Is Bridging Necessary? A Pilot Study of Bridging versus Primary Stentriever-Based Endovascular Reperfusion in Large Anterior Circulation Strokes Ronen R. Leker, MD, FAHA,* Stelios Pikis, MD,† John M. Gomori, MD,‡ and Jose E. Cohen, MD†

Background: We aimed to determine whether bridging provides additional benefits over primary stentriever-based endovascular reperfusion (SER) in patients with proximal middle cerebral artery (pMCA) strokes. Methods: Clinical and radiologic data from consecutive stroke patients with large anterior circulation infarcts involving the pMCA were analyzed. Stroke subtypes were categorized according to Trial of ORG 10172 in Acute Stroke Treatment criteria. Neurologic deficits were assessed with the National Institutes of Health Stroke Scale (NIHSS), and vessel recanalization was determined using the Thrombolysis in Cerebral Infarction scale at the end of SER. Good outcome was defined as a modified Rankin Scale (mRS) score of 2 or lesser. Results: Fifty-seven patients with a median age of 66 years were included. Of those, 24 received prior systemic tissue plasminogen activator and 33 received primary SER. Atrial fibrillation was more common in patients who underwent SER but there were no other between-group differences in baseline variables, procedure-related variables, or outcome parameters. Six patients died and 27 patients achieved an mRS of 2 or less at 90 days. Patients who were treated with tPA before SER needed less stentriever passes to recanalize the occluded vessel, but bridging did not impact the chances for either survival or favorable outcome. Age (odds ratio [OR], .92; 95% confidence interval [CI], .85-.98) and NIHSS score (OR, .12; 95% CI, .02-.78) were the only variables associated with outcome on multivariate analysis. Conclusions: Primary SER and bridging resulted in equally high survival and good outcome rates. Our results suggest that the benefits of primary SER in such critically ill patients may bypass the need for bridging therapy and merit further study. Key Words: Reperfusion—stroke—middle cerebral artery— stentriever—endovascular. Ó 2015 by National Stroke Association

From the *Department of Neurology; †Department of Neurosurgery; and ‡Department of Neuroradiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Received November 16, 2014; revision received December 7, 2014; accepted January 4, 2015. This study was supported by the Peritz and Chantal Scheinberg Cerebrovascular Research Fund and by the Sol Irwin Juni Trust Fund. All the authors hereby declare that they have no disclosures to make. All authors hereby declare that they have no conflicts of interest. Address correspondence to Ronen R. Leker, MD, Department of Neurology, Hadassah-Hebrew University Medical Center, P.O. Box 12000, Jerusalem 91120, Israel. E-mail: [email protected] 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.01.008

Introduction Large hemispheric ischemic stroke occurs in about 10% of all strokes and carries a mortality rate of close to 80%.1 Systemic thrombolysis appears to be of relatively little value in such patients,2,3 and the chances of recanalizing the occluded vessel and restoring perfusion are somewhat higher with endovascular reperfusion therapy.4,5 Bridging therapy with systemic full or reduced dose tissue plasminogen activator (tPA) followed by endovascular procedures has gained acceptance as the procedure of choice in many centers.6-9 However, because early recanalization is of paramount importance in such patients,10,11 others advocate the use of early primary

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endovascular therapy. Furthermore, stentriever-based endovascular reperfusion (SER) is characterized by very rapid recanalization times and has become the mainstay of endovascular procedures.14-16 Given the excellent reperfusion rates and rapid reperfusion achieved with SER, the goal of this preliminary pilot study was to compare outcomes in patients with large anterior circulation stroke treated with bridging to those seen in patients treated with primary SER.

Patients and Methods We recruited consecutive patients presenting with M1 middle cerebral artery occlusions who underwent SER over the span of 48 months (November 2010-October 2014) into our stroke registry. The institutional review board has granted a general permission to collect routine research data on all stroke patients. The diagnosis of proximal middle cerebral artery occlusions involving the M1 segment was established according to clinical findings and proven on computed tomography (CT) angiography, magnetic resonance (MR) angiography, or digital subtraction angiography in all patients. We did not use any specific radiologic inclusion criteria other than stroke with large-vessel occlusion. Patients with hypodensity larger than 1/3 of the involved territorial supply on noncontrast CT were excluded as were patients who underwent multiparametric stroke MR imaging and had no evidence for diffusion–perfusion mismatch. Patients presenting in deep coma (Glasgow Coma Scale ,5) with the absence of brain stem reflexes and those presenting more than 8 hours from symptom onset including those with wake-up strokes were not included. We also excluded patients transferred to our center from other hospitals. Clinical and demographic characteristics accrued included cerebrovascular risk profile, time from symptom onset to initiation of endovascular procedure, and time of onset to reperfusion. Infarct etiology was classified according to TOAST criteria17 as cardioembolic, large artery atherothrombotic, and other classified (eg, dissection) or unclassified. Neurologic deficits were determined with the National Institutes of Health Stroke Scale (NIHSS), and functional deficits before admission and at 90 days after infarct were evaluated with the modified Rankin Scale (mRS) score. Good outcome was defined as an mRS of 2 or lesser. Radiologic parameters were evaluated on entry CT/ MR imaging and on the diagnostic and therapeutic angiography and follow-up CT. The extent of collateral circulation was studied with American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology scale on angiography criteria18,19 and divided into poor (grade 0-2), adequate (grade 3), or very good (grade 4). All included patients received SER with the Solitaire FR device (Covidien, Dublin, Ireland). The patients were

divided between those who received systemic tPA before SER (bridging group) and those who had primary SER. All patients presenting within the first 4.5 hours from symptom onset were first considered for tPA, and only those with contraindications to tPA (eg, international normalized ratio .1.7, known bleeding tendency, recent major surgery, and so forth) were referred to primary SER. Patients who failed to show significant improvement on the NIHSS at the end of tPA infusion were transferred to the angio suite for SER. Failure to achieve significant improvement was defined as a drop of less than 8 points on the NIHSS from presentation. Patients with similar stroke syndrome presenting between 4.5 and 8 hours from onset were taken directly for primary SER. Flow at the end of SER was classified with the Thrombolysis in Cerebral Infarction system.18 The number of passes and the number and types of additional procedural modalities used (if necessary) in all patients were documented. Treatment complications including postprocedure hemorrhage and clinical deterioration without hemorrhage were documented. Statistical evaluations were performed with the SigmaStat package (Systat). For univariate analysis, patients were compared using Student t test or chi-square tests. We then used multivariate logistic regression analysis models that included variables that yielded a P value of less than .2 on the univariate analysis and variables that are known to be associated with outcome such as admission NIHSS, age, and the presence of symptomatic hemorrhage to determine the effects of such variables on survival and good outcome.

Results Over the span of 48 months, we included 57 consecutive patients fulfilling entry criteria. The baseline clinical and radiologic characteristics are presented in Table 1. All patients were independent before the procedure (mRS ,2). Patients were divided (Table 1) into those who received tPA before SER (bridging group; n 5 24) and those who received primary SER with no previous tPA (n 5 33). Age, gender, risk factor profile, stroke etiology, and baseline NIHSS scores did not differ between the groups except for atrial fibrillation, which was more commonly seen in the patients who underwent primary SER (Table 1). Survival rates (87.5% versus 90% for the bridging versus primary SER, respectively), discharge NIHSS scores, as well as the delta between baseline and discharge NIHSS scores and day-90 NIHSS scores did not differ between the groups. Furthermore, the chances for having favorable outcomes (48% versus 59%) did not show statistical significance (Table 1). Similarly, all procedural variables including time from presentation to the emergency department to beginning of SER and time from symptom onset to recanalization, Thrombolysis in Cerebral Infarction scores, collateral

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Table 1. Univariate analysis comparing patients treated with bridging and primary endovascular therapy Variable/group

Bridging (N 5 24), n (%)

Primary SER (N 5 33), n (%)

P

Age 6 SD (median), y Gender (male) Hypertension Ischemic heart disease Atrial fibrillation Diabetes mellitus Hyperlipidemia Smoking Prior stroke TOAST classification Cardioembolic Large vessel Small vessel Other Unknown Admission NIHSS (median) Discharge NIHSS (median) Delta NIHSS (median) Day-90 NIHSS (median) Modified Rankin Scale score day 90 0-2 3 4-5 6

66.8 6 13.7 (66) 8 (33) 16 (67) 10 (42) 8 (33) 9 (37.5) 8 (33) 6 (25) 2 (8)

64.4 6 14.7 (66) 15 (45) 22 (67) 18 (54) 22 (67) 7 (21) 16 (48) 6 (18) 7 (21)

.53 .52 1 .49 .03 .29 .38 .77 .28 .49

16 (67) 5 (21) 0 1 (4) 2 (8) 19.2 6 5.1 (19.5) 7.7 6 5.9 (7) 10.0 6 6.1 (11) 6.9 6 8.7 (4) N 5 21 10 (48) 5 (24) 3 (18) 3 (18)

25 (76) 4 (12) 0 0 4 (12) 19.1 6 5.8 (20) 7.5 6 7.1 (6) 11.1 6 6.9 (10) 6.8 6 6.9 (5.5) N 5 29 17 (59) 5 (17) 4 (14) 3 (10)

.95 .96 .54 .97 .87

Abbreviations: NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation; SER, stentriever-based endovascular recanalization.

status, and the percentages of permanent stents and decompressive hemicraniectomy used did not differ between the groups (Table 2). The rates of asymptomatic and symptomatic intracerebral hemorrhage (sICH) did not differ statistically (Table 2), although there was a trend toward less bleedings in the primary SER group (15%

versus 29% for all ICH and 0% versus 8% for sICH). Patients treated with bridging more often needed 2 or fewer passes of the Solitaire device to achieve recanalization (91% versus 64%; P 5 .04). Multivariate logistic regression analysis controlling for age, prior use of tPA, collateral state, the need for more

Table 2. Comparison of procedure and postprocedure-associated variables Variable/group

Bridging (N 5 24), n (%)

Primary SER (N 5 33), n (%)

P

Onset to SER (median), min ED to SER (median), min Number of passes 1 2 .3 Collateral grade 0-2 3-4 TICI at end of SER 0-2a 2b-3 Permanent stent placed Any ICH Symptomatic ICH

242.6 6 71.6 (232) 148.9 6 62.5 (136)

284.4 6 132.1 (265) 140.2 6 97.0 (113)

.17 .73 .04

14 (61) 7 (30) 2 (9) N 5 23 16 (70) 7 (30)

16 (52) 4 (13) 11 (44) N 5 31 26 (84) 5 (16)

3 (12.5) 21 (87.5) 5 (21) 7 (29) 2 (8)

5 (15) 28 (85) 8 (24) 5 (15) 0 (0)

.26

1

.94 .34 .17

Abbreviations: ED, emergency department; ICH, intracerebral hemorrhage; SER, stentriever-based endovascular recanalization; TICI, Thrombolysis in Cerebral Infarction.

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Table 3. Multivariate analysis on chances for having a favorable outcome (mRS #2) Variable

OR

95% CI

P

Age, y Admission NIHSS .18 Number of passes .1 Collateral grade .2 Bridging with tPA

.92 .12 .25 1.65 .39

.85-.98 .02-.78 .05-1.2 .23-12.0 .08-1.9

.02 .009 .09 .89 .25

Abbreviations: CI, confidence interval; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio.

than 1 pass of the device, and admission NIHSS score (Table 3) identified age, (odds ratio, .91; 95% confidence interval, .85-.98) and admission NIHSS .18 (OR, .09; 95% CI, .008-1.000) as predictors of poor outcome. However, treatment with tPA before SER, collateral state, and the need to use more than a single pass of the retriever did not show a significant impact on outcome. On forward stepwise multivariate analysis controlling for tPA use, collateral state admission NIHSS, age, and the presence of sICH, the only variable that remained significantly associated with increased chances for mortality was sICH (P 5 .03).

Discussion Our results demonstrate that both bridging and primary SER resulted in high survival and good outcome rates in patients with malignant strokes. Excellent reperfusion status was commonly achieved in our patients treated with either primary or secondary SER with rates that are similar to previous studies.14-16 Age, admission NIHSS, and the number of retriever passes used were the only parameters identified as prognostic factors on multivariate analysis. Administration of systemic tPA before SER did not impact the outcome. Interestingly, patients treated with tPA before SER needed less passes of the thrombectomy device to achieve complete recanalization. Thus, prior administration of tPA may make the clot more malleable and friable and more easily extractable. Nevertheless, this does not seem to impact the outcome as long as the clot is finally extracted and the vessel is recanalized. Patients in both groups had similar risk factor profiles and stroke severity except for atrial fibrillation, which was more commonly observed in patients who underwent primary SER. This reflects the fact that patients with atrial fibrillation more often took anticoagulants that prevented prior administration of tPA. Because patients with atrial fibrillation are known to have poor outcomes more frequently than those without atrial fibrillation, we cannot exclude the possibility that this may have impacted the chances of achieving a good functional

outcome, but atrial fibrillation failed to show an impact on outcome in the multivariate model. Our study was performed at a tertiary university stroke center with a very experienced endovascular service, and almost half of the patients in both groups were treated with SER in less than 210 minutes from symptom onset. Therefore, our results may not be generalized to all stroke patients. Nevertheless, our results suggest that bridging with tPA may be unnecessary if SER can be performed relatively quickly. However, it is likely that if SER cannot commence rapidly (eg, if the patient needs transfer to a tertiary stroke center for SER), tPA may still have benefits.10,11 Our results further reiterate the importance of recanalization as a potent mediator influencing the outcome as shown not only for SER10,11 but also for studies using systemic thrombolysis.20 Previous studies exploring the benefits of combined intravenous-intra-arterial strategies focused on endovascular administration of lytic drugs or on the endovascular use of thrombus extraction and aspiration devices.6,8,9,21-23 These studies have generally found an advantage for the use of a bridging strategy and have advocated adopting such a strategy despite somewhat increased rates of ICH and sICH.6,8 More recently, the Interventional Management of Stroke III study failed to show any benefit from bridging therapy over that observed with systemic thrombolysis.24 However, SER leads to much higher recanalization rates that are more often complete and are achieved far more rapidly than with previous devices.14-16 We believe that these advantages of SER justify revisiting the hypothesis that bridging is more advantageous than primary endovascular procedures as done in the present pilot study. Interestingly, collateral grade did not have an impact on outcome in this pilot study in contrast to larger studies.25 This may result from the fact that most of our patients had poor collateral states, whereas patients in previous studies had better collaterals. Our study has several limitations. First, the number of included patients was relatively small limiting its power. Furthermore, because the small sample size may introduce inadequacies in the multivariable analysis, our results should be viewed as tentative. Second, this was an observational study and not a randomized clinical trial comparing primary and secondary SER. Therefore, our results should be viewed as hypothesis generating that suggest the justification of future randomized studies. Nevertheless, the present study further expands the existing knowledge regarding the efficacy of SER in patients with large and often deadly strokes. In conclusion, SER can be beneficial for patients with large hemispheric strokes. Whether bridging with tPA provides any additional benefit or whether primary SER will inevitably replace tPA in these very sick patients

BRIDGING VERSUS PRIMARY ENDOVASCULAR REPERFUSION

should be determined in future randomized controlled studies.

13.

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Is Bridging Necessary? A Pilot Study of Bridging versus Primary Stentriever-Based Endovascular Reperfusion in Large Anterior Circulation Strokes.

We aimed to determine whether bridging provides additional benefits over primary stentriever-based endovascular reperfusion (SER) in patients with pro...
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