Treatment of Ischemic Stroke Outside the 4-Hour Window
For patients presenting between 4.5 and 6 hours after stroke onset, IV tPA should NOT be administered, and treatment should focus on aspirin therapy (160-325 mg within 48 hours), consideration of endovascular therapy for large vessel occlusions, and supportive care including VTE prophylaxis. 1
Time-Based Treatment Algorithm
3 to 4.5 Hour Window
- IV tPA should be administered to eligible patients who can be treated between 3 and 4.5 hours after stroke onset (Class I recommendation, Level B evidence) 1
- Additional exclusion criteria apply in this window beyond standard contraindications: 1
- Age >80 years
- Oral anticoagulant use (regardless of INR)
- Baseline NIHSS >25
- Both history of stroke AND diabetes
Beyond 4.5 Hours
- IV tPA is NOT recommended for patients who cannot be treated within 4.5 hours of symptom onset (Grade 1B recommendation) 1
- The evidence shows increased harm without proven benefit beyond this window 1
Alternative Treatments Beyond 4.5 Hours
Antiplatelet Therapy
- Initiate aspirin 160-325 mg within 48 hours of stroke onset for all patients not receiving thrombolysis 1
- This remains the cornerstone of early treatment outside the thrombolytic window 1
Endovascular Therapy Consideration
- For patients with proximal cerebral artery occlusions who do not meet IV tPA eligibility criteria, intraarterial thrombolysis may be considered within 6 hours of symptom onset (Grade 2C) 1
- Vascular imaging (CTA, MRA, or conventional angiography) should be performed during initial evaluation if endovascular therapy is being considered 1
- This requires specialized facilities and personnel, and the evidence is less robust than for IV tPA 1
Imaging Requirements
- For patients outside the acute reperfusion window (>4.5 hours for IV tPA sites, >8 hours for endovascular sites), imaging workup should focus on: 1
- Vascular imaging (CTA, MRA, or doppler ultrasound) to assess carotid arteries
- Secondary prevention strategies
- Echocardiography for cardiac sources
Supportive Care and VTE Prophylaxis
Thromboprophylaxis
- Initiate prophylactic-dose subcutaneous heparin (UFH or LMWH) or intermittent pneumatic compression devices for patients with restricted mobility (Grade 2B) 1
- LMWH is preferred over UFH for VTE prophylaxis 1
- Pneumatic compression devices should be applied within the first 24 hours of admission 1
Early Mobilization
- Encourage mobilization between 24-48 hours after stroke onset 1
- Avoid very early mobilization (within 24 hours) as this is not recommended 1
Critical Pitfalls to Avoid
Do not administer IV tPA beyond 4.5 hours based on the strong evidence of harm without benefit 1. The meta-analyses show that while there may be some theoretical benefit up to 6 hours, the ATLANTIS trial (3-5 hour window) failed to demonstrate benefit, and current guidelines firmly recommend against treatment beyond 4.5 hours 1.
Do not delay aspirin therapy in patients outside the thrombolytic window—this should be initiated within 48 hours unless there are specific contraindications like hemorrhagic transformation 1.
Do not use full-dose anticoagulation (IV or subcutaneous heparin at therapeutic doses) in acute ischemic stroke, as this is not recommended (Grade 2B against) 1.
Avoid elastic compression stockings alone for VTE prophylaxis—these are not recommended (Grade 2B against) 1.
Special Considerations for Hemorrhagic Transformation
If hemorrhagic transformation is detected on imaging: 2
- For minor transformation (HI1): Aspirin may be initiated within 24-48 hours after confirming no progression
- For higher-grade transformation (HI2, PH1, PH2): Delay antiplatelet therapy for 7-10 days
- The decision balances thromboembolism risk against hemorrhage risk 2