P<0.001)
Detection of atrial fibrillation of any duration
19.7% vs. 4.7% (number needed to screen 7; 95% CI 4.9-10.2; P<0.001)
Anticoagulant therapy at 90 days
52/280 (18.6%) vs. 31/279 (11.1), Absolute difference 7.5% (95% CI: 1.6 to 13.3), P=0.01
Antiplatelet therapy only at 90 days
223/280 (79.6%) vs. 246/279 (88.2%), Absolute difference −8.6% (95% CI: −14.6 to −2.5), P=0.006
Therapy at randomization changed by 90 days from antiplatelet therapy to anticoagulant therapy
38/280 (13.6%) vs. 13/279 (4.7%), Absolute difference 8.9%, (95% CI: 4.2 to 13.6), P <0.001
Therapy at randomization changed by 90 days from anticoagulant therapy to antiplatelet therapy
3/280 (1.1%) vs. 2/279 (0.7%), Absolute difference 0.4%, (95% CI: −1.2 to 1.9), P= 0.66

Subgroup Analysis

AF detection rate was higher among patients who underwent randomization within 3 months after the index stroke or TIA compared with those who underwent randomization 3-6 months after index event (36 of 195 patients [18.5%] vs. 8 of 89 [9.0%]; P=0.049 for linear association).

Adverse Events

Criticisms

Funding

Further Reading

  1. Kernan WN et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014. 45:2160-236.