Thrombolysis Update 2008 mostly a 3 to 4.5 hours post stroke story

Transcription

1 Thrombolysis Update 2008 mostly a 3 to 4.5 hours post stroke story Andrew M. Demchuk, MD FRCPC Director, Calgary Stroke Program Chair, Pillar 2 Acute Care and Emergency Services, APSS Associate Professor, Department of Clinical Neurosciences Adjunct Professor, Department of Radiology University of Calgary

2 Financial Disclosure Received Speaker fees in the past from Hoffman LaRoche (licensure of tpa in Canada). No speaker fees, honoraria, or consultant fees received from Hoffman LaRoche in the past 2 years.

3 Tissue Plasminogen Activator iv Thrombolytic (clot buster) iv tpa for treatment of acute stroke < 3 hours from last known normal FDA approved USA since June 1996 Full approval HPB Canada since February 2005 EU approved since 2003

4 Placebo Cost-effectiveness of tpa Neurology 1998;50: more people out of 100 going home 6 less people out of 100 ending up in nursing home Disposition Home Rehab NH or other Dead hospital days 12.4 rt-pa NH=nursing home

5 Cerebral Blood Flow Critical

6 Infarct Volume min Time

14 Early Recanalization Key!

15 Complete MCA Recanalization 13:02 Time 13:38 TPA bolus Demchuk et al. Circulation 2000;100:

16 iv tpa On the table responders Lazarus effect 1 in 4-5 tpa patients versus 1 in 30 placebo patients

17 TPA Recanalization Rates 1h 2h 24h delzoppo et al 1992 Saqqur et al 2007 Zangerle et al % 6% 46% 26% 30% 53% 35% 44% 68%

18 Rescue ia therapy CTA iv tpa DSA ia tpa MERCI

19 IMS-3 Trial Randomization completed IV+IA/mechanical 2:1 IV tpa alone Angiography IV tpa 0.3 mg/kg over target thrombus identified that is suitable for interarterial intervention No clot stop final 20 minutes Stop IA Therapy: 2 mg-distal, 2 mg-intraclot, 9 mg/hr x 2 hrs, 22 mg max.) Up to 1 FDA/HPB approved Mechanical device for clot extraction/lysis

20 The Art of tpa Decision Making Treat enthusiastically Treat nervously and selectively if at all Young Glucose, BP normal On Protocol Moderate-Severe Stroke Good CT higher ASPECTS Old Glucose, BP Off Protocol Minor Stroke Bad CT ASPECTS<3 Dual antiplatelet therapy

21 < 3 Hours from onset NINDS tpa Trial age < 60 Parts A and B n=174 NNT=4 to cure Recovery Sympt ICH 5% Complete Incomplete Poor Death Placebo rt-pa

22 < 3 Hours from onset NINDS tpa Trial age > 80 Parts A and B n=69 Recovery Complete Incomplete Poor Death Placebo rt-pa

23 Symptomatic ICH risk increases with age sich rate Pooled analysis of tpa trials SITS-MOST Tanne D et al. Circulation 2001

25 Hyperglycemia Tanne D et al. Circulation 2001 Hyperglycemia associated with higher symptomatic ICH rates in NINDS rtpa trial (Bruno et al Neurology).

26 CASES Registry (mrs 0-2) Factor OR (95% CI) bnihss (per 5 pt) 0.58 ( ) Age (per 10 y) 0.78 ( ) ASPECTS (per 2pt) 1.25 ( ) Glucose (per 5mM) 0.57 ( ) Hill MD et al. CASES. CMAJ 2005

27 Systolic BP in ASK trial Symptomatic ICH Rates

28 SITS-MOST and sich

30 Phase IV Experience Cleveland Experience n=70 50% rate of protocol violators Most centers had treats experience 15.7% symptomatic ICH rate n=47 17% rate of protocol violators 6.4% symptomatic ICH rate JAMA 2000;283: n=47 Stroke 2003;34:

31 CASES Registry Protocol Violations & sich Protocol Violation - onset-to-treatment time > 180 minutes, platelet count < , INR > 1.4, tpa dose > 90mg RR p sich 1.8 (95%CI ) 0.06 death at 90d 1.2 (95%CI ) 0.14 Hill MD et al. CASES. CMAJ 2005 (in press)

33 Sweet Spot for tpa; bnihss 6-20

35 PENUMBRA CORE PENUMBRA

36 PENUMBRA CORE

37 PENUMBRA CORE

38 ASPECTS methodology

39 ASPECTS methodology

40 What is hypoattenuated is already infarcted?

41 Case Example C L

42 Case Example - 24h CT

43 What you see is at least what infarcts Dzialowski I et al. ASPECTS ECASS-2. Stroke Penumbra CORE CORE core PENUMBRA

44 ASPECTS correlates to outcome Hill MD et al. CASES. CMAJ 2005

45 ASPECTS 8-10 T ASPECTS 8-10 P ASPECTS 3-7 T ASPECTS 3-7 P ASPECTS <3 T ASPECTS <3 P Death core PENUMBRA n= 201 n= 205 n= 89 n= 97 n= 10 n= 6

46 ASPECTS 8-10 T ASPECTS 8-10 P ASPECTS 3-7 T ASPECTS 3-7 P ASPECTS <3 T ASPECTS <3 P Death CORE Penumbra n= 201 n= 205 n= 89 n= 97 n= 10 n= 6

47 ASPECTS 8-10 T ASPECTS 8-10 P ASPECTS 3-7 T ASPECTS 3-7 P ASPECTS <3 T ASPECTS <3 P Death CORE n= 201 n= 205 n= 89 n= 97 n= 10 n= 6

48 ASPECTS in 3 randomized clinical trials Symptomatic ICH Rate 30 CORE ASPECTS NINDS ATLANTIS ECASS-2 NINDS ATLANTIS ECASS-2 NINDS ATLANTIS ECASS n

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53 Dual Antiplatelet agent and sich n= 965 iv tpa enrolled in SAINT 1 and 2 (unpublished data) age y onset to tpa min mnihss 14 sich: 5.6% (95%CI: %) double antiplatelet tx OR 9.29, , p<0.001 ASPECTS 7: OR 5.63, , p=0.006 higher NIHSS score OR 1.09/pt, , p= % sich rate if ASA+Clopidogrel part of pretreatment med list!

54 MOST IMPORTANT FACTOR Time Dependency

55 The Art of tpa Decision Making Treat enthusiastically Early Young Glucose, BP normal On Protocol Moderate-Severe Stroke Good CT higher ASPECTS Treat nervously and selectively if at all Late Old Glucose, BP Off Protocol Minor Stroke Bad CT ASPECTS<3 Dual antiplatelet therapy

56 NINDS TPA Stroke Study: Time to Treatment and Odds Ratio of Favorable Outcome 8 Odds Ratio Favorable Outcome Benefit for rt-pa No Benefit for rt-pa TIME IS BRAIN!!! Minutes Stroke Onset To Start of Treatment

57 Intracerebral hemorrhage and tpa by time Lancet 2004;363: Interval (min) n Parenchymal hematoma rate (95% CI) % ( ) % ( ) % ( ) % ( ) Multivariate model: tpa tx (p= ), age (p=0.0002) predicted hematoma. Time to treatment (p=0.71), NIHSS (p=0.10) not independent predictors

58 Golden 1 ½ hours of stroke minutes

59 Frequency 215 Time to Treatment Hill MD et al. CASES. CMAJ 2005 (in press) Onset-to-needle time (min)

60 Minimize Delay- Hospital Bypass 8 miles At least 20% of stroke patients arrive at a hospital within 2 hours of symptom onset. Local hospital No CT scanner

61 Minimize Delay- Hospital Bypass vs 40 miles CT scanner 8 miles Local hospital No CT scanner CT scanner but: no stroke expertise limited/delayed CT scan access no tpa in fridge system not primed for speed

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63 Directed Transport to Primary Stroke Centre

65 Transport Protocol

67 EMS Stroke Screening Form

68 How do I organize things to improve early recognition

69 EMS Stroke Screening Form

70 Minimize Delay- Hospital Bypass vs 8 miles 40 miles CT scanner without inhospital night technologist Local hospital No CT scanner 70 miles iv rt-pa vs Helical or multislice CT scanner 24h/365 d coverage Primary Stroke Center

71 EMS Transport to closest institution that provides emergency stroke care

72 CSC PSC Proposed PSC

73 Transfer for Rescue Therapy vs 8 miles 40 miles CT scanner Local hospital No CT scanner 70 miles intraclot lysis vs ICH evacuation 170 miles Early ICA revascularization vs Helical or multislice CT scanner 24h/365d coverage Primary Stroke Center Interventional Facilitiesinterventional neurorad, neurosurgery Comprehensive Stroke Center

74 Telestroke vs 8 miles 40 miles CT scanner Local hospital No CT scanner 70 miles 1. PACS image access 2. Camera for exam 3. Education/support post-tpa vs Helical or multislice CT scanner 24h/365d coverage Primary Stroke Centre Stroke Expertise Comprehensive Stroke Centre

76 How about treating over 3 hrs? Does the pathophysiology of the disease change magically one second past 3 hours?

77 How about treating over 3 hrs? Does the pathophysiology of the disease change magically one second past 3 hours? Of course not. The environment is just getting less favourable to achieve benefit.

78 Diminishing Returns over Time Favorable Outcome (mrs 0-1, BI , NIHH 0-1) at Day 90 Adjusted odds ratio with 95% confidence interval by stroke onset to treatment time (OTT) ITT population (N=2776) Lancet 2004;363: Pooled Analysis NINDS tpa, ATLANTIS, ECASS-I, ECASS-II ~4h 30min

79 Diminishing Returns over Time Favorable Outcome (mrs 0-1, BI , NIHH 0-1) at Day 90 Adjusted odds ratio with 95% confidence interval by stroke onset to treatment time (OTT) ITT population (N=2776) Lancet 2004;363: Pooled Analysis NINDS tpa, ATLANTIS, ECASS-I, ECASS-II ~4h 30min

80 Diminishing Returns over Time Favorable Outcome (mrs 0-1, BI , NIHH 0-1) at Day 90 Adjusted odds ratio with 95% confidence interval by stroke onset to treatment time (OTT) ITT population (N=2776) Courtesy Brott T et al Pooled Analysis NINDS tpa, ATLANTIS, ECASS-I, ECASS-II ~4h 30min NNT 5 NNT 20

81 Intracerebral hemorrhage and tpa by time Lancet 2004;363: Interval (min) n Parenchymal hematoma rate (95% CI) % ( ) % ( ) % ( ) % ( ) Multivariate model: tpa tx (p= ), age (p=0.0002) predicted hematoma. Time to treatment (p=0.71), NIHSS (p=0.10) not independent predictors

82 3-4.5 h Treatment Efficacious NNT ECASS-3: NEJM 2008;359: % Pooled analysis: Lancet 2004;363:

83 Lancet 2008;372:

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86 3-6 hours from onset and baseline MRI Lancet Neurology 2008

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92 3-4.5 h Treatment Efficacious NNT ECASS-3: NEJM 2008;359: % 5% Pooled analysis: Lancet 2004;363:

93 3-4.5 h Treatment Efficacious NNT ECASS-3: NEJM 2008;359: % 5% Pooled analysis: Lancet 2004;363:

94 3-4.5 h Treatment Safe - ECASS-3 NEJM 2008;359:

95 The Art of tpa Decision Making Treat enthusiastically Early Young Glucose, BP normal On Protocol Moderate-Severe Stroke Good CT higher ASPECTS Treat nervously and selectively if at all Late Old Glucose, BP Off Protocol Minor Stroke Bad CT ASPECTS<3 Dual antiplatelet therapy

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97 Guidelines support treatment from 0-4.5h

98 But not at the expense of slowing down!

99 Some caveats: not Health Canada approved to 4.5h yet

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