scholarly journals Tenecteplase versus alteplase for large vessel occlusion recanalization (T-FLAVOR): Trial protocol

2022 ◽  
pp. 239698732110704
Author(s):  
Hiroyuki Kawano ◽  
Teruyuki Hirano ◽  
Manabu Inoue ◽  
Mayumi Fukuda-Doi ◽  
Koji Iwasaki ◽  
...  

Background Tenecteplase has higher fibrin specificity with a longer half-life and the potential to achieve higher rates of recanalization than alteplase. A critical limitation of tenecteplase is no commercial use in Japan and no experience with its administration to Japanese patients. Hypothesis Tenecteplase is superior to alteplase in achieving recanalization on the initial angiogram when administered ≤4.5-hour of stroke onset in patients planned for mechanical thrombectomy (MT) in Japan where alteplase at the unique dose of 0.6mg/kg is officially used. Methods The Tenecteplase versus alteplase For LArge Vessel Occlusion Recanalization (T-FLAVOR) trial is an investigator-initiated, phase II, multicenter, prospective, randomized, open-label, masked-endpoint, superiority study. Eligibility criteria include acute ischemic stroke with pre-stroke modified Rankin Scale score ≤3 and large vessel occlusion (internal carotid artery, middle cerebral artery, or basilar artery) eligible for intravenous thrombolysis ≤4.5-hour and MT ≤6-hour of stroke onset. After completing the safety confirmation phase involving three patients who received non-masked tenecteplase (0.25 mg/kg), 220 patients will be randomized to two groups (1:1), intravenous alteplase (0.6mg/kg, n = 110) or tenecteplase (0.25mg/kg, n = 110), prior to MT. Outcomes In the safety confirmation phase, the primary outcome is symptomatic intracranial hemorrhage (sICH) ≤24-36-hour. In the randomized, comparative phase, the primary efficacy outcome is substantial angiographic reperfusion (mTICI grade 2b/2c/3) or absence of retrievable thrombus on the initial angiogram. The primary safety outcome is sICH ≤24-36-hour and 90-day mortality. Discussion T-FLAVOR may help determine if tenecteplase should be recommended as a routine clinical strategy before MT for Japanese stroke patients. Trial registration jRCTs051210055

2017 ◽  
Vol 13 (3) ◽  
pp. 328-334 ◽  
Author(s):  
Bruce CV Campbell ◽  
Peter J Mitchell ◽  
Leonid Churilov ◽  
Nawaf Yassi ◽  
Timothy J Kleinig ◽  
...  

Background and hypothesis Intravenous thrombolysis with alteplase remains standard care prior to thrombectomy for eligible patients within 4.5 h of ischemic stroke onset. However, alteplase only succeeds in reperfusing large vessel arterial occlusion prior to thrombectomy in a minority of patients. We hypothesized that tenecteplase is non-inferior to alteplase in achieving reperfusion at initial angiogram, when administered within 4.5 h of ischemic stroke onset, in patients planned to undergo endovascular therapy. Study design EXTEND-IA TNK is an investigator-initiated, phase II, multicenter, prospective, randomized, open-label, blinded-endpoint non-inferiority study. Eligibility requires a diagnosis of ischemic stroke within 4.5 h of stroke onset, pre-stroke modified Rankin Scale≤3 (no upper age limit), large vessel occlusion (internal carotid, basilar, or middle cerebral artery) on multimodal computed tomography and absence of contraindications to intravenous thrombolysis. Patients are randomized to either IV alteplase (0.9 mg/kg, max 90 mg) or tenecteplase (0.25 mg/kg, max 25 mg) prior to thrombectomy. Study outcomes The primary outcome measure is reperfusion on the initial catheter angiogram, assessed as modified treatment in cerebral infarction 2 b/3 or the absence of retrievable thrombus. Secondary outcomes include modified Rankin Scale at day 90 and favorable clinical response (reduction in National Institutes of Health Stroke Scale by ≥8 points or reaching 0–1) at day 3. Safety outcomes are death and symptomatic intracerebral hemorrhage. Trial registration ClinicalTrials.gov NCT02388061


Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Jose Bernardo Escribano Paredes ◽  
Julian Klug ◽  
Elisabeth Dirren ◽  
Nicolae Sanda ◽  
Maria Vargas ◽  
...  

Introduction: Endovascular treatment (EVT) is the therapy of choice, in patients with unknown stroke onset (unwitnessed and wake-up strokes) and large vessel occlusion (LVO) with a favorable perfusion pattern. Whether bridging therapy (intravenous thrombolysis (IVT) and EVT) is superior to EVT alone remains unknown. Material and Methods: We retrospectively included all patients admitted to the Geneva University Hospital from 01.2016 to 06.2020 with i) stroke of unknown onset, due to ii) anterior circulation occlusion, with iii) favorable CT perfusion pattern based on the DEFUSE criteria (ischemic core volume< 70ml; mismatch ratio >= 1.8 and mismatch volume >= 15ml), and iv) treated < 4.5 hours after symptom recognition. As a standard of care, the patients fulfilling these inclusion criteria were treated with EVT and IVT or EVT alone when IVT was contraindicated. Outcome measures were any intracerebral bleeding (symptomatic or asymptomatic), mortality and favorable outcome (mRS 0-1) at three months. Results: 32 patients were included (17 treated with EVT alone and 15 with EVT and IVT). Mean age was 69±18 yo. Median NIHSS was 16 (IQR 12-20) and median time from symptom recognition to treatment was 184 (146-226) minutes. Median hypoperfused tissue volume (Tmax > 6s) was 119 ml (80-151) and infarcted core (CBF ratio <30%) 8 ml (0-27). After propensity score weighting, bridging therapy was not associated with an increased risk of intracerebral bleeding (p=0.72) or mortality (p=0.55). The proportion of favorable outcomes at three months was similar between treatment groups (p=0.78). Conclusion: These results suggest that IVT before EVT is a safe therapeutic option in patients with unknown stroke onset selected on perfusion imaging and treated <4.5 hours after symptom recognition. Early administration of IVT may be particularly relevant before interhospital transfer to a comprehensive stroke center for EVT.


Stroke ◽  
2020 ◽  
Vol 51 (8) ◽  
pp. 2540-2543 ◽  
Author(s):  
Simon Escalard ◽  
Benjamin Maïer ◽  
Hocine Redjem ◽  
François Delvoye ◽  
Solène Hébert ◽  
...  

Background and Purpose: Higher rates of strokes have been observed in patients with coronavirus disease 2019 (COVID-19), but data regarding the outcomes of COVID-19 patients suffering from acute ischemic stroke due to large vessel occlusion (LVO) are lacking. We report our initial experience in the treatment of acute ischemic stroke with LVO in patients with COVID-19. Methods: All consecutive patients with COVID-19 with acute ischemic stroke due to LVO treated in our institution during the 6 first weeks of the COVID-19 outbreak were included. Baseline clinical and radiological findings, treatment, and short-term outcomes are reported. Results: We identified 10 patients with confirmed COVID-19 treated for an acute ischemic stroke due to LVO. Eight were men, with a median age of 59.5 years. Seven had none or mild symptoms of COVID-19 at stroke onset. Median time from COVID-19 symptoms to stroke onset was 6 days. All patients had brain imaging within 3 hours from symptoms onset. Five patients had multi-territory LVO. Five received intravenous alteplase. All patients had mechanical thrombectomy. Nine patients achieved successful recanalization (mTICI2B-3), none experienced early neurological improvement, 4 had early cerebral reocclusion, and a total of 6 patients (60%) died in the hospital. Conclusions: Best medical care including early intravenous thrombolysis, and successful and prompt recanalization achieved with mechanical thrombectomy, resulted in poor outcomes in patients with COVID-19. Although our results require further confirmation, a different pharmacological approach (antiplatelet or other) should be investigated to take in account inflammatory and coagulation disorders associated with COVID-19.


2021 ◽  
Vol 14 ◽  
pp. 175628642199901
Author(s):  
Meredeth Zotter ◽  
Eike I. Piechowiak ◽  
Rupashani Balasubramaniam ◽  
Rascha Von Martial ◽  
Kotryna Genceviciute ◽  
...  

Background and aims: To investigate whether stroke aetiology affects outcome in patients with acute ischaemic stroke who undergo endovascular therapy. Methods: We retrospectively analysed patients from the Bernese Stroke Centre Registry (January 2010–September 2018), with acute large vessel occlusion in the anterior circulation due to cardioembolism or large-artery atherosclerosis, treated with endovascular therapy (±intravenous thrombolysis). Results: The study included 850 patients (median age 77.4 years, 49.3% female, 80.1% with cardioembolism). Compared with those with large-artery atherosclerosis, patients with cardioembolism were older, more often female, and more likely to have a history of hypercholesterolaemia, atrial fibrillation, current smoking (each p < 0.0001) and higher median National Institutes of Health Stroke Scale (NIHSS) scores on admission ( p = 0.030). They were more frequently treated with stent retrievers ( p = 0.007), but the median number of stent retriever attempts was lower ( p = 0.016) and fewer had permanent stent placements ( p ⩽ 0.004). Univariable analysis showed that patients with cardioembolism had worse 3-month survival [72.7% versus 84%, odds ratio (OR) = 0.51; p = 0.004] and modified Rankin scale (mRS) score shift ( p = 0.043) and higher rates of post-interventional heart failure (33.5% versus 18.5%, OR = 2.22; p < 0.0001), but better modified thrombolysis in cerebral infarction (mTICI) score shift ( p = 0.025). Excellent (mRS = 0–1) 3-month outcome, successful reperfusion (mTICI = 2b–3), symptomatic intracranial haemorrhage and Updated Charlson Comorbidity Index were similar between groups. Propensity-matched analysis found no statistically significant difference in outcome between stroke aetiology groups. Stroke aetiology was not an independent predictor of favourable mRS score shift, but lower admission NIHSS score, younger age and independence pre-stroke were (each p < 0.0001). Stroke aetiology was not an independent predictor of heart failure, but older age, admission antithrombotics and dependence pre-stroke were (each ⩽0.027). Stroke aetiology was not an independent predictor of favourable mTICI score shift, but application of stent retriever and no permanent intracranial stent placement were (each ⩽0.044). Conclusion: We suggest prospective studies to further elucidate differences in reperfusion and outcome between patients with cardioembolism and large-artery atherosclerosis.


Author(s):  
Sonam Thind ◽  
Ali Mansour ◽  
Scott Mendelson ◽  
Elisheva Coleman ◽  
James Brorson ◽  
...  

Introduction : Acute large vessel occlusion (LVO) can be secondary to thromboembolism or underlying intracranial atherosclerotic disease (ICAD). Data on the management of LVO due to underlying ICAD are scarce. We hypothesized that patients with ICAD would have worse clinical outcomes following mechanical thrombectomy (MT) than those without ICAD. Methods : We performed a retrospective analysis of consecutive patients who underwent MT for LVO in a large academic comprehensive stroke center between 01/2018 and 05/2021. Presence of underlying ICAD at the site of LVO was determined by the treating interventionalist. We compared outcomes including in‐hospital mortality and 90‐day modified Rankin Scale (mRS) between those with and without underlying ICAD, adjusting for relevant covariates using logistic regression. Results : Among 195 patients (mean age 67.4+15.1 years, 56.9% female, 81% black, median NIHSS score 15), underlying ICAD was present in 39 (20.0%). Stent‐retrievers were used 196 patients with only 3 having rescue stent placement. There were no significant differences in baseline factors amongst the two groups except diabetes was more common (69.2% vs. 49.7%, p = 0.028) and intravenous thrombolysis provided less often (17.9% vs. 36.5%, p = 0.027) in those with ICAD. TICI 2B or higher was achieved in 82.1% of ICAD compared with 94.3% of non‐ICAD patients (p = 0.012). Mortality was more common (50.0% vs. 30.8%, p = 0.025) and good functional outcome (mRS 0–2) at 90 days was less common (10.8% vs. 30.0%, p = 0.002) in the ICAD group. Adjusting for age, diabetes, intravenous thrombolysis, baseline NIHSS score, and final TICI score, underlying ICAD was an independent predictor of mRS 0–2 at 90 days (OR 4.5, 95% CI 1.4‐14.2, p = 0.010). Conclusions : Underlying ICAD is associated with 4.5‐fold increase in poor functional outcome in patients with LVO undergoing traditional MT. Further research is needed to understand factors associated with poor outcomes investigate alternative interventional approaches and medical management in this high‐risk population.


Stroke ◽  
2021 ◽  
Author(s):  
Victor Lopez-Rivera ◽  
Sergio Salazar-Marioni ◽  
Rania Abdelkhaleq ◽  
Sean I. Savitz ◽  
Alexandra L. Czap ◽  
...  

Background and Purpose: The optimal endovascular stroke therapy (EVT) care delivery structure is unknown. Here, we present our experience in creating an integrated stroke system (ISS) to expand EVT availability throughout our region while maintaining hospital and physician quality standards. Methods: We identified all consecutive patients with large vessel occlusion acute ischemic stroke treated with EVT from January 2014 to February 2019 in our health care system. In October 2017, we implemented the ISS, in which 3 additional hospitals (4 total) became EVT-performing hospitals (EPHs) and physicians were rotated between all centers. The cohort was divided by time into pre-ISS and post-ISS, and the primary outcome was time from stroke onset to EPH arrival. Secondary outcomes included hospital and procedural quality metrics. We performed an external validation using data from the Southeast Texas Regional Advisory Council. Results: Among 513 patients with large vessel occlusion acute ischemic stroke treated with EVT, 58% were treated pre-ISS and 43% post-ISS. Over the study period, EVT procedural volume increased overall but remained relatively low at the 3 new EPHs (<70 EVT/y). After ISS, the proportion of patients who underwent interhospital transfer decreased (46% versus 37%; P <0.05). In adjusted quantile regression, ISS implementation resulted in a reduction of time from stroke onset to EPH arrival by 40 minutes ( P <0.01) and onset to groin puncture by 29 minutes ( P <0.05). Rates of postprocedural hemorrhage, modified Thrombolysis in Cerebral Infarction (TICI) 2b/3, and 90-day modified Rankin Scale were comparable at the higher and lower volume EPHs. The improvement in onset-to-arrival time was not reflective of overall improvement in secular trends in regional prehospital care. Conclusions: In our system, increasing EVT availability decreased time from stroke onset to EPH arrival. The ISS provides a framework to maintain quality in lower volume hospitals.


Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Shashvat Desai ◽  
Santiago Ortega ◽  
Sunil Sheth ◽  
Mudassir Farooqui ◽  
Victor Lopez Rivera ◽  
...  

Introduction: Patient selection for thrombectomy of acute ischemic stroke (AIS) caused by large vessel occlusion (LVO) in the delayed time window (>6 hours) is dependent on delineation of clinical-core mismatch or radiological target mismatch using perfusion imaging. Selection paradigms not involving advanced imaging and software processing may reduce time to treatment and broaden eligibility. We aim to develop a conversion factor to approximately determine the volume of hypoperfused tissue using the NIHSS score [CAT volume (clinically approximated tissue)] and explore its ability to identify patients eligible for thrombectomy in the late time window. Methods: We performed a retrospective analysis of anterior circulation LVO strokes at three comprehensive stroke centers. Demographic, clinical (NIHSS score, TLKW-time last known well) and imaging [computed tomography with perfusion (CTP) processed using RAPID, IschemaView] information was analyzed. A conversion factor, which is a multiple of the NIHSS score (one multiple for NIHSS score <10 and another for NIHSS score ≥10), was derived to calculate CAT volumes. Accuracy (sensitivity and specificity) of CAT-based thrombectomy eligibility criteria (similar to DEFUSE-3 criteria but using CAT volume instead of Tmax >6 seconds volume) was tested using DEFUSE-3 criteria eligibility as a gold standard. Result: Of the 309 LVO strokes [mean age of 70 ±14, 46% male, median NIHSS 16 (12-20)] included in this study, 38% of patients arrived beyond 6 hours of TLKW. Conversion factors derived (derivation cohort-center A:187) based on median (50 th percentile) values of Tmax >6s volume for NIHSS <10 subgroup was 15 and for NIHSS ≥10 subgroup was 6. Subsequently calculated CAT volume-based eligibility criteria yielded a sensitivity of 100% and specificity of 92% in detecting DEFUSE-3 eligible patients (AUC-0.92 CI-0.82-1) in the validation cohort (center B and C:122). Conclusions: Clinical severity of stroke (NIHSS score) may be used to calculate the volume of hypoperfused tissue during LVO stroke. Clinically approximated hypoperfused tissue (CAT) volumes for NIHSS score <10 (using a factor of 15) and ≥10 (using a factor of 6) subgroups can accurately identify DEFUSE-3 eligible patients.


Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Pierre Seners ◽  
Claire Perrin ◽  
Guillaume Turc

Introduction: Whether thrombectomy added on intravenous thrombolysis (IVT), as compared to IVT alone, is beneficial in minor strokes with large vessel occlusion (LVO) is unknown. To identify predictors of early neurological deterioration (END) following IVT alone may help to select the best candidates for additional thrombectomy. Methods: MINOR-STROKE was a multicentric retrospective registry collecting data of IVT-treated minor strokes (NIHSS≤5) with LVO (internal carotid artery [ICA], M1, M2 or basilar artery; with central reading) treated with or without additional thrombectomy in 45 French stroke units. The patients initially intended for IVT alone, including those who eventually received thrombectomy due to END, were included in the present analysis. END was defined as a ≥4 points on NIHSS within 24hrs following admission. Thrombus length was measured centrally either on T2*-MRI, CT (hyperdense middle cerebral artery) or CT-angiography. Results: Overall, 799 patients were included: mean age 69 years, median NIHSS 3, occlusion located in ICA±M1/M2, proximal M1, distal M1, M2, or basilar artery in 20%, 7%, 19%, 50% and 4% of patients, respectively. Thrombus was visible in 78% of patients (median length 9mm, IQR 6-12mm). END occurred in 15% of patients and was associated with poor 3-month functional outcome (mRS>2: 55% vs. 12% of patients with and without END, respectively). Only 15% of ENDs were due to intracranial haemorrhage. In multivariable analysis, a more proximal occlusion site (M2 [reference], distal M1: OR 2.1 [IC95% 1.1-4.1], proximal M1: OR 3.8 [1.6-9.1], ICA±M1/M2: OR 5.0 [2.6-9.6], basilar artery: OR 4.9 [1.1-4.1]; P <0.001) and a longer thrombus (<6mm [reference], [6-9mm[: OR 1.3 [IC95% 0.6-2.9], [9-12mm[: OR 1.8 [0.8-3.9] and ≥12mm: OR 2.7 [1.3-5.6]; P =0.036) were independently associated with END. END occurred in 33%, 19%, 14%, 7% and 27% of patients with ICA±M1/M2, M1 proximal, M1 distal, M2 and basilar artery, respectively, and in 8%, 10%, 14% et 23% of patients with thrombus length of <6, [6-9[, [9-12[ and ≥12mm, respectively. Conclusion: Our study suggests that thrombus location and length are strong predictors of END in minor strokes with LVO. This may help to select the best candidates for additional endovascular therapy.


Stroke ◽  
2021 ◽  
Author(s):  
Georgios Tsivgoulis ◽  
Aristeidis H. Katsanos ◽  
Jürgen Eggers ◽  
Vincent Larrue ◽  
Lars Thomassen ◽  
...  

Background and Purpose: Evidence about the utility of ultrasound-enhanced thrombolysis (sonothrombolysis) in patients with acute ischemic stroke (AIS) is conflicting. We aimed to evaluate the safety and efficacy of sonothrombolysis in patients with AIS with large vessel occlusion, by analyzing individual patient data of available randomized-controlled clinical trials. Methods: We included all available randomized-controlled clinical trials comparing sonothrombolysis with or without addition of microspheres (treatment group) to intravenous thrombolysis alone (control group) in patients with AIS with large vessel occlusion. The primary outcome measure was the rate of complete recanalization at 1 to 36 hours following intravenous thrombolysis initiation. We present crude odds ratios (ORs) and ORs adjusted for the predefined variables of age, sex, baseline stroke severity, systolic blood pressure, and onset-to-treatment time. Results: We included 7 randomized controlled clinical trials that enrolled 1102 patients with AIS. A total of 138 and 134 confirmed large vessel occlusion patients were randomized to treatment and control groups respectively. Patients randomized to sonothrombolysis had increased odds of complete recanalization compared with patients receiving intravenous thrombolysis alone (40.3% versus 22.4%; OR, 2.17 [95% CI, 1.03–4.54]; adjusted OR, 2.33 [95% CI, 1.02–5.34]). The likelihood of symptomatic intracranial hemorrhage was not significantly different between the 2 groups (7.3% versus 3.7%; OR, 2.03 [95% CI, 0.68–6.11]; adjusted OR, 2.55 [95% CI, 0.76–8.52]). No differences in the likelihood of asymptomatic intracranial hemorrhage, 3-month favorable functional and 3-month functional independence were documented. Conclusions: Sonothrombolysis was associated with a nearly 2-fold increase in the odds of complete recanalization compared with intravenous thrombolysis alone in patients with AIS with large vessel occlusions. Further study of the safety and efficacy of sonothrombolysis is warranted.


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