Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke.
Ontology highlight
ABSTRACT:
SUBMITTER: Alexandrov AV
PROVIDER: S-EPMC6628520 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
Publications
Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke.
Alexandrov Andrei V AV Tsivgoulis Georgios G Köhrmann Martin M Katsanos Aristeidis H AH Soinne Lauri L Barreto Andrew D AD Rothlisberger Travis T Sharma Vijay K VK Mikulik Robert R Muir Keith W KW Levi Christopher R CR Molina Carlos A CA Saqqur Maher M Mavridis Dimitris D Psaltopoulou Theodora T Vosko Milan R MR Fiebach Jochen B JB Mandava Pitchaiah P Kent Thomas A TA Alexandrov Anne W AW Schellinger Peter D PD
Therapeutic advances in neurological disorders 20190712
<h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4 ...[more]
Similar Datasets
Project description:BackgroundNelonemdaz is a multitarget neuroprotectant that selectively blocks N-methyl-D-aspartate receptors and scavenges free radicals, as proven in preclinical ischemia-reperfusion studies. We aimed to evaluate the safety and efficacy of nelonemdaz in patients with acute ischemic stroke receiving endovascular reperfusion therapy.MethodsThis phase II randomized trial involved participants with large-artery occlusion in the anterior circulation at baseline who received endovascular reperfusion therapy <8 hours from symptom onset at 7 referral stroke centers in South Korea between October 29, 2016, and June 1, 2020. Two hundred thirteen patients were screened and 209 patients were randomly assigned at a 1:1:1 ratio using a computer-generated randomization system. Patients were divided into 3 groups based on the medication received-placebo, low-dose (2750 mg) nelonemdaz, and high-dose (5250 mg) nelonemdaz. The primary outcome was the proportion of patients with modified Rankin Scale scores of 0-2 at 12 weeks.ResultsTwo hundred eight patients were assigned to the placebo (n=70), low-dose (n=71), and high-dose (n=67) groups. The groups had similar baseline characteristics. The primary outcome was achieved in 183 patients, and it did not differ among the groups (33/61 [54.1%], 40/65 [61.5%], and 36/57 [63.2%] patients; P=0.5578). The common odds ratio (90% CI) indicating a favorable shift in the modified Rankin Scale scores at 12 weeks was 1.55 (0.92-2.60) between the placebo and low-dose groups and 1.61 (0.94-2.76) between the placebo and high-dose groups. No serious adverse events were reported.ConclusionsThe study arms showed no significant difference in the proportion of patients achieving modified Rankin Scale scores of 0-2 at 12 weeks. Nevertheless, nelonemdaz-treated patients showed a favorable tendency toward achieving these scores at 12 weeks, without serious adverse effects. Thus, a large-scale phase III trial is warranted.RegistrationURL: https://clinicaltrials.gov; Unique identifier: NCT02831088.
| S-EPMC9586831 | biostudies-literature
Project description:BackgroundIn patients with ischemic stroke, endovascular treatment results in a higher rate of recanalization of the affected cerebral artery than systemic intravenous thrombolytic therapy. However, comparison of the clinical efficacy of the two approaches is needed.MethodsWe randomly assigned 362 patients with acute ischemic stroke, within 4.5 hours after onset, to endovascular therapy (intraarterial thrombolysis with recombinant tissue plasminogen activator [t-PA], mechanical clot disruption or retrieval, or a combination of these approaches) or intravenous t-PA. Treatments were to be given as soon as possible after randomization. The primary outcome was survival free of disability (defined as a modified Rankin score of 0 or 1 on a scale of 0 to 6, with 0 indicating no symptoms, 1 no clinically significant disability despite symptoms, and 6 death) at 3 months.ResultsA total of 181 patients were assigned to receive endovascular therapy, and 181 intravenous t-PA. The median time from stroke onset to the start of treatment was 3.75 hours for endovascular therapy and 2.75 hours for intravenous t-PA (P<0.001). At 3 months, 55 patients in the endovascular-therapy group (30.4%) and 63 in the intravenous t-PA group (34.8%) were alive without disability (odds ratio adjusted for age, sex, stroke severity, and atrial fibrillation status at baseline, 0.71; 95% confidence interval, 0.44 to 1.14; P=0.16). Fatal or nonfatal symptomatic intracranial hemorrhage within 7 days occurred in 6% of the patients in each group, and there were no significant differences between groups in the rates of other serious adverse events or the case fatality rate.ConclusionsThe results of this trial in patients with acute ischemic stroke indicate that endovascular therapy is not superior to standard treatment with intravenous t-PA. (Funded by the Italian Medicines Agency, ClinicalTrials.gov number, NCT00640367.).
| S-EPMC3708480 | biostudies-literature
Project description:Background and purposeWe assessed the effect of endovascular treatment in acute ischemic stroke patients with severe neurological deficit (National Institutes of Health Stroke Scale score, ≥20) after a prespecified analysis plan.MethodsThe pooled analysis of the Interventional Management of Stroke III (IMS III) and Multicenter Randomized Clinical Trial of Endovascular Therapy for Acute Ischemic Stroke in the Netherlands (MR CLEAN) trials included participants with an National Institutes of Health Stroke Scale score of ≥20 before intravenous tissue-type plasminogen activator (tPA) treatment (IMS III) or randomization (MR CLEAN) who were treated with intravenous tPA ≤3 hours of stroke onset. Our hypothesis was that participants with severe stroke randomized to endovascular therapy after intravenous tPA would have improved 90-day outcome (distribution of modified Rankin Scale scores), when compared with those who received intravenous tPA alone.ResultsAmong 342 participants in the pooled analysis (194 from IMS III and 148 from MR CLEAN), an ordinal logistic regression model showed that the endovascular group had superior 90-day outcome compared with the intravenous tPA group (adjusted odds ratio, 1.78; 95% confidence interval, 1.20-2.66). In the logistic regression model of the dichotomous outcome (modified Rankin Scale score, 0-2, or functional independence), the endovascular group had superior outcomes (adjusted odds ratio, 1.97; 95% confidence interval, 1.09-3.56). Functional independence (modified Rankin Scale score, ≤2) at 90 days was 25% in the endovascular group when compared with 14% in the intravenous tPA group.ConclusionsEndovascular therapy after intravenous tPA within 3 hours of symptom onset improves functional outcome at 90 days after severe ischemic stroke.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00359424 (IMS III) and ISRCTN10888758 (MR CLEAN).
| S-EPMC4659737 | biostudies-literature
Project description:ObjectiveTo compare the outcomes between endovascular and medical management of acute ischemic stroke in recent randomized controlled trials (RCT).MethodsA systematic literature review was performed, and multicenter, prospective RCTs published from January 1, 2013, to May 1, 2015, directly comparing endovascular therapy to medical management for patients with acute ischemic stroke were included. Meta-analyses of modified Rankin Scale (mRS) and mortality at 90 days and symptomatic intracranial hemorrhage (sICH) for endovascular therapy and medical management were performed.ResultsEight multicenter, prospective RCTs (Interventional Management of Stroke [IMS] III, Local Versus Systemic Thrombolysis for Acute Ischemic Stroke [SYNTHESIS] Expansion, Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy [MR RESCUE], Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands [MR CLEAN], Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness [ESCAPE], Extending the Time for Thrombolysis in Emergency Neurological Deficits-Intra-Arterial [EXTEND-IA], Solitaire With the Intention For Thrombectomy as Primary Endovascular Treatment [SWIFT PRIME], and Endovascular Revascularization With Solitaire Device Versus Best Medical Therapy in Anterior Circulation Stroke Within 8 Hours [REVASCAT]) comprising 2,423 patients were included. Meta-analysis of pooled data demonstrated functional independence (mRS 0-2) at 90 days in favor of endovascular therapy (odds ratio [OR] = 1.71; p = 0.005). Subgroup analysis of the 6 trials with large vessel occlusion (LVO) criteria also demonstrated functional independence at 90 days in favor of endovascular therapy (OR = 2.23; p < 0.00001). Subgroup analysis of the 5 trials that primarily utilized stent retriever devices (≥70%) in the intervention arm demonstrated functional independence at 90 days in favor of endovascular therapy (OR = 2.39; p < 0.00001). No difference was found for mortality at 90 days and sICH between endovascular therapy and medical management in all analyses and subgroup analyses.ConclusionsThis meta-analysis provides strong evidence that endovascular intervention combined with medical management, including IV tissue plasminogen activator for eligible patients, improves the outcomes of appropriately selected patients with acute ischemic stroke in the setting of LVO.
| S-EPMC4664128 | biostudies-literature
Project description:Background and purposeRecent randomized clinical trials (RCTs) have demonstrated benefits of endovascular recanalization therapy (ERT) contrary to earlier trials. We aimed to estimate the benefits of ERT added to standard therapy in acute ischemic stroke.MethodsFrom a literature search of RCTs testing ERT, we performed a meta-analysis to estimate an overall efficacy and safety of ERT for all trials, stent-retriever trials, and RCTs comparing ERT and intravenous tissue plasminogen activator (IV-TPA).ResultsWe identified 15 relevant RCTs including 2,899 patients. For all trials, ERT was associated with increased good outcomes (odds ratio [OR] 1.79; 95% confidence interval [CI] 1.34, 2.40; P<0.001) compared to the control. ERT also increased no or minimal disability outcomes, good neurological recovery, good activity of daily living, and recanalization. ERT did not significantly increase symptomatic intracranial hemorrhage (SICH) (OR 1.19; 95% CI 0.83, 1.69; P=0.345) or death (OR 0.87; 95% CI 0.71, 1.05; P=0.151). In contrast, ERT significantly reduced extreme disability or death (OR 0.77; 95% CI 0.61, 0.97; P=0.025). Restricting to five stent-retriever trials comparing ERT plus IV-TPA vs. IV-TPA alone, the benefit was even greater for good outcome (OR 2.39; 95% CI 1.88, 3.04; P<0.001) and extreme disability or death (OR 0.57; 95% CI 0.41, 0.78; P=0.001). Restricting to eight RCTs comparing ERT (plus IV-TPA in six trials) with IV-TPA alone showed similar efficacy and safety.ConclusionsThis updated meta-analysis shows that ERT substantially improves clinical outcomes and reduces extreme disability or death without significantly increasing SICH compared to standard therapy.
| S-EPMC4635708 | biostudies-literature
Project description:The perceived advantages of endovascular treatment for acute ischemic stroke in terms of recanalization, the multimodal and targeted approaches, and perhaps the more permissive rules on devices than on medications for their licensing favored the assumption that endovascular treatment is superior to intravenous thrombolysis for acute treatment of ischemic stroke, and its adoption in more advanced stroke centers. However, this assumption has been questioned by recent clinical trial experience showing that endovascular treatment is not superior to intravenous thrombolysis. The new evidence has changed the perception and the importance of conducting randomized trials in this area. This summary examines the background and outcomes of the latest experience with endovascular techniques in acute stroke treatment based on historical data. The new challenge is how to study the latest generation of devices called stent retrievers, which are faster in recanalizing and easier to use, in selected patients with acute ischemic stroke. In the meantime, the available evidence does not provide support for the use of endovascular treatment of acute ischemic stroke in clinical practice.
| S-EPMC4066631 | biostudies-literature
Project description:Background and purposeIntravenous alteplase (rtPA) remains the only approved treatment for acute ischemic stroke, but its use remains limited. In a previous pilot dose-escalation study, intravenous tenecteplase showed promise as a potentially safer alternative. Therefore, a Phase IIB clinical trial was begun to (1) choose a best dose of tenecteplase to carry forward; and (2) to provide evidence for either promise or futility of further testing of tenecteplase versus rtPA. If promise was established, then the trial would continue as a Phase III efficacy trial comparing the selected tenecteplase dose to standard rtPA.MethodsThe trial began as a small, multicenter, randomized, double-blind, controlled clinical trial comparing 0.1, 0.25, and 0.4 mg/kg tenecteplase with standard 0.9 mg/kg rtPA in patients with acute stroke within 3 hours of onset. An adaptive sequential design used an early (24-hour) assessment of major neurological improvement balanced against occurrence of symptomatic intracranial hemorrhage to choose a "best" dose of tenecteplase to carry forward. Once a "best" dose was established, the trial was to continue until at least 100 pairs of the selected tenecteplase dose versus standard rtPA could be compared by 3-month outcome using the modified Rankin Scale in an interim analysis. Decision rules were devised to yield a clear recommendation to either stop for futility or to continue into Phase III.ResultsThe trial was prematurely terminated for slow enrollment after only 112 patients had been randomized at 8 clinical centers between 2006 and 2008. The 0.4-mg/kg dose was discarded as inferior after only 73 patients were randomized, but the selection procedure was still unable to distinguish between 0.1 mg/kg and 0.25 mg/kg as a propitious dose at the time the trial was stopped. There were no statistically persuasive differences in 3-month outcomes between the remaining tenecteplase groups and rtPA. Symptomatic intracranial hemorrhage rates were highest in the discarded 0.4-mg/kg tenecteplase group and lowest (0 of 31) in the 0.1-mg/kg tenecteplase group. Neither promise nor futility could be established.ConclusionThis prematurely terminated trial has demonstrated the potential efficiency of a novel design in selecting a propitious dose for future study of a new thrombolytic agent for acute stroke. Given the truncation of the trial, no convincing conclusions can be made about the promise of future study of tenecteplase in acute stroke.
| S-EPMC2860601 | biostudies-literature
Project description:Guidelines have been established for the management of acute ischemic stroke; however, specific recommendations for endovascular revascularization therapy are lacking. Burgeoning investigation of endovascular revascularization therapies for acute ischemic stroke, rapid device development, and a diverse training background of the providers performing the procedures underscore the need for practice recommendations. This review provides a concise summary of the Society of Vascular and Interventional Neurology endovascular acute ischemic stroke roundtable meeting. This document was developed to review current clinical efficacy of pharmacologic and mechanical revascularization therapy, selection criteria, periprocedure management, and endovascular time metrics and to highlight current practice patterns. It therefore provides an outline for the future development of multisociety guidelines and recommendations to improve patient selection, procedural management, and organizational strategies for revascularization therapies in acute ischemic stroke.
| S-EPMC4109230 | biostudies-other
Project description:PURPOSE:Knowledge about the localization and outcome of iatrogenic dissection (ID) during endovascular treatment of acute ischemic stroke (AIS) is limited. We aimed to determine the frequency, clinical aspects and morphology of ID in endovascular AIS treatment and to identify predictors of this complication. METHODS:Digital subtraction angiography (DSA) of ID carried out during endovascular treatment between January 2000 and March 2012 have been re-evaluated. The ID localization and morphology were analyzed and related to the interventional techniques. Baseline clinical and radiological findings, treatment modality and outcome were compared with patients without ID. RESULTS:Out of 866 patients 18 (2%) suffered an ID (44% female, median age 64 years). Localization was extracranial in 15 (83%, 14 internal carotid artery and 1 vertebral artery) and intracranial in 3 (17%; 1 vertebrobasilar dissection and 2 in the anterior circulation). Of the IDs 5 (28%) resulted in a high-degree, 3 (17%) in a moderate, 5 (28%) in a mild and 5 (28%) in no stenosis and 8 IDs were stented in the acute phase. At 3 months 7 (42%) patients had a favorable outcome (modified Rankin score mRS ≤ 2) and 6 (33%) patients had died. Patients with ID had a different stroke etiology (p = 0.041), were more likely to be smokers (44% versus 19%, p = 0.015) and were more likely to be treated with mechanical thrombectomy (100% versus 60%, p < 0.001). Although two ID patients had relevant complications, the outcome did not differ between the groups. CONCLUSION:The occurrence of ID is a rare complication of endovascular AIS treatment associated with smoking and mechanical thrombectomy.
| S-EPMC6394531 | biostudies-other
Project description:Background and purpose Recent randomized clinical trials have proved the efficacy of endovascular treatment of acute ischemic stroke in the anterior circulation. However, the benefit of endovascular treatment of ischemic stroke in the posterior circulation remains to be proven since it was excluded from these trials. We evaluate the benefit of endovascular treatment in posterior circulation strokes. Methods A total of 110 consecutive patients with posterior circulation stroke who underwent endovascular treatment in our institute in the period 1991-2015 were included. Recanalization rate according to modified Treatment in Cerebral Ischemia score and neurological outcome at three months according to modified Rankin Scale were the main outcomes. Collateral circulation, procedural complications and radiological outcome were evaluated in the radiological examinations. Results The median National Institutes of Health Stroke Scale was 31 (IQR: 13-31) and median time from symptom onset to groin puncture was 300 (IQR: 175-463) minutes. Successful recanalization was seen in 80 of 110 patients (73%). Favorable outcome (modified Rankin Scale ≤2) was seen in 38 patients (35%) while moderate favorable outcome (≤3) was seen in 48 patients (44%). Symptomatic intracerebral hemorrhage occurred in 10 patients (9%). An association between collateral circulation, recanalization rate and outcome was seen. Conclusion Endovascular treatment for posterior circulation stroke in this single-center cohort is relatively safe and effective with decreased mortality and increased favorable outcome compared to natural history.
| S-EPMC6050892 | biostudies-other