a b s t r a c t

Background: The American Heart Association/American Stroke Association guidelines strongly recommend a noninvasive intracranial vascular study such as computed tomographic (CT) angiogram in acute stroke patient if endovascular treatment is contemplated.

Objective: The objective was to determine the frequency of change in occlusion site between CT angiogram and cerebral angiogram in acute ischemic stroke patients undergoing endovascular treatment.

Methods: All acute ischemic stroke patients who underwent a CT angiogram and subsequently underwent endovascular treatment were included. The CT and cerebral angiographic images were reviewed independently to determine presence and location of arterial occlusion. Severity of occlusion was classified by a previously de- scribed grading scheme. Clinical outcome at discharge was determined using Modified Rankin scale.

Results: Computed tomographic angiogram was performed in 150 patients (mean age +- SD, 64.7 +- 16 years) be- fore endovascular treatment. The mean interval (+-SD) between CT angiogram and cerebral angiogram was 193

+- 164 minutes, and 65 (43.3%) of 150 patients received intravenous recombinant tissue plasminogen activator before cerebral angiography. Recanalization between CT angiogram and cerebral angiography was seen in 28 (18.7%) patients, whereas worsening of occlusion was seen in 31 (20.7%) patients. We noticed a trend towards higher rates of improvement (60.7% vs 42.0%, P = .07) and favorable outcome at discharge (42.9% vs 28.7%, P = .1) among patients who experienced preprocedure recanalization. After adjusting for age and initial National Institutes of Health Stroke Scale score strata, preprocedure recanalization was not associated with significantly higher rate of favorable outcome (modified Rankin scale, 0-2) at discharge (odds ratio, 2.1; 95% confidence inter- val, 0.8-5.5). After adjusting for age and National Institutes of Health Stroke Scale score strata, preprocedure worsening was not associated with significantly lower rates of favorable outcomes at discharge (odds ratio,0.4; 95% confidence interval, 0.1-1.4).

Conclusions: A relatively high proportion of patients have preprocedure recanalization or worsening between CT angiogram and cerebral angiogram in acute ischemic stroke patients selected for endovascular treatment.

(C) 2015

Background

The American Heart Association/American Stroke Association guide- lines strongly recommend a noninvasive intracranial vascular study such as computed tomographic (CT) angiogram during the initial imag- ing evaluation of the acute stroke patient if either intraarterial throm- bolysis or Mechanical thrombectomy is contemplated (Class I, Level of evidence A) [1]. Several institutions have incorporated CT angiogram

? Financial support: none.

?? Conflict of interest: none.

* Corresponding author at: Department of cerebrovascular diseases and Interventional Neurology, CentraCare Health System, 1406 6th Ave N, St Cloud, MN 56303. Tel.: +1 320 281 5545; fax: +1 320 281 5547.

E-mail address: [email protected] (A.I. Qureshi).

as part of the protocol to triage acute ischemic stroke patients who may be candidates for endovascular treatment [2-4]. The interventional management of Stroke III trial [5] incorporated acute ischemic stroke patient selection based on demonstration of arterial occlusion on CT an- giogram. Overall, 190 of the 423 patients randomized to endovascular treatment had confirmed arterial occlusion by preprocedure CT angio- gram. However, 80 of 423 randomized to endovascular treatment did not receive any endovascular treatment because of lack of occlusion deemed treatable on initial cerebral angiography performed as part of endovascular treatment. Such an observation suggests that status of oc- clusion may have changed with preprocedure recanalization before endovascular treatment. However, the rate and extent of preprocedure change in arterial occlusion between CT angiogram and cerebral angio- gram performed as part of endovascular treatment in acute ischemic stroke patients are not known. We performed this study to determine the frequency of change in occlusion site in acute ischemic stroke

http://dx.doi.org/10.1016/j.ajem.2015.01.054

0735-6757/(C) 2015

632 A.I. Qureshi et al. / American Journal of Emergency Medicine 33 (2015) 631-634

patients undergoing endovascular treatment based on CT angiogram- demonstrated arterial occlusion. Furthermore, we determined the effect of preprocedure recanalization on neurological improvement and out- come at discharge.

Methods

We reviewed all patients who were considered for endovascular treatment between February 2007 and March 2011 at 2 university- affiliated hospitals. The 2 institutions maintained a prospectively col- lected endovascular procedure database that recorded information re- garding the procedural components, devices used, and intraprocedural medication with doses. The protocols for collecting data were approved by the Institutional Review Boards at each institution. The details of these databases have been published previously [6-10].

We analyzed data from patients who had undergone a CT angiogram and had a documented arterial occlusion before performance of cerebral angiogram as part of the endovascular treatment. The presence of car- diovascular risk factors (active cigarette smoking, hypertension, atrial fibrillation, coronary artery disease, hyperlipidemia, diabetes mellitus, prior transient ischemic attack or ischemic stroke), time interval between symptom onset and endovascular treatment, and use of intravenous (IV) recombinant tissue plasminogen activator (rt-PA) were ascertained. The initiation of procedure was defined by time of microcatheter placement at the site of occlusion. Varying combinations of pharmacological agents and/or mechanical thrombus disruption and/ or retrieval were used. The techniques for administration of thrombo- lytics and thrombectomy through the microcatheter are described in detail in previous publications [6,11-14]. We also ascertained National Institutes of Health Stroke Scale scores upon admission and at 24 hours after treatment. Outcomes at time of discharge were assessed using modified Rankin Scale (mRS).

One of the 3 senior endovascular surgical neuroradiology fellows (AM, FS, or DK) reviewed the CT angiographic and cerebral angiographic images without knowledge of clinical outcomes. The site of occlusion and presence or absence of collaterals were identified, and severity of occlusion was categorized into 1 of the 6 grades of a previously validat- ed scheme [15]. Similar to previous studies [16,17], preprocedure recan- alization was defined by a reduction in severity of occlusion by 1 grade or more between CT and cerebral angiographic images. Partial recanali- zation was defined by a reduction of 1 or more grades and complete recanalization was defined by grade of 0 on initial cerebral angiographic images. Preprocedure worsening was defined by an increase in severity of occlusion by 1 grade or more between CT and cerebral angiographic images. Postprocedure recanalization was defined by a reduction in se- verity of occlusion by 1 grade or more between initial and final cerebral angiographic images acquired as part of the endovascular treatment. Neurological improvement was defined by a reduction in NIHSS score of 4 points or greater at 24 hours when compared with baseline score as defined in previous studies [18,19]. Symptomatic intracerbral hemor- rhage (ICH) was defined as the presence of ICH on a noncontrast CT scan and the presence of Neurological deterioration (>=4-point worsening on a NIHSS score compared with previous clinical assessment). Favorable outcome at discharge was defined by an mRS of 0 to 2.

Statistical analysis

The primary objective of the study was to determine the frequency of preprocedure change in occlusion site in acute ischemic stroke pa- tients. If the expected event rate was 15% for preprocedure recanaliza- tion or occlusion, a sample size of 196, 136, and 100 patients would provide a precision of 0.05%, 0.06%, and 0.07%, respectively [20]. A sam- ple size of 150 patients would result in precision of estimate ranging be- tween 0.05% and 0.06% or actual value of preprocedure recanalization or occlusion is within 5% or 6% of calculated value. Continuous and categor- ical data were expressed as means with standard deviation and

frequencies, respectively. We identified any differences in regards to baseline demographic and clinical characteristics, and outcomes be- tween patients with and without preprocedure recanalization using univariate analysis. Univariate comparison was performed using ?² test and analysis of variance for categorical and continuous variables, re- spectively. We performed a logistic regression analysis to determine the effect of preprocedure recanalization on rate of favorable outcome at discharge after adjusting for age and initial NIHSS score strata (0-9, 10-19, and >=20). The NIHSS score was entered as a categorical variable in the multivariate analysis similar to previous studies [21,22]. We en- tered aspirin use in the logistic regression analysis to determine if there was any effect on favorable outcome.

Results

Computed tomographic angiogram was performed in 150 patients (mean age +- SD, 64.7 +- 16 years; 75 were men) before endovascular treatment. The median baseline NIHSS score was 14 (range, 1-42; inter- quartile range, 11). The distribution of patients according to time inter- val between symptom onset and ED arrival was follows: 0 to 3 hours (n = 95), 3 to 6 hours (n = 28), and more than 6 hours (n = 24). The mean interval (+-SD) between symptom onset and CT angiogram was 147 +- 229 minutes. The initial severity of occlusion on CT angiogram was grade 1 (n = 6), grade 2 (n = 28), grade 3A and B (n = 70), grade 4A and B (n = 34), and grade 5 (n = 11). A total of 65 (43.3%) of 151 patients received IV rt-PA before cerebral angiography. The mean interval (+-SD) between CT angiogram and cerebral angiogram was 193 +- 164 minutes. The severity of occlusion on CT angiogram was grade 1 (n = 8), grade 2 (n = 34), grade 3A and B (n = 57), grade 4A and B (n = 37), and grade 5 (n = 13). A total of 28 (18.7%) of 150 patients with CT angiogram-demonstrated occlusion underwent recanalization. No change in occlusion was found in 91 (60.7%) patients, and 31 (20.5%) patients showed worsening in occlusion based on the grading scheme. Of the 28 patients who demonstrated various degrees of preprocedure recanalization, complete recanalization was observed in only 1 (4%) patient (Tables 1 and 2).

There were no differences in the mean age of the patients who did or did not experience preprocedure recanalization. The mean time interval (+-SD) between symptom onset and CT angiogram (220 +- 178 vs 231

+- 211 minutes) and between CT angiogram and cerebral angiogram (158 +- 116 vs 201 +- 173 minutes) was lower in patients who experi- enced preprocedure recanalization compared with those who did not (P = .2). There was no difference in the proportion of patients with hy- pertension, diabetes mellitus, active cigarette smoking, and hyperlipid- emia in patients according to presence or absence of preprocedure recanalization. The proportion of patients on aspirin at presentation was significantly higher (50% vs 22%, P = .01) in patients who experi- enced preprocedure recanalization. The rate of preprocedure recanali- zation was similar in IV rt-PA-treated patients vs untreated patients (46.4% vs 53.6%, P = .7). However, the mean interval (+-SD) between symptom onset and ED arrival was lower (103 +- 139 vs 260 +- 251 minutes, P = b.001), ED arrival and CT angiogram was lower (34 +- 35 vs 66 +-

Table 1

The rates of preprocedure recanalization and worsening of arterial occlusion according to strata defined by time interval between symptom onset and ED arrival

Time interval strata between symptom onset and ED arrival

	0-3 h	3-6 h	N 6 h
IV rt-PA administered, n (%)	58 (89.2)	5 (7.7)	2 (3.1)?
Preprocedure change between
CT angiogram and cerebral angiogram
Preprocedure recanalization	17 (53.6)	7 (25.0)	4 (14.3)
Preprocedure worsening	15 (53.6)	7 (25.0)	6 (21.4)
No change	63 (69.2)	14 (15.4)	14 (15.4)

Symbol used: ?, transferred from another hospital.

A.I. Qureshi et al. / American Journal of Emergency Medicine 33 (2015) 631-634 633

Table 2

Baseline demographic and clinical characteristics and in-hospital outcomes in acute ische- mic stroke patients according to presence or absence of preprocedure recanalization

	Patients without preprocedure recanalization	Patients with preprocedure recanalization	P value
Overall number (%)	122 (81.3)	28 (18.7)
Age mean (SD)	64.7 +- 16	64.6 +- 19	.9
Men	59 (48.4%)	16 (57.1%)	.4
IV rt-PA administered	52 (42.6%)	13 (46.4%)	.4
Endovascular treatment performed	117 (95.9)	27 (96.4)	.8
Postprocedure recanalization	83 (68.0%)	19 (67.9)	.9
Time intervals (mean +- SD)
Onset-ED arrival	192 +- 233	185 +- 174	.8
ED arrival-CT angiogram	57 +- 128	33 +- 43	.3
CT angiogram-cerebral	200 +- 172	158 +- 116	.2
angiogram Cardiovascular risk factors Hypertension	78 (63.4%)	18 (64.3%)	.7
Diabetes mellitus	31 (25.2%)	6 (21.4%)	.8
Active cigarette smoking	24 (19.5%)	4 (14.3%)	.4
Hyperlipidemia	37 (30.1%)	8 (28.6%)	.7
Coronary artery disease	20 (16.3%)	6 (21.4%)	.5
Atrial fibrillation	28 (22.8%)	6 (21.4%)	.7
Use of aspirin	27 (22.0%)	14 (50.0%)	.01
Use of anticoagulation	17 (13.8%)	6 (21.4%)	.4
Outcome

baseline CT angiogram, demonstrating the high utilization in trial cen- ters. The reason for high utilization is related to identification of acute ischemic stroke patients with arterial occlusion by CT angiograms and prevention of unnecessary cerebral angiograms and endovascular treat- ment in patients who do not have an arterial occlusion [25]. Ascertain- ment of variables such as presence of aortic calcification and proximal arterial tortuosity on CT angiogram [26] may provide additional insight regarding anticipated complexity before endovascular treatment. Cer- tain limitations need to be recognized, such as CT angiogram may not be able to differentiate between occlusion and flow alterations of cervical and distal segments of intracranial Internal carotid artery [27,28]. Con- ventional single-phase CT angiogram may underestimate the extent of collateral circulation in patients with Acute arterial occlusion [29,30]. However, despite these limitations, our data support occurrence of preprocedure recanalization and worsening independent of infre- quent variations in appearance [29,30] between the 2 modalities. Our data provide quantitative estimates of preprocedural change in arterial occlusion in patients selected by CT angiogram for endovascular treatment.

The high rates of spontaneous lysis and reocclusion in experimental thrombus-based occlusion models support the dynamic nature of the thrombus [31]. Intrinsic fibrinolytic systems including plasminogen ac- tivators continuously [32,33] induce lysis within an arterial occlusion.

mRS (0-2) at discharge	35 (28.7)	12 (42.9)	.1	Spontaneous recanalization has been observed in 62% of the patients:
NIHSS score improved (>=4 points) at 24 h	50 (42.0)	17 (60.7)	.07	24% before 24 hours and 38% after onset of ischemic stroke [34]. The oc- currence of early recanalization (within 2 hours of IV alteplase bolus or

152 minutes, P = .1), and CT angiogram and cerebral angiogram was lower (173 +- 128 vs 208 +- 187 minutes, P = .1) among IV rt-PA-treat- ed patients. Endovascular treatment was performed in 27 and 117 of 28 and 122 patients with or without preprocedure recanalization, respec- tively. Immediate postprocedure complete recanalization was seen in 19 of 28 and 83 of 122 patients with and without preprocedure recana- lization (P = .9).

There was a trend towards higher rates of improvement (60.7% vs 42.0%, P = .07) and favorable outcome at discharge (42.9% vs 28.7%, P = .1) among patients who experienced preprocedure recanalization compared with those without preprocedure recanalization (patients with no change and those with worsening of occlusion). Those who experienced preprocedural worsening of occlusion had lower rates of improvement (35.5% vs 64.5%, P = .1) and worse rates of favorable outcome at discharge (16.1% vs 83.9%, P = .07) compared with those without preprocedural worsening. After adjusting for age and initial NIHSS score strata, preprocedure recanalization was not associated with significantly higher rate of favorable outcome at discharge (odds ratio, 2.1; 95% confidence interval, 0.8-5.5). After adjusting for age and NIHSS score strata, preprocedure worsening was not associated with significantly lower rates of favorable outcomes at discharge (odds ratio, 0.4; 95% confidence interval, 0.1-1.4). The results were similar after adjusting for aspirin use. No difference was observed in the rate of symptomatic ICH between patients with or without preprocedure recanalization.

Discussion

We found that there were an 18% rate of preprocedure recanaliza- tion and a 21% rate of worsening in occlusion between acquisition of CT angiogram and conventional angiogram in acute ischemic stroke patients. CT angiograms have emerged as the preferred modality in patients with acute ischemic stroke to select patients for endovascular treatment [2,23,24]. Reperfusion treatment was used 3 times more frequently among patients with ischemic stroke who underwent CT angiogram compared with those with CT head alone in United States [24]. In the Interventional Management of Stroke III trial [5], 306 of 656 acute ischemic stroke patients recruited in the trial underwent a

ED arrival) has the highest value in regards to patient outcomes and patient selection for endovascular treatment. The rates of ultraearly recanalization have been previously studied using serial or continuous transcranial Doppler monitoring in acute ischemic stroke pa- tients receiving IV rt-PA [16,17]. Complete and partial recanalization by TCD criteria was observed in 27% and 34% of the patients receiving IV alteplase, respectively, within 2 hours of receiving IV rt-PA bolus [16,17]. However, the results based on serial or continuous TCD moni- toring are limited by absence of temporal windows and false-negative and -positive diagnosis of occlusion by TCD particularly in locations other than proximal Middle cerebral artery [35,36]. We observed that patients who were on aspirin at the time of ischemic Stroke occurrence were more likely to demonstrate preprocedure recanalization. Aspirin has been used as an adjunct to thrombolytics in acute myocardial infarc- tion to increase recanalization and prevent reocclusion [37-39]. Thromboxane A2 contributes to activation and inclusion of platelets in the thrombus [40]. In Experimental models, thromboxane A2 inhibition reduces the time and the total dose of rt-PA necessary to achieve recanalization probably by preventing further platelet activation and deposition on the fibrin mesh already present in the thrombus [40,41].

Certain limitations need to be recognized before interpretation of the data. The actual frequency of preprocedure recanalization and oc- clusion may be within 5% of 6% of the observed value due to limitations posed by sample size of our study as mentioned earlier. Because the results were derived from 2 institutions, differences in diagnostic and management protocols between institutions may limit generalizability. The classification scheme used to characterize the site of angiographic occlusion has been validated and found to have a high Interobserver agreement (? = 0.73) for pretreatment and posttreatment grading of angiographic images [42]. Furthermore, the same individual graded the CT angiographic and angiographic images, ensuring consistency of ascertainment within each patient. However, we acknowledge that certain ascertainments of angiographic changes may be related to vari- ations in image acquisition between the 2 modalities and assessment by different observers. Previous studies have identified a 100% sensitivity and specificity of CT angiogram (compared with cerebral angiogram) for identification of intracranial occlusion [43,44]; and therefore, the error introduced by differences between modalities is expected to be minimal.

634 A.I. Qureshi et al. / American Journal of Emergency Medicine 33 (2015) 631-634

Our observations have implications for both understanding the acute pathophysiology of thrombotic processes involved in acute ische- mic stroke and patient selection for endovascular treatment. Further studies are required to identify factors that contribute to preprocedure recanalization or worsening of arterial occlusion in acute ischemic stroke patients selected for endovascular treatment by CT angiography.

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