Mortality is an important endpoint, so we shouldn’t ignore mortality trends entirely. However, the vast majority of these will be spurious. Thus, we should generally not change practice due to them.

In the history of critical care medicine, no medical therapy has ever reproducibly been shown to improve mortality in multi-center RCTs.

Some treatments have been incorrectly found to improve mortality (e.g. Activated Protein C). Other treatments have likely been incorrectly found to increase mortality.

The standard practice of chasing mortality endpoints with MC-RCTs and a p-value target <0.05 has failed the test of time. There are several reasons that demonstrating mortality in critical care trials is nearly impossible. Over time, mortality rates are falling, which will make it even harder to demonstrate benefit from any treatment.

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