Revisión sistemática y metaanálisis de inhibidores de interleucina-6 para reducir la mortalidad en pacientes hospitalizados con COVID

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.

Systematic review and meta-analysis of interleulin-6 inhibitors in reducing mortality for hospitalized patients with COVID-19

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 unclear. 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 inhibitor (hazard ratio 0.85;confidence interval 95% 0.74-0.99), low heterogeneity (I-2 = 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 patients at high mortality risk, are needed to confirm the benefit of interleukine-6 inhibitors for COVID-19. Sarilumab was underrepresented in the meta-analysis.

Factores asociados a la mortalidad en pacientes hospitalizados por COVID-19 en España. Datos del Registro Español de Resultados de Farmacoterapia frente a COVID-19 (RERFAR)

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.

Factors associated with mortality in patients hospitalized for COVID-19 in Spain. Data from the RERFAR registry

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.

Efficacy of early use of remdesivir: a systematic review of subgroup analysis.

OBJECTIVE: A possible benefit has been suggested for early treatment of severe coronavirus disease 2019 (COVID-19) with remdesivir. The efficacy of this drug is controversial and could significantly influence the efficiency in healthcare systems. The objective is the methodological interpretation of subgroup analyzes according to starting of remdesivir treatment with respect to symptom onset of COVID-19. METHODS: A search in Pubmed® database was performed. Randomized clinical trials (RCTs) with subgroup analysis regarding early and late use of remdesivir were selected. All endpoints were assessed using two methodologies. First methodology considered statistical interaction, pre-specification, biological plausibility, and consistency of results. Second methodology was a validated tool with preliminary questions to discard subset analysis without relevant minimum conditions, and a checklist with recommendations for applicability. RESULTS: A total of 54 results were found and five RCTs were selected. According first methodology, consistent heterogeneity was only found in time to clinical improvement and better clinical status score at day 15 for patients with severe COVID-19 and <7 days of symptoms. About second methodology, these results about early use of remdesivir may be applied to clinical practice with caution. CONCLUSIONS: We developed a systematic search and application of an established methodology for interpretation of subgroup analysis about early use of remdesivir. Results in severe COVID-19 suggested that early use of remdesivir provides a greater benefit in <7 days of symptoms for time to clinical improvement and better clinical status score at day 15. Future studies could use 7-day cut-off of symptoms to evaluate remdesivir.

Impact of the COVID-19 pandemic on clinical lung cancer management

Background and importance The SARS-CoV-2 pandemic could have changed the clinical management of cancer patients because of travel restrictions, overloading of hospital systems and disruption of treatment. Lung cancer patients constitute a vulnerable population due to the particular risk of their disease, chemotherapy or immunotherapy. Aim and objectives To analyse disease management and the clinical impact of the COVID-19 pandemic on non-small cell lung cancer (NSCLC) patients receiving intravenous treatment during the social isolation period compared with the normal situation. Material and methods This retrospective observational cohort study included a 2:1 random sample of NSCLC patients in the 'COVID cohort' (patients in isolation February 2020 to June 2020) and the 'no COVID cohort' (patients treated between February 2019 and June 2019). Collected variables from digital clinical history were age, sex, stage, previous lines, type of treatment, number of medical visits and telephone consults, cycles received, worsening of performance status (PS), respiratory infection (COVID-19 and others), delays, therapeutic rest break, disease progression and deaths. Results COVID cohort (CC): 40 patients, 31 (78%) men;mean 67 years (59-84). Cancer stage: IV (69%), IIIB (28%), IIIA (2%) and IIIC (1%). 12 (30%) patients had not received lines previously. 38% of the population received immunotherapy. Median number of medical visits was 3 (14-1) and median number of telephone consults was 3 (1-8). Median number of cycles was 4 (1-16). PS 0 (58%) and PS 1 (42%). No patient had COVID-19. No COVID cohort' (NCC): 20 patients, 15 (75%) men, mean 67 years (54-85). Cancer stage: stage IV (75%), IIIB (25%). All patients had received lines previously and none had received immunotherapy. Median medical visits was 7 (3- 11) with no telephone consults. Median number of cycles was 3 (1-11). PS 0 (70%) and PS1-2 (30%). The rest of the variables are shown in table 1. Conclusion and relevance In spite of the limitations of the study, the new strategies of clinical management during the COVID-19 pandemic (telephone consults and therapeutic tire) did not appear to affect disease progression and NSCLC patient survival although worsening of performance status was observed.

Subgroup analysis about efficacy of early use of remdesivir in COVID-19

Background and importance A greater benefit was suggested with early treatment with remdesivir against COVID-19. Aim and objectives To develop a systematic review and methodological interpretation of subgroup analyses according to timing of use of remdesivir in COVID-19. Material and methods A bibliographic review in MEDLINE was conducted up to 10 October 2020. The 'Clinical Queries/ Narrow' tool was used with the search strategy: ((Therapy/ Narrow[filter]) AND (remdesivir AND COVID)). Randomised clinical trials (RCTs) with subset analysis about early and late use of remdesivir (≤10 vs >10 days from symptom onset, or ≤9 vs >9 days) were selected. The rest of the studies were excluded. All endpoints with subgroup analysis regarding timing of remdesivir use were assessed. Two methodologies were applied. The first considered statistical interaction among subsets, prespecification, biological plausibility and consistency of the subgroup analyses of similar RCTs.1 The second methodology was a validated tool with preliminary questions to discard subset analysis without minimal relevance, and a checklist.2 This checklist assigned a score related to a recommendation for applicability of subgroup analysis in clinical practice. Results 20 results were found after review;16 studies were excluded because they were not RCTs and 1 study had no efficacy evaluation of remdesivir. Therefore, three RCTs were selected. Endpoints considered were: time to clinical improvement, mortality, viral load, and clinical status at days 11 and 15. According to the first methodology, no statistical interaction was observed in the outcomes of the RCTs. Prespecification was established in time to clinical improvement, and clinical status at day 15 of an RCT. Biological plausibility was described in the subset analysis of each endpoint of the RCTs. No consistency of subgroup analyses were found. The second methodology discarded the applicability of the subset analysis through preliminary questions in two RCTs because of the absence of minimal relevance. For the third RCT, 'null' recommendation (score -3 points) of clinical applicability was reached for clinical status at day 11. Conclusion and relevance No differences were found between early and late use of remdesivir in COVID-19. We developed the first study with a systematic review and methodology about subgroup analysis of timing of use of remdesivir.

4CPS-296 Impact of the COVID-19 pandemic on clinical lung cancer management

4CPS-296 Table 1CC (%) NCC (%) RAR 30% (95% CI) p value Worsening PS 30 0 15.8 to 44.2 <0.05Therapeutic rest break 35 0 20.2 to 49.7 <0.05 Delays 100 30 −90.1 to −49.9 <0.05 Respiratory infections 10 15 −13.2 to 23.2 >0.05 Disease progression 30 45 −11.2 to 41.2 >0.05 Deaths 18 25 −14.8 to 29.8 >0.05 Conclusion and relevanceIn spite of the limitations of the study, the new strategies of clinical management during the COVID-19 pandemic (telephone consults and therapeutic tire) did not appear to affect disease progression and NSCLC patient survival although worsening of performance status was observed.References and/or acknowledgementsConflict of interestNo conflict of interest