Neurology Clinical Trial Database
NAVIGATE ESUS
Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source
Year of Publication: 2018
Authors: Hart RG, Sharma M, Mundl H, et al.
Journal: New England Journal of Medicine
Citation: Hart RG, Sharma M, Mundl H, et al. Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source. N Engl J Med. 2018;378(23):2191–2201.
PDF: Clinical Question
Does rivaroxaban reduce recurrent stroke risk compared to aspirin in patients with embolic stroke of undetermined source (ESUS)?
Study Overview
Objective
Evaluate whether rivaroxaban is superior to aspirin for secondary prevention in patients with embolic stroke of undetermined source (ESUS).
Study Summary
Rivaroxaban 15 mg daily did not reduce recurrent stroke or systemic embolism compared to aspirin and led to significantly higher rates of major bleeding. The trial was terminated early for futility and safety concerns.
Intervention
Rivaroxaban 15 mg daily vs. aspirin 100 mg daily in 7,213 patients with recent ESUS. Randomized, double-blind trial at 459 sites across 31 countries. Median follow-up: 11 months.
Bottom Line
Rivaroxaban was not superior to aspirin in preventing recurrent stroke in ESUS patients and led to significantly more major bleeding, leading to early termination of the trial.
Major Points
- NAVIGATE ESUS was the first large randomized trial testing anticoagulation for Embolic Stroke of Undetermined Source (ESUS), a concept proposed by Hart et al. in 2014 as a therapeutic target within cryptogenic stroke — hypothesizing that most ESUS was cardioembolic and would respond to anticoagulation.
- 7,213 patients across 459 centers in 31 countries — the largest ESUS-specific trial. Used rivaroxaban 15mg once daily (lower dose than AF trials' 20mg) to balance efficacy vs bleeding in a population without confirmed AF.
- Trial stopped early by the data safety monitoring board after a median of only 11 months follow-up (range 1–33; IQR 5–17) due to futility (no efficacy signal) and safety concerns (excess bleeding in rivaroxaban arm).
- Primary endpoint (recurrent stroke or systemic embolism): 5.1%/yr rivaroxaban vs 4.8%/yr aspirin (HR 1.07, 95% CI 0.87–1.33, p=0.52) — completely neutral, with point estimate favoring aspirin. No trend toward benefit at any time point.
- Major bleeding was significantly higher with rivaroxaban: 1.8% vs 0.7%/yr (HR 2.72, 95% CI 1.68–4.39, P<0.001). Life-threatening or fatal bleeding was also more frequent (35 vs 15 events; HR 2.34, 95% CI 1.28–4.29, P=0.004) — a striking safety signal that contributed to early termination.
- Symptomatic intracranial hemorrhage was markedly increased with rivaroxaban (20 vs 5 events; HR 4.02, 95% CI 1.51–10.7; P=0.003), driven predominantly by intracerebral hemorrhage (12 vs 3; HR 4.01, 95% CI 1.13–14.2; P=0.02).
- ESUS definition required: (1) non-lacunar brain infarct on CT/MRI, (2) no extracranial or intracranial atherosclerosis >50% stenosis in the artery supplying the ischemic area, (3) no major cardioembolic source (≥20 hours of cardiac rhythm monitoring required to rule out atrial fibrillation lasting ≥6 minutes; no mechanical prosthetic valve, LV thrombus, or severe mitral stenosis), (4) no other identified specific cause — yet this broad definition likely captured heterogeneous mechanisms.
- Only 34% of patients had cardiac monitoring for ≥48 hours before enrollment (median 24h, IQR 24–48) — meaning occult paroxysmal AF was likely present in a substantial proportion. AF was ultimately identified during follow-up in 3% of participants at a median of 5 months after entry.
- Together with RE-SPECT ESUS (dabigatran, also negative in 2019), definitively closed the door on empiric anticoagulation for unselected ESUS — shifting the field toward ESUS subtyping: PFO closure for shunt-related ESUS, prolonged monitoring for AF detection, and targeted therapy based on mechanism.
- Post-hoc analyses (published separately) suggested patients with left atrial enlargement or elevated NT-proBNP (markers of atrial cardiopathy) may have had a trend toward benefit — spawning the ARCADIA trial testing apixaban specifically in ESUS with atrial cardiopathy biomarkers. (Not part of the primary NEJM publication.)
Design
Study Type: Phase 3, international, randomized, double-blind, event-driven trial
Randomization: 1
Blinding: Double-blind (participants and investigators)
Enrollment Period: December 2014 – September 2017
Follow-up Duration: Median follow-up of 11 months (range 1–33; IQR 5–17)
Centers: 459
Countries: 31 countries globally
Sample Size: 7213
Analysis: Intention-to-treat; Cox proportional hazards regression stratified by age group (<60 vs ≥60 years); log-rank test; Kaplan–Meier estimates
Inclusion Criteria
- Age ≥50 years; patients 50–59 years required at least one additional vascular risk factor (hypertension, diabetes, previous ischemic stroke, active tobacco smoking, or heart failure).
- Ischemic stroke occurring between 7 days and 6 months before screening, confirmed by cerebral imaging (CT or MRI) as non-lacunar.
- No major-risk cardioembolic source: ≥20 hours of cardiac rhythm monitoring completed before randomization to rule out atrial fibrillation lasting 6 minutes or longer; no mechanical prosthetic valve, no left ventricular thrombus, no severe mitral stenosis.
- No extracranial vessel atherosclerosis causing >50% luminal stenosis in arteries supplying the ischemic area (and, when intracranial imaging was performed, no intracranial stenosis >50% due to atherosclerosis).
- No other identified specific cause of stroke.
Exclusion Criteria
- History of atrial fibrillation (paroxysmal, persistent, or permanent).
- Severely disabling stroke (modified Rankin score ≥4 at screening).
- Specific indication for anticoagulation or for antiplatelet therapy.
- Lacunar infarct pattern.
- Intracranial or extracranial arterial stenosis >50% in the territory of the index stroke.
- Presence of implantable loop recorders (excluded due to enhanced AF detection).
- Intracardiac thrombus detected by echocardiography.
- Ongoing regular use of conventional NSAIDs.
- Major bleeding within the previous 6 months, or previous nontraumatic intracranial hemorrhage.
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Age (mean ± SD) - yr | 66.9 ± 9.8 | 66.9 ± 9.8 |
| Male sex - no. (%) | 2204 (61) | 2232 (62) |
| Race (White only) - no. (%) | 2604 (72) | 2612 (72) |
| Race (Asian only) - no. (%) | 698 (19) | 716 (20) |
| Race (Black only) - no. (%) | 60 (2) | 51 (1) |
| Hypertension - no. (%) | 2803 (78) | 2782 (77) |
| Diabetes mellitus - no. (%) | 917 (25) | 889 (25) |
| Previous stroke or TIA - no. (%) | 643 (18) | 620 (17) |
| Current tobacco use - no. (%) | 728 (20) | 756 (21) |
| Median time from qualifying stroke to randomization (IQR) - days | 36.0 (14.0–86.5) | 38.0 (15.0–89.0) |
| Median NIHSS at randomization (IQR) | 1 (0–2) | 1 (0–2) |
| Cardiac rhythm monitoring ≥48 hr - no. (%) | 1217 (34) | 1218 (34) |
| PFO identified - no. (%) | 275 (7.6) | 259 (7.2) |
Arms
| Field | Control | Rivaroxaban 15 mg |
|---|---|---|
| Intervention | Aspirin 100 mg once daily (enteric-coated) plus matching placebo. Standard antiplatelet control arm. Taken with food. | Rivaroxaban 15 mg once daily (immediate-release, film-coated) plus matching placebo (lower dose than the 20 mg AF indication). Direct factor Xa inhibitor — chosen at reduced dose to optimize the risk-benefit ratio in a non-AF population. No renal dose adjustment permitted (CrCl <30 excluded). Taken with food to ensure bioavailability. No INR monitoring needed. Double-blind. |
| Duration | Median follow-up 11 months (stopped early) | Median follow-up 11 months (stopped early) |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Time to first recurrent ischemic, hemorrhagic, or undefined stroke, or systemic embolism (time-to-event analysis) | Primary | 4.8% annual rate (160/3604) | 5.1% annual rate (172/3609) | 1.07 | 0.52 |
| Any recurrent stroke | Secondary | 4.7% annual rate (158/3604) | 5.1% annual rate (171/3609) | HR 1.08 | |
| Ischemic stroke | Secondary | 4.7% annual rate (156/3604) | 4.7% annual rate (158/3609) | HR 1.01 | |
| Hemorrhagic stroke | Secondary | 0.1% annual rate (2/3604) | 0.4% annual rate (13/3609) | HR 6.50 | |
| Systemic embolism | Secondary | 0.1% annual rate (2/3604) | <0.1% annual rate (1/3609) | HR 0.50 | |
| Composite: any recurrent stroke, myocardial infarction, death from cardiovascular causes, or systemic embolism | Secondary | 5.8% annual rate (195/3604) | 6.2% annual rate (207/3609) | HR 1.06 | |
| Any disabling stroke | Secondary | 0.8% annual rate (29/3604) | 1.2% annual rate (41/3609) | HR 1.42 | |
| Myocardial infarction | Secondary | 0.7% annual rate (23/3604) | 0.5% annual rate (17/3609) | HR 0.74 | |
| Death from cardiovascular causes | Secondary | 0.7% annual rate (23/3604) | 1.0% annual rate (34/3609) | HR 1.48 | |
| Death from any cause | Secondary | 1.5% annual rate (52/3604) | 1.9% annual rate (65/3609) | HR 1.26 | |
| Primary safety outcome — Major bleeding (ISTH) | Adverse | 0.7% annual rate (23 patients) | 1.8% annual rate (62 patients) | HR 2.72 (95% CI 1.68–4.39) | <0.001 |
| Life-threatening or fatal bleeding | Adverse | 0.4% annual rate (15 patients) | 1.0% annual rate (35 patients) | HR 2.34 (95% CI 1.28–4.29) | 0.004 |
| Clinically relevant nonmajor bleeding | Adverse | 2.3% annual rate (79 patients) | 3.5% annual rate (118 patients) | HR 1.51 (95% CI 1.13–2.00) | 0.004 |
| Symptomatic intracranial hemorrhage | Adverse | 0.1% annual rate (5 patients) | 0.6% annual rate (20 patients) | HR 4.02 (95% CI 1.51–10.7) | 0.003 |
| Intracerebral hemorrhage | Adverse | 0.1% annual rate (3 patients) | 0.3% annual rate (12 patients) | HR 4.01 (95% CI 1.13–14.2) | 0.02 |
| Subarachnoid hemorrhage | Adverse | 0.0% annual rate (1 patient) | 0.1% annual rate (5 patients) | HR 5.03 (95% CI 0.59–43.0) | 0.10 |
| Subdural or epidural hematoma | Adverse | 0.1% annual rate (2 patients) | 0.1% annual rate (3 patients) | HR 1.51 (95% CI 0.25–9.02) | 0.65 |
Criticisms
- Stopped early at median 11 months — may have missed late-emerging benefit, though the point estimate (HR 1.07) favored aspirin, making late reversal implausible.
- ESUS is a heterogeneous 'wastebasket' diagnosis — lumping PFO-related, atrial cardiopathy, cancer-associated, and aortic arch disease into one category may have diluted a real treatment effect in a subgroup that would benefit from anticoagulation.
- Only 34% of participants had cardiac rhythm monitoring for ≥48 hours before enrollment (median 24h, IQR 24–48) — inadequate in many patients to exclude paroxysmal AF. CRYSTAL AF showed 30% AF detection at 3 years with implantable monitors, meaning occult AF was likely present in some enrollees.
- Used 15 mg rivaroxaban (not the AF dose of 20 mg) — potentially subtherapeutic for truly cardioembolic ESUS, though higher bleeding without efficacy suggests dose was not the issue.
- No renal dose adjustment was permitted (unlike ROCKET AF's 15 mg for CrCl 30–49) — patients with CrCl <30 were excluded entirely.
- No imaging-based stratification: cortical infarcts (likely embolic) vs deep/subcortical infarcts (possibly small vessel) were treated identically, though different mechanisms may warrant different therapies.
- Broad enrollment window (7 days to 6 months post-stroke) — very early randomization may have included patients whose stroke mechanism would have been identified with more time.
- Industry-sponsored (Bayer/Janssen) — same sponsors as ROCKET AF, raising questions about commercial interest in expanding rivaroxaban's indications.
- Life-threatening or fatal bleeding signal was concerning — 35 vs 15 events (HR 2.34) underscores the harm of empiric anticoagulation in a non-AF population.
Funding
Bayer AG and Janssen Research & Development
Based on: NAVIGATE ESUS (New England Journal of Medicine, 2018)
Authors: Hart RG, Sharma M, Mundl H, et al.
Citation: Hart RG, Sharma M, Mundl H, et al. Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source. N Engl J Med. 2018;378(23):2191–2201.
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