Tenecteplase for the treatment of acute ischemic stroke in the extended time window: a systematic review and meta-analysis
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PROVIDER: S-EPMC10771742 | biostudies-literature | 2024 Jan
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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.
| S-EPMC8972028 | biostudies-literature
Project description:Background and objectivesSeveral randomized controlled trials (RCTs) have compared tenecteplase to alteplase for treatment of acute ischemic stroke (AIS). Yet, there is no meta-analysis that includes the latest published RCTs of 2022. We sought to compare the safety and efficacy of tenecteplase vs. alteplase for the treatment of AIS through a meta-analysis of all published RCTs.MethodsA systematic literature review of the English language literature was conducted using PubMed, Web of Science, Scopus, and Embase. We included RCTs that focused on patients with AIS treated with tenecteplase and alteplase. Multiple reviewers screened through potential studies to identify the final papers included in our analysis. Following PRISMA guidelines, multiple authors extracted data to ensure accuracy. Data were pooled using a random-effects model.ResultsNine trials, with 3,706 patients, compared outcomes of patients treated with tenecteplase and alteplase for AIS. Both treatments resulted in comparable rates of modified Rankin Scale (mRS) 0-1 at 90 days (RR = 1.03; 95% CI = 0.97-1.10; P-value = 0.359) and mRS 0-2 at 90 days (RR = 1.03; 95% CI = 0.87-1.22; P-value = 0.749). There was no heterogeneity among included studies regarding mRS 0-1 rates (I2 = 26%; P-value = 0.211); however, there was significant heterogeneity in mRS 0-2 rates (I2 = 71%; P-value = 0.002). Similarly, rates of mortality (RR = 0.97; 95% CI = 0.81-1.16; P-value = 0.746) and symptomatic intracranial hemorrhage (sICH) rates (RR = 1.10; 95% CI = 0.75-1.61; P-value = 0.622) were comparable in both treatment groups. There was no significant heterogeneity among included studies in either mortality (I2 = 30%; P-value = 0.181) or sICH (I2 = 0%; P-value = 0.734) rates. Further analysis comparing dosing of tenecteplase (0.1, 0.25, 0.32, and 0.4 mg/kg) yielded no significant differences for any of the endpoints (mRS 0-1, mRS 0-2, sICH, and mortality) compared to alteplase.DiscussionBased on available evidence from completed RCTs, tenecteplase has proven similar safety and efficacy to alteplase for treatment of AIS.
| S-EPMC9900099 | biostudies-literature
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.
| S-EPMC7606819 | biostudies-literature
Project description:ObjectivesTenecteplase, a modified variant of alteplase with greater fibrin specificity and longer plasma half-life, may have better efficacy and safety than alteplase in patients with acute ischemic stroke (AIS). We aimed to compare the benefits and risks of tenecteplase versus alteplase in the treatment of AIS.MethodsElectronic databases were searched up to 10 February 2023 for randomized controlled trials evaluating the effect of tenecteplase versus alteplase in the treatment of AIS. The primary outcome was functional outcome at 90 days, and secondary outcomes including the symptomatic intracranial haemorrhage (SICH), and major neurological improvement. Subgroup analysis was performed based on the different dosage of tenecteplase.ResultsTen studies with a total of 5123 patients were analysed in this meta-analysis. Overall, no significant difference between tenecteplase and alteplase was observed for functional outcome at 90 days (excellent: OR 1.08, 95%CI 0.93-1.26, I2 = 26%; good: OR 1.04, 95%CI 0.83-1.30, I2 = 56%; poor: OR 0.95, 95%CI 0.75-1.21, I2 = 31%), SICH (OR 1.12, 95%CI 0.79-1.59, I2 = 0%), and early major neurological improvement (OR 1.26, 95%CI 0.80-1.96, I2 = 65%). The subgroup analysis suggested that the 0.25 mg/kg dose of tenecteplase had potentially greater efficacy and lower symptomatic intracerebral haemorrhage risk compared with 0.25 mg/kg dose tenecteplase.ConclusionsAmong AIS patients, there was no significant difference on clinical outcomes between tenecteplase and alteplase. Subgroup analysis demonstrated that 0.25 mg/kg doses of tenecteplase were more beneficial than 0.4 mg/kg doses of tenecteplase. Further studies are required to identify the optimal dosage of tenecteplase.
| S-EPMC10916912 | biostudies-literature
Project description:BackgroundRapid and accurate acute ischemic stroke (AIS) diagnosis is needed to expedite emergent thrombolytic and mechanical thrombectomy treatment. Changes in blood-based protein biomarkers during the first 24 h of AIS, the time window for treatment, could complement imaging techniques and facilitate rapid diagnosis and treatment.MethodsWe performed a systematic review according to PRISMA guidelines. MEDLINE, EMBASE, Cochrane Library, and Web of Science databases were searched for eligible studies comparing levels of blood-based protein biomarkers in AIS patients with levels in healthy controls and stroke mimics. Protein biomarkers from the following pathophysiological categories were included: neurovascular inflammation (MMP-9, TNF-alpha), endothelial integrity (VCAM-1, ICAM-1), cell migration (E-Selectin, P-Selectin, L-Selectin), markers of glial and neuronal origin (GFAP, S100, S100B, NSE), and cardiac dysfunction (BNP, NT-proBNP). The literature search was limited to English-language publications before November 7th, 2023.ResultsA total of 61 studies from 20 different countries were identified, which included in total, 4,644 AIS patients, 2,242 stroke mimics, and 2,777 controls. Studies investigating TNF-alpha, MMP-9, VCAM-1, ICAM-1, E-Selectin, L-Selectin, GFAP, NSE, and S100B showed pronounced methodological heterogeneity, making between-study comparisons difficult. However, in 80% of NT-proBNP and BNP studies, and all P-selectin studies, higher biomarker levels were observed in AIS patients compared to healthy controls and/or patients with stroke mimics.ConclusionNone of the biomarkers included showed sufficient evidence for additional diagnostic benefit for AIS. Comprehensive standardized global multicenter studies are needed to (1) permit comparability, (2) enable valid statements about protein-based biomarkers, and (3) reflect real-world scenarios.
| S-EPMC11291248 | biostudies-literature
Project description:Introduction: Mechanical thrombectomy has improved treatment options and outcomes for acute ischemic stroke with large artery occlusion. However, as the time window of endovascular thrombectomy is extended there is an increasing need to develop immunocytoprotective therapies that can reduce inflammation in the penumbra and prevent reperfusion injury. We previously demonstrated, that by reducing neuroinflammation, KV1.3 inhibitors can improve outcomes not only in young male rodents but also in female and aged animals. To further explore the therapeutic potential of KV1.3 inhibitors for stroke therapy, we here directly compared a peptidic and a small molecule KV1.3 blocker and asked whether KV1.3 inhibition would still be beneficial when started at 72 hours after reperfusion. Methods: Transient middle cerebral artery occlusion (tMCAO, 90-min) was induced in male Wistar rats and neurological deficit assessed daily. On day-8 infarction was determined by T2-weighted MRI and inflammatory marker expression in the brain by quantitative PCR. Potential interactions with tissue plasminogen activator (tPA) were evaluated in-vitro with a chromogenic assay. Results: In a direct comparison with administration started at 2 hours after reperfusion, the small molecule PAP-1 significantly improved outcomes on day-8, while the peptide ShK-223 failed to reduce infarction and neurological deficits despite reducing inflammatory marker expression. PAP-1 still provided benefits when started 72 hours after reperfusion. PAP-1 does not reduce the proteolytic activity of tPA. Discussion: Our studies suggest that KV1.3 inhibition for immunocytoprotection after ischemic stroke has a wide therapeutic window for salvaging the inflammatory penumbra and requires brain-penetrant small molecules.
| S-EPMC10166874 | biostudies-literature
Project description:IntroductionAlteplase is widely used as an intravenous thrombolytic drug in acute ischemic stroke (AIS). Recently however, tenecteplase, a modified form of tissue plasminogen activator, has been shown to increase early recanalization rate and has proven to be non-inferior with a similar safety profile compared to alteplase. This study aims to evaluate the cost-effectiveness of 0.25 mg/kg tenecteplase versus 0.9 mg/kg alteplase for intravenous thrombolysis in AIS patients from the Dutch healthcare payer perspective.MethodsA Markov decision-analytic model was constructed to assess total costs, total quality-adjusted life year (QALY), an incremental cost-effectiveness ratio, and incremental net monetary benefit (INMB) of two treatments at willingness-to-pay (WTP) thresholds of €50,000/QALY and €80,000/QALY over a 10-year time horizon. One-way sensitivity analysis, probabilistic sensitivity analysis, and scenario analysis were conducted to test the robustness of results. Clinical data were obtained from large randomized controlled trials and real-world data.ResultsTreatment with tenecteplase saved €21 per patient while gaining 0.05 QALYs, resulting in INMB of €2381, clearly rendering tenecteplase cost-effective compared to alteplase. Importantly, tenecteplase remained the cost-effective alternative in all scenarios, including AIS patients due to large vessel occlusion (LVO). Probabilistic sensitivity analysis proved tenecteplase to be cost-effective with a 71.0% probability at a WTP threshold of €50,000/QALY.ConclusionsTenecteplase treatment was cost-effective for all AIS patients (including AIS patients with LVO) compared to alteplase. The finding supports the broader use of tenecteplase in acute stroke care, as health outcomes improve at acceptable costs while having practical advantages, and a similar safety profile.
| S-EPMC10472948 | biostudies-literature
Project description:BackgroundThe impact of imaging selection modality on clinical outcomes of endovascular thrombectomy (EVT) in the 6-24-hour time window remains undetermined. We compared the clinical outcomes of a simplified stroke imaging selection modality using non-contrast computed tomography (NCCT)±CT angiography (CTA) with using advanced CT perfusion (CTP).MethodsPubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials were searched from inception to 1 May 2022 to compare NCCT±CTA and CTP for patient selection for EVT in late-presenting stroke with large vessel occlusions (LVO). The primary outcome was the proportion of patients achieving functional independence (modified Rankin Scale score 0-2) within 180 days. The secondary outcomes included mortality within 90 days, successful recanalization, and any intracranial hemorrhage.ResultsA total of 3419 patients in six articles were included in this meta-analysis. There was no significant difference between NCCT±CTA (no-CTP) and CTP in functional independence either in overall or subgroup analysis. However, the mortality in the no-CTP group was higher than in the CTP group. Furthermore, within the DAWN/DEFUSE 3-like subgroup, there were no significant differences in mortality, successful recanalization, and any intracranial hemorrhage between the two groups.ConclusionThere was no significant difference between the simplified NCCT±CTA modality and the advanced CTP modality. The use of NCCT±CTA may represent a reasonable option for selecting patients for EVT in the extended time window, especially in the absence of CTP and acute phase MRI capabilities.
| S-EPMC10803987 | biostudies-literature
Project description:BackgroundAcute 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.MethodsWe 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 disseminationWe will disseminate the results from the present study through submitting it to conferences or peer-reviewed journal.Protocol registryThe 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.
| S-EPMC7717732 | biostudies-literature
Project description:Tenecteplase (TNK), a newer fibrinolytic agent with greater fibrin specificity and longer half-life than alteplase, may has practical advantages over alteplase in acute ischemic stroke (AIS) thrombolysis. We aimed to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare different doses of TNK (0.1, 0.25, 0.4 mg/kg) and alteplase in acute ischemic stroke patients. We systematically searched PubMed, Embase and https://clinicaltrials.gov/ for RCTs comparing TNK with alteplase in this population eligible for thrombolysis. The Cochrane Risk of Bias Tool was used to assess study quality. Random-effects or fixed-effects meta-analysis models were used for evaluating all outcomes. Total 10 RCTs with 5097 patients were included. Compared with alteplase, TNK at doses of 0.25 mg/kg may associated with the greatest odds to achieve 90-day excellent independence (mRS score ≤1), but there were no significant differences between other doses of TNK (0.1 mg/kg and 0.4 mg/kg) and alteplase. Among secondary outcomes, no significant differences were found in functional outcome (mRS score ≤2) and mortality at 90 days between any dose of TNK and alteplase. Compared with alteplase, TNK was effective at doses of 0.1 mg/kg and 0.25 mg/kg without increased risk of symptomatic intracerebral hemorrhage (sICH), but patients treated with TNK 0.4 mg/kg showed increased odds of sICH. In conclusion, compared with alteplase, intravenous thrombolysis with TNK at dose of 0.25 mg/kg has a better efficacy and similar safety profile and is a reasonable option for patients with AIS.
| S-EPMC10781500 | biostudies-literature