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This report presents the work done on the design, publication, and impact of updates on evidence-based COVID-19 interventions, in order to support decision-making with updated evidence syntheses based on living systematic reviews of therapeutic interventions. To this end, a specific working group was created within the National Commission for Health Technology Assessment (CONETEC) of the Ministry of Health of Argentina, in collaboration with the Pan American Health Organization (PAHO). A methodology was designed to develop and publish assessment documents aimed at supporting decision-making. These update reports were based on the exploration of three areas: health effects, feasibility of implementation, and evidence-based recommendations. A color-coded system was used to present the conclusions according to the balance between their positive and negative effects in different clinical scenarios, in order to improve their interpretation and implementation. In 2021, 16 evidence synthesis reports were published (13 original reports and three full updates). These were downloaded many times from the CONETEC website and the Regional Database of Health Technology Assessment Reports of the Americas (BRISA), highlighting the need for robust, up-to-date, reliable evidence summaries adapted for implementation in the country's health system. Other challenges include constant updating of information, appropriate dissemination, and sustained rigorous preparation of the reports.
Este relatório tem como objetivo apresentar o trabalho realizado sobre o delineamento, publicação e impacto das atualizações para intervenções em COVID-19 baseadas em evidências, que visam fornecer sínteses de evidências atualizadas provenientes de revisões sistemáticas vivas sobre intervenções terapêuticas para apoiar a tomada de decisões. Para isso, foi criado um grupo de trabalho específico no âmbito da Comissão Nacional de Avaliação de Tecnologias de Saúde (CONETEC, na sigla em espanhol), do Ministério da Saúde da Argentina, em parceria com a Organização Pan-Americana da Saúde (OPAS). Foi desenhada uma metodologia para a elaboração e publicação de documentos de avaliação destinados a apoiar a tomada de decisões. Esses relatórios de atualização se basearam na exploração de três domínios: efeitos na saúde, viabilidade da implementação e recomendações baseadas em evidências. As conclusões foram adaptadas a uma escala semafórica de acordo com o equilíbrio entre os benefícios e os aspectos negativos para os diferentes cenários clínicos, de forma a melhorar a sua interpretação e aplicação. Durante o ano de 2021, foram publicados 16 relatórios de síntese de evidências (13 originais e 3 atualizações completas), que receberam um número significativo de consultas no site da CONETEC e da Base Regional de Informes de Avaliação de Tecnologias em Saúde das Américas (BRISA). Assim, tornou-se visível a necessidade de contar com resumos de evidências robustos, atualizados e confiáveis adaptados ao contexto de aplicação no sistema de saúde do país. A atualização constante das informações, sua divulgação adequada e a manutenção do rigor na elaboração dos relatórios também apresentam desafios.
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OBJECTIVE: To build and maintain a living database of the Pan American Health Organization/World Health Organization (PAHO/WHO) recommendations developed using GRADE. STUDY DESIGN AND SETTING: Guidelines are identified from WHO and PAHO databases. We periodically extract recommendations, according to the health and wellbeing targets of Sustainable Development Goal 3. RESULTS: As of March 2022, the BIGG-REC (https://bigg-rec.bvsalud.org/en) database hosted 2682 recommendations contained in 285 WHO/PAHO guidelines. Recommendations were classified as follows: communicable diseases (1,581), children's health (1,182), universal health (1,171), sexual and reproductive health (910), non-communicable diseases (677), maternal health (654), COVID-19 (224), use of psychoactive substances (99), tobacco (14) and road and traffic accidents (16). BIGG-REC allows searching by SDG-3, condition or disease, type of intervention, institution, year of publication and age. CONCLUSION: Recommendation maps provide an important resource for health professionals, organizations and Member States that use evidence-informed guidance to make better decisions, providing a source for the adoption or adaptation of recommendations to meet their needs. This one-stop shop database of evidence-informed recommendations built with intuitive functionalities undoubtedly represents a long-needed tool for decision-makers, guideline developers and the public at large.
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Objective To compare the effects of interleukin 6 receptor blockers, tocilizumab and sarilumab, with or without corticosteroids, on mortality in patients with covid-19. Design Systematic review and network meta-analysis. Data sources World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature, and two prospective meta-analyses (up to 9 June 2021). Review methods Trials in which people with suspected, probable, or confirmed covid-19 were randomised to interleukin 6 receptor blockers (with or without corticosteroids), corticosteroids, placebo, or standard care. The analysis used a bayesian framework and assessed the certainty of evidence using the GRADE approach. Results from the fixed effect meta-analysis were used for the primary analysis. Results Of 45 eligible trials (20 650 patients) identified, 36 (19 350 patients) could be included in the network meta-analysis. Of 36 trials, 27 were at high risk of bias, primarily due to lack of blinding. Tocilizumab, in combination with corticosteroids, suggested a reduction in the risk of death compared with corticosteroids alone (odds ratio 0.79, 95% credible interval 0.70 to 0.88;35 fewer deaths per 1000 people, 95% credible interval 52 fewer to 18 fewer per 1000;moderate certainty of evidence), as did sarilumab in combination with corticosteroids, compared with corticosteroids alone (0.73, 0.58 to 0.92;43 fewer per 1000, 73 fewer to 12 fewer;low certainty). Tocilizumab and sarilumab, each in combination with corticosteroids, appeared to have similar effects on mortality when compared with each other (1.07, 0.86 to 1.34;eight more per 1000, 20 fewer to 35 more;low certainty). The effects of tocilizumab (1.12, 0.91 to 1.38;20 more per 1000, 16 fewer to 59 more;low certainty) and sarilumab (1.07, 0.81 to 1.40;11 more per 1000, 38 fewer to 55 more;low certainty), when used alone, suggested an increase in the risk of death. Conclusion These findings suggest that in patients with severe or critical covid-19, tocilizumab, in combination with corticosteroids, probably reduces mortality, and that sarilumab, in combination with corticosteroids, might also reduce mortality. Tocilizumab and sarilumab, in combination with corticosteroids, could have similar effectiveness. Tocilizumab and sarilumab, when used alone, might not be beneficial.
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RESUMEN Este informe tiene por objetivo exponer el trabajo realizado sobre el diseño, la publicación y el impacto de las actualizaciones para intervenciones en COVID-19 basadas en la evidencia, para brindar síntesis de evidencia actualizadas a partir de revisiones sistemáticas vivas sobre intervenciones terapéuticas para dar soporte en la toma de decisiones. Para ello, se generó un grupo específico de trabajo en el ámbito de la Comisión Nacional de Evaluación de Tecnologías de Salud (CONETEC) en el Ministerio de Salud de Argentina en colaboración con la Organización Panamericana de la Salud (OPS). Se diseñó una metodología para elaborar y publicar documentos de evaluación orientados a dar apoyo en la toma de decisiones. Estos informes de actualización se respaldaron en la exploración de tres dominios: los efectos en la salud, la factibilidad de la implementación y las recomendaciones basadas en evidencia. Las conclusiones se adaptaron en un esquema semaforizado según el balance entre los beneficios y los aspectos negativos para los distintos escenarios clínicos, a fin de mejorar su interpretación y aplicación. Durante el año 2021 se publicaron 16 informes de síntesis de evidencia (13 originales y 3 actualizaciones completas) que recibieron un destacado número consultas desde la página web de CONETEC y la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA). Así se hizo visible la necesidad de disponer de resúmenes de evidencia robustos, actualizados y confiables con adaptación al contexto de aplicación en el sistema sanitario del país. El desafío se presenta, además, en la actualización constante de la información, la diseminación apropiada y el sostenimiento en la rigurosidad en el desarrollo de los informes.
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BACKGROUND: Mechanical ventilation is used to treat respiratory failure in coronavirus disease 2019 (COVID-19). PURPOSE: To review multiple streams of evidence regarding the benefits and harms of ventilation techniques for coronavirus infections, including that causing COVID-19. DATA SOURCES: 21 standard, World Health Organization-specific and COVID-19-specific databases, without language restrictions, until 1 May 2020. STUDY SELECTION: Studies of any design and language comparing different oxygenation approaches in patients with coronavirus infections, including severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS), or with hypoxemic respiratory failure. Animal, mechanistic, laboratory, and preclinical evidence was gathered regarding aerosol dispersion of coronavirus. Studies evaluating risk for virus transmission to health care workers from aerosol-generating procedures (AGPs) were included. DATA EXTRACTION: Independent and duplicate screening, data abstraction, and risk-of-bias assessment (GRADE for certainty of evidence and AMSTAR 2 for included systematic reviews). DATA SYNTHESIS: 123 studies were eligible (45 on COVID-19, 70 on SARS, 8 on MERS), but only 5 studies (1 on COVID-19, 3 on SARS, 1 on MERS) adjusted for important confounders. A study in hospitalized patients with COVID-19 reported slightly higher mortality with noninvasive ventilation (NIV) than with invasive mechanical ventilation (IMV), but 2 opposing studies, 1 in patients with MERS and 1 in patients with SARS, suggest a reduction in mortality with NIV (very-low-certainty evidence). Two studies in patients with SARS report a reduction in mortality with NIV compared with no mechanical ventilation (low-certainty evidence). Two systematic reviews suggest a large reduction in mortality with NIV compared with conventional oxygen therapy. Other included studies suggest increased odds of transmission from AGPs. LIMITATION: Direct studies in COVID-19 are limited and poorly reported. CONCLUSION: Indirect and low-certainty evidence suggests that use of NIV, similar to IMV, probably reduces mortality but may increase the risk for transmission of COVID-19 to health care workers. PRIMARY FUNDING SOURCE: World Health Organization. (PROSPERO: CRD42020178187).
Subject(s)
Coronavirus Infections/transmission , Pneumonia, Viral/transmission , Respiration, Artificial/adverse effects , Respiration, Artificial/methods , Aerosols , Animals , Betacoronavirus , COVID-19 , Coronavirus Infections/mortality , Humans , Pandemics , Pneumonia, Viral/mortality , Randomized Controlled Trials as Topic , SARS-CoV-2 , Severe Acute Respiratory Syndrome/transmission , Systematic Reviews as Topic , World Health OrganizationABSTRACT
[This corrects the article DOI: 10.1371/journal.pone.0241955.].
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BACKGROUND: To summarise specific adverse effects of remdesivir, hydroxychloroquine and lopinavir/ritonavir in patients with COVID-19. METHODS: We searched 32 databases through 27 October 2020. We included randomised trials comparing any of the drugs of interest to placebo or standard care, or against each other. We conducted fixed-effects pairwise meta-analysis and assessed the certainty of evidence using the grading of recommendations assessment, development and evaluation approach. RESULTS: We included 16 randomised trials which enrolled 8152 patients. For most interventions and outcomes the certainty of the evidence was very low to low except for gastrointestinal adverse effects from hydroxychloroquine, which was moderate certainty. Compared with standard care or placebo, low certainty evidence suggests that remdesivir may not have an important effect on acute kidney injury (risk difference (RD) 8 fewer per 1000, 95% CI 27 fewer to 21 more) or cognitive dysfunction/delirium (RD 3 more per 1000, 95% CI 12 fewer to 19 more). Low certainty evidence suggests that hydroxychloroquine may increase the risk of cardiac toxicity (RD 10 more per 1000, 95% CI 0 more to 30 more) and cognitive dysfunction/delirium (RD 33 more per 1000, 95% CI 18 fewer to 84 more), whereas moderate certainty evidence suggests hydroxychloroquine probably increases the risk of diarrhoea (RD 106 more per 1000, 95% CI 48 more to 175 more) and nausea and/or vomiting (RD 62 more per 1000, 95% CI 23 more to 110 more) compared with standard care or placebo. Low certainty evidence suggests lopinavir/ritonavir may increase the risk of diarrhoea (RD 168 more per 1000, 95% CI 58 more to 330 more) and nausea and/or vomiting (RD 160 more per 1000, 95% CI 100 more to 210 more) compared with standard care or placebo. DISCUSSION: Hydroxychloroquine probably increases the risk of diarrhoea and nausea and/or vomiting and may increase the risk of cardiac toxicity and cognitive dysfunction/delirium. Lopinavir/ritonavir may increase the risk of diarrhoea and nausea and/or vomiting. Remdesivir may have no important effect on risk of acute kidney injury or cognitive dysfunction/delirium. These findings provide important information to support the development of evidence-based management strategies for patients with COVID-19.
Subject(s)
Adenosine Monophosphate/adverse effects , Alanine/adverse effects , COVID-19 Drug Treatment , Hydroxychloroquine , Lopinavir/adverse effects , Ritonavir/adverse effects , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Drug Combinations , Humans , Hydroxychloroquine/adverse effects , Randomized Controlled Trials as Topic , SARS-CoV-2ABSTRACT
OBJECTIVE: The objective of this systematic review is to summarize the effects of ivermectin for the prevention and treatment of patients with COVID-19 and to assess inconsistencies in results from individual studies with focus on risk of bias due to methodological limitations. METHODS: We searched the L.OVE platform through July 6, 2021 and included randomized trials (RCTs) comparing ivermectin to standard or other active treatments. We conducted random-effects pairwise meta-analysis, assessed the certainty of evidence using the GRADE approach and performed sensitivity analysis excluding trials with risk of bias. RESULTS: We included 29 RCTs which enrolled 5592 cases. Overall, the certainty of the evidence was very low to low suggesting that ivermectin may result in important benefits. However, after excluding trials classified as "high risk" or "some concerns" in the risk of bias assessment, most estimates of effect changed substantially: Compared to standard of care, low certainty evidence suggests that ivermectin may not reduce mortality (RD 7 fewer per 1000) nor mechanical ventilation (RD 6 more per 1000), and moderate certainty evidence shows that it probably does not increase symptom resolution or improvement (RD 14 more per 1000) nor viral clearance (RD 12 fewer per 1000). CONCLUSION: Ivermectin may not improve clinically important outcomes in patients with COVID-19 and its effects as a prophylactic intervention in exposed individuals are uncertain. Previous reports concluding important benefits associated with ivermectin are based on potentially biased results reported by studies with substantial methodological limitations. Further research is needed.
Subject(s)
COVID-19 Drug Treatment , Ivermectin , Bias , Humans , Ivermectin/therapeutic use , Respiration, Artificial , SARS-CoV-2ABSTRACT
OBJECTIVE: To evaluate the efficacy and safety of antiviral antibody therapies and blood products for the treatment of novel coronavirus disease 2019 (covid-19). DESIGN: Living systematic review and network meta-analysis, with pairwise meta-analysis for outcomes with insufficient data. DATA SOURCES: WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, and six Chinese databases (up to 21 July 2021). STUDY SELECTION: Trials randomising people with suspected, probable, or confirmed covid-19 to antiviral antibody therapies, blood products, or standard care or placebo. Paired reviewers determined eligibility of trials independently and in duplicate. METHODS: After duplicate data abstraction, we performed random effects bayesian meta-analysis, including network meta-analysis for outcomes with sufficient data. We assessed risk of bias using a modification of the Cochrane risk of bias 2.0 tool. The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. We meta-analysed interventions with ≥100 patients randomised or ≥20 events per treatment arm. RESULTS: As of 21 July 2021, we identified 47 trials evaluating convalescent plasma (21 trials), intravenous immunoglobulin (IVIg) (5 trials), umbilical cord mesenchymal stem cells (5 trials), bamlanivimab (4 trials), casirivimab-imdevimab (4 trials), bamlanivimab-etesevimab (2 trials), control plasma (2 trials), peripheral blood non-haematopoietic enriched stem cells (2 trials), sotrovimab (1 trial), anti-SARS-CoV-2 IVIg (1 trial), therapeutic plasma exchange (1 trial), XAV-19 polyclonal antibody (1 trial), CT-P59 monoclonal antibody (1 trial) and INM005 polyclonal antibody (1 trial) for the treatment of covid-19. Patients with non-severe disease randomised to antiviral monoclonal antibodies had lower risk of hospitalisation than those who received placebo: casirivimab-imdevimab (odds ratio (OR) 0.29 (95% CI 0.17 to 0.47); risk difference (RD) -4.2%; moderate certainty), bamlanivimab (OR 0.24 (0.06 to 0.86); RD -4.1%; low certainty), bamlanivimab-etesevimab (OR 0.31 (0.11 to 0.81); RD -3.8%; low certainty), and sotrovimab (OR 0.17 (0.04 to 0.57); RD -4.8%; low certainty). They did not have an important impact on any other outcome. There was no notable difference between monoclonal antibodies. No other intervention had any meaningful effect on any outcome in patients with non-severe covid-19. No intervention, including antiviral antibodies, had an important impact on any outcome in patients with severe or critical covid-19, except casirivimab-imdevimab, which may reduce mortality in patients who are seronegative. CONCLUSION: In patients with non-severe covid-19, casirivimab-imdevimab probably reduces hospitalisation; bamlanivimab-etesevimab, bamlanivimab, and sotrovimab may reduce hospitalisation. Convalescent plasma, IVIg, and other antibody and cellular interventions may not confer any meaningful benefit. SYSTEMATIC REVIEW REGISTRATION: This review was not registered. The protocol established a priori is included as a data supplement. FUNDING: This study was supported by the Canadian Institutes of Health Research (grant CIHR- IRSC:0579001321). READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Interim updates and additional study data will be posted on our website (www.covid19lnma.com).
Subject(s)
Antibodies, Viral/therapeutic use , COVID-19/therapy , Cell- and Tissue-Based Therapy/methods , SARS-CoV-2/immunology , Antibodies, Monoclonal/therapeutic use , Antiviral Agents/therapeutic use , Bayes Theorem , COVID-19/immunology , Clinical Trials as Topic , Humans , Immunization, Passive , Network Meta-Analysis , Treatment Outcome , COVID-19 SerotherapyABSTRACT
OBJECTIVE: To determine and compare the effects of drug prophylaxis on SARS-CoV-2 infection and covid-19. DESIGN: Living systematic review and network meta-analysis. DATA SOURCES: World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature to 25 March 2021, and six additional Chinese databases to 20 February 2021. STUDY SELECTION: Randomised trials of people at risk of covid-19 who were assigned to receive prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles. METHODS: Random effects bayesian network meta-analysis was performed after duplicate data abstraction. Included studies were assessed for risk of bias using a modification of the Cochrane risk of bias 2.0 tool, and certainty of evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. RESULTS: The first iteration of this living network meta-analysis includes nine randomised trials-six of hydroxychloroquine (n=6059 participants), one of ivermectin combined with iota-carrageenan (n=234), and two of ivermectin alone (n=540), all compared with standard care or placebo. Two trials (one of ramipril and one of bromhexine hydrochloride) did not meet the sample size requirements for network meta-analysis. Hydroxychloroquine has trivial to no effect on admission to hospital (risk difference 1 fewer per 1000 participants, 95% credible interval 3 fewer to 4 more; high certainty evidence) or mortality (1 fewer per 1000, 2 fewer to 3 more; high certainty). Hydroxychloroquine probably does not reduce the risk of laboratory confirmed SARS-CoV-2 infection (2 more per 1000, 18 fewer to 28 more; moderate certainty), probably increases adverse effects leading to drug discontinuation (19 more per 1000, 1 fewer to 70 more; moderate certainty), and may have trivial to no effect on suspected, probable, or laboratory confirmed SARS-CoV-2 infection (15 fewer per 1000, 64 fewer to 41 more; low certainty). Owing to serious risk of bias and very serious imprecision, and thus very low certainty of evidence, the effects of ivermectin combined with iota-carrageenan on laboratory confirmed covid-19 (52 fewer per 1000, 58 fewer to 37 fewer), ivermectin alone on laboratory confirmed infection (50 fewer per 1000, 59 fewer to 16 fewer) and suspected, probable, or laboratory confirmed infection (159 fewer per 1000, 165 fewer to 144 fewer) remain very uncertain. CONCLUSIONS: Hydroxychloroquine prophylaxis has trivial to no effect on hospital admission and mortality, probably increases adverse effects, and probably does not reduce the risk of SARS-CoV-2 infection. Because of serious risk of bias and very serious imprecision, it is highly uncertain whether ivermectin combined with iota-carrageenan and ivermectin alone reduce the risk of SARS-CoV-2 infection. SYSTEMATIC REVIEW REGISTRATION: This review was not registered. The protocol established a priori is included as a supplement. READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.
Subject(s)
COVID-19 , Carrageenan/pharmacology , Global Health/statistics & numerical data , Hydroxychloroquine/pharmacology , Ivermectin/pharmacology , Anti-Infective Agents/pharmacology , COVID-19/prevention & control , Chemoprevention/methods , Chemoprevention/statistics & numerical data , Humans , SARS-CoV-2 , Treatment Outcome , UncertaintyABSTRACT
BACKGROUND AND PURPOSE: The objective of our systematic review is to identify prognostic factors that may be used in decision-making related to the care of patients infected with COVID-19. DATA SOURCES: We conducted highly sensitive searches in PubMed/MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL) and Embase. The searches covered the period from the inception date of each database until April 28, 2020. No study design, publication status or language restriction were applied. STUDY SELECTION AND DATA EXTRACTION: We included studies that assessed patients with confirmed or suspected SARS-CoV-2 infectious disease and examined one or more prognostic factors for mortality or disease severity. Reviewers working in pairs independently screened studies for eligibility, extracted data and assessed the risk of bias. We performed meta-analyses and used GRADE to assess the certainty of the evidence for each prognostic factor and outcome. RESULTS: We included 207 studies and found high or moderate certainty that the following 49 variables provide valuable prognostic information on mortality and/or severe disease in patients with COVID-19 infectious disease: Demographic factors (age, male sex, smoking), patient history factors (comorbidities, cerebrovascular disease, chronic obstructive pulmonary disease, chronic kidney disease, cardiovascular disease, cardiac arrhythmia, arterial hypertension, diabetes, dementia, cancer and dyslipidemia), physical examination factors (respiratory failure, low blood pressure, hypoxemia, tachycardia, dyspnea, anorexia, tachypnea, haemoptysis, abdominal pain, fatigue, fever and myalgia or arthralgia), laboratory factors (high blood procalcitonin, myocardial injury markers, high blood White Blood Cell count (WBC), high blood lactate, low blood platelet count, plasma creatinine increase, high blood D-dimer, high blood lactate dehydrogenase (LDH), high blood C-reactive protein (CRP), decrease in lymphocyte count, high blood aspartate aminotransferase (AST), decrease in blood albumin, high blood interleukin-6 (IL-6), high blood neutrophil count, high blood B-type natriuretic peptide (BNP), high blood urea nitrogen (BUN), high blood creatine kinase (CK), high blood bilirubin and high erythrocyte sedimentation rate (ESR)), radiological factors (consolidative infiltrate and pleural effusion) and high SOFA score (sequential organ failure assessment score). CONCLUSION: Identified prognostic factors can help clinicians and policy makers in tailoring management strategies for patients with COVID-19 infectious disease while researchers can utilise our findings to develop multivariable prognostic models that could eventually facilitate decision-making and improve patient important outcomes. SYSTEMATIC REVIEW REGISTRATION: Prospero registration number: CRD42020178802. Protocol available at: https://www.medrxiv.org/content/10.1101/2020.04.08.20056598v1.
Subject(s)
Coronavirus Infections/epidemiology , Coronavirus Infections/mortality , Pneumonia, Viral/epidemiology , Pneumonia, Viral/mortality , Aged , Aging , Betacoronavirus , COVID-19 , Comorbidity , Data Management , Female , Humans , Male , Middle Aged , Pandemics , Prognosis , Risk Factors , SARS-CoV-2 , Socioeconomic FactorsABSTRACT
OBJECTIVE: To compare the effects of treatments for coronavirus disease 2019 (covid-19). DESIGN: Living systematic review and network meta-analysis. DATA SOURCES: WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, up to 3 December 2021 and six additional Chinese databases up to 20 February 2021. Studies identified as of 1 December 2021 were included in the analysis. STUDY SELECTION: Randomised clinical trials in which people with suspected, probable, or confirmed covid-19 were randomised to drug treatment or to standard care or placebo. Pairs of reviewers independently screened potentially eligible articles. METHODS: After duplicate data abstraction, a bayesian network meta-analysis was conducted. Risk of bias of the included studies was assessed using a modification of the Cochrane risk of bias 2.0 tool, and the certainty of the evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. For each outcome, interventions were classified in groups from the most to the least beneficial or harmful following GRADE guidance. RESULTS: 463 trials enrolling 166 581 patients were included; 267 (57.7%) trials and 89 814 (53.9%) patients are new from the previous iteration; 265 (57.2%) trials evaluating treatments with at least 100 patients or 20 events met the threshold for inclusion in the analyses. Compared with standard care, three drugs reduced mortality in patients with mostly severe disease with at least moderate certainty: systemic corticosteroids (risk difference 23 fewer per 1000 patients, 95% credible interval 40 fewer to 7 fewer, moderate certainty), interleukin-6 receptor antagonists when given with corticosteroids (23 fewer per 1000, 36 fewer to 7 fewer, moderate certainty), and Janus kinase inhibitors (44 fewer per 1000, 64 fewer to 20 fewer, high certainty). Compared with standard care, two drugs probably reduce hospital admission in patients with non-severe disease: nirmatrelvir/ritonavir (36 fewer per 1000, 41 fewer to 26 fewer, moderate certainty) and molnupiravir (19 fewer per 1000, 29 fewer to 5 fewer, moderate certainty). Remdesivir may reduce hospital admission (29 fewer per 1000, 40 fewer to 6 fewer, low certainty). Only molnupiravir had at least moderate quality evidence of a reduction in time to symptom resolution (3.3 days fewer, 4.8 fewer to 1.6 fewer, moderate certainty); several others showed a possible benefit. Several drugs may increase the risk of adverse effects leading to drug discontinuation; hydroxychloroquine probably increases the risk of mechanical ventilation (moderate certainty). CONCLUSION: Corticosteroids, interleukin-6 receptor antagonists, and Janus kinase inhibitors probably reduce mortality and confer other important benefits in patients with severe covid-19. Molnupiravir and nirmatrelvir/ritonavir probably reduce admission to hospital in patients with non-severe covid-19. SYSTEMATIC REVIEW REGISTRATION: This review was not registered. The protocol is publicly available in the supplementary material. READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This is the fifth version of the original article published on 30 July 2020 (BMJ 2020;370:m2980), and previous versions can be found as data supplements. When citing this paper please consider adding the version number and date of access for clarity.
Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/isolation & purification , Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Respiration, Artificial/statistics & numerical data , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Betacoronavirus/pathogenicity , COVID-19 , Centers for Disease Control and Prevention, U.S./statistics & numerical data , China/epidemiology , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Coronavirus Infections/mortality , Coronavirus Infections/virology , Databases, Factual/statistics & numerical data , Drug Combinations , Evidence-Based Medicine/methods , Evidence-Based Medicine/statistics & numerical data , Glucocorticoids/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Lopinavir/therapeutic use , Network Meta-Analysis , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Randomized Controlled Trials as Topic , Ritonavir/therapeutic use , SARS-CoV-2 , Severity of Illness Index , Standard of Care , Treatment Outcome , United States/epidemiology , COVID-19 Drug TreatmentABSTRACT
OBJECTIVE: Provide a timely, rigorous, and continuously updated summary of the evidence on the role of lopinavir/ritonavir in the treatment of patients with COVID-19. METHODS: We conducted searches in the special L·OVE (Living OVerview of Evidence) platform for COVID-19, a system that performs regular searches in PubMed, Embase, CENTRAL, and other 33 sources. We searched for randomized trials and non-randomized studies evaluating the effect of lopinavir/ritonavir versus placebo or no treatment in patients with COVID-19. Two reviewers independently evaluated potentially eligible studies, according to predefined selection criteria, and extracted data using a predesigned standardized form. We performed meta-analyses using random-effect models and assessed overall certainty in evidence using the GRADE approach. A living, web-based version of this review will be openly available during the COVID-19 pandemic. RESULTS: Our search strategy yielded 862 references. Finally, we identified 12 studies, including two randomized trials, evaluating lopinavir/ritonavir, in addition to standard care versus standard care alone in 250 adult inpatients with COVID-19. The evidence from randomized trials shows lopinavir/ritonavir may reduce mortality (relative risk: 0.77; 95% confidence interval: 0.45 to 1.3; low certainty evidence), but the anticipated magnitude of the absolute reduction in mortality, varies across different risk groups. Lopinavir/ritonavir also had a slight reduction in the risk of requiring invasive mechanical ventilation, developing respiratory failure, or acute respiratory distress syndrome. However, it did not lead to any difference in the duration of hospitalization and may lead to an increase in the number of total adverse effects. The overall certainty of the evidence was low or very low. CONCLUSIONS: For severe and critical patients with COVID-19, lopinavir/ritonavir might play a role in improving outcomes, but the available evidence is still limited. A substantial number of ongoing studies should provide valuable evidence to inform researchers and decision-makers soon.
OBJETIVO: Esta revisión sistemática viva tiene como objetivo entregar un resumen oportuno, riguroso y constantemente actualizado de la evidencia disponible sobre los efectos de lopinavir/ritonavir en pacientes con COVID-19. MÉTODOS: Se realizó una búsqueda en la plataforma L·OVE COVID-19 (Living OVerview of Evidence), un sistema que mantiene búsquedas regulares en PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL) y otras 33 fuentes. Se buscaron ensayos aleatorios y estudios no aleatorios que evaluaran el uso de lopinavir/ritonavir versus placebo o ningún tratamiento en pacientes con COVID-19. Dos revisores evaluaron de forma independiente los artículos potencialmente elegibles, de acuerdo con criterios de selección predefinidos, y extrajeron los datos mediante un formulario estandarizado. Los resultados fueron combinados mediante un metanálisis utilizando modelos de efectos aleatorios y evaluamos la certeza de la evidencia utilizando el método GRADE. Una versión viva de esta revisión estará disponible durante la pandemia de COVID-19. RESULTADOS: La búsqueda inicial arrojó 862 referencias. Finalmente, identificamos 12 estudios incluyendo 2 ensayos aleatorios, que evaluaban lopinavir/ritonavir adicionado al tratamiento estándar versus tratamiento estándar en 250 pacientes adultos hospitalizados con COVID-19. Los resultados provenientes de los ensayos aleatorios muestran que el uso de lopinavir/ritonavir puede reducir la mortalidad (riesgo relativo: 0,77; intervalo de confianza 95%: 0,45 a 1,3; certeza de evidencia baja), pero la magnitud de la reducción absoluta de la mortalidad varía según los diferentes grupos de riesgo. El uso de lopinavir/ritonavir mostró además una ligera reducción en el riesgo de requerir ventilación mecánica invasiva, desarrollar insuficiencia respiratoria o síndrome de dificultad respiratoria aguda. No se observó diferencias en la duración de la hospitalización y su uso puede producir un aumento en el número de efectos adversos totales. La certeza global de la evidencia fue baja o muy baja. CONCLUSIONES: Para pacientes graves y críticos con COVID-19, el uso de lopinavir/ritonavir podría desempeñar un papel en la mejora de los resultados, pero la evidencia disponible aún es limitada. La gran cantidad de estudios en curso deberían proporcionar evidencia valiosa para informar a los investigadores y los tomadores de decisiones en el futuro cercano.
Subject(s)
Antiviral Agents/administration & dosage , Coronavirus Infections/drug therapy , Lopinavir/administration & dosage , Pneumonia, Viral/drug therapy , Ritonavir/administration & dosage , Adult , Antiviral Agents/adverse effects , COVID-19 , Drug Combinations , Humans , Lopinavir/adverse effects , Pandemics , Randomized Controlled Trials as Topic , Ritonavir/adverse effects , Treatment Outcome , COVID-19 Drug TreatmentABSTRACT
Objective: Provide a timely, rigorous, and continuously updated summary of the evidence on the role of lopinavir/ritonavir in the treatment of patients with COVID-19. Methods: We conducted searches in the special L·OVE (Living OVerview of Evidence) platform for COVID-19, a system that performs regular searches in PubMed, Embase, CENTRAL, and other 33 sources. We searched for randomized trials and non-randomized studies evaluating the effect of lopinavir/ritonavir versus placebo or no treatment in patients with COVID-19. Two reviewers independently evaluated potentially eligible studies, according to predefined selection criteria, and extracted data using a predesigned standardized form. We performed meta-analyses using random-effect models and assessed overall certainty in evidence using the GRADE approach. A living, web-based version of this review will be openly available during the COVID-19 pandemic. Results: Our search strategy yielded 862 references. Finally, we identified 12 studies, including two randomized trials, evaluating lopinavir/ritonavir, in addition to standard care versus standard care alone in 250 adult inpatients with COVID-19. The evidence from randomized trials shows lopinavir/ritonavir may reduce mortality (relative risk: 0.77;95% confidence interval: 0.45 to 1.3;low certainty evidence), but the anticipated magnitude of the absolute reduction in mortality, varies across different risk groups. Lopinavir/ritonavir also had a slight reduction in the risk of requiring invasive mechanical ventilation, developing respiratory failure, or acute respiratory distress syndrome. However, it did not lead to any difference in the duration of hospitalization and may lead to an increase in the number of total adverse effects. The overall certainty of the evidence was low or very low. Conclusions: For severe and critical patients with COVID-19, lopinavir/ritonavir might play a role in improving outcomes, but the available evidence is still limited. A substantial number of ongoing studies should provide valuable evidence to inform researchers and decision-makers soon.
ABSTRACT
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.