Angiotensin-converting-enzyme inhibitors and angiotensin II receptor blockers for COVID-19: A living systematic review of randomized clinical trials.

OBJECTIVE: This living systematic review aims to provide a timely, rigorous, and continuously updated summary of the evidence available on the role of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) in the treatment of patients with COVID-19. DATA SOURCES: We conducted searches in PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), grey literature and in a centralized repository in L·OVE (Living OVerview of Evidence), which retrieves articles from multiple sources such as PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, Embase, among other pre-print and protocols repositories. In response to the COVID-19 emergency, L·OVE (Living OVerview of Evidence) was adapted to expand the range of evidence and customized to group all COVID-19 evidence in one place on a daily search basis. The search covered a period of time up to July 31, 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES AND METHODS: We adapted an already published standard protocol for multiple parallel living systematic reviews to this question's specificities. We included randomized trials evaluating the effect of either suspension or indication of angiotensin-converting-enzyme inhibitors or angiotensin II receptor blockers as monotherapy, or in combination versus placebo or no treatment in patients with COVID-19. We searched for randomized trials evaluating the effect of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers versus placebo or no treatment in patients with COVID-19. Two reviewers independently screened each study for eligibility, extracted data, and assessed the risk of bias. We pooled the results using meta-analysis and applied the GRADE system to assess the certainty of the evidence for each outcome. We will resubmit results every time the conclusions change or whenever there are substantial updates. RESULTS: We screened 772 records, but none was considered for eligibility. We identified 55 ongoing studies, including 41 randomized trials evaluating angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers for patients with COVID-19. CONCLUSIONS: We did not find a randomized clinical trial meeting our inclusion criteria, and hence there is no evidence for supporting the role of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in the treatment of patients with COVID-19. A substantial number of ongoing studies would provide valuable evidence to inform researchers and decision-makers in the near future. PROSPERO REGISTRATION NUMBER: CRD42020182495. PROTOCOL PREPRINT DOI: 10.31219/osf.io/vp9nj.

OBJETIVO: Esta revisión sistemática viva tiene como objetivo proporcionar un resumen oportuno, riguroso y continuamente actualizado de la evidencia disponible sobre el rol de los inhibidores de la enzima convertidora de angiotensina (iECA) y los bloqueadores del receptor de angiotensina II (ARA-II) en el tratamiento de pacientes con COVID-19. FUENTES DE DATOS: Realizamos búsquedas en PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), literatura gris y en el repositorio centralizado L·OVE (Living OVerview of Evidence) que recupera artículos de múltiples fuentes como PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, Embase, entre otros repositorios de preprints y protocolos. En respuesta a la emergencia de COVID-19, L·OVE (Living OVerview of Evidence) se adaptó para ampliar el rango de información que cubre y se personalizó para agrupar toda la evidencia en torno a COVID-19 en un solo lugar, en una base de búsqueda diaria. La búsqueda cubrió el período hasta el 31 de julio de 2020. CRITERIOS DE ELEGIBILIDAD PARA LA SELECCIÓN DE ESTUDIOS Y MÉTODOS: Adaptamos un protocolo común ya publicado para múltiples revisiones sistemáticas vivas paralelas a las especificidades de esta pregunta. Se incluyeron ensayos aleatorizados que evaluaban el efecto de la suspensión o la indicación de inhibidores de la enzima convertidora de angiotensina o bloqueadores de los receptores de angiotensina II, como monoterapia o en combinación, versus placebo o ningún tratamiento, en pacientes con COVID-19. Se buscaron ensayos aleatorizados que evaluaran el efecto de los inhibidores de la enzima convertidora de angiotensina/bloqueadores del receptor de angiotensina II versus placebo o ningún tratamiento en pacientes con COVID-19. Dos revisores examinaron de forma independiente la elegibilidad de cada estudio, extrajeron los datos y evaluaron el riesgo de sesgo. Los resultados se agruparon mediante un metanálisis y se aplicó GRADE para evaluar la certeza de la evidencia para cada resultado. Cada vez que cambien las conclusiones o hayan actualizaciones sustanciales, volveremos a enviar un reporte. RESULTADOS: Analizamos 772 artículos, pero ninguno cumplió con los criterios de inclusión. Identificamos 55 estudios en curso, incluidos 41 ensayos aleatorizados que evaluaban inhibidores de la enzima convertidora de angiotensina/bloqueadores del receptor de angiotensina II para pacientes con COVID-19. CONCLUSIONES: No encontramos ningún ensayo clínico aleatorizado que cumpliera con nuestros criterios de inclusión y, por lo tanto, no hay pruebas que respalden el papel de los inhibidores de la enzima convertidora de angiotensina y los bloqueadores de los receptores de angiotensina II en el tratamiento de pacientes con COVID-19. Identificamos un número considerable de estudios en curso que podría proporcionar evidencia valiosa para informar a los investigadores y a los responsables de la toma de decisiones en un futuro próximo.

Macrolides for the treatment of COVID-19: a living, systematic review

OBJETIVO Proporcionar un resumen oportuno, riguroso y continuamente actualizado de la evidencia disponible sobre el papel de los macrólidos para el tratamiento de pacientes con COVID-19. DIDEÑO Revisión Sistemática Viva. BASE DE DATOS: La búsqueda de evidencia se realizó en el repositorio centralizado L·OVE (Living OVerview of Evidence) COVID-19;una plataforma que mapea las preguntas PICO para identificar la evidencia en la base de datos Epistemonikos. En respuesta a la emergencia de COVID-19, L·OVE se adaptó para ampliar el rango de evidencia que cubre y hoy se mantiene a través de búsquedas regulares en 39 bases de datos. MÉTODOS: Se incluyeron estudios experimentales que evaluaban el efecto de los macrólidos, como monoterapia o en combinación con otros fármacos, versus placebo o ningún tratamiento en pacientes con sospecha o confirmación de COVID-19. Se buscó identificar experimentos clínicos aleatorizados que evaluaran macrólidos en infecciones causadas por otros coronavirus, como MERS-CoV y SARS-CoV. Dos revisores examinaron de forma independiente la elegibilidad de cada estudio, extrajeron los datos y evaluaron el riesgo de sesgo. Se evaluó el efecto de los macrólidos sobre la mortalidad por todas las causas;necesidad de ventilación mecánica invasiva;oxigenación por membrana extracorpórea, duración de la estancia hospitalaria, insuficiencia respiratoria, eventos adversos graves, tiempo hasta la negatividad de la RT-PCR del SARS-CoV-2. La certeza de la evidencia para cada desenlace se evaluó siguiendo la aproximación GRADE. Esta revisión se mantendrá viva y disponible abiertamente durante la pandemia de COVID-19. Se someterán actualizaciones de su publicación cada vez que cambien las conclusiones o cuando haya actualizaciones sustanciales. RESULTADOS: Se identificó un experimento clínico aleatorio que evaluó el uso de azitromicina en combinación con hidroxicloroquina en comparación con el uso de hidroxicloroquina sola, en pacientes hospitalizados por COVID 19. Las estimaciones para todos los resultados evaluados resultaron en un poder estadístico insuficiente para llegar a conclusiones válidas. La calidad de la evidencia para los resultados principales fue baja a muy baja. CONCLUSIONES: El uso de macrólidos en el tratamiento de pacientes con COVID 19 no ha mostrado efectos beneficiosos en comparación con el tratamiento estándar. La evidencia para todos los desenlaces no es concluyente. Se necesitan estudios sobre un mayor número de pacientes con COVID 19, para determinar los efectos del uso de macrólidos sobre los desenlaces relacionados con la enfermedad. OBJECTIVE This living, systematic review aims to provide a timely, rigorous, and continuously updated summary of the evidence available on the role of macrolides for treating patients with COVID-19. DESIGN: a living, systematic review. DATABASE: We conducted searches in the centralized repository L·OVE (Living OVerview of Evidence). L·OVE is a platform that maps PICO questions to evidence from the Epistemonikos database. In response to the COVID-19 emergency, L·OVE was adapted to expand the range of evidence it covers and customized to group all COVID-19 evidence in one place. Today it is maintained through regular searches in 39 databases.METHODS: We included randomized trials evaluating the effect of macrolides ­ as monotherapy or in combination with other drugs ­ versus placebo or no treatment in patients with COVID-19. Randomized trials evaluating macrolides in infections caused by other coronaviruses, such as MERS-CoV and SARS-CoV, and non-randomized studies in COVID-19 were searched in case we found no direct evidence from randomized trials. Two reviewers independently screened each study for eligibility, extracted data, and assessed the risk of bias. Measures included all-cause mortality;the need for invasive mechanical ventilation;extracorporeal membrane oxygenation, length of hospital stay, respiratory failure, serious adverse events, time to SARS-CoV-2 RT-PCR negativity. We applied the GRADE approach to assess the certainty of the evidence for each outcome. A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit it every time the conclusions change or whenever there are substantial updates. RESULTS: The search in the L·OVE platform retrieved 424 references. We considered 260 as potentially eligible and were reviewed in full texts. We included one randomized clinical trial that evaluated the use of azithromycin in combination with hydroxychloroquine compared to hydroxychloroquine alone in hospitalized patients with COVID 19. The estimates for all outcomes evaluated resulted in insufficient power to draw conclusions. The quality of the evidence for the main outcomes was low to very low. CONCLUSIONS: Macrolides in the management of patients with COVID 19 showed no beneficial effects compared to standard of care. The evidence for all outcomes is inconclusive. Larger trials are needed to determine the effects of macrolides on pulmonary and other outcomes in COVID-19 patients.

Maternal and perinatal outcomes related to COVID-19 and pregnancy: An overview of systematic reviews.

INTRODUCTION: Evidence about coronavirus disease 2019 (COVID-19) and pregnancy has rapidly increased since December 2019, making it difficult to make rigorous evidence-based decisions. The objective of this overview of systematic reviews is to conduct a comprehensive analysis of the current evidence on prognosis of COVID-19 in pregnant women. MATERIAL AND METHODS: We used the Living OVerview of Evidence (L·OVE) platform for COVID-19, which continually retrieves studies from 46 data sources (including PubMed/MEDLINE, Embase, other electronic databases, clinical trials registries, and preprint repositories, among other sources relevant to COVID-19), mapping them into PICO (population, intervention, control, and outcomes) questions. The search covered the period from the inception date of each database to 13 September 2020. We included systematic reviews assessing outcomes of pregnant women with COVID-19 and/or their newborns. Two authors independently screened the titles and abstracts, assessed full texts to select the studies that met the inclusion criteria, extracted data, and appraised the risk of bias of each included systematic review. We measured the overlap of primary studies included among the selected systematic reviews by building a matrix of evidence, calculating the corrected covered area, and assessing the level of overlap for every pair of systematic reviews. RESULTS: Our search yielded 1132 references. 52 systematic reviews met inclusion criteria and were included in this overview. Only one review had a low risk of bias, three had an unclear risk of bias, and 48 had a high risk of bias. Most of the included reviews were highly overlapped among each other. In the included reviews, rates of maternal death varied from 0% to 11.1%, admission to intensive care from 2.1% to 28.5%, preterm deliveries before 37 weeks from 14.3% to 61.2%, and cesarean delivery from 48.3% to 100%. Regarding neonatal outcomes, neonatal death varied from 0% to 11.7% and the estimated infection status of the newborn varied between 0% and 11.5%. CONCLUSIONS: Only one of 52 systematic reviews had a low risk of bias. Results were heterogeneous and the overlap of primary studies was frequently very high between pairs of systematic reviews. High-quality evidence syntheses of comparative studies are needed to guide future clinical decisions.

Macrolides for the treatment of COVID-19: a living, systematic review. / Macrólidos para el tratamiento de COVID-19: Una revisión sistemática viva.

OBJECTIVE: This living, systematic review aims to provide a timely, rigorous, and continuously updated summary of the evidence available on the role of macrolides for treating patients with COVID-19. DESIGN: A living, systematic review. DATABASE: We conducted searches in the centralized repository L·OVE (Living OVerview of Evidence). L·OVE is a platform that maps PICO questions to evidence from the Epistemonikos database. In response to the COVID-19 emergency, L·OVE was adapted to expand the range of evidence it covers and customized to group all COVID-19 evidence in one place. Today it is maintained through regular searches in 39 databases. METHODS: We included randomized trials evaluating the effect of macrolides as monotherapy or in combination with other drugs versus placebo or no treatment in patients with COVID-19. Randomized trials evaluating macrolides in infections caused by other coronaviruses, such as MERS-CoV and SARS-CoV, and non-randomized studies in COVID-19 were searched in case we found no direct evidence from randomized trials. Two reviewers independently screened each study for eligibility, extracted data, and assessed the risk of bias. Measures included all-cause mortality; the need for invasive mechanical ventilation; extracorporeal membrane oxygenation, length of hospital stay, respiratory failure, serious adverse events, time to SARS-CoV-2 RT-PCR negativity. We applied the GRADE approach to assess the certainty of the evidence for each outcome. A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit it every time the conclusions change or whenever there are substantial updates. RESULTS: The search in the L·OVE platform retrieved 424 references. We considered 260 as potentially eligible and were reviewed in full texts. We included one randomized clinical trial that evaluated the use of azithromycin in combination with hydroxychloroquine compared to hydroxychloroquine alone in hospitalized patients with COVID 19. The estimates for all outcomes evaluated resulted in insufficient power to draw conclusions. The quality of the evidence for the main outcomes was low to very low. CONCLUSIONS: Macrolides in the management of patients with COVID 19 showed no beneficial effects compared to standard of care. The evidence for all outcomes is inconclusive. Larger trials are needed to determine the effects of macrolides on pulmonary and other outcomes in COVID-19 patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO Registration number: CRD42020181032 Protocol preprint DOI: 10.31219/osf.io/rvp59.

OBJETIVO: Proporcionar un resumen oportuno, riguroso y continuamente actualizado de la evidencia disponible sobre el papel de los macrólidos para el tratamiento de pacientes con COVID-19. DISEÑO: Revisión sistemática viva. BASE DE DATOS: La búsqueda de evidencia se realizó en el repositorio centralizado L·OVE (Living OVerview of Evidence) COVID-19; una plataforma que mapea las preguntas PICO para identificar la evidencia en la base de datos Epistemonikos. En respuesta a la emergencia de COVID-19, L·OVE se adaptó para ampliar el rango de evidencia que cubre y hoy se mantiene a través de búsquedas regulares en 39 bases de datos. MÉTODOS: Se incluyeron estudios experimentales que evaluaban el efecto de los macrólidos, como monoterapia o en combinación con otros fármacos, versus placebo o ningún tratamiento en pacientes con sospecha o confirmación de COVID-19. Se buscó identificar experimentos clínicos aleatorizados que evaluaran macrólidos en infecciones causadas por otros coronavirus, como MERS-CoV y SARS-CoV. Dos revisores examinaron de forma independiente la elegibilidad de cada estudio, extrajeron los datos y evaluaron el riesgo de sesgo. Se evaluó el efecto de los macrólidos sobre la mortalidad por todas las causas; necesidad de ventilación mecánica invasiva; oxigenación por membrana extracorpórea, duración de la estancia hospitalaria, insuficiencia respiratoria, eventos adversos graves, tiempo hasta la negatividad de la RT-PCR del SARS-CoV-2. La certeza de la evidencia para cada desenlace se evaluó siguiendo la aproximación GRADE. Esta revisión se mantendrá viva y disponible abiertamente durante la pandemia de COVID-19. Se someterán actualizaciones de su publicación cada vez que cambien las conclusiones o cuando haya actualizaciones sustanciales. RESULTADOS: Se identificó un experimento clínico aleatorio que evaluó el uso de azitromicina en combinación con hidroxicloroquina en comparación con el uso de hidroxicloroquina sola, en pacientes hospitalizados por COVID 19. Las estimaciones para todos los resultados evaluados resultaron en un poder estadístico insuficiente para llegar a conclusiones válidas. La calidad de la evidencia para los resultados principales fue baja a muy baja. CONCLUSIONES: El uso de macrólidos en el tratamiento de pacientes con COVID 19 no ha mostrado efectos beneficiosos en comparación con el tratamiento estándar. La evidencia para todos los desenlaces no es concluyente. Se necesitan estudios sobre un mayor número de pacientes con COVID 19, para determinar los efectos del uso de macrólidos sobre los desenlaces relacionados con la enfermedad. SYSTEMATIC REVIEW REGISTRATION: PROSPERO Registration number: CRD42020181032 Protocol preprint DOI: 10.31219/osf.io/rvp59.

Evidence synthesis relevant to COVID-19: a protocol for multiple systematic reviews and overviews of systematic reviews. / Síntesis de evidencia relevante para COVID-19: protocolo común para múltiples revisiones sistemáticas y revisiones panorámicas.

Introduction: The evidence on COVID-19 is being produced at high speed, so it is challenging for decision-makers to keep up. It seems appropriate, then, to put into practice a novel approach able to provide the scientific community and other interested parties with quality evidence that is actionable, and rapidly and efficiently produced. Methods and analysis: We designed a protocol for multiple parallel systematic reviews and overviews of systematic reviews in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P). We will search for primary studies and systematic reviews that answer different questions related to COVID-19 using both a centralized repository (Epistemonikos database) and a manual search in MEDLINE/PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. We will also search for literature in several other sources. At least two researchers will independently undertake the selection of studies, data extraction, and assessment of the quality of the included studies. We will synthesize data for each question using meta-analysis, when possible, and we will prepare Summary of Findings tables according to the GRADE approach. All the evidence will be organized in an open platform (L·OVE - Living OVerview of Evidence) that will be continuously updated using artificial intelligence and a broad network of experts. Ethics and dissemination: No ethics approval is considered necessary. The results of these articles will be widely disseminated via peer-reviewed publications, social networks, and traditional media, and will be sent to relevant international organizations discussing this topic.