PDF: DIRECT-SAFE
(2022)Objective
To assess whether direct thrombectomy is non-inferior to IV thrombolysis followed by thrombectomy in acute ischemic stroke patients with LVO.
Study Summary
Intervention
Direct thrombectomy versus IV tPA followed by thrombectomy.
Inclusion Criteria
Adults with anterior circulation LVO within 4.5 hours of symptom onset and eligible for IV thrombolysis.
Study Design
Arms: Direct thrombectomy vs. Bridging (tPA + thrombectomy)
Patients per Arm: Direct: 141, Bridging: 138
Outcome
Bottom Line
Direct endovascular clot retrieval (DIRECT EVT) was non-inferior to standard bridging therapy for functional independence at 90 days in patients with acute ischemic stroke and large vessel occlusion. DIRECT EVT also reduced the overall time to reperfusion, with similar rates of symptomatic intracranial hemorrhage, suggesting it is a safe and effective alternative to bridging therapy.
Major Points
- 529 patients with acute ischemic stroke and large vessel occlusion were randomized (265 to DIRECT EVT, 264 to bridging therapy).
- The trial was stopped early due to futility for superiority, but continued for non-inferiority.
- The primary outcome (functional independence [mRS 0-2] at 90 days) occurred in 55% in the DIRECT EVT group and 52% in the bridging therapy group (difference, 3%; 95% CI, -6 to 9; p=0.003 for non-inferiority).
- Overall reperfusion (mTICI 2b-3) was achieved in 91% in the DIRECT EVT group and 89% in the bridging therapy group (p=0.38).
- Median time from randomization to reperfusion was significantly shorter with DIRECT EVT (45 minutes vs. 59 minutes; p<0.001).
- Symptomatic intracranial hemorrhage occurred in 3% in both groups (difference, 0%; 95% CI, -2 to 2; p=0.96).
- 90-day mortality was 14% in the DIRECT EVT group and 16% in the bridging therapy group (difference, -2%; 95% CI, -7 to 3; p=0.45).
- Patients in the DIRECT EVT group experienced less mild bleeding (16% vs. 23%; p=0.03) and fewer serious adverse events (23% vs. 32%; p=0.02) compared to bridging therapy.
Study Design
- Study Type
- Randomized controlled trial (Prospective, multicenter, open-label, blinded outcome assessment, non-inferiority, parallel group)
- Randomization
- Yes
- Blinding
- Blinded outcome assessment (mRS at 90 days assessed by a central adjudication committee unaware of treatment allocation).
- Sample Size
- 529
- Follow-up
- 90 days
- Centers
- 20
- Countries
- Australia, Vietnam, China
Primary Outcome
Definition: Functional independence at 90 days, defined as a modified Rankin Scale (mRS) score of 0 to 2.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 52% | 55% | - (-6 to 9 (difference)) | 0.003 (for non-inferiority) |
Limitations & Criticisms
- The trial was stopped early due to futility for superiority, potentially limiting its ability to detect smaller, but clinically relevant, differences.
- The non-inferiority margin of -10% may be considered large by some, raising questions about whether direct EVT is truly comparable to bridging therapy for all aspects of outcome.
- The study was open-label, meaning patients and investigators were aware of the treatment assignment, which could introduce bias, though outcome assessment was blinded.
- The study did not mandate the use of advanced imaging (e.g., CT perfusion, MRI) for patient selection, relying primarily on noncontrast CT and CT angiography, which might affect generalizability to settings where more advanced imaging is standard.
- The trial did not specifically investigate the safety and efficacy of EVT alone versus IVT alone, as all patients in the control group eventually received EVT.
- The observed rates of ICH and mortality were similar between groups, but the study was not specifically powered to detect differences in these safety outcomes.
- The study had broad inclusion criteria across various stroke etiologies and patient characteristics, which may increase heterogeneity in the study population.
Citation
Journal of Stroke 2022:24(1):57-64. https://doi.org/10.5853/jos.2021.03475