Skip main navigation
×

Carotid Plaque With High-Risk Features in Embolic Stroke of Undetermined Source

Systematic Review and Meta-Analysis
Originally publishedhttps://doi.org/10.1161/STROKEAHA.119.027272Stroke. 2020;51:311–314

Abstract

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.

Methods—

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.

Results—

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).

Conclusions—

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.

Methods

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.

Results

The initial search identified 181 records. Eight articles met the inclusion criteria5–12 (Figure I in the online-only Data Supplement).

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.

Table. Characteristics of the Included Studies

PMIDAuthorYearSample SizeAge (Mean)Age (Median)Women, %HTN, %DM, %Smoking, %DLP, %CAD, %Plaque ImagingImaging Delay, dHigh-Risk FeaturesROB
24330333Bayer-Karpinska et al5201332NA74327222492822MRI (HRBB)< 7Ulceration, intraplaque hemorrhage, and thrombus9
29307510Buon et al6201844NA46.5431425916NACarotid USNAUlceration, echolucency, and thrombus9
27412144Coutinho et al7201685NA70526028NA3420CTA< 10Plaque thickness ≥3 mm10
22498329Freilinger et al820123271.7NA315922634722MRI (HRBB)5.8Ulceration, intraplaque hemorrhage, and thrombus10
26077590Gupta et al920152771NA48782245611MRI (3D-TOF)2.6Intraplaque hemorrhage8
29571754Singh et al1020183574.3NA54742968049MRI (HRBB)NAIntraplaque hemorrhage9
26897689Gupta et al1120165069.5NA50NANANANANAMRI (3D-TOF)1Intraplaque hemorrhage9
26433367Hyafil et al1220161870NA637222172822MRI (HRBB)<14Fibrous cap rupture, intraplaque hemorrhage, and thrombus9

3D-TOF indicates 3-dimensional time of flight; CAD, coronary artery disease; DLP, dyslipidemia; DM, diabetes mellitus; HRBB, high-resolution black blood; HTN, hypertension; MRI, magnetic resonance imaging; NA, not available; PMID, PubMed accession number; ROB, risk of bias score (maximum 10, 8–10 = low risk of bias/high quality, 5–7 = moderate risk of bias/moderate quality, and ≤4 = high risk of bias/low quality); and US, ultrasound.

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).

Figure 1.

Figure 1. Prevalence of ipsilateral carotid plaque with high-risk features in embolic stroke of undetermined source (ESUS). 3D-TOF indicates 3-dimensional time of flight; CT, computed tomography; ES, effect size; ipsi_hr_plaque, ipsilateral carotid plaque with high-risk features; MRI, magnetic resonance imaging; sample_size, number of participants in the study; and year_pub, year of publication.

Figure 2.

Figure 2. Odds ratio of finding plaque with high-risk features in the ipsilateral vs the contralateral carotid in embolic stroke of undetermined source (ESUS). 3D-TOF indicates 3-dimensional time of flight; cont_hr_plaque, contralateral carotid plaque with high-risk features; CT, computed tomography; ipsi_hr_plaque, ipsilateral carotid plaque with high-risk features; MRI, magnetic resonance imaging; OR, odds ratio; sample_size, number of participants in the study; and year_pub, year of publication.

Discussion

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.

Footnotes

The online-only Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.119.027272.

Correspondence to Joseph Kamtchum-Tatuene, MD, Neuroscience and Mental Health Institute, Faculty of Medicine and Dentistry, University of Alberta, 4-065 Katz Group Bldg, 114 St, 87 Ave, Edmonton, T6G 2E1 Alberta, Canada. Email

References

  • 1. Hart RG, Catanese L, Perera KS, Ntaios G, Connolly SJ. Embolic stroke of undetermined source: a systematic review and clinical update.Stroke. 2017; 48:867–872. doi: 10.1161/STROKEAHA.116.016414LinkGoogle Scholar
  • 2. Ntaios G, Perlepe K, Sirimarco G, Strambo D, Eskandari A, Karagkiozi E, et al. Carotid plaques and detection of atrial fibrillation in embolic stroke of undetermined source.Neurology. 2019; 92:e2644–e2652. doi: 10.1212/WNL.0000000000007611CrossrefMedlineGoogle Scholar
  • 3. Ntaios G, Swaminathan B, Berkowitz SD, Gagliardi RJ, Lang W, Siegler JE, et al; NAVIGATE ESUS Investigators. Efficacy and safety of rivaroxaban versus aspirin in embolic stroke of undetermined source and carotid atherosclerosis.Stroke. 2019; 50:2477–2485. doi: 10.1161/STROKEAHA.119.025168LinkGoogle Scholar
  • 4. Saba L, Saam T, Jäger HR, Yuan C, Hatsukami TS, Saloner D, et al. Imaging biomarkers of vulnerable carotid plaques for stroke risk prediction and their potential clinical implications.Lancet Neurol. 2019; 18:559–572. doi: 10.1016/S1474-4422(19)30035-3CrossrefMedlineGoogle Scholar
  • 5. Bayer-Karpinska A, Schwarz F, Wollenweber FA, Poppert H, Boeckh-Behrens T, Becker A, et al. The carotid plaque imaging in acute stroke (CAPIAS) study: protocol and initial baseline data.BMC Neurol. 2013; 13:201. doi: 10.1186/1471-2377-13-201Google Scholar
  • 6. Buon R, Guidolin B, Jaffre A, Lafuma M, Barbieux M, Nasr N, et al. Carotid ultrasound for assessment of nonobstructive carotid atherosclerosis in young adults with cryptogenic stroke.J Stroke Cerebrovasc Dis. 2018; 27:1212–1216. doi: 10.1016/j.jstrokecerebrovasdis.2017.11.043Google Scholar
  • 7. Coutinho JM, Derkatch S, Potvin AR, Tomlinson G, Kiehl TR, Silver FL, et al. Nonstenotic carotid plaque on CT angiography in patients with cryptogenic stroke.Neurology. 2016; 87:665–672. doi: 10.1212/WNL.0000000000002978CrossrefMedlineGoogle Scholar
  • 8. Freilinger TM, Schindler A, Schmidt C, Grimm J, Cyran C, Schwarz F, et al. Prevalence of nonstenosing, complicated atherosclerotic plaques in cryptogenic stroke.JACC Cardiovasc Imaging. 2012; 5:397–405. doi: 10.1016/j.jcmg.2012.01.012CrossrefMedlineGoogle Scholar
  • 9. Gupta A, Gialdini G, Lerario MP, Baradaran H, Giambrone A, Navi BB, et al. Magnetic resonance angiography detection of abnormal carotid artery plaque in patients with cryptogenic stroke.J Am Heart Assoc. 2015; 4:e002012. doi: 10.1161/JAHA.115.002012LinkGoogle Scholar
  • 10. Singh N, Moody AR, Panzov V, Gladstone DJ. Carotid intraplaque hemorrhage in patients with embolic stroke of undetermined source.J Stroke Cerebrovasc Dis. 2018; 27:1956–1959. doi: 10.1016/j.jstrokecerebrovasdis.2018.02.042CrossrefMedlineGoogle Scholar
  • 11. Gupta A, Gialdini G, Giambrone AE, Lerario MP, Baradaran H, Navi BB, et al. Association between nonstenosing carotid artery plaque on MR angiography and acute ischemic stroke.JACC Cardiovasc Imaging. 2016; 9:1228–1229. doi: 10.1016/j.jcmg.2015.12.004CrossrefMedlineGoogle Scholar
  • 12. Hyafil F, Schindler A, Sepp D, Obenhuber T, Bayer-Karpinska A, Boeckh-Behrens T, et al. High-risk plaque features can be detected in non-stenotic carotid plaques of patients with ischaemic stroke classified as cryptogenic using combined (18)F-FDG PET/MR imaging.Eur J Nucl Med Mol Imaging. 2016; 43:270–279. doi: 10.1007/s00259-015-3201-8CrossrefMedlineGoogle Scholar
  • 13. Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease.N Engl J Med. 2017; 377:1319–1330. doi: 10.1056/NEJMoa1709118CrossrefMedlineGoogle Scholar
  • 14. Sharma M, Hart RG, Connolly SJ, Bosch J, Shestakovska O, Ng KKH, et al. Stroke outcomes in the COMPASS Trial.Circulation. 2019; 139:1134–1145. doi: 10.1161/CIRCULATIONAHA.118.035864LinkGoogle Scholar
  • 15. Jickling GC, Stamova B, Ander BP, Zhan X, Liu D, Sison SM, et al. Prediction of cardioembolic, arterial, and lacunar causes of cryptogenic stroke by gene expression and infarct location.Stroke. 2012; 43:2036–2041. doi: 10.1161/STROKEAHA.111.648725LinkGoogle Scholar