Those results feel like definitive advances, but we need to realize their limitations and need for confirmation despite everyone's #pandemic fatigue
There are lot of skeptics in and outside of #Twitter on the results of both trials, strong emotions regarding big-pharma made medications, the way the #EUA was made, also about use of #steroids in the #ICU that has a quite rocky history among those who run those units.
And we need to acknowledge from the outset all sorts of basic, and not so basic, emotions that come in the doing clinical trials, exacerbated by academic cliques, national defense issues (and nationalisms) that can get exacerbated with the strains in health systems.
First hit the (preliminary) results of the #ACTT1 trial, meeting their primary endpoint of a faster time to #Recovery…
Wasn't RECOVERY the name of the other trial, how come it is the outcome of #ACTT?…
We had rarely used ordinal scales before in Infectious Diseases…
It fell like like a #shellshock to many as the #EUA in the US was approved and #remdesivir became available even before we were able to see final results and what does recovery mean anyway?
The hardliners wanted less deaths for sure, but the study was not designed that way.
But both the #ACTT1 and #RECOVERY trial results have perplexing nuances:
– In #RECOVERY, #dexamethasone helped nicely those on #ventilators, but #remdesivir had no effect.
– those on supplemental oxygen, #remdesiver worked beautifully, but the #dexamethasone effect was small
Discouraging was that there was a signal for harm among patients who were hospitalized and did not require oxygen who got #dexamethasone, a big flag in my mind despite any handwaving you want to do, and the effect of #remdesivir was notable, but small given the low placebo events
There were no major effect modifications in the #remdesivir data other than baseline status at randomization, but #dexamethasone was interesting: those younger than 70 who were sick for over 7 days seemed to benefit the most, men more than women. #RECOVERY
#RECOVERY was open label and most importantly, it was not stratified by center, knowing from prior experience and now with data, that care is strongly influenced by local practices and systems being overwhelmed.
BUT sample size was huge for ID trials, so the answer was "#Robust"
So let's take a step back and think the pros and cons of both trials, what we can learn from them and how can we inform and probably confirm these results.
Besides the obvious issues of #bias with open label, non-placebo controlled issues, the main concern from a technical perspective is that both #RECOVERY and #ACTT1 claim effects on different strata, but those strata were selected post-hoc, were not stratified at #randomization
As you make additional comparisons, some other issues become apparent.
#RECOVERY had no limitations in organ disfunction, but I don't think we can attribute the 2xmortality rates solely to that.
#RECOVERY didn't specify an imaging diagnosis of lung disease or confirmation of SARS
The #mortality data for #ACTT1 is posted in their appendix.
Given the number of patients who had finished at the time of their preliminary report, I don't expect sizable changes in their final report, so I decided to compare the mortalities head-to-head with #RECOVERY.
Used the #RECOVERY mortality Y-axis for the comparisons and adjusted the #ACTT1 graphs to scale. Also putting the key numbers in.
The absolute overall death difference is ~3% in both trials, not too exciting if reading from afar.
For patients on #ventilators, dex worked nicely
Many doctors are already giving both to patients, but are we helping them by doing this? Is the combination synergistic, indifferent, antagonistic?
– would remdesivir benefit patients on the ventilator further if used with dexamethasone?
– would dexamethasone antagonize the benefit of remdesivir in those on O2?
But here is the proposal for the #ReDexCoVer trial