Prospective Registry of Carotid Artery Stenting in Japan—Investigation on Device and Antiplatelet for Carotid Artery Stenting Nobuyuki Sakai, MD,* Hiroshi Yamagami, MD,† Yoshihiro Matsubara, PhD,‡ Masayuki Ezura, MD,x Akio Hyodo, MD,k Yuji Matsumaru, MD,{ Shigeru Miyachi, MD,# Yasushi Okada, MD,** Tomoaki Terada, MD,†† Hiroyoshi Yokoi, MD,‡‡ Mitusugu Nakamura, MD,xx Yasushi Matsumoto, MD,kk Chiaki Sakai, MD,{{ and for the IDEALCAST Investigators

Background: Carotid artery stenting (CAS) is minimally invasive but may cause perioperative cerebral infarction associated with distal embolization. We conducted a multicenter prospective observational study on the onset of vascular events after CAS to find out the efficacy and safety of CAS in Japan and to investigate the effects of antiplatelet drugs administered before and after CAS on efficacy and safety of CAS. Methods: A total of 949 patients with cervical carotid artery stenosis were enrolled at 43 institutions in Japan; 934 who had undergone CAS with antiplatelet drugs and followed for 1 year were analyzed. Primary end point was the incidence of the first event of death, ischemic stroke, hemorrhagic stroke, transient ischemic attack, myocardial infarction, or serious hemorrhage within 1 year after enrollment. Comparison of the incidences of events according to antiplatelet drugs was also conducted. Results: The primary end point was observed in 69 patients (7.4%) within 30 days of enrollment and in 40 patients (4.3%) between 31 days and 1 year after enrollment. The incidence of the first event for aspirin 1 cilostazol was significantly lower than that for aspirin 1 clopidogrel (P 5.01), aspirin 1 clopidogrel 1 cilostazol (P 5 .01), and antiplatelet monotherapy (P , .01). Patient age (P 5 .01), presence of ischemic cerebrovascular disease (P 5 .02), presence of antidiabetic drugs (P , .01), femoral artery puncture (P 5 .02), guiding catheter used (P 5 .02), and Angioguard XP used (P 5 .01) were also correlated with the primary end point. Conclusion: Incidences of the primary end point within 30 days and 1 year of enrollment were comparable with previous reports, suggesting that CAS is a useful alternative for carotid endarterectomy in carotid stenosis patients with high risk for carotid endarterec-

From the *Department of Neurosurgery and KCGH Comprehensive Stroke Center, Kobe City Medical Center General Hospital, Kobe; †Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center, Suita; ‡Department of Statistical Analysis, Translational Research Informatics Center, Kobe; xDepartment of Neurosurgery, Sendai Medical Center, Sendai; kDepartment of Neurosurgery, Dokkyo Medical University Koshigaya Hospital, Koshigaya; {Department of Neuroendovascular Therapy, Toranomon Hospital, Tokyo; #Department of Neurosurgery, Nagoya University, Nagoya; **Department of Stroke Neurology, Kyushu Medical Center, Fukuoka; ††Department of Neurosurgery, Wakayama Rosai Hospital, Wakayama; ‡‡Department of Cardiology, Kokura Memorial Hospital, Kitakyushu; xxDepartment of Neurosurgery, Hyogo Brain and Heart Center at Himeji, Himeji; kkDepartment of Intravascular Neurosurgery, Konan Hospital, Sendai; and

{{Division of Neuroendovascular Therapy, Institute of Biomedical Research and Innovation, Kobe. Received May 8, 2013; revision received October 22, 2013; accepted November 20, 2013. Grant support: This study was supported by Sanofi-aventis Co. Ltd. Address correspondence to Nobuyuki Sakai, MD, DMSc, Department of Neurosurgery and KCGH Comprehensive Stroke Center, Kobe City Medical Center General Hospital, Kobe City Hospital Organization, 2-1-1 Minatojima-Minamimachi, Chuo-ku, Kobe 6500047, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2013 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2013.11.018

Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2013: pp 1-11

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2 tomy. Further randomized controlled studies are needed to determine whether differences in mechanism of action of antiplatelet drugs might have contributed to the results of the present study. Key Words: Carotid artery stenosis—stenting— antiplatelet—adverse event. Ó 2013 by National Stroke Association

Introduction Carotid stenosis is a major cause of ischemic cerebrovascular disease. Carotid endarterectomy (CEA) has been established as a useful therapy more effective than pharmacologic treatment in prevention of ischemic cerebrovascular diseases.1 Carotid artery stenting (CAS) has recently become widely performed as a less invasive treatment and has been reported to be as effective as CEA in prevention of cerebral infarction in patients at high risk for perioperative complications for CEA.2 Based on such clinical evidence, relevant guidelines in Japan and the US recommend CAS in patients with high risk for cerebrovascular diseases.3,4 In Japan, stent placement has been conducted in full scale for treatment of carotid stenosis since the 1990s. Precise (Johnson & Johnson K.K., Tokyo, Japan), a carotid artery stent, and Angioguard XP (Johnson & Johnson K.K.), a distal embolic protection filer, have been approved since September 2007 and have been subject to Japanese National Health Insurance coverage since April 2008. CEA is more difficult to perform in Japanese population compared with Western population because the carotid artery bifurcation is located higher in the Japanese.5 Thus, its usefulness anticipated, CAS was performed in 5755 cases and CEA in 3440 cases in 2010.6 However, some reports suggest that CAS is inferior to CEA,7,8 and others fail to prove the noninferiority of CAS to CEA,9 warranting further investigation of usefulness of CAS in various populations. CAS is minimally invasive but may cause perioperative cerebral infarction associated with distal embolization, by displacing atherosclerotic lesions and expanding the intravascular lumen. Also, inserting a foreign material into an artery may cause subacute thrombosis or postoperative thromboembolism. To prevent these perioperative complications, at least 2 antiplatelet drugs, with aspirin as a basic drug, are often used before and after CAS. However, there are no reports regarding the efficacy or safety of antiplatelet drugs with CAS, and which antiplatelet drugs are useful remains unclear. We conducted a multicenter prospective observation study on the onset of vascular events after CAS, the Investigation on Device and Anti-platelet for Carotid Artery Stenting, to find out the efficacy and safety of CAS in Japan and to investigate the effects of antiplatelet drugs administered before and after CAS on efficacy and safety of CAS.

Materials and Methods This study was a multicenter, prospective observational study to investigate the current status and safety of CAS in combination with antiplatelet drugs in 43 institutions in Japan highly experienced with CAS (Appendix). Patients were enrolled between June 2008 and June 2010 and followed with observation for 1 year after enrollment. Inclusion criteria were as follows: (1) CAS was scheduled to be performed for carotid arteriosclerosis or restenosis within 7 days of enrollment; (2) with symptomatic carotid stenosis ($50%) or asymptomatic carotid stenosis ($80%) defined by ultrasonography or angiography; (3) meeting the definition of CEA high risks; (4) oral antiplatelet drugs could be used; (5) life prognosis expected to be 1 year or longer; (6) modified Rankin scale grade 0, 1, 2, or 3, and (7) written consent to participate in this study was obtained. Carotid stenosis rate was measured using the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method when defined by angiography, or when defined by ultrasonography, peak systolic velocity (PSV) at a stenotic site surpassing 150 cm/s and 230 cm/s were diagnosed as the carotid stenosis exceeding 50% and 80%, respectively. Exclusion criteria were as follows: (1) incidence of ischemic stroke within 48 hours before enrollment; (2) incidence of hemorrhagic stroke within 90 days before enrollment; (3) intraluminal thrombus was observed in the target artery; (4) target artery completely occluded; (5) likely to be difficult to place a guiding catheter because of stenosis in the origin of common carotid artery on the treatment side or the brachiocephalic artery; (6) surgery or intravascular treatment scheduled to be performed for intracranial disease within 30 days of enrollment; (7) another invasive treatment was scheduled to be performed within 30 days of enrollment; and (8) the principal investigator or subinvestigator considered that participation in this study was not reasonable for other reasons. The following patient characteristics were checked before CAS: age, sex, body height, body weight, blood pressure (supine position), electrocardiogram, modified Rankin scale, laboratory tests (C-reactive protein, fasting blood glucose level, total cholesterol, triglyceride, highdensity lipoprotein cholesterol, creatinine, aspartate aminotransferase, alanine aminotransferase, white blood cell count, red blood cell count, hemoglobin, and platelet count), history of diabetes, dyslipidemia, hypertension,

IDEALCAST—PROSPECTIVE REGISTRY

smoking habit, and ischemic cerebrovascular diseases (symptomatic cerebral infarction and transient ischemic attack [TIA]), history of ischemic cerebrovascular diseases at the target artery (symptomatic cerebral infarction, ischemic retinopathy, and TIA), history of myocardial infarction/angina pectoris, history of surgery (percutaneous transluminal angioplasty [PTA], CEA, coronary artery bypass grafting, and coronary angiography/stenting), and medication (antiplatelet drugs [aspirin, clopidogrel, cilostazol, and others], anticoagulants, lipid-lowering drugs, antihypertensives, and antidiabetics). Medication status was checked 30 days and 1 year after enrollment. Regarding CAS-related information, the anesthetic method, puncture site, devices/techniques used (guiding system, embolic protection devices, stents, PTA, and aspiration devices) were examined. The target artery was investigated immediately before CAS, immediately after CAS, and at 1 year after enrollment by measuring the stenosis rate using the NASCET method or European Carotid Surgery Trial method or using PSV. Primary end point was the incidence of the first event of the following within 1 year of enrollment: death, ischemic stroke, hemorrhagic stroke, TIA, myocardial infarction (excluding non–Q-wave myocardial infarction), or serious hemorrhage (excluding hemorrhagic stroke). Secondary end points were the overall survival period, incidences of the following events within 30 days and 1 year of enrollment: death and vascular events (ischemic stroke, ipsilateral ischemic stroke, hemorrhagic stroke, TIA, myocardial infarction [excluding non–Q-wave myocardial infarction], or serious hemorrhage [excluding hemorrhagic stroke]) and retreatment of the target artery, such as CEA, intracranial bypass, carotid PTA, or stenting, within 30 days and 1 year of enrollment. For safety assessment, CAS-associated events and adverse drug reactions caused by antiplatelet drugs within 30 days and 1 year of enrollment were investigated. CAS-associated events were perioperative symptomatic embolism, branch artery occlusion, cholesterol embolization syndrome, hyperperfusion syndrome, and puncture site injury. Adverse drug reactions caused by antiplatelet drugs were events that required discontinuation or changes of medications because of rash, hematopathy, hepatopathy, gastrointestinal injury, and palpitations/tachycardia/headache. To ensure the quality of data, source document verification (SDV) was performed in randomly selected 10% of the medical institutions participating in this study (6% at 30 days after enrollment and 4% during follow-up) by directly visiting them. All personnel involved in this study performed their tasks in compliance with the Declaration of Helsinki and Ethical Guidelines for Clinical Research issued by the Ministry of Health, Labor, and Welfare. The principal investigator or subinvestigator fully explained to patients about this study in conjunction with an explanatory

3

document and obtained written voluntary consent to participate from patients.

Statistical Analysis Based on our experience of CAS preceding the present study, the incidence of the first event within 1 year of enrollment (primary end point) was estimated to be approximately 12%; 1015 subjects were necessary to calculate the 95% confidence interval (CI) of the primary end point with an accuracy of less than 62%, thus was set as a target number of participants. To compare distribution ratios, a chi-square test was applied. The period between enrollment and the onset of the first event was referred to as an event-free period. To detect factors affecting the onset of the first event, Cox proportional hazards model was applied. The level of significance (a) was set to .05.

Results A total of 949 patients were enrolled, and 934 were subjected to analysis. Twelve patients were excluded because no CAS was performed and 3 were excluded because no CAS data were entered (Fig 1). The patient characteristics are shown in Table 1. High-risk patients for CEA included 353 patients (37.8%) who were of 75 years or older, 191 patients (20.6%) who had carotid stenosis either in the bifurcation of the second cervical vertebra (high position) or under the clavicle (low position), 169 patients (18.1%) who were unlikely to be tolerant to systemic anesthesia, and 225 patients (24.1%) who were judged at high risk for CEA by the attending physicians. Number of CEA during this study at involved centers was not recorded because treatment decision for revascularization of carotid diseases was different in each center. Of the 934 patients subjected to analysis, 594 patients (63.6%) had a history of ischemic cerebrovascular disease, including 494 (52.9%) who had symptomatic carotid stenosis and a history of ischemic cerebrovascular disease (symptomatic cerebral infarction, TIA, or ischemic retinopathy). In 424 (71.4%) of these 594 patients, ischemic cardiovascular disease had occurred in the previous 6 months. Medications used before CAS are shown in Table 2. CAS was performed within 7 days of enrollment in 929 patients (99.5%) and 7 days after enrollment in 5 patients (.5%). The mean number of days between enrollment and CAS was 1.3 days. Systemic anesthesia was used in 91 patients (9.7%), local anesthesia in 837 (89.6%), and sedative drugs in 26 patients (2.8%). The puncture site was the femoral artery in 893 patients (95.6%) accounting for a major site, artery in the upper arm in 33 (3.5%), common carotid artery in 7 (.8%), and others in 1 patient (.1%). The devices/techniques used were a guiding catheter in 611 patients (65.4%), a long sheath in 327 (35.0%), and direct carotid puncturing in 4 patients (.4%). The devices used for embolism prevention were Angioguard XP in 724 patients

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Figure 1. Number of patients registered and included in analysis. Abbreviations: CAS, carotid artery stenting; CEA, carotid endarterectomy; PTA, percutaneous transluminal angioplasty.

(77.5%), others in 286 (30.6%), and nothing in 1 patient (.1%). The stents used were Precise Carotid Stent in 913 patients (97.7%), others in 22 (2.4%), and nothing in 1 patient (.1%). The stenosis rate measured using the NASCET method significantly lowered from 80.3% immediately before CAS to 12.0% immediately after CAS (P , .01) and 12.8% at 1 year after enrollment (P , .01). The stenosis rate measured using the European Carotid Surgery Trial method also significantly lowered, from 80.1% to 15.0% (P , .01) and 16.5% (P , .01), respectively. The PSV significantly improved from 302.3 cm/s to 77.8 cm/s (P , .01) and 79.2 cm/s (P , .01), respectively. Antiplatelet drugs were used continuously after CAS in 926 patients (99.1%): aspirin in 856 patients (91.7%), clopidogrel in 700 (75.0%), cilostazol in 428 (45.8%), and others in 98 patients (10.5%). The continuous use rate of antiplatelet drugs immediately after CAS and 1 year after CAS (or on the final observation) was 99.2% and 71.6%, respectively, for aspirin, 98.8% and 71.0% for clopidogrel, 99.7% and 62.7% for cilostazol, and 100% and 79.8% for others. The results of the primary end point are shown in Table 3. The first event was observed in 69 patients (7.4%) within 30 days of enrollment, in 40 patients (4.3%) between 31 days and 1 year after enrollment, and in 109 patients (11.7%) throughout the observation period. The incidence of first event tended to be higher in the

asymptomatic stenosis patients than in the symptomatic stenosis patients (Table 4). Within 30 days of enrollment, 4 patients (.4%) died of hemorrhagic stroke (2 patients), myocardial infarction (1 patient), and other cause (1 patient) and 68 patients (7.3%) developed vascular events. During the observation period, 24 patients (2.6%) died and 94 patients (10.1%) developed vascular events. Retreatment of the artery treated with CAS was provided to 8 patients (.9%) within 30 days of enrollment and to 14 patients (1.5%) during the observation period. There were no patients who underwent CEA during the study period. The overall survival rate (secondary end point) was 99.6% (95% CI, 98.9-99.8) at 30 days after enrollment and 97.3% (95% CI, 95.9-98.2) at 1 year after enrollment. CAS-associated events observed during CAS were symptomatic embolism in 38 patients (4.1%) and branch artery occlusion (only cases revealed by imaging during operation) in 7 patients (.8%). CAS-associated events observed during the observation period were cholesterol embolization syndrome in 6 patients (.6%), hyperperfusion syndrome in 14 (1.5%), and puncture site injury in 16 patients (1.7%). Other CAS-associated events were observed in 20 patients (2.1%). The following adverse drug reactions caused by antiplatelet drugs were seen in 34 patients (3.6%) during the

IDEALCAST—PROSPECTIVE REGISTRY

5

Table 1. Baseline characteristics of patients Demographic data

Mean, SD

Age, y Male, n (%) Body height, cm Body weight, kg BMI Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg

72.4 6 7.0 818 (87.6) 161.1 6 7.1 60.4 6 9.3 23.2 6 3.0 132.2 6 16.7 72.2 6 11.7

Number of patients according to the number of risk factors for CEA, n (%)* 1 2 3 4 5

676 (72.4) 209 (22.4) 41 (4.4) 7 (.8) 1 (.1)

Electrocardiography, n (%) Normal Abnormal Atrial fibrillation Left ventricular hypertrophy Others

616 (66.0) 318 (34.1) 57 (6.1) 92 (9.9) 190 (20.3)

Blood test

n

Mean, SD

CRP, mg/dL Fasting blood glucose, mg/dL T-cho, mg/dL TG, mg/dL HDL-cho, mg/dL Cre, mg/dL AST, IU/L ALT, IU/L WBC, /mL RBC, 3104/mL Hb, g/dL PLT, 3104/mL

812 852 836 853 799 925 925 924 923 924 924 924

.45 6 1.2 119.8 6 40.8 172.6 6 34.4 128.3 6 73.0 48.6 6 13.6 1.1 6 .8 23.2 6 11.8 21.7 6 16.4 6313.1 6 1801.9 413.0 6 51.4 12.9 6 1.6 21.3 6 6.2

Current/history of complications, n (%) Lifestyle-related diseases Diabetes mellitus Dyslipidemia Hypertension Smoking History of ischemic cerebrovascular disease Symptomatic cerebral infarction Target artery Excluding target artery TIA Target artery Excluding target artery

899 (96.3) 444 (47.6) 531 (56.9) 795 (85.1) 236 (25.3) 594 (63.6)

327 (35.0) 120 (12.9) 134 (14.4) 24 (2.6) (Continued )

Table 1. (Continued ) Current/history of complications, n (%) Ischemic retinopathy Last onset day ,4 wk before enrollment ,24 wk before enrollment ,48 wk before enrollment $48 wk before enrollment Other medical histories (myocardial infarction and angina pectoris) Myocardial infarction Angina pectoris History of revascularization Carotid PTA CEA CABG PCI

80 (8.6) 116 (12.4) 308 (33.0) 55 (5.9) 113 (12.1) 333 (35.7)

150 (16.1) 218 (23.3) 343 (36.7) 33 (3.5) 41 (4.4) 83 (8.9) 220 (23.6)

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CABG, coronary artery bypass graft; CEA, carotid endarterectomy; CRP, C-reactive protein; Hb, hemoglobin; HDL-cho, high-density lipoprotein cholesterol; Cre, creatinine; PCI, percutaneous coronary intervention; PLT, platelet count; PTA, percutaneous transluminal angioplasty; RBC, red blood cell; T-cho, total cholesterol; TG, triglyceride; TIA, transient ischemic attack; WBC, white blood cell. *Patients who met any of the following criteria were regarded as at high risk for CEA: congestive cardiac failure (NYHA class III or IV) or severe left ventricular dysfunction (LVEF [left ventricular ejection fraction] , 50%); open-chest surgery within 3 months before enrollment; myocardial infarction within 6 months before enrollment; unstable angina pectoris; severe cardiac disease requiring open chest surgery or carotid artery revascularization; severe pulmonary disease requiring long-term oxygen therapy, with PO2 at rest #60 mm Hg or baseline hematocrit t $50%; severe pulmonary disease with FEV1 (forced expiratory volume 1 second) or DLCO (diffusing capacity of the lung for carbon oxide) #50% of its normal value; more than 75 years old; ipsilateral carotid occlusion; ipsilateral pharynx paralysis; restenosis after CEA; history of cervical surgery; stenosis after radiotherapy; carotid stenosis in the bifurcation of the second cervical vertebra (high position) or under the clavicle (low position); high risk for systemic anesthesia; diagnosed by the attending physician at high risk for CEA.

observation period: rash in 7 patients (.8%), hematological disorder in 2 (.2%), hepatic disorder in 1 (.1%), gastrointestinal disorder in 4 (.4%), palpitations/tachycardia/ headache in 9 (1.0%), and others in 12 patients (1.3%). Adverse drug reactions caused by aspirin, clopidogrel, cilostazol, and other antiplatelet drugs were observed in 19 patients (2.0%), 26 (2.8%), 15 (1.6%), and 1 patient (.1%), respectively.

Comparison of the Incidences of Events According to Antiplatelet Drugs The incidence of the first event according to monotherapy or combination of antiplatelet drugs prescribed

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Table 2. Medications before CAS Drug

n (%)

Antiplatelet drug Aspirin Clopidogrel Cilostazol Others Anticoagulant drug Warfarin Argatroban Heparin Others Lipid-lowering drug Statins Others Antihypertensive drug Ca antagonist ACE-I ARB b-blocker (ab-blocker) Diuretic drug Others Antidiabetic drug Insulin Insulin resistance–improving drug Other oral antidiabetic drugs Combinations of antiplatelet drugs Aspirin 1 clopidogrel Aspirin 1 cilostazol Clopidogrel 1 cilostazol Aspirin 1 clopidogrel 1 cilostazol

934 (100) 852 (91.2) 686 (73.5) 367 (39.3) 94 (10.1) 96 (10.3) 85 (9.1) 4 (.4) 8 (.9) 1 (.1) 599 (64.1) 576 (61.7) 61 (6.5) 716 (76.7) 452 (48.4) 82 (8.8) 435 (46.6) 113 (12.1) 96 (10.3) 23 (2.5) 317 (33.9) 76 (8.1) 119 (12.7) 200 (21.4) 476 (51.0) 162 (17.3) 62 (6.6) 118 (12.6)

Abbreviations: ACE-I, Angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CAS, carotid artery stenting.

before CAS is shown in Table 5. The incidence of the first event for aspirin 1 cilostazol was significantly lower than that for aspirin 1 clopidogrel (P 5 .01), aspirin 1 clopidogrel 1 cilostazol (P 5 .01), and other combination of antiplatelet drugs (P , .01). The percentages of patients with symptomatic stenosis according to monotherapy or combination of antiplatelet drugs are shown in Tables 6 and 7. There was no difference in the use of antiplatelet drugs between patients with symptomatic stenosis and those with asymptomatic stenosis. Regarding the percentage of patients having symptomatic stenosis according to the combinations of antiplatelet drugs and the number of risk factors for CEA (Tables 6 and 7), there was no significant difference in the percentages of patients with symptomatic stenosis regardless of combination types of antiplatelet drugs. Based on the above findings, factors affecting the onset of the first event were investigated using a proportional hazards model. Causal relationships of the first event with the event-free period, patient demographic data, laboratory test values, preoperative medications, and tech-

niques for CAS were investigated. Twelve factors for which the P value was below .1 in a significance test of regression coefficients were included in the final model. Factors significantly affecting the onset of the first event were age (P 5 .01), a history of ischemic cerebrovascular disease (P 5 .02), combinations of antiplatelet drugs (P 5 .03), use of antidiabetic drugs (P , .01), femoral artery puncture (P 5 .02), use of a guiding catheter (P 5 .02), and use of Angioguard XP (P 5 .01). Regarding combinations of antiplatelet drugs, when other antiplatelet drugs (or aspirin 1 clopidogrel) were used as references, only the risk ratio for aspirin 1 cilostazol was significantly higher. The risk ratios of the 12 factors against references, their 95% CIs, and their significance are shown in Table 8. As the protocol of the present study prespecified that SDV be carried out in 10% of the participating medical institutions, SDV was carried out in 5 of the 43 institutions and in 91 of the 949 patients. Discrepancies were seen in 6 of the 91 patients (6.6%) and 16 items of the 4919 items (.3%). There were 1 deletion from and 2 additions to medication information and 7 corrections of periods. However, the ratio of discrepancies in number of items was very small and within its acceptable range; thus, it was considered that the discrepancies would not affect the results of this study.

Discussion Though many studies have been reported on CAS and CEA, the usefulness of CAS remains inconclusive. The Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) study2 demonstrated that CAS was noninferior to CEA. However, the Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) study7 and International Carotid Stenting Study (ICSS)8 demonstrated that CAS was inferior to CEA, and the SPACE study9 ruled out that CAS was noninferior to CEA. This inconsistency of results was considered attributable to the fact that only patients at high risk for CEA were enrolled in the SAPPHIRE study. In addition, the differing experience of surgeons for CAS among the studies was considered relevant to the outcomes. The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) conducted in patients with symptomatic carotid stenosis or asymptomatic carotid stenosis at any risk for CEA9 demonstrated that CAS was equivalent to CEA in terms of reduction of cardiovascular events.10 We reported retrospective surveillance of CAS in Japan and concluded that with improvement of devices, increasing experience, and appropriate selection of protection, CAS is continuing to evolve into a safer and more efficacious method of stroke prevention. In this report, the rate of MAE (major adverse event) was 10.2% at filter-protected CAS period.11

IDEALCAST—PROSPECTIVE REGISTRY

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Table 3. Primary end point: first event Within 30 days of enrollment, n (%)

Between 31 d and 1 year after enrollment, n (%)

Observation period, n (%)

69 (7.4) 2 (.2) 39 (4.2) 35 (3.8) 4 (.4) 6 (.6) 14 (1.5) 13 (1.4) 1 (.1) 2 (.2) 4 (.4) 2 (.2) 2 (.2)

40 (4.3) 16 (1.7) 13 (1.4) 6 (.6) 7 (.8) 1 (.1) 2 (.2) 1 (.1) 1 (.1) 2 (.2) 6 (.6) 0 (.0) 0 (.0)

109 (11.7) 18 (1.9) 52 (5.6) 41 (4.4) 11 (1.2) 7 (.8) 16 (1.7) 14 (1.5) 2 (.2) 4 (.4) 10 (1.1) 2 (.2) 2 (.2)

First event Death Ischemic stroke Ipsilateral Nonipsilateral Hemorrhagic stroke TIA Ipsilateral Nonipsilateral Myocardial infarction Serious hemorrhage excluding Hemorrhagic stroke Ischemic stroke 1 TIA Ischemic stroke (ipsilateral) 1 TIA (ipsilateral) Abbreviation: TIA, transient ischemic attack.

In the present study, the incidence of the first event (primary end point) was 7.4% within 30 days of enrollment and 11.7% within 1 year of enrollment. This result is not satisfactory; however, because the first event in the present study included stroke, TIA, death, myocardial infarction, and serious hemorrhage (excluding hemorrhagic stroke), the incidence of the first event appears to be higher. When limited to stroke, death, or myocardial infarction within 30 days of CAS, the incidence observed in the present study was no inferior to those in the abovementioned studies: 4.8% in the SAPPHIRE study, 9.8% in the EVA-3S study, 7.4% in the ICSS, 7.3% in the SPACE study, 5.2% in the CREST study, and 5.3% in this study. Furthermore, the incidence of ipsilateral ischemic stroke within 1 year of CAS was also comparable between the SAPPHIRE study (4.3%) and the present study (4.4%). In the EVA-3S study, ICSS, SPACE study, and CREST study, non–high-risk patients for CEA with symptomatic

carotid stenosis were enrolled, whereas in the present study, high-risk patients for CEA were enrolled. Nevertheless, the incidence of stroke, death, or myocardial infarction in the present study was lower than or similar to the results of above-mentioned studies, suggesting usefulness of CAS in high-risk patients for CEA in the Japanese population. Both the stenosis rate and the PSV improved significantly immediately after CAS, and this significant improvement was maintained over 1 year after enrollment, which might provide favorable outcome. The all-cause mortality within 1 year after enrollment (secondary end point) was 2.7%. Symptomatic carotid stenosis patients and even if asymptomatic, severe carotid stenosis patients (stenosis rate: $80%) who were enrolled in this study are regarded as high-risk patients having advanced arteriosclerosis and may die even if revascularization is applied. In the SAPPHIRE study using patients at high risk for CEA, the mortality within 1

Table 4. Primary end point: first event (symptomatic stenosis/asymptomatic stenosis)

n First event Death Ischemic stroke Hemorrhagic stroke TIA Myocardial infarction Serious hemorrhage excluding hemorrhagic stroke Ischemic stroke 1 TIA

Symptomatic stenosis, n (%)

Asymptomatic stenosis, n (%)

494 66 (13.4) 10 (2.0) 32 (6.5) 5 (1.0) 9 (1.8) 3 (.6) 6 (1.2) 1 (.2)

440 43 (9.8) 8 (1.8) 20 (4.6) 2 (.5) 7 (1.6) 1 (.2) 4 (.9) 1 (.2)

P value

.07

Abbreviation: TIA, transient ischemic attack. Symptomatic stenosis: with a history of either symptomatic stenosis in the target artery, TIA in the target artery, or ischemic retinopathy; asymptomatic stenosis: without any history of symptomatic stenosis in the target artery, TIA in the target artery, or ischemic retinopathy.

N. SAKAI ET AL.

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Table 5. The incidence of the first event according to antiplatelet drugs prescribed before CAS Antiplatelet drug ALL (combination 1 monotherapy) Aspirin Clopidogrel Cilostazol Others Combination therapy Aspirin 1 clopidogrel Aspirin 1 cilostazol Clopidogrel 1 cilostazol Aspirin 1 clopidogrel 1 cilostazol Monotherapy Aspirin Clopidogrel Cilostazol

% (n)

11.7% (100/852) 13.3% (91/686) 9.3% (34/367) 14.9% (14/94) 12.6% (60/476) 5.6%* (9/162) 8.1% (5/62) 14.4% (17/118) 9.1% (1/11) 30.0% (3/10) 0% (0/1)

Abbreviation: CAS, carotid artery stenting. *P 5 .01 vs aspirin 1 clopidogrel, P 5 .01 vs aspirin 1 clopidogrel 1 cilostazol, P , .01 vs other combination of antiplatelet drugs.

year of enrollment was 7.4%. Retreatment of the artery treated with CAS was provided to 8 patients (.9%) within 30 days of enrollment and to 14 patients (1.5%) during the observation period. This retreatment is considered because of technical failures because the carotid artery angioplasty was applied at a very early stage. In this study, the number of institutes with enrollment of 10 or more patients was 31 and the number of institutes with enrollment of less than 10 patients was 12. The respective incidence of MAE was 11.3% and 14.5%, and no significant difference was noted in the incidence of

Table 6. The percentages of patients with symptomatic stenosis according to monotherapy or combination of antiplatelet drugs Antiplatelet drug ALL (combination 1 monotherapy) Aspirin (n 5 852) Clopidogrel (n 5 686) Cilostazol (n 5 367) Others (n 5 94) Combination therapy Aspirin 1 clopidogrel (n 5 476) Aspirin 1 cilostazol (n 5 162) Clopidogrel 1 cilostazol (n 5 62) Aspirin 1 clopidogrel 1 cilostazol (n 5 118) Monotherapy Aspirin (n 5 11) Clopidogrel (n 5 10) Cilostazol (n 5 1)

Table 7. The percentages of patients with symptomatic stenosis according to combinations of antiplatelet drugs and the number of risk factors for CEA

%

52.0 52.0 54.8 51.1 51.3 56.2 50.0 64.5

54.6 50.0 100

Number of risk factor for CEA Antiplatelet drug

1, %

2, %

3, %

Aspirin 1 clopidogrel Aspirin 1 cilostazol Clopidogrel 1 cilostazol Aspirin 1 clopidogrel 1 cilostazol

71.6 76.5 66.1 77.1

23.3 18.5 25.8 20.3

5.0 4.9 8.1 2.5

MAE between both groups. Thus, we consider that there was no difference in the occurrence of MAE among institutes. In addition, all institutes that participated in the study had experienced CAS operators. Given that CAS is conducted not by a single operator but by a team, it is unlikely that operators would influence the occurrence of MAE. The incidence of death, stroke, and MI was 7.1%. Because this study was conducted in patients with high risk to CEA, it would be reasonable that asymptomatic MAE exceeds 3%. It was considered not necessary to concern about 3% targeted as a complication rate of revascularization for asymptomatic carotid stenosis. The incidence of adverse drug reactions caused by antiplatelet drugs during the observation period was 3.6%. The incidence according to antiplatelet drugs was 2.0% for aspirin, 2.8% for clopidogrel, 1.6% for cilostazol, and .1% for others. Cilostazol has been reported to cause palpitations/tachycardia; however, no palpitations/tachycardia was observed in the present study. Because the present study was not a randomized study, use of cilostazol in patients with ischemic heart disease might have been avoided to prevent tachycardia. As for the continuation status of antiplatelet drugs, that immediately after CAS and 1 year after CAS (or on the final observation) was 99.2% and 71.6%, respectively, for aspirin, 98.8% and 71.0% for clopidogrel, 99.7% and 62.7% for cilostazol, and 100% and 79.8% for others. All antiplatelet drugs were almost continuously used before CAS and during the perioperative period. The continuous use rate slightly lowered 1 year after CAS, but there were no substantial differences in the continuous use rate among the antiplatelet drugs. The incidence of the first event according to combinations of antiplatelet drugs before CAS was 12.6% for aspirin 1 clopidogrel, 5.6% for aspirin 1 cilostazol, 8.6% for clopidogrel 1 cilostazol, and 14.4% for aspirin 1 clopidogrel 1 cilostazol. The incidence was significantly lower for aspirin 1 cilostazol. To determine whether there was any bias in prescription of antiplatelet drugs, various background factors were statistically investigated according to concomitant

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Table 8. Factors affecting primary end point P value

Factor

Risk ratio

95% Confidence interval

Sex (vs male) Age (/5 y increase) Electrocardiography (vs normal) Presence of lifestyle disease (vs absence) Presence of ischemic cerebrovascular disease (vs absence) Presence of history of myocardial infarction/angina pectoris (vs absence) Presence of history of revascularization (vs absence) Combinations of antiplatelet drugs Versus other antiplatelet drugs Aspirin 1 clopidogrel Aspirin 1 cilostazol Clopidogrel 1 cilostazol Aspirin 1 clopidogrel 1 cilostazol Versus aspirin 1 clopidogrel Aspirin 1 cilostazol Clopidogrel 1 cilostazol Aspirin 1 clopidogrel 1 cilostazol Other antiplatelet drugs Presence of treatment with antidiabetic drugs (vs absence) Femoral artery puncture (vs others) Guiding catheter (vs others) Angioguard XP (vs others)

.58 1.24 1.04 .42 1.68 1.25

.26-1.13 1.07-1.44 .70-1.54 .20-1.03 1.10-2.62 .71-2.18

.11 .01 .85 .06 .02 .44

1.17

.68-2.02

.57 .03

.99 .37 .56 1.12

.59-1.75 .16-.85 .18-1.43 .56-2.23

.98 .02 .23 .76

.39 .56 1.12 1.01 1.93 .36 1.69 1.91

.18-.75 .19-1.28 .63-1.92 .57-1.69 1.29-2.88 .18-.80 1.08-2.71 1.16-3.40

,.01 .18 .68 .98 ,.01 .02 .02 .01

drugs as follows: demographic data, the number of risk factors for CEA, a history of lifestyle disease and ischemic cerebrovascular disease, and a history of revascularization, with no prescription bias of antiplatelet drugs detected. In addition, regarding the concomitant use of antiplatelet drugs according to the medical institutions, 22 of the 43 institutions used predetermined regimens in more than 80% of the patients. This appears to suggest there was no bias in prescription of antiplatelet drugs. The following factors were detected as significant factors for predicting the primary end point: age (P 5 .01), a history of ischemic cerebrovascular disease (P 5 .02), use of antidiabetic drugs (P , .01), femoral artery puncture (P 5 .02), use of a guiding catheter (P 5 .02), use of Angioguard XP (P 5 .01), and use of aspirin 1 cilostazol (P 5 .02 vs other antiplatelet drugs; P , .01 vs aspirin 1 clopidogrel). Transfemoral approach is a normal route. Another route is needed to be secured for a case with anatomical difficulties to access because of some factors, for which increased risk is expected. It is unknown whether a different device (a guiding catheter or other device [eg, long sheath]) is used based on the patient’s condition, and there may be the difference between institutes. Significantly negative results for Angioguard XP could be caused by inexperience of operators because of operations soon after the introduction of the device, associated with inability to overcome the potential risk of the filter protection. The approved device was only Angioguard

XP at that time. Later, as operators acquired the experience, the procedure for high-risk patients was shifted to a balloon protection. Aspirin inhibits cyclooxygenase-1 activity and suppresses production of prostaglandin and thromboxane A2. Clopidogrel activates platelets and inhibits platelet aggregation by inhibiting platelets from binding to an ADP receptor subtype P2Y12. Cilostazol is a cyclic adenosine monophosphate phosphodiesterase 3 inhibitor and is reported to exert an antiplatelet effect by activating protein kinase A and to exert a vasodilatory effect by suppressing smooth muscle contraction.12 Such differences in mechanism of action might have contributed to the results of the present study. We plan to further investigate and report a relationship between antiplatelet drugs and the results of this study.

Study Limitations This study was an observational study, not a randomized controlled study, and the authors consider that further investigations and randomized comparative studies are warranted to determine the usefulness of CAS and a relationship between medications before and after CAS and the onset of events after CAS.

Conclusions In the present study conducted for 2 years from June 2008, right after CAS became subject to National Health Insurance coverage in Japan, the incidences of the first

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event (primary end point) within 30 days and 1 year of enrollment, were 7.4% and 11.7%, respectively. This suggests that CAS is a useful alternative for CEA in carotid stenosis patients with high risk for CEA. The onset of events after CAS may be associated with the factors including age, a history of ischemic cerebrovascular disease, combinations of antiplatelet drugs before CAS, and the type of a device for embolism prevention.

References 1. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med 1991;325:445-453. 2. Yadav JS, Wholey MH, Kuntz RE, et al, Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy Investigators. Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med 2004;351:1493-1501. 3. Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/ AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/ SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery Developed

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in Collaboration With the American Academy of Neurology and Society of Cardiovascular Computed Tomography. J Am Coll Cardiol 2011;57:1002-1044. Japanese guidelines for the management of stroke. Japan Stroke Society 2009 [in Japanese]. Toyoda A, Shima T, Nishida M, et al. Angiographical evaluation of extracranial carotid artery comparison between Japanese and Hungarian. Brain Nerve 1997; 49:633-637 [in Japanese]. Report on training for medical institutions by the Japan Neurosurgical Society [in Japanese]. Japan Neurological Society, 2011, unpublished. Mas JL, Chatellier G, Beyssen B, et al, EVA-3S Investigators. Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis. N Engl J Med 2006;19:1660-1671. International Carotid Stenting Study investigators, Ederle J, Dobson J, et al. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial. Lancet 2010; 375:985-997. SPACE Collaborative GroupRingleb PA, Allenberg J, et al. 30 day results from the SPACE trial of stentprotected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial. Lancet 2006;368:1239-1247. Brott TG, Hobson RW II, Howard G, et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010;363:11-23. Miyachi S, Taki W, Sakai, et al. Historical perspective of carotid artery stenting in Japan: analysis of 8,092 cases in The Japanese CAS Survey. Acta Neurochir (Wien) 2012;154:2127-2137. Tanaka K, Gotoh F, Fukuuchi Y, et al. Effects of a selective inhibitor of cyclic AMP phosphodiesterase on the pial microcirculation in feline cerebral ischemia. Stroke 1989; 20:668-673.

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Appendix The following investigators participated in the Investigation on Device and Antiplatelet for Carotid Artery Stenting—Central Office: Chiaki Sakai, Kaori Kuronaka, and Ayumi Tsuji; Principal Investigator: Nobuyuki Sakai; Co-principal Investigator: Hiroshi Yamagami; Steering Committee: Masayuki Ezura, Akio Hyodo, Yuji Matsumaru, Shigeru Miyachi, Yasushi Okada, Tomoaki Terada, Hiroyoshi Yokoi, and statistical center; Translational Research Informatics Center: Yoshihiro Matsubara, and Advisory Committee; Mie University: Waro Taki; and Tokyo Women’s Medical University: Shinichiro Uchiyama. In addition to the investigators listed above, the following investigators participated in the study—Himeji Cardiovascular Center: Takashi Mizobe; Konan Hospital: Ryushi Kondo; Kobe City Medical Center General Hospital: Hidemitsu Adachi, Hirotoshi Imamura, Kenichi Todo, and Shiro Yamamoto; Kishiwada Tokusyukai Hospital: Yoshiaki Yokoi; Yamaguchi University: Hideyuki Ishikawa; Tokushima Red Cross Hospital: Koichi Sato; Kurume University: Masaru Hirohata; Toyama University: Naoya Kuwayama; Mie University: Waro Taki, and Hiroshi Sakaida; Toranomon Hospital: Mikito Hayakawa; Okayama University: Kenji Sugiu; Kokura Memorial

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Hospital: Ichiro Nakahara; Shiroyama Hospital: Kenichi Murao; Sapporo Medical University: Masashi Nonaka; Yokkaichi Municipal Hospital: Kiyo Nakabayashi’ Tachikawa General Hospital: Hiroshi Abe; Jichi Medical University: Shigeru Nemoto; Toyohashi Medical Center: Hideki Sakai; Nakamura Memorial Hospital: Toshio Hyogo; Taketo Kataoka, Kyoto University: Akira Ishii; Teine Keijinkai Hospital: Satoshi Ushikoshi; Mihara Memorial Hospital: Kazunori Akaji; National Cerebral and Cardivascular Center: Tetsu Sato; Gifu University: Yukiko Enomoto; Nagoya City Medical University: Mitsuhito Mase; Kagawa University: Masahiko Kawanishi and Atsushi Shindo; Niigata University: Yasushi Ito; Kyusyu Medical Center: Tomoyuki Tsumoto; Matsuda Hospital: Toshinori Nakahara; Geriatrics Research Institute Hospital: Isao Naito and Naoko Miyamoto; Saiseikai Toyama Hospital: Naoya Kubo; Tokushima University: Shunji Matsubara and Junichiro Satomi; Fukuoka University Chikushi Hospital: Kiyoshi Kazekawa; Nagoya University: Takashi Izumi; Nagasaki University: Izumi Nagata and Kentaro Hayashi; Miyazaki University: Hajime Ota; Kanazawa University: Junichiro Hamada and Naoyuki Uchiyama; Osaka Medical University: Terumasa Kuroiwa; and Institute of Biomedical Research and Innovation: Ryuichiro Kajikawa and Tomoyoshi Shigematsu.