Real World Evidence of Neutralizing Monoclonal Antibodies for Preventing Hospitalization and Mortality in COVID-19 Outpatients

Background: Neutralizing monoclonal antibodies (mAbs) are authorized for early symptomatic COVID-19 patients. Whether mAbs are effective against the SARS-CoV-2 Delta variant, among vaccinated patients, or for prevention of mortality remains unknown. Objective: To evaluate the effectiveness of mAb treatment in preventing progression to severe disease during the Delta phase of the pandemic and based on key baseline risk factors. Design, Setting, and Patients: Observational cohort study of non-hospitalized adult patients with SARS-CoV-2 infection from November 2020-October 2021, using electronic health records from a statewide health system plus state-level vaccine and mortality data. Using propensity matching, we selected approximately 2.5 patients not receiving mAbs for each patient who received mAbs. Exposure: Neutralizing mAb treatment under emergency use authorization Main Outcomes: The primary outcome was 28-day hospitalization; secondary outcomes included mortality and severity of hospitalization. Results: Of 36,077 patients with SARS-CoV-2 infection, 2,675 receiving mAbs were matched to 6,677 not receiving mAbs. Compared to mAb-untreated patients, mAb-treated patients had lower all-cause hospitalization (4.0% vs 7.7%; adjusted OR 0.48, 95%CI 0.38-0.60) and all-cause mortality (0.1% vs. 0.9%; adjusted OR 0.11, 95%CI 0.03-0.29) to day 28; differences persisted to day 90. Among hospitalized patients, mAb-treated patients had shorter hospital length of stay (5.8 vs. 8.5 days) and lower risk of mechanical ventilation (4.6% vs. 16.6%). Relative effectiveness was similar in preventing hospitalizations during the Delta variant phase (adjusted OR 0.35, 95%CI 0.25-0.50) and across subgroups. Lower number-needed-to-treat (NNT) to prevent hospitalization were observed for subgroups with higher baseline risk of hospitalization (e.g., multiple comorbidities (NNT=17) and not fully vaccinated (NNT=24) vs. no comorbidities (NNT=88) and fully vaccinated (NNT=81). Conclusion: Real-world evidence demonstrated mAb effectiveness in reducing hospitalization among COVID-19 outpatients, including during the Delta variant phase, and conferred an overall 89% reduction in 28-day mortality. Early outpatient treatment with mAbs should be prioritized, especially for individuals with highest risk for hospitalization.

Clinical Utility of KidneyIntelX in Early Stages of Diabetic Kidney Disease in the CANVAS Trial

<b><i>Introduction:</i></b> KidneyIntelX is a composite risk score, incorporating biomarkers and clinical variables for predicting progression of diabetic kidney disease (DKD). The utility of this score in the context of sodium glucose co-transporter 2 inhibitors and how changes in the risk score associate with future kidney outcomes are unknown. <b><i>Methods:</i></b> We measured soluble tumor necrosis factor receptor (TNFR)-1, soluble TNFR-2, and kidney injury molecule 1 on banked samples from CANagliflozin cardioVascular Assessment Study (CANVAS) trial participants with baseline DKD (estimated glomerular filtration rate [eGFR] 30–59 mL/min/1.73 m² or urine albumin-to-creatinine ratio [UACR] ≥30 mg/g) and generated KidneyIntelX risk scores at baseline and years 1, 3, and 6. We assessed the association of baseline and changes in KidneyIntelX with subsequent DKD progression (composite outcome of an eGFR decline of ≥5 mL/min/year [using the 6-week eGFR as the baseline in the canagliflozin group], ≥40% sustained decline in the eGFR, or kidney failure). <b><i>Results:</i></b> We included 1,325 CANVAS participants with concurrent DKD and available baseline plasma samples (mean eGFR 65 mL/min/1.73 m² and median UACR 56 mg/g). During a mean follow-up of 5.6 years, 131 participants (9.9%) experienced the composite kidney outcome. Using risk cutoffs from prior validation studies, KidneyIntelX stratified patients to low- (42%), intermediate- (44%), and high-risk (15%) strata with cumulative incidence for the outcome of 3%, 11%, and 26% (risk ratio 8.4; 95% confidence interval [CI]: 5.0, 14.2) for the high-risk versus low-risk groups. The differences in eGFR slopes for canagliflozin versus placebo were 0.66, 1.52, and 2.16 mL/min/1.73 m² in low, intermediate, and high KidneyIntelX risk strata, respectively. KidneyIntelX risk scores declined by 5.4% (95% CI: −6.9, −3.9) in the canagliflozin arm at year 1 versus an increase of 6.3% (95% CI: 3.8, 8.7) in the placebo arm (<i>p</i> &#x3c; 0.001). Changes in the KidneyIntelX score at year 1 were associated with future risk of the composite outcome (odds ratio per 10 unit decrease 0.80; 95% CI: 0.77, 0.83; <i>p</i> &#x3c; 0.001) after accounting for the treatment arm, without evidence of effect modification by the baseline KidneyIntelX risk stratum or by the treatment arm. <b><i>Conclusions:</i></b> KidneyIntelX successfully risk-stratified a large multinational external cohort for progression of DKD, and greater numerical differences in the eGFR slope for canagliflozin versus placebo were observed in those with higher baseline KidneyIntelX scores. Canagliflozin treatment reduced KidneyIntelX risk scores over time and changes in the KidneyIntelX score from baseline to 1 year associated with future risk of DKD progression, independent of the baseline risk score and treatment arm.

Clinical Relevance of Absolute BK Polyoma Viral Load Kinetics in Patients With Biopsy Proven BK Polyomavirus Associated Nephropathy

Introduction: The absolute BK viral load is an important diagnostic surrogate for BK polyomavirus associated nephropathy (PyVAN) after renal transplant (KTX) and serial assessment of BK viremia is recommended. However, there is no data indicating which particular viral load change, i.e., absolute vs. relative viral load changes (copies/ml; percentage of the preceding viremia) is associated with worse renal graft outcomes.Materials and Methods: In this retrospective study of 91 biopsy proven PyVAN, we analyzed the interplay of exposure time, absolute and relative viral load kinetics, baseline risk, and treatment strategies as risk factors for graft loss after 2 years using a multivariable Poisson-model.Results: We compared two major treatment strategies: standardized immunosuppression (IS) reduction (n = 53) and leflunomide (n = 30). The median viral load at the index biopsy was 2.15E+04 copies/ml (interquartile range [IQR] 1.70E+03–1.77E+05) and median peak viremia was 3.6E+04 copies/ml (IQR 2.7E+03–3.3E+05). Treatment strategies and IS-levels were not related to graft loss. After correction for baseline viral load and estimated glomerular filtration rate (eGFR), absolute viral load decrease/unit remained an independent risk factor for graft loss [incidence rate ratios [IRR] = 0.77, (95% CI 0.61–0.96), p = 0.02].Conclusion: This study provides evidence for the prognostic importance of absolute BK viremia kinetics as a dynamic parameter indicating short-term graft survival independently of other established risk factors.

Fully Vaccinated and Boosted Patients Requiring Hospitalization for COVID-19: an Observational Cohort Analysis

Objective: Real-world data on the effectiveness of boosters against COVID-19, especially as new variants continue to emerge, is limited. It is our objective to assess demographic, clinical, and outcome variables of patients requiring hospitalization for severe SARS-CoV-2 infection comparing fully vaccinated and boosted (FV&B) and unvaccinated (UV) patients. Methods: This multicenter observational cohort analysis compared demographic, clinical, and outcome variables in FV&B and UV adults hospitalized for COVID-19. A sub-analysis of FV&B patients requiring intensive care (ICU) care versus non-ICU care was performed to describe and analyze common symptom presentations, initial vital signs, initial laboratory workup, and pertinent medication use in these two groups. Results: Between August 12th, 2021 and December 6th, 2021, 4,571 patient encounters had a primary diagnosis of COVID-19 and required inpatient treatment at an acute-care hospital system in Southeastern Michigan. Of the 4,571 encounters requiring hospitalization, 65(1.4%) were FV&B and 2,935(64%) were UV. FV&B individuals were older (74 [67, 81] vs 58 [45, 70]; p <0.001) with a higher proportion of immunocompromised individuals (32.3% vs 10.4%; p<0.001). Despite a significantly higher baseline risk of in-hospital mortality in the FV&B group compared to the UV (Elixhauser 16 vs 8 (p <0.001)), there was a trend toward lower in-hospital mortality (7.7% vs 12.1%; p=0.38) among FV&B patients. Other severe outcomes followed this same trend, with 7.7% of FV&B vs 11.1% UV patients needing mechanical ventilation and 4.6% vs 10.6% of patients needing vasopressors in each group, respectively (p=0.5 and 0.17). Conclusions: Fully vaccinated and boosted individuals requiring hospital-level care for breakthrough COVID-19 tended to have less severe outcomes despite appearing to be higher risk at baseline when compared to unvaccinated individuals during the same time period. Specifically, there was a trend that FV&B group had lower rates of mechanical ventilation, use of vasopressors, and in-hospital mortality. As COVID-19 continues to spread, larger expansive trials are needed to further identify risk factors for severe outcomes among the FV&B population.

Potential application of Rapid Antigen Diagnostic Tests for the detection of infectious individuals attending mass gatherings: a simulation study

Rapid Antigen Diagnostic Tests (RADTs) for the detection of SARS-CoV-2 offer advantages in that they are cheaper and faster than currently used PCR tests but have reduced sensitivity and specificity. One potential application of RADTs is to facilitate gatherings of individuals, through testing of attendees at the point of, or immediately prior to entry at a venue. Understanding the baseline risk in the tested population is of particular importance when evaluating the utility of applying diagnostic tests for screening purposes. We used incidence data to estimate the prevalence of infectious individuals in the community at a particular time point and simulated mass gatherings by sampling from a series of age cohorts. Nine different illustrative scenarios were simulated, small (n=100), medium (n=1000) and large (n=10,000) gatherings each with 3 possible age constructs: mostly younger, mostly older or a gathering with equal numbers from each age cohort. For each scenario, we estimated the prevalence of infectious attendees, then simulated the likely number of positive and negative test results, the proportion of cases detected and the corresponding positive and negative predictive values, and the cost per case identified. Our findings suggest that for each detected individual on a given day, there are likely to be 13.8 additional infectious individuals also present in the community. Prevalence of infectious individuals at events was highest with mostly younger attendees (1.00%), followed by homogenous age gatherings (0.55%) and lowest with mostly older events (0.26%). For small events (100 attendees) the expected number of infectious attendees was less than 1 across all age constructs of attendees. For large events (10,000 attendees) the expected number of infectious attendees ranged from 26 (95% confidence intervals 12 to 45) for mostly older events, to almost 100 (95% confidence intervals 46 to 174) infectious attendees for mostly younger attendees. Given rapid changes in SARS-CoV-2 incidence over time, we developed an RShiny app to allow users to run updated simulations for specific events.

Do baseline characteristics and treatments account for geographical disparities in the outcomes of patients with newly diagnosed atrial fibrillation? The prospective GARFIELD-AF registry

ObjectiveIn patients with newly diagnosed atrial fibrillation (AF), do baseline risk factors and stroke prevention strategies account for the geographically diverse outcomes.DesignGlobal Anticoagulant Registry in the FIELD-Atrial Fibrillation is a prospective multinational non-interventional registry of patients with newly diagnosed AF (n=52 018 patients).SettingInvestigator sites (n=1317) were representative of the care settings/locations in each of the 35 participating countries. Treatment decisions were all determined by the local responsible clinicians.ParticipantsThe patients (18 years and over) with newly diagnosed AF had at least 1 investigator-determined stroke risk factor and patients were not required to meet specific thresholds of risk score for anticoagulant treatment.Main outcomes and measuresObserved 1-year event rates and risk-standardised rates were derived.ResultsRates of death, non-haemorrhagic stroke/systemic embolism and major bleeding varied more than three-to-four fold across countries even after adjustment for baseline factors and antithrombotic treatments. Rates of anticoagulation and antithrombotic treatment varied widely. Patients from countries with the highest rates of cardiovascular mortality and stroke were among the least likely to receive oral anticoagulants. Beyond anticoagulant treatment, variations in the treatment of comorbidities and lifestyle factors may have contributed to the variations in outcomes. Countries with the lowest healthcare Access and Quality indices (India, Ukraine, Argentina, Brazil) had the highest risk-standardised mortality.ConclusionThe variability in outcomes across countries for patients with newly diagnosed AF is not accounted for by baseline characteristics and antithrombotic treatments. Residual mortality rates were correlated with Healthcare Access and Quality indices. The findings suggest the management of patients with AF needs to not only address guideline indicated and sustained anticoagulation, but also the treatment of comorbidities and lifestyle factors.Trial registration numberNCT01090362.

EARLY LENZILUMAB TREATMENT OF COVID-19 PATIENTS USING C-REACTIVE PROTEIN AS A BIOMARKER IMPROVES EFFICACY: RESULTS FROM THE PHASE 3 LIVE-AIR TRIAL

Objective: The LIVE-AIR trial demonstrated that the anti-GM-CSF monoclonal antibody, lenzilumab improved the likelihood of survival without invasive mechanical ventilation (SWOV) in COVID-19 patients; with greatest effect in those with baseline CRP below the median baseline value of 79 mg/L. Similar to GM-CSF, C-reactive protein (CRP) levels are correlated with COVID-19 severity. This current analysis assessed the utility of baseline CRP levels to guide treatment with lenzilumab. Design: LIVE-AIR was a phase 3, double-blind, placebo-controlled trial. Participants were randomized 1:1 and stratified according to age and disease severity, to receive lenzilumab or placebo on Day 0, were followed through Day 28. Setting: Secondary and tertiary care hospitals in the US and Brazil. Participants: 520 hospitalized COVID-19 participants with SpO2≤94% on room air or required supplemental oxygen but not invasive mechanical ventilation were included. Interventions: Lenzilumab (1800mg; divided as 3 doses, q8h) or placebo infusion alongside standard treatments including corticosteroids and remdesivir. Main outcome measures: A multi-variate logistic regression analysis assessed key baseline risk factors for progression to IMV or death. The primary endpoint, SWOV, and key secondary endpoints were analyzed according to baseline CRP levels in all participants with CRP values. Results: The multi-variate analysis demonstrated that elevated baseline plasma CRP was the most predictive feature for progression to IMV or death. SWOV was achieved in 152 (90%; 95%CI: 85to 94) lenzilumab and 183 (79%; 72 to 84) placebo participants with baseline CRP<150 mg/L and its likelihood was greater with lenzilumab than placebo (HR: 2.54; 95%CI, 1.46 to 4.41; p=0.0009) but not in participants with CRP≥150 mg/L at baseline. CRP as a covariate in the overall analysis demonstrated a statistically significant interaction with lenzilumab treatment (p=0.044). Grade ≥ 3 adverse events in participants with baseline CRP<150 mg/L were reported in 18% and 28% in lenzilumab or placebo, respectively. No treatment-emergent serious adverse events were attributable to lenzilumab. Conclusion: These finding suggest that COVID-19 participants with low baseline CRP levels achieve the greatest clinical benefit from lenzilumab and that baseline CRP levels may be a useful biomarker to guide therapeutic intervention. Trial Registration: ClinicalTrials.gov NCT04351152

How Singapore’s Sovereign Debt Risk Has Changed from 2016 to 2021

In this paper, I build an economic model and adapt it to fit Singapore&rsquo;s economic and historical background. My empirical analysis is based on data about external debt to GDP, foreign investment, and net export products and partners. But I also address concerns about risk factors coming from covid and the oil crisis. In my analysis, even in the worst case, Singapore is not going to be worse than the Netherlands in the IIR rating, which corresponds to an IIR rating of 90. In contrast to my baseline, risk assessment for Singapore is a rating of 93.

Impact of a Patient’s Baseline Risk on the Relative Benefit and Harm of a Preventive Treatment Strategy: Applying Trial Results in Clinical Decision Making

Background For translating an overall trial result into an individual patient’s expected absolute treatment effect, differences in relative treatment effect between patients need to be taken into account. The aim of this study was to evaluate whether relative treatment effects of medication in 2 large contemporary trials are influenced by multivariable baseline risk of an individual patient. Methods and Results In 9361 patients from SPRINT (Systolic Blood Pressure Intervention Trial), risk of major adverse cardiovascular events was assessed using a newly derived risk model. In 18 133 patients from the RE‐LY (Randomized Evaluation of Long‐Term Anticoagulant Therapy) trial, risk of stroke or systemic embolism and major bleeding was assessed using the Global Anticoagulant Registry in the Field–Atrial Fibrillation risk model. Heterogeneity of trial treatment effect was assessed using Cox models of trial allocation, model linear predictor, and their interaction. There was no significant interaction between baseline risk and relative treatment effect from intensive blood pressure lowering in SPRINT ( P =0.92) or from dabigatran compared with warfarin for stroke or systemic embolism in the RE‐LY trial ( P =0.71). There was significant interaction between baseline risk and treatment effect from dabigatran versus warfarin in the RE‐LY trial ( P <0.001) for major bleeding. Quartile‐specific hazard ratios for bleeding ranged from 0.40 (95% CI, 0.26–0.61) to 1.04 (95% CI, 0.83–1.03) for dabigatran, 110 mg, and from 0.61 (95% CI, 0.42–0.88) to 1.20 (95% CI, 0.97–1.50) for dabigatran, 150 mg, compared with warfarin. Conclusions Effect modification of relative treatment effect by individual baseline event risk should be assessed systematically in randomized clinical trials using multivariate risk prediction, not only in terms of treatment efficacy but also for important treatment harms, as a prespecified analysis. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01206062.