ARTICLE IN PRESS Concomitant Asymptomatic Intracranial Atherosclerotic Stenosis Increase the 30-Day Risk of Stroke in Patients Undergoing Symptomatic Intracranial Atherosclerotic Stenosis Stenting Jin Zhao, MD,*,† Xiaohui Li, MD,†,1 Lu-Xiang Chi, MD,*,1 Bing-Wu Ma, Yan-Hui Du, MS,‡ Gui-Sheng Chen, MD,‡ Hua-Dong Zhou, MD,§ Jing-Cheng Li, MD,§ Xiao-Jiang Jiang, MD,§ Qing-Wu Yang, MD,‖ Xiong-Fei Zhao,¶ and Xiao-Feng Yao, BM¶ MS,‡ Background: In the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial, 19.1% of ischemic strokes occurred out of the territory of previously symptomatic stenosis during the mean follow-up period of 23.4 months. However, it is unknown how many ischemic strokes were due to a previously asymptomatic intracranial atherosclerotic stenosis (ICAS). The objective of this study was to investigate whether the concomitant asymptomatic ICAS influences the outcome of patients undergoing symptomatic ICAS stenting. Methods: We retrospectively reviewed 576 consecutive patients with nondisabling ischemic stroke (modified Rankin scale score of ≤3) who were treated with symptomatic ICAS (≥70% stenosis) stenting with or without concomitant asymptomatic ICAS. The baseline characteristics and the 30-day primary end points (stroke or death after stenting) were compared by bivariate and multivariable logistic analyses. Results: The 30-day rate of primary end points was 5.2%, which was higher in patients with concomitant asymptomatic ICAS (≥50% stenosis) than in those without asymptomatic ICAS (no stenosis or <50% stenosis) (8.9% versus 3.8%, P = .014). In patients with concomitant asymptomatic ICAS, 25% of ischemic strokes occurred out of the territory of the stented artery, whereas in patients without asymptomatic ICAS, no ischemic stroke occurred out of the territory of the stented artery. Multivariable analysis showed that concomitant asymptomatic ICAS was an independent risk factor for 30-day stroke (odds ratio = 2.37, 95% From the *Department of Cardiology, Southwest Hospital; †Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Chongqing, China; ‡Department of Neurology, Affiliated Hospital of Ningxia Medical University, Yinchuan, China; §Department of Neurology, Daping Hospital; ‖Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing, China; and ¶Department of Neurology, Third Affiliated Hospital of Yanan University, Xianyang, China. Received July 4, 2017; revision received September 12, 2017; accepted September 20, 2017. Address correspondence to Xiaohui Li, MD, Center of Translational Medicine, College of Pharmacy, Third Military Medical University, Gaotanyan 35, Shapingba, Chongqing 400038, China. E-mail: email@example.com.; Address correspondence to Lu-Xiang Chi, MD, Department of Cardiology, Southwest Hospital, Third Military Medical University, Gaotanyan 30, Shapingba, Chongqing 400038, China. E-mail: firstname.lastname@example.org. 1 These authors contributed equally to this work. 1052-3057/$ - see front matter © 2017 Published by Elsevier Inc. on behalf of National Stroke Association. https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.09.032 Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2017: pp ■■–■■ 1 ARTICLE IN PRESS J. ZHAO ET AL. 2 confidence interval, 1.14-5.63; P = .023). Conclusions: Concomitant asymptomatic ICAS (≥50% stenosis) might increase the 30-day risk of stroke in patients undergoing symptomatic ICAS stenting. Key Words: Atherosclerosis—angioplasty— stroke—stent. © 2017 Published by Elsevier Inc. on behalf of National Stroke Association. Introduction Symptomatic intracranial atherosclerotic stenosis (ICAS) is one of the most common causes of stroke and is associated with a high risk of recurrent stroke.1 The recently published Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial2 pointed out that there was a higher risk of stenting for patients with symptomatic ICAS than of medical therapy. The occurrences of primary end points (any stroke or death) in the stent group versus the medical group was 14.7% versus 5.8% at day 30 (P = .0016), and 23% versus 15% during a median followup of 32.4 months (P = .0252). But even in the medical treatment group, the risk is high. When the perioperative strokes were excluded, the rates of subsequent ischemic strokes were almost the same in the 2 groups. Some registry studies of symptomatic ICAS stenting in China3-5 reported a relative lower 30-day rate of primary end points (2.0%-7.8%). This discrepancy might be caused by the different selection of patients and the different treatment methods between them. Further studies are necessary to define the appropriate patient selection and the best therapeutic approach for various patients. The SAMMPRIS trial did not exclude stenosis out of the territory of target intracranial lesion, and 19.1% ischemic strokes occurred out of the territory of the qualifying artery during the mean follow-up period of 23.4 months.2 The ongoing Registry Study of Stenting for Symptomatic Intracranial Artery Stenosis in China excluded more than 70% stenosis in other intracranial arteries than the culprit artery,6 and no ischemic stroke occurred out of the territory of the stented artery within 30 days after stenting.3 Although the Warfarin–Aspirin Symptomatic Intracranial Disease (WASID) trial pointed out that the previously asymptomatic ICAS was the most commonly identified cause of ischemic stroke that occurred out of the territory of the previously symptomatic ICAS.7 However, in the SAMMPRIS trial, patients with previously asymptomatic ICAS were not reported, so it is unknown how many ischemic strokes were due to previously asymptomatic ICAS. In the present study, we retrospectively analyzed 576 consecutive patients with nondisabling ischemic stroke who were treated with symptomatic ICAS stenting with or without concomitant asymptomatic ICAS to evaluate whether the concomitant asymptomatic ICAS influenced the 30-day outcomes of symptomatic ICAS stenting in a Chinese population. Methods Patients Under the approval of the institutional review board of each institution, we retrospectively reviewed the stroke databases of 5 participating institutions. Each institution had at least 100 intracranial stenting per year. Between October 2012 and February 2016, 576 consecutive patients with nondisabling ischemic stroke (modified Rankin scale score of ≤3) who were treated with symptomatic ICAS (≥70% stenosis) stenting with or without concomitant asymptomatic ICAS were selected. Ischemic stroke is defined as a new focal neurological deficit of sudden onset, lasting at least 24 hours, which is not caused by hemorrhage as shown on computed tomography (CT) or magnetic resonance imaging (MRI) of the brain. Symptomatic ICAS was defined as ICAS where the current neurological signs were related to the area of the brain supplied by it. Asymptomatic ICAS was defined as stenosis that had no relation to the current neurological signs and had no old visible infarction in neuroimaging in its respective vascular territory.8 The degree of stenosis was calculated according to the WASID technique.9 According to the criteria used in the SAMMPRIS trial10,11 we included patients who had a nondisabling ischemic stroke within the past 30 days, which were attributable to the 70%-99% atherosclerotic stenosis of 1 major intracranial arteries (intracranial internal carotid artery, middle cerebral artery [MCA] stem [M1], intracranial vertebral artery [VA], or basilar artery [BA]) confirmed by catheter angiography. Patients were excluded if they were over 75 years of age and had an acute ischemic stroke within 7 days; other strokes out of the territory of the symptomatic ICAS; a stroke caused by BA or MCA stenosis at the site of the origin of the perforator; more than 50% tandem ICAS that was proximal or distal to the target intracranial lesion; more than 50% bilateral intracranial VA stenosis; an uncertainty about which artery was symptomatic; an intracranial artery occlusion; more than 50% stenosis of an extracranial carotid artery or an extracranial VA; severe vessel tortuosity that precluded the deployment of endovascular devices; a stenosis greater than 15 mm in length or less than 2 mm in diameter; ARTICLE IN PRESS RISK OF 30-DAY STROKE OF SYMPTOMATIC ICAS STENTING uncontrolled hypertension (systolic >180 mm Hg or diastolic >115 mm Hg); the presence of other potentially embolic diseases; nonatherosclerotic causes of intracranial stenosis; and a known allergy or contraindication to heparin, aspirin, clopidogrel, anesthetics, or contrast agents. Procedure The procedure was performed as we and others described previously.3,12 A combination of aspirin (325 mg/d) and clopidogrel (75 mg/d) was started 3 days before the procedure or a loading dose of 300 mg clopidogrel could be administered at least 4 hours before the procedure. Patients were heparinized with a target activated clotting time of 225-300 seconds. The procedure was performed under local anesthesia and conscious sedation, via a transfemoral approach with a 6F guiding catheter. The stent diameter was undersized with a stent-to-normal vessel ratio of .9:1.0. For patients with smooth arterial access, a Mori A lesion, or mid-BA and distal M1 segment lesions, a balloon-expandable stent (Apollo stent; Minimally Invasive, Shanghai, China) was selected, and the length of the stent was chosen just to cover the stenosis. For patients with a tortuous arterial access, a Mori B lesion, a Mori C lesion, or a lesion with a significant mismatch in the diameter between the proximal and the distal segments, a self-expanding stent (Gateway balloon plus Wingspan stent system; Stryker, Maple Grove, MN) was preferred, and the length of the stent was chosen to cover at least 2 mm of normal vessel segment on both sides of the stenosis. Successful revascularization was defined as the reduction of stenosis to less than 50% with complete enveloping of the lesion after the procedure. Medical management included aspirin 100 mg/d, clopidogrel 75 mg/d for 90 days, and atorvastatin 40 mg/d for at least 6 months after stenting. We targeted a systolic blood pressure lower than 140 mm Hg (<130 mm Hg if diabetic), a low-density lipoprotein cholesterol level lower than 1.81 mmol/L, a fasting blood glucose level lower than 6.1 mmol/L, and a hemoglobin A1c level less than 7%. Lifestyle modifications such as smoking cessation, weight reduction, and physical exercise were advised. Follow-Up The patients were asked to come back for a face-toface interview 30 days after stenting by experienced neurointerventionalists for clinical assessment and evaluation of neurological symptoms. The primary end points were stroke (including ischemic or hemorrhagic stroke) or death. Hemorrhagic stroke was defined as parenchymal hemorrhage, subarachnoid hemorrhage, or intraventricular hemorrhage detected by CT or MRI, associated with seizures or new neurological symptoms or signs (headache, change in the level of consciousness, or focal neurological deficits) lasting 24 hours or longer. Every patient with a suspected stroke underwent brain MRI or 3 CT. Ischemic strokes were classified as in or out of the territory of the stented artery. Medical records, brain CT or MRI, digital subtraction angiography, and follow-up data of each patient were collected and revalued by 2 experienced neurointerventionalists who did not participate in the procedure and were unaware of the research. Consensus from disagreements was reached through discussion. Statistical Analysis The occurrences of 30-day stroke in different groups were compared by chi-square test or Fisher exact test. A similar bivariate analysis was performed between the baseline characteristics and 30-day stroke. Stepwise logistic regression analysis was used to assess the relationship between 30-day stroke and baseline characteristics. A multivariable model was constructed using the backward elimination method. Candidate risk factors for multivariable analysis were those with P values of less than .20 in the bivariate analyses described above. A 2-tailed P value of less than .05 was considered to be statistically significant. Statistical analyses were performed using IBM SPSS (version 20; IBM, Armonk, NY). Results The baseline characteristics of the 576 patients are summarized in Table 1 . The mean age was 55 years, and 358 patients (62.2%) were male. The prevalence of vascular risk factors was 67.7%, 62.5%, 42.7%, and 42.7% for hypertension, diabetes mellitus, hyperlipidemia, and smoking history, respectively. The symptomatic ICAS was located in the intracranial internal carotid artery in 241 patients (41.8%), in the MCA in 130 patients (22.6%), in the intracranial VA in 148 patients (25.7%), and in the BA in 57 patients (9.9%). The patients with a concomitant asymptomatic ICAS of less than 25% stenosis, 25%50% stenosis, 50%-75% stenosis, and 75%-99% stenosis were 47 (8.2%), 40 (6.9%), 120 (20.8%), and 37 (6.4%), respectively. The median time from the qualifying event to endovascular treatment was 13 days. Successful revascularization was achieved in all patients. All patients had a 30-day follow-up. The occurrences of 30-day primary end points in different groups are shown in Table 2 . In patients without asymptomatic ICAS or with a concomitant asymptomatic ICAS of less than 50% stenosis, no ischemic stroke occurred out of the territory of the stented artery. In patients with a concomitant asymptomatic ICAS of 50% stenosis or higher, 9 patients (5.7%) had an ischemic stroke in the territory of the stented artery, 3 patients (1.9%) had an ischemic stroke in the territory of a previously asymptomatic ICAS (i.e., 25% ischemic strokes occurred out of the territory of the stented artery). All hemorrhage strokes occurred in the territory of the stented artery. No death was found. ARTICLE IN PRESS J. ZHAO ET AL. 4 Table 1. Baseline characteristics Patients (N = 576) Characteristic Age (y) Male Hypertension Hyperlipidemia Diabetes mellitus Coronary artery disease Smoking history Absence of statin use before stroke Days from stroke to stenting Symptomatic ICAS location Intracranial ICA MCA Intracranial VA BA Mori classification of symptomatic ICAS Mori A Mori B Mori C Type of stent Balloon-expandable stent Self-expanding stent Concomitant asymptomatic ICAS Patients with concomitant asymptomatic ICAS of less than 25% stenosis Patients with concomitant asymptomatic ICAS of 25%-50% stenosis Patients with concomitant asymptomatic ICAS of 50%-75% stenosis Patients with concomitant asymptomatic ICAS of 75%-99% stenosis 55.1 (10.4) 358 (62.2) 390 (67.7) 360 (62.5) 246 (42.7) 69 (12.0) 246 (42.7) 342 (59.4) 13 (9-15) 241 (41.8) 130 (22.6) 148 (25.7) 57 (9.9) 178 (30.9) 289 (50.2) 109 (18.9) 379 (65.8) 197 (34.2) 244 (42.4) 47 (8.2) 40 (6.9) 120 (20.8) 37 (6.4) Abbreviations: BA, basilar artery; ICA, internal carotid artery; ICAS, intracranial atherosclerotic stenosis; MCA, middle cerebral artery; VA, vertebral artery. Values are mean ± standard deviation, n (%), or median (interquartile range). Table 3 shows that patients with a concomitant asymptomatic ICAS of 50%-75% stenosis had more 30day strokes than those without asymptomatic ICAS (8.3% versus 3.6%, P = .040). Due to the trends shown in Table 3 and the criteria used in the post hoc analyses of the WASID trial,13,14 we then divided the patients into 2 groups: patients without asymptomatic ICAS (no stenosis or <50% stenosis) and patients with concomitant asymptomatic ICAS (≥50% stenosis). Bivariate analysis (Table 4 ) revealed that diabetes mellitus (7.3% versus 3.6%, P = .049) and concomitant asymptomatic ICAS (≥50% stenosis) (8.9% versus 3.8%, P = .014) were related to a higher rate of 30-day stroke. These factors were included in a multivariable analysis, as well as coronary artery disease (P = .075) and absence of statin use before stroke (P = .110). The statistically significant factors identified for the final model were diabetes mellitus (odds ratio [OR] = 2.13, 95% confidence interval [CI], 1.06-4.62; P = .037), the absence of statin use during stroke (OR = 1.97, 95% CI, 1.03-4.58; P = .043), and a concomitant asymptomatic ICAS (OR = 2.35, 95% CI, 1.135.48; P = .019) (Table 5 ). After adjusting for diabetes mellitus and the absence of statin use before stroke, concomitant asymptomatic ICAS was independently associated with 30-day stroke (OR = 2.37, 95% CI, 1.14-5.63; P = .023). Discussion In the present study, the 30-day rate of primary end points was 5.2% (3.8% in patients without asymptomatic ICAS [no stenosis or <50% stenosis] versus 8.9% in patients with concomitant asymptomatic ICAS [≥50% stenosis]), which was lower than that reported in the stent group of the SAMMPRIS trial (14.7%), but was similar to some ongoing registry studies of symptomatic ICAS stenting in China (2.0%-7.8%).3-5 Concomitant asymptomatic ICAS (≥50% stenosis) was an independent risk factor for 30-day stroke (OR = 2.37, 95% CI, 1.14-5.63; P = .023). Table 2. Primary end points within 30 days after stenting Patients with concomitant asymptomatic ICAS 30-d primary end points Ischemic stroke in the territory of previously symptomatic ICAS Ischemic stroke in other territory Hemorrhage stroke Death Patients without asymptomatic ICAS (n = 332) Less than 25% stenosis (n = 47) 25%-50% Stenosis (n = 40) 50%-75% Stenosis (n = 120) 75%-99% Stenosis (n = 37) 12 12 2 1 2 2 10 7 4 2 0 0 0 0 1 0 0 0 0 2 1 0 1 1 0 Abbreviation: ICAS, intracranial atherosclerotic stenosis. Values are n (%). ARTICLE IN PRESS RISK OF 30-DAY STROKE OF SYMPTOMATIC ICAS STENTING 5 Table 3. The occurrences of 30-day stroke in different groups Patients without asymptomatic ICAS Patients with concomitant asymptomatic ICAS of less than 25% stenosis Patients with concomitant asymptomatic ICAS of 25-50% stenosis Patients with concomitant asymptomatic ICAS of 50-75% stenosis Patients with concomitant asymptomatic ICAS of 75-99% stenosis Patients without 30-d stroke Patients with 30-d stroke P Value 320 (96.4) 45 (95.7) 38 (95) 110 (91.7) 33 (89.2) 12 (3.6) 2 (4.3) 2 (5.0) 10 (8.3) 4 (10.8) Ref .688 .654 .040 .065 Abbreviations: ICAS, intracranial atherosclerotic stenosis; Ref, reference. Values are n (%). Several reasons might contribute to the relatively low primary end point rates in the present study. First, the median time from the qualifying event to the stent treatment was 13 days in our study, which was different from the SAMMPRIS trial (7 days) and the ongoing Registry Study of Stenting for Symptomatic Intracranial Artery Stenosis in China (21 days). Exclusion of patients with a recent ischemic stroke may exclude those patients with a high risk of ischemic event recurrence, and therefore, the benefit of stent placement to reduce the stroke recurrence may also be diminished. Second, we excluded patients whose stroke was caused by BA or MCA stenosis at the site of origin of the perforator. Crushing the atherosclerotic plaque by balloon or stent may send debris or thrombus into these perforators or may cause a mechanical obstruction of these perforators, and excessively twisting or tearing perforators by balloon may cause intracranial hemorrhage.15 Third, both balloon-mounted stents and self-expanding stents were used in our study. A self-expanding stent has lower radial force and is less apt at achieving good revascularization in calcified lesions, whereas a balloonmounted stent is more rigid and is difficult to navigate along tortuous vessels. Selection of the suitable stent might get the most advantages. In our study, 25% ischemic stroke occurred out of the territory of the stented artery in patients with concomitant asymptomatic ICAS (≥50% stenosis), and no ischemic stroke occurred out of the territory of the stented artery in patients without asymptomatic ICAS (no stenosis or <50% stenosis) within 30 days after symptomatic ICAS stenting. The China Interventional Stroke Registry (CISR) reported that 23.5% ischemic strokes occurred out of the territory of the stented artery within 30 days after symptomatic ICAS stenting.5 In a review of 2196 patients treated with ICAS stenting for 2314 lesions, the median rates of ischemic events in any territory and ipsilateral ischemic events were 9.4% (range 0%-25%) and 5.4% (range 0%13.7%), respectively, over a median or mean follow-up period ranging from 1 to 67 months.16 The variations in ischemic stroke that occurred out of the territory of the stented artery might be due to the different characteristics of the patients and the different follow-up period. Our study pointed out that the concomitant asymptomatic ICAS (≥50% stenosis) was an independent risk factor for 30-day stroke. This finding could be explained by asymptomatic ICAS activation or progression. Stresses such as physical trauma and inflammation may trigger platelet aggregation, plaque erosion, or rupture in patients with severe atherosclerosis in the cervical and cranial vessels.17 Chronic cerebral hypoperfusion secondary to asymptomatic ICAS progression may confer risk of stroke14 because of a potential disruption of the cerebral autoregulation or of a decreased washout of small emboli.18 Histopathological studies also demonstrated that the fibrous cap of plaques within the intracranial artery was thicker than that of plaques within the coronary and carotid arteries,19-22 combined with the reduced expression of inhibitors of inflammation, 23 the prominent expression of proinflammatory proteasomes,24 and the absence of an external elastic lamina,25 which make it more susceptible to inflammatory changes and plaque instability. Our study concluded that concomitant asymptomatic ICAS (≥50% stenosis) is a risk factor for 30-day stroke in patients undergoing symptomatic ICAS stenting. However, in patients undergoing symptomatic ICAS stenting, there is not enough evidence to stent for the concomitant asymptomatic ICAS. Should these patients not be offered stenting, should the asymptomatic lesions be treated with stent concurrently, or is this just a risk factor for symptomatic ICAS stenting? Further studies should be done to answer these questions. Our study has several limitations. First, our study was a retrospective study and only the 30-day primary end points were examined. Prospective trials with a large population and long follow-up should be done to test the conclusion. Second, patients with transient ischemic attack were not taken into consideration because sometimes it is difficult to distinguish which ICAS was symptomatic. Conclusions In the present study, we retrospectively reviewed 576 consecutive patients with nondisabling ischemic stroke who were treated with symptomatic ICAS stenting with ARTICLE IN PRESS J. ZHAO ET AL. 6 Table 4. Bivariate analyses of baseline characteristics versus the occurrences of 30-day stroke Overall Age ≥55 y <55 y Sex Male Female Hypertension Yes No Hyperlipidemia Yes No Diabetes mellitus Yes No Coronary artery disease Yes No Smoking history Yes No Absence of statin use before stroke Yes No Days from stroke to stenting 13 d or more Less than 13 d Symptomatic artery location Anterior artery Posterior artery Mori type of symptomatic ICAS Mori C type Other types Stent type Self-expanding stent Balloon-expandable stent Concomitant asymptomatic ICAS (≥50% stenosis) With Without Patients with events Table 5. Multivariate logistic regression results for the risk factors associated with 30-day stroke OR (95% CI) P Value 2.13 (1.06-4.62) 1.97 (1.03-4.58) .037 .043 2.35 (1.13-5.48) .019 P Value 311 265 17 (5.5) 13 (4.9) .763 358 218 20 (5.6) 10 (4.6) .601 390 186 23 (5.9) 7 (3.8) .281 360 216 21 (5.8) 9 (4.2) .383 246 330 18 (7.3) 12 (3.6) .049 Diabetes mellitus Absence of statin use before stroke Concomitant asymptomatic ICAS (≥50% stenosis) Abbreviations: CI, confidence interval; ICAS, intracranial atherosclerotic stenosis; OR, odds ratio. 69 507 7 (10.1) 23 (4.5) .075 246 330 16 (6.5) 14 (4.2) .227 342 234 22 (6.4) 8 (3.4) .110 291 285 14 (4.8) 16 (5.6) .665 371 205 18 (4.8) 12 (5.9) .604 109 467 7 (6.4) 23 (4.9) .527 197 379 11 (5.6) 19 (5.0) .770 157 419 14 (8.9) 16 (3.8) .014 Abbreviation: ICAS, intracranial atherosclerotic stenosis. Values are n (%). or without concomitant asymptomatic ICAS. 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