ENCHANTED is an independent, investigator initiated, international collaborative, quasi-factorial randomised controlled trial involving a package of two linked comparative treatment arms, which aims to address four key questions in patients eligible for thrombolysis in the acute phase of ischaemic stroke.
- 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?
- 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)?
- Does low-dose (0.6 mg/kg) i.v. rtPA reduce the risk of symptomatic intracerebral haemorrhage (sICH)?
- Does the addition of intensive BP lowering to thrombolysis with rtPA reduce the risk of any ICH?
Background and Rationale
Modern therapy for acute ischaemic stroke is based on the premise that early vessel re-canalisation and reperfusion are essential for the preservation of brain function and promotion of satisfactory outcome. RtPA is the only approved treatment of acute ischaemic stroke, licensed on the basis of the NINDS trial, where an i.v. dose of 0.9 mg/kg within 3 hours of symptom onset was shown to improve clinical outcomes with an acceptable risk of sICH, although the time criteria for use has recently been extended to 4.5 hours on the basis of subsequent randomised evidence. However, 0.6 mg/kg is the standard approved dose of rtPA in Japan, where non-randomised studies have shown comparable clinical outcomes and a reduced risk of sICH compared to expected rates for the standard dose.
Thus, low dose rtPA (i.e. which generally requires use of a single 50mg vial of Actilyse ® Boehringer Ingelheim) has become an attractive ‘cheaper’ treatment option for patients who cannot afford the full dose (i.e. 2 vials) in much of Asia. In the absence of randomised evidence, however, there is ongoing uncertainty as to whether low-dose rtPA is truly equivalent in efficacy, or even safer, to the standard dose, not just in Asians but in other population groups around the world.
The optimal management of BP in acute ischaemic stroke remains controversial. Although BP levels are commonly elevated, the effects of BP lowering in the hyperacute phase of stroke remain unknown. Guidelines for BP control in acute ischaemic stroke are consistent in contraindicating use of rtPA in patients with systolic BP >185 mmHg and diastolic BP >110 mmHg, but recent data suggests that lower BP levels may achieve better outcomes. The most compelling data are from large-scale prospective registry studies, such as SITS-MOST, where elevated baseline systolic BP are associated with a worse outcome and elevated risk of sICH post-rtPA. None of the recently completed (and ongoing) trialsin the area have been specifically designed to address the role of rapid intensive BP lowering within the first few hours of stroke onset, and in particular, as to whether such treatment improves outcomes after rtPA. The INTERACT pilot study showed that rapid BP lowering (140 mmHg systolic target) is feasible, safe and potential efficacious in attenuating bleeding in brain.
Inclusion Criteria for use of thrombolytic treatment with rtPA
- Adult (age ≥18 years)
- A clinical diagnosis of acute ischaemic stroke confirmed by brain imaging
- Able to receive rtPA treatment within 4.5 hours after the definite time of onset of symptoms
- Have a systolic BP ≤185 mmHg (i.e. the guideline recommended level of eligibility for rtPA; patients with higher BP levels at presentation can still be included provided the BP is reduced to the entry level prior to commencement of the randomised treatment)
- Provide informed consent (or via an appropriate proxy, according to local requirements)
Specific criteria for arm [A] of low-dose vs standard-dose rtPA:
- Able to receive either low-dose or standard-dose rtPA
Specific criteria for arm [B] of intensive BP lowering vs guideline recommended BP control
- Sustained elevated systolic BP level, defined as 2 readings (i.e. ≥150)
- Able to receive either immediate intensive BP lowering or conservative BP management
- Unlikely to potentially benefit from the therapy (e.g. advanced dementia) or very high likelihood of death within 24 hours of stroke onset
- Other medical illness that interferes with outcome assessments and follow-up
Note : Click on the below image to view the ENCHANTED protocol schema