Issue 20 / 28 May 2012

MANY Australian stroke patients could be missing out on the most effective treatment available, with new research backing the use of intravenous thrombolysis in a wider range of patients.

Thrombolytic therapy with intravenous recombinant tissue plasminogen activator (rt-PA) is known to be of net benefit in acute ischaemic stroke patients younger than 80 years treated within 4.5 hours of onset.

However, two new research articles published in The Lancet suggest that a wider range of patients could benefit from the treatment.

The first, the largest study of thrombolysis to date by the International Stroke Trial (IST-3) collaborative group, assessed 3035 patients, including 53% aged over 80 years, at 156 hospitals in 12 countries, including Australia. It found that the treatment improved patients’ functional outcome and did not increase mortality. (1)

When patient outcome was assessed on a five-point scale ranging from no problems to very severe problems or death, patients treated with rt-PA had a 27% greater chance of surviving with less disability than those in the control group.

While rt-PA was associated with an increased risk of symptomatic haemorrhage and death in the first 7 days after treatment, fewer deaths were reported in the rt-PA group than in the control group between 7 days and 6 months, and by 6 months, similar numbers of patients had died in the two groups.

“The data add weight to the policy of treating patients as soon as possible, and also justify extending treatment to patients older than 80 years of age”, the authors wrote.

“The data do not support any restriction of treatment on the basis of stroke severity or the presence of early ischaemic change on the baseline brain scan.”

The second study, a meta-analysis combining the IST-3 trial results with other major trials on rt-PA, found that for every 1000 patients treated with intravenous rt-PA up to 6 hours after stroke, 42 more patients were alive and independent, and 55 more were alive with a favourable outcome at the end of follow-up. (2)

The study also found that among the 1711 patients older than 80 years, the absolute benefits from the treatment were a least as large as for the younger patients, especially with early treatment.

Professor Richard Lindley, a geriatrician from Westmead Clinical School and a coauthor of the second study, told MJA InSight that the uptake of thrombolysis was too low in Australia.

“People miss out because of delays in getting to hospital, within-hospital delays and sometimes reluctance to consider treatment. These new results from the IST-3 trial and the updated thrombolysis systematic review tell us that treatment can be extended to a wider group of people.

“Clinicians should be more confident that a wider group of people can be treated and hospitals need to change their practice to allow this to happen, and happen fast”, he said.

The authors of an accompanying comment in The Lancet wrote that the key message to emerge from the studies was that many patients currently excluded from treatment should now be candidates for treatment. (3)

They said the role of emergency physicians with stroke patients was now “not to identify patients who will be given rt-PA, but to identify the few who will not”.

Associate Professor Peter Hand, co-head of the acute stroke unit at Royal Melbourne Hospital, agreed, describing IST-3 as a landmark trial.

“In Australia, there is widespread variation in use of rt-PA. In some leading centres as many as 15% of patients with acute ischaemic stroke receive treatment. In many centres, no patients are treated”, he said.

He said there remained a small yet vocal group of clinicians who were sceptical of the benefits of rt-PA. “The results of IST-3 and the revised Cochrane Systematic Review should make these clinicians change their practice”, he said.

Although there were clear contraindications to treatment, such as finding haemorrhage on the CT scan, or a therapeutic INR, these were becoming fewer, Professor Hand said.

“Every patient who presents to hospital within 6 hours must be considered eligible for rt-PA until proven otherwise.”

– Amanda Bryan

1. Lancet 2012; Online 23 May
2. Lancet 2012; Online 23 May
3. Lancet 2012; Online 23 May

Posted 28 May 2012

12 thoughts on “Consider thrombolysis in all stroke patients

  1. Lesley says:

    I agree, my son of 14+ years benefitted. Adelaide Aug 2011.

  2. Bryan Walpole. says:

    I once thrombolysed a 65 yo recently retired bank manager, who presented with ischaemic stroke within 3 hours he had a dense R hemiplegia, fully conscious, but went unconscious, fitted, then died, all in a hour from haemorrhage……am quite thoughtful when I do it again!
    I think its essential that any hospital performing thrombolysis had a neurology unit available to participate in the consent and delivery. Emergency physicians job is to identify those eligible, and scan/notify promptly.

  3. C says:

    it is all very well for neurologists to say this when they work at well-resourced tertiary centres with lots of staff, neurology registrars, MRI scanners, etc. However, it is a different kettle of fish for staff at very busy but much less well-resourced peripheral hospitals with no neurology or stroke Units, no MRI scanner, and the emergency department staff are expected to do it all themselves including obtaining informed consent for a treatment that could kill the patient. And no backup services to manage the patient that has a serious cerebral bleed

  4. Simon Brown says:

    These new results make fascinating reading, but the predictable responses by those for and against thrombolysis will be maddeningly predictable! It is sobering to reflect that IST-3 clearly shows (i) no survival benefit by 6 months and (ii) no improvement in need for assisted living by 6 months.

    So, why are some of us so enthusiastic about a treatment that (i) kills us quicker (early mortality is higher for TPA, but it evens out later when those not given TPA start dying) and (ii) has no impact on our ability to live independently?

    The answer here appears to be an improvement in Modified Rankin Score. The question is, was this a post-hoc attempt to find something significant, given that there was no significant difference the “big ticket” primary outcomes that really matters?

    In my professional career we have already seen thrombolysis come and go in the setting of AMI (in favour of acute angioplasty). I suspect – and hope – that we will see a similar progression to better treatment for stroke, although I personally doubt mechanical intervention will be the answer. In the meantime, the question that nags me is, should billions of dollars be spent on thrombolysis with its marginal practical benefit, or on research to find a better magic bullet and/or ways to better target thrombolysis and improve the risk/benefit equation?

  5. Sue Ieraci says:

    The NINDS trial, on which much of the current thinking for stroke thrombolysis is based, showed some improvement in function that was only evident in the least severe strokes. Then, as the author states: “While rt-PA was associated with an increased risk of symptomatic haemorrhage and death in the first 7 days after treatment, fewer deaths were reported in the rt-PA group than in the control group between 7 days and 6 months, and by 6 months, similar numbers of patients had died in the two groups.” And then it is reported that “In some leading centres as many as 15% of patients with acute ischaemic stroke receive treatment. ” And yet, “there remained a small yet vocal group of clinicians who were sceptical of the benefits of rt-PA.” Okay – it kills people acutely, helps only people with the mildest symptoms, and yet, the largest centres are only achieving 15% of eligible patients – and only a “small yet vocal group” is sceptical? I think I might call that an understatement.

  6. Sue Ieraci says:

    A good discussion on the various aspects can be found here:
    http://www.cjem-online.ca/v3/n3/p183

  7. What am I missing? says:

    Could the silent majority point out to the vocal minority why a negative trial is being interpreted as positive. There was no difference in the primary outcome measure, and an increase in those requiring assistance with daily living. The outcome measure was the Oxford Handicap Score which has never been used in previous trials. When registered the study outcome measure was the modified Rankin Score. Why would a trial change it’s outcome measure between initial registration and publication? The subgroup analysis favours the control group for those treated at 3-4.5 hr.. Overall there is a favourable outcome in 37% compared to about 66% for those treated in ECASS 3, yet concludes that the exclusion criteria used in ECASS 3 should now be abandoned. Can somebody tell me what I’m missing?

  8. Harry Karipis says:

    Thrombolysis in stroke has the same basis as people’s religion.Their belief in it can be ‘rational, irrational, non-existent or unknown’. You can prove almost everything with ‘association’ statistics (eg, use of leeches showed improvement for many patients in the middle ages, aspirin in colds causes the cure because when I take it I get better). If we step back for a minute from the science and pseudoscience let’s explore some other observations.

    The push for thrombolysis in stroke began when the drug was losing favour in myocardial infarction in preference for PCI. Time for a new ‘clot’ market?

    The drugs used are not thrombolytics but fibrinolytics and therefore their usefulness beyond the first hour or two is highly questionable. It is being advocated for 6 hours + in stroke. If its effectiveness is markedly reduced after approx 90-120 min in heart attack how can it be effective beyond this in an organ that is more highly oxygen dependent? I do not want to hear the word penumbra in any reply.

    Fibrinolytics in myocardial infarcts had an ‘end of the needle’ impact (symptoms and ECG) that is not reproducible in the stroke studies. How can improvements in clinical function some 6 months down the tract be attributed to a drug that lasts such a short time and given so long ago? How do we know it wasn’t the aspirin?

    When thrombolytic and fibrinolytic therapy began for STEMI the results were excellent and everyone in emergency care came on board and there was widespread and ‘immediate’ uptake. You have to wonder why this has not occurred with stroke over the last at least 17 years. Could all this people be wrong?

    It’s hard to push some things up hill when it has little substance and even less form.

  9. Sue Ieraci says:

    “When thrombolytic and fibrinolytic therapy began for STEMI the results were excellent and everyone in emergency care came on board and there was widespread and ‘immediate’ uptake. You have to wonder why this has not occurred with stroke over the last at least 17 years.” Exactly, Harry Karipis. The pro-thrombolytic-in-stroke community has tried to brand the emergency medicine community as being “ideologically opposed” when, in fact, we are scientifically opposed. You are right – myocardium and brain tissue are very different. We do know, however, that multi-disciplinary rehab is very effective for stroke, with little or no risk of harm. Why not channel more money that way?

  10. Anonymous says:

    I remember watching an episode of ‘Medical Emergency’. A man ( i think in his 30’s) from Sydney underwent a heart transplant in Melbourne. He awoke from the anaesthetic with a dense left hemiplegia. Thrombolysis obviously contraindicated. I thought to myself poor man. Yet they showed him 6 months later with barely noticeable deficit riding his bike and running. Had he received thrombolytics the improvement will have been attributed to them. A second case is of more concern. A man presents with a STEMI in a non PCI centre. Thrombolytics contraindicated due to recent stroke resulting in dense hemiplegia. Transferred to PCI centre where he had received thrombolytics for stroke. Notes indicate not to be registered in trial because of consent issues, but obtained consent from his sister to administer the thrombolytic outside of trial protocol. A failure of thrombolysis that is never registered in the database — bias +++. Just in case it is not clear – thrombolytics may work but it is highly doubtful.

  11. Anonymous says:

    tPA is a fantastic therapy which I am sure has saved lives and improved outcomes for many. BUT I think you want to be pretty damned sure about the nature of the stroke before you deliver it…. I had a haemorrhagic stroke at age 26 and you can bet tPA would have been disastrous if it had been administered.

  12. Jevria Nuredini says:

    My father was 59. Eight weeks ago my father suffered a posterior circulation stroke.
    He arrived at the hospital and received TPA. He was administered the drug at 4 hours of onset
    My father went from a mild stroke to receiving a massive brainstem haemorrhage.
    Compliments of this so-called wonder drug. He lived for 5 days. Now the only time I get to visit him is at his grave. All these people who have this drug administered are nothing more than rats in a lab and these doctors are playing russion roulette with people’s lives.I would never in a million years god forbid I ever have a stroke would ever have that poison injected in me to supposedly help me.

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