Transcript The management of acute stroke in the very elderly with

THROMBOLYSIS FOR STROKE IN
OLDER PEOPLE.
DR AHMED ABDUL-HAMID
CONSULTANT STROKE PHYSICIAN
HULL &EAST YORKSHIRE HOSPITALS TRUST .
STROKE ABOVE AND BELOW
80 YEARS OF AGE.
Stroke tend to be more severe in above the age of 80.
More embolic strokes due to atrial fibrillation and larger
infarcts (more M1 occlusion).
Mortality in above 80y of age is double the mortality of
patients below the age of 80.
Morbidity and total dependency is higher.
More patients with increase cognitive impairment.
STROKE IN THE ELDERLY
>80 Y AGE.
Stroke is the 3rd cause of death in UK and first cause of
acquired adult disability.
Stroke > 80 forms 1/3 of all strokes.
Our population is aging and number of acute stroke >80 will
continue to increase.
Therefore any effective treatment in acute stroke should be
available for this age group.
The evidence for thrombolysis for stroke above the age of 80
is not as below due to exclusion from trials.
THROMBOLYSIS IN ELDERLY
> 80 IN US HOSPITALS
From the National US inpatients sample data base.
TPA TRIALS 18-80
ECASS 1 JAMA Oct 1995
ECASS 2 Lancet 1998
NINDS New England Dec 1995
ATLANTAS A&B JAMA 1999
ECASS 3
Lancet 2008.
NINDS TRIAL 1995
THE POOL ANALYSIS OF
ALL TPA TRIALS 2760
ECASS 1
ECASS 11
NINDS
ATLANTIS A
ATLANTIS B
Combined for favourable out come by mRS , BI
and NIHHS score against time from onset of stoke
to treatment
Lancet 2004
POOL ANALYSIS OF
TPA TRIALS.
ODDS RATIO FOR FAVOURABLE
OUTCOME
Time interval
OTT
Odds ratio
95% conf.
0-90 min
2.8
1.8-4.5
91-180 min
1.6
1.1-2.2
181-270
271-360
1.4
1.2
1.1-1.9
0.9-1.5
HAZARD RATIO FOR
DEATH
0-90 =1.0
91-180 = 1.0
181-270 =1.0
271-360 =1.45
MAJOR ICH
HAEMORRHAGE
ICH occurred in 5.9% of tPA treated patients
compared to 1.1% of placebo patients (p<0.0001)
Median age 72. ICH was associated with age(
p<0.0002) and tpa treatment.
ICH was not associated with OTT but may be
related to protocol deviations ( p= o.052)
ECASS 3
NEJM SEP2008
821 Stroke Patients ( 3- 4.5)hrs
Same inclusion/exclusion criteria NINDS.
After 90 days 52.4% for tPA vs 45.2 % Placebo. Odds ratio
1.32%
Risk of symptomatic ICH 2.4% vs. 0.2%
ECASS 3 821 LANCET 2008
52.4% TPA GROUP
45.2%
PLACEBO
EU & UK APPROVAL OF TPA
FOR STROKE WAS
CONDITIONAL IN 2002
tPA was approved within 3h after stroke but conditional
approval
After 3years reconsideration based on: Safety
Implementation of Thrombolysis in Stroke which is a multi
centre monitoring study for safety and efficacy of
thrombolysis. (SITS-MOST) study.
SIST-MOST: Observational none randomised none blind
study in which primary out come is SICH and death.
Secondary is the functional out come, auditing the safety of
treatment for 3 years.
SITS-MOST
KAROLINSKA
LANCET JAN 2007
6483 patients at 285 centres. In 14 European countries between
Dec 2002 and April 2006.
Acute follow-up up to 7 days this include NIHS scale at 2 hours,
24 hours, 7 days & death at 3 months.
Secondary outcome was mRS at 3 months.
Repeat CT brain scan ( 22-36 hours).
SICH was 1.7% at 24 hours, 7.3% at 7 days (Cochrane definition)
compared to 8.6% in all tPA trials.
Mortality rate at 3 months SITS-MOST was 11.3% compared to
17.3% in the pooled analysis
SITS-MOST/
KAROLINSKA
THROMBOLYSIS IN THE
VERY ELDERLY MISHRA
BMJ 2010.
Controlled comparison of SITS International Stroke Thrombolysis
Registry and Virtual International Stroke Trials Archive.
Collaboration between International Stroke Thrombolysis Registry
(SITS-ISTR) and Virtual International Stroke Trials Archive (VISTA).
Participants 23334 patients from SITS-ISTR (December 2002 to
November 2009) who underwent thrombolysis and 6166 from VISTA
neuroprotection trials (1998-2007) who did not undergo
thrombolysis (as controls).
Comparing functional outcome between those who received
thrombolysis and control. Comparing also between those above 80
and below.
Fig 1 Description of analysed patients from two data sources.
Mishra N K et al. BMJ 2010;341:bmj.c6046
©2010 by British Medical Journal Publishing Group
THROMBOLYSIS IN THE OLD
>80, SITS META-ANALYSIS
SITS/VISTA register 29500 patients.
3472 >80 (2235 had tpa)
>80 had lower level of pre-stroke independence ,more females
60%.
Patients treated with tpa 32.9% (mrs0-2) VS 20.7% (mrs0-2) at 3
months interval.
Absolute risk reduction of disability by 12.2%.
Relative risk reduction 30%.
There was no difference in SICH 1.8 for >80 compared to 1.7 for
<80.
There was higher mortality and the poorer functional outcome in
above 80 which were consistent with the overall worse
prognosis seen in the natural history of this age group.
Fig 2 Scores on modified Rankin scale (from 0=no symptoms from stroke to 6=death) at three
months between patients who underwent thrombolysis with alteplase and controls, indicating
shift towards improved outcomes with thrombolysis.
Mishra N K et al. BMJ 2010;341:bmj.c6046
©2010 by British Medical Journal Publishing Group
Fig 3 Shift towards better outcomes on modified Rankin scale at three months adjusted for
age and baseline severity (defined by National Institutes of Health stroke scale).
Mishra N K et al. BMJ 2010;341:bmj.c6046
©2010 by British Medical Journal Publishing Group
OUTCOME FOR MRS
0-2
Fig 4 Odds ratios for score 0-1 on modified Rankin scale at three months adjusted for age and
baseline National Institutes of Health stroke severity scale in patients who received
thrombolytic therapy.
Mishra N K et al. BMJ 2010;341:bmj.c6046
©2010 by British Medical Journal Publishing Group
SITS &VISTA OUTCOME
BMJ 2010
Outcome in patients with acute ischaemic stroke is
significantly better in those who undergo thrombolysis
compared with those who do not. Increasing age is
associated with poorer outcome but the association between
thrombolysis treatment and improved outcome is maintained
in very elderly people.
We need to thrombolyse 8 > 80 to have one more
independent patient .
Risk of bleed is the same.
Age alone should not be a barrier to treatment.
Criticism no proper RCT trials.
INFLUENCE OF AGE ON OUTCOME
FROM THROMBOLYSIS IN ACUTE
STROKE MISHRA , LEES STROKE J 2010
5817 patients from the VISTA register trials 1998-2007.
Patient from Europe SITS-ISTR were excluded.
1585 (27.2%) received thrombolysis. 301 > 80
Baseline severity was higher by 1 NIHSS point among the
younger patients who received thrombolysis therapy
compared with control group; among patients aged ≥80
years, severity was equal between treated and control
groups.
Comparison between > 80 and below with functional
outcome and neurological outcome.
Figure 1. Diagram showing association of functional outcomes with use of rtPA in the
younger patients (age ≤80 years) and elderly patients (age >80 years) having acute ischemic
stroke.
Mishra N K et al. Stroke. 2010;41:2840-2848
Copyright © American Heart Association, Inc. All rights reserved.
Figure 2. Diagram showing association of neurological outcomes with use of rtPA in the
younger patients (age ≤80 years) and elderly patients (age >80 years) having acute ischemic
stroke.
Mishra N K et al. Stroke. 2010;41:2840-2848
Copyright © American Heart Association, Inc. All rights reserved.
Figure 3. Forest plot showing association of functional outcomes with improved outcomes in
patients who received thrombolytic therapy.
Mishra N K et al. Stroke. 2010;41:2840-2848
Copyright © American Heart Association, Inc. All rights reserved.
Figure 4. Forest plot showing association of neurological outcomes with improved outcomes
in patients who received thrombolytic therapy.
Mishra N K et al. Stroke. 2010;41:2840-2848
Copyright © American Heart Association, Inc. All rights reserved.
IST3 TRIAL & NO:3035
RCT comparison between tpa between 0-6 hours and
standard care.
Randomised patients with higher age , NIHSS and BP .
Base line characteristics between tpa group and standard
care was similar.
Look for functional outcome at 6 monts between
thrombolysis group and standard of care group.
1617 (53%) aged > 80 years.
210 ( 7% ) aged > 90 years.
TIME TO RANDOMIZATION AND AGE
Time (hours) from stroke to randomisation
0-3h
3-4.5h
4.5-6h
Age
<80
177
558
683
Age
>80
672
620
325
All
849
1178
1008
TIME TO RANDOMISATION AND AGE
1400
1200
Number
1000
800
<80 yrs
>80 yrs
600
400
200
0
0-3
3-4.5
4.5-6
Time to randomisation (hrs)
OVERALL - ALL PATIENTS 0-6 HRS:
‘ALIVE AND INDEPENDENT’ (OHS 0-2)
rt-PA
(n=1515)
n
554
(%)
(37%)
control
(n=1520)
n
534
(%)
(35%)
Absolute difference/1000
= 14 more alive and independent
(95% CI -20 to 48) NS
Overall: 6 month OHS
Favourable shift; adjusted common odds ratio 1·27
(95% CI 1·10- 1·47), p=0·001
Ordinal will be more statistically efficient than primary
outcome for subgroup analysis
RESULTS IST3
SUBGROUPS
RATIONALE FOR ADJUSTED
ANALYSES
Baseline data showed important trends with delay from stroke onset
to randomization.
• Older randomized earlier
• More severe stroke early
• Visible ischemia on CT/MR increased with later treatment
Therefore analyses adjusted for these factors
Subgroups: adjusted effect on primary
outcome: ‘alive and independent’
(interaction)
The treatment odds ratio in each subgroup has been adjusted for the
linear effects of the other key variables
AT SIX MONTHS, FOR EVERY 1000
PATIENTS TREATED WITH RT-PA
All ages 0-6 hrs
14 more alive and independent (NS)
29 more ‘favourable outcome’ (p=0·018)
Favourable shift in OHS
(p=0.001)
No difference in deaths
In patients > 80 years 0-6hrs
38 more alive and independent
In patients all ages < 3hrs
80 more alive and independent
96 more alive and independent in above 80.
CONCLUSIONS OF IST3
1) Benefit was greatest with treatment within 3 hours
(80 per 1,000 more alive and independent treated
within 3 hours)
2) Benefit evident
Age > 80 years
Severe stroke
Early ischaemic change seen on baseline scan.
IMPLICATIONS FOR PRACTICE.
IST-3 ENABLES CLINICIANS TO:
Consider thrombolytic treatment for a wider variety of patients,
• Particularly those aged over 80 years
• With more severe strokes
Reinforce their efforts to increase the proportion of ischaemic
strokes treated < 3 hours
Have greater confidence that mortality is not increased by treatment
CONCLUSION
All stroke adult patients should be considered for
thrombolysis what ever their age.
Time window should stay between 0-3 for the above 80.
Above 80 will show more benefit especially when you
consider the higher mortality and morbidity in this age group.
The ICH in thrombolysis is not effected by advancing age.
Careful selection of independent patients with no history of
pre-existing dementia or advance comorbidity is crucial .
RCP GUIDELINES 2012
4.6.1 Recommendations:
A Any patient regardless to age or stroke severity where
treatment can be started within 3 hours with no contraindications should considered for treatment with alteplase.
B Between (3- 4.5) hours patient who are under 80 only
should be considered for treatment if there are no contraindications.