Carotid Stenosis and Stroke: Medicines, Stents, Surgery—“Wait-and-See” or Protect?

Carotid Stenosis and Stroke Mechanisms

Stroke, a vascular disease of the brain, is the most common cause of complex disability and a major cause of death worldwide.[1] [2] [3] Stroke, with its major negative impact on affected individuals, their families, and the society, is one of the most dreaded events in life.[4] Nearly half of stroke survivors will be disabled and dependent, with one in seven requiring permanent institutional care.[4] Because of the profound negative effect of stroke-related mental and physical disabilities upon quality of life, a significant proportion of stroke victims indicate that they would have preferred death over their life after stroke.[4] Only a minority of strokes are preceded by a transient ischemic attack (TIA), a warning that enables timely intervention to reduce the risk of permanent brain damage.[5] [6] Over 80% of strokes occur without any clinical warning.[6] Hence there is a fundamental role for effective preventive measures.[6] [7] [8] Optimal stroke management should be preventive rather than reactive to the devastating event that has already occurred.[5] [7] [8] Despite unquestionable progress in pharmacologic and nonpharmacologic prevention, the burden of cardiovascular disease (including stroke) will not be decreasing—but rather increasing—over the next 25 years.[1] Recent stroke burden estimates for Europe indicate an increase in stroke incidence of +3% by 2047, and an increase by ≈30%% of the number of people living with stroke.[9]

Atherosclerotic carotid artery stenosis is a modifiable, major mechanistic risk factor of ischemic stroke.[2] [10] Plaque rupture and/or erosion can lead to focal thrombus formation that may occlude the lumen, causing a stroke related to hemodynamic compromise.[10] [11] [12] [13] [14] Thrombotic occlusion of the internal carotid artery is poorly responsible to intravenous thrombolysis and is associated with large infarct size and poor functional outcome.[14] [15] [16] [17] Another stroke mechanism is atherothromboembolism to the brain, resulting in occlusion of an intracranial branch vessel(s) and infarction of the brain tissue supplied by these branches.[12] [18] Real-life contemporary scenarios of acute ischemic stroke due to atherothrombotic carotid stenosis are demonstrated in [Fig. 1] (all patients presenting with acute stroke of carotid origin within one month).

Fig. 1 Scenarios of acute ischemic stroke due to atherothrombotic carotid stenosis (patients presenting within one month). This figure presents three types of ischemic stroke, mechanistically related to atherothrombotic carotid stenosis: Panel I exemplifies acute ischemic stroke due to (sub-)occlusion of the carotid artery (extracranial segment) with a large thrombus originating from the atherosclerotic lesion. Panel II shows a tight stenosis as an underlying mechanism. Panel III demonstrates a “tandem” lesion stroke with migration of part of the internal carotid origin thrombus (stenosis progression to thrombotic occlusion) into the intracranial vasculature. Examples are taken from consecutive patients with acute ischemic stroke due to carotid stenosis. The strokes in patients I–III presented without any prior warning symptom(s), consistent with ≈80% of stroke presentations.[6] The imaging timeline is from top to bottom. Cerebral images are in the axial view, except III-D2 that is a coronal presentation. All carotid images are in the coronal view. In patients I and II, the left hemisphere is dominant; in patient III, the right hemisphere. Stenosis severity was 74% (by lumen area)/56% (diameter stenosis) in patient I, 87% (by lumen area)/64% (diameter stenosis) in patient II, and 78% (by lumen area)/61% (diameter stenosis) in patient III.[29] [30] Yellow stars (I-A, III-B1) in patients I and III indicate early cerebral ischemia on cerebral computed tomography (CT) at the time of presentation. In patient II, diffusion-weighted magnetic resonance imaging on admission (II-A1/A2) showed diffusion restriction (hyperintense areas) in the left hemisphere. The lesions were also visible on fluid-attenuated inversion recovery imaging, consistent with established cerebral damage. Patients I and III received intravenous thrombolytic therapy (IVT) which, in both cases, was clinically ineffective, consistent with reported recanalization rates of <10% in carotid occlusion strokes. Patient II presented beyond the 4.5 hour time window for thrombolysis. Yellow arrows depict the culprit (carotid) lesion (I-B1/B2, II-B1/B2, III-B2). Red arrowheads (all B images and III-C) indicate thrombus. Images in C show the CT-angiography at the time of presentation. All three patients show presence of intracranial collaterals; those, however, are rarely able to sustainably compensate an abrupt carotid artery occlusion. Red arrows (D) show the infarcted area at discharge. White arrows (III-D1/D2) depict hemorrhagic transformation that occurred in patient III. Clinical outcomes are provided at the bottom of the figure. A modified Rankin score (mRS) of 2 indicates slight disability (patient able to look after their own affairs without assistance, but unable to carry out all previous activities); mRS 3 signifies moderate disability (patient requires some help, but is able to walk unassisted); mRS 4 represents moderately severe disability (patient unable to attend to own bodily needs without assistance, and unable to walk unassisted). The National Institutes of Health Stroke Scale (NIHSS) represents a clinical stroke severity scale (≤6 minor stroke; >6 major stroke). Extracranial thrombotically active carotid plaque is a major, mechanistic risk factor for ischemic stroke.[10] Strokes in patient I and patient III were likely preventable with low-risk revascularization[20] [57] [58] on top of MMT. Note that the presence of PAD or CAD increases the risk of CS while diabetes (patient I) is an important risk factor for stroke in CS.[35] [36] [37] Patient III was not revascularized due to a wide-spread belief (despite lack of data) in a sufficient MMT protection against CS-related stroke (see text for references). After the stroke, patients I and III were no longer suitable for carotid revascularization due to major loss of cerebral tissue with a mRS ≥3, resulting in a high risk-to-benefit ratio for intervention. Patient II subsequently underwent uncomplicated endovascular revascularization of the culprit lesion 12 days after the event; this did not resolve his pronounced aphasia and stroke-related neurological deficits but would reduce the risk of another stroke. Red arrowheads indicate thrombus. CAD, coronary artery disease; CS, carotid artery stenosis; LECA, left external carotid artery; LICA, left internal carotid artery; MMT, maximal medical therapy;[20] [53] NSTEMI, non-ST-elevation myocardial infarction; Occl, occlusion; PAD, peripheral arterial disease; RECA, right external carotid artery; RICA, right internal carotid artery; RMCA, right middle cerebral artery.

Stroke Occurrence in Carotid Atherosclerosis: Epidemiology

The atherosclerotic carotid disease is responsible for a much greater proportion of strokes than just those presenting with both a carotid lesion and intracerebral artery occlusion in stroke thrombectomy all-comer studies (“tandem occlusions” ; ≈15–20% patients).[12] [18] [19] While in some “tandem” occlusions carotid stenosis is a bystander rather than a mechanistic stroke contributor,[19] evidence shows that isolated extracranial (non-tandem) acute oclusion of internal carotid artery is seen in ≈20% of all-comer patients eligible for thrombolysis, indicating its prevalence similar to that of “tandem” strokes.[14] Most trials of stroke mechanical reperfusion not only excluded patients with “tandem” lesions but also excluded those with isolated acute occlusion of the extracranial internal carotid artery origin (high-risk pathologies).[12] [14] Some other atherothrombotic lesions at the carotid bifurcation may become “insignificant” by angiography (ie., stenosis severity <“50%”) after part of the lesion has embolized to the brain[12] yet may cause recurrent stroke.[21] Although lower proportional contributions of atherosclerotic carotid stenosis to overall stroke burden have been claimed in the past, and medical (non-interventional) therapy was claimed (based on ignoring large-scale randomized evidence such as that from Asymptomatic Carotid Surgery Trial in >3000 patients) to be sufficient to control carotid-related stroke risk,[22] [23] the totality of data today suggests an overall proportion of carotid stenosis-related strokes at the level of at least 30%.[11] [16] [17] [20] [24]

Clinically “significant” atherosclerotic carotid artery disease, usually (though not always rightly, as less severe lesions may cause strokes[21] [25] [26] [27] [28]) defined as ≥50% reduction in diameter at the carotid bifurcation and/or within the proximal internal carotid artery,[29] [30] is present in 2 to 16% of the general population, making it a common pathology.[8] [11] [20] [31] Its prevalence is similar to that of nonvalvular atrial fibrillation (AFib) and, like AFib, it increases with age.[2] Notably, carotid stenosis is more prevalent in patients with diabetes (that is also an idependent risk factor for the lesion symptomatic transformation), coronary artery disease (CAD), and peripheral artery disease.[2] [8] [20] [32] [33] [34] [35] [36] [37] Contemporary clinical data from vascular clinics following patients with known vascular disease, show a yearly stroke rate of ≈2.5% in real-life cohorts, including patients on maximal (by today's criteria) medical therapy (MMT).[20] [38] [39] [40] This exceeds the annual stroke risk of 2.1% per year associated with paroxysmal AFib[41] that has been the main focus of stroke prevention. A recent population-based study in 65-year-old Swedish men showed a 5-year cumulative neurological event rate of 6.5% with carotid stenosis of 50 to 79% (annual rate 1.3%) and 42% with stenosis of 80 to 99% (annual rate 18.4%).[42] Although the stroke risk may be lower in younger individuals with asymptomatic carotid artery stenosis (ASxCS),[8] [22] [23] given that the risk (similar to the stroke risk in AFib[41]) is cumulative over time, it remains very relevant.[8] [19] [20]

Other factors may contribute to stroke risk in patients with ASxCS. These may be related to the atherosclerotic lesion (note modulation of the atherosclerotic plaque rupture and thrombosis by the hemostatic system[43] [44] [45] [46]) or may contribute independently to the increased stroke risk (e.g., coexisting AFib[20] [47]). There are additional concerns raised on the impact of hemodynamically significant carotid atherosclerotic disease in patients with an incompetent circle of Willis and cognitive decline potentially related to hemodynamic insufficiency and subclinical embolism from the lesion.[20] [48] [49] [50] Overall, epidemiologic data indicate that the presence of ASxCS may increase the risk of stroke by more than 50%.[20] [51]

Pharmacomanagement: The Pillar of Therapy to Reduce the Stroke Risk in Patients with Atherosclerotic Carotid Artery Stenosis

Medical therapy reduces stroke risk in ASxCS, but the residual risk remains substantial, particularly in patients with vascular comorbidities or diabetes.[20] [35] [36] [37] [38] [39] [40] [52] The progress in pharmacologic prevention in cardiovascular medicine over the last two decades, including the use (and currently high penetration) of statins, antiplatelet agents, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, has likely led to some reduction in the statistical stroke risk in patients with ASxCS. Subgroup analyses of pharmacologic trials suggest a stroke reduction benefit in ASxCS patients treated with the above medications.[20] [53] [54] Based on this information, all ASxCS patients today should receive MMT to reduce stroke risk. The regimen should include (1) an antiplatelet agent and (2) an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (3) a statin (or other agent to reduce low-density lipoprotein [LDL]-cholesterol) titrated to achieve guideline-recommended LDL-cholesterol levels as well as lifestyle modification.[20] [53] [54] As long-term observational studies and randimozed studies specific to ASxCs patients are lacking, it is not clear to what extent stroke risk with MMT is reduced and to what extent it may be delayed in time. MMT benefit needs to be individually balanced against potential adverse effects, such as an increase in bleeding with antiplatelet therapy[32] and the residual stroke risk while on medications.[20] [39] [53] [54] [55]

Despite the progress that has been made, the transition of a carotid lesion from asymptomatic to symptomatic lesion is far from being eradicated by MMT.[20] [38] [39] [40] This limitation of MMT is clearly demonstrated within the symptomatic patient cohort enrolled into recent clinical studies, a significant proportion of whom suffered a stroke despite MMT[56] [57] [58] (see also [Fig. 1]).

Stroke Risk Factors and Risk Markers in ASxCS

Clinical studies have identified several risk markers and factors for stroke in ASxCS patients.[8] [13] [20] [30] [33] [35] [51] [56] These are depicted in [Fig. 2]. It is unclear why some of these have made it into clinical guidelines[37] [59] while others have not. An update may be appropriate in this respect, to encourage clinical decision making that takes into consideration the totality of evidence.[20] [60]

Fig. 2 The “roulette wheel” of contemporary stroke risk management in carotid stenosis. The stroke risk level in subjects with clinically asymptomatic atherosclerotic carotid artery stenosis (ASxCS) is represented on the top axis; the bottom axis represents measures that counteract the stroke risk level. Ideally, a higher risk level should be matched with a greater magnitude of preventive measures. Clinical data show that, in previously asymptomatic lesions, cumulating risk factors increase the likelihood for a stroke. This is indicated by a risk gradient (blue triangle). Today, in contrast to CHA₂DS₂-VASC and other clinically applicable risk stratification scales in atrial fibrillation (AFib), no validated risk quantification tools exist for ASxCS subjects. The prevalence of ASxCS is similar to that of paroxysmal AFib; the annual stroke risk in ASxCS patients on maximal optimized medical therapy (MMT) is similar to that seen in paroxysmal AFib patients on aspirin (≈2.0–2.5% in ASxCS vs. ≈2.1% in AFib). The stars within the blue triangle of the risk gradient symbolize the random distribution (and, not infrequently, random understanding and use) of characteristics known to increase stroke risk in ASxCS. Evidence from clinical studies shows that these features (such as contralateral transient ischemic attack (TIA) or stroke, ipsilateral silent cerebral infarction, stenosis progression, echolucent plaque, intraplaque hemorrhage, plaque ulceration or large necrotic core) may be differently weighted regarding their impact on stroke risk, hence the stars differ in size. Some have made it into ASxCS patient management guidelines[59] despite poor reproducibility and/or lack of robust data while others (more robust) have not. For instance, today only ≈5% of patients with a recent carotid stenosis-related stroke or TIA have spontaneous embolic signals on transcranial Doppler, questioning (beyond the technical and reproducibility problems) its role in asymptomatic risk stratification. Some other, more obvious, stroke risk factors such as carotid plaque surface irregularity/ulceration or thrombus-containing plaque did not make it to the guidelines, despite their evidenced role. It is important to understand that even ASxCS lesions that are believed to be low risk can become symptomatic and cause stroke, albeit less frequently than those with increased risk characteristics. (note the patient-level stroke hit arrows on the top of the figure). For the patients and their family, the occurrence of an actual stroke event is what matters, rather than continuous linear (or curvilinear) stroke “risk” considerations. Today, there is ample evidence that the carotid plaque itself plays an important, mechanistic part in transforming a lesion from asymptomatic to symptomatic. Apart from the lesion phenotype (that may be dynamic), fundamental fields of the roulette turning wheel are lesion-level stroke factors (such as the “vulnerable” plaque phenotype that may be specific to the imaging technique used) and “vulnerable blood” mechanisms that impact plaque rupture and thrombosis. In addition, in some clinical conditions such as diabetes or thrombophilia, there is a marked increase in stroke risk that partly includes a mechanistic contribution from the carotid lesion. Blue arrows indicate interactions between risk features. Combined analysis of data from two large, randomized trials (Asymptomatic Carotid Atherosclerosis Study and Asymptomatic Carotid Stenosis Trial-1) showed no effect of increasing lumen stenosis (beyond 60%) on stroke risk in ASxCS, consistent with a prevailoing role of the lesion (and patient) risk characteristics over that of the stenosis severity. The 5-year stroke rate was 7.8% with 60–99% stenosis, 7.4% with 70–79% stenosis, and 5.1% with ≥80% stenosis. Thus the severity of luminal stenosis is a poor indicator for stroke risk in ASxCS. Indeed, luminal stenosis is a poor index of the plaque burden and plaque morphology because of the varying vessel compensation for the plaque growth (remodeling). Despite the evidence contradicting the role of the degree of luminal stenosis for stratification of stroke risk in ASxCS, it remains on the roulette wheel. Although no carotid stenosis-specific data are yet available, the hemostatic system is known to critically modulate clinical event risks in atherosclerosis. Recent evidence from studies that have included ASxCS patients indicates that hemostatic modulation may be an important target for pharmacotherapy with low-dose oral antithrombotic agents. In contrast to the knowledge gaps in quantifying a stroke risk gradient in ASxCS, there is significantly more knowledge on how to counteract risk of stroke. MMT, which may reduce or delay stroke risk (but does not universally abolish it), is the main pillar of treatment. MMT should include an antiplatelet agent, an angiotensin-converting enzyme inhibitor or angiotensin receptor inhibitor, and a statin titrated to achieve guideline-recommended LDL cholesterol levels. Indirect evidence from recent low-dose oral antithrombotic agent and proprotein subtilisin/kexin type 9 (PCSK9) inhibitor trials suggests a role for these agents at least in some ASxCS patients. Two trials (Randomized Trial of Stent versus Surgery for Asymptomatic Carotid Stenosis, ACT-1, and Asymptomatic Carotid Stenosis Trial-2, ACST-2) indicated equipoise between surgery (carotid endarterectomy, CEA) and endovascular treatment using, exclusively or mostly, first-generation (single-layer) carotid stents in ASxCS patients. Recent studies suggest that minimally invasive endovascular sealing of high-risk plaque (using plaque-sequestrating stent(s)) may be a safer and more effective treatment modality in carotid stenosis-related stroke prevention. Elimination of plaque, by surgery or sealing, will eliminate further lesional stroke risk (green cross). Patient preference typically points to less invasive management options. Data are accumulating that show that appropriately neuroprotected, minimally invasive plaque sequestration may prove superior to conventional surgery, both short and long term. See text for references. LDL, low-density lipoprotein.

Is It Possible to Quantify Stroke Risk and Target Preventive Measures in Carotid Disease Today?

Evidence suggests that there may be a gradient of stroke risk in ASxCS. Calculation of stroke risk would be clinically useful, helping physicians and patients to make therapeutic decisions. In AFib, clinical decision making is guided by well-defined scales (such as classic CHA₂DS₂-VASC scale or a more recent calculator of absolute stroke risk in AFib, CARS).[55] [61] Regrettably, in carotid disease, for which stroke risk is of similar magnitude, these do not exist. Efforts should be made to develop and validate stroke risk scales in ASxCS similar to the established stroke risk scales in AFib.[20] [33] [38] [51] [56]

The Paramount Role of Imaging in Delineating Stroke Risk

In medicine, as in other areas of life, effective prevention is better than reactive management. Prevention relies on reliable detection of the problem.[7] [8] Detection of ASxCS by ultrasound does not cause harm or necessitate any invasive intervention. However, Failure to identify ASxCS (and, in that, ASxCs with increased stroke risk characteristics) results in lack of any treatment, including pharmacotherapy,[7] [20] [51] [56] and an important missed opportunity to reduce stroke risk. High-risk plaques are not rare in ASxCS.[62] [63] [64] [65] [66] [67] [68] [69] Recent real-life evidence clearly shows that the associated risk of ipsilateral ischemic stroke in ASxCS is greater than previous estimates.[22] [23] Meta-analysis of 64 studies (20,751 participants) showed that over a median observation time of merely 3 years, the high-risk carotid plaque, reproducibly detected by noninvasive imaging, translates into an increased risk of an ipsilateral stroke (odds ratio [OR]: 3.0; 95% confidence interval [CI]: 2.1–4.3).[63] In subjects with severe ASxCS, the OR was similar (3.2; 95% CI: 1.7–5.9), confirming that plaque features may play a more important role than the severity of stenosis.[63] [69] Strokes in relation to high-risk plaques continue to occur in patients on MMT.[56] [66] [67] With the evidence today that noninvasive imaging can reliably identify ASxCS patients at an increased of stroke, the question is not whether to screen or not but rather which populations to target and with which screening techniques.[7] [20] [51] [70] [71] ASxCS screening is cost-effective already when a moderate (such as ≈20%) stroke risk relative reduction is achieved with preventive measures that result from screening.[70]

A multi-society evidence-based guideline recommended that screening for carotid stenosis should be considered for asymptomatic patients with either (1) symptomatic peripheral arterial disease, CAD, or atherosclerotic aortic aneurysm, or (2) two or more of the following risk factors: hypertension, hyperlipidemia, tobacco smoking, a family history of early-onset (less than 60 years) atherosclerotic disease in a first-degree relative, or a family history of ischemic stroke.[62] [71] [72]

The fundamental advantage of noninvasive imaging is that there is no need to enter the body. A disadvantage of computed tomography (CT) or magnetic resonance imaging (MRI) is the limited resolution that prevents analysis of, for instance, the risk-prone thin fibrous cap thickness, which in carotids is ≈160–200 versus ≈65 µm in the coronaries.[11] [65] Similarly, a limitation of transcutaneous ultrasound is its poor reproducibility in plaque evaluation and incomplete three-dimensional information. Because of these inherent limitations, intravascular imaging can serve as an important companion to the noninvasive techniques. In addition to expanding our knowledge by providing unique data on plaque morphology, it may guide development of further treatments.[64] [65] [73] Moreover, intravascular imaging modalities, such as optical coherence tomography or intravascular ultrasound, provide fundamental tools to understand plaque behavior with different stent types and the intravascular consequences of stenting.[64] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] A recent multi-center multi-specialty study (CGUARD OPTIMA; NCT04234854) in 339 consecutive patients with clinically or radiologically symptomatic (mostly “soft”/echolucent and/or thrombus-containing) lesions treated using fully optimized (large-diameter post-dilatation balloons at high pressures) micronet-covered stents demonstrated absence of any intravascular imaging-identified plaque prolapse by corelab analysis and 30-day ipsilateral stroke/death/myocardial infarction rate of 0.57%. Thus today, thrombus-containing and symptomatic carotid lesions, posing an important challenge to single-layer carotid stents,[76] [77] [78] [79] [80] can be safely and effectively neutralized with an antiembolic stent, resulting in the absence of plaque protrusion on routine endovascular imaging, and reaching optimal anatomic reconstruction of artery lumen in association with optimal clinical outcomes.[75] [78] [81] [82] [83]

Another important role for imaging in ASxCS is the detection of subclinical cerebral injuries with MRI or CT (silent infarcts) that increase the risk of subsequent clinically manifested stroke by twofold.[39] Although ASxCS plaque hemorrhage, rupture, and thrombosis are typical features of conversion to a symptomatic plaque, it is important to bear in mind that these are also the mechanisms of “normal” plaque growth,[10] [11] [84] and only in some instances plaque hemorrhage, rupture, and thrombosis events are associated with clinical symptoms. Hence the role of other fundamental players of the plaque symptomatic transformation, such as “vulnerable blood” mechanisms[20] [68] and the hemostatic system that is known to importantly modulate atherothrombotic events ([Fig. 2]).[43] [44] [45] [46]

Conventional Surgery and Conventional CAS

As atherosclerotic carotid stenosis-related strokes are to be prevented rather than experienced,[20] interventional elimination or sequestration of the thromboembolic plaque remains an important consideration in a significant proportion of ASxCS patients.[8] [19] [20] [66] ASxCS revascularization should be (1) safe, (2) effective (short and long term) and, with the first two achieved, (3) minimally invasive. Optimally, it should prevent stroke rather than be performed in reaction to the irreversible cerebral damage that has already occurred[7] [8] ([Fig. 1]). While undertaken to prevent subsequent stroke, an important consideration is that both surgical and endovascular routes of carotid revascularization are themselves associated with the risk of symptomatic and asymptomatic cerebral embolism that needs to be minimized.[20] [49] [79]

One fundamental difference between open surgery and endovascular methods is that by removing the lesion, carotid endarterectomy (CEA) largely eliminates the postprocedural problems that may be related to offending the plaque; however, this is at risk for creating a new source of cerebral emboli such as vessel injury and or dissection flap.[20] [83] In contrast, conventional carotid artery stenting (CAS) does not remove plaque but seeks to stabilize the potentially embolic lesion by restoring laminar flow and covering the lesion with a single-layer metallic stent.[74] [81] [83] Plaque protrusion through the stent struts occurs in 30 to 100% of conventional carotid stents, depending on the plaque morphology and stent design, as well as the sensitivity of the imaging technique used.[8] [74] [85] Plaque protrusion may lead to peri- and postprocedural cerebral embolism and trigger post-CAS neurological events including (mostly minor) strokes.[8] [74] [77] [85] [86] [87] This has been attributed as the primary cause of postprocedure stroke, with ≈2/3 of CAS strokes occurring after the CAS procedure using conventional (single-layer) carotid stents.[8] [74] [77] [81] Thus, while optimized neuroprotection during CAS may minimize intraprocedural cerebral embolism, the risk of early or delayed postprocedural embolism remains a significant issue when using first-generation (single layer) stents.[8] [49] In a recent meta-analysis of 6,526 patients from five trials comparing first-generation stent CAS and CEA,[88] the composite outcome of periprocedural death, stroke, myocardial infarction, or nonperiprocedural ipsilateral stroke was not significantly different between therapies (OR: 1.22; 95% CI: 0.94–1.59). The risk of any periprocedural stroke plus nonperiprocedural, ipsilateral stroke was higher with CAS (OR: 1.50; 95% CI: 1.22–1.84), which was mostly attributed to periprocedural minor stroke (OR: 2.43; 95% CI: 1.71–3.46). CAS was associated with a significantly lower risk of periprocedural myocardial infarction (OR: 0.45; 95% CI: 0.27–0.75); cranial nerve palsy (OR: 0.07; 95% CI: 0.04–0.14); and the composite outcome of death, stroke, myocardial infarction, or cranial nerve palsy during the periprocedural period (OR: 0.75; 95% CI: 0.60–0.93). Despite the lack of plaque elimination and incomplete coverage of the plaque with CAS using first-generation (single-layer) carotid stents, two recent randomized controlled trials (RCTs) have shown equipoise between conventional CAS and conventional CEA.[89] In the Asymptomatic Carotid Trial I (ACT -1), the primary composite 30-day endpoint rate was 3.8% with first-generation CAS and 3.4% with CEA (p = 0.01 for noninferiority).[90] In the second asymptomatic carotid surgery trial (ACST-2) that randomly allocated 3,625 patients to CAS (n = 1811) or CEA (n = 1814) with a mean follow-up of 5 years, more major procedural strokes occurred with CEA (0.99 vs. 0.82%), while CAS was associated with more nondisabling strokes (2.65 vs. 1.60%).[91] There was no statistically significant difference in the incidence of any periprocedural stroke (3.6 vs. 2.4%, p = 0.06) and long-term effects of both procedures were comparable.[91] Similarly, meta-analysis of CEA and CAS outcomes in symptomatic patients has demonstrated similar outcomes in the postprocedural period.[89] These data, taken together with a further reduction in periprocedural stroke rate to <1% by 30 days using micronet-covered stents[92] [93] [94] and coupled with their long-term treatment durability, suggest that a more effective endovascular plaque sealing than that achieved in ACST-2 (with mostly first-generation stents) has the potential to achieve outcomes superior to open surgery.[94] [95] It should be noted that the importance of carotid revascularization endpoints other than stroke risk, such as cognitive or ocular function, is gaining increasing recognition.[49] [50] [96]

Transcervical Access for CAS—Why? (and Its Limitations Today)

Transcervical carotid revascularization (TCR) is a hybrid technique that has gained popularity primarily in the United States with now over 70,000 cases performed. TCR, using surgical access (surgical cut-down), employs a robust transient flow reversal to protect the brain during lesion predilatation, stent delivery and implantation, and postdilatation.[20] [87] [97] One fundamental advantage of this technique, compared with transfemoral or transradial CAS, is that it eliminates the need for transversing the aortic arch and ostial common carotid artery—the CAS stages known to be generating emboli, particularly in elderly patients, or those who have atherosclerotic aortic or ostial lesions, calcified vessels, or a complex/tortuous aortic arch.[97] [98] However, a recent systematic review and meta-analysis of 4,867 TCR procedures in 18 clinical studies showed that symptomatic patients had a higher risk of 30-day stroke or TIA than asymptomatic patients (2.5 vs. 1.2%; OR: 1.99; 95% CI: 1.01–3.92; p = 0.046).[99] Similar, analysis of TCR outcomes in the US Vascular Quality Initiative database identified symptomatic lesion status as an independent predictor of stroke or death by 30 days (OR 14.5, p = 0.01).[100] This indicates a likely contribution of porous plaque coverage with a first-generation (single-layer) stent used in TCA to date to the increased event rate in symptomatic patients. Diffusion-weighted cerebral MRI (DW-MRI), suggest that that the use of a second-generation (plaque-sealing) micronet-covered stent, rather than a prior-generation single-layer stent, may minimize peri- and postprocedural embolism in TCR and optimize clinical outcomes.[97] TOP-GUARD study (NCT04547387), despite a high proportion of increased-risk lesions and clinically symptomatic patients, demonstrated a minimal (<1%) 30-day complication rate with TCAR employing the MicroNET-covered anti-embolic stent.[98] Other important TCR considerations, such as the need to optimally manage the angle upon carotid artery entry (that may pose a challenge), are discussed elsewhere.[20]

Novel Pharmacologic Approaches and Drugs

Thrombosis is known to be the most common precipitant of ischemic stroke.[101] Recently, it has become clear that not only the mechanisms of hemostasis may modulate the atherosclerotic plaque phenotype but also that fibrin clot properties affect the clinical manifestations of atherosclerosis.[43] [44] [45] [46] Elucidation of fibrin clot properties in symptomatic versus asymptomatic carotid stenosis is under investigation in the FIBCAR (FIBrin Clot properties in carotid AtheRosclerotic disease) study in a series of 200 consecutive patients. While this may be hampered by the “future-symptomatics” hiding within the current ASxCS cohort, recent large scale data suggest that pharmacologic modulation of hemostasis may be effective clinically. Analysis of stroke outcomes in the COMPASS (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS) study, in which with ASxCS causing ≥50% luminal stenosis was one of the inclusion criteria, demonstrated that rivaroxaban 2.5 mg twice daily (used on top of 100 mg aspirin) reduced any stroke and disabling stroke better than aspirin alone, without increasing the risk of hemorrhagic stroke.[102] Although no specific sub-analysis is available for the ASxCS patients in COMPASS, reduction in stroke incidence and severity in this study suggests that adding low-dose anticoagulant therapy to antiplatelet therapy might be considered, on an individual basis taking into consideration overall vascular risk, in ASxCS patients—particularly in those with increased stroke risk features who are not candidates for plaque removal or sealing. Finally, indirect evidence from clinical trials of proprotein subtilisin/kexin type 9 (PCSK9) suggests a role for these agents at least in some ASxCS patients, particularly in those with optimized statin therapy but elevated lipoprotein (a).[103] Although the “vulnerable blood” biomarkers, such as cytokines, may be targets for pharmacotherapy (e.g., interleukin-1β targeting with canakinumab), their role may be difficult to dissect as their level in the plasma may not reflect the level in situ within the carotid plaque.[68] Several other novel strategies to induce the atherosclerotic plaque regression and/or pacification (such as inhibition of oxidized LDL and other modified lipid receptors) are currently tested in human trials. The interplay between the risk of atherothrombotic events (including stroke) and fibrin clot properties is gaining increasing relevance. Intensive lowering of LDL-cholesterol has been demonstrated to improve fibrin clot properties.[104] Recent evidence shows that active factor XI (FXI) is associated with the risk of cardiac and vascular events in patients with coronary atherosclerosis, indicating a potential clinically relevant role for FXIa inhibitors as novel antithrombotic agents.[104] This, and other pathways, may play an important role in reducing atherothrombotic stroke risk in carotid atherosclerosis ([Fig. 2]).

Novel Paradigm in Carotid Revascularization: Minimally Invasive Sequestration of Increased Stroke-Risk Lesions

Recent body of evidence indicates that the use of ultra-closed-cell stent systems (manufactured by integrating the nitinol frame with a mesh made of different materials) may not only further reduce the risk of intraprocedural neurologic complications, but also, by preventing plaque protrusion through stent struts,[75] eliminate postprocedural cerebral embolization as demonstrated on DW-MRI.[78] This strategy has been termed intra- and postprocedural (sustained) “embolic prevention.” Sustained embolic prevention is thus complementary to the classic intraprocedural (temporary) “embolic protection” using proximal (flow cessation or reversal) or distal (filter) devices.[87] Recent evidence indicates that incorporation of the sustained embolic prevention technology in otherwise routine CAS may achieve a CEA-like effect, leaving the residual embolic source along with no residual stenosis, in both symptomatic and increased-stroke-risk asymptomatic ASxCS patients, with periprocedural complications <1%.[92] [93]

Three mesh-covered carotid stent designs have been CE-marked.[81] [87] They show fundamental differences in the mesh material and design and in its position in relation to the stent frame (polyethylene terephthalate single-fiber knitted mesh in the CGuard micronet-covered stent, braided metallic mesh inside in the Casper/RoadSaver stent, and perforated polytetrafluoroethylene/teflon membrane outside the Gore stent).[81] [87] These differences, along with those in the nitinol frame construction (braided in Casper/RoadSaver, laser-cut in CGuard, and Gore stent), may translate into important differences in short- and long-term clinical outcomes. Meta-analyses comparing 30-day and 12-month clinical outcomes with the different mesh-covered stents (second-generation carotid stents) in relation to single-layered (first generation) carotid stents and in relation to surgery indicates that the mesh-covered stents' design differences are relevant clinically.[58] [92] [94] The body of prospective evidence is also growing. A recent RCT established a profound (powered) reduction in peri- and postprocedural DW-MRI embolism, an index of stroke risk,[79] with micronet-covered stents versus conventional first-generation carotid stents,[78] translating into improved clinical outcomes.[82] [92] [106] [107] [108] [109] A recent randomized controlled study, appropriately powered for reduction in cerebral embolism by DW-MRI imaging,[78] provides level-1 evidence in support of neuroprotected, minimally invasive sealing of lesions with increased stroke risk, translating into a new carotid revascularization paradigm.[57] [78] [82] [83] [97] In addition, the plaque sealing strategy, paired with optimized intraprocedural neuroptotection,[57] [77] may allow expanding routine percutaneous management to lesions traditionally considered high-risk for CAS, such as highly calcific[109] or highly thrombotic.[75] [97] [108]

Obtaining Evidence That Is Feasible and Understanding What Evidence Is Unlikely To Be Generated

Practicing evidence-based medicine requires integrating individual clinical expertise and the best available external evidence.[60] There will not be an RCT for every treatment in every clinical scenario.[20] [60] The basis for an RCT is the principle of uncertainty—lack of evidence that one treatment type may be better than the other. One fundamental limitation of many RCTs with clinical endpoints today is, apart from large costs and many years required to enroll the high patient numbers needed,[110] that they test treatments that have already obtained some convincing evidence—from prior imaging studies and from increased risk patient cohorts enrolled in registries. Specifically, the RCT null hypothesis may no longer be relevant if there is already some evidence from previous studies indicating that a particular treatment has benefits.[20] [111] Another fundamental basis of RCTs is ethics of patient enrolment that require avoiding subjecting patients to harm. For this reason, patients with an increased risk of a clinical event if left untreated (e.g., a thrombus-containing carotid lesion) typically get treated outside of any RCT,[110] because physicians exercising the “do no harm” principle chose the treatment path (that is usually the preference of the patient and family too). As a result, the RCT ends up primarily enrolling low-risk patients. Such an RCT is ethical, but it is a priori unable to test the effect of the treatment it is supposed to test, because of the bias associated with including low-risk patients. Outcomes of RCTs performed in populations at low-risk of clinical events (such as stroke) should not generalized to the detriment of vulnerable higher risk populations.[20]

Primary stroke prevention by ASxCS revascularization using either CAS or CEA is the focus of the ongoing Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis (CREST-2) trial (NCT02089217). It is important to realize that the success of the CREST-2 study in comparing demonstrating the benefit of revascularization (using either CAS or CEA) against MMT will be critically dependent on randomizing (and maintaining) ASxCS patients with increased stroke risk in the medical-only therapy arm. This is a major challenge as patients with increased risk (and their treating physicians) naturally gravitate outside the RCT toward the intervention that is to be tested in the study.[110] This is evidenced in several recent falsely “neutral” trials in cardiovascular medicine; for example, performing coronary thrombus aspiration, if required, outside the trial and randomizing the remaining patients who are unlikely to require the tested intervention.[111] This is the main reason why, for instance, the Stent-Protected Angioplasty versus Carotid Endarterectomy-2 (SPACE-2) trial which aimed at comparing medical therapy-only versus medical therapy + CAS/CEA in ASxCS, failed to enrol.[109] To provide clinically relevant answers, carotid revascularization RCTs studies should strive to include a preponderance of high-stroke-risk rather than being largely limited to low-risk patients. This aim may be unrealistic for ethical reasons, and registries with external monitoring of clinical events (and independent event adjudication) are likely to play an increasing role in generating evidence relevant to clinical practice. Guideline requirements for level 1 evidence should consider in detail RCT patient selection bias which will affect, a priori, the “answer” the trial would aim to provide.

In real-life clinical practice, almost no patient is an “average” patient (it is as rare as the tip of the Gaussian distribution). It is fundamental to understand individual variations in disease pathology and the risk of symptom occurrence.[19] Safe and more efficacious treatments, including both pharmacotherapy and devices need to be considered on a patient-specific basis, to precisely target and modify the individual disease-related risks are needed.[20] [77]

Conclusions

Strokes, including those of a mechanistic origin from carotid atherosclerosis, should be prevented rather than experienced, with all the consequences,[4] [6] by stroke-affected individuals and their families. Contemporary optimized (“maximal”) pharmacotherapy, the first-line therapeutic approach for ASxCS, paired with lifestyle modification may reduce (or delay) stroke risk. Pharmacotherapy, however, even if maximized, does not sufficiently protect against carotid stenosis-related strokes[20] [38] [40] [53] [56] [66] ([Fig. 1]). MMT patients continue to join the symptomatic cohorts of contemporary carotid revascularization trials.[8] [57] These patients have already experienced symptomatic loss of their brain tissue, demonstrating a failure of the “wait-and-see” strategy in ASxCS (cf. [Fig. 1-II]).

Revascularization, in addition to MMT, ideally should have been offered to these patients prior to the point where they become disabled ([Fig. 1]). Treatment should be preventive rather than reactive and should be safe and effective, including the long-term patient benefit in absence of treatment-related adverse events.[20] [89] Recent evidence indicates that less than 20 unselected patients with a significant carotid stenosis need to be revascularized (number-needed-to-revascularize (NNR)) to prevent one stroke.[111] [112] NNR is likely to be significantly lower in patients with increased lesion-level and/or clinical risk features.[19] [20] [39] [51] [53] [54] [63] [69] That said, the cardinal principle for any preventive therapy (including carotid revascularization to reduce stroke risk) is that the benefit must outweigh the risk.[20]

There is ample current level-1 evidence that percutaneous (e.g., transfemoral or transradial) conventional carotid revascularization using conventional CAS using first generation (single-layered) stents is long-term as safe and effective as conventional surgery. Less invasive surgery, using the transcervical approach with robust, transient flow reversal to protect the brain, is an attractive therapeutic option to operators who wish to avoid traversing the aortic arch.[20] [98] [99] If paired with a plaque-sealing stent,[97] both percutaneous and TCR approaches may prove superior to conventional CEA or conventional CAS using first-generation stents.[92] [94] The risk posed by the intervention, even if small, should always be weighed against the stroke risk in the absence of intervention. The risk analysis should take into account clinical, physiological, imaging (cerebral and other) lesion, and individual patient comorbid characteristics.[19] [20]

Stroke risk stratification in ASxCS remains a major challenge as clinically applicable scales (such as those available to guide therapeutic decision making to reduce stroke risk in paroxysmal AFib[8] [55] [61]) do not yet exist for ASxCS and are sorely needed. Evidence is accumulating that the novel paradigm of percutaneous, appropriately neuroprotected, minimally invasive plaque sealing may demonstrate short- and long-term superiority over other management options.

Progress in medical knowledge must not be neglected. Consistent with the principle of evidence-based medicine, it is the duty of the clinician to apply the best contemporary evidence available rather than passively wait for “further” RCT evidence which may be severely biased by patient selection and may or may not arrive.[20] [60] Decision making that, in contemporary clinical practice, integrates ASxCS patient and lesion-level risk characteristics continues to be evidence-based.[60] Today, the patient plays a central role in decisions regarding their medical care.[20] Patients in at-risk population categories deserve comprehensive information in reaching treatment decisions about therapies designed to prevent stroke.[20] [112] [113] [114] [115] [116] [117] Patients in at-risk categories deserve comprehensive information to assist in treatment decisions regarding therapies designed to prevent stroke.[20] Patient preference typically and overwhelmingly is to receive preventive treatment for stroke which is effective in both short and long term and delivered with a low procedural risk and with least invasiveness.[115] [116] [117] ASxCS patients with diameter stenosis[29] [30] of 60 to 99% and increased risk of stroke should be considered for revascularization.[20] [66] [113]

Patients at increased stroke risk should receive MMT and be offered the opportunity of modern low-risk interventions (minimal periprocedural complication rate, long-term durability) to prevent carotid stenosis-associated strokes. The “wait-for-stroke-to-occur” strategy (i.e., revascularize only once the patient becomes symptomatic) becomes unacceptable when the risk of percutaneous “fix it” intervention is down to the level of approximately 1%[92] [93] [94] compared with the annual stroke risk of up to 2.5% in vascular clinic ASxCS patients on optimized pharmacotherapy.[8] [38] [40] Clinical decision making in ASxCS patients needs to be based on facts ([Figs. 1] and [2]) and not on wishful thinking.[20] [23] [118]

Conflict of Interest

P.M. is a recipient of research grants for basic and clinical investigations in atherosclerosis, and he has proctored and/or consulted for Abbott Vascular, Balton, Gore InspireMD, and Medtronic. P.M. has performed clinical trials of novel minimally invasive methods in carotid revascularization in primary and secondary stroke prevention including CARENET (Co-Principal Investigator), PARADIGM/PARADIGM-Extend (Principal Investigator), OPTIMA (Principal Investigator), TOP-Guard (Principal Investigator), and he is Global Co-Principal Investigator in FDA IDE CGUARDIANS trial. P.M. is the Polish Cardiac Society Board Representative for Stroke and Vascular Interventions and serves on the ESC Stroke Council Scientif Documents Task Force. K.R. reports receiving fees for serving on advisory boards from Abbott Vascular, Cardinal Health, Surmodics, Inari Medical, Volcano/Philips, and Proteon; receiving fees and stock options for serving on advisory boards from Cruzar Systems, Valcare, and Eximo; receiving stock options for serving on advisory boards from Capture Vascular, Shockwave, Micell, Endospan, and Silk Road Vascular; receiving stock options for serving on the advisory boards of and the holding of equity positions in Contego, Access Vascular, and MD Insider; holding stock/stock options in Embolitech, Janacare, Primacea, and PQ Bypass; receipt of a future payout from a previous equity position in Vortex; and receiving grant support paid to his institution from Abbott Vascular, Atrium/Maquet, and Lutonix/Bard. A.H.S. has consulted for Amnis Therapeutics Ltd, Cerebrotech Medical, Systems Inc., CereVasc LLC, Claret Medical Inc., Codman, Corindus Inc., GuidePoint Global Consulting, Medtronic (Formerly Covidien), MicroVention, Neuravi, Penumbra, Pulsar Vascular, Rapid Medical, Rebound Therapeutics Corporation, Silk Road Medical, Stryker, The Stroke Project Inc., Three Rivers Medical Inc., and W.L. Gore & Associates, and is a Board Member of Intersocietal Accreditation Commission. He has been Principal Investigator and/or served on Steering Committees for: Codman & Shurtleff, LARGE Trial, Covidien (Now Medtronic), SWIFT PRIME and SWIFT DIRECT Trials; MicroVention, FRED Trial, CONFIDENCE Study, MUSC, POSITIVE Trial; Penumbra, 3D Separator Trial, COMPASS Trial, INVEST Trial. A.H.S. has financial interests in BuffaloTechnology Partners Inc., Cardinal, International Medical Distribution Partners, Medina Medical Systems, Neuro Technology Investors, StimMed, and Valor Medical. I.Q.G. is Vice President of the World Federation for Interventional Stroke Treatment (WIST).

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Publication History

Received: 11 November 2021

Accepted: 27 September 2022

Accepted Manuscript online:
28 September 2022

Article published online:
10 July 2024