Contents

Search

thrombolysis for ischemic stroke

Epidemiology: - underutilized - administered to only 1.12% of ischemic stroke hospitalizations 1999-2004 [5] Indications: 1) ischemic stroke with onset within 3 hours [23] a) the window may be extended to 4.5 hours [30], unless: [6,7] - taking oral anticoagulants (warfarin) - NIH stroke scale score > 25 - history of both stroke & diabetes b) age > 80 years not a limitation for r-tPA within 4.5 hours [32] - increased risk of intracranial hemorrhage & mortality offset by lower disability from tPA when administered 3-6 hours after symptom onset) [14] c) no benefit of alteplase if given > 4.5 hours after stroke [10] d) hypoperfused but salvageable brain regions on perfusion imaging may benefit from alteplase thrombolysis for up to 9 hours [29] 2) neurological deficit measurable deficit on NIH Stroke scale - > minimal weakness, isolated ataxia, isolated sensory loss or isolated dysarthria - benefit for patients with mild stroke (NIH Stroke scale 0-4) 3) may be benficial for sickle cell patients with ischemic stroke [30] Contraindications: 1) historical a) stroke or serious head trauma within the last 6 months b) major surgery or serious trauma within the past 14 days - this may be relative contraindication [16] c) history of intra-cranial hemorrhage, AV malformation or aneurysm d) GI or urinary tract hemorrhage within the previous 21 days e) arterial puncture at a non-compressible site within the previous 7 days f) lumbar puncture within the previous 7 days g) recent myocardial infarction-induced pericarditis - recent myocardial infarction seems not a contraindication [16] h) patient on anticoagulation therapy - direct oral anticoagulant (DOAC) within the past 48 hours [33] - insufficient evidence of excess harm [35] 2) clinical a) rapidly improving neurologic signs b) minor symptoms, mild, nondisabling stroke symptoms [30] c) systolic blood pressure (BP) > 185 mm Hg d) diastolic BP > 110 mm Hg e) mean arterial pressure > 130 mm Hg f) aggressive BP management needed to control BP g) seizure at onset of stroke h) symptoms suggestive of subarachnoid hemorrhage 3) laboratory a) PT > 15 seconds, INR > 1.7 - some patients on warfarin (INR < 1.8) may safely receive r-tPA following ischemic stroke [15] b) elevation of PTT in a patient who has received heparin within 48 hours of stroke onset c) platelet count < 100,000/mm3 d) serum glucose < 50 mg/dL or > 400 mg/dL e) women of child-bearing age with a positive pregnancy test 4) patient & family do not understand potential benefits & risks 5) age > 80 years [8] 6) diabetes mellitus with prior stroke (MKSAP19) [8] - prior ischemic stroke & diabetes appear not to be contraindications [11] Benefit/risk: - of no benefit [24] - 12 trials of which 2 found benefit & 4 found harm [24] * shorter door-to-needle times for administering tissue plasminogen activator (tPA) associated with lower mortality hospital readmissions at 1 year [31] Procedure: Administration: 1) tissue plasminogen activator (tPA) 0.9 mg/kg, max 90 mg 2) administer 10% of tPA as a bolus 3) administer remaining 90% of tPA as an infusion over 1 hour 4) ultrasound applied to lesion may enhance recanalization [3] 5) IV altepase [30] 6) tenecteplase may be reasonable alternative to alteplase if eligible for arterial thrombectomy [30] 7) argatroban of no benefit added to alteplase [36] Precautions: 1) do not give anticoagulants for 24 hours from start of tPA administration 2) do not give antiplatelet agents for 24 hours from start of tPA administration 3) admit to intensive care unit or acute stroke unit 4) maintain systolic BP < 180 mm Hg & diastolic BP < 105 mm Hg 5) delay central venous line placement or arterial puncture for 24 hours 6) delay inserting indwelling bladder (foley) catheter for > 30 minutes after tPA administration 7) delay nasogastric (NG) tube placement for 24 hours Radiology: - head CT scan without contrast a) no evidence of intracranial hemorrhage b) no early signs of major hemispheric infarct 1] edema, mass effect, sulcal effacement 2] if present re-evaluate time of onset 3 presence of these signs may be associated c) no evidence of prior stroke d) thrombolysis may not benefit small CT perfusion deficits [24] - repeat head CT scan without contrast during or after procedure if patient's neurologic condition deteriorates to rule out intracerebral hemorrhage [8] - MRI to select acute stroke patients for thrombolysis - to identify diffusion-positive, FLAIR-negative lesions eligible patients who awakened from sleep with stroke symptoms or otherwise have unclear time of onset [8] - may lead to favorable outcome but could increase risk [27] Complications: - symptomatic intracerebral hemorrhage [23] - 6.4% of treated patients [8] - mortality is ~50% - incidence may be slightly higher in patients > 80 years of age [12] - if tPA-induced intracerebral hemorrhage suspected - stop infusion, evaluate with another head CT [8] - alteplase associated with higher mortality in 1st week after ischemic stroke, but lower mortality thereafter [26] Management: 1) Blood pressure (BP) management: a) monitor BP for 24 hours after starting tPA administration - every 15 min for 2 hours - every 30 min for 6 hours - hourly for remaining 16 hours - blood pressure should be maintained below 180 mm Hg systolic & 105 mm Hg diastolic for at least the 1st 24 hours post thrombolysis [8] b) when an acute rise in blood pressure is observed - consider intracerebral hemorrhage - stop tPA infusion - obtain head CT c) systolic BP 180-230 or diastolic BP 105-120 (rechecked) - labetolol 10 mg IV, over 1-2 min - nicardipine IV is an alternative - monitor every 10 min - repeat 10-20 mg IV every 10-20 min PRN up to 150 mg - avoid hypotension d) systolic BP > 230 mm Hg or diastolic BP 121-140 mm Hg - labetolol 10 mg IV, over 1-2 min q 10 min up to 150 mg - nicardipine IV is an alternative - if response in inadequate, use sodium nitroprusside e) diastolic BP > 140 mm Hg - nitroprusside 0.5-10 ug/kg/min - monitor closely - nitroprusside effective for malignant hypertension, but may increase intracranial pressure [8] - avoid hypotension 2) Post procedure: - CT angiography to determine eligibility for arterial thrombectomy [8] - aspirin or clopidogrel 24 hours after thrombolysis [8] Notes: - tPA is apparently safe if used in patients with stroke mimetic [9] - outcomes generally better in younger patients [15] - outcomes better with earlier thrombolysis [17] - each minute saved between stroke onset & tPA translates to ~ 2 days of disability-free life [20] - number of patients needed to treat = 4.5 when thrombolysis is given within 1.5 hours of stroke onset [22] - number of patients needed to treat = 18 when given 3-4.5 hours after stroke onset [22] - mobile stroke units afford shorter 'time-to-thrombolysis' -impact on outcomes variable, possibly trending toward improved outcomes [21] - improves quality of life & functional capacity up to 18 months after ischemic stroke [18] - benefit for minor stroke unclear [28]

Related

ischemic stroke mobile stroke unit; STroke Emergency MObile (STEMO)

General

thrombolytic therapy

References

  1. Contributions from Thomas Nowak, Dept of Neurosurgery, UCSF Fresno
  2. Saver JL & Starkman S State of the art medical management of acute ischemic stroke. State of the art medical management of acute ischemic stroke. PMID: 17894994
  3. Journal Watch 24(24):183-84, 2004 Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford SR, Alvarez-Sabin J, Montaner J, Saqqur M, Demchuk AM, Moye LA, Hill MD, Wojner AW; CLOTBUST Investigators. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. N Engl J Med. 2004 Nov 18;351(21):2170-8. PMID: 15548777
  4. Wahlgren N, Ahmed N, Davalos A, Ford GA, Grond M, Hacke W, Hennerici MG, Kaste M, Kuelkens S, Larrue V, Lees KR, Roine RO, Soinne L, Toni D, Vanhooren G; SITS-MOST investigators. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet. 2007 Jan 27;369(9558):275-82. PMID: 17258667
  5. Schumacher HC, Bateman BT, Boden-Albala B, Berman MF, Mohr JP, Sacco RL, Pile-Spellman J. Use of thrombolysis in acute ischemic stroke: analysis of the Nationwide Inpatient Sample 1999 to 2004. Ann Emerg Med. 2007 Aug;50(2):99-107. Epub 2007 May 3. PMID: 17478010
  6. Hacke W et al Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke N Engl J Med. 2008 Sep 25;359(13):1317-29. PMID: 18815396
  7. del Zoppo GJ et al Expansion of the Time Window for Treatment of Acute Ischemic Stroke With Intravenous Tissue Plasminogen Activator A Science Advisory From the American Heart Association/American Stroke Association Stroke 2009 Aug; 40:2945. PMID: 19478221 http://stroke.ahajournals.org/cgi/reprint/STROKEAHA.109.192535
  8. Medical Knowledge Self Assessment Program (MKSAP) 14, 15, 16. 17, 18, 19. American College of Physicians, Philadelphia 2006, 2009, 2012, 2015, 2018, 2021 - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  9. Chernyshev OY et al. Safety of tPA in stroke mimics and neuroimaging-negative cerebral ischemia. Neurology 2010 Apr 27; 74:1340
  10. 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
  11. 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
  12. Mishra N, Ahmed N, Andersen G, et al. Thrombolysis in very elderly people: controlled comparison of SITS International Stroke Thrombolysis Registry and Virtual International Stroke Trials Archive. BMJ 2010; 341:c6046 PMID: 21098614
  13. Toni D et al. Intravenous thrombolysis in young stroke patients: Results from the SITS-ISTR. Neurology 2012 Mar 20; 78:880 PMID: 22402853
  14. The IST-3 Collaborative Group. 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 May 23 PMID: 22632908 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60768-5/fulltext - Wardlaw JM et al. Recombinant tissue plasminogen activator for acute ischaemic stroke: An updated systematic review and meta-analysis. Lancet 2012 May 23 PMID: 22632907 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60738-7/fulltext - Leys D and Cordonnier C. rt-PA for ischaemic stroke: What will the next question be? Lancet 2012 May 23 PMID: 22632906 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60822-8/fulltext
  15. 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
  16. Jauch EC et al AHA/ASA Guideline Guidelines for the Early Management of Patients With Acute Ischemic Stroke. A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. Jan 31, 2013 PMID: 23370205 http://stroke.ahajournals.org/content/early/2013/01/31/STR.0b013e318284056a.full
  17. Saver JL et al Time to Treatment With Intravenous Tissue Plasminogen Activator and Outcome From Acute Ischemic Stroke. JAMA. 2013;309(23):2480-2488 http://jama.jamanetwork.com/article.aspx?articleid=1697967
  18. The IST-3 collaborative group Effect of thrombolysis with alteplase within 6 h of acute ischaemic stroke on long-term outcomes (the third International Stroke Trial [IST-3]): 18-month follow-up of a randomised controlled trial. The Lancet Neurology, Early Online Publication, 21 June 2013 PMID: 23791822 http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(13)70130-3/abstract
  19. Wardlaw JM, Murray V, Berge E, Del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD000213 PMID: 19821269
  20. Meretoja A et al Stroke Thrombolysis. Save a Minute, Save a Day. Stroke. March 13, 2014 PMID: 24627114 https://stroke.ahajournals.org/content/early/2014/03/13/STROKEAHA.113.002910.abstract
  21. Ebinger M et al. Effect of the use of ambulance-based thrombolysis on time to thrombolysis in acute ischemic stroke: A randomized clinical trial. JAMA 2014 Apr 23; 311:1622 PMID: 24756512 http://jama.jamanetwork.com/article.aspx?articleid=1861800 - Grotta JC, Yamal JM, Parker SA et al. Prospective, multicenter, controlled trial of mobile stroke units. N Engl J Med 2021 Sep 9; 385:971. PMID: 34496173 https://www.nejm.org/doi/10.1056/NEJMoa2103879 - Ebinger M, Siegerink B, Kunz A et al. Association between dispatch of mobile stroke units and functional outcomes among patients with acute ischemic stroke in Berlin. JAMA 2021 Feb 2; 325:454. PMID: 33821920 PMCID: PMC7856548 Free PMC article. https://jamanetwork.com/journals/jama/fullarticle/2775714
  22. Gumbinger C et al Time to treatment with recombinant tissue plasminogen activator and outcome of stroke in clinical practice: retrospective analysis of hospital quality assurance data with comparison with results from randomised clinical trials. BMJ 2014;348:g3429 PMID: 24879819 http://www.bmj.com/content/348/bmj.g3429
  23. Emberson J et al Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. The Lancet, Early Online Publication, 6 August 2014 PMID: 25106063 http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2814%2960584-5/abstract
  24. Bivard A et al. Too good to treat? Ischemic stroke patients with small computed tomography perfusion lesions may not benefit from thrombolysis. Ann Neurol 2016 Jun 28 PMID: 27352245
  25. The NNT: Thrombolytics for Acute Ischemic Stroke. http://www.thennt.com/nnt/thrombolytics-for-stroke/
  26. 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
  27. Thomalla G, Simonsen CZ, Boutitie F et al. MRI-guided thrombolysis for stroke with unknown time of onset. N Engl J Med 2018 May 16; PMID: 29766770 Free Article https://www.nejm.org/doi/10.1056/NEJMoa1804355 - Jovin TG. MRI-guided intravenous alteplase for stroke - Still stuck in time. N Engl J Med 2018 May 16 PMID: 29766752 Free Article https://www.nejm.org/doi/10.1056/NEJMe1805796
  28. Khatri P, Kleindorfer DO, Devlin T et al. Effect of alteplase vs aspirin on functional outcome for patients with acute ischemic stroke and minor nondisabling neurologic deficits: The PRISMS randomized clinical trial. JAMA 2018 Jul 10; 320:156. PMID: 29998337PMID: 29998337 https://jamanetwork.com/journals/jama/fullarticle/2687354 - Powers WJ. Intravenous alteplase for mild nondisabling acute ischemic stroke: A bridge too far? JAMA 2018 Jul 10; 320:141. PMID: 29998321 https://jamanetwork.com/journals/jama/fullarticle/2687337
  29. 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; 380:1795-1803. May 9 PMID: 31067369 https://www.nejm.org/doi/full/10.1056/NEJMoa1813046 - Marshall RS Image-Guided Intravenous Alteplase for Stroke - Shattering a Time Window. N Engl J Med 2019; 380:1865-1866. May 9 PMID: 31067378 https://www.nejm.org/doi/full/10.1056/NEJMe1904791
  30. 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 Association. Stroke 2019 Dec; 50:e344. PMID: 31662037 https://www.ahajournals.org/doi/10.1161/STR.0000000000000211
  31. Man S, Xian Y, Holmes DN et al Association Between Thrombolytic Door-to-Needle Time and 1-Year Mortality and Readmission in Patients With Acute Ischemic Stroke. JAMA. 2020;323(21):2170-2184 PMID: 32484532 https://jamanetwork.com/journals/jama/fullarticle/2766633 - Muth CC Long-term Outcomes After Thrombolytic Therapy for Acute Ischemic Stroke. JAMA. 2020;323(21):2184-2185 PMID: 32484521 https://jamanetwork.com/journals/jama/fullarticle/2766614
  32. Bluhmki E et al. Alteplase for acute ischemic stroke in patients aged > 80 years: Pooled analyses of individual patient data. Stroke 2020 Aug; 51:2322. PMID: 32611284 Free PMC article https://www.ahajournals.org/doi/10.1161/STROKEAHA.119.028396
  33. Lou N Holding tPA for All DOAC Users Not the Way to Go, Stroke Docs Say. Clinical conundrum could be solved by a point-of-care DOAC test. MedPage Today March 15, 2021 https://www.medpagetoday.com/neurology/strokes/91633 - Seiffge DJ, Wildon D, Wu TYH et al Administering thrombolysis for acute ischemic stroke in patients taking direct oral anticoagulants: to treat or how to treat. JAMA Neurol 2021. March 15 PMID: 33720313 https://jamanetwork.com/journals/jamaneurology/article-abstract/2777622 - Czap AL, Grotta JC Complexities of reperfusion therapy in patients with ischemic stroke pretreated with direct oral anticoagulants: to treat or not, and how? JAMA Neurol 2021 PMID: 33720276 https://jamanetwork.com/journals/jamaneurology/article-abstract/2777623
  34. Jin C, Huang RJ, Peterson E et al. Intravenous tPA (tissue-ype plasminogen activator) in patients with acute ischemic stroke taking non-vitamin K antagonist oral anticoagulants preceding stroke. Stroke. 2018;49:2237-2240 PMID: 30354981 PMCID: PMC6706353 Free PMC article https://www.ahajournals.org/doi/10.1161/STROKEAHA.118.022128
  35. Hughes S Thrombolysis Safe for Stroke Patients on DOACs? Medscape. Jan 6, 2023 https://www.medscape.com/viewarticle/986623 - Meinel TR, Wilson D, Gensicke H et al Intravenous Thrombolysis in Patients With Ischemic Stroke and Recent Ingestion of Direct Oral Anticoagulants. JAMA Neurol. Published online January 3, 2023 PMID: 36807495 PMCID: PMC9857462 Free PMC article https://jamanetwork.com/journals/jamaneurology/fullarticle/2799622
  36. Chen HS, Cui Y, Zhou ZH et al Effect of Argatroban Plus Intravenous Alteplase vs Intravenous Alteplase Alone on Neurologic Function in Patients With Acute Ischemic Stroke. The ARAIS Randomized Clinical Trial. JAMA. Published online February 9, 2023. PMID: 36757755 https://jamanetwork.com/journals/jama/fullarticle/2801517