Mortality In General Population Research Articles

Randomized Controlled Trial Based US Commercial Payor Cost-Effectiveness Analysis of Endoscopic Sleeve Gastroplasty Versus Lifestyle Modification Alone for Adults With Class I/II Obesity.

Endoscopic sleeve gastroplasty (ESG) is a minimally invasive day procedure that the MERIT randomized controlled trial (RCT) has demonstrated to be an effective and safe method of weight loss versus lifestyle modification alone. We sought to evaluate the cost-effectiveness of ESG from the perspective of a US commercial payer in a cohort of adults with class II and class I obesity with diabetes based on this RCT. We used a Markov modelling approach with BMI group health states and an absorbing death state. Baseline characteristics, utilities, BMI group transition probabilities, and adverse events (AEs) were informed by patient-level data from the MERIT RCT. Mortality was estimated by applying BMI-specific hazard ratios to US general population mortality rates. We used BMI-based health state utilities to reflect the impact of obesity comorbidities and applied disutilities due to ESG AEs. Costs included intervention costs, AE costs, and BMI-based annual direct healthcare costs to account for costs associated with obesity comorbidities. A willingness-to-pay threshold of $100,000 per quality-adjusted life year (QALY) was assumed. In our base-case analysis over a 5-year time horizon, ESG was cost-effective versus lifestyle modification alone with an incremental cost-effectiveness ratio of $23,432/QALY. ESG remained cost-effective in all sensitivity analyses we conducted and was dominant in analyses with longer time horizons. ESG is a cost-effective treatment option for people living with obesity and should be considered in commercial health plans as an additional treatment option for clinically eligible patients.

#1778 Effects of comorbidities, social deprivation and sex on the excess mortality of French ESKD patients on dialysis

Abstract Background and Aims Inequalities in access to care may affect End-stage Kidney Disease (ESKD) patient's overall mortality, i.e. mortality directly or indirectly related to ESRD (excess mortality) as well as mortality related to other causes of death. Previous studies in France have identified sex and comorbidities, especially diabetes and cardiovascular diseases, as factors influencing the overall mortality of ESKD patients, whereas social deprivation was not associated with overall mortality. However, no study has yet examined the impact of these factors on excess mortality in dialysis patients. This study thus aims to quantify the effects of social deprivation, sex and comorbidities on the excess mortality of ESKD patients on dialysis in France. Method This retrospective observational study included adults aged 18-85 years who started dialysis in France between 2017 and 2019, and were followed up until 31 December 2022. Dialysis patients receiving a transplant were censored. Analyses were based on the excess hazard approach: the overall mortality rate was decomposed into the sum of a mortality rate associated with ESKD (the excess rate) and a mortality rate associated with other causes of death (the expected rate). The latter is usually drawn from mortality tables for the general population stratified by demographic covariates. A model is then fitted in order to estimate the excess mortality hazard: the impact of covariates on this hazard is quantified in terms of excess hazard ratios. In France, mortality tables are provided by the “Institut National de la Statistique et des Études Économiques” and stratified by age, calendar year, sex, and “départements” of residence. However, stratification by level of social deprivation or levels of the Charlson Comorbidity Index is not available, which may bias the excess mortality hazard estimates. To assess the impact of using inadequately stratified life tables on estimating excess hazard, we compared the following models using Akaike's Information Criterion: (i) an excess hazard model using the standard life tables and accounting for the hierarchical structure of the data by including a random intercept for the “département” (M0), (ii) an excess hazard model with a model-based life table correction and with (M1) or without (M2) the random intercept at the “département” level, and (iv) an excess hazard model in which the life table correction is achieved by using an individual frailty term (M3). Results 29148 dialysis patients were included in the study, 65% of whom were men. Compared to the other regression models, the excess hazard model (M2) was the best model (AIC: M0 = 58936.69; M1 = 58966.94, M2 = 58870.41, M3 = 58908.59). There were no differences in excess mortality by deprivation status {EHR (Q5 versus others) 1.054 [0.992; 1.120]; p value = 0.088}. Excess mortality was higher for women than for men {HER (women versus men) = 1.083 [1.017; 1.154]; P-value = .012}. Excess mortality was higher in patients with comorbidities than in those without, and in those who started dialysis in emergency compared with those who started on a planned basis. Elderly patients on dialysis had a higher excess hazard than younger patients. The ratio between the other cause mortality of French dialysis patients and general population was equal to 2.18[1.95; 2.45]. This means that the other cause mortality of French dialysis patients is 2.18 higher than that of the general population with the same characteristics (Table 1, Fig. 1). Conclusion Using a methodology allowing to account for the insufficient stratification of population mortality tables, we identified several factors other than sex that might be targeted by public health interventions. For example, improved referral to nephrologists could reduce the impact of emergency dialysis. The extent of these inequalities will be better understood by comparison of these results with those of ESKD patients on dialysis in European countries.

Inter-leg systolic blood pressure difference has been associated with all-cause and cardiovascular mortality: analysis of NHANES 1999–2004

BackgroundInter-leg systolic blood pressure difference (ILSBPD) has emerged as a novel cardiovascular risk factor. This study aims to investigate the predictive value of ILSBPD on all-cause and cardiovascular mortality in general population.MethodsWe combined three cycles (1999–2004) of the National Health and Nutrition Examination Survey (NHANES) data. Levels of ILSBPD were calculated and divided into four groups based on three cut-off values of 5, 10 and 15mmHg. Time-to-event curves were estimated with the use of the Kaplan-Meier method, and two multivariable Cox proportional hazards regression models were conducted to assess the hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause and cardiovascular mortality associated with ILSBPD.ResultsA total of 6 842 subjects were included, with the mean (SD) age of 59.5 (12.8) years. By December 31, 2019, 2 544 and 648 participants were identified all-cause and cardiovascular mortality respectively during a median follow-up of 16.6 years. Time-to-event analyses suggested that higher ILSBPD was associated with increased all-cause and cardiovascular mortality (logrank, p < 0.001). Every 5mmHg increment of ILSBPD brings about 5% and 7% increased risk of all-cause and cardiovascular mortality, and individuals with an ILSBPD ≥ 15mmHg were significantly associated with higher incidence of all-cause mortality (HR 1.43, 95%CI 1.18–1.52, p < 0.001) and cardiovascular mortality (HR 1.73, 95%CI 1.36–2.20, p < 0.001) when multiple confounding factors were adjusted. Subgroup and sensitivity analysis confirmed the relationship.ConclusionsOur findings suggest that the increment of ILSBPD was significantly associated with higher risk of all-cause and cardiovascular mortality in general population.

Cardiorespiratory fitness is a strong and consistent predictor of morbidity and mortality among adults: an overview of meta-analyses representing over 20.9 million observations from 199 unique cohort studies

ObjectiveTo examine and summarise evidence from meta-analyses of cohort studies that evaluated the predictive associations between baseline cardiorespiratory fitness (CRF) and health outcomes among adults.DesignOverview of systematic reviews.Data sourceFive bibliographic...

Non-linear associations of HOMA2-IR with all-cause mortality in general populations: insights from NHANES 1999-2006.

The association between homeostatic model assessment (HOMA2-IR) and mortality in obese and non-obese populations has not been clearly explained. A total of 7,085 individuals aged ≥ 20 years from the 1999-2006 National Health and Nutrition Examination Survey were included in the study. Study endpoints were all-cause and cardiovascular mortality. Multivariate Cox proportional hazards regression models with restricted cubic spline analysis were used for analysis. In the study populations, a total of 1666 all-cause deaths and 555 cardiovascular (CV) deaths were recorded during a mean follow-up of 195.53 months. Notably, a significant difference in obesity was observed in the association between HOMA2-IR and mortality. After adjustment for multiple variables, HOMA2-IR was positively associated with all-cause mortality in all participants, in those with normal BMI, and in those with obesity. Conversely, tertile 2 of HOMA2-IR was associated with a lower risk of all-cause mortality in participants with obesity compared with tertile 1 (adjusted hazard ratio, 0.68; 95% confidence interval, 0.52-0.89; P = 0.005). Results from restricted cubic spline analysis showed a J-shaped association between HOMA2-IR and all-cause and CV mortality. In addition, a nonlinear U-shaped correlation with all-cause (P for nonlinear < 0.001) and CV (P for nonlinear = 0.002) mortality was observed in the population with obesity, with inflection points of HOMA2-IR identified at 1.85 and 1.75. Below the inflection point of 1.85, a negative relationship between HOMA2-IR and all-cause mortality was observed. Elevated HOMA2-IR showed a notable correlation with increased risk of all-cause mortality. It was noteworthy that excessively reduced levels of insulin resistance showed a distinct association with increased mortality in individuals with obesity.

Associations of sleep disorders with all-cause and cause-specific mortality in cancer survivors: a cross-sectional analysis of the NHANES 2005–2016

BackgroundThe circadian clock and endoplasmic reticulum stress signaling play important roles in oncogenesis and development of cancer. Sleep disorders have been linked to an elevated risk of mortality in general populations. Nonetheless, the evidence for the sleep disorders-mortality association among cancer patients is limited. We aimed to prospectively investigate the association of sleep disorders with all-cause, cancer, and cardiovascular disease (CVD) mortality among cancer individuals.MethodsWe assessed 3187 participants with cancer from the National Health and Nutrition Examination Survey 2005–2016 cohorts with a median follow-up time of 83.0 months. Multivariable Cox proportional hazards models estimated the adjusted hazard ratio (HR) and 95% confidence interval (CI).ResultsMultivariable Cox proportional hazards models showed that sleep disorders were associated with a higher risk of all-cause mortality (HR 1.23, 95%CI: 1.06,1.42), cancer mortality (HR 1.30, 95%CI: 1.02, 1.66), and cardiovascular disease mortality (HR 1.35, 95%CI: 1.02, 1.80). After the total group was stratified by gender, the high HRs were observed in men (P < 0.05), not in women. The correlation between sleep disorders and higher long-term mortality was also significant after individuals who died within 2 years of follow-up were excluded, with HR 1.24 (95%CI: 1.07, 1.45) in model I, HR 1.20 (95%CI: 1.02, 1.42) in model II for long-term all-cause mortality, HR (95%CI: 1.00, 1.74) in model I for long-term cancer mortality, and HR 1.5 (95%CI:1.12, 2.02) in model I, HR 1.45 (95%CI: 1.06, 1.99) in model II for long-term CVD mortality.ConclusionsSleep disorders were associated with a higher risk of all-cause mortality, cancer mortality, and CVD mortality, as well as long-term mortality in cancer patients. Our finding underlies the importance of screening for sleep disorders for all cancer survivors and the urge to integrate sleep health as an important part of cancer care more effectively. Male individuals may be particularly vulnerable and could benefit from more frequent screening.

Estimating median overall survival of apalutamide compared to placebo in metastatic hormone-sensitive prostate cancer (mHSPC) populations: Statistical extrapolations of the TITAN study.

223 Background: Apalutamide plus ADT (APA) demonstrated significantly improved overall survival (OS) compared to placebo plus ADT (PBO) for patients with mHSPC in the TITAN study (HR, 0.65; 95% CI, 0.53 to 0.79; P &lt; .0001). At the time of final analysis, the median OS was not reached in the APA arm or subgroups after a median follow up of 44 months. This work aimed to estimate OS medians for APA and PBO arms beyond the TITAN follow-up by fitting validated survival models. Methods: OS was predicted for the overall population treated with APA or PBO, with or without Inverse probability of censoring weighting (IPCW) crossover adjustment, and for the low and high-volume (LVD, HVD), HVD synchronous and HVD metachronous subgroups. General population mortality adjusted TITAN patient-level data was fitted to six parametric models (Weibull, exponential, log-normal, log-logistic, generalized gamma, and Gompertz) using the individual fits approach. Best fit was determined by statistical and visual fits, along with the Akaike Information Criterion (AIC)/Bayesian Information Criterion (BIC) ranking, according to the recommendations of the National Institute for Health and Care Excellence Decision Support Unit 14. Results: Best fit extrapolation estimated median OS of 71.8 months for the overall mHSPC population treated with APA (Table), leading to an estimated median improvement of up to 32 months versus PBO. Median OS values predicted by the other five models ranged from 62.4 to 78.1 months. Across subgroups, best fit models estimated median OS of 113.7 months for APA in LVD and a consistent median OS of 52 months for HVD subgroups. Conclusions: While results of this extrapolation study should not be equated to those of a clinical trial, this analysis meets an evidence gap by predicting median OS in the APA arm of the TITAN study for the overall mHSPC population as well as for various subgroups of this heterogeneous population, strengthening the evidence supporting early treatment with APA across the broad mHSPC population. [Table: see text]

International comparison: Spinal cord injury in the USA and UK.

Long-term survival after spinal cord injury (SCI) has been extensively studied in the US and UK. To compare SCI epidemiology and survival results between the US and UK for the same time period and patient groups. We restricted attention to persons injured at ages 18 and older who had survived at least 2 years post injury and were not ventilator dependent. We performed survival analysis using logistic regression on person-year data with time-dependent covariates. The resulting mortality rates were used to construct life tables in order to obtain life expectancies. The average age at injury, percentage male, and level/grade of injury were rather similar between the two countries. After adjustment for risk factors, UK mortality was 85% of that in the US (95% c.i. 80% to 91%, p < 0.0001). Mortality increased by 0.3% per year over the 1980 to 2012 study period (HR = 1.003); this was not statistically significant (p = 0.44). The US and UK life expectancies are nearly the same percentage of their respective general population values, differing by at most 2%. Long-term mortality after SCI in the UK is roughly 15% lower than that in the US. The general population mortality in the UK is also approximately 15% lower, however, and thus the percentages of normal life expectancy in the two countries prove to be strikingly similar.

Association of Visiting the Physiotherapist with Mortality in the Spanish General Population: A Population-Based Cohort Study.

Background and Objectives: The purpose of this retrospective population-based cohort study was to analyse the association between attendance of physiotherapy with mortality in the Spanish general population and describe the profile of people who do not visit a physiotherapist in Spain. Material and Methods: The data sources were the 2011/2012 National Health Survey (ENSE11) and the national database of death in Spain, and the participants were all adult respondents in the ENSE11. Results: Of 20,397 people, 1101 (5.4%) visited the physiotherapist the previous year, and the cumulative incidence of total mortality was 5.4% (n = 1107) at a mean follow-up of 6.2 years. Visiting the physiotherapist was associated with lower all-cause mortality in the population residing in Spain, quantified at 30.1% [RR = 0.699; 95% CI (0.528-0.927); p = 0.013]. The factors associated with not visiting a physiotherapist were the following: rating one's health as good (9.8%; n = 1017; p < 0.001), not having any hospital admission in the previous year (9.6%; n = 1788; p < 0.001), not having visited the general practitioner in the previous month (9.6%; n = 1408; p < 0.001), and not having attended a day hospital in the previous year (9.7%; n = 1836; p < 0.001). Conclusions: Visiting a physiotherapist was associated with a lower mortality from all causes in the population living in Spain.

Comparative analysis of neutrophil-to-lymphocyte ratio and remnant cholesterol in predicting cardiovascular events and mortality in general adult population

This study aimed to investigate the predictive value of neutrophil-to-lymphocyte ratio (NLR) and Remnant Cholesterol (Remnant-C) in relation to cardiovascular events and all-cause mortality in the general population. A population-based study. We conducted a retrospective cohort study analyzing data from the National Health and Nutrition Examination Survey (NHANES) spanning the years of 2011–2018, with follow-up for mortality status until December 31, 2019. Kaplan‒Meier and Cox proportional hazards regression analyses were used to evaluate the associations between NLR, Remnant-C, and cardiovascular events as well as all-cause mortality. Overall, 9409 individuals with both complete blood count and blood lipids were included in the analysis. Baseline NLR and Remnant-C were calculated. During the follow-up (median, 59.3 months), 177 cardiovascular events and 561 all-cause mortality occurred. In fully adjusted model, people with NLR > 2.26 were significantly associated with higher risk of cardiovascular events (HR 2.14, 95% CI 1.30–3.52, P < 0.001) and all-cause mortality (HR 1.66, 95% CI 1.30–2.12, P < 0.001). NLR exhibited a positive correlation with Remnant-C (r = 0.04, P < 0.001). Elevated NLR levels shown stronger association with cardiovascular events (HR 1.21, 95% CI 1.14–2.28, P < 0.001) compared with Remnant-C (HR 1.02, 95% CI 1.00–1.04, P = 0.020). Our findings suggest that NLR and Remnant-C are potential predictive markers for cardiovascular events in the general population. We observed a correlation between NLR and Remnant-C, and high NLR levels demonstrate a stronger association with the prediction of cardiovascular events and all-cause mortality compared with Remnant-C.

Including uncertainty of the expected mortality rates in the prediction of loss in life expectancy

PurposeThis study introduces a novel method for estimating the variance of life expectancy since diagnosis (LEC) and loss in life expectancy (LLE) for cancer patients within a relative survival framework in situations where life tables based on the entire general population are not accessible. LEC and LLE are useful summary measures of survival in population-based cancer studies, but require information on the mortality in the general population. Our method addresses the challenge of incorporating the uncertainty of expected mortality rates when using a sample from the general population.MethodsTo illustrate the approach, we estimated LEC and LLE for patients diagnosed with colon and breast cancer in Sweden. General population mortality rates were based on a random sample drawn from comparators of a matched cohort. Flexible parametric survival models were used to model the mortality among cancer patients and the mortality in the random sample from the general population. Based on the models, LEC and LLE together with their variances were estimated. The results were compared with those obtained using fixed expected mortality rates.ResultsBy accounting for the uncertainty of expected mortality rates, the proposed method ensures more accurate estimates of variances and, therefore, confidence intervals of LEC and LLE for cancer patients. This is particularly valuable for older patients and some cancer types, where underestimation of the variance can be substantial when the entire general population data are not accessible.ConclusionThe method can be implemented using existing software, making it accessible for use in various cancer studies. The provided example of Stata code further facilitates its adoption.

Lower urinary albumin-to-creatinine ratio predicted all-cause and cardiovascular mortality in Chinese population with diabetes and prediabetes-The Shanghai Changfeng cohort study.

Elevated urinary albumin-to-creatinine ratio (UACR) was associated with increased mortality in general population and diabetic patients. However, whether the association remains similar in the subjects with different status of glucose metabolism was unclear. The optimal level of UACR in predicting mortality also remained unknown. This study aims to investigate the relationship between UACR with all-cause and cardiovascular mortality in population with different status of glucose metabolism and explore the predictive cutoff point of UACR. Six thousand three hundred and eighty-six community-dwelling individuals aged ≥45 years were enrolled and followed for an average of 5.3 years. Cox proportional hazards model was performed to analysis the association of baseline UACR and all-cause as well as cardiovascular mortality according to the status of glucose metabolism. Receiver operating characteristic curve was plotted to explore the optimal predictive cutoff point of UACR. With UACR increasing, both the prevalence of all-cause and cardiovascular death increased. Cox analyses showed baseline UACR independently predicted the risk of all-cause and cardiovascular mortality in the patients with prediabetes mellitus (pre-DM) and diabetes mellitus (DM) but not in subjects with normal glucose tolerance (NGT). When divided by quartiles of UACR, the cumulative survival rate decreased acrossing the quartiles. Compared to the subjects with lowest quartile of UACR, participants with UACR ≥7.40 mg/gCr had a higher risk of all-cause mortality, and participants with UACR ≥16.60 mg/gCr had an increased risk of cardiovascular mortality in all hyperglycemia subjects. The optimal predictive cutoff point of UACR was about 17 mg/gCr. UACR was an independent predictor of all-cause and cardiovascular mortality in population with pre-DM and DM but not in the subjects with NGT. The optimal predictive cutoff point of UACR is about 17 mg/gCr, which was far below the diagnostic cutoff point of microalbuminuria. Earlier interventions of albuminuria should be initiated from very early stage of hyperglycemia to reduce the burden of death in all patients whose glucose metabolism are impaired.

Association of Sedentary Lifestyle with All-Cause and Cause-Specific Mortality in Adults with Reduced Kidney Function.

Key Points Nearly half of individuals with reduced kidney function had sedentary lifestyle, defined as more than 6 hours of sitting a day.Non-Hispanic White individuals and individuals with younger age, obesity, and with diabetes were more likely to have sedentary lifestyles.Spending more than 6 hours a day sedentary increases the future risk of death from all causes and cardiovascular diseases in individuals with reduced kidney function. Background Individuals with CKD tend to have sedentary behavior and decreased physical activity; both are independent predictors of mortality in general population. While physical inactivity correlates to adverse health outcomes in patients with reduced kidney function, it is unclear whether this relationship remains significant for sedentary behavior. Our study purpose was to evaluate the association of sedentary lifestyle with mortality risk in individuals with renal insufficiency. Methods The study population were adult participants of 2007–2016 National Health and Nutrition Examination Survey with eGFR &lt;60 ml/min per 1.73 m2 or self-reporting receiving dialysis (N=1419). Sedentary lifestyle was defined as sedentary time &gt;6 hours per day. Outcome of interest was all-cause and cardiovascular disease (CVD)–related or cancer-related mortality. Results We observed that non-Hispanic White individuals and individuals with younger age and higher educational level were more likely to have sedentary lifestyle. During a median follow-up of 99 (interquartile range, 70–128) months, a total of 458 participants died (3.98 deaths per 1000 person-months); 120 died from CVD and 92 from cancer, respectively. The crude analysis showed that individuals with sedentary lifestyle have higher risk of all-cause and CVD-related but not cancer-related mortality compared with the nonsedentary population. After adjusting for potential confounders, we showed that all-cause mortality and CVD-related mortality were 1.64-fold (95% confidence interval, 1.26 to 2.12) and 1.66-fold (95% confidence interval, 1.03 to 2.67) higher, respectively, in the sedentary population compared with the nonsedentary population. Similar results were observed in the sensitive analyses, in which we excluded individuals with dialysis, eGFR &lt;15 ml/min per 1.73 m2, or mobility disability. Conclusions Our findings suggest that sedentary lifestyle correlated to greater risk of all-cause and CVD-related mortality among individuals with reduced kidney function. Interventions targeting the individuals with risky behaviors may have practical importance for public health.

Sex difference in incidence, risk factors of heart failure and subsequent mortality in general population: Results from the China PEACE million persons project

Abstract Background Epidemiological study of sex differences in incidence and risk factors of heart failure (HF), and subsequent mortality attributed to HF in the Chinese general population is lacking. Purpose To assess the sex differences in the incidence and risk factors of HF, and evaluate the population attributable fractions (PAFs) for the subsequent mortality among the Chinese general population. Methods Data were from a sub-cohort of the Patient-Centered Evaluative Assessment of Cardiac Events (PEACE) Million Persons Project in Southern China. Between 2016 and 2020, 102,358 community residents aged 35 to 75 from 8 sites in Guangdong Province were screened, and 80 individuals with a history of HF were excluded. Participants were divided into two groups by sex and the study outcome was HF incidence. Fine and Gray models were conducted to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) accounting for the competing risk of all-cause mortality. Propensity score matching analysis and subgroup analyses were used to verify the robustness of the results. Adjusted PAFs of HF for all-cause and cardiovascular mortality were evaluated by sex. Results Of the 102,278 participants, 60.5% were women, and the mean age was 54.3 years. Compared with men, women were younger and less likely to smoke and drink, and had lower socioeconomic status and lower comorbid burdens. After a median follow-up of 3.52 years (343758 person-years), 1588 cases of incident HF (4.62 (95% CI: 4.40-4.85) per 1000 person-year) were identified. Compared with men (6.37 (95% CI: 5.95-6.80) per 1000 person-year), women had a lower incidence rate of HF (3.49 (95% CI: 3.24-3.75) per 1000 person-year, P&amp;lt;0.001). After adjusting for the covariates, women had 31% (95% CI: 0.61-0.79) lower risk for HF than men. The results were consistent in the propensity score matching cohort and across all subgroup analyses (all P sex-subgroups interaction &amp;gt;0.05). Although female was associated with a lower risk of HF, women had a higher PAF (24.2, 95% CI: 16.0-31.6) for subsequent cardiovascular mortality than men (16.5, 9%% CI: 11.3-21.5). Several significant differences in modifiable risk factors for HF were also noted between sexes. Conclusion In the Chinese general population, women were associated with a lower risk of HF but they have a higher cardiovascular mortality fraction attributed to HF than men. Sex-specific prevention strategies and therapies for HF should be warranted in the future.Graphic AbstractHF incidence across subgroups by sexes

Soluble transferrin receptor as a marker of tissue iron deficiency: impact on clinical outcomes in patients with heart failure without systemic iron deficiency or anaemia

Abstract Background Soluble receptor of transferrin (sTfR) is a marker of tissue iron status and may help to inform on subtle iron depletion and increased iron demand of functional proteins at tissular level even in the absence of overt systemic iron deficiency or anaemia. Raised sTfR levels have been associated with increased risk of all-cause mortality in general population and in patients with heart failure (HF). However, the prognostic significance of raised sTfR levels in non-anaemic HF patients with otherwise normal systemic iron status has not been evaluated. Purpose The aim of our study was to describe the association between sTfR as a marker of increased iron demand and tissue iron deficiency on outcomes in non-anaemic patients with HF and normal systemic iron status. Methods We conducted an observational, prospective, cohort study of 1120 consecutive patients with chronic HF (DAMOCLES study). For the current sub-study, we selected all patients form the DAMOCLES cohort that had a complete iron status evaluation including sTfR, normal haemoglobin levels and normal systemic iron status. Tissue ID was defined as levels of sTfR&amp;gt; 75th percentile (1.63mg/L). The primary and secondary endpoints were all-cause mortality and HF hospitalization respectively. Multivariate Cox proportional hazards models were constructed to explore the associations between tissue ID and the studied outcomes. In addition, the multivariate parametric and non-parametric associations between sTfR and the β estimated risk of the occurrence of the primary and secondary endpoints were explored using General Additive Models (GAM). All models were adjusted by age, sex, and prognostic factors such as LVEF, NYHA, NT-proBNP levels and iron status parameters among other well-known determinants of HF severity. Results The final study cohort consisted in 215 patients from the DAMOCLES study. Mean age was 70±12 years, mean LVEF was 43±15% and 62 (29%) were women. Mean sTfR values were 1.42±0.66 mg/L. Tissue ID was present in 54 patients (25%). Hospital readmission occurred in 55 patients (25.6%) and death occurred in 60 (27.9%). In multivariate Cox proportional hazards models (table 1) higher levels of sTfR and Tissue ID were significantly associated with the risk all-cause death. This association was not observed for HF readmission. As shown in figure 1 panel A, adjusted GAM showed there was a significant linear association between higher levels of sTfR and the mortality risk. Moreover, the adjusted cumulative risk of all-cause death (Figure 1 panel B) confirmed higher risk of death among patients with tissue ID compared to patients’ levels of sTfR≤ the 75th percentile with early divergence of the curves during follow-up. Conclusions In a cohort of HF patients without iron deficiency or anaemia, higher levels of sTfR indicating tissue ID were associated with increased risk of mortality. This association was linear and was not observed for HF readmission.

The association of non-alcoholic fatty liver disease and advanced hepatic fibrosis with cardiovascular mortality in Taiwanese adults: a longitudinal cohort study

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is prevalent in adults, and advanced hepatic fibrosis (AHF) occurs in the more progressive stage of NAFLD. Despite the known risk of cardiovascular diseases among NAFLD patients, the effect of NAFLD and AHF on cardiovascular mortality (CVM) in general populations remains understudied. Purpose This study aims to examine the association of NAFLD and AHF with CVM in a general population. Methods Participants were enrolled in the Taiwan MJ cohort and attended regular medical check-ups. We derived the death dates and causes up to 31 May 2019 from Taiwan Death Registry and linked them to participants by identity number. CVM included death from heart diseases, hypertension, or atherosclerosis defined by the International Classification of Diseases (ICD) codes (ICD 9: 390-414, 420-429, 440; ICD 10: I01-I02.0, I05-I25, I27, I30-I52, and I70). We excluded regular alcohol drinkers and participants with cardiovascular diseases, hepatitis, cirrhosis, or liver cancer at baseline. The fatty liver index (FLI) was calculated to identify participants with NAFLD, among whom the BARD score was estimated to determine AHF. Cox proportional hazards models with time-varying covariates were applied in the analysis. We also conducted a stratified analysis by sex and age subgroups. Results 404,948 participants were recruited from 1997 to 2016 and followed until 31 May 2019, with a median follow-up duration of 15.1 (IQR: 10.1–19.5) years. There were 2,560 cardiovascular deaths, with an incidence of four deaths per 10,000 person-years. FLI was positively associated with CVM, with a hazard ratio (HR) of 1.301 (95%CI: 1.255–1.348) per standard deviation increase. We identified 41,807 participants with NAFLD (FLI≥60). NAFLD was related to a significantly higher risk of CVM [HR: 1.871 (95%CI: 1.688–2.073)]. Moreover, 17,274 participants with NAFLD developed AHF (BARD≥2). AHF elevated the risk of CVM among participants with NAFLD [HR: 1.388 (95%CI: 1.135–1.698)]. In stratified analysis, significant positive associations were observed in each sex or age subgroup. The CVM hazards of NAFLD were more pronounced in females (HR: 1.921) than in males (HR: 1.741) and higher in adults under 40 years of age at baseline (HR: 4.905) than in older adults (HR: 1.772). Similarly, AHF had a higher HR in females versus males (HR: 1.684 vs. 1.281) and a much higher HR in adults with a NAFLD onset age under 40 versus adults with older onset age (HR: 2.246 vs. 1.258). Conclusions NAFLD remarkably increases CVM in the general population across different sex and age groups. Among people with NAFLD, AHF aggravates the risk of CVM. These adverse effects are relatively prominent in females and adults under middle age.The forest plot of hazard ratios

Abstract 17641: Frequency of Reported Euglycemic Ketoacidosis With Sodium-Glucose Cotransporter-2 Inhibitors is Not Increased in Patients With Heart Failure: Analysis of US Food and Drug Administration Adverse Event Reporting System (FAERS)

Introduction: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are first-line therapy for heart failure (HF) but have an associated risk for euglycemic ketoacidosis. Patients with HF exhibit many additional risk factors for euglycemic ketoacidosis. However, no data describes the incidence or risk of euglycemic ketoacidosis in HF. Hypothesis: Reported incidence of euglycemic ketoacidosis with empagliflozin and dapagliflozin is not higher in patients with HF compared to the general population. Methods: Cases of euglycemic ketoacidosis with empagliflozin and dapagliflozin (single or combination products) were identified in the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2022 to March 2023. HF was identified as those taking at least two of the listed medication categories (angiotensin converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor neprilysin inhibitor, mineralocorticoid receptor antagonist, HF-approved beta blocker) with a loop diuretic or search terms related to cardiac failure from MedDRA. Cases with missing event date, age, gender, and reporter country were removed. Reporting rates of euglycemic ketoacidosis stratified by HF status were examined descriptively. Results: Out of 16,880 adverse event reports involving empagliflozin and dapagliflozin, a total of 432 (2.6%) cases of SGLT2 inhibitor-associated euglycemic ketoacidosis were identified (mean age 65±13 years, 55.6% male, and mean weight of 87±27 kg). Patients who developed euglycemic ketoacidosis were younger and of lower mean weight. The incidence of euglycemic ketoacidosis among patients without HF was 2.8% compared to 0.8% in patients with HF [OR 0.27, 95% CI (0.17, 0.44)]. Mortality or need for hospitalization was not increased in patients experiencing euglycemic ketoacidosis for both the HF cohort (mortality: 5.9% vs. 6.7%; hospitalization: 23.5% vs. 31.1%) and general population (mortality: 0.2% vs. 3.6%; hospitalization: 30.1% vs. 27.3%). Conclusions: Euglycemic ketoacidosis with empagliflozin and dapagliflozin was uncommon, does not appear to be more frequent in patients with HF compared to the general population, and does not appear to be associated with worse outcomes.

Cost-Effectiveness of Axicabtagene Ciloleucel Versus Mosunetuzumab in Relapsed/Refractory Follicular Lymphoma in the US

Introduction Anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapies, including axicabtagene ciloleucel (axi-cel), and CD20 × CD3 T-cell-engaging bispecific monoclonal antibodies, such as mosunetuzumab (mosun), are novel therapies for 3L+ relapsed/refractory (r/r) follicular lymphoma (FL) that have recently been approved by the US Food and Drug Administration. This analysis assessed the cost-effectiveness of axi-cel compared to mosun in r/r 3L+ FL from a US third-party payer perspective. Methods A three-state (progression-free [PF], progressed disease [PD], and death) partitioned-survival model was used to compare the two treatments over a lifetime horizon in a hypothetical cohort of US adults (age ≥18) receiving 3L+ treatment for r/r FL. ZUMA-5 (NCT03105336) and GO29781 (NCT02500407) trial data were used to inform progression-free survival (PFS) and overall survival (OS) for axi-cel and mosun, respectively. Survival curves for axi-cel were estimated using an exponential distribution for both PFS and OS. In the base case analysis, 40% of axi-cel patients alive at 5 years were assumed to experience long-term remission (i.e., functional cure), and therefore followed general population mortality adjusted by a standardized mortality ratio. This assumption was informed by the literature. Mosun survival was modeled via hazard ratios (HRs) applied to axi-cel exponential survival curves. For PFS, the HR value was estimated via a matching indirect comparison to adjust for differences between the trial populations. As a conservative assumption, a HR of 1.0 was used to model mosun OS due to lack of published results. The mosun arm did not include the cure assumption at 5 years because long-term remission is not expected with monoclonal antibodies in r/r FL. Health state utilities (HSU), healthcare resource use (HCRU), and treatment pattern inputs were obtained from literature. Costs for treatment and administration, adverse event management, monitoring resource use, HCRU, and end-of-life were included in the model. Key model outcomes included discounted (at 3% per year) total and incremental costs, life years (LYs), and quality adjusted life years (QALYs), as well as incremental cost-effectiveness ratios (ICERs). Scenario analyses were conducted on the cure assumption and all input parameters were individually varied by ±20% of their base case values in one-way sensitivity analysis (OWSA) to assess parameter uncertainty. Results Axi-cel use led to increases of 1.51 LY and 1.80 QALY (Table 1) compared to mosun. Progression-free survival for axi-cel patients was 7.11 LY compared to 1.80 LY for mosun, which resulted in a PF state cost increase of $215,045 primarily driven by the one-time cost of axi-cel treatment. Conversely, axi-cel costs were $63,000 less than mosun in the PD state, as patients spent less time with PD and had lower costs for subsequent treatment lines. Total incremental costs for axi-cel were $151,425, resulting in an ICER of $84,016/QALY gained. Analysis of lower cure fractions indicated cost-effectiveness across a wide range of values. Additionally, the OWSA indicated the most impactful inputs for the ICER were mean patient age, the relative dose intensity (RDI) of mosun, PF and PD HSUs, and PD HCRU. Inputs with the largest impact on total incremental costs were RDI, HCRU, and CAR-T infusion hospitalization duration. Conclusions Axi-cel is cost-effective versus mosun in r/r 3L+ FL at an ICER of $84,016/QALY gained, which is far lower than the commonly-cited US willingness-to-pay threshold of $150,000/QALY. This analysis demonstrates the value of using axi-cel, reflecting the aggregate benefits of a one-time therapy, reduction in need for subsequent treatment lines, and population segment experiencing effective cure.

Evaluation of Flexible Parametric Relative Survival Approaches for Enforcing Long-Term Constraints When Extrapolating All-Cause Survival

ObjectivesParametric models are used to estimate the lifetime benefit of an intervention beyond the range of trial follow-up. Recent recommendations have suggested more flexible survival approaches and the use of external data when extrapolating. Both of these can be realized by using flexible parametric relative survival modeling. The overall aim of this article is to introduce and contrast various approaches for applying constraints on the long-term disease-related (excess) mortality including cure models and evaluate the consequent implications for extrapolation. MethodsWe describe flexible parametric relative survival modeling approaches. We then introduce various options for constraining the long-term excess mortality and compare the performance of each method in simulated data. These methods include fitting a standard flexible parametric relative survival model, enforcing statistical cure, and forcing the long-term excess mortality to converge to a constant. We simulate various scenarios, including where statistical cure is reasonable and where the long-term excess mortality persists. ResultsThe compared approaches showed similar survival fits within the follow-up period. However, when extrapolating the all-cause survival beyond trial follow-up, there is variation depending on the assumption made about the long-term excess mortality. Altering the time point from which the excess mortality is constrained enables further flexibility. ConclusionsThe various constraints can lead to applying explicit assumptions when extrapolating, which could lead to more plausible survival extrapolations. The inclusion of general population mortality directly into the model-building process, which is possible for all considered approaches, should be adopted more widely in survival extrapolation in health technology assessment.

Associations of serum alkaline phosphatase level with all-cause and cardiovascular mortality in the general population.

There are few population studies on the associations of serum alkaline phosphatase (AlkP) with all-cause and cardiovascular mortality. We aimed to investigate the relevancy of serum AlkP with all-cause and cardiovascular mortality in the general population. Our research included 34,147 adults in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2014. Cox proportional hazards regression models were used to assess the associations of serum AlkP with all-cause and cardiovascular mortality. Mediation analysis was used to analyze mechanisms that might link serum AlkP to all-cause and cardiovascular mortality. After 139.7 ± 57.8 months of follow-up, 5413 participants experienced all-cause death and 1820 participants experienced cardiovascular death. Mortality rates per 1000 person-years from various diseases increased with increasing serum concentrations of AlkP, especially all-cause death, cerebrovascular disease and cardiovascular death. High serum AlkP level significantly increased all-cause and cardiovascular mortality. After multivariate adjustment, the highest AlkP group had the highest risk to experience all-cause (hazard ratio [HR] = 1.30, P < 0.001) and cardiovascular mortality (HR = 1.39, P < 0.001) than the lowest AlkP group. γ-glutamyl transpeptidase (GGT) (13.33% and 15.79%), followed by Vitamin D (8.33% and 7.14%) and C-reactive protein (CRP) (7.69% and 10.35%) were identified as possible major mediators. Higher AlkP concentrations were associated with higher all-cause and cardiovascular mortality, largely related to mediated factors such as GGT, Vitamin D, and CRP. These findings suggest that lower serum AlkP level may reduce all-cause and cardiovascular mortality in general population.