Effect of Intravenous Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Large Vessel Occlusion Ischemic Stroke
Bruce CampbellPeter MitchellLeonid ChurilovNawaf YassiTimothy KleinigRichard DowlingBernard YanSteven BushVincent ThijsRebecca ScroopMarion SimpsonMark BrooksHamed AsadiTeddy Y. WuDarshan ShahTissa WijeratneHenry ZhaoFana AlemsegedFelix NgPeter BaileyHenry E. RiceLaetitia de VilliersHelen M. DeweyPhilip ChoiHelen BrownKendal RedmondDavid LeggettJohn FinkWayne CollecuttThomas KræmerMartín KrauseDennis CordatoDeborah FieldHenry MaBill O’BrienBenjamin ClissoldFerdinand MiteffAnna ClissoldGeoffrey CloudLeslie BolithoLuke BonaviaArup BhattacharyaA. A. WrightAbul MamunFintan O’RourkeJohn WorthingtonAndrew WongChristopher LeviChristopher F. BladinGagan SharmaPatricia DesmondMark ParsonsGeoffrey A. DonnanStephen M. DavisJames A. TaylorCraig KurunawaiEdmund CheongAnna BalabanskiMichael J. WatersJackson HarveyLavenia CagiNicholas H. ChiaAnthony KhooRoy DrewThalia S. FieldThomas J. OxleyCameron WilliamsEdrich RodriguesPatrick SalvarisAngela Dos SantosJo-Lyn NgSkye CooteCarolyn BeltrameElizabeth A. MackeyKanaga LagmaAmy McDonaldDavid M. JacksonJessica TsoleridisLauren PesaventoAshu JhambAmy BrodtmannAlexandra WarwickBronwyn CoultonDennis YoungJustin WhitleyCarol BendallHans T.H. TuSherisse CelestinoEssie LowArman SabetSachin MishraBerzenn UrbiTanya FrostJessie ChenSiew Kar ChenMelissa Y TangKara NowakRodrigo Pereira MartinsChanna SenanayakeCharmaine YamDaniel BarberFrancesca BridgeJoseph WongGrace ThomasJennifer LiuNaila PachaniRose LeeRamesh SahathevanCasey HairTimothy HarringtonBrendan SteinfortKenneth FaulderSusan DayAllan J McDougallCecilia Cappelen‐SmithJason WenderothAndrew CheungNathan ManningAndrew MoeyVanessa MaxwellThanh G. PhanShaloo SinghalJohn LyWinston ChongRonil V. ChandraLee‐Anne SlaterJames EvansDeborah AlchinPaul TalmanCameron ShawAbhishek MalhotraRohitha MakonahalliNeil J. SprattCarlos García-EsperónLara KaauwaiPatrick GrootAnoop MadanCarlos ChungAndrea MooreRobert KronesNancy BilkhuHelen HainesFranz EversheimErin RayTessa CouplandTimothy AngStephen L. WintersDavid BrunacciGeoffrey ParkerKylie TastulaClaire MullerAlan CoulthardJohn CloustonKen MitchellKate MahadyYvonne LiuYe Min KuangAileen WuKaren SmithMichael StephensonEmily AndrewMatthew LigtermoetMatthew Lee-ArcherJohn FinkJames BeharryAndrew LaingMartin KraußJane EagleGerhard UysLauren ArthursonKrishna MandalesonAnne Van BerkelRohan GrimleyWayne SkoienNeil MahantP. Alan BarberBen McGuinnessAyton HopeStefan BrewMaurice MoriartyLily ZhaoMichele SallabergerBarry SnowJohn KolbeR. StarkJohn T. KingRichard MacdonnellJohn AttiaCate D’Este
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Abstract:
Importance
Intravenous thrombolysis with tenecteplase improves reperfusion prior to endovascular thrombectomy for ischemic stroke compared with alteplase.Objective
To determine whether 0.40 mg/kg of tenecteplase safely improves reperfusion before endovascular thrombectomy vs 0.25 mg/kg of tenecteplase in patients with large vessel occlusion ischemic stroke.Design, Setting, and Participants
Randomized clinical trial at 27 hospitals in Australia and 1 in New Zealand using open-label treatment and blinded assessment of radiological and clinical outcomes. Patients were enrolled from December 2017 to July 2019 with follow-up until October 2019. Adult patients (N = 300) with ischemic stroke due to occlusion of the intracranial internal carotid, \basilar, or middle cerebral artery were included less than 4.5 hours after symptom onset using standard intravenous thrombolysis eligibility criteria.Interventions
Open-label tenecteplase at 0.40 mg/kg (maximum, 40 mg; n = 150) or 0.25 mg/kg (maximum, 25 mg; n = 150) given as a bolus before endovascular thrombectomy.Main Outcomes and Measures
The primary outcome was reperfusion of greater than 50% of the involved ischemic territory prior to thrombectomy, assessed by consensus of 2 blinded neuroradiologists. Prespecified secondary outcomes were level of disability at day 90 (modified Rankin Scale [mRS] score; range, 0-6); mRS score of 0 to 1 (freedom from disability) or no change from baseline at 90 days; mRS score of 0 to 2 (functional independence) or no change from baseline at 90 days; substantial neurological improvement at 3 days; symptomatic intracranial hemorrhage within 36 hours; and all-cause death.Results
All 300 patients who were randomized (mean age, 72.7 years; 141 [47%] women) completed the trial. The number of participants with greater than 50% reperfusion of the previously occluded vascular territory was 29 of 150 (19.3%) in the 0.40 mg/kg group vs 29 of 150 (19.3%) in the 0.25 mg/kg group (unadjusted risk difference, 0.0% [95% CI, −8.9% to −8.9%]; adjusted risk ratio, 1.03 [95% CI, 0.66-1.61];P = .89). Among the 6 secondary outcomes, there were no significant differences in any of the 4 functional outcomes between the 0.40 mg/kg and 0.25 mg/kg groups nor in all-cause deaths (26 [17%] vs 22 [15%]; unadjusted risk difference, 2.7% [95% CI, −5.6% to 11.0%]) or symptomatic intracranial hemorrhage (7 [4.7%] vs 2 [1.3%]; unadjusted risk difference, 3.3% [95% CI, −0.5% to 7.2%]).Conclusions and Relevance
Among patients with large vessel occlusion ischemic stroke, a dose of 0.40 mg/kg, compared with 0.25 mg/kg, of tenecteplase did not significantly improve cerebral reperfusion prior to endovascular thrombectomy. The findings suggest that the 0.40-mg/kg dose of tenecteplase does not confer an advantage over the 0.25-mg/kg dose in patients with large vessel occlusion ischemic stroke in whom endovascular thrombectomy is planned.Trial Registration
ClinicalTrials.gov Identifier:NCT03340493Keywords:
Tenecteplase
Stroke
Fibrinolytic agent
Tenecteplase
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Background Tenecteplase, a modified plasminogen activator with higher fibrin specificity and longer half-life, may have advantages over alteplase in acute ischemic stroke thrombolysis. Aims We undertook an individual patient data meta-analysis of randomized controlled trials that compared alteplase with tenecteplase in acute stroke. Methods Eligible studies were identified by a MEDLINE search, and individual patient data were acquired. We compared clinical outcomes including modified Rankin Scale at three months, early neurological improvement at 24 h, intracerebral hemorrhage, symptomatic intracerebral hemorrhage, and mortality at three months between all dose tiers of tenecteplase and alteplase. Results Three relevant studies (Haley et al., Parsons et al., and ATTEST) included 291 patients and investigated three doses of tenecteplase (0.1, 0.25, 0.4 mg/kg). There were no differences between any dose of tenecteplase and alteplase for either efficacy or safety end points. Tenecteplase 0.25 mg/kg had the greatest odds to achieve early neurological improvement (OR [95%CI] 3.3 [1.5, 7.2], p = 0.093), excellent functional outcome (modified Rankin Scale 0–1) at three months (OR [95%CI] 1.9 [0.8, 4.4], p = 0.28), with reduced odds of intracerebral hemorrhage (OR [95%CI] 0.6 [0.2, 1.8], P = 0.43) compared with alteplase. Only 19 patients were treated with tenecteplase 0.4 mg/kg, which showed increased odds of symptomatic intracerebral hemorrhage compared with alteplase (OR [95% CI] 6.2 [0.7, 56.3]). Conclusions While no significant differences between tenecteplase and alteplase were found, point estimates suggest potentially greater efficacy of 0.25 and 0.1 mg/kg doses with no difference in symptomatic intracerebral hemorrhage, and potentially higher symptomatic intracerebral hemorrhage risk with the 0.4 mg/kg dose. Further investigation of 0.25 mg/kg tenecteplase is warranted.
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Abstract Background : Tenecteplase is a tissue plasminogen activator with higher fibrin specificity compared with Alteplase. Accumulating data suggests that intravenous Tenecteplase 0.25mg/kg is non-inferior to Alteplase 0.9mg/kg for acute ischemic stroke. We describe our 10-months experience. Methods : At our MRI-based, urban comprehensive stroke center, we switched the intravenous thrombolytic agent for acute ischemic stroke to Tenecteplase 0.25mg/kg on March 23, 2021. Until January 31, 2022, 62 stroke patients were treated with Tenecteplase. We compared clinical and safety outcomes of Tenecteplase-treated patients with 94 Alteplase-treated patients. Results : During the study period, nine (15%) patients with unknown stroke onset were thrombolyzed with MRI screening. Nineteen (35%) patients underwent subsequent thrombectomy. When compared with Alteplase-treated patients, there was no difference with Tenecteplase-treated patients in 90-day functional outcome, death, symptomatic intracranial hemorrhage, or angioedema. Conclusions : The use of Tenecteplase for stroke thrombolysis was feasible with comparable safety and functional outcomes compared to Alteplase, even when Tenecteplase was administered based on MRI screening to stroke patients with unknown onset.
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Introduction: The encouraging efficacy and safety data on intravenous thrombolysis with tenecteplase in ischemic stroke and its practical advantages motivated our centers to switch from alteplase to tenecteplase. We report its impact on treatment times and clinical outcomes. Methods: We retrospectively analyzed clinical and procedural data of patients treated with alteplase or tenecteplase in a comprehensive (CSC) and a primary stroke center (PSC), which transitioned respectively in 2019 and 2018. Tenecteplase enabled in-imaging thrombolysis in the CSC. The main outcomes were the imaging-to-thrombolysis and thrombolysis-to-puncture times. We assessed the association of tenecteplase with 3-month functional independence and parenchymal hemorrhage (PH) with multivariable logistic models. Results: We included 795 patients, 387 (48.7%) received alteplase and 408 (51.3%) tenecteplase. Both groups (tenecteplase vs alteplase) were similar in terms of age (75 vs 76 years), baseline NIHSS score (7 vs 7.5) and proportion of patients treated with mechanical thrombectomy (24.1% vs 27.5%). Tenecteplase patients had shorter imaging-to-thrombolysis times (27 vs 36 min, p < 0.0001) mainly driven by patients treated in the CSC (22 vs 38 min, p < 0.001). In the PSC, tenecteplase patients had shorter thrombolysis-to-puncture times (84 vs 95 min, p = 0.02), reflecting faster interhospital transfer for MT. 3-month functional independence rate was higher in the tenecteplase group (62.8% vs 53.4%, p < 0.01). In the multivariable analysis, tenecteplase was significantly associated with functional independence (OR a 1.68, 95% CI 1.15–2.48, p < 0.01), but not with PH (OR a 0.68, 95% CI 0.41–1.12, p = 0.13). Conclusion: Switch from alteplase to tenecteplase reduced process times and may improve functional outcome, with similar safety profile.
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Tenecteplase
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Background: IV thrombolysis with alteplase, the only medical treatment currently approved for acute ischaemic stroke, significantly increases the probability of excellent recovery. A recent trial has demonstrated that the modified tissue plasminogen activator tenecteplase at a dose of 0.4mg/kg is of similar safety and efficacy to alteplase in acute stroke. In addition to having simpler administration, tenecteplase 0.25mg/kg is also potentially superior to alteplase with respect to efficacy, based on meta-analysis of small trials. More data are required to establish the true risk-benefit profile compared with alteplase. Objectives & Methods: ATTEST-2 will establish whether tenecteplase is superior to alteplase by undertaking a prospective randomised open blinded end-point (PROBE) trial in patients eligible for IV thrombolysis based on non-contrast CT imaging. The study opened to recruitment in Dec 2016. 60 UK centres will recruit 1870 patients. Outcome: Primary outcome is the distribution of modified Rankin Scale (mRS) outcomes at day 90, determined by the Rankin Focused Assessment method, analysed by ordinal distribution ("shift") analysis of the of scores in intervention and control groups. Conclusion: An agent with superior risk:benefit ratio to alteplase would potentially extend thrombolytic treatment a greater proportion of patients than at present and reduce the need for mechanical thrombectomy. This trial will contribute to the optimisation of reperfusion strategies.
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Madam, Tenecteplase is a recombinant tissue plasminogen activator (tPA) that is used in many countries worldwide for reperfusion in acute ischemic stroke (AIS) and STEMI because of its longer half-life and high fibrin specificity compared to other tPAs (e.g., alteplase) and Streptokinase.1 Tenecteplase binds with fibrin-rich clots using its fibronectin finger-like and kringle-2 domains. The binding allows the protease domain to cleave the Arg/Val bond, converting plasminogen into plasmin, which breaks the fibrin matrix of the thrombus, resulting in clot dissolution. While Stroke and MI remain in the top 5 leading causes of death in Pakistan2, this highly efficient thrombolytic agent is not yet accessible in most hospitals for reperfusion in acute ischemic stroke and myocardial infarction cases. Many studies offer promising results, with tenecteplase being a better thrombolytic agent for acute ischemic stroke and STEMI than alteplase. In India, studies declare tenecteplase effective and safe in STEMI patients with clinically successful thrombolysis reported in 80.67% of patients, while intracranial hemorrhage associated with tenecteplase was only 0.39%.3 Tenecteplase is more efficient and at least as safe as alteplase for acute ischemic stroke. According to a meta-analysis involving 2031 patients, the patients given Tenecteplase showed higher recanalization rates (ARD=0.11, 95%CI) and early neurological improvement (ARD=0.10, 95% CI) compared to patients given alteplase.4 Tenecteplase also has a lower cost and a more favorable pharmacokinetic profile allowing bolus injection. Regrettably, Tenecteplase is not yet accessible in Pakistan due to unclear political and administrative factors, and border restrictions. Studies claim that only six hospitals in Pakistan currently offer intravenous thrombolytic therapy with alteplase, all being private tertiary care hospitals.5 While the world is adopting Tenecteplase instead of alteplase because of its better results, a more favourable side effects profile, and lower cost, our healthcare system is still dependent on SK for IV thrombolysis in cases of STEMI, which too is sometimes not available in many hospitals. In light of available evidence suggesting Tenecteplase as a better alternative to alteplase and Streptokinase, the health government and hospital policymakers should consider introducing tenecteplase in Pakistan as the standard care for STEMI, New Onset LBBB (Left Bundle Branch Block), Acute Ischemic Stroke, Prosthetic Valve Thrombosis, Pulmonary Embolism, and Deep Venous Thrombosis.
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Tenecteplase is a modified tissue plasminogen activator with a longer half-life and higher fibrin specificity than alteplase.We conducted a prospective, nonrandomized, pilot study of 0.1 mg/kg IV tenecteplase given 3 to 6 hours after ischemic stroke onset. For a control group, we used patients contemporaneously treated with sub-3-hour 0.9 mg/kg IV alteplase following standard selection criteria. All patients underwent pretreatment and 24-hour perfusion/angiographic imaging with CT or MRI. Eligibility criteria for tenecteplase (but not alteplase) treatment included a perfusion lesion at least 20% greater than the infarct core, with an associated vessel occlusion. Primary outcomes, assessed blind to treatment group, were reperfusion (reduction in baseline-24-hour mean transit time lesion) and major vessel recanalization.Fifteen patients received tenecteplase, and 35 patients received alteplase. The tenecteplase group had greater reperfusion (mean 74% vs 44% in the alteplase group, p = 0.01) and major vessel recanalization (10/15 tenecteplase vs 7/29 alteplase, p = 0.01). Despite later time to treatment, more tenecteplase patients (10/15 vs 7/35 alteplase, p = 0.001) had major neurologic improvement at 24 hours (NIH Stroke Scale reduction > or = 8). Four of the alteplase patients and none of the tenecteplase patients had parenchymal hematoma at 24 hours.Tenecteplase 0.1 mg/kg, using advanced imaging guidance in an extended time window, may have significant biologic efficacy in acute ischemic stroke. The imaging selection differences between the tenecteplase and alteplase groups prevent a conclusive efficacy comparison. Nonetheless, these results lend support for randomized trials comparing tenecteplase with alteplase, preferably incorporating penumbral/angiographic imaging selection.
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Tenecteplase is a modied tissue plasminogen activator and newer thrombolytic agent. It has a longer half life ,which is more brin specic, produces less systemic depletion of circulating brinogen, and is more resistant to plasminogen activator inhibitor. Because of its pharmacodynamic properties which results in rapid reperfusion and lower intracranial hemorrhages. Hence the objective is to study the efcacy of tenectaplase in acute ischemic stroke including, neurological and functional outcome at 3 months which is assessed by mRS scale and also to know the complications arising out of thrombolysis with tenectaplase. This is Methods- prospective observational study of 40 cases of acute ischemic stroke undergoing thrombolysis with tenecteplase within 4.5 hours of onset. Dose of 0.2 mg /kg of tenecteplase was used for thrombolysis and outcome was evaluated with improvement in NIHSS score at arrival , 24 hrs, 1 week and at discharge, 1 and 3 month and mRS scale at 1 and 3 months. In our study, 67.5% (27 out of 40) patients met the primary clinical efcacy outc Result- ome by achieving an improvement in NIHSS score of 4 or more points at 24 h and 67% (27out of 40 patients) met the secondary clinical efcacy outcome by having an mRS scale of 0 or 1 at 3 months. Adverse events were noted in 7 patients (17.5%) of which 4 developed ICH and 3 patients showed poor clinical outcome. ConclusionTenecteplase appears to be a safe and effective agent for acute ischemic stroke because of signicant improvement in NIHSS , low disability rates were observed in the present study
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Thrombolytic agents, including tenecteplase, are generally used within 4.5 hours after the onset of stroke symptoms. Information on whether tenecteplase confers benefit beyond 4.5 hours is limited. We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving patients with ischemic stroke to compare tenecteplase (0.25 mg per kilogram of body weight, up to 25 mg) with placebo administered 4.5 to 24 hours after the time that the patient was last known to be well. Patients had to have evidence of occlusion of the middle cerebral artery or internal carotid artery and salvageable tissue as determined on perfusion imaging. The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death) at day 90. Safety outcomes included death and symptomatic intracranial hemorrhage. The trial enrolled 458 patients, 77.3% of whom subsequently underwent thrombectomy; 228 patients were assigned to receive tenecteplase, and 230 to receive placebo. The median time between the time the patient was last known to be well and randomization was approximately 12 hours in the tenecteplase group and approximately 13 hours in the placebo group. The median score on the modified Rankin scale at 90 days was 3 in each group. The adjusted common odds ratio for the distribution of scores on the modified Rankin scale at 90 days for tenecteplase as compared with placebo was 1.13 (95% confidence interval, 0.82 to 1.57; P=0.45). In the safety population, mortality at 90 days was 19.7% in the tenecteplase group and 18.2% in the placebo group, and the incidence of symptomatic intracranial hemorrhage was 3.2% and 2.3%, respectively. Tenecteplase therapy that was initiated 4.5 to 24 hours after stroke onset in patients with occlusions of the middle cerebral artery or internal carotid artery, most of whom had undergone endovascular thrombectomy, did not result in better clinical outcomes than those with placebo. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by Genentech; TIMELESS ClinicalTrials.gov number, NCT03785678.)
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