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Abstract Introduction Despite being more common in males, thoracic aortic aneurysms (TAAs) have worse prognosis in females. Females with TAA are 3x more likely to experience acute aortic syndromes, and 40% more likely to die than their male counterparts, but mechanisms underlying this paradox are incompletely understood. The estimated aortic pulse wave velocity (e-PWV) is a marker of aortic stiffness that can be used widely due to its simplicity, as it does not require specialized equipment. We have previously shown that e-PWV was independently associated with faster TAA growth,(1) and that this association was twice as strong in females than males, but the role of e-PWV as a predictor of adverse outcomes in TAA remains unknown. Purpose We sought to evaluate the sex-specific association of e-PWV with adverse outcomes in patients with TAA. Methods We performed a prospective study of 102 males and 48 females with TAA. e-PWV was calculated according to validated equations utilizing age, mean arterial pressure, and presence/absence of cardiovascular risk factors.(2) The primary outcome was a composite of acute aortic syndromes, death, or elective aortic surgery. We used a Cox proportional hazard model to determine the independent association of e-PWV with the primary outcome, adjusted for age, BSA, aneurysm size and location, hypertension, and pulse pressure. Sex-specific models were performed if the interaction of sex*e-PWV was significant (P≤0.05). Univariate logistic regression models were performed to determine the c-statistic for e-PWV in predicting adverse outcomes, and the best e-PWV cutoff for this prediction was established based on sensitivity and specificity. Kaplan-Meier curves were performed using this cut-off. Results A summary of study design and results is presented in Picture 1. Mean age was 62±12 years, 70 (47%) had degenerative etiology, baseline aneurysm size was 46.3±4.3mm, and e-PWV was 9.5±1.9 m/s (not different between sexes, P>0.07 for each). Mean follow-up was 4.6±2.4 years in females and 5.5±2.3 years in males, P=0.031. The primary outcome occurred in 37 (25%) participants (3 dissections, 3 intramural hematomas, 1 aortic rupture, 22 elective surgical repairs and 11 deaths - 3 of which followed surgery). The interaction term sex*e-PWV was significant (P=0.0001), so sex-specific models were performed. e-PWV independently predicted the primary outcome in females (HR for 1m/s increase in e-PWV: 3.4; 95% confidence interval (CI): 1.1-14.7, P=0.033), but not in males (HR: 0.87; 95% CI: 0.50-1.51, P=0.622). In females, e-PWV had a c-statistic of 0.860 for the detection of the primary outcome, with a best e-PWV cutoff of 11.58 m/s (73% sensitivity, 92% specificity). Kaplan-Meier curves for the primary outcome in females using this cutoff are shown in Picture 2. Conclusion e-PWV independently predicts adverse outcomes in females with TAA, highlighting a novel marker for risk stratification and therapeutic targeting.Study summaryKaplan-Meier curves

Vitamin C is a vital nutrient that functions as an antioxidant and is important as a co-factor and regulator of several immune system pathways. The role of vitamin C in the treatment of COVID-19 is largely debatable. We conducted this meta-analysis to evaluate the efficacy and safety of vitamin C in the treatment of COVID-19. We searched several electronic databases from inception to March 2023 to retrieve randomized controlled trials on the use of Vitamin C for COVID-19. RevMan 5.4 was used to calculate risk ratios (RRs) and Mean Differences (MDs) along with confidence intervals (95% CI) using a random-effects model. We included 9 randomized controlled trials in our meta-analysis. Vitamin C did not reduce the all-cause mortality in patients with COVID-19 compared to the standard treatment [RR 0.86, 95% CI: 0.65-1.14; I 2 =66%]. Vitamin C was found to be associated with an increased incidence of ventilation in COVID-19 patients when compared to standard treatment [RR 1.37, 95% CI: 1.18-1.59; I 2 =58%]. There were no significant differences between both groups regarding the incidence of hospitalization [RR 1.00, 95% CI: 0.98-1.02; I 2 =0%], incidence of recovery [RR 1.57, 95% CI: 0.45-5.50; I 2 =52%], hospital mortality [RR 0.68, 95% CI: 0.44-1.06; I 2 =0%] and length of hospital stay [MD -0.63, 95% CI: -3.04 to 1.78; I 2 =81%]. Vitamin C administration did not reduce all-cause mortality in COVID-19 patients. Additional studies are required to evaluate the role of Vitamin C in the prevention and treatment of COVID-19 especially in ICU patients.

e19049 Background: Acala and zanu are 2nd generation Bruton tyrosine kinase inhibitors (BTKis) that have demonstrated improved safety profiles vs 1st generation BTKi ibrutinib in clinical trials. While head-to-head comparison of zanu vs acala is lacking, a recent meta-analysis of clinical trials provided a comprehensive, indirect comparison of the AE profiles in B-cell malignancies (Hwang, Hemasphere. 2023;7(S3):1134). This study aims to evaluate costs and impacts on quality of life (QoL) for zanu vs acala using their AE profiles. Methods: A health economic model was developed to determine cost and QoL associated with AE management for zanu and acala. The incidence rates ( IRs) of all grade and grade ≥3 AEs of interest (n=21, including bleeding events, hypertension, atrial fibrillation, cytopenias, infections, headache, arthralgia, diarrhea) were taken from the meta-analysis. Additional model inputs, such as disutility, average duration of AE, and unit cost of each AE were sourced from published literature and publicly available cost databases in consultation with clinical experts. The model was developed from the US perspective, considering Medicare costs, inflated to 2023 USD. Model outcomes were AE management cost (= IR * unit cost) and quality-adjusted life years (QALYs) lost due to AE (= IR * Disutility * Duration/365.25). Results: In the base-case scenario (considering all AEs), treating a hypothetical cohort of 1000 patients (pts) with zanu instead of acala yielded cost savings of $124K and 3.7 QALY gains (i.e., 3.7 years extra in full health). Subgroup analysis for severe (grade ≥3) and non-severe AEs (grade 1-2) demonstrated similar trends. A sensitivity analysis limited to AEs significantly different between zanu and acala (n=13) yielded consistent results. Additionally, a probabilistic sensitivity analysis, conducted with 1000 iterations to account for uncertainty in model parameters, confirmed robustness of the model, indicating stable conclusions across a wide range of parameter uncertainties. Conclusions: This analysis suggested that zanu is cost-saving and associated with added health benefits compared to acala in terms of AE management in pts with B-cell malignancies. Should these results derived from meta-analysis of clinical trial data be applicable to real-world pt populations across different indications, the potential cost savings could be considerable. These results could be further improved if the differences in efficacy of zanu vs acala are also incorporated. [Table: see text]

AbstractIntroductionWe performed a cross‐sectional study using the Centers for Disease Control and Prevention's (CDC's) Wide‐Ranging Online Data for Epidemiologic Research (WONDER) database to analyze the trends in cardiac implantable electronic device (CIED) infection‐related mortality from 1999 to 2020.MethodsWe analyzed the death certificate data from the CDC WONDER database from 1999 to 2020 for CIED infections in the US population aged ≥25 years using International Classification of Diseases, Tenth Revision (ICD‐10) codes, listed as the underlying or contributing cause of death. Age‐adjusted mortality rates (AAMR) and 95% confidence intervals (CIs) were computed per 1 million population by standardizing crude mortality rates to the 2000 US census population. To assess annual mortality trends, we employed the Joinpoint regression model, calculating the annual percent change (APC) in AAMR and corresponding 95% CIs.ResultsOverall, there was an observed declining trend in AAMRs related to CIED infection‐related mortality. Males accounted for 55% of the total deaths, with persistently higher AAMRs compared to females over the study duration. Both males and females had an overall decreasing trend in AAMRs throughout the study duration. On race/ethnicity stratified analysis, non‐Hispanic (NH) Blacks exhibited the highest overall AAMR, followed by NH American Indians or Alaska Natives, NH Whites, Hispanic or Latinos, and NH Asian or Pacific Islanders. On a stratified analysis based on region, the South region had the highest overall AAMR, followed by the Midwest, West, and Northeast regions.ConclusionOur study demonstrates a significant decline in CIED infection‐related mortality in patients over the last two decades. Notable gender, racial/ethnic, and regional differences exist in the rates of mortality related to CIED infections.

A male patient was evaluated by the dermatology inpatient consult service after a 5-week history of a skin lesion on the right anterior thigh with intermittent itching and mild tenderness to palpation. What is your diagnosis?

Introduction: There is a lack of data on the impact of sex on the outcomes of patients with heart failure (HF) undergoing atrial fibrillation (AF) ablation. Hypothesis: We hypothesized that outcomes of patients with HF undergoing AF ablation differ between males and females and tested this hypothesis using data from a nationally representative sample of the US population. Methods: The National Readmissions Database (NRD) was analyzed from 2016-2019 to identify patients ≥ 18 years old undergoing AF ablation. Patients were then divided into two cohorts based on their sex. A multivariable logistic regression model was used to adjust for confounders. Results: A total of 21,439 patients with HF underwent AF ablation between 2016-2019, of which 8,103 had heart failure with preserved ejection fraction (HFpEF) [64.8% were females], and 13,336 had heart failure with reduced ejection fraction (HFrEF) [38.4% were females]. Crude outcomes are shown in Figure 1. After multivariate adjustment, among patients with HFrEF, females had a longer length of stay (adjusted mean difference (aMD): 0.55 (0.16-0.93) days longer, p<0.01) along with lower odds of routine home discharge (adjusted odds ratio (aOR):0.62; 95% confidence interval (CI):0.55-0.70; p<0.01). Females had similar odds of in-hospital mortality, procedural complications, and 30-day/ 180-day all-cause, heart failure, and arrhythmia-related readmissions as compared to males. Among patients with HFpEF, females had higher odds of 30-day (aOR: 1.91; 95% CI: 1.24-2.93; p<0.01) and 180-day heart failure readmissions (aOR: 1.53; 95% CI: 1.04-2.28; p=0.03) along with lower odds of routine home discharge (aOR:0.67; 95% CI: 0.57-0.78; p<0.01), as compared to males. Conclusion: In conclusion, our results show that females with HFrEF undergoing AF ablation have similar odds of in-hospital/30-day/180-day outcomes whereas females with HFpEF have higher odds of 30-day/180-day HF readmissions, as compared to males.

Introduction: There is a lack of data on procedural safety and outcomes in patients with rheumatic mitral valve disease (RMVD) undergoing atrial fibrillation (AF) ablation. Hypothesis: We hypothesized that the presence of RMVD may affect the outcomes of patients undergoing AF ablation and tested this hypothesis using data from a large, nationally representative sample of the US population. Methods: The National Readmissions Database (NRD) was analyzed from 2016-2019 to identify patients ≥ 18 years old undergoing AF ablation. Patients with RMVD were then identified by using ICD-10 CM codes. A multivariable logistic regression model was used to adjust for confounders. Results: Our cohort included 50,728 weighted AF ablation procedures, of which 3,500 (6.9%) patients had RMVD. Patients with RMVD were older at the time of catheter ablation, with a significantly higher percentage of females, less likely to have paroxysmal AF, and had a higher burden of comorbidities including congestive heart failure, renal failure, and hypertension. On multivariable analysis, the presence of RMVD was associated with higher odds of cardiovascular complications (adjusted odds ratio [aOR] 1.28; 95% confidence interval [CI]: 1.12-1.47; p<0.01) with no difference in the odds of in-hospital mortality or other periprocedural outcomes. Also, RMVD was associated with longer length of stay (adjusted mean difference: +1.06; 95% CI: +0.67 - +1.45; p<0.01) days and lower odds of routine home discharge (aOR:0.77; 95% CI: 0.69-0.87; p<0.01). There was no difference in the odds of 30-day or 180-day all-cause, AF-related, or atrial flutter-related readmissions in patients with RMVD vs. no RMVD (Figure 1). Conclusion: In conclusion, patients with RMVD undergoing AF ablation have higher odds of periprocedural cardiovascular complications with similar odds of 30-day and 180-day all-cause and AF-related readmissions

Introduction: There is limited data on how psychosocial risk factors (PSRFs) affect the outcomes of patients undergoing atrial fibrillation (AF) ablation. Hypothesis: We hypothesized that the presence of PSRFs affects the outcomes of AF ablation and tested this hypothesis using a nationally representative sample of the US population. Methods: The National Readmissions Database (NRD) was analyzed from 2016-2019 to identify patients ≥ 18 years old undergoing AF ablation. Patients were divided into two cohorts based on the presence or absence of ≥1 PSRF. PSRFs were divided into 5 domains including limited cognitive understanding, substance use, psychiatric disease, low socioeconomic status, and uninsured status. A multivariable logistic regression model was utilized to adjust for confounders. Results: Our cohort included 50,623 AF ablation procedures, of which 21,363 (42.2%) had ≥ 1 PSRF. On multivariable analysis, the presence of ≥ 1 PSRF was associated with higher odds of cardiovascular complications (adjusted odds ratio [aOR] 1.11; 95% confidence interval [CI]: 1.02-1.22; p=0.02), peripheral vascular complications (aOR:1.18; 95% CI: 1.01-1.38; p=0.04), pulmonary complications (aOR:1.16; 95% CI: 1.05-1.29; p<0.01) and neurological complications (aOR:1.42; 95% CI: 1.12-1.78; p<0.01), along with higher odds of 30-day all-cause readmissions (aOR:1.30; 95% CI: 1.19-1.43; p<0.01) and atrial fibrillation/flutter related readmissions (aOR:1.27; 95% CI: 1.08-1.50; p<0.01), 90-day all-cause readmissions (aOR:1.30; 95% CI: 1.20-1.40; p<0.01) and atrial fibrillation/flutter related readmissions (aOR:1.22; 95% CI: 1.06-1.41; p<0.01), and 180-day all-cause readmissions (aOR:1.35; 95% CI: 1.24-1.45; p<0.01) (Figure 1). Conclusion: In conclusion, our data suggest an association between PSRFs and worse in-hospital outcomes along with increased all-cause and arrhythmia-related readmissions in patients undergoing AF ablation.

Background:Richter transformation (RT) occurs in up to 10% of patients with chronic lymphocytic leukemia (CLL), typically presents as an aggressive diffuse large B-cell lymphoma (DLBCL) and is associated with poor survival. RT has no approved standard therapy; and clinical trial enrollment is the preferred first line of therapy. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, that inhibits both wildtype and C481-mutant BTK with equal low nM potency, has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval. Pirtobrutinib demonstrated durable overall response rates (ORR) and was well tolerated in patients (pts) with poor-prognosis B-cell malignancies regardless of prior therapy. Here we provide updated safety and efficacy of pirtobrutinib in RT pts from the phase 1/2 BRUIN trial (NCT03740529). Methods: Pts with previously treated, histologically confirmed RT were eligible in the global, multicenter, phase 1/2 BRUIN study. Pts with untreated RT became eligible after Amendment 10. All but one patient received the recommended phase 2 dose of 200 mg daily. Key endpoints included investigator-assessed ORR, DoR per Lugano 2014 criteria, OS, and safety. A data cut of 05 May 2023 was utilized. To assess clonal relationship, IGH rearrangement studies were done on tissue biopsies with RT involvement, and baseline blood or bone marrow (BM) samples with CLL involvement. Results: Among all pts with RT (N=82) the median age was 67 (range, 26-95) and the median total number of lines of prior systemic therapy was 4 (range, 0-13). Pts with prior treatment had a median of 2 CLL-directed therapies and 2 RT-directed therapies. Eight pts did not have a previous line of RT-directed therapy, and 1 patient received neither RT- nor CLL-directed therapy. Common prior RT- and CLL-directed therapies (RT, CLL) included: chemotherapy (76%, 52%), cBTKi (34%, 62%), anti-CD20 antibody (78%, 66%), BCL2i (38%, 49%), stem cell transplant (SCT; 6%, 7%), and CAR-T (11%, 4%). Of 29 pts with bone marrow screening, 41.4% had CLL alone present in BM, 13.8% had DLBCL present and 24.1% had both CLL and DLBCL present. For 39 pts with available PET data, the median SUVmax was 19.1 (range, 2.6-41.2). For all 82 pts, the ORR was 50.0% (95% CI, 38.7-61.3) including complete (13.4%, n=11) and partial (36.6%, n=30) responses. For 61 pts who received prior cBTKi therapy, the ORR was 45.9% (95% CI 33.1-59.2). Among 28 pts with an RT-directed cBTKi and 51 pts with prior CLL-directed cBTKi, the ORR was 42.9% (95% CI, 24.5-62.8) and 43.1% (95% CI, 29.3-57.8), respectively. In 50 pts who discontinued prior cBTKi due to disease progression, the ORR was 42.0% (95% CI, 28.2-56.8). At median follow-up time of 9.7 months, the median DoR for all 82 RT pts was 7.4 months (95% CI, 3.1-19.1) and the estimated rate at 12 months was 45.9% (95% CI, 28.3-61.8). The median time on treatment for the 41pts who responded to treatment was 8.3 months. Eight pts stopped pirtobrutinib to pursue curative-intent allogeneic SCT and DoR was censored at the last preceding disease assessment. At a median survival follow-up of 18.3 months, the median OS for the entire RT cohort was 12.5 months (95% CI, 6.9-20.5). At 18 months, the OS rate was 44.3% (95% CI, 32.5-55.4). Frequent treatment-emergent adverse events (TEAE) in the RT cohort (n=82) were neutropenia/decreased neutrophil count (29.3%, n=24), fatigue (24.4%, n=20) and diarrhea, dyspnea, thrombocytopenia, and pyrexia (18.3% each, n=15). Common grade ≥3 TEAEs were neutropenia/decreased neutrophil count (23.2%, n=19), thrombocytopenia (11.0%, n=9), plus anemia and sepsis (9.8% each, n=8). Any grade hypertension (3.7%, n=3) or atrial fibrillation (1.2%, n=1) were infrequent. Three pts (3.7%) had treatment-related AEs leading to dose reductions, but no pt had a treatment-related AE leading to pirtobrutinib discontinuation. Analyses of clonality will be presented. Conclusions: Continued follow-up from BRUIN demonstrates encouraging response and OS in pts with RT. Pirtobrutinib remains well-tolerated with low rates of discontinuation and manageable safety profile. While RT remains a challenging diagnosis, pirtobrutinib represents a potential treatment option that warrants further investigation.

Background: Despite the efficacy of covalent (c) Bruton tyrosine kinase inhibitors (BTKi) in R/R MCL, disease relapse arises through evolution of resistance mechanisms or development of cBTKi intolerance. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi has favorable oral pharmacology that enables continuous BTK inhibition throughout the daily dosing interval regardless of the intrinsic rate of BTK turnover. Pirtobrutinib is the first BTKi to demonstrate durable efficacy following prior cBTKi therapy in heavily pre-treated R/R MCL and was well-tolerated with a low frequency of treatment discontinuation due to toxicity (Wang et al., JCO, 2023). Pirtobrutinib is approved in the USA to treat relapsed or refractory MCL after at least two lines of systemic therapy including a prior cBTKi. Here, we report updated results of pirtobrutinib therapy in all patients (pts), including those with biologically high-risk R/R MCL with a median survival follow-up of 24.2 months (range, 18.2-29.8). Methods: Pts with R/R MCL received pirtobrutinib monotherapy in the multicenter Phase 1/2 BRUIN trial (NCT03740529). Efficacy was assessed in all cBTKi pre-treated pts, as well as in cBTKi treatment-naïve pts. Key endpoints included overall response rate (ORR) as assessed by independent review committee per Lugano 2014 criteria, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Pts were included across the dose escalation range and expansion (25-300 mg/day) with 93% (n=141) receiving at least one dose of 200 mg/day, the FDA-approved dose. A data cut of 05 May 2023 was utilized. Results: Among all 152 pts with R/R MCL who received a prior cBTKi, the median age was 70 years (range, 46-88), and 52% had intermediate-risk and 28.3% had high-risk sMIPI scores. Median prior lines of therapy were 3 (range, 1-9), including an anti-CD20 antibody (96.7%), chemotherapy (90.1%), immunomodulator (17.1%), stem cell transplant (21.7%), BCL-2 inhibitor (15.8%), CAR-T cell therapy (8.6%), and PI3K inhibitor (3.9%). Among pts with high-risk biomarker data available, 30/60 (50%) had TP53 mutations and 45/63 (71%) had a Ki-67 index of ≥30%. The ORR for cBTKi pre-treated pts was 49.3% (95% CI, 41.1-57.6), including 15.8% complete responses (n=24) and 33.6% partial responses (n=51), whilst cBTKi naïve pts (n=14) had an ORR of 85.7% (95% CI, 57.2-98.2). The ORR among 128 pts who had discontinued a prior cBTKi due to PD and 21 pts who had discontinued for toxicity/other reasons was 43.0% and 90.5%, respectively. Among the 75 responding cBTKi pre-treated pts, the median DOR was 21.6 months (95% CI, 9.2-27.2) at a median follow-up of 24 months. The 18- and 24-month DOR rates were 51.9% (95% CI, 37-64.8) and 38.9% (95% CI, 22.7-54.8), respectively. ORR and DOR by high-risk subgroups (including blastoid/pleomorphic variants, Ki-67 index ≥30%, and TP53 mutations) are shown in Table 1. The 18- and 24-month DOR rates among 12 responding cBTKi naïve pts were both 90.0% (95% CI, 47.3-98.5). The median PFS and OS for cBTKi pre-treated pts was 5.6 months (95% CI, 5.3-9.2), and 23.5 months (95% CI, 17.1-NE), respectively. In the MCL cohort (n=166), the most frequent treatment-emergent adverse events (TEAEs) were fatigue (31.9%), diarrhea (22.3%), and dyspnea (17.5%). The most common Grade ≥3 TEAE was neutropenia/neutrophil count decreased (13.3%) and the rate of Grade ≥3 infections was (19.9%). Grade ≥3 hemorrhage/hematoma (2.4%) and all-grade atrial fibrillation/flutter (3.6%) were infrequent. Overall, 8 pts (5%) had treatment-related AEs leading to dose reductions and 5 (3%) had treatment-related AEs leading to pirtobrutinib discontinuation. Conclusion: Pirtobrutinib continues to demonstrate durable efficacy and a favorable safety profile in heavily pre-treated R/R MCL pts with prior cBTKi therapy. High ORRs were observed in pts who had PD on a prior cBTKi, and in pts with high-risk disease features including blastoid/pleomorphic variants, elevated Ki-67 index, and TP53 mutations.