What is the window period for stroke treatment with thrombolytic therapy using alteplase (tissue plasminogen activator)?

Window Period for Stroke Treatment with Alteplase

The standard window period for intravenous alteplase (rtPA) in acute ischemic stroke is up to 4.5 hours from symptom onset, with the 0-3 hour window being the traditional timeframe and the 3-4.5 hour window representing an evidence-based extension for carefully selected patients. 1

Primary Treatment Windows

0-3 Hour Window (Standard)

• Alteplase should be administered to all eligible patients within 3 hours of stroke onset with established efficacy and safety as the gold standard treatment timeframe 2
• This window has Class I recommendation with the strongest evidence base from the NINDS trial, showing an odds ratio of 1.9 (95% CI 1.2-2.9) for favorable outcomes 1
• Earlier treatment within this window yields progressively better outcomes—delays should be minimized even within the approved timeframe 1, 2

3-4.5 Hour Window (Extended)

• Alteplase administration in the 3-4.5 hour window is a Class I recommendation with Level of Evidence B for appropriately selected patients 1
• The ECASS-3 trial demonstrated 52.4% of rtPA-treated patients achieved modified Rankin Scale 0-1 versus 45.2% with placebo (OR 1.34,95% CI 1.02-1.76, P=0.04) 1, 2
• The benefit is real but more modest than the 0-3 hour window (OR 1.28 vs 1.9) 1

Critical Additional Exclusion Criteria for 3-4.5 Hour Window

Patients must be excluded from the 3-4.5 hour window if they have ANY of the following: 1

• Age >80 years
• Any oral anticoagulant use (regardless of INR value—this differs from the 0-3 hour window where INR ≤1.7 is acceptable)
• Baseline NIHSS score >25
• Combined history of both prior stroke AND diabetes mellitus

Safety Considerations Across Time Windows

Hemorrhage Risk

• Symptomatic intracerebral hemorrhage occurs in 7.9% of patients treated in the 3-4.5 hour window versus 3.5% with placebo (OR 2.38,95% CI 1.25-4.52) 1
• The 0-3 hour window shows slightly lower hemorrhage rates at approximately 7.3% 1
• A clear trend exists: hemorrhage risk increases with later treatment times 3

Mortality

• The 90-day mortality does not significantly differ between rtPA and placebo in the 3-4.5 hour window, though there is a numerical trend toward higher mortality with later treatment 1, 3

Emerging Evidence Beyond 4.5 Hours

Perfusion Imaging-Selected Patients (4.5-9 Hours)

• Recent high-quality evidence from the EXTEND trial (2019) demonstrated that alteplase administered 4.5-9 hours after onset in patients with salvageable tissue on perfusion imaging resulted in 35.4% achieving mRS 0-1 versus 29.5% with placebo (adjusted RR 1.44,95% CI 1.01-2.06, P=0.04) 4
• A 2025 meta-analysis of 8 randomized trials (1,742 patients) showed IVT beyond 4.5 hours achieved higher rates of excellent outcomes (OR 1.43,95% CI 1.17-1.75) but with increased symptomatic ICH (OR 4.25,95% CI 1.67-10.84) 5
• This extended window requires advanced imaging selection and is not yet standard guideline-recommended practice 5, 4

Critical Clinical Pitfalls

• Time is brain: Even within approved windows, every 15-minute delay reduces the probability of good outcome—treatment should be initiated as rapidly as possible 1, 2
• Do not use the 3-4.5 hour window criteria for 0-3 hour patients: The additional exclusions (age >80, any anticoagulant use, etc.) only apply to the extended window 1
• All patients on oral anticoagulants are excluded from the 3-4.5 hour window regardless of INR, whereas INR ≤1.7 may be acceptable in the 0-3 hour window 1
• Real-world registry data suggests outcomes and safety may be less favorable in the 3-4.5 hour window compared to earlier treatment, with trends toward higher hemorrhage (7.8% vs 3.8%) and mortality (28.4% vs 21.4%) 3, 6