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 [36]. 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 [37,41]. In contrast to SAMMPRIS and VISSIT, CASSISS excluded patients with perforator ischemic events in the basal ganglia, thalamus, and https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 11/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate 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 [41]. 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 [37]. 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 [39], 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 [42]. 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 [43,44]. Along those lines, another ICAS registry of patients treated with stenting or angioplasty who failed medical therapy or had with progressive stroke symptoms reported a 90-day ischemic stroke rate of 6.7 percent and 90-day mortality of 11.2 percent [45]. 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 [5,46,47]. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 12/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate 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 [48]. 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 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 13/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate 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 [49]: 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 [50]. 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 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 14/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate 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) [17]. (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 [51]. 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) [52]. Patients with recent ischemic symptoms [51]. 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) [52]. 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 [53]. 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) [54]. 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 [55]. https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 15/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate 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 [56]. 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) [47]. 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 [57]. 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 [58]. 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 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 16/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate 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".) 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). 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 2 an ABCD 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. 2 For patients with a high-risk TIA, defined by an ABCD 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.) https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 17/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate 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".) 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. 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Topic 1101 Version 41.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 23/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate GRAPHICS Stroke probability by stenosis Product-limit estimate of the cumulative probability of an ischemic stroke in the territory of the stenotic artery versus years after randomization, according to percent stenosis ( 70 percent stenosis shown as red solid line, <70 percent stenosis as blue dashed line); log- rank test P 0.0010. Reproduced with permission from Kasner, SE, Chimowitz, MI, Lynn, MJ, et al. Predictors of ischemic stroke in the territory of a symptomatic intracranial arterial stenosis. Circulation 2006; 113:555. Copyright 2006 Lippincott Williams & Wilkins. Graphic 73498 Version 1.0 https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 24/25 7/5/23, 11:54 AM Intracranial large artery atherosclerosis: Treatment and prognosis - UpToDate Contributor Disclosures Tanya N Turan, MD, MSCR No relevant financial relationship(s) with ineligible companies to disclose. Jose Gutierrez, MD, MPH No relevant financial relationship(s) with ineligible companies to disclose. Scott E Kasner, MD Grant/Research/Clinical Trial Support: Bayer [Stroke]; Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbvie [Stroke]; AstraZeneca [Stroke]; BMS [Stroke]; Diamedica [Stroke]; Medtronic [Stroke]. All of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant financial relationship(s) with ineligible companies to disclose. Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence. Conflict of interest policy https://www.uptodate.com/contents/intracranial-large-artery-atherosclerosis-treatment-and-prognosis/print 25/25