Thrombolytic Therapy in Acute Ischemic Stroke.pdf

2015/3/13

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Thrombolytic Therapy in Acute Ischemic Stroke Stroke: An Overview

Definition of Stroke

Stroke (Cerebrovascular accident, CVA): rapidly developing clinical signs of focal or global disturbance of cerebral function, with symptoms lasting 24 hours or longer, or leading to death, with no apparent cause other than a vascular origin

WHO, 1976 Stroke definition by time course: Transient ischemia attack (TIA): ischemic events < 24

hours without apparent permanent neurological deficits Stoke in evolution: progressive neurological deficits

over time suggesting a widening of the area of ischemia Completed stroke: ischemic event with persisted

deficit

Stroke: Pathophysiology

Ischemic Stroke (83%)Hemorrhagic Stroke (17%)

AtherothromboticCerebrovascularDisease (20%)

Embolism (20%)Lacunar (25%)Small vessel disease

Cryptogenic and Other KnownCause (30%)

IntracerebralHemorrhage (59%)

Subarachnoid Hemorrhage (41%)

Albers GW, et al. Chest. 1998;114:683S-698S.Rosamond WD, et al. Stroke. 1999;30:736-743.

CVA Recognition: FAST

F

A

S

T Time: call 119!!

Stroke Warning Symptoms

If you see someone having any of these symptoms call 119 Every minute counts!

Sudden numbness or weakness of face, arm or

leg, especially on one side of the body

Sudden confusion, trouble speaking or

understanding

Sudden trouble seeing in one or

both eyes

Sudden trouble walking, dizziness, loss of balance or

coordination

Sudden severe headache with no

known cause

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Left (Dominant) Hemisphere Stroke: Common Pattern

Right (Non-dominant) Hemisphere Stroke: Common Pattern

Brain Stem / Cerebellum / Post Hemisp. Patterns.

Motor or sensory loss in all four limbs

Crossed signs Limb or gait ataxia Dysarthria Dysconjugate gaze Nystagmus Amnesia Bilateral visual field defects

Stroke: A Treatable Condition...

IV tPA is approved for use within 3 hours of symptom onset (NINDS trial)

Intra-arterial therapy has proven to be safe and effective within 6 hours (PROACT II)

Combined IV/IA may be more effective than IV t-PA (Interventional Management of Stroke -IMS)

Mechanical and laser catheter technologies are showing great promise (Angio-Jet)

TIME LOST?

BRAIN LOST !

IS

Thrombolytic Therapy in Acute Ischemic Stroke

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Case : History O , 50 y/o man HTN, CAD 2014-8-20: Chest pain ER CV ward, Dx: STEMI, s/p

coronary stenting with DES in 2014-8-21 2014-8-23: 18:30 pm Rt limbs weakness, speechlessness and

disturbed consciousness 19:25 pm cranial CT scan: no hemorrhage, 19:40 pm Neurologist consultation, NIHSS: 20,

Case : CT Scan of Brain

20140823 19:25pm

2014-8-23: 20:18 pm infusion of rt-PA (5 mg bolus and 50 mg

iv infusion for 1 hr, total 55 mg, 0.66 mg/Kg), 22:25 pm - NIHSS: 16

2014-8-25: Follow-up image (MRI): no hemorrhage Pt was discharged in 2014-9-16 (NIHSS: 1)

Case : Clinical Course Case : Follow-up Cranial MRI

5 Ps of Acute Ischemic Stroke Treatment

Parenchyma Pipes (arterial flow) Perfusion Penumbra Prevention of complication

Thrombolytic Therapy !?

Key Clinical Questions

What are the benefits and risks of tPA for acute ischemic stroke from:The original NINDS trial?Other studies: ECASS and ATLANTIS

trials?Pooled analysis of combined NINDS,

ECASS and ATLANTIS trial data?

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NINDS rtPA Trial: Two-part Trial

Part 1: test early clinical effect in 24 hours Part 2: 3-month outcome measures (BI, mRS,

GOS, and NIHSS) Randomization rtPA (0.9 mg/kg; 90 mg max) vs. placebo Stratified 0-90 min or 91-180 min after onset

Inclusion criteria: 18 years of age Acute ischemic stroke Clearly defined time of stroke onset ( 180 min.)Measurable neurological deficits Baseline CT scan showing no evidence of intracranial

hemorrhage

The NINDS t-PA Study Group. NEJM. 1995;33:1581-1587

NINDS rtPA Trial: Exclusion Criteria

Rapidly improving or minor symptoms

CT scan with ICH History of ICH Seizure at stroke onset Stroke or serious head

trauma 3 months Major surgery or other

serious trauma 2 wks GI or UT hemorrhage 3

wks SBP>185 or DBP>110

Glc 400 Sx of SAH Arterial puncture at

noncompressible site or LP 1 wk

Plt count 1.7 Clinical presentation

suggesting post-MI pericarditis Pregnant or lactating females


NINDS rtPA Trial: Trial Design

Part 1 Part 2Exclusion criteria

Inclusion criteria

Part 1 Randomization Part 2 Randomization

rtPA(144)

rtPA(168)

Placebo(147)

Placebo(165)

Primary outcome: 4-point improvement on NIHSS or complete resolution at 24 hrs

Primary outcome: global test statistic for favorable outcome (minimal or no disability at 3 months using 4 scales)


NINDS rtPA Trial: Results of Part I

NINDS rtPA Trial: Results of Part II NINDS rtPA Trial: No difference in mortality despite higher initial rates of symptomatic ICH

15.4

6.4 6.4

0.64.52.9

1721

0

5

10

15

20

25

TotalICH

SX ICH@ 36 h

ASX ICH@ 36

90 dDeath

rt-PAPlacebo

*

*

*p=.01

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tPA within 180 minutes: 30% better outcome at 90 days

12% absolute increase in patients with no or minimal disability at 3 months

NNT: 8.3 ICH rate at 36 hours: 3x greater (10.9 vs. 3.5%) Symptomatic ICH rate: 10x greater (6.4 vs. 0.6%) Mortality at 90 days: comparable (17 vs. 21%)

NINDS rtPA Trial: Main Results


NINDS rtPA Trial: Summary


Stroke: The Challenge

Only 1-3% of all stroke victims receive treatment with tPA in the US

25% of Acute MI patients receive treatment (lytics or PTCA) in the US

Mean time to presentation AMI: 3hrs Acute Stroke: 4-10hrs

24-59% patients present within 3 hours 40-76% patients present within 6 hours

Stroke: Reasons for Lack of Treatment

1. Patients inability to recognize stroke symptoms 40% of stroke patients cant name a single sign or

symptom of stroke or stroke risk factor. 75% of stroke patients misinterpret their symptoms 86% of patients believe that their symptoms arent

serious enough to seek urgent care2. Physicians lack of experience with stroke

treatment and therefore reluctance to risk treatment

3. Lack of organized delivery of care in many medical centers throughout the country.

In-Hospital Stroke Primary admission to hospital with a non-stroke

diagnosis Clear onset of new neurological deficits after

admission fulfilling the clinical diagnosis of a stroke Early ischemic changes on neuroimaging

examination 4-15% of all strokes

In-hospital Stroke: Definition

Manawadu et al. PLos ONE. 9(8):e104758

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Most common in-hospital stroke: ischemic stroke Half of all in-hospital strokes occur in surgical or

cardiology patients Stroke: a well-recognized complication in CEA and

cardiac surgery, less frequently in general surgery Cardiac and cerebral

angiography

In-hospital Stroke: Characteristics

Blacker. Lancet Neurol. 2003;2:741-6

Risk factors for stroke associated with cardiac surgery: old age, long duration cardiopulmonary bypass, recent MI, Lt main-stem coronary artery diseases, repeated cardiac surgery, ventricular thrombus, postinfarction angina, cardiac failure, DM, smoking and impaired renal function

Risk factor most consistently linked with perioperative stroke: history of stroke

Other factors: postoperative cardiac arrhythmia, fever, leukocytosis, high DBP, unstable BP, dehydration, Hx of MI

In-hospital Stroke: Risk Factors


The distribution of subtypes of in-hospital stroke is similar to that in the general stroke population

Cardioembolism: a major mechanism in up to 36% of in-hospital stroke Important in the perioperative period, especially

cardiac surgery Fat embolism after orthopaediac surgery Paradoxical embolism

Global or focal cerebral hypoperfusion Carotid stenosis: may be important in general

surgery :

In-hospital Stroke: Mechanism (I)


Hematological factors: Higher concentration of procoagulant proteins in

critically ill patients Changes in clotting factors during some postoperative

settings Dehydration Infections

Manipulation of antiplatelet and anticoagulant medications in the perioperative period

In-hospital Stroke: Mechanism (II)


In-hospital Stroke: Mechanism (III)


In-hospital Stroke: Recognition and Assessment


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Potential advantage of in-hospital stroke: rapid assessment and potential access to interventional therapy such as thrombolysis

Distinction between medical and post-operative patients is important IV thrombolysis is feasible in medical patients IV rt-PA is clearly contraindicated in post-operative

patients, especially cardiac surgery IA thrombolysis or mechanical thrombectomy? Neuroprotection?

In-hospital Stroke: Treatment


Why? Because time is brain

NIH-recommended Emergency Department Response Times

NINDS NIH website. Stroke proceedings. Latest update 2008.

DTN 60 min: the golden hour for evaluating and treating acute stroke

T=0Suspected

stroke patientarrives at stroke unit

10 minInitial MD evaluation

(including patienthistory, lab work

initiation, & NIHSS)

15 minStroke team

notified (including neurologic expertise)

25 minCT scaninitiated

45 minCT & labs interpreted

60 minrt-PA

given if patient

is eligible

IDEALLY performed

pre-hospital

3

tPA

tPA

:

: :

(Stroke code?):3 (or 5) (IV or IA thrombolysis)

!

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Thrombolytic Therapy in Acute Ischemic Stroke.pdf