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Efficacy and Safety of Rivaroxaban Versus Aspirin in Embolic Stroke of Undetermined Source and Carotid Atherosclerosis

Originally publishedhttps://doi.org/10.1161/STROKEAHA.119.025168Stroke. 2019;50:2477–2485

Abstract

Background and Purpose—

The sources of emboli in patients with embolic stroke of undetermined source (ESUS) are multiple and may not respond uniformly to anticoagulation. In this exploratory subgroup analysis of patients with carotid atherosclerosis in the NAVIGATE (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism)-ESUS trial, we assessed whether the treatment effect in this subgroup is consistent with the overall trial population and investigated the association of carotid atherosclerosis with recurrent ischemic stroke.

Methods—

Carotid atherosclerosis was analyzed either as the presence of mild (ie, 20%–49%) atherosclerotic stenosis or, separately, as the presence of carotid plaque. Primary efficacy outcome was ischemic stroke recurrence. Safety outcomes were major bleeding and symptomatic intracerebral bleeding.

Results—

Carotid plaque was present in 40% of participants and mild carotid stenosis in 11%. There was no significant difference in ischemic stroke recurrence between rivaroxaban- and aspirin-treated patients among 490 patients with carotid stenosis (5.0 versus 5.9/100 patient-years, respectively, hazard ratio [HR], 0.85; 95% CI, 0.39–1.87; P for interaction of treatment effect with patients without carotid stenosis 0.78) and among 2905 patients with carotid plaques (5.9 versus 4.9/100 patient-years, respectively, HR, 1.20; 95% CI, 0.86–1.68; P for interaction of treatment effect with patients without carotid stenosis 0.2). Among patients with carotid plaque, major bleeding was more frequent in rivaroxaban-treated patients compared with aspirin-treated (2.0 versus 0.5/100 patient-years, HR, 3.75; 95% CI, 1.63–8.65). Patients with carotid stenosis had similar rate of ischemic stroke recurrence compared with those without (5.4 versus 4.9/100 patient-years, respectively, HR, 1.11; 95% CI, 0.73–1.69), but there was a strong trend of higher rate of ischemic stroke recurrence in patients with carotid plaque compared with those without (5.4 versus 4.3/100 patient-years, respectively, HR, 1.23; 95% CI, 0.99–1.54).

Conclusions—

In ESUS patients with carotid atherosclerosis, we found no difference in efficacy between rivaroxaban and aspirin for prevention of recurrent stroke, but aspirin was safer, consistent with the overall trial results. Carotid plaque was much more often present ipsilateral to the qualifying ischemic stroke than contralateral, supporting an important etiological role of nonstenotic carotid disease in ESUS.

Clinical Trial Registration—

URL: https://www.clinicaltrials.gov. Unique identifier: NCT02313909.

Introduction

See related article, p 2290

Patients with atherosclerotic carotid artery disease are at increased risk for embolic stroke and other major adverse cardiovascular events.1,2 Along with lifestyle modification and other medical interventions such as statins, antiplatelet treatment is a major cornerstone of the prevention of vascular events in this population, both in the primary and secondary prevention setting.1 The role of oral anticoagulation for secondary stroke prevention in patients with cerebrovascular atherosclerosis has been assessed in several randomized clinical trials which found that it confers higher bleeding risk compared with aspirin without any significant reduction of major ischemic events.3–6 Therefore, oral anticoagulation is not recommended over antiplatelet for secondary stroke prevention in patients with carotid atherosclerosis.1

Embolic stroke of undetermined source (ESUS) is a term used to describe patients with cryptogenic ischemic stroke despite adequate diagnostic work-up, that is, nonlacunar strokes without proximal arterial stenosis or a major cardiac source of embolism (like atrial fibrillation)7,8 and with a presumed embolic stroke mechanism. ESUS represents ≈17% of all patients with ischemic stroke and is associated with a substantial rate of stroke recurrence, ≈5% on an annual basis.7,9,10 Among other potential embolic sources, atherosclerotic mild carotid stenoses, and carotid plaques are potential underlying mechanisms of an ESUS.2,8

The NAVIGATE-ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source) recently compared rivaroxaban with aspirin for secondary prevention in patients with recent ESUS.11 It concluded that rivaroxaban was not superior to aspirin for prevention of recurrent stroke and was associated with a higher risk of bleeding.12 The sources of emboli among ESUS patients are multiple, and the response to anticoagulation may not be uniform. It has been suggested that the lack of a stroke reduction by rivaroxaban in the trial could be because of inclusion of patients with carotid atherosclerosis, who may respond better to antiplatelet treatment rather than oral anticoagulation alone.13

In this exploratory subgroup analysis of the NAVIGATE-ESUS trial involving patients with carotid atherosclerosis, we assessed whether the treatment effect in this subgroup is consistent with the results in the overall trial cohort. We also investigated the association between the presence of atherosclerotic mild carotid stenosis and carotid plaque with the risk of future ischemic stroke.

Methods

NAVIGATE-ESUS was an international, double-blinded, randomized phase III trial comparing rivaroxaban 15 mg once daily with aspirin 100 mg once daily in patients with recent ESUS. The design of the NAVIGATE-ESUS trial, the baseline characteristics of the participants, and the results have been previously published.11,12,14 Extracranial arterial imaging with sonography (including transcranial Doppler), computed tomography angiography (CTA), magnetic resonance angiography (MRA), or digital subtraction angiography was required before patient randomization to exclude moderate-to-severe (>50%) atherosclerotic carotid stenosis which was an exclusion criterion if involving the territory of the qualifying stroke. Patients with carotid atherosclerotic plaques causing ≤50% stenosis were included in the analysis regardless of ulceration or other plaque features. Intracranial arterial imaging was not required. Patients with aortic or mild intracranial atherosclerosis were not analyzed separately.

We defined carotid atherosclerosis as the presence of any mild (ie, 20%–49%) atherosclerotic carotid stenosis or any carotid plaque whether bilateral or ipsilateral or contralateral to the qualifying stroke. For the analysis of carotid plaque, we included all patients with available reported data from ultrasound, CTA, MRA, or digital subtraction angiography. The protocol of the NAVIGATE-ESUS trial did not use a specific definition for plaque; therefore, in this analysis, the presence of plaque accepted as reported by the local investigator on the case report forms. The analysis of carotid stenosis was restricted to patients for whom the degree of carotid stenosis ranged between 20% and 49%, as specified on the carotid imaging report of the CTA or the MR angiography but not ultrasound (as the investigators were not required to provide specific values with regard to the degree of stenosis when assessed by ultrasound).

The primary efficacy outcome for all analyses was ischemic stroke recurrence defined as a focal neurological deficit of sudden onset that was due to presumed arterial occlusion persisting for >24 hours and without evidence of primary hemorrhage on brain imaging; if there was a neurological deficit lasting <24 hours, evidence of acute brain infarct had to be present on brain imaging.15 The secondary efficacy outcomes included ischemic stroke recurrence ipsilateral to the carotid lesion, ischemic stroke recurrence ipsilateral to the qualifying stroke, ischemic stroke recurrence of presumed atherosclerotic etiology, stroke recurrence ascribed to ESUS, myocardial infarction or cardiac chest pain requiring hospitalization, and all-cause mortality. The safety outcomes for all analyses were major bleeding as defined by the criteria of the International Society of Thrombosis and Haemostasis16 and symptomatic intracerebral bleeding. Outcome events were taken as adjudicated.

All analyses were performed on the intention-to-treat population. Hazard ratios were estimated by the Cox proportional-hazards model. The cumulative probability of the primary efficacy outcome by treatment and by the presence of carotid stenosis/plaque was estimated by the Kaplan-Meier product-limit method. There was no imputation of missing data. All reported P values are 2-sided.

Ethics approval was obtained from the institutional review board of all participating sites, and written informed consent was obtained from all patients. Requests to access the data set from qualified researchers trained in human subject confidentiality protocols may be sent to the senior author.

Results

Baseline Characteristics

A total of 7213 patients were recruited in the NAVIGATE-ESUS trial (mean age 67 years, 38% women) and followed for a median of 11 months (interquartile range: 5–17 months). A total of 1% of patients were lost to follow-up after a median of 15±9 months and 1% of patients withdrew consent for follow-up after a mean of 5±6 months.

Carotid arteries were imaged by ultrasound in 4553 patients (63.1%), by CTA in 2743 (38.0%), MR angiography in 2380 (33.0%), and conventional angiography in 121 patients (1.68%).

The subanalysis of carotid stenosis was performed in 4644 patients (38.1% women), of whom 490 (10.5%) had mild carotid stenosis. Among patients with carotid stenosis, 249 patients (50.8%) had a lesion ipsilateral to the qualifying stroke, 86 patients (17.5%) contralateral and 9 patients (1.8%) bilateral. The presence of carotid stenosis was associated with advancing age, hypertension, diabetes mellitus, and hyperlipidemia (P<0.001 for all comparisons; Table 1).

Table 1. Baseline Characteristics of Patients Recruited in the NAVIGATE-ESUS Trial in Relation to the Presence of Carotid Stenosis (20%–49%) or Plaque

CharacteristicAny Stenosis* (N=490)No Stenosis (N=4154)P ValueAny Plaque* (N=2905)No Plaque (N=4307)P Value
Rivaroxaban (N=248)Aspirin (N=242)Rivaroxaban (N=1468)Aspirin (N=1437)
Age, y (mean±SD)68.0±9.469.0±9.066.6±9.8<0.00167.7±9.568.1±9.266.3±10.0<0.001
Female76 (31)86 (36)1606 (39)0.02511 (35)513 (36)1753 (41)<0.001
BMI, kg/m2 (mean±SD)26.9±4.927.5±4.627.1±5.20.7227.0±4.827.1±4.727.3±5.20.03
Hypertension201 (81)208 (86)3099 (75)<0.0011199 (82)1206 (84)3180 (74)<0.001
Diabetes mellitus77 (31)89 (37)965 (23)<0.001393 (27)430 (30)982 (23)<0.001
Current smoking60 (24)51 (21)833 (20)0.18369 (25)333 (23)781 (18)<0.001
Hyperlipidemia167 (67)152 (63)2292 (55)<0.001850 (58)800 (56)2344 (54)0.05
Coronary artery disease16 (6)32 (13)243 (6)<0.00193 (6)140 (10)239 (6)<0.001
Peripheral artery disease4 (2)8 (3)67 (2)0.1833 (2)29 (2)62 (1)0.03
Heart failure2 (1)9 (4)95 (2)0.9547 (3)66 (5)125 (3)0.02
Cancer20 (8)29 (12)389 (9)0.65113 (8)115 (8)392 (9)0.06
Renal dysfunction9 (4)6 (2)129 (3)0.9655 (4)52 (4)122 (3)0.04
eGFR, mL/min per 1.73 m277.8±21.677.0±20.979.3±20.20.0579.1±21.579.3±21.778.2±19.80.04
Prior stroke/TIA51 (21)44 (18)728 (18)0.31274 (19)269 (19)720 (17)0.03
NIHSS score at randomization (median, IQR)1.0 (0.0–2.0)1.0 (0.0–2.0)1.0 (0.0–2.0)<0.0011.0 (0.0–2.0)1.0 (0.0–3.0)1.0 (0.0–2.0)<0.001
Time from stroke to randomization, days (median, IQR)42.5 (18.0–93.5)41.5 (14.0–89.0)39.0 (15.0–93.0)0.3831.5 (13.0–80.0)29.0 (13.0–74.0)41.0 (16.0–96.0)<0.001
Left atrial diameter, cm3.9±1.93.7±0.93.8±1.50.713.9±1.63.7±0.73.8±1.50.39
Left ventricular ejection fraction, %62.2±9.062.5±7.962.7±7.80.3862.3±7.861.6±8.862.4±8.00.03
PFO present using either TTE/TEE12 (5)13 (5)396 (10)0.00157 (4)78 (5)399(9)<0.001
Duration of cardiac rhythm monitoring ≥48 h81 (33)101 (42)1715 (41)0.08425 (29)414 (29)1596 (37)<0.001
Statin treatment before randomization157 (63)147 (61)2604 (63)0.78927 (63)909 (63)2598 (60)0.01
Presence of ipsilateral§ stenosis126 (51)123 (51)NA951 (65)935 (65)NA

BMI indicates body mass index; eGFR, estimated glomerular filtration rate; IQR, interquartile range; NA, not applicable; NAVIGATE-ESUS, New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source; NIHSS, National Institutes of Health Stroke Scale; PFO, patent foramen ovale; TEE, transesophageal echocardiography; TIA, transient ischemic attack; and TTE, transthoracic echocardiography.

*Side of stenosis/plaque (n=490): right only (n=135), left only (n=158), and both (n=197).

†Also includes those with missing value for stenosis/plaque.

P value comparing patients with vs without stenosis/plaque: categorical variables—χ2 test (Exact test, where applicable); continuous variables (Test for mean)—2 sample t test/(Test for median)—Kruskal-Wallis test.

§If stenosis/plaque side=qualifying stroke side or bilateral (in either internal, middle, or anterior artery); if stenosis/plaque side=bilateral, then qualifying stroke in any side (in either internal, middle, or anterior artery).

The subanalysis of carotid plaque was performed in 7212 patients (38.5% women), of whom 2905 (40.3%) had a carotid plaque. Among patients with a carotid plaque, 1886 patients (64.9%) had a lesion ipsilateral to the qualifying stroke, 234 patients (8.0%) contralateral and 69 patients (2.4%) bilateral. The presence of carotid plaque was associated with advancing age, hypertension, diabetes mellitus, tobacco smoking, and hyperlipidemia (P<0.001 for all comparisons; Table 1).

Outcome Events by Treatment Allocation in Patients With Carotid Stenosis

Among patients with mild carotid stenosis, the rate of ischemic stroke recurrence during follow-up was not statistically different between rivaroxaban- and aspirin-treated patients (5.0 versus 5.9 per 100 patient-years, respectively, hazard ratio [HR], 0.85; 95% CI, 0.39–1.87; Table 2). The corresponding numbers for patients without carotid stenosis were 4.8 versus 5.0 per 100 patient-years, respectively, HR, 0.96; 95% CI, 0.72–1.27. There was no treatment interaction between rivaroxaban/aspirin and carotid stenosis status (P for interaction 0.78; Table 3). The cumulative probability of first recurrent ischemic stroke by treatment and by the presence of carotid stenosis is presented in the Figure.

Table 2. Outcome Events in the NAVIGATE-ESUS Trial by Treatment Allocation in Patients With Any Carotid Stenosis (Upper) or Plaque (Lower)

CharacteristicRivaroxabanAspirinRivaroxaban vs Aspirin
No. of RandNo. of Events (Events Rate*)No. of RandNo. of Events (Events Rate*)Hazard Ratio (95% CI)P Value
Any stenosis (N=490)
 Efficacy
  Ischemic stroke24812 (5.0)24213 (5.9)0.85 (0.39–1.87)0.69
  Ischemic stroke ipsilateral to the stenosis§2484 (1.6)2428 (3.6)0.46 (0.14–1.54)0.21
  Ischemic stroke ipsilateral to the qualifying stroke2486 (2.5)2428 (3.6)0.69 (0.24–1.99)0.49
  Ischemic stroke of presumed atherosclerotic etiology2480 (0.0)2420 (0.0)NA
  Ischemic stroke presumably ESUS2486 (2.5)2425 (2.2)1.13 (0.35–3.71)0.84
  MI or cardiac chest pain requiring hospitalization2482 (0.8)2423 (1.3)0.63 (0.11–3.77)0.61
  All-cause mortality2484 (1.6)2425 (2.2)0.76 (0.20–2.82)0.68
 Bleeding
  Major2486 (2.5)2421 (0.4)5.67 (0.68–47.08)0.11
  Symptomatic intracerebral2480 (0.0)2420 (0.0)NA
Any plaque (N=2905)
 Efficacy
  Ischemic stroke146876 (5.9)143763 (4.9)1.20 (0.86–1.68)0.28
  Ischemic stroke ipsilateral to the plaque§14684 (0.3)14377 (0.5)0.56 (0.16–1.92)0.36
  Ischemic stroke ipsilateral to the qualifying stroke146832 (2.4)143736 (2.7)0.88 (0.55–1.41)0.59
  Ischemic stroke of presumed atherosclerotic cause14688 (0.6)14373 (0.2)2.64 (0.70–9.95)0.15
  Ischemic stroke presumably ESUS146832 (2.4)143735 (2.7)0.90 (0.56–1.46)0.68
  MI or Cardiac chest pain requiring hospitalization14688 (0.6)14378 (0.6)0.99 (0.37–2.64)0.98
  All-cause mortality146826 (1.9)143723 (1.7)1.13 (0.65–1.98)0.67
 Bleeding
  Major146826 (2.0)14377 (0.5)3.75 (1.63–8.65)<0.01
  Symptomatic intracerebral14683 (0.2)14371 (0.1)2.94 (0.31–28.27)0.35

MI indicates myocardial infarction; NA, not applicable; NAVIGATE-ESUS, New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source.

*Event rates reported in 100-person-years.

†Hazard ratio, 95% CI, and P value presented if hazard ratio is >0.1 and <10.

‡Includes undetermined strokes.

§If side of plaque at baseline=side of recurrent ischemic stroke or bilateral (in either internal, middle, or anterior artery); if side of plaque at baseline=bilateral, then recurrent ischemic stroke in any side (in either internal, middle, or anterior artery).

‖If side of qualifying stroke same as the side of recurrent ischemic stroke or bilateral (in either internal, middle, or anterior artery).

¶Does not include undetermined strokes; only adjudicated ischemic strokes can be further subclassified.

Table 3. Recurrent Ischemic Stroke According to the Presence of Carotid Stenosis or Plaque and to Treatment Assignment

Rivaroxaban AssignedAspirin AssignedHazard Ratio, 95% CIP Interaction
No. of PatientsRecurrent Stroke (Rate per 100 Patient-Years)No. of PatientsRecurrent Stroke (Rate per 100 Patient-Years)
Carotid stenosis—present24812 (5.0)24213 (5.9)0.85 (0.39–1.87)0.78
Carotid stenosis—absent208395 (4.8)207198 (5.0)0.96 (0.72–1.27)
Carotid plaque—present146876 (5.9)143763 (4.9)1.20 (0.86–1.68)0.2
Carotid plaque—absent214183 (4.0)216693 (4.5)0.90 (0.67–1.20)
Figure.

Figure. Kaplan-Meier curves for time to recurrent ischemic stroke by treatment and presence of stenosis (A) and plaque (B).

The rates of the secondary efficacy outcomes were comparable between the 2 treatment arms (Table 2). The rate of major bleeding was numerically higher in the rivaroxaban arm compared with the aspirin arm; no symptomatic intracerebral bleeding occurred (Table 2).

Outcome Events by Treatment Allocation in Patients With Carotid Plaque

Among patients with carotid plaque, the rate of ischemic stroke recurrence during follow-up was not statistically different between rivaroxaban- and aspirin-treated patients (5.9 versus 4.9 per 100 patient-years, respectively, HR, 1.20; 95% CI, 0.86–1.68; Table 2). The corresponding rates for patients without carotid plaque were 4.0 versus 4.5 per 100 patient-years, respectively, HR, 0.90; 95% CI, 0.67–1.2. There was no treatment interaction between patients with and without carotid plaque (P for interaction 0.2; Table 3). The cumulative probability of first recurrent ischemic stroke by treatment and by the presence of carotid plaque is presented in the Figure.

The rates of the secondary efficacy outcomes were comparable between the 2 treatment arms (Table 2). The rate of major bleeding was higher in the rivaroxaban arm compared with the aspirin arm (2.0 per 100 patient-years versus 0.5, HR, 3.75; 95% CI, 1.63–8.65; Table 2).

Efficacy Outcome Events by Presence of Carotid Stenosis

The rate of ischemic stroke recurrence during follow-up was not statistically different between patients with carotid stenosis compared with those without in the overall population of this analysis (5.4 versus 4.9 per 100 patient-years, respectively, HR, 1.11; 95% CI, 0.73–1.69), as well as in the rivaroxaban-treated population (5.0 versus 4.8 per 100 patient-years, respectively, HR, 1.05; 95% CI, 0.57–1.91) and aspirin-treated population (5.9 versus 5.0 per 100 patient-years, respectively, HR, 1.19; 95% CI, 0.67–2.13). The rates of the secondary efficacy outcomes were comparable between patients with carotid stenosis compared with those without in the overall population of this analysis (Table 4), as well as in the rivaroxaban-treated (Table I in the online-only Data Supplement) and the aspirin-treated population (Table II in the online-only Data Supplement).

Table 4. Outcome Events in the Overall Population by Presence of Any Carotid Stenosis

CharacteristicNo. of RandNo. of Events (Events Rate*)No. of RandNo. of Events (Events Rate*)Hazard Ratio (95% CI)P Value
Any StenosisNo Stenosis
Efficacy
Ischemic stroke§49025 (5.4)4154193 (4.9)1.11 (0.73–1.69)0.61
 Ischemic stroke§ ipsilateral to the lesion49012 (2.6)41540 (0.0)NA
 Ischemic stroke§ ipsilateral to the qualifying stroke49014 (3.0)415479 (2.0)1.53 (0.87–2.70)0.14
 Ischemic stroke# of presumed atherosclerotic etiology4900 (0.0)415418 (0.4)NA
 Ischemic stroke# presumably ESUS49011 (2.4)4154105 (2.6)0.90 (0.48, 1.67)0.74
 MI or cardiac chest pain requiring hospitalization4905 (1.1)415425 (0.6)1.71 (0.65–4.47)0.27
 All-cause mortality4909 (1.9)415460 (1.5)1.31 (0.65–2.65)0.44
Bleeding
 Major4907 (1.5)415451 (1.3)1.18 (0.54–2.60)0.68
 Symptomatic intracerebral4900 (0.0)41549 (0.2)NA

ESUS indicates embolic stroke of undetermined source; and MI, myocardial infarction.

*Event rates reported in 100-person-years.

†Hazard ratio, 95% CI, and P value presented if hazard ratio is >0.1 and <10.

‡Also includes those with missing value for stenosis.

§Includes undetermined strokes.

‖If side of stenosis at baseline=side of recurrent ischemic stroke or bilateral (in either internal, middle, or anterior artery); if side of stenosis at baseline=bilateral, then recurrent ischemic stroke in any side (in either internal, middle, or anterior artery).

¶If side of qualifying stroke same as the side of recurrent ischemic stroke or bilateral (in either internal, middle, or anterior artery).

#Does not include undetermined strokes; only adjudicated ischemic strokes can be further subclassified.

Efficacy Outcome Events by Presence of Carotid Plaque

There was a strong trend of a higher rate of ischemic stroke recurrence during follow-up in the overall population of this analysis in patients with carotid plaque compared with those without (5.4 versus 4.3 per 100 patient-years, respectively, HR, 1.23; 95% CI, 0.99–1.54), which reached statistical significance in the rivaroxaban-treated population (5.9 per versus 4.0 per 100 patient-years, respectively, HR, 1.42, 95% CI, 1.04–1.94; Table 5). The rate of ischemic stroke recurrence ipsilateral to the qualifying stroke during follow-up was higher in patients with carotid plaque compared with those without in the overall population of this analysis (2.6 per 100 patient-years versus 1.7, respectively, HR, 1.47; 95% CI, 1.06–2.05), as well as in the aspirin-treated population (2.7 per 100 patient-years versus 1.5, respectively, HR, 1.76; 95% CI, 1.09–2.83).

Table 5. Outcome Events in the Overall Population by Presence of Any Carotid Plaque

CharacteristicNo. of RandNo. of Events (Events Rate*)No. of RandNo. of Events (Events Rate*)Hazard Ratio (95% CI)P Value
Any PlaqueNo Plaque*
Efficacy
 Ischemic stroke2905139 (5.4)4307176 (4.3)1.23 (0.99–1.54)0.07
 Ischemic stroke ipsilateral to the lesion290511 (0.4)43071 (0.0)NA
 Ischemic stroke ipsilateral to the qualifying stroke§290568 (2.6)430772 (1.7)1.47 (1.06–2.05)0.02
 Ischemic stroke of presumed atherosclerotic cause290511 (0.4)430718 (0.4)0.94 (0.45–2.00)0.88
 Ischemic stroke presumably ESUS290567 (2.5)430794 (2.3)1.11 (0.81–1.52)0.52
 MI or cardiac chest pain requiring hospitalization290516 (0.6)430724 (0.6)1.05 (0.56–1.98)0.87
 All-cause mortality290549 (1.8)430768 (1.6)1.15 (0.79–1.66)0.46
Bleeding
 Major290533 (1.2)430752 (1.2)1.00 (0.64–1.54)0.99
 Symptomatic intracerebral29054 (0.1)430711 (0.3)0.57 (0.18–1.79)0.33

ESUS indicates embolic stroke of undetermined source; and MI, myocardial infarction.

*Also includes those with missing value for plaque.

†Includes undetermined strokes.

‡If side of plaque at baseline=side of recurrent ischemic stroke or bilateral (in either internal, middle, or anterior artery); if side of plaque at baseline=bilateral, then recurrent ischemic stroke in any side (in either internal, middle, or anterior artery).

§If side of qualifying stroke same as the side of recurrent ischemic stroke or bilateral (in either internal, middle, or anterior artery).

‖Does not include undetermined strokes; only adjudicated ischemic strokes can be further subclassified.

Discussion

In this exploratory subgroup analysis of the NAVIGATE-ESUS trial involving patients with carotid atherosclerosis, we found no difference in efficacy between rivaroxaban and aspirin for prevention of recurrent ischemic stroke. Aspirin was safer than rivaroxaban, which is consistent with the findings in the overall NAVIGATE-ESUS population.

It has been hypothesized that the absence of benefit for stroke reduction in the NAVIGATE-ESUS trial could be attributed to the inclusion of patients with nonstenotic carotid atherosclerosis, who may respond better to antiplatelet inhibition rather than oral anticoagulation.13 In our analysis, there was no statistically significant treatment interaction between patients with and without carotid stenosis or plaque, however, there were trends of differing treatment effects among participants with versus without carotid atherosclerosis are present (Table 3). Although our null hypothesis is not confirmed, it might be speculated that this represents a type II error because of moderate statistical power.

Our findings confirm previous trials reporting similar efficacy of anticoagulation and aspirin to prevent future ischemic events in patients with stroke and cerebral atherosclerosis. In the open-label, prematurely terminated ESPRIT (European/Australasian Stroke Prevention in Reversible Ischaemia Trial), in patients treated with warfarin (target international normalized ratio [INR] range, 2.0–3.0; mean achieved INR, 2.6; time within target range ≈70%) there were numerically fewer ischemic strokes (7.6% versus 9.9%, respectively, HR, 0.76; 95% CI, 0.51–1.15) and a strong trend for fewer major ischemic events (11.6% versus 15.8%, respectively, HR, 0.73; 95% CI, 0.52–1.01; defined as death from any ischemic vascular condition, nonfatal ischemic stroke, and nonfatal myocardial infarction) compared with aspirin 30 to 325 mg daily.3 In the blinded WARSS (Warfarin Aspirin Recurrent Stroke Study), the rate of ischemic stroke or death was similar between patients treated with warfarin (target INR range, 1.4–2.8; mean achieved INR, 2.1) or aspirin 325 mg daily in the subgroup of patients with severe stenosis or occlusion of a large artery (18.8% versus 15.7%, respectively, HR, 1.22; 95% CI, 0.67–2.22).4 In the prematurely terminated WASID trial (Warfarin-Aspirin Symptomatic Intracranial Disease), the rate of ischemic stroke was similar between patients with symptomatic intracranial arterial stenosis treated with aspirin 1300 mg daily or warfarin (target INR range, 2.0–3.0; mean achieved INR 2.5; 23.6% versus 24.6%, respectively, HR, 0.98; 95% CI, 0.70–1.37).6 In the prematurely terminated SPIRIT study (Stroke Prevention In Reversible Ischemia Trial), the rate of major ischemic events (defined as nonhemorrhagic death from vascular cause, nonfatal ischemic stroke, and nonfatal myocardial infarction) was similar between patients with cerebral ischemic of presumed arterial origin treated with oral anticoagulation (target INR range, 3.0–4.5) and patients treated with aspirin (4.1% versus 4.1%, respectively, HR, 1.03; 95% CI, 0.60–1.75).5 However, despite similar efficacy, oral anticoagulation is not indicated in patients with cerebral atherosclerosis because of higher rates of major bleeding in all aforementioned studies, as well as in the present analysis.

We found that the frequency of ipsilateral carotid stenosis or plaque to a qualifying ESUS stroke is much higher than the contralateral side, supporting a possible etiologic role for carotid atherosclerosis in the qualifying stroke. This is in line with previous studies pointing towards an association between mild carotid atherosclerosis and stroke risk. In a recent analysis of ESUS patients, larger nonstenotic carotid plaques were more prevalent ipsilateral than contralateral to ischemic stroke.17 Also, a strong negative association was reported between nonstenotic carotid plaques and patent foramen ovale in young adults with cryptogenic stroke, pointing towards a causal link between nonstenotic carotid plaques and stroke.18 Similarly, in a recent report, atrial fibrillation was less frequently detected in ESUS patients with nonstenotic carotid plaques compared with those without.19 Furthermore, in a study by Freilinger et al,20 complicated American Heart Association lesion type VI plaques in the carotid arteries of patients with cryptogenic stroke were found in 37.5% of cases ipsilateral to the stroke, compared with no American Heart Association type VI plaques contralateral to the stroke. On the contrary, Li et al21 did not find any evidence of excess atherosclerotic potential in patients with cryptogenic event in the Oxford Vascular Study concluding that the possible etiologic association between nonstenosing atherosclerosis and cryptogenic stroke should be interpreted with caution.21

We found that the presence of mild (20%–49%) carotid stenosis in the NAVIGATE-ESUS population did not increase the risk for ischemic stroke compared with patients without carotid stenosis, even in those patients with carotid stenosis ipsilateral to stroke. The lack of an association between the presence of mild carotid stenosis and ischemic stroke risk in patients with ESUS is compatible with the well-established knowledge that mild carotid stenosis yields relatively low risk for ischemic stroke: in the European Carotid Surgery Trial, the 1-year risk of ischemic stroke in medically treated patients with 20% to 39% symptomatic carotid stenosis was ≈1% to 2%, which is comparable to the risk in patients without carotid stenosis, a finding which could explain the lack of association between the presence of carotid stenosis and ischemic stroke risk in our population.22 On the contrary, we found that the presence of carotid plaque conferred higher risk for ischemic stroke, especially in the same territory of the qualifying stroke; compared to patients without. This is consistent with several recent reports which emphasize the role of carotid plaque as a risk indicator for ischemic stroke in patients with mild or minimal carotid stenosis.17,20,23–25 Other predictors of stroke recurrence in patients with ESUS include the age and the CHADS2 and CHA2DS2-VASc scores.26,27 Our conclusions must be interpreted with caution because this is an exploratory analysis. In trials that the treatment effect on the primary end point is not significant, the results of exploratory subgroup analyses of treatment interactions must be deemed as hypothesis-generating and unsuitable for patient management.28,29 Also, we cannot exclude the possibility of ascertainment bias during data collection: the protocol of the NAVIGATE-ESUS trial did not request that data collectors are blinded to the location of stroke, and therefore, they may be more likely to report the ipsilateral plaque features and degree of stenosis, as opposed to the contralateral side. This may artificially inflate the probability of ipsilateral carotid abnormalities. Further confirmation of this finding is warranted in future studies. In addition, our analysis relied on data reported by the sites without quality-control assessment for the presence of stenosis or plaque. Also, the reliability of using CTA and MRA to measure 20% to 49% carotid stenosis has not been established. Finally, information on ulceration was not available except in a minority of participants.

In conclusion, this exploratory subgroup analysis of the NAVIGATE-ESUS trial in patients with carotid atherosclerosis found no difference in efficacy between rivaroxaban and aspirin. Aspirin was safer than rivaroxaban, consistent with the findings in the overall NAVIGATE-ESUS population. Despite trends in differing treatment effects, there was no significant treatment interaction between patients with and without carotid stenosis or plaque. Carotid plaque was much more often present ipsilateral to the qualifying ischemic stroke than contralateral, supporting an important etiological role of nonstenotic carotid atherosclerosis in ESUS patients.

Footnotes

Guest Editor for this article was Jeffrey L. Saver, MD.

The online-only Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.119.025168.

Correspondence to George Ntaios, MD, MSc (Stroke Medicine), PhD, Department of Internal Medicine, Larissa University Hospital, School of Medicine, University of Thessaly, Biopolis, 41110 Larissa, Greece. Email

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