Rationale, Design, and Progress of the ENhanced Control of Hypertension ANd Thrombolysis Stroke Study (ENCHANTED) Trial: An International Multicenter 2 × 2 Quasi-Factorial Randomized Controlled Trial of Low- vs. Standard-Dose rt-PA and Early Intensive vs. Guideline-Recommended Blood Pressure Lowering in Patients with Acute Ischaemic Stroke Eligible for Thrombolysis Treatment

Huang, Yining; Sharma, Vijay K.; Robinson, Thompson G.; Lindley, Richard I.; Chen, Xiaoying; Kim, Jong Sung; Lavados, Pablo M.; Olavarría, Verónica V.; Arima, Hisatomi; Fuentes, Sully; Nguyen, Huy Thang; Lee, Tsong‐Hai; Parsons, Mark; Levi, Christopher; Demchuk, Andrew M.; Bath, Philip M.; Broderick, Joseph P.; Donnan, Geoffrey A.; Martins, Sheila; Pontes-Neto, Octávio M.; Silva, Federico; Pandian, Jeyaraj Durai; Ricci, Stefano; Stapf, Christian; Woodward, Mark; Wang, Ji‐Guang; Chalmers, John; Anderson, Craig S.

doi:10.1111/ijs.12486

Cited by 84 publications

(64 citation statements)

References 45 publications

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“…The earlier the treatment is given, the greater the proportional benefit. This hypothesis is well confirmed by the recent 'enchanted' clinical trial, which revealed that early intensive BP lowering (<140 mm Hg) could provide more affordable and safer use of thrombolysis treatment for patients with AIS worldwide [26] . Therefore, onset to treatment time could play a role.…”

Section: Discussionmentioning

confidence: 72%

Effects of Early Hypertension Control after Ischaemic Stroke on the Outcome: A Meta-Analysis

Liu

Li²,

Li³

et al. 2015

Cerebrovasc Dis

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Background: Accumulating evidence suggests that high blood pressure (BP) increases the risk of cerebral oedema and haemorrhagic transformation of the ischaemic stroke (IS), and that low BP in acute ischaemic stroke (AIS) is associated with a poor prognosis. The best possible management of hypertension after AIS is still uncertain. Materials and Methods: English databases were searched to identify relevant randomized controlled trials assessing the effects of early BP lowering (started within the first 48 h) after IS on outcome from January 1990 to August 2015. We set strict inclusion criteria and used the Review Manager 5.2 software from Cochrane Collaboration to calculate the combined risk ratio (RR). Result: Eight studies met our criteria. Early BP lowering after AIS did not significantly affect the risk of early and long-term death (RR 1.22; 95% CI 0.69-2.16 and RR 1.03; 95% CI 0.62-1.71), early and long-term dependency (RR 1.02; 95% CI 0.94-1.10 and RR 1.07; 95% CI 0.84-1.36), early and long-term death or dependency (RR 1.04; 95% CI 0.94-1.19 and RR 1.00; 95% CI 0.95-1.05), long-term stroke recurrence (RR 0.74; 95% CI 0.49-1.11), long-term myocardial infarction (RR 0.99; 95% CI 0.27-3.61), and long-term vascular events (RR 0.97; 95% CI 0.72-1.31). Conclusion: Our results revealed neither support nor opposition to early BP lowering (started within 48 h) after AIS; individualized BP management based on the patients' condition may be a good choice.

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Section: Discussionmentioning

confidence: 72%

Effects of Early Hypertension Control after Ischaemic Stroke on the Outcome: A Meta-Analysis

Liu

Li²,

Li³

et al. 2015

Cerebrovasc Dis

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“…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%

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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“…The ENCHANTED trial is an international, multi-centre, prospective, randomised, open-label, blinded-endpoint trial, which used a 2 × 2 quasi-factorial design to assess the effectiveness of low- versus standard-dose alteplase in the completed arm, and more intensive- versus guideline-recommended control of blood pressure in the ongoing arm, full details of which are outlined elsewhere [3, 6]. Patients with a clinical diagnosis of AIS confirmed on brain imaging and fulfilling local criteria for thrombolysis treatment administered within 4.5 h of symptom onset were randomly assigned to the dose-arm between June 18, 2012 and October 14, 2015.…”

Section: Methodsmentioning

confidence: 99%

Lipid-Lowering Pretreatment and Outcome Following Intravenous Thrombolysis for Acute Ischaemic Stroke: A Post Hoc Analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study Trial

et al. 2018

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Background: Debate exists as to whether statin pretreatment confers an increased risk of 90-day mortality and symptomatic intracranial haemorrhage (sICH) in acute ischaemic stroke (AIS) patients treated with intravenous thrombolysis. We assessed the effects of undifferentiated lipid-lowering pretreatment on outcomes and interaction with low-dose versus standard-dose alteplase in a post hoc subgroup analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study. Methods: In all, 3,284 thrombolysis-eligible AIS patients (mean age 66.6 years; 38% women), with information on lipid-lowering pretreatment, were randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 h of symptom onset. Of the total number of patients, 615 (19%) received statin or other lipid-lowering pretreatment. The primary clinical outcome was combined endpoint of death or disability (modified Rankin Scale scores 2–6) at 90 days. Results: Compared with patients with no lipid-lowering pretreatment, those with lipid-lowering pretreatment were significantly older, more likely to be non-Asian and more likely to have a medical history including vascular co-morbidity. After propensity analysis assessment and adjustment for important baseline variables at the time of randomisation, as well as imbalances in management during the first 7 days of hospital admission, there were no significant differences in mortality (OR 0.85; 95% CI 0.58–1.25, p = 0.42), or in overall 90-day death and disability (OR 0.85, 95% CI 0.67–1.09, p = 0.19), despite a significant decrease in sICH among those with lipid-lowering pretreatment according to the European Co-operative Acute Stroke Study 2 definition (OR 0.49, 95% CI 0.28–0.83, p = 0.009). No differences in key efficacy or safety outcomes were seen in patients with and without lipid-lowering pretreatment between low- and standard-dose alteplase arms. Conclusions: Lipid-lowering pretreatment is not associated with adverse outcome in AIS patients treated with intravenous alteplase, whether assessed by 90-day death and disability or death alone.

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Abstract: Low-dose i.v. rt-PA and early intensive BP lowering could provide more affordable and safer use of thrombolysis treatment for patients with AIS worldwide.

Cited by 84 publications

References 45 publications

Effects of Early Hypertension Control after Ischaemic Stroke on the Outcome: A Meta-Analysis

Effects of Early Hypertension Control after Ischaemic Stroke on the Outcome: A Meta-Analysis

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

Lipid-Lowering Pretreatment and Outcome Following Intravenous Thrombolysis for Acute Ischaemic Stroke: A Post Hoc Analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study Trial

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