Low-Versus Standard-Dose Alteplase for Ischemic Strokes Within 4.5 Hours

Kim, Beom Joon; Han, Moon Ku; Park, Tai Hwan; Park, Sang Soon; Lee, Kyung Bok; Lee, Byung Chul; Yu, Kyung Ho; Oh, Mi Sun; Kwan, Jae; Kim, Dae Hyun; Lee, Jun; Lee, Soo Joo; Ko, Young Hwii; Park, Jong‐Moo; Kang, Kyusik; Cho, Yong Jin; Hong, Kyung Soon; Kim, Joon Tae; Choi, Jay Chol; Kim, Dong Eog; Shin, Dong Ick; Kim, Wook Joo; Lee, Jun-Young; Lee, Ji Sung; Yoon, Byung Woo; Gorelick, Philip B.; Bae, Hee Joon

doi:10.1161/strokeaha.115.010180

Cited by 55 publications

(74 citation statements)

References 31 publications

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“…Our trial was driven by concern about high risks of intracerebral hemorrhage with alteplase, particularly among Asians, because preliminary studies have had differing results with respect to the effectiveness and risks of this treatment. 8,11 Using several definitions of symptomatic intracerebral hemorrhage, 22 we observed fewer clinically important cases in the group assigned to low-dose alteplase than in the group assigned to standard-dose alteplase, and the difference in risk was consistent in Asians and non-Asians.…”

Section: Discussionmentioning

confidence: 81%

“…[1][2][3] However, the Japanese drug safety authority has approved the use of alteplase at a dose of 0.6 mg per kilogram after an uncontrolled, open-label study showed that this dose resulted in equivalent clinical outcomes and a lower risk of intracerebral hemorrhage than that reported in published studies in which the 0.9-mg-per-kilogram dose was used. 4 Other registry studies in Asia [5][6][7][8][9][10][11] have shown inconsistent results, but a high risk of symptomatic intracerebral hemorrhage was observed among Asian patients treated with 0.9 mg of alteplase per kilogram in the United States. 12 Differing perceived risks of intracerebral hemorrhage and treatment affordability have led to variations in the doses of intravenous alteplase used to treat patients with acute ischemic stroke in Asia.…”

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confidence: 99%

“…12 Differing perceived risks of intracerebral hemorrhage and treatment affordability have led to variations in the doses of intravenous alteplase used to treat patients with acute ischemic stroke in Asia. [8][9][10][11] The Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) was designed to compare low-dose with standard-dose intravenous alteplase in patients with acute ischemic stroke. Using a quasi-factorial design, we are also assessing the effects of early intensive lowering of blood pressure as compared with guideline-recommended management in patients with elevated blood pressure; this part of the trial is scheduled to be completed in 2018.…”

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confidence: 99%

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Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke

et al. 2016

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BACKGROUNDThrombolytic therapy for acute ischemic stroke with a lower-than-standard dose of intravenous alteplase may improve recovery along with a reduced risk of intracerebral hemorrhage. METHODSUsing a 2-by-2 quasi-factorial open-label design, we randomly assigned 3310 patients who were eligible for thrombolytic therapy (median age, 67 years; 63% Asian) to lowdose intravenous alteplase (0.6 mg per kilogram of body weight) or the standard dose (0.9 mg per kilogram); patients underwent randomization within 4.5 hours after the onset of stroke. The primary objective was to determine whether the low dose would be noninferior to the standard dose with respect to the primary outcome of death or disability at 90 days, which was defined by scores of 2 to 6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Secondary objectives were to determine whether the low dose would be superior to the standard dose with respect to centrally adjudicated symptomatic intracerebral hemorrhage and whether the low dose would be noninferior in an ordinal analysis of modified Rankin scale scores (testing for an improvement in the distribution of scores). The trial included 935 patients who were also randomly assigned to intensive or guideline-recommended blood-pressure control. RESULTSThe primary outcome occurred in 855 of 1607 participants (53.2%) in the low-dose group and in 817 of 1599 participants (51.1%) in the standard-dose group (odds ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; the upper boundary exceeded the noninferiority margin of 1.14; P = 0.51 for noninferiority). Low-dose alteplase was noninferior in the ordinal analysis of modified Rankin scale scores (unadjusted common odds ratio, 1.00; 95% CI, 0.89 to 1.13; P = 0.04 for noninferiority). Major symptomatic intracerebral hemorrhage occurred in 1.0% of the participants in the low-dose group and in 2.1% of the participants in the standard-dose group (P = 0.01); fatal events occurred within 7 days in 0.5% and 1.5%, respectively (P = 0.01). Mortality at 90 days did not differ significantly between the two groups (8.5% and 10.3%, respectively; P = 0.07). CONCLUSIONSThis trial involving predominantly Asian patients with acute ischemic stroke did not show the noninferiority of low-dose alteplase to standard-dose alteplase with respect to death and disability at 90 days. There were significantly fewer symptomatic intracerebral hemorrhages with low-dose alteplase.

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Section: Discussionmentioning

confidence: 81%

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confidence: 99%

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Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke

et al. 2016

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“…Concerns of a higher risk of sICH have led to a wide range of doses of intravenous alteplase being used in many Asian countries in relation to perceived risks and affordability of the treatment. 9 Although 3 studies-2 registries 14,15 and 1 observational 16 -have specifically evaluated outcomes by dose of alteplase in Asian populations, only Chao et al 16 reported a trend toward an adverse effect of prior APT on outcome. In particular, use of clopidogrel or ticlopidine, but not aspirin, was associated with an increased risk of sICH on multivariate analysis.…”

Section: Discussionmentioning

confidence: 99%

Low- Versus Standard-Dose Alteplase in Patients on Prior Antiplatelet Therapy

Robinson

Wang

Arima

et al. 2017

Stroke

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Background and Purpose-Many patients receiving thrombolysis for acute ischemic stroke are on prior antiplatelet therapy (APT), which may increase symptomatic intracerebral hemorrhage risk. In a prespecified subgroup analysis, we report comparative effects of different doses of intravenous alteplase according to prior APT use among participants of the international multicenter ENCHANTED study (Enhanced Control of Hypertension and Thrombolysis Stroke Study). Methods-Among 3285 alteplase-treated patients (mean age, 66.6 years; 38% women) randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 hours of symptom onset, 752 (22.9%) reported prior APT use. Primary outcome at 90 days was the combined end point of death or disability (modified Rankin Scale [mRS] scores, 2-6). Other outcomes included mRS scores 3 to 6, ordinal mRS shift, and symptomatic intracerebral hemorrhage by various standard criteria. Results-There were no significant differences in outcome between patients with and without prior APT after adjustment for baseline characteristics and management factors during the first week; defined by mRS scores 2 to 6 (adjusted odds ratio The sponsors had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to the study data. The corresponding author had final responsibility for the decision to submit the article for publication.

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“…The experience with this approach in other conditions, such as stroke, has been promising. 27 Large patient registries using CDEs and qualitycontrolled samples may provide one method of tracking large numbers of patients longitudinally, and generating relevant data. Another advantage is the ability to blend clinical care with research data collection, which allows faster completion of studies.…”

Section: Variations In Clinical Practice and Thementioning

confidence: 99%

Report of a workshop on research gaps in the treatment of cerebral palsy

et al. 2016

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Cerebral palsy (CP) is heterogeneous in etiology and manifestations, making research into relevant therapies difficult and limiting the generalizability of the results. We report here on the NIH CP symposium, where stakeholders from academic, clinical, regulatory, and advocacy backgrounds discussed the major challenges and needs for moving forward with clinical research in CP, and outlined priorities and action items. New information is constantly generated through research into pathogenesis and etiology. Clinical research and new therapeutic approaches need to keep pace, through large data registry integration and new research designs. Development of standardized data collection, increasing academic focus on CP research, and iterative approaches to treatment throughout the patients' lives, have all been identified as areas of focus. The workshop identified critical gaps and areas of focus to increase the evidence base for therapeutic approaches to determine which treatments work best for which patients in the near future. These include consolidation and optimization of databases and registries, updates to the research methodology, and better integration of resources and stakeholders. DEFINING THE PROBLEM Cerebral palsy (CP) is a group of neurologic disorders of motor control with onset early in development and persistence throughout the lifespan. CP is the most common cause of motor disability in childhood, with an incidence of 2 to 3 per 1,000 live births, occurring 20 to 30 times more frequently in premature or low-birth-weight infants.1 These disturbances of movement and posture cause activity limitations.2 Those activity limitations resulting from spinal or neuromuscular disorders are excluded from the diagnosis. Various etiologies can cause the CP clinical spectrum but all have a disruption of motor control in common. In addition to prematurity, other known etiologies include developmental defects of the brain, perinatal stroke, hypoxia, shock, and fetal or neonatal inflammation/infection. However, CP may also occur in low-risk children for whom there is no obvious etiology or risk factor. CP is often accompanied by comorbidities such as seizures, communication deficits, hearing and vision deficits, and intellectual disability. There is a wide spectrum of functional outcomes from normal educational, career, and social activities to complete disability and dependence.An upper age limit for acquired pathology in the brain leading to CP is not absolute, but the onset of symptoms and the diagnosis are generally expected to occur by the age of 2. Given the heterogeneity in terms of etiology, pathology, clinical manifestations, and progression, it is best to consider CP as a collection of conditions rather than one uniform entity for developing treatment guidelines or conducting research on potential therapies.To address pressing research challenges, the National Institute of Neurological Disorders and Stroke (NINDS) organized a workshop with the main goal of discussing research needed to determine best ...

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Low-Versus Standard-Dose Alteplase for Ischemic Strokes Within 4.5 Hours

Cited by 55 publications

References 31 publications

Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke

Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke

Low- Versus Standard-Dose Alteplase in Patients on Prior Antiplatelet Therapy

Report of a workshop on research gaps in the treatment of cerebral palsy

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