What is the recommended time window for thrombolysis in acute ischemic stroke using intravenous tissue plasminogen activator (tPA) or alteplase?

Time Window for Thrombolysis in Acute Ischemic Stroke

Intravenous thrombolysis with tissue plasminogen activator (tPA/alteplase) should be administered within 4.5 hours of stroke symptom onset, with the greatest benefit occurring within the first 3 hours.

Standard Time Windows for IV Thrombolysis

0-3 Hour Window (Primary Window)

• High-quality evidence supports administration of IV rtPA within the first 3 hours from symptom onset 1
• This time window provides the greatest therapeutic benefit with 154 more excellent outcomes per 1,000 patients 1
• Class I recommendation with Level of Evidence A 2
• No upper age limit within this window

3-4.5 Hour Window (Extended Window)

• IV rtPA should be administered to eligible patients within 3-4.5 hours after stroke onset (Class I recommendation, Level of Evidence B) 1
• The therapeutic benefit is reduced compared to the 0-3 hour window (69 more excellent outcomes per 1,000 patients vs. 154) 1
• Additional exclusion criteria apply in this time window:
  • Age >80 years
  • Oral anticoagulant use regardless of INR
  • NIHSS score >25
  • Combined history of both stroke and diabetes 1

Administration Protocol

• Recommended dose: 0.9 mg/kg (maximum 90 mg) 2
• Administration: 10% as bolus over 1 minute, remaining 90% infused over 60 minutes 2
• Blood pressure must be <185/110 mmHg before treatment and maintained <180/105 mmHg during and after treatment 2

Important Considerations

Time is Brain

• Earlier treatment provides significantly better outcomes 1
• Despite the 4.5-hour window, treatment should be initiated as quickly as possible
• Target door-to-needle time should be a median of 30 minutes, with 90th percentile being 60 minutes 1

Beyond 4.5 Hours

• Routine IV thrombolysis is not recommended beyond 4.5 hours from symptom onset 2
• Recent research has explored extending the window to 9 hours using advanced imaging:
  • The EXTEND trial showed potential benefit in carefully selected patients with salvageable brain tissue on perfusion imaging between 4.5-9 hours 3
  • However, this approach showed increased risk of symptomatic intracerebral hemorrhage (6.2% vs 0.9% with placebo) 3
  • A 2025 meta-analysis found that late window thrombolysis (beyond 4.5 hours) can achieve higher rates of good functional outcomes but with increased symptomatic hemorrhage rates (OR 4.25) 4

Imaging Requirements

• All acute stroke patients presenting within treatment windows should receive brain imaging (CT) and vascular imaging (CTA) 1
• For consideration of extended window treatment, advanced imaging with CT perfusion or MRI with diffusion-weighted imaging may be required to identify salvageable tissue 1, 3

Safety Considerations

• Symptomatic intracerebral hemorrhage is the most significant risk
• In the 3-4.5 hour window, ECASS-3 reported symptomatic ICH in 2.4% of rtPA patients vs 0.2% with placebo 1
• The risk of fatal ICH is significantly increased with thrombolytic therapy (OR 3.70) 1

Special Populations

• Pediatric patients: Limited data exists on thrombolysis in children, with <2% of children with acute ischemic stroke receiving tPA 1
• Wake-up strokes: Traditional time windows may not apply; advanced imaging may help select patients who might benefit from treatment 5, 3

The evidence clearly demonstrates that while the therapeutic window extends to 4.5 hours, the benefit of thrombolysis decreases significantly with time. Therefore, every effort should be made to treat eligible patients as quickly as possible within this window.