Update on Thrombolysis and Thrombectomy · 2016. 9. 19. · hypoperfused but still viable tissue at risk to undergo definite infarction • Recanalization is time-critical because

Seniorprofessur Neurologie UniversitätsKlinikum und Universität Heidelberg

Update on Thrombolysis and

Thrombectomy


I received financial compensation from Boehringer -Ingelheim for my time and efforts as Chairman of the SC of ECASS 1-3 and from Paion for DIAS and DIAS II

I have received honoraria for lectures and advisory boards from BI and Paion

I have received an unrestricted scientific grant by BI to organize the ECASS 4, an IIT sponsored by the University of Heidelberg

I am a member of the SC of SWIFT-PRIME and TASTE

Relevant Disclosures


Introduction:

• The preconditions for recanalization therapies Part I: Thrombolysis

• Penumbra and vessel occlusion • The Dark Ages- Intra-arterial thrombolysis case series • I.V.-Thrombolysis- past and present

The groundbreaking studies

New lytics and Penumbral selection

rtPA in clinical routine

Part II: Mechanical recanalization

• The early cohorts and early RCTs • The new Thrombectomy trials

Summary

Content


Successful recanalization therapies need a perfectly orchestrated stroke management system

Recanalization must be offered to all people qualifying, not only to a handful of those, who live near private hospital

The management system includes

• Recognition (FAST) • EMS and ER • A network of stroke ready hospitals with Stroke Units

connected by teleneurology

• Imaging and interventions • Rehabilitation and prevention

Preconditions for Recanalization Treatment


Stroke ready hospitals offer Imaging (CT, CTA), Stroke Units and co-operation with stroke centers

• They can perform thrombolysis Stroke centers offer MRI, interventions, neuro-ICU facilities

and neurosurgery

• They will receive transferrals from the smaller hospitals for elective therapies

Regional organization of stroke services is key

Preconditions for Recanalization Treatment


The incidence of acute ischemic stroke in Germany is 250-300/100,000/year, a total of 200,000 new strokes every year

In Germany (Population 82 Mio), we have a network of 280 Stroke units, among them 50-60 comprehensive stroke centers

For Argentina (Population 41 Mio), we can expect about 70,000 to 80,000 new strokes per year according to the few epidemiological data available

I believe that both incidence and prevalence numbers are much higher

How Many Patients Qualify for Recanalization?


Under optimal circumstances, about 30% of all stroke patients can qualify for i.v. Thrombolysis

Of them, about 20-30% may also qualify for thrombectomy

Transferral to stroke centers leads to relatively higher numbers of thrombectomy, because the patients come from a larger catchment area

In Heidelberg, a city with a catchment area (Lysis) of 800.000 Inhabitants, we do 300 i.v.rtPA cases per year

The thrombectomy number for the first half of 2016 are already over 800, most of them with rtPA co-treatment

The Buenos Aires metro area (13 Mio) is comparable BW (10.5 Mio) with 15% rtPA (4,500 rtPA cases per year)

How Many Patients Qualify for Recanalization


Part I:

Thrombolysis


• Ischemic stroke is caused by vessel occlusion

• Successful thrombolysis requires both, salvageable tissue

and remaining vessel occlusion

• This is reflected in the „penumbra + mismatch concepts“

already irreversibly damaged infarct core

hypoperfused but still viable tissue at risk to undergo

definite infarction

• Recanalization is time-critical because tissue damage may

progress unless reperfusion occurs

The Rationale of Recanalization


It all started with pilot cases of intra-arterial thrombolytic therapy in cases with acute basilar artery occlusion, and otherwise deadly condition

• Published in German, because leading journals would not accept it for „ethical concerns“

Zeumer, Hacke, Kolmann and Poeck DMW 107 (1981) 728-731

Zeumer, Hacke and Ringelstein AJNR 4(1983) 401-404

The authors received really encouraging reviews:

„Everybody knows that thrombolysis is dangerous

and should be avoided in stroke...

The technique described in this paper is unethical

and should not be studied further...“

The original 1979 film

The Early Thrombolysis Cohorts


ECASS (JAMA 1995)

The NINDS Study leading to 3 h approval (NEJM 1995)

ECASS II (Lancet 1998)

The Pooled Analysis of ATLANTIS, ECASS and NINDS

indicating benefit up to 4.5 h (Lancet 2004)

ECASS 3 confirming the 4.5h time window (NEJM 2008)

The second Pooled Analysis (Lancet 2009)

IST 3 showing that treatment works outside the labelling

and does not cause harm (Lancet 2012)

The STTC*-Analysis (Lancet 2012)

*Stroke Thrombolysis Trialists’ Collaborative Group, Lancet 2012

The Groundbreaking Trials


The Groundbreaking Studies: NINDS 1996

The NINDS Study consisted of Part 1 and 2

Plain CT selection with emphasis on early treatment

A 3 h time window, but one half of the patients had to be

treated within 90 mins

Part 1 (300) was negative, Part 2 (300) with a different

(global) endpoint was positiv and so was the combined

analysis


26%

26%

21%

25%

23%

27%

17%

21%

+13%

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

13% more rt-PA treated patients in favourable outcome (mRS 0-1)

Death mRS

Placebo

(n = 312)

Actilyse

(n = 312)

0 - 1 2 - 3 4 - 5

NINDS-study 1996:

Thrombolysis within 3h increases excellent functional outcome


The Groundbreaking Studies: NINDS 1996

Based on the NINDS study rtPA was approved in the US

for treatment of AIS in the 3 h time window

Because of the relatively small trial and the fact that only a

300 patient substudy was positive, there was a lot of

resistance (ER-physicians) in the US to use rtPA

The lysis rates were in the order of 2-3% for many years


The Groundbreaking Studies: ECASS 3

• Trial designed upon request of EMA • 3-4.5h time window, 821 patients randomized to rtPA

or placebo

• We didn´t believe that it would have a chance to be positive, although we increased the number of patients

from 600 to 800

• It took some time to finalize the trial, recruitment was difficult, but we succeeded


• We were deeply surprised • This time the choice of endpoint didn´t matter • Positive in primary endpoint mRS 0,1, positive in global

outcome and in shift

• An undisputed positive and guideline changing trial

p=0.024*

Intent-to-treat population

Alteplase

(n=418)

mRS score

Placebo

(n=403)

1 2 3 0 4 5 6

27.5

23.3 21.8 16.4

9.3 14.1 24.9

13.7

9.3

8.2

6.7 8.1

11.4 5.2

ECASS 3


The 2008 medical paper of the year

Editors choice - The Lancet

The Groundbreaking Studies: ECASS 3


Stroke Thrombolysis Trialists Cooperation*

„Single patient date prospective pooled analysis“

>6.700 Patienten

Confirms time dependent treatment effect

Indicates increased risk of mortality, mostly over 4.5h

and in severe old patients

Benefit/risk Ratio remains positive despite increased

sICH risk

Stable effect for age, severity in the under 4.5h group

Emberson, Lees, Lyden….Sandercock, Hacke Lancet 2014


Emberson, Lees, Lyden….Sandercock, Hacke: STTC ISC 2014, Lancet 2014



Emberson, Lees, Lyden….Sandercock, Hacke: 2014



Latest News: ENCHANTED-Trial

Rationale

• Testing the hypothesis that low dose (0.6mg/kg) rtPA is equally effective as regular dose (0.9mg/kg) in a

(mostly Asian) population

Design

• 2x2 factorial design of 3,310 patients eligible for rtPA within 4h

• (additionally, patients with elevated BP randomly assigned to early intense or standard BP lowering)

935 patients eligible for that trial included


ENCHANTED-Trial: Low vs High Dose rtPA

Mdn age 67, asians 70%

Results

• Primary outcome mRS 2-6 Low dose 53.2%, regular dose 51.1%

OR 1.09 (95%CI 0.95-1.25)

The upper boundary exceeded the non-inferiority margin

(p for non-inferiority .51)

• Ordinal mRS Common odds 1.0 (95%CI .89-1.13), p non-inferiority .04

• sICH Low dose 1% standard dose 2,,1% p=.01


rtPA in the Field

Results of RCTs and pooled analyses can be repeated

in the field

SITS-MOST

Data from >10.000 thrombolysis patients from a

German state (thromectomy excluded)

15% Lysis rate (25% plus in stroke centers)

Results comparable with pooled data

Gumbinger et al, BMJ 2014


rtPA in the Field

Gumbinger et al, BMJ 2014


Part II:

Intra-arterial Thrombectomy (IAT)


Intraarterial Lysis And Mechanical

Revascularisation

Selection of patients and preparation of the mechanical

intervention may be associated with a longer door to

needle time than IV-rtPA

• Lack of collaterals in proximal occlusion may even shorten the window of opportunity

• On the other hand, once the device is in situ, recanalization may occur faster than with IV rtPA

Nevertheless- „time is brain“ is important here too

Recanalization 8 or 10h after onset may not be beneficial

and in patients with high stroke severity even harmfull


• 2012: Three RCTs are presented (Honululu ISC 2012) and published

IMS III (Broderick et al NEJM 2012)

MR-RESCUE (Kidwell et al NEJM 2012)

SYNTHESIS (Ciccione et al NEJM 2012)

• All studies missed efficacy endpoints

History of Transvascular Stroke Trials

Broderick et al NEJM 2013

Kidwell eta l NEJM 2013

Ciccone eta NEJM 2013


• Reasons include: long time window

use of old devices

underestimation of rtPA response in distal occlusion,

slow recruitment due to treatment outside the trial

treatment with no proof of vessel occlusion

(Furlan and Hacke IJS 2012)

• A subgroup analysis of SWIFT PRIME showed signal of efficacy in early reperfusion and severe stroke

(Khatri et al Lancet Neurology 2012)

History of Transvascular Stroke Trials


New Devices

Early treatment

Severe stroke with proven Carotid T or M1 occlusions

On top of rtPA

Consequences For The New Thrombectomy Trials


Time and Outcome

Grotta and Hacke Stroke 2015

Hacke IJS 2015

Hacke and Diener Nervenarzt 2015


The Thrombectomy Trials


MR CLEAN

ESCAPE

EXTEND IA

SWIFT PRIME REVASCAT

mRS 0-2%

80 -

60 -

40 -

20 -

0 - ctl act ctl act ctl act ctl act ctl act

+ 24%

+ 14% + 16%

+ 31%

+ 21%

Berkhemer et al NEJM 2015, Goyank et al NEJM 2015, Campbell et al NEJM 2015, Saver et al NEJM 2015, Jovin et al NEJM 2015,

Range of Differences: 14-31%

3

3

5

3

7

1 6

0 4

4

1

9

2

9

4

0 3

6 2

8

Good Outcome (mRS 0-2) Compared

Treatment Effects


How Can the Differences in Magnitude of Effects be

explained?

All studies show the same pattern

• Thrombectomy always significantly superior to standard treatment

But: Major differences in the rates of good outcome in

both tx and control arms between trials

*Berkhemer et al NEJM 2015, Goyank et al NEJM 2015, Campbell et al NEJM 2015, Saver et al NEJM 2015, Jovin et al NEJM 2015,


What does this mean for stroke management

structures?

How many patients are candidates?

• A center with 1000 Strokes per year possibly 250 rtPA (25%)

There of 100 endovascular (20%), probably more with referrals

Are there enough endovascular specialists?

• How do we train more? • Also Neurologists?


• Severe AIS with average NIH-SS 17 • CT-selection (the better, the better the outcome) • No age limit • CTA proven Carotid-T or M1 occlusions • Co-Treatment with rtPA • Early treatment with reperfusion or first thrombuspass

below 6h

• Use of Stentriever (Solitaire) Devices • Treatment in large volume endovascular centers and

drip and ship strategies

For which patients do the results apply?


• Mild stroke • M2 Occlusions • Basilar artery occlusion • rtPA uneligable patients • Recanalization not possible within 6 hours • CT: Major infarct, ASPECTS 5 or below, no collaterals

For which patients do the results not apply?


• All trials were CT and CTA based • There were different qualities of CT-assessment

required, but superiority of IAT was also achieved with

plain CT, even without major infarct assessment

ASPECTS 6 or more

RAPID assessment in 141 patients

• The more detailed the assessment was, the better the outcome in both the IAT group and the control

What kind of imaging is necessary?


• In all trials the far majority of patients received rtPA in a 4.5h time window

• The lowest rtPA rate was in ESCAPE (76%) which also allowed rtPA ineligable and wake-up patients

• ECTEND IA and SWIFT PRIME had almost 100% rtPA use

• The number of non-rtPA patients in the individual trials was to small to draw conclusions

• Joint analyses of the trials may give more insight into that question

Is rtPA necessary for the success?


• In one trial, which had the most restrictive inclusion criteria, 1000 patients were treated with rtPA and only

70 patients were randomized

• In general, it appears that about 10% of all ischemic stroke patients present with a severe stroke (NIHSS

over 12), not all in a time window suitable for IAT

• About 20-30% of patients who are treated with rtPA may be candidates for IAT

• This may be more at large referral centers

How many patients are candidates for IAT?


What does this mean for stroke management

structures? Question?

How many endovascular centers do we need?

• The Netherlands (16 Mio inhabitants, 18 centers) 1 center/Million inhabitants

• Berlin (4 Mio): 3 comprehensive stroke Units • BW 10.5 Mio): 7 comprehensive SUs

How can we offer the treatment economically and with

sufficient quality?

• Large centers, minimum treatment numbers, high personal expertise


• If in clinical practice CT criteria are handled not strictly, the time window is not strictly observed and the IAT is

performed with devices other than stentrievers, the

results may be worse

• In clinical routine, it appears unlikely that the results of SWIFT PRIME or EXTEND IA can be repeated

• Results achieved in daily practice may be closer to those of MR CLEAN

What kind of results can we expect in everyday routine?


• A city with 500.000 inhabitants and 5 interventional centers, each doing 20 or less IAT per year, mostly on

workdays, is not well served

• This scenario is not economically sound, lacks quality and experise, and bound to widen the indication for IAT

for financial reasons beyond the evidence

• It also allows not for good training conditions if there is a patient only once in 2 weeks

How many interventional centers do we need?


Excellent News, and a lot of work

in front of us

Overall

Documents

Update on Thrombolysis and Thrombectomy · 2016. 9. 19. · hypoperfused but still viable tissue at risk to undergo definite infarction • Recanalization is time-critical because