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Efficacy and safety of different doses of tenecteplase for the treatment of acute ischemic stroke: A protocol for a systematic review and network meta-analysis.

ABSTRACT: Background: Acute ischemic stroke (AIS) has become the major reason of causing death around the world. As a newer generation fibrinolytic agent, the potential of tenecteplase in treating AIS has been determined in clinical studies and meta-analysis. However, various doses have been prescribed for tenecteplase in clinical practice, and the optimal dose is not yet clear.

Methods: We will perform a systematic search to capture all potential randomized controlled trials (RCTs) of persons with confirmed AIS who were instructed to administer tenecteplase that report at least one outcome in PubMed, Embase, and the Cochrane Library. Two reviewers will independently check the titles, abstracts, and full-texts, extracting data, assessing the risk of bias and evaluating the certainty of evidence. We will use a random-effect model based on the Bayesian framework to completely direct and network meta-analyses. We will also test the robustness of all pooled results through conducting subgroup analyses according to the following criteria: DISCUSSION:: Our systematic review and network meta-analysis will generate several valuable findings and have several strengths including:We therefore believe that findings from this network meta-analysis will benefit future study design and improve evidence-based treatment of AIS.

Ethics and dissemination: We will disseminate the results from the present study through submitting it to conferences or peer-reviewed journal.

Protocol registry: The protocol of our systematic review and network meta-analysis was registered in International Plateform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY) platform with an approval number of INPLASY2020100086 (https://inplasy.com/inplasy-2020-10-0086/). Moreover, this protocol was funded through a protocol registry.

SUBMITTER: Shen T

PROVIDER: S-EPMC7717732 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Efficacy and safety of different doses of tenecteplase for the treatment of acute ischemic stroke: A protocol for a systematic review and network meta-analysis.

Shen Ting T Zhou Jinjian J Zhao Yan Y

Medicine 20201201 49

<h4>Background</h4>Acute ischemic stroke (AIS) has become the major reason of causing death around the world. As a newer generation fibrinolytic agent, the potential of tenecteplase in treating AIS has been determined in clinical studies and meta-analysis. However, various doses have been prescribed for tenecteplase in clinical practice, and the optimal dose is not yet clear.<h4>Methods</h4>We will perform a systematic search to capture all potential randomized controlled trials (RCTs) of person ...[more]

PMID: 33285721

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Project description:Tenecteplase is a fibrinolytic drug with higher fibrin specificity and longer half-life than the standard stroke thrombolytic, alteplase, permitting the convenience of single bolus administration. Tenecteplase, at 0.5 mg/kg, has regulatory approval to treat ST-segment-elevation myocardial infarction, for which it has equivalent 30-day mortality and fewer systemic hemorrhages. Investigated as a thrombolytic for ischemic stroke over the past 15 years, tenecteplase is currently being studied in several phase 3 trials. Based on a systematic literature search, we provide a qualitative synthesis of published stroke clinical trials of tenecteplase that (1) performed randomized comparisons with alteplase, (2) compared different doses of tenecteplase, or (3) provided unique quantitative meta-analyses. Four phase 2 and one phase 3 study performed randomized comparisons with alteplase. These and other phase 2 studies compared different tenecteplase doses and effects on early outcomes of recanalization, reperfusion, and substantial neurological improvement, as well as symptomatic intracranial hemorrhage and 3-month disability on the modified Rankin Scale. Although no single trial prospectively demonstrated superiority or noninferiority of tenecteplase on clinical outcome, meta-analyses of these trials (1585 patients randomized) point to tenecteplase superiority in recanalization of large vessel occlusions and noninferiority in disability-free 3-month outcome, without increases in symptomatic intracranial hemorrhage or mortality. Doses of 0.25 and 0.4 mg/kg have been tested, but no advantage of the higher dose has been suggested by the results. Current clinical practice guidelines for stroke include intravenous tenecteplase at either dose as a second-tier option, with the 0.25 mg/kg dose recommended for large vessel occlusions, based on a phase 2 trial that demonstrated superior recanalization and improved 3-month outcome relative to alteplase. Ongoing randomized phase 3 trials may better define the comparative risks and benefits of tenecteplase and alteplase for stroke thrombolysis and answer questions of tenecteplase efficacy in the >4.5-hour time window, in wake-up stroke, and in combination with endovascular thrombectomy.

Project description:BackgroundThis study aims to assess the efficacy and safety of different doses of intravenous tissue-type plasminogen activator (tPA) for acute ischemic stroke (AIS) by adopting a network meta-analysis (NMA).MethodsStudies comparing different doses of tPA in AIS were identified by retrieving electronic databases. NMAs of outcome measures included favorable functional outcome with a modified Rankin scale score (mRS) of 0 or 1 at 3 months after treatment (3M-FF), the functional independence with a mRS of 0, 1, or 2 at 3 months (3M-FI), symptomatic intracranial hemorrhage (sICH) and 3-month all-cause mortality (3M-M). Symptomatic intracranial hemorrhage (sICH) and 3-month all-cause mortality (3M-M) were assessed. Probability-based ranking and surface under cumulative ranking (SUCRA) were performed to identify the best dose of tPA. Inconsistency was evaluated by node-splitting analysis and a loop-specific approach. Publication bias was analyzed by funnel plots.ResultsA total of 14 studies were included in the quantitative synthesis. The NMA results revealed no difference among low (<0.7 mg/kg), moderate (0.8 mg/kg), and standard (0.9 mg/kg) doses of tPA with regard to efficacy and safety. The SUCRAs of 3M-FF and 3M-FI showed that the standard dose ranked first, the moderate dose ranked second, and the low dose ranked third. The SUCRA of sICH showed that the standard dose ranked first (78.1%), the low dose ranked second (61.0%), and the moderate dose ranked third (11.0%). The SUCRAs of 3-month mortality showed that the standard dose ranked first (73.2%), the moderate dose ranked second (40.8%), and the low dose ranked third (36.1%). No significant inconsistency was shown by node-splitting analysis and no publication bias was shown in funnel plots.ConclusionLower dose tPA was comparable to the standard dose with regard to efficacy and safety. Based on the SUCRA results and American Heart Association/American Stroke Association (AHA/ASA) guidelines, the standard dose was still the optimal selection for AIS.

Project description:To evaluate the effectiveness and safety of the Xingnao Kaiqiao needling method for treating acute ischemic stroke.We retrieved relevant randomized controlled trials involving Xingnao Kaiqiao acupuncture for treatment of acute ischemic stroke. The China National Knowledge Infrastructure, Weipu Information Resources System, Wanfang Medical Data System, Chinese Biomedical Literature Database, Cochrane Library, and PubMed were searched from June 2006 to March 2016.We analyzed randomized and semi-randomized clinical controlled trials that compared Xingnao Kaiqiao acupuncture with various control treatments, such as conventional drugs or other acupuncture therapies, for treatment of acute ischemic stroke. The quality of articles was evaluated according to the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1), and the study was carried out using Cochrane system assessment methods. RevMan 5.2 was used for the meta-analysis of the included studies.The mortality rate, disability rate, activities of daily living (Barthel Index), and clinical efficacy were observed.Twelve studies met the inclusion criteria for this review. The meta-analysis showed that between Xingnao Kaiqiao acupuncture and the control treatment, Xingnao Kaiqiao acupuncture reduced the disability rate [risk ratio (RR) = 0.51, 95% confidence interval (CI) = 0.27-0.98, z = 2.03, P < 0.05], elevated the activities of daily living (weighted mean difference = 12.23, 95% CI: 3.66-20.08, z = 2.80, P < 0.005), and had greater clinical efficacy (RR = 1.61, 95% CI: 1.23-2.09, z = 3.53, P < 0.0004). However, there was no significant difference in mortality rate (RR = 0.61, 95% CI: 0.15-2.45, z = 0.70, P > 0.05).The Xingnao Kaiqiao needling method is effective and safe for acute ischemic stroke. However, there was selective bias in this study, and the likelihood of measurement bias is high. Thus, more high-quality randomized controlled trials are needed to provide reliable evidence of the efficacy and safety of Xingnao Kaiqiao acupuncture in the treatment of acute ischemic stroke.

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.

Dataset Information

Efficacy and safety of different doses of tenecteplase for the treatment of acute ischemic stroke: A protocol for a systematic review and network meta-analysis.

Publications

Efficacy and safety of different doses of tenecteplase for the treatment of acute ischemic stroke: A protocol for a systematic review and network meta-analysis.

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