Introduction  

1. 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 
2. 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 
3. Recent re-analysis of the ECASS III trial has been published using independent patient level data 

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Pharmacology

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:   0.9% sodium chloride   D5W   NOT compatible with lactated ringers

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Overview of the Evidence  

Trials that showed no benefit

	Design/sample size	Time Window	Patient Population	Intervention & Comparison	Outcomes
NINDS-1 (1995)	PRCT (n=291)	≤ 3 hours	•            Mean 67 y •            Median NIHSS 14 •   TTT 0-90 m 47% •  TTT 91-180 m 53%	•       0.9 mg/kg rt-PA (Max 90 mg) •       Placebo	No difference in NIHSS score at 24 hours
ECASS II (1998)	PRCT ( n=800)	≤ 6 hours	•       Median 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)  •       Placebo	No difference in functional outcomes at 90 days No significant difference in morbidity, despite 2.5 fold ↑ SICH in rtPA group
IST-3  (2012)	PRCT (n =3035)	≤ 6 hours	•       1407 patients >80 y • 201 patients >90  y  • TTT 4.2 h	•       0.9 mg/kg t-PA (Max 90 mg) •       Placebo	No 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

	Design/sample size	Time Window	Patient Population	Intervention & Comparison	Outcomes
NINDS-2 (1995)	PRCT (n=333) ≤ 3 hours		• Mean 69 y  • Median NIHSS 14 •  TTT 0-90 m 49%  • TTT 91-180 m 51%	• 0.9 mg/kg rt-PA (Max 90 mg)  • Placebo	•  •  33% more patients treated with t-PA had mRS 0-1 at 90 days  2.9% ↑ fatal ICH in tPA group
ECASS III (2008)	PRCT (n =821)	3-4.5 hours	• Mean 65 y  • Median NIHSS 9  • TTT 4 h	• 0.9 mg/kg t-PA (Max 90 mg)  • Placebo	7% 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 LKN	• Mean 65 y  • Median NIHSS 6  • TTT 10 h	• 0.9 mg/kg rt-PA (Max 90 mg)  • Placebo	11% 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 hours	• Mean 73 y  • Median NIHSS 12  • TTT 7.5 hours	• 0.9 mg/kg rt-PA (Max 90 mg)  • Placebo	Stopped 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.   o  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

	Design/sample size	Time Window	Patient Population	Intervention & Comparison	Outcomes
ECASS-1 (1995)	PRCT (n=620)	≤ 6 hours	• Median 69 y  • Median NIHSS 12  • TTT 4.4 h	• 1.1 mg/kg rt-PA (Max 100 mg)  • Placebo	• No difference in functional outcomes at 90 days  • Significant ↑ 30-day mortality in T-PA group (22.4% vs.  15.8%)
ATLANTISB (1999)	PRCT ( n =613)	3-5 hours	• Mean 65 y  • Median NIHSS 10  • TTT 4.5 h	• 0.9 mg/kg rt-PA (Max 90 mg)  • Placebo	Stopped early   Trend towards ↑ mortality in rt-PA group (11% vs. 7%)
ATLANTIS- A  (2000)	PRCT (n =142)	≤ 6 hours	• Mean 67 y  • Median NIHSS 10  • TTT 4.5 h	• 0.9 mg/kt t-PA (Max 90 mg)  • Placebo	• Stopped 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 hours	Mean 71 y  Median NIHSS 13	0.9 mg/kg t-PA (Max 90 mg)  Placebo	Non-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

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Revisiting the NINDS Study

Reason: the original authors of 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.  

However 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.  

	Original Report (1995)		Re-analysis (2000)
	Rt-PA	Placebo	0-90 min		91-180 min
			Rt-PA	Placebo	Rt-PA	Placebo
NIHSS, mean (SD); median	14	14	15.2 (7.2); 15	15.0 (6.7); 14	13.5 (7.7); 12	15.4 (6.9); 15
NIHSS, groups, percent
0-5			8.3	6.2	19	4.2
10-Jun			19.1	25.5	24.2	27.5
15-Nov			24.8	21.4	17	21
16-20			25.5	25.5	21.6	19.8
>20			2230%	21.4	18.3	27.5

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. 
• In analyses adjusted for baseline imbalances, all efficacy outcomes were no longer significant. •     Increases in symptomatic intracranial hemorrhage remained significant in 5/6 analyses.  

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 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.   

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References  

1. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke a guideline for healthcare professionals from the American Heart Association/American Stroke A. Stroke. 2019;50(12):E344-E418. doi:10.1161/STR.0000000000000211 
2. NINDS rt-PA Stroke Study Group. TISSUE PLASMINOGEN ACTIVATOR FOR ACUTE ISCHEMIC STROKE. N Engl J Med. 1995;333:1581-1587. 
3. 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. doi:10.1016/S01406736(98)08020-9 
4. 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 (the third international stroke trial [IST-3]): A randomised controlled trial. Lancet. 2012;379(9834):2352-2363. doi:10.1016/S0140-6736(12)60768-5 
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6. 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. doi:10.1056/nejmoa1804355 
7. Hacke W, kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA J Am Med Assoc. 1995;274(13):10171025. doi:10.1001/jama.274.13.1017 
8. 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. 
9. 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. 
10. 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 
11. 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 
12. 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. doi:10.1212/WNL.55.11.1649 
13. Alper BS, Foster G, Thabane L, Rae-Grant A, Malone-Moses M, Manheimer E. 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. doi:10.1136/bmjebm-2020-111386