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The Attributable Risk of Nonstenotic Cervical Carotid Plaque in Cryptogenic Embolic Stroke

Originally publishedhttps://doi.org/10.1161/SVIN.122.000727Stroke: Vascular and Interventional Neurology. 2023;3:e000727

Abstract

Nonstenotic plaque (NSP) of a cervical artery feeding the territory of acute cerebral infarction is increasingly recognized as a cause of cryptogenic stroke. While these atherosclerotic lesions are not associated with significant luminal stenosis (<50%), the probability of finding such plaque exceeds chance and is more common in parent vessels rather than vessels supplying brain regions remote from infarction. More than 20%–30% of patients with unilateral hemispheric embolic stroke of undetermined source may be attributable to cervical internal or common carotid NSP. For these patients, randomized clinical trials have not shown a significant benefit of revascularization (endarterectomy or stenting), and optimal secondary prevention strategies rely on risk factor modification and antiplatelet therapy. Heightened awareness of this subtle finding may inform second‐tier diagnostic testing recommendations for occult stroke mechanisms (eg, monitoring for paroxysmal atrial fibrillation or hypercoagulability testing). Furthermore, recognition of NSP as a culprit lesion may lead to more targeted pharmacologic strategies aimed at stabilizing plaque. Recent guidelines have also incorporated evidence of plaque vulnerability (eg, intraplaque hemorrhage or lipid‐rich necrotic core) in decision making regarding revascularization approaches. In this review, the epidemiology and management of NSP in patients with cryptogenic embolic infarction is summarized, with an emphasis on recognition of NSP such that future clinical trials can be designed to test novel interventional strategies against current medical management of embolic stroke of undetermined source.

Nonstandard Abbreviations and Acronyms

CHALLENGE ESUS/CS

Mechanisms of Embolic Stroke of Undetermined Source/Cryptogenic Stroke

CSE

cardiac source of embolism

ESUS

embolic stroke of undetermined source

ICA

internal carotid artery

IPH

intraplaque hemorrhage

LRNC

lipid‐rich necrotic core

NAVIGATE‐ESUS

New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source

NSP

nonstenotic plaque

Clinical Perspective

What Is New?

  • This review summarizes the most commonly encountered, high‐risk features of cervical carotid nonstenotic (<50% luminal narrowing) plaque in patients with an acute cerebrovascular event.

  • Carotid plaque morphology (rather than luminal stenosis alone) plays a key and underappreciated role in embolic stroke risk.

What Are the Clinical Implications?

  • Heightened attention to certain carotid plaque features (eg, echolucency or neovascularization) in the absence of luminal stenosis may identify patients at high risk of stroke recurrence.

  • Future secondary prevention trials are called upon to evaluate whether more aggressive pharmacologic or endovascular/surgical strategies can mitigate stroke risk.

The lack of superiority of anticoagulation over antiplatelet therapy in cryptogenic stroke with embolic topology1, 2 is a testament to the heterogeneity of mechanisms that underlie embolic stroke of undetermined source (ESUS).3 Although the definition of this condition was updated in 2017 as new information had become available,4 the term remains too encompassing and nonspecific for appropriate clinical categorization. Misclassification of patients as having ESUS when they have atriopathy or an alternative cardiac source of embolism (CSE),5, 6 nonstenotic cervical carotid plaque (nonstenotic plaque [NSP]),7, 8 or other clinical profiles9, 10, 11 likely accounts for neutral effects of anticoagulation versus antiplatelet therapy in these patients when they are consolidated as a singular group. While there remains no consensus on the definition of NSP, a pragmatic definition would include, at minimum, 2 criteria: (1) luminal stenosis measuring <50% by North American Symptomatic Carotid Endarterectomy Trial criteria and (2) atherosclerotic plaque with at least 1 high‐risk feature (eg, diameter >3.0 mm or presence of ulceration or intraplaque hemorrhage [IPH]). Whether such a plaque is symptomatic or clinically relevant remains controversial, although a working definition has been recently proposed by Goyal et al.12 Mechanistic differentiation and probabilistic modeling of relevant NSP are key to identifying patients at greatest risk of recurrent stroke when NSP is present.12 Only through high‐quality observational cohort studies or implementation of tiered, clustered randomized clinical trials of patients with cryptogenic embolic stroke will we establish optimal secondary prevention strategies in these patients.

Epidemiology

While evidence implicating NSP in cryptogenic stroke has grown over the past 20 years,13 we have an incomplete understanding of this condition and its attributable risk in stroke. Lack of standardized criteria or thresholds of clinical relevance have limited the generalizability of reported findings and will continue to impede any progress with respect to targeted secondary prevention trials. Internal carotid artery (ICA) plaque thickness, location of the plaque in relation to the carotid bifurcation, and plaque composition may vary between patients, although many may theoretically have experienced a stroke in the setting of NSP.

Of the 20% to 30% of strokes classified as undetermined in origin, only 10% to 15% occur in multiple vascular territories (2%–4% of all ischemic strokes), with another 10% to 15% occurring in isolated posterior circulation regions, leaving 70% to 80% in unilateral anterior circulation regions (Figure 1).7, 8 When this population of unilateral, anterior circulation cryptogenic stroke is selected, the majority will have some degree of cervical carotid atherosclerosis without stenosis, with 1 meta‐analysis indicating that 55% of patients with cryptogenic stroke in any brain region will have some amount of NSP in either carotid artery.14 Unfortunately, because of the variable patterns, composition, and imaging used to identify NSP, estimates of NSP burden are imprecise and can be between 20% and 60%.15, 16, 17

Figure 1.

Figure 1. Estimated global incidence and prevalence rates for NSP. Estimates extrapolated from the Global Burden of Disease Study 2019,18 published observational cohort studies, and a recent meta‐analysis.14 Note that estimates are imprecise because of variable imaging modalities used in identification of NSP, heterogeneous classification of NSP vulnerability, and varying prevalence rates of stroke mechanisms worldwide. Image created using Biorender.com. ESUS indicates embolic stroke of undetermined source; and NSP, nonstenotic plaque.

While the prevalence of carotid NSP may be high in the ESUS population, one should not presume all cases of NSP are responsible for occult embolism. The presence of any atherosclerotic disease of the cervical or intracranial vessels is highly tied to increasing patient age and other comorbidities,19, 20 which may be further associated with a number of other causes of cerebral infarction.21 There is occasional overlap among potential competing mechanisms of cryptogenic cerebral infarction (eg, atrial fibrillation and cervical atherostenosis).22 In a recent multicenter study of patients with ESUS, NSP was as common in patients with left atrial enlargement as those with normal left atrial diameter (63% versus 64%).5 Separately, in their analysis of patients from the NAVIGATE‐ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial versus Aspirin to Prevent Embolism in Embolic Stroke of Undetermined Source) trial, Ntaios et al23 found considerable overlap among patients with various potential embolic sources, including CSE and NSP. While NSP was the third most common potential embolic source in these patients with ESUS (found in 29% of patients), 41% of cryptogenic patients harbored >1 potential (nontraditional) source of embolism. Furthermore, 1 in 7 patients with ESUS had ≥3 competing theoretical mechanisms (including combinations of atriopathy, left ventricular dysfunction, and NSP). In these circumstances, assessing the attributable risk of any NSP poses a major challenge to the mechanistic determination of cryptogenic stroke and subsequently any targeted secondary prevention strategy.

Attributable Risk of NSP

NSP in the cervical ICA is not only a biomarker of systemic atherosclerosis and indicates heightened risk of any vascular event,13 but it is implicated as a causative lesion in many patients with embolic stroke and no other source of embolism. Unfortunately, clinical trials that have demonstrated efficacy in targeted endovascular and surgical intervention for carotid artery disease enrolled patients on the basis of luminal stenosis.24, 25, 26 These data have relied exclusively on the degree of luminal stenosis as operative in cerebral embolism, when in fact the relationship between carotid atherosclerotic disease and cerebral embolism is more complex. Given advances in neuroimaging and growing epidemiologic data, recent guidelines from the American Society of Neuroradiology27 and the European Society of Cardiology28 have called for a paradigm shift in this traditional classification of large‐vessel disease. Plaque composition, progression, and other features carry considerable risk of platelet activation, thrombus formation, and embolization, and should therefore be considered when making targeted treatment decisions (Table 1, Figure 2). While revascularization is still recommended only on the basis of luminal stenosis (symptomatic vessels with >50% narrowing), the 2017 European Society for Vascular Surgery Guidelines have recommended additional imaging to characterize high‐risk NSP while patients are being managed medically.29

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Table 1. High‐Risk Features of Vulnerable Carotid NSP

Plaque featureNotes
Overall thickness7, 8Cumulative thickness of carotid plaque is greater in patients with ESUS and few other competing potential embolic sources. While an absolute thickness of ≥3 mm has reasonable specificity for identifying NSP as a culprit lesion in ESUS, there remain no widely accepted thresholds for NSP thickness.
Rapid progression in thicknessAcceleration in plaque formation, which can be attributable to progressive lipid deposition from uncontrolled vascular risk factors, intraplaque hemorrhage, or other mechanisms.
UlcerationUlcerated plaques have a characteristic “shelf” appearance on vascular imaging, and rapidly attract and activate platelets via exposure to subendothelial proteins.
Intraplaque hemorrhage30, 31 Intraplaque hemorrhage represents deep rupture of neovasculature within the plaque and appears radiographically isodense with some admixed heterogeneity on ultrasound or CTA. Hemorrhage into an atherosclerotic plaque expands the necrotic core and facilitates plaque deposition and macrophage infiltration.
Lipid‐rich necrotic core32, 33, 34Lipid‐rich necrotic cores are found deep within plaque and appear radiographically hypointense and fail to enhance with T1‐weighted MRI.
Neovascularization35Perhaps best seen with T1‐weighted MRI with fat saturation, neovascularization appears as eccentric enhancement and reflects local inflammation, with accelerated plaque progression.
Fibrous cap36, 37A fibrous cap represents at least a grade V atheromatous lesion and is often a focus of inflammatory cell infiltrate and neovascularization, which becomes prone to intraplaque hemorrhage and rupture.
Echolucency38, 39Echolucency reflects lipid‐rich plaque (with or without necrosis) and is be detected on ultrasound or CTA. It is strongly associated with intraplaque hemorrhage.

CTA indicates computed tomography angiography; ESUS, embolic stroke of undetermined source; MRI, magnetic resonance imaging; and NSP, nonstenotic plaque.

Figure 2.

Figure 2. Imaging of nonstenotic plaque in patients with stroke. CTA indicates computed tomography angiography; PDW, proton density–weighted; T1W, T1‐weighted; T2W, T2‐weighted; and TOF, time of flight.

The attributable risk of ischemic stroke to ipsilateral ulcerated or irregular NSP in the ICA has long been understood, with early angiographic data from 1 cohort indicating a 12.5% annual risk of stroke.40 Twenty years ago, investigators from the Northern Manhattan Study performed screening carotid ultrasonography on 1939 stroke‐free community dwellers and found a strong correlation between plaque thickness and ulceration with incident stroke risk, despite the fact that almost 97% of included patients had <40% luminal stenosis.41 The estimated 5‐year risk of ischemic stroke among patients with any plaque was 3.4%, which climbed to 8.5% if the plaque surface was irregular. Unsurprisingly, the majority of index stroke events (70%) occurred in a territory supplied by the artery with NSP. With the advent of more potent lipid‐lowering therapies (eg, statins),42 more aggressive risk factor modification,43 and use of antiplatelet agents,44 the risk of recurrent stroke attributable to carotid atheromatous disease has fallen over time.

When patients with anterior circulation, unilateral hemispheric cryptogenic stroke are found to have any NSP of the carotid bifurcation, the probability of clinically relevant NSP is high. In 1 single‐center analysis of 32 consecutive patients with unilateral anterior infarcts (and ≥2 mm carotid plaque on ultrasonography), investigators found that 37.5% of patients had a high‐risk, American Heart Association grade VI NSP in the carotid artery supplying the infarction (eg, NSP with associated IPH, thrombus, or rupture of a fibrous cap).36 No American Heart Association grade VI plaques were observed in the contralateral vessel. The probability of finding excess NSP in the ipsilateral carotid (rather than contralateral) has been validated in several additional studies.7, 8

The inverse relationship of NSP with other, well‐defined mechanisms of cerebral infarction (including various CSEs) is another strong argument supporting the causative role of NSP in cerebral embolism. In 1 multicenter cohort study, we observed that excess NSP was not only common in ESUS but, perhaps more importantly, it was inversely associated with age.5 Among patients aged <70 years, the predicted probability of finding more ipsilateral than contralateral cervical ICA plaque exceeded chance (chance being 50% likelihood that 1 side would have more plaque than the other). For patients aged <40 years, the probability of excess ipsilateral NSP exceeded 80%. By contrast, older patients in this registry had a higher probability of left atrial enlargement, with presumably atrial fibrillation– or atriopathy‐associated occult embolism. In a separate analysis of 3 prospective stroke registries (n=777 patients with ESUS followed over 2642 years), Ntaios et al16 found atrial fibrillation in patients with NSP with half the frequency as those without NSP (2.9%/100 patient‐years versus 5.0%/100 patient‐years; adjusted hazard ratio[HR], 0.57 [95% CI, 0.34–0.96]). While the probability of finding 1 mechanism reduced the odds of finding the other, the presence of NSP should not preclude a thorough pursuit of a CSE (eg, paroxysmal atrial fibrillation). In that same study, the investigators found that 34.5% of patients with NSP would ultimately develop atrial fibrillation over the subsequent 10 years. The divergent prevalence of NSP and atrial cardiopathy in patients with ESUS have been validated in other cohorts using other biomarkers.45

In addition to atriopathy and atrial fibrillation, other potential embolic sources are found in much lower frequency when there is carotid atherosclerotic disease. In their multicenter registry of 667 patients, the CHALLENGE ESUS/CS (Mechanisms of Embolic Stroke of Undetermined Source/Cryptogenic Stroke) investigators found an inverse association between carotid stenosis and active cancer.46 The odds of inactive cancer were 4 times greater in patients with moderate to severe carotid stenosis (odds ratio, 4.05 [95% CI, 1.60–10.27]); however, this was in reference to the contralateral ICA and did not evaluate the relationship between cancer and NSP. (While the investigators did not report ipsilateral carotid disease severity, 1 in 3 included patients suffered from infarcts in multiple vascular territories, which obscures the conclusions drawn from this association.) The prevalence of patent foramen ovale has also been observed in higher frequency among patients with ESUS when NSP is absent.47, 48

Altogether, these data indicate that high‐risk NSP features or disproportionate plaque thickness may be present in ≥20% of patients with an ipsilateral anterior circulation cryptogenic stroke. Furthermore, NSP may be more responsible for occult embolism in younger patients and patients for whom a CSE (eg, patent foramen ovale, atriopathy) is not found. In light of this growing body of evidence incriminating NSP as causative in historically “cryptogenic” infarction, a recent expert consensus has provided a working definition of symptomatic NSP (Figure 3). These criteria can be useful for identifying patients with unilateral anterior circulation stroke(s) in the presence of a vulnerable NSP. Using this classification schema, NSP can be presumed responsible for the infarction when high‐risk plaque features are present (see below) and when there is evidence of recurrent ischemic injury in the affected carotid artery. When multiple arterial territories are involved, although they may be rarely attributed to bilateral cervical carotid disease,49 this is highly predictive of eventual atrial fibrillation50 or hypercoagulability of malignancy.46 Unfortunately, while this pathway may be elegant, it may oversimplify the attributable risk of stroke to NSP. Particularly in elderly patients, and those with vascular risk factors, cervical and intracranial atherosclerosis is common. Whether such plaque is highly likely to serve as a source of cerebral embolism is highly challenging. Therefore, a host of factors including patient age, radiographic findings, and vascular comorbidities ought to be considered in addition to the presence of a proximal, nonstenotic atherosclerotic lesion (Figure 4).

Figure 3.

Figure 3. Working definition of symptomatic nonstenotic plaque. Definitions taken from Goyal et al.12 Image created using Biorender.com. †High‐risk NSP features include presence of ulceration, thickness >3 mm, intraplaque hemorrhage, fibrous cap rupture, lipid‐rich necrotic core, or echolucency. CSE indicates cardiac source of embolism; ICA, internal carotid artery; and NSP nonstenotic plaque.

Figure 4.

Figure 4. Heat map reflecting attributable risk of NSP in the setting of selected potential embolic sources, radiographic findings, and risk factors. Heat map generated using qualitative estimates of the published literature, reviewed in detail in the main text. Not all potential risk factors or competing embolic sources are shown here. Image created using Biorender.com. HFrEF indicates heart failure with reduced ejection fraction; NSP, nonstenotic plaque; and PFO, patent foramen ovale.

While many of these relationships between NSP and ischemic infarction show evidence of correlation (eg, higher probability of finding NSP in certain clinical scenarios), there is compelling neuroimaging evidence that NSP is directly responsible for cerebral ischemia. Transcranial insonation of the middle cerebral artery distal to carotid NSP may be used to detect asymptomatic microemboli (a biomarker of later stroke risk), even in patients without prior neurologic symptoms.51 The majority of the high‐quality data supporting the use of transcranial Doppler for this indication are derived from patients with stenotic carotid atherosclerosis (>50% narrowing).44, 52, 53 In this population of high‐risk patients with carotid stenosis, vulnerable plaque features (like neovascularization and IPH) have been independently associated with microemboli and parenchymal ischemic burden.53, 54 Furthermore, there is radiographic evidence indicating accumulation of infarcts over time with vulnerable carotid plaque, and a strong relationship between microemboli burden and symptomatic cerebrovascular events.55, 56, 57 Importantly, the risk of cerebral infarction in patients with vulnerable plaques, particularly those with stenotic carotid atherosclerosis, is mitigable with aggressive risk factor modification58 and combination antiplatelet therapy.44, 52

Imaging

As the culprit lesion in a patient with NSP causes minimal or no luminal stenosis, it can only be identified using noninvasive imaging (carotid ultrasound, computed tomography angiography, or magnetic resonance imaging [MRI] with angiography of the cervical vessels). Conventional angiography may identify plaque ulceration or thrombus; however, plaque heterogeneity, soft plaque thickness, IPH, and other clinically relevant findings are best appreciated on noninvasive imaging.

The variable radiographic findings and features of potentially relevant NSP pose another challenge to clinicians. Often when NSP is observed, it is found in both cervical carotid systems.5, 8 Among patients with unilateral hemispheric infarcts, differences in thickness of ipsilateral versus contralateral NSP are on the order of tenths of a millimeter. Therefore, the clinician should be mindful of vulnerable plaque features—in addition to plaque presence and thickness—and incorporate such findings in the etiologic classification of infarction.12

The most well‐described and easily appreciable feature of NSP is its overall thickness, which can be measured using computed tomography angiography, MRI, or carotid ultrasonography. With increasing lipid deposition within the vessel wall, plaque grows eccentrically until fibrofatty changes preclude further outward growth. At this point, the luminal diameter of the vessel will narrow, resulting in stenosis.59 While plaque accumulates eccentrically, it may represent a “vulnerable lesion” even if there is no involvement of or penetration into the vessel lumen. Compared with the degree of luminal carotid stenosis, cumulative plaque thickness has been found more sensitive and specific for identifying a “high‐risk plaque” in 1 cohort of >1000 patients with recent anterior circulation ischemic symptoms (area under the curve, 0.93 versus 0.81; P<0.0001).60 That said, the mean total plaque thickness in patients with ESUS with ipsilateral carotid NSP is typically 2 to 4 mm, and again, differences in ipsilateral versus contralateral NSP axial thickness are often <0.5 mm. Therefore, it would be imprudent to attribute an ischemic lesion to proximal NSP on the basis of plaque thickness alone.

A second feature of vulnerable NSP is the fibrous cap. The presence of a fibrous cap designates the lesion as an American Heart Association grade V lesion,61, 62 and this is the stage at which luminal stenosis typically begins. Radiographically, the fibrous cap is well vascularized, often with inflammatory cell infiltration, which gives rise to enhancement on T1‐weighted imaging. With rupture, the exposed endothelium beneath the fibrous cap is highly thrombogenic and has been associated with a 6‐fold increase in risk of subsequent transient ischemic attack or stroke (HR, 5.93 [95% CI, 2.65–13.29], according to 1 meta‐analysis).37 Unfortunately, ulceration is present in a minority of patients and therefore is an insensitive indicator of symptomatic NSP.

Perhaps more challenging to recognize, but a similarly specific indicator of plaque vulnerability is the presence of IPH. IPH not only carries a nearly 5‐fold risk of future stroke37 but also contributes to plaque thickness and accelerated progression in carotid32 and coronary arteries.63 While IPH may be highly specific for plaque vulnerability, it is difficult to visualize or differentiate from soft plaque or lipid‐rich necrotic core (LRNC). IPH carries a similar density to many adjacent tissues (fibrous and lipid laden), making it a challenge to identify on computed tomography or ultrasonography. Therefore, MRI has been recommended to assist in differentiation.8, 37 In addition to playing a major role in accelerated plaque growth, IPH may play a larger operative role in male patients with cryptogenic stroke.33 Regarding the differential prevalence of IPH in NSP between the sexes, it is possible that the protective effects of estrogen on cardiovascular disease or differential lifestyle behaviors between men and women may be contributory.

A fourth biomarker of plaque vulnerability, LRNC, represents a heterogeneous composition of cholesterol accumulation and dystrophic calcification within a bed of necrotic endothelium. Unlike the overall thickness or ulceration of carotid NSP, LRNC may be difficult to appreciate with conventional computed tomography angiography or T1‐weighted imaging MRI. Ideally, MRI with T1‐ and T2‐weighted imaging sequences, time‐of‐flight magnetic resonance angiography, and proton density weighting are needed to appreciate LRNC. Radiographically, LRNC appears hyperintense on T1‐weighted imaging, and hypo‐ to iso‐intense on T2‐weighted imaging or proton density‐weighted sequences (it can also be hyperintense on T2‐weighted imaging when IPH is also present, depending on the age of the IPH).32 Further confounding our ability to recognize LRNC is the lack of validated thresholds for which LRNC is likely causally related. Like NSP or IPH, LRNC can be simply dichotomized as present or absent64 or can be quantitated volumetrically32, 33; however, this requires additional postprocessing, which may not be readily available in many institutions.

Additional biomarkers of plaque vulnerability are summarized in Table 1.

Current Management Strategies

The mainstay of secondary prevention in patients with stroke that may be attributed to NSP is optimization of vascular risk factors, high‐intensity statin therapy, and antiplatelet therapy. The impact of statin therapy cannot be understated in these circumstances. Randomized clinical trials have confirmed that statin therapy can not only reduce serum low‐density lipoprotein levels, but statins can decrease carotid intima media thickness in subclinical disease,65 reduce local inflammation in symptomatic carotid plaques,66 and dramatically reduce the volume of the LRNC in vulnerable plaques.67 In addition to these pharmacologic and nonpharmacologic interventions, it is reasonable to pursue a comprehensive etiologic workup to exclude competing alternative mechanisms (Figure 3).

There is no high‐quality evidence to support the routine use of endovascular stenting or endarterectomy with carotid NSP. In a prespecified subgroup of patients with <30% stenosis from the European Carotid Surgery Trial, investigators found no effect of endarterectomy on ipsilateral stroke recurrence in patients with a recently symptomatic carotid lesion,68 largely because of the heightened early risk of stroke in the postoperative setting.69 In the subgroup with moderate stenosis (30%–69%), there was also no advantage of endarterectomy in the European Carotid Surgery Trial.70 Similarly, the North American Symptomatic Carotid Artery Trialists and European Carotid Surgery Trialists reported no benefit of endarterectomy with <50% atherosclerotic stenosis of a presumably symptomatic cervical ICA.71 In fact, pooled data indicate that revascularization for <30% stenosis was harmful. Despite the lack of benefit of revascularization (over medical management) for NSP in these randomized trials, several cohort studies suggest that intervention may be associated with better outcomes in patients with high‐risk NSP features.72, 73, 74

It has been >20 years since these early clinical trials tested the effect of revascularization in NSP against medical management. Since that time, we have made tremendous advances in both nonpharmacological techniques—including the development of transcarotid artery revascularization—and high‐intensity statin therapies.67, 75 Many of these effective strategies were not recommended at the time of the early revascularization trials. For example, the “standard” medical management of patients in the North American Symptomatic Carotid Artery Trial did not include routine use of lipid‐lowering therapies (only 40% were treated with such agents).76 Now, statins are almost universally recommended given their clear advantage in reducing carotid intima media thickness and recurrent stroke risk.77 Additionally, short‐term dual antiplatelet therapy is proven to be useful in patients with mild stroke78, 79, 80 and in patients with high‐risk carotid disease.44 Unfortunately, the most well‐studied and efficacious medical therapies have been explored in patients with stenotic ICA disease, which limits our understanding of these therapies in NSP. Data from 2 randomized clinical trials have shown that combination of aspirin with a P2Y12 inhibitor (clopidogrel) is associated with a reduced risk of recurrent high‐intensity transient signals with transcranial insonation44, 52 and numerically fewer recurrent strokes and transient ischemic attacks with dual antithrombotic therapy in 1 trial.44 When considering patients with NSP as opposed to stenotic ICA disease, the Platelet Oriented Inhibition Trial investigators found a suggestion of benefit of combination aspirin with clopidogrel over aspirin monotherapy in preventing recurrent stroke; however, the analysis was underpowered (n=167 patients).81

In addition to considering combination antiplatelet therapy, there has been a growing interest in concomitant low‐dose anticoagulation with platelet inhibition in patients with atherosclerotic disease. The combination of aspirin and low‐dose rivaroxaban (2.5 mg twice daily) was recently shown to be more effective than aspirin alone at reducing cardiovascular events82 and stroke83 in patients with stable peripheral artery disease (including asymptomatic ICA stenosis >50%), in the Cardiovascular Outcomes for People Using Anticoagulation Strategies trial. However, in a secondary analysis of this trial, Perera et al83 found no significant risk reduction of strokes caused by ICA stenosis >50% with aspirin and low‐dose rivaroxaban (HR, 0.85 [95% CI, 0.45–1.60]). It is unclear how prevalent vulnerable NSP was in this trial population or how much NSP mediated the outcome of stroke recurrence, but there is biologic plausibility that Xa inhibition may attenuate endothelial dysfunction via inhibition of protease‐activated receptors 1 and 2.84 The addition of low‐dose aspirin may complement Xa inhibition by preventing platelet activation and aggregation at sites of plaque rupture and inflammation. Together, the combined effect has the potential to reduce stroke in patients with NSP if the risk of bleeding can be adequately mitigated. Presuming the risk of stroke with certain plaque features exceeds the risk of stroke attributable to the presence of stenosis alone,85 it is likely that combination antithrombotic therapy (aspirin+P2Y12 inhibitor, or aspirin+low‐dose rivaroxaban) may be superior to antiplatelet monotherapy, with an acceptable bleeding risk.

Future Directions

NSP remains underdiagnosed, and targeted management strategies require additional exploration in observational cohorts and randomized clinical trials. Randomized clinical trials evaluating the efficacy of revascularization versus best medical management of vulnerable carotid plaques may provide the highest level of evidence for intervention; however, designation of plaque vulnerability remains heterogeneous and lacks standardization even across observational cohort studies. One type of vulnerable plaque (eg, having LRNC) may benefit significantly from endarterectomy or stenting while another type (eg, NSP with thickness >3 mm without IPH) may benefit minimally from revascularization over best medical management. The various plaque features that lead to a classification of “vulnerable plaque” may create significant barriers to a successful randomized clinical trial, and we may be left to recommend practice paradigms based on high‐quality observational cohort data34 or expert consensus.12 In the absence of other criteria, or criteria that require advanced imaging, the previously suggested working definition of symptomatic NSP may be the most sensitive and generalizable approach to identifying patients at risk of recurrent stroke attributable to NSP (Figure 3). However, these criteria warrant validation or even risk stratification as we have successfully seen in other potential embolic sources.86 Perhaps because of a lack of consensus in defining symptomatic NSP, there remain no registered trials that are assessing outcomes associated with revascularization versus best medical management for NSP. The effect of high‐potency statins is well established, but additional studies are called upon to evaluate the potential benefit of combination antithrombotic therapy or revascularization in these patients.

Sources of Funding

None.

Disclosure

The author reports no competing financial interests exist.

Acknowledgments

None.

Footnotes

*Correspondence to: James E. Siegler, MD, Cooper Neurological Institute, Cooper University Hospital, 1 Cooper Plaza, Keleman 548D, Camden, NJ 08103.
Email:

References

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