The Use of Thrombolysis as a Treatment for Acute Stroke

This is Part 2 of two posts

  1. a basic overview of thrombolysis in stroke
  2. a detailed overview of  evidence based research into thrombolysis and CVA

Author: Prof Simon Brown

Yes.  I hear it.  A weathered and worn sigh at the sight of another article debating the pros and cons of the use of tPA in acute ischaemic stroke.  Surely, you say to yourself, do we REALLY need another one?  Hasn’t this issue been thrashed out and mauled until it is bleeding like an iatrogenic coagulopathy?

Yes, this much is true.  But have we come to any sort of resolution? Do we, as a global medical profession, truly know whether or not tPA is a beneficial treatment early on in the presentation of a CVA? And if it is not, how is it that this therapy has become accepted, across the planet, as a standard of care? How can we be armed with the knowledge to inform patients, and treat them as optimally as possible, given the prodigious constraints of understanding in this matter?

And now, certainly in Australia, the debate is spilling over into the public domain.  The SBS Insight program is airing an episode about this controversy on 8 October 2013. If you have arrived here as a result of this program, Prof. Daniel Fatovich has provided a simplified summary of the issues at hand

This post aims to simplify things, to distil and reduce the issues even further, into what is fact, what is truth and what is opinion, and then direct the reader to the range of material that has been published on the subject.  It will be open to comment, so that if the facts, the truths and the opinions are disputed, they can be discussed in a public forum.  Again.

The facts

  • There have been 12 important trials comparing thrombolysis with placebo.
  • Ten studies were negative – that is, there was no difference in primary outcome between those given thrombolysis and those not given thrombolysis
  • Two trials of tPA (ATLANTIS A and ATLANTIS B) and 2 trials of streptokinase (ASK and MAST-E) were stopped early because thrombolysis was causing harm, and patients were dying from intracerebral haemorrhage.
  • Two trials of tPA (NINDS-2 and ECASS-3) were positive.  They found that although patients given tPA were more likely to die in the first few weeks of treatment, later on they did better than those who were not given tPA, in terms of the study primary outcome. In these studies the primary outcomes related to the degree of disability at 3 months, and the investigators found this was reduced at 3 months in patients given tPA.
  • The largest study of tPA thus far (IST-3) found no difference in the primary outcome (“death or dependency at six months”). There was a difference in a secondary outcome which showed improvement in function. This, however, was the result of using a statistical technique (ordinal shift analysis) that may not have been appropriate for that data set.
  • Registry studies have also been used to support the use of tPA, however these are a lower level of evidence compared to clinical trials.

The truth

  • There is widespread agreement that thrombolysis causes an increase in catastrophic cerebral haemorrhage in this group of patients. This causes a number of people to die earlier than expected. This has been consistent throughout the studies.
  • The only two studies finding a treatment benefit from thrombolysis in their primary outcomes (NINDS-2 and ECASS-3) had a problem; the patients given tPA had less severe strokes than those who were not given tPA. Therefore, the findings of a treatment benefit might simply have been due to this initial imbalance or allocation bias.
  • The other study suggesting a benefit (IST-3) also had a problem; it was open label (the patients and doctors knowing which treatment was given) and this would have had an effect on how they interpreted the results of treatment (observer bias).
  • Because of allocation bias in NINDS-2 and ECASS-3, observer bias in IST-3, and the conflicting results with some trials showing serious harm from tPA, the “truth” (whether or not thrombolysis has a positive effect that makes up for the early increase in deaths) is simply not known.
  • Registry studies of large numbers of patients given tPA cannot help us find the truth. Some authors claim that these studies show that patients given tPA earlier, within an hour or so of symptom onset, do better than those given tPA later thereby proving that tPA works. However, the problem here is that patients treated earlier tend to have less severe strokes and/or are more likely to be “stroke mimics” – patients that will get better without treatment. This effect could explain the findings.
  • Some authors have used statistical corrections to adjust for the biases in clinical trials and registry studies. In this situation, different methods can give different results. This means that the choice made by the investigator, or investigator bias, can influence the results. Furthermore, we can never be sure that any statistical correction wholly adjusts for the underlying bias. Therefore, the accepted scientific approach is to make sure bias is eliminated by proper study design in the first place.
  • Therefore, because of all these problems, it cannot be concluded that tPA is a proven treatment for stroke. This doesn’t mean that it doesn’t work; it just means that currently we do notknow whether it works. More research is needed before we can justify the harms to patients.

The opinion

  • Arguments both for and against the use of thrombolysis for stroke are legion. Following a recent debate in the BMJ, a poll of readers found that a slim majority (54%) were against the use of thrombolysis for stroke.
  • The debate over thrombolysis for stroke has been described as “the biggest, baddest controversy in emergency medicine” [Ref- Emergency Medicine News April 2013]. Despite the obvious flaws in the evidence base, clinical guidelines recommend the use of thrombolysis.
  • There is evidence of commercial and professional conflicts of interest behind the groups drafting these guidelines [Refs: Alteplase for stroke; Why we can’t trust clinical guidelines; Ensuring the integrity of clinical practice guidelines]. Some stroke services, academic positions and the National Stroke Foundation have received funding from the manufacturer. It is also worth noting that manufacturer sponsorship has previously resulted in accusations of pushing profits above patient safety. [The story of fenoterol – The Lancet]
  • The primary opinion divergence between opponents and supporters is this: Everyone who interprets the data will be influenced to a different degree by the incontrovertible biases, plus the conflicts of interest.
  • The REAL question is: do we embrace this treatment despite the insufficiency of current evidence, in the hope that it might improve the function of a few, (and as yet unknown which) stroke victims, or do we insist upon further evidence, that will stand up to scientific scrutiny in the form of properly designed trials, so as not to commit patients to an early death from cerebral haemorrhage, for the sake of chasing an uncertain benefit. 

The Conclusion 

Left deliberately blank.

..it is now up to you – the medical and the non-medical public to make up your mind…

The References

  • Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurology 2009 Feb.;8(2):141–150. PMCID 2730486
  • Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurology 2008 Apr.;7(4):299–309.PMID 18296121
  • Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Multicentre Acute Stroke Trial–Italy (MAST-I) Group. The Lancet 1995 Dec.;346(8989):1509 -1514. PMID: 7491044 
  • Thrombolytic therapy with streptokinase in acute ischemic stroke. The Multicenter Acute Stroke Trial–Europe Study Group (MAST-E). N Engl J Med 1996 Jul.;335(3):145–150. PMID: 8657211
  • Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA 1996 Sep.;276(12):961–966. PMID: 8805730
  • Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS (B) Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA 1999 Dec.;282(21):2019–2026. PMID: 10591384 
  • The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g) : results of a double-blind, placebo-controlled, multicenter study. Thrombolytic therapy in acute ischemic stroke study investigators.(ATLANTIS A) Stroke 2000 Apr.;31(4):811–816.  PMID 10753980
  • Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group (NINDS). N Engl J Med 1995 Dec.;333(24):1581–1587. PMID: 7477192
  • Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 1995 Oct.;274(13):1017–1025.1. PMID: 7563451 
  • Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. The Lancet 1998 Oct.;352(9136):1245–1251. PMID: 9788453 
  • Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke (ECASS III). N Engl J Med 2008 Sep.;359(13):1317–1329. PMID: 18815396 
  • The IST-3 collaborative group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet. 2012 May 23. PMID: 22632908

(With great thanks to Andy Neill from Emergency Medicine Ireland for the ready reference list)

Awesome #FOAMed web resources:

And an enormous shout out to Prof Simon Brown, and Prof Daniel Fatovich, who were instrumental in this post.

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Comments

  1. says

    thanks Michelle!
    I look forward to the TV debate this week!

    I wanted to point out a couple of things that seem to get lost in the EBM debate on this topic.

    The thrombolytic trials cited are not all the same. 2 used streptokinase and those 2 were stopped due to harm. Those of us who remember using STK in STEMI, will recall the issues of using it. I believe it is still used in some countries for STEMI. I fail to see how citing those STK trials for stroke and implying that TPA is just as harmful, is good science. I know Newman on his NNT site makes a brief comment that he sees no conflict in doing so but I beg to differ

    Next

    No one has cited this latest RCT
    http://www.nejm.org/doi/full/10.1056/NEJMoa1109842#t=abstract

    Its even Australian so shame on you!
    Ok its not placebo controlled but lets give our neurology colleagues some credit!
    It shows a significant result for improvement in functional outcome of TNK vs TPA. This is in fact consistent with NINDS, ECASS and IST 3. Improvement in functional outcome but not mortality.
    More importantly it demonstrates the use of stricter CT selection criteria and the adoption of more rigorous patient selection than the standard NINDS inclusion criteria.
    i.e trying to find the most suitable candidates

    Ergo

    I see nothing wrong with advancing stroke research and trying to improve on the existing practice/EBM.

  2. Simon Brown says

    Hi Minh

    If one excludes the streptokinase trials, the tally is still 12 tPA studies (Lancet 379:9834, 2364-72) and just focussing on these 12 tPA studies, two were stopped early for harm and only two showing benefit. This is still pretty damning and meta analysis doesn’t help because of high levels of both clinical and statistical heterogeneity (listen to: http://bit.ly/16snl1G).

    The Parson’s et al study you cite that compares alteplase with reteplase is intriguing, but adds relatively little to the debate about whether thrombolysis is efficacious. It is a highly selected population (look at the vast number of patients excluded), very small numbers (only 75 patients in three treatment arms), open label design (a big result killer), differences in proximal MCA strokes between groups, and above all -- how would they have done with no treatment? Perhaps tenecteplase just does less harm than tPA.

    But… it does provide the best contemporary evidence I recall seeing that supports the “open-artery-hypothesis” in the setting of stroke (i.e. a link between opening the artery and better outcome), but given the study’s weaknesses and dismal outcomes from the neurointerventional trials where better opening of arteries achieved nothing, it still leaves us guessing. Maybe selection using CT perfusion imaging is the key, but we simply need more studies. There are a number of ongoing alteplase v reteplase studies that are ongoing…

    Research is indeed the key and we are all promoting this, but part of the mix needs to include another placebo-controlled trial, perhaps using better selection criteria based on lessons learnt in various studies (including Parsons et al) over the last two decades.

    • Simon Brown says

      Grrr- my comments about alteplase versus reteplase. Actually in both places it was supposed to be tenecteplase versus alteplase (thanks for pointing that out to me Minh). Done in a hurry without a proof reader… and I always get these mixed up (nominal aphasia?)

  3. says

    Thanks for the EBM review on this topic, and thanks to the above commentators. My comments are not so scholarly. Just wanted to say, based on what’s been presented so far, I will not be using tPA for stroke. Hopefully in the future either more efficacious interventions will be discovered or inclusion/exclusion criteria will be refined to more accurately select the pt population which is likely to benefit.

  4. Rafi S says

    Much of what is discussed reflects the thoughts of a lot of us, including many of mine.

    What we need to try and change, as an emerge community, it the acceptance of tPA as the magical standard of care for hyper-acute strokes. The philosophical question is do you fight it over the patient’s bed or over research reviews and guideline development committees. The former is more instantly gratifying while the latter is more proper. They are both equally hard, though for different reasons.

    I am not sure which one is better!

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