Furosemide is good for filling the patient’s bladder, but the patient probably did not call for help filling his/her bladder.

- Rogue Medic

Is a clot-busting drug safe for 6 hours after stroke symptom onset – or only for an hour and a half? – Part II

ResearchBlogging.org
 

It has been a couple of months since I wrote Part I and I have not been that motivated to write this part, but Dr. Jerome R Hoffman and Dr. Richelle J Cooper have been busy with the topic. Their paper appears in the current Emergency Medicine Australasia.
 

Just before the release of the results of the third inter-national stroke trial (IST-3),1 the largest trial of thrombolysis in acute ischaemic stroke (AIS), the journal Stroke published a remarkable pre-emptive strike – a commentary in which the author identifies a legion of concerns regarding the study’s methodology, only to reassure us about the study’s value.2 [1]

 

What Dr. Lyden appears to have been trying for is something like this:
 

Friends, Romans, countrymen, lend me your ears;
I come to bury IST-3, not to praise it.
The ICH that we cause lives after us;
The lysed clots are few and far between;
So let it be with IST-3. The noble Hoffman
Hath told you tPA is harmful:
If it were so, it was a grievous fault,
And grievously hath IST-3 answer’d it
[2]

 

The result is inadequate.[3]

The response is another well deserved humiliation at the hands of Drs. Hoffman and Cooper.

This is not as bad as claiming that Hitler liked dogs, so he was really a good person who was just misunderstood. Still, this is a preposterous distortion of the scientific method and an abuse of the trust that we place in doctors.

IST-3[4] is flawed.

The use of tPA at any time before death to any patient who ever had a stroke, and maybe as late as at the funeral, is based on other flawed studies.

Dr. Hoffman continues –
 

In one astonishing section he lucidly catalogues a host of important biases likely to skew the study’s results in ways that increase the chance of finding a spurious benefit from the use of tissue plasminogen activator (tPA) – but then proceeds to trivialise the very concerns he has elucidated.[1]

 

Are these mistakes trivial?

Suppose you agree to treatment with a drug that should provide a benefit (based on this flawed study).

You later find out that the study was rigged.

The drug is really more likely to be harmful.

Would you call that trivial?

You now have a stroke from a clot and a bleed from tPA – and this isn’t even an episode of House, MD.

Trivial?

How trivial is your brain?

Epinephrine in cardiac arrest is similarly based on ignoring the harm to the brains of patients, so maybe the IST-3 authors just know good marks when they see them.
 

The author of this commentary – and by extension the editors of Stroke who approved it – ultimately concludes that despite its many flaws, there is much to learn from IST-3.2 We agree . . . although given that the actual results of IST-3 uniformly failed to show benefit, even in the face of severe bias, we believe the lessons are precisely the opposite of those being trumpeted by the study’s own authors.1[1]

 

That is enough of a preview. The full paper is available for free, so go read it.

IST-3 is an example of using a drug based on wishful thinking, surrogate endpoints, and flawed research, rather than based on valid evidence.

Our patients deserve better.

-

Footnotes:

-

[1] How is more negative evidence being used to support claims of benefit: The curious case of the third international stroke trial (IST‐3).
Hoffman JR, Cooper RJ.
Emerg Med Australas. 2012 Oct;24(5):473-6. doi: 10.1111/j.1742-6723.2012.01604.x. No abstract available.
PMID: 23039286 [PubMed - in process]

Free Full Text from Emergency Medicine Australasia

-

[2] Julius Caesar Act 3, Scene 2 – The Forum
Shakespeare homepage at MIT
Written by William Shakespeare (distorted for my own purposes).
Play

-

[3] In anticipation of International Stroke Trial-3 (IST-3).
Lyden PD.
Stroke. 2012 Jun;43(6):1691-4. Epub 2012 May 3. No abstract available.
PMID: 22556196 [PubMed - indexed for MEDLINE]

-

[4] 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.
IST-3 collaborative group, Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, Murray G, Innes K, Venables G, Czlonkowska A, Kobayashi A, Ricci S, Murray V, Berge E, Slot KB, Hankey GJ, Correia M, Peeters A, Matz K, Lyrer P, Gubitz G, Phillips SJ, Arauz A.
Lancet. 2012 Jun 23;379(9834):2352-63. Epub 2012 May 23. Erratum in: Lancet. 2012 Aug 25;380(9843):730.
PMID: 22632908 [PubMed - indexed for MEDLINE]

Free Full Text from PubMed Central.

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Hoffman, J., & Cooper, R. (2012). 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, 24 (5), 473-476 DOI: 10.1111/j.1742-6723.2012.01604.x

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Lyden PD (2012). In anticipation of International Stroke Trial-3 (IST-3). Stroke; a journal of cerebral circulation, 43 (6), 1691-4 PMID: 22556196

-

IST-3 collaborative group, Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, Murray G, Innes K, Venables G, Czlonkowska A, Kobayashi A, Ricci S, Murray V, Berge E, Slot KB, Hankey GJ, Correia M, Peeters A, Matz K, Lyrer P, Gubitz G, Phillips SJ, & Arauz A (2012). 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, 379 (9834), 2352-63 PMID: 22632908

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Comments

  1. Wow. I’m dumbfounded by some of what I read about the inclusion/exclusion criteria, as well as the comments regarding intracranial hemorrhage, I found in the study proposal: (“The third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke”, Trials. 2008; 9: 37.)

    The “uncertainty principle” they used has to be the LEAST scientific method I’ve read:

    Further inclusion and exclusion criteria are not specified precisely but are guided by the uncertainty principle (or absence of proof for that particular patient). If, for whatever reason, the clinician is convinced that a patient fulfilling the above criteria should be treated, the patient should be treated with rt-PA and NOT randomised. If the clinician is convinced that a patient should not be treated (for whatever reason), the patient should NOT be included in the trial. Patients should only be randomised if they fulfil the eligibility criteria AND the clinician is substantially uncertain about the balance of risks and benefits of rt-PA for that individual.

    Really? If you think t-PA will work, then give it (and to hell with the randomization) and include them; but if you think t-PA is a bad idea for that patient, don’t include them in the placebo group?!? You think there might be some bias introduced by that criteria? [/sarcasm]

    The remarks about intracranial hemorrhage are absolutely unconscionable.

    In the Cochrane review, thrombolytic therapy with rt-PA was associated with a definite risk of fatal intracranial haemorrhage (OR 3.60, 95% CI 2.28 to 5.68, 2p < 0.00001) with no significant heterogeneity. The rt-PA Study Group investigators assessed the effect of several clinical factors: time to treatment, age, and stroke severity on the risk of intracranial bleeding. Treatment with rt-PA was the only independent predictor. Thus, at present, there are insufficient data available to guide clinicians on the factors that influence the occurrence of this most important side effect of treatment.

    (emphasis mpatk)
    Am I misunderstanding this? Are they in such denial that, despite ruling out a number of variables and finding only the treatment is associated with a fatal “side effect”, they’re claiming “insufficient evidence” and going fishing for anything else to blame other than their pet treatment?

    When I joined EMS, I thought that, because of the higher stakes, medical research would be more strictly controlled and “by-the-book” scientific method than the typical academic science research I was familiar with. This study certainly helped shatter that illusion.

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