Mechanical thrombectomy (MT) has become the standard

Transcription

1 Rethinking Thrombolysis in Cerebral Infarction 2b Which Thrombolysis in Cerebral Infarction Scales Best Define Near Complete Recanalization in the Modern Thrombectomy Era? Eric L. Tung, BSc; Ryan A. McTaggart, MD; Grayson L. Baird, PhD; Shadi Yaghi, MD; Morgan Hemendinger, BA; Eleanor L. Dibiasio, BA, MPh; Douglas T. Hidlay, MD; Glenn A. Tung, MD; Mahesh V. Jayaraman, MD Background and Purpose Within the thrombolysis in cerebral infarction (TICI) classification, TICI 2b has been historically considered successful recanalization. Recent studies have suggested that TICI 3 and a proposed TICI 2c should be separately reported from TICI 2b, in both the original (>66% reperfusion) and modified (>50% reperfusion) definitions, because of differences in clinical outcomes with greater reperfusion. The purpose of this study was to evaluate differences in early neurological improvement and independence at 90 days using the original TICI, modified TICI, and modified TICI with 2c scales. Methods A retrospective review of 129 consecutive patients with middle cerebral artery, M1 segment or intracranial internal carotid artery occlusions. Patient angiograms were graded by 2 experienced readers by percentage recanalization. This was then categorized into original TICI, modified TICI (mtici), and mtici with TICI 2c (mtici 2c) grading scales. Comparison of baseline demographics, early neurological improvement, and independence at 90 days was performed. Results A significant difference in early neurological improvement was observed between 2b and 3 (P=0.032), as well as between 2b and 2c (P=0.028) under the mtici 2c grading scale. Similarly, a significant difference in functional independence was observed between 2b and 3 (P=0.037), as well as between 2b and 2c (P=0.047) under the mtici 2c scale. The difference in early neurological improvement or functional independence between 2b and 3 for the original TICI and mtici scales was not significant. When combining the 2c and 3 groups under the mtici 2c scale, there were significant differences between 2b and 2c/3 in regards to both early neurological improvement (P=0.011) and independence (P=0.018). Conclusions Using a TICI grading system that includes an additional category beyond TICI 2b allows for refined prediction of early neurological improvement and functional independence. (Stroke. 2017;48: DOI: /STROKEAHA ) Key Words: angiography endovascular treatment middle cerebral artery stroke thrombectomy Mechanical thrombectomy (MT) has become the standard of care, along with intravenous tissue-type plasminogen activator, for patients with emergent large vessel occlusion in the anterior circulation. 1 5 The thrombolysis in cerebral infarction (TICI) scale is a widely used scoring system to evaluate the degree of reperfusion achieved after MT. 6 8 While it seems intuitive that higher rates of recanalization are associated with improved patient outcomes, there currently exists a lack of consensus regarding the optimal variant of TICI scale. Variations include the original TICI scale (otici), the modified TICI (mtici), and a more recently proposed 6-step grading criteria (mtici 2c). 8 The lack of consensus on the most appropriate scale may be a product of the significant similarity between these 3 scales (Table 1), as well as the lack of studies comparing them. Initially, TICI 2a or better recanalization was considered successful, while more recently, the threshold for successful recanalization has been considered as TICI 2b. 9 However, several recent studies have found that patients who were treated with MT for an anterior circulation emergent large vessel occlusion with otici 3, mtici 2c, or mtici 3 grades of reperfusion had significantly superior clinical outcomes compared with patients with otici 2b and mtici 2b reperfusion These findings suggest that there may be value in distinguishing the TICI 2b classification from classifications corresponding to higher reperfusion when evaluating reperfusion after MT. Received February 27, 2017; final revision received June 28, 2017; accepted July 14, From the Department of Diagnostic Imaging (E.L.T., R.A.M., G.L.B., E.L.D., D.T.H., G.A.T., M.V.J.), Neurology (R.A.M., S.Y., M.H., M.V.J.), and Neurosurgery (R.A.M., M.V.J.), Warren Alpert School of Medicine at Brown University Providence, RI; and Norman Prince Neuroscience Institute (R.A.M., S.Y., G.A.T., M.V.J.) and Lifespan Biostatistics Core (G.L.B.), Rhode Island Hospital. Presented in part at the International Stroke Conference, Houston, TX, February 22 24, Correspondence to Mahesh V. Jayaraman, MD, Department of Diagnostic Imaging, Warren Alpert School of Medicine at Brown University, Rhode Island Hospital, 593 Eddy St, Room 377 Providence, RI mjayaraman@lifespan.org 2017 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 Tung et al Which TICI Best Defines Near Complete Reperfusion 2489 In this study, we examined the ability of a variety of TICI scales to discern differences in early neurological outcome and functional independence at 90 days posttreatment in patients with emergent large vessel occlusion of the middle cerebral artery or internal carotid artery (ICA) treated with MT. This analysis was performed using the otici, mtici, and mtici 2c recanalization scales with the goal of identifying clinically significant differences between these grading systems. Methods Patients Institutional review board approval was obtained for a retrospective review of all MT patients treated at a single comprehensive stroke center between January 1, 2015, and May 31, We included all patients with an ICA or M1 segment of the middle cerebral artery occlusion (n=134). Five patients with missing imaging were excluded, leaving 129 patients for further analysis. We did include patients who had concomitant cervical ICA stenosis or occlusion (tandem lesions). We excluded patients with isolated M2 segment occlusions, as well as those with posterior circulation occlusions. Endovascular Treatment Patients were considered eligible for MT at our institution if they had documented ICA or M1 segment occlusion on computed tomographic angiography, had an admission National Institutes of Health stroke scale (NIHSS) score of 6, treatment could be initiated within 6 hours from symptom onset, and evidence of small to medium infarct core based on assessment of noncontrast computed tomography Alberta Stroke Program Early CT Score of 6. During the later portion of this study, a small number of patients who were beyond 6 hours from symptom onset were treated if they had evidence of small infarct core based on diffusion-weighted imaging on MRI, which we defined as a core lesion of <70 ml. All patients were treated under conscious sedation except those who had been intubated for airway protection. We did not electively intubate any patients. All patients were treated with a triaxial configuration of cervical guide catheter, a local aspiration catheter (ACE64 or ACE68; Penumbra Inc, Alameda, CA), along with a stent-retriever. Both Solitaire (Covidien Medtronic Inc, Mansfield, MA) and Trevo (Stryker Neurovascular Inc, Kalamazoo, MI) devices were used. The local aspiration catheter was placed as close in proximity to the occlusion as safely possible. During the study period, our technique evolved from one where the stent-retriever was withdrawn into the local aspiration catheter to one where both the stentretriever and local aspiration catheter were withdrawn as a unit into a large bore guiding catheter in the cervical ICA. The aspiration on the local catheter was performed by automatic pump. We did not use a balloon guide catheter in any cases in this series. Multiple passes were performed at the discretion of the treating neurointerventionalist, with the goal to achieve at least TICI 2b recanalization. We did not use adjunctive intra-arterial tissue-type plasminogen activator in any cases. Image Analysis Two experienced interventional neuroradiologists (R.A. McTaggart and M.V. Jayaraman) independently evaluated patient angiograms, blinded to all clinical data. Readers estimated the percent recanalization achieved after MT intervention based on the final run of digital subtraction angiography. This percentage recanalization number was then used to assign the TICI grade for both the otici and mtici scales. In addition, readers also separately indicated whether the case qualified as mtici 2c classification. TICI grades for otici, mtici, and mtici 2c scales were determined based on these 2 data points. Cases with score discrepancies were adjudicated, by the same 2 readers in a joint reading session, until a blinded consensus was reached, producing a unified data set. Percent reperfusion was used for 2 reasons: (1) percent is an objective measure that can be simultaneously translated into the 3 scales without the risk of biasing each other; (2) because we are evaluating an alternative scoring system to mtici, it was essential to evaluate perfusion using a metric that was not tied inherently to mtici scoring. In an effort to minimize any anchoring effect because of 50% and 66% perfusion translating back into the mtici system, radiologists explicitly understood that their estimates of perfusion should not correspond with otici or any scale but rather their best guess of actual percent of perfusion. Clinical Assessment The stroke center quality database was queried for the following: patient age, sex, site of intracranial location, whether or not intravenous tissue-type plasminogen activator was administered, time from noncontrast computed tomographic scan to start of angiography, NIHSS at admission and discharge, and modified Rankin Scale score (mrs) at 90 days after treatment. NIHSS at discharge was recorded by the clinical team caring for the patient and performed by certified raters in all cases. The raters were not blinded to the outcome of the procedure. Early neurological improvement was assessed by looking at the change in NIHSS between admission and discharge from acute hospitalization. Independence was defined as a 90-day mrs score of 0 to 2. Whenever possible, the mrs was recorded by the vascular neurologist seeing the patient in clinical follow-up but not blinded to the outcome of the procedure. If this was not possible, then a telephone assessment using a structured interview was used. In 2 patients (1.5%), the 90-day mrs could not be obtained by either in-person or telephone assessment. Statistical Analysis All analyses were conducted using SAS Software 9.4 (SAS Inc, Cary, NC). Agreement between 2 radiologists for each TICI version was calculated using a Cohen s Kappa, Kendall s Tau, and intraclass correlation coefficient with using the SAS macro programs MAGREE and INTRACC, respectively. Differences in NIHSS between otici, mtici, and mtici 2C scores were examined using generalized modeling assuming a normal distribution or ordinal modeling, assuming a binominal distribution (0 6), using the SAS procedure GLIMMIX. Modeling was not adjusted for confounding variables given concerns of overfit, multicollinearity, and interaction effects (violation of Table 1. Comparison of the Existing TICI Grading Scale Criteria TICI Grade Original TICI Modified TICI Modified TICI With 2c 0/1 No/minimal reperfusion No/minimal reperfusion No/minimal reperfusion 2a Partial filling <2/3 territory Partial filling <50% territory Partial filling <50% territory 2b Partial filling 2/3 territory Partial filling 50% territory Partial filling 50% territory 2c Near complete perfusion except slow flow or few distal cortical emboli 3 Complete perfusion Complete perfusion Complete perfusion TICI indicates thrombolysis in cerebral infarction.

3 2490 Stroke September 2017 Table 2. Clinical, Angiographic, and Procedural Details of the Included Patients Item Median (IQR) or Percent (Counts) Demographics Age 77 (65 85) Admission NIHSS 18 (13 22) Male 46.5% (60/129) Angiographic features Site of intracranial occlusion ICA 21.7% (28/129) M1 segment MCA 78.3% (101/129) Presence of concomitant extracranial ICA 16.3% (21/129) stenosis or occlusion Procedural factors Number of passes 1 (1 2) Time from groin puncture to recanalization, min 30 (15 55) Final TICI recanalization result (using mtici 2c scale) mtici 0/1 4.7% (6/129) mtici 2a 13.2% (17/129) mtici 2b 30.2% (39/129) mtici 2c 30.2% (39/129) mtici % (28/129) ICA indicates internal carotid artery; IQR, interquartile range; MCA, middle cerebral artery; mtici, modified TICI; NIHSS, National Institutes of Health Stroke Scale; and TICI, thrombolysis in cerebral infarction. homogeneity of slopes). In addition, we are evaluating the relationship between outcomes and the scale, which is not a possible causative phenomenon. Table 2 baseline characteristics were compared with medians and counts using a Kruskal Wallis test or Fisher s exact test, respectively. Post hoc comparisons between scores were accomplished using Tukey corrections, when appropriate. Significance was established a priori at the 0.05 level, and all interval estimates were calculated for 95% confidence. Results We identified a total of 129 patients with data available for analysis, with a mean age of 77 years, median NIHSS score of 18, and 46.5% male. Baseline demographics for all patients, as well as workflow metrics, and procedural details are summarized in Table 2. In addition, we summarized demographics for groups based on reperfusion grade using the mtici 2c scale in Table 3, and there were no significant differences between these groups. As shown in Figure 1, a significant difference in early neurological improvement was observed between TICI 2b and 3 grades under the mtici 2c scale (Figure 1C; difference in early NIHSS change of 4.4; 95% confidence interval [CI], ). Under the otici and mtici scales (Figure 1A and 1B), the difference in early NIHSS change between 2b and 3 grades was not significant at 1.3 (95% CI, 2.3 to 4.9) and 2.3 (95% CI, 1.3 to 5.9), respectively. Additionally, within the mtici 2c scale (Figure 1C), there was a significant difference in early NIHSS change of 4.1 between 2b and 2c (95% CI, ), as well as 4.2 (95% CI, ) between 2b and combined 2c/3 grades (Figure 1D). Last, no difference was observed between 2c and 3 (0.28; 95% CI, 3.7 to 5.9). As shown in Figure 2, differences in average mrs score at 90 days were statistically significant between 2b and 3 grades (0.44; 95% CI, ; P=0.037) and between 2b and 2c grades (0.38; 95% CI, ; P=0.047) under the mtici 2c scale (Figure 2C). No differences in average mrs were observed between the 2b and 3 grades under both the otici (0.15; 95% CI, 0.2 to 0.5; P=0.4317) and the mtici (0.26; 95% CI, 0.11 to 0.63; P=0.173) scales (Figure 2A and 2B). There was a significant difference in average mrs at 90 days identified between 2b and combined 2c/3 grades (0.41; 95% CI, ; P=0.018) under the mtici 2c grading scale (Figure 2D). Last, no difference was observed between 2c and 3 (0.06; 95% CI, 0.54 to 0.66; P=0.99). We summarize in Table 4 the interrater reliability, which was weaker for otici grading scale with Cohen s kappa coefficient of 0.58 relative to the interrater reliability for both the mtici and mtici 2c grading scales with Cohen s kappa coefficients of 0.62 and 0.61, respectively. Notably, when combining 2c and 3 grades into one category under the mtici 2c Table 3. Clinical Demographics and Workflow Parameters of Patients With TICI 2b, 2c, and 3 Reperfusion Under the mtici 2c Grading Scale mtici 2b (n=39) mtici 2c (n=39) mtici 3 (n=28) P Value Median age Female, n (%) 17 (43.6%) 22 (56.4%) 16 (57.1%) 0.46 IV-tPA administered, n (%) 23 (59.0%) 27 (69.2%) 13 (46.4%) 0.18 Site of occlusion Left hemisphere involved, n (%) 17 (43.6%) 24 (61.5%) 17 (60.7%) 0.23 ICA occlusion or stenosis, n (%) 9 (23.1%) 3 (7.7%) 2 (7.1%) 0.09 M1 occlusion, n (%) 32 (82.0%) 33 (84.6%) 22 (78.6%) 0.77 Median CTA to arterial puncture, min Median NIHSS on admission CTA indicates computed tomographic angiography; ICA, internal carotid artery; IV, intravenous; mtici, modified TICI; NIHSS, National Institutes of Health Stroke Scale; TICI, thrombolysis in cerebral infarction; and tpa, tissue-type plasminogen activator.

4 Tung et al Which TICI Best Defines Near Complete Reperfusion 2491 Figure 1. Comparison of clinical improvement in National Institutes of Health Stroke Scale (NIHSS) at discharge between reperfusion grades under the original TICI (otici; A), modified TICI (mtici; B), modified TICI with TICI 2c (mtici 2c; C), and modified TICI with combined TICI 2c/3 (mtici combined 2c/3; D). Significance (*) established at the 0.05 level. scale, Cohen s kappa coefficient improved to 0.76, thereby, achieving the highest kappa values for all categories, relative to the other grading systems. This improvement is mirrored with both the Kendall s Tau and the intraclass correlation coefficient. As indicated in Table 3, no baseline differences were observed between patients with mtici 2b reperfusion (n=39), 2c reperfusion (n=39), and 3 reperfusion (n=28). Discussion In this study, we show that the ability of separating outcomes between near complete and complete recanalization is dependent on the variant of the TICI scale used. At the same time, we failed to observe statistically significant clinical differences between TICI 2b near complete reperfusion and TICI 3 complete reperfusion categories when comparing patients using the otici and mtici grading scales. However, Figure 2. Comparison of modified Rankin Scale (mrs) at 90 days between reperfusion grades under the original TICI (otici; A), modified TICI (mtici; B), modified TICI with TICI 2c (mtici 2c; C), and modified TICI with combined TICI 2c/3 (mtici combined 2c/3; D). Significance (*) established at the 0.05 level.

5 2492 Stroke September 2017 Table 4. Comparison of Interrater Reliability Between Reperfusion Grades Under the Original TICI, Modified TICI, Modified TICI With TICI 2c, and Modified TICI With Combined TICI 2c/3 Using Cohen s Kappa and Kendall s T Coefficients otici mtici mtici 2c mtici Comb 2c/3 TICI 0/1 kappa TICI 2a kappa TICI 2b kappa TICI 2c kappa TICI 3 kappa Overall kappa Kendall ICC Summary Weak agreement Moderate agreement Moderate agreement Moderate agreement Summary based on interpretation of Cohen s kappa coefficients. ICC indicates intraclass correlation coefficient; mtici, modified TICI; otici, original TICI; and TICI, thrombolysis in cerebral infarction. significant differences in early neurological improvement and functional independence at 90 days were observed between the TICI 2b and both the TICI 2c and TICI 3 categories when using the mtici 2c grading scale. When the mtici 2c grading framework was used, patients with TICI 3 and TICI 2c recanalization had substantially greater early and late neurological improvement than TICI 2b patients. Therefore, by adding an intermediate category between TICI 2b and TICI 3 into our analysis, we were able to observe this difference in clinical outcome. Additionally, we show no statistically significant differences in early neurological outcome or measurement of functional independence at 90 days observed between TICI 2c and TICI 3 patients under the mtici 2c grading scale. After merging the TICI 2c and 3 categories, we observed significantly greater early neurological improvement and rates of functional independence at 90 days compared with those of TICI 2b patients. Our findings complement results found in Almekhlafi et al, 10 a retrospective analysis of 110 patients with anterior circulation strokes that observed improved clinical outcomes as evaluated by change in NIHSS at 24 hours and 90-day mrs with TICI 2c and TICI 3 patients compared with TICI 2b patients. Almekhlafi et al 10 used the otici and mtici 2c scales for their analysis. Our study design expands on the findings of Almekhlafi et al 10 by retrospectively evaluating our patient sample objectively using all 3 current TICI grading scales (otici, mtici, and mtici 2c), an analysis that to our knowledge has never been performed before. Furthermore, for all 3 TICI scales, we compared the clinical outcome of TICI 2b near complete reperfusion with all TICI categories that represent superior reperfusion, while Almekhlafi et al 10 only uses the otici scale for comparisons between otici 2b and mtici 2c. Two recent studies 11,12 observed a significant difference in early neurological outcome as measured by change in NIHSS at discharge between mtici 2b and mtici 3 recanalization patients evaluated using the mtici scale. Our results did not demonstrate the same statistically significant difference in early neurological outcomes between these mtici scale grades. One explanation for this discrepancy is the difference in sample size, as the Kleine study analyzed 277 patients with successful (mtici 2b or greater) recanalization and Dargazanli evaluated 222 patients, while our study included 108 patients with successful recanalization. Another factor that may explain the observed difference was the approach to grading angiograms. The 2 aforementioned studies graded solely using the mtici scale. However, our study design aimed to grade every patient with all 3 TICI scales; thus, the percent of ischemic area reperfused after intervention was obtained from each reader for each case and then converted into corresponding TICI grades in an effort to maintain objectivity between scales. Although this grading discrepancy is small, we hypothesize that it may have led graders those studies to assign many mtici 2c patients to the mtici 3 group because of the minor differences in these grades. If many of the mtici 2c patients were categorized as mtici 3 because of the minor differences, our findings concur with those of Kleine and Dargazanli. This is confirmed by the significant early and late clinical differences we observed between TICI 2b and combined TICI 2c/3 categories under the mtici 2c scale. One potential weakness raised by critics of the mtici 2c grading scale is that the definition for mtici 2c grade lacks concrete parameters to allow for repeatable results among readers. Indeed, the original definition simply lists near complete perfusion except for slow flow or distal emboli in a few distal cortical vessels. Although it is certainly possible that this definition may be difficult to interpret, our interrater reliability under the mtici 2c scale was comparable to both the otici and mtici scales. In some cases, competing flow in distal cortical vessels from pial collaterals may be difficult to distinguish from small distal emboli. There are 2 solutions that may appease critics of the vague parameters of the mtici 2c grading scale. The first is to establish the minimal criteria for successful reperfusion in acute ischemic stroke as TICI 2c. The second is to expand the definition of TICI 3 to include the recanalization involving TICI 2c criteria and using TICI 3 as the criteria for successful reperfusion. Both of these solutions take advantage of our observation that the lack of specificity in the mtici 2c grade

6 Tung et al Which TICI Best Defines Near Complete Reperfusion 2493 cause readers to most often equate mtici 2c reperfusion to mtici 3 reperfusion. The evidence for this observation is the significant increase in Cohen s kappa coefficient after the 2c and 3 categories are combined. Furthermore, both solutions are based on our observations that there are improved clinical outcomes with TICI 2c, 3, or combined 2c/3 reperfusion compared with TICI 2b reperfusion under the mtici 2c grading scale. There are several limitations to this study. First, this is a retrospective study using observational data obtained from a single center. We were able to include almost all consecutive patients eligible for this study to minimize relevant biases. Second, early neurological improvement was measured using change in NIHSS at discharge as opposed to at a fixed point postintervention. It has been shown in the ESCAPE trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times) that early NIHSS improvement is a powerful biomarker of treatment effect. 13 While the angiographic review was blinded to clinical outcomes, the clinical assessments (NIHSS and mrs) were not blinded to the degree of recanalization, which is a potential limitation. Third, there was low interrater reliability in this study. Although the lack of agreement between the blinded graders was greater than expected, it was consistent across all 3 TICI grading scales. Furthermore, this high reader variability is likely attributed to interrater disagreement between TICI 2c and 3 recanalization, as explained earlier. By the nature of our study design, this disagreement resulted in apparently high interrater disagreement of the otici and mtici scales as well. Despite this unexpected disagreement, our concordance, as measured by Intraclass Correlation (Table 4), is comparable to those of a previous study that similarly identified interrater variability involving the otici and mtici scales. 7 In addition, we primarily focused on the grade of revascularization but not explicitly on the time to achieve that level of recanalization as well. A recent analysis has shown that complete (TICI 3) recanalization may mitigate some of the effect of time. 14 A similar analysis using an additional (TICI 2c) scale which also assesses the time to achieve revascularization may be warranted. Finally, we did slowly evolve our technique during the period of this study, as described in the Methods. However, we feel that this change in procedural technique should not skew the results of this study as to which TICI scale is most optimal for detecting clinical change. Conclusions In summary, we confirm that higher levels of recanalization after MT for emergent large vessel occlusion results in greater early neurological improvement and functional independence. We also show that to discern this greater degree of early neurological improvement and functional outcome, a TICI scale which incorporates the TICI 2c grade is needed. Therefore, we challenge mtici 2b as the cutoff for successful recanalization, as others have recently supported, and endorse the adoption of the mtici scale that includes the TICI 2c grade. So that we may improve our ability to evaluate the success of newly proposed equipment and techniques for MT, we propose that TICI 2c reperfusion or an expanded TICI 3 definition be adopted as the threshold for successful MT. None. Disclosures References 1. Berkhemer OA, Fransen PS, Beumer D, van den Berg LA, Lingsma HF, Yoo AJ, et al; MR CLEAN Investigators. A randomized trial of intraarterial treatment for acute ischemic stroke. 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