DIRECT-SAFE Trial: Direct EVT vs Bridging Therapy Within 4.5 Hours
In patients with LVO stroke eligible for IV thrombolysis across Australia, New Zealand, China, and Vietnam, does direct EVT produce outcomes non-inferior to bridging thrombolysis plus EVT within 4.5 hours?
Mitchell et al. (Lancet 2022) · doi:10.1016/S0140-6736(22)00564-5 · 295 patients
Population
Included
- Age 18 or older
- Acute ischemic stroke with LVO of ICA, M1, M2, or basilar artery
- NIHSS 2 or greater
- Eligible for IV thrombolysis within 4.5 hours of symptom onset
- Pre-stroke mRS 0 to 2
- Patients presenting with acute ischemic stroke eligible using standard criteria to receive IV thrombolysis within 4.5 hours of stroke onset
- Patient's age is ≥18 years
- Intra-arterial clot retrieval treatment can commence (groin puncture) within 6 hours of stroke onset
- Arterial occlusion on CTA or MRA of the ICA, M1, M2 or basilar artery
Excluded
- Contraindication to IV thrombolysis
- Pre-stroke mRS greater than 2
- Presentation beyond 4.5 hours from symptom onset
- NIHSS less than 2
- Intracranial hemorrhage (ICH) identified by CT or MRI
- Rapidly improving symptoms at the discretion of the investigator
- Pre-stroke mRS score of ≥4 (indicating previous disability)
- Hypodensity in >1/3 MCA territory on non-contrast CT
- Contraindication to imaging with contrast agents
- Any terminal illness such that patient would not be expected to survive more than 1 year
- Any condition that, in the judgment of the investigator, could impose hazards to the patient if study therapy is initiated or affect the participation of the patient in the study
- Pregnant women
Source: ClinicalTrials.gov NCT03494920· Retrieved 2026-06-08
Non-inferiority design: margin not met
DIRECT-SAFE tested whether direct EVT was acceptably close to bridging thrombolysis (NI margin: -12 pp). Non-inferiority was not demonstrated: the lower CI bound (-15.4 pp) crossed the margin. The adjusted risk difference (-5.1%, CI -15.4% to 5.3%) does not establish equivalence.
Primary Outcome — mRS 0-2 or Pre-stroke Baseline at 90 Days (Non-inferiority)
LVO within 4.5 h; alteplase or tenecteplase in bridging arm
Negligible absolute difference
mRS 0-2 or Pre-stroke Baseline at 90 Days
Study Arms
- Agent
- Mechanical thrombectomy without IV thrombolysis
- Route
- Endovascular (intra-arterial)
- Co-interventions
- Direct thrombectomy with the Trevo device (Stryker) as first-line intervention, no IV thrombolytic; balloon guide/aspiration/additional devices, and stenting or antiplatelet for intracranial atherosclerotic disease, at investigator discretion; heparinised saline flush during the procedure.
Methods/Procedures, Mitchell Lancet 2022 p.118. Trevo first-line. No heparin/antiplatelet/anticoagulant for ≥24 h post-procedure unless stenting required.
- Agent
- IV thrombolytic (alteplase or tenecteplase), then mechanical thrombectomy
- Dose
- Alteplase 0.9 mg/kg (83% of treated) or tenecteplase (17%), per local standard care
- Route
- IV thrombolytic, then endovascular thrombectomy
- Co-interventions
- IV thrombolytic (alteplase or tenecteplase) per standard care at each site, then transfer to angiography minimising delay to puncture; same Trevo-first technique and discretionary adjuncts as the direct arm.
Methods/Procedures, Mitchell Lancet 2022 p.118; agent split from Table 1 p.119 (145 treated: 120 alteplase, 25 tenecteplase). Thrombolytic agent/dose at site discretion.
Trial Design
Type
- International multicenter randomized noninferiority trial
- Direct EVT vs bridging thrombolysis plus EVT
- Included ICA, M1, M2, and basilar occlusions
- Open-label with blinded endpoint assessment
Timeline
Enrolled 2018-2021 across Australia, New Zealand, China, and Vietnam
N
295
Enrollment
295 patients across Australia, New Zealand, China, and Vietnam. PROBE design (open-label, blinded endpoint assessment). Enrolled 2018 to 2021. Bridging arm allowed alteplase or tenecteplase at national standard doses. Published Lancet 2022.
ClinicalTrials.gov
NCT03494920Bedside Pearl
Give IV thrombolysis (alteplase or tenecteplase) in eligible LVO patients within 4.5 hours and do not delay for thrombectomy. DIRECT-SAFE failed non-inferiority by more than 3 percentage points beyond the margin, across diverse geography and vascular anatomy.