Thread by @NickLeeMD

1/ A #MedTweetorial on #HowIReadThisPaper for #DISCOVERYtrial - dex edition on @medrxivpreprint. We’ll be exploring the pre-print, supplement, and trial document. Would love for feedback, thoughts, & comments!

Currently, what is your opinion on using dexamethasone?

2/ Trial info:

▶️RCT, open-label, adaptive
▶️6,425 pts enrolled
▶️Dex 6mg daily for 10d (PO or IV) v usual care (1:2 ratio, respectively)
▶️176 🏥in UK
▶️Prim Outcome: OS

🔑Intention-to-treat
🔑Pre-specified stats plan
🔑Not randomized by O2 status

3/ Results - Table 1
✅Well-balanced between dex & usual care
▶️Younger, less-comorbid cohort on vent
▶️Days of illness ⬆️w/ ⬆️O2

Imbalances in O2/vent cohort raises ❓s
1️⃣How to account for O2 & vent?
2️⃣Can we adjust & trust result?

4/ Results - Fig 1
1️⃣Overall, ⬇️mortality for dex cohort (P < 0.001)

Then pre-specified stratification kicks in (b-d)
2️⃣Trend toward ⬆️mortality w/ dex in pts w/o O2
3️⃣Significantly ⬇️mortality for dex in O2 and vented pts
▶️Sub-groups suggest O2/vent pts driving mortality

5/ Fig 1 cont
Here, worth noting a few items:
▶️No adjustment in these curves
▶️In RCT, can take at face value b/c groups are randomized in equal
🔑Fig. 1B-D - no longer randomized! Sub-set analysis
🔑Per pre-print, RRs not changed w/ adjustment for age

6/ Table 2
I find the effect on the secondary outcome fascinating

❗In pts not-ventilated, dex significant associated w/ reduced risk of intubation
➡️Could alleviate ICU capacity issues

Would like to see further analysis on this, which is complicated by incomplete vent info

7/ The 😈 in the details
If you have to look at one piece of Supplement, look at Supp Fig 2

This is the table oxygen status would have been picked from as the analysis of interest
We see that ⬇️age, male gender, and >7 days symptoms are associated w/ improved outcomes

8/ To my knowledge, they control for younger age in O2/vented patients BUT not these other co-variables

Are outcomes better b/c of dex or b/c ventilated pts are younger and getting over the critical aspects of their illness?

9/ #RECOVERYtrial is a well-run RCT that addresses 🔑 #COVID19 ?s. BUT it is worth acknowledging that the major conclusions stem from sub-group analysis that ⬇️ easy interpretation.

Our interpretation greatly affects how pts will be treated for the next weeks.

10/ More ?s & analysis (most by @iwashyna):
▶️MVA for additional co-variables
▶️Analysis of timing of dex administration
▶️At what level of O2 is impt to give (w/ signal of harm in no O2 this is impt)
▶️Can we avoid intubation with appropriate steroids?

https://twitter.com/iwashyna/status/1275881428056715267

11/ Final take-away for me:
✅for vented pts
✅ for large amounts O2 (eg HFNC) esp if symptoms for several days
❎ for 1-2L NC
❎ for no O2

Why? Overall, even with limitations, well run trial. Mortality signal goes into correct direction w/ invasive ventilation.

12/ Hesitations remain: Where to start treatment - wait until dz more severe - more time from symptoms? How much O2? & I do wonder about ⬆️mortality in this trial compared to others (since # events affects P-values), but I don’t think it’s a reason to hold off tx.

13/ What do you think s/p #MedTweetorial? Who would you prescribe for b/c we may be there sooner than we think unfortunately, and we'll be making these decisions!

14/ Looking forward to the @IDJClub discussion tonight! Should be wonderful and helpful to further discuss this phenomenal preprint.

#MedTwitter #MedStudentTwitter #MedTweetorial #MedPeds #IDJClub