Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials: Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST)

<p><b>Background and Purpose:</b> The Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy (SITS-MOST) unadjusted results demonstrated that intravenous alteplase is well tolerated and that the effects were comparable with those seen in randomized, controlled trials (RCTs) when used in routine clinical practice within 3 hours of ischemic stroke onset. We aimed to identify outcome predictors and adjust the outcomes of the SITS-MOST to the baseline characteristics of RCTs.</p> <p><b>Methods:</b> The study population was SITS-MOST (n=6483) and pooled RCTs (n=464) patients treated with intravenous alteplase within 3 hours of stroke onset. Multivariable, backward stepwise regression analyses (until P≤0.10) were performed to identify the outcome predictors for SITS-MOST. Variables appearing either in the final multivariable model or differing (P<0.10) between SITS-MOST and RCTs were included in the prediction model for the adjustment of outcomes. Main outcome measures were symptomatic intracerebral hemorrhage, defined as National Institutes of Health Stroke Scale deterioration ≥1 within 7 days with any hemorrhage (RCT definition), mortality, and independency as defined by modified Rankin Score of 0 to 2 at 3 months.</p> <p><b>Results:</b> The adjusted proportion of symptomatic intracerebral hemorrhage for SITS-MOST was 8.5% (95% CI, 7.9 to 9.0) versus 8.6% (6.3 to 11.6) for pooled RCTs; mortality was 15.5% (14.7 to 16.2) versus 17.3% (14.1 to 21.1); and independency was 50.4% (49.6 to 51.2) versus 50.1% (44.5 to 54.7), respectively. In the multivariable analysis, older age, high blood glucose, high National Institutes of Health Stroke Scale score, and current infarction on imaging scans were related to poor outcome in all parameters. Systolic blood pressure, atrial fibrillation, and weight were additional predictors of symptomatic intracerebral hemorrhage. Current smokers had a lower rate of symptomatic intracerebral hemorrhage. Disability before current stroke (modified Rankin Score 2 to 5), diastolic blood pressure, antiplatelet other than aspirin, congestive heart failure, patients treated in new centers, and male sex were related to high mortality at 3 months.</p> <p><b>Conclusions:</b> The adjusted outcomes from SITS-MOST were almost identical to those in relevant RCTs and reinforce the conclusion drawn previously in the unadjusted analysis. We identified several important outcome predictors to better identify patients suitable for thrombolysis.</p&gt

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

Sonotrombolisis; Endovascular; Cambio de equilibrio clínicoSonothrombolysis; Endovascular; Equipoise shiftSonotrombolisis; Endovascular; Canvi d'equilibri clínicBackground: 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

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.Peer reviewe

Intensive heart rhythm monitoring to decrease ischemic stroke and systemic embolism - the Find-AF 2 study - rationale and design

Background Atrial fibrillation (AF) is one of the most frequent causes of stroke. Several randomized trials have shown that prolonged monitoring increases the detection of AF, but the effect on reducing recurrent cardioembolism, i.e. ischemic stroke and systemic embolism, remains unknown. We aim to evaluate whether a risk-adapted, intensified heart rhythm monitoring with consequent guideline conform treatment, which implies initiation of oral anticoagulation (OAC), leads to a reduction of recurrent cardioembolism. Methods Find-AF 2 is a randomized, controlled, open-label parallel multicenter trial with blinded endpoint assessment. 5,200 patients ≥ 60 years of age with symptomatic ischemic stroke within the last 30 days and without known AF will be included at 52 study centers with a specialized stroke unit in Germany. Patients without AF in an additional 24-hour Holter ECG after the qualifying event will be randomized in a 1:1 fashion to either enhanced, prolonged and intensified ECG-monitoring (intervention arm) or standard of care monitoring (control arm). In the intervention arm, patients with a high risk of underlying AF will receive continuous rhythm monitoring using an implantable cardiac monitor (ICM) whereas those without high risk of underlying AF will receive repeated 7-day Holter ECGs. The duration of rhythm monitoring within the control arm is up to the discretion of the participating centers and is allowed for up to 7 days. Patients will be followed for at least 24 months. The primary efficacy endpoint is the time until recurrent ischemic stroke or systemic embolism occur. Conclusions The Find-AF 2 trial aims to demonstrate that enhanced, prolonged and intensified rhythm monitoring results in a more effective prevention of recurrent ischemic stroke and systemic embolism compared to usual care

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

Dendritic LSm1/CBP80-mRNPs mark the early steps of transport commitment and translational control

Messenger RNA (mRNA) transport to neuronal dendrites is crucial for synaptic plasticity, but little is known of assembly or translational regulation of dendritic messenger ribonucleoproteins (mRNPs). Here we characterize a novel mRNP complex that is found in neuronal dendrites throughout the central nervous system and in some axonal processes of the spinal cord. The complex is characterized by the LSm1 protein, which so far has been implicated in mRNA degradation in nonneuronal cells. In brain, it associates with intact mRNAs. Interestingly, the LSm1-mRNPs contain the cap-binding protein CBP80 that associates with (pre)mRNAs in the nucleus, suggesting that the dendritic LSm1 complex has been assembled in the nucleus. In support of this notion, neuronal LSm1 is partially nuclear and inhibition of mRNA synthesis increases its nuclear localization. Importantly, CBP80 is also present in the dendrites and both LSm1 and CBP80 shift significantly into the spines upon stimulation of glutamergic receptors, suggesting that these mRNPs are translationally activated and contribute to the regulated local protein synthesis

RNA localization in neurite morphogenesis and synaptic regulation: current evidence and novel approaches

It is now generally accepted that RNA localization in the central nervous system conveys important roles both during development and in the adult brain. Of special interest is protein synthesis located at the synapse, as this potentially confers selective synaptic modification and has been implicated in the establishment of memories. However, the underlying molecular events are largely unknown. In this review, we will first discuss novel findings that highlight the role of RNA localization in neurons. We will focus on the role of RNA localization in neurotrophin signaling, axon outgrowth, dendrite and dendritic spine morphogenesis as well as in synaptic plasticity. Second, we will briefly present recent work on the role of microRNAs in translational control in dendrites and its implications for learning and memory. Finally, we discuss recent approaches to visualize RNAs in living cells and their employment for studying RNA trafficking in neurons

Smaug1 mRNA-silencing foci respond to NMDA and modulate synapse formation

S-foci, the first reported mRNA-silencing foci specific to neurons, may control local mRNA translation in response to NMDA receptor stimulation and synaptic plasticity