Dataset Information

Different dosing regimens of Tenecteplase in acute ischemic stroke: A network meta-analysis of the clinical evidence.

ABSTRACT:

Introduction

Acute ischemic stroke remains the major cause of death and disability and conclusive evidence of Tenecteplase in treating stroke is lacking.

Objective

To conduct a meta-analysis to determine whether Tenecteplase produces better outcomes than Alteplase and a network meta-analysis comparing the different dosing regimens of Tenecteplase.

Methods

Searches were made in MEDLINE, CENTRAL, and ClinicalTrials.gov. The outcome measures are recanalization, early neurological improvement, functional outcomes at 90 days (modified Rankin Scale 0-1 and 0-2), intracranial hemorrhage, symptomatic intracranial hemorrhage, and mortality within 90 days from treatment.

Results

Fourteen studies are included in the meta-analyses and 18 studies in the network meta-analyses. In the meta-analysis, Tenecteplase 0.25 mg/kg has significant results in early neurological improvement (OR = 2.35, and 95% CI = 1.16-4.72) and excellent functional outcome (OR = 1.20, and 95% CI = 1.02-1.42). In the network meta-analysis, Tenecteplase 0.25 mg/kg produces significant results in early neurological improvement (OR = 1.52 [95% CI = 1.13-2.05], p-value = 0.01), functional outcomes (mRS 0-1 and 0-2) (OR = 1.19 [95% CI = 1.03-1.37], p-value = 0.02; OR = 1.21 [95% CI = 1.05-1.39], p-value = 0.01; respectively) and mortality (OR = 0.78 [95% CI = 0.64-0.96], p-value = 0.02) whereas Tenecteplase 0.40 mg/kg increases the chances of symptomatic intracranial hemorrhage (OR = 2.35 [95% CI = 1.19-4.64], p-value = 0.01).

Conclusion

While not conclusive, our study lends evidence to 0.25 mg/kg Tenecteplase dose for ischemic stroke treatment. Further randomized trials need to be done to validate this finding.

Registration

International prospective register of systematic reviews (PROSPERO) - CRD42022339774URL: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=339774.

SUBMITTER: The EZ

PROVIDER: S-EPMC10069195 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

Different dosing regimens of Tenecteplase in acute ischemic stroke: A network meta-analysis of the clinical evidence.

The Ei Zune EZ Lin Ne Naing NN Matar Mazen M Teoh Hock Luen HL Yeo Leonard Leong Litt LLL

European stroke journal 20221013 1

<h4>Introduction</h4>Acute ischemic stroke remains the major cause of death and disability and conclusive evidence of Tenecteplase in treating stroke is lacking.<h4>Objective</h4>To conduct a meta-analysis to determine whether Tenecteplase produces better outcomes than Alteplase and a network meta-analysis comparing the different dosing regimens of Tenecteplase.<h4>Methods</h4>Searches were made in MEDLINE, CENTRAL, and ClinicalTrials.gov. The outcome measures are recanalization, early neurologi ...[more]

PMID: 37021171

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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:BackgroundThe optimal dose of tenecteplase vs. alteplase for acute ischemic stroke (AIS) has yet to be established. Therefore, we included the latest randomized controlled trials (RCT) to assess the efficacy and safety of different doses of tenecteplase vs. alteplase for AIS within 4.5 hours of symptom onset.MethodsLiterature was searched in PubMed, Cochrane Library, Embase, Web of Science, and clinical trial registries until February 12, 2023. Odds ratios (OR) with 95% credible intervals (CrI) were estimated using Bayesian network meta-analysis (NMA). Treatments were ranked based on efficacy and safety using the surface under the cumulative ranking curve (SUCRA).ResultsEleven RCTs with 5,475 patients were included. Tenecteplase 0.25 mg/kg and alteplase 0.9 mg/kg had significantly higher rates of excellent functional outcome (tenecteplase: OR, 1.85; 95% CrI, 1.44-2.37; alteplase: OR, 1.60; 95% CrI, 1.29-1.97) and good functional outcome (tenecteplase: OR, 1.54; 95% CrI, 1.19-1.98; alteplase: OR, 1.40; 95% CrI, 1.14-1.74) than placebo, despite an increased risk of symptomatic intracranial hemorrhage. Furthermore, the NMA (OR, 1.16; 95% CrI, 1.01-1.33) and the pairwise meta-analysis (OR, 1.16; 95% CI, 1.02-1.33; P = 0.03) indicated that tenecteplase 0.25 mg/kg was superior to alteplase 0.9 mg/kg in excellent functional outcome. Alteplase 0.9 mg/kg (OR, 2.54; 95% CrI, 1.45-8.08) significantly increased the risk of any intracranial hemorrhage compared with placebo. SUCRA results demonstrated that tenecteplase 0.25 mg/kg ranked first and tenecteplase 0.4 mg/kg ranked last in efficacy outcomes.ConclusionsThe NMA indicated that tenecteplase 0.25 mg/kg and alteplase 0.9 mg/kg are safe and significantly improve clinical outcomes in patients with AIS within 4.5 h of symptom onset. Furthermore, tenecteplase 0.25 mg/kg provides more benefit and has the potential to replace alteplase 0.9 mg/kg in AIS treatment.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/index.php, identifier: CRD42022343948.

Project description:ImportanceTenecteplase is being evaluated as an alternative thrombolytic agent for the treatment of acute ischemic stroke (AIS) within ongoing randomized clinical trials (RCTs). In addition, nonrandomized clinical experiences with off-label use of tenecteplase vs alteplase for AIS treatment are being published.ObjectiveTo evaluate the available evidence on the safety and efficacy of intravenous tenecteplase compared with intravenous alteplase provided by nonrandomized studies.Data sourcesEligible studies were identified by searching MEDLINE and Scopus databases. No language or other restrictions were imposed. The literature search was conducted on October 12, 2021. This meta-analysis used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was written according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) proposal.Study selectionNonrandomized studies (prospective or retrospective) comparing intravenous tenecteplase (at any dose) with intravenous alteplase in patients with AIS were included in the analysis.Data extraction and synthesisThe crude odds ratios (ORs) and 95% CIs were calculated for the association of tenecteplase vs alteplase with the outcomes of interest and adjusted ORs were extracted if provided. Estimates using random-effects models were pooled.Main outcomes and measuresThe primary outcome was the probability of good functional outcome (modified Rankin scale [mRS] score, 0-2) at 90 days.ResultsSix studies were identified including a total of 1820 patients (618 [34%] treated with tenecteplase). Patients receiving tenecteplase had higher odds of 3-month good functional outcome (crude odds ratio [OR], 1.22; 95% CI, 0.90-1.66; adjusted OR, 1.60, 95% CI, 1.08-2.37), successful recanalization (crude OR, 2.82; 95% CI, 1.12-7.10; adjusted OR, 2.38; 95% CI, 1.18-4.81), and early neurological improvement (crude OR, 4.88; 95% CI, 2.03-11.71; adjusted OR, 7.60; 95% CI, 1.97-29.41). No significant differences were detected in 3-month excellent functional outcome proportions (mRS score 0-1; crude OR, 1.53; 95% CI, 0.81-2.91; adjusted OR, 2.51; 95% CI, 0.66- 9.49), symptomatic intracranial hemorrhage (crude OR, 0.97; 95% CI, 0.44-2.16; adjusted OR, 1.16; 95% CI, 0.13-10.50), or parenchymal hematoma (crude OR, 1.20; 95% CI, 0.24-5.95).Conclusions and relevanceEvidence from nonrandomized studies suggests tenecteplase is as safe as alteplase and potentially associated with improved functional outcomes compared with alteplase. Based on these findings, enrollment in the ongoing RCTs appears to be appropriate.

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.

Dataset Information

Different dosing regimens of Tenecteplase in acute ischemic stroke: A network meta-analysis of the clinical evidence.

Introduction

Objective

Methods

Results

Conclusion

Registration

Publications

Different dosing regimens of Tenecteplase in acute ischemic stroke: A network meta-analysis of the clinical evidence.

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