When Not To Give TPA Steve Phillips Division of Neurology stephen.phillips@nshealth.ca
AstraZeneca Disclosures - 1 I have given CME lectures and served on advisory boards for Boehringer Ingelheim Bristol-Myers Squibb Hoffmann-LaRoche Merck Frosst Pfizer sanofi-aventis Servier The QEII Acute Stroke Program has received support from GlaxoWellcome, Hoffmann-La Roche, Merck Frosst, sanofi-aventis, Servier, Bayer
Disclosures - 2 I was Canadian coordinator for the third International Stroke Trial of t-pa (IST-3) I am a Clinical Advisor for Cardiovascular Health Nova Scotia (CVHNS) I was inaugural co-chair of the Best Practices & Standards Advisory Committee of the Canadian Stroke Strategy
Give em the juice! Michael Hill, MD
IV t-pa works for A broad spectrum treatment mild, moderate, and severe strokes men and women Stroke Thrombolysis Trialists Collaborative Group, 2014 & 2018
Treatment and outcome IV thrombolysis within 6 h of AMI* - alive 35 days later Benefit N / 1000 treated 30 *Fibrinolytic Therapy Trialists' Collaborative Group. Lancet. 1994; 343: 311-22
Treatment and outcome IV thrombolysis within 6 h of AMI* - alive 35 days later IV tpa within 6 h of stroke^ - alive & independent months later Benefit N / 1000 treated 30 42 *Fibrinolytic Therapy Trialists' Collaborative Group. Lancet. 1994; 343: 311-22 ^Emberson J, et al. Lancet. 2014; 384: 1929-35
Treatment and outcome IV thrombolysis within 6 h of AMI* - alive 35 days later IV tpa within 6 h of stroke^ - alive & independent months later IV tpa within 3 h of stroke^ - alive & independent months later Benefit N / 1000 treated 30 42 90 *Fibrinolytic Therapy Trialists' Collaborative Group. Lancet. 1994; 343: 311-22 ^Emberson J, et al. Lancet. 2014; 384: 1929-35
Odds Ratio (95% CI) 3.0 2.6 2.2 Effect of timing of IV t-pa on good outcome (mrs 0-1) 1.8 1.4 1.0 1.0 2.0 3.0 4.5 6.5 Treatment delay (h) Emberson, et al. Lancet 2014; 384: 1929-35
Life is short; and the art long; and the right time an instant; and treatment precarious; and the crisis grievous. Hippocrates (translator Dickinson Richards)
TPA is chemical neurosurgery
A case from the Annals of the QEII Emergency Department
74 year-old woman 10:00 h sudden left arm weakness & slurred speech One month earlier had transient left leg weakness & found to be in AF. Declined anticoagulant therapy Cognitively intact & functionally independent (CIFI) T+33 mins 911 Pre-hospital Acute Stroke Protocol activation T+46 mins triaged into ED
74 year-old woman BP 190/100; AF on ECG Alert Dysarthric Visual fields full Left facial droop, arm paralyzed, leg drift No sensory loss or neglect
Diagnosis Probable ischemic stroke Localization: Syndrome: Severity: Mechanism: Prognosis: Anterior right hemisphere Partial MCA Moderate (NIHSS=8) Probable cardiogenic embolism 45% probability of death or dependency at 1 year
Multimodal CT imaging at T+90 mins Non-contrast CT head
Time-to-Peak Cerebral Blood Flow Cerebral Blood Volume
Labetalol 10 mg IV x2 BP 170/90 PLT 250, INR 1.0 Consent discussion; 7-10% bleeding risk
Consent issues US guidelines recommend obtaining informed consent when feasible Canadian Best Practice Recommendations 2018: TPA is considered standard of care. Routine procedures for emergency consent apply. Obtaining consent delays treatment
In cases of medical emergency when the patient (or substitute decision maker) is unable to consent, a physician has the duty to do what is immediately necessary without consent.
a contemporaneous record (at the time) should be made explaining the circumstances which forced the physician's hand.
And If you don t treat, document why and explain to the patient s family
ED physicians more often sued for not giving tpa for stroke Liang BA, Zivin JA. Empirical characteristics of litigation involving tissue plasminogen activator and ischemic stroke. Ann Emerg Med. 2008; 52: 160-4.
This is not America
or
Labetalol 10 mg IV x2 BP 170/90 PLT 250, INR 1.0 Consent discussion; 7-10% bleeding risk TPA started 2 h 20 m after stroke onset
Labetalol 10 mg IV x2 BP 170/90 PLT 250, INR 1.0 Consent discussion; 7-10% bleeding risk TPA started 2 h 20 m after stroke onset ~1 hour later: BP 180/100, mute, right gaze preference
NCCT 80 mins after start of t-pa Patient deceased 7 hours after stroke onset
Predicting brain hemorrhage after t-pa
age BP blood glucose creatinine prior antiplatelets stroke severity visible infarct on CT cerebral microbleeds very low cerebral blood volume Karaszewski B, et al. J Neurol Neurosurg Psychiatry 2015; 86: 1127-36
first released December 2006 continuously updated since
Acute Ischemic Stroke Treatment. 2018 Update 5.3.i All eligible patients with disabling ischemic stroke should be offered IV t-pa. Eligible patients are those who can receive treatment within 4.5 hours of stroke onset. [Evidence Level A]
Acute Ischemic Stroke Treatment. 2018 Update 5.3.ii All eligible patients should receive IV t-pa as soon as possible after hospital arrival. [Evidence Level A] Target door-to-needle time <60 min in 90% of treated patients & median 30 min. [Evidence Level B]
Update 2018 Thrombolytic Therapy Inclusion Criteria Age >18 <4.5 h since onset (or LSN) Absolute Exclusion Criteria Intracranial hemorrhage (ICH) At risk of major extracranial hemorrhage
Update 2018 Thrombolytic Therapy Patients on a Direct Oral Anticoagulant IV t-pa should not be routinely administered In centers with access to specialized tests of DOAC levels and reversal agents, IV t-pa could be considered
Update 2018 Thrombolytic Therapy Relative Exclusion Criteria History of ICH Stroke or head trauma in prior 3 months Major surgery in prior 14 days Arterial puncture in prior 7 days Refractory hypertension >180/105
Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) PI: Craig Anderson, The George Institute for Global Health, Australia P: Ischemic stroke, <4.5 hours, SBP>140 I: 1. Intensive BP lowering (SBP 130-140) 2. tpa low dose (0.6 mg/kg) C:1. Guideline BP lowering (SBP <180) 2. tpa normal dose O: mrs N: Target 4,800 www.strokecenter.org/trials
Update 2018 Thrombolytic Therapy Relative Exclusion Criteria Blood glucose <2.7 or >22.2 INR >1.7 PTT PLT <100 ASPECTS <6
Alberta Stroke Program Early CT Score Examine all the images at the ganglionic and supra-ganglionic levels Take off 1 pt from 10 for every region affected 8-10 Small core 6-7 Moderate core 0-5 Large core aspectsinstroke.com
Stroke Thrombolysis in Nova Scotia
Stroke Thrombolysis in Nova Scotia 2004/05* 2015^ Ischemic stroke patients 790 1150 Treated with t-pa 3% 13% Arrived in time & treated 11% 40% Median door-to-needle 93 min 68 min *Provincial Stroke Audit ^CVHNS Provincial Stroke Registry
Bleeding Complications sich Nova Scotia 2015 (n=183) 8%* sich=symptomatic intracranial hemorrhage *CT confirmed or death within 48 h post-tpa
Bleeding Complications sich mech Nova Scotia 2015 (n=183) 8% Systematic Review 2012 (n=3548) 8% IST-3 (n=1515) 7% 1% SITS Registry (n=6483) 7% sich=symptomatic intracranial hemorrhage; mech=major extracranial hemorrhage
Update 2018 Thrombolytic Therapy Treatment of Bleeding Complications Insufficient evidence to support use of: cryoprecipitate or fresh-frozen plasma prothrombin complex concentrate platelet transfusion tranexamic acid
When Would I Not Treat? Very mild stroke causing non-impairing deficit Very severe stroke in the frail elderly or terminally ill
What Do We Do?
Insights from 1. Patients who arrive in time but are not thrombolysed 2. Patients whose treatment is complicated by brain hemorrhage Data from QEII Acute Stroke Registry
Acute Ischemic Strokes Admitted Through QEII Emergency Department 2015 2016 2017 Total N 257 264 225 746 TPA 73 (28%) 66 (25%) 52 (23%) 191 (26%)
Acute Ischemic Strokes Admitted Through QEII Emergency Department Arrived <3.5 h but no TPA 2015 2016 2017 Total N 257 264 225 746 TPA 73 (28%) 66 (25%) 52 (23%) 191 (26%) 57 (22%) 51 (19%) 50 (22%) 158 (21%)
Lysed cf Not- lysed (1/3) 2015 2016 2017 TPA No TPA TPA No TPA TPA No TPA Age 75 79 69 76 75 80 % men 66 51 53 71 50 54 % living at home % living alone 97 89 97 94 98 90 21 21 18 8 15 30
Lysed cf Not- lysed (1/3) 2015 2016 2017 TPA No TPA TPA No TPA TPA No TPA Age 75 79 69 76 75 80 % men 66 51 53 71 50 54 % living at home % living alone Untreated patients older 97 89 97 94 98 90 21 21 18 8 15 30
Lysed cf Not- lysed (2/3) 2015 2016 2017 % Prior: TPA No TPA TPA No TPA TPA No TPA stroke 22 37 30 37 12 38 cognition 10 30 14 25 21 38 dependency 10 25 11 27 19 30
Lysed cf Not- lysed (2/3) 2015 2016 2017 % Prior: TPA No TPA TPA No TPA TPA No TPA stroke 22 37 30 37 12 38 cognition 10 30 14 25 21 38 dependency 10 25 11 27 19 30 Untreated patients older; and more likely to have prior stroke, cognitive and functional impairment
Lysed cf Not- lysed (3/3) 2015 2016 2017 TPA No TPA TPA No TPA TPA No TPA % ASP activated 90 58 98 67 98 78 % Mild stroke 1 28 3 22 8 16 % Moderate stroke 64 42 59 63 58 66 % Severe stroke 34 30 38 14 35 18
Lysed cf Not- lysed (3/3) 2015 2016 2017 TPA No TPA TPA No TPA TPA No TPA % ASP activated 90 58 98 67 98 78 % Mild stroke 1 28 3 22 8 16 % Moderate stroke 64 42 59 63 58 66 % Severe stroke 34 30 38 14 35 18 Untreated patients older; more likely to have prior stroke, cognitive and functional impairment, and mild stroke; and less likely to be code strokes
Intracerebral hemorrhage after TPA at the HI
Intracerebral hemorrhage after TPA at the HI 2015 2016 2017 Total TPA [no EVT] 62 52 40 154 ICH, n (%) 3 (4.8) 1 (1.9) 4 (10) 8 (5.2)
TPA [No EVT] ICH No ICH n=8 n=148 Age (median) 75 75 % men 40 60 % prior stroke 13 27 % prior cognition 38 13 % prior dependency 25 13 Bleeders more likely to cognitively impaired, dependent
TPA [No EVT] ICH No ICH n=8 n=148 LSN to TPA (median mins) 184 153 % AF 50 27 % mild stroke 0 5 % moderate stroke 63 68 % severe stroke 37 27 Bleeders more likely to cognitively impaired, dependent, in AF
TPA [No EVT] ICH No ICH Stroke syndrome n=8 n=148 % MCA 75 74 % Lacunar 25 12 Bleeders more likely to cognitively impaired, dependent, in AF, with a lacunar stroke
TPA [No EVT] ICH No ICH n=8 n=148 % death in hospital 38 14 % survivors dependent at discharge 80 51
Last slide No useful clinical tool to predict who will bleed after t-pa Guidelines are helpful! Mild strokes are difficult! Frailty, comorbidity, impaired cognition, and functional dependency may be reasons not to treat There are worse things than dying from a severe stroke
Thanks! Stephen.Phillips@dal.ca
Symptomatic intracranial hemorrhage in systematic review of stroke t-pa trials Treated within 3 h All 5 trials before IST-3 IST-3 All 6 trials (n=1779) Treated between 3 to 6 h OR 4.6 (2.9-7.1) All 6 trials before IST-3 IST-3 All 7 trials (n=4965) OR 3.7 (2.9-4.9) Lancet 2012; 379: 2364-72 0.5 1.0 5.0 10.0
Update 2018 Thrombolytic Therapy Treatment of tpa-induced Angioedema Stop t-pa Airway management Hydrocortisone 100 mg IV Diphenhydramine 50 mg IV Ranitidine 50 mg IV [risk of BP and ICH with nebulized epinephrine]
Door to Image/Needle (minutes) Number of patients Stroke Thrombolysis in Nova Scotia 2012-2015 N, Door-to-CT & Door-to-Needle Times (median, IQR) 120 180 100 160 140 80 120 60 100 80 40 60 20 40 20 0 2012 2013 2014 2015 Calendar Year 0 Number treated 0-3hrs from symptom onset Median door to image Number treated >3hrs from symptom onset Median door to needle
Stroke Thrombolysis in Helsinki 1998-2011 Meretoja A, et al. Neurology. 2012; 79: 306-13
Content Give em the juice Summary of trial data (Emberson paper; Lees ESOC presentation) mild, moderate and severe strokes benefit timing difficulty predicting ICH (Will Whiteley) Canadian Stroke Best Practice Recommendations Local data ischemic stroke patients who arrive in time but are not treated treated patients who bled CVHNS data on bleeding Thrombolysis in the EVT era (TNK_mdhEditorial2018)