Thrombolysis in acute ischaemicstroke

DR.MURALI KRISHNA.CH.V

MD.DM

CONSULTANT NEUROPHYSICIAN

AWARE GLOBAL HOSPITAL,HYDERABAD

• Burden of stroke

• Types ,risk factors.

• Time is brain

• Evidence based thrombolysis.

• How big is the problem of STROKE?

Stroke accounts for 10% of all-cause mortality

Cancer

12%

Stroke

10%

Accidents

Respiratory infections 7%

HIV/AIDS 5%

Chronic obstructive pulmonary

disease 5%

Perinatal causes

DiarrhoeaTuberculosis

3%3%4%

2%

Malaria

Coronary heart disease

13%

American Stroke Association. Heart Disease and Stroke Statistics 2004

9%

27%

Other causes

Since 80s, a significant increase (> 2-fold ) has been noticed in incidence of stoke : 1–2 /1.000 people in USA, 2–2.5/1.000 in Western και 3–3.5/1.000 in Eastern Europe

What is specific to stroke in India?

• Analysis of community surveys from different regions of India shows a

crude stroke prevalence rate of about 203 per 100,000 population

above 20 years of age, with recent study done in eastern population

reaching 504 per 100,000 population

• Most studies carried out in India show that about 10% to 15% of

strokes occur in the population below 40 years, which is a higher

proportion compared with other countries

ACNR •2007

STROKE: A Major Problem for Public Health

increased ~65% until 2025

Broderick JP et al. Stroke 2004;35:205-211

Estimated number of strokes in USA during 2002-2025

Types of ischemic strokes

• Large artery disease ( cervical ICA / Subclavian /

Vertebral): artery to artery embolus / occlusion

• Medium sized artery disease (MCA/ ACA/ Basilar/

PCA) : artery to artery embolus / occlusion

• Small vessel disease (perforators) : occlusion due to

arteriosclerosis (HT)

• Cardiogenic embolus

• Hypercoagulable states

Risk Factors for StrokeModifiable

• Hypertension• Type 2 Diabetes• Cardiac disease• Atrial fibrillation• TIA/prior stroke• Dyslipidemia• Cigarette smoking• Alcohol/cocaine abuse• Physical inactivity• Carotid stenosis• Sickle cell disease• Obesity

Non-modifiable

• Older Age

• Gender

• Race/ethnicity

• Heredity

Circulation. 2001;103:163-182.

2.64

5.4

8.4

1.1 2

19.1

22.4

14.8

27

6.3

3.5

0

5

10

15

20

25

30

A B C D E F

Est

imat

ed 1

0-Y

ear R

ate

(%)

Men Women

10yr risk for Stroke in Adults 55 yrs old according to basic Risk Factors

(Framingham Heart Study)

A B C D E F

Systolic BP 95-105 130-148 130-148 130-148 130-148 130-148 mmHg

Diabetes no no yes yes yes yes

Smoking no no no yes yes yes

Previous AF no no no no yes yes

Previous CVD no no no no no yes

Stroke 1991;22:312-318

A very selfish organ

• The brain requires

20 % of

the total blood

pumped

by the heart.

• No fat for storage

in the brain

• Requires constant

supply of oxygen and glucose.

Stroke ,2006

Every minute if stroke is untreated, the average patient loses 1.9 million neurons, 13.8

billion synapses, and 12 km (7 miles) of axonal fibers.

Each hour in which treatment fails to occur, the brain loses as many neuron as it does in

almost 3.6 years of normal aging.

STROKE IS A DYNAMIC ONGOING PROCESS !!! Every minute 20 lakh neurons die !

PATHOPHYSIOLOGY OF STROKE & PENUMBRA

DWI-PWI …. Mismatch

“Time is Brain”

• Treatment of stroke is a salvage procedure.

Time of treatment in stroke is important for outcome

TOT NNT

108

MANY EVIDENCE BASED ACUTE STROKE THERAPIES AVAILABLE

STROKE UNIT IV THROMBOLYSIS Decom. Craniectomy

Mech. Thrombolysis IA – Thrombolysis & CE PTBA & Stenting

Golden period for stroke Rx esp. 90 min

IV thrombolysis with rt-PA in eligible patients is the standard care according to many national & International guidelines. CLASS I LEVEL A EVIDENCE

1) AHA guidelines2) EUSI guidelines3) ACC guidelines4) ACEP guidelines5) Karolinska stroke update consensus statement6) RCP guidelines (UK)7) Indian stroke association guidelines

IV Thrombolysis 0-3 hrs

- Prospective, randomized, double-blind trial

- 624 patients : half treated within 90 minutes, half treated within 91 to 180 minutes

- t-PA dose : 0.9 mg/kg, maximum dose : 90mg, 10% as IV bolus, remainder via 1-hour infusion

-- Careful attention to BP : < or equal to 185/110

- No ACs or antiplatelet agents for 24 hours

THE HALLMARK STUDYNINDS t-PA Study:

rt-PA Studies: NINDS Parts 1 and 2 – Results

NINDS Investigators. N Engl J Med 1995; 333 (24): 1581–1587.

placebo

rt-PA

modified Rankin Scale (mRS)

17.3 21.4 8.9 12.5 15.5 7.1 17.3

9.1 17.0 12.1 13.3 20.0 7.9 20.6

12.6% more rt-PA treated patients have favourable outcome

3% less rTPA treated patients are dead

0 1 2 3 4 5 6

And this was inspite of a 6.4% risk of ICH in the rTPA group

NINDS TPA Stroke Trial

Global outcome statistic: OR=1.7, 50% v. 38%= 12% benefit

Excellent outcome at 3 months on all scales

52%

38%43%

26%

45%

31%34%

21%

0%

10%

20%

30%

40%

50%

60%

Barthel

Index

Rankin

Scale

Glasgow

Outcome

NIHSS

score

TPA

Placebo

N Engl J Med 1995;333:1581-7

tPa vs time

Number of Patients Who Benefit and Are Harmed per 100

Patients tPA Treated in Each Time Window

27.0

22.2

15.9

5.0

1.3 2.45.0

7.1

0.0

5.0

10.0

15.0

20.0

25.0

30.0

0-90 91-180 181-270 271-360

Benefit

Harm

--Lansberg et al, Stroke 2009

Extended Time Frame for IVT : 3- 4.5 hrs

ECASS- 3

• Window period 3-4.5 hr

• 821 patients were randomized to IV tPA or placebo.

• Major symptomatic hemorrhages occurred in 2.4% of the tPA group versus 0.2% of the placebo group, with no increase in mortality.

• The proportion of patients with minimal or no disability increased from 45% with placebo to 52% with tPA, a 7% absolute improvement.

• The number needed to treat for 1 more patient to have a normal or near normal outcome was 14,

• and the number needed to treat for 1 more patient to have an improved outcome was 8.

• Overall, for every 100 patients treated within the 3- to 4.5-hour window, 16 had a better outcome as a result and 3 had a worse outcome.

• Iv Tpa 3-5 hrs-Vs placibo - ATLANTIS TRIAL-

• Excellent recovery at 90 days -34% vs 31%

• SICH IN First 10 days- 7% vs 1 %.

• Iv tpa up to 6hrs- ECASS 2

• mrs > 2 more in tpa group but not stat significant

• 10% increase in parenchymal hemorrage.

Tpa -age

tpa vs other drugs

IV urokinase

IV streptokinase

IV rt-PA

IV streptokinase

+ aspirin

IA pro-urokinase

IA urokinase

IV desmoteplase

Death or dependency at the end of follow-up

Total

0.91 (0.64, 1.42)

0.94 (0.72, 1.24)

0.77 (0.47, 0.89)

1.09 (0.49, 1.72)

0.55 (0.31, 1.00)

0.57 (0.28, 1.14)

0.85 (0.53, 1.38)

0.82 (0.73, 0.91)

All drugs and rt-PA Summary of effects, 2008; ORs (95% CI)

SICH Late Death or

(incl fatal) Death Dependency

All drugs 3.3 1.3 * 0.8 *

n=7152 2.7 - 4.1 1.1 - 1.5 0.7 - 0.9

p<0.00001 p=0.06 p<0.0001

rt-PA 3.1 1.1 0.8 *

n=3977 2.3 - 4.0 1.0 - 1.4 0.7 - 0.9

p<0.00001 p=0.16 p<0.0001

* Significant heterogeneity confounds interpretation

rt-PA trials: 2003 versus 2008 ORs (95% CI)

SICH Late Death or

(incl fatal) Death Dependency

2003 3.1 1.2 * 0.8 *

n=2955 2.3 - 4.2 0.9 - 1.5 0.7 - 0.9

p<0.00001 p=0.14 p=0.003

2008 3.1 1.1 0.8 *

n=3977 2.3 - 4.0 1.0 - 1.4 0.7 - 0.9

p<0.00001 p=0.16 p<0.0001

* significant heterogeneity confounds interpretation

IA Or iv TPA Or BOTH

Intraarterial TPA.

IA-TPA in selected pts. In < 6 hours due to MCA

& BA occlusion

In BA occlusion it can be given even after > 12

hours.

In future IA-TPA will be rewarding.

PROACT II Trial

• First phase III trial of I.A.T.

• 9 mg Pro-UK + heparin(121) vs IV

heparin(59) within 6h.

• 180 patients, M1 or M2 MCA occlusion.

• Average NIHSS 17.

• Median time to I.A.T 5.7 hours.

PROACT II Trial

• mRS < 2 : 40% VS 25% (+- SIG)

• Recanalisation at 2h: 66% vs 18%

• Hemorrhage at 36h:

– all: 46% vs 16%

– symptomatic: 10% vs 2%

• No difference in mortality

IA vs IV TPA

Advantages of IA over IV

• Wider window : 6 hrs for ant circ & 12-24 hrs for post circ

• Greater recanalisation rate : 65 – 70% (only 30% in IV)

• Especially in large vessel occlusions, i.e ICA, MCA stem, Basilar

• Lesser dose injected directly into clot

• Underlying atheromatous disease can be addressed, e.g intracranial stenting / heparin for unstable plaque

I.A.T. Potential

Disadvantages

• Catheter manipulation

• Systemic heparinisation

• Delay in initiation of thrombolysis

• Skilled facilities

IV plus IA thrombolysisStroke Bridging Trial

• Lewandowski CA et al Stroke 1999

• Randomized pilot study. 35 patients

• tPA IV 0.6 mg/Kg then IA 20 mg

• Symptomatic hemorrhage: 11% both

groups

• Recanalisation at 2h:

– All: 55% IV/IA vs 10% IA

– M1: 100% IV/IA vs 67% (PROACT)

tpa + sonothrombolysis

• CCLOTBUST TRIAL.

• IV tPa + u/s therapy vs iv tPa alone

• Better outcome with sonothrmbolysis i.e better

recanalisation after 2hr.

MANAGEMENT OF ACUTE ISCHEMIC

STROKE -AHA/ASA GUIDELINES

Class I

Benefit >>> Risk

Procedure/ Treatment

SHOULD be

performed/

administered

Class IIa

Benefit >> Risk

Additional studies

with focused

objectives needed

IT IS REASONABLE

to perform

procedure/administer

treatment

Class IIb

Benefit ≥ Risk

Additional studies with

broad objectives

needed; Additional

registry data would be

helpful

Procedure/Treatment

MAY BE

CONSIDERED

Class III

Risk ≥ Benefit

No additional studies

needed

Procedure/Treatment

should NOT be

performed/administered

SINCE IT IS NOT

HELPFUL AND MAY

BE HARMFUL

Level A: Recommendation based on evidence from multiple randomized trials or meta-analyses

Multiple (3-5) population risk strata evaluated; General consistency of direction and magnitude of

effect

Level B: Recommendation based on evidence from a single randomized trial or non-randomized studies

Limited (2-3) population risk strata evaluated

Level C: Recommendation based on expert opinion, case studies, or standard-of-care

Very limited (1-2) population risk strata evaluated

should

is recommended

is indicated

is useful/effective/

beneficial

is reasonable

can be useful/effective/

beneficial

is probably recommended or

indicated

may/might be considered

may/might be reasonable

usefulness/effectiveness is

unknown /unclear/uncertain

or not well established

is not recommended

is not indicated

should not

is not

useful/effective/beneficial

may be harmful

IV Recombinant Tissue Plasminogen

Activator (r-tPA) for Patients

With Acute Ischemic Stroke

In patients with acute ischemic stroke in whom

treatment can be initiated within 3 h of symptom

onset, we recommend IV recombinant tissue

plasminogen activator (r-tPA) over no IV

r-tPA (Grade 1A).

IV Recombinant Tissue Plasminogen Activator (r-

tPA) for Patients

With Acute Ischemic Stroke

In patients with acute ischemic stroke in whom

treatment can be initiated within 4.5 h but not

within 3 h of symptom onset, we suggest IV r-

tPA over no IV r-tPA (Grade 2C).

Intraarterial Thrombolysis in Patients With

Acute Ischemic Stroke

In patients with acute ischemic stroke due to proximal

cerebral artery occlusions who do not meet eligibility

criteria for treatment with IV r-tPA, we suggest

intraarterial (IA) r-tPA initiated within 6 h of symptom

onset over no IA r-tPA (Grade 2C).

Thank u