All Pharmacy Pearls

Introduction

    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

Clinical Detail

Alteplase (Activase)

ParameterAlteplase (Activase)
MOAInitiates 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.
Administration10% 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
CompatibilityMay be diluted in equal volume with:
  • 0.9% sodium chloride
  • D5W

NOT compatible with lactated ringers

Evidence

Trials that showed no benefit

TrialDesign / Sample SizeTime WindowPatient PopulationIntervention & ComparisonOutcomes
NINDS-1 (1995)PRCT (n=291)<= 3 hoursMean 67 y; Median NIHSS 14; TTT 0-90 m 47%; TTT 91-180 m 53%0.9 mg/kg rt-PA (Max 90 mg); PlaceboNo difference in NIHSS score at 24 hours
ECASS II (1998)PRCT (n=800)<= 6 hoursMedian 68 y; Median NIHSS 11; TTT 0-3 h 19.8%; TTT 3-6 h 80.2%0.9 mg/kg rt-PA (Max 90 mg); PlaceboNo difference in functional outcomes at 90 days; No significant difference in morbidity, despite 2.5 fold ↑ SICH in rt-PA group
IST-3 (2012)PRCT (n=3035)<= 6 hours1407 patients >80 y; 201 patients >90 y; TTT 4.2 h0.9 mg/kg t-PA (Max 90 mg); PlaceboNo difference in functional outcomes at 180 days; ↑ 7-day mortality in rt-PA group (11% vs. 7%); ↑ SICH in rt-PA group (7% vs. 1%)

Trials that showed benefit

TrialDesign / Sample SizeTime WindowPatient PopulationIntervention & ComparisonOutcomes
NINDS-2 (1995)PRCT (n=333)<= 3 hoursMean 69 y; Median NIHSS 14; TTT 0-90 m 49%; TTT 91-180 m 51%0.9 mg/kg rt-PA (Max 90 mg); Placebo33% more patients treated with t-PA had mRS 0-1 at 90 days; 2.9% ↑ fatal ICH in t-PA group
ECASS III (2008)PRCT (n=821)3-4.5 hoursMean 65 y; Median NIHSS 9; TTT 4 h0.9 mg/kg t-PA (Max 90 mg); Placebo7% more patients treated with t-PA had mRS 0-1 at 90 days; 2.2% ↑ SICH in rt-PA group
WAKE-UP (2018)PRCT (n=503)≥ 4.5 hours since LKNMean 65 y; Median NIHSS 6; TTT 10 h0.9 mg/kg rt-PA (Max 90 mg); Placebo11% more patients treated with t-PA had mRS 0-1 at 90 days; 8% increase in SICH
EXTEND (2019)PRCT (n=225)4.5-9 hoursMean 73 y; Median NIHSS 12; TTT 7.5 hours0.9 mg/kg rt-PA (Max 90 mg); PlaceboStopped early; mRS 0-1 occurred in 35.4% of the tPa group and 29.5% of the placebo group (adjusted OR 1.44; 95% CI 1.01 – 2.06, p=0.04). In unadjusted primary outcome not statistically significant (OR 1.2, 95% CI 0.82 – 1.76, p=0.35); More symptomatic intracranial hemorrhage in the tPa group (6.2% vs 0.9%)

Trials that showed harm

TrialDesign / Sample SizeTime WindowPatient PopulationIntervention & ComparisonOutcomes
ECASS-1 (1995)PRCT (n=620)<= 6 hoursMedian 69 y; Median NIHSS 12; TTT 4.4 h1.1 mg/kg rt-PA (Max 100 mg); PlaceboNo difference in functional outcomes at 90 days; Significant ↑ 30-day mortality in T-PA group (22.4% vs. 15.8%)
ATLANTIS-B (1999)PRCT (n=613)3-5 hoursMean 65 y; Median NIHSS 10; TTT 4.5 h0.9 mg/kg rt-PA (Max 90 mg); PlaceboStopped early; Trend towards ↑ mortality in rt-PA group (11% vs. 7%)
ATLANTIS-A (2000)PRCT (n=142)<= 6 hoursMean 67 y; Median NIHSS 10; TTT 4.5 h0.9 mg/kg t-PA (Max 90 mg); PlaceboStopped early; More 4-point improvement at 30 days with placebo than alteplase (75% vs 60%); Significant ↑ SICH w/in 10 days of rt-PA treatment (11% vs. 0%); Significant ↑ 90-day mortality in rt-PA group (23% vs. 7%)
EPITHET (2008)PRCT (n=101)3-6 hoursMean 71 y; Median NIHSS 130.9 mg/kg t-PA (Max 90 mg); PlaceboNon-significant difference in their primary outcome, which was a disease oriented imaging outcome; Non-significant difference in mortality (26% with alteplase vs 12% with placebo) in patients with perfusion mismatch

TTT: Time-to-treatment; ITT: Intention-to-treat; PRCT: Prospective Randomized Controlled Trial; LKN: Last Known Normal.

Conclusions

    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]

References

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    1995;333:1581-1587.

    Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with

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  • doi:10.1001/jama.274.13.1017

    • Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. Recombinant Tissue-Type Plasminogen Activator

    (Alteplase) for Ischemic Stroke 3 to 5 Hours After Symptom Onset The ATLANTIS Study: A Randomized Controlled Trial. JAMA.

    1999;282(21):2019-2026.

    Clark WM, Albers GW, Madden KP, Hamilton S. The rtPA (Alteplase) 0-to 6-Hour Acute Stroke Trial, Part A (A0276g) Results of

    a Double-Blind, Placebo-Controlled, Multicenter Study. Stroke. 2000;31:811-816.

    Davis SM, Rey G, Donnan A, et al. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic

    Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol. 2008;7:299-309. doi:10.1016/S1474

    Ma H, Campbell BCV, Parsons MW, et al. Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. N

    Engl J Med. 2019;380(19):1795-1803. doi:10.1056/nejmoa1813046

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    Alper BS, Foster G, Thabane L, Rae-Grant A, Malone-Moses M, Manheimer E. Thrombolysis with alteplase 3-4.5 hours after

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    doi:10.1136/bmjebm-2020-111386

Tags:alteplase acute ischemic stroke thrombolysis intracranial hemorrhage

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