Acute Ischemic Stroke Thrombolysis: Practical Patient Selection, Contraindications, and Treatment Windows

01

The selection decision in one view

For a patient with a clinically suspected acute ischemic stroke, ask seven questions in parallel:

1. What is the relevant treatment time? Establish last known well, symptom discovery, and—when the onset is unknown—the time symptoms were recognized.
2. Is the neurologic deficit disabling for this patient? Do not use the NIHSS score alone to decide.
3. Has intracranial hemorrhage been excluded? Noncontrast CT is sufficient for most standard-window thrombolysis decisions.
4. Does the patient need an advanced-imaging selection pathway? MRI DWI–FLAIR or perfusion imaging applies only to defined unknown-onset or extended-window situations.
5. Is there a contraindication or bleeding-risk feature that changes the balance? Identify true prohibitions, modifiable barriers, and individualized high-risk circumstances.
6. Is blood pressure below the pretreatment threshold? It must be reduced to less than 185/110 mm Hg before IV thrombolysis.
7. Is thrombectomy also indicated? If the patient is eligible for both treatments, give IV thrombolysis promptly and proceed to thrombectomy without waiting to see whether the deficit improves.[1]

02

1. Start with the treatment clock

Known onset or last known well within 4.5 hours

For an otherwise eligible adult with a disabling acute ischemic stroke within 4.5 hours, IV thrombolysis should be given as quickly as possible. The current guideline emphasizes that eligible treatment should not be delayed for advanced multimodal imaging. A noncontrast head CT is generally adequate to exclude hemorrhage and assess whether extensive established infarction makes treatment unsuitable.[1]

The evidence base evolved from the NINDS rt-PA trial, which established benefit with early alteplase treatment, and ECASS III, which supported treatment in selected patients from 3 to 4.5 hours.[2,3] These trials support the evidence base; the 2026 guideline remains the source for the current recommendation.

03

Advanced and variably adopted treatment windows

The pathways below are addressed by the 2026 guideline, but they are not interchangeable with standard IV thrombolysis within 4.5 hours. They depend on trial-defined imaging selection, specialized interpretation or automated software, and center-specific capability. Many comprehensive stroke centers do not apply every pathway routinely. The evidence should therefore be read as applying to patients who resemble the study populations—not to all patients presenting outside the standard window.

Unknown onset or wake-up stroke: what WAKE-UP actually studied

The 2026 guideline states that IV thrombolysis can be beneficial when onset is unknown, treatment can begin within 4.5 hours of symptom recognition, MRI shows a DWI lesion smaller than one-third of the middle cerebral artery territory, and there is no marked corresponding FLAIR signal change.[1] This is a tissue-clock pathway derived primarily from WAKE-UP, not a general indication to treat every wake-up stroke.

Population and selection. WAKE-UP enrolled 503 patients with an unknown onset time. MRI had to show an acute lesion on diffusion-weighted imaging without a clearly visible or marked FLAIR hyperintensity in the same region. Subtle FLAIR change was allowed; trial guidance recommended a lesion-to-mirrored-region FLAIR signal-intensity ratio below 1.2 when quantitative confirmation was needed. DWI lesions larger than one-third of the MCA territory were excluded. Other exclusions included NIHSS greater than 25, a usual contraindication to alteplase, and planned thrombectomy.[1,4]

Methods. This was a multicenter randomized placebo-controlled trial of IV alteplase versus placebo. The primary endpoint was modified Rankin Scale (mRS) 0–1 at 90 days. The trial stopped when funding ended after 503 of a planned 800 participants had been enrolled; 254 were assigned to alteplase and 249 to placebo.[4]

Efficacy and safety. Among patients included in the primary analysis, mRS 0–1 at 90 days occurred in 53.3% with alteplase and 41.8% with placebo (adjusted odds ratio 1.61, 95% CI 1.09–2.36). Symptomatic intracranial hemorrhage occurred in 2.0% and 0.4%, respectively. Mortality was 4.1% with alteplase and 1.2% with placebo; neither safety comparison was statistically conclusive because the event counts were small.[4]

Conclusion and applicability. WAKE-UP showed better functional outcome with alteplase in an MRI-selected unknown-onset population, with numerically more intracranial hemorrhage. Its result depends on reproducible DWI–FLAIR interpretation, excludes patients planned for thrombectomy and those with very severe deficits, and comes from a trial stopped before its planned sample size. A DWI–FLAIR mismatch estimates lesion age; it does not establish the true clock time or eliminate hemorrhagic risk.

Perfusion-selected treatment from 4.5 to 9 hours: what EXTEND studied

The 2026 guideline states that IV thrombolysis can be beneficial for patients who are not eligible for thrombectomy and either present 4.5–9 hours from last known well or awaken with symptoms within 9 hours from the midpoint of sleep, provided automated perfusion imaging demonstrates salvageable tissue.[1]

Population and selection. EXTEND enrolled patients with CT-perfusion or MR diffusion–perfusion evidence of a small ischemic core and larger hypoperfused region. The automated mismatch criteria were:

• ischemic-core volume less than 70 mL;
• hypoperfused-to-core volume ratio greater than 1.2; and
• absolute mismatch volume greater than 10 mL.

Core was defined by relative cerebral blood flow below 30% of normal tissue on CT perfusion or by the DWI lesion; hypoperfused tissue was defined by Tmax greater than 6 seconds on CT or MR perfusion. Patients were treated 4.5–9 hours after onset or after wake-up stroke when within 9 hours of the midpoint of sleep.[1,5]

Methods. EXTEND was a multicenter randomized placebo-controlled trial of alteplase versus placebo. The primary endpoint was mRS 0–1 at 90 days. Enrollment stopped at 225 of a planned 310 participants after publication of another positive trial was judged to remove equipoise; 113 patients received alteplase and 112 placebo.[5]

Efficacy and safety. The primary endpoint occurred in 35.4% with alteplase and 29.5% with placebo (adjusted risk ratio 1.44, 95% CI 1.01–2.06). Symptomatic intracerebral hemorrhage occurred in 6.2% and 0.9%, respectively (adjusted risk ratio 7.22, 95% CI 0.97–53.5). The secondary ordinal mRS analysis did not show a significant overall shift in disability.[5]

Conclusion and applicability. EXTEND supports alteplase for a narrowly selected perfusion-mismatch population, but the absolute difference in mRS 0–1 was modest, hemorrhage was more frequent, and the trial stopped early. Approximately 77% of EXTEND participants had large-vessel occlusions that would now usually prompt thrombectomy evaluation, which limits direct applicability to current comprehensive-center practice.[1]

What the pooled perfusion trials add

An individual-patient-data meta-analysis combined EXTEND, ECASS4-EXTEND, and EPITHET. It included 414 adults treated more than 4.5 hours after onset or after wake-up stroke who had CT-perfusion or MR perfusion–diffusion selection; 213 received alteplase and 201 placebo.[6]

At 90 days, mRS 0–1 occurred in 36% of alteplase-treated patients and 29% of placebo-treated patients (adjusted odds ratio 1.86, 95% CI 1.15–2.99). Symptomatic intracerebral hemorrhage occurred in 5% versus less than 1% (adjusted odds ratio 9.7, 95% CI 1.23–76.55). Mortality was 14% versus 9%, without a statistically established difference.[6]

The pooled analysis strengthens the signal that imaging-selected patients may benefit, but it does not broaden eligibility beyond the trial criteria. The component trials used related but not identical mismatch thresholds, remained relatively small, and selected patients using advanced imaging workflows. “Favorable perfusion” should therefore mean a validated, trial-concordant automated analysis—not an informal visual impression.

Large-vessel occlusion from 4.5 to 24 hours: TRACE-III and TIMELESS answer different questions

The 2026 guideline gives a weaker recommendation: IV thrombolysis may be beneficial for a patient with large-vessel occlusion and salvageable penumbra 4.5–24 hours from onset or last known well when thrombectomy cannot be performed and the decision is directed by clinicians with thrombolysis expertise.[1] This is not a recommendation to substitute thrombolysis for available thrombectomy.

Shared imaging selection. TRACE-III and TIMELESS used a more stringent automated mismatch profile than EXTEND:

• core volume less than 70 mL;
• hypoperfused-to-core ratio greater than 1.8; and
• mismatch volume greater than 15 mL.

Core was defined by relative cerebral blood flow below 30% or DWI; penumbra was defined by Tmax greater than 6 seconds. TRACE-III used iStroke processing, whereas TIMELESS used RAPID.[1]

TRACE-III: patients without timely thrombectomy. TRACE-III randomized 516 patients in China with internal carotid or M1/M2 middle cerebral artery occlusion, trial-concordant salvageable tissue, and no access to thrombectomy. Patients presenting 4.5–24 hours from last known well—including wake-up and unwitnessed strokes—received tenecteplase 0.25 mg/kg or standard medical treatment. Fewer than 2% underwent rescue thrombectomy. The primary endpoint, mRS 0–1 at 90 days, occurred in 33.0% with tenecteplase and 24.2% with standard treatment (relative rate 1.37, 95% CI 1.04–1.81). Mortality was 13.3% and 13.1%; symptomatic intracranial hemorrhage was 3.0% and 0.8%.[19]

TRACE-III supports a possible role for tenecteplase when a trial-selected patient with LVO cannot receive timely thrombectomy. Its population and health-system context are central limitations: the result should not be extrapolated to bypass, defer, or replace available EVT.

TIMELESS: most patients proceeded to thrombectomy. TIMELESS randomized 458 patients with internal carotid or middle cerebral artery occlusion and perfusion-selected salvageable tissue to tenecteplase 0.25 mg/kg or placebo 4.5–24 hours after last known well. It was double-blind and placebo-controlled; 77.3% subsequently underwent thrombectomy. Median time from last known well to randomization was approximately 12 hours with tenecteplase and 13 hours with placebo. The primary ordinal mRS outcome at 90 days did not differ (adjusted common odds ratio 1.13, 95% CI 0.82–1.57). Mortality was 19.7% versus 18.2%, and symptomatic intracranial hemorrhage 3.2% versus 2.3%.[20]

TIMELESS did not show clinical benefit from adding late-window tenecteplase in a population in which most patients received thrombectomy. Taken together, TRACE-III and TIMELESS support the guideline's narrow wording: late-window IV thrombolysis may be considered when EVT is unavailable or substantially delayed, under expert direction, rather than as routine comprehensive-center care.[1,19,20]

04

2. Decide whether the deficit is disabling

A low NIHSS score can still represent a disabling stroke

The current guideline recommends IV thrombolysis for an otherwise eligible patient with a disabling neurologic deficit, regardless of the NIHSS score. Disability is individualized. The same measured deficit may have very different consequences depending on baseline function, occupation, dominant hand, communication demands, mobility, vision, and the patient's priorities.[1]

Potentially disabling examples include clinically important aphasia, hemianopia, dominant-hand weakness, gait-limiting leg weakness, neglect, or a deficit that prevents an essential activity or safe independent function. The question is not “Is the NIHSS low?” but “If this deficit persists, would it prevent this patient from performing an important usual activity?”

Treatment should not be delayed merely to watch for further improvement when a disabling deficit remains. Rapid improvement matters only if the remaining deficit is genuinely nondisabling.

Mild nondisabling deficits are a different group

For patients with mild nondisabling deficits within 4.5 hours, the 2026 guideline does not recommend IV thrombolysis over dual antiplatelet therapy.[1] PRISMS did not demonstrate a functional benefit of alteplase over aspirin in this population and showed greater symptomatic intracranial hemorrhage with alteplase, although the trial ended early and its precision was limited.[7] ARAMIS subsequently found dual antiplatelet therapy noninferior to alteplase for excellent functional outcome in its selected minor nondisabling stroke population.[18]

This recommendation should not be generalized to every patient with a low NIHSS score. The decisive distinction is disabling versus nondisabling, not a single numeric cutoff.

05

3. Perform a focused safety screen

A practical safety screen should separate three kinds of findings:

• conditions that ordinarily preclude IV thrombolysis;
• modifiable barriers, such as blood pressure above the treatment threshold; and
• higher-risk circumstances requiring individualized expert judgment.

The 2026 guideline updates several specific circumstances but does not reproduce a single exhaustive contraindication table. The domains below are therefore a clinical framework, not a replacement for a current institutional checklist.[1,16,17]

Exclude hemorrhage and major alternative emergencies

Do not give IV thrombolysis when brain imaging demonstrates intracranial hemorrhage. A presentation concerning for subarachnoid hemorrhage, infective endocarditis with cerebral embolism, or acute aortic dissection requires a different emergency pathway. A large burden of established infarction or other imaging finding that materially changes hemorrhagic risk also requires expert adjudication.[1,16,17]

Clarify recent bleeding, trauma, and procedures

Rapidly determine whether there is active internal bleeding, recent intracranial or intraspinal surgery, serious recent head trauma, a recent ischemic stroke, recent gastrointestinal bleeding, a noncompressible arterial puncture, or another procedure with a clinically important bleeding site. The timing, severity, anatomic site, hemostasis, and consequence of bleeding are more informative than the word “recent” alone.[16,17]

These circumstances do not all carry the same evidence or recommendation strength. When the answer is uncertain, the decision should be escalated without allowing avoidable information-gathering delays.

Review antithrombotic exposure and hemostasis

Prestroke antiplatelet therapy—even dual antiplatelet therapy—is not by itself a reason to withhold otherwise indicated IV thrombolysis, although symptomatic intracranial hemorrhage risk is higher.[1]

Anticoagulant exposure requires identification of the agent, last dose, renal function, and available drug-specific or conventional coagulation testing. Severe thrombocytopenia or a clinically significant anticoagulant effect may preclude treatment. Recent direct oral anticoagulant exposure remains an area of evolving evidence; do not assume that a normal PT/INR excludes clinically relevant activity for every agent. Follow current expert and institutional pathways rather than extrapolating from warfarin thresholds.[1,16,17]

If there is no clinical reason to suspect an abnormal platelet count or coagulation result, the guideline considers it reasonable not to delay IV thrombolysis while awaiting routine hematologic or coagulation tests. Blood glucose is the one laboratory value that must be checked before treatment because hypoglycemia and severe hyperglycemia can mimic or complicate acute stroke.[1]

Consider cerebral microbleeds without delaying treatment

MRI should not be delayed solely to determine cerebral microbleed burden before otherwise indicated IV thrombolysis. Treatment is reasonable when one to ten microbleeds are already known. With more than ten microbleeds, benefit and risk are less certain and the decision is individualized.[1]

06

4. Meet the blood-pressure requirements

Before IV thrombolysis, reduce blood pressure to:

• systolic less than 185 mm Hg; and
• diastolic less than 110 mm Hg.[1]

If blood pressure cannot be safely maintained below this threshold, IV thrombolysis should not proceed. After treatment, maintain blood pressure below 180/105 mm Hg for at least 24 hours. More intensive routine reduction to a systolic pressure below 140 mm Hg after IV thrombolysis has not shown benefit and is not recommended as a default target.[1]

These thresholds are treatment boundaries, not an invitation to create abrupt hypotension. Drug selection and titration should follow the acute-stroke treatment environment and institutional workflow.

07

5. Choose alteplase or tenecteplase

For an eligible adult treated within 4.5 hours, the 2026 guideline recommends either:

• tenecteplase 0.25 mg/kg IV, maximum 25 mg, given as a single bolus; or
• alteplase 0.9 mg/kg IV, maximum 90 mg, with 10% as an initial bolus and the remainder infused over 60 minutes.[1]

The current recommendation is supported by multiple randomized comparisons, including AcT, TRACE-2, ATTEST-2, TASTE, and ORIGINAL.[8–12] Collectively, these trials support tenecteplase 0.25 mg/kg as an alternative to alteplase in appropriately selected patients. Differences among trial populations, imaging strategies, and analytic designs still matter when applying individual study results.

Tenecteplase 0.4 mg/kg is not recommended for acute ischemic stroke. NOR-TEST 2A raised safety and efficacy concerns with the higher dose.[13]

The standard-window agent recommendation should not be automatically extrapolated to every extended-window scenario. Outside 4.5 hours, use the agent and imaging pathway supported by the applicable evidence and current expert workflow.

08

6. Give thrombolysis when thrombectomy is also planned

If a patient is eligible for both IV thrombolysis and endovascular thrombectomy, IV thrombolysis is recommended. Give it rapidly and continue the thrombectomy workflow; do not wait to see whether the patient improves before proceeding.[1]

EXTEND-IA TNK demonstrated improved early reperfusion with tenecteplase compared with alteplase before thrombectomy in a selected large-vessel-occlusion population.[14] Randomized direct-to-thrombectomy trials and the IRIS individual-patient-data collaboration do not support routinely skipping IV thrombolysis in otherwise eligible patients.[15]

The practical rule is simple: IV thrombolysis should not delay thrombectomy, and thrombectomy evaluation should not delay eligible IV thrombolysis.

09

7. Know the immediate post-thrombolysis priorities

The first 24 hours are part of safe treatment selection because the treating team must be able to provide the required monitoring and respond to deterioration.

The guideline monitoring framework includes:

• admission to a stroke unit or intensive monitoring environment;
• neurologic assessment and blood-pressure measurement every 15 minutes during and after treatment for 2 hours, every 30 minutes for 6 hours, then hourly until 24 hours;
• maintenance of blood pressure below 180/105 mm Hg;
• urgent evaluation and head CT for severe headache, acute hypertension, nausea or vomiting, or neurologic worsening; and
• follow-up CT or MRI at approximately 24 hours before starting antiplatelet or anticoagulant therapy.[1]

When alteplase is still infusing and concerning deterioration occurs, stop the infusion while emergency evaluation proceeds. Intravenous aspirin should not be given concurrently with thrombolysis or within 90 minutes after treatment. The safety of antiplatelet therapy during the first 24 hours remains uncertain and should be considered early only when a compelling competing indication exists.[1]

10

Practical synthesis

An efficient thrombolysis decision preserves speed without replacing judgment with a checkbox:

1. Confirm a clinically meaningful acute deficit and determine whether it is disabling.
2. Establish the relevant time anchor: last known well, symptom discovery, or symptom recognition.
3. Exclude hemorrhage and identify the correct standard- or extended-window imaging pathway.
4. Check glucose, blood pressure, bleeding history, procedures, and antithrombotic exposure in parallel.
5. Treat eligible patients promptly with alteplase or tenecteplase 0.25 mg/kg within the supported window.
6. Continue directly to thrombectomy when indicated.
7. Provide structured neurologic and blood-pressure monitoring for the first 24 hours.

The central distinction is not “minor versus major stroke.” It is whether the deficit is disabling, whether the patient fits a validated time-and-imaging pathway, and whether bleeding risk remains acceptable after rapid focused review.

11

Evidence notes

1. Prabhakaran S, et al. 2026 Guideline for the Early Management of Patients With Acute Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2026;57:e00–e00. doi:10.1161/STR.0000000000000513. Current normative source; the local publisher PDF retains provisional pagination.
2. 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. doi:10.1056/NEJM199512143332401. PMID:7477192.
3. Hacke W, Kaste M, Bluhmki E, et al; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317–1329. doi:10.1056/NEJMoa0804656. PMID:18815396.
4. Thomalla G, Simonsen CZ, Boutitie F, et al; WAKE-UP Investigators. MRI-guided thrombolysis for stroke with unknown time of onset. N Engl J Med. 2018;379:611–622. doi:10.1056/NEJMoa1804355. PMID:29766770.
5. Ma H, Campbell BCV, Parsons MW, et al; EXTEND Investigators. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N Engl J Med. 2019;380:1795–1803. doi:10.1056/NEJMoa1813046. PMID:31067369.
6. Campbell BCV, Ma H, Ringleb PA, et al. Extending thrombolysis to 4.5–9 h and wake-up stroke using perfusion imaging: an individual-patient-data meta-analysis. Lancet. 2019;394:139–147. doi:10.1016/S0140-6736(19)31053-0. PMID:31128925.
7. Khatri P, Kleindorfer DO, Devlin T, et al; PRISMS Investigators. Effect of alteplase vs aspirin on functional outcome for patients with acute ischemic stroke and minor nondisabling neurologic deficits. JAMA. 2018;320:156–166. doi:10.1001/jama.2018.8496. PMID:29998337.
8. Menon BK, Buck BH, Singh N, et al; AcT Trial Investigators. Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada. Lancet. 2022;400:161–169. doi:10.1016/S0140-6736(22)01054-6. PMID:35779553.
9. Wang Y, Li S, Pan Y, et al; TRACE-2 Investigators. Tenecteplase versus alteplase in acute ischaemic cerebrovascular events. Lancet. 2023;401:645–654. doi:10.1016/S0140-6736(22)02600-9. PMID:36774935.
10. Muir KW, Ford GA, Ford I, et al; ATTEST-2 Investigators. Tenecteplase versus alteplase for acute stroke within 4.5 h of onset. Lancet Neurol. 2024;23:1087–1096. doi:10.1016/S1474-4422(24)00377-6. PMID:39424558.
11. Parsons MW, Yogendrakumar V, Churilov L, et al; TASTE Investigators. Tenecteplase versus alteplase for thrombolysis in patients selected by perfusion imaging within 4.5 h. Lancet Neurol. 2024;23:775–786. doi:10.1016/S1474-4422(24)00206-0. PMID:38880118.
12. Meng X, Li S, Dai H, et al. Tenecteplase vs alteplase for patients with acute ischemic stroke: the ORIGINAL randomized clinical trial. JAMA. 2024;332:1437–1445. doi:10.1001/jama.2024.14721. PMID:39264623.
13. Kvistad CE, Næss H, Helleberg BH, et al. Tenecteplase versus alteplase for acute ischaemic stroke in Norway (NOR-TEST 2, part A). Lancet Neurol. 2022;21:511–519. doi:10.1016/S1474-4422(22)00124-7. PMID:35525250.
14. Campbell BCV, Mitchell PJ, Churilov L, et al; EXTEND-IA TNK Investigators. Tenecteplase versus alteplase before thrombectomy for ischemic stroke. N Engl J Med. 2018;378:1573–1582. doi:10.1056/NEJMoa1716405. PMID:29694815.
15. Kaesmacher J, Cavalcante F, Kappelhof M, et al; IRIS Collaborators. Time to treatment with intravenous thrombolysis before thrombectomy and functional outcomes in acute ischemic stroke: a meta-analysis. JAMA. 2024;331:764–777. doi:10.1001/jama.2024.0589. PMID:38324409.
16. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scientific rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke. Stroke. 2016;47:581–641. doi:10.1161/STR.0000000000000086. PMID:26696642.
17. Powers WJ, Rabinstein AA, Ackerson T, et al. 2019 update to the 2018 guidelines for the early management of acute ischemic stroke. Stroke. 2019;50:e344–e418. doi:10.1161/STR.0000000000000211. PMID:31662037. Superseded; used only for historical exclusion-table reconciliation.
18. Chen H-S, Cui Y, Zhou Z-H, et al; ARAMIS Investigators. Dual antiplatelet therapy vs alteplase for patients with minor nondisabling acute ischemic stroke: the ARAMIS randomized clinical trial. JAMA. 2023;329:2135–2144. doi:10.1001/jama.2023.7827. PMID:37367978.
19. Xiong Y, Campbell BCV, Schwamm LH, et al; TRACE-III Investigators. Tenecteplase for ischemic stroke at 4.5 to 24 hours without thrombectomy. N Engl J Med. 2024;391:203–212. doi:10.1056/NEJMoa2402980. PMID:38884324.
20. Albers GW, Jumaa M, Purdon B, et al; TIMELESS Investigators. Tenecteplase for stroke at 4.5 to 24 hours with perfusion-imaging selection. N Engl J Med. 2024;390:701–711. doi:10.1056/NEJMoa2310392. PMID:38329148.

Full source classification, local availability, and exact guideline locators are recorded in `references.json` and `bibliography-audit.md`.

12

References

1. Prabhakaran S, et al. 2026 Guideline for the Early Management of Patients With Acute Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2026;57:e00-e00.
2. 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.
3. Hacke W, Kaste M, Bluhmki E, et al; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317-1329.
4. Thomalla G, Simonsen CZ, Boutitie F, et al; WAKE-UP Investigators. MRI-guided thrombolysis for stroke with unknown time of onset. N Engl J Med. 2018;379:611-622.
5. Ma H, Campbell BCV, Parsons MW, et al; EXTEND Investigators. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N Engl J Med. 2019;380:1795-1803.
6. Campbell BCV, Ma H, Ringleb PA, et al; EXTEND, ECASS-4, and EPITHET Investigators. Extending thrombolysis to 4.5-9 h and wake-up stroke using perfusion imaging: a systematic review and meta-analysis of individual patient data. Lancet. 2019;394:139-147.
7. Xiong Y, Campbell BCV, Schwamm LH, et al; TRACE-III Investigators. Tenecteplase for ischemic stroke at 4.5 to 24 hours without thrombectomy. N Engl J Med. 2024;391:203-212.
8. Albers GW, Jumaa M, Purdon B, et al; TIMELESS Investigators. Tenecteplase for stroke at 4.5 to 24 hours with perfusion-imaging selection. N Engl J Med. 2024;390:701-711.
9. Khatri P, Kleindorfer DO, Devlin T, et al; PRISMS Investigators. Effect of alteplase vs aspirin on functional outcome for patients with acute ischemic stroke and minor nondisabling neurologic deficits: the PRISMS randomized clinical trial. JAMA. 2018;320:156-166.
10. Chen H-S, Cui Y, Zhou Z-H, et al; ARAMIS Investigators. Dual antiplatelet therapy vs alteplase for patients with minor nondisabling acute ischemic stroke: the ARAMIS randomized clinical trial. JAMA. 2023;329:2135-2144.
11. Menon BK, Buck BH, Singh N, et al; AcT Trial Investigators. 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;400:161-169.
12. Wang Y, Li S, Pan Y, et al; TRACE-2 Investigators. Tenecteplase versus alteplase in acute ischaemic cerebrovascular events (TRACE-2): a phase 3, multicentre, open-label, randomised controlled, non-inferiority trial. Lancet. 2023;401:645-654.
13. Muir KW, Ford GA, Ford I, et al; ATTEST-2 Investigators. Tenecteplase versus alteplase for acute stroke within 4.5 h of onset (ATTEST-2): a randomised, parallel group, open-label trial. Lancet Neurol. 2024;23:1087-1096.
14. Parsons MW, Yogendrakumar V, Churilov L, et al; TASTE Investigators. 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;23:775-786.
15. Meng X, Li S, Dai H, et al. Tenecteplase vs alteplase for patients with acute ischemic stroke: the ORIGINAL randomized clinical trial. JAMA. 2024;332:1437-1445.
16. Kvistad CE, Naess H, Helleberg BH, et al. Tenecteplase versus alteplase for the management of acute ischaemic stroke in Norway (NOR-TEST 2, part A): a phase 3, randomised, open-label, blinded endpoint, non-inferiority trial. Lancet Neurol. 2022;21:511-519.
17. Campbell BCV, Mitchell PJ, Churilov L, et al; EXTEND-IA TNK Investigators. Tenecteplase versus alteplase before thrombectomy for ischemic stroke. N Engl J Med. 2018;378:1573-1582.
18. Kaesmacher J, Cavalcante F, Kappelhof M, et al; IRIS Collaborators. Time to treatment with intravenous thrombolysis before thrombectomy and functional outcomes in acute ischemic stroke: a meta-analysis. JAMA. 2024;331:764-777.
19. Demaerschalk BM, Kleindorfer DO, Adeoye OM, et al. Scientific rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2016;47:581-641.
20. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines. Stroke. 2019;50:e344-e418.