Ischemic Stroke Clinical Trial
Official title:
Parallel Group, Randomized Clinical Trial of Direct Intra-arterial Thrombectomy Versus Intravenous Thrombolysis With Intra-arterial Thrombectomy for Patients With Large Vessel Occlusion of the Anterior Circulation
Background: Intravenous thrombolysis (IVT) combined with mechanical thrombectomy (MT) has
been proven safe and effective in patients with acute ischemic stroke (AIS) of anterior
circulation large vessel occlusion (LVO). Despite recanalization, a considerable proportion
of patients do not recover. The incidence of symptomatic intracerebral hemorrhage (sICH) was
similar between combined IVT plus MT and IVT, suggesting that this complication could not be
attributed to the MT, but rather to pre-treatment with IVT. Meanwhile, the incidence of
intracranial atherosclerosis stenosis (ICAS) is higher in Asians. It is not clear whether
patients with ICAS benefit from pretreatment with alteplase or not and how ICAS modifies
treatment effect.
Objective: To assess whether direct MT is non-inferior compared to combined IVT plus MT in
patients with AIS due to an anterior circulation LVO, and to assess treatment effect
modification by presence of ICAD.
Study design: This is a parallel group, RCT of direct MT compared to combined IVT plus MT,
using a non-inferiority design. The trial has observer blinded assessment of the primary
outcome and of neuro-imaging at baseline and follow up. The trial will be executed in
collaboration with MRCLEAN NO-IV investigators.
Study population: Patients with AIS of anterior circulation VLO confirmed by CTA. Initiation
of IVT must be feasible within 4.5 hours from symptom onset. Age must be 18 or over and NIHSS
2 or more.
Main outcomes: The full distribution of the mRS at 3 months. Secondary outcomes: 1. death
within 90 +/- 14 days; 2. pre-interventional reperfusion assessed on first intracranial DSA;
3. eTICI19 score on final angiography of MT; 4. score on the NIHSS at 24 +/- 6 hours and 5-7
days, or at discharge; 5. recanalization rate at 24-72h by CTA; 6. Final lesion volume at 5-7
days on NCCT20; 7. score on the EuroQoL 5-dimensions 5-level (EQ5D-5L)21 and Barthel index22
at 90 +/- 14 days; 8. dichotomous clinical outcome on the mRS at 90 +/- 14 days.
Protocol title: Direct Intra-arterial thrombectomy in order to Revascularize AIS patients
with large vessel occlusion Efficiently in Chinese Tertiary hospitals: a Multicenter
randomized clinical Trial (DIRECT-MT) Rationale: Mechanical thrombectomy (MT) by means of
retrievable stents has been proven safe and effective in patients with acute ischemic stroke
(AIS) with confirmed large vessel occlusion of the anterior circulation and in whom the
procedure can be started within 6 hours from onset. Despite recanalization, a considerable
proportion of patients do not recover. This can be attributed to potential adverse effects of
the intravenous treatment (IVT) prior to MT. These effects could include neurotoxicity, blood
brain barrier leakage and thrombus fragmentation through softening of the thrombus.
Another reason for non-recovery in MRCLEAN was the occurrence of symptomatic intracranial
hemorrhage (sICH) in 7% of patients, which was fatal in 65%. sICH occurred as often in the
intervention as in the control group, suggesting that this complication could not be
attributed to the MT, but rather to pre-treatment with IVT. Therefore, the investigators
hypothesize that direct MT may lead to a 8% absolute increase in good outcome compared to MT
preceded by IVT.
Objective: To assess whether direct MT is non-inferior compared to combined IVT plus MT in
patients with AIS due to an anterior circulation LVO, and to assess treatment effect
modification by presence of ICAD.
Study design: This is a multicenter, prospective, open label parallel group trial with
blinded outcome assessment (PROBE design) assessing non-inferiority of direct MT compared to
combined IVT plus MT.
Study population: Patients with acute ischemic stroke and a confirmed anterior circulation
occlusion by CTA. Initiation of IVT must be feasible within 4.5 hours from symptom onset. Age
must be 18 or over and NIHSS 2 or more.
INCLUSION CRITERIA
- a clinical diagnosis of acute ischemic stroke,
- caused by a large vessel occlusion of the anterior circulation (intracranial carotid
artery or middle M1/proximal M2) cerebral artery confirmed by CTA,
- CT or MRI ruling out intracranial hemorrhage,
- eligible for IVT and MT (within 4.5 hours after symptom onset),
- a score of at least 2 on the NIH Stroke Scale,
- age of 18 years or older,
- written informed consent. EXCLUSION CRITERIA
- Pre-stroke disability which interferes with the assessment of functional outcome at 90
days, i.e. mRS >2
- Any contra-indication for IVT, according to guidelines of the American Heart
Association, i.e.:
- arterial blood pressure exceeding 185/110 mmHg
- blood glucose less than 2.7 or over 22.2 mmol/L
- cerebral infarction in the previous 6 weeks with residual neurological deficit or
signs of recent infarction on neuro-imaging
- serious head trauma in the previous 3 months
- major surgery or serious trauma in the previous 2 weeks
- gastrointestinal or urinary tract hemorrhage in the previous 3 weeks
- previous intracerebral hemorrhage
- use of anticoagulant with INR exceeding 1.7
- known thrombocyte count less than 100 x 109/L
- treatment with direct thrombin or factor X inhibitors
- treatment with heparin (APTT exceeds the upper limit of normal value) in the
previous 48 hours.
Intervention: The intervention group will undergo immediate MT using a stent retriever, as
recommended by the steering committee. The standard care group will receive IVT 0.9 mg/kg
with a maximum dose of 90 mg in one hour, followed by MT using a stent retriever. the
investigators strive to reduce delays associated with IVT administration to a minimum to
adequately assess the effect of IVT itself with MT.
Main study parameters/outcomes: The primary outcome is the score on the modified Rankin Scale
assessed blindly at 90 (+/- 14) days. An common odds ratio, adjusted for the prognostic
factors (age, NIHSS, collateral score), representing the shift on the 6-category mRS scale
measured at 3 months, estimated with ordinal logistic regression, will be the primary effect
parameter.
Secondary outcomes: 1. death within 90 +/- 14 days; 2. pre-interventional reperfusion
assessed on first intracranial DSA; 3. eTICI19 score on final angiography of MT; 4. score on
the NIHSS at 24 +/- 6 hours and 5-7 days, or at discharge; 5. recanalization rate at 24-72h
by CTA; 6. Final lesion volume at 5-7 days on NCCT20; 7. score on the EuroQoL 5-dimensions
5-level (EQ5D-5L)21 and Barthel index22 at 90 +/- 14 days; 8. dichotomous clinical outcome on
the mRS at 90 +/- 14 days.
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