This odd and tragic saga continues: nearly 20 years after the original NINDS publication, we’re still going around and around with re-reviews of the same evidence. The recent news of this past week is the Medicines and Healthcare products Regulatory Agency in the United Kingdom will set up an expert panel to reevaluate the evidence in support of tPA for stroke. In light of a recent positive Cochrane Review, a positive individual patient meta-analysis, and a paucity of substantial new data – I cannot imagine what new insight will be uncovered.
This seems to have been brought about by correspondence, written by a British stroke neurologist, in The Lancet, describing the same series of arguments skeptics have been making for the last decade and a half. There are concerns over inadequate blinding of investigators, noting the alteplase infusion may be visually different from placebo, or that patients treated with alteplase possibly had observable minor bleeds from venipuncture sites. The manufacturer-sponsored nature of ECASS, ECASS II, and ECASS III is again cited, along with baseline imbalance regarding prior strokes favoring the treatment group in ECASS III. ATLANTIS is also mentioned as a negative trial, stopped early by interim futility analysis. He further mentions the lack of difference between <3h and 3-4.5h windows in observational registries, suggesting the underlying time-dependent hypothesis behind treatment with alteplase is flawed. And, most interestingly, he provides a funnel plot of outcomes by treatment center from NINDS, suggesting certain centers suspiciously had disproportionately positive findings.
Again, these are many of the same arguments made by other experts in their critiques of the evidence behind thrombolysis for stroke. As such, the responses – headlined by Peter Sandercock and Joanna Wardlaw – provide some of the same rebuttals as previously seen. Essentially, what it boils down to – again – is you either trust the data, or you don’t. And, given the suppressed evidence associated with Boehringer Ingelheim’s dabigatran product, not trusting the data remains a reasonable standpoint.
Whether the the MHRA enquiry will change any regulatory statutes is another issue entirely, and Ian Hudson states there will be a fair re-appraisal. However, Prof. Simon Brown points us to this interesting blog entry covering Mr. Hudson’s prior time at GlaxoSmithKline. This journalistic endeavor covers his potential role in overlooked safety concerns regarding paroxetine, as well as other conflicts of interest, and implies the enquiry is unlikely to be truly balanced.
Not to sound like a broken record, but only one thing will settle this debate, once and for all – a large, multi-center, randomized trial conducted independently from the manufacturers of alteplase and otherwise biased institutions. And, since the chance of that happening is basically nil – I imagine another decade from now, we’ll still be picking apart stroke research and debating the quality of the evidence.
“Questions about authorisation of alteplase for ischaemic stroke”
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61385-4/fulltext
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61386-6/fulltext
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61387-8/fulltext
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61388-X/fulltext