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Low- versus Standard-Dose Intravenous Alteplase in the Context of Bridging Therapy for Acute Ischemic Stroke: A Korean ENCHANTED Study.

ABSTRACT: BACKGROUND AND PURPOSE:Following the positive results from recent trials on endovascular therapy (EVT), bridging therapy (intravenous alteplase plus EVT) is increasingly being used for the treatment of acute ischemic stroke. However, the optimal dose of intravenous alteplase remains unknown in centers where bridging therapy is actively performed. The optimal dose for eventual recanalization and positive clinical outcomes in patients receiving bridging therapy also remains unknown. METHODS:In this prospective Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) sub-study, we explored the outcomes following treatment with two different doses (low- [0.6 mg/kg] or standard-dose [0.9 mg/kg]) of intravenous alteplase across 12 Korean centers where EVT is actively performed. The primary endpoint was a favorable outcome at 90 days (modified Rankin Scale scores 0 to 1). Secondary endpoints included symptomatic intracerebral hemorrhage (ICH) in all patients, and the recanalization rate and favorable outcome in patients who underwent cerebral angiography for EVT (ClinicalTrials.gov, number NCT01422616). RESULTS:Of 351 patients, the primary outcome occurred in 46% of patients in both the standard-(80/173) and low-dose (81/178) groups (odds ratio [OR], 1.14; 95% confidence interval [CI], 0.72 to 1.81; P=0.582), although ICHs tended to occur more frequently in the standard-dose group (8% vs. 3%, P=0.056). Of the 67 patients who underwent cerebral angiography, there was no significant difference in favorable functional outcome between the standard- and low-dose groups (39% vs. 21%; OR, 2.39; 95% CI, 0.73 to 7.78; P=0.149). CONCLUSIONS:There was no difference in functional outcome between the patients receiving different doses of alteplase in centers actively performing bridging therapy.

SUBMITTER: Kim JS

PROVIDER: S-EPMC5836572 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Low- versus Standard-Dose Intravenous Alteplase in the Context of Bridging Therapy for Acute Ischemic Stroke: A Korean ENCHANTED Study.

Kim Jong S JS Kim Yeon-Jung YJ Lee Kyung Bok KB Cha Jae Kwan JK Park Jong-Moo JM Hwang Yangha Y Kim Eung-Gyu EG Rha Joung-Ho JH Koo Jaseong J Kim Jei J Kim Yong-Jae YJ Seo Woo-Keun WK Kim Dong-Eog DE Robinson Thompson G TG Lindley Richard I RI Wang Xia X Chalmers John J Anderson Craig S CS

Journal of stroke 20180131 1

<h4>Background and purpose</h4>Following the positive results from recent trials on endovascular therapy (EVT), bridging therapy (intravenous alteplase plus EVT) is increasingly being used for the treatment of acute ischemic stroke. However, the optimal dose of intravenous alteplase remains unknown in centers where bridging therapy is actively performed. The optimal dose for eventual recanalization and positive clinical outcomes in patients receiving bridging therapy also remains unknown.<h4>Met ...[more]

PMID: 29402064

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Project description:ObjectiveTo determine any differential efficacy and safety of low- vs standard-dose IV alteplase for lacunar vs nonlacunar acute ischemic stroke (AIS), we performed post hoc analyzes from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) alteplase dose arm.MethodsIn a cohort of 3,297 ENCHANTED participants, we identified those with lacunar or nonlacunar AIS with different levels of confidence (definite/according to prespecified definitions based on clinical and adjudicated imaging findings. Logistic regression models were used to determine associations of lacunar AIS with 90-day outcomes (primary, modified Rankin Scale [mRS] scores 2-6; secondary, other mRS scores, intracerebral hemorrhage [ICH], and early neurologic deterioration or death) and treatment effects of low- vs standard-dose alteplase across lacunar and nonlacunar AIS with adjustment for baseline covariables.ResultsOf 2,588 participants with available imaging and clinical data, we classified cases as definite/probable lacunar (n = 490) or nonlacunar AIS (n = 2,098) for primary analyses. Regardless of alteplase dose received, lacunar AIS participants had favorable functional (mRS 2-6, adjusted odds ratio [95% confidence interval] 0.60 [0.47-0.77]) and other clinical or safety outcomes compared to participants with nonlacunar AIS. Low-dose alteplase (versus standard) had no differential effect on functional outcomes (mRS 2-6, 1.04 [0.87-1.24]) but reduced the risk of symptomatic ICH in all included participants. There were no differential treatment effects of low- vs standard-dose alteplase on all outcomes across lacunar and nonlacunar AIS (all p interaction ≥0.07).ConclusionsWe found no evidence from the ENCHANTED trial that low-dose alteplase had any advantages over standard dose for definite/probable lacunar AIS.Classification of evidenceThis study provides Class II evidence that for patients with lacunar AIS, low-dose alteplase had no additional benefit or safety over standard-dose alteplase.Clinical trial registrationClinicaltrials.gov identifier NCT01422616.

Project description:Background: To date, the role of bridging intravenous thrombolysis before mechanical thrombectomy (MTE) is controversial but still recommended in eligible patients. Different doses of intravenous alteplase have been used for treating patients with acute ischemic stroke from large-vessel occlusion (LVO-AIS) in Asia, largely due to variations in the risks for intracerebral hemorrhage (ICH) and treatment affordability. Uncertainty exists over the potential benefits of treating low-dose alteplase, as opposed to standard-dose alteplase, prior to MTE among patients with LVO-AIS. Aim: The aim of the study was to compare outcomes of low- vs. standard-dose of bridging intravenous alteplase before MTE among LVO-AIS patients. Methods: We performed a retrospective analysis of LVO-AIS patients who were treated with either 0.6 mg/kg or 0.9 mg/kg alteplase prior to MTE at a stroke center in Northern Vietnam. Multivariable logistic regression models, accounting for potential confounding factors including comorbidities and clinical factors (e.g., stroke severity), were used to compare the outcomes between the two groups. Our primary outcome was functional independence at 90 days following stroke (modified Rankin score; mRS ≤ 2). Secondary outcomes included any ICH incidence, early neurological improvement, recanalization rate, and 90-day mortality. Results: We analyzed data of 107 patients receiving bridging therapy, including 73 with low-dose and 34 with standard-dose alteplase before MTE. There were no statistically significant differences between the two groups in functional independence at 90 days (adjusted OR 1.02, 95% CI 0.29-3.52) after accounting for potential confounding factors. Compared to the standard-dose group, patients with low-dose alteplase before MTE had similar rates of successful recanalization, early neurological improvement, 90-day mortality, and ICH complications. Conclusion: In the present study, patients with low-dose alteplase before MTE were found to achieve comparable clinical outcomes compared to those receiving standard-dose alteplase bridging with MTE. The findings suggest potential benefits of low-dose alteplase in bridging therapy for Asian populations, but this needs to be confirmed by further clinical trials.

Project description:ImportanceA lower dose of intravenous alteplase appears to be a safer treatment option than the standard dose, reducing the risk of symptomatic intracerebral hemorrhage. There is uncertainty, however, over how this effect translates into an overall clinical benefit for patients with acute ischemic stroke (AIS).ObjectiveTo assess whether older, Asian, or severely affected patients with AIS who are considered at high risk of thrombolysis may benefit more from low-dose rather than standard-dose alteplase treatment.Design, setting, and participantsThis study is a prespecified secondary analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED), an international, randomized, open-label, blinded, end-point clinical trial of low-dose vs standard-dose intravenous alteplase for patients with AIS. From March 1, 2012, to August 31, 2015, a total of 3310 patients who had a clinical diagnosis of AIS as confirmed by brain imaging and who fulfilled the local criteria for thrombolysis treatment were included in the alteplase-dose arms. Patients were randomly assigned to receive low-dose (0.6 mg/kg; 15% as bolus and 85% as infusion over 1 hour) or standard-dose (0.9 mg/kg; 10% as bolus and 90% as infusion over 1 hour) alteplase. Of the 3310 randomized patients, 13 patients were excluded for missing consent, mistaken randomization, and duplicate randomization numbers. This secondary analysis was conducted between May 1, 2016, and April 28, 2017.Main outcomes and measuresThe primary end point was a poor outcome defined by the combination of death and any disability as scored by the modified Rankin Scale (scores range from 2 to 6, with the highest score indicating death) at 90 days.ResultsOf the 3297 patients included in the analysis, 1248 (37.9%) were women, and the mean (SD) age was 67 (13) years. No significant differences in the treatment effects were observed between low- and standard-dose alteplase for poor outcomes (death or disability) by age, ethnicity, or severity (all P > .37 for interaction). Similarly, the treatment effects of low- vs standard-dose alteplase on function outcome (ordinal shift of the modified Rankin Scale) in Asians (odds ratio, 1.05; 95% CI, 0.90-1.22) was consistent with non-Asians (odds ratio, 0.93; 95% CI, 0.76-1.14) (P = .32 for interaction). There were generally consistent reductions in rates of symptomatic intracerebral hemorrhage with low-dose alteplase, although this reduction was not statistically significant by age, ethnicity, or severity.Conclusions and relevanceThis analysis found that the effects of low-dose alteplase were not clearly superior to the effects of standard-dose alteplase on death or disability in key demographic subgroups of patients with AIS. Further investigation is required to identify patients with AIS who may benefit from low-dose alteplase.Trial registrationclinicaltrials.gov Identifier: NCT01422616.

Project description:Background and purposeWith increasing use of endovascular therapy, physicians' attitudes toward intravenous alteplase in endovascular therapy-eligible patients may be changing. We explored current intravenous alteplase treatment practices of physicians in endovascular therapy- and alteplase-eligible patients with acute stroke using prespecified case scenarios and compared how their current local treatment practices differ compared with an assumed ideal environment.Materials and methodsIn an international multidisciplinary survey, 607 physicians involved in acute stroke care were randomly assigned 10 of 22 case scenarios, among them 14 with guideline-based alteplase recommendations (9 with level 1A and 5 with level 2B recommendation) and were asked how they would treat the patient: A) under their current local resources, and B) under assumed ideal conditions. Answer options were the following: 1) anticoagulation/antiplatelet therapy, 2) endovascular therapy, 3) endovascular therapy plus intravenous alteplase, and 4) intravenous alteplase. Decision rates were calculated, and multivariable regression analysis was performed to determine variables associated with the decision to abandon intravenous alteplase.ResultsIn cases with guideline recommendations for alteplase, physicians favored alteplase in 82.0% under current local resources and in 79.3% under assumed ideal conditions (P < .001). Under assumed ideal conditions, interventional neuroradiologists would refrain from intravenous alteplase most often (6.28%, OR = 2.40; 95% CI, 1.01-5.71). When physicians' current and ideal decisions differed, most would like to add endovascular therapy to intravenous alteplase in an ideal setting (196/3861 responses, 5.1%).ConclusionsIn patients eligible for endovascular therapy and intravenous alteplase, we observed a slightly lower decision rate in favor of intravenous alteplase under assumed ideal conditions compared with the decision rate under current local resources.

Project description:Background and Purpose: We aimed to investigate the effect of Ginkgolide® treatment on neurological function in patients receiving intravenous (IV) recombinant tissue plasminogen activator (rt-PA). Methods: This cluster randomized controlled trial included acute ischemic stroke patients in 24 centers randomized to intervention of intravenous Ginkgolide® or control group within the first 24 h after IV rt-PA therapy (IVT). Clinical outcome at 90 days was assessed with modified Rankin Scale (mRS) score and dichotomized into good outcome (0-2) and poor outcome (3-6). Hemorrhagic transformation represented the conversion of a bland infarction into an area of hemorrhage by computed tomography. Symptomatic intracerebral hemorrhage (sICH) was defined as cerebral hemorrhagic transformation in combination with clinical deterioration of National Institutes of Health Stroke Scale (NIHSS) score ≥4 points at 7-day or if the hemorrhage was likely to be the cause of the clinical deterioration. We performed logistic regression analysis and propensity score matching analysis to investigate the impact of Ginkgolide® treatment with IV rt-PA on good outcome, hemorrhagic transformation and sICH, respectively. Results: A total of 1113 patients were finally included and 513 (46.1%) were in the intervention group. Patients in the Ginkgolide® group were more likely to have good outcomes (78.6 vs. 66.7%, p < 0.01) and lower rate of sICH (0 vs. 2.72%, p < 0.01), compared with patients in the control group. The intra-cluster correlation coefficient (ICC) for good outcome at 90 days was 0.033. Binary logistic regression analysis revealed that treatment with Ginkgolide® was independently associated with 90-day mRS in patients with IV rt-PA therapy (OR 1.498; 95% CI 1.006-2.029, p = 0.009). After propensity score matching, conditional logistic regression showed intervention with Ginkgolide® was significantly associated with 90-day good outcome (OR 1.513; 95% CI 1.073-2.132, p = 0.018). No significant difference in hemorrhage transformation was seen between the 2 matched cohorts (OR 0.885; 95% CI 0.450-1.741, p = 0.724). Conclusion: Using Ginkgolide® within 24-hour after IV rt-PA is effective and safe and might be recommended in combination with rtPA therapy in acute ischemic stroke. Clinical Trial Registration: http://www.clinicaltrials.gov, identifier NCT03772847.

Project description:BackgroundFor acute ischaemic stroke patients, it is uncertain whether intravenous thrombolysis combined with statins might increase the therapeutic effect. Additionally, using high-intensity statins after thrombolysis may increase the risk of bleeding in patients. Asian stroke patients often take low-dose statins. It is speculated that reducing the dose of statins may improve the risk of bleeding.MethodsData from consecutive acute ischaemic stroke patients with intravenous thrombolysis were prospectively collected. Efficacy outcomes included NIHSS (National Institutes of Health Stroke Scale) score improvement at 7 days after admission and mRS (Modified Rankin Scale) improvement at 90 days. Safety outcomes included haemorrhage events (intracerebral haemorrhage and gastrointestinal haemorrhage) in the hospital and death events within 2 years.ResultsThe study finally included 215 patients. The statin group had a higher percentage of NIHSS improvement at 7 days (p < 0.001) and a higher percentage of a favourable functional outcome (FFO, mRS < = 2) (p < 0.001) at 90 days. The statin group had a lower percentage of intracerebral haemorrhage (p < 0.001) and gastrointestinal haemorrhage (p = 0.003) in the hospital and a lower percentage of death events (p < 0.001) within 2 years. Logistic regression indicated that statin use was significantly related to NIHSS improvement (OR = 4.697, p < 0.001), a lower percentage of intracerebral haemorrhage (OR = 0.372, p = 0.049) and gastrointestinal haemorrhage (OR = 0.023, p = 0.016), and a lower percentage of death events (OR = 0.072, p < 0.001).ConclusionFor acute ischaemic stroke patients after intravenous thrombolysis, the use of low-dose statins was related to NIHSS improvement at 7 days and inversely related to haemorrhage events in the hospital and death events within 2 years, especially for moderate stroke or noncardioembolic stroke patients.

Dataset Information

Low- versus Standard-Dose Intravenous Alteplase in the Context of Bridging Therapy for Acute Ischemic Stroke: A Korean ENCHANTED Study.

Publications

Low- versus Standard-Dose Intravenous Alteplase in the Context of Bridging Therapy for Acute Ischemic Stroke: A Korean ENCHANTED Study.

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