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The benefits of remdesivir in the treatment of hospitalized patients with COVID-19 remain debated with the National Institutes of Health and the World Health Organization providing contradictory recommendations for and against use. To evaluate the role of remdesivir for hospitalized inpatients as a function of oxygen requirements. Beginning with our prior systematic review, we searched MEDLINE using PubMed from 15 January 2021 through 5 May 2022. Randomised controlled trials; all languages. All hospitalized adults with COVID-19. Remdesivir, in comparison to either placebo, or standard of care. We used the ROB-2 criteria. The primary outcome was mortality, stratified by oxygen use (none, supplemental oxygen without mechanical ventilation, and mechanical ventilation). We conducted a frequentist random effects meta-analysis on the risk ratio scale and, to contextualize the probabilistic benefits, we also performed a Bayesian random effects meta-analysis on the risk difference scale. A ≥1% absolute risk reduction was considered clinically important. We identified eight randomized trials, totaling 10 751 participants. The risk ratio for mortality comparing remdesivir vs. control was 0.77 (95% CI, 0.5–1.19) in the patients who did not require supplemental oxygen; 0.89 (95% CI, 0.79–0.99) for nonventilated patients requiring oxygen; and 1.08 (95% CI, 0.88–1.31) in the setting of mechanical ventilation. Using neutral priors, the probabilities that remdesivir reduces mortality were 76.8%, 93.8%, and 14.7%, respectively. The probability that remdesivir reduced mortality by ≥ 1% was 77.4% for nonventilated patients requiring oxygen. Based on this meta-analysis, there is a high probability that remdesivir reduces mortality for nonventilated patients with COVID-19 requiring supplemental oxygen therapy. Treatment guidelines should be re-evaluated. [ABSTRACT FROM AUTHOR]

Background: The Systolic Blood Pressure Intervention Trial (SPRINT) was a randomized controlled trial that studied 9361 adults ≥50 years of age with systolic blood pressure >130 mm Hg and ≥1 cardiovascular risk factors. Patients were randomized to intensive (≤120 mm Hg) or standard (≤140 mm Hg) systolic targets. In August 2016, a limited dataset was released for secondary analysis. We hypothesized that excessive lowering of diastolic blood pressure could cause harm. Using the data from SPRINT, we sought to determine whether the development of diastolic hypotension during treatment was associated with adverse outcomes.Methods: We included 8046 patients from SPRINT with a baseline diastolic blood pressure ≥65 mm Hg at study enrollment (4041 intensive target; 4005 standard target). Using Cox proportional hazards models, we evaluated the association between the development of diastolic hypotension (defined as ≤55 mm Hg and modeled as a time-dependent covariate) and the combined outcome of cardiovascular morbidity (myocardial infarction, other acute coronary syndromes, stroke, heart failure) and all-cause death.Results: In multivariable analyses, patients who developed diastolic hypotension had an increased risk for our primary outcome (hazard ratio [HR] 1.67; 95% confidence interval [CI] 1.24-2.26). This was true in both the intensive (HR 1.53; 95% CI, 1.04-2.26) and standard (HR 2.23; 95% CI, 1.40-3.54; P for interaction = .09) treatment arms.Conclusions: We found an association between diastolic hypotension and the combined endpoint of cardiovascular events and all-cause mortality among SPRINT participants with normal to high diastolic blood pressure at entry. Attention to diastolic blood pressure may be important for optimizing outcomes when targeting systolic blood pressure reduction. [ABSTRACT FROM AUTHOR]

Studies comparing shorter and longer antibiotic treatment durations are increasingly common. Randomized controlled trials (RCTs) are an ideal methodological approach to study antibiotic treatment durations; however, these trials can be logistically and financially challenging to conduct. In this narrative review, we sought to compare the strengths and limitations of observational study data with those of RCT data in evaluating antibiotic treatment durations. We used uncomplicated Gram-negative bacteraemia as an illustrative case example because several published RCTs and observational studies have been conducted in similar patient populations. We searched MEDLINE for articles comparing treatment durations for gram-negative bacteremia from inception to June 9th, 2022. We included studies reporting on all-cause mortality and/or relapse at day 28-30. Data comparing short- versus long-course therapy were pooled by Bayesian random effects meta-analyses to assess the odds ratios (OR) of all-cause mortality and relapse at 30 days, stratified by study design. Parameters were summarized with median and 95% highest-density credible intervals (CrI). Posterior probabilities of OR > 1.0 were estimated. Observational studies were further examined to determine if and how they addressed potential sources of bias. We identified 1671 unique records and included 10 studies (seven observational and three RCTs). With respect to 30-day mortality, the Bayesian posterior probability that a longer course of therapy was better (i.e. OR >1.0) was 42% in RCTs (OR, 0.94; 95% CrI, 0.51–1.68) and 91% in observational studies (OR, 1.25; 95% CrI, 0.88–1.73). No observational study fully addressed all potential sources of bias. On the basis of our findings, we discuss future directions for antibiotic treatment duration trials, including approaches to limit sources of bias in observation data and novel trial designs. [ABSTRACT FROM AUTHOR]

Randomized controlled trials (RCT) established the mortality reduction by tocilizumab (Actemra), baricitinib (Olumiant), and sarilumab (Kevzara) in hospitalized COVID-19 patients. However, uncertainty remains about which treatment performs best in patients receiving corticosteroids. To estimate probabilities of noninferiority between baricitinib and sarilumab compared to tocilizumab in patients treated with corticosteroids. PubMed, Embase, Cochrane Library, and MedRxiv. Eligible RCTs assigning hospitalized adults with COVID-19 treated with corticosteroids to tocilizumab or baricitinib or sarilumab versus standard of care or placebo (control). Reviewers independently abstracted published data and assessed study quality with the Risk of Bias 2 tool. Unpublished data, if required, were requested from authors of included studies. The outcome of interest was all-cause mortality at 28 days. Twenty-seven RCTs with 13 549 patients were included. Overall, the risk of bias was low. Bayesian pairwise meta-analyses were used to aggregate results of each treatment versus control. The average odds ratio for mortality was 0.78 (95% credible interval [CrI]: 0.65, 0.94) for tocilizumab; 0.78 (95% CrI: 0.56, 1.03) for baricitinib; and 0.91 (95% CrI: 0.60, 1.40) for sarilumab. The certainty of evidence (GRADE) ranged from moderate to low. Bayesian meta-regressions with multiple priors were used to estimate probabilities of noninferiority (margin of 13% greater effect by tocilizumab). Compared to tocilizumab, there were ≤94% and 90% probabilities of noninferiority with baricitinib and sarilumab, respectively. All but two studies included data with only indirect evidence for the comparison of interest. Among hospitalized COVID-19 treated with corticosteroids, there are high probabilities that both baricitinib and sarilumab are associated with similar mortality reductions in comparison to tocilizumab. [ABSTRACT FROM AUTHOR]

In Staphylococcus aureus bacteremia, mortality rates in randomized controlled trials (RCTs) are consistently lower than observational studies. Stringent eligibility criteria and omission of early deaths in RCTs contribute to this mortality gap. Clinicians should acknowledge the possibility of a lower treatment effect when applying RCT results to bedside care. [ABSTRACT FROM AUTHOR]