Search

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: Upper gastrointestinal bleeding is common among the critically ill. Recently, the Proton Pump Inhibitors (PPIs) vs. Histamine-2 Receptor Blockers for Ulcer Prophylaxis Therapy in the Intensive Care Unit (PEPTIC) trial suggested PPIs might increase mortality. We performed an updated meta-analysis to further inform discussion.Methods: We leveraged 2 recent systematic reviews to identify randomized controlled trials directly comparing PPIs and H-2 Receptor Antagonists (H2RAs) for stress ulcer prophylaxis in critically ill patients and reporting mortality. We extracted mortality data from each study and meta-analyzed them with the PEPTIC trial using a random effects model.Results: Of 28,559 total patients, 14,436 (50.5%) were allocated to PPI and 14,123 to H2RAs (49.5%). Compared to H2RAs, the pooled relative risk for mortality was 1.05 (95% confidence interval 1.00-1.10) with an estimated risk difference for mortality of 9 additional deaths per 1000 patients exposed to PPI (95% confidence interval 0-18); heterogeneity was low (I2 = 0%; P = 0.826).Conclusions: Stress ulcer prophylaxis with PPIs likely increases mortality compared to H2RAs. Whether stress ulcer prophylaxis is beneficial in critical care remains open to further study. [ABSTRACT FROM AUTHOR]

• A Bayesian re-analysis of remdesivir and corticosteroid randomized controlled trials was conducted. • Probabilities that remdesivir and corticosteroids reduced mortality by ≥1% were estimated. • Patients needing mechanical ventilation – 4% for remdesivir and 93% for corticosteroids. • Patients needing supplemental oxygen without mechanical ventilation – 81% for remdesivir and 93% for dexamethasone. • Patients who did not need oxygen support – neither remdesivir nor corticosteroids were likely to decrease mortality meaningfully. The global death toll from coronavirus disease 2019 (COVID-19) has exceeded 2 million, and treatments to decrease mortality are needed urgently. To examine the probabilities of a clinically meaningful reduction in mortality for remdesivir and systemic corticosteroids. This was a probabilistic re-analysis of clinical trial data for corticosteroids and remdesivir in the treatment of hospitalized patients with COVID-19 using a Bayesian random effects meta-analytic approach. Studies were identified from existing meta-analyses performed by the World Health Organization. Posterior probabilities of an absolute decrease in mortality compared with control patients, by subgroups based on oxygen requirements, were calculated for corticosteroids and remdesivir. Probabilities of ≥1%, ≥2% and ≥5% absolute decrease in mortality were quantified. For patients needing mechanical ventilation, the probability of ≥1% absolute decrease in mortality was 4% for remdesivir and 93% for corticosteroids. For patients needing supplemental oxygen without mechanical ventilation, the probability of ≥1% absolute decrease in mortality was 81% for remdesivir and 93% for dexamethasone. Finally, for patients who did not need oxygen support, the probability of ≥1% absolute decrease in mortality was 29% for remdesivir and 4% for dexamethasone. Using a Bayesian analytic approach, remdesivir had low probability of achieving a clinically meaningful reduction in mortality, except for patients needing supplemental oxygen without mechanical ventilation. Corticosteroids were more promising for patients needing oxygen support, especially mechanical ventilation. While awaiting more definitive studies, this probabilistic interpretation of the evidence will help to guide treatment decisions for clinicians, as well as guideline and policy makers. [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]

A letter to the editor and a response by Duminda N. Wijeysundera, W. Scott Beattie, Peter C. Austin, Janet E. Hux and Andreas Laupacis to letters about their article "Outcomes and Processes of Care Related to Preoperative Medical Consultation" in a 2010 issue are presented.

Background: International COVID-19 guidelines recommend thromboprophylaxis for non-critically ill inpatients to prevent thrombotic complications. It is still debated whether full-dose thromboprophylaxis reduces all-cause mortality. The main aim of this updated systematic review and meta-analysis is to evaluate the effect of full-dose heparin-based thromboprophylaxis on survival in hospitalized non-critically ill COVID-19 patients. Methods: A systematic review was performed across Pubmed/Medline, EMBASE, Cochrane Central Register of clinical trials, Clinicaltrials.gov, and medRxiv.org from inception to November 2022. We conducted a meta-analysis of randomized clinical trials (RCTs) comparing full-dose heparin-based anticoagulation to prophylactic or intermediate dose anticoagulation or standard treatment in hospitalized non-critically ill COVID-19 patients. The risk of bias was assessed using the Cochrane risk-of-bias tool for randomized trials and Grading of Recommendations Assessment, Development and Evaluation was applied. The primary outcome was all-cause mortality at the longest follow-up available. Results: We identified 6 multicenter RCTs involving 3297 patients from 13 countries across 4 continents. The rate of all-cause mortality was 6.2% (103/1662) in the full-dose group vs 7.7% (126/1635) in the prophylactic or intermediate dose group (Risk Ratio [RR] = 0.76; 95% confidence interval [CI] = 0.59–0.98; P = 0.037). The probabilities of any mortality difference and of NNT ≤ 100 were estimated at 98.2% and 84.5%, respectively. The risk of bias was low for all included RCTs and the strength of the evidence was "moderate." Conclusion: Our meta-analysis of high-quality multicenter RCTs suggests that full-dose anticoagulation with heparin or low molecular weight heparin reduces all-cause mortality in hospitalized non-critically ill COVID-19 patients. Study registration: PROSPERO, review no. CRD42022348993. [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]

• Styphylococcus aureus bacteremia (SAB) is common in low and middle-income countries (LMIC). • LMIC are poorly represented in SAB research. • In-hospital mortality for SAB is much higher in LMIC than in high-income countries. Staphylococcus aureus bacteremia (SAB) is a common infection worldwide. We compared SAB mortality in low- and middle-income countries (LMIC) versus high-income countries (HIC) in a meta-analysis. We searched MEDLINE, Embase, and Cochrane Database of Systematic Reviews from 1991-2021 and included observational, single-country studies on patients with positive blood cultures for S. aureus. The main outcome was the proportion of patients with SAB who died in the hospital. A generalized linear mixed random-effects model was used to pool estimates, and a meta-regression was used to adjust for study-level characteristics. A total of 332 studies involving 517,671 patients in 39 countries were included. No study was conducted in a low-income country. Only 33 (10%) studies were performed in middle-income countries (MIC), which described 6,216 patients. The pooled in-hospital mortality was 32.4% (95% confidence interval [CI] 27.2%-38.2%, T2 = 0.3063) in MIC and 22.3% (95% CI 20.1%-24.6%, T2 = 0.3257) in HIC. In a meta-regression model, MIC had higher in-hospital mortality (adjusted odds ratio 1.37, 95% CI 1.11-1.71; P = 0.0042) than HIC. In SAB studies, LMIC are poorly represented. In-hospital mortality was significantly higher in MIC than in HIC. Research should be conducted in LMIC to characterize differences in care processes driving the mortality gap. [ABSTRACT FROM AUTHOR]

Precise estimates of mortality in Staphylococcus aureus bacteraemia (SAB) are important to convey prognosis and guide the design of interventional studies. We performed a systematic review and meta-analysis to estimate all-cause mortality in SAB and explore mortality change over time. The MEDLINE and Embase databases, as well as the Cochrane Database of Systematic Reviews, were searched from January 1, 1991 to May 7, 2021. Human observational studies on patients with S. aureus bloodstream infection were included. The study analyzed data of patients with a positive blood culture for S. aureus. Two independent reviewers extracted study data and assessed risk of bias using the Newcastle–Ottawa Scale. A generalized, linear, mixed random effects model was used to pool estimates. A total of 341 studies were included, describing a total of 536,791 patients. From 2011 onward, the estimated mortality was 10.4% (95% CI, 9.0%–12.1%) at 7 days, 13.3% (95% CI, 11.1%–15.8%) at 2 weeks, 18.1% (95% CI, 16.3%–20.0%) at 1 month, 27.0% (95% CI, 21.5%–33.3%) at 3 months, and 30.2% (95% CI, 22.4%–39.3%) at 1 year. In a meta-regression model of 1-month mortality, methicillin-resistant S. aureus had a higher mortality rate (adjusted OR (aOR): 1.04; 95% CI, 1.02–1.06 per 10% increase in methicillin-resistant S. aureus proportion). Compared with prior to 2001, more recent time periods had a lower mortality rate (aOR: 0.88; 95% CI, 0.75–1.03 for 2001–2010; aOR: 0.82; 95% CI, 0.69–0.97 for 2011 onward). SAB mortality has decreased over the last 3 decades. However, more than one in four patients will die within 3 months, and continuous improvement in care remains necessary. [ABSTRACT FROM AUTHOR]

Background Deaths following Staphylococcus aureus bacteremia (SAB) may be related or unrelated to the infection. In SAB therapeutics research, the length of follow-up should be optimized to capture most attributable deaths and minimize nonattributable deaths. We performed a secondary analysis of a systematic review to describe attributable mortality in SAB over time. Methods We systematically searched Medline, Embase, and Cochrane Database of Systematic Reviews from 1 January 1991 to 7 May 2021 for human observational studies of SAB. To be included in this secondary analysis, the study must have reported attributable mortality. Two reviewers extracted study data and assessed risk of bias independently. Pooling of study estimates was not performed due to heterogeneity in the definition of attributable deaths. Results Twenty-four observational cohort studies were included. The median proportion of all-cause deaths that were attributable to SAB was 77% (interquartile range [IQR], 72%–89%) at 1 month and 62% (IQR, 58%–75%) at 3 months. At 1 year, this proportion was 57% in 1 study. In 2 studies that described the rate of increase in mortality over time, 2-week follow-up captured 68 of 79 (86%) and 48 of 57 (84%) attributable deaths that occurred by 3 months. By comparison, 1-month follow-up captured 54 of 57 (95%) and 56 of 60 (93%) attributable deaths that occurred by 3 months in 2 studies. Conclusions The proportion of deaths that are attributable to SAB decreases as follow-up lengthens. Follow-up duration between 1 and 3 months seems optimal if evaluating processes of care that impact SAB mortality. Clinical Trials Registration PROSPERO CRD42021253891. [ABSTRACT FROM AUTHOR]

In multivariable analysis of associations between initial antibiotic therapy and clinical outcomes in 5005 patients with microbiologically confirmed Streptococcus pneumoniae infections,"discordant" empiric antibiotic therapy was not associated with 30-day mortality rate (hazard ratio, 0.94; 95% confidence interval, .67-1.32). [ABSTRACT FROM AUTHOR]