1. AlanYan
ED Registrar, PAH

2.  Ischaemic penumbra
 Best case scenario and pitfalls
 Evidence based medicine?Or not…
 Applicability
 Thrombolysis: AMI vs stroke

5.  0 - No symptoms.
 1 - No significant disability. Able to carry out all usual
activities, despite some symptoms.
 2 - Slight disability. Able to look after own affairs without
assistance, but unable to carry out all previous activities.
 3 - Moderate disability. Requires some help, but able to
walk unassisted.
 4 - Moderately severe disability. Unable to attend to own
bodily needs without assistance, and unable to walk
unassisted.
 5 - Severe disability. Requires constant nursing care and
attention, bedridden, incontinent.
 6 - Dead.

6.  622 patients
 Italian RCT
 Aspirin vs Streptokinase vs both vs neither
 0-6h
 Increased death with both agents
 No significant improvement in all groups in 6-
months

7.  EuropeanCooperative Acute Stroke Study
 Mc-RCT
 620 patients
 rTPA vs placebo
 0-6h
 Primary end-point: MRS at 90 days
 No functional improvement in outcome
 High incidence of ICH and mortality associated with it
TPA Placebo P value
ICH (no.) 19 7 0.02
Death (no.) 117 48 0.04

8.  Post-hoc analysis of the subset of patients
treated withTPA <3h
 87 patients
 Increased parencymal haemorrhage withTPA;
statistically significant
 Increased mortality; not significant
 Improvement of all outcomes (MRS, BI and SSS);
not significant

9.  The National Institute of Neurological Disorders and
Stroke
 DB-RCT; NEJM 1995
 rTPA vs placebo; 0-3h
 Excluded those with high BP (SBP>180)
 NO CT evidence of ischaemic stroke
 Study was divided into 2 parts
 NINDS-1 (291 patients); improvement in NIHSS
≥4 within 24h
 Outcome changed mid-trial…..

10. • 333 patients
• 90days functional outcome using a global test
statistic method (combination of BI, MRS, GOS and
NIHSS)
• Time to treatment was divided into
 0-90min
 91-180min
 And there’s requirement to have equal numbers in
both groups!

11.  RESULTS:-
 Part-1 was a FAIL, results not documented
 Part-2;TPA group fared better in 4 outcomes. (RR 1.7,
p=0.008)
 12% absolute difference in MRS (improvement of 4
points or complete recovery)
 NNT=8
 ICH 6.4% (TPA) vs 0.6% (placebo), 2.9% died as a
result
 FDA approval and licensed for stroke thrombolysis
<3h !!!

12.  4 primary outcomes combined?!
 Poorly matched groups with more severe
strokes on placebo arm

13.  MAST-E (n=310)
 Streptokinase vs placebo
 0-6h, moderate-severe stroke
 Stopped early with mortality 34% at 10 days vs
18% with placebo
 Increased ICH (21% vs 3%)

14.  N= 340
 Streptokinase vs placebo
 0-4h
 Stopped early due to increased mortality

15.  N=800
 Alteplase vs placebo
 0-6h
 MRS at 3 months
 Moderate-severe stroke with no major evidence of
infarct on CT
 No statistical significant differences in favourable
outcome in 90days (40% vs 36% p=0.27)
 No statistical significant differences in 30 or 90days
mortality
 Alteplase group has higher incidence of ICH and
cerebral oedema

16.  Alteplase vs placebo
 ATLANTIS-A (0-3h) n=142 – stopped early
due to increased mortality (23% vs 7% at
3months)
 ATLANTIS-B (3-5h) n=613 – stopped early due
to
 No difference in favourable outcome at 3 months
 Non-significant increased in mortality (11% vs 7%)
 “unlike to be proved beneficial”, planned n=968

17.  N=821
 Alteplase vs placebo
 3-4.5h
 Excluded severe stroke, large infarct on CT and
age ≥80
 Primary outcome = MRS <2 at 90 days
 Results
 52% (TPA) vs 47% (placebo) had MRS <2 at 3 months
 No difference in mortality at 3 months
 Symptomatic ICH at record low 2.4% forTPA (still x10
more than placebo at 0.2%)

18.  This is probably explained by
“In our study, we modified the ECASS definition of symptomatic intracranial
hemorrhage by specifying that the hemorrhage had to have been identified
as the predominant cause of the neurologic deterioration.”
BUT when you apply this

19.  Poorly matched groups with more severe strokes on
placebo arm
 NIHSS score 10 vs 9
 14% had previous stroke in placebo vs 7%
 More patients would have had their MRS>0 before they
even had their 2nd stroke
 More statistics adjustment by investigators after
publication
 A positive trial by their trial design and definitions
 This trial enabled recommendations that tPA is safe for
3-4.5 hrs.This despite that all prior trials treating
patients at the same time periods were killing patients
and were terminated early

20.  Mc-international RCT
 N= 3035
 Alteplase vs placebo
 3-6h
 Primary outcome OHS <2
 1st trial to include ≥80yo (a group comprising
significant proportion with stroke)
 Uncommonly for stroke trial, both arms were
extremely well balanced

21.  3000 patients recruited over 10 years! (2/year/centre)
 Half over 80yo
 Mainly treated at 4.2h (pretty realistic)
 NO statistical difference in primary outcome at 6
months
 Although at post-hoc data analysis, found a 2%
benefit in primary outcome (alive and independent
35% vs 37%)
 The difference is too small to be statistically
significant and estimated NTT = 50

22.  Not surprisingly, none of the other
combinations of scores that did not show a
statistically significant difference in outcome
were reported
 Patients who gotTPA more likely to go HDU
(24% vs 17%)
 Big spike in early death (11% vs 7%), but
overall mortality was identical in 6-month
 ICH (7% vs 1%)

23.  In other words from a different perspective…
 If the numbers were true, this would mean
 7% more HDU admission
 3% increase in depth in 1st 7 days
 1% increase in ICH
 1% increase in allergic reaction
 No overall mortality benefit withTPA
 No significant difference in QOL overall if treated >3h
 Positive outcome (alive and fully independent) in
>80yo subgroup if treated within 3h (80/1000)

24. “Non-significant primary outcome, may have small
improvement in functional outcome based on
secondary ordinal analysis, but the number is too
small to be statistically significant, and the benefit
did not seem to be diminished in elderly patients
≥80”
 http://www.youtube.com/watch?v=E9oRXu2OR
CY&feature=player_embedded
 http://www.thennt.com/nnt/thrombolytics-for-
stroke/#ref13

26.  12 trials (n=7012)
 MRS (0-2) at 6-month 46.3% (TPA) vs 42.1
(placebo); 55/1000 treated with favourable
outcome
 Benefit greater if treated ≤3h; 40.7% (TPA) vs
31.7% (placebo); 87/1000 treated with favourable
outcome
 SICH 7.7% (TPA) vs 1.8% (placebo)
 No. of death within 7 days 8.9% (TPA) vs 6.4%
(placebo)

27.  Reported benefits for 3 months appear to be sustained for 12
and 18 months
 Experts from many specialist societies support its use
 Review of the evidence by independent reviewers support its
use
 NNT for treatment < 3 hours is approximately 11 - after 3
hours is probably no less than 25 - 30, if at all
 IST-3 suggests efficacy of tPA in patients > 80 years of age
when treated within 3 hours
 Any reduction in disability should be considered significant
given the effect on individuals and the total stroke burden on
society

28.  The first 2 trials showing a positive effect of tPA had
significant imbalance of stroke severity favouring tPA
 The third trial (IST3), which was well balanced regarding
stroke severity between groups demonstrated a much
reduced efficacy of tPA than previously reported
 Evidence to support efficacy is based on the results of three
manufacturer sponsored trials involving a relatively small
number of patients
 Too many post-hoc analysis deriving subgroups and meta
analyses (supporting evidence from ECASS was due to a
post-hoc analysis and only included 87 patients)
 Multiple other randomised thrombolytic trials have shown
no benefit or patient harm (and yet been ignored)

29.  <10% had a stroke, presents to ED, get seen, get a CT, CT gets
interpreted and decision made to thrombolyse within 3h
 Applying NNT=11, this 10% may well be <0.5-1.0%
 Potential disruption of care for other patients who may benefit
more from treatment than the patient receiving thrombolysis
 Preferential allocation of resources e.g. CT, higher triage priority
 Ongoing patient monitoring during and following tPA reduces care
to other ED patients
 Stroke mimics?
 Consent issues
 Cost efficacy?
 Subject to protocol violation (>3h)

30.  AMI
 Simple work-up
 Pathological process similar (thrombosis)
 At least 6h time-frame for treatment
 Availability for rescue PCI if failed thrombolysis
 Clear mortality benefit
 Small functional benefit
 Proven repeatedly in multiple large RCTs
▪ >100,000 patients involved

31.  Stroke
 Complex work-up
 Different pathological processes (thrombosis, emboli,
small vessels degeneration)
 0-3h timeframe (NNT=11)
 Early mortality rate
 High rate of ICH (6.4% vs <1% in AMI)
 Small functional benefit (if any)
 Small number of RCTs
▪ So far approximately 7000 patients involved

32.  ACEM position
“There is insufficient evidence for stroke thrombolysis to be considered a
‘standard of care’.The College accepts and endorses management of stroke
within the expert framework detailed in the National Stroke Foundation’s Clinical
Guidelines for Stroke Management 2010.”
 ACEP position
“Level A recommendation for tPA use within 3 hours
Level B recommendation for tPA use 3-4.5 hours”
 CAEP position
“Current evidence suggests that, in a small subset of acute stroke patients who
can be treated within 3 hours of symptom onset, the administration of tissue
plasminogen activator (t-PA) confers a modest outcome benefit, but that this
benefit is associated with an increased risk of intracranial hemorrhage that can be
severe or fatal.The data show that t-PA therapy must be limited to carefully
selected patients within established protocols. Further evidence is necessary to
support the widespread application of stroke thrombolysis outside research
settings.”

33.  The amount of debate about thrombolytic
therapy in stroke is disproportionate to its
overall clinical importance
 Although thrombolytic therapy in stroke is
useful, the number of patients likely to
benefit is <1% of total patients with stroke
 Effective treatments are available for a much
greater number of patients than for those
eligible for thrombolytic therapy

34. ThankYou