EXTEND-IA
Extending the Time for Thrombolysis in Emergency Neurological Deficits–Intra-Arterial
Year of Publication: 2015
Authors: Campbell BCV, Mitchell PJ, Yan B, ..., Levi CR
Journal: New England Journal of Medicine
Citation: N Engl J Med 2015;372:1009–18
PDF: Clinical Question
Does the addition of endovascular thrombectomy to intravenous tPA improve reperfusion and clinical outcomes in patients with large-vessel occlusion stroke?
Bottom Line
Endovascular thrombectomy with the Solitaire device significantly improved early reperfusion, functional outcomes, and reduced infarct growth compared to IV tPA alone in patients with large-vessel occlusion and favorable imaging profile.
Major Points
- One of five landmark 2015 thrombectomy RCTs. Unique contribution: first to use automated CT perfusion (RAPID software) for patient selection and first to demonstrate perfusion imaging-guided thrombectomy efficacy.
- Conducted in Australia and New Zealand (14 centers) — the only 2015 trial from the Southern Hemisphere.
- Stopped early after just 70 patients (target 100) at the first planned interim analysis — the smallest of the 2015 trials but with the largest effect sizes.
- Primary outcome was reperfusion at 24h on perfusion imaging: 100% thrombectomy vs 37% control (p<0.001) — a near-perfect primary endpoint.
- Functional independence (mRS 0–2 at 90 days): 71% vs 40% (OR 3.1, p=0.01) — the highest absolute rate of independence in any 2015 thrombectomy trial.
- Median 24h infarct volume: 13 mL thrombectomy vs 57 mL control (p<0.001) — demonstrating that thrombectomy dramatically reduces infarct growth.
- Pioneered use of RAPID automated perfusion software for patient selection: ischemic core <70 mL, mismatch ratio >1.2. This became the standard imaging paradigm for DAWN, DEFUSE 3, and subsequent trials.
- Occlusion sites: ICA or proximal MCA (M1). Required IV tPA eligibility (bridging therapy mandatory, similar to SWIFT PRIME).
- 90-day mortality: 9% vs 20% (p=0.18) — numerically the largest mortality reduction among 2015 trials, though not significant due to small sample size.
- sICH: 6% thrombectomy vs 0% control (p=0.49) — higher in intervention group, though not significant; highlights that highly selected patients still carry procedural risk.
- Solitaire FR stent retriever was the exclusive device used — results specific to this device platform.
Design
Study Type: Prospective, randomized, open-label, blinded endpoint (PROBE) multicenter trial
Randomization: 1
Blinding: Outcome assessors were blinded; patients and physicians were unblinded
Enrollment Period: August 2012 – November 2014
Follow-up Duration: 90 days
Centers: 14
Countries: Australia, New Zealand
Sample Size: 70
Analysis: Modified intention-to-treat; ordinal logistic regression for mRS; between-group comparisons using chi-square and Mann–Whitney U test
Inclusion Criteria
- Age ≥18 years
- Ischemic stroke with disabling neurologic deficit
- Occlusion of internal carotid or proximal middle cerebral artery
- Within 6 hours of symptom onset
- Eligible for IV tPA
- Favorable CT perfusion profile (ischemic core <70 mL, mismatch ratio >1.2)
Exclusion Criteria
- Large core infarct on imaging
- Rapidly improving symptoms
- Contraindications to tPA or endovascular therapy
- Intracranial hemorrhage or severe comorbidity
- Pre-stroke disability (mRS >2)
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Median Age (IQR) - yr | 69 (57–77) | 68 (56–76) |
| Male Sex - % | 49 | 51 |
| Atrial fibrillation - % | 43 | 31 |
| Hypertension - % | 60 | 57 |
| Diabetes mellitus - % | 14 | 17 |
| Hyperlipidemia - % | 37 | 31 |
| Prior stroke - % | 9 | 9 |
| Current smoker - % | 14 | 17 |
| Median NIHSS (IQR) | 15 (11–20) | 13 (9–19) |
| ASPECTS ≥8 - % | 91 | 91 |
| Occlusion site - ICA - % | 20 | 23 |
| Occlusion site - M1 MCA - % | 80 | 77 |
| Median ischemic core volume (IQR) - mL | 12 (0–30) | 12 (0–25) |
| Median mismatch volume (IQR) - mL | 66 (43–113) | 68 (37–96) |
| Median time onset to IV tPA (IQR) - min | 123 (90–178) | 122 (85–175) |
| Median time onset to randomization (IQR) - min | 187 (132–243) | 180 (130–240) |
Arms
| Field | Control | IV tPA + Thrombectomy |
|---|---|---|
| Intervention | IV alteplase 0.9 mg/kg (max 90 mg), 10% bolus + 60-min infusion, started within 4.5h of onset. Standard post-tPA care including BP monitoring (<180/105), neurological assessments every 15 min for first 2h, and 24h CT scan before starting antithrombotics. No endovascular intervention permitted. | IV alteplase (same protocol) followed by endovascular thrombectomy using Solitaire FR stent retriever as rapidly as possible within 6 hours of onset. Access via femoral artery with 8F guide catheter. Solitaire deployed across clot, left in situ 3–5 min, then withdrawn under continuous aspiration. Up to 3 passes allowed before considering rescue therapy. Conscious sedation preferred over general anesthesia (though both permitted). Automated RAPID CT perfusion software used to confirm target mismatch at enrollment. |
| Duration | 90 days follow-up | 90 days follow-up |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Percentage of ischemic territory reperfused at 24 hours as measured by perfusion imaging | Primary | 37% | 100% | <0.001 | |
| Functional independence (mRS 0–2 at 90 days) | Secondary | 40% | 71% | 3.1 | 0.01 |
| Median infarct volume at 24 hrs | Secondary | 57 mL | 13 mL | <0.001 | |
| Mortality at 90 days | Secondary | 20% | 9% | 0.18 | |
| Symptomatic ICH | Adverse | 0% | 6% | 0.49 | |
| Device-related complications | Adverse | N/A | None reported |
Subgroup Analysis
Benefit was consistent across prespecified subgroups: age (<70 vs ≥70), sex, baseline NIHSS (<15 vs ≥15), occlusion site (ICA vs M1), and ischemic core volume (<20 mL vs ≥20 mL). All subgroups showed a consistent trend favoring thrombectomy for both reperfusion and functional outcome. Patients with smaller baseline cores had larger absolute benefits. The perfusion imaging selection ensured all patients had salvageable penumbra — this homogeneity limited the ability to identify subgroups that might not benefit. Trial too small (n=70) for meaningful interaction testing.
Criticisms
- Smallest of the 2015 thrombectomy trials (n=70) — stopped at first interim analysis, raising concerns about effect size overestimation.
- Highly selected population: required CT perfusion with automated RAPID software, IV tPA eligibility, and favorable mismatch profile — may not generalize to patients without perfusion imaging access.
- Open-label design (PROBE) — knowledge of treatment assignment could influence post-procedure care intensity and rehabilitation referral patterns.
- 100% reperfusion rate at 24h in control group seems high for IV tPA alone — may reflect favorable patient selection or perfusion imaging threshold effects.
- sICH was numerically higher in thrombectomy group (6% vs 0%), though not significant — concerning signal in such a small trial.
- Exclusive use of Solitaire FR device — results cannot be directly extrapolated to aspiration-first techniques or other device platforms.
- Australia/New Zealand healthcare system context — workflow and access patterns may differ from North American and European settings.
- CT perfusion availability required at enrolling sites — limits applicability in settings without 24/7 perfusion imaging capability.
- Mandatory IV tPA excludes patients with contraindications to thrombolysis — later studies (MR CLEAN subgroups) showed benefit of direct thrombectomy.
Funding
National Health and Medical Research Council of Australia; Covidien provided Solitaire devices but had no role in study design or analysis
Based on: EXTEND-IA (New England Journal of Medicine, 2015)
Authors: Campbell BCV, Mitchell PJ, Yan B, ..., Levi CR
Citation: N Engl J Med 2015;372:1009–18
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