What are the indications for recombinant tissue plasminogen activator (rtPA) in adults with acute ischemic stroke?

Indications for rtPA in Acute Ischemic Stroke

Administer IV rtPA (0.9 mg/kg, maximum 90 mg) to adults with acute ischemic stroke who meet eligibility criteria within 3 hours of symptom onset, and consider extending treatment to 4.5 hours for carefully selected patients without additional exclusion factors. 1

Primary Indication: 0-3 Hour Window

The core indication for rtPA is acute ischemic stroke with measurable neurologic deficit presenting within 3 hours of symptom onset in patients ≥18 years old. 1 This represents the FDA-approved indication with the strongest evidence (Class I, Level of Evidence A). 1

Key inclusion criteria:

• Diagnosis of ischemic stroke causing measurable neurologic deficit 1
• Symptom onset <3 hours before treatment initiation 1
• Age ≥18 years 1
• CT scan showing no evidence of intracranial hemorrhage 1
• Blood pressure controlled to <185/110 mm Hg 1

Extended Indication: 3-4.5 Hour Window

Patients presenting between 3-4.5 hours after symptom onset may receive rtPA if they meet standard criteria AND do not have additional exclusion factors. 1 This recommendation is based on the ECASS-3 trial and carries a Class I, Level of Evidence B recommendation, though it was not FDA-approved as of 2010. 1

Additional exclusion criteria for the 3-4.5 hour window:

• Age >80 years 1
• Severe stroke (NIHSS >25) 1
• Taking any oral anticoagulant regardless of INR 1
• History of both diabetes AND prior ischemic stroke 1

Critical Exclusion Criteria (All Time Windows)

Absolute contraindications that preclude rtPA administration:

• Head trauma or prior stroke in previous 3 months 1
• Symptoms suggesting subarachnoid hemorrhage 1
• History of previous intracranial hemorrhage 1
• Arterial puncture at noncompressible site in previous 7 days 1
• Elevated blood pressure (systolic >185 mm Hg or diastolic >110 mm Hg) that cannot be controlled 1
• Evidence of active bleeding on examination 1
• Platelet count <100,000/mm³ 1
• Heparin received within 48 hours with elevated aPTT 1
• Current anticoagulant use with INR >1.7 or PT >15 seconds 1
• Blood glucose <50 mg/dL 1
• CT demonstrating multilobar infarction (hypodensity >1/3 cerebral hemisphere) 1

Practical Implementation Requirements

rtPA should only be administered in settings with:

• A clearly defined protocol 1
• A knowledgeable stroke team 1
• Institutional commitment to acute stroke care 1
• Rapid access to CT imaging (ideally completed within 25 minutes of ED arrival) 1
• Immediate laboratory capabilities 1

The evidence demonstrates that protocol violations are associated with increased symptomatic intracranial hemorrhage and death. 1 Hospitals treating fewer than 5 stroke patients per year with rtPA show increased mortality risk. 1

Time-Critical Considerations

Onset time is defined as either witnessed symptom onset OR last known normal time. 1 Treatment can be initiated before coagulation studies are available in patients without recent anticoagulant or heparin use, but must be discontinued if INR >1.7 or platelet count <100,000/mm³. 1

The benefit of rtPA is time-dependent, with earlier treatment producing superior outcomes. 2 The number needed to treat is 8 within the 0-3 hour window, with 13% more patients achieving excellent functional outcomes. 2 However, symptomatic intracranial hemorrhage occurs in 6.4% of treated patients versus 0.6% of placebo patients. 2

Common Pitfalls to Avoid

Do not administer rtPA if:

• Blood pressure cannot be maintained below 185/110 mm Hg despite antihypertensive therapy 1
• Neurologic signs are rapidly improving to normal and near baseline 1
• Patient is taking direct oral anticoagulants (DOACs), which substantially elevate bleeding risk 2
• The 3-hour window has passed and the patient meets any of the additional 3-4.5 hour exclusion criteria 1

The ATLANTIS trial demonstrated no benefit and increased hemorrhage risk when rtPA was administered between 3-5 hours without the careful patient selection criteria later established by ECASS-3. 3

Alternative Reperfusion Strategies

For patients ineligible for IV rtPA, intra-arterial fibrinolysis may be reasonable in carefully selected cases, though this has not received FDA approval. 1 Catheter-based thrombectomy is performed at centers with appropriate resources and expertise. 1