The Cochrane systematic review of the 11 complete trials of rt-PA for thrombolysis encompasses 3,977 total patients. IST-3 enrolled 3,035, nearly doubling our cohort of randomized data. Unfortunately, this influx of new data does very little to resolve any of the outstanding issues regarding stroke care.
Before even looking at the results, it’s particularly important to wade through the dense study design and methods – and realize this is a non-blinded study in which patients were enrolled if the treating clinician was “uncertain of the benefits or harms of TPA”. Considering this study began back in 2003, prior to ECASS III, a large chunk of their enrolled patients fell into the 3-4.5 hour time frame, with the remaining majority falling into the up to six hour limit. The other major area of interest this study was intended to evaluate was the efficacy and safety in patients aged >80 years of age, of which they enrolled 1,616. And, in a shocking twist, this study actually manages to enroll TPA and control cohorts with nearly identical baseline variables.
IST-3 is negative for the primary endpoint, which is the proportion of patients functionally independent at six months (Oxford Handicap Score 0-2, a scoring system similar to the Modified Rankin Score), with a 95% CI of 0.95 to 1.35. On ordinal secondary analysis, there are non-significant trends towards improvements in OHS favoring rt-PA, which is probably what you’ll hear when people refer to IST-3 as “positive.”
Then, regarding the patients aged >80, there is a trend towards benefit with TPA, CI 0.97-1.88. Unfortunately, in a neutral study, that means there is actually a trend towards harm in ages <80, CI 0.67-1.26. Likewise, between 4.5-6 hours, there is a trend towards benefit with TPA, CI 0.89-1.93. Therefore, between 3 and 4.5 hours, there is a trend towards harm with TPA, CI 0.50-1.07. TPA is also essentially neutral or trends towards harm up until NIHSS 14, with more pronounced benefit shown in severe strokes.
Interestingly enough, the “blinded” phase of the study trended towards favoring control, CI 0.42-1.98, while the open phase favored TPA, CI 0.89-1.45.
So, what does this all mean? It means, there’s still plenty of shades of grey open for interpretation and discussion. Indeed, when added into the systematic review, IST-3 brings several of the previously significant benefits back into the nonsignificant range. To me, this reinforces what I’ve been arguing for awhile – that the focus shouldn’t be on massive expansion of TPA eligibility, but specifically targeting those who have the best benefit/harm profile.
As with any major stroke trial, many of the investigators have financial associations with Boehringer Ingelheim.
“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”