Carotid Plaque With High-Risk Features in Embolic Stroke of Undetermined Source
Background and Purpose—
An ipsilateral mild carotid stenosis, defined as plaque with <50% luminal narrowing, is identified in nearly 40% of patients with embolic stroke of undetermined source and could represent an unrecognized source of atheroembolism. We aimed to summarize data about the frequency of mild carotid stenosis with high-risk features in embolic stroke of undetermined source.
We searched Pubmed and Ovid-Embase for studies reporting carotid plaque imaging features in embolic stroke of undetermined source. The prevalence of ipsilateral and contralateral mild carotid stenosis with high-risk features was pooled using random-effect meta-analysis.
Eight studies enrolling 323 participants were included. The prevalence of mild carotid stenosis with high-risk features in the ipsilateral carotid was 32.5% (95% CI, 25.3–40.2) compared with 4.6% (95% CI, 0.1–13.1) in the contralateral carotid. The odds ratio of finding a plaque with high-risk features in the ipsilateral versus the contralateral carotid was 5.5 (95% CI, 2.5–12.0).
Plaques with high-risk features are 5 times more prevalent in the ipsilateral compared with the contralateral carotid in embolic stroke of undetermined source, suggesting a relationship to stroke risk.
Embolic stroke of undetermined source (ESUS) represents 17% (9%–25%) of all ischemic strokes.1 An ipsilateral mild carotid stenosis (plaque with <50% luminal narrowing) is identified in nearly 40% of patients with ESUS and may represent a source of atheroembolism.2,3 Vascular imaging is used to assess carotid plaque features other than degree of stenosis that may be important to estimate the stroke risk, notably intraplaque hemorrhage, large lipid-rich necrotic core, thin or ruptured fibrous cap, silent embolic infarcts, progression, irregularity or ulceration, echolucency, neovascularization, inflammation, large juxta-liminal hypoechoic area, large plaque volume, microembolic signals, and impaired cerebrovascular reserve.4 Patients with ESUS that have a high-risk plaque may benefit from specific interventions to prevent stroke. We aimed to summarize data on the frequency of mild carotid stenosis with high-risk features in ESUS.
This report is compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The data supporting the findings of this study are available from the corresponding author upon reasonable request.
We searched Medline and Ovid-Embase for observational studies reporting carotid plaque imaging results in ESUS, from inception to July 15, 2019 (Table I in the online-only Data Supplement). The titles and abstracts were screened, and full-texts of potentially eligible records were retrieved for further assessment. Disagreements about study inclusion were resolved through consensus (Drs Kamtchum-Tatuene and Jickling). The risk of bias was assessed using the Risk of Bias Tool for Prevalence Studies (Table II in the online-only Data Supplement) with the aim of excluding all studies with high risk of bias from the quantitative synthesis.
We extracted first author’s name, year of publication, study design, sample size, mean age, proportion of women, frequency of cardiovascular risk factors, type of index event (stroke or transient ischemic attack), imaging modality, onset-to-imaging time, side, and frequency of mild carotid stenosis with high-risk features.
Analyses were performed with STATA (version 13, StataCorp, College Station, TX). Heterogeneity between studies was assessed using the χ2 test on the Cochran Q statistic and quantified by the I2 index. The prevalence of ipsilateral and contralateral mild carotid stenosis with high-risk features was pooled using random-effect meta-analysis after stabilizing the variance of each study with the Freeman-Tukey double arc-sine transformation. Small-study effect was assessed by visual inspection of funnel plots and formally tested using the Egger test. Statistical tests were 2-sided and statistical significance defined as P≤0.05.
All studies were prospective and enrolled 323 participants with unilateral anterior circulation ischemic stroke (Table). Plaque imaging was performed within 14 days of stroke onset using magnetic resonance imaging,5,8–10 computed tomography angiography,7 or ultrasound.6 Ulceration, intraplaque hemorrhage, thrombus, fibrous cap rupture, echolucency, or plaque thickness ≥3 mm were the high-risk features considered.
|PMID||Author||Year||Sample Size||Age (Mean)||Age (Median)||Women, %||HTN, %||DM, %||Smoking, %||DLP, %||CAD, %||Plaque Imaging||Imaging Delay, d||High-Risk Features||ROB|
|24330333||Bayer-Karpinska et al5||2013||32||NA||74||32||72||22||49||28||22||MRI (HRBB)||< 7||Ulceration, intraplaque hemorrhage, and thrombus||9|
|29307510||Buon et al6||2018||44||NA||46.5||43||14||2||59||16||NA||Carotid US||NA||Ulceration, echolucency, and thrombus||9|
|27412144||Coutinho et al7||2016||85||NA||70||52||60||28||NA||34||20||CTA||< 10||Plaque thickness ≥3 mm||10|
|22498329||Freilinger et al8||2012||32||71.7||NA||31||59||22||63||47||22||MRI (HRBB)||5.8||Ulceration, intraplaque hemorrhage, and thrombus||10|
|26077590||Gupta et al9||2015||27||71||NA||48||78||22||4||56||11||MRI (3D-TOF)||2.6||Intraplaque hemorrhage||8|
|29571754||Singh et al10||2018||35||74.3||NA||54||74||29||6||80||49||MRI (HRBB)||NA||Intraplaque hemorrhage||9|
|26897689||Gupta et al11||2016||50||69.5||NA||50||NA||NA||NA||NA||NA||MRI (3D-TOF)||1||Intraplaque hemorrhage||9|
|26433367||Hyafil et al12||2016||18||70||NA||63||72||22||17||28||22||MRI (HRBB)||<14||Fibrous cap rupture, intraplaque hemorrhage, and thrombus||9|
The pooled prevalence of mild carotid stenosis with high-risk features was 32.5% (95% CI, 25.3–40.2) in the ipsilateral carotid (Figure 1) and 4.6% (95% CI, 0.1–13.1) in the contralateral carotid (Figure II in the online-only Data Supplement). There was no small-study effect (Figure III in the online-only Data Supplement). The odds ratio of finding a mild carotid stenosis with high-risk features in the ipsilateral versus the contralateral carotid was 5.5 (95% CI, 2.5–12.0; Figure 2). The odds ratio of finding a ruptured fibrous cap in the ipsilateral versus the contralateral carotid was 17.5 (95% CI, 2.2–140.1; Table III in the online-only Data Supplement). In the sensitivity analysis, similar results were obtained after excluding studies with sample size <20 or with potential population overlap11,12 (Figures IV and V in the online-only Data Supplement).
Mild stenosis with high-risk features was 5 times more prevalent in the ipsilateral compared with the contralateral carotid in ESUS, suggesting a relationship to stroke risk. Our findings align with the results of AF-ESUS study showing that patients with ESUS and ipsilateral mild carotid stenosis had a lower 10-year probability of atrial fibrillation detection, thus making a cardioembolic source less probable.2 Moreover, in NAVIGATE-ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus Aspirin to Prevent Embolism in Embolic Stroke of Undetermined Source), patients with ESUS and ipsilateral mild carotid stenosis did not benefit from anticoagulation.3 In COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies),13 Rivaroxaban-Aspirin combination was more effective than Aspirin or Rivaroxaban for prevention of noncardioembolic strokes and represents a potential therapeutic option in patients with ESUS and an ipsilateral mild carotid stenosis. However, recent strokes were excluded and some participants had asymptomatic ≥50% carotid stenosis.14 Therefore, further trials are needed to investigate the benefit of Rivaroxaban-Aspirin combination in patients with recent ESUS and an ipsilateral mild carotid stenosis. Dual antiplatelet therapy with high-dose statins, endarterectomy, or stenting also represents potential treatment options.
All studies used a single plaque imaging modality, which may have led to underestimation of the prevalence of high-risk plaques in ESUS since various imaging modalities have different sensitivity and specificity for detection of high-risk features.4 Besides features visible on plaque magnetic resonance imaging, high-risk features identified by other imaging modalities may be useful: microembolic signals (transcranial Doppler), large plaque volume (3-dimensional ultrasound), plaque neovascularization (contrast-enhanced ultrasound), and plaque inflammation (positron emission tomography-computed tomography).4 Combination of vascular imaging and blood biomarkers may also be useful to refine stroke risk stratification in patients with ESUS and ipsilateral mild carotid stenosis. RNA biomarker panels that predict stroke cause with >90% sensitivity and specificity15 can be integrated into multiparameter scores to predict causality of an ipsilateral mild carotid stenosis in ESUS and better stratify the risk of recurrence before inclusion in trials.
Sources of Funding
Dr Jickling receives research support from the Canadian Institutes of Health Research (CIHR), the National Institutes of Health (NIH), the Heart and Stroke Foundation (HSF), the Canada Foundation for Innovation (CFI), and the University Hospital Foundation.
Drs Kamtchum-Tatuene and Jickling conceived the study. Dr Kamtchum-Tatuene performed the literature search, selected the articles, extracted the data, performed the analyses and drafted the article. Drs Wilman, Saqqur, Shuaib, and Jickling contributed to data interpretation and critically revised the article. All authors approved the final version. Dr Kamtchum-Tatuene is the guarantor of the review.
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