Vitamin C Flops for Severe COVID-19

Intravenous vitamin C did little to increase days free of organ support in adult patients hospitalized with COVID-19, two harmonized clinical trials known as LOVIT-COVID and REMAP-CAP found.

Among critically ill patients given vitamin C, the median number of organ-support free days was 7 versus 10 in the control group, with an adjusted OR of 0.88 (95% CI 0.73-1.06), reported Neill K. J. Adhikari, MDCM, MSc, of the Sunnybrook Health Sciences Centre in Toronto, and co-authors in JAMA.

Of patients who were not critically ill, the median number of organ-support free days was a similar 22 days in each arm, with an adjusted OR of 0.80 (95% CI 0.60-1.01).

Survival to hospital discharge in critically ill patients was 61.9% in the vitamin C group versus 64.6% in the control group. Among non-critically ill patients, survival to discharge was 85.1% and 86.6%, respectively.

For critically ill patients, the posterior probability for efficacy of vitamin C therapy was 8.6%, 91.4% for harm, and 99.9% for futility. The posterior probabilities for non-critically ill patients were 17.8% for efficacy, 82.2% for harm, and 98.1% for futility. Recruitment for the trials, which ran from 2020 through 2022, stopped in July 2022 because statistical triggers for futility and harm in the REMAP-CAP trial were reached.

“We were surprised by these results,” Adhikari wrote in an email to MedPage Today. “Although the results do not completely exclude the possibility that vitamin C is effective, they are far more consistent with vitamin C being ineffective.”

Following a single-center study in 2017 that appeared to show a significant decrease in sepsis mortality with the administration of vitamin C, hydrocortisone, and thiamine, a number of larger clinical trials showed that ultimately, there was no benefit with vitamin C in patients with sepsis. But before the results of these trials were widely known and after the start of the pandemic, interest in vitamin C as a potential treatment for COVID-19 arose, especially since COVID-19 patients had low vitamin C. A meta-analysis of nine smaller trials, the study authors wrote, suggested vitamin C might reduce hospital COVID-19 mortality.

Researchers began the current two trials separately to get more definitive results and ultimately combined their efforts into a single study encompassing 90 ICUs and 40 non-ICU hospital sites in four continents, with a unified intervention, outcome measure set, and statistical analysis plan.

Patients admitted to an ICU who received respiratory or cardiovascular organ support at randomization were classified as critically ill; all others were classified as not critically ill. The two groups (1,568 critically ill and 1,022 not critically ill) were randomized into vitamin C and control groups, which had patients combined from both initial trials. Control patients from the blinded LOVIT-COVID trial received placebo, while in the open-label REMAP-CAP, control patients received no vitamin C.

Care was at clinician discretion. Intervention group patients had 50 mg/kg of body weight of vitamin C administered intravenously every 6 hours for 96 hours, with a maximum of 16 doses given. Follow-up was in the hospital for the primary outcome, and by telephone at 6 months for other outcomes.

The primary outcome was a composite of “organ support-free days,” defined as days alive and free of respiratory and cardiovascular organ support up to day 21 and survival to hospital discharge, on an ordinal scale from -1 (death in the hospital) to 22, with higher numbers denoting faster recovery.

“From the standpoint of the bedside clinician, the results of the harmonized trial are clear: vitamin C should not be used as a treatment for hospitalized patients with COVID-19,” observed Craig Jabaley, MD, and Craig Coopersmith, MD, both of Emory University in Atlanta, in an accompanying editorial.

“Although the allure of vitamin C may continue to tempt clinicians, the results from the harmonized LOVIT-COVID and REMAP-CAP trials should lead clinicians to use therapies that have been demonstrated to be beneficial in patients with COVID-19 as opposed to one that is almost certainly ineffective and potentially harmful,” they wrote.

The researchers acknowledged limitations including combined data from two differently designed trials, fewer patients in the placebo-controlled LOVIT-COVID trial, and the possibility of differential care in the open-label REMAP-CAP study. Some data were unavailable, including individual vaccination status, vitamin C product received, and baseline vitamin C levels.

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