This review helps pharmacists understand how imaging-based patient selection and tenecteplase have widened thrombolysis eligibility and where the extended-window evidence still falls short.
Imaging-based selection now extends intravenous thrombolysis to 9 hours and wake-up stroke, and tenecteplase has become an equal first-line agent to alteplase within 4.5 hours, but adding a late-window lytic on top of thrombectomy in perfusion-selected large-vessel occlusion has not improved functional outcomes.
Acute ischemic stroke (AIS) reperfusion has shifted from a strict clock-based model toward tissue-based, imaging-selected eligibility, allowing thrombolysis in wake-up and late-presenting patients. Tenecteplase has moved from an alternative to an equal first-line thrombolytic within 4.5 hours, largely on the strength of workflow advantages and noninferiority data. The central unresolved tension is whether a late-window lytic adds anything for patients already headed to endovascular thrombectomy.
The 2026 American Heart Association/American Stroke Association (AHA/ASA) guideline elevated tenecteplase 0.25 mg/kg to equal footing with alteplase (Class of Recommendation [COR] 1) and newly endorsed extended-window intravenous thrombolysis from 4.5 to 9 hours or wake-up stroke with salvageable penumbra (COR 2a), building on WAKE-UP (DWI-FLAIR mismatch) and EXTEND (perfusion mismatch to 9 hours). At the same time, the TIMELESS trial showed that late-window tenecteplase in perfusion-selected large-vessel occlusion (LVO) patients proceeding to thrombectomy improved recanalization but not 90-day disability, tempering enthusiasm for extending lytics into the thrombectomy pathway.
The extended-window recommendations in the 2026 AHA/ASA guideline map directly onto WAKE-UP and EXTEND, which used MRI or perfusion mismatch rather than documented onset time. TIMELESS and a supporting Stroke trial complicate the picture by showing that reperfusion gains from late-window tenecteplase do not translate into functional benefit when thrombectomy follows quickly, so the guideline endorsement of extended-window lysis applies to thrombolysis candidates broadly, not to routinely adding a lytic on top of planned thrombectomy.
| Source | Key finding | Grade / Verdict |
|---|---|---|
|
Tenecteplase Shortens Stroke Treatment and Transfer Times
Study · JAMA network open
real-world workflow evidence Observational data show tenecteplase is associated with faster door-to-needle and door-in-door-out times than alteplase, though it cannot prove better outcomes.
|
Mean door-to-needle 47.0 vs 52.7 minutes, adjusted difference -3.13 minutes | Grade: Low Confirmatory |
|
D-Dimer/Fibrinogen Ratio Predicts Poor Post-Thrombolysis Stroke Outcomes
Study · Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis
exploratory biomarker signal Elevated baseline D-dimer/fibrinogen ratio flags higher-risk thrombolysis patients but adds marginal prognostic value over the NIHSS and does not alter treatment.
|
D-dimer/fibrinogen ratio AUC 0.704; adding it to NIHSS raised AUC only 0.825 to 0.851 | Grade: Low Hypothesis-generating |
|
IV Thrombolysis Before Thrombectomy Improves Recanalization in Extended Window
Study · European journal of neurology
bridging-therapy support In perfusion-selected extended-window LVO, bridging intravenous alteplase before thrombectomy improved recanalization without added hemorrhage, arguing against reflexively skipping the lytic.
|
Successful recanalization 91.2% with IVT+MT vs 80.6% direct MT (aOR 0.38, 95% CI 0.18-0.78) | Grade: Low Confirmatory |
|
TIMELESS: Late-Window Tenecteplase Fails to Improve Stroke Outcomes
Study · New England Journal of Medicine
pivotal negative late-window trial TIMELESS shows late-window tenecteplase improves recanalization but not function or safety in perfusion-selected LVO patients proceeding to thrombectomy.
|
90-day disability shift not improved: adjusted common OR 1.13, 95% CI 0.82-1.57, P=0.45 | Grade: High Confirmatory |
|
Tenecteplase Boosts Late-Window Reperfusion but Not 90-Day Function
Study · Stroke
confirmatory surrogate-disconnect trial Late-window tenecteplase tripled reperfusion without symptomatic hemorrhage but showed no functional benefit and a worrisome trend in the endovascular subgroup.
|
Reperfusion-without-sICH composite 33.3% vs 10.8% (aRR 3.0, 95% CI 1.6-5.7), no 90-day mRS benefit | Grade: Low Hypothesis-generating |
|
MRI Mismatch Extends Alteplase to Unknown-Onset Stroke
Study · New England Journal of Medicine
practice-changing imaging-selection trial WAKE-UP established DWI-FLAIR mismatch as an imaging clock that identifies wake-up and unknown-onset patients who benefit from standard-dose alteplase.
|
Favorable 90-day outcome +11.5 percentage points, adjusted OR 1.61 (95% CI 1.09-2.36), NNT ~9 | Grade: Moderate Practice-changing |
|
Perfusion-Selected Alteplase Extends Thrombolysis Window to 9 Hours
Study · New England Journal of Medicine
extended-window foundation trial EXTEND showed perfusion-mismatch selection can extend alteplase to 9 hours and wake-up stroke, with a modest adjusted benefit offset by a higher hemorrhage rate.
|
Excellent outcome 35.4% vs 29.5%, adjusted RR 1.44 (95% CI 1.01-2.06); sICH near 6% | Grade: Moderate Hypothesis-generating |
|
2026 AHA/ASA Acute Ischemic Stroke Guideline: Major Shifts in Thrombolysis, EVT, and Systems
Guideline · Stroke
guideline backbone The 2026 AHA/ASA guideline codifies tenecteplase as equal first-line therapy and endorses imaging-selected extended-window and wake-up thrombolysis.
|
Tenecteplase 0.25 mg/kg equal to alteplase within 4.5 hours (COR 1); extended-window lysis 4.5-9 hours (COR 2a) | Grade: High Practice-changing |
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