Prospective Acute Ischemic Stroke Outcomes After Endovascular Therapy: A Real-World Experience

Peer-Review Reports

Prospective Acute Ischemic Stroke Outcomes After Endovascular Therapy: A Real-World Experience Sabareesh K. Natarajan1,3, Yuval Karmon1,3, Kenneth V. Snyder1,3, Hajime Ohta1,3, Erik F. Hauck1,3, L. Nelson Hopkins1,2,3, Adnan H. Siddiqui1,2,3, Elad I. Levy1,2,3

Key words 䡲 Acute ischemic stroke 䡲 Atrial fibrillation 䡲 Endovascular therapy 䡲 Symptomatic intracranial hemorrhage 䡲 Time window Abbreviations and Acronyms AbESTT-II: Abciximab in Emergency Stroke Treatment Trial-II ACA: Anterior cerebral artery AHA/ASA: American Heart Association/American Stroke Association AIS: Acute ischemic stroke ASPECTS: Alberta Stroke Programme Early CT Score BA: Basilar artery CI: Confidence interval CT: Computed tomography CTA: Computed tomography angiography CTP: Computed tomography perfusion EC-IC: Extracranial-intracranial ECASS: European Cooperative Acute Stroke Study IA: Intra-arterial IAT: Intra-arterial pharmacologic thrombolysis ICA: Internal carotid artery ICA-T: Internal carotid artery-terminus IMS: Interventional Management of Stroke IQ: Interquartile IV: Intravenous IVT: Intravenous thrombolysis MCA: Middle cerebral artery MERCI: Mechanical Embolus Removal in Cerebral Ischemia mRS: Modified Rankin scale NCCT: Non-contrast computed tomography NIHSS: National Institutes of Health Stroke Scale OR: Odds ratio PCA: Posterior cerebral artery PROACT: Prolyse in Acute Cerebral Thromboembolism rt-PA: Recombinant tissue plasminogen activator SICH: Symptomatic intracranial hemorrhage TIA: Transient ischemic attack TIMI: Thrombolysis in Myocardial Infarction WUS: Wake-up stroke From the 1Department of Neurosurgery and Toshiba Stroke Research Center and 2Department of Radiology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo; and 3Department of Neurosurgery, Millard Fillmore Gates Hospital, Kaleida Health, Buffalo, New York, USA To whom correspondence should be addressed: Elad I. Levy, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2010) 74, 4/5:455-464. DOI: 10.1016/j.wneu.2010.06.035 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter © 2010 Elsevier Inc. All rights reserved.

䡲 OBJECTIVE: To report results of endovascular therapy for acute ischemic stroke (AIS) in patients who were not candidates for intravenous thrombolysis (IVT) or in whom IVT failed. 䡲 METHODS: Prospectively collected data for patients treated between January 2006 and June 2009 were analyzed retrospectively. After careful patient and therapy selection, 213 AIS patients with a mean NIHSS score of 14.2 at presentation underwent intervention. End points analyzed were Thrombolysis in Myocardial Infarction (TIMI) 2/3 reperfusion, symptomatic intracranial hemorrhage (SICH) rates, and 90-day outcomes (modified Rankin Scale [mRS] and mortality). Multivariate binary logistic regression analysis was used to assess independent predictors of end points. 䡲 RESULTS: Of 189 patients with anterior circulation occlusions, 135 were treated within 0 – 8 hours, 33 were treated after 8 or more hours, and 21 were treated after wake-up stroke (WUS). Among 24 patients treated with posterior circulation occlusions, 4 had WUS. After treatment, 72.3% patients had TIMI 2/3 reperfusion; SICH rate was 8.7%; at 90 days, 36.6% recovered to mRS 2 or less. SICH rate was higher in patients with anterior circulation strokes who received treatment 8 or more hours after symptom onset (odds ratio [OR] ⴝ 3.8) and patients with WUS (OR ⴝ 4.9). In patients treated within 8 hours of onset of symptoms of anterior circulation stroke, SICH rate was only 6.7%. There was no difference in outcomes in patients with WUS compared with patients treated less than 8 hours after stroke onset. 䡲 CONCLUSIONS: This is the first and largest prospective study to the authors’ knowledge that shows endovascular therapy for AIS patients in a real-world setting. High recanalization rates with low SICH rates were achieved using careful patient and therapy selection.

INTRODUCTION Recent American Heart Association/American Stroke Association (AHA/ASA) guidelines (8) recommend evaluating patients for treatment with intravenous (IV) recombinant tissue plasminogen activator (rt-PA) up to 3– 4.5 hours after stroke, on the basis of European Cooperative Acute Stroke Study (ECASS) III data (14). Less than 1% of patients with acute ischemic stroke (AIS) in the United States receive intravenous thrombolysis (IVT) primarily because of a delay in presentation for treatment (4), although this number may increase with the extended time window of 4.5 hours (8). Approximately 16%–28% of AIS patients have

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wake-up stroke (WUS). These patients are not aware of the time of stroke symptom onset and are excluded from most reperfusion clinical trials (10, 33). Prolyse in Acute Cerebral Thromboembolism (PROACT) (7, 12), Mechanical Embolus Removal in Cerebral Ischemia (MERCI) (13, 36), multiMERCI (35), and Penumbra (29) studies have shown evidence for endovascular AIS therapy up to 8 hours from stroke symptom onset. None of the interventional stroke trials used perfusion imaging for the selection of patients for revascularization therapy, however, and the revascularization tools were prespecified. The number of stroke patients meeting the inclusion criteria in these trials was very small, and many

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screened patients were excluded. These studies do not capture the results of stroke intervention in a real-world setting. The recanalization rates of IV rt-PA for proximal, large-vessel arterial occlusions are poor and range from only 10% for internal carotid artery (ICA) occlusion to 30% for middle cerebral artery (MCA) occlusion (41). IVT is not as effective for the treatment of thromboembolic obstruction of these large, proximal vessels compared with more distal, smaller vessels (32). Early reocclusion after thrombolysis has been shown in 34% of patients receiving IV rt-PA (20, 31). Theoretically, mechanical revascularization strategies increase the benefit of therapy by increasing the recanalization rate and decrease the risk of symptomatic intracranial hemorrhage (SICH) by avoiding the use of thrombolytics. This concept becomes increasingly relevant and important as the time window from stroke symptom onset increases and in patients with large-vessel occlusion. At our center, multimodal computed tomography (CT) stroke imaging, including noncontrast cranial CT scan, CT angiography (CTA), and whole-brain CT perfusion (CTP) (on a 64-slice scanner from January 2006 through September 2008 and a 320slice CT scanner from October 2008 through June 2009), is used to identify patients who are at high risk for SICH. This imaging protocol has allowed us to select patients who would benefit from revascularization and to choose revascularization tools that would allow revascularization beyond the traditional 8-hour time window and in patients with WUS. We previously reported the results after endovascular therapy of a small series of 30 patients with anterior/posterior circulation strokes who presented more than 8 hours after stroke onset or with WUS (27). In this report, we present the prospectively collected results after endovascular therapy to treat AIS in patients who were not candidates for IVT or in whom IVT failed and who were selected for revascularization based on CTP imaging findings. Although CTP was used in all of these patients, it was mainly used as an adjunctive research tool to help us understand how this technology could be included in our decision-making process. We have become increasingly familiar with the nuances of using this tool in the decisionmaking process. The primary aim of this

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study is to report the prospective outcomes after endovascular AIS therapy in a realworld setting where the outcomes of all consecutive patients treated with endovascular therapy at a single center were evaluated without restricting the analysis to time windows, individual therapeutic tools, occlusion locations, or prespecified inclusion or exclusion criteria. The detailed results of the CTP data will be reported separately.

selected based on premorbid functional status and large, at-risk penumbra with limited core infarct and no basal ganglionic core. Only patients with NIHSS score of 8 or greater were selected for revascularization, although we did not have a cutoff for the upper limit of NIHSS score in patients we treated. In patients with NIHSS score greater than 20, a strict risk-benefit analysis was performed before selection for intervention that was based on premorbid functional status, size of infarct, and risk of SICH.

METHODS Study Design Registry data were collected prospectively for patients who had endovascular therapy for AIS between January 2006 and June 2009 at the Millard Fillmore Gates Hospital (a University at Buffalo affiliate). De-identified data were reviewed and analyzed retrospectively after University at Buffalo Institutional Review Board approval with a waiver of informed consent.

Patient Selection A team of endovascular neurosurgeons and stroke neurologists made all treatment decisions. All patients with AIS were proactively screened with CTA to identify largevessel occlusion (cervical ICA, petrous ICA, intracranial ICA, MCA-M1, MCA-M2, anterior cerebral artery [ACA]-A1, intracranial vertebral artery, basilar artery [BA], posterior cerebral artery [PCA]-P1, PCA-P2) up to 12 hours after waking up with a stroke, within 24 hours of symptom onset of anterior circulation stroke, or within 48 hours of symptom onset of posterior circulation stroke. Patients who had contraindications for IVT or in whom IVT failed (either NIHSS score did not improve by 4 points after the first hour of IVT, or NIHSS score improved and then declined after IVT) were evaluated for endovascular stroke therapy. All patients who were evaluated for endovascular therapy had CTP imaging to estimate the ischemic core (cerebral blood volume lesion with ⬍2 mL/100 g of tissue) and penumbra (increased mean transit time ⬎145%) in the occluded territory by comparison with the contralateral territory. Patients who had a penumbra occupying greater than 50% of the occluded territory were identified as patients who would benefit from revascularization. Patients 75 years old or older were

Patients at High Risk for Symptomatic Intracranial Hemorrhage Patients with any of the following characteristics were categorized as high risk for SICH: stroke symptom onset 8 or more hours before treatment or WUS, with early ischemic changes involving more than one third of the occluded territory; Alberta Stroke Programme Early CT Score (ASPECTS) (3) of less than 7; or early ischemic changes in the basal ganglia. We learned during the process of treating these patients that CTP imaging documenting a core lesion occupying greater than 30% of the occluded territory or with core involving the basal ganglia presented a high SICH risk. We have learned that CTP may be unreliable in predicting the core in the first 1–2 hours after stroke onset. In patients at high risk for SICH, revascularization was opted only after strict risk-benefit analysis. Diffusion-weighted magnetic resonance imaging was not used for decision making in any patient in this study.

Therapy Selection Mechanical maneuvers for revascularization, including current U.S. Food and Drug Administration (FDA)–approved modalities (Merci, Concentric Medical, Mountain View, CA, USA; and Penumbra, Penumbra, Inc., Alameda, CA, USA), were our team’s first choice for endovascular therapy in preference to intra-arterial pharmacologic thrombolysis (IAT). Wingspan (Boston Scientific, Natick, MA, USA) or Enterprise (Codman & Shurtleff, Inc., Raynham, MA, USA) stents, coronary balloon-mounted stents, balloon angioplasty, and extracranial stents were used as a bailout maneuver for patients in whom vessels could not be recanalized with current FDA-approved modalities and who had an occlusion at a

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site where a stent could be placed under a Humanitarian Device Exemption or on a compassionate-use basis. Early in our experience, we used the Merci device and mechanical thrombus disruption (wire manipulation and angioplasty) for mechanical therapy. Initially, we used the Wingspan stent as a revascularization tool after the aforementioned revascularization tools failed to recanalize the target vessel. Toward the end of this experience, we received approval from the FDA to use the Wingspan stent as a primary revascularization tool in 20 patients (previously reported in the Stent-Assisted Recanalization in acute Ischemic Stroke [SARIS] trial (24)). We started using the Penumbra device in the latter part of the experience (when it became available) and currently have switched to using the Penumbra device in preference to the Merci device. IAT was used only as an adjunct to mechanical therapy or when an occlusion was located at a site that was inaccessible with currently available mechanical devices. IA eptifibatide was used when reocclusion owing to thrombus formation was seen after recanalization during the procedure and in distal vessels that could not be reached via endovascular devices if the patient had contraindications for rt-PA. In patients considered at high risk for SICH, revascularization was avoided unless the patient was young, presentation was within 8 hours, and the occlusive lesion could be reached with mechanical revascularization tools. IAT and IA eptifibatide were not used in patients at high risk for SICH. Our protocol for patient and therapy selection is summarized in Figure 1. Perioperative Protocol Endovascular stroke therapy was carried out under conscious sedation to allow continuous monitoring of the patient’s neurologic examination, unless there was a specific indication for general anesthesia (e.g., large dominant-hemisphere stroke, airway compromise, or an uncooperative patient). Every patient considered for endovascular treatment was given a bolus of IV heparin that was weight-adjusted to maintain the activated coagulation time in the range of 250 –300 seconds. If eptifibatide was used during the procedure, the activated coagulation time was maintained at less than 200 seconds to minimize bleeding. If the patient was not taking aspirin or clopidogrel

Figure 1. Flow chart of the authors’ protocol for patient and therapy selection. See Abbreviations and Acronyms list for all abbreviations.

(or ticlopidine), a loading dose of aspirin (650 mg; enteric-coated, if necessary) was administered immediately before the procedure. Patients considered for stent placement were given a loading dose of either clopidogrel (600 mg) or ticlopidine (1 g). Aspirin (325 mg daily; enteric-coated, if necessary) and clopidogrel (75 mg daily)

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were continued after stent placement (aspirin for lifetime; clopidogrel or ticlopidine for 90 days). After revascularization therapy, patients were observed in the intensive care unit for 12–24 hours, during which time a blood pressure no greater than 150/90 mm Hg was maintained to avoid reperfusion injury. All stroke patients were

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evaluated by a stroke neurologist who performed an extensive work-up to identify stroke etiologies and subsequently devised interventions for comorbidities, including management of obesity and lifestyle modification.

Data Collection The following data were collected:

y Patient characteristics: Age; sex; comorbid conditions; smoking status; previous stroke or transient ischemic attack (TIA); IVT failure; antiplatelet, warfarin, or statin therapy at presentation; time of stroke onset, if known; presentation NIHSS score; occlusion location; occlusion severity graded by Thrombolysis in Myocardial Infarction (TIMI) score (39).

y Treatment characteristics: Time to treatment (time IVT was started or groin was punctured for angiography if patient had only endovascular revascularization), intervention type, eptifibatide use.

y Outcomes: TIMI 2/3 recanalization after intervention, complications after intervention, intracranial hemorrhage rates (symptomatic if NIHSS score decreased by ⱖ4 points), 90-day outcomes (mortality and modified Rankin Scale [mRS] score 0 –2 [good outcome], mRS 3– 6 [poor outcome]). Presentation NIHSS, TIMI, and outcome mRS scores were obtained by NIHSS-certified members of the endovascular team by face-to-face interview or by telephonic interview if the patient was unable to come to the clinic.

End Points and Covariates The following end points were analyzed: TIMI 2/3 recanalization rate, SICH, 90-day mortality, and poor 90-day outcome. The covariates analyzed were age (dichotomized as ⱖ75 and ⬍75 years); sex; diabetes; hypertension; hyperlipidemia; atrial fibrillation; smoking status; post-IVT failure; NIHSS score (dichotomized as ⱖ20 and ⬍20); time of stroke treatment (categorized as anterior circulation stroke ⬍8 hours, anterior circulation stroke ⱖ8 hours, anterior circulation WUS, and posterior circulation stroke); occlusion locations (extracranial occlusion, tandem extracranial-intracranial [EC-IC] occlusion, carotid-terminus occlu-

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sion, MCA-M1 or MCA-M2 occlusion [or both]); types of therapies (IAT, Penumbra suction, Merci retrieval, intracranial stent placement, intracranial thrombus disruption other than stent placement [wire manipulation and angioplasty], extracranial stenting, and IA eptifibatide administration).

had previous stroke (ipsilateral in 24, contralateral in 13, bilateral in 4); and 21 patients had previous TIA (ipsilateral in 19, contralateral in 1, bilateral in 1). Some of the patients included in this study have been included as a part of previous studies (24, 26).

Statistical Analysis Age and NIHSS score, which are continuous variables, were dichotomized into categorical variables for regression analysis. Univariate analysis of the covariates was performed to look for predictors of end points with P ⬍ 0.2. Multivariate stepwise backward logistic regression analysis was built with all these covariates (those having P values ⬍ 0.2) identified by univariate analysis to determine independent predictors of the following end points: recanalization (TIMI 2/3), SICH, 90-day mortality, and 90day worse outcome. In the model built to determine predictors of recanalization, SICH was not included as a covariate. All statistical analysis was done using SPSS 17.0 software (SPSS Inc., Chicago, IL, USA). Adjusted odds ratios (ORs) with 95% confidence intervals (CI) were derived for significant predictors from the multivariate model (P ⬍ 0.05 was considered significant).

Occlusions There were 189 patients with anterior circulation occlusions (MCA-M1 in 109, MCA-M2 in 73, extracranial carotid in 38, carotidterminus in 35, ACA in 17, petrous ICA in 10) and 24 patients with posterior circulation occlusions (distal BA in 12, proximal BA in 9, PCA–P1 segment in 4, PCA–P2 segment in 5). Occlusion grades at presentation were TIMI 0 in 178 patients and TIMI 1 in 35 patients. Of the patients with anterior circulation occlusions, 66 had multiple occlusion sites (tandem EC-IC occlusions in 26 patients [of these, 6 had multiple intracranial occlusions] and multiple intracranial occlusions in 40 patients). In the posterior circulation, there were no extracranial occlusions, and six patients had multiple intracranial occlusions.

RESULTS Demographics This study included 213 patients (25 with WUS; 188 with known time of stroke onset) with mean presentation NIHSS score of 14.2 ⫾ 5.3 (median 15, interquartile [IQ] range 10 –18). The average age was 68.5 years ⫾ 17.1 (median 73 years, IQ range 60 – 81 years). There were 93 men and 120 women; 51 (23.9%) patients were known to have diabetes, 135 (63.4%) were known to have hypertension, 79 (37.1%) were known to have dyslipidemia, 77 (36.2%) had a history of atrial fibrillation, and 81 (38.0%) were smokers. Of patients, 77 were on antiplatelet therapy (aspirin in 51, clopidogrel in 12, aspirin and clopidogrel in 12, aspirin and extended-release dipyridamole in 2); 34 were on warfarin therapy (among them, 5 were also taking aspirin and 2 were taking aspirin and clopidogrel), and 52 were on statin therapy. Fifty-five patients had previous stroke or TIA (7 had both); 41 patients

Treatment Characteristics The average time from stroke onset to initiation of revascularization therapy in the anterior circulation was 356 minutes ⫾ 340 (median 260 minutes, range 34 –1126 minutes [18.8 hours]) (treatment within 0 – 8 hours, n ⫽ 135 patients; treatment after ⱖ8 hours, n ⫽ 33 patients), and 21 patients were treated after WUS. Among 24 patients with posterior circulation occlusions, the average time to treatment initiation was 262 minutes ⫾ 292 (median 148 minutes, range 50 –1370 minutes), and 4 of these patients had WUS (included with the posterior circulation stroke cohort for analysis). The average groin puncture–to–recanalization time was 78.0 minutes ⫾ 40.4 (median 72 minutes) in patients with anterior or posterior circulation strokes who achieved TIMI 2/3 recanalization. A total of 188 patients were treated primarily by endovascular therapy because they had large-vessel occlusions; 25 patients had endovascular therapy after failed IVT. Mechanical therapies included Merci retrieval in 115 patients, intracranial stent placement in 61 patients, intracranial mechanical thrombus disrup-

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DISCUSSION

Table 1. End Points Achieved According to Time of Stroke Treatment

N

TIMI 2/3 Recanalization Rate (%)

⬍8 hours AC

135

68.9

6.7

40

25.2

ⱖ8 hours AC

33

69.7

15.2

18.2

33.3

WUS AC

21

81

14.3

42.9

23.8

PC

24

87.5

8.3

37.5

37.5

Time of Stroke Treatment

SICH Rate (%)

mRS 0–2 at 90 Days

Mortality at 90 Days

TIMI, thrombolysis in myocardial infarction; SICH, symptomatic intracranial hemorrhage; mRS, modified Rankin scale; AC, anterior circulation; WUS, wake-up stroke; PC, posterior circulation.

tion other than stents (including microwire manipulation and balloon angioplasty) in 56 patients, extracranial stenting in 41 patients, and Penumbra aspiration in 18 patients. Fifty-five patients received IA eptifibatide; all 213 patients received heparin. IAT was used in 86 patients.

Outcomes Of 213 patients, 154 (72.3%) had excellent (TIMI 3 in 75 patients) to good (TIMI 2 in 79 patients) flow after endovascular treatment. Post-treatment hemorrhage occurred in 68 patients (31.9%) (HI 1 in 25, HI 2 in 20, PH 1 in 15, PH 2 in 9 [ECASS II grades (23)]). SICH occurred in 19 patients (8.9%) (TIMI 2/3 in 15, TIMI 0/1 in 4), and subarachnoid hemorrhage occurred in 25 patients (11.7%). Seven patients had intraprocedural perforations that were managed conservatively and were not associated with further complications. Myocardial infarction occurred in 4 patients, renal failure occurred in 3 patients, and access-site complications occurred in 13 patients. At 90 days, the overall mortality was 27.7% (n ⫽ 59), and 36.6% (n ⫽ 78) recovered to mRS 0 –2. Outcomes were available for all study patients at 90 days, and there were no missing data or any patients lost to follow-up. The end points achieved according to the time of stroke treatment are shown in Table 1.

Univariate Analysis for Predictors In the univariate analysis, the significant predictors for an inability to achieve TIMI 2/3 recanalization were carotid-terminus occlusion (P ⫽ 0.028) and time category of stroke onset (anterior circulation occlusion with known time onset compared with WUS and posterior circulation occlusion,

P ⫽ 0.044). Significant predictors of SICH were atrial fibrillation (P ⫽ 0.039) and tandem EC-IC occlusion (P ⫽ 0.049). Significant predictors of a poor 90-day outcome (mRS 3– 6) were age 75 years or older (P ⫽ 0.012), SICH (P ⫽ 0.013), and tandem occlusion (P ⫽ 0.05). The only significant predictor of 90-day mortality was atrial fibrillation (P ⫽ 0.014). Other predictors that had a P value ⬍ 0.2 for all the end points and that were included in the respective multivariate models are shown in Table 2.

Multivariate Analysis of Predictors In the multivariate analysis, carotid-terminus occlusion was the only independent predictor of inability to achieve TIMI 2/3 recanalization (P ⫽ 0.03). The independent predictors of higher SICH rate were atrial fibrillation (P ⫽ 0.012), tandem EC-IC occlusion (P ⫽ 0.025), 8-hour or later anterior circulation strokes (P ⫽ 0.04), and wake-up anterior circulation strokes (P ⫽ 0.047). In patients with atrial fibrillation, SICH rate was not higher in patients who were on anticoagulation therapy at presentation. The independent predictors of 90-day worse outcome (mRS 3– 6) were age 75 years or older (P ⫽ 0.003), tandem EC-IC occlusion (P ⫽ 0.03), and SICH after treatment (P ⫽ 0.036). The only independent predictor of 90-day mortality was atrial fibrillation (P ⫽ 0.01). Male patients showed a tendency for higher 90-day mortality (P ⫽ 0.07), and patients receiving treatment 8 hours or more after anterior circulation stroke trended to having worse 90-day outcome (P ⫽ 0.068). Adjusted OR (OR adjusted for variations in other predictors) and 95% CI are shown in Table 3.

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In this prospective study of 213 patients with AIS who were selected for revascularization therapy, we were able to attempt endovascular therapy safely in patients with anterior circulation strokes up to 18.8 hours after stroke onset, with posterior circulation strokes, and with WUS. To our knowledge, this is the largest and only prospective study in which endovascular therapy for AIS was used beyond traditional time windows. Although CTP imaging was performed on all these patients, it was mainly used as an adjunctive research tool during the initial period of this study. We now have accumulated data over the study period that are being analyzed but are not included as a part of this report. Patients with carotid-terminus occlusion had a significantly lower chance of achieving TIMI 2/3 recanalization (57.1%). TIMI 2/3 recanalization was achieved in 72.3% of patients in the total group and in 75.3% after the exclusion of patients with carotidterminus occlusion. Patients with ICA-terminus (ICA-T) occlusions have been reported to have lower recanalization rates (48%) and poorer response to IVT than patients with MCA occlusions (41). Small retrospective studies (2, 21, 37) show poor recanalization rates (0%–12.5%) with IAT and worse outcomes in these patients (16% mRS ⱕ2 at 3 months). Improved recanalization rates (63%) and outcomes (25% mRS ⱕ2 at 3 months) have been reported with Merci retrieval (11). In our series, the recanalization rate for ICA-terminus occlusions was low (57.1%); nevertheless, 25.7% of these patients recovered to mRS 2 or less at 3 months. The ability to recanalize distal ICA occlusions may be low because of a larger clot burden, especially in patients who have clots extending into the A1 and the M1 segments. Of the 19 patients who had SICH, only 10.5% of patients recovered to mRS 0 –2, and SICH was an independent predictor of worse outcome (OR 5.1, P ⫽ 0.036). This finding re-emphasizes the importance of avoiding SICH and using the risk of SICH as an important component in the decisionmaking process. Despite achieving such high recanalization rates and treating patients beyond the traditional time windows, the overall SICH rate (8.9%) was acceptable. Patients treated with 8-hour or later anterior circulation strokes and WUS had

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Table 2. Predictors with P Value ⬍ 0.2 by Univariate Analysis Entered in Multivariate Models for Respective End Points

End Points Recanalization (TIMI 2/3)

SICH

mRS 3–6 (poor outcome) at 90 days

Mortality at 90 days

Predictors

P Value

Patients Achieving End Point vs the Rest* (%)

Carotid terminus occlusion

0.028

57.1 vs 75.3

Time category (⬍8 hours, ⱖ8 hours, WUS, PC)

0.044

69, 70, 81, 88

Atrial fibrillation

0.071

64.9 vs 76.5

Hypertension

0.075

68.1 vs 79.5

Penumbra

0.1

88.9 vs 70.7

Intracranial thrombus disruption

0.119

64.3 vs 75.2

Atrial fibrillation

0.039

14.3 vs 5.9

Tandem occlusion

0.049

19.2 vs 7.5

Extracranial carotid occlusion

0.101

15.8 vs 7.4

Time category (⬍8 hours, ⱖ8 hours, WUS, PC)

0.171

6.7, 15.2, 14.3, 8.3

Merci retrieval

0.186

11.3 vs 6.1

Age ⱖ75 years

0.012

72.6 vs 55.9

SICH

0.013

89.5 vs 60.8

Tandem occlusion

0.05

80.8 vs 61

Merci retrieval

0.081

68.7 vs 57.1

Eptifibatide

0.114

54.5 vs 68.5

Time category (⬍8 hours, ⱖ8 hours, WUS, PC)

0.119

60, 81.8, 57.1, 62.5

Carotid terminus occlusion

0.143

74.3 vs 61.2

Atrial fibrillation

0.014

37.7 vs 22.1

Intracranial stenting

0.097

19.7 vs 30.9

M1 MCA

0.112

22.9 vs 32.7

Age ⱖ75 years

0.149

32.6 vs 23.7

Male

0.163

33.3 vs 23.3

Note: Italicized predictors were the only significant predictors with P value ⬍ 0.05 by univariate analysis. TIMI, thrombolysis in myocardial infarction; WUS, wake-up stroke; PC, posterior circulation; SICH, symptomatic intracranial hemorrhage; mRS, modified Rankin scale; MCA, middle cerebral artery. *The rest are patients not having the particular predictor.

significantly higher SICH rates (15.2% and 14.3%). In patients with less than 8-hour anterior circulation strokes, SICH rate was only 6.7%. This finding emphasizes the need for careful patient and therapy selection to achieve high recanalization rates with acceptable SICH rates, even beyond the 8-hour time window. Patients with 8-hour or later anterior circulation stroke had higher SICH rates and showed a trend toward a worse outcome (only 18.2% recovering to mRS 0 –2 at 90 days), whereas there was no difference in

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outcome in patients with WUS (42.9% recovering to mRS 0 –2 at 90 days) compared with less than 8-hour anterior circulation strokes. These results may be explained by the fact that patients with WUS are a mixed group of patients who are less than 8 or 8 or more hours from stroke symptom onset when they present for treatment; some WUS patients might be in the high-risk SICH group. The number of WUS patients in this study may not be large enough to detect difference in outcomes. Conflicting results for WUS treatment have been re-

ported. Barreto et al. (5) reported that among patients receiving IVT, patients with WUS and patients treated within 3 hours had similar outcomes, whereas in the posthoc analysis of WUS in the AbESTT-II trial, poorer outcomes were reported after treatment (1). The present study is to our knowledge the first to show comparative effectiveness of endovascular therapy for WUS and anterior circulation strokes within 8 hours of symptom onset. This finding needs to be evaluated in larger randomized trials. In posterior circulation strokes, the evolution of clinical symptoms is often gradual, making precise assessment of the time of stroke symptom onset and of the time window for treatment difficult. Atherothrombosis (unstable plaque with thrombus) is more common in posterior circulation strokes, making the risk of reocclusion after recanalization higher (6, 15, 18, 42). A meta-analysis of IAT in BA occlusion (34) showed a recanalization rate of 64% and a mortality rate of 87% in patients in whom recanalization was not achieved, with a significant (P ⬍ 0.001) reduction in mortality to 37% among patients in whom recanalization was achieved. Among patients with posterior circulation stroke in the present series, the recanalization rate was 87.5%, SICH rate was 8.3%, and 37.5% of patients recovered to mRS 0 –2 at 90 days, even after treating patients up to 22.8 hours after posterior circulation stroke onset. Despite the selection of patients for revascularization beyond the traditional time window and treating WUS and posterior circulation strokes, 36.6% patients had a good outcome at 90 days, and the mortality rate (27.7%) was acceptable. In our series, age was an important predictor of outcome. Among patients younger than 75 years, 44.1% recovered to mRS 0 –2, and the mortality rate was only 23.3% at 90 days. A systematic review (9) suggested that older patients are less likely to have a favorable functional outcome, are more likely to have a higher mortality rate, and have a similar risk of SICH. In a multicenter IVT study (40), patients older than 80 years had a higher mortality, but there were no differences for SICH or for favorable outcome. Our patients with atrial fibrillation had higher SICH rates (14.3%) that could not be explained by their anticoagulation status, and the presence of atrial fibrillation was

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ENDOVASCULAR STROKE THERAPY BEYOND TRADITIONAL TIME WINDOWS

Table 3. Significant Independent Predictors of End Points by Multivariate Analysis End Points

Predictors

Adjusted OR

95% CI

P Value

Recanalization

Carotid terminus

0.431

0.202–0.921

0.03

SICH

Atrial fibrillation

3.934

1.358–11.399

0.012

Tandem occlusion

3.908

1.184–12.905

0.025

ⱖ8 hours anterior circulation

3.819

1.066–13.682

0.04

mRS 3–6 at 90 days

Mortality at 90 days

WUS anterior circulation

4.914

1.025–23.57

0.047

Age ⱖ75 years

2.533

1.373–4.672

0.003

Tandem occlusion

3.326

1.123–9.849

0.03

Merci retrieval

1.956

1.067–3.587

0.03

SICH

5.139

1.109–23.804

0.036

ⱖ8 hours anterior circulation

2.547

0.934–6.944

0.068

Atrial fibrillation

2.258

1.210–4.212

0.01

Male

1.773

0.955–3.291

0.07

Note: Italics denote predictors showing a trend. OR, odds ratio; CI, confidence interval; SICH, symptomatic intracranial hemorrhage; WUS, wake-up stroke; mRS, modified Rankin scale.

the only independent predictor of mortality (OR 2.26, P ⫽ 0.01). Atrial fibrillation is a surrogate parameter of cardioembolic stroke with well-known higher bleeding rates in patients receiving IVT (19, 22, 28, 38). The Interventional Management of Stroke (IMS) I study showed a significant increased risk of SICH in patients with atrial fibrillation (16). In the future, this cohort may be considered high risk for SICH after stroke intervention, and avoidance of pharmacologic thrombolysis and eptifibatide use in these patients may reduce the incidence of SICH. Patients with tandem EC-IC occlusions had higher SICH rates (OR 3.91, P ⫽ 0.025) and worse 90-day outcomes (OR 3.33, P ⫽ 0.03). Small retrospective series (25, 30) report the presence of a tandem EC-IC lesion as a predictor for poor outcome and lower chance of recanalization with IVT. Consequently, authors recommend these patients undergo more aggressive revascularization procedures. In our series, good recanalization rates (73.1%) were achieved in patients with tandem occlusions, albeit with higher SICH rates (19.2%), and only 19.2% patients recovered to mRS 0 –2 at 90-days. These patients need to be categorized as high risk for SICH and need better risk-benefit analysis before revascularization. Patients in our series who underwent revascularization with a Merci device (n ⫽ 115) had comparable recanalization rates

(71.3%) but had a higher chance of a worse outcome (OR 1.96, P ⫽ 0.03) (only 31.3% recovered to mRS 0 –2). These patients had higher SICH rates (11.3%), although Merci revascularization was not an independent predictor of SICH by multivariate analysis. This finding may be explained by our policy of confining patients at high risk for SICH to endovascular therapy with only mechanical devices. Only 18 patients had revascularization with a Penumbra device because we started using it at the end of 2008. The recanalization rate associated with this device was 88.9%, SICH rate was 11%, and 38.9% recovered to mRS 0 –2. Our assessment of the Penumbra device is limited because of the small number of treated occlusions. These mechanical devices need to be evaluated in multicenter randomized trials. In the present study, 61 (28.6%) patients had intracranial stent placement (with balloon-expandable or self-expanding stents) for revascularization. Although stent placement requires perioperative and postoperative antiplatelet therapy, SICH rate in these patients was only 11.5%. In our series, the mortality for the intracranial stenting group was only 19.7%; and 37.7% recovered to mRS 0 –2 at 90 days. The recanalization rate was 73.8%. With self-expanding intracranial stents, the recanalization rate was 100%, and 45% recovered to mRS 0 –2 at 90 days (24, 26). The main limitations of the use of intravascular stents for stroke revas-

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cularization are the ability to navigate to more distal occlusions, the need to use more than one stent for long occlusions, and the lack of long-term follow-up. Recanalization was not an independent predictor of 90-day outcomes in our study. In patients who achieved TIMI 2/3 recanalization, SICH rate was 9.7%, and 38.3% recovered to mRS 0 –2. In patients who did not achieve TIMI 2/3 recanalization, SICH rate was 6.8%, and only 32.2% patients recovered to mRS 0 –2. These differences were not statistically significant because the study was not powered to detect these differences. This contrasts with the results of the MERCI trial and the multi-MERCI trial, in which a statistically significant difference in outcomes between these groups was shown, even though only approximately 80 patients were included in each arm. In our study, there were only 59 patients in the nonrecanalized group, however. We treated patients 8 hours after stroke onset and patients with WUS, which are groups that could potentially have worse outcome despite TIMI 2/3 recanalization compared with patients treated within 8 hours of stroke symptom onset. Our study data are not directly comparable with the trial data in Table 3 because of contrasts in patient characteristics, treatment selection, and study design. Table 4 re-emphasizes the fact that in the present study, we were able to achieve high recanalization rates, acceptable SICH rates, and comparable outcomes even after treating patients beyond traditional time windows and a low SICH rate in patients with less than 8-hour anterior circulation strokes. This study emphasizes the importance of careful patient and treatment selection and shows the feasibility of endovascular revascularization beyond traditional time windows. The main limitations of this study are that it was from a single center, it was not randomized, and a detailed analysis of CTP parameters has not been included in this report. The subgroup analysis and the prediction of end points may not be accurate because patients were preselected into these groups, and the study may have been underpowered to identify other important predictors of end points. The experience at our center and our treatment protocols may not be comparable to or in agreement with experience and treatment protocols at other centers, and the 320-slice CT scanner is not

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Type of Study

Treatment

Time Window from Symptom Onset (hours)

Mean Presentation NIHSS

Recanalization Rate (%)

SICH Rate (%)

mRS <2 or <1* at 3 Months (%)

Mortality at 3 Months (%)

Study

No. Patients

PROACT I

40 (26 vs 14)

RCT

IA r-prourokinase (6 mg) ⫹ IV heparin (high or low dose) vs IV heparin (high or low dose)

0–6 (only MCA occlusions)

17 vs 19

57.7 vs 14.3

15.4 vs 7.1

30.8 vs 21.4*

26.9 vs 42.9

PROACT II

180 (121 vs 59)

RCT

IA r-prourokinase (9 mg) ⫹ IV heparin (low dose) vs IV heparin (low dose)

0–6 (only MCA occlusions)

17 vs 17

66 vs 18

10 vs 2

40 vs 25

25 vs 27

43, 30*

16%

Prospective

IV rt-PA (0.6 mg/kg) ⫹ IA rt-PA (4 mg in clot ⫹ 9 mg/hr) (if clot identified by angiography after IVT) ⫹ low-dose IV heparin

0–3

18

56

6.30

IMS II

81 (IAT, 55)

Prospective

IV rt-PA (0.6 mg/kg) ⫹ IA rt-PA (22 mg over 2 hours using EKOS MicroLysUS infusion catheter [EKOS, Bothell, WA, USA]) or normal catheter) (if clot identified by angiography after IVT) ⫹ low-dose IV heparin

0–3

19

58

9.90

46

16

MERCI

141

Prospective

IA Merci (generation I) ⫹ IAT, no IVT

0–8

20

60.3 (48 device alone)

7.80

36

34

Multi MERCI

164

Prospective

IA Merci (generation I and II) ⫹ IAT ⫹ IVT allowed

0–8

19

68 (55 device alone)

9.80

36

26

Penumbra

125

Prospective

IA Penumbra ⫹ IAT

0–8

17

81.6 (device alone)

11.20

25

32.80

Present study (all patients)

213

Prospective

Any endovascular revascularization

0–18.8 hours including posterior circulation strokes and WUS

14.2

72.3

8.9

36.6

27.7

Present study (0–8 hours anterior circulation subgroup)

135

Prospective

Any endovascular revascularization

0–8 (anterior circulation)

14.5

68.9

6.7

40.0

25.2

Note: Randomized controlled trials (RCT) results are presented for treatment group versus control group. NIHSS, National Institutes of Health Stroke Scale; mRS, modified Rankin scale; PROACT, prolyse in acute cerebral thromboembolism; rt-PA, recombinant tissue plasminogen activator; IA, intra-arterial; IV, intravenous; IMS, interventional management of stroke; MERCI, mechanical embolus removal in cerebral ischemia.

PEER-REVIEW REPORTS

80 (IAT, 62)

ENDOVASCULAR STROKE THERAPY BEYOND TRADITIONAL TIME WINDOWS

WORLD NEUROSURGERY, DOI:10.1016/j.wneu.2010.06.035

IMS I

SABAREESH K. NATARAJAN ET AL.

462 Table 4. Comparison of Previous Interventional Stroke Trials with the Present Study

PEER-REVIEW REPORTS SABAREESH K. NATARAJAN ET AL.

available at many stroke centers. Another limitation of this study is that the outcomes of patients treated with IVT during this time at our center are unavailable for comparison. Because the study data were collected prospectively, it may be comparable, albeit with the above-mentioned limitations, to the prospective nonrandomized IMS (16, 17), MERCI (13, 36), multi-MERCI (35), and Penumbra studies (29).

CONCLUSIONS To our knowledge, this is the first and the largest prospective study that shows the feasibility of endovascular revascularization in a real-world setting. It also shows the importance of careful patient and therapy selection in achieving higher recanalization rates with acceptable SICH rates.

ACKNOWLEDGMENTS The authors thank Rocco A. Paluch, MA, for verifying the statistical methods used in this report; Paul H. Dressel, BFA, for preparation of the illustration; and Debra J. Zimmer, AAS CMA-A, for editorial assistance.

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Conflict of interest statement: Dr. Hopkins receives research study grants from Abbott (ACT 1 Choice), Boston Scientific (CABANA), Cordis (SAPPHIRE WW), and ev3/ Covidien Vascular Therapies (CREATE) and a research grant from Toshiba (for the Toshiba Stroke Research Center); has an ownership/financial interest in AccessClosure, Boston Scientific, Cordis, Micrus, and Valor Medical; serves on the Abbott Vascular Speakers’ Bureau; receives honoraria from Bard, Boston Scientific, Cordis, and from the following for speaking at conferences - Complete Conference Management, Cleveland Clinic, and SCAI; receives royalties from Cordis (for the AngioGuard device), serves as a consultant to or on the advisory board for Abbott, AccessClosure, Bard, Boston Scientific, Cordis, Gore, Lumen Biomedical, and Toshiba; and serves as the conference director for Nurcon Conferences/Strategic Medical Seminars LLC. Dr. Levy receives research grant support (principal investigator: Stent-Assisted Recanalization in acute Ischemic Stroke, SARIS), other research support (devices), and honoraria from Boston Scientific and

research support from Codman & Shurtleff, Inc. and ev3/ Covidien Vascular Therapies; has ownership interests in Intratech Medical Ltd. and Mynx/Access Closure; serves as a consultant on the board of Scientific Advisors to Codman & Shurtleff, Inc.; serves as a consultant per project and/or per hour for Codman & Shurtleff, Inc., ev3/Covidien Vascular Therapies, and TheraSyn Sensors, Inc.; and receives fees for carotid stent training from Abbott Vascular and ev3/Covidien Vascular Therapies. Dr. Levy receives no consulting salary arrangements. All consulting is per project and/or per hour. Dr. Siddiqui has received research grants from the National Institutes of Health (coinvestigator: NINDS 1R01NS064592-01A1, Hemodynamic induction of pathologic remodeling leading to intracranial aneurysms) and the University at Buffalo (Research Development Award); holds financial interests in Hotspur, Intratech Medical, StimSox, and Valor Medical; serves as a consultant to Codman & Shurtleff, Inc., Concentric Medical, ev3/Covidien Vascular Therapies, GuidePoint Global Consulting, and Penumbra; belongs to the speakers’ bureaus of Codman & Shurtleff, Inc. and Genentech; serves on an advisory board for Codman & Shurtleff; and has received honoraria from Abbott Vascular, American Association of Neurological Surgeons’ courses, an emergency medicine conference, Genentech, Neocure Group LLC, an Emergency Medicine Conference, and from Abbott Vascular and Codman & Shurtleff, Inc. for training other neurointerventionists in carotid stenting and for training physicians in endovascular stenting for aneurysms. Dr. Siddiqui receives no consulting salary arrangements. All consulting is per project and/or per hour. Dr. Hauck, Dr. Natarajan, Dr. Ohta, and Dr. Snyder report no disclosures. received 25 March 2010; accepted 17 June 2010 Citation: World Neurosurg. (2010) 74, 4/5:455-464. DOI: 10.1016/j.wneu.2010.06.035 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter © 2010 Elsevier Inc. All rights reserved.

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