The VITAMINS trial was not the only trial investigating the efficacy of the hydrocortisone/vitamin C/thiamine cocktail in severe sepsis – and will thus not be the last word on the matter, by any chance. This is one of what is sure to be a slow trickle of other relevant data – as much as anything can break through the cacophony of the coronavirus pandemic.
This is a small trial, just 137 patients, and they used ascorbic acid 1,500 mg q6h, thiamine 200 mg q12, and hydrocortisone 50 mg q6h or a matching saline placebo for a four day course of treatment. Open-label corticosteroids were permissible per the clinical judgement of treating clinicians. The primary outcome was – wait for it – resolution of shock and change in SOFA score. This is, unfortunately, a change from their original primary outcome – in-hospital mortality. The original primary outcome is not mentioned in their manuscript, however, and includes a power calculation based on their secondary outcome – and this power calculation serendipitously matches their original anticipated study size as seen on clinicaltrials.gov.
There are circumstances in which changing the primary outcome is reasonable based on new, outside information obtained during the course of a study. That is not the case here. Moreover, and less appetizing, the new primary outcome is conveniently the only outcome measured significantly favoring the intervention. The authors tracked WBC counts, platelet counts, lactates, SOFA scores, fluid balance, procalcitonin clearance, ICU length-of-stay, hospital mortality, ICU mortality, and more, ad nauseaum. It is clear their original primary outcome would not have reached statistical significance because mortality was far too low – 16% with the intervention, 19% for control – based on sample size. However, the correct thing to do is simply run the trial out and have a reasonable academic discussion of the observed findings, not change to a disease-oriented surrogate.
Because, after all this, the authors make a fair bit of hay of their observed difference in shock resolution, a finding favoring the intervention by nearly a day. However, there were differences[1] in the groups at baseline specifically regarding the initiation of vasopressors – and this probably trickles down to the duration of vasopressors, as well. This study probably mostly shows just how difficult it is to do a study in intensive care, and how robust a sample size is required. Giving patients vitamins is unlikely to cause specific harms, but it doesn’t seem to be all that helpful. Remember – reliably useful treatments give reliably positive results.
“Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis: The ORANGES Trial”
https://www.sciencedirect.com/science/article/pii/S0012369220304554
- Differences reported with a p-value, no less. There is no reason to report p-values for baseline characteristics in a randomized trial. A p-value here describes the likelihood an observation occurred by chance alone, but, obviously, because it was randomized, the chance it occurred by chance alone is 100%.