March 2012

Background
Pathophysiology: Stroke is an emergency
Thrombolysis: Act FAST
The only approved and recommended therapy of AIS
Time dependence
Essential improvement of patient care: implementation of stroke centres
The situation: thrombolysis is underused
How to improve: optimisation of stroke management
Pre-hospital
In-hospital
Networks
Telemedicine

Studies and registries
Guidelines
Actilyse
® product details
Prescribing information
Appendix
Impressum

 Stroke is the third most common cause of death in developed countries, exceeded only by coronary heart disease and cancer
 795,000 new or recurrent strokes occur per year in the US, accounting for approximately 1 in 18 deaths
 The prevalence of stroke in the US is about 7 million (3.0%) at an estimated cost in 2010 of 73.7 billion US-$
 In Europe, the incidence of stroke varies from 101.1 to 239.3 per 100,000 in men and 63.0 to 158.7 per 100,000 in women
 The estimated cost of stroke in Europe in 2010 was approx. € 64.1 billion
 In China, the prevalence of stroke ranges between 1.8% (rural areas) and
9.4% (urban areas)
 Worldwide, China has one of the highest rates of mortality (19.9% of all deaths in China), along with Africa and parts of South America
Gustavsson et al. Eur Neurpsychopharmacol 2011;21:718-779.
AHA and Stroke Statistics Writing Group. Circulation 2010;123:e1-e192.
EROS Investigators. Stroke 2009;40:1557-1563.
Sousa et al. Lancet 2009;374:1821-1830. The Atlas of heart disease and stroke, WHO 2004.

Cryptogenic
30%
Cardiac embolism
20%
12%
Haemorrhagic
Other
5%
Atherosclerotic cerebrovascular disease
20%
Small vessel disease
“lacunes”
25%
Ischaemic stroke
88%
Albers et al. Chest 2004;126 (3 Suppl):438S-512S.
Thom et al. American Heart Association. Circulation 2006;113:e85-e151.

 TIA was traditionally defined as a neurological deficit, which resolves completely within 24 hours
 However, up to 1/3, and in selected patient samples (aphasia and/or hemiparesis lasting for more than 6 h) up to 80% of such defined TIAs show lesions on diffusion weighted imaging (DWI)
 The recently recommended definition of TIA has
2 principles:
 Acute onset neurological dysfunction, due to focal brain or retinal ischaemia, which completely resolves within 60 min
 No evidence of cerebral ischaemia
 TIA is a strong prognostic factor for a subsequent stroke
Gorelick. J Med 2009;2:1-8.
Albers et al. N Engl J Med 2002;347:1713-1716.
Ovbiagele et al. Stroke 2003;34:919-924.
Coull et al. BMJ 2004;328;326.

Potential to Reverse Neurologic Impairment With
Thrombolytic Reperfusion
Ischaemic core
(brain tissue destined to die)
Penumbra
(salvageable brain area)
An untreated patient loses approximately 1.9 million neurons every minute in the ischaemic area
Reperfusion offers the potential to reduce the extent of ischaemic injury
Saver. Stroke 2006;37:263-266.
González. Am J Neuroradiol 2006;27:728-735.
Donnan. Lancet Neurol 2002;1:417-425.

Excitotoxicity
Peri-infarct depolarisations
Inflammation
Apoptosis
Minutes Hours Days
Time
Estimated Pace of Neural Circuitry Loss In Typical Large-Vessel
Supratentorial Acute Ischaemic Stroke
Neurons Lost Synapses Lost Myelinated Fibres Lost Accelerated Aging
Per Stroke
Per Hour
Per Minute
Per Second
1.2 billion
120 million
1.9 million
32,000
8.3 trillion
830 billion
14 billion
230 million
7140 km
714 km
12 km
200 m
36 y
3.6 y
3.1 wk
8.7 h
Saver. Stroke 2006;37:263-266.

 Acute stroke must be considered on the same level of emergency as an acute myocardial infarction
 Uniform emergency phone number available in most parts of
Europe (European SOS no.112), although each country still has its own number as well (e.g. 15 (FR), 999 (UK))
 Paramedics or emergency doctors dispatched to the scene can reliably recognise stroke symptoms after training
 Consultation of primary care physicians* almost doubles the time from onset to hospital arrival
 EMS transportation should use priority signals
*Primary care physicians means general practitioners, and not the physician who has the first contact to the patient
EMS, emergency medical services
Kothari et al. Stroke 1995;26:937-941.
Kothari et al. Stroke 1995;26:2238-2241.
Kaste et al. Cerebrovasc Dis 2000;10(Suppl 3):S1-S11.

 1.9 million neurons are lost every minute in the acute phase of an ischaemic stroke if left untreated
 The 2004 and 2010 pooled analyses of rt-PA trials for ischaemic stroke showed that the earlier treatment is initiated, the better the outcome
 NINDS recommends a door-to-needle time (DTN) of 1 hour or less
 Streamlining of local guidelines and standard operating procedures may shorten the DTN in experienced stroke centres to <30 min on average
Saver. Stroke 2006;37:263-266.
The ATLANTIS, ECASS, and NINDS rt-PA Study Group Investigators. Lancet 2004;363:768-774.
NINDS NIH website. Stroke proceedings. Latest update 2008.

Thrombolysis: Number of Patients Needed to Treat (NNT) to
Achieve Excellent Recovery (mRS 0-1 )
≤ 90 mins NNT=4 to 5
90 min - 3 h
3 - 4.5 h mRS, modified Rankin Scale
NNT=9
NNT=14
Lees et al. Lancet 2010;375:1695-1703.

Numbers needed to treat (NNT) to reach a modified Rankin score of 0-1
5
4
NNT
4 - 5
3
NNT
9
NNT
14
Odds ratio estimated by model
95% CI for estimated odds ratio
2
0
60 90 120 150 180 210
OTT (min)
240
OTT, time from stroke onset to start of treatment (and not from hospital arrival time)
270 300 330 360
Wahlgren et al. Lancet 2008;372:1303-1309.
Lees et al. Lancet 2010;375:1695-1703.

18
16
14
12
10
8
6
4
2
0
Only 11% of all thrombolysed AIS patients receive rt-PA within 90 min of symptom onset
0.2
0.3
0.8
11%
1.6
AIS, acute ischaemic stroke
2.9
4.7
3.2
90
OTT (min)
7.8
8.5
9.2
10.6
10.7
10.2
13.9
15.3
180
Wahlgren et al. Lancet 2008;372:1303-1309.
Lees et al. Lancet 2010;375:1695-1703.

Survival curves for patients admitted to a stroke unit or a conventional ward
100
Stroke unit
75
50
Conventional ward
25
0
0
Number at risk
Stroke unit 4936
Conventional ward 6636
12
3859
4709
24
Time (months)
3649
4398
Candelise et al. Lancet 2007;369:299-305.

6%
4%
2%
0%
10%
A
8%
University hospital
Specialised non-univ. hospital
Community hospital
2003 2004 2005 2006
B
Medicine
Neurology
C
Stroke unit
General ward
2003 2004 2005 2006 2007 2008 2003 2004 2005 2006 2007 2008

The use of thrombolysis in Sweden increased from 0.9% in 2003 to 6.6% in 2008
 In 2008, patients admitted to a stroke unit were 5 times more likely to receive thrombolysis than those admitted to general wards
Eriksson et al. Stroke 2010;41:1115-1122.

Stroke unit care reduces death at 30 days across all age groups
The intensity of organised care received affects outcomes across all age groups
SU, stroke unit
OCI, organised care index, refers to patients receiving 0, 1, 2, or 3 of the following: physiotherapy, occupational therapy, admission to a stroke unit, stroke team assessment
Saposnik et al. Stroke 2009;40:3321-3327.

 Stroke centre designation improves:
 Quality of care
 Patient access
 Timely evaluation
 Stroke units improve early survival across age groups
 Stroke units are more cost effective than care on other hospital wards/teams
 Higher stroke care volume is related to less urinary tract infections, pneumonia, and a lower mortality rate
Norrving & Adams. Stroke 2006;37:326-328;
Duncan et al. Stroke 2002;33:167-178; Gropen et al. Neurology 2006;67:88-93;
Stradling et al. Neurology 2007;68:469-470; Saposnik et al. Neurology 2007;69:1142-51.

 Remember: ACT Fast → Time is brain!
 Most effective are:
 Early recognition of stroke symptoms, including public education
 Establishment of stroke networks
 Prioritisation and direct transfer to specialised stroke centres or stroke units
 Management by multidisciplinary teams
 Act fast to initiate treatment with thrombolysis as early as possible
 The earlier treatment of acute ischaemic stroke with thrombolysis is initiated, the better the outcome

 Only 2-12% of AIS patients receive IV thrombolysis with rt-PA
 In two thirds of cases that receive rt-PA, the doorto-needle time is >60 min
 Problems included:
 Delayed arrival (outside the time window)
 rt-PA was not available at the hospital
 In-hospital delays beyond the time of eligibility for rt-PA
 Prolonged time to imaging (CT or MRI) after arrival
 Improvement of pre- and in-hospital procedures can increase the number of patients who receive rt-PA
Etgen et al. Acta Neurol Scand 2011;123:390-395;
Roos et al. Cerebrovasc Dis 2011;31:33.

 Campaigns
 Target the general public as stroke witnesses
 Symptom awareness
 Awareness to take action
 Keep the message easy
 The ultimate aim is to keep the time to treatment as short as possible
 Public awareness campaigns can increase ambulance dispatches for stroke
Example of a German stroke awareness campaign

 Rapid patient recognition and reaction to stroke warning signs
 Rapid emergency medical services (EMS) dispatch
 Rapid EMS system transport and hospital pre-notification
 Delivery direct to imaging
 Rapid in-hospital diagnosis and treatment
 Effective EMS systems can minimise delays in pre-hospital dispatch, assessment, and transport, and ultimately increase the number of stroke patients reaching the hospital and being prepared for thrombolytic therapy within the approved time window
AHA. Circulation 2005;112:111-120.
Wojner-Alexandrov. Stroke 2005;36:1512-1518.
Deng et al. Neurology 2006;66:306-312.

Cincinnati Stroke Scale: A Checklist for Emergency
Medical Dispatchers
3-Question Checklist
1. Ask patient to smile
Normal
Slight difference
Obvious difference
Cannot complete at all
2. Ask patient to raise both arms above head
Both arms raise equally
One arm higher than the other
Cannot complete request at all
3. Ask patient to say “the early bird catches the worm”
Said correctly
Slurred speech
Garbled or not understood
Cannot complete request at all
Score
0
1
3
0
1
0
3
3
Total score:

3 Clear evidence of stroke
2 Strong evidence of stroke
1 Partial evidence of stroke
0 No evidence of stroke
Govindarajan et al. BMC Neurology 2011;11:14.

Hospital Arrival Times and Thrombolysis Rates in AIS
Patients According to Mode of Transport
% patients arriving within 2 h of stroke onset according to transport mode
80
70
389/524
2,668/3,794
Direct transport to a stroke unit
Indirect: transferred from a peripheral hospital
% thrombolysed patients according to transport mode
35
30
(n=2,501 thrombolysed patients)
44/153
60
25
180/745
3,499/6,767
50
20
40
38/111
280/708
15
1,050/5,842
165/1,102
30
351/1,425
10 978/11,289
20
5 84/2,442
10
74.2 34.2
70.3
39.5
51.7 24.6
0
HEMS AMBP
HEMS, helicopter emergency service
AMBP, ambulance with accompanying physician
AMB, ambulance without accompanying physician
AMB
0
HEMS AMBP AMB
Reiner-Deitemyer et al. Stroke 2011;42(5):1295-1300.
Reiner-Deitemyer et al. Stroke 2011;42(5):1295-1300.

Pre-admission Notification by EMS:
The Best Way to Shorten Door-to-Needle Time
Ischaemic strokes admitted at the Lille University Hospital
After emergency call
= 50%
No emergency call
= 50%
Thrombolysis rate: 22.5%
Median DNT: 41 min
Thrombolysis rate: 5.1%
Median DNT: 57 min
Not adjusted on case-mix. A part of the difference may be explained by differences in profiles
Didier Leys, personal communication.

Interaction Between Pre- and Intra-hospital Services
 Regional committee with EMS, ED, neurologists, radiologists, rehab physicians, patients organisations, administration and health authorities to organise stroke care at the regional level (3 per year)
 Joint teaching activities (national training program for stroke)
 Annual meeting with all physicians in the area, involved in stroke care for continuous training
 Population campaigns
 Registries to evaluate the network
EMS, emergency medical services
ED, emergency doctor

 Prenotification that patient is on the way and direct access to imaging
 Rapid triage by emergency physician or paramedic before arrival
 Vital parameters stabilised (O
2
, temperature)

2 medium-large bore venous lines with cristalloid infusions on one or both
 POC test for blood glucose (100-180 mg/dl) and INR
 BP optimum (150-160 mmHg systolic)

NIHSS assessment
 Priority CT/imaging access

Use scales such as ASPECTS
 Rapid read, always neurologist and radiologist to analyse images
 Set-up that allows weighing the patient e.g. lying in CT/imaging
 Decision to treat and bolus application in the CT/imaging suite
 Decision whether to perform additional imaging or rescue treatment in
CT/imaging suite
Fonarow et al. Stroke 2011;42:2983-2989;
Adams et al. Stroke 2007;38:1655-1711.

Doctors who have more time, take more time, but the sooner thrombolysis is initiated, the greater the benefit
2:30
2:00
1:30
1:00
0:30
0:00
0:00 0:30 1:00 1:30 2:00 2:30
Time from symptom onset to arrival
(Prehospital time)
SITS-Database https://sitsinternational.org

 A multidimensional initiative from the AHA/ASA
 Aim: to ensure that as many patients as possible with AIS achieve a DTN ≤60 min
 10 key best practice strategies, associated with faster DTN:
1. EMS pre-notification
2. Rapid triage protocol and stroke team notification
3. Single call to active stroke team
4. Stroke tools
5. Rapid imaging and interpretation
6. Rapid laboratory testing and POC test
7. Premixing rt-PA
8. Rapid access to rt-PA
9. Team-based approach
10. Rapid data feedback
 Follow-up will be after 1 year, in line with GWTG-Stroke data and rate of improvement in DTN
Fonarow et al. Stroke 2011;42:2983-2989.
AIS, acute ischaemic stroke
DTN, door-to-needle time
POC, point of care

NIH-recommended Emergency Department
Response Times
DTN ≤60 min
: the “ golden hour ” for evaluating and treating acute stroke
T=0
Suspected stroke patient arrives at stroke unit
≤10 min
Initial MD evaluation
(including patient history, lab work initiation, & NIHSS)
IDEALLY performed prehospital
≤ 15 min
Stroke team notified
(including neurologic expertise)
≤ 25 min
CT scan initiated
≤ 45 min
CT & labs interpreted
≤ 60 min rt-PA given if patient is eligible
NINDS NIH website. Stroke proceedings. Latest update 2008.

Preparing the Patient for rt-PA in 30 min
(Optimally 15 min)
Vital parameters, sugar, INR
History, Labs, call CT
NIHSS
To CT
CT
Reading
Measure / Estimate weight
Prepare rt-PA, inject
5min (3min)
3min (2min)
5min (2min)
CT (with rt-PA at hand)
5min (2min)
5min (4min)
3min (1min)
ICH ?
Large and/or demarcated infarction ?
1min (0min)
3min (1min)
Personal communication, Peter Schellinger, Jan 2011.

Stroke networks and protocols are essential to ensure as many patients as possible are treated as quickly as possible
Emergency Services
Paramedics / Physicians
Central Admission
Neuro Emergency Room
Outpatient Care / GP
Neuroradiology
Ultrasound
Rehabilitation
Geriatric Rehabilitation
Stroke Unit
Neurocritical Care Unit
Hacke. Personal communication, unpublished.

 Centralised emergency number ensures one stop access to stroke care
 Call centre triages patients prior to dispatch of emergency team
 Transport patient to a stroke centre as quickly as possible after symptom onset

Direct transport to stroke centre
 Rapid transfer from non-stroke centre

Telemedicine
 24/7 acute specialty cover within a region
 Ensure the right care for the right patient at the right time
 Ongoing coordination of multiple clinical services throughout stroke care
Carr et al. Acad Emerg Med 2010;17:1354-1358.
Rymer. OMAG Mar-Apr 2010, available online.

Ensure the right care for the right patient at the right time
24/7 acute specialty cover within a region
Direct transport to stroke centre
Ongoing coordination of multiple clinical services throughout stroke care
Stroke
Networks
Centralised emergency number ensures one stop access to stroke care
Call centre triages patients prior to dispatch of emergency team
Transport patient to a stroke centre as quickly as possible after symptom onset
Telemedicine
Rapid transfer from nonstroke centre
Carr et al. Acad Emerg Med 2010;17:1354-1358.
Rymer. OMAG Mar-Apr 2010, available online.

Geography, lack of knowledge and poor funding are the 3 main reasons for unequal access to stroke care, and the rationale behind telemedicine
Remote rural area
Geography
Stroke facilities not available
Public awareness
Knowledge
Costs and funding
* Refers to physicians not working in a stroke unit
Funding
Inexperienced* physicians
<24/7 access to facilities

 Specialised stroke wards in community hospitals
 24-hour availability of diagnostics/monitoring
 Stroke teams
 Standardised stroke care protocols
 Comprehensive stroke training for all staff
 Continuous quality management
 Telemedicine network

Community hospital
CT scan
Can overcome geographical barriers, may save money and improve knowledge in acute stroke care
ICU stroke unit
24-h emergency MRI
24-h stroke neurologist nurses, rehab …

TEMPiS: Telethrombolysis as Effective as Stroke
Centres and RCTs
2 university stroke centres
132 rt-PA patients
(69.6 years, NIHSS 11)
24-h telemedicine image transmission
Continuous stroke teaching
11.5% death
30.9% good outcome (mRS ≤1)
RCT, randomised controlled trial mRS, modified Rankin Scale
12 community hospitals
170 rt-PA patients
(69.4 years, NIHSS 12)
11.2% death
39.5% good outcome (mRS ≤1)
Schwab et al. Neurology 2007;69:898-903.

TEMPiS: Telemedicine Networks Can Improve Other
Aspects of Stroke Care
Use of telemedicine not only gives patients rapid access to specialised care, but can also increase accessibility to other stroke services
Audebert et al. Lancet Neurol 2006;5:742-748.

Death (%)
Severe disability at home or institutional care (%)
Without severe disability at home (%)
TEMPiS Control
(N=1,883) (N=1,085)
23 25
23
54
31
44 p
<0.001*
*unadjusted outcome compared with
“death” and “institutional care” and “at home with severe disability”
Audebert et al.
Stroke 2009;40:902-908.

Telemedicine in Acute Stroke
Learnings from TEMPiS
 Telemedicine-guided thrombolysis
 Is feasible
 Is safe and efficient
 TEMPiS improves many other aspects of acute stroke care
 Marked reduction of “death and dependency”
(mRS >3)
Audebert et al. Stroke 2009;40:902-908.
Schwab et al. Neurology 2007;69:898-903.

arrival quick check transport preparation transport handover registration nursing admission medical history bodycheck neuro exam blood tests
CTapplic.
trans port
CTexam
Lab results
 IV-thrombolysis is the second most powerful AIS intervention available (after stroke unit)
 Stroke experts are needed
 Optimisation of infrastructure will
 Increase thrombolysis rates
 Improve safety
 Shorten time to treatment
 TeleStroke can help to achieve treatment goals (best within
TeleStroke units)
 Take every effort to shorten time to treatment
Audebert. Presentation at the ESC in Hamburg, 2011.

Summary: The Emergency Physician ’s Perspective arrival quick check transport preparation transport handover registration nursing admission medical history bodycheck neuro exam blood tests
CTapplic.
trans port
CTexam
Lab results
 Education campaigns
 Calling the right number
 Early stroke recognition
 Prenotification of patient arrival
 Preparation of patient for thrombolysis, including iv access, blood samples, etc
 Take every effort to shorten time to treatment
 Use of protocols
 Organisation and evaluation of networks
Lambert. Presentation at the ESC in Hamburg, 2011.

arrival quick check transport preparation transport handover registration nursing admission medical history bodycheck neuro exam blood tests
CTapplic.
trans port
CTexam
Lab results pre-hospital in-hospital
 Raise public awareness
 Improve pre-hospital stroke recognition
 Optimisation of infrastructure
 Networking
 Immediate transfer to stroke centre
 Monitoring of processes
Audebert. Presentation at the ESC in Hamburg, 2011.

 Thrombolysis with rt-PA initiated within 3 h of symptom onset is the only approved treatment for acute ischaemic stroke
 Efficacy is highest if initiated within 90 min
 Many stroke victims do not reach a centre equipped to administer rt-PA in time
 Worldwide, <5% of acute ischaemic stroke patients are treated with rt-PA within 3 hours of stroke symptom onset
NINDS Trialists N Engl J Med 1995;333:1581-1587.
Hacke et al. Lancet 2004;363:768-774.
Ingall. Stroke 2009;40:2264-2265.

 rt-PA was approved by the EU regulatory authority EMEA in
2002 for use within 3 h of ischaemic stroke with two postapproval requirements:
 All patients should be registered in the SITS internet database and entered into an observational safety study, SITS-MOST
 A randomised trial of rt-PA versus placebo, with an extended therapeutic window greater than 3 hours
 The pooled analysis of individual patient data (N=2,775) from
6 trials of i.v. rt-PA vs. placebo showed that the effective treatment window may extend to 4.5 hours
Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:1317-1329.
Hacke et al. Lancet 2004;363:768-774.

Objective
 To assess efficacy and safety of rt-PA between 3 and 4.5 hours after stroke onset in the European setting
Primary Endpoint: Disability at day 90
 Favourable (mRS ≤1) vs. unfavourable outcome (mRS 2-6)
Secondary Endpoint
 Global outcome analysis at day 90, combining mRS (0-1), Barthel
Index ≥95, NIHSS (0-1), Glasgow Outcome Scale (1)
Safety Endpoints
 Included mortality at 90 days, any ICH, SICH
Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:1317-1329.

Disability at Day 90, mRS ≤1
Analysis rt-PA n/N (%)
Unadjusted 219/418 (52.4%)
Adjusted* −
Placebo n/N (%)
182/403
(45.2%)
−
OR
(95% CI)
1.34
(1.02−1.76)
1.42
(1.02−1.98) p
0.04
‡
0.04
§
0.5 1 1.5
Favours placebo Favours rt-PA
ITT, intent-to-treat
*Adjusted for NIHSS score at presentation and the time to start of treatment
‡ p value was obtained by the Pearson chi-square test of proportions
§ p value was obtained by stepwise logistic regression
Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:1317-1329.

Day 90: NINDS global endpoint statistic
(mRS 0-1 ; BI ≥95; NIHSS ≤1 or >8 point improvement; GOS 1) rt-PA
(N=418)
Placebo
(N=403)
OR
(95% CI) p
Global outcome mRS score ≤1
BI score ≥95
NIHSS score
GOS score 1
≤1 n/a
219 (52.4%)
265 (63.4%)
210 (50.2%)
213 ( 51.0%) n/a
182 (45.2%)
236 (58.6%)
174 (43.2%)
183 (45.4%)
1.28
(1.00
–1.65)
1.34
(1.02
–1.76)
1.23
(0.93
–1.62)
1.33
(1.01
–1.75)
1.25
(0.95
–1.64)
0.05
0.04
0.16
0.04
0.11
‡
‡
‡
‡
0.5 1 1.5
Favours placebo Favours rt-PA
ITT, intent
–to-treat; ‡ p value was obtained by the Pearson chi-square test of proportions
Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:1317-1329.

ECASS 3: Functional Efficacy Endpoints at 90 Days
(PP Population)
730 patients (out of 821 randomised)
Endpoint day
90 mRS score 0-1 rt-PA
(N=375)
206 (54.9%)
Global outcome statistic
(unadjusted) n/a
Placebo
(N=355)
161 (45.4%) n/a
OR
(95% CI)
1.47
(1.10−1.97)
1.39
(1.07−1.80) p
0.01
‡
0.02
0.5 1 1.5
Favours placebo Favours rt-PA mRS, modified Rankin Scale
PP, per protocol
‡ p value was obtained by the Pearson chi-square test of proportions
Bluhmki et al. Lancet Neurol 2009;8:1095-1102.

ECASS 3: Distribution of Scores on the mRS at 90
Days for the Per-Protocol Populations
Per-protocol population
Patients p=0.016
‡ stratified on Cochran
–Mantel–Haenszel test, adjusted for baseline NIHSS scores and time-to-treatment onset
Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:1317-1329.

 rt-PA administered 3-4.5 hours after stroke symptom onset is effective
 Significantly more patients benefitted vs. placebo in terms of:
• Disability at day 90, mRS 0-1
•
Overall greater functionality/independence (global outcome statistic) at day 90
• Improved neurological functioning (NIHSS 0-1 or >8 point improvement) at day 30
•
Independence (mRS 1-2) at day 30 in the PP population mRS, modified Rankin Scale
PP, per protocol
NIHSS, National Institute of Health Stroke Scale
Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:1317-1329.

Overall mortality
ITT, intent-to-treat
10%
8%
6%
4%
2%
0%
Mortality by time interval
1.0%
3.8%
0.7%
4.5%
After day 90 (7 deaths)
Days 8 –90 (34 deaths)
Days 1 –7 (25 deaths)
3.2%
2.9% rt-PA rt-PA
(N=418)
32 (7.7%)
Placebo
Placebo
(N=403)
OR
(95% CI)
34 (8.4%) 0.90
(0.54
–1.49) p
0.68
0.5 1 1.5
Favours rt-PA Favours placebo
Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:1317-1329.

 sICH (symptomatic intracranial haemorrhage)
 Significant difference in sICH rates (2.14% absolute difference), although the incidence of sICH among rt-PA-treated patients was low (2.4%)
 Mortality
 Low overall mortality rate (approximately 8%), not different between treatment arms
 Probably due to the mild to moderate initial stroke severity
 Consistent with results from other randomised controlled trials of thrombolysis in acute ischaemic stroke
 No safety concerns in the longer time window
Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:1317-1329.

 Additional outcome analyses included functional endpoints at day 90 or day 30
 mRS 0-1 [day 30], mRS 02, Barthel Index ≥85, and global outcome statistic [day 30] and treatment response (8-point improvement from baseline or 0-1 score on NIHSS)
 A stratified responder analysis by baseline NIHSS
 The subgroup analyses were based on the mRS 0-1 at day 90, sICH, and death mRS, modified Rankin Scale sICH, symptomatic intracranial haemorrhage
NIHSS, National Institutes of Health Stroke Scale
Bluhmki et al. Lancet Neurol 2009;8:1095-1102.

ECASS 3 – Subgroup Analysis of Favourable Outcome
(mRS 0-1): Demographics (ITT) rt-PA
% (n/N)
Placebo
% (n/N)
NIHSS at baseline
0-9
10-19
≥20
Age
<65
≥65
Gender
Male
Female
Time to treatment
181-210 min
211-240 min
241-270 min
73% (156/215)
34% (57/166)
16% (6/37)
67% (128/190)
31% (50/161)
8% (4/52)
57% (105/184)
49% (144/234)
53% (139/264)
52% (80/154)
58% (23/40)
49% (93/191)
56% (98/174)
45% (70/155)
45% (112/247)
42% (97/231)
50% (85/171)
40% (17/42)
47% (91/193)
43% (64/148) mRS, modified Rankin scale
ITT, intent-to-treat
OR
(95% CI)
1.28 (0.84-1.96)
1.16 (0.73-1.84)
2.32 (0.61-8.9)
1.61 (1.05-2.48)
1.15 (0.80-1.64)
1.54 (1.08-2.19)
1.09 (0.71-1.69)
1.99 (0.83-4.79)
1.06 (0.71-1.59)
1.69 (1.09-2.63) p
0.631
0.230
0.237
0.212
1
Favours placebo Favours rt-PA
Bluhmki et al. Lancet Neurol 2009;8:1095-1102.

ECASS 3 – Subgroup Analysis of Favourable Outcome
(mRS 0-1): Risk factors (ITT) rt-PA
% (n/N)
Placebo
% (n/N)
OR
(95% CI) p
Diabetes
No
Yes
Prior stroke
No
Yes
Hypertension
No
Yes
Atrial flutter/ fibrillation
No
Yes mRs, modified Rankin scale
ITT, intent-to-treat
54% (191/356)
45% (28/62)
52% (199/387)
63% (20/32)
57% (90/157)
49% (129/261)
44% (149/335)
49% (33/67)
47% (163/345)
33% (19/57)
44% (66/149)
46% (116/253)
1.45 (1.07-1.95)
0.85 (0.42-1.70)
1.19 (0.89-1.59)
3.33 (1.35-8.22)
1.69 (1.07-2.66)
1.15 (0.82-1.63)
0.167
0.033
0.190
56% (205/365)
26% (14/53)
47% (163/347)
35% (19/55)
1.45 (1.08-1.94)
1.69 (0.30-1.55)
0.092
1
Favours placebo Favours rt-PA
Bluhmki et al. Lancet Neurol 2009;8:1095-1102.

 Subgroup results
For mRS 0-1 all subgroups were in favour of rt-PA; most notably no interaction by age and stroke severity was established
 Additional endpoints mRS 0-1, 02, Barthel index ≥85 and global outcome statistic and treatment response (8 point improvement from baseline or 0-1 on the NIHSS) stratified responder analysis mRS, modified Rankin scale
NIHSS, National Institutes of Health Stroke Scale
Bluhmki et al. Lancet Neurol 2009;8:1095-1102.

 Intravenous rt-PA initiated 3-4.5 h after onset of stroke symptoms is:
 An effective treatment for patients with AIS, who cannot be thrombolysed within 3 h, with no relevant increase in intracranial bleeding compared with treatment within 3 h
 A viable therapeutic option for the many patients previously excluded from thrombolysis by missing the narrow treatment timeframe
 Favourable across a broad range of subgroups of patients
 This finding opens a window of opportunity for later-arriving stroke patients
 However …
AIS, acute ischaemic stroke
Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:1317-1329.
Bluhmki et al. Lancet Neurol 2009;8:1095-1102.

 … having more time does not mean we should take more time
 Patients need to be treated as early as possible with rt-PA, to maximise the benefit therefore networks have to work fast!
There may be more time for the patients, but not for the treating physicians
Hacke et al; the ECASS 3 Investigators . N Engl J Med 2008;359:1317-1329.
Bluhmki et al. Lancet Neurol 2009;8:1095-1102.

 Provides a better understanding of stroke systems of care for patients with acute ischaemic stroke
 A multidisciplinary team is required to implement changes, including healthcare professionals and professional organisations
 Extension of the treatment window to 4.5 hours will impact all stages of stroke networks from dispatchers and emergency medicine services to acute stroke units and imaging facilities
 The balance of costs and benefits (in terms of gain in QALYs) favours treatment with rt-PA in the 3-4.5 hour time window after stroke onset vs. non-thrombolytic therapy
Tung et al. Stroke 2011;42:2257-2262.
Ingall. Stroke 2009;40:2264-2265.

Following confirmation by ECASS 3 of the extended time window to 4.5 hours for the administration of rt-PA to patients with an acute ischaemic stroke, delays in administration were not confirmed and the proportion of patients with a DTN <60 min increased
Guideline publication
ECASS 3 publication
Minnerup et al. Stroke 2011;42:2838-2843.

 Mismatch concept
 Mismatch decreases over time, but may be found in individual patients as late as 24 hours or more, depending on individual symptoms
 This may help to increase the time window and also allow treatment in patients without known onset of stroke
 Practical issues
 15-20 minutes scan time
 Some patients do not tolerate MR study
 Overall feasibility in experienced centres >90%
Warach et al. Ann. Neurol 2000;48:713-722.
Kidwell et al. Stroke 2002;33:95-98.
Jansen et al. Der Nervenarzt 1998;69:465-471.
Schellinger, Fiebach. In Fiebach, Schellinger 2003;6:31-34.

 Historically defined on MRI as the difference in volume of DWI lesion and PWI lesion
 PWI > DWI by at least 20%
 Uncorrected / unthresholded time-based perfusion parameter map
(TTP, MTT)
 Isotropic DWI
 Limitations
 DWI lesion reversibility in a minority of patients
 Therefore, DWI lesion is an approximation of infarct
 PWI without any thresholding identifies all brain tissue with hypoperfusion
MRI, magnetic resonance imaging; DWI, diffusion weighted imaging; PWI, perfusion weighted imaging
TTP, time to peak; MTT, mean transit time

 Clinical DWI mismatch
 Higher NIHSS score than DWI lesion size would suggest
 MRA DWI mismatch
 MRA vessel occlusion more proximal and involving more brain tissue than infarcted on DWI
 FLAIR DWI mismatch
 Positive lesion on DWI but not seen on FLAIR images

Paradigm: MRI-Based Studies and
Individual Therapeutic Approach
Acute ischaemic stroke
Baseline 4-8h after rt-PA
Reperfusion
Acute tissue at risk
Healthy brain
Interim lesion
Tissue at risk
(penumbra)
30 days
Higher chance for better outcome
Higher chance for poorer outcome
Final lesion
Dead brain
(ischaemic core)

Example: Imaging on Presentation of Acute
Ischaemic Stroke

Rationale for (MRI-)Mismatch Based Thrombolysis
 Time from symptom onset and (more or less) normal CT is an excellent tool to screen for patients likely responsive to rt-PA
 The earlier the time, the smaller the core
 The earlier the time, the likelier no demarcation as also seen on normal CT
 The earlier the time, the larger the tissue at risk
 Note: After 3-4.5h patients still have a reduced benefit
 Unselected treatment (CT, NIHSS, time 4.5-9h) leads to low or no benefit with higher risk of bleeding and mortality (pooled analyses)
 Therefore, selection of suitable patients beyond established time windows is a worthwhile target
 This includes patients with unknown time window

Objective
 To determine whether MRI profiles can help to predict clinical response in patients with ischaemic stroke treated with iv thrombolysis at 3-6 hours after onset
Key Results
 Target Mismatch pattern was associated with substantial benefit from early reperfusion in 67%
 Malignant MRI pattern was associated with high risk of fatal
SICH following reperfusion
 Small DWI and PWI lesions are associated with favourable outcomes
Albers et al; the DEFUSE Investigators. Ann Neurol 2006;60:508-517.

MRI profile
Target mismatch with early reperfusion
Target mismatch without early reperfusion
Malignant profile
N
15
16
6
Mean age (y)
78.3
Median baseline
NIHSS score
14
68.0
68.3
13
18.5
Favourable clinical response*
67%**
(42-84)
19%
(7-43)
17%
(3-56)
* Improvement of 8 points or more in the NIHSS score between baseline and 30 days or a score of 0-1 at 30 days
** p≤0.01, compared with target mismatch without early reperfusion
Target mismatch excludes patients with malignant mismatch
Albers et al. Ann Neurol 2006;60:508-517.

 Large dataset
 More than 500 MRI-based rt-PA treated patients
 Comparison
 Standard CT based rt-PA <3 hours
 MR-based rt-PA <3 hours
 MR-based rt-PA >3 hours (-17 hours)
Schellinger et al. Stroke 2007;38:2640-2645.

Symptomatic ICH
Age
NIHSS
Use of MRI
Good outcome
Age and NIHSS
Use of MRI >3h
Use of MRI <3h
OR=1.033, 95% CI 1.006-1.060, p=0.016
OR=1.057, 95% CI 1.010-1.106, p=0.016
OR=0.520, 95% CI 0.270-0.999, p=0.05
OR=0.973 and 0.862, for both, p<0.001
OR=1.467, 95% CI 1.017-2.117, p=0.040
OR=1.36, 95% CI 0.841-1.534, p=NS
Conclusion
 MRI-based thrombolysis within and beyond the 3-h time window is at least as safe and possibly more effective than CT-based thrombolysis
Schellinger et al. Stroke 2007;38:2640-2645.

Hypotheses
 PI/DWI mismatch represents potentially salvageable tissue in the ischaemic penumbra
 rt-PA will attenuate infarct growth by increased perfusion of the penumbra
Objective
 To determine whether rt-PA administered 3-6 hours after stroke onset decreases infarct growth in patients with a known PI/DWI mismatch
Design
 Randomised, double-blind, placebo-controlled trial
Davis et al. Lancet Neurol 2008;7:299-309.

Primary measure
Ratio of geometric means (rt-PA/placebo)
Secondary growth measures
Median relative growth
Growth >0%
Geometric mean growth (baseline lesion >5 ml) p
0.24
0.05
0.03
0.01
Davis et al. Lancet Neurol 2008;7:299-309.

EPITHET Clinical Outcomes:
Rankin Day 90 in Mismatch Patients
Functional outcome in mismatch patients
Patients mRS, modified Rankin Scale
Davis et al. Lancet Neurol 2008;7:299-309.

EPITHET Clinical Outcomes:
Rankin Day 90 in Mismatch Patients mRS 0-2 mRS 0-1
NIHSS improvement ≥8 or NIHSS ≤1 rt-PA
(N=42)
45%
(19/42)
36%
(15/42)
50%
(21/42)
Placebo
(N=43)
40%
(17/43)
21%
(9/43)
37%
(16/43) p
0.60
0.13
0.23
Results suggest, in mismatch patients a Phase III trial of rt-PA vs placebo 3-6 hours could be powered with <200 patients per arm mRS, modified Rankin Scale
Davis et al. Lancet Neurol 2008;7:299-309.

 EPITHET study confirms the results of DEFUSE
 Reperfusion is associated with a better outcome and a reduced infarct growth p
Infarct growth
Median relative growth
Median absolute growth
Clinical outcomes
Good neurological outcome
Good functional outcome
Reperfusion
N=30
0.86
(0.34 to 1.75)
-1.0
(-9.0 to 11.2)
N=30
22
(73%)
19
(63%)
No reperfusion
N=47
2.07
(1.19 to 3.65)
43.6
(4.0 to 92.3)
N=47
13
(27%)
15
(32%)
<0.0001
<0.0001
<0.0001
0.007
Davis et al. Lancet Neurol 2008;7:299-309.

 CT is sufficient for exclusion of intracranial haemorrhage and therefore decision making for or against thrombolysis
 Infarct detection <3h is achieved in only a third of ischaemic strokes
 MRI is more sensitive than CT
 Perfusion/diffusion MRI can add more information about the penumbra and potentially salvageable tissue after acute ischaemic stroke
 Specific patient profiles on MRI can help to identify subgroups of patients that may benefit from early reperfusion with thrombolytic therapy outside of approved time windows
Albers et al; the DEFUSE Investigators. Ann Neurol 2006;60:508-517.
Davis et al. Lancet Neurol 2008;7:299-309.
Schellinger et al. Neurology 2010;75:177-185.

Cochrane Meta-Analysis of IV rt-PA Versus Control
(including ECASS 3)
Mori 1992
ECASS 1995
NINDS 1995
ECASS II 1998
13/19 10/12
201/313 217/307
179/312 229/312
244/409 248/391
ATLANTIS B 1999 161/307 162/306
ATLANTIS A 2000 64/71 56/71
Wang 2003
EPITHET 2008
29/67
34/52
26/33
37/49
ECASS 3 2008 140/418 155/403
Subtotal (95% Cl) 1968 1884
Total events: 1065 (Thrombolysis), 1140 (Control)
Heterogeneity: Chi 2 =23.25, df=8 (p=0.003); I 2 =66%
Test for overall effect: Z=4.03 (p=0.000055)
0.1
1.0
10
Favours thrombolysis Favours control
0.4% 0.43 [0.07, 2.62]
11.3% 0.74 [0.53, 0.68]
11.3% 0.49 [0.35, 0.68]
15.8% 0.85 [0.64, 1.13]
12.8% 0.98 [0.71, 1.35]
1.4% 2.45 [0.93, 6.44]
1.4%
1.7%
0.21 [0.08, 0.54]
0.61 [0.26, 1.46]
15.7% 0.81 [0.61, 1.07]
71.7% 0.76 [0.66, 0.87]
Wardlaw et al. Cochrane Database of Systematic Reviews 2009;4: CD000213. DOI:
10.1002/14651858.CD000213.pub2.

Updated Pooled Analysis
(Including ECASS 3 and EPITHET)
 Data from ECASS 3 and EPITHET were added to the pool of common data elements from the 6 previous trials of rt-PA for acute ischaemic stroke
 N=3,670 patients (old analysis N=2,779)
 1,850 patients treated with rt-PA;1,820 patients given placebo
 Men: 60%
 Median age: 68 years (IQR 59-74)
 Median NIHSS: 11 (IQR 7-16)
 Median time-window: 240 min (IQR 180-284)
 Separate analyses at four OTT intervals (0-90 min, 91-180 min,
181-270 min, 271-360 min) were undertaken
Hacke et al. Lancet 2004;363:768-774.
Lees et al.
Lancet 2010;375:1695-1703.

Comparison of Pooled Analysis Data with ECASS 3
The earlier you treat, the greater the benefit
Time
Window
0-90
91-180
181-270 Pooled
ECASS 3
271-360
Adjusted OR (95% CI)
2.81
1.55
1.40
(1.75-4.50)
1.12-2.15)
(1.05-1.85)
1.42
1.15
(1.02-1.98)
(0.90-1.47)
0.1
1.0
Odds Ratio (95% CI)
10.0
Pooled data analysis of NINDS, ATLANTIS and ECASS I and II trials (green) showing odds ratios and
95% confidence intervals for favourable outcome in different time windows from onset, adjusted for prognostic confounders, with ECASS 3 outcome superimposed (blue)
Hacke et al; the ECASS 3 Investigators. N Engl J Med 2008;359:1317-1329.
Hacke et al. Lancet 2004;363:768-774.

Updated Pooled Analysis:
Favourable Outcome (mRS 0-1) vs. Time
5
4
3
OR
2.55
Odds ratio (OR)
OR
1.64
OR
1.34
OR
1.22
2
1
0
60 90 120 150
NNT
4-5
NNT, Number needed to treat
OTT, Time from stroke onset to start of treatment mRS, modified Rankin Scale
180 210 240
OTT (min)
NNT
9
270
NNT
14
300 330 360
NNT
21
Lees et al. Lancet 2010;375:1695-1703.

Updated Pooled Analysis:
Mortality
0-90 min
91-180 min
181-270 min
271-360 min
0-360 min
Placebo n/N (%)
31/151
(20.5%)
49/315
(15.6%)
82/811
(10.0%)
55/542
(10.2%)
217/1820
(11.9%)
*OR adjusted for NIHSS, age, diastolic blood pressure rt-PA n/N (%)
3/161
(18.6%)
51/303
(16.8%)
89/809
(10.6%)
86/757
(15.0%)
257/1849
(13.9%)
OR*
(95%CI)
0.78
(0.41-1.48)
1.13
(0.70-1.82)
1.22
(0.87-1.71)
1.49
(1.00-2.21)
1.19
(0.96-1.47)
Lees et al. Lancet 2010;375:1695-1703.
p
0.440
0.608
0.252
0.050
0.108

Updated Pooled Analysis:
Interpretation
 Patients with ischaemic stroke selected by clinical symptoms and CT benefit from intravenous rt-PA when treated up to 4.5 h
 No increase in mortality with rt-PA use up to 4.5 h
 The earlier treatment with rt-PA is administered, the greater the benefit
 To maximise benefit, every effort should be taken to shorten delay in initiation of treatment
 Beyond 4.5 h, risk might outweigh benefit
Lees et al. Lancet 2010;375:1695-1703.

 SITS (Safe Implementation of Treatments in Stroke) is an internet-based interactive thrombolysis register
 The SITS register is an instrument for clinical centres to follow their own treatment results and compare them with other centres in their own or in collaborating countries
 The SITS register is the technical basis for the
International Stroke Treatment Register (SITS-ISTR) and
SITS Stroke Monitoring Study (SITS-MOST) www.sitsinternational.org

 www.sitsinternational.org
 >60,167 patients added into the
SITS register by December 2011
 Recruitment is ongoing
 Now 1,273 registered centres
 55 participating countries in four continents www.sitsinternational.org

 Randomised controlled trials show thrombolysis to be beneficial when given within 3 hours of ischaemic stroke
 rt-PA was approved by the EU regulatory authority EMEA in
2002 for use within 3 hours of ischaemic stroke on two conditions:
 That patients be registered in the SITS internet database and entered into an observational safety study, SITS-MOST
AND
 A new, randomised trial of rt-PA versus placebo, ECASS 3, be launched, with an extended therapeutic window greater than 3 hours
Wahlgren et al; the SITS-MOST Investigators. Lancet 2007;369:275-282.

 An observational safety monitoring study within the EU, plus
Norway, Iceland, and Switzerland
 A cohort of the existing online stroke register SITS-International
Stroke Thrombolysis Register (SITS-ISTR)
Objective
 To assess whether intravenous rt-PA, when given as thrombolytic therapy within 3 hours of the onset of ischaemic stroke is as safe and effective in routine clinical practice as reported in randomised controlled clinical trials
Wahlgren et al; the SITS-MOST Investigators. Lancet 2007;369:275-282.

Primary outcome
 Symptomatic intracerebral haemorrhage*
 Death within 3 months
Secondary outcome
 Functional independence (mRS ≤2 at 3 months)
 SICH according to NINDS and Cochrane reviews §
 SICH according to ECASS (I + II) #
 Complete recovery (mRS ≤1 at 3 months)
*Defined as local or remote parenchymal haemorrhage type 2 on the 22 –36 hour post-treatment imaging scan; plus deterioration of
NIHSS by ≥4 points; or leading to death
§ Any haemorrhage + deterioration of NIHSS ≥1
# Any haemorrhage + deterioration of NIHSS ≥4
Wahlgren et al; the SITS-MOST Investigators. Lancet 2007;369:275-282.

Modified Rankin scores (mRS) at 3 months in SITS-MOST and
RCTs for placebo and rt-PA patients mRS
Pooled placebo
0 –3 h (N=465)
Pooled rt-PA
0 –3 h (N=463)
SITS-MOST
(N=6,136)
RCT, randomised controlled trial
Wahlgren et al; the SITS-MOST Investigators. Lancet 2007;369:275-282.

 Mortality rates within the first 3 months were lower in SITS-MOST
(11.3%) than in RCTs (17.3%)
 Functional independence at 3 months was higher in SITS-MOST
(54.8%) than in RCTs (50.1%)
 The results of SITS-MOST confirm that routine use of rt-PA within 3 hours of ischaemic stroke has a safety profile at least as good as that seen in RCTs
 SITS-MOST showed that safety could be maintained across centres, regardless of experience in acute stroke thrombolysis
 SITS-MOST demonstrates the advantage of establishing stroke centres for treating stroke patients and the need for a multidisciplinary approach to ensure recognition of symptoms, rapid transportation, accurate diagnosis, & effective treatment
RCT, randomised controlled trial
Wahlgren et al; the SITS-MOST Investigators. Lancet 2007;369:275-282.
Wahlgren et al. Lancet 2007;369:826.

 SITS-MOST, the largest monitored stroke register to date, with over 6,000 patients, demonstrated that broad implementation of thrombolysis with rt-PA in acute stroke treatment is as safe and effective as in randomised controlled clinical trials
 SITS-MOST confirmed the existing European labelling of rt-PA for thrombolysis of acute ischaemic stroke
Wahlgren et al; the SITS-MOST Investigators.
Lancet 2007;369:275-282.

 Centres participating in the SITS database are required to enter all patients into SITS-ISTR (International stroke treatment register), regardless of whether they fulfil the SITS-MOST criteria or not
 Between December 2002 and February 2010, SITS-ISTR looked at a cohort of patients (N=2,376) treated with rt-PA within 3-4.5 hours after the onset of ischaemic stroke and compared the outcome with that of patients treated within the
3-hour time window (N=21,566)
 Outcome measures were:
 sICH within 24 hours
 Mortality
 Independence (mRS 0-2) at 3 months
Ahmed et al; for the SITS Investigators. Lancet Neurol 2010;9:866-874.

No significant difference for any outcome measure between patients treated within 0-3 hours or at 3-4.5 hours after stroke onset
0 - 3 h 3 - 4.5 h Unadjusted results Adjusted results n/N (%) sICH (SITS-MOST definition) sICH (ECASS II definition) sICH (NINDS definition)
Mortality at 3 months
Mortality at 7 days
Functionally independent at 3 months (mRS 0-2)
Minimal or no disability at 3 months (mRS 0-1) mRS, modified Rankin Scale
352/21204
(1.7%)
1020/21206
(4.8%)
1515/21245
(7.1%)
2287/18583
(12.3%)
1307/20956
(6.2%)
10531/18317
(57.5%)
7467/18317
(40.8%) n/N (%)
52/2317
(2.2%)
121/2304
(5.3%)
171/2317
(7.4%)
218/1817
(12.0%)
132/2259
(5.8%)
1075/1784
(60.3%)
793/1784
(44.5%)
Odds ratio
(95% CI)
1.36
(1.01-1.83)
1.10
(0.90-1.33)
1.04
(0.88-1.22)
0.97
(0.84-1.13)
0.93
(0.78-1.12)
1.12
(1.02-1.24)
1.16
(1.05-1.28) p value
0.04
0.46
0.02
0.003
0.35
0.66
0.70
Odds ratio
(95% CI)
1.44
(1.05-1.97)
1.27
(1.03-1.55)
1.18
(0.99-1.41)
1.26
(1.07-1.49)
1.22
(1.00-1.48)
0.84
(0.75-0.95)
0.92
(0.83-1.03) p value
0.02
0.02
0.06
0.005
0.052
0.005
0.17
Ahmed et al; for the SITS Investigators. Lancet Neurol 2010;9:866-874.

Proportion of patients in the 3-4.5 h and within 3 h cohorts according to the modified Rankin scale (mRS) score at 3 months mRS
0 1 2 3 4 5 6
3−4.5 h
(n=1,784)
20% 20% 17% 13% 12% 5% 12%
Within 3 h
(n=18,317)
22% 22% 16% 12% 11% 5% 12%
0% 20% 40% 60%
Patients (%)
80%
 Functional independence at 3 months was almost identical in the 2 treatment groups
100%
Ahmed et al; for the SITS Investigators. Lancet Neurol 2010;9:866-874.

 Early treatment with thrombolysis has been confirmed and leads to better outcomes
 SITS-ISTR confirms the safety and efficacy of rt-PA for the thrombolysis of ischaemic stroke within the approved 3-hour time window as well as in the 3-4.5 hour time window
 SITS-ISTR confirms the results of SITS-MOST and reinforces the results of ECASS 3
 These results should provide more patients with access to thrombolysis which should be administered as early as possible
 However, “ time is brain ” and patients should be treated as early as possible after stroke
Ahmed et al; for the SITS Investigators. Lancet Neurol 2010;9:866-874.
Wahlgren et al. SITS Investigators. Lancet 2008;372:1303-1309.

 Patients >80 years are underrepresented in approval relevant studies
 SITS NEW focused on Asian patients (48 stroke centres from Korea, China, India and Singapore participated)
 Objective was to evaluate if the results for the use of intravenous rt-PA within 3 hours of symptom onset are consistent compared to rest of the world

Rationale
 The datasets from many studies investigating risk factors, aetiology, prevalence, ethnic disparity and potential benefits of stroke treatment regimens reside in industry and academic archives long after the studies have been published
 The importance of this stored information is often underestimated
 By collating these datasets, a large and rich pool of information can be utilised for novel analyses of the natural history of homogeneous subgroups of stroke patients
Objective
 To establish a comprehensive resource comprising patient data from acute stroke clinical trials, on which novel analyses to inform clinical trial design could be performed
Ali et al. Stroke 2007;38:1905-1910.

 VISTA contains 29 anonymised acute stroke clinical trials and one acute stroke registry
 Over 27,500 patients with either ischaemic or haemorrhagic stroke
 Patients aged 18-103 years
 Medical history and onset-to-treatment time are readily available, and computed tomography lesion data are available for selected trials
 Outcome measures include Barthel Index, Scandinavian
Stroke Scale, National Institutes of Health Stroke Scale,
Orgogozo Scale, and modified Rankin Scale
Ali et al. Stroke 2007;38:1905-1910 .

VISTA: Baseline Stroke Severity Predicts Outcome with Thrombolysis
In a non-randomised comparison of 5,817 patients from the VISTA database, outcomes with thrombolysis were significantly better across baseline NIHSS levels 5 to 24
NIHSS at baseline
1-4
5-8
9-12
13-16
17-20
21-24
≥ 25
0.2
0.5
Favours control
Forest plot OR (95%Cl)
1.14 (0.30, 4.35)
1.25 (0.98, 1.59)
1.32 (1.07, 1.62)
1.63 (1.30, 2.05)
1.67 (1.32, 2.12)
1.56 (1.14, 2.14)
1.12 (0.66, 1.90)
CMH p
0.82
0.04
0.01
< 0.05
< 0.05
< 0.05
0.08
Sample size
Alteplase/Control rt-PA/Control
8/161
278/934
404/942
342/814
311/736
178/466
64/179
1 2
Favours alteplase
5
Mishra et al; VISTA Collaborators. Stroke 2010;41:2612-2617.

Odds ratios (OR) with 95% confidence intervals for better outcome are estimated from ordinal logistic regression, adjusted for age and NIHSS
Forest plot OR (95%Cl) Age decile
21-30
31-40
41-50
51-60
61-70
71-80
81-90
91-100
1.14 (0.30, 4.35)
1.25 (0.98, 1.59)
1.32 (1.07, 1.62)
1.63 (1.30, 2.05)
1.67 (1.32, 2.12)
1.56 (1.14, 2.14)
1.12 (0.66, 1.90)
CMH p
0.82
0.04
0.01
< 0.05
< 0.05
< 0.05
0.08
Sample size rt-PA/Control
8/161
278/934
404/942
342/814
311/736
178/466
64/179
0.01
0.1
0.2 0.5
1 2
Favours control
5
Favours rt-PA
Mishra NK, et al. Stroke 2010;41:2840-2848.

Diabetes mRS
NIHSS SITS recorded only Rankin
Previous stroke mRS
NIHSS SITS recorded only Rankin mRS
Diabetes & prior stroke
NIHSS
No diabetes/stroke interaction: p=0.9
No diabetes/stroke interaction: p=0.5
SITS recorded only Rankin
0.5
Favours Control
1 2
Favours Thrombolysis
5 0.5
Favours Control
1 2
Favours Thrombolysis
5
Mishra et al, for VISTA & SITS Collaborators. Cerebrovascular Diseases 2010 [abstract from ESC];
Mishra et al, for VISTA Collaborators. Diabetes Care 2010 PMID 20843977.

 rt-PA is an approved* and recommended treatment
 Age restriction
 Age >80 years does not appear to influence response to rt-PA

No loss of benefit or enhanced ICH with age <90 years
 Severity restriction
 Efficacy extends across NIHSS up to 24
 Diabetes and prior stroke restriction

No interaction between diabetes and prior stroke
* Marketing approval does not extend to >25 NIHSS; diabetes with prior stroke; or in some countries, >80 years (e.g. EU, although relaxed to a warning in others, e.g. Australia)

 AHA
(The American Heart Association) www.americanheart.org
 ESO
(The European Stroke Organisation) www.eso-stroke.org

AHA/ASA Guidelines
Recommendations on Emergency Systems
 Suspected acute stroke patients should be identified rapidly by dispatch centres, which should dispatch the highest level of care available in the shortest possible time
 EMS should briefly assess the patient on site (Class I, LOE B)
 EMS should begin initial stroke management in the field (Class I,
LOE B)
 Patients should be transported rapidly for evaluation and treatment to the closest stroke facility (Class I, LOE B) and the
EMS should inform the ED prior to arrival
 Telemedicine can be an effective method to provide expert stroke care to patients located in rural areas (Class IIA, LOE B)
 Pre-hospital providers, emergency physicians, and stroke experts should collaborate to develop training, assessment and transportation protocols
EMS, emergency medical services
ED, emergency department
Acker et al. Stroke 2007;38:3097-3115.
Adams et al. Stroke 2007;38:1655-1711.

AHA/ASA Guidelines
Recommendations on Stroke Centres
 Creation of primary stroke centres is strongly recommended (Class I, LOE B)
 Development of comprehensive stroke centres is recommended (Class I, LOE C)
 Certification of stroke centres by an external body
(e.g. JCAHO) is encouraged (Class I, LOE B)
 Patients with suspected stroke should bypass hospitals without stroke resources and go to the closest facility capable of treating acute stroke
(Class I, LOE B)
Adams et al. Stroke 2007;38:1655-1711.
JCAHO, Joint Commission on the
Accreditation of Healthcare Organisations

AHA Guidelines for the Early Management of Adults with Ischaemic Stroke
 I.V. rt-PA (0.9 mg/kg, maximum 90 mg) with 10% of the dose given as a bolus followed by an infusion over 60 minutes for selected patients within 3 hours of onset of ischaemic stroke
(Class I, Level A)
 I.V. administration of streptokinase is not recommended for management of ischaemic stroke (Class III, Level A)
 Brain imaging (either CT or MRI) should be interpreted by an experienced clinician (Class I, Level C) before starting thrombolytic therapy (Class I, Level A)
 Additional information in the diagnosis of ischaemic stroke may be provided by multimodal CT or MRI (Class I, Level A)
Del Zoppo et al; AHA Stroke Council. Stroke 2009;40:2945-2948.

AHA Guidelines for Cardiopulmonary Resuscitation and
Emergency CV Care
 Several studies have documented a higher likelihood of good to excellent functional outcome when rt-PA is administered to adult patients with acute ischaemic stroke within 3 hours of symptom onset
 Treatment of carefully selected patients with acute ischaemic stroke with IV rt-PA between 3 and 4.5 hours after onset of symptoms has also been shown to improve clinical outcome, although the degree of clinical benefit is smaller than that achieved with treatment within 3 hours
 Administration of IV rt-PA to patients with acute ischaemic stroke who meet the NINDS or ECASS 3 eligibility criteria is recommended if rt-PA is administered by physicians in the setting of a clearly defined protocol, a knowledgeable team, and institutional commitment (Class I, LOE B)
Jauch et al. Circulation 2010;122(suppl.3):S818-S828.

ESO Guidelines for the Management of Ischaemic
Stroke and Transient Ischaemic Attack
 In patients admitted within 3 hours of stroke onset brain CT should be obtained to guide routine thrombolysis treatment with rt -PA (Class I, Level A)
 I.V. rt-PA (0.9 mg/kg body weight, max. 90 mg), with
10% of the dose given as a bolus followed by a 60minute infusion, is recommended within 4.5 hours of onset of ischaemic stroke (Class I, Level A)
 The use of multimodal imaging may be useful for patient selection for thrombolysis but is not recommended for routine clinical practice (Class III,
Level C)
ESO Guidelines 2009 Update. www.eso-stroke.org

ESO Guidelines: Recommendations for
Stroke Services and Stroke Units
 All stroke patients should be treated in a stroke unit
(Class I, Level A)
 Acute stroke patients should have access to high technology medical and surgical stroke care when required (Class III, Level B)
 The development of clinical networks, including telemedicine, is recommended to expand access to high technology specialist stroke care (Class II,
Level B)
ESO Guidelines 2009 Update. www.eso-stroke.org

®

®
 Actilyse
®
, rt-PA, is a serine protease, similar to naturally occurring tissue plasminogen activator (t-PA)
 Mode of action
 With high affinity, Actilyse
® binds to and activates plasminogen attached to the fibrin netting of a blood clot
 Plasminogen is converted to plasmin, which catalyses the breakdown of fibrin to its degradation products, resulting in break up of the clot
 The affinity for freely circulating plasminogen is low, so
Actilyse ® has highly effective local fibrinolytic effects and relatively few systemic effects
Hoylaerts et al. J Biol Chem 1982;257:2912-2919.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg,
Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in.
1.
Actilyse®
NAME OF THE MEDICINAL PRODUCT
Powder and solvent for solution for injection and infusion
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
1 vial with powder contains:
10 mg alteplase (corresponding to 5,800,000 IU) or
20 mg alteplase (corresponding to 11,600,000 IU) or
50 mg alteplase (corresponding to 29,000,000 IU), respectively.
Alteplase is produced by recombinant DNA technique using a Chinese hamster ovary cell-line. The specific activity of alteplase in-house reference material is 580,000 IU/mg. This has been confirmed by comparison with the second international WHO standard for t-PA. The specification for the specific activity of alteplase is 522,000 to 696,000 IU/mg.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Powder and solvent for solution for injection and infusion.
The powder is presented as a colourless to pale yellow lyophilizate cake.
4.
4.1
CLINICAL PARTICULARS
Therapeutic indications:
Thrombolytic treatment in acute myocardial infarction
-90 minutes (accelerated) dose regimen (see section 4.2): for patients in whom treatment can be started within 6 h after symptom onset
-3 h dose regimen (see section 4.2): for patients in whom treatment can be started between 6 - 12 h after symptom onset provided that the diagnosis has been clearly confirmed.
Actilyse has proven to reduce 30-day-mortality in patients with acute myocardial infarction.
Thrombolytic treatment in acute massive pulmonary embolism with haemodynamic instability
The diagnosis should be confirmed whenever possible by objective means such as pulmonary angiography or non-invasive procedures such as lung scanning.
There is no evidence for positive effects on mortality and late morbidity related to pulmonary embolism.
Fibrinolytic treatment of acute ischaemic stroke
Treatment must be started as early as possible within 4.5 hours after onset of stroke symptoms and after exclusion of intracranial haemorrhage by appropriate imaging techniques (e.g. cranial computerised tomography or other diagnostic imaging method sensitive for the pre sence of haemorrhage). The treatment effect is time-dependent; therefore earlier treatment increases the probability of a favourable outcome.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg,
Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in.
4.2
Posology and method of administration
Actilyse should be given as soon as possible after symptom onset. The following dose guidelines apply.
Under aseptic conditions the content of an injection vial of Actilyse (10 mg or 20 mg or 50 mg) is dissolved with water for injections according to the following table to obtain either a final concentration of 1 mg alteplase/ml or 2 mg alteplase/ml:
Actilyse vial
Final concentration
(a) 1 mg alteplase/ml (ml)
(b) 2 mg alteplase/ml (ml)
10 mg 20 mg 50 mg
Volume of water for injections to be added to dry powder:
10
5
20
10
50
25
The reconstituted solution should then be administered intravenously. It may be diluted further with sterile sodium chloride 9 mg/ml (0.9 %) solution for injection up to a minimal concentration of 0.2 mg/ml. A dilution of the reconstituted solution with sterilised water for injections or in general, the use of carbohydrate infusion solutions, e.g. dextrose is not recommended. Actilyse should not be mixed with other medicinal products neither in the same infusion-vial nor the same catheter (not even with heparin). For further practical instructions for preparation and handling see sections 6.2 and 6.6.
The experience in children and adolescents is limited. Actilyse is contraindicated for the treatment of acute stroke in children and adolescents (see section 4.3).

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg,
Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in.
Myocardial infarction a) 90 minutes (accelerated) dose regimen for patients with myocardial infarction, in whom treatment can be started within 6 hours after symptom onset:
15 mg as an intravenous bolus
50 mg as an infusion over 30 minutes followed by an infusion of 35 mg over 60 minutes until the maximal dose of 100 mg
Concentration of alteplase
1 mg/ml 2 mg/ml
15
50
35
7.5
25
17.5
In patients with a body weight below 65 kg the dose should be weight adjusted according to the following table:
15 mg as an intravenous bolus and 0.75 mg/kg body weight (bw) over 30 minutes (maximum 50 mg) followed by an infusion of 0.5 mg/kg body weight (bw) over 60 minutes
(maximum 35 mg)
Concentration of alteplase
1 mg/ml 2 mg/ml
15 ml/kg bw
0.75
0.5
7.5
ml/kg bw
0.375
0.25

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg,
Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in. b)
10 mg as an intravenous bolus
50 mg as an infusion over the first hour followed by infusions of 10 mg over 30 minutes until the maximal dose of 100 mg over 3 hours
3 h dose regimen for patients, in whom treatment can be started between 6 and 12 hours after symptom onset:
Concentration of alteplase
1 mg/ml 2 mg/ml
10
50
5
25 ml/30 min
10 ml/30 min
5
In patients with a body weight below 65 kg the total dose should not exceed 1.5 mg/kg.
The maximum dose of alteplase is 100 mg.
Adjunctive therapy:
Antithrombotic adjunctive therapy is recommended according to the current international guidelines for the management of patients with STelevation myocardial infarction; acetylsalicylic acid should be initiated as soon as possible after symptom onset and continued with lifelong treatment unless it is contraindicated.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg,
Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in.
Pulmonary embolism
A total dose of 100 mg of alteplase should be administered in 2 hours. Most experience is available with the following dose regimen:
10 mg as an intravenous bolus over 1 - 2 minutes followed by an intravenous infusion of 90 mg over 2 hours
Concentration of alteplase
1 mg/ml 2 mg/ml
10
90
5
45
The total dose should not exceed 1.5 mg/kg in patients with a body weight below 65 kg.
Adjunctive therapy:
After treatment with Actilyse heparin therapy should be initiated (or resumed) when aPTT values are less than twice the upper limit of normal.
The infusion should be adjusted to maintain aPTT between 50 - 70 seconds (1.5 to 2.5 fold of the reference value).
Acute ischaemic stroke
Treatment must only be performed under the responsibility and follow-up of a physician trained and experienced in neurovascular care, see sections 4.3 and 4.4.
The recommended dose is 0.9 mg alteplase/kg body weight (maximum of 90 mg) infused intravenously over 60 minutes with 10% of the total dose administered as an initial intravenous bolus.
Treatment with Actilyse must be started as early as possible within 4.5 hours of the onset of symptoms. Beyond 4.5 hours after onset of stroke symptoms there is a negative benefit risk ratio associated with Actilyse administration and so it should not be administered (see section 5.1). 5
Adjunctive therapy:
The safety and efficacy of this regimen with concomitant administration of heparin and acetylsalicylic acid within the first 24 hours of onset of the symptoms have not been sufficiently investigated. Administration of acetylsalicylic acid or intravenous heparin should be avoided in the first 24 hours after treatment with Actilyse. If heparin is required for other indications (e.g. prevention of deep vein thrombosis) the dose should not exceed 10,000 IU per day, administered subcutaneously.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg,
Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Additional contraindications in acute myocardial infarction, acute pulmonary embolism and acute ischaemic stroke:
Actilyse is contraindicated in cases where there is a high risk of haemorrhage such as:
• significant bleeding disorder at present or within the past 6 months
• known haemorrhagic diathesis
• patients receiving oral anticoagulants, e.g. warfarin sodium
• manifest or recent severe or dangerous bleeding
• known history of or suspected intracranial haemorrhage
• suspected subarachnoid haemorrhage or condition after subarachnoid haemorrhage from aneurysm
• any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery)
• recent (less than 10 days) traumatic external heart massage, obstetrical delivery, recent puncture of a non-compressible blood-vessel (e.g. subclavian or jugular vein puncture)
• severe uncontrolled arterial hypertension
• bacterial endocarditis, pericarditis
• acute pancreatitis
• documented ulcerative gastrointestinal disease during the last 3 months, oesophageal varices, arterial-aneurysm, arterial/venous malformations
• neoplasm with increased bleeding risk
• severe liver disease, including hepatic failure, cirrhosis, portal hypertension (oesophageal varices) and active hepatitis
• major surgery or significant trauma in past 3 months.
Additional contraindications in acute myocardial infarction:
• any known history of haemorrhagic stroke or stroke of unknown origin
• known history of ischaemic stroke or transient ischaemic attack (TIA) in the preceding 6 months, except current acute ischaemic stroke within 3 hours.
Additional contraindications in acute pulmonary embolism:
• any known history of haemorrhagic stroke or stroke of unknown origin
• known history of ischaemic stroke or transient ischaemic attack (TIA) in the preceding 6 months, except current acute ischaemic stroke within 3 hours.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg,
Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in.
4.4
Additional contraindications in acute ischaemic stroke:
•symptoms of ischaemic attack beginning more than 4.5 hours prior to infusion start or symptoms for which the onset time is unknown and could potentially be more than 4.5 hours ago (see section 5.1)
•minor neurological deficit or symptoms rapidly improving before start of infusion
•severe stroke as assessed clinically (e.g. NIHSS>25) and/or by appropriate imaging techniques
•seizure at onset of stroke
•evidence of intracranial haemorrhage (ICH) on the CT-scan
•symptoms suggestive of subarachnoid haemorrhage, even if CT-scan is normal
•administration of heparin within the previous 48 hours and a thromboplastin time exceeding the upper limit of normal for laboratory
•patients with any history of prior stroke and concomitant diabetes
•prior stroke within the last 3 months
•platelet count of below 100,000/mm 3
•systolic blood pressure > 185 or diastolic BP > 110 mm Hg, or aggressive management (intravenous pharmacotherapy) necessary to reduce BP to these limits
•blood glucose < 50 or > 400 mg/dl.
Use in children and, adolescents
Actilyse is not indicated for the treatment of acute stroke in paediatric patients under 18 years.
Use in elderly patients
Actilyse is not indicated for the treatment of acute stroke in adults over 80 years of age.
Special warnings and precautions for use
Special warnings and precautions in acute myocardial infarction, acute pulmonary embolism and acute ischaemic stroke:
Thrombolytic/fibrinolytic treatment requires adequate monitoring. Actilyse should only be used by physicians trained and experienced in the use of thrombolytic treatments and with the facilities to monitor that use. It is recommended that when
Actilyse is administered standard resuscitation equipment and pharmacotherapy be available in all circumstances.
The risk of intracranial haemorrhage is increased in elderly patients, therefore in these patients the risk/benefit evaluation should be carried out carefully.
As yet, there is only limited experience with the use of Actilyse in children and adolescents.
As with all thrombolytic agents, the expected therapeutic benefit should be weighed up particularly carefully against the possible risk, especially in patients with
•small recent traumas, such as biopsies, puncture of major vessels, intramuscular injections, cardiac massage for resuscitation
•conditions with an increased risk of haemorrhage which are not mentioned in section 4.3.
The use of rigid catheters should be avoided.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg,
Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in.
Additional special warnings and precautions in acute myocardial infarction:
A dose exceeding 100 mg of alteplase must not be given because it has been associated with an additional increase in intracranial bleeding.
Therefore special care must be taken to ensure that the dose of alteplase infused is as described in section 4.2.
There is limited experience with readministration of Actilyse. Actilyse is not suspected to cause anaphylactic reactions. If an anaphylactoid reaction occurs, the infusion should be discontinued and appropriate treatment initiated.
The expected therapeutic benefit should be weighed up particularly carefully against the possible risk, especially in patients with systolic blood pressure > 160 mm Hg.
GPIIb/IIIa antagonists:
Concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.
Additional special warnings and precautions in acute pulmonary embolism: same as for acute myocardial infarction (see above)
Additional special warnings and precautions in acute ischaemic stroke:
Special precautions for use:
Treatment must only be performed under the responsibility and follow-up of a physician trained and experienced in neurovascular care.
Special warnings / conditions with a decreased benefit/risk ratio:
Compared to other indications patients with acute ischaemic stroke treated with Actilyse have a markedly increased risk of intracranial haemorrhage as the bleeding occurs predominantly into the infarcted area. This applies in particular in the following cases:
•all situations listed in section 4.3. and in general all situations involving a high risk of haemorrhage
•small asymptomatic aneurysms of the cerebral vessels
•with later time-to-treatment from onset of stroke symptoms the net clinical benefit is reduced and may be associated with a higher risk of ICH and death compared to patients treated earlier. Therefore, the administration of Actilyse should not be delayed.
•patients pre-treated with acetyl salicylic acid (ASA) may have a greater risk of intracerebral haemorrhage, particularly if Actilyse treatment is delayed.
Blood pressure (BP) monitoring during treatment administration and up to 24 hours seems justified; an intravenous antihypertensive therapy is also recommended if systolic BP > 180 mm Hg or diastolic BP > 105 mm Hg.
The therapeutic benefit is reduced in patients that had a prior stroke or in those with known uncontrolled diabetes, thus the benefit/risk ratio is considered less favourable, but still positive in these patients.
In patients with very mild stroke , the risks outweigh the expected benefit (see section 4.3).
Patients with very severe stroke are at higher risk for intracerebral haemorrhage and death and should not be treated (see section
4.3).
Patients with extensive infarctions are at greater risk of poor outcome including severe haemorrhage and death. In such patients, the benefit/risk ratio should be thoroughly considered.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg,
Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in.
4.5
4.6
4.7
In stroke patients the likelihood of good outcomes decreases with increasing age, increasing stroke severity and increased levels of blood glucose on admission while the likelihood of severe disability and death or relevant intracranial bleedings increases, independently from treatment. Patients over 80, patients with severe stroke (as assessed clinically and/or by appropriate imaging techniques) and patients with blood glucose levels < 50 mg/dl or >400 mg/dl at baseline should not be treated with Actilyse (see section 4.3).
Data available from ECASS III and the pooled analysis indicate that the net clinical benefit becomes smaller in elderly with increasing age compared to younger patients as benefit from treatment with Actilyse appears to decrease and the risk of mortality appears to increase with increasing age.
Other special warnings:
Reperfusion of the ischaemic area may induce cerebral oedama in the infarcted zone.
Due to an increased haemorrhagic risk, treatment with platelet aggregation inhibitors should not be initiated within the first 24 hours following thrombolysis with alteplase.
Interaction with other medicinal products and other forms of interaction
No formal interaction studies with Actilyse and medicinal products commonly administered in patients with acute myocardial infarction have been performed.
The risk of haemorrhage is increased if coumarine derivatives, oral anticoagulants, platelet aggregation inhibitors, unfractionated heparin or LMWH or active substances which interfere with coagulation are administered (before, during or within the first 24 hours after treatment with Actilyse) (see section 4.3).
Concomitant treatment with ACE inhibitors may enhance the risk of suffering an anaphylactoid reaction, as in the cases describing such reactions a relatively larger proportion of patients were receiving ACE inhibitors concomitantly.
Concomitant use of GPIIb/IIIa antagonists increases the risk of bleeding.
Pregnancy and lactation
There is very limited experience with the use of alteplase during pregnancy and lactation. Studies in animals have shown reproductive toxicity (see section 5.3). In cases of an acute life-threatening disease the benefit has to be evaluated against the potential risk. It is not known if alteplase is excreted into breast milk.
Effects on ability to drive and use machines
Not relevant.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg,
Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in.
4.8 Undesirable effects
Adverse reactions listed below are classified according to frequency and system organ class. Frequency groupings are defined according to the following convention: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare
(≥1/10,000 to <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data).
Except for intracranial haemorrhage as adverse reaction in the indication stroke and reperfusion arrhythmias in the indication myocardial infarction, there is no medical reason to assume that the qualitative and quantitative adverse reaction profile of Actilyse in the indications pulmonary embolism and acute ischaemic stroke is different from the profile in the indication myocardial infarction.
Haemorrhage
The most frequent adverse reaction associated with Actilyse is bleeding resulting in a fall in haematocrit and/or haemoglobin values: very common : bleeding from damaged blood vessels (such as haematoma), injection site haemorrhage (puncture site haemorrhage, catheter site haematoma, catheter site haemorrhage) common : intracranial haemorrhage (such as cerebral haemorrhage, cerebral haematoma, haemorrhagic stroke, haemorrhagic transformation of stroke, intracranial haematoma, subarachnoid haemorrhage) in the treatment of acute ischaemic stroke.
Symptomatic intracerebral haemorrhage represents the major adverse reaction in the treatment of acute ischaemic stroke (up to
10 % of patients without any increase of overall mortality and without any relevant increase in overall mortality and severe disability combined, i.e. mRS of 5 and 6), respiratory tract haemorrhage (such as pharyngeal haemorrhage, epistaxis, haemoptysis), gastrointestinal haemorrhage (such as gastric haemorrhage, gastric ulcer haemorrhage, haemorrhage, rectum, haematemesis, melaena, mouth haemorrhage, gingival bleeding), ecchymosis, urogenital haemorrhage (such as haematuria, haemorrhage urinary tract), blood transfusion (necessary) uncommon : intracranial haemorrhage (such as cerebral haemorrhage, cerebral haematoma, haemorrhagic stroke, haemorrhagic transformation of stroke, intracranial haematoma, subarachnoid haemorrhage) in the treatment of acute myocardial infarction and acute pulmonary embolism, ear haemorrhage, haemopericardium, retroperitoneal haemorrhage (such as retroperitoneal haematoma) rare : bleeding in parenchymatous organs (such as hepatic haemorrhage, pulmonary haemorrhage) very rare : eye haemorrhage
Death and permanent disability are reported in patients who have experienced stroke (including intracranial bleeding) and other serious bleeding episodes.
If a potentially dangerous haemorrhage occurs in particular cerebral haemorrhage, the fibrinolytic therapy must be discontinued. In general, however, it is not necessary to replace the coagulation factors because of the short half-life and the minimal effect on the systemic coagulation factors. Most patients who have bleeding can be managed by interruption of thrombolytic and anticoagulant therapy, volume replacement, and manual pressure applied to an incompetent vessel. Protamine should be considered if heparin has been administered within 4 hours of the onset of bleeding. In the few patients who fail to respond to these conservative measures, judicious use of transfusion products may be indicated. Transfusion of cryoprecipitate, fresh frozen plasma, and platelets should be considered with clinical and laboratory reassessment after each administration. A target fibrinogen level of 1 g/l is desirable with cryoprecipitate infusion. Antifibrinolytic agents are available as a last alternative.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg,
Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in.
Immune system disorders uncommon : hypersensitivity reactions / anaphylactoid reactions (e.g. allergic reactions including rash, urticaria, bronchospasm, angio-oedema, hypotension, shock or any other symptom associated with allergic reactions) very rare : serious anaphylaxis
Transient antibody formation to Actilyse has been observed in rare cases and with low titres, but a clinical relevance of this finding could not be established.
Nervous system disorders very rare : events related to the nervous system (e.g. epileptic seizure, convulsion, aphasia, speech disorder, delirium, acute brain syndrome, agitation, confusion, depression, psychosis) often in association with concurrent ischaemic or haemorrhagic cerebrovascular events.
Cardiac disorders
As with other thrombolytic agents, the following events have been reported as sequelae of myocardial infarction and / or thrombolytic administration.
very common : recurrent ischaemia / angina, hypotension and heart failure / pulmonary oedema, reperfusion arrhythmias (such as arrhythmia, extrasystoles, AV block I ° to complete, atrial fibrillation / flutter, bradycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia / fibrillation, electromechanical dissociation [EMD]) common : cardiac arrest, cardiogenic shock and reinfarction uncommon : mitral regurgitation, pulmonary embolism, other systemic embolism / cerebral embolism, ventricular septal defect
These cardiac events can be life-threatening and may lead to death.
Vascular disorders uncommon : embolism (thrombotic embolisation), which may lead to corresponding consequences in the organs concerned
Gastrointestinal disorders common : nausea, vomiting
Investigations very common : blood pressure decreased common : body temperature increased
Injury and poisoning and procedural complications rare : fat embolism (cholesterol crystal embolisation), which may lead to corresponding consequences in the organs concerned
4.9 Overdose
The relative fibrin specificity notwithstanding, a clinical significant reduction in fibrinogen and other blood coagulation components may occur after overdosage. In most cases, it is sufficient to await the physiological regeneration of these factors after the Actilyse therapy has been terminated. If, however, severe bleeding results, the infusion of fresh frozen plasma or fresh blood is recommended and if necessary, synthetic antifibrinolytics may be administered.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg,
Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in.
5.PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: antithrombotic agent, ATC code: B 01 A D 02
The active ingredient of Actilyse is alteplase, a recombinant human tissue-type plasminogen activator, a glycoprotein, which activates plasminogen directly to plasmin. When administered intravenously, alteplase remains relatively inactive in the circulatory system. Once bound to fibrin, it is activated, inducing the conversion of plasminogen to plasmin leading to the dissolution of the fibrin clot.
Due to its relative fibrin-specificity alteplase at a dose of 100 mg leads to a modest decrease of the circulating fibrinogen levels to about 60 % at 4 hours, which is generally reverted to more than 80 % after 24 hours. Plasminogen and alpha-2-antiplasmin decrease to about 20 % and 35 % respectively after 4 hours and increase again to more than 80 % at 24 hours. A marked and prolonged decrease of the circulating fibrinogen level is only seen in few patients.
In a study including more than 40,000 patients with an acute myocardial infarction (GUSTO) the administration of 100 mg alteplase over 90 minutes, with concomitant intravenous heparin infusion, led to a lower mortality after 30 days (6.3 %) as compared to the administration of streptokinase, 1.5 million U over 60 minutes, with subcutaneous or intravenous heparin (7.3 %).
Actilyse-treated patients showed higher infarct related vessel patency rates at 60 and 90 minutes after thrombolysis than the streptokinase-treated patients. No differences in patency rates were noted at 180 minutes or longer.
30-day-mortality is reduced as compared to patients not undergoing thrombolytic therapy.
The release of alpha-hydroxybutyrate-dehydrogenase (HBDH) is reduced. Global ventricular function as well as regional wall motion is less impaired as compared to patients receiving no thrombolytic therapy.
Myocardial infarction
A placebo controlled trial with 100 mg alteplase over 3 hours (LATE) showed a reduction of 30-day-mortality compared to placebo for patients treated within 6-12 hours after symptom onset. In cases, in which clear signs of myocardial infarction are present, treatment initiated up to 24 hours after symptom onset may still be beneficial.
Pulmonary embolism
In patients with acute massive pulmonary embolism with haemodynamic instability thrombolytic treatment with Actilyse leads to a fast reduction of the thrombus size and a reduction of pulmonary artery pressure. Mortality data are not available.
Acute stroke
In two USA studies (NINDS A/B) a significant higher proportion of patients, had a favourable outcome with alteplase, compared to placebo (no or minimal disability). These findings were confirmed in the ECASS III trial (see paragraph below), after in the meantime two European studies and an additional USA study had failed to provide the respective evidence in settings essentially not compliant with the current EU product information.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg,
Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in.
The ECASS III trial was a placebo-controlled, double-blind trial conducted in patients with acute stroke in a time-window of 3 to 4.5 hours in Europe.
Treatment administration in the ECASS III study was in line with the European SmPC for Actilyse in its stroke indication, except the upper end of the time of treatment window i.e. 4.5 hours. The primary end point was disability at 90 days, dichotomized for favourable (modified Rankin scale [mRS] 0 to 1) or unfavourable (mRS 2 to 6) outcome. A total of 821 patients (418 alteplase/403 placebo) were randomized. More patients achieved favourable outcome with alteplase (52.4%) vs. placebo (45.2%; odds ratio [OR] 1.34; 95% CI 1.02 - 1.76; P=0.038). The incidence of symptomatic intracranial haemorrhage was higher with alteplase vs. placebo (27.0% vs 17.6%, p=0.0012; Mortality was low and not significantly different between alteplase (7.7%) and placebo (8.4%; P=0.681). Subgroup results of ECASS III confirm that a longer OTT is associated with an increasing risk for mortality and symptomatic intracranial haemorrhage. The results of ECASS III show a positive net-clinical benefit for ACTILYSE in the 3 to
4.5 hour time window, while pooled data demonstrate that the net-clinical benefit is no longer favourable for alteplase in the time window beyond 4.5 hours.
The safety and efficacy of ACTILYSE for acute ischaemic stroke treatment up to 4.5 hours time stroke onset time to start of treatment (OTT) has been assessed by an ongoing registry (SITS-ISTR: The Safe Implementation of Thrombolysis in Stroke registry). In this observational study safety outcome data of 21.566 treated patients in the 0 to 3 hour time window were compared with data from 2.376 patients treated between 3 to 4.5 hours after onset of AIS. The incidence of symptomatic intracranial haemorrhage (according to the SITS-MOST definition) was found to be higher in the 3 to 4.5 hour time window (2.2%) as compared with the up to 3 hour time window (1.7%). Mortality rates at 3 months were similar comparing the 3 to
4.5 hour time window (12.0%) with the 0 to 3.0 hours time window (12.3%) with an unadjusted OR 0.97 (95% CI: 0.84-1.13, p=0.70) and an adjusted
OR 1.26 (95% CI: 1.07-1.49, p=0.005. The SITS observational data support clinical trial evidence of stroke onset time to start of treatment (OTT) as an important predictor of outcome following acute stroke treatment with alteplase.
5.2 Pharmacokinetic properties
Alteplase is cleared rapidly from the circulating blood and metabolised mainly by the liver (plasma clearance 550 - 680 ml/min.). The relevant plasma half-life t1/2 alpha is 4-5 minutes. This means that after 20 minutes less than 10 % of the initial value is present in the plasma. For the residual amount remaining in a deep compartment, a beta-half-life of about 40 minutes was measured.
5.3 Preclinical safety data
In subchronic toxicity studies in rats and marmosets no unexpected undesirable effects were found. No indications of a mutagenic potential were found in mutagenic tests.
In pregnant animals no teratogenic effects were observed after intravenous infusion of pharmacologically effective doses. In rabbits embryotoxicity
(embryolethality, growth retardation) was induced by more than 3 mg/kg/day. No effects on peri-postnatal development or on fertility parameters were observed in rats with doses up to 10 mg/kg/day.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg,
Netherlands, Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in.
6.PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Powder for solution: Arginine
Phosphoric acid, dilute
Polysorbate 80
Solvent:
Water for injections
The pH of the reconstituted solution is 7.3 ± 0.5
6.2 Incompatibilities
The reconstituted solution may be diluted with sterile sodium chloride 9 mg/ml (0.9 %) solution for injection up to a minimal concentration of 0.2 mg alteplase per ml.
Further dilution, the use of water for injections for dilution or in general the use of carbohydrate infusion solutions, e.g. dextrose, is not recommended due to increasing formation of turbidity of the reconstituted solution.
Actilyse should not be mixed with other medicinal products neither in the same infusion vial nor the same catheter (not even with heparin).
6.3 Shelf life
10 mg, 20 mg and 50 mg pack sizes: 3 years
After reconstitution, an immediate use is recommended. However, the in-use stability has been demonstrated for 24 hours at 2 ° C
– 8 ° C and for 8 hours at 25 ° C
6.4 Special precautions for storage
Store in the original package in order to protect from light.
For 10 mg, 20 mg and 50 mg pack sizes: Do not store above 25 ° C.
For storage conditions of the reconstituted medicinal product, see section 6.3.

This is the SPC as approved for Austria, Belgium, Denmark, Finland, France, Germany, Ireland, Luxembourg, Netherlands,
Portugal, Spain, Sweden, UK. For product use, please check the local SPC of the country you live in.
6.5
Nature and contents of container
Powder for solution:
10 ml, 20 ml or 50 ml sterilised glass vials, sealed with sterile siliconised grey butyl-type stoppers with aluminium/plastic flip-off caps.
Solvent:
For the 10 mg, 20 mg and 50 mg pack sizes, the water for injections is filled into either 10 ml, 20 ml or 50 ml vials, depending on the size of the powder vials. The water for injections vials are sealed with rubber stoppers and aluminium/plastic flip-off caps.
Transfer cannulas (included with pack sizes of 20 mg and 50 mg only)
Pack sizes:
10 mg:
1 vial with 467 mg powder for solution for injection and infusion
1 vial with 10 ml of water for injections
20 mg:
1 vial with 933 mg powder for solution for injection and infusion
1 vial with 20 ml of water for injections
1 transfer cannula
50 mg:
1 vial with 2333 mg powder for solution for injection and infusion
1 vial with 50 ml of water for injections
1 transfer cannula
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
For reconstitution to a final concentration of 1 mg altpelase per ml the full volume of solvent provided should be transferred to the vial containing the
Actilyse powder. To this purpose a transfer cannula is included with the 20 mg and 50 mg pack sizes, which is to be used. For the 10 mg pack sizes a syringe should be used.
For reconstitution to a final concentration of 2 mg alteplase per ml only half of the solvent provided should be used. In these cases always a syringe should be used to transfer the required amount of solvent to the vial containing the Actilyse powder.
A table giving the volumes of solvent required for reconstitution to the final concentrations for each pack size is provided in section 4.2.
When reconstituting the product from the respective amount of powder and solvent, the mixture should only be agitated gently until complete dissolution.
Any vigorous agitation should be avoided to prevent foam formation.
The reconstituted preparation is a clear and colourless to pale yellow solution. Prior to administration it should be inspected visually for particles and colour.
The reconstituted solution is for single use only. Any unused solution should be discarded.
7. MARKETING AUTHORISATION HOLDER
Boehringer Ingelheim International GmbH, Binger Str. 173, D-55216 Ingelheim am Rhein, Germany

NINDS
 A haemorrhage was considered symptomatic if it was not seen on a previous CT scan and there had subsequently been either a suspicion of haemorrhage or any decline in neurologic status
 To detect intracranial haemorrhage, CT scans were required at 24 h and 7 –10 days after the onset of stroke and when clinical findings suggested haemorrhage sICH, symptomatic intracranial haemorrhage

ECASS II
 Any intracranial bleed and ≥4 points worsening on the
NIHSS (same as ECASS 3 definition, except that causal relationship between haemorrhage and clinical deterioration not required)
SITS-MOST
 Local or remote parenchymal haematoma type II on the
22 –36 h post-treatment imaging scan, combined with a neurologic deterioration of ≥4 points on the NIHSS from baseline, or from the lowest NIHSS value between baseline and 24 h, or leading to death

Published by
Boehringer Ingelheim GmbH www.actilyse.com
Realisation infill healthcare communication www.infill.com
Supported by
Professors Peter Schellinger & Patrick Goldstein