Are thrombolytics, such as alteplase (tissue plasminogen activator), administered in acute ischemic stroke cases beyond 4.5 hours after symptom onset?

Thrombolytic Therapy in Acute Ischemic Stroke Beyond 4.5 Hours

Yes, thrombolytics are now administered beyond the traditional 4.5-hour window in selected patients with acute ischemic stroke, specifically up to 9 hours from symptom onset when perfusion imaging shows salvageable brain tissue. 1, 2, 3

Standard Time Windows for Thrombolytic Therapy

The established time windows for IV alteplase administration are:

• 0-3 hours: Strongest recommendation (Class I, Level A) with the greatest benefit-to-risk ratio 1, 2
• 3-4.5 hours: Recommended (Class I, Level B) with additional exclusion criteria 1, 2:
  • Age >80 years
  • History of both diabetes and prior stroke
  • NIHSS score >25
  • Use of oral anticoagulants (regardless of INR)
  • Imaging evidence of ischemic injury involving more than one-third of MCA territory

Extended Time Windows (Beyond 4.5 Hours)

Advanced Imaging-Based Selection

For patients presenting beyond 4.5 hours, thrombolytics can be administered in specific scenarios:

• 4.5-9 hours from symptom onset: IV alteplase can be considered for patients with CT or MRI core/perfusion mismatch 1
• Wake-up strokes or unclear onset time >4.5 hours: IV alteplase can be beneficial if MRI shows DWI-FLAIR mismatch 1
• Recent evidence: The HOPE trial demonstrated benefit of IV alteplase in the 4.5-24 hour window for patients with salvageable brain tissue identified by perfusion imaging, showing increased functional independence (40% vs 26%) despite higher symptomatic hemorrhage rates (3.8% vs 0.5%) 3

Administration Protocol

When administering alteplase in extended time windows:

• Dose: 0.9 mg/kg (maximum 90 mg)
• Administration: 10% as bolus, remainder over 60 minutes 1, 2
• Pre-treatment requirements:
  • Blood pressure <185/110 mmHg
  • Blood glucose assessment (treat if <60 mg/dL)
  • Neuroimaging to exclude hemorrhage
  • Advanced imaging (CT perfusion or MRI DWI-FLAIR/perfusion) to identify salvageable tissue

Important Considerations

• Time-dependent efficacy: Earlier treatment consistently leads to better outcomes 2
• Patient selection: Careful selection based on imaging is critical for extended time windows 1, 3
• Hemorrhage risk: Symptomatic intracranial hemorrhage risk increases in extended time windows (3.8% vs 0.5% in the HOPE trial) 3
• Mechanical thrombectomy: For large vessel occlusions, mechanical thrombectomy may be considered up to 24 hours in patients with favorable imaging 1

Pitfalls to Avoid

• Rigid time window application: Don't automatically exclude patients beyond 4.5 hours without considering imaging-based selection criteria
• Delaying treatment: Even with extended windows, treatment should be initiated as quickly as possible
• Overlooking contraindications: Standard contraindications still apply in extended time windows
• Neglecting post-treatment monitoring: Close neurological monitoring every 15 minutes for the first 2 hours is essential to detect potential hemorrhagic complications 2

The extension of thrombolytic therapy beyond 4.5 hours represents a significant advancement in stroke care, allowing more patients to benefit from reperfusion therapy when appropriate imaging selection criteria are applied.