For two decades, intravenous thrombolysis for acute ischemic stroke was governed by the clock: treat within 4.5 hours or not at all. That paradigm is now shifting toward a "tissue over time" approach, in which advanced perfusion imaging — rather than a fixed time cut-off — identifies who still has salvageable brain and might benefit from thrombolysis. Tenecteplase, a bioengineered thrombolytic given as a single bolus, sits at the centre of this shift.
Tenecteplase in the extended window (4.5–24 hours)
TRACE-III studied Chinese patients with anterior-circulation large-vessel occlusion, salvageable tissue on perfusion imaging, and no access to endovascular thrombectomy (EVT). Tenecteplase (0.25 mg/kg, max 25 mg) given 4.5–24 hours after onset produced more frequent excellent outcomes than standard medical care (modified Rankin Scale [mRS] 0–1 at 90 days: 33.0% vs 24.2%; relative rate 1.37, 95% CI 1.04–1.81). Mortality was similar (13.3% vs 13.1%), but symptomatic intracranial hemorrhage (sICH) was higher with tenecteplase (3.0% vs 0.8%).
TIMELESS tested tenecteplase against placebo in the same 4.5–24-hour window, but here most patients also underwent EVT. There was no significant difference in 90-day functional outcome (adjusted common odds ratio 1.13, 95% CI 0.82–1.57). sICH was similar (3.2% vs 2.3%), as was mortality (19.7% vs 18.2%). A key caveat: a large proportion of patients received thrombectomy very rapidly after the study drug, which may have blunted any measurable benefit of thrombolysis on top of EVT.
Other studies — including ROSE-TNK and CHABLIS-T II — support the feasibility of tenecteplase in the extended window and suggest benefit in carefully selected patients, particularly when imaging identifies tissue that is at risk but not yet infarcted.
What's new (2025–2026)
The most important recent addition is the HOPE trial, which extended the concept from tenecteplase to alteplase and, notably, included both large-vessel and more distal occlusions. In perfusion-selected patients with no plan for thrombectomy, intravenous alteplase (0.9 mg/kg) given 4.5–24 hours after onset improved functional independence (mRS 0–1 at 90 days: 40% vs 26%; adjusted relative risk 1.52). sICH was higher with alteplase (3.8% vs 0.51%), but mortality was identical (11% in both groups). HOPE reinforces the imaging-guided, late-window strategy while underscoring the consistent trade-off: better function at the cost of a small excess of bleeding, without a mortality penalty.
Subsequent 2026 analyses have begun to examine intravenous tenecteplase given before thrombectomy in the late window, aiming to clarify whether bridging thrombolysis adds value when EVT is already planned — a question TIMELESS left open.
Safety profile
Across the extended-window trials, the pattern is consistent: a modest absolute increase in symptomatic intracranial hemorrhage (roughly 3% with a lytic vs under 1–2% without) and no signal of increased mortality. The bleeding excess is the principal reason careful, imaging-based patient selection is essential outside the traditional window.
Tenecteplase versus alteplase within 4.5 hours
For patients treated inside the established window, tenecteplase (0.25 mg/kg) is at least non-inferior to alteplase (0.9 mg/kg), with comparable rates of parenchymal hematoma, intracranial bleeding, and major extracranial bleeding (as shown in ATTEST-2 and the ORIGINAL trial). Its major practical advantage is administration: a single bolus rather than a one-hour infusion, which simplifies logistics, speeds treatment, and eases patient transfer.
Tenecteplase with interventional management
For large-vessel occlusion, endovascular thrombectomy remains the gold standard, delivering large gains in disability-free survival over medical therapy alone. When thrombolysis precedes EVT ("bridging"), meta-analyses and target-trial emulations show no clear increase in functional independence over EVT alone, but a possible favorable shift across the disability scale — especially when treatment is early — without a rise in sICH. Both alteplase and tenecteplase are reasonable bridging agents in suitable patients; the key remains imaging-based selection.
Summary of key trials
| Study / comparison | Time window | Outcome (mRS 0–1 at 90d) | sICH | Mortality | Notes |
|---|---|---|---|---|---|
| TRACE-III (TNK vs standard care) | 4.5–24 h, no EVT | 33.0% vs 24.2% | 3.0% vs 0.8% | 13.3% vs 13.1% | Better outcome, more sICH |
| TIMELESS (TNK vs placebo) | 4.5–24 h, mostly EVT | No significant difference | 3.2% vs 2.3% | 19.7% vs 18.2% | Effect likely diluted by rapid EVT |
| HOPE (alteplase vs standard care) | 4.5–24 h, no planned EVT | 40% vs 26% | 3.8% vs 0.51% | 11% vs 11% | Includes distal occlusions |
| ATTEST-2 (TNK vs alteplase) | ≤4.5 h | Non-inferior | Similar | Similar | Comparable efficacy and safety |
| EVT vs medical management | ≤6–24 h, LVO | ~35–50% with EVT | No excess | Lower with EVT | Standard of care in LVO |
Points for clinical practice
Tenecteplase is a promising option for extending thrombolysis toward 24 hours, particularly where thrombectomy is unavailable, but it carries a small increased risk of symptomatic hemorrhage. Advanced perfusion imaging is essential when treating outside the 4.5-hour window. Thrombectomy remains the standard for large-vessel occlusion, and bridging thrombolysis appears safe and may modestly help selected subgroups. The direction of travel across TRACE-III, TIMELESS, and now HOPE is clear: selection is moving from the clock to the tissue.
Further reading: TRACE-III (Xiong et al., NEJM 2024); TIMELESS (Albers et al., NEJM 2024); HOPE (Zhou et al., JAMA 2025); ATTEST-2 (Parsons et al., Lancet Neurology 2024); ORIGINAL (Wu et al., JAMA 2024).