Intravenous vitamin C for patients hospitalized with COVID-19: two harmonized randomized clinical trials

15 páginasImportancia: La eficacia de la vitamina C para pacientes hospitalizados con COVID-19 es incierta. Objetivo: Determinar si la vitamina C mejora los resultados de los pacientes con COVID-19. Diseño, entorno y participantes: Dos ensayos clínicos aleatorizados armonizados prospectivamente reclutaron a pacientes gravemente enfermos que recibían apoyo orgánico en unidades de cuidados intensivos (90 sitios) y a pacientes que no estaban gravemente enfermos (40 sitios) entre el 23 de julio de 2020 y el 15 de julio de 2022, en 4 continentes. Intervenciones: Los pacientes fueron aleatorizados para recibir vitamina C administrada por vía intravenosa o control (placebo o ninguna vitamina C) cada 6 horas durante 96 horas (máximo de 16 dosis). Principales resultados y medidas: El resultado primario fue una combinación de días sin soporte orgánico definidos como días vivos y sin soporte orgánico respiratorio y cardiovascular en la unidad de cuidados intensivos hasta el día 21 y supervivencia hasta el alta hospitalaria. Los valores variaron desde -1 día sin soporte orgánico para pacientes que experimentaron muerte intrahospitalaria hasta 22 días sin soporte orgánico para aquellos que sobrevivieron sin necesitar soporte orgánico. El análisis primario utilizó un modelo logístico acumulativo bayesiano. Un odds ratio (OR) mayor que 1 representó eficacia (supervivencia mejorada, más días sin soporte orgánico o ambos), un OR menor que 1 representó daño y un OR menor que 1,2 representó futilidad. Resultados: Se dio por finalizada la inscripción después de que se cumplieran los factores estadísticos desencadenantes de daño y futilidad. Los ensayos tenían datos de resultados primarios para 1568 pacientes en estado crítico (1037 en el grupo de vitamina C y 531 en el grupo de control; edad media, 60 años [RIC, 50-70 años]; 35,9% eran mujeres) y 1022 pacientes que no estaban en estado crítico (456 en el grupo de vitamina C y 566 en el grupo de control; edad media, 62 años [RIC, 51-72 años]; 39,6% eran mujeres). Entre los pacientes gravemente enfermos, la mediana del número de días sin soporte orgánico fue de 7 (RIC: -1 a 17 días) para el grupo de vitamina C frente a 10 (RIC: -1 a 17 días) para el grupo de control (OR proporcional ajustado, 0,88 [intervalo de credibilidad del 95 % {ICr}, 0,73 a 1,06]) y las probabilidades posteriores fueron del 8,6 % (eficacia), el 91,4 % (daño) y el 99,9 % (inutilidad). Entre los pacientes que no estaban gravemente enfermos, la mediana del número de días sin soporte orgánico fue de 22 (RIC, 18 a 22 días) para el grupo de vitamina C frente a 22 (RIC, 21 a 22 días) para el grupo de control (OR proporcional ajustado, 0,80 [ICr del 95 %, 0,60 a 1,01]) y las probabilidades posteriores fueron del 2,9 % (eficacia), del 97,1 % (daño) y superiores al 99,9 % (futilidad). Entre los pacientes gravemente enfermos, la supervivencia hasta el alta hospitalaria fue del 61,9 % (642/1037) para el grupo de vitamina C frente al 64,6 % (343/531) para el grupo de control (OR ajustado, 0,92 [ICr del 95 %, 0,73 a 1,17]) y la probabilidad posterior fue del 24,0 % para la eficacia. Entre los pacientes que no estaban gravemente enfermos, la supervivencia hasta el alta hospitalaria fue del 85,1% (388/456) para el grupo de vitamina C frente al 86,6% (490/566) para el grupo de control (OR ajustado, 0,86 [ICr del 95%, 0,61 a 1,17]) y la probabilidad posterior fue del 17,8% para la eficacia. Conclusiones y relevancia: En pacientes hospitalizados con COVID-19, la vitamina C tuvo baja probabilidad de mejorar el resultado compuesto primario de días sin soporte orgánico y supervivencia hospitalaria

Intravenous Vitamin C for Patients Hospitalized with COVID-19

Importance:The efficacy of vitamin C for hospitalized patients with COVID-19 is uncertain.Objective:To determine whether vitamin C improves outcomes for patients with COVID-19.Design, Setting, and Participants:Two prospectively harmonized randomized clinical trials enrolled critically ill patients receiving organ support in intensive care units (90 sites) and patients who were not critically ill (40 sites) between July 23, 2020, and July 15, 2022, on 4 continents.Interventions:Patients were randomized to receive vitamin C administered intravenously or control (placebo or no vitamin C) every 6 hours for 96 hours (maximum of 16 doses).Main Outcomes and Measures:The primary outcome was a composite of organ support–free days defined as days alive and free of respiratory and cardiovascular organ support in the intensive care unit up to day 21 and survival to hospital discharge. Values ranged from –1 organ support–free days for patients experiencing in-hospital death to 22 organ support–free days for those who survived without needing organ support. The primary analysis used a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented efficacy (improved survival, more organ support–free days, or both), an OR less than 1 represented harm, and an OR less than 1.2 represented futility.Results:Enrollment was terminated after statistical triggers for harm and futility were met. The trials had primary outcome data for 1568 critically ill patients (1037 in the vitamin C group and 531 in the control group; median age, 60 years [IQR, 50-70 years]; 35.9% were female) and 1022 patients who were not critically ill (456 in the vitamin C group and 566 in the control group; median age, 62 years [IQR, 51-72 years]; 39.6% were female). Among critically ill patients, the median number of organ support–free days was 7 (IQR, −1 to 17 days) for the vitamin C group vs 10 (IQR, −1 to 17 days) for the control group (adjusted proportional OR, 0.88 [95% credible interval {CrI}, 0.73 to 1.06]) and the posterior probabilities were 8.6% (efficacy), 91.4% (harm), and 99.9% (futility). Among patients who were not critically ill, the median number of organ support–free days was 22 (IQR, 18 to 22 days) for the vitamin C group vs 22 (IQR, 21 to 22 days) for the control group (adjusted proportional OR, 0.80 [95% CrI, 0.60 to 1.01]) and the posterior probabilities were 2.9% (efficacy), 97.1% (harm), and greater than 99.9% (futility). Among critically ill patients, survival to hospital discharge was 61.9% (642/1037) for the vitamin C group vs 64.6% (343/531) for the control group (adjusted OR, 0.92 [95% CrI, 0.73 to 1.17]) and the posterior probability was 24.0% for efficacy. Among patients who were not critically ill, survival to hospital discharge was 85.1% (388/456) for the vitamin C group vs 86.6% (490/566) for the control group (adjusted OR, 0.86 [95% CrI, 0.61 to 1.17]) and the posterior probability was 17.8% for efficacy.Conclusions and Relevance:In hospitalized patients with COVID-19, vitamin C had low probability of improving the primary composite outcome of organ support–free days and hospital survival.Trial Registration:ClinicalTrials.gov Identifiers: NCT04401150 (LOVIT-COVID) and NCT02735707 (REMAP-CAP)

Does intensive insulin therapy really reduce mortality in critically ill surgical patients? A reanalysis of meta-analytic data

Two recent systematic reviews evaluating intensive insulin therapy (IIT) in critically ill patients grouped randomized controlled trials (RCTs) by type of intensive care unit (ICU). The more recent review found that IIT reduced mortality in patients admitted to a surgical ICU, but not in those admitted to medical ICUs or mixed medical-surgical ICUs, or in all patients combined. Our objective was to determine whether IIT saves lives in critically ill surgical patients regardless of the type of ICU. Pooling mortality data from surgical and medical subgroups in mixed-ICU RCTs (16 trials) with RCTs conducted exclusively in surgical ICUs (five trials) and in medical ICUs (five trials), respectively, showed no effect of IIT in the subgroups of surgical patients (risk ratio = 0.85, 95% confidence interval (CI) = 0.69 to 1.04, P = 0.11; I2 = 51%, 95% CI = 1 to 75%) or of medical patients (risk ratio = 1.02, 95% CI = 0.95 to 1.09, P = 0.61; I2 = 0%, 95% CI = 0 to 41%). There was no differential effect between subgroups (interaction P = 0.10). There was statistical heterogeneity in the surgical subgroup, with some trials demonstrating significant benefit and others demonstrating significant harm, but no surgical subgroup consistently benefited from IIT. Such a reanalysis suggests that IIT does not reduce mortality in critically ill surgical patients or medical patients. Further insights may come from individual patient data meta-analyses or from future large multicenter RCTs in more narrowly defined subgroups of surgical patients

Rosiglitazone: can meta-analysis accurately estimate excess cardiovascular risk given the available data? Re-analysis of randomized trials using various methodologic approaches

<p>Abstract</p> <p>Background</p> <p>A recent and provocative meta-analysis, based on few outcome events, suggested that rosiglitazone increased cardiovascular mortality and myocardial infarction. However, results of meta-analyses of trials with sparse events, often performed when examining uncommon adverse effects due to common therapies, can vary substantially depending on methodologic decisions. The objective of this study was to assess the robustness of the rosiglitazone results by using alternative reasonable methodologic approaches and by analyzing additional related outcomes.</p> <p>Findings</p> <p>In duplicate and independently, we abstracted all myocardial and cerebrovascular ischemic events from all randomized controlled trials listed on the manufacturer's web site meeting inclusion criteria of the original meta-analysis (at least 24 weeks of rosiglitazone exposure in the intervention group and any control group without rosiglitazone). We performed meta-analyses of these data under different methodologic conditions. An unconfounded comparison that includes only trials (or arms of trials) in which medications apart from rosiglitazone are identical suggests higher risks than previously reported, making even the risk of cardiovascular death statistically significant. Alternatively, meta-analysis that includes all trials comparing a treatment arm receiving rosiglitazone to any control arm without rosiglitazone (as in the original meta-analysis) but also including trials with no events in both the rosiglitazone and control arms (not incorporated in the original meta-analysis), shows adverse but non-statistically significant effects of rosiglitazone on myocardial infarction and cardiovascular mortality. Rosiglitazone appears to have inconsistent effects on a wider range of cardiovascular outcomes. It increases the risk of a broad range of myocardial ischemic events (not just myocardial infarction). However, its effect on cerebrovascular ischemic events suggests benefit, although far from statistically significant.</p> <p>Conclusion</p> <p>We have shown that alternative reasonable methodological approaches to the rosiglitazone meta-analysis can yield increased or decreased risks that are either statistically significant or not significant at the p = 0.05 level for both myocardial infarction and cardiovascular death. Completion of ongoing trials may help to generate more accurate estimates of rosiglitazone's effect on cardiovascular outcomes. However, given that almost all point estimates suggest harm rather than benefit and the availability of alternative agents, the use of rosiglitazone may greatly decline prior to more definitive safety data being generated.</p

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors