Ep. 119 - CRASH 3

Hallo zusammen

Dem Monatsthema treu (Neuroanästhesie/SHT) gibt es heute etwas zu einer prominenten Studie zum Thema Tranexamsäure beim Schädelhirntrauma.

Es gibt unzählige FOAM-Seiten mit entsprechenden Kommentare zu dem Trial. Quintessenz ist, dass der Benefit von TXA nicht so gross ist, wie von den Autoren behauptet. Allerdings ist wahrscheinlich irgendeine Art Benefit zu erwarten bei GCS 9-15, wenn innerhalb 3h verabreicht ohne grosses Nebenwirkungsrisiko.

• Der primary outcome "head injury-related death in hospital within 28 days of injury in patients randomly assigned within 3 h of injury" war unverändert im Vergleich zu Placebo

  • Der primary outcome wurde sogar noch während der laufenden Studie noch verändert - nicht gerade ein Qualitätsmerkmal...

• Kein Unterschied in neurologischem Outcome

• In einer Subgruppenanalyse fand sich einer Mortalitätsreduktion (SHT-assoziert) bei milden bis mittleres SHT (GCS 9-15)

First10EM - > Link

"Unfortunately, instead of presenting this trial for what it is (a negative trial, with some potentially hopeful data points worthy of future research and maybe even clinical consideration), this trial has been promoted with a degree of spin and hype that leaves science far behind. The spin starts in the paper itself, where claims of a significant benefit are made in the abstract and first sentence of the discussion section, despite the fact that the primary outcome of the trial was negative. In this respect, I think the Lancet failed miserably in both editing and peer review (much like it did with the WOMAN trial.) Things got much worse as this trial was released to the public with infographics claiming that “TXA could save 1 in 5 patients” and an official video claiming TXA “could save 10s of thousands of lives.”

Those are pretty bold claims for a study that demonstrated no difference in mortality."

Entsprechende Infografik:

Und eine korrigierte Version von The Skeptics Guide to EM

Noch eine sehr wichtige Bemerkung von Justin Morgenstern von First10EM ist folgende:

Were the patients too sick?

So we better talk about the subgroups that have got everyone so excited.

There is a sweet spot in medicine (and in clinical trials) where patients are just sick enough to benefit from a therapy. Too sick, and they will die whether or not we treat them. Too well, and they will live, with or without our interventions. Only patients in the Goldilocks zone can benefit from our medical interventions.

This is an incredibly important consideration when looking at negative trials. If almost everyone enrolled has a dismal outcome, you won’t be able to demonstrate a benefit, even if the medication might be helping some patients. (Think about cardiac arrest research, for example.) On the other hand, if almost everyone survives, it can again be difficult to show a benefit, even if it really exists among the sickest patients. (It is possible that this is what happened in the WOMAN trial.) We need to find the right subset of patients in order for our interventions to work.

In CRASH 3, they ultimately enrolled a lot of patients with very severe head injuries. If all of these patients were destined to have bad outcomes, it would have been harder to demonstrate a benefit from TXA, even if it existed for healthier patients. For that reason, partway through the trial they decided to add a sensitivity analysis that excluded patients with a GCS of 3 or with bilateral unreactive pupils. It still didn’t quite reach statistical significance, but it was close. (Really, all that this type of sensitivity analysis does is make the sample size of the trial smaller. If you really didn’t think TXA could help these patients, it would have made more sense to exclude them from the outset. Instead, they just end up negating the value of their sample size calculation.)

In diesem Sinne...

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