My conclusion on this is that it seems to be useless. NO protocol generated. Whatever the hell endovascular equipoise shift is?
Did your stroke hospital answer this question from June 2013? Or were they incompetent like usual? And the board of directors are so fucking incompetent that they allow incompetence to run rampant in their hospital?
Is Sonothrombolysis an Effective Stroke Treatment?
The latest here.
Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke
Abstract
Background:
Methods:
Results:
Introduction
Review of the results of this RCT revealed heterogeneity of patient recruitment among centers, a finding that potentially reflected practice drift at sites that were also participating in concurrent mechanical thrombectomy trials, reflecting loss of equipoise in favor of open-label mechanical thrombectomy or preferential endovascular trial recruitment among patients with large vessel occlusions (LVOs). This concern has also been corroborated by the substantial representation (28%) of patients with baseline National Institutes of Health Scale (NIHSS) scores of 10 or 11 enrolled into the trial (Figure 1), given the lower positive predictive value of a cut-off of 10 points in NIHSS score compared with the cut-off of 12 points in detecting LVO in AIS patients.4

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).
In view of these considerations, we performed an additional post hoc analysis in order to explore how practice drift in favor of endovascular thrombectomy might have affected the findings of the sonothrombolysis trial.
Methods
Trial design and study population
Investigational procedure
Primary and secondary outcomes
Other secondary efficacy endpoints included the differences in NIHSS scores between the two groups at 2 h, 24 h, day 7, and day 90, the differences in mRS scores at day 7 and the difference in rates of dichotomous 90 day mRS 0–1 and mRS 0–2 between the two groups.3,5 We also further assessed the rates of dramatic clinical recovery at 2 h, clinical recovery at 24 h, and clinical recovery at day 90 (defined as a reduction of 10 or more points in NIHSS compared with pretreatment, or a total NIHSS score of 3 or less), neurological improvement at 24 h (defined as a reduction of 5 or more points on NIHSS compared with the pretreatment score), and neurologic worsening at 24 h (defined as an increase of 4 or more points on NIHSS compared with the pretreatment score).3,5
Symptomatic intracranial hemorrhage (sICH) per study protocol was defined as neurological deterioration (⩾4 points worsening on the NIHSS compared with the best prior examination) within 24 h after tPA bolus with documented parenchymal hemorrhage type 2 or remote parenchymal hemorrhage type 2.3,5 All prespecified adverse events were reported by the blinded clinical investigators of the participating centers, while reviewed and adjudicated by a blinded independent adjudication panel within the Data and Safety Monitoring Board (DSMB) committee.3,5
Endovascular equipoise shift definition
In order to explore the potential impact of shifting treatment practice at centers participating in endovascular trials on CLOTBUST-ER, an additional post hoc analysis was performed after excluding those subjects that were recruited at centers meeting following criteria: (1) centers with 24/7 available endovascular services; and (2) decline in equal randomization rates between sonothrombolysis and endovascular trials or (3) decline in preference to randomize patients with LVO to CLOTBUST-ER (opting instead to treat them with interventional treatment as standard of care). Investigators from these centers have openly stated during the Steering Committee meetings that they were consistently selecting AIS patients with LVO presence on baseline computed tomography angiography (CTA) for enrollment in endovascular trials that were competing with CLOBUST-ER (ESCAPE, REVASCAT, SWIFT PRIME), while they preferred to enroll only patients with no vessel occlusion (lacunar strokes) or distal vessel occlusion on CTA in the CLOBUST-ER trial. These centers were subsequently considered to be prone to patient selection bias due to the expressed treatment preference in favor of mechanical thrombectomy (MT) and were excluded from the present analyses. The centers that were involved in RCTs of MT and decided to equally randomize patients in MT and sonothrombolysis RCTs were not excluded from the present analyses. No further clarifications (e.g. by self-report questionnaires or telephone interviews) were made.
The Steering Committee was blinded to the 3 month functional outcomes of all patients during the process of identifying centers that met these criteria. Interaction testing using proportional odds and binary logistic regression was performed between the dichotomous variable ‘perceived endovascular equipoise shift’ and ‘treatment assignment’.
Statistical analysis
Results
A total of 52 patients (7.7%) were enrolled at 7 centers with perceived endovascular equipoise shift. Post hoc sensitivity analysis in the intention-to-treat population showed a significant (p < 0.01) interaction of perceived endovascular equipoise shift on the effect of sonothrombolysis on 3 month functional outcome compared with standard tPA treatment [adjusted common odds ratio (cOR) for Global outcome in centers with perceived endovascular equipoise shift: 0.22, 95% CI 0.06–0.75; p = 0.02; adjusted cOR for Global outcome in centers without endovascular equipoise shift: 1.20, 95% CI 0.89–1.62; p = 0.24); Figure 2].

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.
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.
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Table 1. Baseline characteristics of the study population after removing centers with perceived endovascular equipoise shift.


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.
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.
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Table 2.
Primary and secondary efficacy outcomes in the intention-to-treat
population after removing centers with perceived endovascular equipoise
shift.

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Table 3.
Safety variables and serious adverse events within 90 days after
randomization after removing centers with perceived endovascular
equipoise shift.

Discussion
Enhancing current reperfusion treatments remains an important global priority for acute stroke treatment. This applies equally in healthcare systems with developed endovascular treatment networks, where a substantial proportion of patients commence IVT prior to prolonged inter-hospital transfer to endovascular centers, and in the many healthcare systems where endovascular treatment is unavailable or very poorly available.8,9 Endovascular treatment implementation requires reorganization of the stroke infrastructure, including a network referral to comprehensive stroke centers from secondary and primary stroke care centers.10 It is known that AIS patients with direct admission to a comprehensive stroke center with endovascular capacities have better 90 day functional outcomes compared with those referred from a primary stroke care center.11 Given that inter-hospital transfer is a critical and as yet unavoidable component in the treatment of patients with LVO transferred for mechanical thrombectomy, with the time from arrival to primary stroke care center to arrival in the comprehensive stroke center exceeding 120 min even in high-volume primary stroke centers,12 it becomes apparent that ancillary methods to facilitate vessel reperfusion need to be developed for use in settings where MT is still totally unavailable and for use during patient transfer to the comprehensive stroke center.
Endovascular treatment has become the standard of care for patients with LVO. Since endovascular treatment facilities are concentrated in the same large academic centers that recruit a high proportion of patients in clinical trials, it has become extremely challenging for clinical trials of alternative pharmacological or nonpharmacological reperfusion therapies to initiate and sustain patient recruitment.13 Although there is still room for improvement to enhance the effectiveness of endovascular treatments and to expand their application to a larger subset of stroke patients,14 all ancillary therapies for acute LVO treatment have the extremely difficult task of proving their additive effect on top of the huge effect size of endovascular treatment.15
Our experience in CLOTBUST-ER indicates that the increasing implementation of endovascular therapies across major academic stroke centers raises significant challenges for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies if undertaken at the same centers. After taking into account that the positive results of recent thrombectomy trials have positioned CTA as standard of care in AIS patients with LVO,16 we have redesigned the operator-independent ultrasound device used in CLOTBUST-ER to take advantage of CTA-located LVO to increase the insonation of the occlusion by only insonating the suboccipital, the right transtemporal, or the left transtemporal window in accordance with the occlusion location identified on the CTA. This new device will be tested in the recently launched TRUST trial (ClinicalTrials.gov identifier: NCT03519737), in which all patients with LVO who meet standard tPA criteria and are being transferred from primary to comprehensive stroke centers (‘drip-and-ship’) will be randomized to ultrasound or no ultrasound with the primary endpoint being complete recanalization at receiving hospitals on digital subtraction angiography prior to thrombectomy.17 The results of TRUST trial will provide definitive answers regarding the efficacy of sonothrombolysis for improving tPA-induced reperfusion rates in AIS patients with LVO.
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