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 
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
The result is inadequate.
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 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.
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.
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
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.
 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]
 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]
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
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