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Alteplase for Acute Ischemic Stroke

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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 

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  

Overview of the Evidence  

Trials that showed no benefit

 Design/sample sizeTime WindowPatient PopulationIntervention & ComparisonOutcomes
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)  •       PlaceboNo 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 sizeTime WindowPatient PopulationIntervention & ComparisonOutcomes
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 sizeTime WindowPatient PopulationIntervention & ComparisonOutcomes
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 
TTT: Time-to-treatment; ITT: Intention-to-treat; PRCT: Prospective Randomized Controlled Trial;   

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-PAPlacebo0-90 min 91-180 min 
   Rt-PAPlaceboRt-PAPlacebo
NIHSS, mean (SD); median 141415.2 (7.2); 1515.0 (6.7); 1413.5 (7.7); 1215.4 (6.9); 15
NIHSS, groups, percent       
0-5   8.36.2194.2
10-Jun  19.125.524.227.5
15-Nov  24.821.41721
16-20   25.525.521.619.8
>20   2230%21.418.327.5
The higher median NIHSS baseline scores in the placebo at 91-180 min group resulted in an overestimation of rt-PA’s efficacy in the original NINDS trial that even the original authors had to announce in their conclusions of their 2000 reanalysis.  

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.  

 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.   

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 
  5. 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. doi:10.1056/nejmoa0804656 
  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 

Fibrinolytics for STEMI

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Introduction

  1. Percutaneous coronary intervention (PCI) is the preferred reperfusion strategy during a cardiac arrest; thrombolytic therapy is an option without PCI capability, followed by transfer to a PCI capable center. 
  2. Thrombolytic therapy is most effective when administered within 30 minutes of first medical contact, however, may be considered within 12 – 24 hours of symptom onset and ongoing ischemia or extensive ST elevation. 
  3. During ACS-Induced Cardiac Arrest, the goal for fibrinolysis is 30 minutes and reperfusion with PCI is preferred, however, if PCI is delayed, fibrinolytics therapy could be considered.

Pharmacology

 AlteplaseTenecteplase
MOAInitiates fibrinolysis by binding to fibrin in a thrombus and converts entrapped plasminogen to plasmin Promotes initiation of fibrinolysis by binding to fibrin and converting plasminogen to plasmin; similar to alteplase but more fibrin specific 
DoseWeight based: > 67kg: infuse 15mg IV bolus over 1-2 minute, followed by 50mg infusion over 30 minutes, then 35mg over 1 hour (max total dose 100mg)   ≤ 67kg: : infuse 15mg IV bolus over 1-2 minutes, followed by 0.75mg/kg infusion over 30 minutes, then 0.5mg/kg over 1 hour (max total dose 100mg)Weight based: < 60kg: 30mg  ≥ 60 to < 70kg: 35mg ≥ 70 to < 80kg: 40mg  ≥ 80 to < 90kg: 45mg  ≥ 90kg: 50mg 
Administration•      Bolus administered over 1 minute followed by infusion •      Single bolus over 5 seconds 
PK/PDDuration: 1 hour after infusion terminated  Distribution: approximates plasma volume Half-life elimination: 5 minutes  Excretion: hepatic and plasma clearance Distribution: weight related  Metabolism: hepatic  Half-life elimination: biphasic; initial 20-24 min, terminal 90-130 min  Excretion: plasma clearance 
Adverse EffectsIntracranial hemorrhage Ecchymosis  GI/GU hemorrhage  Sepsis  Cerebrovascular accident Hemorrhage and hematoma  Cerebrovascular accident
Drug Interactions and WarningsTranexamic acid, avoid combination  Internal bleeding, thromboembolic events, cholesterol embolization Tranexamic acid, avoid combination  Internal bleeding, thromboembolic events, arrhythmias
Contraindications Active internal bleeding  Ischemic stroke within 3 months except when within 4.5 hours Severe uncontrolled hypertension Active internal bleeding Severe uncontrolled hypertension Recent intracranial/intraspinal surgery Ischemic stroke within 3 months
Compatibility    May be diluted in equal volume with: 0.9% sodium chloride  D5W•      Incompatible with dextrose 

Overview of Evidence

Author, year Design/ sample sizeIntervention & ComparisonOutcome
Guillermin 2016aMeta-analysis of RCT (n=18,208)•      Tenecteplase 30-50mg vs alteplase 80-100mg Bleeding 4.8% in tenecteplase vs 5.8% alteplase (p=0.0002)  No difference in mortality at 30 days 
 Llevadot 2001 Retrospective review (38 studies) Reteplase Anoteplase TenecteplaseTenecteplase and reteplase associated with accelerated infusion and more convenient by bolus administration  Administration of a less fibrin-specific agent may cause greater systemic coagulopathy with potential for more bleeding 
Boersma 1996Retrospective review (n=50,246) •      Fibrinolytic therapy vs placebo •      Mortality reduction in patients treated within 2 hours compared to later (p=0.001) 
GUSTO 1993Randomized, controlled trial (n=41,021) Streptokinase + SQ heparin Streptokinase + IV heparin Alteplase + IV heparin Alteplase + Streptokinase + IV heparin  Atleplase administered over 1.5 hours with IV heparin provide survival over standard therapy Thrombolytic therapy administered within 2448 hours of admission  
Armstrong 2013bRandomized controlled trial (n=1892)•      PCI vs bolus tenecteplase, clopidogrel, and enoxaparin Tenecteplase administration prehospital resulted in effective reperfusion when PCI was not completed within 1 hour  Fibrinolytic therapy associated with increase risk of intracranial bleeding 
  Cardiac Arrest Data
Bottiger 2001Prospective cohort (n=40)•      Alteplase 50 mg bolus, repeat 50 mg in 30 minutes vs placebo•      Increase in ROSC (68% vs 44%), ICU admission compared to placebo
Schreiber 2002Retrospective chart review (n=157) •      Alteplase 15mg bolus followed by 50mg infusion over 30 min and 35mg over 60 min•      Thrombolytic therapy achieved better functional neurological recovery more frequently (p=0.03) 
Lederer 2004Retrospective chart review (n=108)•      Alteplase 100 mg (15 mg followed by 85 mg over 90 min)81% of patients who received thrombolytic therapy were discharged without neurological deficit  67% of patients were still alive 5-10 years after the event 
Li 2006Meta-analysis•      Alteplase 15mg bolus followed by 50mg infusion over 30 min and 35mg over 60 minThrombolytic therapy improved the rate of ROSC (p < 0.01)  48% of patients had acute coronary artery obstruction 
Bottiger 2008Randomized, double-blind, multicenter trial (n=1050)Tenecteplase 30mg if < 60kg Tenecteplase 35mg if 60-69kg  •                 Tenecteplase 40mg if 70-79kg  Tenecteplase 45mg if 80-89kg  Tenecteplase 50mg if > 90kg  Placebo No difference in tenecteplase and placebo in 30-day survival, ROSC, survival, or neurologic outcomes  Increased intracranial hemorrhages in tenecteplase patients
RuizBailen 2001Retrospective cohort (n=303) Streptokinase  Alteplase accelerated regimen  Alteplase double bolus Systemic thrombolysis patients had a lower mortality, less mechanical ventilation, fewer CPR attempts (p < 0.0001)  No fatal hemorrhagic complications 
aAdministered as tenecteplase 30-50mg bolus and alteplase 15mg bolus followed by 0.75mg/kg infusion over 30 min  bHalf-dose tenecteplase administered in patients ≥ 75 years old cReteplase administered as two boluses of 10 million units given 30 minutes apart 

Conclusions

  1. Evidence supports PCI is the first line option for management of patients requiring reperfusion during cardiac arrest when a STEMI is suspected 
  2. Available evidence suggests tenecteplase and alteplase are appropriate fibrinolytic therapies when PCI is unavailable
  3. Tenecteplase is an alternative fibrinolytic therapy and has been evaluated safe and efficacious as a bolus dose of 30-50mg
  4. When alteplase is the only fibrinolytic therapy available, there is data to support bolus therapy +/-  a weight based infusion during cardiac arrest
  5. Thrombolytic agents administered during CPR can improve the rate of survival but are associated with a risk of severe bleeding 

References

  1. Lexicomp [Electronic version]. Macedonia, OH: Truven Wolters Kluwer Health. Retrieved January 26, 2021, from https://online.lexi.com/lco/action/login.
  2. Guillermin A, Yan D, Perrier A, Marti C. Safety and efficacy of tenecteplase versus alteplase in acute coronary syndrome: a systematic review and meta-analysis of randomized trials. Arch Med Sci 2016; 12, 6: 1181–1187.
  3. Llevadot J, Giugliano R, Antman E. Bolus fibrinolytic therapy in acute myocardial infarction. JAMA. 2001; 286(4): 442-449.
  4. Boersma E, Maas A, Deckers J, Simoons M. Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet. 1996; 348: 771-775. 
  5. GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. NEJM. 1993; 329(10): 673-682. 
  6. Armstrong P, Gershlick A, Goldstein P, Wilcox R, Danays T, Lambert Y, Sulimov V, Ortiz F, Ostojic M, Welsh R, Carvalho A, Nanas J, Arntz H, Halvorsen S, Huger K, Grajek S, Fresco C, Bluhmki E, Regelin A, Vandenberghe K, Bogaerts K, de Werf F. Fibrinolysis or primary PCI in STSegment elevation myocardial infarction. NEJM. 2013; 268(15):1379-1387. 
  7. Wilcox R. Randomized, double-blind comparison of reteplase double-bolus administration with streptokinase in acute myocardial infarction (INJECT): trial to investigate equivalence. Lancet. 1995; 346(8971):329-336.  
  8. Van de Werf F, Cannon CP, Luyten A, Houbracken K, McCabe CH, Berioli S, Bluhmki E, Sarelin H, Wang-Clow F, Fox NL, Braunwald E. Safety assessment of single-bolus administration of TNK tissue-plasminogen activator in acute myocardial infarction: the ASSENT-1 trial. The ASSENT-1 Investigators. Am Heart J. 1999 May;137(5):786-91. doi: 10.1016/s0002-8703(99)70400-x. PMID: 10220625.
  9. Lederer W, Lichtenberger C, Pechlaner C, et al. Recombinant tissue plasminogen activator during cardiopulmonary resuscitation in 108 patients with out-of-hospital cardiac arrest. Resuscitation. 2001;50(1):71—76.
  10. Schreiber W, Gabriel D, Sterz F, et al. Thrombolytic therapy after cardiac arrest and its effect on neurological outcome. Resuscitation. 2002;52(1):63—69.
  11. Lederer W, Lichtenberger C, Pechlaner C, et al. Longterm survival and neurological outcome of patients who received recombinant tissue plasminogen activator during out-of-hospital cardiac arrest. Resuscitation. 2004;61(2):123—129.
  12. Li X, Fu QL, Jing XL, et al. A meta-analysis of cardiopulmonary resuscitation with and without the administration of thrombolytic agents. Resuscitation. 2006;70(1):31—36.
  13. Bottiger BW, Arntz HR, Chamberlain DA, et al. Thrombolysis during resuscitation for out-of-hospital cardiac arrest. NEJM. 2008;359(25):2651—2662.
  14. Kurkciyan I, Meron G, Sterz F, et al. Major bleeding complications after cardiopulmonary resuscitation: impact of thrombolytic treatment. J Intern Med. 2003;253(2):128-135.
  15. Ruiz-Bailén M, Aguayo de, Serrano-Córcoles M, Diáz-Castellanos M, Ramos-Cuadra J, Reina-Toral A. Efficacy of thrombolysis in patients with acute myocardial infarction requiring cardiopulmonary resuscitation. Intensive Care Med. 2001;27(6): 1050-1057.
  16. Richling N, Herkner H, Holzer M, Riedmueller E, Sterz F, Schreiber W. Thrombolytic therapy vs primary percutaneous intervention after ventricular fibrillation cardiac arrest due to acute ST-segment elevation myocardial infarction and its effect on outcome. Am J Emerg Med. 2007 Jun;25(5):545-50. doi: 10.1016/j.ajem.2006.10.014. PMID: 17543659.
  17. Böttiger B, Bode C, Kern S, et al. Efficacy and safety of thrombolytic therapy after initially unsuccessful cardiopulmonary resuscitation: a prospective clinical trial. Lancet. 2001;357(9268):1583-1585.