Intracranial large artery atherosclerosis: Treatment and prognosis

INTRODUCTION — Atherosclerotic stenosis of the major intracranial arteries, also known as intracranial atherosclerosis (ICAS) or cerebral atherosclerosis, is an important cause of ischemic stroke. This topic focuses on the treatment and prognosis of ICAS. The epidemiology, clinical manifestations, and diagnosis of ICAS are reviewed separately. (See "Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis".)

Other ischemic stroke subtypes are discussed elsewhere. (See "Stroke: Etiology, classification, and epidemiology" and "Clinical diagnosis of stroke subtypes" and "Lacunar infarcts" and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".)

TREATMENT OF ACUTE STROKE OR TIA — The initial treatment of acute stroke or transient ischemic attack (TIA) due to ICAS is similar to the treatment of acute ischemic stroke or TIA attributed to other mechanisms, as reviewed in detail separately. (See "Initial assessment and management of acute stroke".)

Of utmost importance, timely restoration of blood flow using reperfusion therapies (intravenous thrombolysis and/or mechanical thrombectomy) is the most effective way to salvage ischemic brain tissue that is not already infarcted. There is a relatively narrow time window during which this can be accomplished, since the benefit of these interventions decreases over time. Thus, an important aspect of the hyperacute phase of acute ischemic stroke management is the rapid determination of patients who are eligible for intravenous thrombolysis and mechanical thrombectomy. (See "Approach to reperfusion therapy for acute ischemic stroke" and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use" and "Mechanical thrombectomy for acute ischemic stroke".)

Antiplatelet therapy has an important role in the both the acute and chronic phase of ischemic stroke management, as discussed below. (See 'Antiplatelet therapy' below.)

SECONDARY PREVENTION

Our approach — For patients with transient ischemic attack (TIA) or ischemic stroke attributed to ICAS, we employ intensive medical therapy that includes antiplatelet therapy and strict control of vascular risk factors including the use of antihypertensive agents; low density lipoprotein cholesterol (LDL-C) lowering therapy; and physical activity and other lifestyle modification (eg, smoking cessation, weight control, salt restriction, and a healthy diet) [1]. (See 'Antiplatelet therapy' below and 'Risk factor management' below.)

Intensive medical therapy is superior to intracranial arterial stenting for patients with recent stroke or TIA attributed to severe ICAS. (See 'Stenting' below.)

Antiplatelet therapy — Aspirin and other antithrombotic agents should not be given for the first 24 hours following treatment with intravenous thrombolysis. Otherwise, antiplatelet therapy should be started for most patients without an indication for anticoagulation as soon as possible after the diagnosis of TIA or ischemic stroke is confirmed, even before the evaluation for ischemic mechanism is complete. This issue is reviewed in detail elsewhere. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Treatment on presentation'.)

For patients without serious bleeding complications who are not on anticoagulation or antiplatelet therapy at baseline, we start antiplatelet therapy as soon as possible while evaluating the ischemic stroke mechanism, as follows:

●For patients with a recent (within 30 days) stroke or TIA attributed to atherosclerotic intracranial large artery stenosis of 70 to 99 percent, we suggest short-term (up to 90 days) dual antiplatelet therapy (DAPT) with aspirin (325 mg daily) plus clopidogrel (300 to 600 mg loading dose, followed by 75 mg daily), rather than aspirin monotherapy, followed by long-term aspirin monotherapy [1-3].

●For patients with a recent minor stroke (NIHSS score ≤5) or TIA attributed to atherosclerotic intracranial large artery stenosis of 50 to 69 percent, options for initial treatment include aspirin monotherapy or short-term (21-day) DAPT. For patients with brain ischemia attributed to atherosclerotic intracranial large artery stenosis of 50 to 69 percent who have a low-risk TIA, defined by an ABCD² score <4, or a moderate to major ischemic stroke, defined by a National Institutes of Health Stroke Scale (NIHSS) score >5, we start treatment with aspirin (325 mg daily) alone. For patients with a high-risk TIA, defined by an ABCD² score ≥4, or minor ischemic stroke, defined by a NIHSS score ≤5, we begin with dual antiplatelet therapy (DAPT) for 21 days using aspirin (160 to 325 mg loading dose, followed by 50 to 100 mg daily) plus clopidogrel (300 to 600 mg loading dose, followed by 75 mg daily) rather than aspirin alone.

For long-term stroke prevention (beyond the 21- or 90-day duration of DAPT), we recommend treatment with aspirin. Clopidogrel monotherapy or the combination drug aspirin-extended-release dipyridamole are reasonable alternatives to aspirin but have not been specifically studied in ICAS. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".)

Exceptions may include patients with a concurrent indication for anticoagulation, as discussed separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Cardioembolic source' and "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Treatment on presentation'.)

●Evidence supporting short-term DAPT – Accumulating data suggest that short-term (up to 90 days) DAPT may be beneficial for patients with acute stroke or TIA attributed to high-grade ICAS.

•Short-term DAPT with aspirin and clopidogrel – The lower rates of recurrent stroke in SAMMPRIS patients on DAPT compared with similar patients from WASID, combined with the supportive CHANCE and CLAIR data, make a compelling argument to continue DAPT up to 90 days in patients with severe ICAS. Most importantly, the high risk of recurrent stroke from ICAS that persists beyond the first month distinguishes these patients from other stroke subtypes and argues for longer DAPT treatment.

The multicenter SAMMPRIS trial enrolled patients with 70 to 99 percent stenosis of a major intracranial artery who had a TIA or ischemic stroke within 30 days prior to study entry; in the aggressive medical treatment arm of the trial, the short-term use of DAPT with aspirin and clopidogrel for the first 90 days after enrollment may have contributed to the relatively low rate of combined stroke and death at one year of 12.2 percent [4,5]. This contrasts with findings from a post hoc analysis of the WASID trial, which enrolled patients with a stroke or TIA attributed to a 50 to 99 percent intracranial stenosis; the subgroup of patients in WASID who would have met the SAMMPRIS trial entry criteria (ie, 70 to 99 percent intracranial large artery stenosis and TIA or stroke within 30 days prior to study entry) and who were treated with aspirin or warfarin had a combined stroke and death rate at one year of 23 percent [6].

Additional support for DAPT comes from a subgroup analysis of patients with ICAS in the CHANCE trial, which reported that those treated with DAPT had a lower rate of early recurrent stroke than those on monotherapy, although the difference was not statistically significant [7]. Similarly, the CLAIR study showed that patients with middle cerebral artery (MCA) stenosis on DAPT had significantly lower rates of microemboli distal to the stenosis when compared with those on aspirin alone and a lower (nonsignificant) rate of recurrent stroke [8].

•Short-term DAPT with aspirin and ticagrelor – The THALES trial compared ticagrelor (90 mg twice daily after 180 mg loading dose) plus aspirin (75 to 100 mg once daily after 300 to 325 mg loading dose) among patients with recent non-cardioembolic stroke with NIHSS ≤5 or high-risk TIA or symptomatic >30 percent intracranial or extracranial stenosis. A subgroup analysis of THALES patients with ICAS ≥30 percent ipsilateral to the qualifying ischemic event found lower rates of ischemic stroke in those on combination ticagrelor plus aspirin compared with those on aspirin alone at 30 days (9.5 versus 15.2 percent, hazard ratio [HR] 0.66, 95% CI 0.47–0.93) [9]. Unlike other ICAS trials wherein the stenosis was determined by the investigator to be symptomatic for study qualification, the stenosis in this THALES analysis may have been incidental (eg, a 40 percent cavernous carotid stenosis ipsilateral to a lenticulostriate stroke). Additionally, the treatment duration was limited to 30 days, as were the reported outcomes. Given that ICAS stroke risk remains high beyond 30 days and the bleeding risk with ticagrelor and aspirin reported in THALES, additional long-term and comparative data are needed to better understand the role of this combination compared with other DAPT options.

Additional support for the use of short-term DAPT in the setting of acute minor ischemic stroke or high-risk TIA comes from several randomized trials and meta-analyses not limited to patients with symptomatic ICAS, as reviewed in detail separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack", section on 'Efficacy of DAPT'.)

●Evidence supporting long-term antiplatelet therapy – Aspirin, clopidogrel, and the combination aspirin-extended-release dipyridamole have been established as effective for prevention of recurrent ischemic stroke in the patients with a history of noncardioembolic ischemic stroke or TIA of atherothrombotic, lacunar (small vessel occlusive), or cryptogenic type. Since antiplatelet drugs are effective in this larger group of patients with different types of noncardioembolic ischemic stroke, they are likely to be effective in patients with ICAS, a subgroup that appears to be at particularly high risk of recurrent ischemic stroke. However, antiplatelet drugs have not been compared with placebo or with each other in randomized controlled trials specifically for patients with stroke or TIA attributed to ICAS. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".)

Cilostazol is a phosphodiesterase 3 inhibitor and antiplatelet agent with vasodilating and possible antiatherogenic effects [10]. Early randomized trials conducted in East Asia failed to show a benefit of cilostazol plus aspirin compared with aspirin alone or clopidogrel plus aspirin for reducing stroke risk due to ICAS [11,12]. Later randomized trials from East Asia of cilostazol in combination with aspirin or clopidogrel showed a benefit for stroke prevention in patients with ICAS, but the findings may not be generalizable to all populations [13,14]. The CATHARSIS trial compared cilostazol plus aspirin with aspirin alone in patients with symptomatic 50 to 99 percent ICAS [13]. At two years, rates of vascular events and silent brain infarcts were lower in those on dual therapy (10.7 versus 25 percent, HR 0.37, 95% CI 0.14-0.97) without an increased bleeding risk. Similarly, among ICAS patients in the CSPS.com trial, with 0.5- to 3.5-year follow-up, those randomly assigned to cilostazol plus aspirin or clopidogrel had a lower rate of ischemic stroke compared with patients randomly assigned to placebo plus aspirin or clopidogrel (4.5 versus 9.9 percent, HR 0.48, 95% CI 0.21-1.11) and no increased bleeding risk [14]. In addition, other randomized trials support the safety and efficacy of cilostazol for secondary ischemic stroke prevention in East Asian populations, as described elsewhere. (See "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke", section on 'Cilostazol'.)

Other antiplatelet agents such as prasugrel and vorapaxar are not well studied in this population.

●No role for oral anticoagulation – There is randomized trial evidence that oral anticoagulation with warfarin is harmful for patients with TIA or stroke due to ICAS. The WASID trial enrolled patients with TIA or nondisabling stroke caused by an angiographically verified 50 to 99 percent stenosis of a major intracranial artery; patients were randomly assigned to treatment with either warfarin (target international normalized ratio [INR] 2.0 to 3.0) or aspirin (1300 mg/day) [15]. The study was stopped prematurely because of safety concerns for patients in the warfarin arm after enrolling 569 patients with an average follow-up of 1.8 years. Aspirin treatment was associated with a significantly lower rate of death than warfarin (4.3 versus 9.7 percent, HR 0.46, 95% CI 0.23-0.90). The composite rate of ischemic stroke, brain hemorrhage, or death from vascular cause other than stroke was similar between aspirin and warfarin treatment (22.1 versus 21.8 percent, hazard ratio [HR] 1.04, 95% CI 0.73-1.48). The rate of ischemic stroke recurrence in the territory of the stenotic intracranial artery was high for both aspirin and warfarin treatment (15.0 versus 12.1 percent, HR 1.26, 95% CI 0.81-1.97) and primarily occurred within the first year from the qualifying event, suggesting that neither aspirin alone nor warfarin was particularly effective for preventing early recurrent stroke. Of note, the WASID trial was performed before the era of intensive risk factor management that included statin therapy for aggressive LDL-lowering.

The efficacy of direct (non-vitamin K) oral anticoagulants (DOACs) for prevention of stroke due to ICAS has not been systematically studied, but the ongoing Comparison of Anticoagulation and Antiplatelet Therapies for Intracranial Vascular Atherostenosis (CAPTIVA) trial is randomizing patients with stroke due to severe ICAS to aspirin plus either clopidogrel, ticagrelor, or low-dose rivaroxaban [16].

Risk factor management — Management of risk factors including hypertension, hyperlipidemia, physical inactivity, obesity, diabetes, and smoking is a critical component of the treatment of patients with atherosclerotic cardiovascular disease, including those with ischemic stroke. Post hoc analyses from the WASID trial showed that patients with ICAS and poorly controlled blood pressure or elevated cholesterol during follow-up had a significantly higher rate of stroke, myocardial infarction, or vascular death compared with patients with good control of these risk factors [17,18]. In addition, post hoc analyses of patients in the aggressive medical management only arm of the SAMMPRIS trial (see 'Stenting' below) found that intensive treatment of blood pressure and LDL-C was important to prevent recurrent vascular events and that physical inactivity was the most important independent predictor of vascular events and stroke [19].

Given that risk factor control reduces the risk of vascular events and recurrent stroke in patients with heterogeneous causes of stroke (see "Overview of secondary prevention of ischemic stroke"), combined with the post hoc analyses described above [17-19], it is likely that patients with stroke due to ICAS have better outcomes with intensive risk factor control that includes antihypertensive therapy, LDL-C lowering therapy, and lifestyle modification. (See "Overview of secondary prevention of ischemic stroke".)

●Antihypertensive therapy – We treat all patients with hypertension using nonpharmacologic therapy (ie, salt restriction, adequate potassium intake, weight control, healthy diet, limited alcohol intake, and exercise) and pharmacologic therapy. For patients with hypertension, we suggest targeting a systolic blood pressure (SBP) of <140 mmHg [1-3]. In the absence of definitive data supporting lower SBP targets in patients with ICAS, we advise caution when pursuing lower targets of SBP (eg, SBP <130 or <120), especially in patients with ICAS and fluctuating neurological symptoms, a recent stroke, or documented low flow on quantitative magnetic resonance angiography. More research is needed to establish an alternative blood pressure target for such patients.

The optimal target blood pressure to reduce the risk of recurrent ischemic stroke in patients with stroke due to ICAS is informed largely by post hoc analyses and data from a randomized controlled trial. The WASID and SAMMPRIS clinical trials demonstrated that in the vast majority of stable patients with stroke due to ICAS, lowering SBP to <140 mmHg was safe and was associated with a reduced risk of recurrent stroke [17-20]. However, targets below 140 mmHg were not studied in those analyses, and emerging data suggests caution should be advised with lower targets. As an example, a randomized controlled trial from Korea of 132 patients with recent subacute stroke due to ICAS found the group assigned to aggressive blood pressure control (mean SBP 124.6 mmHg) had a tendency toward larger infarct volume and more fluid-attenuated inversion recovery lesions on magnetic resonance imaging (MRI) at follow-up compared with the group assigned to standard blood pressure control (mean SBP 132 mmHg) [21]. In the MYRIAD observational study of patients with symptomatic ICAS, a change in systolic blood pressure from baseline to six- to eight-week follow-up was an independent predictor of early recurrent stroke [22]. Another study found that patients with ICAS who had a low translesional pressure gradient (measured using computational fluid dynamics from computed tomographic angiography) and a mean SBP <130 mmHg during follow-up had an increased risk of recurrent stroke in the territory compared with patients who had a SBP of 130 to 150 mmHg during follow-up [23]. Similarly, a post hoc analysis of the VERiTAS study of patients with posterior circulation stenosis reported that patients with both low flow on quantitative MRI and a mean SBP <140 mmHg had a higher risk of stroke compared with patients lacking one or both of these factors [20].

Specific aspects of the pharmacologic and nonpharmacologic evaluation and management of hypertension are discussed in greater detail separately. (See "Overview of hypertension in adults" and "Salt intake and hypertension" and "Potassium and hypertension" and "Diet in the treatment and prevention of hypertension" and "Overweight, obesity, and weight reduction in hypertension" and "Exercise in the treatment and prevention of hypertension".)

●LDL-C lowering therapy – For patients with a history of ischemic stroke or TIA, independent of the baseline LDL-C level, we recommend lifelong high-intensity statin therapy (atorvastatin 40 to 80 mg or rosuvastatin 20 to 40 mg); we prefer the highest approved dose in most cases. For patients who do not tolerate these doses, the maximally tolerated dose of a statin should be used. For patients whose LDL-C is ≥70 mg/dL (1.8 mmol/L) on high-intensity statin therapy, we recommend adding ezetimibe or a PCSK9 inhibitor to statin therapy. In most cases, this second drug will be ezetimibe for reasons of cost and convenience.

For patients who do not tolerate any statin regimen, we start ezetimibe. For those patients whose LDL-C remains above 70 mg/dL (1.8 mmol/L), we consider adding a PCSK9 inhibitor.

This approach is similar to that presented in many societal guidelines, including the 2022 American Academy of Neurology guidelines [1] and the 2019 multisociety American guidelines [24]; recommendations from the 2019 European Society of Cardiology are somewhat more aggressive for the highest-risk patients [25].

There is overwhelming evidence from randomized trials that LDL-C lowering reduces the risk of cardiovascular events including ischemic stroke. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

Data specific to patients with ICAS has also emerged for the use of high-intensity statins and targeting LDL <70 mg/dL (1.8 mmol/L). A single-center randomized controlled trial of 120 patients from China with symptomatic MCA or basilar stenosis found a lower rate of recurrent cerebrovascular events during follow-up in those treated with high-intensity statins compared with low- and standard-intensity statins [26]. A post hoc analysis of 277 patients from the medical arm of the SAMMPRIS trial showed a lower risk of recurrent stroke and vascular events with lower LDL-C when analyzed as a continuous variable, but achieving the target LDL-C <70 mg/dL was associated with only a trend toward benefit [19]. However, the TST trial of over 2800 patients with recent ischemic stroke or TIA and atherosclerosis (including ICAS) found lower rates of recurrent vascular events, particularly stroke, in those assigned to the LDL target of <70 mg/dL compared with those assigned to a target range of 90 to 110 mg/dL [27]. (See "Overview of secondary prevention of ischemic stroke", section on 'LDL-C lowering therapy'.)

●Lifestyle modification – A number of behavioral and lifestyle modifications may be beneficial for reducing the risk of ischemic stroke and cardiovascular disease [1]. These include smoking cessation, regular aerobic physical activity, limited alcohol consumption, weight control, salt restriction, and a Mediterranean diet. Physical activity, in particular, is strongly recommended for patients with ICAS since it was independently associated with lower rates of recurrent stroke, myocardial infarction, and vascular death in the medically treated patients in the SAMMPRIS trial (odds ratio [OR] 0.6, 95% CI 0.4–0.8), with higher rates of activity increasing the protective effect [19]. (See "Overview of secondary prevention of ischemic stroke", section on 'Lifestyle modification'.)

●Glycemic control – Tight glucose control reduces microvascular complications. Diet, exercise, oral hypoglycemic drugs, and insulin are proven methods to achieve glycemic control. A reasonable goal of therapy for most patients with diabetes is a hemoglobin A1C value of ≤7 percent. However, the available evidence has not demonstrated a consistent beneficial effect of intensive glucose-lowering therapy or lifestyle modification for reducing macrovascular outcomes (eg, stroke and death) in patients with type 2 diabetes. (See "Overview of secondary prevention of ischemic stroke", section on 'Glycemic control' and "Overview of primary prevention of cardiovascular disease".)

Failure of medical therapy — Although unproven, therapies of last resort for patients who have recurrent ischemic stroke due to ICAS despite maximal medical therapy include endovascular stenting (see 'Stenting' below) or submaximal angioplasty (see 'Submaximal angioplasty' below) as reviewed in the sections below. However, there are no comparative data from randomized trials demonstrating benefit of these treatments over medical therapy that can be used to guide management for patients with recurrent stroke in this setting.

Intracranial arterial stenting and other interventional procedures are not recommended for patients with a first stroke or TIA attributable to severe intracranial artery stenosis [1-3], since results from the SAMMPRIS and VISSIT trials showed that medical management was superior to intracranial stenting (see 'Stenting' below). In the United States, the policy of the Centers for Medicare and Medicaid Services is not to reimburse for intracranial angioplasty with or without stenting outside the context of a clinical trial [28].

Other interventions are not routinely used because of lack of evidence or evidence of harm:

●Intracranial angioplasty without stenting has been studied only in small observational studies [29]. There are numerous drawbacks to intracranial angioplasty, including immediate elastic recoil of the artery, intimal damage, dissection, acute vessel closure, residual stenosis >50 percent following the procedure, and high restenosis rates [30-32]. A 2019 systematic review and meta-analysis of balloon angioplasty for ICAS including 25 studies and 674 patients showed a 30-day stroke and death rate of 16.3 percent in patients with severe stenosis [33]. Therefore, angioplasty alone has largely been replaced with submaximal angioplasty to minimize periprocedural complications.

●Extracranial-intracranial bypass, or direct bypass, was mostly abandoned for the treatment of ICAS after the extracranial-intracranial (EC-IC) bypass trial results were reported in 1985 [34]. In that study, 1377 patients with symptomatic extracranial carotid occlusion, distal carotid occlusive disease, or MCA stenosis were randomly assigned to either medical therapy alone (usually aspirin) or to extracranial-intracranial anastomosis surgery (joining the superficial temporal artery and the middle cerebral artery) combined with medical therapy. The mean follow-up was 56 months. The results demonstrated that EC-IC bypass was ineffective for preventing stroke in these patients [34]. Subgroup analyses showed that EC-IC bypass was ineffective in patients with distal carotid stenosis, and was actually hazardous in patients with MCA stenosis [34,35]. In 109 patients with ≥70 percent MCA stenosis, stroke frequency was significantly higher for patients who had EC-IC compared with medically treated patients (44 versus 24 percent). Subsequent trials have also failed to show benefit of EC-IC bypass for stroke prevention in patients with symptomatic ICA or MCA stenosis or occlusion [36,37].

●Indirect bypass, also known as encephaloduroarteriosynangiosis (EDAS), is an investigational surgical procedure that showed some early promising results for stroke prevention in ICAS in a two-center prospective uncontrolled study [38]. However, evidence of efficacy from randomized trials is needed before the procedure is widely adopted to treat medically refractory ICAS.

Stenting — Several multicenter randomized trials described below (SAMMPRIS [4,5], VISSIT [39], CASSISS [40]) and a 2023 meta-analysis that included these three trials and another trial from China [41] found that patients with symptomatic ICAS (n = 989) treated with angioplasty and stenting had worse outcomes or no benefit compared with those who received medical therapy alone [42]. Endovascular therapy plus medical treatment led to higher rate of death or stroke at 30 days (12 percent, versus 4 percent for medical therapy alone, absolute risk increase 8 percent, risk ratio [RR] 2.93, 95% CI 1.81-4.75) and at one year (20 versus 13 percent, absolute risk increase 7 percent, RR 1.49, 95% CI 1.12-1.99) [42].

Given these data, we recommend against intracranial stenting for patients with recent stroke or TIA attributed to ICAS [1-3]. All patients should be treated with intensive medical therapy that includes antiplatelet therapy and strict control of vascular risk factors, as described above. (See 'Secondary prevention' above.)

●SAMMPRIS trial – The multicenter SAMMPRIS trial enrolled patients with 70 to 99 percent stenosis of a major intracranial artery who had a TIA or ischemic stroke within 30 days prior to study entry [4,5]. Patients were randomly assigned to treatment with intracranial angioplasty and stenting using the Wingspan system plus aggressive medical management, or to treatment with aggressive medical management alone. Aggressive medical therapy consisted of aspirin 325 mg daily for the duration of follow-up, clopidogrel 75 mg daily for 90 days after enrollment, and intensive risk factor management with a target blood pressure of <140/90 mmHg (or <130/80 mmHg if diabetic) and an LDL-C target of <70 mg/dL (<1.81 mmol/L).

Trial enrollment in SAMMPRIS was halted prematurely after recruitment of 451 of the planned 764 patients because the 30-day rate of stroke or death was higher for patients treated with angioplasty and stenting compared with those treated with medical therapy alone (14.7 versus 5.8 percent) [4]. The periprocedural rate of stroke was higher than expected for the stenting group, and the early stroke rate was lower than estimated for the medical management group.

Of the 33 early symptomatic stroke events in the stenting group, 25 occurred within one day of the procedure, and the remaining 8 occurred within six days of the procedure [43]. Of the early strokes, symptomatic intracranial, subarachnoid, or intraventricular hemorrhage occurred in 10 patients (4.5 percent), resulting in death in 4 patients (1.8 percent). By contrast, there were 12 early strokes in the medical management group, and none were hemorrhagic. In the stenting group, the main cause of the early ischemic strokes was occlusion of perforating vessels. Of the early hemorrhagic strokes, approximately one-half involved predominantly subarachnoid bleeding that was evident immediately after the procedure, while the rest were intraparenchymal hemorrhages that were attributed to reperfusion.

At study end, with a median follow-up of 32 months, the rate of stroke or death remained significantly higher for the angioplasty and stenting group compared with the medical management group (19.7 versus 12.6 percent at one year, and 23.9 versus 14.9 percent at three years) [5]. These long-term differences were driven largely by the 30-day outcomes, since the rates of stroke and death beyond 30 days were similar for the two groups, demonstrating no long-term benefit from stenting.

●VISSIT trial – The VISSIT trial randomly assigned 112 patients with symptomatic ICAS to treatment with a balloon-expandable stent plus medical therapy or to medical therapy alone. It was terminated early by the sponsor due to the low likelihood of detecting superiority of stenting over medical therapy [39]. At 30 days, the rate of the primary safety outcome, a composite of any stroke, death, or intracranial hemorrhage, was significantly higher in the stent group compared with the medical group (24 versus 9 percent). At 12 months, the rate of the primary outcome measure, a composite of stroke and TIA in the same territory, was significantly higher in the stent group (36 versus 15 percent).

●CASSISS trial – The CASSISS trial, conducted at eight sites in China, was an open-label, randomized trial of 358 patients with symptomatic ICAS enrolled at least three weeks after the index stroke that compared angioplasty and stenting with the Wingspan stenting system with medical therapy [40,44]. In contrast to SAMMPRIS and VISSIT, CASSISS excluded patients with perforator ischemic events in the basal ganglia, thalamus, and brainstem and patients with MRI evidence of recent stroke by diffusion-weighted imaging (DWI) at the time of randomization in order to reduce the risk of periprocedural complications and symptomatic intracranial hemorrhage that was seen in earlier trials [44]. CASSISS reported a lower primary endpoint rate (a composite of any stroke or death within 30 days or stroke in territory within one year) than prior trials in both the stenting and medical groups (8 versus 7.2 percent, respectively), likely because of the lower-risk population enrolled and differences in event ascertainment during follow-up [40]. Nevertheless, the CASSISS trial found no benefit over medical therapy from angioplasty and stenting with the Wingspan stenting system for any of the primary or secondary outcome measures. Periprocedural brain hemorrhage affected four patients in the stenting group (two of which were fatal) versus none in the medical group. There was a trend toward higher three-year mortality in the stenting arm (4.4 versus 1.3 percent, 95% CI 0.77-18.13).

Although stenting for stroke prevention in patients with ICAS has been shown to be harmful in these randomized trials [42], some physicians treat with stenting as a last resort for patients with high-grade intracranial large artery stenosis who have multiple symptomatic ischemic events. Results from the WEAVE study, an open-label, single-arm postmarket surveillance study of the WINGSPAN stent, suggested that stenting appeared safe with a relatively low risk of recurrent stroke in highly-selected patients with symptomatic ICAS who are at least seven days from their most recent ischemic event and have had two or more recurrent ischemic events in the vascular territory of the stenotic intracranial large artery despite optimal medical management [45]. However, patients were only required to be followed for 72 hours or until discharge, and in some cases, assessments were done by phone if the patient was already discharged. Additionally, the stroke and death rate in WEAVE for patients with ICAS who did not meet strict US Food and Drug Administration criteria (eg, did not fail medical therapy, were less than seven days since last stroke, or more than two strokes) was approximately 24 percent [46,47]. Along those lines, another ICAS registry of patients treated with stenting or angioplasty who failed medical therapy or had progressive stroke symptoms reported a 90-day ischemic stroke rate of 6.7 percent and 90-day mortality of 11.2 percent [48]. Given the high complication rates and low-quality evidence supporting safety in these uncontrolled studies, randomized controlled trials are needed before stenting is adopted as a rescue therapy even in those who have failed medical therapy. Analyses of the SAMMPRIS trial found no benefit for stenting for any subgroup of patients, including those patients with a prior ischemic stroke in the territory of the symptomatic intracranial artery and those who had their qualifying ischemic event on antithrombotic therapy [5,49,50].

Submaximal angioplasty — Submaximal angioplasty involves angioplasty alone with slow expansion of a balloon undersized to 50 to 70 percent of nominal vessel diameter to limit periprocedural complications. A 2020 meta-analysis identified nine studies (eight retrospective) with 395 patients who had 408 procedures with submaximal angioplasty [51]. The pooled periprocedural complication rate for stroke or death was approximately 5 percent, while the pooled rate beyond 30 days was approximately 4 percent. Technical success reported in six studies was achieved in approximately 96 percent of procedures. These results compare favorably with periprocedural event rates observed in the stenting and medical treatment arms of the SAMMPRIS and VISSIT trials described above. (See 'Stenting' above.)

These limited data suggest that submaximal angioplasty may be a promising strategy for safe revascularization in the future, but more research is needed before it is widely used in practice.

Recommendations of others — The 2021 American Heart Association/American Stroke Association recommendations for intracranial stenosis are as follows [2]:

●For patients with a stroke or TIA attributable to a 50 to 99 percent stenosis of a major intracranial artery, aspirin 325 mg daily is recommended in preference to warfarin.

●For patients with recent stroke or TIA (within 30 days) attributable to severe stenosis (70 to 99 percent) of a major intracranial artery, the addition of clopidogrel 75 mg daily to aspirin for up to 90 days is reasonable.

●For patients with a stroke or TIA attributable to severe stenosis (70 to 99 percent) of a major intracranial artery, the addition of cilostazol 200 mg daily to aspirin or clopidogrel might be considered.

●For patients with recent (within 24 hours) minor stroke or high-risk TIA and concomitant ipsilateral >30 percent stenosis of a major intracranial artery, the addition of ticagrelor 90 mg twice daily to aspirin for up to 30 days might be considered.

●For patients with a stroke or TIA attributable to a 50 to 99 percent stenosis of a major intracranial artery, maintenance of SBP below 140 mm Hg, high-intensity statin therapy, and at least moderate physical activity are recommended.

●For patients with stroke or TIA attributable to severe stenosis (70 to 99 percent) of a major intracranial artery, angioplasty or stenting should not be performed as initial treatment, even for patients who were taking an antithrombotic agent at the time of the stroke or TIA.

●In patients with severe stenosis (70 to 99 percent) of a major intracranial artery and actively progressing symptoms or recurrent TIA or stroke after institution of aspirin and clopidogrel therapy, achievement of SBP <140 mmHg, and high-intensity statin therapy (so-called medical failures), the usefulness of angioplasty alone or stent placement to prevent ischemic stroke in the territory of the stenotic artery is unknown.

●For patients with a stroke or TIA attributable to moderate stenosis (50 to 69 percent) of a major intracranial artery, angioplasty or stenting is associated with excess morbidity and mortality compared with medical management alone.

Recommendations from the 2017 update to the Canadian stroke best practice recommendations for ICAS are as follows [52]:

●Intracranial stenting is not recommended for the treatment of recently symptomatic intracranial 70 to 99 percent stenosis.

●As in the medical management arm of the SAMMPRIS trial, dual antiplatelet therapy with aspirin and clopidogrel started within 30 days of stroke or TIA and treatment for up to 90 days should be considered for patients on an individual basis, along with aggressive management of all vascular risk factors including blood pressure, lipids, diabetes mellitus, and other at-risk lifestyle patterns.

●In patients managed with maximal medical therapy in the presence of intracranial stenosis who experience a recurrent stroke, there is lack of clear evidence to guide further management decisions; intracranial angioplasty (with or without stenting) may be reasonable in carefully selected patients.

Recommendations from the UK National Institute for Health and Care Excellence (NICE) state that endovascular stent insertion for intracranial atherosclerotic disease should only be used in the context of research, noting that evidence shows a significant risk of periprocedural stroke and death [53].

PROGNOSIS

Risk and location of recurrent stroke — ICAS is associated with a high risk of recurrent stroke. As an example, a randomized controlled trial (WASID) published in 2005 that compared warfarin with aspirin in 569 patients with symptomatic stenosis (50 to 99 percent) of a major intracranial found that the ischemic stroke rate in the territory of the stenotic artery at one year was 11 to 12 percent in both treatment groups [15]. The risk of recurrent stroke is likely lower in the modern era with the advent of intensive medical therapy (ie, dual antiplatelet therapy for three months followed by long-term antiplatelet therapy, antihypertensive, and high-intensity LDL-C lowering treatment), as suggested by stroke rates among medically treated patients in the SAMMPRIS and VISSIT trials. Patients in the medical arm of SAMMPRIS treated with dual-antiplatelet therapy and intensive risk factor control had a lower primary endpoint rate at six months compared with similar patients from WASID with severe stenosis treated with aspirin alone (approximately 9 versus 18 percent, respectively) [18]. (See 'Stenting' above.)

Populations at high risk of recurrent stroke — Available evidence suggests there may be subgroups of patients with ICAS who are at particularly high risk of stroke:

●Patients with severe intracranial large artery stenosis [54]. In the prospective WASID trial, severe stenosis (≥70 percent) was associated with a significantly higher risk of stroke in the same territory compared with stenosis <70 percent (hazard ratio [HR] 2.03, 95% CI 1.29-3.22) (figure 1) [55].

●Patients with recent ischemic symptoms [54]. WASID also demonstrated that patients with symptoms within the prior 17 days were at significantly higher risk of stroke in the same territory compared with patients whose symptoms were more remote (HR 1.67, 95% CI 1.1-2.9) [55].

●Patients with borderzone infarcts and impaired collateral flow. In a post hoc analysis of a subgroup of SAMMPRIS patients with middle cerebral artery stenosis, patients with borderzone pattern of infarcts and those who had impaired collateral flow had the highest risk of recurrent stroke (37 percent) compared with those without impaired collaterals or other infarct patterns [56].

●Patients with clinically significant hemodynamic intracranial stenosis, described below. (See 'Implications of hemodynamic stenosis' below.)

●Women. The WASID trial found that the frequency of the combined end point of stroke or vascular death in patients with symptomatic intracranial arterial stenosis was greater in women than in men (28.4 versus 16.6 percent, respectively; HR 1.58, 95% CI 1.01-2.48) [57]. In addition, women had a higher risk of recurrent ischemic stroke than men (HR 1.85, 95% CI 1.14-3.01).

In the medical treatment arm of the SAMMPRIS trial, which enrolled patients with ischemic stroke or transient ischemic attack (TIA) attributed to severe (70 to 99 percent) stenosis of a major intracranial artery, high-risk features for recurrent stroke were the presence of an old infarct in the territory of the stenosis, presentation with stroke, and absence of statin use at trial entry [58].

Implications of hemodynamic stenosis — Intracranial stenosis considered "hemodynamically significant" purely on clinical grounds emerged as another potential risk factor for recurrent ischemic stroke in the GESICA study, a prospective observational report that enrolled 102 patients with ≥50 percent symptomatic intracranial large artery atherosclerotic stenosis [59]. Intracranial stenosis was classified as hemodynamic in GESICA if symptoms related to the stenosis occurred during a change in body position from supine to prone, during effort/exertion, or with the introduction or increase of antihypertensive medication. Patients with a hemodynamic stenosis had a higher frequency of recurrent ischemic stroke or TIA in the territory of the stenotic artery than those without a hemodynamic stenosis (61 versus 32 percent). By contrast, among patients in the SAMMPRIS trial with a 70 to 99 percent stenosis who had qualifying symptoms suggestive of hypoperfusion (same definition as above) and were assigned to the aggressive medical management group (n = 31), the two-year probability of an outcome event (ie, 30-day stroke and death and later strokes in the territory of the qualifying artery) was only 7 percent (95% CI 1.8-25.3) [50].

The observational VERITAS study analyzed hemodynamics for 72 patients with recent posterior circulation TIA or stroke and >50 percent atherosclerotic stenosis or occlusion of the vertebral and/or basilar arteries [60]. Low blood flow in these arteries, as determined by quantitative magnetic resonance angiography (QMRA), was associated with an increased risk for subsequent vertebrobasilar stroke (adjusted HR 11.55, 95% CI 1.88-71.00). By contrast, the MyRIAD observational cohort of 105 patients with 50 to 99 percent intracranial stenosis in either the anterior or posterior circulation did not show an association between low flow (as measured by QMRA and perfusion MRI) and recurrent infarcts [61]. Given that measures of hemodynamic stability (eg, clinical symptoms, perfusion or flow imaging) inconsistently predict ischemic risk, further research is needed to identify a more accurate biomarker that may be used to select patients at high risk due to hypoperfusion.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Occlusive carotid, aortic, renal, mesenteric, and peripheral atherosclerotic disease".)

SUMMARY AND RECOMMENDATIONS

●The initial treatment of acute stroke or transient ischemic attack (TIA) due to intracranial large artery atherosclerosis (ICAS) is similar to the treatment of acute ischemic stroke or TIA attributed to other mechanisms. An important aspect of the hyperacute phase of acute ischemic stroke management is the rapid determination of patients who are eligible for intravenous thrombolysis and mechanical thrombectomy. (See "Initial assessment and management of acute stroke" and "Approach to reperfusion therapy for acute ischemic stroke".)

●All patients with recent ischemic stroke or TIA attributed to an intracranial large artery stenosis should receive intensive medical therapy with antiplatelet therapy and strict control of vascular risk factors, including the use of antihypertensive agents, low density lipoprotein cholesterol (LDL-C) lowering therapy, physical activity, and other lifestyle modification (eg, smoking cessation, weight control, salt restriction, and a healthy diet). (See 'Our approach' above.)

●For patients with a recent (within 30 days) TIA or stroke attributed to atherosclerotic intracranial large artery stenosis of 70 to 99 percent, we suggest dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel (rather than aspirin monotherapy) for up to 90 days (Grade 2C). For patients with brain ischemia attributed to atherosclerotic intracranial large artery stenosis of 50 to 69 percent who have a low-risk TIA, defined by an ABCD² score <4, or a moderate to major ischemic stroke, defined by a National Institutes of Health Stroke Scale (NIHSS) score >5, we start treatment with aspirin alone. For patients with a high-risk TIA, defined by an ABCD² score ≥4, or minor ischemic stroke, defined by a NIHSS score ≤5, we begin with dual antiplatelet therapy (DAPT) for 21 days using aspirin plus clopidogrel rather than aspirin alone. For long-term stroke prevention (beyond the 21- or 90-day duration of DAPT), we treat with aspirin monotherapy. Clopidogrel monotherapy or the combination drug aspirin-extended-release dipyridamole are reasonable alternatives to aspirin but have not been specifically studied in ICAS. (See 'Antiplatelet therapy' above.)

●We treat all patients with hypertension with nonpharmacologic therapy (ie, salt restriction, adequate potassium intake, weight control, healthy diet, limited alcohol intake) and pharmacologic therapy. For patients with hypertension who have a stroke or TIA attributed to intracranial large artery stenosis of 50 to 99 percent, we suggest targeting a systolic blood pressure (SBP) of <140 mmHg rather than a lower target SBP (Grade 2C). (See 'Risk factor management' above.)

●For patients with TIA or ischemic stroke of atherosclerotic origin, including those with symptomatic ICAS, we use high-intensity statin therapy with atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily; we prefer the highest approved dose in most cases. We also target treatment to achieve a low-density lipoprotein cholesterol (LDL-C) level <70 mg/dL. (See 'Risk factor management' above and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

●For patients with recent (within 30 days) stroke or TIA attributed to intracranial large artery stenosis of 70 to 99 percent, we recommend against intracranial stenting because there is evidence of harm with higher rates of stroke or death compared with medical therapy alone (Grade 1B). (See 'Our approach' above and 'Stenting' above.)

●Although unproven, therapies of last resort for patients who have recurrent ischemic stroke due to ICAS despite maximal medical therapy include indirect bypass, endovascular stenting, or submaximal angioplasty. However, there are no comparative data from randomized trials to suggest these treatments provide benefit over medical therapy. (See 'Failure of medical therapy' above.)

●ICAS is associated with a high risk of recurrent stroke. Subgroups that may be at particularly high risk of stroke in the territory of the affected vessel include patients with clinically significant hemodynamic intracranial stenosis, patients with borderzone infarct pattern and impaired collateral flow, patients with severe (≥70 percent) intracranial stenosis, patients with recent ischemic symptoms, and women. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marc I Chimowitz, MD, and Cathy A Sila, MD, who contributed to earlier versions of this topic review.