ABSTRACT
ObjectiveAssess the impact of allocation concealment and blinding on the results of trials addressing COVID-19 therapeutics. Data sourcesWorld Health Organization (WHO) COVID-19 database and the Living Overview of the Evidence (L-OVE) COVID-19 platform by the Epistemonikos Foundation (up to February 4th 2022) MethodsWe included trials that compared drug treatments, antiviral antibodies and cellular therapies with placebo or standard care. For the five most commonly reported outcomes, if sufficient data were available, we performed random-effects meta-regression comparing the results of trials with and without allocation concealment and trials in which both healthcare providers and patients were blinded with trials in which healthcare providers and/or patients were aware of the intervention. A ratio of odds ratios (ROR) > 1 or a difference in mean difference (DMD) > 0 indicates that trials without allocation concealment or open-label trials produced larger effects than trials with allocation concealment or blinded trials. ResultsAs of February 4th 2022, we have identified 488 trials addressing COVID-19 drug treatments and antiviral antibodies and cellular therapies. Of these, 436 trials reported on one or more of our outcomes of interest and were included in our analyses. We found that trials without allocation concealment probably overestimate mortality (ROR 1.14 [95% CI 0.92 to 1.41]), need for mechanical ventilation (ROR 1.26 [95% CI 0.97 to 1.64]), admission to hospital (ROR 1.93 [95% CI 0.83 to 4.48]), duration of hospitalization (DMD 1.94 [95% CI 0.86 to 3.02]), and duration of mechanical ventilation (DMD 2.64 [95% CI -0.90 to 6.18]), but results were imprecise. We did not find compelling evidence that double-blind and open-label trials produce consistently different results for mortality (ROR 1.00 [95% CI 0.87 to 1.15]), need for mechanical ventilation (ROR 1.03 [95% CI 0.84 to 1.26]), and duration of hospitalization (DMD 0.47 days [95% CI -0.38 to 1.32]). We found that open-label trials may overestimate the beneficial effects of interventions for hospitalizations (ROR 1.87 [95% CI 0.95 to 3.67] and duration of mechanical ventilation (DMD 1.02 days [95% CI -1.30 to 3.35]), but results were imprecise. ConclusionWe found compelling evidence that, compared to trials with allocation concealment, trials without allocation concealment may overestimate the beneficial effects of treatments. We did not find evidence that trials without blinding addressing COVID-19 interventions produce consistently different results from trials with blinding. Our results suggest that consideration of blinding status may not be sufficient to judge risk of bias due to imbalances in co-interventions. Evidence users may consider evidence of differences in co-interventions between trial arms when judging the trustworthiness of open-label trials. We suggest, however, evidence users to remain skeptical of trials without allocation concealment. Whats new?O_ST_ABSkey findingsC_ST_ABSTrials without blinding did not produce consistently different results from trials with blinding. Additional informationPrevious studies have had conflicting results with regards to the effects of blinding on trial results. Our study supports the assertion that results from blinded trials may not differ significantly from unblinded ones. ImplicationsOur study suggest that risk of bias assessment of blinding needs to be more nuanced and that lack of blinding may not be a definite indication of risk of bias.
ABSTRACT
ObjectiveTo compare the effects of interleukin-6 (IL-6) receptor blockers, with or without corticosteroids, on mortality in patients with COVID-19. DesignSystematic review and network meta-analysis Data sourcesWHO COVID-19 database, a comprehensive multilingual source of global covid-19 literature, and two prospective meta-analyses Study selectionTrials in which people with suspected, probable, or confirmed COVID-19 were randomized to IL-6 receptor blockers (with or without corticosteroids), corticosteroids, placebo, or standard care. ResultsWe assessed the risk of bias of included trials using a modification of the Cochrane risk of bias tool. We performed a Bayesian fixed effect network meta-analysis and assessed the certainty of evidence using the GRADE approach. We identified 45 eligible trials (20,650 patients), 36 (19,350 patients) of which could be included in the network meta-analysis. 27 of 36 trials were rated at high risk of bias, primarily due to lack of blinding. Tocilizumab (20 more per 1000, 15 fewer to 59 more; low certainty) and sarilumab (11 more per 1000, 38 fewer to 55 more; low certainty) alone may not reduce the risk of death. Tocilizumab, in combination with corticosteroids, probably reduces the risk of death compared to corticosteroids alone (35 fewer per 1000, 52 fewer to 18 more; moderate certainty) and sarilumab, in combination with corticosteroids, may reduce the risk of death compared to corticosteroids alone (43 fewer, 73 fewer to 12 more; low certainty). Tocilizumab and sarilumab, both in combination with corticosteroids, may have similar effects (8 more per 1000, 20 fewer to 35 more; low certainty). ConclusionIL-6 receptor blockers, when added to standard care that includes corticosteroids, in patients with severe or critical COVID-19, probably reduce mortality. Tocilizumab and sarilumab may have similar effectiveness. Systematic review registrationNA What is already known on this topic?O_LIIL-6 receptor blockers have immunosuppressive effects that may be important in COVID-19 patients with immune system dysfunction and inflammation C_LIO_LICorticosteroids reduce the risk of death in patients with severe or critical COVID-19 C_LI What this study addsO_LIOur systematic review and network meta-analysis provides a comprehensive review of the evidence addressing the effects of IL-6 receptor blockers, alone or in combination with corticosteroids, in COVID-19 C_LIO_LIIL-6 receptor blockers when added to a standard care that includes corticosteroids, in patients with severe or critical COVID-19, probably reduce mortality. C_LIO_LITocilizumab and sarilumab in combination with corticosteroids may have similar effectiveness for reducing mortality. C_LI
ABSTRACT
Since the beginning of the SARS-CoV 2 pandemic, healthcare authorities have made clear that it is crucial to track and identify COVID-19 symptoms and seek medical attention in the presence of the first warning signs, as immediate medical attention can improve the patients prognosis. Therefore the present work aims to analyze the risks associated with the time between the patients first symptoms and hospitalization followed by death. A cross-sectional study was performed among Mexican population diagnosed with COVID-19 and hospitalized from March to January 2021. Four different Bayesian models were developed to asses the risk associated with different patient trajectories: symptoms-hospitalization and hospitalization-death. Comorbidities that could worsen the patient outcome were included as linear predictions; these analyses were further broken down to the different states of the Mexican Republic and the healthcare providers within. Model III was chosen as the best performance through a validation of leaving one out (LOO). Increased risk for hospitalization was observed at the global population level for chronic renal disease, whereas for death such was the case for COPD and the interaction of diabetes:hypertension:obesity. Our results show that there are differences in mortality between the states without accounting for institution and it is related to the prompt time of death or viceversa. Regarding the 6 healthcare providers included in the analysis differences were also found. While state-managed hospitals and private sector showed lower risks, in contrast the IMSS seems to be the one with the highest risk. The proposed modelling can be helpful to improve healthcare assistance at a regional level, additionally it could inform statistical parameter inference in epidemiological models.
