In an adult patient with acute ischemic stroke, how long after symptom onset can tissue plasminogen activator (tPA) be administered for thrombolysis?

Thrombolysis Time Window for Acute Ischemic Stroke

For acute ischemic stroke, administer IV tPA within 4.5 hours of symptom onset, with the strongest evidence supporting treatment within 3 hours (Grade 1A) and weaker evidence for the 3-4.5 hour window (Grade 2C); do not give IV tPA beyond 4.5 hours. 1

Time-Based Treatment Algorithm

0-3 Hours: Strongest Recommendation

• Strongly recommend IV r-tPA (Grade 1A evidence) for all eligible patients when treatment can be initiated within 3 hours of clearly defined symptom onset 1, 2, 3
• This represents the highest quality evidence with 154 more favorable events per 1,000 patients treated (NNT=8 for minimal or no disability) 2, 3
• The benefit is greatest when treatment occurs as rapidly as possible within this window 1, 2

3-4.5 Hours: Conditional Recommendation

• Suggest IV r-tPA (Grade 2C evidence) for carefully selected patients meeting ECASS III inclusion/exclusion criteria when treatment can be initiated between 3-4.5 hours 1, 2, 3
• This window provides a smaller benefit of 69 more favorable events per 1,000 patients (NNT=14) 2, 3
• The symptomatic ICH risk is NNH=23 in this extended window 2
• This use is not FDA-approved but is supported by guideline recommendations 1

Beyond 4.5 Hours: Do Not Use IV tPA

• Recommend against IV r-tPA beyond 4.5 hours from symptom onset (Grade 1B) 1, 2, 3
• The ATLANTIS trial demonstrated no benefit and increased harm when IV tPA was given between 3-5 hours, with significantly increased symptomatic ICH (7.0% vs 1.1%, P<0.001) and fatal ICH (3.0% vs 0.3%, P<0.001) 4

Alternative Therapies Beyond Standard Window

Intraarterial Thrombolysis (6-Hour Window)

• Consider intraarterial r-tPA (Grade 2C) for patients with proximal cerebral artery occlusions who do not meet IV tPA eligibility criteria, if treatment can be initiated within 6 hours of symptom onset 1, 3
• This is a weaker recommendation for carefully selected patients 3

Mechanical Thrombectomy

• Mechanical thrombectomy may be considered in carefully selected patients with large vessel occlusions, particularly when presenting within 6-12 hours with favorable imaging 2
• This should be used in conjunction with IV tPA when eligible, without delaying door-to-needle time 2
• The American College of Chest Physicians suggests against routine mechanical thrombectomy (Grade 2C), though carefully selected patients who value uncertain benefits over risks may choose this intervention 1

Dosing Protocol

• Administer IV r-tPA at 0.9 mg/kg (maximum dose 90 mg) 2, 3, 5
• Give 10% as an initial bolus, with the remaining 90% infused over 60 minutes 1, 6

Critical Safety Considerations

Hemorrhagic Risk

• Baseline symptomatic ICH rate is 4-6% with proper dosing and patient selection 2
• Symptomatic ICH occurs in 6.4% of tPA-treated patients vs 0.6% of placebo patients within 36 hours 6
• Watch closely for symptomatic ICH in the first 36 hours after tPA administration 2

Absolute Contraindications

• Never give tPA to patients on direct oral anticoagulants (DOACs) due to substantially elevated bleeding risk 2
• Exclude patients with evidence of intracranial hemorrhage on pre-treatment imaging 5
• Avoid tPA in cases of hemorrhagic transformation (HI2 or higher) in existing infarcts 2
• Do not treat if combined infarct volume exceeds one-third of MCA territory equivalent 2

Relative Considerations

• Patients on antiplatelet therapy have a 3% absolute increased risk of symptomatic ICH but can still receive tPA at standard dosing 2
• Patients with NIHSS 5-22 show the most benefit from tPA 2
• Mild to moderate strokes (NIHSS <20) and patients <75 years have the greatest potential for excellent outcomes 2

Post-Treatment Management

• Delay antiplatelet therapy for 24 hours after tPA administration 2
• Administer aspirin 160-325 mg within 24-48 hours for patients not receiving anticoagulation (Grade 1A) 1, 2, 3, 5
• Consider dual antiplatelet therapy (aspirin plus clopidogrel) for 21 days for minor stroke or high-risk TIA when initiated within 12-24 hours 2

Common Pitfalls to Avoid

• Do not delay treatment for difficult IV access; consider alternative access methods 3
• Establish IV access in the non-paretic arm when possible to preserve the affected limb for rehabilitation 3
• The door-to-needle time goal is 60 minutes; every minute counts as "time is brain" 7
• Engage in shared decision-making with patients/surrogates before administering tPA, discussing both benefits and harms with realistic expectations 2