Alteplase for Acute Ischemic Stroke

Alteplase (rt-PA) has been used for acute ischemic stroke since its approval by the FDA in 1996 after publication of

promising results of the NINDS trial

NINDS trial has been criticized for its strict inclusion criteria and all major clinical trials since have sought to show benefit in

those patients excluded from the NINDS trial

Recent re-analysis of the ECASS III trial has been published using independent patient level data

Alteplase (Activase)

MOA

Initiates fibrinolysis by binding to fibrin in a thrombus and converts entrapped

plasminogen to plasmin

Dose

Patient weight <100 kg: 0.09 mg/kg (10% of 0.9 mg/kg dose) as an IV bolus over 1

minute, followed by 0.81 mg/kg (90% of 0.9 mg/kg dose) as a continuous infusion

over 60 minutes.

Patient weight >=100 kg: 9 mg (10% of 90 mg) as an IV bolus over 1 minute,

followed by 81 mg (90% of 90 mg) as a continuous infusion over 60 minutes.

Administration

10% given as IV bolus over 1 minute; remainder infused over 1 hour

PK/PD

Duration: 1 hour after infusion terminated, bleeding risk can occur past 1 hour

Distribution: approximates plasma volume

Half-life elimination: 5 minutes

Excretion: hepatic and plasma clearance

Adverse Effects

Intracranial hemorrhage

Angioedema

GI/GU hemorrhage

Drug Interactions

and Warnings

Tranexamic acid, avoid combination

Internal bleeding, thromboembolic events, cholesterol embolization

Contraindications

Active internal bleeding

Ischemic stroke within 3 months except when within 4.5 hours

Severe uncontrolled hypertension

Compatibility

May be diluted in equal volume with:

Trials that showed no benefit

Design/sample

size

Time Window

Patient

Population

Intervention & Comparison

Outcomes

NINDS-1

(1995)2

PRCT (n=291)

<= 3 hours

Mean 67 y

Median NIHSS 14

TTT 0-90 m 47%

TTT 91-180 m 53%

mg)

Placebo

No difference in

NIHSS score at 24

hours

ECASS II

(1998)3

PRCT ( n=800)

<= 6 hours

Median 68 y

Median NIHSS 11

TTT 0-3 h 19.8%

TTT 3-6 h 80.2%

Currently, the AHA recommends for eligible patients the benefit of alteplase therapy is time dependent, and treatment should

be initiated as quickly as possible.

Baseline imbalances favoring rt-PA in the NINDS trial and the ECASS III trial could be considered controversial, considering

these trials were instrumental for drug approval and time window expansion.

A re-analysis cannot overturn the original findings of a study, only increase or decrease the confidence in the findings it

presented.

The decision to use rt-PA for an acute ischemic stroke should continue to consider potential benefits with consideration for

upfront risk of fatal ICH.

(Britany Byrkit & [email protected]

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2019 update to the 2018 guidelines for the early management of acute ischemic stroke a guideline for healthcare

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doi:10.1161/STR.0000000000000211

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