RESUMO
BACKGROUND: Tenecteplase is an effective thrombolytic agent for eligible patients with stroke who are treated within 4.5 hours after the onset of stroke. However, data regarding the effectiveness of tenecteplase beyond 4.5 hours are limited. METHODS: In a trial conducted in China, we randomly assigned patients with large-vessel occlusion of the middle cerebral artery or internal carotid artery who had salvageable brain tissue as identified on perfusion imaging and who did not have access to endovascular thrombectomy to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or standard medical treatment 4.5 to 24 hours after the time that the patient was last known to be well (including after stroke on awakening and unwitnessed stroke). The primary outcome was the absence of disability, which was defined as a score of 0 or 1 on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability), at day 90. The key safety outcomes were symptomatic intracranial hemorrhage and death. RESULTS: A total of 516 patients were enrolled; 264 were randomly assigned to receive tenecteplase and 252 to receive standard medical treatment. Less than 2% of the patients (4 in the tenecteplase group and 5 in the standard-treatment group) underwent rescue endovascular thrombectomy. Treatment with tenecteplase resulted in a higher percentage of patients with a modified Rankin scale score of 0 or 1 at 90 days than standard medical treatment (33.0% vs. 24.2%; relative rate, 1.37; 95% confidence interval, 1.04 to 1.81; P = 0.03). Mortality at 90 days was 13.3% with tenecteplase and 13.1% with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage within 36 hours after treatment was 3.0% and 0.8%, respectively. CONCLUSIONS: In this trial involving Chinese patients with ischemic stroke due to large-vessel occlusion, most of whom did not undergo endovascular thrombectomy, treatment with tenecteplase administered 4.5 to 24 hours after stroke onset resulted in less disability and similar survival as compared with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage appeared to be higher. (Funded by the National Natural Science Foundation of China and others; TRACE-III ClinicalTrials.gov number, NCT05141305.).
Assuntos
Fibrinolíticos , AVC Isquêmico , Tenecteplase , Ativador de Plasminogênio Tecidual , Humanos , Tenecteplase/uso terapêutico , Tenecteplase/efeitos adversos , Fibrinolíticos/uso terapêutico , Fibrinolíticos/efeitos adversos , Fibrinolíticos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Ativador de Plasminogênio Tecidual/uso terapêutico , Ativador de Plasminogênio Tecidual/efeitos adversos , Feminino , Idoso , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/cirurgia , Trombectomia , Tempo para o Tratamento , Hemorragias Intracranianas/etiologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/cirurgiaRESUMO
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).
Assuntos
Isquemia Encefálica , AVC Isquêmico , Imagem de Perfusão , Tenecteplase , Trombectomia , Ativador de Plasminogênio Tecidual , Humanos , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/mortalidade , Isquemia Encefálica/cirurgia , Fibrinolíticos/administração & dosagem , Fibrinolíticos/efeitos adversos , Fibrinolíticos/uso terapêutico , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/diagnóstico por imagem , Perfusão , Imagem de Perfusão/métodos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/cirurgia , Tenecteplase/administração & dosagem , Tenecteplase/efeitos adversos , Tenecteplase/uso terapêutico , Trombectomia/efeitos adversos , Trombectomia/métodos , Ativador de Plasminogênio Tecidual/administração & dosagem , Ativador de Plasminogênio Tecidual/efeitos adversos , Ativador de Plasminogênio Tecidual/uso terapêutico , Resultado do Tratamento , Método Duplo-Cego , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/mortalidade , AVC Isquêmico/cirurgia , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/cirurgia , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/tratamento farmacológico , Doenças das Artérias Carótidas/cirurgia , Encéfalo/irrigação sanguínea , Encéfalo/diagnóstico por imagem , Tempo para o TratamentoRESUMO
BACKGROUND: Individuals with minor ischaemic stroke and intracranial occlusion are at increased risk of poor outcomes. Intravenous thrombolysis with tenecteplase might improve outcomes in this population. We aimed to test the superiority of intravenous tenecteplase over non-thrombolytic standard of care in patients with minor ischaemic stroke and intracranial occlusion or focal perfusion abnormality. METHODS: In this multicentre, prospective, parallel group, open label with blinded outcome assessment, randomised controlled trial, adult patients (aged ≥18 years) were included at 48 hospitals in Australia, Austria, Brazil, Canada, Finland, Ireland, New Zealand, Singapore, Spain, and the UK. Eligible patients with minor acute ischaemic stroke (National Institutes of Health Stroke Scale score 0-5) and intracranial occlusion or focal perfusion abnormality were enrolled within 12 h from stroke onset. Participants were randomly assigned (1:1), using a minimal sufficient balance algorithm to intravenous tenecteplase (0·25 mg/kg) or non-thrombolytic standard of care (control). Primary outcome was a return to baseline functioning on pre-morbid modified Rankin Scale score in the intention-to-treat (ITT) population (all patients randomly assigned to a treatment group and who did not withdraw consent to participate) assessed at 90 days. Safety outcomes were reported in the ITT population and included symptomatic intracranial haemorrhage and death. This trial is registered with ClinicalTrials.gov, NCT02398656, and is closed to accrual. FINDINGS: The trial was stopped early for futility. Between April 27, 2015, and Jan 19, 2024, 886 patients were enrolled; 369 (42%) were female and 517 (58%) were male. 454 (51%) were assigned to control and 432 (49%) to intravenous tenecteplase. The primary outcome occurred in 338 (75%) of 452 patients in the control group and 309 (72%) of 432 in the tenecteplase group (risk ratio [RR] 0·96, 95% CI 0·88-1·04, p=0·29). More patients died in the tenecteplase group (20 deaths [5%]) than in the control group (five deaths [1%]; adjusted hazard ratio 3·8; 95% CI 1·4-10·2, p=0·0085). There were eight (2%) symptomatic intracranial haemorrhages in the tenecteplase group versus two (<1%) in the control group (RR 4·2; 95% CI 0·9-19·7, p=0·059). INTERPRETATION: There was no benefit and possible harm from treatment with intravenous tenecteplase. Patients with minor stroke and intracranial occlusion should not be routinely treated with intravenous thrombolysis. FUNDING: Heart and Stroke Foundation of Canada, Canadian Institutes of Health Research, and the British Heart Foundation.
Assuntos
Fibrinolíticos , AVC Isquêmico , Tenecteplase , Humanos , Tenecteplase/uso terapêutico , Tenecteplase/administração & dosagem , Masculino , Feminino , AVC Isquêmico/tratamento farmacológico , Fibrinolíticos/uso terapêutico , Fibrinolíticos/administração & dosagem , Idoso , Pessoa de Meia-Idade , Resultado do Tratamento , Estudos Prospectivos , Padrão de Cuidado , Ativador de Plasminogênio Tecidual/uso terapêutico , Ativador de Plasminogênio Tecidual/administração & dosagem , Terapia Trombolítica/métodosRESUMO
BACKGROUND: ST-segment-elevation myocardial infarction (STEMI) guidelines recommend pharmaco-invasive treatment if timely primary percutaneous coronary intervention (PCI) is unavailable. Full-dose tenecteplase is associated with an increased risk of intracranial hemorrhage in older patients. Whether pharmaco-invasive treatment with half-dose tenecteplase is effective and safe in older patients with STEMI is unknown. METHODS: STREAM-2 (Strategic Reperfusion in Elderly Patients Early After Myocardial Infarction) was an investigator-initiated, open-label, randomized, multicenter study. Patients ≥60 years of age with ≥2 mm ST-segment elevation in 2 contiguous leads, unable to undergo primary PCI within 1 hour, were randomly assigned (2:1) to half-dose tenecteplase followed by coronary angiography and PCI (if indicated) 6 to 24 hours after randomization, or to primary PCI. Efficacy end points of primary interest were ST resolution and the 30-day composite of death, shock, heart failure, or reinfarction. Safety assessments included stroke and nonintracranial bleeding. RESULTS: Patients were assigned to pharmaco-invasive treatment (n=401) or primary PCI (n=203). Median times from randomization to tenecteplase or sheath insertion were 10 and 81 minutes, respectively. After last angiography, 85.2% of patients undergoing pharmaco-invasive treatment and 78.4% of patients undergoing primary PCI had ≥50% resolution of ST-segment elevation; their residual median sums of ST deviations were 4.5 versus 5.5 mm, respectively. Thrombolysis In Myocardial Infarction flow grade 3 at last angiography was ≈87% in both groups. The composite clinical end point occurred in 12.8% (51/400) of patients undergoing pharmaco-invasive treatment and 13.3% (27/203) of patients undergoing primary PCI (relative risk, 0.96 [95% CI, 0.62-1.48]). Six intracranial hemorrhages occurred in the pharmaco-invasive arm (1.5%): 3 were protocol violations (excess anticoagulation in 2 and uncontrolled hypertension in 1). No intracranial bleeding occurred in the primary PCI arm. The incidence of major nonintracranial bleeding was low in both groups (<1.5%). CONCLUSIONS: Halving the dose of tenecteplase in a pharmaco-invasive strategy in this early-presenting, older STEMI population was associated with electrocardiographic changes that were at least comparable to those after primary PCI. Similar clinical efficacy and angiographic end points occurred in both treatment groups. The risk of intracranial hemorrhage was higher with half-dose tenecteplase than with primary PCI. If timely PCI is unavailable, this pharmaco-invasive strategy is a reasonable alternative, provided that contraindications to fibrinolysis are observed and excess anticoagulation is avoided. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02777580.
Assuntos
Infarto do Miocárdio , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Idoso , Tenecteplase/uso terapêutico , Fibrinolíticos/efeitos adversos , Ativador de Plasminogênio Tecidual/efeitos adversos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Intervenção Coronária Percutânea/efeitos adversos , Infarto do Miocárdio/tratamento farmacológico , Hemorragias Intracranianas/induzido quimicamente , Hemorragia/induzido quimicamente , Resultado do Tratamento , Anticoagulantes/uso terapêutico , Terapia Trombolítica/efeitos adversosRESUMO
BACKGROUND: Understanding sex differences in stroke care is important in reducing potential disparities. Our objective was to explore sex differences in workflow efficiency, treatment efficacy, and safety in the AcT trial (Alteplase Compared to Tenecteplase). METHODS: AcT was a multicenter, registry-linked randomized noninferiority trial comparing tenecteplase (0.25 mg/kg) with alteplase (0.9 mg/kg) in acute ischemic stroke within 4.5 hours of onset. In this post hoc analysis, baseline characteristics, workflow times, successful reperfusion (extended Thrombolysis in Cerebral Infarction score ≥2b), symptomatic intracerebral hemorrhage, 90-day functional independence (modified Rankin Scale score, 0-1), and 90-day mortality were compared by sex. Mixed-effects regression analysis was used adjusting for age, stroke severity, and occlusion site for outcomes. RESULTS: Of 1577 patients treated with intravenous thrombolysis (2019-2022), 755 (47.9%) were women. Women were older (median, 77 [68-86] years in women versus 70 [59-79] years in men) and had a higher proportion of severe strokes (National Institutes of Health Stroke Scale score >15; 32.4% versus 24.9%) and large vessel occlusions (28.7% versus 21.5%) compared with men. All workflow times were comparable between sexes. Women were less likely to achieve functional independence (31.7% versus 39.8%; unadjusted relative risk, 0.80 [95% CI, 0.70-0.91]) and had higher mortality (17.7% versus 13.3%; unadjusted relative risk, 1.33 [95% CI, 1.06-1.69]). Adjusted analysis showed no difference in outcomes between sexes. CONCLUSIONS: Differences in prognostic factors of age, stroke severity, and occlusion site largely accounted for higher functional dependence and mortality in women. No sex disparities were apparent in workflow quality indicators. Given the integration of the AcT trial into clinical practice, these results provide reassurance that no major sex biases are apparent in acute stroke management throughout participating Canadian centers. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.
Assuntos
AVC Isquêmico , Tenecteplase , Ativador de Plasminogênio Tecidual , Feminino , Humanos , Masculino , Canadá , AVC Isquêmico/tratamento farmacológico , Tenecteplase/efeitos adversos , Ativador de Plasminogênio Tecidual/efeitos adversos , Resultado do Tratamento , Fluxo de Trabalho , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos de Equivalência como AsuntoRESUMO
BACKGROUND: AST-004, a small molecule agonist of the adenosine A1 and A3 receptors, is a potential cerebroprotectant for patients with acute stroke and is currently in clinical trials. Drug-drug interactions are critically important to assess in the context of acute stroke care. Lytic therapy with tPA (tissue-type plasminogen activator)-induced plasmin formation (alteplase) is the only available pharmacotherapy for acute stroke. Consequently, it is imperative to evaluate potential interactions between AST-004 and tPAs such as alteplase and tenecteplase. METHODS: The interactions between AST-004 and tPAs were evaluated in 3 ways in preparation for AST-004 phase II trials. First, the metabolic stability of AST-004 was determined in the presence of alteplase and plasmin. Second, the potential for AST-004 to influence the thrombolytic efficacy of alteplase and tenecteplase was evaluated with an in vitro assay system utilizing a fluorogenic substrate of plasmin. Finally, the potential for AST-004 to influence the thrombolytic efficacy of alteplase was also determined with an in vitro thrombolysis assay of human blood thrombi. RESULTS: Neither alteplase nor plasmin affected the stability of AST-004 in vitro. In 2 different in vitro systems, AST-004 had no effect on the ability of alteplase or tenecteplase to generate plasmin, and AST-004 had no effect on the thrombolytic efficacy of alteplase to lyse blood clots in human blood. CONCLUSIONS: These studies indicate that there will be no interactions between AST-004 and tPAs such as alteplase or tenecteplase in patients with stroke undergoing thrombolytic therapy.
Assuntos
Interações Medicamentosas , Fibrinolíticos , Tenecteplase , Ativador de Plasminogênio Tecidual , Ativador de Plasminogênio Tecidual/uso terapêutico , Humanos , Tenecteplase/uso terapêutico , Fibrinolíticos/uso terapêutico , Fibrinolíticos/farmacologia , Agonistas do Receptor A1 de Adenosina/farmacologia , Agonistas do Receptor A1 de Adenosina/uso terapêutico , Receptor A3 de Adenosina/metabolismo , Fibrinolisina , Acidente Vascular Cerebral/tratamento farmacológico , Receptor A1 de Adenosina/metabolismoRESUMO
BACKGROUND: Recent evidence from thrombolysis trials indicates the noninferiority of intravenous tenecteplase to intravenous alteplase with respect to good functional outcomes in patients with acute stroke. We examined whether the health-related quality of life (HRQOL) of patients with acute stroke differs by the type of thrombolysis treatment received. In addition, we examined the association between the modified Rankin Scale score 0 to 1 and HRQOL and patient-reported return to prebaseline stroke functioning at 90 days. METHODS: Data were from all patients included in the AcT trial (Alteplase Compared to Tenecteplase), a pragmatic, registry-linked randomized trial comparing tenecteplase with alteplase. HRQOL at 90-day post-randomization was assessed using the 5-item EuroQOL questionnaire (EQ5D), which consists of 5 items and a visual analog scale (VAS). EQ5D index values were estimated from the EQ5D items using the time tradeoff approach based on Canadian norms. Tobit regression and quantile regression models were used to evaluate the adjusted effect of tenecteplase versus alteplase treatment on the EQ5D index values and VAS score, respectively. The association between return to prebaseline stroke functioning and the modified Rankin Scale score 0 to 1 and HRQOL was quantified using correlation coefficient (r) with 95% CI. RESULTS: Of 1577 included in the intention-to-treat analysis patients, 1503 (95.3%) had complete data on the EQ5D. Of this, 769 (51.2%) were administered tenecteplase and 717 (47.7%) were female. The mean EQ5D VAS score and EQ5D index values were not significantly higher for those who received intravenous tenecteplase compared with those who received intravenous alteplase (P=0.10). Older age (P<0.01), more severe stroke assessed using the National Institutes of Health Stroke Scale (P<0.01), and longer stroke onset-to-needle time (P=0.004) were associated with lower EQ5D index and VAS scores. There was a strong association (r, 0.85 [95% CI, 0.81-0.89]) between patient-reported return to prebaseline functioning and modified Rankin Scale score 0 to 1 Similarly, there was a moderate association between return to prebaseline functioning and EQ5D index (r, 0.45 [95% CI, 0.40-0.49]) and EQ5D VAS scores (r, 0.42 [95% CI, 0.37-0.46]). CONCLUSIONS: Although there is no differential effect of thrombolysis type on patient-reported global HRQOL and EQ 5D-5L index values in patients with acute stroke, sex- and age-related differences in HRQOL were noted in this study. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.
Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Feminino , Masculino , Ativador de Plasminogênio Tecidual , Tenecteplase/efeitos adversos , Fibrinolíticos , AVC Isquêmico/tratamento farmacológico , Qualidade de Vida , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/induzido quimicamente , Canadá , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/induzido quimicamente , Terapia Trombolítica , Resultado do TratamentoRESUMO
BACKGROUND: There is increasing interest in replacing alteplase with tenecteplase as the preferred thrombolytic treatment for patients with acute ischaemic stroke. We aimed to establish the non-inferiority of tenecteplase to alteplase for these patients. METHODS: In this multicentre, prospective, open-label, blinded-endpoint, randomised controlled, non-inferiority trial, adults with an acute ischaemic stroke who were eligible for standard intravenous thrombolysis but ineligible for endovascular thrombectomy were enrolled from 53 centres in China and randomly assigned (1:1) to receive intravenous tenecteplase (0·25 mg/kg, maximum dose of 25 mg) or intravenous alteplase (0·9 mg/kg, maximum dose of 90 mg). Participants had to be able to receive treatment within 4·5 h of stroke, have a modified Rankin Scale (mRS) score of no more than 1 before enrolment, and have a National Institutes of Health Stroke Scale score of 5-25. Patients and treating clinicians were not masked to group assignment; clinicians evaluating outcomes were masked to treatment type. The primary efficacy outcome was the proportion of participants who had a mRS score of 0-1 at 90 days, assessed in the modified intention-to-treat population (all randomly assigned participants who received the allocated thrombolytic), with a non-inferiority margin of 0·937 for the risk ratio (RR). The primary safety outcome was symptomatic intracranial haemorrhage within 36 h, assessed in all participants who received study drug and had a safety assessment available. The trial is registered with ClinicalTrials.gov, NCT04797013, and has been completed. FINDINGS: Between June 12, 2021, and May 29, 2022, 1430 participants were enrolled and randomly assigned to tenecteplase (n=716) or alteplase (n=714). Six patients assigned to tenecteplase and seven to alteplase did not receive study product, and five participants in the tenecteplase group and 11 in the alteplase group were lost to follow-up at 90 days. The primary outcome in the modified intention-to-treat population occurred in 439 (62%) of 705 in the tenecteplase group versus 405 (58%) of 696 in the alteplase group (RR 1·07, 95% CI 0·98-1·16). The lower limit of the RR's 95% CI was greater than the non-inferiority margin. Symptomatic intracranial haemorrhage within 36 h was observed in 15 (2%) of 711 in the tenecteplase group and 13 (2%) of 706 in the alteplase group (RR 1·18, 95% CI 0·56-2·50). Mortality within 90 days occurred in 46 (7%) individuals in the tenecteplase group versus 35 (5%) in the alteplase group (RR 1·31, 95% CI 0·86-2·01). INTERPRETATION: Tenecteplase was non-inferior to alteplase in people with ischaemic stroke who were eligible for standard intravenous thrombolytic but ineligible for or refused endovascular thrombectomy. FUNDING: National Science and Technology Major Project, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Natural Science Foundation of China, and China Shijiazhuang Pharmaceutical Company Recomgen Pharmaceutical (Guangzhou).
Assuntos
Isquemia Encefálica , AVC Isquêmico , Tenecteplase , Ativador de Plasminogênio Tecidual , Adulto , Humanos , Isquemia Encefálica/tratamento farmacológico , Fibrinolíticos/uso terapêutico , Hemorragias Intracranianas , AVC Isquêmico/tratamento farmacológico , Estudos Prospectivos , Tenecteplase/uso terapêutico , Ativador de Plasminogênio Tecidual/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVE: Tenecteplase improves reperfusion compared to alteplase in patients with large vessel occlusions. To determine whether this improvement varies across the spectrum of thrombolytic agent to reperfusion assessment times, we performed a comparative analysis of tenecteplase and alteplase reperfusion rates. METHODS: Patients with large vessel occlusion and treatment with thrombolysis were pooled from the Melbourne Stroke Registry, and the EXTEND-IA and EXTEND-IA TNK trials. The primary outcome, thrombolytic-induced reperfusion, was defined as the absence of retrievable thrombus or >50% reperfusion at imaging reassessment. We compared the treatment effect of tenecteplase and alteplase, accounting for thrombolytic to assessment exposure times, via Poisson modeling. We compared 90-day outcomes of patients who achieved reperfusion with a thrombolytic to patients who achieved reperfusion via endovascular therapy using ordinal logistic regression. RESULTS: Among 893 patients included in the primary analysis, thrombolytic-induced reperfusion was observed in 184 (21%) patients. Tenecteplase was associated with higher rates of reperfusion (adjusted incidence rate ratio [aIRR] = 1.50, 95% confidence interval [CI] = 1.09-2.07, p = 0.01). Findings were consistent in patient subgroups with first segment (aIRR = 1.41, 95% CI = 0.93-2.14) and second segment (aIRR = 2.07, 95% CI = 0.98-4.37) middle cerebral artery occlusions. Increased thrombolytic to reperfusion assessment times were associated with reperfusion (tenecteplase: adjusted risk ratio [aRR] = 1.08 per 15 minutes, 95% CI = 1.04-1.13 vs alteplase: aRR = 1.06 per 15 minutes, 95% CI = 1.00-1.13). No significant treatment-by-time interaction was observed (p = 0.87). Reperfusion via thrombolysis was associated with improved 90-day modified Rankin Scale scores (adjusted common odds ratio = 2.15, 95% CI = 1.54-3.01) compared to patients who achieved reperfusion following endovascular therapy. INTERPRETATION: Tenecteplase, compared to alteplase, increases prethrombectomy reperfusion, regardless of the time from administration to reperfusion assessment. Prethrombectomy reperfusion is associated with better clinical outcomes. ANN NEUROL 2023;93:489-499.
Assuntos
Isquemia Encefálica , Acidente Vascular Cerebral , Humanos , Tenecteplase/uso terapêutico , Ativador de Plasminogênio Tecidual , Isquemia Encefálica/tratamento farmacológico , Acidente Vascular Cerebral/tratamento farmacológico , Fibrinolíticos/uso terapêutico , Reperfusão/métodos , Resultado do TratamentoRESUMO
The treatment of acute ischemic stroke continues to advance. The mainstay of treatment remains intravenous thrombolysis with alteplase. Recent studies demonstrated that later treatment with alteplase is beneficial in patients selected with advanced imaging techniques. Tenecteplase has been evaluated as an alternative thrombolytic drug and evidence suggests that it is as least as effective as alteplase and may lyse large vessel clots more effectively. Endovascular therapy with mechanical thrombectomy has now been shown to be beneficial up to 24 hours after stroke onset in carefully selected patients with proximal, large vessel occlusions. Ongoing studies are evaluating the effectiveness of thrombectomy in patients with more distal vessel occlusions and patients with proximal large vessel occlusions with larger ischemic core volumes and also in patients with milder neurological deficits. Cytoprotection is another potential acute stroke therapy that has not demonstrated efficacy in prior clinical trials. It should be reconsidered as an adjunct to reperfusion and a variety of new clinical trials can be envisioned to evaluate the potential benefits of cytoprotection in patients before and after reperfusion.
Assuntos
Isquemia Encefálica , Procedimentos Endovasculares , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/tratamento farmacológico , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/métodos , Fibrinolíticos/efeitos adversos , Humanos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológico , Tenecteplase/uso terapêutico , Trombectomia/efeitos adversos , Trombectomia/métodos , Terapia Trombolítica/efeitos adversos , Terapia Trombolítica/métodos , Ativador de Plasminogênio Tecidual , Resultado do TratamentoRESUMO
The treatment of acute ischemic stroke has improved in last few decades. While meta-analyses of several trials have established the safety and efficacy of Intravenous (IV) Tenecteplase thrombolysis, concomitant continuous transcranial doppler (TCD) ultrasound administration has not been assessed in any clinical trial. The aim of this study was to determine the effects of continuous 2 MHz TCD ultrasound during IV Tenecteplase thrombolysis for Middle cerebral artery (MCA) stroke. A total of 19 patients were included, 13 received TCD ultrasound and 6 sham TCD with IV Tenecteplase. TCD spectrum and difference in Pre and post TCD parameters were measured. Asymptomatic hemorrhagic transformation of infarct was seen in two patients. There was no mortality or clinical worsening in the sonothrombolysis group as against sham sonothrombolysis group. Median of peak systolic velocity was increased in both the sonothrombolysis (P = 0.0002) and sham sonothrombolysis group (P-value = 0.001). The difference in change in mean flow velocity between two groups, sonothrombolysis (11 cm/sec) and sham sonothrombolysis (3.5 cm/sec) were also significantly different (P = 0.014). This pilot work has established safety of continuous 30 min TCD application along with IV Tenecteplase thrombolysis and it concludes that concomitant 2 MHz TCD ultrasound administration significantly increased the MCA blood flow compared to chemothrombolysis alone.CTRI Registered Number: CTRI/2021/02/031418.
Assuntos
Fibrinolíticos , AVC Isquêmico , Tenecteplase , Terapia Trombolítica , Ativador de Plasminogênio Tecidual , Ultrassonografia Doppler Transcraniana , Humanos , Tenecteplase/administração & dosagem , Tenecteplase/uso terapêutico , Ultrassonografia Doppler Transcraniana/métodos , Masculino , Pessoa de Meia-Idade , Feminino , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/terapia , AVC Isquêmico/diagnóstico por imagem , Terapia Trombolítica/métodos , Fibrinolíticos/uso terapêutico , Fibrinolíticos/administração & dosagem , Idoso , Ativador de Plasminogênio Tecidual/administração & dosagem , Ativador de Plasminogênio Tecidual/uso terapêutico , Infarto da Artéria Cerebral Média/terapia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Resultado do Tratamento , Terapia CombinadaRESUMO
BACKGROUND: Tenecteplase (TNK) is gaining recognition as a novel therapy for acute ischemic stroke (AIS). Despite TNK offering a longer half-life, time and cost saving benefits and comparable treatment and safety profiles to Alteplase (ALT), the adoption of TNK as a treatment for AIS presents challenges for hospital systems. OBJECTIVE: Identify barriers and facilitators of TNK implementation at acute care hospitals in Texas. METHODS: This prospective survey used open-ended questions and Likert statements generated from content experts and informed by qualitative research. Stroke clinicians and nurses working at 40 different hospitals in Texas were surveyed using a virtual platform. RESULTS: The 40 hospitals had a median of 34 (IQR 24.5-49) emergency department beds and 42.5 (IQR 23.5-64.5) inpatient stroke beds with 506.5 (IQR 350-797.5) annual stroke admissions. Fifty percent of the hospitals were Comprehensive Stroke Centers, and 18 (45 %) were solely using ALT for treatment of eligible AIS patients. Primary facilitators to TNK transition were team buy-in and a willingness of stroke physicians, nurses, and pharmacists to adopt TNK. Leading barriers were lack of clinical evidence supporting TNK safety profile inadequate evidence supporting TNK use and a lack of American Heart Association guidelines support for TNK administration in all AIS cases. CONCLUSION: Understanding common barriers and facilitators to TNK adoption can assist acute care hospitals deciding to implement TNK as a treatment for AIS. These findings will be used to design a TNK adoption Toolkit, utilizing implementation science techniques, to address identified obstacles and to leverage facilitators.
Assuntos
AVC Isquêmico , Tenecteplase , Humanos , Fibrinolíticos/uso terapêutico , AVC Isquêmico/tratamento farmacológico , Estudos Prospectivos , Tenecteplase/uso terapêutico , Ativador de Plasminogênio Tecidual/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Tenecteplase (TNK) is considered a promising option for the treatment of acute ischemic stroke (AIS) with the potential to decrease door-to-needle times (DTN). This study investigates DTN metrics and trends after transition to tenecteplase. METHODS: The Lone Star Stroke (LSS) Research Consortium TNK registry incorporated data from three Texas hospitals that transitioned to TNK. Subject data mapped to Get-With-the-Guidelines stroke variables from October 1, 2019 to March 31, 2023 were limited to patients who received either alteplase (ALT) or TNK within the 90 min DTN times. The dataset was stratified into ALT and TNK cohorts with univariate tables for each measured variable and further analyzed using descriptive statistics. Logistic regression models were constructed for both ALT and TNK to investigate trends in DTN times. RESULTS: In the overall cohort, the TNK cohort (n = 151) and ALT cohort (n = 161) exhibited comparable population demographics, differing only in a higher prevalence of White individuals in the TNK cohort. Both cohorts demonstrated similar clinical parameters, including mean NIHSS, blood glucose levels, and systolic blood pressure at admission. In the univariate analysis, no difference was observed in median DTN time within the 90 min time window compared to the ALT cohort [40 min (30-53) vs 45 min (35-55); P = .057]. In multivariable models, DTN times by thrombolytic did not significantly differ when adjusting for NIHSS, age (P = .133), or race and ethnicity (P = .092). Regression models for the overall cohort indicate no significant DTN temporal trends for TNK (P = .84) after transition; nonetheless, when stratified by hospital, a single subgroup demonstrated a significant DTN upward trend (P = 0.002). CONCLUSION: In the overall cohort, TNK and ALT exhibited comparable temporal trends and at least stable DTN times. This indicates that the shift to TNK did not have an adverse impact on the DTN stroke metrics. This seamless transition is likely attributed to the similarity of inclusion and exclusion criteria, as well as the administration processes for both medications. When stratified by hospital, the three subgroups demonstrated variable DTN time trends which highlight the potential for either fatigue or unpreparedness when switching to TNK. Because our study included a multi-ethnic cohort from multiple large Texas cities, the stable DTN times after transition to TNK is likely applicable to other healthcare systems.
Assuntos
Fibrinolíticos , AVC Isquêmico , Sistema de Registros , Tenecteplase , Terapia Trombolítica , Tempo para o Tratamento , Humanos , Texas/epidemiologia , Fibrinolíticos/administração & dosagem , Fibrinolíticos/efeitos adversos , Masculino , Feminino , Fatores de Tempo , Idoso , Tempo para o Tratamento/tendências , Tenecteplase/uso terapêutico , Tenecteplase/administração & dosagem , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/diagnóstico , Terapia Trombolítica/tendências , Terapia Trombolítica/efeitos adversos , Pessoa de Meia-Idade , Resultado do Tratamento , Idoso de 80 Anos ou mais , Ativador de Plasminogênio Tecidual/administração & dosagem , Ativador de Plasminogênio Tecidual/efeitos adversosRESUMO
OBJECTIVES: Tenecteplase (TNK) is a promising alternative to alteplase (ALT) as the thrombolytic agent for acute ischemic stroke (AIS). However, its clinical outcomes in certain populations remain unclear. This study aimed to compare the efficacy and safety among different doses of TNK in AIS patients. METHODS: We searched PubMed, Scopus, Cochrane Central Register of Controlled Trials, and Embase for studies comparing at least one dose of TNK to another dose of TNK or ALT 0.90 mg/kg. We conducted Bayesian network meta-analyses to estimate the relative risks (RRs) and 95% credible intervals (CrIs) for all outcomes using ALT 0.90 mg/kg as the reference. The treatments were ranked according to their surface under the cumulative ranking (SUCRA) values. RESULTS: We included 11 trials from 16 publications comprising 5423 participants. There were no significant differences between any doses of TNK and ALT for reperfusion, 3-month modified Rankin Score (mRS) 0-1 (rank 1st: TNK 0.25 mg/kg; SUCRA = 0.68), mRS 0-2 (rank 1st: TNK 0.25 mg/kg; SUCRA = 0.86), mortality (rank 1st: TNK 0.25 mg/kg; SUCRA = 0.82), intracranial hemorrhage (ICH) (rank 1st: TNK 0.25 mg/kg; SUCRA = 0.88), symptomatic ICH (sICH) (rank 1st: TNK 0.10 mg/kg; SUCRA = 0.70), and parenchymal hematoma (rank 1st: TNK 0.10 mg/kg; SUCRA = 0.68). TNK 0.40 mg/kg had a significantly higher sICH rate compared to TNK 0.25 mg/kg (RR = 2.39, 95% CrI = 1.00-7.92). Among elderly patients, TNK 0.25 mg/kg had a significantly lower rate of sICH than ALT 0.9 mg/kg (RR = 3.0 × 10-13, 95% CrI = 3.4 × 10-40-0.07). CONCLUSIONS: TNK has efficacy and safety outcomes comparable to those of ALT. TNK 0.25 mg/kg may be the optimal dose of TNK for patients with AIS.
Assuntos
Fibrinolíticos , AVC Isquêmico , Metanálise em Rede , Tenecteplase , Humanos , Fibrinolíticos/administração & dosagem , Fibrinolíticos/efeitos adversos , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/diagnóstico , Tenecteplase/administração & dosagem , Tenecteplase/efeitos adversos , Resultado do Tratamento , Idoso , Masculino , Feminino , Pessoa de Meia-Idade , Terapia Trombolítica/efeitos adversos , Fatores de Risco , Idoso de 80 Anos ou mais , Fatores de Tempo , Recuperação de Função Fisiológica , Avaliação da Deficiência , Ativador de Plasminogênio Tecidual/administração & dosagem , Ativador de Plasminogênio Tecidual/efeitos adversosRESUMO
OBJECTIVES: Central and branch retinal artery occlusions are disabling ischemic strokes of the retina for which established acute treatments are lacking. This is the first published report of the use of intravenous tenecteplase (TNK) for retinal artery occlusion, in which we describe the clinical course of four patients with central retinal artery occlusion (CRAO) and one patient with branch retinal artery occlusion (BRAO). MATERIALS AND METHODS: Patients were retrospectively recruited to the study from two stroke centers. Clinical course was determined from review of electronic medical records. The primary outcomes of interest were short and long term complications as well as visual acuity at presentation and at any subsequent follow up. RESULTS: There were no hemorrhagic complications. None of the four patients with CRAO experienced functional visual recovery (defined as improvement to 20/100 or better). The patient with BRAO had functional visual recovery. CONCLUSIONS: Intravenous TNK may be a safe and reasonable treatment for CRAO and BRAO.
Assuntos
Oclusão da Artéria Retiniana , Humanos , Tenecteplase , Estudos Retrospectivos , Oclusão da Artéria Retiniana/diagnóstico por imagem , Oclusão da Artéria Retiniana/tratamento farmacológico , Retina , Progressão da DoençaRESUMO
BACKGROUND: In recent years, there have anecdotal reports of intra-arterial thrombolysis (IAT) for the treatment of spinal cord ischemia (SCI) with encouraging results. We describe a patient with acute cervical SCI who underwent IAT with Tenecteplase at our institution. CASE PRESENTATION: A 20-year-old man presented to the emergency department with a 12-hour history of progressive onset upper and lower extremity numbness, weakness, and urinary incontinence after sustaining a fall. MRI of cervical spine demonstrated T2 and STIR hyperintensity in the ventral aspect of the spinal cord spanning the C3, C4, and C5 levels suggestive of SCI. He demonstrated progression of neurologic deficits to C4 ASIA B spinal cord injury with complete loss of motor function, diminished sensation, and absent rectal tone. Emergent angiography was performed with prominent anterior spinal supply via the left ascending cervical artery. A total of 30 mg of Tenecteplase was administered intra-arterially in the bilateral vertebral arteries, bilateral ascending cervical arteries, and bilateral inferior thyroid arteries. Two-week post-intervention neurologic examination demonstrated improvement in injury level and severity. The patient was C6 ASIA C SCI, with 2/5 strength in the distal upper and lower extremities and improved sensation. CONCLUSION: IAT with Tenecteplase may be a feasible option for the treatment of acute spinal cord ischemia in carefully selected patients.
Assuntos
Medula Cervical , Isquemia do Cordão Espinal , Masculino , Humanos , Adulto Jovem , Adulto , Tenecteplase , Medula Espinal , Isquemia do Cordão Espinal/diagnóstico por imagem , Isquemia do Cordão Espinal/tratamento farmacológico , Isquemia do Cordão Espinal/etiologia , Vértebras Cervicais/diagnóstico por imagem , Isquemia , Terapia TrombolíticaRESUMO
BACKGROUND: Tenecteplase (TNK) is emerging as an alternative to alteplase (ALT) for thrombolytic treatment of acute ischemic stroke (AIS). Compared to ALT, TNK has a longer half-life, shorter administration time, lower cost, and similarly high efficacy in treating large vessel occlusion. Nevertheless, there are barriers to adopting TNK as a treatment for AIS. This study aimed to identify thematic barriers and facilitators to adopting TNK as an alternative to ALT as a thrombolytic for eligible AIS patients. METHODS: Qualitative research methodology using hermeneutic cycling and purposive sampling was used to interview four stroke clinicians in Texas. Interviews were recorded and transcribed verbatim. Enrollment was complete when saturation was reached. All members of the research team participated in content analysis during each cycle and in thematic analysis after saturation. RESULTS: Interviews were conducted between November 2022 and February 2023 with stroke center representatives from centers that either had successfully adopted TNK, or had not yet adopted TNK. Three themes and eight sub-themes were identified. The theme "Evidence" had three sub-themes: Pro-Con Balance, Fundamental Knowledge, and Pharmacotherapeutics. The theme "Process Flow" had four subthemes: Proactive, Reflective self-doubt, Change Process Barriers, and Parameter Barriers. The theme "Consensus" had one sub-theme: Getting Buy-In. CONCLUSION: Clinicians experience remarkably similar barriers and facilitators to adopting TNK. The results lead to a hypothesis that providing evidence to support a practice change, and identifying key change processes, will help clinicians achieve consensus across teams that need to 'buy in' to adopting TNK for AIS treatment.
Assuntos
AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Tenecteplase/efeitos adversos , AVC Isquêmico/diagnóstico , AVC Isquêmico/tratamento farmacológico , Resultado do Tratamento , Ativador de Plasminogênio Tecidual/efeitos adversos , Fibrinolíticos/efeitos adversos , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/tratamento farmacológico , Pesquisa QualitativaRESUMO
INTRODUCTION: Tenecteplase has been compared to alteplase in acute stroke randomized trials, with similar outcomes and safety measures, but higher doses of tenecteplase have been associated with higher hemorrhage rates in some studies. Limited data are available on the safety of tenecteplase outside of clinical trials. METHODS: We examined the safety measures of intracranial hemorrhage, angioedema, and serious extracranial adverse events in a 21-hospital integrated healthcare system that switched from alteplase (0.9 mg/kg, maximum dose 90 mg) to tenecteplase (0.25 mg/kg, maximum dose 25 mg) for acute ischemic stroke. RESULTS: Among 3,689 subjects, no significant differences were seen between tenecteplase and alteplase in the rate of intracranial hemorrhage (ICH), parenchymal hemorrhage, or volume of parenchymal hemorrhage. Symptomatic hemorrhage (sICH) was not different between the two agents: sICH by NINDS criteria was 2.0 % for alteplase vs 2.3 % for tenecteplase (P = 0.57), and sICH by SITS criteria was 0.8 % vs 1.1 % (P = 0.39). Adjusted logistic regression models also showed no differences between tenecteplase and alteplase: the odds ratio for tenecteplase (vs alteplase) modeling sICH by NINDS criteria was 0.9 (95 % CI 0.33 - 2.46, P = 0.83) and the odds ratio for tenecteplase modeling sICH by SITS criteria was 1.12 (95 % CI 0.25 - 5.07, P = 0.89). Rates of angioedema and serious extracranial adverse events were low and did not differ between tenecteplase and alteplase. Elapsed door-to-needle times showed a small improvement after the switch to tenecteplase (51.8 % treated in under 30 min with tenecteplase vs 43.5 % with alteplase, P < 0.001). CONCLUSION: In use outside of clinical trials, complication rates are similar between tenecteplase and alteplase. In the context of a stroke telemedicine program, the rates of hemorrhage observed with either agent were lower than expected based on prior trials and registry data. The more easily prepared tenecteplase was associated with a lower door-to-needle time.
Assuntos
Angioedema , Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Ativador de Plasminogênio Tecidual/efeitos adversos , Tenecteplase/efeitos adversos , Fibrinolíticos/efeitos adversos , AVC Isquêmico/diagnóstico , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/induzido quimicamente , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/induzido quimicamente , Hemorragias Intracranianas/induzido quimicamente , Hemorragias Intracranianas/tratamento farmacológico , Angioedema/induzido quimicamente , Resultado do Tratamento , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/induzido quimicamenteRESUMO
INTRODUCTION: Data on prior use of Tenecteplase versus Alteplase in acute stroke management by mechanical thrombectomy are controversial. Our primary objective was to make a comprehensive comparative assessment of clinical and angiographic efficacy and safety outcomes in a large prospective observational study. METHODS: We included stroke patients who were eligible for intravenous thrombolysis and endovascular thrombectomy between 2019 and 2021, from an ongoing registry in twenty comprehensive stroke centers in France. We divided patients into two groups based on the thrombolytic agent used (Alteplase vs Tenecteplase). We then compared their treatment times, and their angiographic (TICI scale), clinical (mRS at three months and sICH) and safety outcomes after controlling for potential confounders using propensity score methods. RESULTS: We evaluated 1131 patients having undergone thrombectomy for the final analysis, 250 received Tenecteplase and 881 Alteplase. Both groups were of the same median age (75 vs 74 respectively), and had the same baseline NIHSS score (16) and ASPECTS (8). There was no significant difference for First Pass Effect (OR 0.93, 95 % CI 0.76-1.14, p = 0.75), time required for reperfusion (OR 0.03, 95 % CI 0.09-0.16, p = 0.49), or for final reperfusion status. Clinically, functional independence at 90 days was similar in both groups (OR 0.82, 95 % CI 0.61-1.10, p = 0.18) with the same risk of sICH (OR 1.36, 95 % CI 0.77-2.41, p = 0.28). However, Tenecteplase patients had shorter imaging-to-groin puncture times (99 vs 142 min, p < 0.05). CONCLUSIONS: Tenecteplase showed no better clinical or angiographic impact on thrombectomy compared to Alteplase. Nevertheless, it appeared associated with a shorter thrombolysis-to-groin puncture time.
Assuntos
Fibrinolíticos , Sistema de Registros , Tenecteplase , Trombectomia , Ativador de Plasminogênio Tecidual , Humanos , Tenecteplase/uso terapêutico , Masculino , Feminino , Ativador de Plasminogênio Tecidual/uso terapêutico , Idoso , Fibrinolíticos/uso terapêutico , Trombectomia/métodos , Estudos Prospectivos , Resultado do Tratamento , Angiografia Cerebral , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/tratamento farmacológico , França , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/cirurgiaRESUMO
INTRODUCTION: Acute ischemic stroke is a neurologic emergency, requiring rapid recognition and treatment with intravenous thrombolysis. Since the publication of the 2019 American Heart Association/American Stroke Association Guidelines that recommend tenecteplase as an alternative agent, several centers across the United States are transitioning from alteplase to tenecteplase as the agent of choice for thrombolysis in acute ischemic stroke. METHODS: Our health system transitioned to tenecteplase for the treatment of acute ischemic stroke in 2021 due to increasing evidence for efficacy and potential for improved door-to-needle time. Herein we describe our experience and provide guidance for other institutions to implement this change. CONCLUSION: Emergency nurses are vital to the care of acute ischemic stroke patients. There are several pharmacologic and logistical differences between alteplase and tenecteplase for this indication. This paper outlines these key differences.