Cumulative Incidence Of Mortality Research Articles

Machine-learning based subgroups of AL amyloidosis and cumulative incidence of mortality and end stage kidney disease.

Immunoglobulin light chain (AL) amyloidosis is a multisystem disease with varied treatment options and disease-related outcomes. Current staging systems rely on a limited number of cardiac, renal, and plasma cell dyscrasia biomarkers. To improve prognostication for all-cause mortality and end-stage kidney disease (ESKD), we applied unsupervised machine learning using a comprehensive set of clinical and laboratory parameters. Our study cohort comprised 2067 patients with newly diagnosed, biopsy-proven AL amyloidosis from the Boston University Amyloidosis Center. Variables included 31 clinical symptoms and 28 baseline laboratory values. Our clustering algorithm identified three subgroups of AL amyloidosis (low-risk, intermediate-risk, and high-risk) with distinct clinical phenotypes and median overall survival (OS) estimates of 6.1, 3.7, and 1.2 years, respectively. The 10-year adjusted cumulative incidences of all-cause mortality were 66.8% (95% CI 63.4-70.1), 75.4% (95% CI 72.1-78.6), and 90.6% (95% CI 87.4-93.3) for low, intermediate, and high-risk subgroups. The 10-year adjusted cumulative incidences of end-stage kidney disease (ESKD) were 20.4% (95% CI 6.1-24.5), 37.6% (95% CI 31.8-43.8), and 6.7% (95% CI 2.8-11.3) for low-risk, intermediate-risk, and high-risk subgroups. Finally, we trained a classifier for external validation with high cross-validation accuracy (85% [95% CI 83-86]) using a subset of easily obtainable clinical parameters. This marks an initial stride toward integrating precision medicine into risk stratification of AL amyloidosis for both all-cause mortality and ESKD.

All-cause and cause-specific mortality risk and loss in life expectancy associated with incident type 2 diabetes onset age and duration.

Evidence on type 2 diabetes onset age and duration on mortality risk has been limited by short follow-up, inadequate control for confounding, missing repeated measurements, and inability to cover the full range of onset age, duration, and major causes of death. Moreover, scarce data dissect how type 2 diabetes onset age and duration shape life expectancy. We evaluate prospectively these topics based on 270,075 eligible participants in the Nurses' Health Studies and Health Professionals Follow-up Study, leveraging repeated measurements throughout up to 40 years of follow-up. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). In fully adjusted analyses, incident early onset type 2 diabetes (diagnosed <40 years of age) was associated with significantly higher mortality from all-causes (HR, 95% CI was 3.16, 2.64-3.79; vs. individuals without type 2 diabetes), cardiovascular disease (6.56, 4.27-10.1), respiratory disease (3.43, 1.38-8.51), neurodegenerative disease (5.13, 2.09-12.6), and kidney disease (8.55, 1.98-36.9). The relative risk elevations declined dramatically with each higher decade of age at diagnosis for deaths from most of these causes, though the absolute risk difference increased continuously. A substantially higher cumulative incidence of mortality and a greater loss in life expectancy were associated with younger age at type 2 diabetes diagnosis. Longer disease duration was associated with generally higher relative and absolute risk of mortality. Early onset of type 2 diabetes and longer disease duration are associated with substantially increased risk of all-cause and cause-specific mortality and greater loss in life expectancy.

Sex differences and long-term clinical outcomes after transcatheter aortic valve replacement: A SWEDEHEART study

Previous studies on the impact of sex differences after transcatheter aortic valve replacement (TAVR) have shown conflicting results. The aim was to analyze the risk of long-term mortality, heart failure hospitalization, myocardial infarction, stroke, bleeding and aortic valve reintervention in females versus males after TAVR. This nationwide, population-based cohort study included all patients who underwent TAVR in Sweden between 2008 and 2022 from the SWEDEHEART register. Additional baseline and outcome data were gathered from other national health data registers. Regression standardization was used to adjust for differences between the sexes. Of 10,475 patients, 4,886 (47%) were female and 5,589 (53%) were male. The mean age was 81 years. The cumulative incidence of mortality at 1, 5, and 10 years was 8% vs. 10%, 38% vs. 45%, and 75% vs. 82% for females and males, respectively. After regression standardization, the risk of all-cause mortality was lower for females (absolute difference at 10 years of 6.4%, 95% confidence interval [CI] 4.4%-8.4%). The mean follow up was 3.1 years (maximum 14.1 years). Females also had a lower risk of major bleeding than males (absolute survival difference at 10 years of 4.0%, 95% CI 1.9%-6.2%), but there was no difference in the risk of heart failure, myocardial infarction, stroke, or reintervention between the sexes. Females had a higher survival rate and a lower bleeding risk than males after TAVR. Sex-specific factors are important to consider in the management of patients after TAVR.

Impact of peri-operative frailty and operative stress on post-discharge mortality, readmission and days at home in Medicare beneficiaries.

Understanding how patients' frailty and the physiological stress of surgical procedures affect postoperative outcomes may inform risk stratification of older patients undergoing surgery. The objective of the study was to examine the association of peri-operative frailty with mortality, 30-day readmission and days at home after non-cardiac surgical procedures of different physiological stress. This retrospective study used Medicare claims data from a 7.125% random sample of Medicare fee-for-service beneficiaries from 2015 to 2019 who were aged ≥ 65 years and underwent non-cardiac surgical procedure listed in the Operative Stress Score categories. The exposure of the study was claims-based frailty index (robust, < 0.15; pre-frail, 0.15 to < 0.25; mildly frail, 0.25 to < 0.35; and moderate-to-severely frail, ≥ 0.35) with Operative Stress Score categories being 1, very low stress to 5, very high stress. The primary outcome was all-cause mortality at 30 days and 365 days after the surgical procedure. In total, 1,019,938 patients (mean (SD) age of 76.1 (7.3) years; 52.3% female; 16.8% frail) were included. The cumulative incidence of mortality generally increased with Operative Stress Score category, ranging from 5.0% (Operative Stress Score 2) to 24.9% (Operative Stress Score 4) at 365 days. Within each category, increasing frailty was associated with mortality at 30 days (hazard ratio comparing moderate-to-severe frailty vs. robust ranged from 1.59-3.91) and at 365 days (hazard ratio 1.30-4.04). The variation in postoperative outcomes by patients' frailty level was much greater than the variation by the operative stress category. These results emphasise routine frailty screening before major and minor non-cardiac procedures and the need for greater clinician awareness of postoperative outcomes beyond 30 days in shared decision-making with older adults with frailty.

ASSOCIATION BETWEEN LOW LEVEL BLOOD LEAD EXPOSURE AND MORTALITY IN US ADULTS WITH CHRONIC KIDNEY DISEASE

Objective: This study aimed to explore the association between blood lead and both chronic kidney disease (CKD) and cardiovascular and all-cause mortality among participants with or without CKD in the US adults. Design and method: Date from the National Health and Nutrition Examination Survey (2007-20018) was used and all participants were followed up regularly until December 31, 2019. CKD was defined as an eGFR &lt;60 ml/min/1.73 m2 and/or a urine albumin and creatinine ratio &gt;= 30 mg/g. Logistic regression models were constructed to explore the associations between blood lead and CKD. The Kaplan–Meier analysis with a log-rank test was performed to estimate the cumulative incidence of mortality between groups. Cox proportional-hazards models were used to explore the associations between blood lead and cardiovascular and all-cause mortality. Results: Totally, this study enrolled 22,951 participants, including 4,078 CKD participants. Multivariable logistic regression analysis showed that higher level of blood lead (&gt;=1.82 vs. &lt;0.73) was associated with the increased risk of CKD (OR:1.35, 95% CI: 1.13–1.62, p=0.001). During a mean follow-up duration of 85.21±43.58 months, a total of 2,139 all-cause mortality and 525 cardiovascular mortality were recorded. In multivariable Cox model, compared with the lowest quartiles, highest blood lead level (&gt;=1.82 vs. &lt; 0.73) was associated with a higher risk of cardiovascular mortality (HR:3.36, 95% CI: 1.32–8.53) and all-cause mortality (HR:1.85, 95% CI: 1.18–2.90) in participants with CKD. Conclusions: In conclusion, in this US cohort, low level blood lead exposure may also be a predictive factor for CKD, and increasing blood lead concentrations significantly contributed to enhanced risk of cardiovascular and all-cause mortality in CKD patients. Hence, the reduce of blood lead exposure may reduce risk of mortality in high-risk individuals with CKD.

Death after cure: Mortality among pulmonary tuberculosis survivors in rural Uganda

ObjectivesTo determine the incidence of mortality and its predictors among pulmonary tuberculosis (PTB) survivors treated at a rural Ugandan tertiary hospital. MethodsWe conducted a retrospective chart review of data between 2013 and 2023. We included all people that met the World Health Organisation's definition of tuberculosis cure and traced them or their next of kin to determine vital status (alive/deceased). We estimated the cumulative incidence of mortality per 1000 population, crude all-cause mortality rate per 1000 person-years, and median years of potential life lost for deceased individuals. Using Cox proportional hazard models, we investigated predictors of mortality. ResultsOf 334 PTB survivors enrolled, 38 (11.4%) had died. The cumulative incidence of all-cause mortality was 113.7 per 1000 population, and the crude all-cause mortality rate was 28.5 per 1000 person-years. The median years of potential life lost for deceased individuals was 23.8 years (IQR: 9.6-32.8). Hospitalization (adjusted hazard ratio (aHR): 4.3, 95% CI: 1.1-16.6) and unemployment (aHR: 7.04, 95% CI: 1.5-31.6) at TB treatment initiation predicted mortality. ConclusionPTB survivors experience post high mortality rates after TB cure. Survivors who were hospitalized and unemployed at treatment initiation were more likely to die after cure. Social protection measures and long-term follow-up of previously hospitalized patients could improve the long-term survival of TB survivors.

Time to death and its predictors among neonates admitted with sepsis in neonatal intensive care unit at comprehensive specialized hospitals in Northeast Ethiopia.

In impoverished nations like Ethiopia, neonatal sepsis contributes significantly to neonatal mortality. Despite variations in the specific timing of death and predictors of neonatal mortality associated with sepsis across different settings, there's limited documented information in the Neonatal Intensive Care Units of northeastern Ethiopia. Consequently, the aim of this study was to determine time to death and its predictors among neonates with sepsis admitted to Neonatal Intensive Care Units in comprehensive specialized hospitals in northeastern Ethiopia. A prospective cohort study conducted at the institution level involved 306 neonates diagnosed with sepsis. Data collection utilized face-to-face interviews and chart reviews. Subsequently, the data were inputted into Epi-data version 4.6 and later analyzed using STATA version 17. The median time to death was determined, and both the Kaplan-Meier curve and log-rank test were applied. Furthermore, a Cox proportional hazard regression model was utilized to identify predictors of neonatal mortality associated with sepsis. The cumulative incidence of mortality among neonates admitted with sepsis was 34% (95% CI: 28.9%-39.5%). The neonatal mortality rate stood at 51 (95% CI: 42.1, 62) per 1,000 neonates admitted to the intensive care units with sepsis over a total of 1,854 person-days of observation. Additionally, the median time to death was 13 days (IQR = 5-23 days). Tachypnea [AHR 6.2 (95% CI: 1.5-9.7)], respiratory distress syndrome [AHR 2.1 (95% CI: 1.3-3.5)], lethargy [AHR 1.8 (95% CI: 1.2-2.6)], preterm birth [AHR 1.8 (95% CI: 1.2-2.7)], continuous positive airway pressure use [AHR 2.1 (95% CI: 1.3-3.4)], home delivery [AHR 2.63 (95% CI: 1.1-6.4)], Subgalea hemorrhage [AHR 1.8 (95% CI: 1.1-3.9)], and low platelet count [AHR 5.9 (95% CI: 2.3-8.6)] were found to be predictors of time to death in neonates with sepsis. The study revealed an alarmingly high neonatal mortality rate among septic neonates, underscoring the urgency for intervention. Enhancing the quality of care in neonatal intensive care units, bolstering infection prevention during procedures such as continuous positive airway pressure, exercising caution with locally made accessories, and reinforcing a culture of institutional delivery are critical in curbing neonatal sepsis-related mortalities.

Abstract MP31: Incident Type 2 Diabetes Onset Age and Duration, Mortality Risk, and Loss in Life Expectancy

Introduction: Evidence on the relationship between type 2 diabetes onset age, duration, and mortality risk has been influenced by limited follow-up, inadequate control for confounding, and inability to cover the full range of onset age, duration, and the full spectrum of major causes of death. Moreover, there are scarce data dissecting how type 2 diabetes onset age and duration shape life expectancy. Hypothesis We assessed the hypothesis that early onset of type 2 diabetes and longer disease duration may be associated with higher risk of all-cause and cause-specific mortality and greater loss in life expectancy. Methods: We prospectively followed 270,075 eligible participants in the Nurses’ Health Study, Nurses’ Health Study II, and Health Professionals Follow-up Study longitudinal cohorts for up to 40 years. The exposures include type 2 diabetes onset age (&lt;40, ≥40 to &lt;50, ≥50 to &lt;60, ≥60 to &lt;70, ≥70 to &lt;80, and ≥80 years) and duration (&lt;10, ≥10 to &lt;20, ≥20 to &lt;30, and ≥30 years). Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for age and a wide spectrum of potential confounders. Results: We documented 73,076 deaths during 8,166,216 person-years of follow-up. In fully-adjusted analyses, incident early-onset type 2 diabetes (diagnosed &lt;40 years of age) was associated with significantly higher mortality from all-causes (HR, 95% CI was 3.16, 2.64-3.79; vs. individuals without type 2 diabetes), cardiovascular disease (6.56, 4.27-10.1), respiratory disease (3.43, 1.38-8.51), neurodegenerative disease (5.13, 2.09-12.6), kidney disease (8.55, 1.98-36.9), and suggestively increased mortality from diabetes-related cancer (1.63, 0.94-2.83) and obesity-related cancer (1.63, 0.92-2.88). The relative risk elevations declined dramatically with each higher decade of age at type 2 diabetes diagnosis for deaths from most of these causes, though the absolute risk difference increased continuously. A substantially higher cumulative incidence of mortality and a greater loss in life expectancy were associated with younger age at type 2 diabetes diagnosis. Comparing individuals with early-onset type 2 diabetes to those without type 2 diabetes, their estimated multivariable-adjusted cumulative incidence of all-cause mortality at age 80 was 0.43 vs. 0.20, and the estimated life expectancy loss at age 40 was 2.5 years. Longer disease duration was associated with generally higher relative and absolute risk of mortality. Conclusions: Early onset of type 2 diabetes and longer disease duration are associated with substantially increased risk of all-cause and cause-specific mortality and greater loss in life expectancy. The effect of early-onset type 2 diabetes on mortality risk is stronger than that of later-onset type 2 diabetes.

Predictors of loss to follow up among adults on antiretroviral therapy before and after the start of treat-all strategy in public health facilities of Hawassa city, Ethiopia: A Competing risk regression.

Treat-all strategies improved patient outcomes, despite higher rates of loss to follow-up compared to the pre-treat era. Patients in Ethiopia experienced a higher rate of LTFU during the treat-all strategy period; however, studies did not identify contributing factors in comparison with previous strategies. This study aimed to assess the incidence and predictors of loss to follow-up before and after the start of the treat-all strategy among adults on anti-retroviral therapy in public health facilities in Hawassa City, Ethiopia. An institution-based retrospective follow-up study was conducted among 1190 randomly selected adults on antiretroviral therapy in public health facilities in Hawassa City. Using the Open Data Kit (ODK), data were collected from medical records and exported to Stata version 16 and R 4.2.1 for analysis. A Grays test and cumulative incidence curve were used to compare the cumulative incidence function of loss to follow-up. Bivariable and multivariable competing risk regression were fitted to identify predictors of LTFU and variables with a p-value <0.05 were considered significant. The cumulative incidence of lost-to-follow-up was 4.92(3.84,6.3) and 8.67(7.26,10.3) per 100 person-years (PY) in pre-treat all and treat all cohorts, respectively. The cumulative incidence of mortality was 5.86(4.67,7.35) and 3(2.26,4.12) per 100 PY in pre-treat and treat all cohorts, respectively. Fair/poor adherence (aSHR:5.17; (95% CI 1.97, 13.51), underweight (aSHR:2.13; 95% CI: 1.15-3.93) and WHO stage III/IV (aSHR:2.69; 95% CI: 1.27, 5.71) were predictors of loss up in pre-treat all, whereas fair/poor adherence (aSHR = 2.07; 95% CI: 1.18, 3.68), underweight (aSHR:1.71; 95% CI: 1.13, 2.56), and CD4 cell >350 cell/m3 (aSHR: 1.67; 95% CI: 1.05, 2.65) predicts of loss up in treat all cohorts. This study demonstrated that the incidence of loss to follow-up was considerably higher in the treat-all period as compared to the pre-treat-all era. Poor medication compliance, underweight, and a CD4 level >350 cells/m3 contributed to the higher rate of LTFU in the treat-all strategy. Targeted interventions, such as nutritional support and strengthening medication adherence counseling, should be implemented to maintain treatment retention and reduce antiretroviral therapy dropout rates.

Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort

Individuals with rare kidney diseases account for 5-10% of people with chronic kidney disease, but constitute more than 25% of patients receiving kidney replacement therapy. The National Registry of Rare Kidney Diseases (RaDaR) gathers longitudinal data from patients with these conditions, which we used to study disease progression and outcomes of death and kidney failure. People aged 0-96 years living with 28 types of rare kidney diseases were recruited from 108 UK renal care facilities. The primary outcomes were cumulative incidence of mortality and kidney failure in individuals with rare kidney diseases, which were calculated and compared with that of unselected patients with chronic kidney disease. Cumulative incidence and Kaplan-Meier survival estimates were calculated for the following outcomes: median age at kidney failure; median age at death; time from start of dialysis to death; and time from diagnosis to estimated glomerular filtration rate (eGFR) thresholds, allowing calculation of time from last eGFR of 75 mL/min per 1·73 m2 or more to first eGFR of less than 30 mL/min per 1·73 m2 (the therapeutic trial window). Between Jan 18, 2010, and July 25, 2022, 27 285 participants were recruited to RaDaR. Median follow-up time from diagnosis was 9·6 years (IQR 5·9-16·7). RaDaR participants had significantly higher 5-year cumulative incidence of kidney failure than 2·81 million UK patients with all-cause chronic kidney disease (28% vs 1%; p<0·0001), but better survival rates (standardised mortality ratio 0·42 [95% CI 0·32-0·52]; p<0·0001). Median age at kidney failure, median age at death, time from start of dialysis to death, time from diagnosis to eGFR thresholds, and therapeutic trial window all varied substantially between rare diseases. Patients with rare kidney diseases differ from the general population of individuals with chronic kidney disease: they have higher 5-year rates of kidney failure but higher survival than other patients with chronic kidney disease stages 3-5, and so are over-represented in the cohort of patients requiring kidney replacement therapy. Addressing unmet therapeutic need for patients with rare kidney diseases could have a large beneficial effect on long-term kidney replacement therapy demand. RaDaR is funded by the Medical Research Council, Kidney Research UK, Kidney Care UK, and the Polycystic Kidney Disease Charity.

ALBI Grade Is Associated with Clinical Outcomes of Critically Ill Patients with AKI: A Cohort Study with Cox Regression and Propensity Score Matching.

The albumin-bilirubin (ALBI) grade has surfaced as a viable substitute for assessing liver functional reserve in individuals afflicted with hepatocellular carcinoma (HCC). ALBI grade also demonstrates the capacity to stratify distinct patient subcohorts bearing disparate prognostic implications in not only HCC but also other inflammatory diseases like acute pancreatitis. However, the association between ALBI grade and clinical outcomes of acute kidney injury (AKI) remains mysterious. The dataset was sourced from the Multiparameter Intelligent Monitoring in Intensive Care Database IV (MIMIC-IV) version 2.0. ALBI grade was calculated in a nomogram utilizing albumin and bilirubin. In order to ascertain the connection between ALBI grades and clinical outcomes of patients with AKI, Cox proportional hazards regression analysis was employed with in-hospital, 30- and 90-day mortality as end points, respectively. The Kaplan-Meier (K-M) curve was employed to gauge the cumulative incidence of mortality based on various ALBI grades. To explore potential nonlinear relationships, the Restricted Cubic Spline (RCS) approach was adopted. Furthermore, a subgroup analysis was conducted to validate the durability of the correlation between ALBI grade and in-hospital mortality. Furthermore, equilibrium of confounding variables was also achieved through the application of propensity score matching (PSM). The study encompassed a total of 12,518 patients (ALBI grade 1 : 2878, grade 2 : 6708, and grade 3 : 2932). Patients with heightened ALBI grades displayed a significant correlation with increased mortality in both univariate and various multivariate Cox regression models. RCS depicted a predominantly linear relationship. The robustness of the correlation was also affirmed across multifarious subpopulations through subgroup analysis. The association still remains after PSM. Elevated ALBI grade was associated with worse clinical outcomes of critically ill patients with AKI.

Results of a Phase 1/2 Study of Lower Dose CPX-351 for Patients with Int-2 or High Risk IPSS Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia after Failure to Hypomethylating Agents

INTRODUCTION: Hypomethylating agents (HMAs) are the standard of care for patients (pts) with higher-risk myelodysplastic syndromes (HR-MDS) and chronic myelomonocytic leukemia (CMML). HMA failure (HMA-F) is associated with poor outcomes and median survival of 4 to 6 months. CPX-351 is a drug liposomal encapsulation of cytarabine (araC) and daunorubicin (dauno) at a synergistic 5:1 molar ratio approved for the treatment of pts with therapy-related acute myeloid leukemia (AML) or AML with MDS-related changes. Here we present the results of a phase I-II study of lower dose CPX-351 for HR-MDS and CMML after HMA-F. METHODS: We conducted a phase I/II clinical trial of CPX-351 for pts with MDS or CMML after HMA-F with Int-2 or High risk by IPSS, or Int-1 with &amp;gt;10% bone marrow (BM) blasts. The study included an initial phase I dose-escalation portion, following a 3+3 design, followed by a phase II dose expansion portion. Dose escalation included 4 dose levels of CPX-351: 10 units/m 2 (dauno 4.4mg/m 2 and araC 10mg/m 2), 25 units/m 2 (dauno 11mg/m 2 and araC 25mg/m 2), 50 units/m 2 (dauno 22mg/m 2 and araC 50mg/m 2) and 75 units/m 2 (dauni 33mg/m 2 and araC 75mg/m 2). Therapy was administered intravenously on days 1, 3 and 5 of 28-day cycles during induction and on days 1 and 3 of re-induction or consolidation. Re-induction was allowed in pts not achieving response after induction. The primary end point was to evaluate safety and determine the maximum tolerated dose of CPX-351. Responses were evaluated following 2006 IWG criteria. The Kaplan-Meir product-limit method was used to estimate median survival. RESULTS: Between June 2019 and September 2022, 23 pts have been treated: 15 in the phase I portion, and 8 in the phase II. A total of 17 pts had MDS, and 6 had CMML. Four (17%) pts had intermediate-1 risk IPSS and &amp;gt;10% blasts, 15 (65%) had intermediate-2 and 4 (17%) had high-risk IPSS. Median number of prior therapies was 1 (range 1-4) including 4 (17%) pts with failure to prior venetoclax therapy and 2 (9%) with prior HSCT. In the phase I portion, 3 pts received CPX-351 at dose level 1, 3 at dose level 2, 3 at dose level 3 and six at dose level 4. One pt treated at dose level 4 developed grade 2 congestive heart failure with grade 2 reduction in left-ventricular ejection fraction (LVEF). No additional DLTs were detected during the 28-day DLT evaluation window. The initial two pts treated at the P2RD of 75units/m 2 during phase II experienced cardiac complications: grade 3 congestive heart failure without reduction in LVEF and grade 3 right-sided heart failure, respectively. Study was amended to continue further treatment in phase II at dose level 3 (50units/m 2). Most common adverse events (AEs) were lower extremity edema (n=12, 52%), febrile neutropenia (n=11, 48%), dyspnea (n=10, 44%), mucositis (n=10, 44%), constipation (n=9, 39%), diarrhea (n=9, 39%), and generalized muscle weakness (n=9, 39%). Most common grade 3-4 AEs were febrile neutropenia (n=11, 48%), neutropenia (n=5, 22%), lung infection (n=4, 17%), diarrhea (n=4, 17%) and thrombocytopenia (n=3, 13%). The 4-week and 8-week cumulative incidences of mortality were 0% and 4%, respectively. Median number of days to cycle 2 was 47 days (range 30-83). Dose reductions of CPX-351 occurred in 4 (17%) pts. Median number of cycles was 3 (range 1-9). Median cycles to best response was 1 (range 1-3). Among pts with HR-MDS, the ORR was 71% (n=12): CR in 1 (6%), mCR with HI in 1 (6%) and mCR in 11 (59%) pts (Fig 1A). Among pts with BM blast reduction to &amp;lt;5% by the end of cycle 1, 11 (65%) and 9 (53%) had ANC recovery to &amp;gt;0.5x10 9/L and &amp;gt;1x10 9/L, respectively, and 8 (47%) and 6 (35%) had platelet recovery to &amp;gt;50x10 9/L and &amp;gt;100x10 9/L, respectively. Based on 2023 IWG response criteria, the ORR was 59% (n=10) including CR in 1 (6%), CR bilineage (CRbi) in 4 (24%) and CR unilineage in 5 (29%). Of 11 (65%) pts with baseline cytogenetic abnormalities, 2 (18%) and 2 (18%) achieved complete and partial cytogenetic responses, respectively. Three (13%) pts underwent HSCT at time of best response. Among pts with CMML (n=6), only one (17%) achieved response. Median response duration was 4.5 months (95% CI 0.7-8.2 months) and the median OS was 12.6 months (95% CI 3.6-21.7 months) (Fig 1B). CONCLUSIONS: Lower doses of CPX-351 in HR-MDS after HMA-F can induce clinically meaningful responses and be used as a bridge to allogeneic stem-cell transplant. Therapy is associated with median OS of 12.6 months in this population with expected survival of 4-6 months.

Results of a Phase II Study of Cladribine, Low Dose Cytarabine and Venetoclax, Alternating with Azacitidine and Venetoclax in Patients with Higher Risk Chronic Myelomonocytic Leukemia or Myelodysplastic Syndromes

INTRODUCTION: Clinical responses to hypomethylating agents (HMAs) in patients (pts) with higher-risk myelodysplastic syndromes (HR-MDS) and myeloproliferative chronic myelomonocytic leukemia (CMML) remain short-lived, with high risk of transformation to acute myeloid leukemia (AML). Prior data suggests use of the purine analogue cladribine can induce monocyte apoptosis and is active in AML, particularly in combination with low dose cytarabine (LDAC) and venetoclax. We aimed to evaluate the safety and activity of cladribine, LDAC and venetoclax in HR-MDS and CMML. METHODS: We designed a phase II basket clinical trial of cladribine combined with LDAC and venetoclax alternating with azacitidine and venetoclax for pts with HR-MDS or CMML. Pts were divided into 4 cohorts: cohort A: MDS with int-1 to high risk by IPSS and &amp;gt;5% blasts with prior HMA-failure (HMA-F); cohort B: CMML-1/CMML-2 with prior HMA-F; cohort C: previously untreated MDS with Int-2 or High risk by IPSS and &amp;gt;10% bone marrow (BM) blasts; cohort D: previously untreated CMML-2 or CMML-1 with at least one high-risk feature (extramedullary disease, splenomegaly of &amp;gt;5cm below costal margin, platelets &amp;lt;100x10 9/L, Hgb level &amp;lt;10g/dL, WBC &amp;gt;13x10 9/L, clonal cytogenetic abnormality [other than monosomy Y]). HMA-F was defined as no response after 6 cycles of therapy with HMA or relapse/progression after any number of cycles. Induction consisted of cladribine 5mg/m 2 daily IV on days 1-3, cytarabine 20mg s.c bid days 1-5 and venetoclax 400mg daily days 1-5. Re-induction was allowed in pts not achieving response after induction. Consolidations consisted of azacitidine 75mg/m 2 daily days 1-7 with venetoclax 400mg daily days 1-7 alternating with cladribine 5mg/m 2 days 1-3, cytarabine 20mg s.c bid days 1-5 and venetoclax 400mg days 1-5 every two 28-day cycles. The primary end point was to evaluate safety, efficacy, and tolerability of the combination. Responses were evaluated following 2006 IWG criteria. The Kaplan-Meir product-limit method was used to estimate median survival. RESULTS: Between October 2022 and June 2023, 20 pts have been treated: 10, 5, 3 and 2 in cohorts A, B, C and D, respectively. Thirteen pts had MDS, and 7 had CMML. Median age was 74 years (range 52-83). Among MDS pts, 8 (62%) had int-2 and 5 (38%) had high risk by IPSS. By the Molecular IPSS, 10 (79%) had very high, 1 (8%) had high, 1 (8%) had moderate high and 1 (8%) had low risk. Among CMML pts, 4 (57%) had high, 2 (29%) had intermediate-2 and 1 (14%) had intermediate-1 risk by the CPSS Molecular score. Among HMA-F cohorts, median number of prior therapies was 1 (range 1-4), median cycles of prior HMA was 6 (range 2-63) and 4 (27%) pts had failure to prior venetoclax therapy. Most common adverse events (AEs) were hypoalbuminemia (40%), nausea (40%), sinus bradycardia (40%), alanine aminotransferase increase (35%), constipation (35%), lower extremity edema (35%), fatigue (35%) and hypocalcemia (35%) Most common grade 3-4 AEs were leukopenia (20%) and febrile neutropenia (15%). The 4-week and 8-week cumulative incidences of mortality were 0%. Median number of cycles was 2 (range 1-6). Median cycles to best response was 1 (range 1-3). Among HMA naïve pts (cohorts C and D), the ORR was 80% (n=4): CR in 2 (40%), mCR in 2 (40%). Based on 2023 IWG response criteria, responses in cohort C (n=3) included: CR in 2 (67%) and CR bilineage (CRbi) in 1 (33%). Based on 2015 IWG MDS/MPN criteria, responses in cohort D (n=2) included optimal marrow response and clinical benefit in 1 (50%) and 1 (50%) pts, respectively. Among HMA-F pts (cohorts A and B) the ORR was 20%: 1 CR (10%) and 1 (10%) mCR with HI. Median follow up is 5.3 months (95% CI 2.4-81). Median EFS is 2.1 months in cohorts A and B and not reached in C and D (Fig 1A). Median OS has not been reached for all cohorts (Fig 1B). At the time of data cut-off, all pts in cohorts C and D discontinued study to proceed with hematopoietic stem-cell transplantation (HSCT). Among cohorts A and B, 2 pts (13%) discontinued study to proceed with HSCT, 5 (33%) due to transformation to AML, 2 (13%) due to no response, 2 (13%) due to physician choice, 1 (7%) due to patient choice and 2 (13%) pts remain on study. CONCLUSIONS: Preliminary data suggests the use of cladribine, LDAC and venetoclax can be safely administered in pts with very high risk MDS and CMML with early promising results in pts with de novo disease.

Abstract 16935: Distressed Community Index in Patients Undergoing Carotid Artery Stenting in Medicare-Linked Vascular Quality Initiative Registry

Introduction: Patients with high community-level socioeconomic distress have worse cardiovascular outcomes, yet its impact on carotid artery stenting (CAS) outcomes is unknown. We assessed the association between the Distressed Community Index (DCI), a zip-code level measure of community distress, with post-CAS mortality and stroke. Methods: We used the Vascular Quality Initiative database linked with Medicare claims outcomes data to identify patients undergoing CAS between 2015 and 2019. From a time-dependent ROC curve and using Youden index, we classified patients as high community distress if DCI≥65. Thirty-six-month cumulative mortality incidence using Kaplan-Meier by DCI groups, and hierarchical Cox regression with random intercept for site for linear DCI were used. For stroke, we used 36-month cumulative incidence function by DCI groups, and Fine and Gray models accounting for competing risk of death for linear DCI. Models were later adjusted for patient and procedural characteristics. Results: The final complete-case cohort included 8,595 patients (2,580/30% DCI≥65), had a mean age of 74.7 (±7.8) years, was 92.7% white and 97.6% non-Hispanic/Latino. The 36-month cumulative mortality incidence was similar in both groups (26.0% vs 22.5%, P=0.236). A 10-point increase in DCI did not increase mortality risk (unadjusted HR 1.00; 95% CI 0.98-1.03 and adjusted HR 1.01; 95% CI 0.87-1.17). At 36 months the high community distress group experienced higher stroke risk (29.8% vs 22.9%, P=0.008). However, a 10-point increase in DCI did not increase stroke risk (unadjusted sub-HR: 1.01; 95% CI 0.99-1.03, adjusted sub-HR: 1.00; 95% CI 0.98-1.02). Conclusions: In this selective set of patients with underrepresentation of demographic groups, for those who get prioritized to CAS, higher community distress was associated with an increased unadjusted 36-month stroke risk by DCI group. However, a 10-point increase in DCI was nonsignificant regardless of adjustment.

Abstract 13901: Deep Learning-Based Digital Biomarker to Diagnose Hypertension and Stratify Cardiovascular Risk From the Electrocardiogram

Background/Aim: Hypertension affects nearly half of US adults and is a major modifiable risk factor for cardiovascular disease (CVD). Guidelines recommend serial blood pressure (BP) measurement under controlled conditions or ambulatory BP monitoring, but BP is often measured intermittently under suboptimal conditions, leading to underdiagnosis and undertreatment. We developed a deep learning model (HTN-AI) to identify hypertension and stratify risk of hypertension-associated CVD from 12-lead ECGs. Methods: HTN-AI is a convolutional neural network trained to detect prevalent hypertension or elevated baseline BP (systolic ≥ 140 mmHg or diastolic ≥ 90 mmHg) using 747,992 ECGs from 106,879 adults receiving primary or cardiology care at Massachusetts General Hospital (MGH). Associations between HTN-AI-predicted risk of hypertension and CVD (all-cause mortality, heart failure [HF], myocardial infarction [MI], stroke, and aortic dissection) were assessed in 56,730 primary care patients at Brigham and Women’s Hospital (BWH) with cumulative incidence analysis and cause-specific hazard regression. Results: In an MGH test sample and the BWH sample, HTN-AI discriminated prevalent hypertension or elevated baseline BP (AUC 0.791 and 0.762, respectively). Quintiles of HTN-AI risk stratified cumulative incidence of mortality (Figure), HF, MI, stroke, and aortic dissection (p &lt; 0.001 for all). HTN-AI risk was significantly associated with age- and sex-adjusted risk of incident mortality (HR per SD: 1.85 [95% CI: 1.77-1.92], p&lt;0.001), HF (3.55 [3.25-3.88], p&lt;0.001), MI (2.33 [2.20-2.47], p&lt;0.001), stroke (1.74 [1.64-1.86], p&lt;0.001), and aortic dissection (1.80 [1.41-2.31], p&lt;0.001). Conclusion: A deep learning model, HTN-AI, discriminates patients with hypertension and stratifies risk of incident CVD using 12-lead ECGs. HTN-AI has the potential to facilitate diagnosis of hypertension and serve as a novel digital biomarker for hypertension-associated CVD.

Results of Phase I/II Study of Azacitidine in Combination with Quizartinib for Patients with Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms with FLT3 or CBL Mutations

Introduction: FMS-like tyrosine kinase 3 ( FLT3) mutations occur in approximately 1% of patients (pts) with newly diagnosed myelodysplastic syndrome (MDS) and up to 19% of pts at time of failure to hypomethylating agents (HMA). In addition, mutations in the Casitas B-lineage Lymphoma gene ( CBL) are observed in 10% of pts with MDS/MPN and up to 15% of pts with CMML. Preclinical studies suggest that CBL-mutant cells are dependent on FLT3 signaling. Here we present results of a phase I-II study of the FLT3 inhibitor quizartinib in combination with azacitidine for pts with FLT3 and CBL mutant MDS and MDS/MPN. Methods: We conducted a phase I/II clinical trial of azacitidine in combination with quizartinib for pts with MDS and MDS/MPN with detectable FLT3 and/or CBL mutations and with/without prior failure to HMA (HMA-F). The study included an initial phase I dose-escalation portion, following a 3+3 design, followed by a phase II dose expansion portion. Dose escalation included 3 dose levels of quizartinib: 30, 40 and 60 mg administered p.o daily on days 1-28 of each 28 day cycle. Therapy consisted on quizartinib (at corresponding dose level) in combination with azacitidine 75 mg/m 2/day i.v os s.c on days 1-5. The primary endpoint was to evaluate safety, tolerability and maximum tolerated dose of quizartinib. Responses were evaluated following 2006 IWG criteria. The Kaplan-Meier product-limit method was used to estimate median survival. Results: Between July 2020 and June 2023 a total of 16 pts have been treated: 12 in the phase I portion and 4 in the phase II. A total of 4 pts had MDS with excess blasts, 2 had MDS/MPN with neutrophilia and 10 had CMML. Eight (50%) pts had FLT3-ITD mutations and 8 (50%) had CBL mutations. Four (25%) pts had HMA-F one of which had received 4 lines of therapy including hematopoietic stem-cell transplant (HSCT) prior to enrollment. Based on the Molecular IPSS, 8 (50%), 3 (19%) and 5 (31%) pts had very high, high and moderate high risk disease. Among CMML pts, 3 (30%) pts had high and 7 (70%) had intermediate-2 risk by CPSS-Molecular score. In the phase I portion, 3 pts received quizartinib at dose level 1, 3 at dose level 2 and 6 at dose level 3. No dose limiting toxicities were detected during the 28-day DLT evaluation window. Dose level 2 was selected as the P2RD. Most common adverse events (AEs) were constipation (56%), fatigue (50%), insomnia (44%), anorexia (38%), cough (38%), diarrhea (38%) and arthralgia (31%). Most common grade 3-4 AEs were anemia (31%), thrombocytopenia (31%), lung infection (13%), skin infection (13%), hyponatremia (13%) and sepsis (13%). Arrythmias were observed 5 pts: atrial fibrillation (grade 2, n=2; grade 3, n=1), Mobitz type II atrioventricular block (grade 3, n=1), atrial flutter (grade 2, n=1), QTC prolongation (grade 2, n=1). The 4-week and 8-week cumulative incidences of mortality were 0%. Median number of days to cycle 2 was 30 (range 27-51). Median number of days to cycle 2 of therapy by dose level were: 30, 30 and 37 days for dose levels 1, 2 and 3, respectively (p=0.301). Dose reductions due to myelosuppression were required in 5 (31%) pts including dose reductions of azacitidine in 3 pts and of quizartinib in 3 pts. Median number of cycles was 4 (range 1-17). Median cycles to to best response was 1 (range 1-6). The overall response rate was 69% (n=11): CR in 1 (6%), mCR with HI in 2 (13%), mCR in 8 (50%) pts. FLT3 mutant pts were more likely to respond to therapy (100% vs 50%, p=0.038). Clearance (n=6, 75%) or allelic burden reductions (n=2, 25%) of FLT3-ITD mutations were observed in all FLT3 mutant pts. No clearance of CBL mutations were observed. Dynamics of absolute neutrophil count, platelets and hemoglobin during cycle 1 are shown in Figure 1A. Median response duration was 3.5 months (range 0-22 moths). With a median follow up of 19.1 months (95% CI 2.6-35.6), the median event-free survival has not been reached and the median overall survival is 17.5 months (NR vs 10.1 months in FLT3 vs CBL mutant pts, p=0.084, Figure 1B) Five (31%) pts discontinued study to proceed with HSCT at time of best response, 3 (19%) due to transformation to AML, 2 (12%) due to pt choice, 1 (6%) due to treating physician choice and 1 (6%) due to relapse. Four (25%) pts remain on study. Conclusion: Therapy with azacitidine in combination with quizartinib for pts with higher-risk MDS and MDS/MPN with FLT3 or CBL mutations has acceptable toxicity profile and is associated with promising responses mainly among FLT3-mutant pts.

Comparison of Perioperative Safety of Carotid Artery Stenting and Endarterectomy in the Treatment of Carotid Artery Stenosis: A Meta-Analysis of Randomized Controlled Trials

Current management guidelines for the treatment of carotid stenosis are controversial. We performed this meta-analysis to evaluate the perioperative safety of carotid artery stenting (CAS) and endarterectomy. We systematically searched EMBASE, PubMed, Web of Science, and the Cochrane Library from inception to November 10, 2022, for randomized controlled trials that compared CAS with carotid endarterectomy (CEA) among patients with carotid stenosis. The analyzed outcomes mainly included stroke, death, myocardial infarction (MI), cranial nerve palsy, the cumulative incidence of mortality, stroke, or MI and the cumulative incidence of death or stroke in the perioperative periods. The risk ratio (RR) and 95% confidence interval (95% CI) were calculated and pooled. Subgroup analyses were based on whether patients were symptomatic or asymptomatic. We assessed the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Seventeen randomized controlled trials with 12,277 participants (6514 and 5763 in the CAS and CEA groups, respectively) were included. Pooled analysis demonstrated that compared with CEA, CAS was associated with decreased risks of perioperative MI (RR=0.47, 95% CI=0.29∼0.77) and perioperative cranial nerve palsy (RR=0.02, 95% CI=0.01∼0.06) but higher risks of perioperative stroke (RR=1.48, 95% CI=1.18∼1.87) and cumulative incidence of death or stroke (RR=1.52, 95% CI=1.20∼1.93). The perioperative safety was equivalent between CAS and CEA. However, CEA may be preferred when considering both procedural safety and long-term efficacy in preventing recurrent stroke.

Long-Term Results and Risk Factors of Treatment for Post-Infarction Ventricular Septal Rupture: A Single-Center Experience

Background: Ventricular septal rupture (VSR) following myocardial infarction (MI) is a rare but lethal complication. We analyzed the long-term results and risk factors for survival in the treatment of VSR. Methods: From January 2012 to December 2021, 115 consecutive patients with post-MI VSR were admitted to our hospital. Depending on different treatment methods patients were divided into following three groups: medical, transcatheter intervention, and surgical repair. During the study, relevant clinical data, operation-related conditions, and follow-up data were analyzed. The Kaplan–Meier method and log-rank test were used to determine the cumulative incidence of mortality. The independent risk factors for patient mortality were evaluated by multivariate logistic regression. Results: The mean follow-up time was 43.4 ± 34.7 months. The overall in-hospital, 30-day, and long-term mortality rates were 24.3%, 38.3%, and 51.3%, respectively. In the medical group, the in-hospital and 30-day mortality rates were 46.7 % (21/45) and 82.2 % (37/45), respectively, with only three patients alive at follow-up. In the transcatheter intervention group, 30-day and long-term mortality rates were 12% and 28%, respectively. In the surgical repair group, 30-day and long-term mortality rates were 8.9% and 22.2%, respectively. Compared with the surgery-group patients, patients with transcatheter intervention had a longer time from VSR to intervention. Logistic regression analysis revealed that age, previous infarction, Killip class, serum creatinine, Troponin T, N-terminal pro-B-type natriuretic peptide, and medical strategy were risk factors for all-cause mortality. Conclusions: The 30-day and long-term outcomes of patients treated with surgical repair and transcatheter intervention were significantly better than medically treated patients.

Radiotherapy Effect on Long-Term Net Survival Benefit for Early-Stage Diffuse Large B-Cell Lymphoma in the Rituximab Era

It is controversial whether to add consolidative radiotherapy (RT) after chemoimmunotherapy in the first-line treatment for diffuse large B-cell lymphoma (DLBCL). This study aimed to investigate the long-term net survival benefit of RT for early-stage DLBCL in the rituximab era. The data of 10,841 adult patients with early-stage DLBCL from the Surveillance, Epidemiology, and End Results (SEER) database between 2002 and 2015 were extracted and analyzed. The patients had received combined modality treatment (CMT, chemotherapy plus RT) or chemotherapy alone. Linear regression analysis was performed for RT utilization by year of diagnosis. Competing risk analysis was used to evaluate the cumulative incidence of mortality according to the cause of death. Inverse probability of treatment weighting (IPTW) was used to balance the distribution of covariates between treatment arms. Relative survival (RS), standardized mortality ratio (SMR), and transformed Cox regression were performed to estimate the net survival benefit of RT by controlling for background mortality. Linear regression revealed that the slope of the best-fit line for RT utilization over time was negative between 2002 and 2015 (m = -0.006, P = 0.003). A total of 4,648 deaths were recorded among 10,841 patients; 55.6% were lymphoma-related death (LRD), and 44.4% were attributed to other causes. Patients initially treated with CMT had a lower cumulative incidence of LRD than chemotherapy alone (HR 0.63, 95% CI: 0.57-0.69; P < 0.001). The 10-year overall survival (OS) rate of 66.1%, RS rate of 85.0%, and SMR of 1.71 achieved with CMT were significantly better than chemotherapy alone (OS, 53.0%; RS, 69.8%; SMR, 2.62; P < 0.001). By IPTW and multivariable analysis, the addition of RT remained associated with better OS (HR 0.67, 95% CI: 0.62-0.71; P < 0.001) and RS (HR 0.69, 95% CI: 0.65-0.74; P < 0.001). RT was associated with better long-term net survival in patients with early-stage DLBCL in the rituximab era.

Decreased lymphoma-related deaths and improved long-term relative survival with radiotherapy for early-stage diffuse large B-cell lymphoma in the rituximab era

BackgroundWe aimed to investigate the incidence of lymphoma-related death (LRD) and the long-term net survival benefit of radiotherapy (RT) for early-stage diffuse large B-cell lymphoma (DLBCL) in the rituximab era. Methods10,841 adults diagnosed with early-stage DLBCL between 2002–2015 were retrospectively analyzed using data from the Surveillance, Epidemiology, and End Results database. Primary therapy was categorized into combined-modality treatment (CMT, n = 3,631) and chemotherapy alone (n = 7,210). Competing risk analysis was used to evaluate the cumulative incidence of mortality. Inverse probability of treatment weighting (IPTW) was used to balance groups. The net survival benefit of RT was estimated through relative survival (RS), standardized mortality ratio (SMR), and transformed Cox regression, while controlling for background mortality. ResultsPatients initially treated with CMT had a lower cumulative incidence of LRD compared to those who received chemotherapy alone (HR 0.63, 95%CI: 0.57–0.69; P < 0.001). The 10-year overall survival (OS), RS, and SMR for CMT were 66.1%, 85.0%, and 1.71 respectively, which were significantly better than those for chemotherapy alone (53.0%; 69.8%; 2.62; all P < 0.001). IPTW and multivariable analysis revealed that the addition of RT led to better OS (HR 0.67, 95%CI: 0.62–0.71; P < 0.001) and RS (HR 0.69, 95%CI: 0.65–0.74; P < 0.001). Moreover, compared with chemotherapy alone, the benefit of OS and RS for CMT increased over time within 10 years of diagnosis. ConclusionRT reduced LRD and improved the long-term net survival in early-stage DLBCL in the rituximab era. Further prospective studies are warranted to assess the specific patient population that would benefit the most from consolidative RT in early-stage DLBCL.