Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED)
- Conditions
- Ischemic StrokeHigh Blood Pressure
- Interventions
- Drug: Low-dose rtPADrug: Standard-dose rtPAOther: Intensive blood pressure (BP) loweringOther: BP management policies
- Registration Number
- NCT01422616
- Lead Sponsor
- The George Institute
- Brief Summary
ENCHANTED is an independent, investigator initiated, international collaborative, quasi-factorial randomised controlled trial involving a package of 2 linked comparative randomised treatment arms, which aims to address 4 key questions in patients eligible for thrombolysis in the acute phase of ischaemic stroke. (1) Does low-dose (0.6 mg/kg) intravenous (i.v.) recombinant tissue plasminogen activator (rtPA) provide equivalent benefits compared to standard-dose (0.9 mg/kg) rtPA? (2) Does intensive blood pressure (BP) lowering (130-140 mmHg systolic target) improve outcomes compared to the current guideline recommended level of BP control (180 mmHg systolic target)? (3) Does low-dose (0.6 mg/kg) intravenous (i.v.) recombinant tissue plasminogen activator (rtPA) reduce the risk of symptomatic intracerebral haemorrhage (sICH)? (4) Does the addition of intensive BP lowering to thrombolysis with rtPA reduce the risk of any intracerebral haemorrhage (ICH)?
The rtPA dose arm of the study addressing questions (1) and (3) concluded with a publication of the results in May 2016. The BP intensity arm of the study addressing questions (2) and (4) concluded with a publication of the results in February 2019.
- Detailed Description
This study is an international, multicentre, prospective, fixed-time point (optional) randomisation for two arms (\[A\] 'dose of rtPA' and \[B\] 'level of BP control'), open-label, blinded endpoint (PROBE) controlled trial that involved 4587 patients (3310 for rtPA arm {recruitment completed in August 2015} and 2227 for BP arm {recruitment completed in April 2018} with 939 overlap) with acute ischaemic stroke recruited from over 100+ Clinical Centres from Australia, Asia, Europe and South America.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 4587
- Adult (age ≥18 years)
- A clinical diagnosis of acute ischaemic stroke confirmed by brain imaging
- Able to receive treatment within 4.5 hours after the definite time of onset of symptoms
- Have a systolic BP ≤185 mmHg
- Provide informed consent (or via an appropriate proxy, according to local requirements)
Specific criteria for arm [A] of low-dose vs standard-dose rtPA (Recruitment completed in August 2015.):
- Able to receive either low-dose or standard-dose rtPA
Specific criteria for arm [B] of intensive BP lowering vs guideline recommended BP control
- Patient will or has received thrombolysis treatment with rtPA, either randomised dose within the trial or physician decided dose rtPA outside of the trial
- Sustained elevated systolic BP level, defined as 2 readings ≥ 150 mmHg
- Able to commence intensive BP lowering treatment within 6 hours of stroke onset
- Able to receive either immediate intensive BP lowering or conservative BP management
- Unlikely to potentially benefit from the therapy (e.g. advanced dementia), or a very high likelihood of death within 24 hours of stroke onset.
- Other medical illness that interferes with outcome assessments and follow-up [known significant pre-stroke disability (mRS scores 2-5)].
- Specific contraindications to rtPA (Actilyse) or any of the blood pressure agents to be used.
- Participation in another clinical trial involving evaluation of pharmacological agents.
- Need for following concomitant medication, including phosphodiesterase inhibitors and monoamine oxidase inhibitors.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- FACTORIAL
- Arm && Interventions
Group Intervention Description Low-dose rtPA (Recruitment completed in August 2015) Low-dose rtPA low-dose 0.6 mg/kg (maximum of 60 mg) i.v. rtPA Standard-dose rtPA (Recruitment completed in August 2015) Standard-dose rtPA standard-dose 0.9 mg/kg (maximum of 90 mg) i.v. rtPA Early intensive BP lowering Intensive blood pressure (BP) lowering The trial is an assessment of BP lowering management strategies, using routinely available drugs. Intensive blood pressure (BP) lowering to a target systolic BP range 130-140 mmHg within one hour and to maintain this level for at least 72 hours (or until hospital discharge or death if this should occur earlier). A standardised i.v. BP lowering regimen using locally available and approved i.v. BP lowering agents (e.g. Labetalol Hydrochloride, Metoprolol tartrate, Hydralazine Hydrochloride, Glycerol Trinitrate, Phentolamine mesylate, Nicardipine, Urapidil, Esmolol, Clonidine, Enalaprilat, Nitroprusside) will be used, commenced in the emergency department and later in a high dependency area (e.g. acute stroke or neurointensive care unit) as is usual for patients receiving rtPA. Control / guideline-based BP management BP management policies The trial is an assessment of BP lowering management strategies, using routinely available drugs. Patients allocated to the control group will receive management of BP that is based on a standard guideline, as published by the American Heart Association (AHA). For this group, the attending clinician may consider commencing BP treatment if the systolic level is greater than 180 mmHg, however and the first line treatment will be oral (including nasogastric if required) and/or transdermal routes. Should control of systolic BP not be achieved via these routes, i.v. treatment may be started until the target systolic BP of 180 mmHg is achieved.
- Primary Outcome Measures
Name Time Method Combined death and disability 90 days Unadjusted modified Rankin Scale \[mRS\] score 2-6
- Secondary Outcome Measures
Name Time Method Admission to residential care 90 days Neurological deterioration 72 hours deterioration in NIHSS score
Symptomatic intracerebral hemorrhage 36 hours Brain imaging (or necropsy) confirmed ICH with deterioration in NIH Stroke Scale (NIHSS) score or death, as defined by the NINDS trial criteria
Death or disability by the alternative, ordinal shift analysis 90 days Unadjusted death or functional outcome by the alternative ordinal shift analysis of scores on the modified Rankin Scale \[mRS\]
Death at 7 and 90 days Death and 7 and 90 days
Disability 90 days mRS score 2-5
Health-related quality of life 90 days Health-related quality of life by the EuroQoL
Health service use 90 days Health service use for calculation of resources and costs
Symptomatic intracerebral hemorrhage (ICH) within 7 days By various other centrally adjudicated criteria, including ECASS2, ECASS3, IST-3 criteria, and fatal ICH within 7 days
Any intracerebral hemorrhage (ICH) any time during 90 days Centrally adjudicated review of brain imaging for any evidence of ICH
Death or disability in as treated per-protocol population 90 days Adjusted analysis of the modified Rankin Scale \[mRS\] score 2-6
Death or neurological deterioration 72 hours Death or neurological deterioration (defined by 4 points or more increase in NIHSS score from baseline)
Length of initial acute hospital stay within 90 days Length of hospital stay in days
Recurrent acute myocardial infarction and ischemic stroke within 90 days Recurrent acute myocardial infarction and ischemic stroke
Trial Locations
- Locations (1)
Royal Prince Alfred Hospital
🇦🇺Sydney, New South Wales, Australia