High Blood Pressure, Ischemic Stroke
Conditions
Keywords
Ischemic stroke, High blood pressure, Thrombolysis, Antihypertensive drugs, Disability, Clinical trial
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.
Interventions
DRUGLow-dose rtPA
Patients allocated to low-dose will receive 0.6 mg/kg (maximum of 60 mg) i.v. (15% bolus \[maximum bolus dose of 9mg\] and 85% infusion over 60 mins) recombinant tissue plasminogen activator (rtPA).
DRUGStandard-dose rtPA
Patients allocated to standard-dose will receive 0.9 mg/kg (maximum of 90 mg) i.v. (10% bolus and 90% infusion over 60 mins) rtPA.
OTHERIntensive blood pressure (BP) lowering
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 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. The trial is an assessment of BP lowering management strategies, using routinely available drugs. There is some flexibility in the use of particular BP lowering agents to achieve BP targets.
OTHERBP management policies
Patients allocated to the control group will receive management of BP that is based on a standard guideline, as published by the 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. The trial is an assessment of BP lowering management strategies, using routinely available drugs. There is some flexibility in the use of particular BP lowering agents to achieve BP targets.
Sponsors
National Health and Medical Research Council, Australia
The Stroke Association, United Kingdom
Conselho Nacional de Desenvolvimento Científico e Tecnológico
Takeda
The George Institute
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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
Exclusion criteria
* 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Combined death and disability | 90 days | Unadjusted modified Rankin Scale \[mRS\] score 2-6 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| Neurological deterioration | 72 hours | deterioration in NIHSS score |
| Health-related quality of life | 90 days | Health-related quality of life by the EuroQoL |
| Admission to residential care | 90 days | — |
| 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 SITS-MOST criteria |
| 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 death or functional outcome by the binary and alternative ordinal shift analysis of scores on the modified Rankin Scale \[mRS\] |
| 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 |
| Health service use | 90 days | Health service use for calculation of resources and costs |
Countries
Australia
Outcome results
None listed