I just wanted to repost this link to an article fo

I just wanted to repost this link to an article for everyone to consider the impact of a study using the primary endpoint of mortality (any cause).

My feeling that the CD12 results will either be one for the history books, or it will be tossed into the dumpster of futility.

https://emcrit.org/pulmcrit/mortality/

Quote:

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For nearly all studies, mortality is a foolish primary endpoint.
Many critical care trials are designed to look for a mortality benefit with a target p-value <0.05. This is a recipe for confusion:

If the trial is positive, it usually winds up having a moderately positive p-value (e.g., 0.02-0.05) with a low fragility index (Ridgeon 2016). Although technically a “positive” trial, these results are not robust – they might represent chance alone. Shooting for a p-value <0.05 is major cause of poor replicability. Some authors have proposed targeting a lower p-value (e.g. p<0.005) or a higher fragility index in order to improve reproducibility (Johnson 2013, Ridgeon 2016).
If the trial is negative, this doesn't rule out a meaningful mortality benefit. Mortality is a profoundly important outcome, so even small differences in mortality are important (e.g. 1-5% difference). Unfortunately, most trials lack sufficient power to confidently exclude a 10% mortality benefit (Harhay 2014). Investigators often predict that their intervention will cause an unrealistically large improvement in mortality, which leads to their studies being small and underpowered (a mistake known as “delta inflation”)(Ridgeon 2017).
In short, nearly all studies are underpowered to definitively address mortality. They are doomed from inception to either be weakly positive or weakly negative, failing to answer the intended question. This spawns meta-analyses, which attempt to combine underpowered studies – often with conflicting and indecisive results as well.

Many therapies for sepsis have been rejected on the basis of a lack of mortality benefit. It's likely that some of these therapies have benefit, which couldn't be proven for reasons explored above. For example, an IL-1 receptor antagonist was shown to reduce mortality by 3%, but this intervention was rejected because the difference wasn't statistically significant (Opal 1997). A 3% absolute reduction in mortality would be clinically meaningful, but this study was underpowered to determine whether this was statistically significant (2).

The only trials for which a mortality endpoint could make sense are cardiology mega-trials or massive, pragmatic trials involving several thousand patients (e.g. CRASH-2). These studies have enough power to robustly investigate a mortality endpoint. Unfortunately, this sort of trial is rarely achieved in critical care.

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