EXTEND Trial: tPA for Acute Ischemic Stroke (4.5-9 Hours)
In patients with acute ischemic stroke presenting 4.5 to 9 hours after onset, or on awakening from sleep, does IV alteplase improve outcomes when imaging shows salvageable brain tissue?
Ma et al. (NEJM 2019) · doi:10.1056/NEJMoa1813046 · 225 patients
Population
Included
- Age 18 years or older
- Acute ischemic stroke with onset 4.5 to 9 hours prior (or wake-up stroke)
- CT perfusion or DWI/FLAIR mismatch confirming ischemic penumbra
- Core infarct volume under 70 mL on perfusion imaging
- Penumbra volume over 10 mL
- Penumbra-to-core ratio above 1.2
- At least 18 years of age
- Excellent functional status before enrollment (modified Rankin scale score below 2)
- Stroke with a clinical severity score at presentation of 4 to 26 on the National Institutes of Health Stroke Scale (NIHSS)
- Hypoperfused but salvageable regions of brain detected on automated perfusion imaging (CT perfusion or perfusion-diffusion MRI)
- Assigned intervention able to be initiated between 4.5 and 9.0 hours after the onset of stroke, or on awakening with stroke symptoms if within 9 hours from the midpoint of sleep
- Perfusion lesion to ischemic-core mismatch ratio greater than 1.2, absolute mismatch volume greater than 10 mL, and ischemic-core volume less than 70 mL
- Occlusion of a large cerebral vessel was not a prerequisite for inclusion
Excluded
- Prior stroke within 3 months
- Intracranial hemorrhage on baseline imaging
- NIHSS above 25 or below 4
- Blood glucose below 50 or above 400 mg/dL
- Platelet count below 100,000
- Anticoagulation with INR above 1.7 or direct anticoagulant taken within 48 hours
- Any standard contraindication to IV alteplase
- Investigator was considering the use of endovascular thrombectomy at the time of enrollment
- Ischemic-core volume of 70 mL or greater on perfusion imaging
- Premorbid modified Rankin scale score of 2 or higher
- NIHSS score below 4 or above 26
- Additional inclusion and exclusion details provided in the trial Supplementary Appendix
Source: Ma et al., New England Journal of Medicine 2019· Retrieved 2026-06-09
Primary Outcome
mRS 0-1 at 90 Days
Study Arms
- Agent
- Alteplase
- Dose
- 0.9 mg/kg (maximum 90 mg)
- Route
- Intravenous
- Frequency
- 10% as a bolus, 90% as an infusion over 1 hour
- Co-interventions
- Guideline-based care for acute stroke recommended for all patients.
Initiated between 4.5 and 9.0 hours after stroke onset, or on awakening with stroke symptoms.
- Agent
- Matching placebo
- Route
- Intravenous
- Frequency
- 10% as a bolus, 90% as an infusion over 1 hour (matched to alteplase)
- Co-interventions
- Guideline-based care for acute stroke recommended for all patients.
Boehringer Ingelheim provided the alteplase and matching placebo.
Safety
Symptomatic ICH within 36h
6.2%
0.9%
Parenchymal hematoma type 2 with NIHSS increase of 4 or more points within 36h of intervention. Adjusted RR 7.22 (95% CI 0.97 to 53.54), P=0.053. Source: Ma et al., NEJM 2019 Table 2 p.1800.
Mortality at 90 days
11.5%
8.9%
Death within 90 days after intervention. Adjusted RR 1.17 (95% CI 0.57 to 2.40), P=0.67. Not significantly different between groups. Source: Ma et al., NEJM 2019 Table 2 p.1800.
Trial Design
Type
- Multicenter randomized controlled trial
- Placebo-controlled
- Perfusion imaging selection (CTP or DWI)
- 1:1 allocation (Alteplase vs. Placebo)
Timeline
Enrolled 2010-2018
N
225
Enrollment detail
113 alteplase / 112 placebo (225 of 310 planned). Stopped early in June 2018 at 73% enrollment after interim efficacy signal.
Subgroup composition
Wake-up stroke: 65% of participants. Window 4.5 to 6 hours: 10%. Window 6 to 9 hours: 25%. No significant treatment-by-subgroup interaction was detected.
ClinicalTrials.gov
NCT00887328Bedside Pearl
Symptomatic ICH ran 6.2% vs 0.9% in EXTEND. When you consent, quote both numbers: the 6 extra recoveries and the 5 extra hemorrhages per 100 treated. The trial's answer applies to perfusion-selected patients only.