What are the current guidelines for intravenous rt‑PA (alteplase) use in acute ischemic stroke, including dosing, time window, eligibility criteria, contraindications, and the role of tenecteplase as an alternative?

Current Guidelines for rt-PA (Alteplase) in Acute Ischemic Stroke

Intravenous alteplase at 0.9 mg/kg (maximum 90 mg) should be administered to eligible acute ischemic stroke patients within 4.5 hours of symptom onset, with 10% given as a bolus over 1 minute followed by 90% infused over 60 minutes. 1

Time Windows and Eligibility

0–3 Hour Window

• All eligible patients presenting within 3 hours of symptom onset should receive alteplase (Class I, Level A recommendation). 1
• Treatment within this window produces a 12% absolute increase in achieving minimal or no disability (modified Rankin Scale 0-1: 39% vs 26% with placebo), with a number needed to treat of 8.3. 2
• Earlier treatment is superior—each 15-minute delay reduces the likelihood of favorable outcome. 1, 2
• The odds ratio for favorable outcome when treated within 1.5 hours is 2.81 (95% CI, 1.75–4.50) compared with placebo. 1

3–4.5 Hour Window (ECASS III Criteria)

• Alteplase should be administered to eligible patients in the 3–4.5 hour window (Class I, Level B recommendation). 1
• The odds ratio for favorable outcome in this window is 1.40 (95% CI, 1.05–1.85). 1
• Additional exclusion criteria apply in this extended window: 1
  • Age > 80 years
  • Any oral anticoagulant use (regardless of INR)
  • NIHSS score > 25
  • History of both diabetes mellitus AND prior stroke

Standard Dosing Protocol

• Total dose: 0.9 mg/kg with an absolute maximum of 90 mg. 3, 2
• Initial bolus: 10% of total dose (0.09 mg/kg) given IV push over exactly 1 minute. 3, 2
• Continuous infusion: Remaining 90% (0.81 mg/kg) infused over 60 minutes. 3, 2
• No dose adjustment is required based on age or NIHSS severity. 3

Absolute Contraindications

Imaging-Based Exclusions

• Intracranial hemorrhage on non-contrast CT scan. 4, 2
• Extensive hypoattenuation involving > 1/3 of the middle cerebral artery territory on CT. 4, 2

Timing Exclusions

• Symptom onset > 4.5 hours or unclear/unwitnessed onset where last known well exceeds the applicable time window. 4, 2
• Wake-up stroke where patient was last known well > 4.5 hours prior. 4

Recent Events

• Ischemic stroke within the preceding 3 months. 4
• Severe head trauma or intracranial/spinal surgery within 3 months. 4
• History of intracranial hemorrhage at any time. 4
• Gastrointestinal malignancy or GI bleeding within 21 days. 4
• Therapeutic-dose low-molecular-weight heparin within 24 hours. 4

Laboratory Contraindications

• Platelet count < 100,000/mm³. 4
• INR > 1.7 or PT > 15 seconds. 4
• aPTT > 40 seconds. 4
• Direct oral anticoagulants (direct thrombin or factor Xa inhibitors) unless laboratory tests are normal or no dose received for > 48 hours with normal renal function. 4

Blood Pressure

• Blood pressure that cannot be safely reduced to < 185/110 mmHg before treatment. 4, 2

Pre-Treatment Requirements

• Non-contrast CT or MRI must be performed immediately to exclude hemorrhage. 2
• Blood glucose must be > 50 mg/dL (> 3.3 mmol/L)—this is the only mandatory laboratory test before initiating alteplase. 3, 2
• Blood pressure must be lowered to < 185/110 mmHg before starting alteplase. 3, 2
• Other laboratory tests (CBC, electrolytes, creatinine, INR, PTT) should be obtained but do not delay treatment unless coagulopathy is suspected. 3

Conditions That Are NOT Contraindications

• Antiplatelet monotherapy or dual antiplatelet therapy (e.g., aspirin + clopidogrel) does not preclude alteplase. 4, 2
• End-stage renal disease on hemodialysis is not a contraindication if aPTT is normal. 4, 2
• Age > 80 years is NOT a contraindication in the 0–3 hour window (only excluded in the 3–4.5 hour window). 1, 2
• High NIHSS score (severe stroke) is NOT a contraindication in the 0–3 hour window (NIHSS > 25 only excluded in the 3–4.5 hour window). 3, 2
• Cervical artery dissection is not a contraindication. 4
• Menstruation is not a contraindication. 4
• Pregnancy is not an absolute contraindication, though risks and benefits must be carefully weighed. 4

Post-Administration Management

• Monitor neurological status every 15 minutes during infusion, every 30 minutes for 6 hours, then hourly until 24 hours. 2
• Blood pressure monitoring: every 15 minutes for 2 hours, every 30 minutes for 6 hours, then hourly to 24 hours; maintain ≤ 180/105 mmHg. 2
• If severe headache, acute hypertension, nausea, or vomiting occur, stop the infusion immediately and obtain emergent CT. 2
• Avoid antithrombotic agents (aspirin, anticoagulants) for 24 hours after alteplase. 3, 2, 5
• Obtain follow-up CT at 24 hours before starting anticoagulant or antiplatelet therapy. 2
• Delay placement of nasogastric tubes, indwelling bladder catheters, and intra-arterial pressure catheters. 2
• Monitor for angioedema, which can cause partial airway obstruction. 2

Integration with Endovascular Therapy

• Eligible patients should receive IV alteplase even when mechanical thrombectomy is being considered. 2
• Do NOT wait to assess response to IV alteplase before proceeding with catheter angiography for thrombectomy. 2
• If large-vessel occlusion is suspected (NIHSS ≥ 6, cortical signs), obtain CT angiography immediately after non-contrast CT, but do not delay alteplase infusion. 2
• Combined IV alteplase plus mechanical thrombectomy achieves recanalization rates of 72–88% with modern stent retrievers. 2

Tenecteplase as an Alternative

• Tenecteplase is emerging as a potential alternative to alteplase with benefits including single-bolus administration and potentially improved recanalization rates. 6
• Current evidence supports tenecteplase particularly in patients with large-vessel occlusion undergoing endovascular therapy, though alteplase remains the FDA-approved standard. 6

Common Pitfalls to Avoid

• Do not withhold alteplase solely because of high NIHSS in the 0–3 hour window—severe strokes still benefit despite higher hemorrhage risk. 3, 2
• Do not delay alteplase for vascular imaging or patient transfer when IV thrombolysis eligibility is established. 3
• Do not wait for the full laboratory panel before administering alteplase—only glucose assessment is mandatory pre-treatment. 3, 2
• Do not confuse the 0–3 hour and 3–4.5 hour eligibility criteria—the extended window has additional exclusions. 1
• Treatment can be initiated before platelet count and coagulation studies in appropriate patients, but must be stopped if contraindications are discovered. 4