IV tpa and mechanical thrombectomy case selection

Transcription

1 IV tpa and mechanical thrombectomy case selection 22 April 2017, Deidre De Silva SGH campus, NNI, Singapore

2 OUTLINE Reperfusion concept Case Selection factors IV tpa & Mechanical Thrombectomy Evidence Absolute indications/ contraindications Relative indications/ contraindications Pushing the boundaries Protocols, Audits

3 Reperfusion Treatment: IV tpa & Mechanical Thrombectomy Recanalization of Arterial Occlusion Reperfusion of Salvageable Tissue Attenuation of Infarct Growth Improved Neurological & Functional Outcomes

4 Reperfusion Strategies Acute intravenous thrombolysis: Alteplase Endovascular Treatment (EVT) Mechanical Thrombectomy Intra-arterial Angioplasty & stenting

5 Case Selection Absolute indication/ CI easy decision Relative indication/ CI Consider all factors together, weighing benefit:risk Pushing boundaries Starting service more experienced More data from RCT, post-hoc analyses, registries, Protocols and audits To influence case selection guides for your centre

6 IV tpa: Evidence in window BENEFITS Functional independence (mrs 0-1) NNT 8-14 Any functional Improvement NNT 3 No change in survival RISKS sich Harm of sich with poor function NNH 126 In 3 h window Any sich 0.6% in placebo arm; 6.6% in tpa arm Extracranial Haemorrhage Allergy

7 A b s o l u t e R e l a t I v e

8 IV tpa: absolute indications Ischemic stroke Time window: 4.5 hours Time of onset: estimation

9 IV tpa: absolute contraindications - History Bleeding risks Major surgical procedure in last 14 days Minor surgical procedure in last 7 days Arterial puncture in non-compressive site in last 7 days GIT or GUT bleeding in last 21 days Significant trauma including HI in last 3 months CPR with chest compressions in last 10 days Intracranial vascular malformation/ tumour (relative in some cases) Bleeding diastheses INR >1.7, DOAC in last 48 hours

10 IV tpa: absolute contraindications - Exam & Investigations Blood pressure >185/110 mmhg (LOWER IT) Injuries indicating recent significant trauma Haemorrhage on brain imaging Extensive Early ischemic change STEMI (to discuss later)

11 Exclude Haemorrhage: CT vs MRI (Kidwell, JAMA 2004) 200 stroke patients: 169 IS, 27 HS, 4 both MRI followed by CT Acute haemorrhage CT + CT - P value MRI + MRI >0.99 MRI + CT - : 4 hemorrhagic transformation of infarct CT + MRI - : 3 interpreted as chronic hemorrhage on MRI, 1 was SAH MRI & CT equivalent for acute haemorrhage 96% concordance

12 Detect Ischemia: HEME AICS 170 IS patients, <6 hours, MRI before CT Sensitivity to detect ischemic change DWI CT P value Unblinded 82% 21% p<0.001 Blinded 70% 18% p<0.001 Factors for detection on DWI but not CT lower baseline NIHSS & smaller DWI lesion

13 CT: Insular Ribbon CT: Grey-white, loss of sulci CT: Lentiform nucleus obscuration MRI: DWI and ADC

14 CT ASPECTS (Barber, Lancet 2000) IS treated with IV tpa <=7 predictor of poor outcome predictor of sich OR 14 (1.8 to 117)

15 DWI ASPECTS (Singer, Stroke 2009) IV or IA tpa sich risk 0-7 = 15.1%, 8-10 = 2.6%; p=0.004

16 What is brain imaging for? To exclude hemorrhage To assess if there is extensive early ischemic change If possible to exclude stroke mimics CT is adequate for case selection for IV tpa

17 RELATIVE CONTRA- INDICATIONS De Keyser, Stroke 2007 Variations between guidelines

18 SMART STUDY Only inclusion criterion: time <4.5hours Only exclusion criterion: acute ICH 138 ischemic stroke patients, IV tpa <4.5hours 89% had at least 1 contraindication 59% have mrs 0-1 sich (?criteria) 1.5% Mortality 7% Thrombolysis rate 20% J of stroke and CVD 2016

19 Contraindications What is the evidence behind these? Are we denying patients proven treatment although there may not be increased risk?

20 IV tpa: relative contraindications - a selection Older age Mild Resolving Severe Many others.

21 AGE High prevalence of octogenarians in stroke cohorts 27% in US National Inpatient Sample Post-stroke outcome (without tpa) is poorer in elderly AHA/ASA GWTG study Death at dc: 90 (10.3%) vs >80 (7.7%) vs young (4%)

22 2 RCTs with data for >80 yo

23 Mortality: IV TPA vs placebo Mortality at 3 month in >80 yo NINDS: tpa 52.5% vs placebo 48.3% (p=0.73) SITS-ISTR+VISTA: tpa 13.6% vs placebo 14.8%

24 Studies of older vs younger - caution with interpretation Good functional outcome at 3 mths Meta-analysis of 13 obs studies >80 had 50% lower chance (OR 0.49; 95% CI ) In-hospital Mortality SPORTRIAS >80yo 2X higher risk (OR 2.13) sich Metaanalysis, Bhatnagar JNNP 2011 no statistically significant (OR 1.31;95%CI, )

25 My Opinion: Age >80 years NOT A CONTRAINDICATION Use biological age rather than chronological age Consider other factors With tpa among >80 yo vs <80 yo higher mortality poorer functional outcome but similar extent with natural history There is a clear treatment effect IV tpa vs placebo

26 Mild/ Rapidly improving symptoms Common 31-58% Too good to treat or improving symptoms as reason to NOT treat Some have poor prognosis 11% not discharged home 33% died or disabled at discharge Smith, Stroke 2005 Barber, Neurology 2001 Khatri, Stroke 2010

27 Minor neurological deficits Limitations of NIHSS What we think is minor can be disabling

28 Mild: NINDs data For 5 definitions of minor stroke (Eg.NIHSS 0-1 for each item, NIHSS <=9) tpa vs placebo mrs 0-2 OR 2.0 (1.4 to 2.9) sich 0-4% NIHSS 5 Only 58 cases, unable to draw conclusions Ann Emerg Med 2005 Khatri, Stroke 2010

29 My opinio: Mild deficits I would not consider it a contraindication Poor natural history (1/3 dead or disabled) Treatment benefit with tpa (OR 2) Acceptable risk of sich 0-4%

30 Rapid improving symptoms - considerations Improvement can be incomplete Disabling deficit remains once improvement plateaus Deterioration may follow, due to persistent occlusion or subsequent reocclusion

31 AHA/ASA recommendations

32 My opinion: Rapidly improving symptoms Should treat Clinical picture ischemic penumbra present Mild deficits can be disabling Clinical experience of mild severe

33 Severe neurological deficit More severe stroke patients arrive early Pooled NINDS, ECASS & ATLANTIS studies Hacke, Lancet 2004

34 Natural history Severe neuro deficits Chances of good outcome with severe stroke is lower (NINDS placebo arm) Treatment effect (IST 3)

35 Safety in severe stroke?? Higher stroke severity larger infarct size higher risk of haemorrhagic transformation Higher risk of sich (observational study, Tanne) NIHSS >20: 11 times higher than NIHSS <=5

36 Safety in severe stroke SITS-ISTR study, NIHSS>25 vs (Mazya, Neurology 2015) Possible selection bias

37 Severe stroke: Guidelines

38 My opinion: Severe neuro deficits Caution Not an absolute contraindication Poor outcome without treatment Some form of rescue Consider in context of other factors Discussion with family Explain higher risk of sich to patient/ family

39 IV tpa: Pushing the boundaries Time window

40 Wake up stroke/ Onset unknown 14-28% of all IS are wake-up strokes Currently excluded from reperfusion treatment

41 DWI: Strict FLAIR (Thomalla, Ann Neurol 2009) Negative FLAIR and positive DWI < 3 hours high specificity 0.93, high PPV 0.94 low sensitivity 0.48, low NPV 0.43 Identify those highly likely <3 h from onset

42 Meta-analysis: Strict FLAIR Wouters, Front Neurol 2014 <3 h <4.5 h 0.84 ( ) 0.81 ( )

43 Select in vs Select out! Selecting patients with greater potential to benefit ISCHAEMIC PENUMBRA Excluding patients with higher sich risk LARGE PWI LESION ARTERIAL OBSTRUCTION EXTENSIVE LEUKOARIOSIS

44 Ischemic Penumbra Astrup, Stroke 1977 Kidwell, Stroke 2004

45 ACUTE DAY 3-5 DAY 90 NO REPERFUSION/ RECANALIZATION GROWTH GROWTH Magnetic Resonance Imaging (MRI) mismatch REPERFUSION/ RECANALIZATION ATTENUATED GROWTH ATTENUATED GROWTH

46 Penumbral imaging PWI on MRI CT perfusion Automated software

47 EPITHET (Davis, Lancet Neurol 2008) RCT Included patients with mismatch pattern tpa vs placebo in 3-6 h tpa Placebo p value (n=37) (n=43) Geometric mean growth ratio (t-test) Median growth ratio 1.18 ( ) 1.79 ( ) 0.05 (Wilcoxon)

48 DEFUSE (Albers, Ann Neurol 2006) 74 IS patients treated with IV tpa Patients with mismatch Early reperfusion associated good clinical outcome (OR 5.4; p = 0.039) Patients with no mismatch No benefit from early reperfusion

49 MR RESCUE (Kidwelll, NEJM 2014) Compare treatment effect of EVT vs no EVT in patients with vs without mismatch Day 90 mrs Embolectomy penumbral Std care Penumbral Embolectomy Nonpenumbral Mean Std care Nonpenumbral Interaction of treatment group by penumbral pattern p=0.14

50 My opinion: Ischemic Penumbra Measures/ Threshold for penumbra - debatable Trials using mismatch for patient selection Trend for surrogate outcomes (infarct growth in EPITHET) No interaction of treatment vs penumbral pattern (MR RESCUE) Role still unclear, more studies needed

51 Arterial Obstruction CTA/ MRA/ Angiography

52 Arterial Obstruction Predictive information on recanalisation Presence, Site, Length

53 PRESENCE OF ARTERIAL OBSTRUCTION IN EPITHET & DEFUSE (De Silva, Ann Neurol 2011) Baseline arterial status Obstruction N= 72 Normal flow N= 44 INFARCT GROWTH Placebo tpa 44mL 6mL (7 to 81) (-3 to 15) 5mL 0mL (-1 to 12) (-2 to 0) P value Difference in treatment effect (infarct growth attenuation): 32 ml (95% CI: 21 to 43) p<0.001

54 SITE OF ARTERIAL OBSTRUCTION IN EPITHET (De Silva, Stroke, 2010) tpa Placebo p value Middle cerebral artery (MCA) obstruction Geometric mean growth Internal carotid artery (ICA) obstruction Geometric mean growth The treatment benefit of tpa over placebo in attenuating infarct growth was greater for MCA than ICA obstruction (p=0.060)

55 Clot Burden Clot length (Riedel, Stroke 2011) NNCT 2.5 mm, all IVT < 5 mm high recanalisation rate >8mm <1% recanalisation rate predictive power of thrombus length for IVT recanalization (P<0.001)

56 My Opinion: Arterial Obstruction No role in routine clinical practice for IV tpa for decision-making May influence our prognostication to respond to IV tpa (eg. ICA vs MCA, high clot burden) Possible selection strategy for IVT in trials Investigating new modalities (Tenecteplase) Investigating wider windows Some idea of further treatment after IV tpa With EVT

57 LEUKOARAIOSIS & IV tpa Neumann-Haefelin, Stroke 2006 (449 pts) Pre treatment MRI IV tpa <6 h Moderate/ Severe LA No/ Mild LA Multivariate OR (age, NIHSS, treatment) sich 10.5% 3.8% 2.9 (p=0.03) Willer, JSCVD 2015 (1623 pts) Pre treatment CT IV tpa <6 h LA positive LA negative P value OR sich 7.3% 3.8% (95% CI )

58 Cerebral Microbleeds & IVT -Meta-analysis, 790 pts (JNNP 2012) Pre-tx MRI tpa sich 7.4% vs 4.4%, p=0.08

59 My opinion: LA and cerebral MBs Not an absolute contraindication Consider if you have the information In conjunction with all other factors No need to get MRI just to look for these in detail CT with suffice Look at prior imaging if any They do portend a higher risk of sich

60 IV tpa: Protocol

61 IV tpa: Audits

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63 Audit cases not treated - Reasons - Outcomes

64 Mechanical Thrombectomy Much less data

65 Mechanical thrombectomy in 6-8 h BENEFITS Functional Independence mrs 0-2 NNT =5 mrs 0-1 NNT =7 Any functional improvement NNT 2.6 sich risk same as IV alteplase No change in survival Without EVT treatment: 75% will have mrs 3-6

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67 Mechanical Thrombectomy: Risks sich: similar to IV tpa alone Extracranial bleeding and allergic reaction if IA/ IV tpa given Survival: no difference Complications related to procedure itself vessel dissection <=5% vessel perforation <=5% Clot migration with extension of infarction <=5% Embolization to new territories outside occluded vessel <=10% Groin hematoma <=11% Others: SAH, Vasospasm, Groin pseudoaneurysm Complications of sedation/ GA

68 Mechanical Thrombecomy: absolute indications Time window 6 h- 8h Large arterial obstruction CT/CTA or MRI/MRA (whichever is fastest) IV tpa bolus before CTA or MRA 3 SCENARIOS Contraindication to systemic fibrinolysis Eg. Trauma, therapeutic OAC Following IV tpa 4.5 to 8 hours

69 Mechanical Thrombecomy: absolute contraindications BP Similar to IV tpa? Less data New data out yesterday on MR CLEAN (in Stroke) Early ischemic change Some controversy In my opinion, is a major factor ASPECTS<=6

70 Mechanical Thrombecomy: Relative indications Distal arterial obstruction eg. Distal M2 / M3 Rate of recanalisation? Clinical benefit? Trauma to arteries and veins?

71 Mild NIHSS Older age Mechanical Thrombecomy: Relative contraindications relative paucity of data in terms of benefit &risks cost-effectiveness Irregular & tortuous morphology for technical considerations

72 Leukoaraiosis & EVT (Shi, Stroke 2011) Pre-intervention MRI EVT (91 pts) Incidence of Parenchymal Haemorrhage (PH) Moderate/ Severe LA in DWM Mild/ No LA in DWM P value EVT alone 23.1% (of 13) 15.2% (of 46) 0.68 EVT + IVT 60% (of 10) 27.3% (of 22) 0.12 Moderate/ Severe LA in DWM (EVT± IVT) independent predictors of PH OR, 6.26; 95% CI, ; P=0.005

73 CMB & EVT (Shi, J Neurointerv Surg. 2015) Pre-intervention MRI EVT (105 pts) Incidence of Parenchymal Haemorrhage (PH) CMBs No CMBs P value EVT ± IVT 16.2% 19.5% 0.68

74 Mechanical Thrombecomy: Pushing the boundaries Collaterals: multiphase CTA

75 Multiphase CTA: Case 1 56 male Day 1 post hernia operation Left MCA syndrome NIHSS 19 CT Aspects= 6

76 Left M1 obstruction

77 Poor collaterals

78 Poor collaterals

79 Large final infarct despite EVT

80 Multiphase CTA: Case 2 55 Male Day 1 Post STEMI, S/P PCI Left cortical syndrome NIHSS 7

81 T occlusion

82 Good collaterals- seen on phase 2

83 Good collaterals

84 Post EVT; mrs =2 on dc

85 Mechanical Thrombecomy: Protocol Initial Phase 1 revisions

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88 Mechanical Thrombectomy: Audit

89 Treated and Not Treated - indications and CI -processes (microtimes) -outcomes

90 Thank You

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97 RCT data numbers

98 DWI: Subtle FLAIR <4.5 h Sensitivity improved (0.86) Specificity decreased (0.48) Disadvantage: increase inter-rater variability Other modalities No clear differentiation of time with PWI volume, DWI volume PWI/DWI mismatch, CBF/CBV mismatch

99 MALIGNANT PROFILE: DEFUSE (Albers, Ann Neurol 2006) MRI pattern associated with sich & poor outcome with reperfusion Large DWI lesion and/or a large PWI lesion Empirical definition: Baseline DWI >= 100ml and/or Baseline PWI (T max delay>8sec) >= 100ml

100 PWI volume Mylnash, Stroke 2011 (EPITHET & DEFUSE) Impact of early reperfusion Predictor of poor outcome mrs 5-6 Optimal definition: PWI (Tmax>8 s) >85 ml Poor clinical outcome mrs 5-6 Parenchymal haemorrhage Reperfusi on No reperfusion P value 89% 39% % 11% <0.01

101 PWI volume (EPITHET + DEFUSE) Impact of IV tpa versus placebo Poor clinical outcome mrs 5-6 Optimal definition= PWI (Tmax >8 s) >125 ml PPV for mrs 5-6 IV tpa 89% Placebo 33% PPV OR 16.0 (95% CI )

102 PWI profile (Tmax >8 seconds) EPITHET & DEFUSE OR for mrs 5-6, comparing >125mL vs 125mL tpa arm = 34.8 (95%CI ) placebo arm = 2.1 (95%CI ) OR significantly higher for tpa (p=0.029) De Silva, ISC 2010

103 PWI profile (Tmax >8 seconds) PWI Tmax >8s volume >125 ml PPV (%) tpa 89 Placebo 33 PPV OR 16.0 (95% CI ) De Silva, ISC 2010

104 Decision-making for IV tpa for PWI (Tmax >8) >125mL What will likely happen if I give tpa? What is likely natural history without tpa? Will tpa increase risk of harm/ poor outcome, over natural history? 89% will have poor outcome 33% will have poor outcome Yes by 16-fold

105 Recent MI as CI Recent MI not listed as a contraindication for IV use for Activase, Actilyse Thrombolysis used for MI: Dosing of alteplase similar Stroke not uncommon after recent MI 23.9 per 1000 person-months in first 30 days

106 Clinical trials of IV alteplase Landmark NINDS trial Recent MI in prior 3 mth an exclusion No basis explained Subsequent trials (ECASS, ALTANTIS, EPITHET) Followed NINDS NEJM 1995 Hacke, NEJM 2008

107 Paucity of data on stroke patients with recent MI No cohort studies Treated with IV thrombolysis Natural history without thrombolysis Only 3 reports describing 5 patients since US licensing in 1996 all STEMI Logic of negligible risk with NSTEMI

108 Time Window for Risk Ischemic focus maximally soft at 4-5 days of MI, extending to 2 weeks Fibrosis and scarring complete by week 6-7 Infarcted myocardium showing coagulative necrosis and depleted collagen Well-healed myocardial infarct with replacement of the necrotic fibers by dense collagenous scar. Cotran, WB Saunders 1989

109 My opinion: Recent MI NSTEMI very low risk STEMI consider urgent 2D echo to confirm: consider EVT