Introduction

Historically, IV thrombolysis for acute ischemic stroke was limited to 4.5 hours from symptom onset. The 2026 AHA/ASA guideline reflects a shift toward tissue-based selection, allowing selected patients to be considered out to 24 hours when advanced imaging shows salvageable penumbra.1

Wake-up and unwitnessed-onset strokes represent a large group of patients who may otherwise be excluded. Extended-window thrombolysis asks a more precise question: is there still tissue to save, and is IV thrombolysis the best available reperfusion option?

Key Points

  • Imaging selection, not the clock, defines eligibility. CTP, MRI DWI/FLAIR mismatch, or perfusion-diffusion mismatch is central.
  • Non-contrast CT alone is not enough for wake-up stroke selection; TWIST was negative.
  • Alteplase has robust evidence in WAKE-UP, EXTEND, and HOPE.
  • Tenecteplase appears most useful in late-window settings when EVT is not planned or immediately available.

Alteplase vs Tenecteplase

ParameterAlteplaseTenecteplase
Dose0.9 mg/kg IV, max 90 mg. Give 10% as bolus over 1 min, then infuse the remainder over 60 min.0.25 mg/kg IV bolus, max 25 mg, over 5-10 seconds.
Extended-window dataWAKE-UP, EXTEND, HOPE, and pooled perfusion-guided analyses support use with advanced imaging selection.TRACE-III supports benefit in non-EVT settings; TIMELESS showed no added functional benefit when EVT was planned.
LogisticsInfusion can complicate transfer and handoff.Single bolus is transfer-friendly and operationally simpler.
SafetysICH signal increases in extended-window trials, but mortality was not increased.sICH generally similar to alteplase in late-window evidence; selection and EVT pathway matter.

Clinical Pearl

Late-window thrombolysis is not simply alteplase versus tenecteplase. First decide whether the patient has salvageable tissue, whether there is LVO, and whether EVT is available without delay.

Key Evidence

StudyPopulationPractical Takeaway
WAKE-UP2Wake-up or unknown onset stroke selected by MRI DWI/FLAIR mismatch.Alteplase improved excellent outcome at 90 days; established MRI-guided unknown-onset thrombolysis.
EXTEND34.5-9 hr or wake-up stroke selected by CTP or MRI mismatch.Alteplase improved mRS 0-1 but increased sICH; mortality not significantly different.
TWIST5Wake-up stroke selected by non-contrast CT alone.Negative trial; NCCT alone is inadequate for extended-window selection.
TIMELESS64.5-24 hr, LVO with salvageable tissue; most underwent EVT.Tenecteplase did not improve functional outcome when EVT was planned and accessible.
TRACE-III74.5-24 hr LVO with salvageable tissue and no planned EVT.Tenecteplase improved excellent functional outcome; key evidence for non-EVT settings.
HOPE84.5-24 hr selected by CTP or MRI mismatch, not planned for EVT.Alteplase improved functional independence with increased sICH but no mortality increase.

Decision Points

Confirm tissue

Use CTP, DWI/FLAIR mismatch, or perfusion-diffusion mismatch. Do not use non-contrast CT alone for wake-up selection.

No EVT pathway

Late-window IV thrombolysis may be the most impactful intervention when thrombectomy is not planned or available.

EVT available

Prioritize thrombectomy for LVO. Do not delay EVT for late-window IV thrombolysis without clear added benefit.

Pharmacist checkpoint

Verify last-known-well uncertainty, advanced imaging selection, weight-based dose, contraindications, blood pressure control, antithrombotic history, and whether the patient is being transferred for EVT.

Clinical Conclusions

Imaging selection is the gate. Extended-window thrombolysis should be driven by salvageable tissue, not time alone.

Alteplase has the most mature extended-window evidence. WAKE-UP, EXTEND, and HOPE support advanced imaging-selected treatment.

Tenecteplase depends on workflow. TRACE-III supports non-EVT late-window use, while TIMELESS did not show added benefit when EVT was planned.

sICH risk increases, but mortality did not. The functional benefit can outweigh hemorrhagic cost when patients are selected appropriately.

Full Reference List

  1. Prabhakaran S, Gonzalez NR, Zachrison KS, et al. 2026 Guideline for the Early Management of Patients With Acute Ischemic Stroke. Stroke. 2026.
  2. Thomalla G, Simonsen CZ, Boutitie F, et al. MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset. N Engl J Med. 2018;379(7):611-622.
  3. Ma H, Campbell BCV, Parsons MW, et al. Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. N Engl J Med. 2019;380(19):1795-1803.
  4. Campbell BCV, Ma H, Ringleb PA, et al. Extending thrombolysis to 4.5-9 h and wake-up stroke using perfusion imaging. Lancet. 2019;394(10193):139-147.
  5. Roaldsen MB, Eltoft A, Wilsgaard T, et al. Tenecteplase in wake-up stroke assessed by non-contrast CT. Lancet Neurol. 2023;22(2):117-126.
  6. Albers GW, Jumaa M, Purdon B, et al. Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection. N Engl J Med. 2024;390(8):701-711.
  7. Xiong Y, Campbell BCV, Schwamm LH, et al. Tenecteplase for Ischemic Stroke at 4.5 to 24 Hours without Thrombectomy. N Engl J Med. 2024;391(3):203-212.
  8. Zhou Y, He Y, Campbell BCV, et al. Alteplase for Acute Ischemic Stroke at 4.5 to 24 Hours. JAMA. 2025;334(9):788-797.
  9. Wang Z, Li J, Wang X, Yuan B, Li J, Ma Q. Tenecteplase for Acute Ischemic Stroke at 4.5 to 24 Hours. Stroke. 2026;57(1):50-62.
  10. Powers WJ, Rabinstein AA, Ackerson T, et al. 2019 Update to the 2018 Guidelines for Early Management of AIS. Stroke. 2019;50(12):e344-e418.
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