Stroke Thrombolysis:Too early or too late

Alan YanED Registrar, PAH

Key Issues

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

Ischaemic penumbra

Modified Rankin Scale

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.

MAST-1 (1995)

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

NEGATIVE

ECASS-1 (1995)

European Cooperative 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 itTPA Placebo P value

ICH (no.) 19 7 0.02

Death (no.)

117 48 0.04

NEGATIVE

ECASS-1 (1995)

Post-hoc analysis of the subset of patients treated with TPA <3h 87 patients Increased parencymal haemorrhage with

TPA; statistically significant Increased mortality; not significant Improvement of all outcomes (MRS, BI

and SSS); not significant

NEGATIVE

NINDS (1995)

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…..

NEGATIVE

NINDS-2 (1995)

• 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!

NINDS-2

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 !!!

POSITIVE

NINDS (1995)Criticisms

4 primary outcomes combined?! Poorly matched groups with more

severe strokes on placebo arm

MAST-E (NEJM;1996)

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%)

NEGATIVE

ASK (JAMA; 1996)

N= 340 Streptokinase vs placebo 0-4h Stopped early due to increased

mortalityNEGATIVE

ECASS 2 (Lancet;1998)

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

NEGATIVE

ATLANTIS (JAMA;1999-2000)

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

NEGATIVE

ECASS 3 (NEJM;2008)

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% for TPA (still

x10 more than placebo at 0.2%)

POSITIVE

ECASS 3

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

ECASS 3

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

IST-3 (Lancet;2012)

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

IST-3Results 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

IST-3

Not surprisingly, none of the other combinations of scores that did not show a statistically significant difference in outcome were reported

Patients who got TPA 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%)

IST-3 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 with TPA No significant difference in QOL overall if treated

>3h Positive outcome (alive and fully independent) in

>80yo subgroup if treated within 3h (80/1000)

IST-3

“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=E9oRXu2ORCY&feature=player_embedded

http://www.thennt.com/nnt/thrombolytics-for-stroke/#ref13

The final Straw…

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)

Evidence for efficacy

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

Evidence against efficacy 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)

As for applicability in ED? <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)

Thrombolysis: Stroke vs AMI 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

Thrombolysis: Stroke vs AMI 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

What do the colleges say? 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 hoursLevel 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.”

Summary 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

Thank You