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OBJECTIVE: One year after the declaration of the SARS-CoV-2 pandemic, only dexamethasone has clearly shown a reduction in mortality for COVID-19 hospitalized patients. For interleukin-6 inhibitors, results are variable and nclear. The objective was to review and analyze the effect of tocilizumab and sarilumab on survival in this setting. METHOD: The PRISMA statements were fulfilled for the systematic review. A systematic search in Medline, Embase and medRxiv was conducted to identify randomized controlled trials with tocilizumab or sarilumab in hospitalized patients with COVID-19. Mortality data from non-critical and critical patients were extracted. A random-effects (DerSimonian-Laird) meta-analysis was performed for both subgroups and the whole population using MAVIS software v. 1.1.3. Similarity and homogeneity among trials were assessed. RESULTS: Twenty-five and 23 articles were identified in Medline and Embase, respectively, five were trials with tocilizumab and/or sarilumab; two more were identified at medRxiv. Seven randomized clinical trials fulfilled the inclusion criteria. Another trial was pre-published and included post-hoc. The meta-analysis, with eight randomized clinical trials and 6,340 patients, showed a benefit on mortality for interleukin-6 heterogeneity (I2 = 7%), but a low similarity among studies. The results showed no differences among critical and non-critical patients. A sensitivity analysis excluding non-similar or heterogeneous studies showed different results, without benefit and with low precision of the result in non-critical patients. CONCLUSIONS: A benefit in mortality for interleukine-6 inhibitors was found, but with important differences among the scenarios analyzed in the clinical trials. Positive results are mainly caused by two randomized clinical trials which are similar in concomitant use of steroids and veryhigh mortality in critical patents. Sarilumab was poorly represented in the meta-analysis. Nevertheless, an association between the benefit and the critical/non-critical condition was not found. More randomized clinical trials, mainly focused in atients at high mortality risk, are needed to confirm the benefit of interleukine- 6 inhibitors for COVID-19. Sarilumab was underrepresented in the meta- analysis. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved. OBJETIVO: Un año después de la declaración de la pandemia por SARS‑CoV-2, solo dexametasona había mostrado claramente una reducción de la mortalidad en pacientes hospitalizados por COVID-19. Los resultados de los inhibidores de interleucina 6 son diversos y poco claros. El objetivo de este trabajo es revisar y analizar el efecto de tocilizumab y sarilumab sobre la supervivencia de los pacientes en este escenario.Método: La revisión sistemática siguió las recomendaciones de PRISMA. Se realizó una búsqueda sistemática en Medline, Embase y medRxiv para identificar ensayos controlados aleatorizados con tocilizumab o sarilumab en pacientes hospitalizados con COVID-19. Se recopilaron los datos de mortalidad de pacientes críticos y no críticos y se llevó a cabo un metaanálisis de efectos aleatorios (Der Simonian-Laird) para ambos subgrupos y para toda la población, usando el software MAVIS v. 1.1.3. La similitud y homogeneidad entre los ensayos fue evaluada. RESULTADOS: Se identificaron 25 y 23 artículos en Medline y Embase, respectivamente;cinco eran ensayos con tocilizumab y/o sarilumab; se identificaron dos más en medRxiv. En total, siete ensayos clínicos aleatorizados cumplieron los criterios de inclusión. Posteriormente, se prepublicó otro ensayo que cumplía los criterios de inclusión y se incorporó al análisis. El metaanálisis, con ocho ensayos clínicos aleatorizados y 6.340 pacientes, mostró un beneficio sobre la mortalidad para los inhibidores de interleucina-6 (hazard ratio 0,85;intervalo de confianza al 95% 0,74-0,99), con baja h terogeneidad (I2 = 7%), pero reducida similitud entre los estudios. Los resultados no mostraron diferencias entre pacientes críticos y no críticos. Un análisis de sensibilidad excluyendo estudios heterogéneos o no similares mostró resultados diferentes, sin beneficio y con baja precisión del resultado en pacientes no críticos. CONCLUSIONES: Se encontró un beneficio en la mortalidad de los inhibidores de la interleucina 6, pero con importantes diferencias entre los escenarios analizados en los ensayos clínicos. Los resultados positivos se eben principalmente a dos ensayos que son similares en el uso concomitante de esteroides y una mortalidad muy alta en pacientes críticos. Sarilumab estuvo escasamente representado en el metaanálisis. Sin embargo, el metaanálisis por subescenarios no encontró una relación entre el beneficio y la condición de pacientes críticos/no críticos. Se necesitan más ensayos clínicos aleatorizados, principalmente enfocados en pacientes con alto riesgo de mortalidad, para confirmar el beneficio de los inhibidores de interleucina-6 en COVID-19.
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6ER-022 Table 1Odds ratio results from logistic regression analysisFactor OR Lower 95% CI Upper 95%CI Factor OR Lower 95% CI Upper 95%CI A02B 1.46 0.427 4.991 N02B 0.814 0.513 1.291 A10B 1.246 0.816 1.904 N03A 0.715 0.443 1.154 A11C 0.875 0.535 1.431 N05A* 0.353 0.137 0.91 A12A 1.192 0.73 1.948 N05B 0.98 0.649 1.482 B01A* 1.95 1.004 3.824 N06A 1.002 0.671 1.497 C03C 1.088 0.72 1.642 R03A 0.997 0.628 1.583 C07A 1.206 0.8 1.818 R03B 0.881 0.541 1.435 C10A 0.988 0.626 1.561 Total prescribed drugs* 1.182 1.078 1.297 H02A 0.875 0.431 1.778 Gender 1.011 0.651 1.57 M05B 1.016 0.581 1.776 Age 1.022 0.991 1.054 N02A 0.819 0.524 1.279 CI, confidence interval;OR, odds ratio. *p<0.05.Conclusion and relevanceIn this preliminary analysis of 930 PEP, B01A (antithrombotic drugs) and a number of total prescribed drugs were SS factor associated with a higher risk of admission, meanwhile N05A (antipsychotics) showed a protective trend.References and/or acknowledgementsConflict of interestNo conflict of interest
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OBJECTIVE: To determine the baseline characteristics associated with higher mortality at 42 days in patients hospitalized for COVID-19 in Spain. METHOD: The study analyzed a prospective cohort of hospitalized COVID-19 patients. The dependent variable was 42-day mortality. Data on the subjects' demographic and clinical characteristics, comorbidities, usual therapy and supportive interventions and treatments was collected within 48 hours from admission. To determine the potential association of the data with mortality, a multivariate analysis was performed using logistic regression. RESULTS: 15,628 patients were included, 18.2% of whom (n = 2,806) died during the study period. According to the multivariate analysis, the variables that were significantly associated (p < 0.05) with mortality upon admission were: being referred from a nursing home (OR 1.9);having a high respiratory rate (OR 1,5);having moderate (OR 1.7) or severe (OR 2.9) pneumonia (CURB-65);aspartate aminotransferase transaminase ≥ 100 IU/l (OR 2.1); lactate dehydrogenase ≥ 360 IU/L (OR 1.6);procalcitonin > 0.5 ng/mL (OR 1.8);creatine kinase ≥ 294 U/L (OR 1.5);D-dimer > 3,000 ng/mL (OR 1.5); hemoglobin < 11.6 g/dL (OR 1.4) and C-reactive protein > 120 mg/L (OR 1.2; requiring respiratory support within the first 48 hours (oxygen therapy [OR 2.0], non-invasive ventilation [OR 2.8], and mechanical ventilation [OR 3.5]); and being treated with interferon-beta (OR 1.5). On the contrary, being under 80 years of age was associated with lower mortality. CONCLUSIONS: The analysis, based on the data in the RERFAR registry, showed that the factors associated with poorer prognosis were older age, assessed using the CURB-65 scale, level of respiratory support required, severe pneumonia (CURB-65), hypertransaminasemia, elevated creatine kinase, lactate dehydrogenase, and D-dimer levels, anemia, and elevated respiratory rate. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved. OBJETIVO: Determinar las características basales que se asocian a una mayor mortalidad a los 42 días en aquellos pacientes hospitalizados por COVID-19 en España.Método: Cohorte prospectiva de pacientes COVID-19 hospitalizados. La variable dependiente fue la mortalidad a los 42 días. Además, se recogieron características demográficas, clínicas, comorbilidades, tratamiento habitual, intervenciones de soporte y tratamientos en las primeras 48 horas del ingreso. Para determinar la asociación con la mortalidad, se realizó un análisis multivariante mediante regresión logística. Resultados: Se incluyeron 15.628 pacientes, de ellos falleció el 18,2% (n = 2.806). El análisis multivariante mostró que las variables asociadas significativamente (p < 0,05) con la mortalidad al ingreso fueron: proceder de un centro sociosanitario (odds ratio OR 1,9), frecuencia respiratoria (odds ratio 1,5), gravedad de neumonía (CURB-65) moderada (odds ratio 1,7) o alta (odds ratio 2,9), transaminasa aspartato aminotransferasa ≥ 100 UI/l (odds ratio 2,1), lactato-deshidrogenasa ≥ 360 UI/l (odds ratio 1,6), procalcitonina > 0,5 ng/ml (odds ratio 1,8), creatina- quinasa ≥ 294 U/l (odds ratio 1,5), dímero D > 3.000 ng/ml (odds ratio 1,5), hemoglobina < 11,6 g/dl (odds ratio 1,4) y proteína C reactiva > 120 mg/l (odds ratio 1,2), necesidad de soporte respiratorio en las primeras 48 horas (odds ratio 2,0 de oxigenoterapia;odds ratio 2,8 ventilación no invasiva y odds ratio 3,5 ventilación mecánica) y tratamiento con interferón-beta (odds ratio 1,5). Por el contrario, ser menor de 80 años se asoció a una menor mortalidad. Conclusiones: El análisis del Registro Español de Resultados de farmacoterapia frente a COVID-19 muestra que los factores asociados a peor pronóstico son: mayor edad, valoración mediante la escala CURB‑65, el nivel de requerimiento de soporte respiratorio, neumonía grave (CURB‑65), hipertransaminasemia, elevación de creatina-quinasa, lactato- deshidrogenasa, y dímero-D, anemia y elevación de la frecuencia respiratoria.
ABSTRACT
Objective: To determine the baseline characteristics associated with higher mortality at 42 days in patients hospitalized for COVID-19 in Spain. Method: The study analyzed a prospective cohort of hospitalized COVID-19 patients. The dependent variable was 42-day mortality. Data on the subjects' demographic and clinical characteristics, comorbidities, usual therapy and supportive interventions and treatments was collected within 48 hours from admission. To determine the potential association of the data with mortality, a multivariate analysis was performed using logistic regression. Results: 15,628 patients were included, 18.2% of whom (n = 2,806) died during the study period. According to the multivariate analysis, the variables that were significantly associated (p < 0.05) with mortality upon admission were: being referred from a nursing home (OR 1.9);having a high respiratory rate (OR 1,5);having moderate (OR 1.7) or severe (OR 2.9) pneumonia (CURB-65);aspartate aminotransferase transami- nase >= 100 IU/l (OR 2.1);lactate dehydrogenase >= 360 IU/L (OR 1.6);procalcitonin > 0.5 ng/mL (OR 1.8);creatine kinase >= 294 U/L (OR 1.5);D-dimer > 3,000 ng/mL (OR 1.5);hemoglobin < 11.6 g/dL (OR 1.4) and C-reactive protein > 120 mg/L (OR 1.2;requiring respiratory support within the first 48 hours (oxygen therapy [OR 2.0], non-invasive ventilation [OR 2.8], and mechanical ventilation [OR 3.5]);and being treated with interferon-beta (OR 1.5). On the contrary, being under 80 years of age was associated with lower mortality. Conclusions: The analysis, based on the data in the RERFAR registry, showed that the factors associated with poorer prognosis were older age, assessed using the CURB-65 scale, level of respiratory support required, severe pneu-monia (CURB-65), hypertransaminasemia, elevated creatine kinase, lactate and D-dimer levels, anemia, and elevated rate.