Response from Drs Hoffman and Cooper to Stroke thrombolysis: Leaving the past, understanding the present and moving forward …


We were pleased to read the letter by Bladin et al., even despite its barely civil tone, because it reflects so clearly the quality of thinking of many of those who insist that thrombolysis has been proven to be beneficial in acute ischemic stroke.[1] As we noted in our editorial,[2] we believe this is far from the truth, and that the best evidence – supported by the IST-3 Trial,[3] despite its manifest flaws – strongly suggests not only an absence of benefit, but also probable harm.

Bladin et al. start out by claiming that our editorials are ‘full of distortions and factual errors’, but it is hard to find any specifics in their letter.[1] Perhaps they are referring to our statement that IST-3's authors relied inappropriately on a secondary outcome measure, as they note that it was actually a ‘preplanned secondary outcome measure!’ We plead guilty, and our only defence is to ask readers to decide for themselves whether our calling a ‘preplanned secondary outcome measure’ a ‘secondary outcome measure’ is indeed a factual error.

Other than that, they fail to cite even one single instance to support such a broad and damning claim. This, of course, makes it difficult for us to respond, but we will reiterate that there is nothing remotely inaccurate about stating that the primary analysis of IST-3 – the proportion of patients alive and independent, as defined by an Oxford Handicap Score of 0–2 at 6 months – found no difference between treatment groups.

Bladin et al. next go on to pillory the graphic reanalysis of NINDS,[4] of which one of us was the first author, claiming that it has already been ‘thoroughly discredited’. The evidence they provide for such a comprehensively definitive statement is … a letter to the editor of the journal in which that paper was published, disagreeing with its conclusions![5] We will not review here the assertions in that letter, but are happy to refer readers to the paper itself,[4] the dissenting letter[5] and our reply[6] – unlike these correspondents, we ask only that each reader decide for himself or herself.

Perhaps in the future they will cite their current letter as proof that this editorial has been thoroughly discredited.

Bladin et al. then make the claim that ‘the purported methodologic weaknesses of IST-3 are actually its strengths’. Based on our long careers as teachers of clinical epidemiology and critical appraisal, we are confident that few, if any, methodologists would agree with this rather extraordinary comment. But unlike some of our critics, we have no interest in relying on supposed expertise to make our point; instead, we merely ask readers to decide for themselves about the methodologic quality of such ‘strengths’ as the study's relying for its primary outcome on a non-specified analysis, by an unblinded family member, of a metric that – even when done in person, based on a complete neurologic evaluation, by a trained neurologist, who has been blinded to treatment group – has been shown to be highly unreliable.

Finally, Bladin et al. accuse us of making tired arguments that have previously been answered. We agree that we have long made many of these same arguments, to which we believe the evidence from IST-3 – despite its biases – adds even more weight. As to their being ‘answered’, however, that is only true if one considers ignoring the facts we cite (none of which are in fact inaccurate). Their letter, like the positive ‘spin’ that is being widely applied to IST-3, takes evidence and blithely turns it on its head and insists that ‘expert’ claims, no matter how outrageous, dare not be challenged.

We reject such thinking and ask the journal's readership to do so as well – not because you have any need to trust us, but because you are each able to decide for yourselves.

Competing interests

JRH has consulted on lawsuits involving allegations of negligence related to non-use of thrombolysis in stroke. He donates all fees from such consulting to charity and takes no personal reimbursement for any such work. He has no other potential conflict to declare. RJC has no competing interests to declare.