Risk of Cardiovascular Events after Covid-19: a double-cohort study

Objective: To determine absolute and relative risks of either symptomatic or asymptomatic SARS-CoV-2 infection for late cardiovascular events and all-cause mortality. Methods: We conducted a retrospective double-cohort study of patients with either symptomatic or asymptomatic SARS-CoV-2 infection [COVID-19(+) cohort] and its documented absence [COVID-19(-) cohort]. The study investigators drew a simple random sample of records from all Oregon Health & Science University (OHSU) Healthcare patients (N=65,585) with available COVID-19 test results, performed 03.01.2020 - 09.13.2020. Exclusion criteria were age < 18y and no established OHSU care. The primary outcome was a composite of cardiovascular morbidity and mortality. All-cause mortality was the secondary outcome. Results: The study population included 1355 patients (mean age 48.7 ± 20.5 y; 770(57%) female, 977(72%) white non-Hispanic; 1072(79%) insured; 563(42%) with cardiovascular disease (CVD) history). During a median 6 months at risk, the primary composite outcome was observed in 38/319 (12%) COVID-19(+) and 65/1036 (6%) COVID-19(-) patients (p=0.001). In Cox regression adjusted for demographics, health insurance, and reason for COVID-19 testing, SARS-CoV-2 infection was associated with the risk of the primary composite outcome (HR 1.71; 95%CI 1.06-2.78; p=0.029). Inverse-probability-weighted estimation, conditioned for 31 covariates, showed that for every COVID-19(+) patient, the average time to all-cause death was 65.5 days less than when all these patients were COVID-19(-): average treatment effect on the treated -65.5 (95%CI -125.4 to -5.61) days; p=0.032. Conclusions: Either symptomatic or asymptomatic SARS-CoV-2 infection is associated with increased risk of late cardiovascular outcomes and has a causal effect on all-cause mortality in a late post-COVID-19 period.

Cardiovascular Characteristics and Outcomes of Young Patients with COVID-19

Although 18–45-year-old (y-o) patients represent a significant proportion of patients hospitalized for COVID-19, data concerning the young population remain scarce. The Critical COVID France (CCF) study was an observational study including consecutive patients hospitalized for COVID-19 in 24 centers between 26 February and 20 April 2020. The primary composite outcome included transfer to the intensive care unit (ICU) or in-hospital death. Secondary outcomes were cardiovascular (CV) complications. Among 2868 patients, 321 (11.2%) patients were in the 18–45-y-o range. In comparison with older patients, young patients were more likely to have class 2 obesity and less likely to have hypertension, diabetes and dyslipidemia. The primary outcome occurred less frequently in 18–45-y-o patients in comparison with patients > 45 years old (y/o) (16.8% vs. 30.7%, p < 0.001). The 18–45-y-o patients presented with pericarditis (2.2% vs. 0.5%, p = 0.003) and myocarditis (2.5% vs. 0.6%, p = 0.002) more frequently than patients >45 y/o. Acute heart failure occurred less frequently in 18–45-y-o patients (0.9% vs. 7.2%, p < 0.001), while thrombotic complications were similar in young and older patients. Whereas both transfer to the ICU and in-hospital death occurred less frequently in young patients, COVID-19 seemed to have a particular CV impact in this population.

Colchicine Is Safe Though Ineffective in the Treatment of Severe COVID-19: a Randomized Clinical Trial (COLCHIVID)

Background Colchicine is an available, safe, and effective anti-inflammatory drug and has been suggested as a COVID-19 treatment, but its usefulness in hospitalized severe COVID-19 patients has not been thoroughly demonstrated. Objective To address the safety and efficacy of colchicine in hospitalized patients with severe COVID-19. Design We conducted a triple-blind parallel non-stratified placebo-controlled clinical trial. Participants We recruited 116 hospitalized patients with severe COVID-19 in Mexico. Interventions Patients were randomized to receive 1.5 mg of colchicine or placebo at the time of the recruitment in the study (baseline) and 0.5 mg BID PO to complete 10 days of treatment. Main Measures The primary composite outcome was the progression to critical disease or death. Besides, we evaluated immunological features at baseline and after recovery or disease progression in 20 patients. Key Results Fifty-six patients were allocated to colchicine and 60 patients received placebo. The study was suspended after the second interim analysis demonstrated colchicine had no effect on the primary outcome (OR 0.83, 95%CI 0.35–1.93, P = 0.67), nor in the days of ICU and hospital stays. Adverse events were similar between groups (OR 1.63, 95% CI 0.66–3.88, P = 0.37). After colchicine treatment, patients had higher BUN and lower serum levels of IL-8, IL-12p70, and IL-17A. Conclusions Colchicine is safe but not effective in the treatment of severe COVID-19. Trial Registration ClinicalTrials.gov Identifier: NCT04367168.

Risk Stratification for Acute Arterial and Venous Thromboembolism using CHA 2DS 2-VASc Score in Hospitalized COVID-19 Patients: A Multicenter Study

Introduction: Arterial and venous thromboembolism are common complications in COVID-19. Micro-macro thrombosis-related organ dysfunction can confer an increased risk for mortality. The optimal dosage of anticoagulation (AC) in COVID-19 patients remains unclear. Interim data from adaptive randomized control trials (ATTACC, REMAP-CAP, and ACTIV-4a) showed divergent results of therapeutic AC (TAC) versus usual care AC for the primary outcome of organ support free days in hospitalized COVID-19 patients. Components of CHA 2DS 2-VASc, a model originally built for predicting ischemic stroke in atrial fibrillation, are consistent with independent risk factors for COVID-19 severity and mortality. Herein, we analyzed the performance of the CHA 2DS 2-VASc model in hospitalized COVID-19 patients for predicting arterial and venous thromboembolic events, which could potentially aid in risk stratification of hospitalized patients and guide AC dosing. Methods: This is a large, retrospective, multicenter cohort study that included all adult patients from one tertiary care and five community hospitals with PCR-proven SARS-CoV-2 infection between 3/1/2020 and 12/1/2020. The primary composite outcome was acute arterial thromboembolism (ATE) and venous thromboembolism (VTE). We identified patients with ATE [cerebrovascular accident (CVA), myocardial infarction (MI) including both ST-segment elevation MI and non-ST-segment elevation MI], and VTE [deep vein thrombosis (DVT) and pulmonary embolism (PE)] using ICD -10 codes. Mean and standard deviation were reported for continuous variables; proportions were reported for categorical variables. To compare the groups, the Chi-square test was used for categorical variables, and the t-test was used for continuous variables. CHA 2DS 2-VASc scores were calculated on admission and were used as a measure of the predictive accuracy of the scoring system. Sensitivity and specificity with different cut-offs of CHA 2DS 2-VASc scores were calculated. All statistical tests were 2-sided with an α (significance) level of 0.05. All data were analyzed using R version 4.0.5. Results: Among 3526 patients, a total of 619 patients had thromboembolic events: 383 had ATE and 236 had VTE. Of 383 patients who had ATE, 350 patients were found to have acute MI, 48 had CVA, and 15 had both MI and CVA. In patients with VTE, 134 had DVT, 168 had PE, and 66 had both DVT and PE (Figure 1). We analyzed the primary composite outcome of ATE and VTE (group 1) vs no ATE and VTE (group 2). Baseline characteristics are included in Table 1. The in-patient all-cause mortality rate was 28.4% in group 1 vs 12.6% in group 2 (p&lt;0.001). The mean hospital length of stay was 12.3 days in group 1 vs 8.8 days in group 2 (p&lt;0.001). Group 1 had a mean CHA 2DS 2-VASc score of 3.3 ±1.6. vs 2.7±1.7 in group 2 (p&lt;0.001) (Figure 2). At CHA 2DS 2-VASc scores of 3 and 4, the model had a specificity of 46% and 67% and sensitivity of 68% and 42% respectively for predicting ATE/VTE. The CHA 2DS 2-VASc score of 5 had a specificity of 86% and sensitivity of 25%. The score of 7 had 98% specificity but 3% sensitivity (Table 2). Conclusion: Our results suggest that the CHA 2DS 2-VASc model for arterial and venous thromboembolism has a moderate performance. The CHA 2DS 2-VASc score of 5 has a high specificity, though low sensitivity, for predicting thromboembolism. The CHA 2DS 2-VASc score can be used as an adjunct risk stratification tool to initiate TAC. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

600. The Effect of Medication-Assisted Treatment on Completion Rates of Outpatient Parenteral Antibiotic Therapy

Background Injection drug use is a nationwide epidemic associated with an increased risk of invasive Staphylococcus aureus (S. aureus) infections. Medication-assisted treatment (MAT) is effective in reducing substance use and increasing adherence to inpatient medical therapy in persons with injection drug use (PWID). Studies assessing the impact MAT has on completion of outpatient parenteral antibiotic therapy (OPAT) are limited. Methods This was a single-center, retrospective, cohort study at The Ohio State University Wexner Medical Center in patients admitted from 12/1/2017 to 12/1/2019 with a diagnosis of S. aureus bacteremia who were identified as PWID either by ICD-9 or 10 code or chart review. A formal MAT program was established on 11/30/2018. Patients were assigned to the pre-MAT group if they were discharged prior to 11/30/2018 and to the MAT group with treatment after 11/30/2018. We evaluated a composite outcome of failure to complete OPAT, recurrence of S. aureus bacteremia during the OPAT period and readmission within 30 days. A multivariable logistic regression analysis was performed to examine the association between MAT therapy and the primary composite outcome, while adjusting for proven confounders. Results A total of 700 patients were identified with 644 patients omitted based on exclusion criteria. The study population included 27 in the Pre-MAT group and 17 in the MAT. Median age was 37 years (IQR 30.6 - 46.1). There was a higher number of females in the MAT therapy group compared to the pre-MAT group (82% vs. 33%, p=0.002). Patients in the pre-MAT group had a significantly longer length of stay (25 days vs. 17 days, p=0.01). The primary composite outcome was met if a patient did not complete their OPAT, if they had a recurrence of S. aureus bacteremia during their OPAT or if they were readmitted to the hospital within 30 days. In the pre-MAT group 14/27 (52%) met the composite outcome versus 6/17 (35%) of the MAT group (p=0.28). Conclusion Patients in the MAT group met the composite outcome 17% less than those in the pre-Mat group which is suggestive of the impact MAT has on completion of OPAT therapy; however, this study did not reach statistical significance as it was underpowered. Further longitudinal evaluation with greater sample size is needed to fully evaluate this intervention. Disclosures Mohammad Mahdee Sobhanie, M.D., Regeneron (Scientific Research Study Investigator)Regeneron (Scientific Research Study Investigator, Was a sub-investigator for Regeneron 2066 and 2069)

1114. Effectiveness and Safety of Beta-lactam Antibiotics with and without Therapeutic Drug Monitoring in Patients with Pseudomonas aeruginosa Pneumonia or Bloodstream Infection

Background Pseudomonas aeruginosa (PSAR) is challenging to treat due to its multiple resistance mechanisms, limited anti-PSAR agents, and population pharmacokinetic (PK) variances. Beta-lactam antibiotics (BLA) are commonly used to treat PSAR infections and although they have a wide therapeutic index, suboptimal exposures may lead to treatment failure and antimicrobial resistance while high exposure may result in adverse effects. Certain patient populations may benefit from BLA therapeutic drug monitoring (TDM) due to their significant PK variability. The purpose of this study was to compare clinical outcomes in patients with PSAR pneumonia (PNA) or bloodstream infection (BSI) receiving BLA with and without the guidance of TDM. Methods Retrospective, parallel cohort study conducted at UF Shands Gainesville and UF Health Jacksonville evaluating five years of patients with PSAR PNA or BSI. TDM group was defined for routine BLA TDM compared to nonroutine BLA TDM service (non-TDM). Patients were excluded if they died before a culture result, transferred in with a positive PSAR culture, were transplant recipients, cystic fibrosis or burn injury patients. The primary outcome was a composite of presumed clinical cure defined as the absence of the following: all-cause in-hospital mortality, escalation, and/or additional antimicrobial therapy for PSAR infection after 48 hours of treatment with primary susceptible regimen due to worsening clinical status or transfer to a higher level of care. Results Two-hundred patients were included (TDM n=95; non-TDM n=105). The overall primary composite outcome of presumed clinical cure occurred in 73% of patients (82% and 75% of the TDM and non-TDM cohorts, respectively; p=0.301). A post-hoc multivariate analysis was conducted to assess predictors of not attaining clinical cure. Conclusion While there was no difference in the primary composite outcome of presumed clinical cure, future studies can use these data to assess TDM patient selection and whether a bundled care approach of BLA regimens with known clinical benefit, early TDM-guided dose optimization, and continued clinical assessment improves outcomes in patients with PSAR PNA or BSI compared to use of each modality individually. Disclosures All Authors: No reported disclosures

190. Outcomes of Early Ceftaroline-based Combination Therapy for Methicillin-resistant Staphylococcus aureus Bacteremia

Background Monotherapy with vancomycin (VAN) or daptomycin (DAP) remains the guideline-driven standard of care for methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B) despite concerns regarding efficacy. While combination therapy is often utilized as salvage treatment for persistent MRSA-B, growing data suggest a potential benefit of combination therapy with ceftaroline as initial therapy for MRSA-B. In light of these data, we updated practice guidance at our institution for management of MRSA-B in March 2020 to favor initial combination therapy with ceftaroline. Herein, we present an assessment of outcomes of patients with MRSA-B initiated on early combination therapy. Methods This was a single-center, retrospective, cohort study of adult patients admitted to the University of Virginia with MRSA-B between July 1, 2018 and February 28, 2021. Patients were considered to have received combination therapy if they received VAN or DAP plus ceftaroline (CPT) within 5 days of index blood culture, and monotherapy if during that period they received VAN and/or DAP alone. The primary outcome was a composite of persistent bacteremia, 30-day all-cause mortality, and 30-day bacteremia recurrence. Time to microbiological cure and safety outcomes were also assessed. A propensity score-weighted logistic regression was conducted. A post-hoc analysis of the primary composite outcome was performed in which patients were only deemed to have received combination therapy if it was started within 72 hours. Results Of 94 patients included, 57 received monotherapy (55 VAN, 2 DAP) and 37 received combination therapy with CPT (30 VAN, 7 DAP). There was no difference between groups for the primary composite outcome in the primary analysis (OR 2.7, 95% CI 0.95-7.72) or the post-hoc analysis (OR 2.37, 95% CI 0.68-8.22). Time to microbiological cure was not different between groups (mean difference 1.47, 95% CI 0.20-2.74). Safety outcomes were similar. Conclusion In this retrospective study, there was no clear benefit or harm of early initiation of combination therapy for MRSA-B. Additional study of initial combination therapy with ceftaroline is warranted given the small number of subjects in the study presented. Disclosures All Authors: No reported disclosures

191. Oral Antibiotic Step-Down Therapy for Non-Staphylococcal Gram-Positive Bloodstream Infections

Background Bloodstream infections are traditionally treated with intravenous (IV) antimicrobial therapy, which may increase length of stay and healthcare costs. The purpose of this study is to evaluate if oral antibiotic step-down therapy for non-staphylococcal gram-positive bloodstream infections (GP-BSIs) is non-inferior to IV antibiotics. Methods This single-center, retrospective cohort study included patients with a non-Staphylococcus aureus, non-Staphylococcus lugdunensis GP-BSI from January 2017 to December 2019. Patients were excluded if they fit any of the following criteria: organism identified as contaminant, polymicrobial BSI, recurrent BSI within the past 90 days, or receipt of an effective antibiotic for a duration longer than what is indicated for BSI treatment. Patients were categorized into those who received an IV antibiotic for the total duration of therapy and those who received an oral step-down antibiotic for at least one-third of the treatment course. The primary composite outcome was the incidence of 90-day clinical failure consisting of 90-day all-cause mortality, change in therapy due to inadequate clinical response, and 90-day BSI recurrence. The secondary outcomes included the individual components of the primary composite outcome, line-related complications, and hospital length of stay. Bivariate analysis was conducted to assess for predictors of 90-day clinical failure. Results A total of 308 patients were included (oral group, n=94; IV group, n=214). Pitt Bacteremia Scores were low overall, but higher in the IV group (0 vs 1, p=0.045). The oral group had a higher proportion of GP-BSI caused by streptococcal species (76% vs 61%, p&lt; 0.001). The oral group had a lower incidence of 90-day clinical failure and was found to be noninferior to the IV group (9% vs 14%; mean difference -5%, 90% CI -12.7 to 2.6). The IV group had a longer hospital length of stay (4 vs 6 days, p&lt; 0.001), however there were no other significant differences in secondary outcomes. Bivariate analysis found no significant predictors of 90-day clinical failure. Conclusion Oral antibiotic step-down therapy was found to be non-inferior to IV antibiotic therapy, and thus may be an alternative option for the treatment of non-staphylococcal GP-BSIs. Disclosures All Authors: No reported disclosures

Development and internal validation of a model predicting severe maternal morbidity using pre-conception and early pregnancy variables: a population-based study in Ontario, Canada

Background Improvement in the prediction and prevention of severe maternal morbidity (SMM) - a range of life-threatening conditions during pregnancy, at delivery or within 42 days postpartum - is a public health priority. Reduction of SMM at a population level would be facilitated by early identification and prediction. We sought to develop and internally validate a model to predict maternal end-organ injury or death using variables routinely collected during pre-pregnancy and the early pregnancy period. Methods We performed a population-based cohort study using linked administrative health data in Ontario, Canada, from April 1, 2006 to March 31, 2014. We included women aged 18–60 years with a livebirth or stillbirth, of which one birth was randomly selected per woman. We constructed a clinical prediction model for the primary composite outcome of any maternal end-organ injury or death, arising between 20 weeks’ gestation and 42 days after the birth hospital discharge date. Our model included variables collected from 12 months before estimated conception until 19 weeks’ gestation. We developed a separate model for parous women to allow for the inclusion of factors from previous pregnancy(ies). Results Of 634,290 women, 1969 experienced the primary composite outcome (3.1 per 1000). Predictive factors in the main model included maternal world region of origin, chronic medical conditions, parity, and obstetrical/perinatal issues – with moderate model discrimination (C-statistic 0.68, 95% CI 0.66–0.69). Among 333,435 parous women, the C-statistic was 0.71 (0.69–0.73) in the model using variables from the current (index) pregnancy as well as pre-pregnancy predictors and variables from any previous pregnancy. Conclusions A combination of factors ascertained early in pregnancy through a basic medical history help to identify women at risk for severe morbidity, who may benefit from targeted preventive and surveillance strategies including appropriate specialty-based antenatal care pathways. Further refinement and external validation of this model are warranted and can support evidence-based improvements in clinical practice.

Increased serum catalytic iron may mediate tissue injury and death in patients with COVID-19

The pathophysiology and the factors determining disease severity in COVID-19 are not yet clear, with current data indicating a possible role of altered iron metabolism. Previous studies of iron parameters in COVID-19 are cross-sectional and have not studied catalytic iron, the biologically most active form of iron. The study was done to determine the role of catalytic iron in the adverse outcomes in COVID-19. We enrolled adult patients hospitalized with a clinical diagnosis of COVID-19 and measured serum iron, transferrin saturation, ferritin, hepcidin and serum catalytic iron daily. Primary outcome was a composite of in-hospital mortality, need for mechanical ventilation, and kidney replacement therapy. Associations between longitudinal iron parameter measurements and time-to-event outcomes were examined using a joint model. We enrolled 120 patients (70 males) with median age 50 years. The primary composite outcome was observed in 25 (20.8%) patients—mechanical ventilation was needed in 21 (17.5%) patients and in-hospital mortality occurred in 21 (17.5%) patients. Baseline levels of ferritin and hepcidin were significantly associated with the primary composite outcome. The joint model analysis showed that ferritin levels were significantly associated with primary composite outcome [HR (95% CI) = 2.63 (1.62, 4.24) after adjusting for age and gender]. Both ferritin and serum catalytic iron levels were positively associated with in-hospital mortality [HR (95% CI) = 3.22 (2.05, 5.07) and 1.73 (1.21, 2.47), respectively], after adjusting for age and gender. The study shows an association of ferritin and catalytic iron with adverse outcomes in COVID-19. This suggests new pathophysiologic pathways in this disease, also raising the possibility of considering iron chelation therapy.