RESEARCH ARTICLE
Mechanical Recanalization in Basilar Artery Occlusion: The ENDOSTROKE Study Oliver C. Singer, MD,1 Joachim Berkefeld, MD,2 Christian H. Nolte, MD,3 Georg Bohner, MD,4 Hans-Peter Haring, MD,5 Johannes Trenkler, MD,6 Klaus Gr€ oschel, MD,7 Wibke M€ uller-Forell, MD,8 Kurt Niederkorn, MD,9 Hannes Deutschmann, MD,10 Tobias Neumann-Haefelin, MD,11 Carina Hohmann, PhD,12 Matthias Bussmeyer,13 Anastasios Mpotsaris, MD,14,15 Anett Stoll, MD,16 Albrecht Bormann, MD,17 Johannes Brenck, MD,18 Marc U. Schlamann, MD,19 Sebastian Jander, MD,20 Bernd Turowski, MD,21 Gabor C. Petzold, MD,22 Horst Urbach, MD,23 and David S. Liebeskind, MD,24 for the ENDOSTROKE Study Group Objective: A study was undertaken to evaluate clinical and procedural factors associated with outcome and recanalization in endovascular stroke treatment (EVT) of basilar artery (BA) occlusion. Methods: ENDOSTROKE is an investigator-initiated multicenter registry for patients undergoing EVT. This analysis includes 148 consecutive patients with BA occlusion, with 59% having received intravenous thrombolysis prior to EVT. Recanalization (defined as Thrombolysis in Cerebral Infarction [TICI] score 2b–3) and collateral status (using the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology collateral grading system) were assessed by a blinded core laboratory. Good (moderate) outcome was defined as a modified Rankin Scale score of 0 to 2 (0–3) assessed after at least 3 months (median time to follow-up 5 120 days). Results: Thirty-four percent had good and 42% had moderate clinical outcome; mortality was 35%. TICI 2b–3 recanalization was achieved by 79%. Age, hypertension, National Institutes of Health Stroke Scale scores, collateral status, and the use of magnetic resonance imaging prior to EVT predicted clinical outcome, the latter 3 remaining independent predictors in multivariate analysis. Independent predictors of recanalization were better collateral status and the use of a stent retriever. However, recanalization did not significantly predict clinical outcome.
View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.24336 Received Mar 26, 2014, and in revised form Nov 28, 2014. Accepted for publication Dec 7, 2014. Address correspondence to Dr Singer, Department of Neurology, Goethe-University, Schleusenweg 2–16, D-60528 Frankfurt/Main, Germany. E-mail: [email protected] From the 1Department of Neurology and 2Institute of Neuroradiology, Goethe University, Frankfurt, Germany; 3Department of Neurology and 4Institute of Diagnostic and Interventional Radiology and Nuclear Medicine, Charit e Hospital, Berlin, Germany; 5Department of Neurology and 6Institute of Radiology, Wagner-Jauregg Hospital, Linz, Austria; 7Department of Neurology and 8Institute of Neuroradiology, Mainz University Hospital, Mainz, Germany; 9Department of Neurology and 10Department of Radiology, Division of Neuroradiology, Medical University of Graz, Graz, Austria; 11 Department of Neurology and 12Departments of Neurology and Pharmacy, Fulda Hospital, Fulda, Germany; 13Department of Neurology and 14 Institute of Radiology and Neuroradiology, Vest Hospital, Recklinghausen, Germany; 15Institute of Radiology, Division of Neuroradiology, Cologne University Hospital, Cologne, Germany; 16Department of Neurology and 17Institute of Radiology, Altenburger Land Hospital, Altenburg, Germany; 18 Department of Neurology and 19Institute of Diagnostic and Interventional Radiology and Neuroradiology, Essen University Hospital, Essen, Germany; 20 Department of Neurology and 21Institute of Diagnostic and Interventional Radiology, Medical Faculty, Heinrich Heine University, D€ usseldorf, Germany; 22 German Center for Neurodegenerative Diseases and Department of Neurology, Bonn University Hospital, Bonn, Germany; 23Department of Neuroradiology, Freiburg University Hospital, Freiburg, Germany; and 24UCLA Stroke Center and Department of Neurology, University of California, Los Angeles, Los Angeles, CA
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Interpretation: Beside initial stroke severity, the collateral status predicts clinical outcome and recanalization in BA occlusion. Our data suggest that the use of a stent retriever is associated with high recanalization rates, but recanalization on its own does not predict outcome. The role of other modifiable factors, including the choice of pretreatment imaging modality and time issues, warrants further investigation. ANN NEUROL 2015;77:415–424
B
asilar artery (BA) occlusion is among the most severe medical conditions, with very high fatality rates.1 However, due to a relative lack of scientific evidence, treatment approaches to BA occlusion are heterogeneous. In the past, many case series and smaller studies investigated the role of endovascular stroke treatment (EVT) in BA occlusion, as recently reviewed by Mattle et al.2 Most studies are characterized by either small patient samples, heterogeneous treatment approaches, the use of outdated EVT techniques (ie, intra-arterial thrombolysis without mechanical recanalization), or the use of first-generation mechanical recanalization devices (MERCI retriever, Penumbra device). The largest study published to date on treatment issues in BA occlusion did not find an overall outcome difference between patients undergoing intravenous (IV) thrombolysis or intra-arterial (IA) treatment.3 Recent technical developments in EVT have led to an increasing use of stent retrievers, especially in anterior circulation stroke. Stent retrievers have proven to be superior over first-generation mechanical recanalization devices and are characterized by their easy and quick handling.4,5 Nevertheless, studies on the role of stent retrievers in BA occlusion are sparse and their use in larger-scaled studies on BA occlusion was limited.3,6–8 The Endovascular Stroke Treatment (ENDOSTROKE) registry was launched in 2011 to study the spreading use of EVT in German and Austrian stroke centers with regard to its safety, technical success, and clinical efficacy. The aim of the present study was to comprehensively analyze the role of EVT in BA occlusion, focusing on factors influencing clinical outcome and recanalization rates in a large multicenter sample treated with current generation EVT approaches.
Patients and Methods ENDOSTROKE is an observational, international registry of consecutive patients aged 18 years or older who presented with an acute ischemic stroke in whom a mechanical revascularization procedure was attempted for intracranial large-vessel occlusion (ie, of the middle cerebral artery, distal internal carotid artery, or BA). Details concerning its aims and structure have been published earlier.9 In brief, only centers at which both neurologists and neurointerventionalists consented to participate in the registry were eligible for ENDOSTROKE. Centers were allowed to retrospectively include patients in the registry if patients were treated within the past 3 years and if clinical follow-up informa-
416
tion was available. To avoid selection bias, all centers were obliged to enter all consecutive patients in the registry, including those being retrospectively entered in the database and those with unsuccessful treatment. The ENDOSTROKE registry was launched on January 1, 2011 and included patients being treated until June 2013. All participating centers were monitored at the end of the recruitment period with the primary aim of avoiding selection bias by cross-checking neurointerventional logs with the database. Furthermore, source data of the medical records were compared with the online database. The study protocol was approved by the ethics committee of the Frankfurt University Medical Center, Frankfurt, Germany. The requirement for additional local ethical approval differed between participating centers and was obtained if required. Written informed consent was obtained from the patient or patient’s representative, as required by national and local guidelines. ENDOSTROKE is registered with ClinicalTrials.gov (NCT1399762).
Patient Selection For the present analysis, we included patients with angiographically (diagnostic run of digital subtraction angiography before endovascular procedure) confirmed BA occlusion (n 5 173). Patients in whom no attempt of mechanical recanalization procedure (ie, due to spontaneous recanalization) was done were excluded (n 5 4), as well as patients without long-term followup information available (n 5 21), leaving 148 patients. Twenty-one of these patients were treated before the start of the registry and were retrospectively entered in the database.
Procedures Data were recorded in an online database and were entered with a center-specific login and password. Definitions of the variables collected were incorporated in the electronic data entry form and specified in a separate guideline, being available at all participating centers. Data on baseline characteristics, stroke risk factors, estimated time of symptom onset, clinical presentation, stroke severity (assessed by the National Institutes of Health Stroke Scale [NIHSS]), pre- and post-treatment imaging findings, type and timing of angiographic treatment, complications, presumed cause of stroke, cause of death, and outcome follow-up using the modified Rankin Scale (mRS) obtained either via a structured telephone interview or by postal questionnaire were collected. Follow-up mRS was assessed at least 3 months after the intervention, but intervals were occasionally longer in retrospectively entered patients. The median time to follow-up was 120 days.
Angiography Data For central review, angiography data were available from 141 patients and anonymized images were transmitted electronically
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TABLE 1. Univariate Analysis of Clinical and Imaging Parameters on Outcome in BA Occlusion
Parameter
Overall
Good Outcome, mRS 5 0–2
Poor Outcome, mRS 5 3–6
p
Age, yr, median (IQR)
71 (61–77)
68 (59–73)
73 (63–80)
0.035a
NIHSS, points, median (IQR)
20 (9–28)
9 (5–17)
24 (15–30)
9 hours, and “unknown.”
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Angiographic images were rated by the core laboratory, but other imaging-related data (ie, extent of early ischemic lesions on pretreatment computed tomography [CT] or magnetic resonance imaging [MRI], post-treatment lesion size, and occurrence of intracranial hemorrhage [ICH] or subarachnoid hemorrhage [SAH]) were assessed by the local investigators.11,12 Early ischemic changes (EIC) were assessed on nonenhanced CT scans or diffusion-weighted imaging. EIC were rated as being absent or present within brainstem structures. For purposes of standardization between the centers, the time of the first angiographic image was defined as the start of the procedure and the time of the last angiographic series was defined as the time point of recanalization. Although the exact device used for EVT was recorded, we chose to summarize the devices according to their main mode of action into stent retrievers (eg, Solitaire [Covidien, Dublin, Ireland], Trevo [Stryker, Mountain View, CA], Acandis Aperio [Acandis, Pforzheim, Germany], Mindframe [MindFrame, Lake Forest, CA], Preset [Phenox, Bochum, Germany], Revive [Codman, San Jose, CA], Bonnet [Phenox]) and non–stent retrievers (MERCI [Stryker], Penumbra [Penumbra, Alameda, CA], Phenox clot retriever [Phenox], Catch device [Balt Extrusion, Montmorency, France]). The most frequently used stent retriever was the Solitaire device (n 5 77), followed by the Trevo device (n 5 34); the most frequently used non–stent retriever was the Penumbra device (n 5 32), followed by the MERCI device (n 5 9). The primary outcome measure was the proportion of patients with good clinical outcome on follow-up examination. Good clinical outcome was defined as an mRS score of 0, 1, or 2. Moderate clinical outcome was defined as an mRS score of 0, 1, 2, or 3. Recanalization was defined as a TICI score of 2b or 3 at the end of the endovascular procedure confirmed by the core laboratory.
Statistical Analysis Data are presented as median (interquartile range [IQR]) or No. (%), unless indicated otherwise. For consistency reasons, only nonparametric tests were used because several parameters, including age and NIHSS, were not normally distributed (Kolmogorov–Smirnov test, p < 0.0001). Univariate analysis was performed using the Mann–Whitney U test, Kruskal–Wallis test, or chi-square test, where appropriate. Parameters with a probability value < 0.2 in univariate analysis on clinical outcome or recanalization were incorporated in multivariate analysis using a fixed binary logistic regression. Significance level was set to p < 0.05. Statistical analysis was performed using SPSS 22 (IBM SPSS Statistics, Armonk, NY).
Results A total of 148 patients with angiographically proven BA occlusion being treated with EVT at 11 academic stroke centers of the ENDOSTROKE registry were available for final analysis. Baseline characteristics and imaging-related issues are summarized in Table 1. Median age was 71 (IQR 5 61–77) years, and median NIHSS at admission March 2015
FIGURE 1: Key outcome parameters in basilar artery occlusion. The proportion of patients within each group is shown. mRS 5 modified Rankin Scale; TICI 5 Thrombolysis in Cerebral Infarction.
was 20 (IQR 5 9–28). CT was the preferred initial imaging modality, used in 82%. For central angiographic reading, 141 data sets (95% of study population) were available. Exact sites of angiographically confirmed basilar occlusion were: proximal BA occlusion, 33%; mid-BA occlusion, 41%; distal BA occlusion, 26%, with numerical but nonsignificant differences in median NIHSS scores: proximal BA, 23 (IQR 5 10–30); mid-BA, 17 (IQR 5 10–27); distal BA, 15 (IQR 5 7–28; p 5 0.154, Kruskal–Wallis test). According to the ASITN/SIR collateral grading system, 20% had poor collaterals (grades 0– 1), 47% had moderate collaterals (grade 2), and 33% had good collaterals (grades 3–4) prior to EVT. Fifty-nine percent of patients received IV thrombolysis prior to EVT, in 15% IV thrombolysis was followed by IA thrombolysis in combination with mechanical recanalization, 15% were treated with IA thrombolysis and mechanical recanalization, and 26% received mechanical recanalization therapy without additional thrombolytic therapy (Table 2). In 118 (84%) patients, a stent retriever was used, either as the only device or in combination with others. In 69% of cases, 1 device was used; 2 devices were used in 25% and 3 in 6%. In approximately 60% of patients, EVT was started within 6 hours, and in 17% treatment started later than 6 hours after symptom onset. Symptom onset was unknown in 22% of patients (see Table 2). Good clinical outcome (mRS 5 0–2) was reached by 50 (34%) and moderate clinical outcome (mRS 5 0– 3) by 62 (42%). Mortality was 35%; 43 patients (29%) died during the hospital stay. TICI 2b–3 recanalization was achieved in 79% (111 of 141 patients with available angiographic data; see Table 2, Fig 1). 419
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TABLE 3. Multivariate Analysis of Predictors of Outcome or Recanalization
Predictor
p
OR
95% Confidence Interval
NIHSS
6 hours (and 24% in patients with unknown symptom onset) strongly argues against a strict adherence to rigid time limits in BA occlusion. Our study has to deal with all limitations of a nonrandomized observational registry study. All participating centers had individual protocols for referral of patients to EVT, and we did not systematically assess the numbers of patients with BA occlusion not undergoing EVT. No central reading of EIC on CT or MRI was done, precluding robust statements on the clinical importance of the site and size of EICs prior to EVT and the exact role of MRI for patient selection. Conversely, strengths of our study are—besides its large size—its investigator-initiated multicenter design without industrial sponsoring, the assessment of angiographic data by a blinded core laboratory, the monitoring of all participating centers to minimize reporting bias within the registry, and the focus on patients undergoing EVT procedures in angiographically proven vessel occlusion with current state-of-the art EVT approaches. Volume 77, No. 3
Singer et al: Recanalization in BA Occlusion
In conclusion, this study emphasizes the impact of several patient- and procedure-related factors on outcome in patients undergoing EVT for BA occlusion. The most important patient-related factors determining clinical outcome are initial stroke severity and collateral status, the latter also determining recanalization success. The use of a stent retriever was associated with high recanalization rates, but recanalization on its own did not predict clinical outcome. The roles of pretreatment imaging modality and of time issues for patient selection need further investigation, as does the role of EVT compared to IV thrombolysis in BA occlusion.
Idec, Bayer, Novartis, Merck Serono. A.M.: speaking fees, Penumbra. D.S.L.: consultancy, Covidien, Stryker.
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Acknowledgment We thank B. Poltrum, T. Gattringer, C. Schneider, F. J. Bode, M. Gliem, J.-I. Lee, C. Weimar, D. Strenge, S.-J. You, H. Braun, S. Issar, S. T€ ut€unc€ u, E. Hofmann, K. Nußbaumer, M. Sonnberger, and J. Meggeneder for technical assistance, data management and/or data monitoring.
Authorship O.C.S.: study design, data analysis, manuscript preparation; J.Be.: study design, data collection, manuscript preparation; C.H.N.: data collection, study design; G.B.: data collection; H.-P.H: data collection; J.T.: data collection; K.G.: data collection; W.M.-F.: data collection; K.N.: data collection; H.D.: data collection; T.N.-H: data collection, scientific advice, study design; C.H.: data collection; M.B.: data collection; A.M.: data collection; A.S.: data collection; A.B.: data collection; J.Br.: data collection; M.U.S.: data collection; S.J.: data collection; B.T.: data collection; G.C.P.: data collection; H.U.: data collection; D.S.L.: blinded angiographic rating, scientific advice, correction of manuscript.
Potential Conflicts of Interest J.Be.: scientific advisory board, Acandis; consultancy, Siemens, Sequent Medical. C.H.N.: consultancy, Boehringer Ingelheim, Pfizer Pharma, Bristol-Myers Squibb; grants/ grants pending, German Ministry of Education and Research; speaking fees, Pfizer Pharma, Boehringer Ingelheim. H.-P.H.: consultancy, Boehringer Ingelheim, BristolMyers Squibb, Pfizer, Daiichi Sankyo; speaking fees, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Daiichi Sankyo, Bayer. J.T.: consultancy, Codman; travel expenses, Microvention, Stryker. K.G.: consultancy, Boehringer Ingelheim, Bayer; speaking fees, Boehringer Ingelheim, Bayer, BMS, Pfizer, Sanofi-Aventis. K.N.: consultancy, speaking fees, Boehringer Ingelheim. H.D.: travel expenses, Covidien, Microvention. C.H.: travel expenses, Bayer Vital. M.B.: speaking fees, Biogen Idec; travel expenses, Biogen March 2015
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Alqadri S, Adil MM, Watanabe M, Qureshi AI. Patterns of collateral formation in basilar artery steno-occlusive diseases. J Vasc Interv Neurol 2013;6:9–13.
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Volume 77, No. 3
Mechanical Recanalization in Basilar Artery Occlusion: The ENDOSTROKE Study Oliver C. Singer, MD,1 Joachim Berkefeld, MD,2 Christian H. Nolte, MD,3 Georg Bohner, MD,4 Hans-Peter Haring, MD,5 Johannes Trenkler, MD,6 Klaus Gr€ oschel, MD,7 Wibke M€ uller-Forell, MD,8 Kurt Niederkorn, MD,9 Hannes Deutschmann, MD,10 Tobias Neumann-Haefelin, MD,11 Carina Hohmann, PhD,12 Matthias Bussmeyer,13 Anastasios Mpotsaris, MD,14,15 Anett Stoll, MD,16 Albrecht Bormann, MD,17 Johannes Brenck, MD,18 Marc U. Schlamann, MD,19 Sebastian Jander, MD,20 Bernd Turowski, MD,21 Gabor C. Petzold, MD,22 Horst Urbach, MD,23 and David S. Liebeskind, MD,24 for the ENDOSTROKE Study Group Objective: A study was undertaken to evaluate clinical and procedural factors associated with outcome and recanalization in endovascular stroke treatment (EVT) of basilar artery (BA) occlusion. Methods: ENDOSTROKE is an investigator-initiated multicenter registry for patients undergoing EVT. This analysis includes 148 consecutive patients with BA occlusion, with 59% having received intravenous thrombolysis prior to EVT. Recanalization (defined as Thrombolysis in Cerebral Infarction [TICI] score 2b–3) and collateral status (using the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology collateral grading system) were assessed by a blinded core laboratory. Good (moderate) outcome was defined as a modified Rankin Scale score of 0 to 2 (0–3) assessed after at least 3 months (median time to follow-up 5 120 days). Results: Thirty-four percent had good and 42% had moderate clinical outcome; mortality was 35%. TICI 2b–3 recanalization was achieved by 79%. Age, hypertension, National Institutes of Health Stroke Scale scores, collateral status, and the use of magnetic resonance imaging prior to EVT predicted clinical outcome, the latter 3 remaining independent predictors in multivariate analysis. Independent predictors of recanalization were better collateral status and the use of a stent retriever. However, recanalization did not significantly predict clinical outcome.
View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.24336 Received Mar 26, 2014, and in revised form Nov 28, 2014. Accepted for publication Dec 7, 2014. Address correspondence to Dr Singer, Department of Neurology, Goethe-University, Schleusenweg 2–16, D-60528 Frankfurt/Main, Germany. E-mail: [email protected] From the 1Department of Neurology and 2Institute of Neuroradiology, Goethe University, Frankfurt, Germany; 3Department of Neurology and 4Institute of Diagnostic and Interventional Radiology and Nuclear Medicine, Charit e Hospital, Berlin, Germany; 5Department of Neurology and 6Institute of Radiology, Wagner-Jauregg Hospital, Linz, Austria; 7Department of Neurology and 8Institute of Neuroradiology, Mainz University Hospital, Mainz, Germany; 9Department of Neurology and 10Department of Radiology, Division of Neuroradiology, Medical University of Graz, Graz, Austria; 11 Department of Neurology and 12Departments of Neurology and Pharmacy, Fulda Hospital, Fulda, Germany; 13Department of Neurology and 14 Institute of Radiology and Neuroradiology, Vest Hospital, Recklinghausen, Germany; 15Institute of Radiology, Division of Neuroradiology, Cologne University Hospital, Cologne, Germany; 16Department of Neurology and 17Institute of Radiology, Altenburger Land Hospital, Altenburg, Germany; 18 Department of Neurology and 19Institute of Diagnostic and Interventional Radiology and Neuroradiology, Essen University Hospital, Essen, Germany; 20 Department of Neurology and 21Institute of Diagnostic and Interventional Radiology, Medical Faculty, Heinrich Heine University, D€ usseldorf, Germany; 22 German Center for Neurodegenerative Diseases and Department of Neurology, Bonn University Hospital, Bonn, Germany; 23Department of Neuroradiology, Freiburg University Hospital, Freiburg, Germany; and 24UCLA Stroke Center and Department of Neurology, University of California, Los Angeles, Los Angeles, CA
C 2015 American Neurological Association V 415
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Interpretation: Beside initial stroke severity, the collateral status predicts clinical outcome and recanalization in BA occlusion. Our data suggest that the use of a stent retriever is associated with high recanalization rates, but recanalization on its own does not predict outcome. The role of other modifiable factors, including the choice of pretreatment imaging modality and time issues, warrants further investigation. ANN NEUROL 2015;77:415–424
B
asilar artery (BA) occlusion is among the most severe medical conditions, with very high fatality rates.1 However, due to a relative lack of scientific evidence, treatment approaches to BA occlusion are heterogeneous. In the past, many case series and smaller studies investigated the role of endovascular stroke treatment (EVT) in BA occlusion, as recently reviewed by Mattle et al.2 Most studies are characterized by either small patient samples, heterogeneous treatment approaches, the use of outdated EVT techniques (ie, intra-arterial thrombolysis without mechanical recanalization), or the use of first-generation mechanical recanalization devices (MERCI retriever, Penumbra device). The largest study published to date on treatment issues in BA occlusion did not find an overall outcome difference between patients undergoing intravenous (IV) thrombolysis or intra-arterial (IA) treatment.3 Recent technical developments in EVT have led to an increasing use of stent retrievers, especially in anterior circulation stroke. Stent retrievers have proven to be superior over first-generation mechanical recanalization devices and are characterized by their easy and quick handling.4,5 Nevertheless, studies on the role of stent retrievers in BA occlusion are sparse and their use in larger-scaled studies on BA occlusion was limited.3,6–8 The Endovascular Stroke Treatment (ENDOSTROKE) registry was launched in 2011 to study the spreading use of EVT in German and Austrian stroke centers with regard to its safety, technical success, and clinical efficacy. The aim of the present study was to comprehensively analyze the role of EVT in BA occlusion, focusing on factors influencing clinical outcome and recanalization rates in a large multicenter sample treated with current generation EVT approaches.
Patients and Methods ENDOSTROKE is an observational, international registry of consecutive patients aged 18 years or older who presented with an acute ischemic stroke in whom a mechanical revascularization procedure was attempted for intracranial large-vessel occlusion (ie, of the middle cerebral artery, distal internal carotid artery, or BA). Details concerning its aims and structure have been published earlier.9 In brief, only centers at which both neurologists and neurointerventionalists consented to participate in the registry were eligible for ENDOSTROKE. Centers were allowed to retrospectively include patients in the registry if patients were treated within the past 3 years and if clinical follow-up informa-
416
tion was available. To avoid selection bias, all centers were obliged to enter all consecutive patients in the registry, including those being retrospectively entered in the database and those with unsuccessful treatment. The ENDOSTROKE registry was launched on January 1, 2011 and included patients being treated until June 2013. All participating centers were monitored at the end of the recruitment period with the primary aim of avoiding selection bias by cross-checking neurointerventional logs with the database. Furthermore, source data of the medical records were compared with the online database. The study protocol was approved by the ethics committee of the Frankfurt University Medical Center, Frankfurt, Germany. The requirement for additional local ethical approval differed between participating centers and was obtained if required. Written informed consent was obtained from the patient or patient’s representative, as required by national and local guidelines. ENDOSTROKE is registered with ClinicalTrials.gov (NCT1399762).
Patient Selection For the present analysis, we included patients with angiographically (diagnostic run of digital subtraction angiography before endovascular procedure) confirmed BA occlusion (n 5 173). Patients in whom no attempt of mechanical recanalization procedure (ie, due to spontaneous recanalization) was done were excluded (n 5 4), as well as patients without long-term followup information available (n 5 21), leaving 148 patients. Twenty-one of these patients were treated before the start of the registry and were retrospectively entered in the database.
Procedures Data were recorded in an online database and were entered with a center-specific login and password. Definitions of the variables collected were incorporated in the electronic data entry form and specified in a separate guideline, being available at all participating centers. Data on baseline characteristics, stroke risk factors, estimated time of symptom onset, clinical presentation, stroke severity (assessed by the National Institutes of Health Stroke Scale [NIHSS]), pre- and post-treatment imaging findings, type and timing of angiographic treatment, complications, presumed cause of stroke, cause of death, and outcome follow-up using the modified Rankin Scale (mRS) obtained either via a structured telephone interview or by postal questionnaire were collected. Follow-up mRS was assessed at least 3 months after the intervention, but intervals were occasionally longer in retrospectively entered patients. The median time to follow-up was 120 days.
Angiography Data For central review, angiography data were available from 141 patients and anonymized images were transmitted electronically
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TABLE 1. Univariate Analysis of Clinical and Imaging Parameters on Outcome in BA Occlusion
Parameter
Overall
Good Outcome, mRS 5 0–2
Poor Outcome, mRS 5 3–6
p
Age, yr, median (IQR)
71 (61–77)
68 (59–73)
73 (63–80)
0.035a
NIHSS, points, median (IQR)
20 (9–28)
9 (5–17)
24 (15–30)
9 hours, and “unknown.”
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Angiographic images were rated by the core laboratory, but other imaging-related data (ie, extent of early ischemic lesions on pretreatment computed tomography [CT] or magnetic resonance imaging [MRI], post-treatment lesion size, and occurrence of intracranial hemorrhage [ICH] or subarachnoid hemorrhage [SAH]) were assessed by the local investigators.11,12 Early ischemic changes (EIC) were assessed on nonenhanced CT scans or diffusion-weighted imaging. EIC were rated as being absent or present within brainstem structures. For purposes of standardization between the centers, the time of the first angiographic image was defined as the start of the procedure and the time of the last angiographic series was defined as the time point of recanalization. Although the exact device used for EVT was recorded, we chose to summarize the devices according to their main mode of action into stent retrievers (eg, Solitaire [Covidien, Dublin, Ireland], Trevo [Stryker, Mountain View, CA], Acandis Aperio [Acandis, Pforzheim, Germany], Mindframe [MindFrame, Lake Forest, CA], Preset [Phenox, Bochum, Germany], Revive [Codman, San Jose, CA], Bonnet [Phenox]) and non–stent retrievers (MERCI [Stryker], Penumbra [Penumbra, Alameda, CA], Phenox clot retriever [Phenox], Catch device [Balt Extrusion, Montmorency, France]). The most frequently used stent retriever was the Solitaire device (n 5 77), followed by the Trevo device (n 5 34); the most frequently used non–stent retriever was the Penumbra device (n 5 32), followed by the MERCI device (n 5 9). The primary outcome measure was the proportion of patients with good clinical outcome on follow-up examination. Good clinical outcome was defined as an mRS score of 0, 1, or 2. Moderate clinical outcome was defined as an mRS score of 0, 1, 2, or 3. Recanalization was defined as a TICI score of 2b or 3 at the end of the endovascular procedure confirmed by the core laboratory.
Statistical Analysis Data are presented as median (interquartile range [IQR]) or No. (%), unless indicated otherwise. For consistency reasons, only nonparametric tests were used because several parameters, including age and NIHSS, were not normally distributed (Kolmogorov–Smirnov test, p < 0.0001). Univariate analysis was performed using the Mann–Whitney U test, Kruskal–Wallis test, or chi-square test, where appropriate. Parameters with a probability value < 0.2 in univariate analysis on clinical outcome or recanalization were incorporated in multivariate analysis using a fixed binary logistic regression. Significance level was set to p < 0.05. Statistical analysis was performed using SPSS 22 (IBM SPSS Statistics, Armonk, NY).
Results A total of 148 patients with angiographically proven BA occlusion being treated with EVT at 11 academic stroke centers of the ENDOSTROKE registry were available for final analysis. Baseline characteristics and imaging-related issues are summarized in Table 1. Median age was 71 (IQR 5 61–77) years, and median NIHSS at admission March 2015
FIGURE 1: Key outcome parameters in basilar artery occlusion. The proportion of patients within each group is shown. mRS 5 modified Rankin Scale; TICI 5 Thrombolysis in Cerebral Infarction.
was 20 (IQR 5 9–28). CT was the preferred initial imaging modality, used in 82%. For central angiographic reading, 141 data sets (95% of study population) were available. Exact sites of angiographically confirmed basilar occlusion were: proximal BA occlusion, 33%; mid-BA occlusion, 41%; distal BA occlusion, 26%, with numerical but nonsignificant differences in median NIHSS scores: proximal BA, 23 (IQR 5 10–30); mid-BA, 17 (IQR 5 10–27); distal BA, 15 (IQR 5 7–28; p 5 0.154, Kruskal–Wallis test). According to the ASITN/SIR collateral grading system, 20% had poor collaterals (grades 0– 1), 47% had moderate collaterals (grade 2), and 33% had good collaterals (grades 3–4) prior to EVT. Fifty-nine percent of patients received IV thrombolysis prior to EVT, in 15% IV thrombolysis was followed by IA thrombolysis in combination with mechanical recanalization, 15% were treated with IA thrombolysis and mechanical recanalization, and 26% received mechanical recanalization therapy without additional thrombolytic therapy (Table 2). In 118 (84%) patients, a stent retriever was used, either as the only device or in combination with others. In 69% of cases, 1 device was used; 2 devices were used in 25% and 3 in 6%. In approximately 60% of patients, EVT was started within 6 hours, and in 17% treatment started later than 6 hours after symptom onset. Symptom onset was unknown in 22% of patients (see Table 2). Good clinical outcome (mRS 5 0–2) was reached by 50 (34%) and moderate clinical outcome (mRS 5 0– 3) by 62 (42%). Mortality was 35%; 43 patients (29%) died during the hospital stay. TICI 2b–3 recanalization was achieved in 79% (111 of 141 patients with available angiographic data; see Table 2, Fig 1). 419
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TABLE 3. Multivariate Analysis of Predictors of Outcome or Recanalization
Predictor
p
OR
95% Confidence Interval
NIHSS
6 hours (and 24% in patients with unknown symptom onset) strongly argues against a strict adherence to rigid time limits in BA occlusion. Our study has to deal with all limitations of a nonrandomized observational registry study. All participating centers had individual protocols for referral of patients to EVT, and we did not systematically assess the numbers of patients with BA occlusion not undergoing EVT. No central reading of EIC on CT or MRI was done, precluding robust statements on the clinical importance of the site and size of EICs prior to EVT and the exact role of MRI for patient selection. Conversely, strengths of our study are—besides its large size—its investigator-initiated multicenter design without industrial sponsoring, the assessment of angiographic data by a blinded core laboratory, the monitoring of all participating centers to minimize reporting bias within the registry, and the focus on patients undergoing EVT procedures in angiographically proven vessel occlusion with current state-of-the art EVT approaches. Volume 77, No. 3
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In conclusion, this study emphasizes the impact of several patient- and procedure-related factors on outcome in patients undergoing EVT for BA occlusion. The most important patient-related factors determining clinical outcome are initial stroke severity and collateral status, the latter also determining recanalization success. The use of a stent retriever was associated with high recanalization rates, but recanalization on its own did not predict clinical outcome. The roles of pretreatment imaging modality and of time issues for patient selection need further investigation, as does the role of EVT compared to IV thrombolysis in BA occlusion.
Idec, Bayer, Novartis, Merck Serono. A.M.: speaking fees, Penumbra. D.S.L.: consultancy, Covidien, Stryker.
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Acknowledgment We thank B. Poltrum, T. Gattringer, C. Schneider, F. J. Bode, M. Gliem, J.-I. Lee, C. Weimar, D. Strenge, S.-J. You, H. Braun, S. Issar, S. T€ ut€unc€ u, E. Hofmann, K. Nußbaumer, M. Sonnberger, and J. Meggeneder for technical assistance, data management and/or data monitoring.
Authorship O.C.S.: study design, data analysis, manuscript preparation; J.Be.: study design, data collection, manuscript preparation; C.H.N.: data collection, study design; G.B.: data collection; H.-P.H: data collection; J.T.: data collection; K.G.: data collection; W.M.-F.: data collection; K.N.: data collection; H.D.: data collection; T.N.-H: data collection, scientific advice, study design; C.H.: data collection; M.B.: data collection; A.M.: data collection; A.S.: data collection; A.B.: data collection; J.Br.: data collection; M.U.S.: data collection; S.J.: data collection; B.T.: data collection; G.C.P.: data collection; H.U.: data collection; D.S.L.: blinded angiographic rating, scientific advice, correction of manuscript.
Potential Conflicts of Interest J.Be.: scientific advisory board, Acandis; consultancy, Siemens, Sequent Medical. C.H.N.: consultancy, Boehringer Ingelheim, Pfizer Pharma, Bristol-Myers Squibb; grants/ grants pending, German Ministry of Education and Research; speaking fees, Pfizer Pharma, Boehringer Ingelheim. H.-P.H.: consultancy, Boehringer Ingelheim, BristolMyers Squibb, Pfizer, Daiichi Sankyo; speaking fees, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Daiichi Sankyo, Bayer. J.T.: consultancy, Codman; travel expenses, Microvention, Stryker. K.G.: consultancy, Boehringer Ingelheim, Bayer; speaking fees, Boehringer Ingelheim, Bayer, BMS, Pfizer, Sanofi-Aventis. K.N.: consultancy, speaking fees, Boehringer Ingelheim. H.D.: travel expenses, Covidien, Microvention. C.H.: travel expenses, Bayer Vital. M.B.: speaking fees, Biogen Idec; travel expenses, Biogen March 2015
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