title: 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.
abstract: BACKGROUND
  Controversy exists over the optimal dose of intravenous (i.v.) recombinant tissue plasminogen activator (rt-PA) and degree of blood pressure (BP) control in acute ischaemic stroke (AIS). Asian studies suggest low-dose (0·6 mg/kg) is more efficacious than standard-dose (0·9 mg/kg) i.v. rt-PA, and guidelines recommend reducing systolic BP to <185 mmHg before and <180 mmHg after use of i.v. rt-PA, despite observational studies indicating better outcomes at much lower (<140 mmHg) systolic BP levels in this patient group.
  
  
  OBJECTIVE
  The study aims to assess in thrombolysis-eligible AIS patients whether: (i) low-dose (0·6 mg/kg body weight; maximum 60 mg) i.v. rt-PA has non-inferior efficacy and lower risk of symptomatic intracerebral haemorrhage (sICH) compared to standard-dose (0·9 mg/kg body weight; maximum 90 mg) i.v. rt-PA; and (ii) early intensive BP lowering (systolic target 130-140 mmHg) has superior efficacy and lower risk of any ICH compared to guideline-recommended BP control (systolic target < 180 mmHg).
  
  
  METHODS
  The ENhanced Control of Hypertension And Thrombolysis strokE stuDy (ENCHANTED) trial is an independent,2 × 2 quasi-factorial, active-comparison, prospective, randomized, open blinded endpoint (PROBE), clinical trial that is evaluating Arm [A] 'rt-PA dose' and/or Arm [B] 'BP control', using central Internet randomization and data collection in patients fulfilling local criteria for thrombolysis and clinician uncertainty over the study treatments. The treatment arms will be analyzed separately.
  
  
  RESULTS
  The primary study outcome in both trial Arms is death or disability according to the modified Rankin scale (mRS, scores 2-6) assessed at 90 days. Secondary outcomes include sICH, any ICH, a shift ('improvement') in function across mRS scores, separately on death and disability, early neurological deterioration, recurrent major vascular events, health-related quality of life, length of hospital stay, need for permanent residential care, and health care costs.
  
  
  RESULTS
  Following launch of the trial in February 2012, the study has recruited more than 2500 patients across a global network of approximately 100 sites in 15 countries. The required sample sizes are 3300 for Arm [A] and 2300 for Arm [B], which will provide >90% power to detect non-inferiority of low-dose i.v. rt-PA and superiority of intensive BP lowering on the primary clinical outcome, respectively.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing, China.
authors.forename: Yining
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Division of Neurology, Department of Medicine, National University Hospital and YLL School of Medicine, National University of Singapore, Singapore.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Sharma
authors.affiliation: Department of Cardiovascular Sciences and NIHR Biomedical Research Unit, University of Leicester University, Leicester, UK.
authors.forename: Thompson
authors.initials: T
authors.lastname: Robinson
authors.affiliation: The George Institute for Global Health, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia.
authors.forename: Richard I
authors.initials: RI
authors.lastname: Lindley
authors.affiliation: The George Institute for Global Health, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Chen
authors.affiliation: Asan Medical Center, University of Ulsan, Seoul, South Korea.
authors.forename: Jong Sung
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Clinica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile.|Universidad de Chile, Santiago, Chile.
authors.forename: Pablo
authors.initials: P
authors.lastname: Lavados
authors.affiliation: Clinica Alemana de Santiago, Universidad del Desarrollo, Santiago, Chile.
authors.forename: Verónica
authors.initials: V
authors.lastname: Olavarría
authors.affiliation: The George Institute for Global Health, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia.
authors.forename: Hisatomi
authors.initials: H
authors.lastname: Arima
authors.affiliation: The George Institute for Global Health, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia.
authors.forename: Sully
authors.initials: S
authors.lastname: Fuentes
authors.affiliation: Stroke Unit, People's 115 Hospital, Ho Chi Minh City, Vietnam.
authors.forename: Huy Thang
authors.initials: HT
authors.lastname: Nguyen
authors.affiliation: Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Tsong-Hai
authors.initials: TH
authors.lastname: Lee
authors.affiliation: John Hunter Hospital, Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Parsons
authors.affiliation: John Hunter Hospital, Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia.
authors.forename: Christopher
authors.initials: C
authors.lastname: Levi
authors.affiliation: Calgary Stroke Program, Department of Clinical Neurosciences and Radiology, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Demchuk
authors.affiliation: Stroke trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK.
authors.forename: Philip M W
authors.initials: PM
authors.lastname: Bath
authors.affiliation: Departments of Neurology and Rehabilitation Medicine and Radiology, University of Cincinnati Neuroscience Institute, University of Cincinnati Academic Health Center, Cincinnati, OH, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Broderick
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Donnan
authors.affiliation: Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio grande do Sul, Rio Grande do Sul, Brazil.
authors.forename: Sheila
authors.initials: S
authors.lastname: Martins
authors.affiliation: Stroke Service - Neurology Division, Department of Neuroscience and Behavior, Ribeirão Preto School of Medicine, University of Sao Paulo, Ribeirão Preto, SP, Brazil.
authors.forename: Octavio M
authors.initials: OM
authors.lastname: Pontes-Neto
authors.affiliation: Fundación Cardiovascular, Bucaramanga, Colombia.
authors.forename: Federico
authors.initials: F
authors.lastname: Silva
authors.affiliation: Department of Neurology, Christian Medical College, Ludhiana, India.
authors.forename: Jeyaraj
authors.initials: J
authors.lastname: Pandian
authors.affiliation: Direttore, UO Neurologia, USL Umbria 1, Sedi di Città di Castello e Branca, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ricci
authors.affiliation: Department of Neurology, APHP - Hôpital Lariboisière and DHU NeuroVasc Paris - Sorbonne, Univ Paris Diderot - Sorbonne Paris Cité, Paris, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Stapf
authors.affiliation: The George Institute for Global Health, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Woodward
authors.affiliation: The Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Jiguang
authors.initials: J
authors.lastname: Wang
authors.affiliation: The George Institute for Global Health, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Chalmers
authors.affiliation: The George Institute for Global Health, Royal Prince Alfred Hospital and University of Sydney, Sydney, Australia.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Anderson
mesh_terms: D002545:Brain Ischemia / Q000150:complications; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D007391:International Cooperation; D008297:Male; D020521:Stroke / Q000188:drug therapy* / Q000209:etiology; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator
keywords: Alteplase; acute ischaemic stroke; dose; hypertension; rt-PA; thrombolysis