Baricitinib reduces 30-day mortality in older adults with moderate-to-severe COVID-19 pneumonia.

BACKGROUND: Older adults are at the highest risk of severe disease and death due to COVID-19. Randomized data have shown that baricitinib improves outcomes in these patients, but focused stratified analyses of geriatric cohorts are lacking. Our objective was to analyze the efficacy of baricitinib in older adults with COVID-19 moderate-to-severe pneumonia. METHODS: This is a propensity score [PS]-matched retrospective cohort study. Patients from the COVID-AGE and Alba-Score cohorts, hospitalized for moderate-to-severe COVID-19 pneumonia, were categorized in two age brackets of age <70 years old (86 with baricitinib and 86 PS-matched controls) or ≥70 years old (78 on baricitinib and 78 PS-matched controls). Thirty-day mortality rates were analyzed with Kaplan-Meier and Cox proportional hazard models. RESULTS: Mean age was 79.1 for those ≥70 years and 58.9 for those <70. Exactly 29.6% were female. Treatment with baricitinib resulted in a significant reduction in death from any cause by 48% in patients aged 70 or older, an 18.5% reduction in 30-day absolute mortality risk (n/N: 16/78 [20.5%] baricitinib, 30/78 [38.5%] in PS-matched controls, p < 0.001) and a lower 30-day adjusted fatality rate (HR 0.21; 95% CI 0.09-0.47; p < 0.001). Beneficial effects on mortality were also observed in the age group <70 (8.1% reduction in 30-day absolute mortality risk; HR 0.14; 95% CI 0.03-0.64; p = 0.011). CONCLUSIONS: Baricitinib is associated with an absolute mortality risk reduction of 18.5% in adults older than 70 years hospitalized with COVID-19 pneumonia.

JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality.

Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.

Evaluation of non-HDL cholesterol as a predictor of non-fatal cardiovascular events in a prospective population cohort. / Valoración del colesterol no HDL como predictor de episodios cardiovasculares no mortales en una cohorte prospectiva de origen poblacional.

INTRODUCTION: Non-HDL cholesterol (non-HDL-C) is becoming relevant both in its participation in cardiovascular risk assessment and as a therapeutic target. The objective of the present study was to assess the independent predictive capacity of both non-HDL-C and LDL-C (the main priority in dyslipidemias to reduce cardiovascular risk), in cardiovascular morbidity in a population-based sample. METHODS: A prospective cohort study involving 1186 individuals in the non-HDL-C group and 1177 in the LDL-C group, followed for 10.7years (SD=2.2), who had not had any previous cardiovascular event. The predictor variables included in the adjustment were: gender, age, arterial hypertension, diabetes mellitus, smoker status and non-HDL-C in one group. In the other group, consisting of patients presenting TG levels of 400mg/dL, non-HDL-C was replaced by LDL-C. Survival curves (Kaplan-Meier) were calculated and two Cox regression models were applied, one for each group. RESULTS: Non-HDL-C group presented 6.2% of non-fatal cardiovascular episodes during follow-up and the LDL-C group 6.0%. After adjustment, for each 30mg/dL increase in non-HDL-C, the incidence of new non-fatal cardiovascular events increased by 31% (HR=1.31, 95%CI: 1.06-1.61; P=.018) and in the LDL-C group by 27% (HR=1.27, 95%CI: 0.97-1.61, P=.068). CONCLUSIONS: After a follow-up of 10.7years, non-HDL-C has been shown in our population as a prognostic factor of non-fatal cardiovascular disease, but not LDL-C, although its HR is close to statistical significance.

[Relationship between inflammation marker and all-cause and cardiovascular mortality in a prospective cohort study]. / Relación entre el proceso inflamatorio y la mortalidad de origen cardiovascular y por todas las causas en un estudio de cohortes prospectivo de base poblacional.

INTRODUCTION: Inflammation is present in every stage of the atherosclerosis process, therefore, inflammation hallmarks such as the fibrinogen can be related to the complications in which it intervenes, mortality is one of them. The objective of this study is to assess the association of the fibrinogen with all-cause mortality in men from general population sample obtained by random sampling in the Spanish region of Albacete. METHODS: A total of 506men without cardiovascular events with 10.6years (SD=2.3) of follow-up, volunteered to participate in a prospective cohort study. The assessment of the fibrinogen as a predictor variable has been calculated after adjusting it by age, hypertension, diabetes mellitus, obesity, total cholesterol, HDL-cholesterol/triglycerides ratio, and smoking habit applying a Cox regression model. The adjustment has been made by adding the fibrinogen to the model, as a qualitative variable (<400 and ≥400mg/dl). RESULTS: The average age of the participants was 46.6years old (DE=16.8). After the adjustment, the hyperfibrinogenemia (≥400mg/dl) showed a hazard ratio (HR) for all-cause mortality of 1.85 (95%CI: 1.05-3.26) and for cardiovascular mortality HR=2.69 (95%CI: 1.09-6.63). CONCLUSIONS: In men without cardiovascular events of our study, fibrinogen was showed as an independent predictor of all-cause mortality and cardiovascular mortality.