recent advances in iv thrombolytic therapy for ischemic...

台東馬偕

洪國華

急性缺血性中風溶栓治療之最新進展RECENT ADVANCES IN THROMBOLYTIC THERAPY

FOR ACUTE ISCHEMIC STROKE

2012-12-13

腦中風的主要分類

1. Imaging of brain before any specific

therapy

2. IV tPA for selected patients within 3

hours

3. Aspirin 160~325 mg within 48 hours

4. Stroke unit

治療缺血性中風最重要的常規AHA/ASA Guideline Class I Procedure/Treatment, Level A Evidence

斑塊破裂之發展史

缺血性中風的致病機轉

Source: G. W. Albers, etc Antithrombotic and thrombolytic therapy for ischemic stroke: the Seventh

ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126 (3 suppl.): 483S–512S

小動脈疾病

大動脈疾病

心因性

其他

RED CLOT

救治缺血半陰影區是治療缺血性中風的首要目標

血流量不可逆腦損傷

良性延遲供血區

對外宣導：把握黃金三小時

對內宣導：把握黃金60分鐘

腦中風急診病患處置流程三重點

啟動

急性腦中風

處置流程

急診護理師 □ 通知 Neuro

□ Vital signs

□ IV (N/S)抽血

□ EKG

神經內科醫師 □ NIHSS

□ 適用 iv tPA

□ 不適用 iv tPA

神經外科醫師 □ 手術

□ 不手術

急診醫師 □ Brain CT

□ 顱內出血？

□ iv tPA禁忌症？

檢傷護理師 □ FAST (

1.臨床懷疑是急性缺血性腦中風，中風時間

明確在3小時內

2.腦部電腦斷層沒有顱內出血

3.年齡在18歲到80歲之間（年齡在18歲以

下或80歲以上治療與否，應由醫師審慎評

估病患整體狀況並與病患及家屬充份溝通

後再作決定。）

急性中風靜脈注射RT-PA之收案條件

……罹患腦中風的病人只有不到三分之一的機會，可恢復

到正常的功能。您若使用這種血栓溶解劑將會增加百分

之三十三復原的機會…

…rt-PA是目前所能建議的最好治療方式，但有危險性：

一百個使用這種血栓溶解劑rt-PA治療的病人，將會有六

個病人(十倍於不用這種血栓溶解劑治療的病人)，可能

引起腦部出血的危險，也可能會因而死亡。但是，研究

顯示此種藥物，並不會增加死亡率……

急性中風靜脈注射RT-PA之病人告知書

如何減少症狀性腦內出血的危險？

過去病史、臨床現況、生化及影像所見

• 曾有顱內出血病史

• 過去對本藥之主成份Actilyse或賦型劑過敏者

• 最近3個月內有中風病史

• 最近3個月內有嚴重性頭部創傷

• 最近3個月內發生過急性心肌梗塞

• 最近21天內曾有胃腸道或泌尿系統出血

• 最近14天內曾動過大手術或有嚴重創傷

• 過去10天內曾對無法壓制之部位施行血管穿刺

（如鎖骨下或頸靜脈穿刺）

排除條件 1：過去病史（必須均為“否”）

• 發作的時間已超過3小時或症狀發作時間不明

• 症狀已迅速改善或症狀輕微（例如NIHSS＜4分）

• 嚴重之中風（例如NIHSS＞25）

• 中風發作時併發癲癇（影像檢查能確定為缺血性中風則

不在此限）

• 收縮壓＞185 mmHg

• 舒張壓＞110 mmHg

排除條件2A：臨床現況（必須均為“否”）

• 顱內腫瘤、動靜脈畸形或血管瘤

• 出血性視網膜病變，如糖尿病性（視覺障礙可能為出血

性視網膜病變的指標）或其他出血性眼疾

• 細菌性心內膜炎，心包炎

• 有懷疑主動脈剝離之證據

排除條件2B：臨床現況（必須均為“否”）

• 嚴重肝病，包括肝衰竭、肝硬化、肝門脈高壓（食道靜

脈曲張）及急性肝炎

• 急性胰臟炎

• 身體任何部位有活動性內出血

• 其他（例如在排除條件未提到但會增加出血危險的狀況，

如活動性肺結核、洗腎患者、嚴重心衰竭、身體太衰弱

者或其他）

排除條件2C：臨床現況（必須均為“否”）

• 發作前48小時內使用heparin且aPTT過高

• 病人正接受口服抗凝血劑且INR＞1.7

• 血小板＜100,000 / mm3

• 血糖＜50mg/dl或＞400mg/dl（血糖>200mg/dl即須非

常小心）

排除條件 3：生化所見（必須均為“否”）

• 影像評估為嚴重之中風（電腦斷層大於1/3中大腦動脈灌

流區之低密度變化，或中線偏移）

排除條件 4：影像所見（必須均為“否”）

• 過去10天內分娩

• 控制不良之糖尿病

排除條件 5：其他（因風險增加，施打與否需與病患與家屬做充分溝通）

NINDS-TPA TRIALS 1 AND 2

Image courtesy of UCLA Stroke Center

mRS

mRS

Modified Rankin Scale

6

5

4

3

2

1

mRS=0

13%

7%

20%

20%

13%

27%

40%

47%

Favorable outcome

台東馬偕醫院急性腦梗塞病人靜脈溶栓治療之成果FROM JULY 2006 TO JUNE 2011

At 3 month follow-up

PLUMBER

WE CAN’T DO IT

OURSELVES

RECENT ADVANCES IN THROMBOLY TIC THERAPY FOR

ACUTE ISCHEMIC STROKE

1. Can thrombolysis risks be reduced by using better

fibrinolytics?

2. Can efficacy be further enhanced by other

recanalization stragedies?

3. Can the time window be extended?

4. Can more people be treated?

Not fibrin-specific

Decrease blood levels of fibrinogen, coagulation

factors & von Willebrand factor

Immunological side effects

It is recommended that this medication

should not be used again after 4 days from

the first administration

Only have historical importance

FIRST GENERATION FIBRINOLYTICS

(STREPTOKINASE, UROKINASE)

More fibrin-specific

Less immunological side effects (1~5% angioedema for IV

rt-PA)

Pro-urokinase

IA thrombolytic agent in PROACT II trial for MCA occlusion

Alteplase (rt-PA)

The only FDA approved fibrinolytic drug in acute

ischemic stroke

Short half-life (4–6 min)

Might damage blood–brain barrier

SECOND GENERATION FIBRINOLYTICS

(ALTEPLASE, PRO-UROKINASE)

Modified forms of alteplase


Longer half-life

Applied in only trials

Higher recanalization rate compared to alteplase

Similar outcome as alteplase?

THIRD GENERATION FIBRINOLYTICS

(RETEPLASE, TENECTEPLASE)

Produced by genetic methods


No neurotoxicity

Half-l ife of about four hours

Desmoteplase In Acute Stroke (DIAS) trial

Randomized, placebo-controlled trial with a 3 to 9-h time window

DIAS-2

Neither 90 nor 125-µg/kg were effective

DIAS-3 & DIAS-4

IV bolus dose of 90 µg/kg

Inclusion: Patients with occlusion or high-grade stenosis (TIMI 0-1) in

proximal cerebral arteries as assessed by MRA or CTA

FOURTH GENERATION OF FIBRINOLYTICS

(DESMOTEPLASE)

1. Can thrombolysis risks be reduced by using

better fibrinolytics?







1. IV thrombolysis

rtPA

2. IA thrombolysis

rtPA, pro-urokinase, urokinase

3. Mechanical thrombectomy

Merci Retriever

Penumbra Aspiration System

Solitaire FR Revascularization Device

RECANALIZATION STRATEGIES FOR


Basilar artery: 30% [7]

Terminal part of the ICA: 6%[9]

M1 part of the MCA: 30% [4]

M2 part of the MCA: 44% [3]

Tandem ICA and MCA occlusion: 27%[5+6]

SUCCESS RATES OF IV ALTEPLASE

IN RECANALIZATION

Alexandrov, A. V. (2010b). Current and future recanalisation strategies

for acute ischemic stroke (Review). J. Intern. Med. 267, 209–219.

9

IA & IV THROMBOLYSIS

Partial or complete recanalization : IA vs IV = 64.6% vs 17.8%; OR=6.42;

95% CI= 3.67 to 11.24 (Source: IA Fibrinolysis for Ischemic Stroke: Meta-

Analysis Stroke. 2010;41:932-937)

ATHEROSCLEROTIC PLAQUE粥狀硬化斑塊

Hansson et al. Nature Reviews Immunology 6, 508-519 (July 2006) | doi:10.1038/nri1882

纖維帽（fibrous cap）

富含脂肪的核心（lipid core）

RUPTURED PLAQUE

MERCI CLOT RETRIEVAL DEVICE

ENDOVASCULAR VS IV THROMBOLYSIS

Current Cardiology Reviews, 2010, Vol. 6, No. 3

Intra-arterial thrombolysis

Mechanical thrombectomy

Intravenous thrombolysis

Control groups






Control groups

17.8% (4~68%)






Control groups






Control groups

17.8% (4~68%)

腦缺血發作三小時內接受靜注ALTEPLASE造成的改變

PERPLEXED PLUMBER

Transcranial Doppler

Vm = 59 cm/sec

PI = 0.59

THROMBOLYSIS IN BRAIN

ISCHEMIA (TIBI) FLOW GRADES

2 MHz transcranial Doppler ultrasound (TCD)

Vibration and thermal effects improve breakdown of

the clot

5 m micro bubbles given intravenously can further

enhance thrombolysis

Efficacy depends on the presence of the bone

window & the technique of the operator

ULTRASOUND-ENHANCED INTRAVENOUS

THROMBOLYSIS

Considered to be an experimental method

急性缺血性中風之銜接治療(STROKE. 2012;43:1302 -1308. )

The pooled estimate for recanalization rate was 69.6% (95% CI,

63.9%–75.0%)

Meta-analysis on cl inical outcomes showed a pooled estimate of

48.9% (95% CI, 42.9%–54.9%) for favorable outcome

17.9% (95% CI, 12.7%–23.7%) for mortality

8.6% (95% CI, 6.8%–10.6%) for symptomatic ICH

CRUDE ODDS RATIOS OF

FAVORABLE OUTCOMES

Time to intravenous treatment is critical to improve recanalization rates and

favorable outcomes.


MORTALITY OUTCOMES


SICH OUTCOMES

THE FUTURE OF ACUTE STROKE THERAPY

www.frontiersin.org May 2011 | Volume 2 | Article 32

8h

EMERGENCY PLUMBERS

Phase III randomized multicenter open-label clinical trial

IV rt-PA initiated within 3 h of stroke onset

Stopped after 656 of the intended 900 patients were

enrolled for there was a very low likelihood of finding a 10%

difference in favorable clinical outcome at 90 days (modified

Rankin Scale score of 0~2) in combined treatment arm

INTERVENTIONAL MANAGEMENT OF

STROKE III (IMS III) TRIAL

IV-rtPA vs

IV-rtPA + IA-rtPA via standard microcatheter

IV-rtPA + IA-rtPA via EKOS micro-infusion catheter

IV-rtPA + Merci Retriever IA-rtPA

IV-rtPA + Penumbra Aspiration System IA-rtPA

IV-rtPA + Solitaire FR Revascularization Device IA-rtPA

EKOS MICRO-INFUSION CATHETERPROVIDES CONCURRENT LOW - INTENSIT Y ULTRASOUND ENERGY

MERCI RETRIEVER

PENUMBRA ASPIRATION SYSTEM

SOLITAIRE FR

REVASCULARIZATION DEVICE

1. Clinical outcome of patients presenting with moderate to

severe stroke (NIHSS 8) treated with IV-rtPA alone

2. Efficacy of IA-rtPA therapy for acute ischemic stroke

3. Safety and efficacy of the MERCI retriever, EKOS catheter,

Penumbra aspiration devices and Solitaire FR device

stent-retriever and their combination with IA-rtPA

4. Angiographic features as predictors of outcome in IA

therapy

IMS III TRIALWILL PROVIDE INDEPENDENT DATA ON

I THINK I FOUND THE

PROBLEM

Chance to become symptom-free or have minimal

residual symptoms if treated with IV thrombolysis

0~60 min: 1 out of 2

60~90 min: 1 out of 4

90~180 min: 1 out of 9

180~270 min: 1 out of 21

TIME LOST IS BRAIN LOST!

Marler et al., 2000; Saver et al., 2010

ECASS-III

INCLUSION AND EXCLUSION

CRITERIA OF ECASS IIIEuropean Cooperative Acute Stroke Study III

ECASS 3: DISTRIBUTION OF SCORES ON

THE MODIFIED RANKIN SCALE

mRS 0 & 1 were more

frequent in rt-PA treated

group (52 vs. 45%, p=0.04)

3 months after treatment

Mortality in the rt-PA

treated group was not

significantly different

Symptomatic ICH were

more frequent in the rt-PA

group (2.4 vs. 0.2%,

p=0.001)

Death < 7 days:11% in tPA group vs 7% in control group (p=0.001) (+4%)

Death between 7 and 180 days: 16% vs 20% respectively (-4%)

A signif icant shift toward lower (better) scores in treated vs untreated

patients (adjusted common OR 1.27, 95% CI 1.10 -1.47, p=0.001)

IST-33/4 WERE TREATED AFTER 3 HOURS

2012 LANCET META-ANALYSIS

IV ALTEPLASE IN STROKE

RANDOMISED CONTROLLED TRIALS OF

ALTEPLASE IN ACUTE ISCHEMIC STROKE

www.thelancet.com Published online May 23, 2012 DOI:10.1016/S0140-6736(12)60738-7

IST-3 EARLY OUTCOME

IST-3 FINAL OUTCOME

BENEFIT DID NOT SEEM TO BE

DIMINISHED IN ELDERLY PATIENTS

Time Topics Speaker Moderator

14:30 -- 14:40 Opening Remarks 李宗海教授

14:40 – 15:00 rt-PA治療從3小時延長至4.5小時之建議趙雅琴醫師劉嘉為主任

15:00—15:20 rt-PA治療對年齡超過80歲之建議陳志弘醫師林瑞泰主任

15:20—15:40 rt-PA治療在服用新型口服抗凝血劑患者之建議張谷州醫師盧玉強主任

15:40 –16:00 Break ALL

16:00 – 16:20Beyond Time is Brain: The role of Functional

Neuroimaging in Thrombolytic Therapy 鄧木火教授胡漢華教授

16:20 – 17:10 Panel Discussion

許世斌主任龔嘉德主任林志隆主任洪國華主任李垂勳主任謝鎮楊醫師

林祖功主任戴志達主任

17:10---17:20 Closing Remarks 胡漢華教授

南區急性腦中風RT-PA治療準則修訂研討會會議日期： 2012年12月16日 (週日)

1. Alteplase (rt-PA) is the only FDA approved fibrinolytic drug

in acute ischemic stroke.

2. Time to IV rt-PA is critical to improve outcome.

3. Bridging therapy is associated with acceptable safety and

efficacy in ischemic stroke patient.

4. The usefulness of mechanical thrombectomy is not yet

established.

5. Thrombolysis is of net benefit in ischemic stroke patients

who are over 80 y/o and treated within 4.5 hours.

TAKE HOME MESSAGE

BYE-BYE!

項目計分腦死深度昏迷嚴重失語言語障礙無法測試

1. Level of Consciousness : a. Responsiveness 0~3 3 3 0 0

b. Questions 0~2 2 2 2 1 1

c. Commands 0~2 2 2 0 0

2. Horizontal Eye Movement 0~2 2 1~2

3. Visual Field Test 0~3 3 3

4. Facial Palsy 0~3 3 3

5. Motor Arm a. Left 0~4 4 4 96

b. Right 0~4 4 4 96

6. Motor Leg a. Left 0~4 4 4 96

b. Right 0~4 4 4 96

7. Limb Ataxia 0~2 2 0 0

8. Sensory 0~2 2 2 0~1

9. Language 0~3 3 3 3

10. Dysarthria 0~2 2 2 2 96 96

11. Extinction and Inattention 0~2 2 2 0

Total 0~42 42 39~40

美國國家衛生研究院腦中風量表(NIHSS)

Score Stroke Severity

0 No Stroke Symptoms

1~4 Minor Stroke

5~15 Moderate Stroke

16~20 Moderate to Severe Stroke

21~42 Severe Stroke

NIH STROKE SCALE & STROKE SEVERITY

TIMI 0 flow (no perfusion)

Absence of any antegrade flow beyond a coronary occlusion.

TIMI 1 flow (penetration without perfusion)

Faint antegrade coronary flow beyond the occlusion, with

incomplete filling of the distal coronary bed.

TIMI 2 flow (partial reperfusion)

Delayed or sluggish antegrade flow with complete filling of the

distal territory.

TIMI 3 flow (complete perfusion)

Normal flow which fills the distal coronary bed completely

TIMI GRADE FLOWTIMI=“THROMBOLYSIS IN MYOCARDIAL INFARCTION”

Grade 0: No Perfusion and no antegrade flow beyond the

point of occlusion.

Grade 1: Penetration with minimal perfusion

Grade 2: Partial perfusion

2a: Only partial filling (

0 完全無症狀

1有症狀，但無顯著殘障：可以自己執行所有經常性的日常生活任務及活動者

2稍有殘障：不能執行所有發病前能從事的活動，但是未經協助也可以照顧自己的生活

3中度殘障：日常生活需要一些幫忙，但不經協助也可以獨自行走

4中度至重度殘障：若不經協助，則不能行走，也不能執行日常生活的需求

5 重度殘障：臥床、失禁，且需人長期照顧者

6 死亡

MODIFIED RANKIN SCALE

HEMORRHAGIC

TRANSFORMATION

HI 1 HI 2

PH 1 PH 2

Source: M. Fiorelli, et al., Hemorrhagic

transformation within 36 hours of a

cerebral infarct: relationships with early

clinical deterioration and 3-month outcome

in the European Cooperative Acute Stroke

Study I (ECASS I) cohort. Stroke 1999; 30:

2280–4

Hemorrhagic infarct

-------------------------------------------

Parenchymal hemorrhage

SOLITAIRE

recent advances in iv thrombolytic therapy for ischemic...

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