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EXTEND-IA TNK Part 2

Effect of Intravenous Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Large Vessel Occlusion Ischemic Stroke

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Year of Publication: 2020

Authors: Bruce C. V. Campbell, Peter J. Mitchell, Leonid Churilov, ..., Bernard Yan

Journal: JAMA

Citation: JAMA. 2020;323(13):1257–1265. doi:10.1001/jama.2020.1511

Link: https://jamanetwork.com/journals/jama/fullarticle/2762902

Clinical Question

Does a higher dose (0.40 mg/kg) of tenecteplase improve cerebral reperfusion before thrombectomy compared to the standard dose (0.25 mg/kg) in patients with large vessel occlusion ischemic stroke?

Study Overview

Objective

Tenecteplase versus tPA in patients with LVO within 4.5h from onset.

Study Summary

Tenecteplase significantly improves reperfusion outcomes before thrombectomy compared to alteplase, suggesting it should be the thrombolytic of choice in this setting.

Intervention

Single bolus of tenecteplase at a dose of 0.25 mg/kg.

Patients per Arm

Tenecteplase: 150, Alteplase: 150

Bottom Line

Tenecteplase 0.40 mg/kg did NOT improve cerebral reperfusion prior to EVT vs 0.25 mg/kg (19.3% vs 19.3%; adjusted RR 1.03; P=0.89) in LVO stroke. No differences in functional outcomes, mortality, or sICH. Pooled analysis with original EXTEND-IA TNK confirmed tenecteplase superiority over alteplase (20.0% vs 9.9% reperfusion; RR 1.90; P=0.04). Rural patients had 2x higher reperfusion (34% vs 17%; P=0.001) due to longer lysis-to-puncture time. ICA occlusions: 0% reperfusion.

        Major Points
        No dose-response: identical reperfusion 19.3% each (adjusted RR 1.03; P=0.89). 0.25 mg/kg is sufficient for LVO.
sICH numerically higher with 0.40 mg/kg: 4.7% vs 1.3% (RR 3.50; P=0.12, NS). 4/7 were wire perforation–related.
Rural patients: 34% vs 17% reperfusion (RR 2.15; P=0.001) — longer lysis-to-puncture (152 vs 41 min) allows more thrombolytic dwell time.
ICA occlusions: 0/66 achieved substantial reperfusion. 15% had partial ACA territory recanalization.
Pooled with original EXTEND-IA TNK: tenecteplase 20.0% vs alteplase 9.9% (RR 1.90; P=0.04). Ordinal mRS common OR 1.50 (P=0.04).
mRS 0-2 at 90d: 59% vs 56% (adjusted RR 1.08; P=0.40). Death: 17% vs 15% (P=0.35).
Adaptive re-estimation after 240 patients: conditional power <1% for 15% effect — confirmed futility of expanding.
300 patients, 28 AU/NZ sites, PROBE design. Randomized 1:1 within 4.5h of onset.
Lysis-to-puncture overall: 45 vs 48 min. Rural 167 vs 146 min. Metropolitan 44 vs 41 min.
Supports standardizing tenecteplase at 0.25 mg/kg for EVT-eligible LVO stroke.

      

Design

Study Type: Multicenter, randomized, open-label, blinded-endpoint trial

Randomization: 1

Blinding: Blinded endpoint assessment

Enrollment Period: December 2017 – July 2019

Follow-up Duration: 90 days

Centers: 28

Countries: Australia, New Zealand

Sample Size: 300

Analysis: Modified Poisson regression for primary/secondary outcomes, intention-to-treat; prespecified adaptive sample size re-estimation

Inclusion Criteria

Age ≥18 years
Acute ischemic stroke with large vessel occlusion (ICA, MCA, basilar)
Eligible for IV thrombolysis within 4.5 hours of symptom onset
Planned endovascular thrombectomy

Exclusion Criteria

Pre-stroke mRS >3
Extensive early ischemic change on noncontrast CT
Contraindications to thrombolysis or thrombectomy

Arms

Field	Tenecteplase 0.40 mg/kg	Control
Intervention	Tenecteplase 0.40 mg/kg IV bolus (max 40 mg) before thrombectomy	Tenecteplase 0.25 mg/kg IV bolus (max 25 mg) before thrombectomy
Duration	Single dose	Single dose

Outcomes

Outcome	Type	Control	Intervention	P-value
Substantial reperfusion (>50% of involved territory) prior to thrombectomy	Primary	19.3%	19.3%	0.89
mRS score at 90 days \| 95% CI: 0.74–1.24	Secondary	Median 2	Median 2	0.73
Functional independence (mRS 0–2 or no change) \| 95% CI: 0.90–1.29	Secondary	56%	59%	0.40
Freedom from disability (mRS 0–1 or no change) \| 95% CI: 0.84–1.29	Secondary	49%	49%	0.69
Early neurological improvement \| 95% CI: 0.91–1.27	Secondary	62%	68%	0.39
Death	Adverse		17% (0.40 mg/kg) vs 15% (0.25 mg/kg); P=0.35
Symptomatic intracranial hemorrhage	Adverse		4.7% vs 1.3%; P=0.12
Parenchymal hematoma	Adverse		2.7% vs 4.0%; P=0.52

Subgroup Analysis

Reperfusion benefit seen in rural patients likely due to longer time between thrombolysis and puncture; no dose-by-location interaction

Criticisms

Study not powered to detect minimal clinically important differences (~3–5%)
Wide confidence intervals due to small sample size
Generalizability may be limited to LVO population
Slight imbalance in core volume between arms (non-significant)

Funding

National Health and Medical Research Council of Australia, National Heart Foundation of Australia, iSchemaView (provided RAPID software)

Based on: EXTEND-IA TNK Part 2 (JAMA, 2020)