Lipoprotein(a) (Lp(a)) is associated with atherothrombosis through several mechanisms, including putative antifibrinolytic properties. In the ASPREE randomized trial of daily low-dose aspirin for primary prevention in older adults, 72% of trial participants in Australia provided baseline blood samples from which Lp(a) and related oxidized phospholipids and plasminogen have been measured in a specialized laboratory at University of California San Diego. Recent findings from our group suggest that aspirin may benefit older individuals with genotypes associated with elevated lipoprotein(a). We present an analysis plan to address key hypotheses relating to whether the effects of aspirin on cardiovascular disease might vary based on a person's measured levels of lipoprotein(a), oxidized phospholipid levels present on protein carriers apoB-100 (OxPL-apoB), Lp(a) (OxPL-apo(a)) and plasminogen (OxPL-PLG), and plasminogen. The analysis plan also articulates safety analyses involving major hemorrhage.

BACKGROUND:Cerebral small vessel disease and alterations in retinal vascular calibre (RVC) are recognised precursors of stroke, dementia, and cognitive decline. We aimed to assess the effect of low-dose aspirin on white matter hyperintensity (WMH), a marker of cerebral small vessel disease, and changes in RVC. METHODS:We conducted a prospectively planned exploratory neurovascular substudy (ENVIS-ion) of the Aspirin in Reducing Events in the Elderly (ASPREE) double-blinded randomised clinical trial of 19 114 older adults (aged ≥70 years), who had no previous cardiovascular disease, stroke, or cognitive impairment at baseline. Participants were allocated to daily enteric-coated aspirin 100 mg or matching placebo using computer-generated randomisation and underwent MRI of the brain and fundus photography at two clinical trials sites in Australia at baseline and after 3 years. WMH and RVC measures were assessed by graders blinded to study treatment allocation. The effects of aspirin on total and regional WMH volumes (as a percentage of total brain volume) and RVC over time were analysed using linear models. ASPREE is registered with ClinicalTrials.gov, NCT01038583, and the International Standard Randomised Controlled Trial Number Registry, ISRCTN83772183. FINDINGS:Between April, 2010, and April, 2012, 610 participants from the eligible ASPREE cohort of 2346 individuals were enrolled in the ENVIS-ion substudy. Of the 610 participants (mean age 75·2 years [SD 4·1], 289 [47%] male and 321 [53%] female), 312 were assigned to receive aspirin and 298 to placebo. Over 3 years, the aspirin group had a greater increase in the percentage of deep WMH (β 0·14 [95% CI 0·01 to 0·27]) but there was no difference between aspirin and placebo groups in changes from baseline to 3 years in total brain WMH (0·05 [-0·02 to 0·11]) or periventricular WMH (0·03 [-0·03 to 0·09]). There was no evidence of an aspirin effect on RVC. The rate of major haemorrhage was higher in the aspirin arm for the ASPREE study (hazard ratio 1·38, 95% CI 1·18 to 1·62). INTERPRETATION:In this exploratory study, there was no evidence that low-dose aspirin in healthy older adults had any effect on RVC or attenuated the progression of WMH during a 3-year period. FUNDING:National Health and Medical Research Council of Australia.

BACKGROUND AND AIMS:Patients with heart failure with reduced ejection fraction (HFrEF) derive less benefit from cardiac resynchronization therapy (CRT) if they have coexisting atrial fibrillation (AF). Observational data suggest that atrioventricular node ablation (AVNA) may enhance CRT efficacy in this population. This trial aimed to evaluate the effect of AVNA compared with medical rate control therapy (MRCT) on CRT outcomes in patients with HFrEF and permanent AF. METHODS:The CAAN-AF trial was an international, prospective, multicentre, randomized controlled trial evaluating the impact of AVNA in patients with HFrEF, permanent AF, and CRT-defibrillators (CRT-D). Participants were randomly assigned (1:1) to AVNA or MRCT targeting a resting heart rate <90 bpm. All participants received device optimization. The primary endpoint was a composite of all-cause mortality and nonfatal heart failure events. Secondary endpoints included cardiovascular mortality, unplanned hospitalizations, ventricular arrhythmias requiring device therapy, 6-min walk distance (6MWD), and quality of life. RESULTS:With early termination of the trial due to futility, a total of 143 patients were randomized (67 to AVNA, 76 to MRCT). Baseline characteristics were similar across groups. No significant difference was found in the primary endpoint [47 vs. 46 events; incident rate ratio (IRR), 1.16; 95% confidence interval (CI), 0.60-2.24]. Secondary outcomes, including cardiovascular mortality (odds ratio, 1.93; 95% CI 0.60-6.20), unplanned hospitalizations (IRR, 1.01; 95% CI 0.71-1.74), ventricular arrhythmias requiring device therapy (IRR, 0.68; 95% CI 0.17-2.63), 6MWD, and SF-36 scores, also showed no significant differences. CONCLUSIONS:This randomized trial of patients with permanent AF and CRT-D found no evidence of a reduction in all-cause mortality and nonfatal heart failure events with AVNA compared with MRCT. TRIAL REGISTRATION:NCT01522898.

Importance:The risk of cognitive decline and dementia following cardiovascular disease (CVD) events is well recognized. However, it remains unclear whether cognitive changes observed after such events reflect a process that begins prior to the event itself. Objective:To compare the cognitive trajectories of older adults preceding an incident CVD event with those of a matched control group without an event. Design, Setting, and Participants:Data for this nested case-control study were obtained from a prospective cohort of older, community-dwelling individuals (aged ≥65 years) in Australia and the US with no history of CVD at the time of study enrollment in the Aspirin in Reducing Events in the Elderly (ASPREE) randomized clinical trial and the extension (ASPREE-XT) observational study. The ASPREE trial was conducted between March 2010 and December 2014, with follow-up to June 2017. The ongoing ASPREE-XT trial continued annual follow-up; this study reports data through December 2022. Case patients with an adjudicated CVD event, including fatal coronary heart disease (CHD), nonfatal myocardial infarction (MI), fatal or nonfatal stroke, and hospitalization for heart failure (HHF), were matched by age, sex, and educational attainment to control participants without a CVD event. Data were analyzed from June to December 2024. Exposures:Cognitive function as assessed by the Modified Mini-Mental State Examination, the Hopkins Verbal Learning Test-Revised, the Symbol Digit Modalities Test, and the Controlled Oral Word Association Test. Main Outcomes and Measures:Linear mixed-effects models were used to estimate the trajectories of cognitive function among case patients with a CVD event and control participants. Results:Over 11 years, 1934 CVD events occurred among 19 114 participants. In this analysis, 1887 of 1934 case patients (97.6%) with adjudicated CVD events were matched to 7548 control participants (N = 9435; overall median age, 75.7 years [IQR, 72.4-80.0 years]; 4970 males [52.7%]). Individuals with incident CVD events had lower cognitive function, starting at between 3 and 8 years before the event, compared with those without CVD. Faster declines in global cognition (β, -0.19 [95% CI, -0.33 to -0.06]), episodic memory (β, -0.04 [-0.11 to -0.03]), processing speed (β, -0.28 [95% CI, -0.48 to -0.07]), and verbal fluency (β, -0.15 [95% CI, -0.27 to -0.04]) in the years prior to the CVD event were also observed compared with control participants. Composite global cognition (β, -0.11 [95% CI, -0.17 to -0.06]) and executive function scores (β, -0.07 [95% CI, -0.11 to -0.03]), but not memory, also declined faster. Similar cognitive trajectories were observed for fatal CHD, stroke, and HHF; however, this pattern was not observed for nonfatal MI, in which case patients and control participants showed comparable trends. Conclusions and Relevance:In this case-control study of community-dwelling older adults, deterioration in cognitive function was prominent prior to CVD events, suggesting that this decline may be associated with subsequent CVD events. These findings may help inform future research aimed at understanding the association between cognitive change and CVD.

Background This study aims to quantify transition probabilities between frailty states (not-frail, pre-frail, frail) and from different frailty states to the occurrence of a cardiovascular disease (CVD) event; and to examine how age, sex and sociodemographic factors influence these transitions. Methods 18,077 initially healthy individuals (91% Caucasians, 56% females) aged ≥65 years enrolled in the ASPREE study who had no prior CVD event and ADL (Activity of Daily Living) disability at recruitment were followed for a median of 7.4 years. Frailty was annually assessed using a 64-item Frailty Index. Continuous-time multi-state Markov modelling was used. Results The estimated transition probabilities from frail to CVD increased over time (11% at five years, and 18% at ten years) and consistently exceeded the corresponding five- and ten-year transition probabilities from pre-frail to CVD (8% and 14% respectively). Compared to males, females had a 26% higher relative risk of progressing to a pre-frail/frail state; however, they had about 50% lower relative risk of transitioning from pre-frail/frail to CVD. Older age, socioeconomic and geographic disparities were associated with up to 38% higher relative risk of worsening frailty and progression to CVD. Similar findings were observed when using the Fried phenotype. Conclusion The probability of transiting from pre-frail/frail to CVD increased over time, even among initially healthy older people. Targeted prevention strategies may be helpful to delay frailty progression and reduce CVD risk in older age, particularly socioeconomically disadvantaged individuals or those residing outside major cities, and different approaches may be required in females and males.

OBJECTIVE:To examine the prevalence of health risk factors by rurality status and the association of rurality and incidence of disability-free survival (DFS), its components (death, dementia and physical disability), cardiovascular disease (CVD), cancer and underlying cause of death. METHODS:Data came from the ASPirin in Reducing Events in the Elderly (ASPREE) trial and observational extension, ASPREE-XT. Community-dwelling Australians aged 70 years or older, with no prior CVD events, dementia or independence-limiting physical disability, were recruited through General Practitioners between 2010 and 2014. Area of residence was classified as major cities, inner regional or outer regional/remote. Major incident health events were adjudicated by expert panels. RESULTS:Participants (n = 16,697, median age 74 years; 55% female) were followed over a median 8.3 years. A small, but statistically significant higher prevalence of many health risk factors was found for individuals living outside metropolitan areas. Rurality was not associated with the incidence of DFS, dementia, physical disability or CVD events in adjusted Cox proportional hazards regression models. Compared to major cities, individuals in outer regions/remote areas had an increased risk of all-cause death (HR: 1.17; 95% CI 1.02, 1.34) which appeared to be driven by fatal CVD (HR: 1.40; 95% CI 1.02, 1.83), while those in inner regions had a lower cancer incidence (HR: .89; 95% CI .82, .98). CONCLUSIONS:Incidence of DFS, dementia and physical disability did not differ according to rurality. Heightened risk of mortality was evident outside urban areas, possibly reflecting inequitable health service and access. Lower cancer incidence in inner regions requires further investigation.

Importance:Coronary artery calcium (CAC) scoring provides prognostic information, especially in patients at intermediate risk for coronary artery disease (CAD). However, the benefit of combining CAC score with a primary prevention strategy has not been tested in a randomized trial. Objective:To assess whether combining the CAC score with a prevention strategy can be used to limit plaque progression in intermediate-risk patients with a family history of premature CAD. Design, Setting, and Participants:Prospective, randomized, open-blinded end point clinical trial in 7 hospitals across Australia (between 2013 and 2020; the last date of follow-up was June 5, 2021). Asymptomatic people aged 40 to 70 years with a first-degree relative with CAD onset at younger than 60 years old or second-degree relative with onset at younger than 50 years old were recruited from the community. Interventions:Intermediate-risk participants underwent CAC scoring. Those with a CAC score greater than 0 but less than 400 underwent coronary computed tomography angiography (CCTA) and were randomized to CAC score-informed prevention or usual care. Main Outcomes and Measures:Follow-up CCTA was obtained at 3 years, with plaque volume measured by an independent core laboratory. The primary outcome was total plaque volume, with further analysis for calcified and noncalcified plaque volume. Results:This study included 365 participants (mean [SD] age, 58 [6] years; 57.5% male); 179 in the CAC score-informed and 186 in the usual care groups. Compared with usual care, the CAC score-informed group showed a sustained reduction in total (mean [SD], -3 [31] mg/dL vs -56 [38] mg/dL; P < .001) and LDL (mean [SD], -2 [31] vs -51 [36] mg/dL; P < .001) cholesterol levels at 3 years, which was associated with a reduction in pooled cohort equation risk calculation (mean [SD], 2.1% [2.9%] vs 0.5% [2.9%]; P < .001). Plaque progression was greater in usual care than CAC score-informed participants for total plaque volume (mean [SD], 24.9 [37.7] mm3 vs 15.4 [30.9] mm3; P = .009), noncalcified plaque volume (mean [SD], 15.7 [32.2] mm3 vs 5.6 [28.5] mm3; P = .002), and fibrofatty and necrotic core plaque volume (mean [SD], 4.5 [25.8] mm3 vs -0.8 [12.6] mm3; P = .02). These plaque volume changes were independent of other risk factors including baseline plaque volume, blood pressure, and lipid profile. Conclusions and Relevance:The combination of CAC score with a primary prevention strategy in intermediate-risk patients with a family history of CAD was associated with reduction of atherogenic lipids and slower plaque progression compared with usual care. These data support the use of CAC score to assist intensive preventive strategies in intermediate-risk patients. Trial Registration:anzctr.org.au Identifier: ACTRN12614001294640.

AIMS:Individuals with cardiovascular disease (CVD) are more likely to become frail. However, no study has determined whether an incident CVD event alters frailty trajectories in older individuals. This study aims to determine the extent to which an incident CVD event modifies frailty trajectories and to identify factors that influence those changes. METHODS:19,111 individuals (56.4%, women) ≥aged 65 years, who had no prior CVD event or other major health conditions at baseline, were followed for up to 11 years. Frailty was measured annually using the 64-item deficit-accumulation frailty index (FI) and Fried phenotype (Fried). Incident CVD events, including stroke, myocardial infarction and hospitalization for heart failure (HHF), were adjudicated by international experts. Linear mixed models were used to measure frailty changes. RESULTS:Over a median 8.3-year follow-up, frailty trajectories increased over time and 1934 incident CVD events occurred. Following a CVD event, individuals had a short-term increase in both FI (adjusted-betas: 3.65; 95%CI, 3.34 to 3.96) and Fried (adjusted-beta: 0.32; 95%CI, 0.26 to 0.38). Afterwards, only FI continued to increase over time (adjusted-beta: 0.41, 95%CI, 0.21 to 0.62). Among the CVD events, HHF and stroke were associated with the greatest increase in frailty. Of the factors examined, being >80 years, women, living alone, or residing in regional/remote areas were associated with greater frailty burden. CONCLUSION:Our findings provide evidence that incident CVD event increases frailty burden, highlighting the need for targeted intervention to minimise frailty-related clinical complications for those most at risk.

Background Frailty is a significant concern for older adults and can increase after a major health event. This study examined the risk of incident frailty after a cardiovascular disease (CVD) event among community-dwelling older people aged  ≥  65 years and explored whether sociodemographic factors, polypharmacy, and pre-event frailty influence their risk of developing frailty after a CVD event. Methods This study included a cohort of 738 participants (38.5% women) from the ASPREE study who were not classified as frail before their CVD event. Frailty was measured annually using the 64-item deficit-accumulation frailty index. Results Over an average 2.6 years after a CVD event, 333 individuals had incident frailty. In logistic regression models, increased chronological age, being a woman, and having polypharmacy were associated with 4% to 83% increased odds of developing frailty after a CVD event. Individuals with CVD residing in the inner regional area had about 50% higher odds of having frailty than those living in cities. This association was more evident among stroke survivors, with both inner regional (adjusted odds ratio [OR] 2.13) and outer regional or remote residents (adjusted OR 2.37) having greater odds of frailty. Individuals who were classified as pre-frail before their CVD event, had notably higher odds of progressing to frailty after the CVD event (adjusted OR 3.41). Conclusions Our community-based study provides robust evidence that individuals who were women, older, pre-frail, with polypharmacy, and living in regional or remote areas have a markedly greater odds of developing frailty after a CVD event.

Background:Atrial fibrillation (AF) is associated with aging and increased risk of stroke and dementia. We examined the association between incident AF and cognitive trajectories in older adults using longitudinal data from the ASPirin in Reducing Events in the Elderly (ASPREE) study. Methods:ASPREE was a multi-center randomized, double-blind, placebo-controlled trial of low-dose (100 mg) aspirin in healthy older adults. In this analysis, participants were aged ≥70 years with no history of cardiovascular disease, AF, or a diagnosis of dementia. We used a case ascertainment approach to identify participants with new onset of probable AF over trial participation, defined by new anticoagulant use, incident medically documented diagnosis, or irregular heart rate at study visits prompting diagnosis. We generated z -scores for cognitive assessments for global cognition (3MS, Modified Mini-Mental State Examination), verbal fluency/executive function (Controlled Oral Word Association Test, COWAT-F), delayed memory (Hopkins Verbal Learning Test-Revised, HVLT-R), and attention/processing speed (Symbol Digit Modalities Test, SDMT). Baseline cognition and trajectories were compared between probable AF and no AF (control group) using linear mixed-effects models. Results:Of 14,577 participants (mean age = 75.2 ± 4.3 years; 57.8% female), 978 (6.7%) developed probable AF. Baseline cognitive scores did not differ between groups. Compared to controls, those with AF showed greater decline over five years: 0.12 z -score (95% CI: 0.05, 0.20) in 3MS, 0.10 (95% CI: 0.07, 0.12) in COWAT, 0.10 (95% CI: 0.10, 0.16) in SDMT, and 0.11 (95% CI: 0.08, 0.14) in HVLT. APOE ℰ4 allele carriage was associated with greater decline among those with AF. Conclusions:In initially healthy older adults, those who developed AF had comparable cognitive profiles at baseline but exhibited greater cognitive decline over 5 years than those who did not. A diagnosis of AF may be a trigger for cognitive evaluation in older individuals. Clinical Trial Registration:www.clinicaltrials.gov/study/NCT01038583.

Background: Social determinants of health (SDoH) significantly impact cardiovascular disease (CVD) risk. This study aims to identify SDoH clusters and explore their cumulative effects on CVD risk. Methods: Data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial, ASPREE eXTension study, and ASPREE Longitudinal Study of Older Persons (ALSOP) were used. The study participants were community-dwelling healthy individuals (5884 men and 7012 women) aged 70+ years. These participants were followed for 12 years (median: 8.4 years). The K-prototype algorithm to identify clusters of SDoH and the Cox model to evaluate the association between the SDoH clusters and CVD events were used. Causal Survival Forest was employed to explore the heterogenous treatment effect (HTE) of the SDoH clusters on CVD events. Results: Two SDoH clusters, disadvantageous and advantageous, were identified. The advantageous group were more economically stable, socially active, and had positive neighbourhood factors. Being membership in the advantageous group was statistically significantly associated with a 31 % reduced risk of CVD events among women. By taking the disadvantageous SDoH group as the control group and the advantageous group as the treated group, there was indication of HTE on CVD among women; women who were in the treated group had delayed onset of CVD and the treatment could benefit specific groups, including smokers, individuals on anti-hypertensive medication, and older adults. However, among men there was no statistically significant association and HTE. Conclusion: The study highlights the interconnectedness of SDoH and their greater impact on women's CVD risk compared to men.

BACKGROUND:Polygenic risk scores (PRSs) may enhance atrial fibrillation (AF) risk prediction when added to conventional risk factors. Most AF-PRS studies, however, focus on individuals with existing cardiovascular disease, rather than initially healthy older adults followed prospectively. OBJECTIVES:The objective of the study was to evaluate the predictive performance of a recent (2025) AF-PRS for incident AF in a cohort of healthy older individuals without prior cardiovascular events. METHODS:AF-PRS was calculated in 12,906 individuals aged ≥65 years without prior cardiovascular disease or AF at enrollment into the ASPREE (Aspirin in Reducing Events in the Elderly) trial. Cox proportional hazards models assessed HRs) per SD of AF-PRS, alone and with clinical risk factors (age, sex, body mass index, hypertension, diabetes, dyslipidaemia, thyroid-stimulating hormone, smoking, and alcohol). We compared AF-PRS to clinical scores (Cohorts for Heart and Aging Research in Genomic Epidemiology [CHARGE]-AF and hypertension, age, raised body mass index, male sex, sleep apnea, smoking, and Alcohol score[HARMS2-AF]). Model performance was evaluated using Harrell's C-index and likelihood ratio tests. Sex-stratified analysis was also conducted. RESULTS:Over a median 4.5-years of follow-up, 654 incident AF cases occurred. AF-PRS was associated with incident AF (adjusted HR: 1.74 per SD; 95% CI: 1.58-1.84) (compared to CHARGE-AF [HR: 1.50] and HARMS2-AF [HR: 1.32] [all P < 0.0001]). Individuals in the highest AF-PRS quintile had 5.44-fold higher risk than those in the lowest (P < 0.0001). The AF-PRS showed stronger association in women than men (HR: 7.09 vs 4.51; interaction P = 0.007). AF-PRS improved prediction beyond clinical factors, increasing the C-index by 8.2% (0.63 → 0.71), 9.5% over CHARGE-AF (0.61 → 0.70), and 10.5% over HARMS2-AF (0.57 → 0.65). CONCLUSIONS:The use of an AF-PRS improves risk prediction of incident AF above clinical risk factors in older individuals without cardiovascular disease.

Animal studies and meta-analysis of human observational data suggest that pneumococcal polysaccharide vaccination (PPV) could be protective against atherosclerosis; however, to the authors’ knowledge, no randomized clinical trial has been conducted. To determine whether pneumococcal vaccination (Pneumovax [Merck Sharp & Dohme Corp]) decreases the composite primary outcome of fatal and nonfatal acute coronary syndrome and ischemic stroke in people at increased risk, with an average follow-up of 7 years after immunization. This was a double-blind, placebo-controlled, parallel-arm randomized clinical trial conducted at 6 centers across Australia. Participants were community-dwelling adults 55 to 60 years of age at baseline in 2016 to 2017, with at least 2 risk factors (obesity, hypertension, or hypercholesterolemia) for cardiovascular disease (CVD) but no prior CVD event or indication for early pneumococcal vaccination. Data were analyzed from February 2023 to December 2024 using competing risk proportional hazards regression models, stratified by sex and center. Participants received either 23-valent PPV (PPV23) or placebo (saline). The primary outcome was a composite of fatal and nonfatal myocardial infarction or ischemic stroke, ascertained via electronic medical records from emergency department, admitted patient, and mortality data collections using International Statistical Classification of Diseases, Tenth Revision, Australian Modification ( ICD-10-AM ) codes. A total of 4725 participants (mean [SD] age, 58.0 [1.7] years; 2433 male [52%]) were included in this study. There was no significant difference in the primary outcome (58 of 2366 events in the active PPV23 group compared with 64 of 2357 events in the control group, hazard ratio, 0.90; 95% CI, 0.63-1.28; P = .57). Similarly, no significant differences occurred in the exploratory outcomes of all-cause mortality, all-cause hospital presentations, and CVD-related hospital procedures. These results are tempered by the lower than expected event rate leading to low power. Results of this randomized clinical trial found that PPV23 did not reduce the rates of fatal and nonfatal acute coronary syndrome and ischemic stroke, although the study was underpowered. ANZCTR Identifier: ACTRN12615000536561

Importance:Animal studies and meta-analysis of human observational data suggest that pneumococcal polysaccharide vaccination (PPV) could be protective against atherosclerosis; however, to the authors' knowledge, no randomized clinical trial has been conducted. Objective:To determine whether pneumococcal vaccination (Pneumovax [Merck Sharp & Dohme Corp]) decreases the composite primary outcome of fatal and nonfatal acute coronary syndrome and ischemic stroke in people at increased risk, with an average follow-up of 7 years after immunization. Design, Setting, and Participants:This was a double-blind, placebo-controlled, parallel-arm randomized clinical trial conducted at 6 centers across Australia. Participants were community-dwelling adults 55 to 60 years of age at baseline in 2016 to 2017, with at least 2 risk factors (obesity, hypertension, or hypercholesterolemia) for cardiovascular disease (CVD) but no prior CVD event or indication for early pneumococcal vaccination. Data were analyzed from February 2023 to December 2024 using competing risk proportional hazards regression models, stratified by sex and center. Interventions:Participants received either 23-valent PPV (PPV23) or placebo (saline). Main Outcomes and Measures:The primary outcome was a composite of fatal and nonfatal myocardial infarction or ischemic stroke, ascertained via electronic medical records from emergency department, admitted patient, and mortality data collections using International Statistical Classification of Diseases, Tenth Revision, Australian Modification (ICD-10-AM) codes. Results:A total of 4725 participants (mean [SD] age, 58.0 [1.7] years; 2433 male [52%]) were included in this study. There was no significant difference in the primary outcome (58 of 2366 events in the active PPV23 group compared with 64 of 2357 events in the control group, hazard ratio, 0.90; 95% CI, 0.63-1.28; P = .57). Similarly, no significant differences occurred in the exploratory outcomes of all-cause mortality, all-cause hospital presentations, and CVD-related hospital procedures. These results are tempered by the lower than expected event rate leading to low power. Conclusions and Relevance:Results of this randomized clinical trial found that PPV23 did not reduce the rates of fatal and nonfatal acute coronary syndrome and ischemic stroke, although the study was underpowered. Trial Registration:ANZCTR Identifier: ACTRN12615000536561.

Background:This study examined the associations between music-related leisure activities (listening to music or playing a musical instrument) and incident cardiovascular disease (CVD) events, changes in systolic and diastolic blood pressure (SBP, DBP) and heart rate (HR) among community-dwelling Australians aged ≥70 years. Whether these associations varied by gender and age was also explored. Methods:Longitudinal data from individuals enrolled in the ASPREE-XT study were analyzed. Participants had no prior CVD events or known life-limiting health conditions at baseline. Cox proportional-hazard regression and linear mixed models were used. Results:Among 10,591 participants followed for a median of 5.5 years, 780 incident CVD events occurred. After adjustment for sociodemographic factors, often listening to music was associated with a 23 % lower risk and always listening to music with an 18 % lower risk of incident CVD events. These associations attenuated after further adjustment for behaviors and clinical measures. Playing a musical instrument was not associated with incident CVD events. Findings did not differ by gender or age group (p-interaction>0.05). No associations were found between music-related activities and changes in SBP, DBP and HR. However, always listening to music was associated with an increase in HR per year among women (adjusted-beta, 0.13). Among people aged ≥74 years, often/always playing musical instruments was associated with an increase in SBP (adjusted-beta, 0.44) and DBP (adjusted-beta, 0.17) per year. Conclusion:Our preliminary findings provide little evidence of a link between listening to music and a reduced CVD risk, other than that through associated behavioral factors.

BACKGROUND:Recent evidence underscores the significant impact of social determinants of health (SDoH) on cardiovascular disease (CVD). However, available CVD risk assessment tools often neglect SDoH. This study aimed to integrate SDoH with traditional risk factors to predict CVD risk. METHODS:The data was sourced from the ASPirin in Reducing Events in the Elderly (ASPREE) longitudinal study, and its sub-study, the ASPREE Longitudinal Study of Older Persons (ALSOP). The study included 12,896 people (5884 men and 7012 women) aged 70 or older who were initially free of CVD, dementia, and independence-limiting physical disability. The participants were followed for a median of eight years. CVD risk was predicted using state-of-the-art machine learning (ML) and deep learning (DL) models: Random Survival Forest (RSF), Deepsurv, and Neural Multi-Task Logistic Regression (NMTLR), incorporating both SDoH and traditional CVD risk factors as candidate predictors. The permutation-based feature importance method was further utilized to assess the predictive potential of the candidate predictors. RESULTS:Among men, the RSF model achieved relatively good performance (C-index = 0.732, integrated brier score (IBS) = 0.071, 5-year and 10-year AUC = 0.657 and 0.676 respectively). For women, DeepSurv was the best-performing model (C-index = 0.670, IBS = 0.042, 5-year and 10-year AUC = 0.676 and 0.677 respectively). Regarding the contribution of the candidate predictors, for men, age, urine albumin-to-creatinine ratio, and smoking, along with SDoH variables, were identified as the most significant predictors of CVD. For women, SDoH variables, such as social network, living arrangement, and education, predicted CVD risk better than the traditional risk factors, with age being the exception. CONCLUSION:SDoH can improve the accuracy of CVD risk prediction and emerge among the main predictors for CVD. The influence of SDoH was greater for women than for men, reflecting gender-specific impacts of SDoH.

BACKGROUND:Current cardiovascular disease (CVD) risk prediction models tailored for older adults are inadequate. This study aimed to validate, update and assess the utility of widely used CVD risk prediction models including American College of Cardiology/American Heart Association, 2008 Framingham, GloboRisk, National Vascular Disease Prevention Alliance and Predict1 originally developed for middle-aged population, as well as an age-specific Systematic COronary Risk Evaluation 2-Older Person model, in Australian and the US community-dwelling older adults. METHODS:Participants, without history of CVD events, dementia or physical disability, enrolled in the ASPREE (ASPirin in Reducing Events in the Elderly) clinical trial and ASPREE-eXTention observational post-trial follow-up, were considered for CVD risk prediction. The main outcome was predicted CVD risk from adjudicated CVD events. The performance of the original, recalibrated (adjusting models' intercept and slope) and updated (adjusting models' coefficients) models was evaluated by discrimination (C statistic), calibration (calibration plots) and clinical utility (decision curves). Models were extended by incorporating predictors including serum creatinine, depression and socioeconomic status index (Index of Relative Socio-economic Advantage and Disadvantage, IRSAD) into models' equation, and the changes in discrimination were evaluated. RESULTS:Among 15 618 adults (mean age 75 (4.4) years), 520 men and 498 women experienced CVD events over a median follow-up of 6.3 (IQR: 5.2-7.7) years. Following updating, the discrimination power of models increased for both sexes (C statistics ranged 0.62-0.64 for men and 0.68-0.69 for women). Updated models indicated good calibration, with an added net benefit at the risk thresholds ranging from 4%-10% for women to 5%-12% for men. Incorporating IRSAD, depression and serum creatinine did not improve CVD risk discrimination of updated models. CONCLUSIONS:Updating models, by adjusting model coefficients to better reflect the characteristics and risk factors of older adults, improves CVD risk prediction in a large cohort of relatively healthy Caucasian population aged 70+. Further external validation in diverse older populations including those with frailty and multimorbidity is recommended before clinical implementation.

PURPOSE:We aimed to determine whether commonly recommended CVD risk equations would inform a risk-benefit discussion on the role for aspirin as a primary prevention strategy for CVD in older persons. We assessed aspirin's effect on CVD and major haemorrhage on the basis of baseline levels of CVD risk using risk scores pertaining to the older age groups. METHODS:We used a) the Framingham (FRS), b) the Atherosclerotic Cardiovascular Disease (ASCVD), and c) the European SCORE2-OP equations to calculate 10-year predicted CVD risk. Participants were classified into predicted risk tertiles (T): lower (T1), intermediate (T2) and higher (T3) risk. We identified CVD and major haemorrhagic events utilising each risk equation's definition of CVD. RESULTS:The CVD event rate increased from T1 to T3 using all risk equations. For participants with greatest CVD risk (T3) according to FRS and ASCVD, aspirin versus placebo was associated with a proportional 28% (95% CI: 54 to 95%) and 25% (95% CI: 57 to 97%) reduction in CVD risk respectively. However, there was no significant effect of aspirin for individuals with low (T1) or moderate (T2) risk, nor according to the SCORE2-OP tertiles.Rates of major haemorrhagic events were highest in all T3 groups. Aspirin was associated with a significant increase in bleeding events versus placebo in all T1 groups and FRS and SCORE2-OP T2 groups. The reduction in CVD events in FRS and ASCVD T3 groups was offset by a 32% and 15% increased risk of bleeding respectively. CONCLUSION:In older persons with no prior cardiovascular events, current CVD risk scores do not identify any subgroups with overall net clinical benefit from low dose aspirin.

OBJECTIVE:Reports have linked both high and low serum uric acid (SUA) levels to adverse health outcomes. This study aimed to establish a reference interval for SUA in older adults and assessed its association with clinically relevant outcomes in relatively healthy, community-dwelling individuals aged ≥70 years old. METHODS:The study used data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial. In Australia, 11,878 ASPREE participants had baseline SUA measurements (median age 74 years old). The study sample (n = 11,446; 55% women) comprised individuals with baseline SUA measurements, excluding those on urate-lowering medication. The reference sample (n = 10,501; 55% women) was established after further exclusion of participants with impaired renal function, defined as an estimated glomerular filtration rate <45 mL/min/1.73m2. Reference intervals (2.5th and 97.5th percentile) were stratified by sex, and Cox proportional hazard models assessed associations between SUA levels and relevant clinical outcomes. RESULTS:SUA reference intervals were 0.24 to 0.54 mmol/L for men and 0.19 to 0.48 mmol/L for women. After adjusting for potential confounders, no association was observed between SUA levels and all-cause mortality, disability-free survival, cardiovascular disease, major adverse cardiovascular events, cancer incidence and mortality, or dementia in either the study or reference samples. In women, however, low SUA levels were associated with an increased risk of fractures (hazard ratio 1.23; 95% confidence interval 1.04-1.46). CONCLUSION:Although previous reports have linked abnormal SUA levels to adverse health outcomes, our findings show no associations within the reference range, except for an increased fracture risk among women with low SUA levels.