Transcript Folie 1 - Stroke in Stoke

Safe
Implementation
of Thrombolysis
in Stroke
Slide presentation adapted from http://www.acutestroke.org/
In 2002, European Union regulatory authority EMEA approved rt-PA
for stroke CONDITIONALLY
• Within 3 hours of an
ischaemic stroke
• Age 18-80
• In high quality stroke centres
with stroke units with certain
monitoring requirements
There were two major conditions for this approval:
EU approval
with conditions:
• Safety monitoring of
all treated patients in
SITS (SITS-MOST) until
2005 (prolonged to April
2006)
• RCT to study effect
of rt-PA in patients with
symptoms onset since
3–4.5h (ECASS III)
Recruitment
Patients
SITS-MOST
2003-2006:
6,483 patients
285 active centres
Centres
7,000
300
6,000
250
5,000
200
4,000
150
3,000
100
2,000
50
1,000
0
0
2003:1 2003:2 2004:1 2004:2 2005:1 2005:2 2006:1
Results, baseline:
Variables
SITS-MOST
Pooled RCT
Pooled RCT
Placebo 0-3h
Alteplase 0-3h
n=465
n=464
Data are median (IQR) or %
n=6483
Age, years
68 (59-75)
67.1 (60- 74)
69.6 (61- 75)
Females
39.8
40.2
40.1
Hypertension
58.7
60.7
59.7
Diabetes Mellitus
16.0
18.9
21.1
Atrial Fibrillation
23.9
20.0
20.7
7.5
15.3
13.2
Previous stroke
10.1
12.7
13.8
Aspirin
29.8
28.8
36.4
Congestive heart failure
Lancet 2007; 369: 275-282.
Results, baseline:
Variables
Data are median (IQR) or %
NIHSS, excluding item 12
Blood glucose (mg/dl)
Weight in kg
Systolic blood pressure (mm
Hg)
Diastolic blood pressure
(mm Hg)
Stroke onset to treatment
time (minutes)
SITS-MOST
n=6483
Pooled RCT
Pooled RCT
Placebo 0-3h
Alteplase 0-3h
n=465
n=464
12 (8-17)
14 (9-19)
13 (8-18)
116 (101-139)
124 (106-151)
119 (104-158)
75 (68-85)
79.4 (66- 90.7)
75 (65-84)
150 (137-166)
152 (140- 170)
156 (140-170)
81 (74-90)
86 (77-95.5)
84 (78-92)
140 (115-165)
138 (90-165)
140 (90-168)
Lancet 2007; 369: 275-282.
Type of haemorrhages at 22-36h imaging:
HI 1: small petechiae along the margins of the infarct
HI 2: a more confluent petechiae within the infarct area but without space-occup. effect
PH 1: blood clot(s) not exceed. 30% of the infarct area w. some mild space-occup. effect
1.1
PH 2: blood clots exceeding 30% of the infarct area with significant space occup. effect
1.7
5.4
HI 1
HI 2
2.5
PH 1
PH 2
PHr 1
PHr 2
2.6
4.0
Lancet 2007; 369: 275-282.
SITS-MOST main outcomes 2003-2006, compared with active arms of
randomised controlled trials (proportions and 95% confidence intervals)
SITS-MOST Results
RCT Active arm
Preliminary Clinical Outcome, 95% CI
0% 2% 4% 6% 8% 10% 15% 20% 25%
SICH
107/ 6444
1.4 1.7 2.0
*at post-treatment imaging 22-36h
40% 45% 50% 55%
SITS definition of SICH:
PH2* +
NIHSS ≥ 4 points or death
within 24 hours
Lancet 2007; 369: 275-282.
SITS-MOST main outcomes 2003-2005, compared with active arms of
randomised controlled trials (proportions and 95% confidence intervals)
SITS-MOST Results
RCT Active arm
Preliminary Clinical Outcome, 95% CI
0% 2% 4% 6% 8% 10% 15% 20% 25%
SICH
296/ 6442
*at post-treatment imaging <7d
4.1 4.6 5.1
40% 45% 50% 55%
ECASS definition of SICH:
Any haemorrhage +
NIHSS ≥ 4 points or death
within 7 days
Lancet 2007; 369: 275-282
SITS-MOST main outcomes 2003-2005, compared with active arms of
randomised controlled trials (proportions and 95% confidence intervals)
SITS-MOST Results
RCT Active arm
Preliminary Clinical Outcome, 95% CI
0% 2% 4% 6% 8% 10% 15% 20% 25%
SICH
468/ 6438
*at post-treatment imaging <7d
6.7 7.3 7.9
40% 45% 50% 55%
RCT definition of SICH:
Any haemorrhage +
NIHSS ≥ 1 points or death
within 7 days
Lancet 2007; 369: 275-282
SITS-MOST main outcomes 2003-2005, compared with active arms of
randomised controlled trials (proportions and 95% confidence intervals)
SITS-MOST Results
RCT Active arm
Preliminary Clinical Outcome, 95% CI
0% 2% 4% 6% 8% 10% 15% 20% 25%
Mortality
701/ 6218
10.5 11.3 12.1
Independence 3 months
(mRankin0-2)
3362/ 6136
SICH (any worsening +
any bleeding)
468/ 6438
40% 45% 50% 55%
53.5 54,8 56.0
6.7 7.3 7.9
Lancet 2007; 369: 275-282.
Result of SITS-MOST compared with randomised
controlled trials – modified Rankin Scale at 3 months
RCT placebo
13
16
11
14
20
7
18
mRS 0
mRS 1
mRS 2
+10%
RCT active rt-PA
20
22
8
14
12
7
18
mRS 3
mRS 4
mRS 5
+4,8%
SITS-MOST
0%
19
19,9
20%
15,9
40%
14,7
60%
Recovered
Red colours: ADL*-independent
Blue colours: ADL*-dependent
Black colour: Dead
mRS 6
13,9
5,3 11,4
80%
100%
Dead
*Activities of daily living
Lancet 2007; 369: 275-282.
Main outcome by site’s previous experience with thrombolysis in
stroke before joining SITS-MOST
Pooled RCT
SITS-MOST
RCT
SITS-MOST, Experienced
SITS-MOST, New
Experienced
New
1%
2%
SICH rates per
SITS-MOST
1.6 (1.3-2.0)
1.7 (1.2- 2.6)
NA
SICH rates per
NINDS/Coch
rane
7.3 (6.6- 8.0)
7.3 (6.1- 8.7)
8.6 (6.3- 11.6)
10.6 (9.8- 11.6)
13.3 (11.6- 15.1)
17.3 (14.1- 21.1)
54.4 (53.0- 55.8)
56.0 (53.4- 58.5)
50.1 (45.5- 54.7)
Mortality within 3
months
Independence
(mRS, 0-2) at
3 months
3%
6%
8%
10%
12%
14%
16%
18%
20%
45%
50% 55%
60%
Lancet 2007; 369: 275-282.
Conclusions:
 These data confirm that intravenous alteplase is safe and effective
in routine clinical use when used within 3h of stroke onset, even
by centres with limited prior experience of thrombolytic therapy for
acute stroke.
 SITS-MOST has fulfilled its purpose outlined by EMEA to show that
i.v stroke thrombolysis is safe under the treatment conditions
 Now it is also important that ECASS 3 is completed successfully so
that we can receive a permanent licence for rt-PA
 The findings should encourage wider use of thrombolytic therapy
for suitable patients treated in stroke centres.
Further conclusions: safe but still underused
 Although the recruitment to SITS-MOST and SITS-ISTR (more
than 12,000) is beyond expectations, less than 2% of all stroke
patients receive thrombolysis in EU
 Following the publication of SITS-MOST main outcomes
national publications for each EU country are planned to state
the current level of thrombolysis implementation
 This will also be the starting point for the project
SITS 2009 @ 5% , which aims to reach this level of
implementation (or more) in 3 years – all current SITS centres
and those not yet active are invited to participate
Why should clinicians spend time putting patients into SITS?
Ongoing audit of local results against national and international standards
Especially important when starting a thrombolysis service
Instant summaries of outcomes for the local centre downloadable form the site
But: important to include all patients. Selective use of the database will bias outcomes.
SITS thrombolysis register Jun 2009
No registered
% much better in 24 h
% much better at 7d
% no symptoms at all at 3 mo
Stoke
105
40%
54%
25%
UK
3,194
33%
43%
15%
World
27,988
31%
41%
18%
% SICH*
% signif. deterioration<=24 h
% deaths
0%
9%
22%
1%
9%
22%
1%
12%
14%
Door to needle time
Onset to needle time
82 min** 66 min 65 min
150 min 150 min 145 min
Age
Baseline NIHSS
TACI
67
14
51%
68
14
48%
67
12
36%
*defined as confluent haemorrhage (not just petechial) and clinical deterioration
e.g. NIHSS change>4 within 24 h or death and PH2 or PHr2 at 22-36 h.
** 98 min to Jan 2008! 85 min to March 2008! And 62 min from May 2009
ECASS III
RCT alteplase versus placebo 3-4.5 h post stroke onset
N=821
Median time to treatment 3:59 h:min
tPA
Placebo
Favourable outcome
e.g.Rankin 0-1 at 3 mo
52%
45%
p=0.04
Symptomatic ICH
2.4%
0.2%
P=0.008
Mortality
7.7%
8.4%
P=0.7
ECASS III caveats
• Baseline imbalance NIHSS 1 point worse
in placebo group at randomization
• SC heparin was allowed
EPITHET Study
• 101 patients, median NIHSS 14
• mismatch in perfusion-weighted MRI (PWI) and
diffusion-weighted MRI (DWI) before and 3-5 d
after rx
• alteplase 3-6 h after stroke onset
• non-significantly lower infarct growth and
significantly increased reperfusion in patients
who had mismatch
• Phase III trials beyond 3 h warranted
Davis et AK, Lancet Neurol. 2008;7(4):299-309.
What % of stroke patients received
thrombolysis for stroke in USA in 2007?
• rt-PA approved for stroke since 1995
• Audit of 4,750 hospitals, ~ 500,000 patients
with ischaemic stroke (2005-7)
• ~12,000 (2.4%) patients treated with rt-PA
• Proportion treated varied: 0-23%
• 60% of hospitals did not give rt-PA at all.
Kleindorfer et al AHA Stroke Conference 2009
What % of stroke patients received
thrombolysis for stroke in USA in 2007?
• rt-PA approved for stroke since 1995
• Audit of 4,750 hospitals, ~ 500,000 patients
with ischaemic stroke (2005-7)
• ~12,000 (2.4%) patients treated with rt-PA
• Proportion treated varied: 0-23%
• 60% of hospitals did not give rt-PA at all.
Kleindorfer et al AHA Stroke Conference 2009
Cochrane systematic review of of
thrombolysis with rt-PA
• 11 trials, including ECASS-3
• 3977 patients tpa vs control
• RCT data on only 42 patients > 80 yrs
• Follow-up short: primary outcome @
3months.
Wardlaw J, Murray V, et al, Cochrane Database Systematic Reviews (in Press)
IV rt-PA < 6h. ~4000 patients, 1920 outcome
events ‘death or dependency (mRS 3-6)’
926
999
Odds ratio = 0.78 (0.68-.88)
Heterogeneity (Chi2 p=0.007) I2 = 62%
Test for overall effect p=0.0001
Wardlaw J, Murray V, et al, Cochrane Database Systematic Reviews (submitted)
Third International Stroke Trial. A large
randomised trial to answer the question: can a
wider variety of patients be treated?
Target: 6000 patients from 300 centres in
36 Countries
IST-3 collaborators meeting Capetown 2006
IST3
Why another trial?
Areas of Uncertainty to explore

Risks
• Symptomatic cerebral haemorrhage
• Death

Benefits
• Reduced ‘death or dependency’
• ?reduction in massive cerebral oedema?

Subgroup analyses: effect of
•
•
•
•
•
Time to treatment
Age
Stroke severity
Risk factors for intracerebral haemorrhage
Appearance of CT scan
Mild, or rapidly improving strokes
(NIHSS < 4)
• 2 hours ago, this man
developed right hemiparesis,
now rapidly improving.
• NIHSS < 4, so rt-PA not
approved
• Many such patients recover
without rt-PA,
• BUT 15-30% later
deteriorate suddenly ->
disabling stroke
• IST-3 will include ~ 600 with
NIHSS < 5
Vertebro-basilar territory
ischaemic strokes
• Acute cerebellar infarct
• Excluded from previous
trials of iv rt-PA
• Time window for
treatment unclear
• Is there benefit from iv
thrombolysis for such
patients?
• IST-3 will include ~ 200
Stroke patients > 80 years
• Patients over 80 have
been excluded from
randomised trials and
the licence
• In the UK 30% of all
strokes are aged > 80 =
31,000 ischaemic stroke
patients each year
automatically excluded
from thrombolysis
• IST-3 will recruit > 1000
patients > 80
Severe stroke (NIHSS > 25)
• This man had a large
MCA infarct
• NIHSS > 25,
• rt-PA not approved for him
• He spent many months in
hospital
• He was very disabled
• IST-3 will include ~ 300
such patients
Impact of iv rt-PA on
symptomatic cerebral oedema
Odds ratio 0.79 (0.62- 1.01) p = 0.06
Slide from IST-3 presentation P. Sandercock ESC Stockholm 27 05 2009
Wardlaw et al 2008
Taking part in IST-3


Support form IST-3 team
Extends therapeutic window, more
experience in thrombolysis
Consent for IST-3
10% (one in 10) will make a better
than expected recovery
5% (one in 20) will have a fatal brain
haemorrhage
If IST-3 positive, how many stroke patients per
year in UK might avoid being ‘dead or
dependent’ with each treatment?
UK has 130,000 strokes/yr
% treated
Number
treated
per year
Number
avoiding
death/dep.
Aspirin
80%
104000
1350
Stroke Unit
60%
78000
4370
2.4%
3100
200
30%
39000
1800
Thrombolysis < 3h
1
Thrombolysis < 6h
2
1. USA 2004 MEDPAR average. Kleindorfer. Stroke 2008: 39: 924-8
2. If IST-3 widens treatment indication?
Slide from IST-3 presentation P. Sandercock ESC Stockholm 27 05 2009
DIAS-2: Clinical response rates at
90 days
End point
Placebo,
n=63 (%)
90 µg/kg,
n=57 (%)
125 µg/kg,
n=66 (%)
Clinical response rate 46.0
47.4
36.4
All-cause mortality at 4 (6.3)
90 days
3 (5.3)
14 (21.2)
ICH at 72 h
2 (3.5)
3 (4.5)
0 (0)
Hacke W et al. 16th European Stroke Conference; June
1, 2007; Glasgow, Scotland.
DIAS-4
• Desmoteplase 90ug/kg bolus
• Within 9 h of symptom onset
• All patients need CT angio before
randomization
• Inclusion depends on results of CT angio
LINKS
 http://www.acutestroke.org/
for SITS
google sits stroke
 http://www.dcn.ed.ac.uk/ist3/ for IST3
google ist3
 http://www.thrombolysis.info/ for thrombolysis docs
google thrombolysis.info
Research and Governance
 SITS Register
 ECASS-3
 IST-3
 DIAS-3
C. Roffe
4-day Thrombolysis Course Stafford University 10 06 09