Schrödinger’s Fence

…or, where we currently sit on the matter of thrombolysis in Acute Stroke.

This is Part 3 of three posts

An Opinion Piece 

Firstly, most sincere and heartfelt apologies to you all, good readers, regarding the use of the Schrödinger’s Cat analogy here. As you are all well aware, Erwin Schrödinger (Austrian Physicist, in 1935) proposed this rather absurd construct to explain the contradictions of quantum physics, whereby the cat, in the box, was either alive or dead, because of the random nature of the decay of a radioactive atom, allowing the cat, until the box is opened, to be both alive AND dead.

How has this any relevance to the current state of play of thrombolysis for acute strokes in the ED?? Possibly in no way whatsoever, but I have been struggling to come to terms with understanding our current position, and more importantly, the implication it has for my practice, my specialty and the way I teach my junior staff.

This juncture seems to be one of ‘fence sitting’ and by my reckoning this position is either one of great sagacity/wisdom, or great cowardice/avoidance.  Could it be both simultaneously?

The Evidence

As proponents and partakers of the FOAMed paradigm, I have no doubt that you have all had the opportunity to digest the opinions of the Titans regarding the journey that the use of thrombolytics has taken in the therapy of acute CVAs. If not, drop everything, don’t even breathe, until you’ve listened to the David Newman and Ashley Shreves podcast on SMART EM, and have read Andy Neill’s multi-part summary 

The other must reads are:

  • Daniel M Fatovich, Stephen P MacDonald, Simon G Brown: Thrombolysis in acute ischaemic stroke The Lancet, Volume 380, Issue 9847, Page 1053, 22 September 2012 [The Lancet]
  • Daniel M Fatovich: Believing is seeing: Stroke thrombolysis remains unproven after the third international stroke trial (IST-3) Emergency Medicine Australasia (2012) 24, 477–479 [EMA Full Text]
  • Ryan Radecki: The Third International Stroke Trial: IST-3 [Emergency Medicine Literature of Note] (plus the fabulous comment from Greg Press)
  • Jerome R Hoffman, Richelle J Cooper: How is more negative evidence being used to support claims of benefit: The curious case of the third international stroke trial (IST-3) Emergency Medicine Australasia (2012) 24, 473–476 [EMA Free Full Text]

The conclusions are reasonably uniform throughout all of these pieces.  Almost all of them carefully dissect the data and conclusions drawn from the totality of trials investigating the utility of thrombolysis in acute stroke, and feel that the summaries and recommendations by the authors do not stand up to the highest level of scientific scrutiny (particularly in regard to the most recent, and largest trial, IST-3)

For reference, the IST-3 paper is included here, the comment published in the same Lancet journal edition and the current Cochrane Review on the subject.

  • 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. The Lancet, Volume 379, Issue 9834, Pages 2352 – 2363, 23 June 2012 [Lancet Reference]
  • Didier Leys, Charlotte Cordonnier: rt-PA for ischaemic stroke: what will the next question be? The Lancet, Volume 379, Issue 9834, Pages 2320 – 2321, 23 June 2012 [Lancet Comment]
  • Wardlaw JM, Murray V, Berge E, del Zoppo GJ Thrombolysis for acute ischaemic stroke [Cochrane review]

Jerry Hoffman talks about IST-3 in the August 2012 edition of Emergency Medicine Abstracts (start at 39 min 20 seconds):

To hear more of this fascinating discussion, we greatly look forward to the presentations at SMACC 2013 by Domnhall Brannigan, and by David Newman at the ACEM winter symposium in Broome, in June 2013.

BUT where are we left currently??

On the damned fence!

Now, I have no role to play in trying to explain the nuances of the literature; the pros and the cons.  I am possibly statistically disabled.  I have a major issue with trying to understand the numbers wielded with such finesse by others, (and yes, let’s admit it, with direction sense, and parking.  I may have had a stroke in the mathematical analysis part of my brain – where was that tPA when I needed it, huh!?) So I am intensely grateful to those that can, and choose to share it. With these at my side, I have read the papers, and have come to a conclusion, which I know is shared by many others in the critical care world.

Currently there is no credible evidence that thrombolysis is clearly beneficial in acute stroke.  There is no mortality benefit (in fact, there is an overall increase in mortality with thrombolysis, primarily early on), and there is inconsistent evidence for an improved functional outcome across all groups (when considering the enormous heterogeneity of the reporting in the 12 major trials).  All of the reviewers mentioned above, however, have recognized that within the data, there is evidence that there must be some groups of stroke patients who have benefited from thrombolysis, but to date it is NOT CLEAR WHO IT IS (because of the multiple confounders with time to therapy, age, severity of stroke, amongst others).  Thus, we cannot yet definitively say that we are either harming or helping any subset of patients, or more importantly, the individual patient as they come through our ED door with an acute stroke.

This would all be fine and dandy – there are many therapies that yet ‘show promise’ but are not yet accepted, and are awaiting definitive proof (or, the absence of nullification).

But the problem here is that many of us work in departments where the neurology team FIRMLY believes that acute strokes ought to be thrombolysed.

Regarding the fence sitting – if you are one of the camp that believes that thrombolysis has little mortality and morbidity benefit to the patient in front of you, then you may think you are NOT a fence sitter, however if you then allow the neurology team to administer the therapy to the patient, because of the oft-spouted line that the Stroke Team will bear responsibility for the patient, long after your measly 4 hours is up, then perhaps you do still sit on that fence, more in action, rather than thought.

I bring this little personalized rant up, only in that I found myself using that line whilst teaching registrars, and then examining the principle behind it, trying to weigh up whether this was a cop out, or it was a wise path to take.  Hence the dichotomous title.

As a final little debate, I’d like to share a few of my internal conflicts about this situation.

FORthis being a position of wisdom, sense and perspicacity

  • There may not be any clear evidence for or against, therefore coming out punching on one side or the other may prove to be utterly incorrect come the next major definitive trial and a reversal (insert sense of optimism here)
  • It is not appropriate to fight this out over individual patients – it is tough enough to try and practice beneficence, without showing the patient that this may be in doubt
  • The neurologists are a smart bunch – it is presumed that they feel the data ought to be interpreted in the best interests of the individual and the population

FORthis being a position of pusillanimity and possibly cowardice

  • If you strongly believe that harm can be done to your patient, would this not be the time to intervene, or perhaps you may be less likely to identify those patients who the Stroke Team may consider for lysis?
  • By being complicit in a system that prioritises these patients for acute thrombolysis, are you not possibly diverting resources away from other patients, in the community, in the pre-hospital setting and the Emergency Department?

OR – could we completely destroy the binary/dualism theme and introduce another variable here?

  • Should we ‘hold fast’ and hope that, like has happened with reperfusion in acute myocardial infarction, technology and new, possibly physical (as opposed to pharmacological), interventions will soon burst onto the evidence-based stage?
  • CT perfusion scans may be a far greater diagnostic and stratifying tool than we have presently.  In combination with CT angiograms they have the ability to quantify not only cerebral perfusion, but cerebral blood volume, thus confirming salvagability of cerebral parenchyma REGARDLESS of time.
  • Interventional radiological embolectomy/direct catheter thrombolysis techniques – are they the new PCI?
  • Again – both of these topics are going to be debated in the first 6 months of next year, at the places to be (Sydney, and Broome)

A meagre mention should always be made regarding stroke units – the NNT for stroke units compared with general ward care for patients who were living at home at the end of 5 years? It would be a wonderful thing to see a drug have that kind of power. Stroke unit beds are monumentally short in Australia. Does seem rather a shame in the face of this evidence.

It seems a difficult jungle to navigate at this time.

Please add comments, join the discussion (although quantum mechanics purists, consider your retribution comments pre-empted)

I am seriously looking forward to conversations at the upcoming extraordinary conferences

And my final word? 

Wouldn’t it be a fine thing to tally up all the money spent on these trials, and compare that to a known stroke intervention – primary prevention?

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