Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke

Background: Results of our recently published phase III randomized clinical trial of ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high frequency ultrasound device revealed heterogeneity of patient recruitment among centers. Methods: We performed a post hoc analysis after excluding subjects that were recruited at centers reporting a decline in the balance of randomization between sonothrombolysis and concurrent endovascular trials. Results: From a total of 676 participants randomized in the CLOTBUST-ER trial we identified 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline serum glucose showed a significant (p < 0.01) interaction of perceived endovascular equipoise shift on the association between sonothrombolysis and 3 month functional outcome [adjusted common odds ratio (cOR) in centers with perceived endovascular equipoise shift: 0.22, 95% CI 0.06–0.75; p = 0.02; adjusted cOR for centers without endovascular equipoise shift: 1.20, 95% CI 0.89–1.62; p = 0.24)]. After excluding centers with perceived endovascular equipoise shift, patients randomized to sonothrombolysis had higher odds of 3 month functional independence (mRS scores 0–2) compared with patients treated with tPA only (adjusted OR: 1.53; 95% CI 1.01–2.31; p = 0.04). Conclusion: Our experience in CLOTBUST-ER indicates that increasing implementation of endovascular therapies across major academic stroke centers raises significant challenges for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies

Safety and efficacy of sonothrombolysis for acute ischaemic stroke: a multicentre, double-blind, phase 3, randomised controlled trial

Background: Pulsed-wave ultrasound increases the exposure of an intracranial thrombus to alteplase (recombinant tissue plasminogen activator), potentially facilitating early reperfusion. We aimed to ascertain if a novel operator-independent transcranial ultrasound device delivering low-power high-frequency ultrasound could improve functional outcome in patients treated with alteplase after acute ischaemic stroke. Methods: We did a multicentre, double-blind, phase 3, randomised controlled trial (CLOTBUST-ER) at 76 medical centres in 14 countries. We included patients with acute ischaemic stroke (National Institutes of Health Stroke Scale score ≥10) who received intravenous thrombolysis (alteplase bolus) within 3 h of symptom onset in North America and within 4·5 h of symptom onset in all other countries. Participants were randomly allocated (1:1) via an interactive web response system to either active ultrasound (2 MHz pulsed-wave ultrasound for 120 min [sonothrombolysis]; intervention group) or sham ultrasound (control group). Ultrasound was delivered using an operator-independent device, which had to be activated within 30 min of the alteplase bolus. Participants, investigators, and those assessing outcomes were unaware of group assignments. The primary outcome was improvement in the modified Rankin Scale score at 90 days in patients enrolled within 3 h of symptom onset, assessed in the intention-to-treat population as a common odds ratio (cOR) using ordinal logistic regression shift analysis. This trial is registered with ClinicalTrials.gov, number NCT01098981. The trial was stopped early by the funder after the second interim analysis because of futility. Findings: Between August, 2013, and April, 2015, 335 patients were randomly allocated to the intervention group and 341 patients to the control group. Compared with the control group, the adjusted cOR for an improvement in modified Rankin Scale score at 90 days in the intervention group was 1·05 (95% CI 0·77–1·45; p=0·74). 51 (16%) of 317 patients in the intervention group and 44 (13%) of 329 patients in the control group died (unadjusted OR 1·24, 95% CI 0·80–1·92; p=0·37) and 83 (26%) and 79 (24%), respectively, had serious adverse events (1·12, 0·79–1·60; p=0·53). Interpretation: Sonothrombolysis delivered by an operator-independent device to patients treated with alteplase after acute ischaemic stroke was feasible and most likely safe, but no clinical benefit was seen at 90 days. Sonothrombolysis could be further investigated either in randomised trials undertaken in stroke centres that are dependent on patient transfer for endovascular reperfusion therapies or in countries where these treatments cannot yet be offered as the standard of care

Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke

Background: Results of our recently published phase III randomized clinical trial of ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high frequency ultrasound device revealed heterogeneity of patient recruitment among centers. Methods: We performed a post hoc analysis after excluding subjects that were recruited at centers reporting a decline in the balance of randomization between sonothrombolysis and concurrent endovascular trials. Results: From a total of 676 participants randomized in the CLOTBUST-ER trial we identified 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline serum glucose showed a significant (p < 0.01) interaction of perceived endovascular equipoise shift on the association between sonothrombolysis and 3 month functional outcome [adjusted common odds ratio (cOR) in centers with perceived endovascular equipoise shift: 0.22, 95% CI 0.06–0.75; p = 0.02; adjusted cOR for centers without endovascular equipoise shift: 1.20, 95% CI 0.89–1.62; p = 0.24)]. After excluding centers with perceived endovascular equipoise shift, patients randomized to sonothrombolysis had higher odds of 3 month functional independence (mRS scores 0–2) compared with patients treated with tPA only (adjusted OR: 1.53; 95% CI 1.01–2.31; p = 0.04). Conclusion: Our experience in CLOTBUST-ER indicates that increasing implementation of endovascular therapies across major academic stroke centers raises significant challenges for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies

Supplement Mandava Santosh Kent_Neurology_align_with_proof

Supplement Mandava Santosh Kent_Neurology_align_with_proo

Data from: Pooled analysis suggests benefit of catheter-based hematoma removal for intracerebral hemorrhage

Objective: To develop models of outcome for intracerebral hemorrhage (ICH) to identify promising and futile interventions based on their early phase results without need for correction for baseline imbalances. Methods: We developed a pooled outcome model from the control arms of randomized control trials and tested different interventions against the model at comparable baseline conditions. Eligible clinical trials and large case series were identified from multiple library databases. Models based on baseline factors reported in the control arms were tested for the ability to predict functional outcome (modified Rankin Scale score) and mortality. Interventions were grouped into blood pressure control, fibrinolytic-assisted hematoma evacuation, hemostatic medications, and neuroprotective agents. Statistical intervals around the model were generated at the p = 0.1 level to screen how each trial’s outcome compared to expected outcome. Results: Fourteen control arms with 3,386 patients were used to develop 7 alternate models for functional outcome. The model incorporating baseline NIH Stroke Scale, age, and hematoma volume yielded the best fit (adjusted R2 = 0.89). All early phase treatments that eventually resulted in negative late phase trials were identified as negative by this method. Early phase fibrinolytic-assisted hematoma evacuation studies showed the most promise trending toward improved functional outcome with no suggestion of an increase in mortality, supporting its further study. Conclusions: We successfully developed an outcome model for ICH that identified interventions destined to be negative while identifying a promising one. Such an approach may assist in prioritizing resources prior to multicenter trial

Influence of racial differences on outcomes after thrombolytic therapy in acute ischemic stroke

Background: The National Institutes of Neurological Disorders and Stroke and the European Co-operative Acute Stroke III trials enrolled a largely Caucasian population, but the results are often extrapolated onto non-Caucasians. A limited number of nonrandomized studies have proposed that non-Caucasian patients show differential response to tissue plasminogen activator.&lt;p&gt;&lt;/p&gt; Aims and/or hypothesis: We examined if non-Caucasian patients of mixed national origin within the Virtual International Stroke Trials Archives neuroprotection trials responded differently to tissue plasminogen activator compared with Caucasians.&lt;p&gt;&lt;/p&gt; Methods: We matched patients within each race-subtype for age, baseline National Institutes of Health Stroke Scales, and diabetes status, and excluded outliers. We tested for an interaction of race ethnicity with tissue plasminogen activator on predicting outcomes at α = 0·05. We compared 90-day ordinal outcome (modified Rankin Scale; primary analysis) and dichotomized outcomes (modified Rankin Scale 0–1; modified Rankin Scale 0–2; survival) within individual race ethnicity.&lt;p&gt;&lt;/p&gt; Results: One thousand nine hundred forty-six thrombolysed patients (125 Blacks, 39 Asians, and 1821 Caucasians) were matched with 1946 non-thrombolysed patients in each race ethnicity group. Postmatching, there were no imbalances in baseline National Institutes of Health Stroke Scales and age between the groups (P &#62;0·05). The interaction of tissue plasminogen activator with race ethnicity was nonsignificant in ordinal (P = 0·4) and in dichotomized outcome models (P &#62; 0·05). Ordinal odds for improved outcomes were 1·5 for all patients (P &#60; 0·05). Ordinal odds for Caucasians were 1·5 (P &#60;0·05); for Blacks, 2·1 (P&#60; 0·05); and for Asians, 1·2 (P&#62; 0·05; 1·6 after 1:2 matching with nonthrombolysed, because of small numbers). Dichotomized functional outcomes improved after thrombolysis overall, in Caucasians, in Blacks (modified Rankin Scale 0–2 only), and in Asians (after 1:2 matching; P &#62; 0·05). Odds for survival were consistent across all groups.&lt;p&gt;&lt;/p&gt; Conclusions: These results do not suggest a differential response to tissue plasminogen activator based on race ethnicity. Among Asians, data were particularly sparse, and results should be interpreted with caution

Box plots of error rates for the full ordinal scale of mRS (mRS 0.6), considering mRS 0 to 3 as individual grades and collapsing mRS grades 4 to 6 (mRS 0.3,4–6), dichotomizing at various cut-points of mRS 1 (mRS 0–1, 2–6), mRS 2 (mRS 0–2, 3–6), mRS 3 (mRS 0–3, 4–6) and mRS 4 (mRS 0–4, 5–6).

<p>van Swieten’s inter-rater reliability matrix used as confusion matrix. (p<.001 ANOVA; post-hoc testing shows that all dichotomization errors are lower than either full scale errors with mRS 0–4 dichotomization the lowest; p<.05).</p

Shannon’s information transmission model adapted to scoring of a patient on the 7 point modified Rankin Scale.

<p>A noise or error source is assumed to be in the channel between the sender represented by the ‘True Rankin’ score and the receiver represented by the ‘Observed Rankin’ score.</p

Error percentages for 38 studies for the full ordinal scale (mRS 0.6), partially collapsed ordinal scale (mRS 0.3, 4–6) and dichotomization (mRS 0–1, 2–6; mRS 0–2, 3–6; mRS 0–3, 4–6; mRS 0–4, 5–6) and trichotomization (mRS 0–1, 2–4, 5–6; mRS 0–2, 3–4, 5–6) cut-points.

<p>Error percentages for 38 studies for the full ordinal scale (mRS 0.6), partially collapsed ordinal scale (mRS 0.3, 4–6) and dichotomization (mRS 0–1, 2–6; mRS 0–2, 3–6; mRS 0–3, 4–6; mRS 0–4, 5–6) and trichotomization (mRS 0–1, 2–4, 5–6; mRS 0–2, 3–4, 5–6) cut-points.</p