NAVIGATE ESUS

Published

Hart RG, et al. "Rivaroxaban for stroke prevention after embolic stroke of undetermined source". The New England Journal of Medicine. 2018. 378(23):2191-2201.
PubMed • Full text • PDF • ClinicalTrials.gov

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 embolic stroke of unknown source (ESUS), and had increased bleeding compared to ASA.

Major Points

Single-agent antiplatelet therapy in patients with recent ischemic strokes was established by IST (1997; aspirin) and CAPRIE (1996; clopidogrel). Anticoagulation has been the mainstay to reduce AF-associated stroke risk since AFASAK (1989; warfarin) and SPAF (1991; warfarin), and more recently with DOACs with RE-LY (2009; dabigatran), ARISTOTLE (2011; apixaban), and ROCKET AF (2011; rivaroxaban). The selection of anticoagulation versus antiplatelet medications for stroke prevention for those without AF was studied in WARSS (2001), which compared lower-INR-targeting warfarin versus aspirin. There was no difference in recurrent stroke between arms, but warfarin was associated with greater bleeding risk. The role of DOACs for non-AF strokes termed embolic stroke of unknown source (ESUS) was unknown.

Published in 2018, New Approach riVaroxaban Inhibition of Factor Xa in a Global trial versus ASA to prevenT Embolism in Embolic Stroke of Undetermined Source (NAVIGATE ESUS) enrolled 7,213 adults with recent ESUS, defined by non-lacunar stroke without clear cardiac origin or carotid artery stenosis. Participants were randomized to rivaroxaban 15 mg daily vs. aspirin 100 mg daily. While this aspirin dose is in line with other secondary prevention trials for recurrent stroke, the dose of rivaroxaban 15 mg daily was unusual in its selection, since it's not a dose commonly used in clinical practice, with usual AF dosing being at 20 mg daily and VTE prophylaxis being at 10 mg daily. The authors selected this dose to avoid excess bleeding risks, while still retaining efficacy against AF-associated stroke. Even with this lower dose, the trial was stopped early for harm given higher bleeding risk among those receiving rivaroxaban. There was no difference in the primary outcome of recurrent stroke or systemic embolism. Of note, the RE-SPECT ESUS trial was published in 2019 and similarly found more bleeding and similar stroke events with dabigatran compared to aspirin. The currently enrolling ARCADIA trial is comparing apixaban to aspirin in individuals with cryptogenic stroke and evidence of atriopathy defined by objective criteria, such as elevated NT-proBNP. It is possible that a more selected group with greater risk of AF may benefit from anticoagulation.

WARSS, NAVIGATE ESUS, and RE-SPECT ESUS provide evidence that individuals with ESUS event and no known AF derived no additional benefit, and experienced more harm from bleeding events, with anticoagulation instead of aspirin.

Guidelines

AHA Stroke (2021, adapted)

• Among individuals with ESUS, use of DOACs to reduce recurrent stroke risk is not recommended (COR 3/no benefit; LOE B-R)

Design

• Double-blinded randomized control trial
• N=7213
  • ASA, n=3604
  • Rivaroxaban, n=3609
• Setting: 459 centers in 31 countries
• Enrollment: 2014-2017
• Mean follow-up: Median 11 months (stopped early for harm)
• Analysis: Intention-to-treat
• Primary outcomes:
  • Efficacy: Recurrent stroke (ischemic or hemorrhagic) or systemic embolism
  • Safety: Major bleeding

Population

Many details were published elsewhere.

Inclusion Criteria

• Aged ≥50 years
  • If <60 years, ≥ 1 vascular risk factor, including hypertension, DM, prior stroke, smoking, or HF
  • In late 2015, the protocol was amended to exclude those aged 18 to <50 years of age
• Stroke or TIA occurring >7 days & <6 months prior that is not lacunar, and absence of severe carotid atherosclerosis or likely cardioembolic source
• CT or MRI imaging of stroke
• No clear source of stroke
• Other specific cause of stroke (for example, arteritis, dissection, migraine/vasospasm, drug abuse)

Exclusion Criteria

• As above, the index stroke:
  • Wasn't lacunar and wasn't associated
  • Wasn't associated with >50% stenosis in extracranial vessel supplying the affected region
  • No obvious cardiac source (AF on >20h monitoring, LV thrombus on echo, mechanical prosthetic cardiac valve/severe MS)
• Severely disabling stroke, defined by ≥4 score on the modified Rankin scale
• Indication for chronic anticoagulation or antiplatelet therapy
• 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
• Current or planned implantable loop recorder placement
• Coagulopathy from liver disease

Baseline Characteristics

Given for Rivaroxaban group

• Demographics: Age 67 years, 62% men, 72% White race, 1% Black race, 20% Asian race, 6% other race
• Anthropometrics: BMI 27 kg/m², BP 135/79
• Medical problems: HTN 77%, DM 25%, smoker 21%, prior stroke/TIA 17%
• Medications: Aspirin before index stroke 17%, statin after randomization 78%
• Stroke details: Single acute lesion 90%, multiple lesions 10%, NIHSS 1, modified rankin 1, time from stroke to randomization 38 days, any intracranial vascular imaging 78%, cardiac rhythm monitoring ≥48 hours 34%

Interventions

• Patients were randomized to a group:
  • Rivaroxaban - at 15 mg po qday. WJC ed note: This is an atypical dose of rivaroxaban, see "Criticisms" section below.
  • Aspirin - at 100 mg daily
• Both groups had placebo of the other study medication.

Outcomes

Comparisons are rivaroxaban vs. ASA

Primary Outcomes

Efficacy

Recurrent stroke (ischemic or hemorrhagic) or systemic embolism

5.1% vs. 4.8%/year (HR 1.07; 95% CI 0.87 to 1.33; P=0.52)

Safety

Major bleeding

1.8% vs. 0.7%/year (HR 2.72; 95% CI 1.68-4.39; P<0.001)

Secondary Outcomes

Stroke type

Any: 5.1% vs. 4.7%/year (HR 1.08; 95% CI 0.87-1.34)

Ischemic: 4.7% vs. 4.7%/year (HR 1.01; 95% CI 0.81-1.26)

Hemorrhagic: 0.4% vs. 0.1%/year (HR 6.50; 95% CI 1.47-28.8)

Any disabling: 1.2% vs. 0.8%/year (HR 1.42; 95 CI 0.88-2.28)

Systemic embolism

<0.1% vs 0.1% (HR 0.50; 95% CI 0.05-5.51)

MI

0.5% vs. 0.7%/year (HR 0.74; 9% CI 0.39-1.38)

Any stroke, MI, CVD mortality, or systemic embolism

6.2% vs. 5.8%/year (HR 1.06; 95% CI 0.87-1.29)

Mortality

All-cause: 1.9% vs. 1.5%/year (HR 1.26; 95% CI 0.87-1.81)

CVD: 1.0% vs. 0.7% (HR 1.48; 95% CI 0.87-2.52)

Bleeding type

Life-threatening or fatal: 1.0% vs. 0.4%/year (HR 2.34; 95% CI 1.28-4.29)

Clinically relevant non-major bleeding: 3.5% vs. 2.3%/year (HR 1.51; 95% CI 1.13-2.00)

Symptomatic intracranial hemorrhage: 0.6% vs. 0.1%/year (HR 4.02; 95% CI 1.51-10.7)

Intracerebral hemorrhage: 0.3% vs. 0.1%/year (HR 4.01; 95% CI 1.13-14.2)

SAH: 0.1% vs. <0.1%/year (HR 5.03; 95% CI 0.59-43.0)

Subdural/epidural hematoma: 0.1% vs. 0.1%/year (HR 1.51; 95% CI 0.25-9.02)

Subgroup Analysis

There were no major differences in the efficacy endpoint by age, sex, race, BMI, weight, history of stroke, time since randomization, duration of cardiac monitoring, history of hypertension, or history of diabetes. The authors note that heterogeneity might be present, with greater benefit in aspirin among those in east asia, and those with eGFR >80. Subgroup analysis by the safety endpoint was not provided.

Adverse Events

In general, they were similar between groups, see Supplemental Table s3.

Criticisms

• Non-standard rivaroxaban dosing at 15 mg daily. The authors address this selection in their design paper as being selected to balance risk of bleed with efficacy.
• Excluded individuals with ILR or planning for ILR, who might be individuals more likely to have AF and possibly benefit from DOAC therapy for stroke risk reduction.

Funding

Bayer and Janssen, the makers of Xarelto/rivaroxaban