Introduction

  1. Alteplase (rt-PA) has been used for acute ischemic stroke since FDA approval in 1996, following the NINDS trial.
  2. The NINDS trial has been criticized for its strict inclusion criteria; major trials since have sought to show benefit in patients NINDS excluded.
  3. A recent re-analysis of the ECASS III trial using independent patient-level data has been published.

Clinical Detail

PropertyAlteplase (Activase)
MechanismInitiates fibrinolysis by binding fibrin in a thrombus and converting entrapped plasminogen to plasmin.
Dose
  • 0.9 mg/kg total (max 90 mg): 10% as an IV bolus over 1 minute, then 90% as an infusion over 60 minutes.
  • ≥100 kg: 9 mg bolus then 81 mg infusion.
Administration10% as an IV bolus over 1 minute; the remainder infused over 1 hour.
PK / PD
  • Duration ~1 hour after the infusion ends (bleeding risk can persist).
  • Distribution approximates plasma volume.
  • Half-life ~5 minutes.
  • Hepatic and plasma clearance.
Adverse effectsIntracranial hemorrhage, angioedema, GI/GU hemorrhage.
Interactions & warningsAvoid combination with tranexamic acid; internal bleeding, thromboembolic events, cholesterol embolization.
Contraindications
  • Active internal bleeding
  • Ischemic stroke within 3 months (except the qualifying event within 4.5 hours)
  • Severe uncontrolled hypertension
CompatibilityMay be diluted in equal volume with 0.9% sodium chloride or D5W. Not compatible with lactated Ringer's.

Evidence

Trials are grouped by their primary finding (no benefit / benefit / harm), with the treatment time window for each.

Trial (year)Design / sampleTime windowPopulationIntervention & comparisonOutcomes
Trials that showed no benefit
NINDS-1 (1995)PRCT (n=291)≤3 hMean 67 y; median NIHSS 140.9 mg/kg rt-PA (max 90 mg)
vs placebo		No difference in NIHSS at 24 hours.
ECASS II (1998)PRCT (n=800)≤6 hMedian 68 y; median NIHSS 110.9 mg/kg rt-PA (max 90 mg)
vs placebo		No difference in functional outcome at 90 days; no significant difference in morbidity despite a higher SICH rate with rt-PA.
IST-3 (2012)PRCT (n=3035)≤6 h1407 patients >80 y; mean TTT 4.2 h0.9 mg/kg t-PA (max 90 mg)
vs placebo		No difference in functional outcome at 180 days; increased early (7-day) mortality (11% vs 7%) and SICH (7% vs 1%) with rt-PA.
Trials that showed benefit
NINDS-2 (1995)PRCT (n=333)≤3 hMean 69 y; median NIHSS 140.9 mg/kg rt-PA (max 90 mg)
vs placebo		More patients treated with t-PA had mRS 0–1 at 90 days; ~2.9% increase in fatal ICH with t-PA.
ECASS III (2008)PRCT (n=821)3–4.5 hMean 65 y; median NIHSS 90.9 mg/kg t-PA (max 90 mg)
vs placebo		More patients treated with t-PA had mRS 0–1 at 90 days; ~2.2% increase in SICH with rt-PA.
WAKE-UP (2018)PRCT (n=503)Unknown onset (MRI-selected)Mean 65 y; median NIHSS 60.9 mg/kg rt-PA (max 90 mg)
vs placebo		More patients treated with t-PA had mRS 0–1 at 90 days; symptomatic intracranial hemorrhage 2.0% vs 0.4%; mortality 4.1% vs 1.2% (p=0.07, not significant).
EXTEND (2019)PRCT (n=225)4.5–9 hMean 73 y; median NIHSS 120.9 mg/kg rt-PA (max 90 mg)
vs placebo		mRS 0–1 in 35.4% (t-PA) vs 29.5% (placebo) (adjusted RR 1.44, 95% CI 1.01–2.06, p=0.04); more SICH with t-PA (6.2% vs 0.9%).
Trials that showed harm
ECASS-1 (1995)PRCT (n=620)≤6 hMedian 69 y; median NIHSS 121.1 mg/kg rt-PA (max 100 mg)
vs placebo		No difference in functional outcome at 90 days; no significant difference in overall ICH or 30-day mortality, but more large parenchymal hemorrhages with the higher 1.1 mg/kg dose (which is why 0.9 mg/kg later became standard).
ATLANTIS-B (1999)PRCT (n=613)3–5 hMean 65 y; median NIHSS 100.9 mg/kg rt-PA (max 90 mg)
vs placebo		Stopped early; trend toward increased mortality with rt-PA (11% vs 7%).
ATLANTIS-A (2000)PRCT (n=142)≤6 hMean 67 y; mean NIHSS 130.9 mg/kg t-PA (max 90 mg)
vs placebo		Stopped early; significant increase in SICH (11% vs 0%) and 90-day mortality (23% vs 7%) with rt-PA.
EPITHET (2008)PRCT (n=101)3–6 hMean 71 y; median NIHSS 130.9 mg/kg t-PA (max 90 mg)
vs placebo		Non-significant difference in the primary (imaging) endpoint of infarct growth; no clear clinical benefit demonstrated.
Recent Evidence — Tenecteplase (non-inferiority vs alteplase)
AcT (Menon 2022)RCT, North America≤4.5 hStroke eligible for IV thrombolysisTenecteplase 0.25 mg/kg
vs alteplase 0.9 mg/kg		Tenecteplase non-inferior to alteplase (first North American RCT).
TRACE-2 (Wang 2023)RCT, China≤4.5 hStroke not undergoing thrombectomyTenecteplase 0.25 mg/kg
vs alteplase 0.9 mg/kg		Tenecteplase non-inferior to alteplase.
ORIGINAL (Meng 2024)RCT, China≤4.5 hStroke eligible for IV thrombolysisTenecteplase
vs alteplase		Tenecteplase non-inferior to alteplase.
TASTE (Parsons 2024)RCT, perfusion-selected≤4.5 hPerfusion-imaging–selected strokeTenecteplase 0.25 mg/kg
vs alteplase 0.9 mg/kg		Met non-inferiority in the per-protocol analysis but not in intention-to-treat — not a clean positive.

TTT: time-to-treatment; ITT: intention-to-treat; SICH: symptomatic intracranial hemorrhage; mRS: modified Rankin Scale; PRCT: prospective randomized controlled trial.

Conclusions

  • The AHA recommends that, for eligible patients, the benefit of alteplase is time-dependent and treatment should begin as quickly as possible.
  • Baseline imbalances favoring rt-PA in the NINDS and ECASS III trials remain a point of debate, given those trials were instrumental for approval and time-window expansion.
  • A re-analysis cannot overturn a study's original findings; it can only increase or decrease confidence in them.
  • The decision to use rt-PA for acute ischemic stroke should continue to weigh potential benefit against the upfront risk of fatal intracranial hemorrhage.
  • Tenecteplase (0.25 mg/kg) has shown non-inferiority to alteplase across multiple recent RCTs (AcT, TRACE-2, ORIGINAL), and many centers are transitioning to it; the perfusion-selected TASTE trial met non-inferiority per-protocol but not on intention-to-treat.

References

  • Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update. Stroke. 2019;50(12):e344-e418. doi:10.1161/STR.0000000000000211
  • The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581-1587.
  • Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet. 1998;352(9136):1245-1251. doi:10.1016/S0140-6736(98)08020-9
  • Sandercock P, Wardlaw JM, Lindley RI, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (IST-3): a randomised controlled trial. Lancet. 2012;379(9834):2352-2363. doi:10.1016/S0140-6736(12)60768-5
  • Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-1329. doi:10.1056/NEJMoa0804656
  • 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. doi:10.1056/NEJMoa1804355
  • Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274(13):1017-1025. doi:10.1001/jama.274.13.1017
  • Clark WM, Wissman S, Albers GW, et al. Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS study: a randomized controlled trial. JAMA. 1999;282(21):2019-2026.
  • Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g). Stroke. 2000;31:811-816.
  • Davis SM, Donnan GA, Parsons MW, et al. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol. 2008;7(4):299-309. doi:10.1016/S1474-4422(08)70044-9
  • 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. doi:10.1056/NEJMoa1813046
  • Marler JR, Tilley BC, Lu M, et al. Early stroke treatment associated with better outcome: the NINDS rt-PA Stroke Study. Neurology. 2000;55(11):1649-1655. doi:10.1212/WNL.55.11.1649
  • Alper BS, Foster G, Thabane L, et al. Thrombolysis with alteplase 3-4.5 hours after acute ischaemic stroke: trial reanalysis adjusted for baseline imbalances. BMJ Evid Based Med. 2020;25(5):168-171. doi:10.1136/bmjebm-2020-111386
  • Recent evidence added on review (2022–2025)
  • Menon BK, Buck BH, Singh N, et al. Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada (AcT): a pragmatic, multicentre, open-label, registry-linked, randomised, controlled, non-inferiority trial. Lancet. 2022;400(10347):161-169. doi:10.1016/S0140-6736(22)01054-6
  • Wang Y, Li S, Pan Y, et al. Tenecteplase versus alteplase in acute ischaemic cerebrovascular events (TRACE-2): a phase 3, multicentre, open-label, randomised controlled, non-inferiority trial. Lancet. 2023;401(10377):645-654. doi:10.1016/S0140-6736(22)02600-9
  • Meng X, Li S, Dai H, et al. Tenecteplase vs alteplase for patients with acute ischemic stroke: the ORIGINAL randomized clinical trial. JAMA. 2024;332(17):1437-1445. doi:10.1001/jama.2024.14721
  • Parsons MW, Yogendrakumar V, Churilov L, et al. Tenecteplase versus alteplase for thrombolysis in patients selected by use of perfusion imaging within 4.5 h of onset of ischaemic stroke (TASTE): a multicentre, randomised, controlled, phase 3 non-inferiority trial. Lancet Neurol. 2024;23(8):775-786. doi:10.1016/S1474-4422(24)00206-0
  • Muir KW. Should we switch to tenecteplase for all ischemic strokes? Evidence and logistics. Int J Stroke. 2025;20(3):261-267. doi:10.1177/17474930241307098
Tags:alteplase acute ischemic stroke thrombolysis intracranial hemorrhage

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