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Pharmacy & Acute Care University
Pharmacy & Acute Care University

Fibrinolytics for STEMI

Jimmy February 16, 2023
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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.
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