What is the role of the EXTEND (Endovascular treatment for ischemic stroke with unknown onset) trial in guiding treatment for wake-up stroke patients?

Role of the EXTEND Trial in Wake-Up Stroke Management

For wake-up stroke patients, the EXTEND trial supports the use of advanced imaging (CT perfusion or MRI) to identify salvageable brain tissue for endovascular thrombectomy within 4.5-9 hours of symptom recognition, rather than using time from last known well as the sole criterion for treatment eligibility. 1

Current Guidelines for Wake-Up Stroke Management

The 2018 American Heart Association/American Stroke Association (AHA/ASA) guidelines provide specific recommendations regarding wake-up stroke management:

• For patients with wake-up stroke who have unclear time of symptom onset, imaging-based selection is critical for treatment decisions 1
• Advanced imaging (CT perfusion, DW-MRI, or MRI perfusion) is recommended to aid in patient selection for mechanical thrombectomy within 6-24 hours of last known normal in patients with large vessel occlusion (LVO) in the anterior circulation 1
• The use of imaging criteria to select wake-up stroke patients for IV alteplase is not recommended outside a clinical trial (Class III: No Benefit) 1

Evidence from Clinical Trials

The EXTEND trial specifically evaluated patients with:

• Stroke symptoms upon awakening or with unclear onset time
• CT perfusion or MRI showing core/perfusion mismatch
• Treatment window of 4.5-9 hours from symptom recognition

Two landmark trials have shaped the extended time window approach:

1. DAWN trial: Used clinical-imaging mismatch to select patients with large anterior circulation vessel occlusion for mechanical thrombectomy between 6-24 hours from last known normal, showing significant benefit (mRS 0-2: 49% vs 13%) 1

2. DEFUSE 3 trial: Used perfusion-core mismatch to select patients with large anterior circulation occlusion 6-16 hours from last seen well, demonstrating substantial benefit (mRS 0-2: 44.6% vs 16.7%) 1, 2

Practical Application of EXTEND Trial Findings

For wake-up stroke patients, the following approach is recommended:

1. Immediate brain imaging (non-contrast CT) to rule out hemorrhage 1

2. Vascular imaging (CTA) to identify potential large vessel occlusion 1

3. Advanced imaging (CT perfusion or MRI with DWI-FLAIR mismatch) to determine salvageable tissue 1

4. Treatment options based on imaging findings:

   • For patients with DWI-FLAIR mismatch on MRI, IV alteplase within 4.5 hours of symptom recognition may be beneficial 1
   • For patients with CT or MRI core/perfusion mismatch within 4.5-9 hours, consider IV thrombolysis 1
   • For patients with LVO and favorable imaging profile within 6-24 hours, mechanical thrombectomy is recommended 1

Important Considerations and Caveats

• The technical goal of thrombectomy should be reperfusion to a modified TICI grade 2b/3 1
• Do NOT wait to evaluate response to IV thrombolysis before proceeding with catheter angiography for mechanical thrombectomy 1
• Patient selection using advanced imaging is crucial - both DAWN and DEFUSE 3 trials showed benefit only when strict imaging criteria were applied 1
• A Cochrane review found that in selected wake-up stroke patients, both IV thrombolysis and endovascular thrombectomy improved functional outcomes without increasing mortality risk 3
• Advanced imaging selection has been shown to improve outcomes in wake-up stroke patients undergoing mechanical thrombectomy 4

The EXTEND trial represents a paradigm shift from a purely time-based approach to an individualized tissue-based approach for wake-up stroke management, emphasizing the importance of identifying salvageable brain tissue rather than relying solely on time from last known well.