What are the indications, dosing, contraindications, and management steps for intravenous alteplase thrombolytic therapy in acute ischemic stroke?

Thrombolytic Treatment for Acute Ischemic Stroke

Intravenous alteplase at 0.9 mg/kg (maximum 90 mg) is the standard thrombolytic therapy for acute ischemic stroke, administered within 4.5 hours of symptom onset, with 10% given as a bolus over 1 minute and the remaining 90% infused over 60 minutes. 1, 2, 3

Time Windows and Eligibility

0–3 Hour Window (Broadest Eligibility)

• All patients meeting basic criteria should receive alteplase within 3 hours, regardless of age >80 years, stroke severity (including NIHSS >25), or current antiplatelet therapy (single or dual). 1, 2, 4
• Treatment in this window produces a 12% absolute increase in achieving minimal or no disability (39% vs 26% with placebo), with a number-needed-to-treat of 8.3. 2
• Earlier treatment yields exponentially better outcomes—each 15-minute delay reduces the probability of favorable outcome. 1, 2
• When initiated within 1.5 hours, the odds of favorable outcome are 2.81 times higher than placebo (95% CI 1.75–4.50). 2

3–4.5 Hour Extended Window (Additional Exclusions Apply)

• Alteplase may be given between 3 and 4.5 hours if patients satisfy ECASS III criteria, with an odds ratio of 1.40 for favorable outcome versus placebo (95% CI 1.05–1.85). 1, 2
• Four additional exclusion criteria apply in this window: age >80 years, any oral anticoagulant use (regardless of INR), NIHSS >25, or combined history of diabetes AND prior stroke. 1, 2, 3
• The AHA/ASA gives a Grade 1B recommendation against IV alteplase beyond 4.5 hours from symptom onset. 2

Beyond 4.5 Hours (Imaging-Selected Patients)

• The WAKE-UP trial demonstrated that patients with unknown stroke onset time selected by DWI-FLAIR mismatch pattern achieved significantly higher rates of favorable outcome (53.3% vs 41.8%, adjusted OR 1.61,95% CI 1.06–2.36) when treated with alteplase. 1
• Parenchymal hemorrhage type 2 risk was higher (4% vs 0.4%), though confidence intervals were wide due to early trial termination. 1

Dosing Protocol

Standard Regimen:

• Total dose: 0.9 mg/kg body weight (absolute maximum 90 mg) 1, 2, 3
• Initial bolus: 10% of total dose (0.09 mg/kg) administered IV push over exactly 1 minute 2, 3
• Continuous infusion: Remaining 90% (0.81 mg/kg) infused over 60 minutes 2, 3

Critical dosing error to avoid: Never use the myocardial infarction alteplase protocol for stroke—this is a potentially harmful mistake. Always verify you are using the stroke-specific 0.9 mg/kg protocol. 3

Mandatory Pre-Treatment Requirements

Imaging

• Non-contrast CT or MRI must be performed immediately to exclude intracranial hemorrhage—this is the only mandatory imaging before alteplase. 1, 2, 4
• For patients with suspected large vessel occlusion (severe deficit, NIHSS ≥6, cortical signs) presenting within 6 hours, obtain CTA from aortic arch to vertex immediately after non-contrast CT, but do not delay alteplase for this study. 2
• CT perfusion is NOT required for patients presenting within 4.5 hours without large vessel occlusion—obtaining unnecessary perfusion imaging only delays treatment. 2

Laboratory

• Only bedside capillary glucose must be checked before alteplase—do not wait for complete laboratory panels. 1, 2, 3
• Glucose must be >50 mg/dL (>2.7 mmol/L); treat hypoglycemia with IV dextrose before proceeding. 2
• Obtain routine blood work (CBC, coagulation, renal function, cardiac enzymes) and ECG, but do not let these results delay treatment. 2

Blood Pressure Management

• Systolic/diastolic BP must be lowered to <185/110 mmHg before initiating alteplase. 1, 2, 3, 4
• Maintain BP <180/105 mmHg for the first 24 hours after infusion. 1, 2
• Use labetalol or IV β-blockers in low doses for BP control. 1

Absolute Contraindications

The following are absolute contraindications to alteplase 1, 2, 4:

• Intracranial hemorrhage on initial CT scan
• History of any prior intracranial hemorrhage
• Active internal bleeding
• Platelet count <100,000/mm³
• INR >1.7
• aPTT >40 seconds or PT >15 seconds
• Prior ischemic stroke within the preceding 3 months
• Severe head trauma within the preceding 3 months
• Intracranial or intraspinal surgery within the prior 3 months
• Clinical presentation suggesting subarachnoid hemorrhage
• Structural gastrointestinal malignancy or GI bleeding within the past 21 days
• Glucose <50 mg/dL or >400 mg/dL (treat and recheck before proceeding)

Relative Contraindications (Case-by-Case Assessment)

The following may be reasonable to treat with careful consideration 1:

• Warfarin use with INR ≤1.7 or PT <15 seconds (Class IIb)
• Seizure at stroke onset when residual deficits are clearly stroke-related, not postictal (Class IIa)
• Lumbar puncture within the prior 7 days (Class IIb)
• Major non-head trauma within 14 days—weigh bleeding risk against stroke disability (Class IIb)
• Major surgery within 14 days—consider surgical-site hemorrhage risk (Class IIb)
• History of GI/genitourinary bleeding (low bleeding risk reported; Class IIb)
• Menstruation without menorrhagia (Class IIa) or with menorrhagia but stable hemodynamics (Class IIb)
• Extracranial cervical arterial dissection (Class IIa)
• Intracranial arterial dissection (Class IIb)
• Pre-existing disability (mRS ≥2) or dementia—consider quality of life, social support, and goals of care (Class IIb)

Special Clinical Scenarios

Mild or Rapidly Improving Stroke

• Patients with moderate to severe stroke who demonstrate early improvement but remain moderately impaired should receive alteplase (Class IIa). 1
• For mild but potentially disabling symptoms, treatment may be considered, though the risk-benefit ratio requires careful assessment (Class IIb). 1, 4

Severe Stroke

• Very severe stroke (NIHSS >25) is NOT a contraindication within the 0–3 hour window. 2, 4
• The benefit of alteplase between 3 and 4.5 hours for NIHSS >25 is uncertain (Class IIb). 1

Elderly Patients

• Age >80 years is NOT a contraindication in the 0–3 hour window. 1, 2, 4
• Symptomatic intracerebral hemorrhage rates in patients ≥80 years are comparable to younger patients. 2
• Age >80 years is an exclusion criterion only in the 3–4.5 hour window. 1, 2

Posterior Circulation Stroke

• The identical dosing protocol (0.9 mg/kg) and eligibility criteria used for anterior circulation strokes apply to posterior circulation strokes. 2
• No adjustment in dose or protocol is required for basilar or posterior cerebral artery occlusions. 2

Integration with Mechanical Thrombectomy

Critical workflow principles:

• Administer IV alteplase even when the patient is being evaluated for or will undergo mechanical thrombectomy. 1, 2, 4
• Do NOT delay IV thrombolysis while obtaining vascular imaging or assessing thrombectomy eligibility. 1, 2, 3, 4
• Do NOT wait to assess the response to IV thrombolysis before proceeding to catheter angiography for thrombectomy. 1, 2
• For patients with large vessel occlusion in the anterior circulation within 6–24 hours of last known well, use advanced imaging (CTP or DW-MRI) to determine thrombectomy eligibility. 2

Endovascular Therapy Evidence

• Mechanical thrombectomy with second-generation stent retrievers achieves 72–88% recanalization rates versus near-zero with IV therapy alone for high clot burden. 2
• The 2015 landmark trials (MR CLEAN, ESCAPE, SWIFT PRIME, EXTEND-IA, REVASCAT) showed a number-needed-to-treat of approximately 3–4 patients for one additional good outcome. 2
• DAWN and DEFUSE-3 trials extended the thrombectomy window to 24 hours and 16 hours respectively for highly selected patients with favorable imaging profiles. 1

Intraarterial Thrombolysis

• Mechanical thrombectomy with stent retrievers is recommended over intraarterial thrombolysis as first-line therapy. 1
• Intraarterial thrombolysis may be considered as rescue therapy when early recanalization with IV thrombolysis is not achieved, particularly for large clot burden in proximal vessels (MCA, carotid terminus, basilar artery). 2
• Intraarterial thrombolysis initiated within 6 hours might be considered for patients with contraindications to IV alteplase, though consequences are uncertain (Class IIb). 1

Hemorrhagic Complications

• Symptomatic intracranial hemorrhage occurs in 2.4%–6.4% of patients treated with standard-dose alteplase. 1, 2
• Baseline NIHSS >20 is a stronger predictor of symptomatic hemorrhage than age alone. 2
• Hyperglycemia (glucose >11.1 mmol/L or >200 mg/dL) significantly increases hemorrhagic risk—patients with baseline glucose >11.1 mmol/L experienced a 36% risk of symptomatic ICH. 2
• Angioedema is a potential adverse effect that can cause partial airway obstruction. 2

Post-Treatment Monitoring Protocol

Neurological monitoring 2:

• Every 15 minutes during the infusion
• Every 30 minutes for the subsequent 6 hours
• Hourly until 24 hours post-treatment

If severe headache, acute hypertension, nausea, or vomiting occur:

• Stop the infusion immediately
• Obtain emergent CT scan 2

Blood pressure monitoring 2:

• Every 15 minutes for the first 2 hours
• Every 30 minutes for the next 6 hours
• Hourly thereafter up to 24 hours
• Maintain ≤180/105 mmHg after alteplase

Procedural delays:

• Delay placement of nasogastric tubes, indwelling bladder catheters, and intra-arterial pressure catheters until after the monitoring period. 2

Follow-up imaging and medications:

• Obtain follow-up CT scan at 24 hours before starting anticoagulant or antiplatelet therapy. 2
• Defer anticoagulants and antiplatelet agents for at least 24 hours after alteplase. 2
• Aspirin (160–300 mg) should be administered 24–48 hours after stroke onset; for those treated with alteplase, aspirin is generally delayed until 24 hours later. 1

Institutional Requirements for Optimal Outcomes

The effectiveness of alteplase is less well established in hospitals lacking an organized stroke system 1, 2:

• 24/7 rapid CT access (third-generation or higher helical scanner)
• Dedicated stroke team
• Continuous neurological monitoring capability
• Blood-pressure management protocols
• Neurosurgical consultation availability
• Target door-to-needle time <60 minutes in 90% of patients, with optimal median of 30 minutes 3, 4

Critical Pitfalls to Avoid

• Waiting for complete laboratory panels beyond bedside glucose—this causes harmful treatment delays. 2, 4
• Delaying IV thrombolysis to obtain or interpret CTA for thrombectomy evaluation—give alteplase first. 2, 3, 4
• Withholding alteplase from patients >80 years old in the 0–3 hour window—age alone is not a contraindication in this time frame. 2, 4
• Excluding patients with NIHSS >25 in the 0–3 hour window—severe stroke is not a contraindication early. 2, 4
• Obtaining CT perfusion for patients within 4.5 hours without large vessel occlusion—this provides no actionable information and only delays treatment. 2
• Using the myocardial infarction alteplase dosing protocol—always verify the stroke-specific 0.9 mg/kg regimen. 3
• Waiting to assess alteplase response before initiating thrombectomy evaluation—proceed directly to angiography if large vessel occlusion is present. 1, 2, 4