Is IV thrombolysis with alteplase (tissue plasminogen activator) indicated for acute ischemic stroke beyond 4.5 hours of symptom onset?

IV Thrombolysis Beyond 4.5 Hours in Acute Ischemic Stroke

Yes, IV thrombolysis with alteplase can be indicated beyond 4.5 hours in highly selected patients who demonstrate salvageable brain tissue on advanced neuroimaging, specifically those with perfusion mismatch on CT/MRI perfusion imaging (4.5-9 hours) or DWI-FLAIR mismatch on MRI (wake-up strokes), provided mechanical thrombectomy is not indicated or planned. 1

Evidence-Based Indications Beyond 4.5 Hours

Perfusion Imaging-Selected Patients (4.5-9 Hours)

The most recent 2023 World Stroke Organization guidelines explicitly recommend considering IV alteplase for patients presenting 4.5-9 hours after symptom onset who demonstrate CT or MRI core/perfusion mismatch, specifically when mechanical thrombectomy is either not indicated or not planned. 1 This represents the strongest current guideline recommendation for extended window thrombolysis.

The landmark 2025 HOPE trial—the highest quality and most recent evidence—demonstrated that alteplase administered 4.5-24 hours after stroke onset in perfusion imaging-selected patients significantly improved functional independence (40% vs 26% achieving mRS 0-1, adjusted RR 1.52, P=0.004), despite increased symptomatic intracranial hemorrhage (3.8% vs 0.51%). 2 Importantly, mortality was identical between groups (11% in both), indicating the bleeding risk did not translate to increased death. 2

A 2025 meta-analysis of 8 randomized trials (1,742 patients) confirmed that IVT beyond 4.5 hours increases odds of excellent functional outcomes (OR 1.43) and good functional outcomes (OR 1.36), with numerically superior results when patients were selected using perfusion imaging (OR 1.45) compared to DWI-FLAIR mismatch (OR 1.34). 3

Wake-Up Stroke with DWI-FLAIR Mismatch

For patients who awaken with stroke symptoms or have unclear time of onset >4.5 hours from last known well, IV alteplase administered within 4.5 hours of stroke symptom recognition can be beneficial if MRI demonstrates DWI-FLAIR mismatch. 1 This imaging pattern identifies strokes likely <4.5 hours old based on the evolution of ischemic changes on MRI sequences. 4

The 2018 AHA/ASA guidelines explicitly contraindicate alteplase for wake-up strokes beyond 4.5 hours from last known well without advanced imaging selection. 1 However, the 2023 WSO guidelines supersede this with the DWI-FLAIR mismatch approach. 1

Critical Selection Criteria

Imaging Requirements

• CT or MRI perfusion imaging demonstrating core/perfusion mismatch (substantial salvageable penumbra) for the 4.5-9 hour window 1
• MRI with DWI-FLAIR mismatch for wake-up strokes or unclear onset time 1
• Absence of intracranial hemorrhage on any imaging modality 1
• No extensive early ischemic changes (>1/3 MCA territory involvement remains a relative contraindication) 1, 5

Clinical Requirements

• Mechanical thrombectomy must not be indicated or planned (this is a critical caveat—if EVT is available and indicated, proceed directly to EVT with or without bridging thrombolysis) 1
• Standard alteplase contraindications still apply (active bleeding, recent surgery, uncontrolled hypertension >185/110 mmHg, etc.) 1
• Blood glucose must be checked and corrected if <60 mg/dL or >400 mg/dL 1

Safety Considerations and Common Pitfalls

The symptomatic intracranial hemorrhage risk increases substantially in the extended window (3.8% in HOPE trial vs historical 2.4% in the 3-4.5 hour ECASS III trial), but this must be weighed against the 14% absolute increase in functional independence. 2, 6 The 2025 meta-analysis confirmed a 4.25-fold increased odds of symptomatic ICH with extended window thrombolysis. 3

Critical pitfall: Do not use extended window thrombolysis in patients who are candidates for mechanical thrombectomy—the guidelines explicitly state this approach is for patients where EVT is "not indicated or not planned." 1 If large vessel occlusion is present, prioritize EVT.

Time calculation pitfall: For wake-up strokes, the "last known well" time is when the patient went to sleep, not when they woke up. 1 Without DWI-FLAIR mismatch imaging, these patients cannot receive thrombolysis if >4.5 hours from last known well. 1

Practical Algorithm for Extended Window Thrombolysis

1. Confirm time from symptom onset or last known well is >4.5 hours but <9 hours (or <24 hours if robust perfusion mismatch) 1, 2

2. Obtain advanced neuroimaging:

   • CT or MRI perfusion to assess core/perfusion mismatch, OR
   • MRI with DWI-FLAIR sequences for wake-up strokes 1

3. Verify mechanical thrombectomy is not indicated:

   • Perform CT angiography to exclude large vessel occlusion
   • If LVO present, proceed to EVT instead 1

4. Confirm standard alteplase eligibility criteria:

   • BP <185/110 mmHg (treat aggressively if needed)
   • No active bleeding or recent surgery
   • Normal coagulation parameters (INR <1.7, platelets >100,000)
   • Blood glucose 60-400 mg/dL 1, 5

5. Administer alteplase 0.9 mg/kg (max 90 mg) if perfusion mismatch or DWI-FLAIR mismatch present 1, 2

The Canadian 2018 guidelines note that randomized trials were ongoing at that time and recommended reviewing guidance when results became available. 1 The HOPE trial results now provide that evidence, strongly supporting extended window thrombolysis in perfusion-selected patients. 2