Believing is seeing: Stroke thrombolysis remains unproven after the third international stroke trial (IST‐3)

Abstract

In John Medina’s book, Brain Rules, he highlights that we see with our brains in ways that often fool us into experiencing what we expect to find, rather than what we actually encounter. He describes how a group of researchers dropped red dye into white wines to see how oenologists would assess them. Their noses were fooled and every one of them used the vocabulary of red wines to describe the white wines. Similarly, Jonah Lehrer’s book, The Decisive Moment, reported a functional magnetic resonance imaging experiment where expensive wines made parts of the prefrontal cortex more excited (even though the scientists had tricked the participants by swapping the price labels, so the participants’ brains became more excited with what they thought was more expensive wine). This neuroscience research highlights that expectations have powerful effects that influence what we believe. So it is with the controversy on the use of tissue plasminogen activator (tPA) in acute ischaemic stroke. Supporters believe in one study (the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group [NINDS] New England Journal of Medicine 1995) that ‘proves’ that it should be given within 3 h, and see the evidence in that light. Those who consider the case for tPA still unproven prefer to look at the totality of the evidence. In 2008, the European Cooperative Acute Stroke Study III (ECASS III) was published, suggesting that the time window for delivery of thrombolysis could be increased to 4.5 h. However, significant methodological and analytical flaws have dogged this study, much like criticisms of NINDS have persisted since 1995. One of the main criticisms of ECASS III was the primary endpoint chosen, a modified Rankin Scale (mRS) of 0–1 versus mRS of 2–6. A mRS of 2 (slight disability; unable to perform all previous activities but able to look after own affairs without assistance) is grouped together with a mRS of 6 (dead). This is not an appropriate end-point stratification. Once the end-point is reclassified into mRS 0–2 versus 3–6, all purported benefits of tPA disappear. It is also an inconvenient truth that the ATLANTIS trial, which had virtually the same design as ECASS III, caused harm and was stopped early. A recent graphic reanalysis of the original NINDS data suggests that imbalance in baseline stroke severity was likely responsible for most, if not all, the difference in outcome between treatment groups. Each group experienced virtually identical change in National Institutes of Health Stroke Scale (D-NIHSS). D-NIHSS improved slightly in almost all NINDS subjects, regardless of treatment, whereas a very few improved a lot, and a few (most of whom were extremely sick at baseline) died. D-NIHSS, the only metric recorded both before and after treatment, thus allows for estimation of the effect of treatment independent of confounding by severity. Although more tPA patients did end up with only a small deficit, this paralleled the similarly greater number of tPA patients who started with a very mild stroke. Graphic depiction of the response to treatment of every single NINDS subject allows readers to judge for themselves whether there was even a hint that treatment modality, or time to treatment, had any independent effect on outcome above that of initial stroke severity. Critics correctly note that D-NIHSS is not a perfect metric, because it is not truly linear: a change of X points at one end of the scale is not necessarily the same as a similar change at the other end. However, this