Thrombolysis for Ischemic Stroke: Past, Present, and Future. LGH Stroke Symposium Oct 26, 2013

Transcription

1 Thrombolysis for Ischemic Stroke: Past, Present, and Future LGH Stroke Symposium Oct 26,

2 2

3 Thrombolytic Therapy

4 Outcomes at 3 Months from tpa Treatment of Stroke 4

5 Historical Landmarks 5

6 Other Thrombolytics 6

7 Schwamm et al Circulation: Cardiovascular Quality and Outcomes.2013; 6: The frequency of IV tpa use among all AIS patients, regardless of contraindications, nearly doubled from 2003 to Treatment with tpa has expanded to include more patients with mild deficits, nonwhite race/ethnicity, and oldest old age. 7

8 Guidelines: Metrics for Selection Age Time of symptom onset Baseline BP Glucose Stroke severity (NIHSS) Early CT changes (ASPECTS) 8

9 Guideline: Contraindications Intracranial hemorrhage (ICH) BP > 185/110 after 2 attempts to reduce Surgery/trauma within 14 days, arterial puncture (non-compress) 7 days. Active internal bleeding Hematological abnormalities or coagulopathy INR >1.7, APTT >40, platelets <100K/mm3 Warfarin INR > 1.7 or PT > 15s/ newer oral Acs Modifiable BP/Glucose elevation 9

10 Potentially Treatable Outside Guidelines Depends on judgement of risk/benefit Up to 6 hrs Mild with rapidly improving symptoms Seizure at onset Anticoagulation Dementia, malignancy, pregnancy 10

11 Guidelines: Inclusion Criteria Acute ischemic stroke with known time of onset Likely disabling, no improvement or recovery Initiate treatment within 4.5 hrs Age > 18 years 11

12 Examination Factors 12

13 Imaging Non-contrast CT or MRI Completed within 20 mins/read within 20 mins Scales useful; > one third MCA territory hypoattenuation ASPECTS predictive Multi-modal imaging assessment e.g perfusion/diffusion mismatch/tcd 13

14 Assessing the viability of tissue: the importance of imaging in informed patient selection for thrombolysis. Balami J S et al. Brain 2013;brain.awt201 The Author (2013). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please journals.permissions@oup.com 14

15 Image Post Processing in Stroke Predict the evolution of the infarct Discriminate viable/infarcted tissue (penumbra) Replace time as a therapeutic window Define the risk of hemorrhage on reperfusion 15

16 Stroke Pathology: the Ischemic Cascade Penumbra Infarct Ischemic penumbra Cells surrounding infarct, with 20-50% of normal cerebral blood flow Cells endangered but not yet irreversibly damaged Infarct Cells with <20% of normal cerebral blood flow for >3-4 minutes ATP and intracellular calcium Excitotoxicity ( glutamate) Ca 2+ -activated proteases Lipases Free radicals Irreversible cell damage 16

17 STROKE IN EVOLUTION 7 Hours 72 Hours 3 Months ADC w Maps T 2 Maps Qualitative BAT at 7 hours T 1 Images

18 Ischemia at 10 Hours Diffusion Image, b=900 s/mm 2 Qualitative Perfusion Deficit The mismatch in diffusion and perfusion deficits may be attributable to the ischemic penumbra

19 Failure of Penumbral Identity to Influence Outcome the slaying of a beautiful hypothesis by an ugly fact From Kidwell CS et al, NEJM, March,

20 Pre-Thrombolysis Management Blood Pressure High BP increases hemorrhage risk Reduce BP to <185 mmhg/<110 mmhg Do not treat non-responders Pretreatment does not increase hemorrhage risk IV labetalol preferred Aggressive BP Rx after thrombolysis 20

21 Pre-Thrombolysis Management Glucose Hyperglycemia associated with recanalization failure, less neurological improvement, larger infarct size, worse 3 mth clinical outcome, risk of symptomatic hemorrhage, and mortality Recommend ultra-early glycemic control with rapid action insulin to <10 mmol/l; maintain mmol/l 21

22 Post-thrombolysis Management Hyper-acute stroke unit 24 hrs for hemodynamic and neuro monitoring Expect neuro deterioration even after improvement. Look for symptomatic hemorrhage, edema and recurrent stroke Variable BP and glucose linked to above Follow up brain imaging at 24 hrs. Hemorrhage may require blood products and NS consult. Hyperdense MCA sign may need pre-emptive surgical decompression 22

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24 Risk of Symptomatic Intracranial Hemorrhage Depending on definition risk % Identifiers baseline NIHSS, glucose, systolic BP, age, bodyweight, OTN, platelet inhibitors, history of hypertension. Post-thrombolysis BP Imaging of edema/mass effect, early CT changes, MRI permeability changes, DWI volume Scoring systems e.g SITS-ISTR >10 = 70 fold risk 24

25 All Symptomatic ICHs within 36 hours of stroke onset and t-pa are displayed Group, T. N. t-p. S. S. Stroke 1997;28:

26 DWI : 8 Hours T1 Post-Gd : 8 Hours Qualitative Analysis of Perfusion Images at 8 Hrs Hemorrhage ISODATA of Perfusion Images at 8 Hrs T2 Image TE = 90 ms at 30 Hrs Initial CT Report was negative for hemorrhage!!

27 Stroke Chain of Survival Detection Dispatch Delivery Door Data Decision Drug Disposition Patient or bystander recognition of stroke signs and symptoms Immediate activation of and priority EMS dispatch Prompt triage and transport to most appropriate stroke hospital and prehospital notification Immediate ED triage to high-acuity area Prompt ED evaluation, stroke team activation, laboratory studies, and brain imaging Diagnosis and determination of most appropriate therapy; discussion with patient and family Administration of appropriate drugs or other interventions Timely admission to stroke unit, intensive care unit, or transfer 27

28 Time of Onset to Needle NINDS 3 hrs FDA approved ECASS III 4.5 hrs approved EMA Benefit best early and falls off after 4.5 IST-3 6 hrs improved functional outcome 6 months/ early deaths 28

29 JAMA. 2013;309(23):

30 Importance of time: Effect of rtpa on Patient Outcome at End of Follow-up. Balami J S et al. Brain 2013;brain.awt201 The Author (2013). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please journals.permissions@oup.com 30

31 Time to t-pa Treatment and Outcome JAMA. 2013;309(23):

32 Outcome at Six Months of t-pa Within Six Hours IST-3 Trial Lancet

33 Non-responders Only around 50% improve due to:- Site of occlusion Collateral capacitance Clot burden Clot composition and age 33

34 Predictors of Poor Outcome 34

35 Mild Stroke/Rapid Improvement 35

36 Thrombolysis for Indeterminate onset e.g Wake-Up Stroke Up to 25% wake up with stroke No different baseline characteristics to awake. Early CT changes no different No increased risk of ICH Consider using tissue window (CT/CT angiography/tcd) for good outcome DWI/Flair mismatch Treat if clinical and imaging criteria allow. 36

37 Thrombolysis in Dementia, Malignancy and Pregnancy 37

38 Seizures and Surgery 38

39 Anticoagulation Indicated with INR < 1.7 (AHA/ASA) Two studies show increased ICH in one but not another but same outcome as t-pa. New oral anticoagulants no data. 39

40 Are we doing all that we can? 40

41 Baseline Variable Associated Continuous Deterioration After t-pa Baseline Variable CT findings of early ischemia DFI Within 24 Hours CD Within 24 Hours 1.91 (1.13, 3.23) Aspirin use at baseline 0.53 (0.32, 0.88) 41

42 Ischemic Stroke Severity: Last Dose 1 Month Before Stroke Mild Moderate Severe Fatal Placebo 42.8 (n=222) Atorvastatin (n=175) Improvement in atorvastatin group (%) Proportion of patients (%) P = Results were similar after adjusting for age, gender, and severity of baseline event (P=0.044) *Percent of patients with no recurrent event is not shown to scale. Subjects with missing severity for first event are excluded. Stroke severity determined by Rankin Scale: 0/1=mild, 2/3=moderate, 4/5=severe.

43 Ischemic Stroke Severity: Last Dose > 1 Month Before Stroke Mild Moderate Severe Fatal Placebo (n=42) Atorvastatin (n=34) Improvement in atorvastatin group (%) 14.6 Proportion of patients (%) P = Results were similar after adjusting for age, gender, and severity of baseline event (P=0.658) *Percent of patients with no recurrent event is not shown to scale. Subjects with missing severity for first event are excluded. Stroke severity determined by Rankin Scale: 0/1=mild, 2/3=moderate, 4/5=severe.

44 Potential Mechanisms of Aspirin or Statin Stroke Prevention - Pleotropism Anti-inflammatory effect Improved endothelial dysfunction enos upregulated Positive effect on fibrinolytic and platelet function Adhesion molecule blockade Cytoprotection Upregulated enos

45 The THRombolysis and STatins (THRaST) Study Neurologic improvement (odds ratio [OR] 1.68, 95% confidence interval [CI] ; p < 0.001), Major neurologic improvement (OR 1.43, 95% CI ; p = 0.006), Favorable functional outcome (OR 1.63, 95% CI ; p = 0.003), and a Reduced risk of neurologic deterioration (OR: 0.31, 95% CI ; p < 0.001) and death (OR 0.48, 95% CI ; p = 0.007). Cappellari, Manuel MD et al Neurology, Feb

46 Image Post Processing in Stroke Predict the evolution of the infarct Discriminate viable/infarcted tissue (penumbra) Replace time as a therapeutic window Define the risk of hemorrhage on reperfusion 46

47 Beyond the Human Eye Beyond the Human Eye

48 ACUTE vs. CHRONIC ISCHEMIA Diffusion Image b = 900 s/mm 2 T 2 Image Fig 1

49 Heterogeneous ADC w Regions in Stroke Lesion Diffusion Image T2 Image Zones of Stroke ADC w Map 0.60 N 1.15 N 1.41 N

50 Segmentation DWI Segmentation DWI,T2,T1

51 3-Dimensional MR Tissue Signature Model ADC, T2, T1 Intensity Ischemic tissue classification : 3 types Salvageable Transition to Necrosis Necrotic CSF - end-point in evolution of ischemic tissue

52 3-D MR SIGNATURE MODEL a=angle between CN &TN b=angle between CN &TC Take Ratio of b/a 3 C b 2 a N Ratio Ratio of of ADCw Test Ratio of T Ratio of T1 Intensity Ratio of T1 Intensity

53 Fig 13

54 Tissue Classification: Ratio of Angles TISSUE RANGE OF b/a Salvageable b/a < 0.33 Transitional b/a >0.33 <0.67 Necrotic b/a > 0.67

55 Percent of Maximim Volume Temporal Evolution of MR Signatures in Stroke Salvage able Transitional Ne crotic Total Volume Time of MR Study (Hours)

56 Rankin S core Relation of Rankin Score to Change in Stroke Volume 6 5 R 2 = D Volume from Acute to S ub-acute (arb. units)

57 Percentage of Necrotic Tissue Correlation of Percent of Necrotic Tissue with Rankin Score Hyperacute Cases (< 12 Hours) Rankin Score r 2 = 0.6 p < 0.05

58 Are We Doing All We Can? 58

59 Are we doing all we can? Although the time window for thrombolysis has been extended it remains that treatment at the earliest time is imperative. Health systems should react. The art of patient selection for treatment at extended time windows must be replaced by tested scientific protocol. Multimodal brain imaging and image post-processing will be critical to safely extend the time window. Thrombolysis plus should include approaches that prevent re-occlusion, hemorrhage and edema. Cytoprotective approaches post thrombolysis must be rigorously tested. 59

60 Some Recommended Reading Jauch EC et al. Guidelines for the early management of patients with acute ischemic stroke. Stroke 2013;44: Balami et al. The exact science of stroke thrombolysis and the quiet art of patient selection. Brain 2013: 1-26 IST-3. Lancet 2012;379: Saver JL. Time to treatment with intravenous tissue plasminogen activator and outcome from acute ischemic stroke. JAMA 2013; 309:23 60