Editorial <\/p>\n\n\n\n
October 25, 2023<\/p>\n\n\n\n
Vitamin C is an essential nutrient, functioning as an antioxidant, immunomodulator, and cofactor for numerous enzymes. Vitamin C represents the definitive treatment for scurvy, which results from vitamin C deficiency. However, beyond this unequivocally beneficial indication, the history of vitamin C as a therapeutic is decidedly more checkered. Varying doses of vitamin C have been proposed to treat a large number of conditions and diseases ranging from cancer to cardiovascular disease to dementia to the common cold; however, despite numerous clinical trials, there is little evidence to support its routine use for any of these indications.<\/a><\/p>\n\n\n\n Interest in vitamin C recently spiked after the publication of a study in which administration of vitamin C, in combination with hydrocortisone and thiamine, led to a mortality rate of less than 10% in 47 patients with sepsis compared with greater than 40% in a similarly sized retrospective cohort.1<\/a><\/sup> Despite the inherent limitations of a small, single-center, unblinded, pre-post trial, the remarkable decrease in mortality stood in stark contrast to the near-uniform failure of clinical trials in patients with sepsis. Hope that vitamin C could lead to miraculous improvements in a syndrome responsible for 20% of the world\u2019s deaths2<\/a><\/sup> led to significant coverage of the study in the lay press that was disproportionate to its limitations and ultimately prompted multiple randomized clinical trials of vitamin C either alone or in combination with other therapies for patients with sepsis. Unfortunately, larger trials showed either no benefit or harm with vitamin C in patients with sepsis, and meta-analyses have therefore recommended against use of vitamin C in this population.3<\/a><\/sup>-5<\/a><\/sup><\/a><\/p>\n\n\n\n Before the results of these larger sepsis trials were known, vitamin C was proposed as a potential therapeutic for COVID-19, a form of viral sepsis.6<\/a><\/sup> A physiological rationale for this existed in light of vitamin C\u2019s antioxidant properties and role in preventing microvascular thrombosis, as well as low vitamin C levels in patients with COVID-19 and acute respiratory distress syndrome.7<\/a><\/sup> Furthermore, small trials showed promising results, suggesting more definitive trials were needed.<\/a><\/p>\n\n\n\n In this issue of JAMA<\/em>, investigators from the Lessening Organ Dysfunction with Vitamin C for COVID-19 (LOVIT-COVID) trial and the Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) trial report the results from 2 harmonized randomized clinical trials investigating the effect of vitamin C on COVID-19 in hospitalized adults.8<\/a><\/sup> The LOVIT-COVID and REMAP-CAP trials were initially designed as independent studies of the identical intervention; LOVIT-COVID planned to use a frequentist approach and REMAP-CAP planned to use a bayesian approach. Prior to enrolling any patients, the investigators of both trials converged onto a shared intervention, outcome measure set, and statistical analysis plan. However, each trial remained unique because the LOVIT-COVID trial was blinded and placebo-controlled, whereas the REMAP-CAP trial was open label without placebo. In addition, each trial had separate data and safety monitoring boards and the interim analyses for each trial were distinct.<\/a><\/p>\n\n\n\n All patients randomized to the intervention received vitamin C (50 mg\/kg of body weight administered intravenously every 6 hours for 96 hours). A pre hoc determination was made to separate critically ill patients from those who were not critically ill in light of the differential response to pharmacological therapy in patients with COVID-19 depending on the severity of illness. Critical illness was defined as admission to an intensive care unit and receipt of either respiratory support or cardiovascular support. A total 2613 patients were randomized (392 in the LOVIT-COVID trial and 2221 in the REMAP-CAP trial); there were 1568 critically ill patients from 90 sites and 1022 patients who were not critically ill from 40 sites requiring either no respiratory support or low-flow oxygen. Nearly all patients received concomitant steroids.<\/a><\/p>\n\n\n\n The primary outcome was a composite of organ support\u2013free days alive and free from respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. The primary outcome was categorized on an ordinal scale, spanning from \u22121 organ support\u2013free days (representing in-hospital death) to 22 organ support\u2013free days (indicating no requirement for organ support) and analyzed with a bayesian cumulative logistic model. This approach combines prior beliefs or knowledge with observed data, resulting in posterior probabilities that reflect updated beliefs about treatment efficacy. The bayesian approaches provide nuanced measures of confidence in the treatment effect, allowing for a sophisticated interpretation of the results, such as the likelihood of an intervention\u2019s efficacy or potential harm. One of the strengths of bayesian statistics is its capacity to incorporate prior knowledge, including effectively \u201cborrowing\u201d information across patient subgroups or, in harmonized trials, across studies.<\/a><\/p>\n\n\n\n The study was terminated when stopping criteria for futility and harm for both critically ill patients and those who were not critically ill were reached in the REMAP-CAP trial. For the critically ill patients, the median number of organ support\u2013free days was 7 in the vitamin C group vs 10 in the control group with a posterior probability of 8.6% for efficacy with vitamin C, 91.4% for harm, and 99.9% for futility.8<\/a><\/sup> For the patients who were not critically ill, the median number of organ support\u2013free days was 22 in both the vitamin C group and the control group with a posterior probability of 2.9% for efficacy with vitamin C, 97.1% for harm, and greater than 99.9% for futility.8<\/a><\/sup>These findings were consistent across myriad sensitivity analyses and the secondary and subgroup analyses did not suggest a posterior probability of 33% or greater for efficacy with vitamin C for any of the examined outcomes.<\/a><\/p>\n\n\n\n This study represents another in a growing list of randomized clinical trials failing to demonstrate a benefit with vitamin C for treating infection or sepsis wherein the high probability of futility convincingly supports the null hypothesis that vitamin C is not superior to placebo or no treatment. Even more concerning is the possibility that vitamin C is detrimental in patients with COVID-19 because the probability of harm exceeded 90% for organ support\u2013free days in both critically ill patients and those who were not critically ill. This is consistent with an increased risk of death and persistent organ dysfunction found using both frequentist and bayesian analysis in the LOVIT trial, which evaluated vitamin C in adult patients with sepsis who were receiving vasopressor therapy in the intensive care unit.4<\/a><\/sup>,9<\/a><\/sup> Notably, the LOVIT trial was published in the middle of enrollment of the harmonized trial of vitamin C for COVID-19, leading to new statistical triggers for futility and harm.<\/a><\/p>\n\n\n\n The study by the LOVIT-COVID and REMAP-CAP investigators8<\/a><\/sup> has a number of notable strengths. First, harmonization enabled 2 entirely different trials to more rapidly reach definitive conclusions than either could have done alone. It is extremely difficult to imagine this occurring even 5 years ago prior to the COVID-19 pandemic. Both the LOVIT-COVID and REMAP-CAP trials had different designs, statistical analysis plans, enrollment goals, geographic locations, and leadership teams. Historically, each trial would have proceeded with knowledge of the other, resulting in complementary publications. That the investigators were willing to put aside differences to end up with a harmonized study made up of 2 trials is both unique and worthy of significant praise.<\/a><\/p>\n\n\n\n Second, even though the exclusion criteria and blinding differed between the 2 trials, the findings withstood sensitivity analyses accounting for these differences. Introduction of some associated bias cannot be ruled out, but the fact that conclusions were similar between the trials increases confidence in the results. Third, confidence in generalizability is increased by enrolling similar numbers of patients from Asia, North America, and Europe as well as a significant population from Australia.<\/a><\/p>\n\n\n\n Fourth, the robust comparative analysis uses the strengths of a bayesian approach, but it should be acknowledged that the frequentist approach is more familiar (and more understandable) to most clinicians. More often than not, similar conclusions will be drawn regardless of whether a frequentist or bayesian analysis is used; however, there are numerous instances when negative trials that cannot reject the null hypothesis in a frequentist model may be interpreted differently when a bayesian analysis is used, highlighting the potential value of bayesian methods in gauging the degree of certainty in clinical research.10<\/a><\/sup>,11<\/a><\/sup><\/a><\/p>\n\n\n\n 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. Even though prior, significantly smaller trials showed a potential benefit for vitamin C in patients with COVID-19,12<\/a><\/sup> there is a well-known risk of bias with small studies, and the harmonized trial8<\/a><\/sup> in totality strongly supports futility with vitamin C with the chance of harm being significantly greater than the small possibility of efficacy.<\/a><\/p>\n\n\n\n Treatment options for bacterial sepsis differ greatly from those for viral sepsis caused by COVID-19. Clinicians have minimal therapeutic options beyond antimicrobial therapy and supportive care in patients with bacterial sepsis.13<\/a><\/sup> However, in patients hospitalized with COVID-19, there are numerous effective therapeutics that, depending on the stage of the disease, can target either the host response (eg, corticosteroids, baricitinib, tocilizumab, infliximab, abatacept) or the virus (eg, remdesivir).14<\/a><\/sup> Although the allure of vitamin C may continue to tempt clinicians, the results from the harmonized LOVIT-COVID and REMAP-CAP trials8<\/a><\/sup> 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.<\/p>\n","protected":false},"excerpt":{"rendered":" Editorial October 25, 2023 Vitamin C fo […]<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":[],"categories":[24,23],"tags":[],"_links":{"self":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/24922"}],"collection":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=24922"}],"version-history":[{"count":1,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/24922\/revisions"}],"predecessor-version":[{"id":24923,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/24922\/revisions\/24923"}],"wp:attachment":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=24922"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=24922"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=24922"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}