Alteplase for Acute Ischemic Stroke

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. This landmark trial has been criticized for its strict inclusion criteria, and all major clinical trials since have sought to show benefit in patients excluded from the NINDS trial. Recent re-analyses of both the NINDS and ECASS III trials have been published using independent patient-level data.

Key Points

Alteplase (rt-PA) has been used for acute ischemic stroke since FDA approval in 1996 after the NINDS trial
NINDS trial has been criticized for its strict inclusion criteria and baseline imbalances favoring rt-PA
Recent re-analysis of the ECASS III trial using independent patient-level data has been published

Pharmacology of Alteplase

Parameter	Details
Mechanism of Action	Initiates fibrinolysis by binding to fibrin in a thrombus and converts entrapped plasminogen to plasmin.
Dose	Weight <100 kg 0.09 mg/kg (10% of 0.9 mg/kg dose) IV bolus over 1 min, then 0.81 mg/kg (90%) infusion over 60 min Weight ≥100 kg 9 mg (10% of 90 mg) IV bolus over 1 min, then 81 mg (90%) infusion over 60 min
Administration	10% given as IV bolus over 1 minute; remainder infused over 1 hour
PK/PD	Duration: 1 hr after infusion terminated Distribution: approx. plasma volume Half-life: 5 minutes Excretion: hepatic & plasma clearance
Adverse Effects	Intracranial hemorrhage Angioedema GI/GU hemorrhage
Drug Interactions & 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	Compatible 0.9% NaCl, D5W Not Compatible Lactated Ringer’s

Clinical Pearl

Total dose is 0.9 mg/kg (max 90 mg). Administer 10% as IV bolus over 1 minute and infuse the remaining 90% over 60 minutes. Bleeding risk persists beyond the 1-hour infusion duration.

Overview of the Evidence

10 Studies

Trials That Showed No Benefit

Trial / Year	Design (n)	Window	Population	Key Outcomes
NINDS-1² (1995)	PRCT n=291	≤3 hrs	Mean 67 y, Median NIHSS 14, TTT 0–90 min 47%, 91–180 min 53%	No difference in NIHSS at 24 hrs
ECASS II³ (1998)	PRCT n=800	≤6 hrs	Median 68 y, NIHSS 11, TTT 0–3 h 19.8%, 3–6 h 80.2%	No difference in functional outcomes at 90 days 2.5-fold increase in SICH in rt-PA group
IST-3⁴ (2012)	PRCT n=3,035	≤6 hrs	1,407 pts >80 y, 201 pts >90 y, TTT 4.2 h	No difference at 180 days ↑ 7-day mortality rt-PA (11% vs 7%), ↑ SICH (7% vs 1%)

Trials That Showed Benefit

Trial / Year	Design (n)	Window	Population	Key Outcomes
NINDS-2² (1995)	PRCT n=333	≤3 hrs	Mean 69 y, Median NIHSS 14, TTT 0–90 min 49%, 91–180 min 51%	33% more mRS 0–1 at 90 days 2.9% increase in fatal ICH
ECASS III⁵ (2008)	PRCT n=821	3–4.5 hrs	Mean 65 y, Median NIHSS 9, TTT 4 h	7% more mRS 0–1 at 90 days 2.2% increase in SICH
WAKE-UP⁶ (2018)	PRCT n=503	≥4.5 hrs since LKN	Mean 65 y, Median NIHSS 6, TTT 10 h	11% more mRS 0–1 at 90 days 8% increase in SICH
EXTEND¹¹ (2019)	PRCT n=225	4.5–9 hrs	Mean 73 y, Median NIHSS 12, TTT 7.5 h	mRS 0–1: 35.4% vs 29.5% (adj OR 1.44) Stopped early. Unadjusted outcome not significant. SICH 6.2% vs 0.9%

Trials That Showed Harm

Trial / Year	Design (n)	Window	Population	Key Outcomes
ECASS-1⁷ (1995)	PRCT n=620	≤6 hrs	Median 69 y, NIHSS 12, TTT 4.4 h. Higher dose: 1.1 mg/kg (max 100 mg)	Significant ↑ 30-day mortality (22.4% vs 15.8%)
ATLANTIS-B⁸ (1999)	PRCT n=613	3–5 hrs	Mean 65 y, NIHSS 10, TTT 4.5 h	Stopped early; trend ↑ mortality (11% vs 7%)
ATLANTIS-A⁹ (2000)	PRCT n=142	≤6 hrs	Mean 67 y, NIHSS 10, TTT 4.5 h	Significant ↑ 90-day mortality (23% vs 7%) Stopped early. SICH 11% vs 0%. Placebo had better 30-day improvement (75% vs 60%)
EPITHET¹⁰ (2008)	PRCT n=101	3–6 hrs	Mean 71 y, NIHSS 13	Non-significant ↑ mortality (26% vs 12%) In perfusion mismatch patients. Primary imaging outcome non-significant.

TTT: Time-to-treatment; ITT: Intention-to-treat; PRCT: Prospective Randomized Controlled Trial; SICH: Symptomatic intracranial hemorrhage; mRS: modified Rankin Scale; NIHSS: National Institutes of Health Stroke Scale; LKN: Last known normal

Revisiting the NINDS Study

The original authors of the NINDS rt-PA stroke study (1995) performed further analysis after patients treated earlier did not seem to benefit compared to those treated later, contrary to an expected difference. When the baseline NIHSS scores were shown by time-to-treatment instead of treatment group, baseline differences between the rt-PA and placebo groups became apparent.¹²

NIHSS	Original Report (1995)		Re-analysis 0–90 min		Re-analysis 91–180 min
NIHSS	rt-PA	Placebo	rt-PA	Placebo	rt-PA	Placebo
Mean (median)	14	14	15.2 (15)	15.0 (14)	13.5 (12)	15.4 (15)
NIHSS 0–5 (%)	—	—	8.3	6.2	19.0	4.2
NIHSS 6–10 (%)	—	—	19.1	25.5	24.2	27.5
NIHSS >20 (%)	—	—	22.3	21.4	18.3	27.5

Key Finding

The higher median NIHSS baseline scores in the placebo group at 91–180 minutes resulted in an overestimation of rt-PA’s efficacy in the original NINDS trial that even the original authors acknowledged in their 2000 re-analysis conclusions.

ECASS III Re-analysis

Previously reported unadjusted analyses were based on modified NIHSS score. The secondary efficacy outcome was no longer significant using the original NIHSS score.¹³

In analyses adjusted for baseline imbalances, all efficacy outcomes were no longer significant.

Increases in symptomatic intracranial hemorrhage remained significant in 5 out of 6 analyses.

Clinical Conclusions

Bottom Line

The decision to use rt-PA for an acute ischemic stroke should continue to consider potential benefits with consideration for the upfront risk of fatal intracranial hemorrhage. Baseline imbalances in key trials remain controversial.

AHA recommends for eligible patients the benefit of alteplase therapy is time dependent, and treatment should be initiated as quickly as possible.¹

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

Continue to weigh potential benefits against the upfront risk of fatal ICH when considering rt-PA use.

Full Reference List

13 refs

Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update. Stroke. 2019;50(12):E344-E418.
NINDS rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581-1587.
Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet. 1998;352(9136):1245-1251.
Sandercock P, Wardlaw JM, Lindley RI, et al. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (IST-3). Lancet. 2012;379(9834):2352-2363.
Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-1329.
Thomalla G, Simonsen CZ, Boutitie F, et al. MRI-guided thrombolysis for stroke with unknown time of onset. N Engl J Med. 2018;379(7):611-622.
Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke (ECASS). JAMA. 1995;274(13):1017-1025.
Clark WM, Wissman S, Albers GW, et al. Recombinant tissue-type plasminogen activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset: The ATLANTIS Study. 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). 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). Lancet Neurol. 2008;7:299-309.
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.
Marler JR, Tilley BC, Lu M, et al. Early stroke treatment associated with better outcome: The NINDS rt-PA stroke study. Neurology. 2000;55(11):1649-1655.
Alper BS, Foster G, Thabane L, et al. Thrombolysis with alteplase 3-4.5 hours after acute ischaemic stroke: Trial reanalysis adjusted for baseline imbalances. BMJ Evidence-Based Med. 2020;0(0):172-179.