860652 research-article20192019 TAN0010.1177/1756286419860652Therapeutic Advances in Neurological DisordersAV Alexandrov, G Tsivgoulis Therapeutic Advances in Neurological Disorders Original Research Endovascular equipoise shift in a Ther Adv Neurol Disord 2019, Vol. 12: 1–12 phase III randomized clinical trial of DOI: 10.1177/ https://doi.org/10.1177/1756286419860652 https://doi.org/10.1177/1756286419860652 1756286419860652 sonothrombolysis for acute ischemic stroke © The Author(s), 2019. Article reuse guidelines: sagepub.com/journals- permissions Andrei V. Alexandrov , Georgios Tsivgoulis, Martin Köhrmann, Aristeidis H. Katsanos, Lauri Soinne, Andrew D. Barreto, Travis Rothlisberger, Vijay K. Sharma, Robert Mikulik, Correspondence to: Keith W. Muir, Christopher R. Levi, Carlos A. Molina, Maher Saqqur, Dimitris Mavridis, Andrei V. Alexandrov Department of Neurology, Theodora Psaltopoulou, Milan R. Vosko, Jochen B. Fiebach, Pitchaiah Mandava, Thomas University of Tennessee A. Kent, Anne W. Alexandrov and Peter D. Schellinger, for the CLOTBUST-ER Trial Health Science Center, 855 Monroe Avenue, Suite 415, Investigators Memphis, TN 38163, USA. avalexandrov@att.net Georgios Tsivgoulis Abstract Department of Neurology, University of Tennessee Background: Results of our recently published phase III randomized clinical trial of Health Science Center, ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high Memphis, TN, USA Second Department frequency ultrasound device revealed heterogeneity of patient recruitment among centers. of Neurology, ‘Attikon’ Methods: We performed a post hoc analysis after excluding subjects that were recruited at University Hospital, School of Medicine, National and centers reporting a decline in the balance of randomization between sonothrombolysis and Kapodistrian University of concurrent endovascular trials. Athens, Athens, Greece Martin Köhrmann Results: From a total of 676 participants randomized in the CLOTBUST-ER trial we identified Department of Neurology, 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Universitaetsklinikum Erlangen, Erlangen, Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Germany Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline Department of Neurology, University Duisburg- serum glucose showed a significant (p < 0.01) interaction of perceived endovascular equipoise Essen, Essen, Germany shift on the association between sonothrombolysis and 3 month functional outcome [adjusted Aristeidis H. Katsanos Second Department common odds ratio (cOR) in centers with perceived endovascular equipoise shift: 0.22, 95% CI of Neurology, ‘Attikon’ 0.06–0.75; p = 0.02; adjusted cOR for centers without endovascular equipoise shift: 1.20, 95% University Hospital, School of Medicine, National and CI 0.89–1.62; p = 0.24)]. After excluding centers with perceived endovascular equipoise shift, Kapodistrian University of Athens, Athens, Greece patients randomized to sonothrombolysis had higher odds of 3 month functional independence Department of Neurology, (mRS scores 0–2) compared with patients treated with tPA only (adjusted OR: 1.53; 95% CI St Josef Hospital, Ruhr 1.01–2.31; p = 0.04). University Bochum, Bochum, Germany Conclusion: Our experience in CLOTBUST-ER indicates that increasing implementation of Lauri Soinne endovascular therapies across major academic stroke centers raises significant challenges Department of Neurology, Helsinki University for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies. Hospital and Clinical Neurosciences, Neurology, University of Helsinki Helsinki, Finland Keywords: endovascular, equipoise shift, intracranial hemorrhage, mechanical thrombectomy, Andrew D. Barreto outcome, recanalization, sonothrombolysis, stroke, ultrasound-enhanced thrombolysis Department of Neurology, University of Texas Health Science Center at Houston, Received: 16 March 2019; revised manuscript accepted: 7 May 2019. Houston, TX, USA Travis Rothlisberger Cerevast Therapeutics, Inc., Redmond, WA, USA Introduction outcomes in patients with acute ischemic stroke Vijay K. Sharma Yong Loo Lin School Preliminary evidence has indicated that the addi- (AIS) with proximal intracranial occlusions.1,2 of Medicine, National tion of high-frequency, pulsed-wave ultrasound to Nevertheless, the largest to date phase III rand- University of Singapore and Division of Neurology, tissue plasminogen activator (tPA) may increase omized-controlled clinical trial (RCT) evaluating Department of Medicine, the odds of recanalization and favorable functional the safety and efficacy of ultrasound-enhanced National University journals.sagepub.com/home/tan 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Neurological Disorders 12 Hospital, Singapore, Singapore thrombolysis (sonothrombolysis) using an operator-­ Investigational procedure Robert Mikulik independent high-frequency ultrasound device All eligible subjects received full-dose intravenous International Clinical compared with intravenous thrombolysis (IVT) tPA (0.9 mg/kg; 90 mg maximum; 10% bolus fol- Research Centre and Department of Neurology, alone reported that delivery of sonothrombolysis lowed by 90% intravenous infusion over 60 min) St. Anne’s University was feasible and safe, but failed to offer addi- and activation of the headframe within 30 min of Hospital in Brno and Medical Faculty, Masaryk University, tional clinical benefit in AIS patients with baseline tPA bolus to achieve maximum overlap between Brno, Czech Republic moderate-to-severe stroke.3 exposure to the device and tPA infusion.3,5 All Keith W. Muir subjects regardless of device activation time were Institute of Neuroscience and Psychology, University Review of the results of this RCT revealed hetero- required to wear the headframe for a total of of Glasgow, Queen Elizabeth geneity of patient recruitment among centers, a 120 min. Devices were programmed based on a University Hospital, Glasgow, UK finding that potentially reflected practice drift at randomization code that maintained blinding of Christopher R. Levi sites that were also participating in concurrent treating physicians, patients, and the sponsor to Department of Neurology, mechanical thrombectomy trials, reflecting loss of treatment group assignment (active or sham).3,5 John Hunter Hospital, University of Newcastle, equipoise in favor of open-label mechanical Newcastle, Australia thrombectomy or preferential endovascular trial Carlos A. Molina Stroke Unit, Department of recruitment among patients with large vessel Primary and secondary outcomes Neurology, Vall d’Hebron occlusions (LVOs). This concern has also been The primary efficacy outcome was assessed using University Hospital, Vall d’Hebron Research Institute, corroborated by the substantial representation modified Rankin scale (mRS) scores at 90 ± 10 days Autonomous University of (28%) of patients with baseline National Institutes from randomization, ascertained by trained and Barcelona, Barcelona, Spain of Health Scale (NIHSS) scores of 10 or 11 certified personnel blinded to treatment assign- Maher Saqqur Department of Medicine enrolled into the trial (Figure 1), given the lower ment.3,5 The primary analysis included a cumula- (Neurology), University of positive predictive value of a cut-off of 10 points tive ordinal logistic regression (shift analysis of Alberta, Edmonton, Alberta, Canada in NIHSS score compared with the cut-off of mRS scores in the direction of functional improve- Neuroscience Institute, 12 points in detecting LVO in AIS patients.4 ment) for those subjects enrolled within 3 h of Hamad Medical Corporation, stroke symptom onset according to the US Food Doha, Qatar In view of these considerations, we performed an and Drug Administration regulatory requirements Dimitris Mavridis Department of Primary additional post hoc analysis in order to explore (‘US’ primary outcome).3,5 This analysis was Education, School of how practice drift in favor of endovascular repeated for all patients who were enrolled within Education, University of Ioannina, Ioannina, Greece thrombectomy might have affected the findings of 4.5 h (‘Global’ primary outcome).3,5 Theodora Psaltopoulou the sonothrombolysis trial. Department of Hygiene, Epidemiology and Medical Other secondary efficacy endpoints included the Statistics, Medical School, differences in NIHSS scores between the two National and Kapodistrian University of Athens, Athens, Methods groups at 2 h, 24 h, day 7, and day 90, the differ- Greece ences in mRS scores at day 7 and the difference Milan R. Vosko Trial design and study population in rates of dichotomous 90 day mRS 0–1 and Department of Neurology 2, Med Campus III, Kepler The Combined Lysis of Thrombus using mRS 0–2 between the two groups.3,5 We also fur- University Hospital, Linz, Ultrasound and Systemic tPA for Emergent ther assessed the rates of dramatic clinical recov- Austria Revascularization (CLOTBUST-ER) was a mul- ery at 2 h, clinical recovery at 24 h, and clinical Jochen B. Fiebach Center for Stroke Research tinational, double-blind, sham-controlled RCT.5 recovery at day 90 (defined as a reduction of 10 Berlin, Charité-University Detailed descriptions of the methods and results or more points in NIHSS compared with pre- Medicine Berlin, Berlin, Germany of the CLOTBUST-ER trial are available in rel- treatment, or a total NIHSS score of 3 or less), Pitchaiah Mandava evant publications.3,5 In brief, AIS patients aged neurological improvement at 24 h (defined as a Thomas A. Kent 18–80 years with baseline NIHSS scores of reduction of 5 or more points on NIHSS com- Stroke Outcomes Laboratory, Department of ⩾10 points who were eligible for intravenous tPA pared with the pretreatment score), and neuro- Neurology, Baylor College of treatment within a 4.5 h treatment window world- logic worsening at 24 h (defined as an increase of Medicine, Houston, TX, USA Michael E. DeBakey VA wide and within a 3 h treatment window in North 4 or more points on NIHSS compared with the Medical Center Stroke America were randomized 1:1 to active ultra- pretreatment score).3,5 Program and Center for Translational Research on sound + tPA (intervention group) or to sham Inflammatory Diseases, ultrasound + tPA (control group) using web- Symptomatic intracranial hemorrhage (sICH) per Houston, TX, USA based central randomization.3,5 The trial was study protocol was defined as neurological deterio- Anne W. Alexandrov Department of Neurology, approved by the institutional review board at each ration (⩾4 points worsening on the NIHSS com- University of Tennessee site or national ethics committee.3 Written pared with the best prior examination) within 24 h Health Science Center, Memphis, TN, USA informed consent was obtained from the patient after tPA bolus with documented parenchymal or a legal representative before enrolment.3 hemorrhage type 2 or remote parenchymal 2 journals.sagepub.com/home/tan AV Alexandrov, G Tsivgoulis et al. Australian Catholic University, Sydney, Australia Peter D. Schellinger Departments of Neurology and Neurogeriatry, John Wesling Medical Center Minden, Ruhr University Bochum, Minden, Germany Figure 1. Overview of the distribution of the (a) National Institutes of Health Stroke Scale (NIHSS) scores of all patients with acute ischemic stroke and (b) patients with acute ischemic stroke and NIHSS scores 10 points or greater randomized in the CLOTBUST-ER trial (blue bars). Indirect comparison with NIHSS scores of patients with acute ischemic stroke randomized in the National Institute for Neurological Disorders rt-PA Stroke Trial (red line). hemorrhage type 2.3,5 All prespecified adverse and adjudicated by a blinded independent adjudi- events were reported by the blinded clinical inves- cation panel within the Data and Safety Monitoring tigators of the participating centers, while reviewed Board (DSMB) committee.3,5 journals.sagepub.com/home/tan 3 Therapeutic Advances in Neurological Disorders 12 Endovascular equipoise shift definition The Steering Committee was blinded to the 3 A number of CLOTBUST-ER centers were con- month functional outcomes of all patients during currently participating in ongoing endovascular the process of identifying centers that met these thrombectomy trials. Following the presentation criteria. Interaction testing using proportional of the results of MR CLEAN (Multicenter odds and binary logistic regression was performed Randomized Clinical Trial of Endovascular between the dichotomous variable ‘perceived Treatment for Acute Ischemic Stroke in the endovascular equipoise shift’ and ‘treatment Netherlands) in October 2014,6 a slowing of assignment’. recruitment rates during the first months of 2015 was detected. This led to repeated Steering Committee discussions regarding potential con- Statistical analysis flicts between CLOTBUST-ER and ongoing All reported analyses were performed in the inten- mechanical thrombectomy trials. The Global and tion-to-treat population. The primary endpoint National Principal Investigators contacted cent- analysis was performed in subjects who received ers with perceived conflicts due to competing tPA within 3 h of symptom onset, using the pro- endovascular reperfusion therapies during con- portional odds logistic regression (polr command duct of CLOTBUST-ER to verify and address in R) over the 90 day mRS distribution after col- these concerns as well as to discuss their continu- lapsing grades 5 and 6.3,5 For all secondary effi- ation in CLOTBUST-ER. As result of these dis- cacy and safety outcomes we performed unadjusted cussions, one center had to stop enrollment. and adjusted analyses for confounders (baseline NIHSS, age, baseline serum glucose, time to tPA In order to explore the potential impact of shifting bolus) that were chosen by the steering committee treatment practice at centers participating in end- prior to unblinding of the data. Prespecified sec- ovascular trials on CLOTBUST-ER, an addi- ondary outcomes were tested in the unadjusted tional post hoc analysis was performed after analyses with Fisher’s two-sided test of proportion excluding those subjects that were recruited at and confidence intervals (CIs) were provided. centers meeting following criteria: (1) centers Interaction testing using proportional odds and with 24/7 available endovascular services; and (2) binary logistic regression was performed between decline in equal randomization rates between the dichotomous variable ‘perceived endovascular sonothrombolysis and endovascular trials or (3) equipoise shift’ and ‘treatment assignment’. The decline in preference to randomize patients with threshold of statistical significance for interaction LVO to CLOTBUST-ER (opting instead to treat testing was set at p < 0.1 them with interventional treatment as standard of care). Investigators from these centers have openly stated during the Steering Committee Results meetings that they were consistently selecting AIS A total of 676 participants were randomized in the patients with LVO presence on baseline com- CLOTBUST-ER trial (335 to the intervention puted tomography angiography (CTA) for enroll- group and 341 to the control group) at a total of ment in endovascular trials that were competing 76 medical centers between August 2013 and with CLOBUST-ER (ESCAPE, REVASCAT, April 2015. CLOTBUST-ER was stopped early SWIFT PRIME), while they preferred to enroll for futility at the second interim analysis by the only patients with no vessel occlusion (lacunar DSMB according to prespecified stopping rules. strokes) or distal vessel occlusion on CTA in the Subjects who were enrolled in the study at the CLOBUST-ER trial. These centers were subse- time of the futility determination were followed quently considered to be prone to patient selec- until 90 days post-tPA administration by the site tion bias due to the expressed treatment preference investigators. A significant (Pearson chi-squared: in favor of mechanical thrombectomy (MT) and 106.379; df = 75; p = 0.01) variation in the reported were excluded from the present analyses. The rates of favorable functional outcomes (mRS centers that were involved in RCTs of MT and scores of 0–1) was documented across participat- decided to equally randomize patients in MT and ing centers after analyzing both treatment groups sonothrombolysis RCTs were not excluded from combined. Moreover, this variation persisted in the present analyses. No further clarifications the reported rates of 3 month functional inde- (e.g. by self-report questionnaires or telephone pendence (Pearson chi-squared: 92.181; df = 75; interviews) were made. mRS scores of 0–2; p = 0.09) and in the 4 journals.sagepub.com/home/tan AV Alexandrov, G Tsivgoulis et al. Figure 2. Subgroup analysis of the primary global outcomes according to potential endovascular equipoise shift. The forest plot shows the effect size in the primary global outcome variable (common odds ratio for improvement on the modified Rankin scale at 90 days of patients treated with intravenous thrombolysis within 4.5 h from stroke onset) analyzed according to ordinal logistic regression after collapsing mRS scores 5 and 6 and adjusting for age, National Institutes of Health Stroke Scale (NIHSS) score at baseline; time from stroke onset to tPA (tissue plasminogen activator) bolus and baseline serum glucose according to potential endovascular equipoise shift. The thresholds for age and NIHSS score (range, 0–42, with higher scores indicating more severe neurologic deficits) were chosen at the median. The threshold for time from stroke onset to tissue plasminogen activator bolus was prespecified. distribution of reported 3 month mRS scores group) did not differ in any of the baseline char- (Pearson chi-squared: 491.188; df = 450; p = 0.09). acteristics (Table 1). The distribution of the mRS scores of patients randomized within 3 A total of 52 patients (7.7%) were enrolled at 7 and 4.5 h are shown in Figure 3A and B, respec- centers with perceived endovascular equipoise tively. Sonothrombolysis was not associated shift. Post hoc sensitivity analysis in the inten- with higher likelihood of functional improve- tion-to-treat population showed a significant ment compared with IVT [adjusted cOR for (p < 0.01) interaction of perceived endovascular Global outcome: 1.20 (95% CI 0.89–1.62); equipoise shift on the effect of sonothrombolysis p = 0.24]. Patients randomized to sonothrom- on 3 month functional outcome compared with bolysis had higher odds of 3 month functional standard tPA treatment [adjusted common odds independence (mRS scores 0–2) compared with ratio (cOR) for Global outcome in centers with patients treated with tPA only (adjusted OR: perceived endovascular equipoise shift: 0.22, 1.53; 95% CI 1.01–2.31; p = 0.04 and adjusted 95% CI 0.06–0.75; p = 0.02; adjusted cOR for OR: 1.47; 95% CI 1.02–2.13; p = 0.04 for Global outcome in centers without endovascu- patients randomized within 3 and 4.5 h, respec- lar equipoise shift: 1.20, 95% CI 0.89–1.62; tively). No difference between the two groups p = 0.24); Figure 2]. was evident on the probability of favorable func- tional outcome at 3 months (adjusted OR: 1.17, After excluding patients from centers with per- 95% CI 0.80–1.72, p = 0.41). The sensitivity ceived endovascular equipoise shift, the two analyses between the two groups in terms of groups of the remaining study population (310 other secondary efficacy outcomes are presented in the intervention group and 314 in the control in Table 2. journals.sagepub.com/home/tan 5 Therapeutic Advances in Neurological Disorders 12 Table 1. Baseline characteristics of the study population after removing centers with perceived endovascular equipoise shift. Variables Intervention (n = 310) Control (n = 314) p Mean age ± SD, years 67.1 ± 10.3 67.0 ± 10.6 0.86 Male sex, n (%) 175 (56.4) 187 (59.5) 0.47 Median NIHSS score (IQR), points 15 (11–18) 14 (11–18) 0.81 Hypertension, n (%) 178 (57.4) 194 (61.8) 0.29 Diabetes mellitus, n (%) 68 (21.9) 75 (23.9) 0.57 Atrial fibrillation, n (%) 56 (18.1) 53 (16.9) 0.75 Prestroke modified Rankin scale score 0–1, n (%) 309 (99.7) 312 (99.4) >0.99 Mean systolic blood pressure before tPA bolus ± SD, mmHga 150.0 ± 20.2 150.4 ± 20.1 0.81 Mean diastolic blood pressure before tPA bolus ± SD, mmHgb 81.4 ± 13.4 81.8 ± 13.0 0.71 Mean serum glucose before tPA bolus ± SD, mg/dl 139.4 ± 50.5 138.0 ± 53.5 0.74 Median time from symptom onset to tPA bolus (IQR), min 117.5 (95.0–161.5) 128.0 (97.2–165.8) 0.12 Time from symptom onset to tPA bolus within 3 h, n (%) 255 (82.3) 262 (83.4) 0.74 Median time from symptom onset to headframe activation (IQR), min 136 (118–182) 150 (116–188) 0.38 Intervention: sonothrombolysis. Control: intravenous thrombolysis. aMissing data in 7 and 13 patients in the intervention and control arms respectively. bMissing data in 6 and 13 patients in the intervention and control arms respectively. IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation; tPA, tissue plasminogen activator. The sensitivity analyses of safety outcomes outcome in a randomized controlled trial. The between the two groups are presented in Table 3. findings indicate a significant interaction between The two groups did not differ in any of the safety the effect of sonothrombolysis on outcome and outcomes including symptomatic (OR: 1.01, center experience with endovascular treatment. 95% CI 0.35–2.92, p > 0.99) and asymptomatic The presence of equipoise shift in favor of endo- intracranial hemorrhage, cerebral edema, brain vascular treatment is further portrayed by the fact herniation, and death. The two groups also did that in the CLOTBUST-ER trial the median not differ in any of the serious adverse events with baseline NIHSS score in the interventional group the exception of nausea (12.6% versus 7.3%; was 15 (11–18), whereas more than one-quarter p = 0.03) and atrial fibrillation (9.3% versus 4.5% (28%) of included patients presenting with base- without exclusion of patients with atrial fibrilla- line NIHSS scores of 10 or 11 points (Figure 1).3 tion at baseline assessment, p = 0.02; 7.7% versus This varies considerably from the patient popula- 3.8% after exclusion of patients with atrial fibril- tion with severe stroke (NIHSS⩾10) included in lation at baseline assessment, p = 0.04), which the previous phase II RCT of sonothrombolysis were more common in the intervention group. (CLOTBUST) that reported a median NIHSS of 17 (14–21) for the intervention group with only 14% of the study population with severe stroke Discussion presenting with baseline NIHSS scores of 10 or In the present post hoc analysis of the 11 points.7 CLOTBUST-ER trial we explored the potential interaction of shift in treatment practice in favor Enhancing current reperfusion treatments remains of endovascular thrombectomy and the effect an important global priority for acute stroke treat- of sonothrombolysis on 3 month functional ment. This applies equally in healthcare systems 6 journals.sagepub.com/home/tan AV Alexandrov, G Tsivgoulis et al. Figure 3. Modified Rankin scale scores at 90 days in the intention-to-treat population that was treated with intravenous thrombolysis within 3 h (‘US’ primary outcome) after removing centers with perceived endovascular equipoise shift (A). Modified Rankin scale scores at 90 days in the intention-to-treat population that was treated with intravenous thrombolysis within 4.5 h (‘Global’ primary outcome) after removing centers with perceived endovascular equipoise shift (B). Shown is the distribution of scores on the modified Rankin scale. Scores range from 0 to 6, with 0 indicating no symptoms, 1 no clinically significant disability, 2 slight disability (patient is able to look after own affairs without assistance, but is unable to carry out all previous activities), 3 moderate disability (patient requires some help, but is able to walk unassisted), 4 moderately severe disability (patient is unable to attend to bodily needs without assistance and unable to walk unassisted), 5 severe disability (patient requires constant nursing care and attention), and 6 death. journals.sagepub.com/home/tan 7 Therapeutic Advances in Neurological Disorders 12 Table 2. Primary and secondary efficacy outcomes in the intention-to-treat population after removing centers with perceived endovascular equipoise shift. Variables Intervention Control Unadjusted p Adjusteda p (n = 310) (n = 314) OR (95% CI) OR (95% CI) Primary outcome: ordinal analysis of mRS score at 90 days (median, IQR) USb 2.0 (1.0–4.0) 3.0 (1.0–4.0) 1.22 (0.88–1.68) 0.22 1.20 (0.87–1.68) 0.27 Globalc 2.0 (1.0–4.0) 3.0 (1.0–4.0) 1.16 (0.86–1.54) 0.33 1.20 (0.89–1.62) 0.24 Secondary outcomes mRS score at 7 days or discharged US 3.0 (1.0–4.0) 4.0 (1.0–5.0) 1.18 (0.86–1.63) 0.30 1.20 (0.86–1.67) 0.27 mRS score at 7 days or discharged Global 3.0 (1.0–4.0) 4.0 (1.0–5.0) 1.12 (0.84–1.50) 0.43 1.22 (0.90–1.64) 0.20 mRS score at 90 days 0–1; USb, n (%) 80 (34.5%) 69 (29.6%) 1.25 (0.85–1.85) 0.27 1.30 (0.85–2.00) 0.22 mRS score at 90 days 0–1; Globalc, n (%) 94 (33.2%) 88 (31.2%) 1.10 (0.77–1.56) 0.65 1.17 (0.80–1.72) 0.41 mRS score at 90 days 0–2; USb, n (%) 122 (52.6%) 103 (44.2%) 1.40 (0.97–2.02) 0.08 1.53 (1.01–2.31) 0.04 mRS score at 90 days 0–2; Globalc, n (%) 144 (50.9%) 125 (44.3%) 1.30 (0.93–1.81) 0.13 1.47 (1.02–2.13) 0.04 Independent functional outcome at 92 (39.7%) 82 (35.2%) 1.21 (0.83–1.76) 0.34 1.25 (0.84–1.86) 0.27 90 dayse; USb, n (%) Independent functional outcome at 109 (38.5%) 102 (36.2%) 1.10 (0.79–1.55) 0.60 1.18 (0.83–1.69) 0.36 90 dayse; Globalc, n (%) Dramatic clinical recovery at 2 hf; US, 54 (22.0%) 52 (20.5%) 1.10 (0.71–1.69) 0.74 1.12 (0.72–1.74) 0.63 n (%) Dramatic clinical recovery at 2 hf; Global, 56 (18.8%) 57 (18.7%) 1.00 (0.67–1.51) 1.00 1.05 (0.68–1.61) 0.84 n (%) Clinical recovery at 24 hg; US, n (%) 78 (32.6%) 90 (36.1%) 0.86 (0.59–1.24) 0.45 0.85 (0.58–1.25) 0.42 Clinical recovery at 24 hg; Global, n (%) 95 (32.8%) 102 (34.3%) 0.93 (0.66–1.31) 0.73 0.96 (0.68–1.37) 0.84 Neurological improvement at 24 hh; US, 141 (59.0%) 139 (55.8%) 1.14 (0.79–1.63) 0.52 1.16 (0.80–1.69) 0.43 n (%) Neurological improvement at 24 hh; Global, 169 (58.3%) 163 (54.9%) 1.15 (0.83–1.59) 0.45 1.20 (0.86–1.69) 0.29 n (%) Neurological deterioration at 24 hi; US, 20 (8.4%) 17 (6.8%) 1.25 (0.63–2.44) 0.61 1.17 (0.58–2.37) 0.66 n (%) Neurological deterioration at 24 hi; Global, 26 (9.0%) 19 (6.4%) 1.44 (0.78–2.67) 0.28 1.29 (0.69–2.44) 0.43 n (%) NIHSSj at day 7 US, median (IQR) 5 (1–10.25) 6 (1–13) 0.25 NIHSSj at day 7 Global, median (IQR) 5 (1–11) 6 (1–12.75) 0.24 NIHSSk at day 90 US, median (IQR) 2 (0–5) 2 (0–5) 0.37 NIHSSk at day 90 Global, median (IQR) 2 (0–6) 2 (0–6) 0.26 (Continued) 8 journals.sagepub.com/home/tan AV Alexandrov, G Tsivgoulis et al. Table 2. (Continued) Variables Intervention Control Unadjusted p Adjusteda p (n = 310) (n = 314) OR (95% CI) OR (95% CI) Duration of hospital stay until discharge; 7 (5–10.25) 7 (5.0–11.00) 0.77 US, days, median (IQR)l Duration of hospital stay until discharge; 7 (5–12) 7 (4.75–11.00) 0.92 Global, days, median (IQR)m Intervention: sonothrombolysis. Control: intravenous thrombolysis. aORs were adjusted for age, NIHSS score at baseline; time from stroke onset to tPA bolus, and baseline serum glucose. bPatients treated with intravenous thrombolysis within 3 h from symptom onset; there were 23 and 28 patients with missing data in the intervention and control arms, respectively. cPatients treated with intravenous thrombolysis within 4.5 h from symptom onset; there were 27 and 32 patients with missing data in the intervention and control arms, respectively. dThere were 26 subjects in the intervention arm 20 subjects in the control arm missing day 7 or discharge mRS in the US cohort. There were 31 subjects in the intervention arm and 25 in the control arm missing day 7 or discharge mRS for the Global cohort. eIndependent functional outcome adjusting for pretreatment NIHSS assessed at 90 ± 10 days post-treatment includes a mRS score of 0–1 for subjects with pretreatment NIHSS 10–14, or a mRS score of 0–2 for subjects with pretreatment NIHSS > 14. fDramatic clinical recovery assessed at 120 ± 15 mins after headframe activation includes a reduction of 10 or more points on NIHSS compared with pretreatment, or a total NIHSS score of 3 or less. There were 31 and 33 patients with missing data in the intervention and control arms, respectively, for the US outcome of dramatic clinical recovery. There were 36 and 39 patients with missing data in the intervention and control arms, respectively, for the Global outcome of dramatic clinical recovery. gClinical recovery assessed at 24 ± 2 h after headframe activation includes a reduction of 10 or more points on NIHSS compared with pretreatment, or a total NIHSS score of 3 or less. There were 37 and 37 patients with missing data in the intervention and control arms, respectively, for the US outcome of clinical recovery. There were 44 and 45 patients with missing data in the intervention and control arms, respectively, for the Global outcome of dramatic clinical recovery. hNeurological improvement assessed at 24 ± 2 h after headframe activation requires a reduction of 5 or more points on NIHSS compared with the pretreatment score. There were 37 and 37 patients with missing data in the intervention and control arms, respectively, for the US outcome of neurological improvement at 24 h. There were 44 and 45 patients with missing data in the intervention and control arms, respectively, for the Global outcome of neurological improvement at 24 h. iNeurological worsening assessed at 24 ± 2 h after headframe activation requires an increase of 4 or more points on NIHSS compared with the pretreatment score. There were 37 and 37 patients with missing data in the intervention and control arms, respectively, for the US outcome of neurological worsening at 24 h. There were 44 and 45 patients with missing data in the intervention and control arms, respectively, for the Global outcome of neurological worsening at 24 h. jThere were 31 subjects in the intervention arm 24 subjects in the control arm missing day 7 NIHSS in the US cohort. There were 39 subjects in the intervention arm and 32 in the control arm missing day 7 NIHSS for the Global cohort. kThere were 92 subjects in the intervention arm 102 subjects in the control arm missing day 90 NIHSS in the US cohort. There were 111 subjects in the intervention arm and 118 in the control arm missing day 90 NIHSS for the Global cohort. lThere were 39 and 29 patients with missing data in the intervention and control arms respectively. mThere were 47 and 38 patients with missing data in the intervention and control arms, respectively. Common ORs were computed using ordinal logistic regression analyses after collapsing mRS scores 5 and 6. CI, confidence interval; IQR, interquartile range; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; SD, standard deviation; tPA, tissue plasminogen activator. with developed endovascular treatment networks, functional outcomes compared with those referred where a substantial proportion of patients com- from a primary stroke care center.11 Given that mence IVT prior to prolonged inter-hospital inter-hospital transfer is a critical and as yet una- transfer to endovascular centers, and in the many voidable component in the treatment of patients healthcare systems where endovascular treat- with LVO transferred for mechanical thrombec- ment is unavailable or very poorly available.8,9 tomy, with the time from arrival to primary stroke Endovascular treatment implementation requires care center to arrival in the comprehensive stroke reorganization of the stroke infrastructure, includ- center exceeding 120 min even in high-volume ing a network referral to comprehensive stroke primary stroke centers,12 it becomes apparent that centers from secondary and primary stroke care ancillary methods to facilitate vessel reperfusion centers.10 It is known that AIS patients with direct need to be developed for use in settings where MT admission to a comprehensive stroke center with is still totally unavailable and for use during patient endovascular capacities have better 90 day transfer to the comprehensive stroke center. journals.sagepub.com/home/tan 9 Therapeutic Advances in Neurological Disorders 12 Table 3. Safety variables and serious adverse events within 90 days after randomization after removing centers with perceived endovascular equipoise shift. Variables Intervention Control OR (95% CI) p (n = 310) (n = 314) Symptomatic intracranial hemorrhage at 24 ha, n (%) 7 (2.3%) 7 (2.2%) 1.01 (0.35–2.92) >0.99 Symptomatic intracranial hemorrhage at 36 hb, n (%) 8 (2.6%) 8 (2.5%) 1.01 (0.37–2.73) >0.99 Asymptomatic intracranial hemorrhage at 24 h, n (%) 35 (11.3%) 22 (7.0%) 1.69 (0.97–2.95) 0.07 Death, n (%) 48 (17.0%) 43 (15.3%) 1.14 (0.72–1.78) 0.65 Death due to serious adverse event, n (%) 35 (11.3%) 34 (10.8%) 1.05 (0.63–1.73) 0.90 Serious adverse events, n (%) 84 (27.1%) 79 (25.2%) 1.11 (0.77–1.58) 0.59 Cerebral edema, n (%) 16 (5.2%) 9 (2.9%) 1.84 (0.80–4.24) 0.16 Brain herniation, n (%) 11 (3.5%) 4 (1.3%) 2.85 (0.90–9.05) 0.07 Midline shift, n (%) 8 (2.6%) 9 (2.9%) 0.90 (0.34–2.36) >0.99 Study discontinuation due to adverse events, n (%) 19 (6.1%) 25 (8.0%) 0.75 (0.41–1.40) 0.44 Most common adverse event (headache), n (%) 59 (19.0%) 51 (16.2%) 1.21 (0.80–1.83) 0.40 Second most common adverse event, (pyrexia), n (%) 31 (10.0%) 38 (12.1%) 0.81 (0.49–1.33) 0.44 Third most common adverse event (nausea), n (%) 39 (12.6%) 23 (7.3%) 1.82 (1.06–3.13) 0.03 Fourth most common adverse event (constipation), n (%) 28 (9.0%) 31 (9.9%) 0.91 (0.53–1.55) 0.78 Fifth most common adverse event (pneumonia/aspiration 33 (10.6%) 25 (8.0%) 1.38 (0.80–2.38) 0.30 pneumonia), n (%) Atrial fibrillation as adverse event, n (%) 29 (9.3%) 14 (4.5%) 2.21 (1.14–4.27) 0.02 Atrial fibrillation as adverse event after exclusion of patients 24 (7.7%) 12 (3.8%) 2.11 (1.04–4.30) 0.04 with atrial fibrillation at baseline, n (%) Intervention: sonothrombolysis. Control: intravenous thrombolysis. asICH is defined as neurological deterioration (⩾4 points worsening on the NIHSS compared with the best prior examination) within 24 h after rt-PA bolus with documented parenchymal hemorrhage type 2 or type 2 remote (PH2/PH2r) where PH2 is defined as ICH volume at least one-third of the infarct volume, or death due to hemorrhage within 24 h after rt-PA bolus. bsICH is defined as neurological deterioration (⩾4 points worsening on the NIHSS compared with the best prior examination) within 36 h after rt-PA bolus with documented parenchymal hemorrhage type 2 or type 2 remote (PH2/PH2r) where PH2 is defined as ICH volume at least one-third of the infarct volume, or death due to hemorrhage within 36 h after rt-PA bolus. CI, confidence interval; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; OR, odds ratio; sICH, symptomatic intracranial hemorrhage; rt-PA, recombinant tissue plasminogen activator. Endovascular treatment has become the standard endovascular treatments and to expand their of care for patients with LVO. Since endovascular application to a larger subset of stroke patients,14 treatment facilities are concentrated in the same all ancillary therapies for acute LVO treatment large academic centers that recruit a high propor- have the extremely difficult task of proving their tion of patients in clinical trials, it has become additive effect on top of the huge effect size of extremely challenging for clinical trials of alterna- endovascular treatment.15 tive pharmacological or nonpharmacological rep- erfusion therapies to initiate and sustain patient Our experience in CLOTBUST-ER indicates recruitment.13 Although there is still room for that the increasing implementation of endovas- improvement to enhance the effectiveness of cular therapies across major academic stroke 10 journals.sagepub.com/home/tan AV Alexandrov, G Tsivgoulis et al. centers raises significant challenges for clinical randomized and nonrandomized studies. Stroke trials aiming to test noninterventional or adju- 2010; 41: 280–287. vant reperfusion strategies if undertaken at the 2. Ricci S, Dinia L, Del Sette M, et al. same centers. After taking into account that the Sonothrombolysis for acute ischaemic stroke. positive results of recent thrombectomy trials Cochrane Database Syst Rev 2012; 10: CD008348. have positioned CTA as standard of care in AIS 3. Alexandrov AV, Köhrmann M, Soinne L, et al. patients with LVO,16 we have redesigned the Efficacy and safety of sonothrombolysis for acute operator-independent ultrasound device used in ischemic stroke: a multi-centre, double-blind, CLOTBUST-ER to take advantage of CTA- phase 3, randomised controlled trial. Lancet located LVO to increase the insonation of the Neurol 2019; 18: 338–347. occlusion by only insonating the suboccipital, the right transtemporal, or the left transtemporal 4. Fischer U, Arnold M, Nedeltchev K, et al. window in accordance with the occlusion loca- NIHSS score and arteriographic findings in acute ischemic stroke. Stroke 2005; 36: 2121–2125. tion identified on the CTA. This new device will be tested in the recently launched TRUST trial 5. Schellinger PD, Alexandrov AV, Barreto AD, (ClinicalTrials.gov identifier: NCT03519737), et al; CLOTBUST-ER Investigators. Combined in which all patients with LVO who meet stand- lysis of thrombus with ultrasound and systemic ard tPA criteria and are being transferred from tissue plasminogen activator for emergent primary to comprehensive stroke centers (‘drip- revascularization in acute ischemic stroke and-ship’) will be randomized to ultrasound or (CLOTBUST-ER): design and methodology of a multinational phase 3 trial. Int J Stroke 2015; 10: no ultrasound with the primary endpoint being 1141–1148. complete recanalization at receiving hospitals on digital subtraction angiography prior to 6. Berkhemer OA, Fransen PS, Beumer D, et al. thrombectomy.17 The results of TRUST trial will A randomized trial of intraarterial treatment for provide definitive answers regarding the efficacy acute ischemic stroke. N Engl J Med 2015; 372: of sonothrombolysis for improving tPA-induced 11–20. reperfusion rates in AIS patients with LVO. 7. Barlinn K, Tsivgoulis G, Barreto AD, et al. Outcomes following sonothrombolysis in severe Funding acute ischemic stroke: subgroup analysis of the The authors disclosed receipt of the following finan- CLOTBUST trial. Int J Stroke 2014; 9: 1006– cial support for the research, authorship, and/or 1110. publication of this article: RM has been supported 8. Tsivgoulis G, Safouris A, Katsanos AH, et al. by the National Program of Sustainability II (MEYS Mechanical thrombectomy for emergent large CR; project number LQ1605) and by FNUSA- vessel occlusion: a critical appraisal of recent ICRC (project number CZ.1.05/1.1.00/02.0123; randomized controlled clinical trials. Brain Behav OP VaVpI); AHK has been supported by a Research 2016; 6: e00418. Experience Fellowship from the European Academy 9. Fischer U, Aguiar de Sousa D, Norrving B, et al. of Neurology. Status and perspectives of acute stroke care in Europe. Stroke 2018; 49: 2281–2282. Conflict of interest statement The authors declare that there is no conflict of 10. Daubail B, Ricolfi F, Thouant P, et al. Impact of interests. mechanical thrombectomy on the organization of the management of acute ischemic stroke. Eur ORCID iD Neurol 2016; 75: 41–47. Andrei V. Alexandrov https://orcid.org/0000- 11. Ismail M, Armoiry X, Tau N, et al. 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