Search

BACKGROUND AND AIMS: Polyvascular disease is an independent predictor of major adverse cardiovascular events (MACE). The relationship between the number of diseased arterial beds and MACE is unknown. How MACE risk changes in individuals with type 2 diabetes (T2D) is also understudied. Furthermore, it is unknown whether heart failure (HF) status and hemoglobin A1c (HbA1c) levels influence outcomes in polyvascular disease. This analysis from the Exenatide Study of Cardiovascular Event Lowering trial (EXSCEL) aimed to examine the risk associated with increasing number of diseased arterial beds on MACE and all-cause mortality (ACM). METHODS: Cox models were used to test associations between the number of diseased arterial beds and MACE and ACM. Prespecified interaction testing between number of diseased arterial beds with baseline HF, HbA1c (≤8% vs. >8%), and treatment assignment was performed. RESULTS: Overall, 14,751 participants were included; 26.5% were without atherosclerosis, 58.9% had 1-bed, 12.3% had 2-bed, and 2.3% had 3-bed disease. An increasing burden of atherosclerotic disease was associated with increasing risk of MACE (adjusted HR [aHR] 1.71 [95% CI 1.46–2.02]; 2.61 [2.17–3.15]; 3.46 [2.69–4.45] for 1, 2, and 3 beds, respectively, p < 0.001 for all) and ACM (1.94 [1.56–2.42]; 3.03 [2.33–3.95]; 3.66 [2.59–5.18] for 1, 2, and 3 beds, respectively, p < 0.001 for all). Prespecified interaction testing did not reveal any significant associations. CONCLUSIONS: In patients with T2D, compared to those without atherosclerotic vascular disease, risk of MACE and ACM increases incrementally with each additional diseased arterial bed.

Background COVID-19 shifted antibiotic stewardship program resources and changed antibiotic use (AU). Shifts in patient populations with COVID surges, including pauses to surgical procedures, and dynamic practice changes makes temporal associations difficult to interpret. Our analysis aimed to address the impact of COVID on AU after adjusting for other practice shifts. Methods We performed a longitudinal analysis of AU data from 30 Southeast US hospitals. Three pandemic phases (1: 3/20–6/20; 2: 7/20–10/20; 3: 11/20–2/21) were compared to baseline (1/2018–1/2020). AU (days of therapy (DOT)/1000 patient days (PD)) was collected for all antimicrobial agents and specific subgroups: broad spectrum (NHSN group for hospital-onset infections), CAP (ceftriaxone, azithromycin, levofloxacin, moxifloxacin, and doxycycline), and antifungal. Monthly COVID burden was defined as all PD attributed to a COVID admission. We fit negative binomial GEE models to AU including phase and interaction terms between COVID burden and phase to test the hypothesis that AU changes during the phases were related to COVID burden. Models included adjustment for Charlson comorbidity, surgical volume, time since 12/2017 and seasonality. Results Observed AU rates by subgroup varied over time; peaks were observed for different subgroups during distinct pandemic phases (Figure). Compared to baseline, we observed a significant increase in overall, broad spectrum, and CAP groups during phase 1 (Table). In phase 2, overall and CAP AU was significantly higher than baseline, but in phase 3, AU was similar to baseline. These phase changes were separate from effects of COVID burden, except in phase 1 where we observed significant effects on antifungal (increased) and CAP (decreased) AU (Table). Conclusion Changes in hospital AU observed during early phases of the COVID pandemic appeared unrelated to COVID burden and may have been due to indirect pandemic effects (e.g., case mix, healthcare resource shifts). By pandemic phase 3, these disruptive effects were not as apparent, potentially related to shifts in non-COVID patient populations or ASP resources, availability of COVID treatments, or increased learning, diagnostic certainty, and provider comfort with avoiding antibacterials in patients with suspected COVID over time. Disclosures Melissa D. Johnson, PharmD, Biomeme: Licensed Transcriptional Signature for Candidemia|Charles River Laboratories: Grant/Research Support|Entasis Therapeutics: Advisor/Consultant|Merck & Co. Inc: Advisor/Consultant|Merck & Co. Inc: Grant/Research Support|Pfizer, Inc.: Advisor/Consultant|Scynexis Inc.: Grant/Research Support|Theratechnologies: Advisor/Consultant Angelina Davis, PharmD, M.S., Merck & Co.: Honoraria Sonali D. Advani, MBBS, MPH, FIDSA, Locus Biosciences: Advisor/Consultant|Locus Biosciences: Honoraria|Sysmex America: Advisor/Consultant Ibukun Kalu, MD, Pfizer, Inc.: Institutional support for clinical trial Rebekah W. Moehring, MD, MPH, FIDSA, FSHEA, UpToDate, Inc.: Author Royalties.

Background The impact of the US Centers for Medicare & Medicaid Services (CMS) Severe Sepsis and Septic Shock: Management Bundle (SEP-1) core measure on overall antibacterial utilization is unknown. Methods We performed a retrospective multicenter longitudinal cohort study with interrupted time–series analysis to determine the impact of SEP-1 implementation on antibacterial utilization and patient outcomes. All adult patients admitted to 26 hospitals between 1 October 2014 and 30 September 2015 (SEP-1 preparation period) and between 1 November 2015 and 31 October 2016 (SEP-1 implementation period) were evaluated for inclusion. The primary outcome was total antibacterial utilization, measured as days of therapy (DOT) per 1000 patient-days. Results The study cohort included 701 055 eligible patient admissions and 4.2 million patient-days. Overall antibacterial utilization increased 2% each month during SEP-1 preparation (relative rate [RR], 1.02 per month [95% confidence interval {CI}, 1.00–1.04]; P = .02). Cumulatively, the mean monthly DOT per 1000 patient-days increased 24.4% (95% CI, 18.0%–38.8%) over the entire study period (October 2014–October 2016). The rate of sepsis diagnosis/1000 patients increased 2% each month during SEP-1 preparation (RR, 1.02 per month [95% CI, 1.00–1.04]; P = .04). The rate of all-cause mortality rate per 1000 patients decreased during the study period (RR for SEP-1 preparation, 0.95 [95% CI, .92–.98; P = .001]; RR for SEP-1 implementation, .98 [.97–1.00; P = .01]). Cumulatively, the monthly mean all-cause mortality rate/1000 patients declined 38.5% (95% CI, 25.9%–48.0%) over the study period. Conclusions Announcement and implementation of the CMS SEP-1 process measure was associated with increased diagnosis of sepsis and antibacterial utilization and decreased mortality rate among hospitalized patients.

Objectives: To describe the study design and clinical characteristics of patients in the Sertraline Pediatric RegIstry for The Evaluation of Safety (SPRITES). Methods: SPRITES is an open-label post...

Background Left ventricular assist devices (LVAD) are increasingly used for durable mechanical circulatory support in advanced heart failure. While LVAD therapy provides substantial improvement in mortality and quality of life, long-term therapy confers increased risk for device complications. We evaluated if cardiac computed tomography (CCT) improves the detection of cardiomechanical complications among patients with LVAD and suspected device malfunction. Methods In this study, we compared the diagnostic performance of CCT and transthoracic echocardiography (TTE) for the identification of cardiomechanical LVAD complications, including thrombus or neointimal hyperplasia, inflow cannula malposition with dynamic obstruction, fixed outflow obstruction, device infection, and severe aortic regurgitation. Complications were confirmed with surgical evaluation, pathologic assessment, or response to therapeutic intervention. Results Among 58 LVAD patients, who underwent CCT and TTE for suspected LVAD dysfunction, there were 49 confirmed cardiomechanical LVAD complications among 43 (74.1%) patients. The most common LVAD complication was thrombus or neointimal hyperplasia (65.3%), followed by dynamic obstruction (26.5%). Individually, CCT identified 29 of the 49 (59.2%) confirmed LVAD cardiomechanical complications, whereas TTE alone identified a complication in 11 cases (22.4%). However, diagnostic performance was greatest when the two modalities were used in combination, yielding a sensitivity of 67%, specificity of 93%, PPV of 97%, NPV of 47% and diagnostic accuracy of 73%. Conclusion The novel and complementary use of CCT with TTE for the evaluation of suspected device malfunction improves the accurate identification of cardiomechanical LVAD complication compared to either modality alone.

The COVID-19 pandemic had a considerable impact on US healthcare systems, straining hospital resources, staff, and operations. However, a comprehensive assessment of the impact on healthcare associated infections (HAIs) across different hospitals with varying level of infectious disease (ID) physician expertise, resources, and infrastructure is lacking.This retrospective longitudinal multi-center cohort study included central-line-associated bloodstream infections (CLABSIs), catheter-associated urinary tract infections (CAUTIs), C. difficile infections (CDIs), and ventilator-associated events (VAEs) from 53 hospitals (academic and community) in Southeastern United States from January 1, 2018 to March 31, 2021. Segmented negative binomial regression generalized estimating equations models estimated changes in monthly incidence rates in the baseline (01/2018 - 02/2020) compared to the pandemic period (03/2020 - 03/2021, further divided into three pandemic phases).CLABSIs and VAEs increased by 24% and 34% respectively during the pandemic period. VAEs increased in all phases of the pandemic, while CLABSIs increased in later phases of the pandemic. CDI trend increased by 4.2% per month in the pandemic period. On stratifying the analysis by hospital characteristics, the impact of the pandemic on healthcare-associated infections was more significant in smaller sized and community hospitals. CAUTIs did not change significantly during the pandemic across all hospital types.CLABSIs, VAEs, and CDIs increased significantly during the pandemic, especially in smaller community hospitals, most of which lack ID physician expertise. Future efforts should focus on better understanding challenges faced by community hospitals, strengthening infection prevention infrastructure, and expanding the ID workforce, particularly to community hospitals.

Background: EXSCEL (Exenatide Study of Cardiovascular Event Lowering) assessed the impact of once-weekly exenatide 2 mg versus placebo in patients with type 2 diabetes mellitus, while aiming for glycemic equipoise. Consequently, greater drop-in of open-label glucose-lowering medications occurred in the placebo group. Accordingly, we explored the potential effects of their unbalanced use on major adverse cardiovascular events (MACE), defined as cardiovascular death, nonfatal myocardial infarction or nonfatal stroke, and all-cause mortality (ACM), given that some of these agents are cardioprotective. Methods: Cox hazard models were performed by randomized treatment for drug classes where >5% open-label drop-in glucose-lowering medication occurred, and for glucagon-like peptide-1 receptor agonists (GLP-1 RAs; 3.0%) using three methodologies: drop-in visit right censoring, inverse probability for treatment weighting (IPTW), and applying drug class risk reductions. Results: Baseline glucose-lowering medications for the 14 752 EXSCEL participants (73.1% with previous cardiovascular disease) did not differ between treatment groups. During median 3.2 years follow-up, open-label drop-in occurred in 33.4% of participants, more frequently with placebo than exenatide (38.1% versus 28.8%), with metformin (6.1% versus 4.9%), sulfonylurea (8.7% versus 6.9%), dipeptidyl peptidase-4 inhibitors (10.6% versus 7.5%), SGLT-2i (10.3% versus 8.1%), GLP-1 RA (3.4% versus 2.4%), and insulin (13.8% versus 9.4%). The MACE effect size was not altered meaningfully by right censoring, but the favorable HR for exenatide became nominally significant in the sulfonylurea and any glucose-lowering medication groups, while the ACM HR and p-values were essentially unchanged. IPTW decreased the MACE HR from 0.91 ( P =0.061) to 0.85 ( P =0.008) and the ACM HR from 0.86 ( P =0.016) to 0.81 ( P =0.012). Application of literature-derived risk reductions showed no meaningful changes in MACE or ACM HRs or P values, although simulations of substantially greater use of drop-in cardioprotective glucose-lowering agents demonstrated blunting of signal detection. Conclusions: EXSCEL-observed HRs for MACE and ACM remained robust after right censoring or application of literature-derived risk reductions, but the exenatide versus placebo MACE effect size and statistical significance were increased by IPTW. Effects of open-label drop-in cardioprotective medications need to be considered carefully when designing, conducting, and analyzing cardiovascular outcome trials of glucose-lowering agents under the premise of glycemic equipoise. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01144338.

Background Sepsis guidelines recommend daily review to de-escalate or stop antibiotics in appropriate patients. This randomized, controlled trial evaluated an opt-out protocol to decrease unnecessary antibiotics in patients with suspected sepsis. Methods We evaluated non–intensive care adults on broad-spectrum antibiotics despite negative blood cultures at 10 US hospitals from September 2018 through May 2020. A 23-item safety check excluded patients with ongoing signs of systemic infection, concerning or inadequate microbiologic data, or high-risk conditions. Eligible patients were randomized to the opt-out protocol vs usual care. Primary outcome was post-enrollment antibacterial days of therapy (DOT). Clinicians caring for intervention patients were contacted to encourage antibiotic discontinuation using opt-out language. If continued, clinicians discussed the rationale for continuing antibiotics and de-escalation plans. To evaluate those with zero post-enrollment DOT, hurdle models provided 2 measures: odds ratio of antibiotic continuation and ratio of mean DOT among those who continued antibiotics. Results Among 9606 patients screened, 767 (8%) were enrolled. Intervention patients had 32% lower odds of antibiotic continuation (79% vs 84%; odds ratio, 0.68; 95% confidence interval [CI], .47–.98). DOT among those who continued antibiotics were similar (ratio of means, 1.06; 95% CI, .88–1.26). Fewer intervention patients were exposed to extended-spectrum antibiotics (36% vs 44%). Common reasons for continuing antibiotics were treatment of localized infection (76%) and belief that stopping antibiotics was unsafe (31%). Thirty-day safety events were similar. Conclusions An antibiotic opt-out protocol that targeted patients with suspected sepsis resulted in more antibiotic discontinuations, similar DOT when antibiotics were continued, and no evidence of harm. Clinical Trials Registration NCT03517007.

Background Catheter ablation is an important rhythm control therapy in patients with atrial fibrillation (AF) with concomitant heart failure (HF). The objective of this study was to assess the comparative efficacy of AF ablation patients with ischemic vs nonischemic heart failure. Methods We conducted a retrospective, observational cohort study of patients with HF who underwent AF ablation. Outcomes were compared based on HF etiology and included in‐hospital events, symptoms (Mayo AF Symptom Inventory [MAFSI]), and functional status (New York Heart Association class) and freedom from atrial arrhythmias at 12 months. Results Among 242 patients (n = 70 [29%] ischemic, n = 172 [71%] nonischemic), patients with nonischemic cardiomyopathy were younger (mean age 64 ± 11.5 vs 69 ± 9.1, P = .002), more often female (36% vs 17%, P = .004), and had higher mean left‐ventricular ejection fraction (47% vs 42%, P = .0007). There were no significant differences in periprocedural characteristics, including mean procedure time (243 ± 74.2 vs 259 ± 81.8 minutes, P = .1) and nonleft atrial ablation (17% vs 20%, P = .6). All‐cause adverse events were similar in each group (15% vs 17%, P = .7). NYHA and MAFSI scores improved significantly at follow‐up and did not differ according to HF etiology (P = .5; P = .10‐1.00 after Bonferroni correction). There were no significant differences in freedom from recurrent atrial arrhythmia at 12‐months between ischemic (74%) and nonischemic patients (78%): adjusted RR 0.63, 95% confidence interval 0.33‐1.19. Conclusions Catheter ablation in patients with AF and concomitant heart failure leads to significant improvements in functional and symptom status without significant differences between patients with ischemic vs nonischemic HF etiology., Catheter ablation is an important rhythm control therapy in patients with atrial fibrillation (AF) with concomitant heart failure (HF). The objective of this study was to assess the comparative efficacy of AF ablation patients with ischemic versus nonischemic heart failure. We found that catheter ablation in patients with AF and concomitant heart failure leads to significant improvements in functional and symptom status without significant differences between patients with ischemic versus nonischemic HF etiology.

Background Medicare insurance claims may provide an efficient means to ascertain follow-up of older participants in clinical research. We sought to determine the accuracy and completeness of claims- versus site-based follow-up with clinical event committee (+CEC) adjudication of cardiovascular outcomes. Methods We performed a retrospective study using linked Medicare and Duke Database of Clinical Trials data. Medicare claims were linked to clinical data from 7 randomized cardiovascular clinical trials. Of 52,476 trial participants, linking resulted in 5,839 (of 10,497 linkage-eligible) Medicare-linked trial participants with fee-for-service A and B coverage. Death, myocardial infarction (MI), stroke, and revascularization incidences were compared using Medicare inpatient claims only, site-reported events (+CEC) only, or a combination of the 2. Randomized treatment effects were compared as a function of whether claims-based, site-based (+CEC), or a combined system was used for event detection. Results Among the 5,839 study participants, the annual event rates were similar between claims- and site-based (+CEC) follow-up: death (overall rate 5.2% vs 5.2%; adjusted κ 0.99), MI (2.2% vs 2.3%; adjusted κ 0.96), stroke (0.7% vs 0.7%; adjusted κ 0.99), and any revascularization (7.4% vs 7.9%; adjusted κ 0.95). Of events detected by claims yet not reported by CEC, a minority were reported by sites but negatively adjudicated by CEC (39% of MIs and 18% of strokes). Differences in individual case concordance led to higher event rates when claims- and site-based (+CEC) systems were combined. Randomized treatment effects were similar among the 3 approaches for each outcome of interest. Conclusions Claims- versus site-based (+CEC) follow-up identified similar overall cardiovascular event rates despite meaningful differences in the events detected. Randomized treatment effects were similar using the 2 methods, suggesting claims data could be used to support clinical research leveraging routinely collected data. This approach may lead to more effective evidence generation, synthesis, and appraisal of medical products and inform the strategic approaches toward the National Evaluation System for Health Technology.

Background: Once-weekly exenatide (EQW) had a neutral effect on hospitalization for heart failure (HHF) in the EXSCEL study (Exenatide Study of Cardiovascular Event Lowering), with no differential treatment effect on major adverse cardiac events by baseline heart failure (HF) status. EQW’s effects on secondary end points based on HHF status have not been reported. The objective was to explore the effects of EQW on secondary end points in patients with and without baseline HF and test the effects of EQW on recurrent HHF events. Methods: The prespecified analysis of the randomized controlled EXSCEL trial, which enrolled patients with type 2 diabetes mellitus with and without additional cardiovascular disease, analyzed EQW effects on all-cause death, each major adverse cardiac event component, first HHF, and repeat HHF, by baseline HF status (regardless of ejection fraction). A subgroup analysis of the population stratified by preserved or reduced baseline ejection fraction was performed. Results: Of 14 752 EXSCEL participants, 2389 (16.2%) had HF at baseline. Compared with those without HF at baseline, patients with preexisting HF were older, and more likely to be male and white, with a higher burden of other cardiovascular diseases. Overall, those assigned to EQW had a lower incidence of all-cause death (hazard ratio [HR], 0.86 [95% CI, 0.77–0.97]) and the composite outcome of all-cause death or HHF (HR, 0.89 [95% CI, 0.80–0.99]). When stratified by presence or absence of baseline HF, there was no observed reduction in all-cause death with EQW with baseline HF (HR, 1.05 [95% CI, 0.85–1.29]), while the risk of mortality was reduced with EQW in the no-HF group (HR, 0.79 [95% CI, 0.68–0.92]) with an interaction P value of 0.031. The reduction in all-cause death or HHF seen with EQW in patients without baseline HF (HR, 0.81 [95% CI, 0.71–0.93]) was not seen in patients with baseline HF (HR, 1.07 [95% CI, 0.89–1.29]; interaction P =0.015). First, plus recurrent, HHF was reduced in the exenatide group versus placebo (HR, 0.82 [95% CI, 0.68–0.99]; P =0.038). Conclusions: In EXSCEL, the use of EQW in patients with or without HF was well tolerated, but benefits of EQW on reduction in all-cause death and first hospitalization for HF were attenuated in patients with baseline HF. Clinical Trial Registration: https://www.clinicaltrials.gov . Unique identifier: NCT01144338.

We analyzed antibiotic use data from 29 southeastern US hospitals over a 5-year period to determine changes in antibiotic use after the fluoroquinolone US Food and Drug Administration (FDA) advisory update in 2016. Fluoroquinolone use declined both before and after the FDA announcement, and the use of select, alternative antibiotics increased after the announcement.Fluoroquinolones are among the 4 most commonly prescribed antibiotic classes.1,2 Postmarketing reports of serious adverse events linked to fluoroquinolones include tendonitis, neuropathy, hypoglycemia, psychiatric side effects, and possible aortic vessel rupture, leading to safety label changes in July 2008 and August 2013.3 In July 2016, the US Food and Drug Administration (FDA) strengthened the “black box” warning following an initial safety announcement in May 2016, recommending avoidance of fluoroquinolones for uncomplicated infections such as acute exacerbation of chronic bronchitis, uncomplicated urinary tract infections, and acute bacterial sinusitis.4 Concerns over safety and the association with Clostridiodes difficile infection have led inpatient antimicrobial stewardship programs (ASPs) to develop initiatives to promote avoidance of quinolones. The objective of this study was to quantify the effect of the 2016 FDA “black box” update on inpatient antibiotic use among a cohort of southeastern US hospitals.

Risk prediction following acute coronary syndrome (ACS) remains challenging. Data-driven machine-learning algorithms can potentially identify patients at high risk of clinical events. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial randomized 18,144 post-ACS patients to ezetimibe + simvastatin or placebo + simvastatin. We performed hierarchical cluster analysis to identify patients at high risk of adverse events. Associations between clusters and outcomes were assessed using Cox proportional hazards models. The primary outcome was cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, unstable angina hospitalization, or coronary revascularization ≥30 days after randomization. We evaluated ezetimibe's impact on outcomes across clusters and the ability of the cluster analysis to discriminate for outcomes compared with the Global Registry of Acute Coronary Events (GRACE) score. Five clusters were identified. In cluster 1 (n = 13,252), most patients experienced a non-STEMI (54.8%). Cluster 2 patients (n = 2,719) had the highest incidence of unstable angina (n = 83.3%). Cluster 3 patients (n = 782) all identified as Spanish descent, whereas cluster 4 patients (n = 803) were primarily from South America (56.2%). In cluster 5 (n = 587), all patients had ST elevation. Cluster analysis identified patients at high risk of adverse outcomes (log-rank p0.0001); Cluster 2 (vs 1) patients had the highest risk of outcomes (hazards ratio 1.33, 95% confidence interval 1.24 to 1.43). Compared with GRACE risk, cluster analysis did not provide superior outcome discrimination. A consistent ezetimibe treatment effect was identified across clusters (interaction p = 0.882). In conclusion, cluster analysis identified significant difference in risk of outcomes across cluster groups. Data-driven strategies to identify patients who may differentially benefit from therapies and for risk stratification require further evaluation.

Severe combined immunodeficiency (SCID) is a syndrome characterized by profound T-cell deficiency that is universally fatal in infancy unless immune reconstitution is achieved by hematopoietic stem cell transplantation, gene therapy, or enzyme replacement. Published long-term clinical follow-up is limited for transplanted patients with SCID.To characterize the long-term outcomes of patients with SCID treated at a single center.We examined the clinical outcomes of 177 successive SCID infants given allogeneic bone marrow over 38 years without pretransplant chemotherapy or post-transplant graft-versus-host disease prophylaxis. A total of 90% received T-cell-depleted haploidentical parental marrow. Clinical status was assessed by questionnaires delivered by mail or electronically. Molecular type of SCID, demographics, and type, date and age of transplant were obtained from a database.Eighty-eight questionnaires were completed for survivors ranging in age from 2 to 38 years. Survival remained higher in those transplanted before 3.5 months of age. Half of the cohort remained on immunoglobulin replacement. Health conditions reported included rashes, anxiety, depression, warts, and mouth ulcers. Most reported that these were transient, self-resolving issues. Attention-deficit/hyperactivity disorder, warts, and learning disabilities were reportedly more prevalent than in the general population. Most reported having no active concerns about their health. We found substantial scholastic achievement, with half of adult patients reporting college attendance. Most patients had a healthy body mass index.Overall, our findings are consistent with those in the last update in 2009 in this population. Age at transplant remains a key variable in survival.

Background The COVID-19 pandemic had a considerable impact on US healthcare systems, straining hospital resources, staff, and operations. Our objective was to evaluate the impact of COVID-19 pandemic on incidence and trends of healthcare-associated infections (HAIs) in a network of hospitals. Methods This was a retrospective review of central-line-associated bloodstream infections (CLABSIs), catheter-associated urinary tract infections (CAUTIs), C. difficile infections (CDI), and ventilator-associated events (VAE) in 51 hospitals from 2018 to 2021. Descriptive statistics were reported as mean hospital-level monthly incidence rates (IR) and compared using Poisson regression GEE models with period as the only covariate. Segmented regression (SR) analysis was performed to estimate changes in monthly IR of CAUTIs, CLABSIs and CDI in the baseline period (01/2018 – 02/2020) and the Pandemic period (03/2020 – 03/2021). SR model was not appropriate for VAE based on the plot. All models were constructed using SAS v.9.4 (SAS Institute, Cary NC). Results Compared to the baseline period, CLABSIs increased significantly by 50% from 0.6 to 0.9/ 1000 catheter days (P< 0. 001). In contrast, no significant changes were identified for CAUTI (P=0.87). Similar trends were seen in SR models for CLABSI and CAUTI (Figures 1, 2 and Table 1). While overall CDIs decreased significantly from 3.5 to 2.5/10,000 patient days in the pandemic period (P< 0.001), SR model showed increasing pandemic trend change (Figure 3). VAEs increased > 700% from 6.9 to 59.7/1000 ventilator days (P=0.15), but displayed considerable variation during the pandemic period (Figure 4). Compared to baseline period, there was a significant increase in central line days (647 vs 677, P=0.02), ventilator days (156 vs 215, P< 0.001), but no change in urinary catheter days (675 vs 686, P=0.32) during the pandemic period. Figure 1: Segmented Regression model showing baseline and pandemic period trends of CLABSI Figure 2: Segmented Regression model showing baseline and pandemic period trends of CAUTI Figure 3: Segmented Regression model showing baseline and pandemic period trends of C. difficile (HO-CDI) infections Conclusion The COVID-19 pandemic was associated with substantial increases in CLABSIs and VAEs, no change in CAUTIs, and an increasing trend in CDI incidence. These variations in trends of different HAIs are likely due, in part, to unique characteristics of the underlying infection, resource shortages, staffing concerns, increased device use, changes in testing practices, and the limitations of surveillance definitions. Figure 4: Trend of Ventilator-Associated Events (VAE) in the baseline and pandemic period (Segmented Regression model not appropriate) Disclosures Sonali D. Advani, MBBS, MPH, Nothing to disclose David J. Weber, MD, MPH, Merck (Individual(s) Involved: Self): Consultant; PDI (Individual(s) Involved: Self): Consultant; Pfizer (Individual(s) Involved: Self): Consultant; Sanofi (Individual(s) Involved: Self): Consultant; UVinnovators (Individual(s) Involved: Self): Consultant

Background Traditional approaches for SSI surveillance have deficiencies that can delay detection of SSI outbreaks and other clinically important increases in SSI rates. Optimized SPC methods for SSI surveillance have not been prospectively evaluated. Methods We conducted a prospective multicenter stepped wedge cluster RCT to evaluate the performance of SSI surveillance and feedback performed with optimized SPC plus traditional surveillance methods compared to traditional surveillance alone. We divided 13 common surgical procedures into 6 clusters (Table 1). A cluster of procedures at a single hospital was the unit of randomization and analysis, and 105 total clusters across 29 community hospitals were randomized to 12 groups of 8-10 clusters (Figure 1). After a 12-month baseline observation period (3/2016-2/2017), the SPC surveillance intervention was serially implemented according to stepped wedge assignment over a 36-month intervention period (3/2017-2/2020) until all 12 groups of clusters had received the intervention. The primary outcome was the overall SSI prevalence rate (PR=SSIs/100 procedures), evaluated with a GEE model with Poisson distribution. Table 1 Figure 1 Schematic for stepped wedge design. The 12-month baseline observation period was followed by the 36-month intervention period, comprised of 12 3-month steps. Results Our trial involved prospective surveillance of 237,704 procedures that resulted in 1,952 SSIs (PR=0.82). The overall SSI PR did not differ significantly between clusters of procedures assigned to SPC surveillance (781 SSIs/89,339 procedures; PR=0.87) and those assigned to traditional surveillance (1,171 SSIs/148,365 procedures; PR=0.79; PR ratio=1.10 [95% CI, 0.94–1.30]; P=.25) (Table 2). SPC surveillance identified 104 SSI rate increases that required formal investigations, compared to only 25 investigations generated by traditional surveillance. Among 10 best practices for SSI prevention, 453 of 502 (90%) SSIs analyzed due to SPC detection of SSI rate increases had at least 2 deficiencies (Table 3). Table 2 Poisson regression models comparing surgical site infection (SSI) prevalence rates for procedure clusters receiving statistical process control surveillance to SSI rates for clusters receiving traditional control surveillance. Table 3 Compliance with 10 best practices for surgical site infection (SSI) prevention among 502 SSIs analyzed during SSI investigations generated by statistical process control surveillance. Conclusion SPC methods more frequently detected important SSI rate increases associated with deficiencies in SSI prevention best practices than traditional surveillance; however, feedback of this information did not lead to SSI rate reductions. Further study is indicated to determine the best application of SPC methods to improve adherence to SSI quality measures and prevent SSIs. Disclosures Arthur W. Baker, MD, MPH, Medincell (Advisor or Review Panel member) Susan S. Huang, MD, MPH, Medline (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)Molnlycke (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)Stryker (Sage) (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)Xttrium (Other Financial or Material Support, Conducted studies in which participating hospitals and nursing homes received contributed antiseptic and cleaning products)

AIMS: Although models exist to predict amputation among people with type 2 diabetes with foot ulceration or infection, we aimed to develop a prediction model for a broader range of major adverse limb events (MALE)—including gangrene, revascularization, and amputation—among individuals with type 2 diabetes. METHODS: In a post-hoc analysis of data from the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial, we compared participants who experienced MALE with those who did not. A multivariable model was constructed and translated into a risk score. RESULTS: Among the 14,752 participants with type 2 diabetes in EXSCEL, 3.6% experienced MALE. Characteristics associated with increased risk of MALE were peripheral artery disease (PAD) (HR(adj) 4.83, 95% CI 3.94–5.92), prior foot ulcer (HR(adj) 2.16, 95% CI 1.63–2.87), prior amputation (HR(adj) 2.00, 95% CI 1.53–2.64), current smoking (HR(adj) 2.00, 95% CI 1.54–2.61), insulin use (HR(adj) 1.86, 95% CI 1.52–2.27), coronary artery disease (HR(adj) 1.67, 95% CI 1.38–2.03), and male sex (HR(adj) 1.64, 95% CI 1.31–2.06). Cerebrovascular disease, former smoking, age, glycated haemoglobin, race, and neuropathy were also associated significantly with MALE after adjustment. A risk score ranging from 6-96 points was constructed, with a C-statistic of 0.822 (95% CI 0.803–0.841). CONCLUSIONS: The majority of MALE occurred among participants with PAD, but participants without a history of PAD also experienced MALE. A risk score with good performance was generated. Although it requires validation in an external dataset, this risk score may be valuable in identifying patients requiring more intensive care and closer follow-up.

Cardiovascular (CV) outcome studies of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shifted the paradigm of type 2 diabetes management given their benefits regarding a reduction in major adverse CV events. However, the relationship between GLP-1 RAs and coronary revascularization remains poorly understood. In this EXSCEL post-hoc analysis, we used univariate Cox proportional models and Kaplan Meier survival analysis to evaluate the effect of once-weekly exenatide (EQW) on a composite outcome of hospitalization for acute coronary syndrome (ACS) or coronary revascularization. Similar models were utilized to evaluate the relationship between significant participant characteristics within the entire study population and the composite outcome. Of the 14,736 participants in EXSCEL with complete follow-up data, 1642 (11.1%) experienced an ACS or coronary revascularization event during a median follow-up of 3.3 years (interquartile range, 2.3-4.4). EQW had no effect on hospitalization for ACS or coronary revascularization (HR 1.00, 95% CI 0.91-1.10). Among EXSCEL participants, enrollment in Latin America (HR 0.51, 95% CI 0.43-0.60) and a history of peripheral artery disease (HR 0.79, 95% CI 0.70-0.90) were associated with a reduced risk for coronary revascularization, whereas enrollment in North America (HR 1.92, 95% CI 1.74-2.12), a history of CV disease (HR 3.24, 95% CI 2.78-3.78), and a previous myocardial infarction (HR 1.54, 95% CI 1.39-1.71) were associated with increased risk for study end points. EQW had no association with hospitalization for ACS or coronary revascularization. Participant enrollment location and CV disease burden may play a role in the variable CV efficacy of GLP-1 RAs that has been observed in trials thus far.

Background Antimicrobial stewardship programs (ASPs) promote the principle of de-escalation: moving from broad- to narrow-spectrum agents and stopping antibiotics when no longer indicated. A standard, objective definition of de-escalation applied to electronic data could be useful for ASP assessments. Methods We derived an electronic definition of antibiotic de-escalation and performed a retrospective study among 5 hospitals. Antibiotics were ranked into 4 categories: narrow-spectrum, broad-spectrum, extended-spectrum, and agents targeted for protection. Eligible adult patients were cared for on inpatient units, had antibiotic therapy for at least 2 days, and were hospitalized for at least 3 days after starting antibiotics. Number of antibiotics and rank were assessed at 2 time points: day of antibiotic initiation and either day of discharge or day 5. De-escalation was defined as reduction in either the number of antibiotics or rank. Escalation was an increase in either number or rank. Unchanged was either no change or discordant directions of change. We summarized outcomes among hospitals, units, and diagnoses. Results Among 39 226 eligible admissions, de-escalation occurred in 14 138 (36%), escalation in 5129 (13%), and antibiotics were unchanged in 19 959 (51%). De-escalation varied among hospitals (median, 37%; range, 31–39%, P Conclusions Our electronic de-escalation metric demonstrated variation among hospitals, units, and diagnoses. This metric may be useful for assessing stewardship opportunities and impact.

The natural history of patients hospitalized for acute coronary syndrome (ACS) with pre-existing versus (vs) de novo heart failure (HF) has not been previously reported over an extended duration of follow-up. The IMPROVE-IT trial enrolled 18,144 patients hospitalized for ACS and randomized them to combination simvastatin (40 mg)/ezetimibe (10 mg) vs simvastatin (40 mg). Subjects were divided into 3 groups: pre-existing HF (i.e., defined by past medical history), de novo HF (i.e., defined by Killip class II or greater during index admission), and no HF. The final analytical cohort included 14,792 patients (82%) with HF status recorded at baseline. In total, 790 patients (5.3%) reported a pre-existing diagnosis of HF and 1374 patients (9.3%) experienced de novo HF. Patients with pre-existing or de novo HF were older, more likely to be woman, and had a greater prevalence of atrial fibrillation and diabetes mellitus. The incidences of death/HF-hospitalizations at 5 years were 32%/20% for pre-existing HF, 18%/7% for de novo HF, and 8%/3% for no HF. After adjusting for potential confounders, a history of pre-existing or de novo HF was independently associated with increased risk of death (pre-existing HF: hazard ratio [HR] 1.93, 95% confidence interval [CI] 1.68 to 2.22, p < 0.001; de novo HF: HR 1.51, 95% CI 1.33 to 1.72, p < 0.001) and hospitalizations for HF (pre-existing HF: HR 2.96, 95% CI 2.36 to 3.71, p < 0.001; de novo HF: HR 1.88, 95% CI 1.49 to 2.38, p < 0.001). There was no interaction among baseline HF status (i.e., pre-existing or de novo), lipid lowering therapy (i.e., simvastatin/ezetimibe vs simvastatin alone), and clinical outcomes. In conclusion, patients hospitalized for ACS with pre-existing or de novo HF were older and had a greater burden of medical co-morbidities. In conclusion, HF was independently associated with increased risk of long-term morbidity and mortality with the pre-existing HF cohort demonstrating the highest overall risk.

Summary Background The hospital environment is a source of pathogen transmission. The effect of enhanced disinfection strategies on the hospital-wide incidence of infection has not been investigated in a multicentre, randomised controlled trial. We aimed to assess the effectiveness of four disinfection strategies on hospital-wide incidence of multidrug-resistant organisms and Clostridium difficile in the Benefits of Enhanced Terminal Room (BETR) Disinfection study. Methods We did a prespecified secondary analysis of the results from the BETR Disinfection study, a pragmatic, multicentre, crossover cluster-randomised trial that assessed four different strategies for terminal room disinfection in nine hospitals in the southeastern USA. Rooms from which a patient with a specific infection or colonisation (due to the target organisms C difficile , meticillin-resistant Staphylococcus aureus , vancomycin-resistant enterococci (VRE), or multidrug-resistant Acinetobacter spp ) was discharged were terminally disinfected with one of four strategies: standard disinfection (quaternary ammonium disinfectant, except for C difficile , for which 10% hypochlorite [bleach] was used; reference); standard disinfection and disinfecting ultraviolet light (UV-C), except for C difficile , for which bleach and UV-C was used (UV strategy); 10% hypochlorite (bleach strategy); and bleach and UV-C (bleach and UV strategy). We randomly assigned the sequence of strategies for each hospital (1:1:1:1), and each strategy was used for 7 months, including a 1-month wash-in period and 6 months of data collection. The prespecified secondary outcomes were hospital-wide, hospital-acquired incidence of all target organisms (calculated as number of patients with hospital-acquired infection with a target organism per 10 000 patient days), and hospital-wide, hospital-acquired incidence of each target organism separately. BETR Disinfection is registered with ClinicalTrials.gov, number NCT01579370. Findings Between April, 2012, and July, 2014, there were 271 740 unique patients with 375 918 admissions. 314 610 admissions met all inclusion criteria (n=73 071 in the reference study period, n=81 621 in the UV study period, n=78 760 in the bleach study period, and n=81 158 in the bleach and UV study period). 2681 incidenct cases of hospital-acquired infection or colonisation occurred during the study. There was no significant difference in the hospital-wide risk of target organism acquisition between standard disinfection and the three enhanced terminal disinfection strategies for all target multidrug-resistant organisms (UV study period relative risk [RR] 0·89, 95% CI 0·79–1·00; p=0·052; bleach study period 0·92, 0·79–1·08; p=0·32; bleach and UV study period 0·99, 0·89–1·11; p=0·89). The decrease in risk in the UV study period was driven by decreases in risk of acquisition of C difficile (RR 0·89, 95% CI 0·80–0·99; p=0·031) and VRE (0·56, 0·31–0·996; p=0·048). Interpretation Enhanced terminal room disinfection with UV in a targeted subset of high-risk rooms led to a decrease in hospital-wide incidence of C difficile and VRE. Enhanced disinfection overcomes limitations of standard disinfection strategies and is a potential strategy to reduce the risk of acquisition of multidrug-resistant organisms and C difficile . Funding US Centers for Disease Control and Prevention.

Objective The optimal treatment of nonconvulsive seizures in critically ill patients is uncertain. We evaluated the comparative effectiveness of the antiseizure drugs lacosamide (LCM) and fosphenytoin (fPHT) in this population. Methods The TRENdS (Treatment of Recurrent Electrographic Nonconvulsive Seizures) study was a noninferiority, prospective, multicenter, randomized treatment trial of patients diagnosed with nonconvulsive seizures (NCSs) by continuous electroencephalography (cEEG). Treatment was randomized to intravenous (IV) LCM 400mg or IV fPHT 20mg phenytoin equivalents/kg. The primary endpoint was absence of electrographic seizures for 24 hours as determined by 1 blinded EEG reviewer. The frequency with which NCS control was achieved in each arm was compared, and the 90% confidence interval (CI) was determined. Noninferiority of LCM to fPHT was to be concluded if the lower bound of the CI for relative risk was >0.8. Results Seventy-four subjects were enrolled (37 LCM, 37 fPHT) between August 21, 2012 and December 20, 2013. The mean age was 63.6 years; 38 were women. Seizures were controlled in 19 of 30 (63.3%) subjects in the LCM arm and 16 of 32 (50%) subjects in the fPHT arm. LCM was noninferior to fPHT (p = 0.02), with a risk ratio of 1.27 (90% CI = 0.88-1.83). Treatment emergent adverse events (TEAEs) were similar in both arms, occurring in 9 of 35 (25.7%) LCM and 9 of 37 (24.3%) fPHT subjects (p = 1.0). Interpretation LCM was noninferior to fPHT in controlling NCS, and TEAEs were comparable. LCM can be considered an alternative to fPHT in the treatment of NCSs detected on cEEG. Ann Neurol 2018;83:1174-1185.

Patient days and days present were compared to directly measured person time to quantify how choice of different denominator metrics may affect antimicrobial use rates. Overall, days present were approximately one-third higher than patient days. This difference varied among hospitals and units and was influenced by short length of stay.Infect Control Hosp Epidemiol 2018;39:612–615

AIM Pooled efficacy studies suggest that glycaemic responses to dipeptidyl-peptidase 4 inhibitors in type 2 diabetes are greatest in Asians, who may also respond better to alpha-glucosidase inhibitors. We assessed the glycaemic impact of sitagliptin by race in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), and whether this was enhanced in Asians with concomitant acarbose therapy. MATERIALS AND METHODS TECOS enrolled 14 671 patients with type 2 diabetes, cardiovascular disease and HbA1c of 48-64 mmol/mol (6.5%-8.0%), and randomized them, double-blind, to sitagliptin or placebo. There were 3265 patients (22.3%) from Asian countries. Background glucose-lowering therapies were unaltered for the first 4 months post randomization unless clinically essential, facilitating comparison of sitagliptin-associated effects in self-identified East Asian, Other (South) Asian, White Caucasian, Hispanic, Black and Indigenous groups. RESULTS Median baseline HbA1c by race was 54 to 57 mmol/mol (7.1%-7.4%). Mean 4-month reduction in placebo-adjusted HbA1c was greatest in East Asians (-6.6 mmol/mol [-0.60%] vs ≤6.0 mmol/mol [≤0.55%] in other groups), with significantly greater reduction vs the 2 largest groups (White Caucasians, Other Asians; P

OBJECTIVETo summarize and discuss logistic and administrative challenges we encountered during the Benefits of Enhanced Terminal Room (BETR) Disinfection Study and lessons learned that are pertinent to future utilization of ultraviolet (UV) disinfection devices in other hospitalsDESIGNMulticenter cluster randomized trialSETTING AND PARTICIPANTSNine hospitals in the southeastern United StatesMETHODSAll participating hospitals developed systems to implement 4 different strategies for terminal room disinfection. We measured compliance with disinfection strategy, barriers to implementation, and perceptions from nurse managers and environmental services (EVS) supervisors throughout the 28-month trial.RESULTSImplementation of enhanced terminal disinfection with UV disinfection devices provides unique challenges, including time pressures from bed control personnel, efficient room identification, negative perceptions from nurse managers, and discharge volume. In the course of the BETR Disinfection Study, we utilized several strategies to overcome these barriers: (1) establishing safety as the priority; (2) improving communication between EVS, bed control, and hospital administration; (3) ensuring availability of necessary resources; and (4) tracking and providing feedback on compliance. Using these strategies, we deployed ultraviolet (UV) disinfection devices in 16,220 (88%) of 18,411 eligible rooms during our trial (median per hospital, 89%; IQR, 86%–92%).CONCLUSIONSImplementation of enhanced terminal room disinfection strategies using UV devices requires recognition and mitigation of 2 key barriers: (1) timely and accurate identification of rooms that would benefit from enhanced terminal disinfection and (2) overcoming time constraints to allow EVS cleaning staff sufficient time to properly employ enhanced terminal disinfection methods.TRIAL REGISTRATIONClinical trials identifier: NCT01579370Infect Control Hosp Epidemiol 2018;39:157–163

Hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for patients with sickle cell disease (SCD). Though HSCT can reverse the SCD phenotype, both acute kidney injury (AKI) and chronic kidney disease (CKD) have been associated with HSCT. SCD alters renal function thus the impact of HSCT on renal function in SCD patients is a critical area of exploration. Here, we report the effect of HSCT on renal function in people with SCD. This study analyzes data from 195 patients who received HLA-matched sibling or haploidentical HSCT for SCD at Imperial College London (ICL), National Institutes of Health (NIH), and University of Illinois Chicago (UIC). The former is a pediatric cohort and all sites employed a nonmyeloablative conditioning. Patients' renal function was assessed at baseline and annually thereafter for up to 3-years. We examined the prevalence of CKD before and after HSCT, estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR) trends after HSCT, and the incidence of AKI within 100 days of HSCT. We defined and staged AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria; we calculated eGFR with the CKD- epidemiology collaboration (CKD-EPI) equation for adults and Bedside Schwartz for children. The median eGFR declined annually but remained within the normal range throughout the follow-up period: the baseline median eGFR was 138 ml/min/1.73m 2 and declined by 7 in the first year of follow-up and by additional decreases of 5 and 3.6 ml/min/1.73m 2 in subsequent years (p-values of 0.07, 0.0002, and 0.0002 for years 1, 2, and 3 for comparison to baseline from regression model of eGFR). No differences in eGFR were seen for covariates in the model: haploidentical vs. matched sibling, engraftment status, gender, or site. The downward eGFR trend may represent an improvement in renal function toward normal as hyperfiltration (eGFR ≥150 ml/min/1.73m 2) was present in 28% of patients at baseline and steadily declined to 7% by 3 years post-HSCT. There was a corresponding increase in patients with normal eGFR (60-149 ml/min/1.73m 2) from 59% at baseline to 88% at 3 years post-HSCT. Among the ICL and NIH cohorts (UIC excluded due to use of a different AKI determination strategy), 58% of patients developed AKI in the early post-HSCT period. 67% of AKI cases were mild, stage 1; 25% were moderate, stage 2; and 8% were severe, stage 3 AKI. This study demonstrates that HSCT in patients with SCD is associated with a transient increase in UACR but not associated with a significant increase in CKD prevalence by 3-years post-HSCT. The stability of UACR compared to baseline by the 3-year time point suggests that even more mild renal damage may stabilize after HSCT. While there is a substantial decline in eGFR from baseline to each annual follow-up, the proportion of patients whose eGFR was in the normal range increased as the prevalence of hyperfiltration decreased. Finally, while AKI occurred in more than half the patients in our cohort, the preponderance developed only mild AKI. Therefore, our data indicate that nonmyeloablative HSCT for SCD does not lead to significant kidney dysfunction post-HSCT. Disclosures Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Diamantidis: United Health Group: Consultancy.

Systolic blood pressure (SBP) treatment targets for adults with diabetes mellitus remain unclear. SBP levels among 12 275 adults with diabetes mellitus, prior cardiovascular disease, and treated hypertension were evaluated in the TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin) randomized trial of sitagliptin versus placebo. The association between baseline SBP and recurrent cardiovascular disease was evaluated using multivariable Cox proportional hazards modeling with restricted cubic splines, adjusting for clinical characteristics. Kaplan–Meier curves by baseline SBP were created to assess time to cardiovascular disease and 2 potential hypotension-related adverse events: worsening kidney function and fractures. The association between time-updated SBP and outcomes was examined using multivariable Cox proportional hazards models. Overall, 42.2% of adults with diabetes mellitus, cardiovascular disease, and hypertension had an SBP ≥140 mm Hg. The association between SBP and cardiovascular disease risk was U shaped, with a nadir ≈130 mm Hg. When the analysis was restricted to those with baseline SBP of 110 to 150 mm Hg, the adjusted association between SBP and cardiovascular disease risk was flat (hazard ratio per 10-mm Hg increase, 0.96; 95% confidence interval, 0.91–1.02). There was no association between SBP and risk of fracture. Above 150 mm Hg, higher SBP was associated with increasing risk of worsening kidney function (hazard ratio per 10-mm Hg increase, 1.10; 95% confidence interval, 1.02–1.18). Many patients with diabetes mellitus have uncontrolled hypertension. The U-shaped association between SBP and cardiovascular disease events was largely driven by those with very high or low SBP, with no difference in cardiovascular disease risk between 110 and 150 mm Hg. Lower SBP was not associated with higher risks of fractures or worsening kidney function.

Efficacy of statin-based therapies in reducing cardiovascular mortality in individuals with CKD seems to diminish as eGFR declines. The strongest evidence supporting the cardiovascular benefit of statins in individuals with CKD was shown with ezetimibe plus simvastatin versus placebo. However, whether combination therapy or statin alone resulted in cardiovascular benefit is uncertain. Therefore, we estimated GFR in 18,015 individuals from the IMPROVE-IT (ezetimibe plus simvastatin versus simvastatin alone in individuals with cardiovascular disease and creatinine clearance >30 ml/min) and examined post hoc the relationship of eGFR with end points across treatment arms. For the primary end point of cardiovascular death, major coronary event, or nonfatal stroke, the relative risk reduction of combination therapy compared with monotherapy differed by eGFR (P=0.04). The difference in treatment effect was observed at eGFR≤75 ml/min per 1.73 m2 and most apparent at levels ≤60 ml/min per 1.73 m2. Compared with individuals receiving monotherapy, individuals receiving combination therapy with a baseline eGFR of 60 ml/min per 1.73 m2 experienced a 12% risk reduction (hazard ratio [HR], 0.88; 95% confidence interval [95% CI], 0.82 to 0.95); those with a baseline eGFR of 45 ml/min per 1.73 m2 had a 13% risk reduction (HR, 0.87; 95% CI, 0.78 to 0.98). In stabilized individuals within 10 days of acute coronary syndrome, combination therapy seemed to be more effective than monotherapy in individuals with moderately reduced eGFR (30–60 ml/min per 1.73 m2). Further studies examining potential benefits of combination lipid-lowering therapy in individuals with CKD are needed.

Chronic kidney disease (CKD) is a common complication and a significant contributor to morbidity and mortality for patients with sickle cell disease (SCD). Hematopoietic stem cell transplantation (HSCT) is a curative strategy for SCD and potentially life-saving therapy. Though HSCT can reverse the SCD phenotype, acute and chronic kidney dysfunction may be an unintended consequence. The incidence of acute kidney injury (AKI) and the effect of different HSCT regimens on progression or amelioration of CKD in adults with SCD have not previously been reported. This cohort study analyzes prospectively collected data from 106 patients transplanted for SCD at the National Institutes of Health (NIH) Clinical Center, including HLA-matched sibling (N=71) and haploidentical HSCT (N=26) where nonmyeloablative conditioning was given, as well as gene therapy (N=9), where a myeloablative regimen was employed. Patients' renal function was assessed at baseline and annually thereafter for up to 3-years. We sought to define 1) the prevalence of CKD before and after HSCT 2) the incidence of CKD after HSCT 3) estimated glomerular filtration rate (eGFR) trends after HSCT 4) urine albumin to creatinine ratio (UACR) change after HSCT and 5) the incidence of AKI within 100 days of HSCT. We defined and staged AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria (stage 1: 1.5-1.9 times baseline serum creatinine increase or ≥0.3 mg/dl increase; stage 2: 2-2.9 times baseline; stage 3: 3 times baseline, increase in creatinine to ≥4.0 mg/dl, or initiation of renal replacement therapy). The baseline prevalence of CKD was 6% when defined conservatively (eGFR The median eGFR remained within the normal range throughout the follow-up period but declined annually: the baseline median eGFR was 139.7 ml/min/1.73m2 and declined by 7.6, 11.6, and 20.9 ml/min/1.73m2 each year post-HSCT (p0.05 for each variable). This eGFR trend represents an improvement in renal function toward the normal range: there was a statistically significant decrease in hyperfiltration (eGFR ≥150 ml/min/1.73m2), which was present in 34% patients at baseline but steadily declined to 12% by 3 years post-HSCT (p = 0.0006 for adjusted longitudinal model). There was a corresponding increase in patients with normal eGFR (60-149 ml/min/1.73m2) from 60% at baseline to 80% at 3 years post-HSCT. UACR showed an increase in the year following transplant that subsequently dissipated. Median UACR at baseline was 24.3 mg/g with annual follow-up median values of 62.2, 38.9 and 36.2 mg/g (p-values of 0.007, 0.41, and 0.69 for comparison to baseline from regression model of log transformed UACR). In our cohort, 58% of patients experienced AKI in the first 100 days post-HSCT; which is consistent with previous data. 77% of those were mild, stage 1; 13% were moderate, stage 2; and 10% were severe, stage 3 AKI. This study demonstrates that HSCT in patients with SCD is not associated with a significant increase in CKD incidence or prevalence at 2 and 3 years post-HSCT. While there is a substantial decline in eGFR from baseline to each annual follow-up, the proportion of patients whose eGFR was in the normal range increased and the prevalence of hyperfiltration decreased. The stability of UACR after an initial increase at the 1-year time point further suggests that even more mild renal damage may stabilize after transplant. Finally, AKI occurred in over half of the patients in our cohort, though the preponderance developed mild AKI. Disclosures Diamantidis: United Health Group: Membership on an entity's Board of Directors or advisory committees.

The long-term prognostic impact of post-discharge bleeding in the unique population of patients with acute coronary syndrome (ACS) treated without percutaneous coronary intervention (PCI) remains unexplored.The aim of this study was to assess the association between post-discharge bleeding and subsequent mortality after ACS according to index strategy (PCI or no PCI) and to contrast with the association between post-discharge myocardial infarction (MI) and subsequent mortality.In a harmonized dataset of 4 multicenter randomized trials (APPRAISE-2 [Apixaban for Prevention of Acute Ischemic Events-2], PLATO [Study of Platelet Inhibition and Patient Outcomes], TRACER [Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome], and TRILOGY ACS [Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes]), the association between post-discharge noncoronary artery bypass graft-related GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate, severe, or life-threatening bleeding (landmark 7 days post-ACS) and subsequent all-cause mortality was evaluated in a time-updated Cox proportional hazards analysis. Interaction with index treatment strategy was assessed. Results were contrasted with risk for mortality following post-discharge MI.Among 45,011 participants, 1,133 experienced post-discharge bleeding events (2.6 per 100 patient-years), and 2,149 died during follow-up. The risk for mortality was significantly higher 30 days (adjusted hazard ratio: 15.7; 95% confidence interval: 12.3 to 20.0) and 30 days to 12 months (adjusted hazard ratio: 2.7; 95% confidence interval: 2.1 to 3.4) after bleeding, and this association was consistent in participants treated with or without PCI for their index ACS (p for interaction = 0.240). The time-related association between post-discharge bleeding and mortality was similar to the association between MI and subsequent mortality in participants treated with and without PCI (p for interaction = 0.696).Post-discharge bleeding after ACS is associated with a similar increase in subsequent all-cause mortality in participants treated with or without PCI and has an equivalent prognostic impact as post-discharge MI.