Penumbral Imaging-Based Thrombolysis with Tenecteplase Is Feasible up to 24 Hours after Symptom Onset

Kate, Mahesh; Wannamaker, Robert; Kamble, Harsha; Riaz, Parnian; Gioia, Laura; Buck, Brian; Jeerakathil, Thomas; Smyth, Penelope; Shuaib, Ashfaq; Emery, Derek; Butcher, Ken

doi:10.5853/jos.2017.00178.e1

Cited by 12 publications

(6 citation statements)

References 30 publications

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“…Michel et al [14] randomly assigned stroke patients occurring in the middle cerebral artery territory to alteplase venous thrombolysis, with an average last proof of well-being time point of 564 min (9.4 h), or placebo, and an average last proof of well-being of 437.5 min (7.3 h), and the results showed that thrombolytic therapy is feasible in patients with unknown stroke. Kate et al [15] reported patients were treated with tenecteplase at a median of 9.6 h after symptom onset with a range of 5.1 to 23.7 h and supported the feasibility of tenecteplase treatment in patients with 4 to 24 h of ischemic penumbral onset. In addition, we also performed subgroup analysis through different ages, NIHSS scores, and time windows and demonstrated that patients in the IVT group had better favorable functional outcomes at age ≤70 years, NIHSS ≤10, and time windows >9 h than the patients in the CG.…”

Section: Discussionmentioning

confidence: 86%

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Intravenous thrombolysis for acute ischemic stroke with extended time window

Xue

Wen

et al. 2021

Chinese Medical Journal

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Background: Intravenous thrombolysis (IVT) is an effective way for treating acute ischemic stroke (AIS). However, its effects have not been established among AIS patients with unclear stroke symptoms or with stroke onset for >4.5 h. Methods: We searched PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials and Google Scholar databases for randomized controlled trials that compared IVT (IVT group) and placebo or usual care (control group [CG]) in AIS patients with disease onset for >4.5 h. The outcomes of interest included the favorable functional outcome (defined as modified Rankin Scale [mRS] scores 0–1) at 90 days, the functional independence (defined as mRS scores 0–2) at 90 days, proportion of patients with symptomatic intracerebral hemorrhage (sICH) and death at 90 days. We assessed the risk of bias using the Cochrane tool. Pre-specified subgroup analyses were performed by age (≤70 years or >70 years), National Institute of Health Stroke Scale (NIHSS, ≤10 or >10) and time window (4.5–9.0 h or >9.0 h). Results: Four trials involving 848 patients were eligible. The risk of bias of included trials was low. Patients in the IVT group were more likely to achieve favorable functional outcomes (45.8% vs. 36.7%; OR 1.48, 95% CI 1.12–1.96) and functional independence (63.8% vs. 55.7%; OR 1.43, 95% CI 1.08–1.90) at 90 days, but had higher risk of sICH (3.0% vs. 0.5%; OR 5.28, 95% CI 1.35–20.68) at 90 days than those in the CG. No significant difference in death at 90 days was found between the two groups (7.0% vs. 4.1%; OR 1.80; 95% CI 0.97–3.34). Conclusions: Use of IVT in patients with extended time window may improve their functional outcomes at 90 days, although IVT may induce increased risk of sICH. Care of these patients should well balance the potential benefits and harms of IVT.

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Section: Discussionmentioning

confidence: 86%

“…The flow diagram was summarized [Figure 1]. A total of five trials were finally evaluated [14–18] . After reading the full text, only four RCTs [14,16–18] involving 848 patients met the inclusion criteria.…”

Section: Resultsmentioning

confidence: 99%

Intravenous thrombolysis for acute ischemic stroke with extended time window

Xue

Wen

et al. 2021

Chinese Medical Journal

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“…5 Phase II studies indicated a potential benefit of tenecteplase for the treatment of AIS, [6][7][8] and a proof of concept study demonstrated feasibility of treatment up to 24 h after onset. 9 The most recent American Heart Association/American Stroke Association (AHA/ ASA) AIS guidelines recognized tenecteplase as a reasonable alternative to alteplase in limited patient populations. 10 This trial will evaluate whether treatment with IV tenecteplase, administered 4.5-24 h after a patient's last-known well time with or without endovascular thrombectomy (EVT), is superior to placebo in patients who have a large vessel occlusion (LVO) and evidence of salvageable tissue on their baseline computed tomography (CT) perfusion or magnetic resonance perfusion imaging.…”

Section: Introduction and Rationalementioning

confidence: 99%

“…5 Phase II studies indicated a potential benefit of tenecteplase for the treatment of AIS, 6–8 and a proof of concept study demonstrated feasibility of treatment up to 24 h after onset. 9 The most recent American Heart Association/American Stroke Association (AHA/ASA) AIS guidelines recognized tenecteplase as a reasonable alternative to alteplase in limited patient populations. 10…”

Section: Introduction and Rationalementioning

confidence: 99%

A Phase III, prospective, double-blind, randomized, placebo-controlled trial of thrombolysis in imaging-eligible, late-window patients to assess the efficacy and safety of tenecteplase (TIMELESS): Rationale and design

Albers

Campbell

Lansberg

et al. 2022

International Journal of Stroke

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Rationale: While thrombolysis is standard of care for patients with acute ischemic stroke (AIS) within 4.5 hours of symptom onset, the benefit of tenecteplase beyond this time window is less certain. Aim: The TIMELESS trial (NCT03785678) aims to determine if treatment with tenecteplase increases the proportion of good clinical outcomes among patients with stroke due to a large vessel occlusion who present beyond 4.5 hours after symptom onset. Sample size estimates: A total of 456 patients will provide ≥90% power to detect differences in the distribution of modified Rankin Scale scores at Day 90 at the 2-sided 0.049 significance level. Methods and design: TIMELESS is a phase III, double-blind, randomized, placebo-controlled trial of tenecteplase with or without endovascular thrombectomy in patients with AIS and evidence of salvageable tissue via imaging who present within the 4.5–24-hour time window with an internal carotid artery (ICA) or middle cerebral artery (MCA) occlusion. Study outcomes: The primary efficacy objective of tenecteplase compared with placebo will be evaluated with ordinal modified Rankin Scale scores at Day 90. Safety will be evaluated via incidence of symptomatic intracranial hemorrhage, incidence and severity of adverse events and mortality rate. Discussion: Results from TIMELESS will contribute to understanding of the safety and efficacy of tenecteplase administered 4.5–24 hours following symptom onset for patients with an ICA or MCA occlusion.

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“…In the EXTEND trial, evidence has shown thrombolysis with rt-PA to be effective and improve overall outcome when administered in a window of 4.5-9 hours after symptom onset [ 17 , 18 ]. Along these lines, imaging-based intravenous thrombolysis with Tenecteplase is efficacious up to 24 hours after symptom onset in selected patients [ 19 ]. A study reanalyzed the data of the DEFUSE 3 trial and suggested that approximately 20% of patients with LVO who are not treated with thrombectomy had a salvageable penumbra for at least an additional 24 hours [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Macrophage Infiltration Reduces Neurodegeneration and Improves Stroke Recovery after Delayed Recanalization in Rats

Pang

Matei

Peng

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. Recent cerebrovascular recanalization therapy clinical trials have validated delayed recanalization in patients outside of the conventional window. However, a paucity of information on the pathophysiology of delayed recanalization and favorable outcomes remains. Since macrophages are extensively studied in tissue repair, we anticipate that they may play a critical role in delayed recanalization after ischemic stroke. Methods. In adult male Sprague-Dawley rats, two ischemic stroke groups were used: permanent middle cerebral artery occlusion (pMCAO) and delayed recanalization at 3 days following middle cerebral artery occlusion (rMCAO). To evaluate outcome, brain morphology, neurological function, macrophage infiltration, angiogenesis, and neurodegeneration were reported. Confirming the role of macrophages, after their depletion, we assessed angiogenesis and neurodegeneration after delayed recanalization. Results. No significant difference was observed in the rate of hemorrhage or animal mortality among pMCAO and rMCAO groups. Delayed recanalization increased angiogenesis, reduced infarct volumes and neurodegeneration, and improved neurological outcomes compared to nonrecanalized groups. In rMCAO groups, macrophage infiltration contributed to increased angiogenesis, which was characterized by increased vascular endothelial growth factor A and platelet-derived growth factor B. Confirming these links, macrophage depletion reduced angiogenesis, inflammation, neuronal survival in the peri-infarct region, and favorable outcome following delayed recanalization. Conclusion. If properly selected, delayed recanalization at day 3 postinfarct can significantly improve the neurological outcome after ischemic stroke. The sanguineous exposure of the infarct/peri-infarct to macrophages was essential for favorable outcomes after delayed recanalization at 3 days following ischemic stroke.

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Penumbral Imaging-Based Thrombolysis with Tenecteplase Is Feasible up to 24 Hours after Symptom Onset

Abstract: We apologize for any inconvenience that this may have caused.

Cited by 12 publications

References 30 publications

Intravenous thrombolysis for acute ischemic stroke with extended time window

Intravenous thrombolysis for acute ischemic stroke with extended time window

A Phase III, prospective, double-blind, randomized, placebo-controlled trial of thrombolysis in imaging-eligible, late-window patients to assess the efficacy and safety of tenecteplase (TIMELESS): Rationale and design

Macrophage Infiltration Reduces Neurodegeneration and Improves Stroke Recovery after Delayed Recanalization in Rats

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