IST-3, despite its pro-tPA bias, was a negative trial for the primary endpoint. But, that hasn’t stopped folks from looking at secondary outcomes and slicing it into subgroups and claiming – victory!
The root of the issue is: in a negative trial, when you pull out a subgroup with positive outcomes, naturally there must be a counterweight subgroup with worse outcomes. The trouble with the true believers/sponsored representatives is they focus only on the positive subgroup for hypothesis generation, and neglect the negative bits.
This latest rehash of IST-3 focuses on patients with high predicted risk of sICH or poor functional outcome. These authors reviewed all the published prognostication tools and developed their own from the patient data in IST-3. For what it’s worth, most of the tools performed approximately the same: fair to poor. The best AUC for prediction of sICH was 0.68 and the best AUC for prediction of post-tPA poor outcome was 0.80.
Then, these authors stratified the groups into low-, medium-, and high-risk for sICH or poor functional outcome with tPA, and compared the outcomes to the placebo group in IST-3. For these subgroups, these authors found patients stratified as high-risk by the various scores tended to have better outcomes when treated with tPA compared with placebo. Thus they conclude: “These data suggest that intravenous rtPA has an absolute beneficial effect in patients at a high predicted risk of sICH or poor functional outcome.”
… which is a fine and reasonable hypothesis given their baseline assumptions. However, they never acknowledge the biases of IST-3 or the greater context of a negative trial – the counterweight that tPA is thereby futile or harmful in those at low- or medium-risk for poor outcome.
Of course, when most authors are funded by Boehringer Ingelheim to fly about the world and describe the wonders of tPA, it’s no surprise they choose to focus only on the conclusions that might lead to more tPA use, rather than narrowed, more appropriate tPA use.
“Targeting Recombinant Tissue-Type Plasminogen Activator in Acute Ischemic Stroke Based on Risk of Intracranial Hemorrhage or Poor Functional Outcome: An Analysis of the Third International Stroke Trial”
https://stroke.ahajournals.org/content/early/2014/03/06/STROKEAHA.113.004362.abstract