What is the evidence for thrombolysis with alteplase (tissue plasminogen activator, tPA) after 4.5 hours based on perfusion studies?

Thrombolysis After 4.5 Hours Based on Perfusion Studies

Intravenous alteplase administered beyond 4.5 hours up to 24 hours after stroke onset provides functional benefit in highly selected patients with salvageable brain tissue identified by perfusion imaging, despite an increased risk of symptomatic intracranial hemorrhage. 1

Evidence for Extended Window Thrombolysis

MRI-Based Selection (DWI-FLAIR Mismatch)

• For patients with unknown time of onset or wake-up stroke presenting beyond 4.5 hours, IV alteplase can be beneficial when MRI demonstrates DWI-FLAIR mismatch. 2, 3
• This approach demonstrates clinical benefit with no defined upper time limit for patients who would otherwise meet standard alteplase criteria but have unknown onset time. 2
• Consultation with a stroke specialist should be obtained when considering alteplase after 4.5 hours. 2

CT Perfusion-Based Selection

• Selection of patients for IV alteplase after 4.5 hours based on CT, CTA, and CTP remains unproven at this time according to 2018 Canadian guidelines. 2
• However, the most recent 2025 HOPE trial (the highest quality and most recent evidence) demonstrates that perfusion imaging selection (ischemic core ≤70 mL, penumbra ≥10 mL, mismatch ≥20%) identifies patients who benefit from alteplase 4.5-24 hours after onset. 1
• In HOPE, 40% of alteplase-treated patients achieved functional independence (mRS 0-1) versus 26% with standard treatment (adjusted RR 1.52,95% CI 1.14-2.02). 1

Meta-Analysis Evidence

• A 2025 meta-analysis of 8 randomized trials (1,742 patients) showed that IVT beyond 4.5 hours achieved higher rates of excellent functional outcomes (OR 1.43,95% CI 1.17-1.75) and good functional outcomes (OR 1.36,95% CI 1.12-1.66) at 90 days. 4
• Perfusion imaging selection yielded numerically higher odds of excellent outcomes (OR 1.45) compared to DWI-FLAIR mismatch selection (OR 1.34). 4

Safety Considerations

Hemorrhage Risk

• Symptomatic intracranial hemorrhage rates are significantly increased with extended window thrombolysis: 3.8% with alteplase versus 0.51% with standard treatment in HOPE (adjusted RR 7.34). 1
• The meta-analysis showed a 4-fold increase in symptomatic ICH (OR 4.25,95% CI 1.67-10.84). 4
• Importantly, hyperglycemia (glucose >11.1 mmol/L) substantially increases hemorrhage risk to 36% and should be a major consideration. 5

Mortality

• Mortality at 90 days does not significantly differ between extended window thrombolysis and standard care (11% in both groups in HOPE; OR 1.28,95% CI 0.87-1.89 in meta-analysis). 1, 4

Practical Algorithm for Extended Window Treatment

Patient Selection Criteria (4.5-24 Hours)

1. Obtain perfusion imaging (CTP or MRI-DWI with perfusion) to identify salvageable tissue. 2, 1
2. Confirm imaging criteria: ischemic core ≤70 mL, penumbra ≥10 mL, mismatch ≥20%. 1
3. Exclude patients with extensive early infarct changes (ASPECTS score can be used). 2
4. Ensure blood glucose is not severely elevated (>11.1 mmol/L represents substantially increased hemorrhage risk). 5
5. Confirm no initial plan for endovascular thrombectomy (these patients were excluded from HOPE). 1

For Unknown Onset Time (Including Wake-Up Stroke)

• Use MRI with DWI-FLAIR mismatch as selection criteria if patient would otherwise meet standard alteplase eligibility. 2, 3
• This approach has demonstrated clinical benefit with Level A evidence. 2

Important Caveats

Mechanical Thrombectomy Considerations

• Patients with large vessel occlusion should be evaluated for mechanical thrombectomy (6-24 hour window) using perfusion imaging. 2
• The extended window thrombolysis evidence applies primarily to patients not undergoing thrombectomy. 1
• Do not delay mechanical thrombectomy evaluation to obtain MRI for thrombolysis selection. 2

Imaging Modality Limitations

• MRI scanning can be challenging to obtain urgently in emergency settings, which must be considered in decision-making. 2
• CT perfusion is more readily available but had less robust evidence until the recent HOPE trial. 2, 1

Time Dependency

• Earlier treatment within the extended window is likely better, as the pooled analysis showed diminishing benefit approaching 270 minutes and potential harm beyond this. 6
• The HOPE trial included patients up to 24 hours, but the median time to treatment and distribution within this window were not specified in the abstract. 1

Historical Context

• Older 2007 guidelines suggested potential benefit up to 4.5 hours based on pooled analysis, noting that penumbral imaging modalities may allow better patient selection beyond 3 hours. 2
• This prediction has now been validated by the 2025 HOPE trial using perfusion imaging. 1