Statistical Analysis Plan for Evaluating Low- vs. Standard-Dose Alteplase in the Enhanced Control of Hypertension and Thrombolysis Stroke Study (Enchanted)

Anderson, Craig S.; Woodward, Mark; Arima, Hisatomi; Chen, Xiaoying; Lindley, Richard I.; Wang, Xia; Chalmers, John

doi:10.1111/ijs.12602

Cited by 28 publications

(34 citation statements)

References 21 publications

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“…14 Differential patient recruitment resulted in the part of the trial dealing with alteplase dose being completed faster than the part dealing with intensity of blood-pressure control. For the primary analysis, we used an unadjusted logisticregression model to test whether low-dose alteplase was noninferior to the standard dose.…”

Section: Resultsmentioning

confidence: 99%

“…17 A new assumption-free approach 21 was used to confirm the conclusion. We also performed secondary analyses of the primary outcome with adjustment for minimization and key prognostic covariates 14 , as well as secondary analyses in the per-protocol population according to criteria outlined in the Supplementary Appendix. Multiple imputation was to be used if more than 10% of observations were missing.…”

Section: Resultsmentioning

confidence: 99%

“…13,14 An international steering committee, whose members designed the trial with an advisory committee, was responsible for the conduct and reporting of the trial. The George Institute for Global Health coordinated the trial, managed the database, and performed the analyses.…”

Section: Trial Design and Oversightmentioning

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: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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

et al. 2016

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“…Finally, this study did not prove non-inferiority of low-dose IV tPA and did not show superiority to the standard dose of IV tPA either. 37 Despite these concerns, ENCHANTED performed well. It was one of the trials which showed that statistical hypothesis testing would not match the clinical performances.…”

Section: Discussionmentioning

confidence: 99%

Low-dose intravenous tissue plasminogen activator for acute ischaemic stroke: an alternative or a new standard?

et al. 2016

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BackgroundWith the recent publication of a large clinical trial on the use of a lower dose of intravenous (IV) tissue plasminogen activator (tPA) for acute ischaemic stroke (AIS), the concept of using a different dose has been debated. We intend to review the literature on using a lower dose of IV tPA and gain a better understanding of the impact of different IV doses on the treatment of patients with AIS.MethodsA comprehensive literature search of the related topics in PubMed, EMBASE, Web of Science and MEDLINE was carried out. Key words used include low dose IV tPA, thrombolysis, Alteplace and tPA for AIS. Findings were tabulated according to the size of the cohort studied, outcome, adverse event and level of evidence. The results of all studies using lower doses were analysed for efficacy and adverse events.ResultsFrom 1992 to 2016, there were 23 trials that included 10 950 patients published on the use of lower doses of IV tPA for AIS. Doses ranged from 0.5, 0.6, 0.75 to 0.85 mg/kg. Most were observational, retrospective and registry studies. One was a prospective open-label randomised controlled trial. 13 trials combined lower doses of IV tPA with a glycoprotein IIb/IIIa inhibitor or thrombectomy. Patients treated with lower doses of IV tPA showed a trend of lower rate of symptomatic intracranial haemorrhage and mortality at 3 months but slightly more disability.ConclusionsLower doses of IV tPA showed less haemorrhagic events but were not more effective compared with the standard dose. The optimal low dose of IV tPA remains unclear. Patients with AIS with a high risk of developing sypmtomatic intracranial haemorrhage might benefit from lower dose IV tPA, such as 0.6 mg/kg.

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“…Therefore, the optimal dose of alteplase may vary according to ethnicity and age. Currently, the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) is assessing the safety/efficacy of two doses of alteplase (0.6, 0.9 mg/kg) in Australia, Brazil, Chile, China, Colombia, Hong Kong, Italy, Korea, Norway, Singapore, Taiwan, Thailand, the United Kingdom, and Vietnam [11]. ENCHANTED will reveal the optimal dose of alteplase according to ethnicity and age.…”

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confidence: 99%