What is the approach to thrombolysis with tissue plasminogen activator (tPA) in patients with wake-up stroke?

Thrombolysis in Wake-up Stroke

Patients with wake-up stroke should receive thrombolysis with tPA if they have favorable imaging findings, particularly diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) mismatch on MRI, or CT perfusion imaging showing salvageable brain tissue, even when time of onset is unknown. 1, 2

Current Guidelines and Evidence

Patient Selection for Wake-up Stroke Thrombolysis

• Wake-up strokes account for approximately 25% of all strokes, with patients waking up with symptoms and an unknown time of onset 3
• Traditional time-based criteria (within 4.5 hours of symptom onset) exclude these patients from receiving potentially beneficial thrombolytic therapy 1
• Current evidence supports using imaging-based selection rather than time-based selection for wake-up stroke patients 1, 2

Imaging Selection Criteria

• MRI-based selection:

  • DWI-FLAIR mismatch (acute ischemic lesion visible on diffusion-weighted imaging but not yet visible on FLAIR) indicates the stroke is likely within the 4.5-hour treatment window 4
  • This approach is being tested in clinical trials such as WAKE-UP 4

• CT-based selection:

  • CT perfusion imaging can identify salvageable brain tissue (penumbra) in patients with unknown time of onset 1
  • The mismatch between perfusion deficit and established infarct core represents potentially salvageable tissue 5

Efficacy and Safety

• Meta-analysis data shows that tPA administration in wake-up stroke patients selected by imaging criteria results in:

  • 61% of patients achieving good functional outcome (mRS 0-2) at 90 days 1
  • 21% higher relative likelihood of good outcome compared to no treatment (RR 1.21,95% CI: 1.01-1.46) 1
  • Symptomatic intracerebral hemorrhage (sICH) rate of 3% (95% CI: 2.5%-4.1%) 1
  • Although sICH risk is higher with tPA (RR 4.00,95% CI: 2.85-5.61), the overall benefit outweighs this risk 1

• The EXTEND trial and related studies demonstrated that patients with salvageable brain tissue treated 4.5-9 hours after onset or with wake-up stroke had:

  • Better functional outcomes with alteplase compared to placebo (36% vs 29% achieving excellent outcome) 2
  • Higher symptomatic hemorrhage risk (5% vs <1%) that did not negate the overall benefit 2

Implementation Considerations

• Rapid access to advanced neuroimaging (MRI with DWI/FLAIR or CT perfusion) is essential for proper patient selection 1
• Treatment decisions should be made in consultation with stroke specialists, particularly when uncertainty exists regarding imaging interpretation 6
• Door-to-needle time targets should still be prioritized, with a goal of less than 60 minutes in 90% of treated patients and a median time of 30 minutes 6

Common Pitfalls and Caveats

• Failure to recognize that many wake-up strokes likely occur close to awakening, making patients potentially eligible for treatment 3
• Relying solely on time-based criteria rather than tissue-based imaging selection for treatment decisions 1
• Delaying treatment due to uncertainty - when in doubt about CT imaging interpretation, promptly consult with a radiologist 6
• Not considering thrombolysis in wake-up stroke patients due to outdated protocols that strictly adhere to time windows rather than tissue viability 2

By using advanced imaging to identify patients with salvageable brain tissue, thrombolytic therapy can be safely and effectively extended to wake-up stroke patients who would otherwise be denied this potentially beneficial treatment.