AlanYan
ED Registrar, PAH
 Ischaemic penumbra
 Best case scenario and pitfalls
 Evidence based medicine?Or not…
 Applicability
 Thrombolysis: A...
 0 - No symptoms.
 1 - No significant disability. Able to carry out all usual
activities, despite some symptoms.
 2 - S...
 622 patients
 Italian RCT
 Aspirin vs Streptokinase vs both vs neither
 0-6h
 Increased death with both agents
 No ...
 EuropeanCooperative Acute Stroke Study
 Mc-RCT
 620 patients
 rTPA vs placebo
 0-6h
 Primary end-point: MRS at 90 d...
 Post-hoc analysis of the subset of patients
treated withTPA <3h
 87 patients
 Increased parencymal haemorrhage withTPA...
 The National Institute of Neurological Disorders and
Stroke
 DB-RCT; NEJM 1995
 rTPA vs placebo; 0-3h
 Excluded those...
• 333 patients
• 90days functional outcome using a global test
statistic method (combination of BI, MRS, GOS and
NIHSS)
• ...
 RESULTS:-
 Part-1 was a FAIL, results not documented
 Part-2;TPA group fared better in 4 outcomes. (RR 1.7,
p=0.008)
...
 4 primary outcomes combined?!
 Poorly matched groups with more severe
strokes on placebo arm
 MAST-E (n=310)
 Streptokinase vs placebo
 0-6h, moderate-severe stroke
 Stopped early with mortality 34% at 10 days v...
 N= 340
 Streptokinase vs placebo
 0-4h
 Stopped early due to increased mortality
 N=800
 Alteplase vs placebo
 0-6h
 MRS at 3 months
 Moderate-severe stroke with no major evidence of
infarct on CT
...
 Alteplase vs placebo
 ATLANTIS-A (0-3h) n=142 – stopped early
due to increased mortality (23% vs 7% at
3months)
 ATLAN...
 N=821
 Alteplase vs placebo
 3-4.5h
 Excluded severe stroke, large infarct on CT and
age ≥80
 Primary outcome = MRS ...
 This is probably explained by
“In our study, we modified the ECASS definition of symptomatic intracranial
hemorrhage by ...
 Poorly matched groups with more severe strokes on
placebo arm
 NIHSS score 10 vs 9
 14% had previous stroke in placebo...
 Mc-international RCT
 N= 3035
 Alteplase vs placebo
 3-6h
 Primary outcome OHS <2
 1st trial to include ≥80yo (a gr...
 3000 patients recruited over 10 years! (2/year/centre)
 Half over 80yo
 Mainly treated at 4.2h (pretty realistic)
 NO...
 Not surprisingly, none of the other
combinations of scores that did not show a
statistically significant difference in o...
 In other words from a different perspective…
 If the numbers were true, this would mean
 7% more HDU admission
 3% in...
“Non-significant primary outcome, may have small
improvement in functional outcome based on
secondary ordinal analysis, bu...
 12 trials (n=7012)
 MRS (0-2) at 6-month 46.3% (TPA) vs 42.1
(placebo); 55/1000 treated with favourable
outcome
 Benef...
 Reported benefits for 3 months appear to be sustained for 12
and 18 months
 Experts from many specialist societies supp...
 The first 2 trials showing a positive effect of tPA had
significant imbalance of stroke severity favouring tPA
 The thi...
 <10% had a stroke, presents to ED, get seen, get a CT, CT gets
interpreted and decision made to thrombolyse within 3h
 ...
 AMI
 Simple work-up
 Pathological process similar (thrombosis)
 At least 6h time-frame for treatment
 Availability f...
 Stroke
 Complex work-up
 Different pathological processes (thrombosis, emboli,
small vessels degeneration)
 0-3h time...
 ACEM position
“There is insufficient evidence for stroke thrombolysis to be considered a
‘standard of care’.The College ...
 The amount of debate about thrombolytic
therapy in stroke is disproportionate to its
overall clinical importance
 Altho...
ThankYou
Stroke thrombolysis
Stroke thrombolysis
Stroke thrombolysis
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Stroke thrombolysis

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  • 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 &lt;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.
  • Non-contrast CTCTA (distal MCA thrombosis)CBVCTA MappingPost f/u CT 24h
  • 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 (&lt;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
  • Stroke thrombolysis

    1. 1. AlanYan ED Registrar, PAH
    2. 2.  Ischaemic penumbra  Best case scenario and pitfalls  Evidence based medicine?Or not…  Applicability  Thrombolysis: AMI vs stroke
    3. 3.  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.
    4. 4.  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
    5. 5.  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
    6. 6.  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
    7. 7.  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…..
    8. 8. • 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!
    9. 9.  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 !!!
    10. 10.  4 primary outcomes combined?!  Poorly matched groups with more severe strokes on placebo arm
    11. 11.  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%)
    12. 12.  N= 340  Streptokinase vs placebo  0-4h  Stopped early due to increased mortality
    13. 13.  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
    14. 14.  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
    15. 15.  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%)
    16. 16.  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
    17. 17.  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
    18. 18.  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
    19. 19.  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
    20. 20.  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%)
    21. 21.  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)
    22. 22. “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
    23. 23.  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)
    24. 24.  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
    25. 25.  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)
    26. 26.  <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)
    27. 27.  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
    28. 28.  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
    29. 29.  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.”
    30. 30.  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
    31. 31. ThankYou
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