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EXTEND-IA

Extending the Time for Thrombolysis in Emergency Neurological Deficits–Intra-Arterial

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Year of Publication: 2015

Authors: Campbell BCV, Mitchell PJ, Kleinig TJ, ..., Churilov L

Journal: New England Journal of Medicine

Citation: N Engl J Med 2015;372:1009–18

Link: https://doi.org/10.1056/NEJMoa1414792

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1414792

Clinical Question

Does the addition of endovascular thrombectomy to intravenous tPA improve reperfusion and clinical outcomes in patients with large-vessel occlusion stroke?

Study Overview

Objective

To evaluate whether early thrombectomy using Solitaire improves outcomes compared to alteplase alone in patients with LVO and salvageable tissue.

Study Summary

Thrombectomy with Solitaire after alteplase led to better reperfusion, early neurologic improvement, and improved functional outcomes versus alteplase alone.

Intervention

IV alteplase (0.9 mg/kg) with or without Solitaire thrombectomy. Endovascular therapy started within 6 hours after onset and completed within 8 hours.

Patients per Arm

Thrombectomy: 35, Alteplase: 35

Bottom Line

Endovascular thrombectomy with the Solitaire FR 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 (10 enrolling 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.
Coprimary outcomes were reperfusion at 24h on perfusion imaging (100% endovascular vs 37% control, p<0.001) and early neurologic improvement at 3 days (80% vs 37%, p=0.002).
Functional independence (mRS 0–2 at 90 days): 71% vs 40% (adjusted OR 4.2, 95% CI 1.4–12, p=0.01) — the highest absolute rate of independence in any 2015 thrombectomy trial.
Median infarct growth at 24h: 10.9 mL endovascular vs 35.3 mL alteplase-only (p=0.007) — demonstrating that thrombectomy substantially reduces infarct progression.
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 eligible: ICA, M1 or M2 segment of MCA. Required IV tPA eligibility (bridging therapy mandatory, similar to SWIFT PRIME).
90-day mortality: 9% endovascular vs 20% alteplase-only (adjusted p=0.31; unadjusted p=0.18) — numerically the largest mortality reduction among 2015 trials, though not significant due to small sample size.
sICH: 0% endovascular vs 6% alteplase-only (p=0.49) — no sICH in the endovascular arm; both sICH events in the control arm were fatal.
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 – October 2014

Follow-up Duration: 90 days

Centers: 10

Countries: Australia, New Zealand

Sample Size: 70

Analysis: Intention-to-treat; van Elteren (stratified Wilcoxon rank-sum) test for reperfusion; logistic regression for early neurologic improvement adjusted for age and baseline NIHSS; Wilcoxon–Mann–Whitney generalized odds ratio for the ordinal mRS analysis

Inclusion Criteria

Ischemic stroke with disabling neurologic deficit
Occlusion of internal carotid artery or M1 or M2 segment of middle cerebral artery on CT angiography
Able to receive IV alteplase within 4.5 hours of symptom onset
Endovascular therapy initiable (groin puncture) within 6 hours of onset and completed within 8 hours
Salvageable tissue on CT perfusion imaging with ischemic core <70 mL (RAPID software)
Pre-stroke functional independence (mRS <2)

Exclusion Criteria

Large ischemic core (≥70 mL) on CT perfusion
Contraindications to IV alteplase
Pre-stroke disability (mRS ≥2)
Standard clinical contraindications to endovascular therapy

Baseline Characteristics

Characteristic	Control	Active
Mean Age ± SD - yr	70.2 ± 11.8	68.6 ± 12.3
Male Sex - %	49	49
Median NIHSS (IQR)	13 (9–19)	17 (13–20)
Atrial fibrillation - %	31	34
Hypertension - %	66	60
Diabetes - %	23	6
Smoking - %	43	34
Serum glucose (mean ± SD) - mmol/L	7.6 ± 3.6	7.1 ± 2.5
Cardioembolic occlusion - %	40	66
Large-artery occlusion - %	37	20
Undetermined or other - %	23	14
Occlusion site - ICA - %	31	31
Occlusion site - M1 MCA - %	51	57
Occlusion site - M2 MCA - %	17	11
Median ischemic core volume (IQR) - mL	18 (4–29)	12 (4–32)
Median perfusion-lesion volume (IQR) - mL	115 (72–158)	106 (76–137)
Median time onset to hospital arrival (IQR) - min	80 (56–115)	78 (54–112)
Median time onset to IV tPA (IQR) - min	145 (105–180)	127 (93–162)

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. No endovascular intervention permitted.	IV alteplase (same protocol) followed by endovascular thrombectomy with the Solitaire FR stent retriever as rapidly as possible; groin puncture within 6 hours of onset and procedure completed within 8 hours. Conscious sedation or general anesthesia at neurointerventionist discretion. Solitaire deployed at site of occlusion and removed under negative-pressure aspiration. 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
Coprimary: (1) Reperfusion at 24 h — percentage reduction in perfusion-lesion volume between baseline and 24-hour imaging; (2) Early neurologic improvement — ≥8-point reduction on NIHSS or NIHSS 0 or 1 at day 3	Primary	Median reperfusion 37% (IQR −0.5 to 96); Early neurologic improvement 13/35 (37%)	Median reperfusion 100% (IQR 100 to 100); Early neurologic improvement 28/35 (80%)		<0.001 (reperfusion); 0.002 (early neurologic improvement)
Functional independence (mRS 0–2 at 90 days)	Secondary	14/35 (40%)	25/35 (71%)	4.2 (adjusted OR, 95% CI 1.4–12)	0.01
Excellent outcome (mRS 0–1 at 90 days)	Secondary	10/35 (29%)	18/35 (51%)	2.4 (adjusted OR, 95% CI 0.87–6.6)	0.09
Ordinal mRS shift at 90 days	Secondary	Median 3 (IQR 1–5)	Median 1 (IQR 0–3)	Wilcoxon–Mann–Whitney generalized OR 2.0 (95% CI 1.2–3.8)	0.006
Median infarct growth at 24 hrs	Secondary	35.3 mL	10.9 mL		0.007
Mortality at 90 days	Secondary	7/35 (20%)	3/35 (9%)	0.45 (adjusted OR, 95% CI 0.1–2.1)	0.31 (adjusted, prespecified primary); 0.18 (unadjusted)
Median home time (days out of first 90)	Secondary	15	73		0.001
Symptomatic ICH	Adverse	2/35 (6%)	0/35 (0%)		0.49
Parenchymal hematoma	Adverse	3/35 (9%)	4/35 (11%)		0.99
Embolization to new territory	Adverse	N/A	2/35 (6%) — no clinical symptoms
Groin hematoma requiring transfusion	Adverse	N/A	Reported in the endovascular-therapy group

Subgroup Analysis

Formal subgroup analyses were not performed due to the small sample size (n=70); the authors explicitly noted that meaningful subgroup analyses would require individual-patient meta-analysis of multiple trials. Perfusion imaging selection ensured all patients had salvageable penumbra, limiting the ability to identify subgroups that might not benefit.

Criticisms

Smallest of the 2015 thrombectomy trials (n=70) — stopped early at first interim analysis, raising concerns about effect size overestimation (acknowledged by the authors).
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.
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.
Only 10 of 14 planned centers actually enrolled patients — trial recruitment was concentrated in a limited number of high-volume sites.

Funding

National Health and Medical Research Council of Australia (grants 1043242 and 1035688); Royal Australasian College of Physicians; Royal Melbourne Hospital Foundation; National Heart Foundation of Australia; National Stroke Foundation of Australia; state government of Victoria. Covidien supplied the Solitaire FR device and an unrestricted grant for trial infrastructure but had no role in study design, conduct, or manuscript preparation.

Based on: EXTEND-IA (New England Journal of Medicine, 2015)