Historical Reference Page
This is a historical reference page. This trial preceded the modern evidence base. It is presented as a predecessor reference. See ESCAPE (2015) for the modern successor trial that established EVT as standard of care.
SYNTHESIS Expansion Trial: Endovascular Therapy Alone Versus IV Alteplase for Acute Ischemic Stroke
In patients with acute ischemic stroke within 4.5 hours, is endovascular therapy alone superior to IV alteplase in achieving disability-free survival (mRS 0-1) at 90 days?
Ciccone et al. (NEJM 2013) · doi:10.1056/NEJMoa1213701 · 362 patients
Population
Included
- Age 18 to 80 years
- Acute ischemic stroke with limb paresis or aphasia
- Onset within 4.5 hours (IV alteplase arm) or 6 hours (endovascular arm)
- Eligible for IV alteplase or endovascular therapy
- CT excluding hemorrhage
Population and time window
- Patients with acute stroke and an age of 18 to 80 years
- Intracranial hemorrhage ruled out
- A clearly defined time of stroke onset that allowed for immediate initiation of intravenous t-PA therapy (defined as within 4.5 hours after symptom onset) or for the administration of endovascular treatment as soon as possible (within 6 hours after symptom onset)
- All patients underwent randomization within 4.5 hours after symptom onset
Excluded
- Intracranial hemorrhage on baseline CT
- Rapidly resolving symptoms
- Contraindication to IV alteplase (in alteplase arm)
- Large established infarct on baseline CT
- Severe pre-stroke disability
Per protocol
- Inclusion and exclusion criteria are listed in detail in the protocol available at NEJM.org; comprehensive exclusion criteria are not reproduced in the main publication text
Source: Ciccone et al., NEJM 2013· Retrieved 2026-06-09
Primary Outcome — Disability-Free Survival (mRS 0-1) at 90 Days
362 patients; endovascular therapy alone vs IV alteplase within 4.5 hours
In 362 patients with ischemic stroke, endovascular therapy alone was not superior to IV alteplase in achieving disability-free survival (mRS 0-1) at 90 days. The primary endpoint was achieved in 30.4% of the endovascular group versus 34.8% of the alteplase group (adjusted OR 0.71, 95% CI 0.44 to 1.14, p=0.16). Results numerically favored IV alteplase, though this difference did not reach statistical significance. Notably, the endovascular arm received no pre-procedure IV alteplase, and the endovascular treatment window extended to 6 hours versus 4.5 hours for the alteplase arm.
Visualization not shown for predecessor reference pages. See source paper for figures.
Trial Design
SYNTHESIS Expansion randomized patients with ischemic stroke to endovascular therapy alone (without IV alteplase) or IV alteplase (0.9 mg/kg standard dose within 4.5 hours). The endovascular group had a longer treatment window, up to 6 hours from onset. Endovascular therapy used intra-arterial recombinant tPA and first-generation mechanical devices. Enrollment did not require CTA or MRA confirmation of large-vessel occlusion, meaning a substantial proportion of enrolled patients may have had occlusions not amenable to endovascular retrieval. This design difference from IMS-III (which used bridging therapy) makes direct comparison difficult.
Safety
Symptomatic intracranial hemorrhage was similar between groups (6% endovascular vs 6% alteplase). Mortality at 3 months was 10% versus 8%, a non-significant difference (p=0.53). No significant safety signal in either direction.