Atherosclerotic Cardiovascular Disease Events Research Articles

Abstract 18584: Predictive Accuracy Of The Pooled Cohort Equations For Estimating Atherosclerotic Cardiovascular Disease Risk Among Women Exposed To Potentially Cardiotoxic Breast Cancer Therapies

Introduction: Risk estimation is a critical component in clinical decision making for preventive cardiovascular care. Suboptimal identification and management of cardiovascular disease (CVD) risk, may contribute to excess CVD morbidity and mortality among breast cancer (BC) patients and survivors. This study aimed to assess the performance of the Pooled Cohort Equations (PCEs) in predicting atherosclerotic cardiovascular disease (ASCVD) events among a real-world population of adult women treated for BC. Methods: Using electronic medical record data collected between Jan. 1, 2011 and Jan. 31, 2023, this external validation study retrospectively identified a cohort of BC women, age 40-79, without history of ASCVD in the one year prior to initiation of a potentially cardiotoxic BC therapy. For all cohort members with cholesterol and blood pressure measurements recorded within one year prior to the index cancer therapy exposure (n=1,239), a 5-year ASCVD risk estimate was calculated. Predictive accuracy of the risk estimate was assessed using a Poisson model-based framework for calibration, including evaluation of calibration-in-the-large, the calibration slope, and calibration plots. To account for potential biases related to informative censoring, calibration was assessed among an inverse probability of censoring weighted (IPCW) pseudopopulation with stabilized and unstabilized weights, and a complete case cohort (n=306). Results: Among the IPCW pseudopopulation, calibration-in-the-large, expressed as a standardized incidence ratio, was 1.85 (95% CI: 1.73, 1.98), indicating that, on average, women in this subpopulation experience a significantly higher number of ASCVD events than expected from baseline PCE risk estimates. The calibration slope, estimated at 0.55 (95% CI: 0.45, 0.66), and evaluation of calibration plots, further indicate particularly poor performance of the PCEs at low and high levels of estimated risk. Findings were consistent across the assessed populations. Conclusions: When calculated prior to initiation of a potentially cardiotoxic BC therapy, the PCEs significantly underestimate 5-year ASCVD risk for BC women, indicating this commonly used ASCVD risk estimate is poorly calibrated for this subpopulation.

Abstract 16897: The Association of Lipoprotein(a) With Major Adverse Cardiovascular Events Among Individuals With and Without Baseline Atherosclerotic Cardiovascular Disease: The Mass General Brigham Lp(a) Registry

Introduction: Lipoprotein(a) [Lp(a)] is associated with increased atherosclerotic cardiovascular disease (ASCVD) events. However, whether the optimal Lp(a) threshold for risk-assessment should differ based on baseline ASCVD status is unknown. Hypothesis: To assess the association between Lp(a) and major adverse cardiovascular events (MACE) among patients with and without a history of ASCVD. Methods: Retrospective cohort of patients with Lp(a) measured at two academic medical centers in Boston, MA from 2000-2019. To assess the association of Lp(a) with incident MACE (cardiovascular mortality, myocardial infarction, or ischemic stroke), the following Lp(a) percentile groups were generated: 1 st -50 th (0 - 41 nmol/L; reference), 51 st -70 th (42 - 111 nmol/L), 71 st -90 th (112 - 215 nmol/L), 91 st -100 th (>216 nmol/L). Individuals with severe renal dysfunction or a malignant neoplasm were excluded. Cox proportional hazards modeling was used to assess the association of Lp(a) percentile group with MACE. Results: After applying eligibility criteria, 16,419 patients (median age 60, 41% female) were analyzed with a median follow up of 11.9 years. Patients with ASCVD were older and had higher rates of cardiovascular risk factors. Among the 10,181 (62%) patients with a history of ASCVD, individuals in the 71 st -90 th and 91 st -100 th percentile groups had similarly increased hazards of MACE (adjusted HR = 1.33, p<0.001 and adjusted HR = 1.34, p<0.001 respectively). Among the 6,238 individuals without baseline ASCVD, only individuals in the 91 st -100 th Lp(a) percentile group had a significantly increase hazard of MACE (adjusted HR 2.05, p<0.001), Figure . Conclusions: In a large, contemporary US cohort, elevated Lp(a) is independently associated with long-term MACE among individuals with and without baseline ASCVD. Our results suggest that the Lp(a) threshold for risk assessment may be lower in secondary prevention when compared with primary prevention.

Abstract 14720: Persistence and Adherence to Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies and Ezetimibe in Real - World Settings

Introduction: Non-statin cholesterol-lowering therapies (proprotein convertase subtilisin/kexin type 9 monoclonal antibodies [PCSK9mAb] and ezetimibe) have been shown to reduce atherosclerotic cardiovascular disease (ASCVD) events in randomized clinical trials of patients treated with statin therapy. Effectiveness in the real world, however, is contingent on treatment persistence and adherence. Aim: To estimate the proportion of patients who were on therapy, persistent and had high adherence at 365 days following the initiation of a PCSK9mAb versus ezetimibe in real-world clinical practice. Methods: We included adults initiating a PCSK9mAb (n= 16,588, 44% ≥ 65 years, 56% male, 78% with ASCVD) or ezetimibe (n=83,086, 35% ≥ 65 years, 51% male, 46% with ASCVD) from Medicare and MarketScan commercial health insurance databases between 7/2015 and 12/2019. We assessed 3 outcomes using pharmacy claims within 365 days following initiation (assessment period): 1) percentage of patients on therapy: percentage of patients with medication supply in the last 60 of 365 days following initiation; 2) persistence: not having a gap of ≥ 60 days between the last day of supply from one pharmacy claim and the next claim; 3) high adherence: having a day of supply for ≥ 80% of the 365 days. Results: Percentage on therapy, persistence, and high adherence were higher among patients on PCSK9mAb versus ezetimibe at 365 days (Table 1). When, restricted to participants who were persistent at 365 days, adherence to both PCSK9mAb and ezetimibe was high. The adjusted multivariable-adjusted risk ratio [95% CI] for percentage on therapy, persistent and having high adherence to PCSK9mAb versus ezetimibe was: 1.20 [1.18, 1.21], 1.22 [1.20, 1.24], and 1.16 [1.14, 1.18]. Conclusions: Patients initiating PCSK9mAb were more likely to be on therapy, persistent and with high adherence at 365 days compared to their counterparts who initiated ezetimibe. Funding: Amgen Inc.

Abstract 13124: Better Prognostic Value of Single Time Coronary Artery Calcium Score Over the 30-y Averaged Pooled Cohort Equation in Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study

Background: Cardiovascular disease (CVD) risk prediction in the 75-and-older population is challenging in part because traditional risk factors at older age may not reflect the risk factor profile over the life course. In this regard, coronary artery calcium (CAC) can be considered an integrated biomarker of exposure to CVD risk factors. However, the predictive value of a single time point CAC at older age vs. the cumulative exposure of traditional risk factors over three decades is unknown. Methods: In 1,875 ARIC participants (age 75-94 years) without a history of coronary heart disease (CHD), stroke, and heart failure (HF) at Visit 7 (2018-2019), we assessed the association of Visit 7 CAC vs. a weighted average of Pooled Cohort Equation (PCE) calculated 10-year atherosclerotic CVD (ASCVD) risk from Visit 1 (1987-89) to Visit 7 with the risk of ASCVD (CHD or stroke), HF, and all-cause mortality using adjusted Cox models. Risk prediction improvement was assessed using Harrel’s C-statistics. Results: The median CAC was 221 (IQI 35-743), and the median averaged PCE score was 15.0% (IQI 10.4%-21.2%). Over a median follow-up of 2.1 (IQI 1.7-2.5) years, there were 48 ASCVD events, 36 HF events, and 85 deaths. A higher CAC score was associated with a higher risk of ASCVD and HF, even after adjusting for averaged PCE (adjusted hazard ratio 3.33 [95% CI 1.53, 7.26] and 5.57 [1.95, 15.89] for CAC 1000+ vs. 0-99, respectively), but not all-cause mortality ( Table ). In contrast, averaged PCE was not associated with ASCVD or HF independent of CAC. However, averaged PCE showed robust associations with all-cause mortality. Notably, the addition of CAC to averaged PCE significantly improved risk prediction of HF, whereas adding averaged PCE to CAC did not significantly improve the risk prediction for any adverse outcome. Conclusions: The present study shows that a single time point CAC outperforms 30-y cumulative exposure of PCE for ASCVD and HF prediction in the 75-and-older population.

Abstract 13692: Incidence, Recurrence, and Ethnicity Specific Risk Factors for Premature Coronary Artery Disease in South Asians and Europeans

Introduction: Premature coronary artery disease (CAD) incidence is increasing globally. South Asians (SA) have a disproportionately high burden of atherosclerotic cardiovascular disease (ASCVD). However, the effect of SA ethnicity on the risk of recurrent events in patients with premature CAD has not been prospectively evaluated. Methods: Patients in the SAVEBC and UK biobank (UKB) registries were enrolled and stratified by ethnicity and presence of premature CAD. The co-primary outcomes were to compare proportion of premature CAD and the incidence of recurrent ASVCD events. Secondary exploratory outcomes included describing demographic, physical, biochemical variables between cohorts. Results: 11,136 patients were included, 1,129 (143 SA; 21%) were from SAVEBC and 10,007 (400 SA; 4.0%) from UKB. There was a higher proportion of premature CAD in SA compared to Caucasians in UKB (5.2% vs. 2.0%, p < 0.001). Similarly, SA were overrepresented in SAVEBC (21% of cohort vs. 7.9% of British Columbia population). SA compared to Caucasians with premature CAD had increased prevalence of diabetes (SAVEBC: 20.1% vs 13.8%, p=0.08; UKB: 37.5% vs 18.0%, p<0.001), and lower mean HDL cholesterol (SAVEBC: 1.4±0.4 vs 1.5±0.4, p=0.21; UKB: 1.1±0.3 vs 1.2±0.3, p<0.001). SA had more diffuse disease reflected by more coronary segments affected (4.9±3.0 vs. 4.1±2.6, p=0.05), and a trend towards more affected coronary vessels compared to Caucasians (1.31±1.4 vs. 0.61±0.91, p=0.14). SA had greater incidence of recurrent ASCVD vs. Caucasians (4.19 vs. 3.08 events per 100 P-Y; incidence rate ratio p-value < 0.001). SA had higher risk of recurrent ASCVD events (HR 1.35, 95% CI 1.13,1.61, p<0.001). SA ethnicity remained a predictor of recurrent events on adjusted COX regression (HR 1.24, 95% CI 1.03,1.48, p=0.02). Conclusion: Using two prospective registries, SA had a higher proportion of premature CAD and recurrent cardiovascular events with shorter time to recurrent events. Some risk may be explained by adverse cardiometabolic profiles, however significant risk mechanisms are yet to be elucidated. Understanding the unique mechanisms of cardiovascular risk in SA is critical to appropriately identify high-risk individuals and initiate contemporary preventative therapies.

Abstract 11370: Comparing Coronary Artery Cross-Sectional Area Among Asymptomatic South Asian, White, and Black Participants: The Masala and Cardia Studies

Introduction: South Asian individuals have high risk of atherosclerotic cardiovascular disease (ASCVD). Some investigators suggest smaller coronary artery size may be partially responsible. Hypothesis: We hypothesized that South Asian participants would have smaller left anterior descending artery (LAD) cross sectional area (CSA) than Black and White participants, and that this association would be attenuated after adjusting for body size (BMI and height) and cardiovascular risk factors. Methods: We compared the LAD CSA (lumen and arterial wall) among South Asians in the Mediators of Atherosclerosis in South Asians Living in America study with White and Black participants in the Coronary Artery Risk Development in Young Adults study, adjusting for BMI, height, and other ASCVD risk factors. We used thin-slice non-contrast cardiac computed tomography to measure LAD CSA. We used linear regression models to explore differences by race/ethnicity in LAD CSA after adjusting for demographic, BMI, height, coronary artery calcium (CAC), and ASCVD risk factors. Results: We included 3,353 participants: 513 South Asian (44% women), 1286 Black (60% women), and 1554 White (54% women). After adjusting for age, BMI, height, there was no difference in LAD CSA between South Asian and White participants by sex. However, South Asian participants had smaller LAD CSA compared to Black participants by sex. After full adjustment for ASCVD risk factors, LAD CSA values were: South Asian women (19.9 mm 2 , 95% CI [18.8 - 20.9]) and men (22.3 mm 2 , 95% CI [21.4 - 23.2]; White women (20.0 mm 2 , 95% CI [19.4 - 20.5]) and men (23.6 mm 2 , 95% CI [23.0 - 24.2]); and Black women (21.6 mm 2 , 95% CI [21.0 - 22.2]) and men (26.0 mm 2 , 95% CI [25.3 - 26.7]) ( Figure 1 ). Conclusions: After accounting for differences in body size, South Asian participants had smaller LAD CSA compared to Black participants, but similar to White participants. Future studies should determine whether LAD CSA is associated with future ASCVD events.

Abstract 12346: Atherosclerotic Cardiovascular Disease Risk Associated With Social Determinants of Health at Individual and Area Levels

Introduction: Adverse social determinants of health (SDOH) are associated with an increased risk for atherosclerotic cardiovascular disease (ASCVD). However, it is unclear if the ASCVD risks associated with area-level SDOH are similar to those with individual-level measures. Further, SDOH are not included in the Pooled Cohort Equations (PCEs) when estimating 10-year ASCVD risk. Studies have shown that PCEs systematically underestimate risk for socially deprived individuals. Aims To examine the association of individual- and area-level SDOH including education, income, and employment with incident ASCVD. Also, we assessed if adding SDOH to the PCEs improves risk prediction accuracy. Methods: We pooled data from four cohorts: Jackson Heart Study, Multi-Ethnic Study of Atherosclerosis, Framingham Heart Study Offspring Cohort, and Reasons for Geographic and Racial Differences in Stroke Study. We excluded participants with a history of ASCVD. Individual-level SDOH were based on participants’ self-report and area-level SDOH were derived by linking participants’ addresses to US Census tract data. We used Cox proportional hazards models to assess the associations between SDOH and ASCVD. We also assessed the changes in discrimination (Harrell’s C-index) and calibration (Integrated Brier Score) after adding SDOH to risk prediction models. Results: We analyzed data from 27,603 participants (mean age 61.4 years, 59% women, and 49% White). During a median follow-up of 13 years, 2,839 incident ASCVD events occurred. Both individual- and area-level SDOH were associated with ASCVD ( Figure, Panel A ). Adding both individual- and area-level SDOH to risk prediction modestly improved model discrimination and calibration in Black men and women ( Figure, Panels B & C ), and also improved calibration in non-Black women. Conclusions: The findings suggest that SDOH may be considered in the development of future ASCVD risk assessment tools, particularly among Black individuals.

Abstract 15944: Aspirin Use for Primary Prevention in High-Risk Patients: Insights From a Large Healthcare Network

Background: Recently, the value of routine use of aspirin in primary prevention for atherosclerotic cardiovascular disease (ASCVD) has come into question. We investigated patients with a high 10-year ASCVD risk profile to evaluate the magnitude of protection afforded by aspirin with and without statin in prevention of ASCVD events. Methods: Primary prevention patients were stratified based on 10-year ASCVD risk (High [20%]). Aspirin use was categorized over the 6-year follow-up period as “None”, “seldom” (<30% of follow up time), “sometimes” (>30 to =<70%), and often used (≥70% of the time). Cox regression models were used to assess HRs of MI, ischemic stroke and mortality with aspirin or statin use alone compared to a combination of aspirin and statin. Results: 69,955 patients qualified as “high” 10-year ASCVD risk. In fully adjusted models, aspirin use ≥ 30% was associated with significantly lower risk of MI [HR ASA use ≥ 70% 0.76 (0.72-0.80), p <0.001], ischemic stroke [HR ASA use ≥ 70% 0.83 (0.77-0.90), p <0.007], and mortality [HR ASA use ≥ 70% 0.78 (0.74-0.82), p <0.001] in high-risk patients compared to no aspirin use ( Table ). Compared to patients on both a statin and aspirin, patients on statin alone had increased risk of MI [HR 1.30 (1.06-1.60), p = 0.013]. Patients on aspirin alone had increased risk of MI [HR 1.74 (1.34-2.26), p <0.001] and mortality [HR 1.70 (1.27-2.28), p < 0.0004] versus those on aspirin and statin. Patients not on any aspirin or statin were at significantly increased risk for MI [HR 2.28 (2.08-2.49), p<0.001], ischemic stroke [HR 1.77 (1.56-2.00), p<0.001), and mortality [HR 2.16 (1.60-2.90), p<0.001] compared to those taking both aspirin and statin. Conclusions: Low dose aspirin may still have a role in primary prevention of ASCVD events amongst high-risk patients when added to statin therapy. Risk-benefit profile of each high-risk primary prevention patient should be assessed for initiating or discontinuing low dose aspirin therapy

Abstract 17498: Association Between 5-Year Change in Cardiovascular Risk and Atherosclerotic Cardiovascular Disease Incidence: A Multicohort Study

Introduction: Early measurement of atherosclerotic cardiovascular disease (ASCVD) risk factors contains valuable information about an individual's risk history. Hypothesis: Individuals with different historical cardiovascular risk statuses have varied risks of future ASCVD incidence. Methods: We analyzed pooled data from 7 community-based prospective cohort studies with up to 20-year follow-ups ( panel A ). White or Black participants aged 40-75 years without prevalent ASCVD were included. Cardiovascular risk was assessed using the pooled cohort equation and was categorized into non-high (<20%) or high risk (≥20%). Changes in CVD risk over a 5-year interval were considered. The main outcome is incident ASCVD. Results: Among 11026 participants (mean [SD] age,60.0 [8.1] years). 4272 (38.7%) were female and 3127 (28.4%) were Black. During a median follow-up of 9.9 years, 2560 (23.2%) ASCVD events occurred. Compared to individuals with consistently high risk, participants with non-high to high risk (HR 0.67; 95%CI 0.59-0.77), high to non-high risk (HR 0.57; 95%CI 0.41-0.80), and consistently non-high risk (HR 0.33; 95%CI 0.29-0.37) had a lower risk of incident ASCVD. Compared to individuals with consistently non-high risk, participants with high to non-high risk (HR 1.74; 95%CI 1.26-2.41), non-high to high risk (HR 2.04; 95%CI 1.84-2.27), and consistently high risk (HR 3.03; 95%CI 2.69-3.42) had an increased risk of incident ASCVD ( panel B ). Conclusions: Changes in the CVD risk status over time inform dissimilar ASCVD risk than a single risk assessment. Dynamic risk evaluation might enable more accurate cardiovascular risk stratification and decision on preventive interventions should take historical risk status into account.

Genome-Wide Association Study of Cardiovascular Resilience Identifies Protective Variation in the CETP Gene.

Background The risk of atherosclerotic cardiovascular disease (ASCVD) increases sharply with age. Some older individuals, however, remain unaffected despite high predicted risk. These individuals may carry cardioprotective genetic variants that contribute to resilience. Our aim was to assess whether asymptomatic older individuals without prevalent ASCVD carry cardioprotective genetic variants that contribute to ASCVD resilience. Methods and Results We performed a genome-wide association study using a 10-year predicted ASCVD risk score as a quantitative trait, calculated only in asymptomatic older individuals aged ≥70 years without prevalent ASCVD. Our discovery genome-wide association study of N=12 031 ASCVD event-free individuals from the ASPREE (Aspirin in Reducing Events in the Elderly) trial identified 2 independent variants, rs9939224 (P<5×10-8) and rs56156922 (P<10-6), in the CETP (cholesteryl ester transfer protein) gene. The CETP gene is a regulator of plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and lipoprotein(a) levels, and it is a therapeutic drug target. The associations were replicated in the UK Biobank (subpopulation of N=13 888 individuals aged ≥69 years without prevalent ASCVD). Carriers of the identified CETP variants (versus noncarriers) had higher plasma high-density lipoprotein cholesterol levels, lower plasma low-density lipoprotein cholesterol levels, and reduced risk of incident ASCVD events during follow-up. Expression quantitative trait loci analysis predicted the identified CETP variants reduce CETP gene expression across various tissues. Previously reported associations between genetic CETP inhibition and increased risk of age-related macular degeneration were not observed among the 3917 ASPREE trial participants with retinal imaging and genetic data available. Conclusions Common genetic variants in the CETP gene region are associated with cardiovascular resilience during aging. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583.

Validation of the Framingham General Cardiovascular Risk Score and Pooled Cohort Equations in a Community-Based Population: A Prospective Cohort Study Analysis 2006-2017.

The 10-year atherosclerotic cardiovascular disease (ASCVD) risk - as assessed using the Framingham general cardiovascular risk score (FRS-CVD) or pooled cohort equations (PCE) - is commonly used in Western cohorts for the primary prevention of cardiovascular disease (CVD). However, the FRS-CVD and PCE have not been validated in Taiwanese cohorts. We aimed to validate the FRS-CVD and PCE for assessing the 10-year ASCVD risk using a Taiwanese community-based population. We extracted patient data from the Landseed Integrated Outreaching Neighborhood Screening registry, a community-based prospective cohort study established in 2006. Cardiovascular events from 2006 to 2017 were determined from electronic medical records. The discriminative power and calibration of the FRS-CVD and PCE were evaluated. Overall, 5,139 subjects were analyzed; the 10-year follow-up rate was 99.6%. The mean age at baseline was 52.8 ± 13.1 years, and 44.6% of the subjects were male. In total, 430 of 4,631 (9.3%) and 227 of 4,022 (5.6%) of the FRS-CVD- and PCE-like cohorts, respectively, had ASCVD events. The calibration χ2 of the FRS-CVD was 7.0267 (p = 0.6343) in males and 7.8845 (p = 0.5458) in females; the χ2 of PCE was 13.007 (p = 0.1623) in males and 38.785 (p < 0.001) in females. The area under the receiver operating characteristic curve (AUROC) of the FRS-CVD was 0.76 (0.72-0.79) in males and 0.71 (0.67-0.74) in females; the AUROC of PCE was 0.68 (0.62-0.73) in males and 0.61 (0.56-0.67) in females. Except for PCE in females, the FRS-CVD and PCE provided good calibration and modest discrimination in statin-naïve Taiwanese individuals without prior CVD.

Social disadvantage, coronary artery calcium, and their interplay in the prediction of atherosclerotic cardiovascular disease events

Background and aimsSocial determinants of health (SDOH) are key for the identification of populations at increased risk of atherosclerotic cardiovascular disease (ASCVD). However, whether at the individual level SDOH improve current ASCVD risk prediction paradigms beyond traditional risk factors and the coronary artery calcium (CAC) score, is unknown. We evaluated the interplay between CAC and SDOH in ASCVD risk prediction. MethodsMESA is a prospective study of US adults free of clinical ASCVD at baseline. We used an SDOH index inclusive of 14 determinants from 5 domains. The index ranged 0–1 and was divided into quartiles, with higher ones representing worse SDOH. Cox regression was used to evaluate the adjusted associations between CAC, SDOH, their interplay, and ASCVD events. The C-statistic was computed to assess improvement in risk discrimination for prediction of ASCVD events. ResultsWe included 6479 MESA participants (50% with CAC = 0, 24% CAC>100). ASCVD incidence increased with increasing CAC scores across SDOH quartiles. The lowest incidence was noted in those with CAC = 0 and favourable SDOH (2/1000 person-years) and highest in those with CAC>100 and most unfavourable SDOH (20.6/1000 person-years). While CAC was strongly associated with ASCVD across SDOH quartiles, SDOH was weakly associated with ASCVD across CAC strata. CAC improved the discriminatory ability of all prediction models beyond traditional risk factors, the improvement in C-statistic ranging +0.02 - +0.05. Improvements with SDOH were smaller, and were none on top of CAC. ConclusionsCAC improves ASCVD risk stratification across the spectrum of social vulnerability, while SDOH fail to improve risk prediction beyond traditional RFs and CAC.

Serum proteomic profiling of carotid arteriopathy: A population outcome study

Background and aimsCirculating proteins reflecting subclinical vascular disease may improve prediction of atherosclerotic cardiovascular disease (ASCVD). We applied feature selection and unsupervised clustering on proteomic data to identify proteins associated with carotid arteriopathy and construct a protein-based classifier for ASCVD event prediction. Methods491 community-dwelling participants (mean age, 58 ± 11 years; 51 % women) underwent carotid ultrasonography and proteomic profiling (CVD II panel, Olink Proteomics). ASCVD outcome was collected (median follow-up time: 10.2 years). We applied partial least squares (PLS) to identify proteins linked to carotid intima-media thickness (cIMT). Next, we assessed the association between future ASCVD events and protein-based phenogroups derived by unsupervised clustering (Gaussian Mixture modelling) based on proteins selected in PLS. ResultsPLS identified 19 proteins as important, which were all associated with cIMT in multivariable-adjusted linear regression. 8 of the 19 proteins were excluded from the clustering analysis because of high collinearity. Based on the 11 remaining proteins, the clustering algorithm subdivided the cohort into two phenogroups. Compared to the first phenogroup (n = 177), participants in the second phenogroup (n = 314) presented: i) a more unfavorable lipid profile with higher total cholesterol and triglycerides and lower HDL cholesterol (p ≤ 0.014); ii) higher cIMT (p = 0.0020); and iii) a significantly higher risk for future ASCVD events (multivariable-adjusted hazard ratio (95 % CI) versus phenogroup 1: 2.05 (1.26–3.52); p = 0.0093). The protein-based phenogrouping supplemented ACC/AHA 10-year ASCVD risk scoring for prediction of a first ASCVD event. ConclusionsFocused protein-based phenogrouping identified individuals at high risk for future ASCVD and may complement current risk stratification strategies.

Performance of the ACC/AHA Pooled Cohort Cardiovascular Risk Equations in Clinical Practice

BackgroundThe performance of the American College of Cardiology/American Heart Association pooled cohort equation (PCE) for atherosclerotic cardiovascular disease (ASCVD) in real-world clinical practice has not been evaluated extensively. ObjectivesThe goal of this study was to test the performance of PCE to predict ASCVD risk in the community, and determine if including individuals with values outside the PCE range (ie, age, blood pressure, cholesterol) or statin therapy initiation over follow-up would significantly affect PCE predictive capabilities. MethodsThe PCE was validated in a community-based cohort of consecutive patients who sought primary care in Olmsted County, Minnesota, between 1997 and 2000, followed-up through 2016. Inclusion criteria were similar to those of PCE derivation. Patient information was ascertained by using the record linkage system of the Rochester Epidemiology Project. ASCVD events (nonfatal and fatal myocardial infarction and ischemic stroke) were validated in duplicate. Calculated and observed ASCVD risk and c-statistics were compared across predefined groups. ResultsThis study included 30,042 adults, with a mean age of 48.5 ± 12.2 years; 46% were male. Median follow-up was 16.5 years, truncated at 10 years for this analysis. Mean ASCVD risk was 5.6% ± 8.73%. There were 1,555 ASCVD events (5.2%). The PCE revealed good performance overall (c-statistic 0.78) and in sex and race subgroups; it was highest among non-White female subjects (c-statistic 0.81) and lowest in White male subjects (c-statistic 0.77). Out-of-range values and initiation of statin medication did not affect model performance. ConclusionsThe PCE performed well in a community cohort representing real-world clinical practice. Values outside PCE ranges and initiation of statin medication did not affect performance. These results have implications for the applicability of current strategies for the prevention of ASCVD.

Economic burden of atherosclerotic cardiovascular disease: a matched case–control study in more than 450,000 Swedish individuals

AimTo examine direct and indirect costs, early retirement, cardiovascular events and mortality over 5 years in people with atherosclerotic cardiovascular disease (ASCVD) and matched controls in Sweden.MethodsIndividuals aged ≥ 16 years living in Sweden on 01 January 2012 were identified in an existing database. Individuals with ASCVD were propensity score matched to controls without ASCVD by age, sex and educational status. We compared direct healthcare costs (inpatient, outpatient and drug costs), indirect costs (resulting from work absence) and the risk of stroke, myocardial infarction (MI) and early retirement.ResultsAfter matching, there were 231,417 individuals in each cohort. Total mean per-person annual costs were over 2.5 times higher in the ASCVD group versus the controls (€6923 vs €2699). Indirect costs contributed to 60% and 67% of annual costs in the ASCVD and control groups, respectively. Inpatient costs accounted for ≥ 70% of direct healthcare costs. Cumulative total costs over the 5-year period were €32,011 in the ASCVD group and €12,931 in the controls. People with ASCVD were 3 times more likely to enter early retirement than controls (hazard ratio [HR] 3.02 [95% CI 2.76–3.31]) and approximately 2 times more likely to experience stroke (HR 1.83 [1.77–1.89]) or MI (HR 2.27 [2.20–2.34]).ConclusionASCVD is associated with both economic and clinical impacts. People with ASCVD incurred considerably higher costs than matched controls, with indirect costs resulting from work absence and inpatient admissions being major cost drivers, and were also more likely to experience additional ASCVD events.

The Role of Triglyceride-rich Lipoproteins and Their Remnants in Atherosclerotic Cardiovascular Disease.

Atherosclerotic cardiovascular disease (ASCVD) is the world's leading cause of death. ASCVD has multiple mediators that therapeutic interventions target, such as dyslipidaemia, hypertension, diabetes and heightened systemic inflammatory tone, among others. LDL cholesterol is one of the most well-studied and established mediators targeted for primary and secondary prevention of ASCVD. However, despite the strength of evidence supporting LDL cholesterol reduction by multiple management strategies, ASCVD events can still recur, even in patients whose LDL cholesterol has been very aggressively reduced. Hypertriglyceridaemia and elevated levels of triglyceride-rich lipoproteins (TRLs) may be key contributors to ASCVD residual risk. Several observational and genetic epidemiological studies have highlighted the causal role of triglycerides within the TRLs and/or their remnant cholesterol in the development and progression of ASCVD. TRLs consist of intestinally derived chylomicrons and hepatically synthesised very LDL. Lifestyle modification has been considered the first line intervention for managing hypertriglyceridaemia. Multiple novel targeted therapies are in development, and have shown efficacy in the preclinical and clinical phases of study in managing hypertriglyceridaemia and elevated TRLs. This comprehensive review provides an overview of the biology, pathogenicity, epidemiology, and genetics of triglycerides and TRLs, and how they impact the risk for ASCVD. In addition, we provide a summary of currently available and novel emerging triglyceride-lowering therapies in development.

A-203 An Equation based on the Standard Lipid Panel for Calculating Low-Density Lipoproteins-Triglycerides

Abstract Background There is growing evidence that low-density lipoprotein-triglyceride (LDL-TG) may be a better biomarker to define atherosclerotic cardiovascular disease (ASCVD) risk than LDL-cholesterol (LDL-C), which is currently used to stratify risk and as a treatment goal. Because LDL-TG typically requires additional advanced lipid testing, we developed an equation for estimating LDL-TG (eLDL-TG) from the results of the standard lipid panel. Methods Results from a general dyslipidemic population (N = 40 202), which were obtained with beta-quantification (BQ) reference method, were randomly divided into a training and validation datasets and used to develop the equation for estimating LDL-TG shown in Fig. 1A. Association of Sampson-NIH-LDL-C (NIH-LDL-C) and eLDL-TG with ASCVD risk markers was done in the National Heart and Nutrition Examination Survey (NHANES) (N = 37 053) and with ASCVD events in the Atherosclerosis Risk in Communities (ARIC) study (N = 14 749). Results The comparison between eLDL-TG and measured LDL-TG was only modest (R2 = 0.601, slope = 0.611), but eLDL-TG (Fig. 1B) showed better risk stratification than NIH-LDL-C (Fig. 1C) by survival curve analysis in ARIC. Moreover, receiver-operating characteristic (ROC) analysis showed that eLDL-TG was better than all other lipid-marker tests for ASCVD events (AUC: eLDL-TG = 0.633, HDL-C = 0.627, sdLDL-C = 0.621, remnant-cholesterol = 0.613, NonHDL-C = 0.613, TG = 0.603, apoB = 0.598, NIH-LDL-C = 0.590, TC = 0.568). In NHANES, eLDL-TG was more strongly associated with hypertriglyceridemia, obesity, diabetes, metabolic syndrome and increased high-sensitivity C-reactive protein than NIH-LDL-C. Inclusion of eLDL-TG in a Cox-Proportional Hazards Model along with other conventional risk factors (age, sex, race, diabetes, systolic blood pressure, smoking, HDL-C, and total cholesterol) did not further improve risk prediction. Conclusions Like LDL-C, LDL-TG can also be estimated from the results of the standard lipid panel. It is a better univariate risk marker than LDL-C and hence can be useful for initial ASCVD risk stratification.

A-205 Optimized Time Interval for the Measurement of Plasma Lipids for Assessing Cardiovascular Disease Risk

Abstract Background The measurement of plasma lipids are used to predict atherosclerotic cardiovascular disease (ASCVD) risk and for the management of lipid-lowering therapy. The general recommendation is that plasma lipids should be measured at least every 5 years, but the ideal time may vary depending on the baseline risk, which we examined in this study. Methods Using lipid values and other risk factors from the National Health and Nutrition Examination Survey (NHANES) (no diabetes, no lipid medications, n = 9704), which is designed to be representative of the US-general population, we calculated a baseline 10-year ASCVD risk with the pooled cohort risk equations (PCE). Future 10-year risk scores were estimated by chronologically increasing age of the subjects and projecting future systolic blood pressure (SBP) and lipid changes, using the mean-percentile age group change in the NHANES population for SBP (no hypertension medications, n = 17 329) and the Lifelines Cohort study for lipids (no CVD or lipid medications, n = 133 540). Crossing high-risk (&amp;gt;20%/10-years; 25% decison limit) and intermediate risk (&amp;gt;7.5%/10-years; 50% decision limit) PCE thresholds were calculated by baseline age to determine the best time intervals for testing lipids. Results As shown in the figure, the likelihood of crossing the intermediate or high-risk threshold depends on the baseline risk. Individuals that are close to one of the risk thresholds are more likely to cross it in the subsequent years. Based on this analysis, we recommend the following time intervals for lipid testing: Baseline risk &amp;lt; 5%/10-year: 5-years, baseline risk 5–15%/10-year: 3-years, baseline risk 16–20%/10-year: 1–2 years. Conclusions More frequent lipid testing than once every 5 years is desirable, because it would identify at risk patients sooner and allow for earlier therapeutic intervention, which has been shown to increase the effectiveness of statin therapy for reducing ASCVD events.

PCSK9 inhibition in atherosclerotic cardiovascular disease.

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) represent a novel class of hypolipidemic drugs, providing an additional therapeutic option over conventional hypolipidemic treatments. Given the constantly lowering recommended LDL-C goals, low goal achievement rate and low compliance with treatment, new hypolipidemic drug classes may substantially contribute to residual risk reduction for atherosclerotic cardiovascular disease (ASCVD). This review aims to summarize contemporary evidence on the clinical role of PCSK9i in ASCVD prevention. PubMed and MEDLINE databases were searched for keywords in studies on PCSK9i and ASCVD. Approved PCSK9i are the monoclonal antibodies (Mabs), evolocumab and alirocumab, targeting PCSK9, and inclisiran, a small interfering RNA inhibiting PSCK9 synthesis. Overall, PCSK9i effectively reduced LDL-C and other atherogenic lipoproteins, including apolipoprotein B and lipoprotein(a) primarily. PSCK9i Mabs improved imaging markers reflecting coronary atherosclerotic plaque vulnerability and reduced ASCVD events in high-risk patients after short-term treatment ( < 3 years follow-up). They are currently indicated as a third-line treatment for secondary prevention and primary prevention in patients with familial hypercholesterolemia at high risk of not achieving their LDL-C goals. Patients with higher baseline ASCVD risk receive greater benefits from PCSK9i. Recent evidence suggests that evolocumab was effective and safe after long-term treatment. Ongoing trials investigate new therapeutic indications for PCSK9i while their cost-effectiveness is still being considered. PCSK9i is a novel hypolipidemic drug class currently indicated for reducing residual risk in secondary ASCVD prevention and high-risk patients.

Association between 5-year change in cardiovascular risk and the incidence of atherosclerotic cardiovascular diseases: a multi-cohort study

BackgroundThe influence of the historical cardiovascular risk status on future risk of atherosclerotic cardiovascular disease (ASCVD) is poorly understood. We aimed to investigate the association between 5-year changes in cardiovascular risk and ASCVD incidence.MethodsWe analyzed pooled data from seven community-based prospective cohort studies with up to 20 years of follow-up data. The study populations included White or Black participants aged 40–75 years without prevalent ASCVD. Cardiovascular risk was assessed using the pooled cohort equation and was categorized into non-high (< 20%) or high risk (≥ 20%). Changes in cardiovascular disease (CVD) risk over a 5-year interval were recorded. The main outcome was incident ASCVD.ResultsAmong 11,026 participants (mean [SD] age, 60.0 [8.1] years), 4272 (38.7%) were female and 3127 (28.4%) were Black. During a median follow-up period of 9.9 years, 2560 (23.2%) ASCVD events occurred. In comparison with individuals showing a consistently high CVD risk, participants whose CVD risk changed from non-high to high (hazard ratio [HR], 0.67; 95% confidence interval [CI] 0.59–0.77) or high to non-high (HR, 0.57; 95% CI 0.41–0.80) and those with a consistently non-high risk (HR, 0.33; 95% CI 0.29–0.37) had a lower risk of incident ASCVD. In comparison with individuals showing a consistently non-high CVD risk, participants whose CVD risk changed from high to non-high (HR, 1.74; 95% CI 1.26–2.41) or from non-high to high risk (HR, 2.04; 95% CI 1.84–2.27) and those with a consistently high risk (HR 3.03; 95% CI 2.69–3.42) also showed an increased risk of incident ASCVD.ConclusionsIndividuals with the same current CVD risk status but different historical CVD risks exhibited varying risks of future ASCVD incidents. Dynamic risk evaluation may enable more accurate cardiovascular risk stratification, and decision-making regarding preventive interventions should take the historical risk status into account.Graphical