ABSTRACT
Objective To determine and compare the effects of drug prophylaxis on severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) infection and 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 to 19 January 2021, and six additional Chinese databases to 20 January 2021. Study selection Randomized trials in which people at risk of covid-19 were randomized to drug prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles. Methods After duplicate data abstraction, we conducted random-effects bayesian network meta-analysis. We assessed risk of bias of the included studies using a modification of the Cochrane risk of bias 2.0 tool and assessed the certainty of the evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach. Results The first iteration of this living network meta-analysis includes nine randomized trials: six addressing hydroxychloroquine (6,059 participants), one addressing ivermectin combined with iota-carrageenan (234 participants) and two addressing ivermectin alone (540 participants), all compared to standard care or placebo. Hydroxychloroquine has no important effect on admission to hospital (risk difference (RD) 1 fewer per 1,000, 95% credible interval (CrI) 3 fewer to 4 more, high certainty) or mortality (RD 1 fewer per 1,000, 95% CrI 2 fewer to 3 more, high certainty). Hydroxychloroquine probably has no important effect on laboratory-confirmed infection (RD 2 more per 1,000, 95% CrI 18 fewer to 28 more, moderate certainty), probably increases adverse effects leading to drug discontinuation (RD 19 more per 1,000, 95% CrI 1 fewer to 70 more, moderate certainty) and may have no important effect on suspected, probable or laboratory-confirmed infection (RD 15 fewer per 1,000, 95% CrI 64 fewer to 41 more, low certainty). Due to serious risk of bias and very serious imprecision, and thus very low certainty evidence, the effects of ivermectin combined with iota-carrageenan on laboratory-confirmed infection (RD 52 fewer per 1,000, 95% CrI 58 fewer to 37 fewer), and ivermectin alone on laboratory-confirmed infection (RD 50 fewer per 1,000, 95% CrI 59 fewer to 16 fewer) and suspected, probable or laboratory-confirmed infection (RD 159 fewer per 1,000, 95% CrI 165 fewer to 144 fewer) remain uncertain. Conclusion Hydroxychloroquine prophylaxis does not have an important effect on hospital admission and mortality, probably increases adverse effects, and probably does not have an important effect on laboratory-confirmed SARS-CoV-2 infection. Because of serious risk of bias and very serious imprecision, we are 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. Funding This study was supported by the Canadian Institutes of Health Research (grant CIHR-IRSC:0579001321). Reader 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)
Coronavirus Infections , Laboratory Infection , COVID-19ABSTRACT
Background: The coronavirus disease (Covid-19) pandemic has produced a large number of clinical trial reports with unprecedented rapidity, raising concerns about methodological quality and potential for research waste. Objectives: To describe the characteristics of randomized clinical trials (RCTs) investigating prophylaxis or treatment of Covid-19 infection and examine the effect of trial characteristics on whether the study reported a statistically significant effect on the primary outcome(s). Study Design: Meta-epidemiological study of Covid-19 treatment and prophylaxis RCTs. Eligibility criteria: English-language RCTs (peer-reviewed or preprint) that evaluated pharmacologic agents or blood products compared to standard care, placebo, or an active comparator among participants with suspected or confirmed Covid-19 or at risk for Covid-19. We excluded trials of vaccines or traditional herbal medicines. Information sources: We searched 25 databases in the US Centre for Disease Control Downloadable Database from January 1 to October 21, 2020. Trial appraisal and synthesis methods: We extracted trial characteristics including number of centres, funding sources (industry versus non-industry), and sample size. We assessed risk of bias (RoB) using the modified Cochrane RoB 2.0 Tool. We used descriptive statistics to summarize trial characteristics and logistic regression to evaluate the association between RoB due to the randomization process, centre status (single vs. multicentre), funding source, and sample size, and statistically significant effect in the primary outcome. Results: We included 91 RCTs (46,802 participants) evaluating Covid-19 therapeutic drugs (n = 76), blood products (n = 9) or prophylactic drugs (n = 6). Of these, 40 (44%) were single-centre, 23 (25.3%) enrolled < 50 patients, and 28 (30.8%) received industry funding. RoB varied across trials, with high or probably high overall RoB in 75 (82.4%) trials, most frequently due to deviations from the intended protocol (including blinding) and randomization processes. Thirty-eight trials (41.8%) found a statistically significant effect in the primary outcome. RoB due randomization (odds ratio [OR] 3.77, 95% confidence interval [CI], 1.47 to 9.72) and single centre trials (OR 3.15, 95% CI, 1.25 to 7.97) were associated with higher likelihood of finding a statistically significant effect. Conclusions: There was high variability in RoB amongst Covid-19 trials. RoB attributed to the randomization process and single centre status were associated with a three-fold increase in the odds of finding a statistically significant effect. Researchers, funders, and knowledge users should remain cognizant of the impact of study characteristics, including RoB, on trial results when designing, conducting, and appraising Covid-19 trials. Registration number: CRD42020192095
Subject(s)
COVID-19 , Coronavirus InfectionsABSTRACT
Background: 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. Methods: 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. We included studies that assessed patients with confirmed or suspected SARS-CoV-2 infection 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. Findings: 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 infection: 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. Interpretation: Identified prognostic factors can help clinicians and policy makers in tailoring management strategies for patients with COVID-19 infection while researchers can utilise our findings to develop multivariable prognostic models that could eventually facilitate decision-making and improve patient important outcomes. Funding Statement: NoneDeclaration of Interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, no other relationships or activities that could appear to have influenced the submitted work.