Expanding Indications for IV Thrombolysis in Acute Ischemic Stroke

Since the original NINDS trial in 1995, the eligibility criteria for intravenous alteplase have progressively widened. Early limitations—such as narrow time windows, strict age cutoffs, and exclusion of patients with unknown onset—have given way to a more nuanced, individualized approach to thrombolytic therapy.

Time Windows: From 3 Hours to 24 Hours

Current guidelines endorse IV alteplase within 4.5 hours of stroke onset for most patients. This expanded window was based on ECASS III, which showed benefit in the 3–4.5h range with acceptable hemorrhagic risk⁽¹⁾.

Patients with unknown time of onset—such as wake-up strokes—are eligible if MRI mismatch (DWI positive, FLAIR negative) confirms likely onset within 4.5 hours. This approach is supported by the WAKE-UP trial⁽²⁾.

More recent trials have pushed the boundaries further:

• TRACE III (2024) evaluated alteplase in LVO patients selected by perfusion mismatch 4.5–24h from onset, showing improved functional outcome (mRS 0–1 in 45% vs. 29%)⁽³⁾.
• CHABLIS-T II used CT perfusion in anterior LVO up to 24h; mRS 0–2 in 47% vs. 20%⁽⁴⁾.
• TIMELESS studied tenecteplase in LVO with perfusion mismatch; results were neutral overall, but a subgroup with good collaterals may benefit⁽⁵⁾.

Patient Factors: Age, Baseline Function, Stroke Severity

Guidelines no longer impose an upper age limit; patients >80 years are eligible if otherwise appropriate. Similarly, patients with preexisting disability (mRS ≥2) can receive alteplase if the stroke is expected to cause new, disabling deficits. Decision-making should incorporate goals of care, functional prognosis, and patient preferences.

Stroke severity is not an exclusion. Very severe (NIHSS >25) or mild-but-disabling strokes can be treated. For non-disabling symptoms (e.g., isolated numbness, mild dysarthria), thrombolysis is not recommended.

Conclusion

The modern approach to IV thrombolysis emphasizes tissue and clinical viability over rigid time rules. Imaging selection with MRI or CT perfusion, patient-centered evaluation of risks and benefits, and growing evidence from trials like TRACE III and CHABLIS-T II continue to expand access to reperfusion therapy.