Atherosclerotic Cardiovascular Disease Research Articles

Abstract 4122948: Lipoprotein(a) associated risk of atherosclerotic cardiovascular disease is independent of C-reactive protein

Background: Elevated lipoprotein(a), present in 1 in 5 individuals, is considered a causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Recent studies have reached contrasting conclusions on whether low-grade inflammation measured by elevated C-reactive protein (CRP) modifies the risk of ASCVD from high lipoprotein(a). We tested the hypothesis that high lipoprotein(a) associates with risk of recurrent ASCVD irrespective of elevated or low CRP. Additionally, we performed meta-analyses of previous studies on lipoprotein(a)-associated ASCVD risk stratified by CRP levels and by incident or recurrent events. Methods: We included 3,543 individuals with prevalent ASCVD from the Copenhagen General Population Study (CGPS), a contemporary, prospective Danish cohort study. Hazard ratios (HR) for ASCVD were examined using multivariable adjusted Cox regressions stratified by CRP (<2 mg/L and ≥2 mg/L). Random-effects meta-analyses in primary (incident events) and secondary (recurrent events) prevention were conducted separately, including studies on lipoprotein(a) and risk of ASCVD stratified by CRP. Results: During a median of 7.5 years of follow-up of 3,543 CGPS participants with established ASCVD, 1,425 experienced a recurrent ASCVD event. Multivariable adjusted HRs for ASCVD for high vs. low lipoprotein(a) were 1.41 (95% confidence interval: 1.19-1.67) and 1.31 (1.08-1.59) in individuals with low or elevated CRP with no evidence of effect modification (Figure 1A, p for interaction=0.11). When risk estimates for ASCVD were summarized in separate meta-analyses for primary and secondary prevention settings, a 50 mg/dL higher lipoprotein(a) was robustly associated with increased risk of ASCVD irrespective of CRP levels (Figure 1B). In primary prevention, a 50 mg/dL higher lipoprotein(a) associated with similar summary HRs of 1.18 (1.15-1.20) in low CRP vs. 1.16 (1.14-1.19) in elevated CRP, and likewise in secondary prevention settings, with similar HRs of 1.10 (1.07-1.14) and 1.14 (1.10-1.17), respectively. Conclusion: High lipoprotein(a) was associated with increased risk of ASCVD irrespective of CRP levels both in primary and secondary prevention settings.

Abstract 4134911: Coronary Artery Calcium Predicts Cardiovascular Events in Individuals with Controlled Atherosclerotic Risk Factors: A Multi-Cohort Study

Background: There is residual risk of atherosclerotic cardiovascular disease (ASCVD) that remains despite adequate risk factor (RF) control. Coronary artery calcium (CAC) has demonstrated value in ASCVD risk stratification. We evaluated the value of CAC in identifying residual risk of ASCVD events among those with traditional RF control. Methods: Participants without clinical ASCVD were pooled from the Multi-Ethnic Study of Atherosclerosis, Heinz Nixdorf Recall Study, Framingham Heart Study, and Jackson Heart Study. RF control was classified as “guideline-concordant” and “optimal” (Figure 1). Participants were stratified by the number of controlled RFs at baseline and CAC score (CAC = 0, 1-99, ≥100). Cox proportional hazards models examined the association between CAC and incident ASCVD events. Results: The study included 14,780 individuals (mean age 58 years (SD: 11), 54% female, 59% White, 27% Black, 50% CAC = 0). Over a median follow-up of 14.6 years, there were 1,441 incident ASCVD events. The distribution of CAC and ASCVD event incidence is shown in Panel A; 10% of those with 3 optimal RFs and 19% of those with 3 guideline-concordant RFs controlled had CAC > 100. The rate of ASCVD events decreased with more RFs controlled and increased with higher CAC. Overall, optimal RF control was associated with lower ASCVD event rates compared to guideline-concordant control. At every level of RF control, CAC > 100 was associated with increased HRs for incident ASCVD (Panel B). Those with CAC ≥ 100 and controlled RFs experienced ASCVD rates numerically comparable to or exceeding those with uncontrolled RFs but CAC = 0 (Panel A). Adjusted HR (95% CI) for ASCVD events with CAC > 100 compared to CAC = 0 was 5.0 (2.0, 12.9) in optimal RF control and 3.7 (2.6, 5.4) in guideline-concordant RF control. Conclusion: There is significant heterogeneity in residual ASCVD risk among those with optimal or guideline-concordant traditional RF control and CAC can help identify this risk. Irrespective of RF control, a higher CAC burden was associated with increased ASCVD risk. Future studies could use CAC testing to identify those with higher residual ASCVD risk despite effective traditional RF control to target for novel therapies.

Abstract 4124875: Association between Elevated Lipoprotein(a) and Cardiovascular Events and Mortality in a Nationally Representative Sample of US Medicare, Medicaid, and Commercial Enrollees with ASCVD

Background: Elevated lipoprotein(a) [Lp(a)] is an independent and causal risk driver for atherosclerotic cardiovascular disease (ASCVD). Few patients with ASCVD receive Lp(a) screening and real-world data assessing the association between elevated Lp(a) and risk of cardiovascular (CV) events and mortality is limited. Objectives: To examine the association of elevated Lp(a) and risk of CV events and death in an ASCVD population using large US health claims databases. Methods: Patients with ASCVD were pooled from US Medicare, commercial, and Medicaid health plans from 2017 to 2022. Lp(a) levels were linked at the patient level from HealthVerity Lab Data and categorized as: <30 mg/dL (<75 nmol/L), ≥30-<50 mg/dL ( > 75-<125 nmol/L), ≥50-<70 mg/dL ( > 125-<175 nmol/L), ≥70-<90 mg/dL (≥175-<225 nmol/L) and ≥90 mg/dL (≥225 nmol/L). Patients were followed from the 1 st ASCVD diagnosis (index) to insurance plan disenrollment, death, or end of study. Cox regression, adjusted for age, sex, race, insurance, comorbidities, LDL-C, and other risk factors, measured the association between Lp(a) levels and risk of CV events and death. Results: Of 28.8 million ASCVD patients, 180,240 (0.6%) had Lp(a) levels: mean(±SD) age 68.6±1 years, 50.1% male, 5.9% Black, 2.8% Hispanic, 2.1% Asian, 72.8% Medicare, 21.8% commercial, and 5.4% Medicaid. Mean follow-up was 3.7 years; 23.3% and 15.7% had Lp(a) ≥50mg/dL [≥125 nmol/L] and ≥70 mg/dL (≥175 nmol/L), respectively. Black patients had highest median Lp(a) (50 mg/dL/111 nmol/L), followed by Asian (13.5 mg/dL/35.5 nmol/L), White (13 mg/dL/32 nmol/L), and Hispanic (11.5 mg/dL/29 nmol/L) patients. Lp(a) levels of ≥30-<50 mg/dL, ≥50-<70 mg/dL, ≥70-<90 mg/dL, and ≥90 mg/dL were associated with 7%, 10%, 16%, and 26% greater risks of CV events vs. <30 mg/dL (p-values <0.0001; cumulative incidence reported in Figure 1). All-cause mortality risk was also greater for those with Lp(a) ≥90 mg/dL vs. <30 mg/dL: hazard ratio (HR)=1.11, p=0.003. Similar trends persisted for patients with LDL-C ≤70 mg/dL. Conclusion: In this national-scale real-world cohort of patients with ASCVD, Lp(a) testing is infrequent and elevated Lp(a) levels were significantly associated with a greater risk of CV events and mortality.

Abstract 4137191: Association of Cost-Related Medication Non-Adherence with Food Insecurity in U.S. Adults with Atherosclerotic Cardiovascular Disease

Background: The association of cost-related medication non-adherence (CRN) with food insecurity (FI) is not well described in those with atherosclerotic cardiovascular disease (ASCVD). Research Questions: Is FI associated with CRN in those with ASCVD, and does enrollment in the Supplemental Nutrition Assistance Program (SNAP) modify this effect? Methods: Data from the National Health Interview Survey (NHIS) 2011-2018 cycles were analyzed. A total of 22,304 adults (weighted: 17.7 million) with ASCVD and available food security, medication adherence and linked mortality data from the National Death Index were included. FI was defined as 3 or more affirmative responses to the USDA food security survey. CRN was identified by an affirmative response to delayed prescription filling, took less medication, or skipped medication doses to save money in the past 12 months. Analyses accounted for the complex survey design to obtain nationally representative estimates. Survey-weighted logistic regression was used to determine predictors of CRN, and Cox regression was used for mortality analyses. Results: Among adults with ASCVD, 13.3% (95% CI 12.7-13.9%; 2.34 million) reported CRN, 15.0% (95% CI 14.3-15.7%; 2.65 million) reported FI, and 5.7% (95% CI 5.3-6.2%; 1.01 million) reported both concomitantly. Those reporting CRN were more likely to be younger, female, non-white, without health insurance, below the federal poverty limit, have lower educational attainment, more comorbidities, and report FI. FI and SNAP enrollment were significantly associated with CRN after multivariable adjustment (adjusted odds ratio [aOR] 4.35 [95% CI 3.74-5.05] and 1.28 [95% CI 1.06-1.55], respectively). A significant interaction was observed between FI and SNAP enrollment (Pint = 0.001), and FI was associated with lower odds of CRN among the SNAP-enrolled versus unenrolled (aOR 2.50 [95% CI 1.98-3.14] vs 5.74 [95% CI 4.82-6.85]) (Figure 1). CRN and food security were not significant predictors of all-cause or cardiovascular mortality in the fully adjusted models. Conclusion: Among adults with ASCVD, FI and SNAP enrollment independently predict CRN. Among adults with ASCVD and FI, more than one third reported CRN and those without SNAP had more than twice the odds of CRN. Greater SNAP enrollment may improve medication adherence in those with ASCVD and FI.

Abstract 4137461: Elevated Lipoprotein(a) Increases Cardiovascular-Related Healthcare Resources Utilization and Costs among US Medicare, Medicaid, and Commercial Enrollees with ASCVD

Background: Elevated lipoprotein(a) [Lp(a)] is a recognized genetic, independent, and causal risk driver for atherosclerotic cardiovascular disease (ASCVD). Less is known about how elevated Lp(a) affects downstream cardiovascular (CV)-related healthcare resource utilization (HCRU) and costs in patients with ASCVD. Objective: To assess the association of Lp(a) levels with CV-related HCRU (hospitalizations, outpatient and emergency department [ED) visits), and CV-related costs for patients with ASCVD in a national-scale multi-insurance cohort. Methods: Patients with ASCVD were pooled from US Medicare, commercial, and Medicaid health plans from 2017 to 2022. Lp(a) levels (mg/dL and nmol/L) were linked at the patient level with HealthVerity Lab Data. Elevated Lp(a) was defined as Lp(a)≥70mg/dL (≥ 175 nmol/L) and normal Lp(a) was defined as Lp(a)<30mg/dL (<75 nmol/L). Generalized linear models with log link negative binomial distribution (HCRU) and log link gamma distribution (costs) adjusted for age, sex, race, insurance type, comorbidities, statin use, and prior hospitalizations, measured the association of Lp(a) levels with the annualized rate of CV-related hospitalizations, ED visits, and outpatient visits (incidence rate ratio [IRR]) and CV-related costs (annualized cost ratio). Results: A total of 180,240 ASCVD patients were identified with Lp(a) values. Median (IQR) Lp(a) was 14 mg/dL (4 mg/dL – 48 mg/dL) or 35 nmol/L (12 nmol/L – 114 nmol/L). Mean (SD) age was 68.6 (12.0) years with 49.9% being female; 72.8% of patients were from Medicare, followed by commercial (21.8%) and Medicaid (5.4%). Fully adjusted CV-related HCRU was significantly higher in those with elevated Lp(a) compared to normal Lp(a): inpatient hospitalizations (IRR=1.11), outpatient visits (IRR=1.11) and ED visits (IRR=1.06), all p <0.001 (IRR and 95% CI reported in Table 1). Patients with elevated Lp(a) had 14% higher CV-related annualized healthcare costs than patients with normal Lp(a) (p <0.001) with significantly higher CV-related HCRU beginning with Lp(a) levels >30 mg/dL (>75 nmol/L). Conclusion: Elevated Lp(a) was significantly associated with greater CV-related HCRU and costs in patients with ASCVD.

Abstract 4138332: Lipoprotein (a), Triglyceride-Glucose Index and Incident Atherosclerotic Cardiovascular Disease (ASCVD): Analysis of the UK Biobank

Background: The triglyceride-glucose index (TyG), an inexpensive novel surrogate marker for insulin resistance, and lipoprotein (a) [Lp(a)] are both risk factors for atherosclerotic cardiovascular disease (ASCVD). However, it is uncertain whether TyG modifies the relationship of Lp(a) with incident ASCVD. Objective: To investigate the relationship of Lp(a) and TyG with the risk of incident ASCVD. Methods: We included UK Biobank participants without ASCVD at enrollment. Baseline TyG was calculated as ln[fasting triglycerides (mg/dL) × fasting plasma glucose (mg/dL)/2]. We classified TyG values as high (≥75th percentile) or low (<75th percentile), and Lp(a) levels, in nmol/L, as <125 or ≥125. Participants were then stratified into four groups: Group-1: Low TyG with Lp(a), <125, Group-2: Low TyG with Lp(a) ≥125, Group-3: High TyG with Lp(a) <125, and Group-4: High TyG with Lp(a) ≥125. We used multivariable Cox regression to estimate the risk of ASCVD (a composite of peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, and cardiovascular mortality) of TyG and Lp(a) adjusted for the other, and in the four combination groups. Results: Eligible participants (N=254,377) had a mean (SD) age of 56.0 (8.1) years, and 53.2% were female. The median follow-up was 14.6 years. In separate models additionally adjusted for cardiovascular risk factors (see Figure legend), the hazard ratio (HR [95% CI]) for ASCVD was 1.18(1.13–1.23) for Lp(a) ≥125 nmol/L (vs. <125 nmol/L), adjusted for TyG, and 1.09(1.05–1.13) for high TyG (vs. low), adjusted for Lp(a). A statistically significant interaction between TyG and Lp(a) was observed in the fully adjusted model (p <0.001). Compared to Group-1 (low TyG with Lp(a) <125nmol/L), the adjusted HR (95% CI) of incident ASCVD in Group-2, -3 and -4 were: 1.07(1.04–1.13), 1.15 (1.09–1.21) and 1.34(1.25–1.44), respectively (Figure). Conclusions: These findings demonstrate that TyG and Lp(a) are associated with incident ASCVD risk independently of each other. Moreover, TyG modified the effect of Lp(a) on ASCVD, suggesting that insulin resistance may amplify the atherogenic, inflammatory, and/or thrombotic effects of Lp(a), thereby further increasing ASCVD risk.

Abstract 4137922: Cardiovascular Prognosis of Statin Users Developing Diabetes in Secondary Prevention: A Prospective Multicenter Study

Background: In primary prevention, statin use with new-onset diabetes mellitus (DM) was associated with increased atherosclerotic cardiovascular disease (ASCVD) risk. In high-risk and secondary prevention settings, the cardiovascular prognosis of statin users progressing to new-onset DM remains unclear. Methods: We collected data from inpatients with or without baseline ASCVD from four medical centers affiliated to Qingdao University. Patients were categorized into 4 phenotypes: (1) statin non-users without diabetes; (2) statin users with incident diabetes; (3) statin users with pre-existing diabetes; and (4) statin users without diabetes. The primary outcome was ASCVD events. The stratified Cox proportional hazard model was used to investigate the association between the four distinct phenotypes and the risk of ASCVD. Results: Among 12,800 high-risk patients, over a median follow-up of 118 days (interquartile range, 48-379 days), 1447 ASCVD events were documented. Compared with statin non-users without diabetes, statin users without diabetes (hazard ratio [95% confidence interval], 0.77 [0.65, 0.91], P=0.001) and statin users with pre-existing diabetes (0.80 [0.66, 0.99], P=0.035) were associated with lower risk of ASCVD, whereas statin users with new-onset diabetes were not (0.91 [0.70, 1.19], P=0.50), overall P for trend =0.013.( Figure 1 ) In patients with baseline ASCVD (i.e., secondary prevention settings), we observed similar findings ( Figure 2 ) Conclusions: In high-risk patients with pre-existing ASCVD, new-onset diabetes after statin use was likely associated with compromised cardiovascular benefits of statins.

Abstract 4137527: Evaluation of 10-Year Atherosclerotic Cardiovascular Risk Prediction Performance using the PREVENT versus Pooled Cohort Equations in a US Integrated Healthcare System

Background: The American Heart Association published the new PREVENT equations for estimating atherosclerotic cardiovascular disease (ASCVD) risk. Question: Do the PREVENT equations improve risk prediction for 10-year ASCVD compared with the pooled cohort equations (PCEs) in a large diverse population? Aim: To assess ASCVD risk prediction performance of the two PREVENT equations [PREVENT Base, PREVENT Base plus optional predictors including urine albumin-to-creatinine ratio, glycated hemoglobin, and social deprivation index (PREVENT Full)] compared with the PCEs. Methods: We included adults aged 40-75 years without a history of ASCVD or diabetes from Kaiser Permanente Southern California in 2009 and followed them through 2019. Outcome was incident ASCVD defined as myocardial infarction, fatal coronary heart disease, fatal and nonfatal stroke. We compared model discrimination (Harrell’s C), mean calibration (estimated as the ratio of predicted to observed event rates), and calibration curve among the overall population and stratified by sex and race/ethnicity. Results: Of the 559,111 adults (mean age 54, 11% Black, 32% Hispanic), 10,695 developed an ASCVD event during a median follow-up of 10 years. Harrell’s C among the overall population was 0.741 (95% CI 0.736-0.745) for PREVENT Base, 0.743 (0.738-0.748) for PREVENT Full, and 0.741 (0.736-0.746) for the PCEs ( Table ). Compared with the PCEs, both PREVENT equations improved Harrell’s C in men but not in women, and in Black adults but not in other racial/ethnic groups. Both PREVENT equations were well-calibrated (mean calibration ranged 0.83-1.37; calibration slope ranged 0.71-1.28), while the PCEs overestimated 10-year ASCVD risk (mean calibration ranged 1.80-2.20; calibration slope ranged 0.34-0.45) ( Table & Figure ). Conclusion: Compared with the PCEs, both PREVENT Base and Full equations improved calibration in predicting 10-year ASCVD risk, with minimal improvement in discrimination in men and Black adults only.

Abstract 4136273: A Machine Learning Approach to Simplify Risk Stratification of Patients with Atherosclerotic Cardiovascular Disease

Introduction: The 2018 AHA/ACC/Multisociety Blood Cholesterol Guideline recommends that patients with atherosclerotic cardiovascular disease (ASCVD) be classified as very high-risk (VHR) or not very high-risk (NVHR). This designation is based on the presence of > 2 major ASCVD events (recent acute coronary syndrome [ACS], history of myocardial infarction [MI], history of ischemic stroke, symptomatic peripheral artery disease [PAD]) or 1 major ASCVD event and > 2 high-risk conditions (age ≥65 years, heterozygous familial hypercholesterolemia, history of coronary revascularization, diabetes, hypertension, chronic kidney disease, current smoking, persistently elevated LDL-cholesterol [LDL-C], history of heart failure). While this approach was initially instituted to better predict future ASCVD events alone, more intensive LDL-C lowering is now recommended for those at VHR (LDL-C treatment threshold of 55 mg/dL for VHR patients vs 70 mg/dL for NVHR patients). We aimed to simplify ASCVD risk stratification in patients with clinical ASCVD using machine learning models. Methods: We used electronic health record data (Providence Health system) from 2022 to identify patients with ASCVD based on ICD-10 codes. Patient demographics, comorbidities, and laboratory data stratified patients as VHR or NVHR. Then, a classification and regression tree analysis was performed, with the outcome being VHR classification. Patients were randomly assigned to either the testing or training dataset in equal proportion. Variables in the model included age, sex, race, ethnicity, and the Guideline criteria. Model performance was assessed using misclassification rate and area under the receiver operative curve (AUC). Results: A total of 491,514 patients with ASCVD were included, of which 56% were male, 77% were white, and the mean (SD) age was 72.5 (13.0) years. Over half of patients (59%) were VHR. Those with recent ACS, history of MI, history of ischemic stroke, or PAD were classified as VHR 93%, 92%, 84%, and 91%, respectively. Presence of hypertension in these patients increased the likelihood of being VHR to 97%, 97%, 94%, and 98%, respectively. The misclassification rate and AUC for the testing set were 6.8% and 96.2%, respectively. Conclusions: Most patients with a major ASCVD event and hypertension were found to be VHR. Relying on these two factors alone can help simplify risk assessment. This approach may also help increase use of guideline-recommended LDL-C lowering therapy.

Abstract 4134572: Assessing Sex Differences in the Relationship Between Social Isolation and Incident Atherosclerotic Cardiovascular Disease and Death Using Data from the U.S. Health and Retirement Study

Background: Inadequate social connection has been associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) and mortality. There are insufficient and conflicting data on whether sex differences play a role in this relationship. Therefore, we sought to further examine the relationship between sex, social isolation, and these subsequent events. Methods: We analyzed Health and Retirement Study (HRS) and RAND data collected biennially from 8,987 individuals enrolled from 2004-2020 who completed at least 1 Leave Behind Questionnaire (LBQ). Social isolation was determined from LBQ data using a previously validated 6-item scale where scores of 3 or greater indicated social isolation. Development of ASCVD was classified as new self-reported myocardial infarction or stroke at any follow-up assessment. Mortality was determined with RAND longitudinal data, which was available for all individuals. We examined the incidence of ASCVD in socially isolated and not socially isolated individuals using a cumulative incidence function accounting for the competing risk of death. Results: Mean age at baseline LBQ survey was 55.7 years and 43% of the sample were male. In the sample, 23% identified as Black, 63% identified as White, and 13% identified as Other. Social isolation was present in 1,653 (18%) individuals at their baseline survey. ASCVD developed in 484 (5%) participants, and 593 (7%) participants died over the study’s follow-up period. Cumulative incidence analysis showed no significant difference in ASCVD incidence between socially isolated and non-socially isolated groups for either sex (male p-value: 0.15; female: 0.09) (Figure). However, the incidence of death was significantly increased for both socially isolated sexes (male p-value: <0.001; female: <0.001). Conclusion: While socially isolated participants were not at significantly increased risk of incident ASCVD, they were at significantly increased risk of mortality, irrespective of sex. This highlights the need for continued public health initiatives that foster social connection to enhance the well-being of the general population. The study is limited by reliance on self-report for ASCVD, which may underestimate disease incidence.

Abstract 4136554: Comparison of short- and long-term atherosclerotic cardiovascular disease risk assessment tools in US young adults

Background: In 2023, the AHA published the PREVENT equations for estimating atherosclerotic cardiovascular disease (ASCVD) risk in adults aged 30-79 years. Research Questions: In young adults aged 20-39 years, does PREVENT improve risk prediction for 10- and 30-year ASCVD compared with existing risk assessment tools recommended in the current US guidelines (i.e., Pooled Cohort Equations [PCEs] and Pencina et al. equations)? Aims: To compare the performance of PREVENT vs. PCEs in predicting 10-year ASCVD, and PREVENT vs. Pencina equations in predicting 30-year ASCVD in young adults. Methods: We analyzed data from two complementary sources: (1) pooled data from two large cohorts: Coronary Artery Risk Development in Young Adults (CARDIA) and Framingham Heart Study (FHS; including the Offspring, Third Generation, Omni 1, and Omni 2 cohorts), and (2) electronic health records from Kaiser Permanente Southern California (KPSC). We included adults aged 20-39 years without a history of ASCVD at baseline. The outcome was incident ASCVD (defined as myocardial infarction, fatal coronary heart disease, fatal and nonfatal stroke) at 10 or 30 years. Model discrimination (Harrell’s C) and mean calibration (estimated as the ratio of predicted to observed event rates) were calculated for the overall population and stratified by sex and race/ethnicity. Results: We included 7,606 young adults (mean age 29 years, 53% female, 30% Black) from the pooled cohorts, and 284,667 (mean age 32 years, 61% female, 8% Black, 46% Hispanic) from KPSC. When predicting 10-year risk, PREVENT improved discrimination in both the pooled cohort (ΔHarrell’s C=0.052; 95% CI: 0.014, 0.095) and KPSC (ΔHarrell’s C=0.039; 95% CI: 0.028, 0.049) compared with the PCEs. PREVENT had good calibration (mean calibration ranged from 0.77 to 1.54), whereas the PCEs overestimated 10-year risk (mean calibration ranged from 1.99 to 4.82). When predicting 30-year risk, discrimination was similar for PREVENT and Pencina equations, but both algorithms underestimated 30-year risk with PREVENT showing worse calibration (mean calibration 0.61). Conclusion: PREVENT improved 10-year ASCVD risk prediction in young adults compared to the PCEs but underestimated 30-year risk.

Abstract 4124446: Traditional Risk Factors, Cardiovascular Health, and Elevated Lipoprotein(a): The Multi-Ethnic Study of Atherosclerosis

Introduction: One in five individuals have elevated lipoprotein(a) [Lp(a)], an inheritable risk factor that is causally associated with atherosclerotic cardiovascular disease (ASCVD). Whether individuals with elevated Lp(a) derive similar benefit from control of ASCVD risk factors has not been well-studied. Hypothesis: The magnitude of benefit associated with optimal cardiovascular health will be similar across the spectrum of Lp(a). Aim: To assess the association of traditional risk factor burden and Life’s Simple 7 (LS7) score with incident ASCVD across Lp(a) values. Methods: We studied 6,676 participants from the Multi-Ethnic Study of Atherosclerosis who underwent Lp(a) testing and were followed for incident ASCVD events (coronary heart disease and stroke). Elevated Lp(a) was defined as > 50 mg/dL. As defined by the American Heart Association, LS7 metrics included smoking, physical activity, body mass index, diet, total cholesterol, blood pressure, and glucose. Multivariable Cox proportional hazards regression assessed the association of traditional risk factor burden and LS7 score (poor: 0-8, average: 9-10, optimal: 11-14) with incident ASCVD for individuals with and without elevated Lp(a) during a median follow-up of 17.7 years. Results: The mean age was 62.1 years, 53% were women, and 61% were non-white. The median Lp(a) was 17 mg/dL and 20% had Lp(a) > 50 mg/dL. Individuals with Lp(a) > 50 mg/dL had the highest burden of traditional risk factors except cigarette smoking. Compared to those with a poor LS7 score, those with an optimal LS7 score had a lower ASCVD risk that was significant for participants with Lp(a) <50 mg/dL (HR=0.37, 95% CI: 0.25-0.55), but borderline significant for participants with Lp(a) > 50 mg/dL (HR=0.41, 95% CI: 0.16-1.02). Individuals with Lp(a) > 50 mg/dL had the highest absolute event rates across all LS7 categories, and there was no significant interaction between Lp(a) and LS7 score on incident ASCVD (p-interaction=0.64, Figure ). Conclusions: Participants with an optimal LS7 score had similar reduction in ASCVD risk regardless of their Lp(a) burden. These results emphasize the importance of a healthy lifestyle and ASCVD risk factor control among patients with elevated Lp(a).

Abstract 4120131: Absence of standard modifiable risk factors (SMuRF-less) among 5002 Middle Eastern patients with atherosclerotic cardiovascular disease: (Interim analysis from the Jo-SMuRF Study)

Introduction: A growing number of patients develop atherosclerotic cardiovascular disease (ASCVD) despite the absence of standard modifiable risk factors i.e. hypertension (HTN), type 2 diabetes (T2D), dyslipidemia (DSL), and cigarette smoking (SMuRF-less). There is scarcity of studies on prevalence and clinical profiles of SMuRF-less patients in the Middle Ease (ME). Aim: To study the prevalence and clinical features of ME patients with ASCVD who are SMuRF-less vs. those with ≥ 1 SMuRFs, presence of other risk factors and utilization of secondary preventive medications in the 2 groups, and one year survival. Methods: Clinical details of adult patients with ASCVD who participated in 5 previous registries were analyzed according to the absence or presence of ≥ 1 SMuRFs. Results: Of the 5002 patients included in the analysis, 676 (13.5%) were SMuRF-less and 4326 (86.5%) had ≥ 1 SMuRFs. Prevalence of the 4 SMuRFs in the whole cohort was 53.5% HTN, 47.8% T2D, 40.2% smoking, and 37.5% DSL, and the SMuRF group was 61.9%, 55.2%, 46.5%, and 43.4%, respectively. Compared with the SMuRFs group, patients in the SMuRFless group were younger (mean age 52±11.4 years vs. 56.3±11.5 years, respectively, p<0.001) and more likely to be women than men (38.6% vs. 27.9%, p<0.0001). Furthermore, SMuRF-less patients had lower mean body mass index, and less prevalence of metabolic syndrome, heart failure, and family history of ASCVD. Utilization of secondary cardiovascular prevention medications was significantly less in the SMuRF -less group than those with SMuRFs; dual antiplatelet therapy (36.4% vs. 69.5%), statins (66.3% vs. 87.4%), B blockers (57.5% vs. 70.5%), and renin-angiotensin inhibitors (35.2% vs. 55.3%, respectively, all p<0.001. Of the subgroup with one year follow up after percutaneous coronary intervention (N=2641), mortality rate was not different in the 2 groups; 1.4% vs. 1.8%, p=0.98. Conclusions: In this first study of SMuRFs in ASCVD patients in the Middle East, SMuRF-less patients account for nearly 14% of the studied cohort. These patients were younger, had less comorbid disease, received less guidelines-recommended prevention medication, and had same one year event rate compared with patients who have SMuRFs.

Abstract 4118451: A Real-world Evaluation of Longitudinal Healthcare Expenses in a Health System Registry of Type-2 Diabetes Mellitus and Cardiovascular Disease Enabled by the 21 st Century Cures Act

Background: An evaluation of the longitudinal burden of healthcare expenses in type-2 diabetes mellitus (T2DM) is limited to self-selected cohorts and claims-based or self-reported spending. Leveraging the 21 st Century Cures Act rule that made reporting hospital-level service prices mandatory, we demonstrate healthcare spending in T2DM with and without cardiovascular disease in a diverse multisite EHR-based T2DM cohort. Methods: Patients with T2DM seeking regular care (≥ 1 visit/2 years) across 5 hospitals and a large outpatient network (2013-2023) in the Yale New Haven Health System (YNHHS). Cohorts were defined by the presence of atherosclerotic cardiovascular disease (ASCVD) and/or heart failure (HF) before or up to 1 year after the T2DM diagnosis. We used the YNHHS chargemaster file to extract Medicare and insurance-negotiated cash prices. We linked census data using residential zip codes to estimate household income, used multivariable logistic regression to identify factors associated with financial hardship (health expenses >20% of income), and evaluated expenses during the last year of life. All values were inflation-adjusted to 2023 US$. Results: Overall, 106881 patients with T2DM followed for 5.4 years (3.1-7.5) had 147919 hospitalizations, representing $3.41B in expected healthcare expenses. 8% of patients with T2DM without ASCVD/HF, 14% with ASCVD, 23% with HF, and 28% with ASCVD and HF had a financial obligation for healthcare above the threshold for financial hardship. Compared with White patients, Black and Hispanic patients were more likely, and Asians were less likely to have financial hardship (OR: Black, 1.81 [1.73-1.91]; Hispanic, 1.39 [1.31-1.48]; Asian, 0.46 [0.37-0.57]), after accounting for age, sex, and comorbidities. Comorbid HF at baseline portended 2x higher odds of financial hardship (OR: HF, 2.20 [2.00-2.42]; ASCVD and HF, 1.98 [1.84-2.14]) compared with T2DM alone. Care in the last year of life represented 72-80% of overall health expenses, with 55-61% of patients at risk for financial hardship across cohorts. Conclusion: A digital individualized expense-linked registry of patients enabled by recent US price transparency rules defined that annually, one-fifth of patients with T2DM and cardiovascular disease had healthcare events exceeding 20% of their annual income, and vulnerable racial/ethnic minorities were at high risk for financial toxicity.

Abstract 4133830: Uncovering the Gaps: Analyzing Prescribing Patterns of Combination Therapy with SGLT2-inhibitors and GLP-1 Receptor Agonists in Established Atherosclerotic Cardiovascular Disease (ASCVD) and Type 2 Diabetes (T2DM)

Introduction: Combination therapy with SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1RA) reduces major cardiovascular events (MACE) and improves HbA1c, blood pressure, weight, and renal disease progression. The European Society of Cardiology recommends this therapy for ASCVD and T2DM, independent of HbA1c. This study evaluates prescribing patterns in the Internal Medicine Residency Clinics for patients with ASCVD and T2DM. Aims: To investigate demographic and social determinants of health (SDOH) influencing the prescription of combination therapy versus no therapy in an outpatient population and identify factors affecting prescribing patterns and guideline adherence. Methods: We reviewed 828 electronic records of T2DM and ASCVD patients from March 2024. Patients were grouped into combination therapy (SGLT2i and GLP1RA) and no therapy groups. Data on demographics (Table 1) and SDOH (Table 2) were analyzed. Patients on monotherapy or those who did not complete the SDOH questionnaire were excluded. Descriptive statistics were used to summarize demographics. Welch’s t-test compared continuous variables, and chi-square or Fisher’s exact tests compared categorical variables. Analyses were done with SAS 9.4 with significance at 0.05. Results: Age significantly differed between groups (t = 4.56, p < .05), with older patients less likely to receive therapy. Sex was also significant (p < .05); more females were in the no therapy group. No significant association was found between SDOH and combination therapy (p > .05). Conclusion: Over 90% of patients with T2DM and ASCVD were not on optimal medical therapy to reduce MACE, with nearly half on no medications. This highlights the need for increased awareness and targeted interventions to improve outcomes. Future research will explore insurance status and physician awareness to address prescription discrepancies. Limitations: Patients with a GFR <30 are precluded from SGLT2i usage but were not excluded from this study.

Abstract 4140116: Adherence to Lipid Lowering Therapy among US Veterans with Atherosclerotic Cardiovascular Disease

Introduction/Background: US Veterans experience a high burden of cardiovascular disease (CVD). Improved adherence to lipid-lowering therapy (LLT) is strongly associated with reducing low-density lipoprotein cholesterol (LDL-C), which has the potential to reduce morbidity and mortality among Veterans with atherosclerotic cardiovascular disease (ASCVD). Goals/Aims: To describe adherence to statin and non-statin LLT among US Veterans with ASCVD. Methods/Approach: Using Veterans’ Health Administration (VHA) electronic health records from January 1, 2003, to December 31, 2019, we identified regular users of the VHA who were on at least one LLT within 12-months after ASCVD diagnosis. ASCVD diagnosis was identified using ICD9/10 and Current Procedural Terminology codes. Medication possession ratio (MPR) was calculated as the sum of days’ supply for all fills of a given LLT during 12-, 24-, and 36-month follow-up, divided by the number of days in the follow-up period. Medication adherence was defined as MPR ≥ 0.80. Results/Data (descriptive and inferential statistics): The total number of Veterans on an LLT within 12-months after ASCVD diagnosis was 2,194,684 [mean (SD) age=68 (10) years, 98% male, and 75% white race]. Overall proportion of patients who were adherent to LLT was 68%, 64%, and 62%, at 12-, 24-, and 36-months post ASCVD diagnosis, respectively (Table). Conclusion(s): Suboptimal adherence to LLT was observed in one third of US Veterans with ASCVD. Adherence rates were highest in the first 12 months post ASCVD diagnosis. Future studies are needed to understand factors contributing to low and declining LLT adherence over time among Veterans.

Abstract 4134977: Utility of Coronary Artery Calcium Scoring in Low-Risk Patients: the Multi-Ethnic Study of Atherosclerosis (MESA)

Introduction: Coronary artery calcium (CAC) scoring is a powerful tool for atherosclerotic cardiovascular disease (ASCVD) risk assessment. Guidelines recommend consideration of CAC scoring in intermediate risk patients, but it’s utility in low and borderline risk patients is less clear. Methods: We used data from 2,894 participants from MESA with low (<5%) or borderline (5-<7.5%) 10-year ASCVD risk defined by the pooled cohort equations (PCE). We evaluated the association between CAC score and coronary heart disease (CHD) and ASCVD risk using multivariable adjusted Cox proportional hazard models. We also evaluated if the addition of CAC to the pooled cohort equations (PCE) improved risk prediction using Harrell’s C-index and net reclassification improvement (NRI). Results/Data: Mean age was 54.1 ± 5.8 years with 66.9% women. Among low-risk individuals, the ASCVD event rate was 3.3% with CAC=0, and 7.8% with CAC>0, and 4.7% vs. 11.4% among borderline-risk individuals. Natural-log transformed CAC score was associated with increased ASCVD risk in low-risk (HR 1.35, 95% CI 1.22-1.50) and borderline-risk (HR 1.29, 95% CI 1.15-1.45) individuals. Similar results were seen for CHD with higher HRs ( Table 1 ). The addition of CAC to the PCE improved the C-index (SE) among low/borderline risk individuals from 0.620 (0.023) to 0.671 (0.024). Continuous NRI was also significant with the addition of CAC to the PCE in low/borderline risk (0.422, 95% CI 0.248-0.611). Greater improvement was seen for CHD ( Table 2 ). Conclusions: The presence of CAC in low and borderline risk individuals is associated with increased ASCVD and CHD risk. The addition of CAC scoring to the PCE improved risk prediction in low and borderline risk individuals, suggesting potential clinical utility in this population.

Abstract 4136716: Frailty and Malnutrition Predict Mortality in Older Adults with Atherosclerotic Cardiovascular Disease

Background: Frailty and malnutrition are related geriatric syndromes but it remains unknown if both provide independent prognostic information in older adults with atherosclerotic cardiovascular disease (ASCVD). Aims: We compared the prognostic value of combined frailty and malnutrition assessment with either parameter alone in predicting all-cause mortality. Methods: We analyzed 719 older adults (>70 years old) with prevalent ASCVD from visit-6 of the Atherosclerosis Risk in Communities Study. ASCVD was defined as prevalent coronary heart disease, stroke, or history of MI at visit-6. Malnutrition was assessed using the geriatric nutritional risk index (score <98), and physical frailty was determined using the Fried frailty phenotype. Participants were categorized as high-risk if both frail and malnourished, intermediate-risk if frail or malnourished, and low-risk if neither. Cox regression and model performance metrics were used to assess frailty, malnutrition, and their combination, both alone and in conjunction with a base model. Results: The mean age of the cohort was 80.5±4.5 years and 39.4% were women. A total of 67.2% had frailty, 13.4% had malnutrition and 11.1% had both. Median follow-up was 580 days with 61 mortality events. Compared to low-risk adults, intermediate-risk (2.3 [1.04-5.0], p=0.039) and high-risk (OR 3.1 [95% CI 1.1-8.5], p=0.027) adults had significantly higher adjusted risk of mortality (Figure). In contrast, frailty or malnutrition alone were not statistically significant predictors after multivariable adjustment. Addition of the combined risk to the base model led to a modest increase in the c-index compared to the malnutrition model (0.668 vs. 0.647) but not the frailty model (0.668 vs 0.667). There was no significant improvement in reclassification or integrated discrimination index, but the combined model had superior goodness-of-fit than the frailty and malnutrition models, as demonstrated by a difference >|2.0| in the Akaike information criterion (-3.4&-13.5 respectively). Conclusion: Frailty and malnutrition are highly overlapping syndromes. Incorporation of readily available nutritional risk measures to traditional frailty assessment may improve risk prediction in older adults with ASCVD.

Abstract 4136592: Comparative performance of PREVENT and Pooled Cohort Equations to predict cardiovascular disease in multisite healthcare populations

Introduction: The American Heart Association’s race-agnostic Predicting Risk of cardiovascular EVENTs (PREVENT) framework has emerged to better capture multilevel determinants of health in contemporary population. Whether PREVENT better predicts incident atherosclerotic cardiovascular disease (ASCVD) than the preceding Pooled Cohort Equations (PCE) is unknown in healthcare populations. We evaluated calibration and discrimination of the two equations across three major U.S. healthcare networks. Methods: We retrospectively evaluated electronic health records of 209,879 individuals (Mass General Brigham [MGB]: 118,801; Mount Sinai Healthcare System: 38,834; Penn Medicine: 52,424) aged 40-79 years and without prior ASCVD between 2010-2012. Calibration was assessed using discordance ratio between 10-year observed and predicted risk. Discrimination was evaluated by Harrell’s C-index. Results: Based on PREVENT, the mean [SD] estimated 10-year ASCVD risk ranged from 5.5 [4.7] % in MGB (mean age 56y, 42% female), 6.6 [5.6]% in Mount Sinai (59y, 54% female), and 6.4 [5.2]% in Penn (60y, 55% female). PREVENT substantially underestimated empirical 10-year ASCVD incidence in MGB (16.9%) and Mount Sinai (10.9%), whereas it closely mirrored the observed rate in Penn (5.5%). Both PCE and PREVENT had comparable discrimination C-index [95% CI] across MGB (0.69 [0.69-0.70] vs. 0.69 [0.68-0.69]), Mount Sinai (0.72 [0.71-0.73] vs. 0.70 [0.70-0.71]), and Penn (0.68 [0.67-0.69] vs. 0.67 [0.66-0.68]). Nevertheless, compared to PREVENT, PCE demonstrated better overall calibration in MGB (-70% vs. -42%) and Mount Sinai (-36% vs. +5%), whereas largely overestimated risk in Penn (+3% vs +94%). Calibration varied across demographics with PREVENT consistently underestimating risk in Hispanics, Asians, Black and African Americans across all sites, whereas PCE largely overestimated risk for White or multiracial Penn healthcare patients. Conclusions: The race-agnostic PREVENT model discriminated ASCVD incidence comparably or better than the race-informed PCE across three geographically distinct academic health systems in the Northeast. However, calibration metrics between the two models varied widely across health systems and demographics.

Abstract 4131439: Routine Social Isolation Screening Among Adults with Cardiovascular Disease: A Survival Analysis

Background: Evidence linking social isolation to cardiovascular disease morbidity and mortality has grown in recent years. Still, information on how this may manifest in real world settings and its implications for screening practices is limited. In 2019, our large national integrated health care system implemented screening for social isolation as part of a broader universal social risk assessment. This repository of screening data was joined to administrative claims to test these associations in real world data and explore differences by demographic and medical factors. Methods: Social isolation responses recorded from 2019-2022 were included for a cohort of adult health plan members with documented atherosclerotic cardiovascular disease (ASCVD). We selected a single random assessment for each member and retained any other responses for sensitivity analyses. Cohort members had at least 10 months of enrollment surrounding assessment date for use as the baseline period and were followed for 365 days. We used cox proportional hazards regression with right censoring for coverage gaps to estimate the risk of all-cause mortality conferred by social isolation. We used Poisson regression to model the rate of inpatient stays. Results: There were 881 deaths among 7,484 members (18% of those with social isolation; 11% of those without). The isolated group skewed less male (54% vs. 65%, p <0.001) and older (68.4 [SD 12.7] vs. 67.5 [SD 12.6] years, p <0.05) than those not isolated. At baseline, the isolated group had higher rates of mean inpatient stays (2.3 [SD 1.9] vs. 1.9 [SD 1.6], p <0.001), ED visits (1.2 [SD 1.9] vs. 0.9 [SD 1.6], p < 0.001), and smoking (50% vs. 44%, p < 0.05), and a higher mean Charlson Comorbidity Index (CCI) (3.6 [SD 2.6] vs. 3.0 [SD 2.4], p < 0.001). Adjusted survival models suggested an independent 33% increase in all-cause mortality risk among those screening positive for social isolation (1.33 HR 95% CI 1.10, 1.62). Adjusted Poisson models found a similar increase in inpatient stays (1.36 IRR 95% CI 1.14, 1.62). Conclusions: Our findings corroborate the association between social isolation and morbidity and mortality among those with known ASCVD. The effect for social isolation was similar in magnitude to clinical comorbidities and smoking, suggesting that routine screening for social isolation may provide valuable information for assessing and managing the risk of death among patients with ASCVD.