C.08a-Diagnosis-and-Treatment-of-Acute-Ischemic-Stroke-Presentation-ppt.pptx

Important for medical students

1. DIAGNOSIS AND TREATMENT OF ACUTE ISCHEMIC STROKE

2. Michael R. Dobbs, MD, MHCM Vice Dean for Clinical Affairs and Chief Medical Officer Professor and Chair Department of Neurology UT Health Rio Grande Valley Emeritus Medical Director – Stroke Care Network Bryan J. Eckerle, MD, MSc Inpatient Neurologist Norton Healthcare Original Authors: Contributing Authors: Harold Brown, BSN, RN Nurse Educator, Stroke Care Network Emeritus Stroke RN UKHC CSC Kelley L. Elkins, BSN, RN Quality & Research Associate Former Quality & Education Coordinator SCN Emeritus Stroke Program Coordinator UKHC CSC Lisa Bellamy, BHS, RN, CPHQ Managing Director - Stroke Care Network Emeritus Stroke Program Coordinator UKHC CSC Jessica Lee, MD, FAAN, FANA, FAHA Professor & Vice Chair for Quality Department of Neurology Medical Director, UK Comprehensive Stroke Program University of Kentucky Casey Okong’o, MSN, RN, CNRN, SCRN Nurse Educator, Stroke Care Network

3. disclosures No relevant disclosures

4. objectives Upon completion of this activity, learners will be able to: Explain the diagnosis and treatment of acute ischemic stroke Review treatment time windows for acute ischemic stroke Discuss post-thrombolytic management

5. What is a stroke? It is not an accident, thus neurologists prefer not to use the term “cerebrovascular accident”

6. Transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia without acute infarction 1 TIA is associated with high incidence of subsequent stroke 2-17% followed by stroke 2 25% mortality in one year 2 – clinically diagnosed TIA patients have been found to have infarction on DWI-MRI 3   Transient Ischemic Attack ( TIA ) Definition tissue-based versus time-based 1 2009 DWI-MRI: Distinguishes between TIA and AIS Predicts TIAs at highest risk for AIS 1. Easton, et al 2009; 2. Tsao, et al 2023; 3. Al-Khaled 2014

7. Epidemiology : Stroke in the U.S. Prevalence: 3.3% in U.S. Increases with advancing age in both males and females Over 9.4 million > 20 years of age have had a stroke People with a disability have a higher prevalence of stroke (6.6%) Incidence: ~795,000 new or recurrent strokes each year Projections show by 2030, an additional 3.4 million will have stroke Disability: Stroke is a leading cause of disability in the U.S.  Reduces mobility in more than half of survivors > 65 years old Mortality: Stroke is the 5 th leading cause of death in the U.S.  Every 3 minutes 17 seconds someone dies of stroke (was 3 min and 33 sec) 160,264 Americans each year Cost:  $56.5 billion annually ( 2018/19 direct & indirect ) (increased from $49.8 billion) Tsao et al., 2023

8. Leading Causes of Death in US for 2020

9. TIME IS BRAIN The average stroke patient loses approximately 1.9 million neurons every one minute As many as 14 billion synapses may be lost during every one minute that a stroke goes untreated Meretoja et al., 2014 Saver, 2006 “Save a minute, save a day” TIME FRAME NEURONS LOST AGES THE BRAIN BY Every second 32,000 8.7 hours Every minute 1.9 million 3.1 weeks Every hour 120 million 3.6 years 10 hours 1.2 billion 36 years

10. Points of Origin Inpatient Stroke Alert ED from Outside Hospital ED from Scene

11. Rule-out hemorrhage and/or other non-stroke cause of symptoms … not to diagnose ischemic stroke Why CT first thing? Ischemia: Appears normal while acute Can look dark, but may take 8-72 hours to show up Edema: Will look dark and may have mass effect Hemorrhage: Is bright when acute Becomes the same color as brain tissue when subacute Darkens over time

12. Early Head CT Findings in Ischemic Stroke Head CT often without acute abnormalities i.e., a normal head CT does not exclude acute ischemic stroke May see: Loss of gray-white junction/cortical ribbon Blurring of the basal ganglia or internal capsule Effacement of sulci Hyperdense vessel (thrombus) Massive core infarct (>1/3 hemisphere) may show up in the hyper-acute phase

13. Early Parenchymal Changes:

14. Two Days After Admission:

15. Intracerebral Hematoma:

16. Initial ED Assessment of suspected Stroke

17. Misdiagnosis and Atypical Signs & Symptoms Posterior Circulation Stroke: 20-25% of strokes In a 2016 study of missed ischemic stroke diagnoses in the ED, posterior circulation strokes were 3x more likely to be missed than strokes in the anterior circulation 2 5 D’s of Posterior Circulation Stroke Dizziness Diplopia Dysarthria Dysphagia Dystaxia Also consider: headache and nausea and vomiting 2 Brain Stem Stroke: Included in the category of posterior circulation, but unique because they can demonstrate “crossed signs” Arch et al., 2016 Powers et al., 2019

18. Vertigo: Brain stem stroke? H ead I mpulse, N ystagmus, and T est of S kew HiNTs exam: “ HiNTs to INFARCT” With hours or days of vertigo Differentiates Acute Vestibular Syndrome (AVS) versus brainstem stroke 3 part exam: Head impulse Nystagmus Test of Skew Kattah et al., 2009 More sensitive (100%) than early MRI in AVS 96% specific for stroke

19. HiNTs : H ow to Perform Head Impulse Test -Have patient fix their eyes on your nose -Move their head in horizontal plane left and right -Look for catch up saccade When head is turned towards normal side, vestibular ocular reflex remains intact and eyes continue to fixate on visual target When head is turned towards affected side, vestibular ocular reflex fails and eyes make a corrective saccade to re-fixate on visual target Nystagmus -Observe for nystagmus in primary, right, and left gaze Test of Skew -Have patient look at your nose with their eyes and cover one eye -Rapidly uncover the eye and watch to see if the eye moves to re-align -Repeat for both eyes

20. HiNTs : Interpretation Reassuring Findings ( not stroke ) ALL of below: Worrisome Findings ANY of below : Head impulse Test Abnormal – due to dysfunction of the peripheral nerve Nystagmus None or horizontal , unilateral only Test of Skew Normal Head impulse Test Normal, with continuous, ongoing vertigo and spontaneous nystagmus Nystagmus Bidirectional or any vertical component Test of Skew abnormal – dysconjugate gaze is a sign of a central lesion

21. STROKE MIMICS Metabolic disorders Hypo and Hyperglycemia Migraine Seizures: Todd’s Paralysis Bell’s Palsy Syncope Transient global amnesia Peripheral nerve disorders Intracranial masses Hypertensive Crisis Psychogenic presentations Can you think of another common mimic? Urinary Tract Infection (UTI) Arch et al., 2016 Powers et al., 2019

22. If NIHSS > 6 consider pre-notification of EMS for inter-facility transport to TSC or CSC Best Practice = Door to CT Can anonymize registration of patient RN can quickly assess ABCs and assess glucose Assessment can begin while CT being interpreted Obtain actual weight ASAP <24 hours from LKW

23. Powers et al., 2019 DNV: D2AST < 15 m DNV: D2 connected contact < 20 m ED STROKE ALERT : TURNAROUND TIME GOALS * DNV ASR D2N Goals: ≤ 60 min. ≥ 75% ≤ 45 min. ≥ 50% DNV GL Healthcare USA, Inc., 2023 (ASR)

24. Common reasons for delay It is important to analyze delays in treatment in order to consider potential opportunities for improvement

25. GOAL: DOOR TO NEEDLE “Establishing and monitoring target time goals for ED door-to-treatment IV fibrinolysis time can be beneficial to monitor and enhance system performance” ([e9] COR I; LOE B-NR) Each 15-minute interval decrease in D2N is associated with a 5% decrease in the odds of in-hospital mortality Door-to-needle goals: < 60 minutes 85% < 45 minutes 75% < 30 minutes 50% Powers et al., 2019

26. Intravenous Thrombolysis Activase ® (alteplase) A R ecombinant T issue P lasminogen A ctivator ( rt -PA ) IV alteplase is the only medical therapy which is FDA-approved for treatment of ischemic stroke at this time FDA approved within 3 hours of last known well for selected patients ([e19] COR I; LOE A) Evidence-based practice includes 3 – 4.5 hour window for selected patients ([e20] COR I; LOE B-R) Cleared primarily by the liver with an initial pharmacological half-life of fewer than 5 minutes and a terminal half-life of 72 minutes Powers et. al., 2018 Only ~5% of stroke patients receive alteplase Mostly due to time delays Powers et. al., 2019

27. Ninds trial (1995) Neurologically normal at 3 months 55% relative increase 12% absolute increase Very robust effect: NNT = 8 Symptomatic ICH was 6.4% in the original trial Update: Actual clinical practice: 3.3% 7 BENEFITS Marler, et at., 2000 Risk of ICH increases with protocol violations: Alteplase protocol violations, poor blood pressure and sugar control, using prohibited agents, wrong dose Marler , et at., 2000 Gladstone & Black, 2001 RISKS

28. Effects of ALTEPLASE: Over Time 60 70 80 90 100 110 120 130 140 150 160 170 180 8 7 6 5 4 3 2 1 Benefit for Thrombolytic No benefit for Thrombolytic Minutes from stroke onset to start of treatment Odds ratio for favorable outcome at 3 months μ Marler , et at., 2000

29. IV Alteplase: Dose As a high-risk medication, your organization may benefit from a process for Dual Signature with administration Alteplase dose for stroke is 0.9 mg/kg (Maximum total dose of 90 mg) Use actual body weight All excess alteplase ( above calculated dose ) needs to be removed from vial prior to bolus and infusion Document waste 10% of the total calculated dose is initial IV bolus over 1 minute Drip the remainder of the alteplase over 60 minutes No medication should be added to alteplase Piggyback: IV normal saline Infused at the same rate To clear the line and infuse entire calculated dose of alteplase ( including the volume left in the IV tubing ) Powers et al., 2019

30. Intravenous Thrombolysis TNKase® (tenecteplase) A tissue plasminogen activator A genetically modified variant of alteplase Greater fibrin specificity “It may be reasonable to choose tenecteplase ( single IV bolus of 0.25-mg/kg, maximum 25 mg) over IV alteplase in patients without contraindications for IV fibrinolysis who are also eligible to undergo mechanical thrombectomy.” (Powers, 2019 [ e28] COR IIb; LOE BR) “Tenecteplase administered as a 0.4-mg/kg single IV bolus has not been proven to be superior or noninferior to alteplase but might be considered as an alternative to alteplase in patients with minor neurological impairment and no major intracranial occlusion.” (Powers, 2019 [ e28] COR Iib; LOE BR) “The current body of clinical trial evidence and American Heart Association/American Stroke Association Guidelines support the potential of tenecteplase as an option for stroke thrombolysis within 4.5 hours from time last known well. ” ( Warach , 2020) “Current clinical practice guidelines for stroke include intravenous tenecteplase at either dose as a second-tier option.” ( Warach , 2020) Powers et. al., 2018 Not yet FDA approved for Ischemic Stroke Quicker administration Longer half-life Powers et. al., 2019 Warach et al., 2020

31. A cT TRIAL Intravenous Alteplase Compared to Tenecteplase in Acute Ischemic Stroke ( AcT ) (Phase 3) Menon et al., 2022

32. IV Tenecteplase: Dose Tenecteplase dose for stroke is 0.25mg/kg (actual body weight) MAXIMUM DOSE of 25 mg Total concentration per vial is 5mg/mL IV push over five seconds Not compatible with any dextrose containing solutions Flush IV with normal saline before and after tenecteplase administration You will never administer a full vial to treat stroke The stroke dosage is not listed on the box As a high-risk medication, your organization may benefit from a process for Dual Signature with administration Refer to hospital specific: Tenecteplase Stroke Dosing table

33. Inclusion criteria Contraindications Warnings considered Both time windows Call for consultation Risks, benefits & alternatives Verbal consent If no written consent required by your organization LVO considered Plan for transfer Consultation Documentation Tool

34. IV THROMBOLYTIC: Consent Considerations IV thrombolytic in suspected stroke patients is considered emergent treatment. A separate consent is NOT required, unless required by your organization. IF your organization requires a consent, it can’t delay treatment Required documentation includes that “risks, benefits and alternatives” were explained and written or verbal consent obtained (when possible) (e19) Powers et al., 2019

35. IV THROMBOLYTIC : Eligibility CRITERIA Clinical diagnosis of ischemic stroke causing measurable neurological deficit Mild with disabling deficits through severe Rapidly improving Computed tomography (CT) rules out hemorrhage or non-stroke cause of deficit 18 years old or older Time to treatment < 3 hours of confirmed time Last Known Well, or 4.5 hours with additional warning Powers et. al., 2019

36. IV THROMBOLYTIC : Eligibility considerations Single deficit : lasting impact 1 Early improvement is a risk factor for subsequent deterioration 3 AHA/ASA recommends taking disabling deficits and potential for disability into account when assessing stroke severity 3 Many with low National Institute of Health Stroke Scale (NIHSS) or with initial improvement can still have significant disability 2 The NIHSS should not be used alone to rule-out stroke 4 1. Proctor, 2016 2. Khatri et al., 2012 3. Powers et al., 2019 4. Martin- Schild et al., 2011

37. IV Thrombolytic : CONTRAINDICATIONS Unclear onset Sustained/uncontrolled BP > 185/110 mmHg Current intracranial hemorrhage Suspicion of subarachnoid hemorrhage Intra-axial intracranial neoplasm History of intracranial/intraspinal surgery within 3 months Severe head trauma within 3 months Gastrointestinal: malignancy or active internal bleeding within 21 days Bleeding diathesis Platelets < 100,000/mm 3 International Normalized Ratio (INR) > 1.7 Activated partial thromboplastin time > 40 seconds Treatment dose of low molecular weight heparin within 24 hours (not prophylactic dose) Direct thrombin inhibitors or direct factor Xa inhibitors ( unless not taken within 48 hours or absence of therapeutic effect on appropriate screening tests ) Infective endocarditis Aortic Arch dissection Prothrombin time > 15 seconds Warfarin use with INR > 1.7 Powers et al., 2019

38. IV thrombolytic: Warnings Recent intracranial hemorrhage Ischemic stroke within 3 months Extensive regions of clear hypo-attenuation on initial CT Un-ruptured/unsecured AVM >10 mm un-ruptured/unsecured aneurysm Major surgery within 14 days Major trauma within 14 days Arterial puncture of non-compressible vessel within 7 days Recent gastrointestinal or genitourinary hemorrhage Malignancy with life expectancy less than 6 months History bleeding diathesis Hemorrhagic ophthalmic condition Acute pericarditis Left sided heart thrombus History of myocardial infarction involving left anterior myocardium within 3 months Pregnancy/postpartum < 14 days Recent/active vaginal bleeding causing clinically significant anemia Sustained blood glucose levels <50 and > 400 mg/ dL > ten cerebral microbleeds by previous imaging Call for Expert Consultation Powers et al., 2019

39. IV thrombolytic: 3 - 4.5 hour Window 3-hour window contraindications and warnings continue to apply … Stroke symptoms ( NIHSS greater than 25) is uncertain Powers et al., 2019

40. IV Thrombolytic: BP Management Before giving IV thrombolytic, the recommendation is to safely lower blood pressure ( < 185/110 mm Hg) with antihypertensive agents. Assessing the stability of the blood pressure before starting IV thrombolytic After increase BP measurements if SBP > 180 or DBP > 105, administer antihypertensive medications to maintain BP at or below these levels for a least the first 24 hours. Other agents ( eg , Hydralazine, Enalaprilat) may also be considered Powers et al., 2019

41. Labs Blood glucose is the only lab value that must be checked on every patient prior to the initiation of IV thrombolytic. Given the extremely low risk of unsuspected abnormal platelet counts or coagulation studies in a population, it may be reasonable not to delay the start of IV thrombolytic due to labs pending with no reason(s) to suspect an abnormal result. If patient known to be on warfarin, need PT/INR measurement with INR <1.7 to be eligible for thrombolytics Other potential labs ( not needed for treatment decision – do NOT delay ): CBC with diff. BMP or CMP Troponin Type & Scree n Powers et al., 2019

42. D irect o ral a nti c oagulants ( doac s ) apixaban (Eliquis) betrixaban ( Bevyxxa ) dabigatran (Pradaxa) Consensus Statement Last dose within 48 hours = Contraindication to IV thrombolytic Or presence of therapeutic effect on appropriate screening tests = contraindication to IV thrombolytic If reason to suspect abnormal platelet counts or coagulation studies aPTT for heparin; PT/INR for warfarin; Anti-factor Xa for LMWH; Direct thrombin assay for dabigatran and direct factor Xa assays for rivaroxaban, edoxaban , & apixaban edoxaban ( Savaysa ) rivaroxaban (Xarelto) Powers et al., 2019

43. During and 24 hours After IV T hrombolytic The following should be avoided : BP Elevations > SBP 180 and DBP 105 Antithrombotics Invasive procedures, invasive lines, catheters or tubes (unless deemed medically necessary) ([e27] Table 9) Powers et al., 2019

44. During and 24 hours After IV Thrombolytic The following may be avoided : Mobilization Safety may be maximized when on bedrest precautions initially however early mobilization is also beneficial High-dose mobilization within 24 hours may result in a poor outcome at 3 months ([e43] COR III; LOE B-R) Work with the physician and therapist to determine patient-specific safety measures Keep NPO until IV Thrombolytic is complete & no side effects are observed, and until dysphagia screen or evaluation passed Powers et al., 2019

45. COMPLICATIONS Hemorrhage: Monitoring during and after IV thrombolytic for bleeding Intracranial bleeding Internal bleeding Superficial bleeding Management of hemorrhage: Reversal agents Hospital protocols Orolingual Angioedema: Angioedema is a rare (1-2%), but potentially serious complication Especially experienced by those on ACE inhibitors Can be asymmetric and can occur contralateral to the ischemia Powers et al., 2019

46. GENERAL considerations Powers et al., 2019

47. General considerations Powers et al., 2019

48. ISCHEMIC STROKE: BP Greater than 220/120 mm Hg Antihypertensive treatment in the first 48-72 hours is uncertain Might be reasonable to lower BP in a well-controlled manner Lower by 15% during the first 24 hours following the stroke ([e38] COR IIb ; LOE C-EO) Dropping too quickly or too much can cause a loss of cerebral perfusion pressure IF > 220/120 and no thrombolytic or EVT and no comorbid condition requiring tighter control Powers et al., 2019

49. ISCHEMIC STROKE: BP Less than 220/120 mm Hg Antihypertensive treatment in the first 48-72 hours is not effective to prevent death or dependency ([e38] COR III; LOE A) Elevated blood pressure can improve cerebral perfusion pressure IF < 220/120 and no thrombolytic or EVT and no comorbid condition requiring tighter control Constant relationship between MAP & CPP MAP - ICP=CPP To Calculate MAP: [(DBP x 2) + SBP] ÷ 3 Goal is CPP > 60 Powers et al., 2019

50. BP Management: Lower Limits “The BP level that should be maintained in patients with AIS to ensure the best outcome is not known.” Some observational studies show an association between worse outcomes and lower BPs, whereas others do not.” 14 Will likely depend on stroke subtype and other patient comorbidities “Arterial hypotension on admission in acute ischemic stroke patients has been associated with poor outcomes in multiple studies.” The exact definitions of arterial hypotension needs to be individualized Extreme arterial hypotension is clearly detrimental Decreases perfusion to multiple organs, especially the ischemic brain Ischemic brain vulnerable due to impaired cerebral autoregulation Hypotension and hypovolemia should be corrected to maintain systemic perfusion levels necessary to support organ function. 14 ([e38] COR I; LOE C-EO) Powers et al., 2019

51. Thrombolytic Given … Now What?

52. LVO Designation Stroke process due to occlusion of large vessel Analogy STEMI = ST Elevation Myocardial Infarction LVO = L arge V essel O cclusion 30 – 50% of ischemic strokes Endovascular Therapies (EVT) *** Mechanical Endovascular Retrieval (MER ) *** Fraser, 2015

53. What Constitutes Large Vessel? !  

54. E ndo v ascular t herapies ( EVT ) Mechanical thrombectomy is reasonable in selected patients up to 24 hours of last known well ([e30] COR IIa ; LOE B-R) Patients (if eligible) should receive IV thrombolytic even if endovascular therapies are being considered. MR-CLEAN EXTEND-IA SWIFT PRIME ESCAPE ANGEL - ASPECT SELECT2 DAWN (NNT=2) DEFUSE 3 (NNT=3) CLINICAL TRIALS: Powers et al., 2019 Clot Retrieval Devices

55. CASE SCENARIO 68 year old female with history of peripheral vascular disease, hypertension, and atrial fibrillation While watching TV with husband, patient began having a left facial droop and left sided weakness. Her husband noticed this and called 911. Patient presented to ER with left-sided weakness, left facial droop, and no movement of left upper extremity. Neurologic exam also revealed right gaze deviation; the patient could not move her eyes past midline. Admission NIHSS = 13 A non-contrast CT of the brain was obtained on arrival at the ER and it identified a dense right middle cerebral artery sign, without significant loss of gray-matter differentiation an indication that this patient was an interventional candidate. She was not a candidate for IV Thrombolytic because she was on Coumadin with INR>1.7 Angiography revealed a complete occlusion of the right M1 middle cerebral artery and the distal branches.

56. OUTCOME: Immediately after the procedure, the patient was identified to have increased movement of the left lower and upper extremities Patient did not qualify for acute rehab and is home doing well with outpatient therapy

57. Transfer considerations These patients might benefit from a higher level of care: What is a high NIHSS? > 6 = Large Vessel Occlusion (LVO) > 10 for non LVO High NIHSS giving IV thrombolytic High NIHSS within 24 hours (interventional candidate) High NIHSS with Multiple Chronic Conditions (MCC) Symptomatic brain edema Moderate to large ICH Any spontaneous SAH Ischemic symptoms that worsen when BP drops Posterior circulation ischemia or hemorrhage Crescendo or shuttering TIA

58. CONCLUSIONS Stroke remains the 5 th leading cause of death in the U.S. Patients with stroke and TIA are at increased risk for future stroke as well as MI and death IV thrombolytic is safe and effective for ischemic stroke treatment in selected patient up to 4.5 hours Endovascular therapy is recommended up to 24 hours of last known well EVT beyond 24 hours may be considered in select cases An experienced Stroke Neurologist is a phone call away

59. Web-based physician education We know how demanding a physician schedule is and how difficult it can be to attend live training sessions. These web-based learning modules were created to provide an alternative to in-person training. Each module is fully accredited and can be done online at a time convenient for you. C.08b) Physician Enduring Webinar Presentation Flyer The Stroke Care Network is pleased to offer fully accredited web-based physician education .

60. REFERENCES Al-Khaled M. Magnetic resonance imaging in patients with transient ischemic attack. Neural Regen Res. 2014 Feb 1;9(3):234-5. doi : 10.4103/1673-5374.128211. PMID: 25206806; PMCID: PMC4146153 Arch, A. E., Weisman, D. C., Coca, S., Nystrom, K. V., Wira , C. R., & Schindler, J. L. (2016). Missed ischemic stroke diagnosis in the emergency department by emergency medicine and neurology services. Stroke, 27(3), 668-673. https://doi.org/10.1161/STROKEAHA.115.010613 Berkhemer , O. A., Fransen , P. S., Beumer , D., van den Berg, L. A., Lingsma , H. F., Yoo , A. J., … Dippel , D. W. (2015). A randomized trial of intraarterial treatment for acute ischemic stroke. New England Journal of Medicine, 372(1), 11-20. doi : 10.1056/NEJMoa1411587 Centers for Disease Control and Prevention, Division for Heart Disease and Stroke Prevention. (2017a). Stroke fact sheet . Retrieved from https://www.cdc.gov/dhdsp/maps/national_maps/stroke_all.htm DNV GL Healthcare USA, Inc (January 2023). Acute Stroke Ready Certification Requirements (ASR) Revision 23-0 Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, … Sacco RL. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. Stroke . 2009;40:2276–2293 Fraser, J. (Director) (2015, July 24). Opening the Floodgates: Update on ground-breaking changes in management of acute stroke. Network Summit. Lecture conducted from Stroke Care Network, Lexington, KY

61. Gadhia , J., Starkman , S., Ovbiagele , B., Ali, L., Liebeskind , D., & Saver, J. (2010). Assessment of figures to visually convey benefit and risk of stroke thrombolysis. Stroke, 41(2), 300-306. https://doi.org/10.1161/STROKEAHA.109.566935 Gladstone, D. J., & Black, S. E. (2001). Update on intravenous tissue plasminogen activator for acute stroke: from clinical trials to clinical practice. CMAJ, 165(3), 311-317. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC81334/ Kattah , J. C., Talkad , A. V., Wang, D. Z., Hsieh, Y., & Newman- Toker , D. E. (2009). HINTS to diagnose stroke in the acute vestibular syndrome: Three-step bedside oculomotor examination more sensitive that early MRI diffusion-weighted imaging. Stroke, 40(1). https://doi.org/10.1161/STROKEAHA.109.551234 Khatri, P., Conaway, M. R., & Johnston, K. C. (2012). Ninety-day outcome rates of a prospective cohort of consecutive patients with mild ischemic stroke. Stroke, 43(2), 560-562. https://doi.org/10.1161/STROKEAHA.110.593897 Martin- Schild , S., Albright, K. C., Tanksley , J., Pandav , V., Jones, E. B., Grotta , J. C. & Savitz , S. I. (2011). Zero on the NIHSS does not equal the absence of stroke. Annals of Emergency Medicine, 57(1). 42-45. http://www.annemergmed.com/article/S0196-0644(10)01197-2/pdf Meretoja , A., Keshtkaran , M., Saver, J. L., Tatlisumak , T., Parsons, M. W., Kaste , M., … Churilov , L. (2014). Stroke Thrombolysis: Save a minute, save a day. Stroke, 49 (3). https://doi.org/10.1161/STROKEAHA.113.002910 Menon B, Buck B, Singh N, et al. Intravenous tenecteplase compared with alteplase for acute ischaemic stroke in Canada ( AcT ): a pragmatic, multicentre , open-label, registry-linked, randomised , controlled, non-inferiority trial. Lancet 2022;400:161-169. https://www.ncbi.nlm.nih.gov/pubmed/35779553 Powers, W. J., Rabinstein , A. A., Ackerson, T., Adeoye , O. M., Bambakidis , N. C., Becker, K., … Tirschwell , D. L. (2019). 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, 50(12). doi : 10.1161/str.0000000000000211 REFERENCES

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63. Alteplase for Cerebral Ischemia within 3 Hours of Onset - Changes in Outcome Due to Treatment Gadhia et al., 2010 ALTEPLASE: OUTCOMES APPENDIX A Use with patient education

64. ALTEPLASE: Preparation Appendix B 2 IV access sites: Alteplase Fluids and/or medication Alteplase Kit: Alteplase Vial Vial of Sterile Water (USP) Transfer device Other Items Needed: Alcohol swabs 2 Syringes Bolus Waste alteplase Large bore needles Handwashing Gloves

65. ALTEPLASE: RECONSTITUTION Appendix c All medication above the calculated dose should be discarded *Document waste* Activase will remain stable at room temperature for up to 8 hours Keep vial upright ~2 minutes Slight foaming is normal Print slide & post in ED Clouds over water and then flip your world Genentech (2015)

66. Management: s ich appendix d Class IIb , LOE C-EO Stop alteplase infusion CBC, PT (INR), aPTT, fibrinogen level, and type and cross-match Emergent nonenhanced head CT Cryoprecipitate (includes factor VIII): 10 U infused over 10–30 min (onset in 1 h, peaks in 12 h); administer additional dose for fibrinogen level of <150 mg/dL Tranexamic acid 1000 mg IV infused over 10 min OR ε- aminocaproic acid 4–5 g over 1 h, followed by 1 g IV until bleeding is controlled (peak onset in 3 h) Hematology and neurosurgery consultations Supportive therapy, including BP management, ICP, CPP, MAP, temperature, and glucose control Table 6. Management of Symptomatic Intracranial Bleeding Occurring Within 24 Hours After Administration of IV alteplase for Treatment of AIS Powers et. al., 2019

67. 17. Yaghi et al., 2017 Reversal agents: sich appendix e

68. Orolingual Angioedema APPENDIX F Class IIb , LOE C-EO Maintain airway Endotracheal intubation may not be necessary if edema is limited to anterior tongue and lips. Edema involving larynx, palate, floor of mouth, or oropharynx with rapid progression (within 30 min) poses higher risk of requiring intubation. Awake fiberoptic intubation is optimal. Nasal-tracheal intubation may be required but poses risk of epistaxis post-IV alteplase. Cricothyroidotomy is rarely needed and also problematic after IV alteplase. Discontinue IV alteplase infusion and hold ACE Inhibitors Administer IV methylprednisolone 125 mg Administer IV diphenhydramine 50 mg Administer ranitidine 50 mg IV or famotidine 20 mg IV If there is further increase in angioedema, administer epinephrine (0.1%) 0.3 mL subcutaneously or by nebulizer 0.5 mL Icatibant , a selective bradykinin B2 receptor antagonist, 3 mL (30 mg) subcutaneously in abdominal area; additional injection of 30 mg may be administered at intervals of 6 h not to exceed total of 3 injections in 24 h; and plasma-derived C1 esterase inhibitor (20 IU/kg) has been successfully used in hereditary angioedema and ACEI-related angioedema Supportive care Table 7. Management of Orolingual Angioedema Associated With IV alteplase Administration for AIS Powers et. al., 2019

69. MER Clinical trials appendix g

70. The basis of new Guidelines: DAWN appendix g Randomized 1:1 ratio to thrombectomy plus standard medical therapy vs. medical therapy alone Internal carotid artery or middle cerebral artery occlusion (LVO) 6 to 24 hours from onset Defined mismatch between infarct volume and clinical syndrome CTA or MRA and CT or MR perfusion Demonstrated good outcome at 90 days mRS of 0-2 in thrombectomy group 49% vs. 13% in medical therapy arm Recanalization at 24 hours 77% in thrombectomy group vs. 36% in medical therapy group NNT= 2

71. The basis of new Guidelines: DEFUSE-3 appendix g 1:1 randomization Internal carotid artery or middle cerebral artery occlusion (LVO) 6 to 16 hours from onset Defined mismatch between infarct volume and clinical syndrome CTA or MRA and CT or MR perfusion Benefit in functional outcome at 90 days in the treated group mRS score 0–2, 44.6% versus 16.7%; RR, 2.67 NNT= 3

72. Tenecteplase appendix H Authors Population Severity of Stoke Intervention Result Conclusion Campbell BCV, et al. N Engl J Med. (2018) Non-inferiority; 101 patients in each group; 12 centers in Australia, 1 in New Zealand Median NIHSS: 17; Range 12-42 1:1 Alteplase 0.9mg/kg (Max 90 mg) vs. Tenecteplase 0.25 mg/kg Efficacy: Primary outcome of reperfusion >50% of involved ischemic territory occurred in 22% of the patients in Tenecteplase group vs 10% treated with Alteplase (incidence difference, 12%; (95% CI, 2 to 21); incidence ratio, 2.2 (95% CI, 1.1 to 4.4); P=0.002 for noninferiority; P=0.03 for superiority). Tenecteplase resulted in a better 90-day functional outcome than alteplase (median mRS : 2 vs. 3; OR: 1.7 (95% CI, 1.0 to 2.8; P=0.04). Safety: Symptomatic ICH occurred in 1% of the patients in each group Tenecteplase was non-inferior to alteplase in restoring perfusion in territory of proximal cerebral artery occlusion, had better functional outcomes, with no difference in incidence of hemorrhage and had faster deliver. Campbell BC, et al. Int J Stroke. (2020) Non-inferiority; Tenecteplase: n=100; Alteplase: n=104; 11 hospitals in Norway. NIHSS (Tenecteplase vs. Alteplase) Mean: 13.4 vs. 13.2 Median: 11.5(8–17) vs. 11 (8–17.5) Moderate (6–14): 64 (64) vs. 66 (63.5) Severe (≥15): 35 (35) vs. 38 (36.5) 1:1 Tenecteplase 0·4 mg/kg IV bolus (Max 40 mg) vs. Alteplase (0.9 mg/kg IV (Max 90 mg)   Efficacy: Primary outcome of mRS score 0–1 at 3 months occurred in 32% of patients in Tenecteplase vs. 51% of patients in Alteplase (Unadjusted OR 0.45 [95% CI 0.25–0.80]; p=0.0064). Major neurological improvement at 24 h occurred in 53 (58%) patients in the Tenecteplase group vs. 73 (74%) patients in the alteplase group (unadjusted OR 0.48 [95% CI 0.26–0.88]; p=0.018). Safety: ICH occurred in 21% of patients in Tenecteplase vs 7% in alteplase (unadjusted OR 3.68 [95% CI 1.49–9.11]; p=0.003). Tenecteplase is non-inferior at a dose of 0·4 mg/kg to a standard dose of alteplase in moderate or severe ischemic stroke. Menon BK, et al. Lancet. (2022) Phase 3 noninferiority; Tenecteplase: n=806; Alteplase: n=771; 22 sites in Canada Distribution of NIHSS: Mild (<8): 614 (39.4%) Moderate (8-15): 500 (32%) Severe (>15):446 (28.6%) 1:1 Alteplase 0.9mg/kg (Max 90 mg) vs. Tenecteplase 0.25 mg/kg body weight Efficacy: Primary outcome of 90–120-day mRS (0-1) occurred in 296 (36.9%) patients for Tenecteplase vs 266 (34.8%) for Alteplase (Risk difference: 2.1% (95% CI: -2.6 to 6.9).   Safety: No difference in death at 90 days, 24-hour symptomatic ICH, or SAH. Tenecteplase is comparable to alteplase in patients presenting with AIS with similar impact on function, quality of life and safety outcomes. Roaldsen MB, et al. Lancet Neurol. (2023) RCT; Tenecteplase: n=288; Control: n=290; 77 hospitals in 10 countries (Denmark, Estonia, Finland, Latvia, Lithuania, New Zealand, Norway, Sweden, Switzerland, and the UK). NIHSS Tenecteplase vs. Control Mild (0–7): 171 (59%) vs. 176 (61%) Moderate (8–14): 80 (28%) vs. 77 (27%) Severe (≥15): 37 (13%) vs. 37 (13%) 1:1 IV Tenecteplase 0.25 mg/kg (Max 25 mg) vs. control (no thrombolysis) Efficacy: Primary outcome of better functional outcome, according to mRS score at 90 days in which Tenecteplase was not associated with better outcomes (adjusted OR 1·18, 95% CI 0·88–1·58; p=0·27). Safety: Mortality at 90 days did not significantly differ between treatment groups within 90 days with 28 [10%] patients in the Tenecteplase group and 23 [8%] in the control group (adjusted HR 1.29, 95% CI 0.74–2.26). Any ICH occurred in 33 (11%) of patients receiving Tenecteplase versus 30 (10%) patients in the control group (adjusted OR 1.14, 0.67–1.94). Treatment with Tenecteplase was not associated with better functional outcome in patients with wake-up stroke at 90 days. Li S, Pan Y, et al. Stroke Vasc Neurol. (2022) Phase 2 randomized active comparator; Tenecteplase: 0.1 mg/kg (N=60); 0.25 mg/kg (N=57); 0.32 mg/kg (N=60); Alteplase: 0.9 mg/kg (N=59); 22 stroke units in China NIHSS Median (IQR):   Tenecteplase (0.1, 0.25, 0.32): 7.0 (5.0–10.0); 8.0 (5.0–12.0); 7.5 (6.0–12.0)   Alteplase: 8.0 (5.0–12.0) 1:1:1:1 Tenecteplase 0.1, 0.25, 0.32 mg/kg (Max of 40 mg) vs. Alteplase 0.9 mg/kg (Max of 90 mg) Efficacy: The primary efficacy outcome of improvement on NIHSS at 14 days in the 0.1 mg/kg, 0.25 mg/kg and 0.32 mg/kg of Tenecteplase group and the alteplase group was 63.3%, 77.2%, 66.7% and 62.7%. No significant differences in secondary outcomes.   Safety: No significant difference was found in all safety outcomes of symptomatic ICH, Death, Asymptomatic ICH, other extracranial bleeding, or serious adverse event. The results showed that intravenous Tenecteplase given within 3 hours of symptom onset, is a well-tolerated option in patients with AIS in China.

73. Tenecteplase appendix H Authors Population Severity of Stoke Intervention Result Conclusion Wang Y, et al. Lancet. (2023) Phase 3 non-inferiority trial; 1430 participants; Tenecteplase (n=716); Alteplase (n=714); 53 centers in China NIHSS Tenecteplase vs. Alteplase Median: 7 (5–10) vs. 7 (6–10) ≤7: 419 (59%) vs. 387 (55%) 8–14: 228 (32%) vs. 261 (37%) ≥15: 63 (9%) vs. 59 (8%) 1:1 Tenecteplase IV 0.25 mg/kg (max 25 mg) vs. Alteplase IV 0.9 mg/kg (max 90 mg) Efficacy: Primary efficacy outcome of participants with an excellent functional outcome, defined as an mRS score of 0–1 at 90 days occurred in 439/705 (62%) in Tenecteplase group vs. 405/696 (58%) in alteplase group (OR 1.19 (0.96 to 1.47). Safety: Symptomatic ICH within 36 h occurred in 15 (2%) of 711 patients in the Tenecteplase group and 13 (2%) of 706 in the alteplase group (RR 1.18, 95% CI 0.56–2.50). Deaths occurred in 46 (7%) patients in the Tenecteplase group vs. 35 (5%) in Alteplase group (RR 1.31 (0.86–2.01); p=0.22). Tenecteplase was non-inferior (and not superior) to alteplase for AIS within 4.5 h of symptom onset. Kvistad CE, et al. Stroke. (2019)   Phase 3 randomized trial; Tenecteplase (n=163); Alteplase (n=185); 11 hospitals with stroke units in Norway NIHSS Tenecteplase vs Alteplase Median Moderate (6 to 14): 8 (7–10) vs. 8 (7–11) Median Severe ( ≥15): 18.5 (17-22) vs. 18.5 (17-21)   1:1 to receive Tenecteplase 0·4 mg/kg (to a maximum of 40 mg) or alteplase 0·9 mg/kg (to a maximum of 90 mg), Efficacy & Safety: moderate stroke (n=261), there were no differences in rates of favorable outcome, symptomatic ICH, or mortality between Tenecteplase and alteplase. In patients with severe stroke (n=87), there were no differences in outcome, frequency of symptomatic ICH, or mortality at 7 days, but all-cause mortality at 90 days was increased in patients treated with Tenecteplase (10 [26.3%] versus 4 [9.1%]; P=0.045).   Similar rates of favorable out- come and symptomatic ICH in patients with moderate and severe ischemic were seen between patients treated with Tenecteplase 0.4 mg/kg as compared with alteplase for AIS. Long-term mortality was increased in patients with severe stroke receiving Tenecteplase. Kvistad CE, et al. Lancet Neurol. (2022) Phase 3 Randomized non-inferiority trial; Tenecteplase (n=100) and alteplase (n=104); 11 hospitals with stroke units in Norway NIHSS Tenecteplase vs Alteplase Moderate (6–14): 64 (64.0) vs. 66 (63.5) Severe (≥15): 35 (35.0) vs. 38 (36.5) Tenecteplase IV 0·4 mg/kg vs. Alteplase 0·9 mg/kg Efficacy: A favorable functional outcome was reported less frequently in patients receiving Tenecteplase (31 [32%] of 96 patients) compared with alteplase (52 [51%] of 101 patients; unadjusted OR 0·45 [95% CI 0·25–0·80]; p=0·0064). Safety: Any intracranial hemorrhage was significantly more frequent with tenecteplase (21 [21%] of 100 patients) than with alteplase (seven [7%] of 104 patients; unadjusted OR 3·68 [95% CI 1·49–9·11]; p=0·0031). Mortality at 3 months was also significantly higher with Tenecteplase (15 [16%] of 96 patients) than with alteplase (five [5%] of 101 patients; unadjusted OR 3·56 [95% CI 1·24–10·21]; p=0·013). Tenecteplase at a dose of 0·4 mg/kg yielded worse safety and functional outcomes compared with alteplase. The trial was stopped early for safety reasons and Part B is ongoing with a lower dose of Tenecteplase (0·25 mg/kg). Acute ischemic stroke (AIS); Modified Rankin Scale ( mRS ); Intracerebral hemorrhage (ICH); Subarachnoid hemorrhage (SAH)