What is the timeline for using thrombolysis with tissue plasminogen activator (tPA) for acute ischemic stroke?

From the Guidelines

Intravenous tissue plasminogen activator (tPA) should be administered within 4.5 hours of acute ischemic stroke symptom onset. The standard treatment for acute ischemic stroke is time critical, and the current standard treatment is intravenous (i.v.) thrombolysis using tissue plasminogen activator 1.

Key Considerations

• The treatment window for tPA administration is up to 4.5 hours after symptom onset, with earlier administration providing better outcomes 1.
• Mechanical thrombectomy is recommended in addition to i.v. thrombolysis to treat patients with demonstrable proximal artery occlusions in the anterior circulation who can be treated within 24 hours of symptom onset 1.
• If i.v. thrombolysis is contraindicated, mechanical thrombectomy is recommended as the first line of treatment 1.

Administration Guidelines

• The standard dose of tPA is 0.9 mg/kg (maximum 90 mg), with 10% given as an initial bolus and the remainder infused over 60 minutes.
• Before administering tPA, a non-contrast CT scan must be performed to rule out hemorrhagic stroke, and the patient's blood pressure should be controlled below 185/110 mmHg.
• Treatment within the first 3 hours offers the greatest benefit, while the 3-4.5 hour window requires additional patient selection criteria, excluding those over 80 years old, with severe stroke (NIHSS >25), taking oral anticoagulants, or with both previous stroke and diabetes 1.

Rationale

• tPA works by converting plasminogen to plasmin, which breaks down fibrin clots obstructing blood flow to brain tissue.
• The narrow treatment window exists because the risk of hemorrhagic transformation increases with time as the blood-brain barrier becomes more compromised, while the potential benefit of restoring blood flow diminishes as irreversible neuronal damage progresses.

From the Research

Timeline for Using Thrombolysis with tPA for Acute Ischemic Stroke

• The use of tissue plasminogen activator (tPA) for acute ischemic stroke has been studied in various trials, with the timeline for treatment being a crucial factor in determining its efficacy and safety 2, 3, 4, 5, 6.
• Early studies, such as the pilot randomized trial of tPA in acute ischemic stroke, suggested that treatment within 90 minutes of symptom onset may be associated with early neurological improvement 6.
• The initial approved use of tPA was limited to within 3 hours of symptom onset, as demonstrated by the study published in The New England Journal of Medicine in 1995, which showed that treatment with intravenous tPA within three hours of the onset of ischemic stroke improved clinical outcome at three months 5.
• However, subsequent studies, such as the ATLANTIS study published in JAMA in 1999, found no significant benefit of tPA when administered between 3 and 5 hours after symptom onset, and the risk of symptomatic intracerebral hemorrhage increased with tPA treatment 2.
• Later studies, including the meta-analysis published in Stroke in 2009, demonstrated a benefit of tPA treatment in the 3- to 4.5-hour time window, with an increased chance of favorable outcome and no significant difference in mortality compared to placebo-treated patients 3.
• A study published in JAMA in 2013 analyzed data from 58,353 patients with acute ischemic stroke treated with tPA within 4.5 hours of symptom onset and found that faster onset-to-treatment time was associated with reduced in-hospital mortality, symptomatic intracranial hemorrhage, and higher rates of independent ambulation at discharge and discharge to home 4.

Key Findings

• Treatment with tPA within 3 hours of symptom onset is associated with improved clinical outcome at three months 5.
• The risk of symptomatic intracerebral hemorrhage increases with tPA treatment, particularly when administered between 3 and 5 hours after symptom onset 2.
• Faster onset-to-treatment time is associated with reduced in-hospital mortality, symptomatic intracranial hemorrhage, and higher rates of independent ambulation at discharge and discharge to home 4.
• The 3- to 4.5-hour time window for tPA treatment is beneficial, with an increased chance of favorable outcome and no significant difference in mortality compared to placebo-treated patients 3.