Tenecteplase vs Alteplase for Acute Ischemic Stroke

Introduction

Intravenous alteplase (0.9 mg/kg, given as a 10% bolus followed by a 60-minute infusion) has been the global standard for thrombolysis in acute ischaemic stroke (AIS) within 4.5 hours of onset.
Tenecteplase is a bioengineered variant of tissue plasminogen activator (tPA) with greater fibrin specificity and a longer half-life, allowing it to be given as a single intravenous bolus rather than a bolus-plus-infusion.
The single-bolus administration is operationally attractive — it simplifies dosing, shortens door-to-needle workflow, and is easier to continue during interhospital “drip-and-ship” transfers for thrombectomy.
The AcT trial (Menon et al., Lancet 2022) was a pragmatic Canadian non-inferiority trial that tested whether tenecteplase 0.25 mg/kg could replace alteplase for the general thrombolysis-eligible population.

Clinical Detail

Agent comparison

	Alteplase (tPA)	Tenecteplase (TNK)
AIS dose	0.9 mg/kg (max 90 mg): 10% (0.09 mg/kg) as a bolus, then remaining 0.81 mg/kg over 60 min	0.25 mg/kg single IV bolus (max 25 mg) — the stroke dose validated in AcT, TRACE-2, ATTEST-2
Administration	Bolus + 60-minute infusion (infusion pump required)	Single bolus over ~5–10 seconds — no infusion pump
Fibrin specificity / half-life	Lower fibrin specificity; shorter plasma half-life (bolus + infusion needed)	Higher fibrin specificity; longer half-life (enables single bolus)
Treatment window	≤4.5 h from last-known-well (standard eligibility)	≤4.5 h in the pivotal trials (AcT, TRACE-2, ATTEST-2)
Mechanism	Recombinant tPA; converts plasminogen to plasmin to lyse fibrin clot	Modified tPA (3 amino-acid substitutions); same plasmin-mediated fibrinolysis, more fibrin-selective

Dose and administration values per the AcT protocol (Menon 2022) and the pivotal trial reports cited below. Confirm against institutional protocol and product labeling before use.

The 0.25 vs 0.4 mg/kg distinction is clinically load-bearing. The stroke-validated tenecteplase dose is 0.25 mg/kg. A higher 0.4 mg/kg dose conferred no additional reperfusion benefit before thrombectomy (EXTEND-IA TNK Part 2) and was associated with worse functional outcomes and higher mortality in moderate-to-severe stroke (NOR-TEST 2 Part A, stopped early for safety). Do not substitute the 0.4 mg/kg dose.

Evidence

Trial, Year	Design (n)	TNK dose vs comparator	Primary outcome
AcT (Menon), 2022	Pragmatic, open-label, non-inferiority RCT (n=1,577 ITT)	TNK 0.25 mg/kg vs alteplase 0.9 mg/kg, ≤4.5 h	mRS 0–1 at 90–120 d: 36.9% vs 34.8% (risk difference +2.1%, 95% CI −2.6 to 6.9; non-inferiority margin −5% met). sICH 3.4% vs 3.2%; 90-d death 15.3% vs 15.4%.
EXTEND-IA TNK (Campbell), 2018	RCT, LVO pre-thrombectomy (n=202)	TNK 0.25 mg/kg vs alteplase 0.9 mg/kg, ≤4.5 h	Substantial reperfusion at initial angiogram: 22% vs 10% (difference 12 points, 95% CI 2 to 21; P=0.002 non-inferiority, P=0.03 superiority). 90-d mRS median 2 vs 3 (cOR 1.7, 95% CI 1.0–2.8). sICH 1% each.
EXTEND-IA TNK Part 2 (Campbell), 2020	Dose-comparison RCT, LVO (n=300)	TNK 0.40 mg/kg vs TNK 0.25 mg/kg	Reperfusion >50% before thrombectomy: 19.3% vs 19.3% (no difference) — higher dose gave no benefit. sICH 4.7% vs 1.3%; death 17% vs 15%.
NOR-TEST (Logallo), 2017	Phase 3 superiority RCT (n=1,100); mostly minor stroke (median NIHSS 4)	TNK 0.40 mg/kg vs alteplase 0.9 mg/kg	mRS 0–1 at 3 mo: 64% vs 63% (OR 1.08, 95% CI 0.84–1.38) — not superior; similar safety. Mild-stroke population limits generalisability.
NOR-TEST 2 Part A (Kvistad), 2022	Phase 3 non-inferiority RCT, moderate–severe stroke (NIHSS ≥6); stopped early for safety (n=204)	TNK 0.40 mg/kg vs alteplase 0.9 mg/kg	mRS 0–1 at 3 mo: 32% vs 51% (OR 0.45, 95% CI 0.25–0.80) — worse with TNK. Any ICH 21% vs 7%; 3-mo mortality 16% vs 5%. The 0.40 mg/kg dose was harmful here.
TRACE-2 (Wang), 2023	Phase 3 non-inferiority RCT, China, thrombectomy-ineligible (n=1,430)	TNK 0.25 mg/kg vs alteplase 0.9 mg/kg, ≤4.5 h	mRS 0–1 at 90 d: 62% vs 58% (RR 1.07, 95% CI 0.98–1.16; non-inferiority margin 0.937 met). sICH 2% vs 2%; 90-d death 7% vs 5%.
ATTEST-2 (Muir), 2024	Phase 3 non-inferiority RCT, UK (n=1,777)	TNK 0.25 mg/kg vs alteplase 0.9 mg/kg, ≤4.5 h	90-d mRS ordinal shift: OR 1.07 (95% CI 0.90–1.27; non-inferiority P<0.0001; superiority P=0.43) — non-inferior, not superior. sICH 2% vs 2%; death 8% vs 8%.

mRS = modified Rankin Scale; LVO = large-vessel occlusion; sICH = symptomatic intracranial haemorrhage; cOR = common odds ratio. All doses, sample sizes, and outcome values verified against the primary PubMed records (see EVIDENCE-PACKET.md).

Conclusions

At 0.25 mg/kg, tenecteplase is non-inferior to alteplase 0.9 mg/kg for standard thrombolysis within 4.5 hours (AcT, TRACE-2, ATTEST-2), with comparable rates of symptomatic intracranial haemorrhage and mortality.
Before thrombectomy for large-vessel occlusion, tenecteplase 0.25 mg/kg produced higher early reperfusion and better function than alteplase (EXTEND-IA TNK).
The single-bolus administration is the practical advantage — simpler preparation, faster door-to-needle times, and no infusion to maintain during transfer.
Use the 0.25 mg/kg dose. The 0.40 mg/kg dose showed no added benefit (EXTEND-IA TNK Part 2) and caused harm in moderate-to-severe stroke (NOR-TEST 2 Part A).
The current 2026 AHA/ASA acute ischaemic stroke guideline (which replaces the 2018 guideline and its 2019 update) recommends tenecteplase 0.25 mg/kg as a Class 1 option, co-equal to alteplase, for eligible patients within 4.5 hours — a marked strengthening from the 2019 update, which had listed it only as a reasonable alternative. Many centers have adopted tenecteplase as the preferred agent. Verify your institution's stroke protocol and formulary before use.

References