DEFUSE 3 Trial: Thrombectomy for Ischemic Stroke (6-16 Hours)
In anterior LVO patients 6–16 hours from last known well with RAPID-defined perfusion mismatch, does endovascular thrombectomy improve the mRS distribution at 90 days compared with standard medical therapy?
Albers et al. (NEJM 2018;378(8):708–718) · doi:10.1056/NEJMoa1713973 · 182 patients
Population
Included
- Anterior LVO (ICA or M1)
- 6–16 hours from last known well
- Pre-stroke mRS 0–1
- RAPID perfusion mismatch: core <70 mL, mismatch ratio ≥1.8, mismatch volume ≥15 mL
Clinical Inclusion Criteria
- Signs and symptoms consistent with the diagnosis of acute anterior circulation ischemic stroke
- Age 18-90 years
- Baseline NIHSS is ≥6 and remains ≥6 immediately prior to randomization
- Endovascular treatment can be initiated (femoral puncture) between 6 and 16 hours of stroke onset. Stroke onset is defined as the time the patient was last known to be at their neurologic baseline (wake-up strokes are eligible if they meet the above time limits)
- Modified Rankin Scale less than or equal to 2 prior to qualifying stroke (functionally independent for all ADLs)
- Patient/Legally Authorized Representative has signed the Informed Consent form
Neuroimaging Inclusion Criteria
- ICA or MCA-M1 occlusion (carotid occlusions can be cervical or intracranial; with or without tandem MCA lesions) by MRA or CTA, AND a Target Mismatch Profile on CT perfusion or MRI (ischemic core volume <70 mL, mismatch ratio ≥1.8, and mismatch volume ≥15 mL)
Alternative Neuroimaging Inclusion Criteria (if perfusion imaging or CTA/MRA is technically inadequate)
- (A) If CTA (or MRA) is technically inadequate: Tmax >6 s perfusion deficit consistent with an ICA or MCA-M1 occlusion AND Target Mismatch Profile (ischemic core volume <70 mL, mismatch ratio >1.8, and mismatch volume >15 mL as determined by RAPID software)
- (B) If MRP is technically inadequate: ICA or MCA-M1 occlusion (carotid occlusions can be cervical or intracranial; with or without tandem MCA lesions) by MRA (or CTA, if MRA is technically inadequate and a CTA was performed within 60 minutes prior to the MRI) AND DWI lesion volume <25 mL
- (C) If CTP is technically inadequate: Patient can be screened with MRI and randomized if neuroimaging criteria are met
Excluded
- Onset <6 hours (use early-window evidence)
- Onset >16 hours (use DAWN window)
- Pre-stroke mRS ≥2
- Posterior circulation occlusion (see ATTENTION/BAOCHE)
- Core ≥70 mL or mismatch ratio <1.8
Clinical Exclusion Criteria
- Other serious, advanced, or terminal illness (investigator judgment) or life expectancy is less than 6 months
- Pre-existing medical, neurological or psychiatric disease that would confound the neurological or functional evaluations
- Pregnant
- Unable to undergo a contrast brain perfusion scan with either MRI or CT
- Known allergy to iodine that precludes an endovascular procedure
- Treated with tPA >4.5 hours after time last known well
- Treated with tPA 3-4.5 hours after last known well AND any of the following: age >80, current anticoagulant use, history of diabetes or prior stroke, NIHSS >25
- Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency; recent oral anticoagulant therapy with INR >3 (recent use of one of the new oral anticoagulants is not an exclusion if estimated GFR >30 mL/min)
- Seizures at stroke onset if it precludes obtaining an accurate baseline NIHSS
- Baseline blood glucose of <50 mg/dL (2.78 mmol) or >400 mg/dL (22.20 mmol)
- Baseline platelet count <50,000/µL
- Severe, sustained hypertension (Systolic BP >185 mmHg or Diastolic BP >110 mmHg)
- Current participation in another investigational drug or device study
- Presumed septic embolus; suspicion of bacterial endocarditis
- Clot retrieval attempted using a neurothrombectomy device prior to 6 hrs from symptom onset
- Any other condition that, in the opinion of the investigator, precludes an endovascular procedure or poses a significant hazard to the subject if an endovascular procedure was performed
Neuroimaging Exclusion Criteria
- ASPECTS score <6 on non-contrast CT (if patient is enrolled based on CT perfusion criteria)
- Evidence of intracranial tumor (except small meningioma), acute intracranial hemorrhage, neoplasm, or arteriovenous malformation
- Significant mass effect with midline shift
- Evidence of internal carotid artery dissection that is flow limiting or aortic dissection
- Intracranial stent implanted in the same vascular territory that precludes the safe deployment/removal of the neurothrombectomy device
- Acute symptomatic arterial occlusions in more than one vascular territory confirmed on CTA/MRA (e.g., bilateral MCA occlusions, or an MCA and a basilar artery occlusion)
Source: ClinicalTrials.gov NCT02586415· Retrieved 2026-06-08
Primary Outcome — Ordinal mRS Shift
Ordinal-shift design: Primary endpoint is the full mRS distribution analyzed by ordinal logistic regression (common OR 2.77, 95% CI 1.63–4.70). The mRS 0–2 dichotomization shown below is a secondary outcome; its NNT 3.6 is derived from the secondary, not the primary.
mRS 0–2 at 90 Days (secondary)
Study Arms
- Agent
- Thrombectomy with any FDA-approved thrombectomy device, at the neurointerventionalist's discretion. Carotid angioplasty ± stenting permitted for cervical ICA atherosclerotic stenosis/occlusion.
- Route
- Endovascular
- Frequency
- Single procedure, 6–16 h from last-known-well. Protocol required femoral puncture within 90 minutes after the end of qualifying imaging. General anesthesia discouraged. Intra-arterial t-PA not allowed.
- Duration
- One-time procedure
- Co-interventions
- Standard medical therapy per current AHA guidelines (BOTH groups). IV t-PA allowed only if begun within 4.5 h of onset.
Technique, 90-min puncture target, GA-discouraged, no-IA-tPA, and AHA-guideline medical therapy in both groups from Albers NEJM 2018 p.710. Technical success = TICI 2b/3.
- Agent
- Standard medical therapy per current AHA guidelines (no thrombectomy)
- Route
- Medical
- Co-interventions
- Standard medical therapy per current AHA guidelines (BOTH groups). IV t-PA allowed only if begun within 4.5 h of onset.
Control = AHA-guideline standard medical therapy (Albers NEJM 2018 p.710). IV t-PA use low (intervention 11%, control 9%; Table 1). Source: NCT02586415.
Safety
Symptomatic ICH
7%
4%
7% EVT vs 4% control (P=0.75). No significant difference.
90-day mortality
14%
26%
14% EVT vs 26% control (P=0.05). Borderline significant secondary outcome. Directional benefit.
Trial Design
Type
- Multicenter randomized open-label trial
- Blinded-endpoint assessment
- Perfusion imaging selection (CTP/MRI)
- 1:1 allocation (Thrombectomy vs. Medical)
Timeline
Enrolled 2016-2017
N
182
Enrollment
182 patients (92 EVT / 90 medical) at 38 US centers. Enrolled May 2016 – Dec 2017. Stopped early at pre-specified interim. Published NEJM 2018.
ClinicalTrials.gov
NCT02586415Bedside Pearl
In anterior LVO 6–16 hours from LKW with RAPID-defined penumbra (core <70 mL, mismatch ≥1.8 and ≥15 mL), EVT triples functional independence (45% vs 17%). Primary endpoint is the ordinal mRS shift (common OR 2.77, CI 1.63–4.70); NNT 3.6 derived from the mRS 0–2 secondary.
See also