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alteplase (Activase)

Tradename: Activase. Indications: 1) arterial thrombosis a) post myocardial infarction clot lysis 1] within 4-6 hours of symptom onset 2] ongoing symptoms b) unstable angina - benefit over streptokinase in middle aged men with anterior myocardial infarction c) acute ischemic stroke: within 4.5 hours of onset [7,8,10,12] - recent use of direct-acting oral anticoagulants not associated with increased risk or intracranial hemorrhage among patients with acute ischemic stroke treated with alteplase [20] d) occluded AV cannula [18] 4) venous thrombosis a) deep vein thrombosis & venous thromboembolism - life-threatening pulmonary embolism b) central venous catheter occlusion 6) hemolytic uremic syndrome [18] Contraindications: 1) absolute contraindications a) previous hemorrhagic stroke within 1 year b) known intracranial neoplasm c) active internal bleed d) suspected aortic dissection 2) relative contraindications a) blood pressure > 180/110 b) current anticoagulation therapy (warfarin) c) recent trauma (surgery, head, CPR) d) active peptic ulcer disease 5) NO IM injections 3) prior ischemic stroke & diabetes appear not to be contraindications [13] 4) some patients on warfarin (INR < 1.8) may safely receive r-tPA following ischemic stroke [14] tPA is apparently safe if used in patients with stroke mimetic [11] Pregnancy category: C Safety in lactation: ? Dosage: 1) GUSTO accelerated dose for acute MI: a) 15 mg IV bolus (no bolus [4]), then b) 0.75 mg/kg (max 50 mg) over 30 min, then c) 0.5 mg/kg (max 35 mg) over next 60 min* d) up to 100 mg over 90 min e) concurrent heparin infusion* 2) arterial thrombus a) 100 mg IV over 2 hours, followed by b) IV heparin when aPTT returns to < 2x normal* 3) acute ischemic stroke: a) FIRST rule out hemorrhage b) 0.9 mg/kg IV (max 90 mg) 1] bolus with 10% of dose over 1-2 minutes IV 2] remainder of dose is given over 1 hour c) NO aspirin or heparin with 1st 24 hours after tPA 3) pulmonary emobolus a) 50 mg total dose (max) b) 10 ug bolus followed by 40 mg infusion over 2 hours c) 0.5 mg/kg total dose for patients weighing <50 kg [17] * Intravenous (IV) heparin should be used in conjunction with t-PA for the 1st 48 hours after thrombolysis. Heparin infusion is adjusted to achieve aPTT of 50-70 sec. Pharmacokinetics: 1) thrombolytic & fibrinolytic activity is dose-dependent 2) rapid onset of action 3) metabolized by the liver 4) excreted in the urine 5) distribution phase is approximately 5 minutes 6) 1/2life is approximately 26 mintues Adverse effects: 1) bleeding [7] 2) bruising 3) cerebral bleeding (within 36 hours) [6] a) 0.4-0.7% [4] b) risk increased with unsuccessful recanalization [9] 4) alteplase associated with higher mortality in 1st week after ischemic stroke, but lower mortality thereafter [19] 5) hypotension 6) allergic reactions 7) muscle pain 8) fever 9) reperfusion arrhythmias 10) nausea/vomiting Mechanism of action: 1) relatively fibrin-selective plasminogen activator [4] 2) minimizes systemic lytic states

Related

reteplase (Retevase) tenecteplase (TNKase) thrombolytic therapy

General

recombinant tissue plasminogen activator (TPA, t-PA, rt-PA,)

References

  1. Clinical Diagnosis and Management by Laboratory Methods, 18th ed, J.B. Henry (ed), W.B. Saunders, Philadelphia, PA, 1991 pg 739
  2. Baron M, Norman DG, Campbell ID. Protein modules. Trends Biochem Sci. 1991 Jan;16(1):13-7. Review. PMID: 2053133
  3. Fibrinolysis, Thrombosis, & Hemostasis: Concepts, Perspectives, and Clinical Applications. S Sherry, Lea & Febiger, Philadelphia, 1992, pg 71
  4. Medical Knowledge Self Assessment Program (MKSAP) 11, 15, 16, 17. American College of Physicians, Philadelphia 1998, 2009, 2012, 2015
  5. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  6. Ovbiagele B, In: Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 29-Oct 2, 2004
  7. Brown DL, Barsan WG, Lisabeth LD, Gallery ME, Morgenstern LB. Survey of emergency physicians about recombinant tissue plasminogen activator for acute ischemic stroke. Ann Emerg Med. 2005 Jul;46(1):56-60. PMID: 15988427
  8. National Institute of Neurological Disorders Stroke rt-PA Stroke Study Group. Recombinant tissue plasminogen activator for minor strokes: the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study experience. Ann Emerg Med. 2005 Sep;46(3):243-52. PMID: 16126134
  9. Saqqur M et al. Symptomatic intracerebral hemorrhage and recanalization after IV rt-PA: A multicenter study. Neurology 2008 Oct 21; 71:1304. PMID: 18753474 - Tanne D and Levine SR. Safer thrombolysis for acute ischemic stroke: Is early recanalization the key? Neurology 2008 Oct 21; 71:1300. PMID: 18936422
  10. Prescriber's Letter 16(7): 2009 COMMENTARY: Expanding the Window for Administration of tPA in Ischemic Stroke GUIDELINES: Expansion of the Time Window for Treatment of Acute Ischemic Stroke with Intravenous Tissue Plasminogen Activator (AHA/ASA, 2009) GUIDELINES: Early Management of Adults with Ischemic Stroke (AHA/ASA, 2007) Detail-Document#: 250717 (subscription needed) http://www.prescribersletter.com - del Zoppo GJ et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. Stroke. 2009 May 28. [Epub ahead of print] PMID: 19478221 DOI: 10.1161/STROKEAHA.109.192535. - Hacke W et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-29. PMID: 18815396 - Saver JL et al Number needed to treat to benefit and to harm for intravenous tissue plasminogen activator therapy in the 3 to 4.5 hour window. Joint outcome table analysis of the ECASS 3 trial. Stroke. 2009 Jun 4. [Epub ahead of print] PMID: 19498197 DOI:10.1161/STROKEAHA.108.543561. - Lansberg MG et al Treatment time-specific number needed to treat estimates for tissue plasminogen activator therapy in acute stroke based on shifts over the entire range of the modified Rankin Scale Stroke. 2009 Jun;40(6):2079-84. Epub 2009 Apr 16. Review. PMID: 19372447 - Lansberg MG et al Efficacy and Safety of Tissue Plasminogen Activator 3- to 4.5-Hours After Acute Ischemic Stroke. A Metaanalysis. Stroke. 2009 May 28. [Epub ahead of print] PMID: 19478213
  11. Chernyshev OY et al. Safety of tPA in stroke mimics and neuroimaging-negative cerebral ischemia. Neurology 2010 Apr 27; 74:1340
  12. Lees KR et al. Time to treatment with intravenous alteplase and outcome in stroke: An updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010 May 15; 375:1695. PMID: 20472172 - Saver JL and Levine SR. Alteplase for ischaemic stroke - Much sooner is much better. Lancet 2010 May 15; 375:1667. PMID: 20472152
  13. Mishra NK et al. Thrombolysis outcomes in acute ischemic stroke patients with prior stroke and diabetes mellitus. Neurology 2011 Nov 22; 77:1866 PMID: 22094479
  14. Xian Y et al Risks of Intracranial Hemorrhage Among Patients With Acute Ischemic Stroke Receiving Warfarin and Treated With Intravenous Tissue Plasminogen Activator JAMA. 2012;307(24):2600-2608 PMID: 22735429 http://jama.jamanetwork.com/article.aspx?articleid=1199153 - Alberts MJ Cerebral Hemorrhage, Warfarin, and Intravenous tPA: The Real Risk Is Not Treating JAMA. 2012;307(24):2637-2639 PMID: 22735434 http://jama.jamanetwork.com/article.aspx?articleid=1199130
  15. Department of Veterans Affairs, VA National Formulary
  16. Activase; Note: Clinical information on Activase http://www.gene.com/gene/products/information/cardiovascular/activase/insert.jsp#pharmacology - Retavase; Note: Clinical information on Retavase http://www.retavase.com/pdf/Retavase_PI.pdf
  17. Sharifi M et al. Moderate pulmonary embolism treated with thrombolysis (from the "MOPETT" trial). Am J Cardiol 2013 Jan 15; 111:273. PMID: 23102885
  18. Deprecated Reference
  19. Berge E, Cohen G, Roaldsen MB et al. Effects of alteplase on survival after ischaemic stroke (IST-3): 3 year follow-up of a randomised, controlled, open-label trial. Lancet Neurol 2016 Sep; 15:1028. PMID: 27450474
  20. Kam W, Holmes DN, Hernandez AF et al. Association of recent use of non-vitamin K antagonist oral anticoagulants with intracranial hemorrhage among patients with acute ischemic stroke treated with alteplase. JAMA 2022 Feb 22; 327:760-771. PMID: 35143601 PMCID: PMC8832308 (available on 2022-08-10) https://jamanetwork.com/journals/jama/fullarticle/2789099