Clinical Content
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February 16, 2023

Fibrinolytics for STEMI

J

Jimmy

PharmD


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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

Alteplase Tenecteplase
MOA Initiates 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.
Dose Weight based:
>67kg: infuse 15mg IV bolus over 1–2 min, followed by 50mg infusion over 30 min, then 35mg over 1 hour (max 100mg)
≤67kg: infuse 15mg IV bolus over 1–2 min, followed by 0.75mg/kg infusion over 30 min, then 0.5mg/kg over 1 hour (max 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/PD Duration: 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 Effects Intracranial hemorrhage, ecchymosis, GI/GU hemorrhage, sepsis, cerebrovascular accident. Hemorrhage and hematoma, cerebrovascular accident.
Drug Interactions & Warnings Tranexamic 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 or D5W. Incompatible with dextrose.

Overview of Evidence

Author, Year Design / Sample Size Intervention & Comparison Outcome
Guillermin 2016a Meta-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, tenecteplase Tenecteplase and reteplase associated with accelerated infusion and more convenient bolus administration. Less fibrin-specific agents may cause greater systemic coagulopathy with potential for more bleeding.
Boersma 1996 Retrospective review (n=50,246) Fibrinolytic therapy vs placebo Mortality reduction in patients treated within 2 hours compared to later (p=0.001).
GUSTO 1993 Randomized, controlled trial (n=41,021) Streptokinase + SQ heparin; streptokinase + IV heparin; alteplase + IV heparin; alteplase + streptokinase + IV heparin Alteplase administered over 1.5 hours with IV heparin provided survival benefit over standard therapy. Thrombolytic therapy administered within 24–48 hours of admission.
Armstrong 2013b Randomized controlled trial (n=1,892) PCI vs bolus tenecteplase, clopidogrel, and enoxaparin Tenecteplase prehospital resulted in effective reperfusion when PCI was not completed within 1 hour. Fibrinolytic therapy associated with increased risk of intracranial bleeding.
Cardiac Arrest Data
Bottiger 2001 Prospective cohort (n=40) Alteplase 50mg bolus, repeat 50mg in 30 min vs placebo Increase in ROSC (68% vs 44%) and ICU admission compared to placebo.
Schreiber 2002 Retrospective 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 2004 Retrospective chart review (n=108) Alteplase 100mg (15mg followed by 85mg over 90 min) 81% of patients discharged without neurological deficit. 67% of patients still alive 5–10 years after the event.
Li 2006 Meta-analysis Alteplase 15mg bolus followed by 50mg infusion over 30 min and 35mg over 60 min Thrombolytic therapy improved the rate of ROSC (p<0.01). 48% of patients had acute coronary artery obstruction.
Bottiger 2008 Randomized, double-blind, multicenter trial (n=1,050) Tenecteplase 30mg if <60kg
Tenecteplase 35mg if 60–69kg
Tenecteplase 40mg if 70–79kg
Tenecteplase 45mg if 80–89kg
Tenecteplase 50mg if >90kg
vs placebo 		No difference between tenecteplase and placebo in 30-day survival, ROSC, or neurologic outcomes. Increased intracranial hemorrhages in tenecteplase patients.
RuizBailen 2001 Retrospective cohort (n=303) Streptokinase; alteplase accelerated regimen; alteplase double bolus Systemic thrombolysis patients had lower mortality, less mechanical ventilation, fewer CPR attempts (p<0.0001). No fatal hemorrhagic complications.

a Administered as tenecteplase 30–50mg bolus and alteplase 15mg bolus followed by 0.75mg/kg infusion over 30 min.
b Half-dose tenecteplase administered in patients ≥75 years old.
c Reteplase 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 as 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, et al. Fibrinolysis or primary PCI in ST-segment 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). Lancet. 1995;346(8971):329–336.
  8. Van de Werf F, Cannon CP, Luyten A, et al. Safety assessment of single-bolus administration of TNK tissue-plasminogen activator in acute myocardial infarction: the ASSENT-1 trial. Am Heart J. 1999;137(5):786–791.
  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. Long-term 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 Hoyos E, Serrano-Córcoles M, et al. 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, et al. Thrombolytic therapy vs primary percutaneous intervention after ventricular fibrillation cardiac arrest due to acute ST-segment elevation myocardial infarction. Am J Emerg Med. 2007;25(5):545–550.
  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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