Prospective study of symptomatic atherothrombotic intracranial stenoses
The GESICA Study*
M. Mazighi, MD; R. Tanasescu, MD; X. Ducrocq, MD; E. Vicaut, MD, PhD; S. Bracard, MD; E. Houdart, MD; and F. Woimant, MD

Abstract—Background: Symptomatic intracranial atherothrombotic stenoses (ICAS) are associated with high rates of cerebrovascular ischemic events. Objective: To conduct a prospective multicenter study to evaluate the natural history of ICAS and, in those patients refractory to medical treatment, the outcomes associated with intracranial angioplasty. Methods: Patients aged 18 to 80 were enrolled with symptoms attributed to a single ICAS of Ն50%. Optimal medical therapy of vascular risk factors and preventive antithrombotic therapy were at the discretion of the local investigator. Patients were eligible for intracranial angioplasty after experiencing recurrent stroke despite medical therapy. Neurologic and ultrasonographic examinations were performed at study inclusion, 3 months after enrollment, and every 6 months of follow-up thereafter, for 36 months. Results: One hundred two patients were included, with a mean age of 63.3 Ϯ 10.4 years. Intracranial artery stenoses involved the vertebral artery in 22.5%, the basilar artery in 25.5%, the middle cerebral artery in 26.5%, and the internal carotid artery in 25.5%. In 27.4% of the patients, the stenoses had clinical hemodynamic characteristics. During a mean follow-up of 23.4 months, 38.2% of the patients had a cerebrovascular event: ischemic stroke in 13.7% and TIA in 24.5%. Among patients with a hemodynamically significant stenosis, 60.7% had a recurrent stroke or TIA in the territory of the stenotic artery; this association was significant in univariate analysis. Twenty-eight patients underwent an endovascular procedure with a neurologic periprocedural complication rate of 14.2%. The overall vascular death rate was 8.8%. Conclusions: Despite medical treatment, the 2-year recurrence rate of ischemic events in the territory of the stenotic artery was 38.2%. Cardiovascular events occurred in 18.6% of patients. Clinically significant hemodynamic stenoses were associated with stroke recurrence and may help identify a high risk subset of patients.
NEUROLOGY 2006;66:1187–1191

The development of noninvasive vascular imaging techniques such as transcranial color-coded duplex scanning and MR angiography (MRA) allows more extensive noninvasive investigations of stroke patients and the accurate diagnosis of intracranial atherothrombotic stenoses (ICAS). The majority of these stenoses are due to atherosclerosis; however, the natural history and prognosis of ICAS are poorly understood, especially in Caucasian patients, in whom cervical lesions are widely prominent. ICAS are estimated to represent 5 to 10% of ischemic strokes,1 and the annual risk of recurrent stroke varies from 10 to 50%.2,3 The initial retrospective Warfarin–Aspirin Symptomatic Intracranial Disease (WASID) Study suggested that warfarin was more effective than aspirin at preventing recurrences.4 However, the recent prospective WASID trial was stopped early owing to safety concerns related to an excess of adverse events in the warfarin group.5 Many unanswered questions exist regarding the optimal management of ICAS: What is the risk of fur-

ther stroke or other vascular events? Are the recurrences due to embolic or hemodynamic mechanisms? What is the best medical treatment? In whom should intracranial angioplasty be considered? From 1999 to 2003, we conducted a prospective study called GESICA (Groupe d’Etude des Ste ´ noses Intra-Cra ˆ niennes Athe ´ romateuses symptomatiques) aimed at evaluating the natural history of symptomatic ICAS and intracranial angioplasty in those patients refractory to medical treatment.
Methods. GESICA was a prospective, multicenter, nonrandomized study. Twenty-one neurologic centers participated in the study. From April 1999 to December 2003, all patients diagnosed as having a recent (Ͻ6 months) TIA or minor (nondisabling) ischemic stroke (IS) related to an ICAS were included. The main inclusion criteria are listed in table 1. This database was collected by two of the investigators in two of the centers (F.W. and X.D.). At inclusion, patients were investigated for history of TIA or stroke, coronary artery disease (CAD), peripheral arterial disease (PAD), vascular risk factors, and current medical treatment. A systematic diagnostic workup, including cervical color-coded duplex scanning, transcranial ultrasound, MRA, EKG, transesophageal

*See the Appendix for a complete list of the GESICA Study members. From the Departments of Neurology (F.W.) and Neuroradiology (M.M., E.H.), Ho ˆ pital Lariboisie ` re, and Centre de Recherche Clinique (E.V.), Ho ˆ pital Fernand Widal, Paris, and Departments of Neurology (R.T., X.D.) and Neuroradiology (S.B.), Ho ˆ pital Central, Nancy, France. Disclosure: The authors report no conflicts of interest. Received July 26, 2005. Accepted in final form January 18, 2006. Address correspondence and reprint requests to Dr. M. Mazighi, Service de Neuroradiologie, Ho ˆ pital Lariboisie ` re, 2 rue Ambroise Pare, 75010 Paris, France; e-mail: Copyright © 2006 by AAN Enterprises, Inc. 1187

was performed to exclude other potential causes of stroke. if symptoms related to the stenosis occurred during a change of position (supine to prone). diagnostic workup was repeated with digital subtraction angiography (DSA). ultrasonography was obtained. Results. The mean age at admission for index stroke was 63. All data were entered into the Statview software for analysis and were summarized as median (interquartile distance) or mean (ϮSD).Table 1 Selection criteria for the GESICA Study Age Ն18 TIA or IS in territory of intracranial stenosis TIA or IS onset Յ6 months Cerebral nonischemic lesion ruled out by appropriate imaging Modified Rankin score Յ2 at time of inclusion NIHSS score Ͻ15 at inclusion Absence of handicap interfering with neurologic or functional evaluation Stenosis of ICA. The stenoses were considered to be atherothrombotic if the patient had at least two of the following vascular risk factors: hypertension. VA ϭ vertebral artery. ICA ϭ internal carotid artery. location of stenotic arteries. or VA. diabetes. If a new TIA or stroke occurred. if clinically appropriate. hypercholesterolemia. peripheral artery disease. angio-CT. and all patients gave written informed consent for participation. Statistical analysis. the middle cerebral artery (MCA). Supplementary visits were planned for the occurrence of a new vascular event. by a neurologist.5% of the patients were men. Intracranial stenosis (50 to 99%) had to be demonstrated by either DSA or ultrasonography and confirmed by one of the following methods: MRA. preexisting atherosclerotic stenosis (Ͼ20%) in another location.8%) of patients were enrolled at two centers. intracranial angioplasty was offered to the patient. Each angiogram was evaluated for stenoses pre and post angioplasty. BA ϭ basilar artery. history of CAD. The angiograms were reviewed retrospectively and independently at separate reading sessions by two neuroradiologists. Diagnostic cerebral DSA was performed in each patient. BA ϭ basilar artery. MCA ϭ middle cerebral artery. PAD. The clinical features of the patients are provided in table 3. according to the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification. vascular risk factors. 71. In the current study. DSA ϭ digital subtraction angiography. A CT scan was obtained within 24 hours in each case or immediately after neurologic deterioration during hospitalization. Stenoses were graded by the peak systolic velocity measurement on ultrasonography. echocardiography. and patients were . GESICA ϭ Groupe d’Etude des Ste ´ noses Intra-Cra ˆ niennes Athe ´romateuses symptomatiques. We assumed that some patients included in the study would develop recurrent events related to their ICAS. Angioplasty method. pre-existing atherosclerotic stenosis (Ͼ20%) in another location. As per prespecified protocol. or BA Presumed due to atheroma* Stenosis Ն50% Stenosis confirmed by either MRA. smoking. smoking. and recurrent cerebrovascular and other vascular events were used as categorical variables. A parallel study was conducted for patients refractory to medical treatment. IS ϭ ischemic stroke. pre-existing atherosclerotic stenosis (Ͼ20%) in another location. or the presence of aortic plaques. All tests were two sided with a significance level fixed at 5%. or MCA. or BA Presumed due to atheroma* Stenosis Ն50% Length of stenosis is short (length Ͻ3ϫ diameter of artery as measured just before or just after stenosis) Good distal flow No endoluminal thrombus Modified Rankin score Յ2 before qualifying event NIHSS score Ͻ15 at inclusion * The stenoses were considered to be atherothrombotic if the patient had at least two of the following vascular risk factors: hypertension. or the introduction or increase of an antihypertensive medication. They constitute a subgroup (GESICA angioplasty) of the cohort of patients of the GESICA Study. the degree of stenosis was measured at its point of maximal narrowing and compared with the normal section of the vessel distal to the stenosis ([normal lumen diameter Ϫ residual lumen]/normal lumen diameter) or proximal to the stenosis if ectasia or a bifurcation was identified downstream of the stenosis. VA ϭ vertebral artery. or the presence of aortic plaques. either TIA or IS despite receiving appropriate medical treatment. Independent-sample t test and ␹2 test or Fisher exact test were used for continuous or categorical variables. A total of 102 patients with symptomatic intracranial stenosis (50 to 99%) of the anterior or posterior circulation were included in the study.3 Ϯ 10. respectively. although the majority (59. becoming mandatory for more aggressive treatment as angioplasty. or the intracranial vertebral artery (VA). IS ϭ ischemic stroke. all patients were examined at 3 months and every 6 months thereafter for clinical symptoms and signs. MCA ϭ middle cerebral artery. patients were admitted to the intensive care unit for postoperative observation and management.6 Optimal medical therapy for risk factors and preventive antithrombotic therapy was at the discretion of the local investigator. and hypercoaguability workup. history of coronary artery disease. The study protocol was approved by the Ethic Committee of the Hospital Central of Nancy (Comite ´ Consultatif des Protections des Personnes se pre ˆ tant a ` la Recherche Biome ´ dicale de Lorraine). Stenoses eligible for the study had to be located either in the intracranial carotid artery (ICA). ICA ϭ internal carotid artery. All patients gave written informed consent prior to the procedure. No indication was given for the use of either oral anticoagulant or antiplatelet therapy. peripheral artery disease. Table 2 Supplementary selection criteria for patients included in angioplasty group Age Ն18 and Ͻ80 Recurrent episodes such as TIA or minor IS in territory of intracranial stenosis under appropriate antithrombotic treatment Another cause than ischemia ruled out by appropriate imaging Stenosis of either ICA. whenever possible. Stenoses were classified clinically as hemodynamic. history of coronary artery disease. diabetes. NIHSS ϭ NIH Stroke Scale.4 years (38 to 93 years). smoking. or VA. NIHSS ϭ NIH Stroke Scale. hypercholesterolemia.7 For angiography. Following each procedure. GESICA angioplasty. or MCA. The procedure was performed under general anesthesia. The patients received two antiplatelet agents (aspirin and clopidogrel) 5 days prior to the procedure and continued for 1 month. and. hypercholesterolemia. an 1188 NEUROLOGY 66 April (2 of 2) 2006 effort. or DSA No other severe life-threatening disease known Follow-up presumed possible during study period * Stenoses were considered atherothrombotic if the patient had at least two of the following vascular risk factors: hypertension. diabetes. angiography. the basilar artery (BA). sex. or the presence of aortic plaques. The criteria for the selection of these patients (table 2) were designed to include only those patients with symptoms clearly related to the ICAS and refractory to medical treatment. or CT. All 21 centers actively enrolled patients.

4 73 (71.4%. multiple TIAs (40.1 62. Among patients with a hemodynamic stenosis. recurrent strokes were noticed in two (7.4 months.9) 63. Recurrent strokes affected the anterior circulation for 19 patients (18. During a mean follow-up of 23. (e.5 (Ϯ0.9%). atrial fibrillation. The mean time from the symptomatic event to intracranial angioplasty was 1.0%.3 Ϯ 10.05.1%. Among the 38 patients with other associated intracranial lesions.7 65.2 71. and one nonfatal minor IS (modified Rankin Scale score ϭ 0 after 26 months of follow-up). In two patients. The mean time from symptomatic event to inclusion was 1.0 50.0 39. table 4).4 months).5 56.1 56.5%). 38.6 43.5%). y Male Race Caucasian Other Hypertension Diabetes mellitus Ever smoker Cholesterol Ͼ200 mg/dL History of coronary artery disease Peripheral arterial disease Values (except for age) are n (%). in the BA in 35.. In univariate analysis. Hypertension (73.6%) and the posterior circulation for 20 patients (19.3%. The association of recurrent strokes and Values for stroke recurrence are percentages. The qualifying events for the patients included in the study were a single TIA (7.8 33.7% with one anticoagulant. Cerebrovascular events were discovered within a median time of 2 months (3. 31. the BA in 26 patients (25. ICA ϭ internal carotid artery.9) 75 (73.1%) patients: one TIA (no restenosis on April (2 of 2) 2006 NEUROLOGY 66 1189 .7% had a recurrent IS or TIA in the territory of the stenotic artery.g. and in the VA in 13.5%).4 52. 92. the functional status of the studied population was high. At baseline.5%) and an IS in 14 patients (13.7%). respectively.7 73.9%).6) 61 (59.3%. other mechanism of stroke.1% of the patients without associated intracranial stenosis had a recurrent event. whereas only 31.7 38. single stroke (47.2 66.5) months.2% of the patients had a stroke or a TIA in the same territory of the stenotic intracranial artery.5 months (17. % stroke.7% of patients.4% of the patients and associated ICAS were noticed in 41%. 2 and 9 months after the procedure).5 months. history of smoking (70.5%). an association between the parameter and the stroke recurrence was considered significant if p Ͻ 0.9 43.3 52.5 43. After univariate analysis. 50% had a recurrent stroke.8) 34 (33.7 50. 99 (97.0 41. BA ϭ basilar artery.5 months).1%). and hypercholesterolemia (50%) were the three most common vascular risk factors (table 3).8%. The stenoses involved the following intracranial arteries: the VA in 23 patients (22.5) 31 (30.9% and IS in 37. 13 of whom received a stent.7% were treated with another antithrombotic combination (two antiplatelet agents: 8.4% with one antiplatelet agent and one anticoagulant. 15. patient refusal (n ϭ 1).009 NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS predominantly Caucasian (97. In a mean follow-up of 19.9 37. The degree of stenosis was assessed by angiography in 62. MCA ϭ middle cerebral artery.0 p 0.5%). APD ϭ antiplatelet drug.4% patients received a modified Rankin Scale Score of 0 (no symptoms) or 1 (able to perform all the previous activities despite symptoms).8 28.0 58.6) Table 4 Patient characteristics and frequency of stroke recurrence No Patients.Table 3 Baseline characteristics of 102 patients with intracranial symptomatic stenoses Age.0 50. and other causes (n ϭ 3). Neurologic periprocedural complications were observed in 14.3 50. and 14. the MCA in 27 patients (26.1) 3 (2. and the ICA in 26 patients (25. the hemodynamic significance (see Methods) of the stenosis appeared to be the unique element associated with stroke recurrence (table 4). Recurrent recurrent n stroke. The stenoses had clinical hemodynamic characteristics in 27. whereas noncerebrovascular events arose within a median time of 20. 38. % Hemodynamic stenosis Male Female Diabetes Hypertension Hypercholesterolemia Smoking Anticoagulant One APD Two APDs Anticoagulant ϩ 1 APD Anticoagulant ϩ 2 APDs BA VA MCA ICA Coexistent stenoses 28 73 29 31 75 61 72 16 39 9 32 6 26 23 27 26 38 60.3) 6 (5.6 36. multiple intracranial stenoses was not significant in univariate analysis (table 4).9%. Cerebrovascular events resulting in angioplasty were TIAs in 62.4 56.5%).7%).2 (Ϯ1.3 71. two fatal strokes (one hemorrhagic and one ischemic responsible for death. 60. one IS and one TIA were observed in other territories than in the symptomatic stenotic artery.2% patients including one death (one arterial rupture).6 48. Patients experiencing a recurrent stroke had a symptomatic stenosis in the ICA in 29. subtherapeutic international normalized ratio (n ϭ 1).6%). The cerebrovascular events were a TIA in 25 patients (24.5%).4) 72 (70. n ϭ 1). Twenty patients underwent an endovascular procedure.7% of the patients without a hemodynamic stenosis had a recurrent event.3 61. two antiplatelet agents with one anticoagulant: 5.2% patients were treated with a single antiplatelet agent.4 63.3 26.7 28. After inclusion. whereas only 35. An endovascular procedure was not performed in nine patients with recurrent strokes in the territory of the stenotic artery due to arterial occlusion (n ϭ 3).9) months. and multiple strokes (3.3 34. VA ϭ intracranial artery.7 47. in the MCA 22.

L. Moret..D. At the end of the follow-up study. LaTimone.-F. J. MD. Paris). MD (Service de Neurologie [J. 38.M. Meder. J.]. F.7%) and symptomatic PAD in 5 patients (4.A. Le ´ vrier.. L. Martin.. D. Touze ´ .B. Centre Hospitalo-Universitaire.-M. Berge. C. estimated at 5. Centre Hospitalo-Universitaire. occurred in 14 patients (13. F. Service de Neuroradiologie [S. S.3 to 28%.-F. Exploration fonctionelle [A. MD. P.-C. A. MD.]. T. M. Centre Hospitalo-Universitaire. warfarin should not be used in preference to aspirin. In our series. These characteristics. recurrent cerebral ischemic events occurred in a median time of 2 months following the first qualifying event. it would be of interest to know whether arterial blood pressure should be lowered or not. MD (Service de Neurologie [M.].. explaining the clinical severity of the recruited patients. complementary ultrasonographic explorations with assessment of hypoperfusion or high-intensity transient signals are required to identify the mechanism of IS. which may be a result of referral bias. P. Orgogozo. based on clinical criteria.3%. These results illustrate the need for mandatory screening for CAD in patients with symptomatic intracranial stenosis. E. Besanc ¸ on).]. Zuber. Woimant. MD. Intracranial atherosclerosis is a severe disease with recurrent annual strokes rates of 4% to 24% per year.C. MD. E.]. MD.23 Although the aim of the study was not to compare the efficacy and tolerance of different preventive treatments. Dubas.].22 but the high rate of IS despite antithrombotic agents highlights the need to consider endovascular treatment as a therapeutic option.8-21 In patients with symptomatic ICAS failing medical therapy. Blard. Nine patients died in the group without angioplasty: five of CAD. MD. are not dependent on a specific imaging technique.7% IS and 24. Bakouche.M.G. Fondation Rothschild. E. Based on the postangioplasty complication rate in our series. MD. MD.]. Centre Hospitalo-Universitaire. D.3 In the GESICA Study. R. J. Centre Hospitalo-Universitaire. Nı ˆmes). Paris). Bracard.-F. O. Dupuy. 3 of whom had a history of previous PAD.]. Moulin. R. Neuroradiologie [E.. Ducrocq. As an example.]. the hemodynamic characteristics of the intracranial stenosis predicted stroke recurrence after univariate analysis.B. predominantly due to CAD. a relatively high neurologic periprocedural morbidity/mortality rate of 14. reaching 55.T. MD (Service de Neurologie [L. MD. Defining a group of patients at higher risk is relevant when determining the benefit of an interventional approach.]. J.B.B.]. and are useful in selecting patients who will derive a benefit from angioplasty when antithrombotic therapy remains unsuccessful. MD.7% in a mean time of 21.30 a similar stroke recurrence after intracranial 1190 NEUROLOGY 66 April (2 of 2) 2006 stenting was reported.8% in patients without endovascular treatment. MD (Service de Neurologie [X. MD (Service de Neurologie [F.B. that is.27-31 In accordance with these results. Service de Neuroradiologie [J.-C. and three of nonvascular causes.-M. Discussion. Service de Neuroradiologie [J. Service de Neuroradiologie [O.]. L. Pierot.D. Cognard.-M. Nonetheless. A. MD. Service de Neuroradiologie [J. MD (Service de Neurologie [P.O. Arquizan. Service de Neuroradiologie [C. The short time for recurrence argues for an aggressive frontline therapeutic strategy.2% of patients experienced a recurrent cerebrovascular event in the territory of the stenotic artery at 2-year follow-up (13.W. Therefore. Service de Neuroradiologie [J.-M. Service de Neuroradiologie [A. Bonneville. this technique should be reserved for patients experiencing medical treatment failure and should be performed only by skilled operators.9%). one of IS (other territory than the related intracranial symptomatic stenosis). MD.24-26 The increasing enthusiasm for intracranial intervention should be dampened some by the neurologic periprocedural complication rate. S. Houdart. Marseille). MD (Service de Neurologie [J.ultrasonography) and one stroke (related to the disclosure of atrial fibrillation). Giroud.-F. MD. M. In GESICA.5% TIAs). M. acute coronary syndromes. MD (Service de Neurologie [M. the death rate reached 11. MD (Services de Neurologie [F.G.2% was observed in our population. J. C. Chollet. MD. Lacour.3. Service de . MD. Centre Hospitalo-Universitaire.].-L. 2 of the 28 patients treated by angioplasty had recurrent neurologic events within a mean follow-up of 19 months: a TIA and an IS. Tanasescu. Ho ˆ pital Sainte Anne.].H. Bouly. J. the lack of standardized therapy for antithrombotic or antihypertensive medication is a limitation. Angers).. Checoury. as some patients with ICAS are at risk of hemodynamic ischemia.5 which revealed a significant increase of hemorrhagic complications in the warfarin-treated group.5 months.. Mas. ICAS are characterized by high and early recurrences of strokes and delayed cardiovascular events.P. Nancy). it is premature to recommend intracranial angioplasty as a primary treatment for this condition until more safety data are available.B. MD (Service de Neurologie [J. The death rate reached 8. Service de Neuroradiologie [O. MD.M. Labauge. The identification of the patients that may benefit from angioplasty and the long-term vascular follow-up are main issues.]. Pasco. Paris). J. Another limitation is that two centers enrolled the majority of patients (59. O.].]. M. Noncerebrovascular events.8) months. The disparity observed in the antithrombotic regimens likely reflects the lack of consensus between the investigators regarding the therapeutic management of this disease. Ho ˆ pital Central. A. are easy to assess.]. Dijon). the stroke rate may be even higher.Z.]. Bouchareine. J. Despite optimal medical treatment. Milandre. MD.M.T.]. Montpellier). J. The GESICA Study demonstrates that the patient population with symptomatic intracranial stenosis is at high risk of recurrent vascular events. MD. M. Centre Hospitalo-Universitaire. Service de Neuroradiologie [A. This raises the important issue of whether the proposed treatment of intracranial stenting improves the natural history of this disease.C. MD (Service de Neurologie [T. The IS was confounded by the presence of atrial fibrillation. A. In the SSYLVIA multicenter trial. A.L. MD. This study was conducted before the results of the WASID prospective trial. MD. Mazighi.8% within a median time of 36 days. Milhaud. MD. acute coronary syndromes and symptomatic PAD occurred in 18. MD (Service de Neurologie [F.M.8%). Toulouse-Purpan).8 (Ϯ14. Bonafe.]. During the follow-up. M. In this condition. Ho ˆ pital Lariboisie ` re. with a rate at 1 year of 7. C..].M. Appendix The GESICA Study investigators are as follows: F. Bordeaux).-L. MD (Service de Neurologie.6% of the patients in a median time of 20.].].M. Based on this trial.B. Centre Hospitalo-Universitaire.M. The importance of this atherothrombotic burden is illustrated by the associated CAD or PAD present in more than 30% of the patients.D. X.

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