2. Ischaemic penumbra
Best case scenario and pitfalls
Evidence based medicine?Or not…
Applicability
Thrombolysis: AMI vs stroke
3.
4.
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
25.
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
Ischaemic core – rapid neuronal death within the immediate territory of occluded artery within minutes, resulting in necrosisIschaemic penumbra – delayed infarct in which neurons might die off many hours after the initial insult, postulated <8h, due to presence of collateral circulationThe penumbra is where pharmacologic interventions are most likely to be effective.Therefore, timely recanalization of the occluded vessel should theoretically restore perfusion inthe penumbra, and prevent further secondary insult.
75 hospitals in EUA total of 620 patients with acute ischemic hemispheric stroke and moderate to severe neurologic deficit and without major early infarct signs on initial computed tomography (CT).Conclusion: thrombolysis in stroke cannot currently be recommended for use in unselected populations of ischaemic stroke patients
NINDS 1: 24h with reason to compare this with thrombolysis in AMI
Barthel index/ modified rankin scale/glasgow outcome score/ national institute of health stroke scaleIt is very difficult to have a stroke, get into hospital, get seen, get a CT, and a decision made to receive TPA all in 90minMost patients will fall into 91-180min group. Both x2 previous RCT has an average mean time for TPA at around 4h mark
That was a cheat – the more you have, the more likely you are going to have one turn positiveIf you look at the table from the paper with baseline characteristics on NIHSS score, the look well-matchedHowever, Mann from Western Journal of Emergency Medicine put some work into it and eventually got the full data set from NINDS investigator and now we found significant difference in both groupsThe patients in placebo group have more severe strokesThis doesn’t mean there’s fabrication of data or bias with randomisation, but if you only have 150 patients in each arm, this variation is easily possible
Long study; took 4 years to recruit 800 patients from 130 centres, that’s 1.5patient/year in each centre
Remember, investigators can modify definition of SICH however they want to make the numbers better
BY far the largest RCT ever conducted12 countries, 150 centres
OHS at 6-month done with postal survey and telephone interview rather than face-to-face assessment
Peter Sandercock (IST-3 investigator) statement on May 2012 at Lisbon
Stroke mimics up to 5-10%Consent difficult to obtain from patients who are obtunded/cognitive impaired, ?validity of consent from familyThe beneficial population in ED is way too small (<1%) to justify the resource and money spent on this instance (research/cost of thrombolysis), money should be channeled towards stroke prevention and aftercare (rehab)
Debates relating to surrounding issues of - validity of key study results- credibility of research- accurate representation of data and selective reporting of results- role of industry in research- level of evidence required to institute significant practice changeallocation of resources between acute stroke care and other careEffectiveTxaspirin- anticoagulation for high risk AF- surgery for carotid stenosis- aggressive blood pressure control