SỰ CẦN THIẾT PHÂN LOẠI CHẨN ĐOÁN ĐỘT QUỴ NHỒI MÁU NÃO CẬP NHẬT CÁC NGHIÊN CỨU MỚI TỪ HỘI NGHỊ ĐỘT QUỴ HOA KỲ & ĐỘT QUỴ CHÂU ÂU 2016

Transcription

1 SỰ CẦN THIẾT PHÂN LOẠI CHẨN ĐOÁN ĐỘT QUỴ NHỒI MÁU NÃO CẬP NHẬT CÁC NGHIÊN CỨU MỚI TỪ HỘI NGHỊ ĐỘT QUỴ HOA KỲ & ĐỘT QUỴ CHÂU ÂU 2016 GS.TS Lê Văn Thính BVBM-ĐHYHN TS.BS Nguyễn Huy Thắng BV115-TP HCM

2 Outline 1 STROKE CLASSIFICATION 2 ENCHANTED 3 ARUBA

3 STROKE CLASSIFICATION 1.0 OCSP CLASIFICATION (BAMFORD) TOAST CLASIFICATION

4 Phân Loại Đột Quỵ 4

5 Small vessel disease 30-40% Cardioembolism 10-20% CÁC NGUYÊN NHÂN ĐỘT QUỴ Large artery disease 30-40% Uncommon cause of Stroke Stroke of undetermined etiology

6 Phân Loại Đột Quỵ Thiếu Máu Oxfordshire classification (OCSP) Trial of Org in Acute Stroke Treatment (TOAST) 6

7 Toàn Bộ Tuần Hoàn Trước PHÂN LOẠI BAMFORD Một phần Tuần Hoàn Trước Tuần Hoàn Sau Hội chứng NMN lổ khuyết 7

8 8

9 9

10 Phân loại TOAST 10

11 Bệnh lý xơ vữa mạch máu lớn Significant (>50%) stenosis Occlusion of a major brain artery or branch cortical artery Presumably due to atherosclerosis 11

12

13 MFV 240cm/s

14 Thuyên tắc não do huyết khối từ tim

15

16 BN nữ, 37T, rung nhĩ, hẹp 2 lá

17

18 Atrial myxoma Thrombus of the left ventricle 18

19 Small-artery occlusion (Lacune) LS: H/c nhồi máu não lổ khuyết, không có t/c vỏ não T/C: Tiểu đường, THA CT/MRI: bình thường, tổn thương thân não hoặc vùng dưới vỏ <1.5cm Duplex/arteriography: Không ghi nhận tắc hẹp ĐM lớn 50%

20

21 Stroke of undetermined etiology Các khảo sát cân lâm sàng không xác định được nguyên nhân đột quỵ. Chưa hoàn tất các khảo sát CLS 2 nguy cơ có thể là nguyên nhân của đột quỵ 21

22

23 So Sánh 2 Phân Loại Đột Quỵ

24

25 25

26 Distribution of symptomatic atherosclerotic vascular lesions in 1,000 acute stroke patients InCr ICA 7% PCA 7% VA 11% ACA 6% MCA 37% PROSAC 9 university hospitals Using DWI and MRA Throughout Korea, ICAS:ECAS = 7:3 BA 9% ExCr ICA 23% Kim JS et al. Stroke 2012

27 Risk factors dyslipidemia, Mets syndrome Genes Vascular tortuosity Contamination ICAS vs. ECAS

28 Limitations in resolution (often flow dependent) Artifact Can not evaluate vessel wall pathology

29 45-yr old man without risk factors -- Diagnosis?

30 High resolution vessel wall MRI

31 Patients who visited AMC with (1) unilateral MCA disease ( 50% stenosis or occlusion), (2) were 55 years old and had no or minimal ( 1) atherosclerotic risk factors (3) suspected as having ICAS on MRA We excluded patients with a confirmed diagnosis HR-MRI performed Ahn SH, Kim JS et al, Stroke 2015

32 Stroke mechanisms of ECAS Mostly, artery to artery embolism Vulnerable plaque, platelet aggregation Inflammation & Hemodynamic- not major stroke Platelet aggregation ++

33 Mechanisms of stroke in ICAS Perforator (branch) occlusion Artery to artery embolism Platelet aggregation ++ In situ Thrombotic occlusion

34 Kết Luận Trong chẩn đoán ĐQ, việc phân loại ĐQ là rất quan trọng và cần thiết. Từ phân loại ĐQ, thầy thuốc có thể xác định nguyên nhân và cơ chế của ĐQ, trên cơ sở đó sẽ có lựa chọn điều trị thích hợp.

35 ENCHANTED 2.0 Answer reliably efficacy and safety questions in acute IS Compared to standard-dose (0.9 mg/kg) rtpa, low-dose (0.6 mg/kg) i.v. rtpa

36

37 Background intravenous alteplase recombinant tissue plasminogen activator - rtpa Proven medical reperfusion treatment for acute ischaemic stroke within 4.5 hours of symptom onset, but risk of symptomatic intracerebral haemorrhage (ICH) risk of early death Most regulatory authorities - approved dose 0.9mg/kg Japan approval - lower dose (0.6mg/kg) Variable dose in Asia related to patient affordability and clinician concern over ICH risk 37

38 Dual aims: to answer reliably efficacy and safety questions in acute ischaemic stroke Hypotheses - compared to standard-dose (0.9 mg/kg) rtpa, low-dose (0.6 mg/kg) i.v. rtpa is: non-inferior - clinical outcome (mrs 2-6) at 90- days 2. safer - lower risk of major sich? Compared to guideline recommended BP control (<185 mmhg systolic target before initiation of rtpa), is rapid intensive BP lowering ( mmhg SBP target): 3. superior - clinical outcomes (mrs 2-6) at 90-days

39 ENCHANTED clinical network Norway (1 site) United Kingdom (26 sites) China (27 sites) + Hong Kong (1 site) S Korea (12 sites) Italy (3 sites) Taiwan (8 sites) Thailand (1 site) Vietnam (6 sites) Colombia (2 sites) Singapore (1 site) Chile (4 sites) Brazil (6 sites) Australia (4 sites) 39

40 Major findings of ENCHANTED In thrombolysis-eligible patients with acute ischaemic stroke, lower dose (0.6mg/kg) dose rtpa : Not shown to be noninferior to standard-dose (0.9 mg/kg) for primary outcome (conventional binary 0-1 vs 2-6 mrs) Shown to be noninferior to standard-dose (0.9mg/kg) with respect to global functional outcome (shift on mrs) Comparable EQ-5D and all other clinical measures Caused fewer deaths, less ICH, and less fatal ICH Consistency of findings in all pre-specified subgroups 40

41 Implications for Clinicians In thrombolysis-eligible acute ischaemic stroke patients, low-dose rtpa: Is safer - fewer symptomatic or fatal ICH, and fewer deaths Is non-inferior (ie equally effective) for global functional recovery (shift), both ITT and PP Low-dose alteplase to be seriously considered for all patients with acute ischaemic stroke considered at high risk of ICH, regardless of age, ethnicity and severity 41

42 A Randomized trial of Unruptured Brain AVMs Five-year Results 3.0 Compare best possible AVM eradication vs Medical management alone

43 43

44 BN nữ, 35 tuổi, nhập viện vì co giật. Được chẩn đoán AVM 3cm vùng đính P, có nguy cơ vỡ rất cao. Được can thiệp thành công bằng kỹ thuật can thiệp nội mạch 44 Author 00 Month Year

45 A Randomized trial of Unruptured Brain AVMs Five-year Results Stapf C 1,2,3 Overbey JR 4 Mohr JP 1 Moskowitz AJ 4 Vicaut E 2 Parides MK 4 for the international ARUBA Investigators 1 Stroke Center, Columbia University, New York, NY 2 Univ Paris Diderot Sorbonne Paris Cité, Paris, France 3 CRCHUM, Université de Montréal, Montreal, QC, Canada 4 InCHOIR, lcahn Sch of Med at Mount Sinai, New York, NY Christian Stapf, M.D. Full Professor Department of Neurosciences Université de Montréal Principal Scientist, CRCHUM Attending Vascular Neurologist, CHUM

46 Brain Arteriovenous Malformations Clinical issues: Hemorrhage Epilepsy Focal deficits Headaches Asymptomatic Al-Shahi R & Stapf C, Practical Neurology, 2005 USA / Canada: 5000 new cases detected per year (mean age: 40 years) 3000 (60%) diagnosed unruptured

47 ARUBA International Americas Europe Australasia Multidisciplinary Neurosurgery Neuroradiology Radiotherapy* Neurology * Local or associated site Prospective Internet-based Real time Online Monitoring Randomized 1:1 400 patients planned NIH/NINDS Funding DSMB

48 ARUBA International Americas Europe Australasia Prospective Internet-based Real time Online Monitoring Standard of care Best possible AVM eradication versus Medical management alone Experimental study arm

49 ARUBA Inclusion: Unruptured Brain AVM confirmed by MRI Age > 18 years Informed consent Exclusion: Previous AVM hemorrhage Prior AVM treatment AVM considered untreatable for eradication

50 ARUBA Primary Endpoint: Time to Death or Symptomatic Stroke Symptomatic Hemorrhage or Infarction CT / MRT Secondary Endpoint: Neurological Deficit Rankin Scale 2 Status 5 years post randomization

51 ARUBA A Randomized trial of Unruptured Brain AVMs Year 1-5 Year DSMB: April 15, 2013 Enrollment stopped! n=226 55% mean follow-up 33 3 months

52 ARUBA A Randomized trial of Unruptured Brain AVMs Year 1-5 Year July 15, 2015 Data locked n=226 mean follow-up 50.4 months n=110 Medical management n=116 Interventional treatment

53 Demographics ARUBA Patient baseline profiles (n=226 AVM patients) Age (yrs), mean Female gender Clinical Presentation Seizure Asymptomatic Mod. Rankin Score mrs 0 mrs 1 ARUBA cohort n= (±12) 94 (42%) 97 (43%) 94 (42%) 108 (48%) 118 (52%)

54 ARUBA Patient baseline profiles (n=226 AVM patients) ARUBA cohort n=226 Scotland 1 n=204 Finland 2 n=187 Demographics Age (yrs), mean 44 (±12) 47 (±16) 36 (±15)* Female gender 94 (42%) 83 (41%) 80 (43%) Clinical Presentation Seizure 97 (43%) 85 (42%) n.a. Asymptomatic 94 (42%) 101 (50%) n.a. Mod. Rankin Score mrs (48%)* 26 (13%) n.a. mrs (52%) 104 (51%) n.a. * p< Al-Shahi Salman R, et al. JAMA. 2014;311: Laakso A, et al. Neurosurgery. 2008;63:

55 ARUBA Spetzler Martin Grading Scale Patient baseline profiles (n=226 AVM patients) AVM anatomy bavm size <3cm Lobar location Infratentorial location Eloquent location Spetzler-Martin I Spetzler-Martin II Spetzler-Martin III Spetzler-Martin IV Spetzler-Martin V ARUBA cohort n= (62%) * 205 (91%) 13 (6%) 107 (47%) 65 (29%) * 72 (32%) * 64 (29%) Scotland 1 Size of AVM n=204 Small (<3 cm) 1 Medium (3-695 cm) (47%) 2 Large (>6 cm) (92%) 7 (3%) Location 104 (51%) Noneloquent site (15%) Eloquent site* 51 (25%) Venouse drainage 41 (20%) Superficial 0 Finland 2 n= (22%) 137 (73%) * 10 (5%) n.a. 13 (7%) 15 (27%) 61 (33%) 23 (10%) 18 (9%) 46 (25%) * Deep 0 2 (1%) 1 14 (8%) * * p< Al-Shahi Salman R, et al. JAMA. 2014;311: Laakso A, et al. Neurosurgery. 2008;63:

56 ARUBA Primary outcome, n=226 As Randomized (time to 1 st stroke or death)

57 ARUBA Primary outcome, n=226 As Randomized (time to 1 st stroke or death)

58 ARUBA Primary outcome, n=226 As Randomized (time to 1 st stroke or death) NNH: 5 (95% CI 3-13)

59 Outcome per Randomization (intention to treat) ARUBA Interventional Therapy (N=116) n % Medical Management (N=110) n % P Value Symptomatic stroke or death < Any incident stroke Hemorrhagic Ischemic < Any death AVM-related Not AVM-related Outcome on Treatment ** (per protocol) Interventional Therapy (N=106) n % Medical Management (N=120) n % P Value Symptomatic stroke or death < Any incident stroke Hemorrhagic Ischemic < Any death AVM-related Not AVM-related ** N=8 (3.5%) patientsrandomizedto MM crossed over to IT. N=15 (6.6%) patients randomized to IT never received therapy. N=3 suffered a stroke prior to the initiation of IT

60 ARUBA Primary outcome, n=226 As Treated (time to 1 st stroke or death)

61 ARUBA Primary outcome, n=226 As Treated (time to 1 st stroke or death) NNH: 3 (95% CI 2-6)

62 ARUBA Secondary Outcome Death or disability (mrs 2) at 5 years

63 ARUBA Secondary Outcome Death or disability (mrs 2) at 5 years

64 ARUBA Secondary Outcome Death or disability (mrs 2) at 5 years 38% 18%

65 ARUBA Secondary Outcome Death or disability (mrs 2) at 5 years 38% 18% 40% 17%

66 Event Type ARUBA Harm, n=226 Serious Adverse Events (as randomized) Interventional (n=116) Medical (n=110) N Rate per N Rate per Events pat/year Events pat/year Stroke Any <0.001 Hemorrhagic <0.001 Ischemic Focal Deficit* Any <0.001 Persistent Reversible Epileptic seizures Headache episode * unrelated to stroke, epilepsy p

67 Primary outcome subgroup analyses (as randomized) Medical managementbetter Preventive intervention better

68 Primary outcome subgroup analyses (as randomized) Medical managementbetter Preventive intervention better

69 ARUBA Secondary analyses: outcome by treatment modality Interventional treatment received n=106 patients Cumulative treatment modalities Primary endpoint* n (row %) Documented AVM obliteration** n (row %) Any endovascular (n=66) 33 (50.0) 34 (51.5) Any surgery (n=22) 9 (41.0) 21 (95.5) Any radiotherapy (n=57) 21 (36.8) 12 (21.1) * Primary endpoint: Symptomatic stroke or death ** DocumentedAVM removal required cerebral angiography by study protocol. For n=16 (15%) patients, the AVM status was unknown, n=43 (41%) had a documented AVM remnant on last follow-up imaging.

70 ARUBA Secondary analyses: outcome by treatment modality Interventional treatment received n=106 patients Cumulative treatment modalities Primary endpoint n (row %) Documented AVM obliteration** n (row %) Any endovascular (n=66) 33 (50.0) 34 (51.5) Any surgery (n=22) 9 (41.0) 21 (95.5) Any radiotherapy (n=57) 21 (36.8) 12 (21.1) Monomodal treatment (n=68) Endovascular (n=28) 14 (50.0) 14 (50.0) Surgery (n=7) 2 (28.6) 7 (100.0) Radiotherapy (n=33) 8 (24.2) 6 (18.2) Multimodal treatment (n=38) Endovascular and Surgery (n=14) 6 (42.9) 14 (100.0) Endovascular and Radiotherapy (n=23) 12 (52.2) 6 (26.1) Endovascular and Surgery and Radiothx (n=1) 1 (100.0) 0 (0.0) ** DocumentedAVM removal required cerebral angiography by study protocol. For n=16 (15%) patients, the AVM status was unknown, n=43 (41%) had a documented AVM remnant on last follow-up imaging.

71 ARUBA First pragmatic management trial in patients diagnosed with an unruptured brain AVM Data based on a representative study cohort. Bias (if any) favoring intervention.

72 Lessons learnt: ARUBA 1.Patients with unruptured brain AVMs are at risk for stroke. Spontaneous annual hemorrhage rate: 2.1% (95% CI: ) 2.The risk increases with the initiation of interventional therapy: Risk of death and stroke: by factor 4.5 Risk of functional deficits : by factor 2.5 No benefit for: Epilepsy, headaches 3.High risk across all treatment modalities and AVM subgroups

73 ARUBA Largest effect ever seen in a primary stroke prevention trial: Risk reduction of 78% (for stroke and death) Treatment of choice available world-wide at low-cost Trial results should be systematically disclosed to patients

74 ARUBA Largest effect ever seen in a primary stroke prevention trial: Risk reduction of 78% (for stroke and death) Treatment of choice available world-wide at low-cost Trial results should be systematically disclosed to patients Conclusion: Based on current knowledge, preventive interventions for unruptured AVMs may be dangerous: NNH = 5 (over 5 years) cannot be safely recommended should only be offered as part of a controlled clinical study

75 ARUBA Largest effect ever seen in a primary stroke prevention trial: Risk reduction of 78% (for stroke and death) Treatment of choice available world-wide at low-cost Trial results should be systematically disclosed to patients Conclusion: Based on current knowledge, preventive interventions for unruptured AVMs. may be dangerous: NNH = 5 (over 5 years) cannot be safely recommended should only be offered as part of a controlled clinical study

76 Conclusion 1 Standard dose IV thrombolysis is still recommended for Asian stroke patients. Low-dose alteplase to be considered for all patients with acute ischaemic stroke considered at high risk of ICH 2 For unruptured AVMs, just do LESS for MUCH MORE

77

78 WITHOUT HEALTH, THERE IS NO HAPPINESS THOMAS JEFFERSON THANK YOU FOR YOUR ATTENTION!