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Stroke Thrombolysis, a whistle stop tour of the evidence

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Gareth Hardy

on 17 January 2013

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Transcript of Stroke Thrombolysis, a whistle stop tour of the evidence


WONDERLAND A QUICK GUIDE TO THE EVIDENCE BASE FOR STROKE THROMBOLYSIS OR..... "Why, sometimes I've believed as many as six impossible things before breakfast" Lewis Carrol - Alice's Adventures in Wonderland DOWN THE RABBIT HOLE 622 patients
All strokes included within 6 HOURS
Randomised between ASPIRIN vs STREPTOKINASE
vs BOTH vs NEITHER "There is insufficient evidence for stroke thrombolysis to be considered a ‘standard of care" Significant increase in death with both: O.R 3.5.
No significant improvement in outcome at 6/12 in any group NEGATIVE ECASS I
JAMA 1995 620 patients
Moderate to severe strokes
Major infarct on CT excluded
Randomised between
rTPA and placebo No significant improvement
in primary end point#
(disability at 90 days) NEGATIVE CONCLUSION
"....since treating ineligible patients is associated with an unacceptable increase of hemorrhagic complications and death, intravenous thrombolysis cannot currently be recommended for use in an unselected population of acute ischemic stroke patients" NINDS 1
NEJM 1995 DBRCT of rTPA vs PLACEBO 0-3 hours 291 patients Excluded really high BP, and those with evidence of ischaemic stroke on initial CT Outcome was
NIHSS of >4 above initial score
within 24
hours Outcome: patients were assessed at 90 days as
FAVOURABLE (0-1 on Modified Rankin Scale)
UNFAVOURABLE (2-6 on MRS) NEGATIVE NINDS 2 Outcome changes mid trial 333 patients within 3 hours POSITIVE!!! 12% absolute improvement in this outcome **NNT = 8** HAVE A THINK....
coming didn't you?) IT HAS BEEN subsequently NOTED THAT THE CONTROL GROUP of NINDS HAD MORE SEVERE STROKES THAN THE rTPA GROUP.... It was due to NINDS that rTPA was initially licensed and started routine use for strokes <3 hours old MAST E
NEJM 1996 STREPTOKINASE vs PLACEBO 310 patients (they wanted 620) Outcome was disability/death at 6 months STOPPED EARLY FOR HARM

34% dead at 10 days with treatment
18.2% with placebo ASK Trial JAMA 1996 340 patients (target was 600)

Thrombolysed within 4 hours using streptokinase. Trend for decreased disability, but increased mortality STOPPED EARLY FOR HARM! ECASS 2
Lancet 1998 800 patients
Alteplase vs placebo
0-6 hours No significant
difference in
primary outcome
(Rankin scale 0-2) NEGATIVE ATLANT|S
JAMA 1999 Atlantis A:
0-3 hours
142 patients
Trend for increased mortality Stopped early Atlantis B
3-5 hours
613 patients
Increased mortality and disability Stopped early tPA vs placebo NEGATIVE IST 3 RCT
<6 HOURS 3035
patients IST 3 was designed
to look at the
excluded from
previous trials eg those >80yrs
or 3-6 hours Non blinded Patients selected if the clinician felt thrombolysis was "promising but unproven" rT-PA vs placebo. Groups well matched. Outcome: Patients alive and independent at 6 months 1.4% absolute reduction in death/disability NON SIGNIFICANT FOR PRIMARY OUTCOME Conclusion:

“thrombolysis improved functional outcome“
“benefit did not seem to be diminished in elderly patients“ Huh? Benefit on 'secondary ordinal analysis' This provoked some controversy... A proper conclusion based on the findings of IST-3 is that no benefit was detected. Perhaps more importantly, the increase in early deaths and the advantageous study design raise concerns that an important aggregate harm of thrombolytic treatment might have been masked. Newman, Shreves
The Lancet, Volume 380, Issue 9847, Pages 1053 - 1054, 22 September 2012 In reality, the results of IST-3 were clear: no benefit, but a definite increase in the risk of early death. Daniel M Fatovich a, Stephen P MacDonald b, Simon G Brown a
he Lancet, Volume 380, Issue 9847, Page 1053, 22 September 2012 Despite these concerns, IST 3 was used as basis for changing practice. In the UK the Royal College of Physicians guidance was updated to suggest thrombolysis for groups of patients such as those >80yrs,those presenting 3-4.5 hours after onset or those with severe strokes. Others were not as convinced... Australian College for Emergency Medicine, July 2012 Latest systematic review The Lancet, Volume 379, Issue 9834, Pages 2364 - 2372, 23 June 2012 About 7000 patients
rT-PA only, <6 hours. NNT: 23 for MRS 0-2 at 6 months No difference in overall mortality
NNH 40 for death within 7 days Breakdown for time to treatment: 0-3 hours
NNT 11 for MRS 0-2 at 6 months
Trend towards increased early deaths 3-6 hours
No significant improvement Curiouser and curiouser..... Does the evidence base support the adoption of stroke thrombolysis as a standard of care? "Begin at the beginning and go on till you come to the end: then stop." Do 'early deaths' matter if overall mortality is unchanged (loss of 'life days')? Are the outcome measures in these trials appropriate? Are dichotomous outcomes best here or should we be aiming to show improvements in outcome scores? Is it ethical to provide a treatment you do not think will help? Is informed consent' for stroke thrombolysis possible? With thanks to
Dr Andy Neil:


http://smartem.org/podcasts/smart-thrombolytics-acute-stroke Is the systematic review biased if several of the negative trials were stopped early? ECASS III
NJEM 2008 DBRCT TPA vs placebo
821 patients
3 - 4.5 hours
Excluded severe strokes, and >80yrs *** POSITIVE! *** 7% more patients MRS <2 in treatment group NNT 14 Bias towards treatment group?

Placebo group had more severe strokes (significant) and more likely to have had previous stroke (significant) ECASS III was the trial that prompted recommendations for thrombolysis use up to 4.5 hours Outcome: MRS <2 at 90 days
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