High dose vs. Low dose steroids in hospitalised COVID 19 patients. St Emlyn's. • St Emlyn's

We’ve reported on the RECOVERY trial several times already on the blog. It stands out as the most important trial of therapeutics in hospitalised patients with COVID19. In the last month the RECOVERY trial has released the result that High dose steroids are not of benefit to hospitalised patients with COVID-19, and in fact may be harmful . We are already very familiar with the trial and it’s processes having reported the results on the blog already. We are therefore pretty confident about the methodology.

To briefly summarise the trial so far

Eligibility: Hospitalised patients with COVID19.

Principle Outcome: 28 day mortality

Drugs shown to work
- Dexamethasone
- Tocilizumab
- REGN monoclonal antibodies in patients with low levels of their own antibodies at admission.
- Baricitinib

Drugs shown to have no benefit
- Hydroxychloroquine

Drugs still being randomised
- Empagilflozin
- Sotrovimab
- Molnupiravir
- Paxlovid

Back in June 2020, the first significant result from the trial was the finding that dexamethasone was of benefit in hospitalised patients requiring oxygen. This was a game changer and is a therapy that has undoubtedly saved many, many lives. However, there was still uncertainty as to the best regime/dose for patients as that original trial used a reasonably modest dose of 6mg dexamethasone per day. We now have the results from the latest arm of the RECOVERY trial which tested high dose (20mg/day) vs. low dose steroids (the previous regime of 6mg/day) in a similar cohort of patients, and with the same outcomes as previous arms of the study. The data has been published as a pre-print on the medRxiv server. As always we strongly recommend you read the full paper yourself.

RECOVERY pre-print out.
In hypoxic hospitalised COVID-19 patients requiring either no oxygen or simple oxygen only, higher dose corticosteroids significantly increased the risk of death compared to usual care, which included low dose corticosteroids.https://t.co/01RDdO4Gfc
— Peter Horby (@PeterHorby) December 19, 2022

Tell me about the patients.

Patients were eligible if they were hospitalised adults with clinical evidence of hypoxia (i.e. receiving oxygen or with oxygen saturation <92% on room air). 1272 patients were randomised into the trial. 99% of patients were on oxygen (I’m not entirely sure what happened with the other 1%, but suspect something changed between randomisation/screening/therapy).

They were randomly allocated (1:1) to either usual care with higher dose corticosteroids (dexamethasone 20 mg once daily for 5 days followed by 10 mg once daily for 5 days or until discharge if sooner) or usual standard of care alone (which includes dexamethasone 6 mg once daily for 10 days or until discharge if sooner). The 6mg dose is the standard regime that we have been using since the original RECOVERY trial publication demonstrating a significant benefit to the use of steroids. Interestingly, and in contrast to past RECOVERY publications the patient population was much more international. 745 (59%) were in Asia, 512 (40%) in the UK and 15 (1%) in Africa. 248 (19%).

What about the outcomes?

The primary outcome was 28-day mortality.

What are the main results?

The trial was partially stopped early following an interim review by the data monitoring committee. The stopping of recruitment specifically applies to patients requiring simple supplemental oxygen or no oxygen, but not those who require ECMO or ventilation (the trial continues in this more severe cohort). There is always a risk in stopping trials early, and in general data monitoring committees require a significant burden of evidence to do so. I think this is met in this case. The sample here is a predefined subgroup and the strength of the effect is statistically and clinically very significant, but we must be mindful that stopping early may influence (and potentially overestimate) the true effect size.

For 28 day mortality there was a significant DISadvantage to the higher dosage. 121 (18%) of 659 patients allocated to higher dose corticosteroids versus 75 (12%) of 613 patients allocated to usual care died within 28 days (rate ratio [RR] 1·56; 95% CI 1·18-2·06; p=0·0020). There was also an excess of pneumonia reported to be due to non-COVID infection (10% vs. 6%; absolute difference 3.7%; 95% CI 0.7-6.6) and an increase in hyperglycaemia requiring increased insulin dose (22% vs. 14%; absolute difference 7.4%; 95% CI 3.2-11.5).

Interestingly the 28-day hospital discharge rate was not significantly different (80% for high dose vs. 82.4% for low dose) suggesting that patient stay in the differential survivors is quite long. We should also reiterate that the 28-day survival rate for the RECOVERY trial is quite short for such a life threatening illness that often requires a critical care stay. Further outcome data for all the RECOVERY interventions at the 6-month mark is being gathered and I hope to see that data published in time.

But increasing dose of corticosteroids (dexamethasone 20mg daily for 5 days then 10mg daily for 5 days) results in worse survival than low dose (dexamethasone 6mg for 10 days) in pts with hypoxia but not requiring ventilatory supporthttps://t.co/QzLNql7y5L pic.twitter.com/dmNTgCnyNi
— Martin Landray (@MartinLandray) December 19, 2022

There are a number of other caveats to the results. This is an open label trial which may lead to bias, and the paper is currently a pre-print on the web. It is yet to undergo formal peer review and publication. The trial also has a relatively low number of patients receiving other therapies such as Tocilizumab and Baricitinib which have been demonstrated to be advantageous in certain groups. This may have been due to availability issues, but it does mean that this trial is unable to look at potential benefits or harms of co-administration of these drugs.

What do these results mean in practice?

On the basis of this paper, and from what we know of the RECOVERY trial methodology we would advocate standard dose steroids in hospitalised patients requiring oxygen with COVID19 infection. We look forward to the full paper and 6-month outcomes to give further insights.

Further reading