What are the absolute and relative contraindications for tissue plasminogen activator (tPA) in a patient with acute ischemic stroke?

Absolute and Relative Contraindications for tPA in Acute Ischemic Stroke

The absolute contraindications to IV tPA include: intracranial hemorrhage on CT, blood pressure ≥185/110 mmHg that cannot be controlled, symptom onset >4.5 hours, and current use of direct oral anticoagulants (DOACs). 1, 2, 3, 4

Absolute Contraindications

Time-Based Exclusions

• Symptom onset beyond 4.5 hours is an absolute contraindication (Grade 1B recommendation against use) 1, 3, 4
• Treatment beyond this window has not demonstrated benefit and carries unacceptable hemorrhage risk 4

Blood Pressure Criteria

• Systolic BP ≥185 mmHg or diastolic BP ≥110 mmHg that remains elevated despite aggressive treatment 2, 3, 4
• If blood pressure cannot be reduced below these thresholds with labetalol or nicardipine, tPA must not be administered 2, 3
• Post-treatment, BP must be maintained <180/105 mmHg with monitoring every 15 minutes during infusion and for 2 hours after 2, 4

Imaging Findings

• Intracranial hemorrhage on non-contrast CT scan 3
• Extensive early ischemic changes involving >1/3 of the middle cerebral artery territory 3

Anticoagulation Status

• Patients currently taking direct oral anticoagulants (DOACs) such as apixaban should NOT receive tPA due to substantially elevated bleeding risk 2, 3
• This represents an absolute contraindication in current practice 3

Hypersensitivity

• Known hypersensitivity to alteplase or any component of the formulation 5

Relative Contraindications

Minor Stroke Presentations

• Minor strokes should NOT be excluded from tPA consideration, as patients may still benefit significantly 2, 3, 4
• The original NINDS trial exclusion criteria have proven unnecessarily restrictive in real-world practice 6
• Patients with mild to moderate strokes (NIHSS <20) had the greatest potential for excellent outcomes 2

Antiplatelet Therapy

• Prior antiplatelet therapy is a relative contraindication requiring careful risk-benefit assessment 2, 3
• Proceed with standard tPA dosing (0.9 mg/kg) while accepting a 3% absolute increased risk of symptomatic intracranial hemorrhage compared to those not on antiplatelet therapy 2, 3

Extended Time Window (3-4.5 Hours)

• Between 3-4.5 hours, tPA may be offered using ECASS III criteria (Grade 2C recommendation) 1, 3, 4
• This window has smaller but clinically meaningful benefit (NNT=14 vs NNT=8 for 0-3 hour window) 1, 3
• Risk of symptomatic intracranial hemorrhage increases to 8% (NNH=23) compared to 6-7% in the 0-3 hour window (NNH=17) 1

Critical Risk-Benefit Considerations

Hemorrhage Risk

• Baseline symptomatic intracranial hemorrhage rate is 6-7% with tPA versus 1% with placebo in the 0-3 hour window 1, 2
• The NINDS trial demonstrated symptomatic ICH in 6.4% of tPA-treated patients versus 0.6% of placebo patients 2
• This risk must be weighed against improved functional outcomes 1

Mortality Considerations

• tPA does not alter 90-day mortality 1
• The NINDS trial showed 17% mortality in the tPA group versus 21% in placebo (not statistically significant) 1
• Patients and surrogates tend to overestimate benefits and underestimate harms associated with symptomatic intracranial hemorrhage 1

Functional Outcome Benefits

• Within 0-3 hours: NNT=8 for minimal or no disability at 90 days 1, 3
• Within 3-4.5 hours: NNT=14 for minimal or no disability at 90 days 1, 3
• Earlier treatment provides substantially greater benefit, with odds ratio of 2.11 for excellent recovery when treated within 90 minutes versus 1.69 for treatment at 90-180 minutes 2, 4

Common Pitfalls to Avoid

• Do not exclude patients with minor strokes from consideration - they may still benefit and should undergo the same evaluation process 2, 3, 4
• Do not administer anticoagulants or antiplatelet agents for 24 hours after tPA 2, 3
• Do not treat patients on DOACs - this is an absolute contraindication regardless of timing or severity 2, 3
• Do not proceed if BP cannot be controlled below 185/110 mmHg - this represents an absolute contraindication 2, 3, 4
• Relaxed application of some original NINDS exclusion criteria might increase thrombolysis rates up to 20% with comparable outcomes 6