Is recombinant tissue plasminogen activator (rTPA) (alteplase) not indicated after the golden period?

rtPA Administration Beyond the Golden Period in Acute Ischemic Stroke

rtPA can be administered up to 4.5 hours after stroke onset in carefully selected patients, though the traditional 3-hour window remains the standard treatment timeframe with established efficacy and safety. 1

Extended Time Window (3-4.5 hours)

• The American Heart Association/American Stroke Association (AHA/ASA) recommends rtPA administration to eligible patients within 3-4.5 hours after stroke onset (Class I Recommendation, Level of Evidence B) 2
• Treatment in this extended window requires additional exclusion criteria beyond those for the standard 0-3 hour window 2:
  • Age > 80 years
  • Severe stroke (NIHSS > 25)
  • Taking oral anticoagulants regardless of INR
  • History of both diabetes and prior ischemic stroke

Evidence Supporting Extended Window

• The ECASS-3 trial demonstrated that patients treated with rtPA between 3-4.5 hours had better outcomes than those receiving placebo (52.4% vs. 45.2% favorable outcomes) 3
• A pooled analysis of rtPA trials showed that the adjusted odds ratio for favorable outcome crossed unity at 4.5 hours, suggesting potential benefit up to this timepoint 2
• The benefit-to-risk ratio decreases as time from symptom onset increases, with diminishing returns after 4.5 hours 1

Risks and Considerations

• Symptomatic intracranial hemorrhage rates are higher with delayed treatment:
  • 2.4% with rtPA vs. 0.2% with placebo in the 3-4.5 hour window 3
  • 7.0% vs. 1.1% in patients treated between 3-5 hours in the ATLANTIS study 4
• Studies examining rtPA beyond 4.5 hours have shown unfavorable risk-benefit profiles:
  • The ATLANTIS trial found no significant benefit for rtPA administered 3-5 hours after onset, with increased hemorrhage risk 4
  • A similar study examining the 0-6 hour window (with most patients treated after 3 hours) found no benefit at 30 and 90 days with increased mortality (23% vs. 7%) 5

Clinical Decision Algorithm

1. Determine precise time of symptom onset (last known normal)

2. For patients presenting within 3 hours:

   • Apply standard inclusion/exclusion criteria 2
   • Administer rtPA as soon as possible (0.9 mg/kg, maximum 90 mg, with 10% as bolus and remainder over 60 minutes)

3. For patients presenting between 3-4.5 hours:

   • Apply standard criteria PLUS additional exclusion criteria 2
   • Proceed with rtPA only if all criteria are met

4. For patients presenting after 4.5 hours:

   • rtPA is not recommended due to unfavorable risk-benefit profile 4, 5

Important Clinical Considerations

• Earlier treatment within any window period is associated with better outcomes - "time is brain" 1
• Institutional experience matters - outcomes may be worse in centers treating fewer than 5 stroke patients per year with rtPA 2
• Strict adherence to protocols is essential to minimize hemorrhagic complications 2
• The decision to use rtPA should be made by physicians with expertise in acute stroke care 2

Common Pitfalls

• Delaying treatment within the approved window reduces chances of good outcomes 1
• Protocol violations increase risk of symptomatic intracerebral hemorrhage and death 2
• Treating patients with contraindications, particularly in the extended time window 2
• Failure to recognize that the extended window has additional exclusion criteria beyond the standard 0-3 hour window 2