What are the time windows for thrombolysis with tissue plasminogen activator (tPA) and endovascular treatment in a patient presenting with acute ischemic stroke?

Time Windows for Thrombolysis and Endovascular Treatment in Acute Ischemic Stroke

For IV tPA, treat within 3 hours of symptom onset as the strongest recommendation, consider treatment up to 4.5 hours in select patients, and do not treat beyond 4.5 hours; for intraarterial thrombolysis, the window extends to 6 hours in patients with proximal cerebral artery occlusions who cannot receive IV tPA. 1

IV tPA Time Windows

0-3 Hour Window (Strongest Evidence)

• Administer IV tPA within 3 hours of symptom onset - this carries a Grade 1A recommendation (strongest level of evidence) from the American College of Chest Physicians 1
• The American College of Emergency Physicians similarly provides a Level A recommendation for treatment within this window to improve functional outcomes 1
• Dosing: 0.9 mg/kg (maximum 90 mg total), with 10% given as IV bolus over 1 minute, followed by 90% infused over 60 minutes 2
• The landmark NINDS trial demonstrated that despite a symptomatic intracranial hemorrhage rate of 6.4% (versus 0.6% in placebo), patients were at least 30% more likely to have minimal or no disability at 3 months 3

3-4.5 Hour Window (Conditional Recommendation)

• Consider IV tPA between 3-4.5 hours - this carries a Grade 2C recommendation (weaker evidence) from the American College of Chest Physicians 1
• The American College of Emergency Physicians provides a Level B recommendation for this window, noting that as of their 2013 guideline, this indication was not FDA-approved 1
• Use the same dosing protocol as the 0-3 hour window 2
• The ECASS III inclusion/exclusion criteria should be applied for this extended window 1

Beyond 4.5 Hours

• Do not administer IV tPA beyond 4.5 hours - this carries a Grade 1B recommendation against treatment from the American College of Chest Physicians 1
• The ATLANTIS trial demonstrated no significant benefit when treating between 3-5 hours, with increased symptomatic ICH (7.0% vs 1.1%, P<0.001) and fatal ICH (3.0% vs 0.3%, P<0.001) 4

Intraarterial Thrombolysis Time Window

0-6 Hour Window for Proximal Occlusions

• Consider intraarterial tPA within 6 hours for patients with acute ischemic stroke due to proximal cerebral artery occlusions who do not meet eligibility criteria for IV tPA (Grade 2C recommendation) 1
• This approach is based on the PROACT 1, PROACT 2, and MELT trials, which evaluated patients with middle cerebral artery occlusions 1
• The majority of patients in these trials would have been ineligible for IV tPA because treatments were initiated outside the 4.5-hour window 1

Important Caveats for Intraarterial Therapy

• IV tPA is preferred over intraarterial tPA when patients meet eligibility criteria for both, as the evidence quality is higher for IV administration (Grade 2C) 1
• The combination of IV/IA tPA is not recommended over IV tPA alone (Grade 2C), though carefully selected patients who highly value uncertain benefits may choose this approach 1
• Mechanical thrombectomy alone received a Grade 2C recommendation against use in the 2012 guidelines, though this predates more recent thrombectomy trials 1

Critical Time-Dependent Principles

"Time is Brain" Concept

• Within any chosen time window, treat as rapidly as possible - earlier treatment provides substantially greater benefit 1, 2
• Treatment within 90 minutes yields an odds ratio of 2.11 for excellent recovery, compared to 1.69 for treatment at 90-180 minutes 2
• The average door-to-needle time in early clinical practice was approximately 100 minutes (41 minutes to CT scan, 59 minutes from CT to treatment), which should be minimized 5

Post-Treatment Management

• Do not administer antiplatelet or anticoagulant therapy for 24 hours after tPA 2
• After this 24-hour period, initiate aspirin 160-325 mg within 48 hours of stroke onset (Grade 1A) 1
• Monitor blood pressure every 15 minutes during infusion and for 2 hours after, then every 30 minutes for 6 hours, maintaining BP <180/105 mmHg 2

Common Pitfalls to Avoid

• Do not exclude patients with minor strokes from consideration for tPA within the appropriate time windows, as they may still benefit 2, 6
• Do not treat if blood pressure cannot be controlled below 185/110 mmHg before initiating tPA, as this is an absolute contraindication 2
• Do not use tPA in patients on direct oral anticoagulants due to substantially elevated bleeding risk 2
• The effectiveness of tPA is less well established in institutions without proper systems to safely administer the medication 1