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. 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. Numbers within coloured cells are percentages 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). 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). Number of patients shown for age groups do not add up to 29 228 because numbers of patients ages <21 (n=38) and >100 (n=2) were too low to allow any comparison. All patients aged <21 were from SITS and underwent thrombolysis; 15 patients reached a 90 day modified Rankin score of 0, 10 patients attained a score of 1, eight patients reached a score of 2, one patient achieved a score of 3, and two a score of 4; two died. Two patients aged 101 did not undergo thrombolysis in VISTA neuroprotection trials; they achieved modified Rankin score of 0 and 4 at 90 days 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. 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. 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. Each box of the horizontal bar corresponds to the mRS category specified by the color code. Upper horizontal bar belongs to control group of young and elderly patients and lower to the rtPA-treated patients in each age group. Numbers in each box denote the percent of total patients belonging to a specific treatment category (rtPA or control) and representing the mRS score corresponding to the box. 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. 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. Each box of the horizontal box corresponds to the mRS category specified by the color code. Upper horizontal bar belongs to control group of young and elderly patients and lower to the rtPA-treated patients in each age group. Numbers in each box denote the percent of total patients belonging to a specific treatment category (rtPA or control) and representing the mRS score corresponding to the box. 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. Figure 3. Forest plot showing association of functional outcomes with improved outcomes in patients who received thrombolytic therapy. Patients are shown stratified by age groups and corresponding forest plot, OR, CI, CMH P, and sample size are marked. 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. Figure 4. Forest plot showing association of neurological outcomes with improved outcomes in patients who received thrombolytic therapy. Patients are shown stratified by age groups and corresponding forest plot, OR, CI, CMH P, and sample size are marked. 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. ( 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 >80 672 620 325  All  849 1178 1008

Time to randomisation and age

Overall - all patients 0-6 hrs: ‘alive and independent’ (OHS 0-2) rt-PA (n=1515) control (n=1520) n (%) 554 (37%) 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. Again reduce number of words

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 contra- indications 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 contra- indications.