Welcome to the world of vascular neurology.
The results of IST3 fall in line with what is already known from multiple clinical trials. While there is skepticism among the ER community, this trial has in many ways solidified what was already known and also highlights the importance of time windows (unlike suggested by the prior post) as well as the practicality of conducting clinical trials with newer agents (desmoteplase, tnk, plasmin
). This had become quite evident when people were discussing the results in Lisbon at the European stroke conference where the results were presented this year.
Let me explain The trial was designed and done to expand stroke thrombolysis and include pts routinely excluded from acute trials like age>80 yrs and also investigate if we can expand the time windows to 6 hrs. The authors (in the results section of the manuscript clearly mention that the benefit was most evident in patients treated within 3 h, but there was insufficient power to examine decay of benefit with time).
Secondly, pts in this trial were treated at much later times median time to treatment 4.2 hrs (IQR 3.2-5.2) hrs. Pts in prior trials were treated much earlier. The investigators also mention that the proportion of patients with a definitely visible ischaemic lesion (vs only possible or no early ischaemic change) on baseline imaging rose with time; and all these pts were included in the treatment as well as control groups. Remember that these pts had strokes that were more evolved. It clearly explains that the rates of good functional outcome at 6 months overall were similar in the 2 groups (though pts treated within 3 hrs did well, and we cannot say anything about 3-4.5 hrs from this data, again specified by the authors in the article in Lancet).
This trials has some similarities to the first ECASS done in Europe and published in JAMA in 1995. Pts were treated with TPA vs placebo within 6 hrs and TPA dose was (1.1 mg/kg unlike the FDA approved 0.9 which has been used in all trials since). As I mentioned earlier, some results from IST3 were like ECASS-1 with overall outcomes for benefit similar in TPA and controls. So, overall the IST3 again confirms that the earlier you treat, the better.
What is new though? You can safely use TPA in pts over 80 yrs.
What about adverse events in IST3? Pts in the TPA group bled more in the first 7 days. This was also noticed in the first ECASS trial. The TPA gp had higher mortality till day 7, but till 6 months there were no differences in the 2 groups (since there were more deaths in the non-TPA gp). Again similar to ECASS (1) where pts treated with TPA upto 6 hrs had higher rates of large intracerebral hemorrhages.
In other words safety as well as efficacy with TPA is time dependent.
Implications of IST3
1. TPA is safe in elderly (who were excluded even in ECASS3 at time windows 3-4.5 hrs).
2. TPA is effective in earlier time windows (upto 3 hrs, this trial doesnt have enough data for 3-4.5 hrs, but ECASS-3 does. But do not go beyond 4.5 hrs.
3. Importantly we do not have to exclude pts>80 from thrombolytic treatment trials
How do these results influence real life treatments? In the words of Lee Schwamm, ECASS3 resulted in more pts being treated beyond 180 min (say 190 230 min). Prior to ECASS3 many pts (at numerous places) would run out of the 3 hr time window (by few minutes) while in the ER (for many reasons) and would not receive TPA (which could be administered at 200 min). IST3 tells us that push hard and be quick so you can start TPA (in eligible pts) at 270 min (4.5 hrs) and this can also be done safely in pts over 80 yrs. Many clinicians do not treat pts in this age group.
Time windows remain important in acute stroke therapy. Mismatch criteria alone cannot be applied practically and scientifically in many cases due to many reasons (topic for another discussion).
I am looking forward to results from DIAS4 (desmoteplase at upto 9 hrs). This will add more to what we already know.
