Atherosclerotic Cardiovascular Disease Risk Research Articles

Zerlasiran—A Small-Interfering RNA Targeting Lipoprotein(a)

ImportanceElevated lipoprotein(a) increases the risk of atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis.ObjectiveTo evaluate the effects of zerlasiran, a small-interfering RNA targeting hepatic synthesis of apolipoprotein(a), on lipoprotein(a) serum concentration.Design, Setting, and ParticipantsA multicenter trial in patients with stable ASCVD with serum lipoprotein(a) concentrations greater than or equal to 125 nmol/L at 26 sites in Europe and South Africa between January 3, 2023, and April 27, 2023, with last follow-up on July 1, 2024.InterventionsParticipants randomized to receive a subcutaneous dose of placebo every 16 weeks for 3 doses (n = 23) or every 24 weeks for 2 doses (n = 24) or zerlasiran 450 mg every 24 weeks for 2 doses (n = 45), 300 mg every 16 weeks for 3 doses (n = 42), or 300 mg every 24 weeks for 2 doses (n = 44).Main Outcome and MeasuresThe primary outcome was the time-averaged percent change in lipoprotein(a) concentration from baseline to 36 weeks, with follow-up to 60 weeks.ResultsAmong 178 patients, mean (SD) age was 63.7 (9.4) years, 46 (25.8%) were female, with a median (IQR) baseline lipoprotein(a) concentration of 213 (177-282) nmol/L; 172 patients completed the trial. Compared with the pooled placebo group, the least-squares mean time-averaged percent change in lipoprotein(a) concentration from baseline to week 36 was −85.6% (95% CI, −90.9% to −80.3%), −82.8% (95% CI, −88.2% to −77.4%), and −81.3% (95% CI, −86.7% to −76.0%) for the 450 mg every 24 weeks, 300 mg every 16 weeks, and 300 mg every 24 weeks groups, respectively. Median (IQR) percent change in lipoprotein(a) concentration at week 36 was −94.5% (−97.3% to −84.2%) for the 450 mg every 24 weeks group, −96.4% (−97.7% to −92.3%) for the 300 mg every 16 weeks group, and −90.0% (−93.7% to −81.3%) for the 300 mg every 24 weeks group. The most common treatment-related adverse effects were injection site reactions, with mild pain occurring in 2.3% to 7.1% of participants in the first day following drug administration. There were 20 serious adverse events in 17 patients, none considered related to the study drug.ConclusionsZerlasiran was well-tolerated and reduced time-averaged lipoprotein(a) concentration by more than 80% during 36 weeks of treatment in patients with ASCVD.Trial RegistrationClinicalTrials.gov Identifier: NCT05537571

Smoking cessation and atherosclerotic cardiovascular events and mortality in chronic kidney disease.

Smoking cessation is recommended to reduce excess atherosclerotic cardiovascular disease (ASCVD) and mortality in patients with chronic kidney disease (CKD). However, this recommendation is largely based on observational studies on the general population Therefore, we aimed to evaluate the association of smoking dose and smoking cessation duration with ASCVD and mortality in patients with CKD. We compiled a comprehensive pooled dataset comprising 66 245 participants with CKD from the KNOW-CKD and the UK Biobank cohort. Additionally, we included 307 353 participants without CKD from the UK Biobank cohort. Participants were categorized according to smoking dose and duration of smoking cessation base on a questionnaire. The primary outcome was a composite of ASCVD events or all-cause mortality. Over a median follow-up period of 13.2 years, 14 671 (22.1%) participants reached the primary outcome. In the pooled CKD cohort, compared to never smokers, former and current smokers exhibited a 1.30- and 2.14-fold higher risk of the primary outcome, respectively. Among former smokers, the hazard ratios (HRs) (95% confidence intervals [CIs]) for smoking loads<20 and≥20 pack-years were 1.05 (1.00-1.10) and 2.14 (2.05-2.25), respectively. The increased risk of the primary outcome was attenuated by longer smoking cessation. The HRs (95% CIs) for smoking cessation of<10 years, 10-20 years, and≥20 years were 1.75 (1.65-1.86), 1.43 (1.34-1.52), and 1.11 (1.06-1.16), respectively, compared with never smokers. This association was also observed in individuals without CKD, but the risk was comparable between former smokers with smoking cessation≥20 years and non-smokers, suggesting that a longer cessation is required in patients with CKD to offset the smoking-related adverse effects. Among former smokers with CKD, the risk of ASCVD or mortality was substantially attenuated with less smoking load and a longer duration of smoking cessation.

Effectiveness of treat-to-target cholesterol-lowering interventions on cardiovascular disease and all-cause mortality risk in the community-dwelling population: a target trial emulation.

Little is known about the long-term effectiveness of risk-based treat-to-target cholesterol-lowering interventions on cardiovascular risk. Here, we show the emulated effectiveness of guideline-recommended low-density and non-high-density lipoprotein cholesterol-lowering interventions using the absolute risk reduction (ARR) and the restricted mean event-free time-based number needed to treat (NNT). With 5,375 participants, the 29-year risks for cardiovascular disease (CVD), all-cause mortality, and atherosclerotic CVD were 18.6%, 25.6%, and 17.7%, respectively. Long-term treat-to-target interventions showed significant reductions in CVD (ARR -2.3%, 95%CI -3.4% to -0.8%; NNT 115), all-cause mortality (-3.0%, -4.3% to -1.8%; 95), and atherosclerotic CVD (-2.6%, -3.5% to -1.2%; 104). Such effects appear more pronounced in women, smokers, and those with body mass index < 24 kg/m² or higher adherence rates.

The Emerging Potential of Apolipoprotein C-III Inhibition for ASCVD Prevention: A State-of-the-Art Review.

Multiple agents are being developed that inhibit apolipoprotein (apo) C-III. This state-of-the-art review examines their potential for atherosclerotic cardiovascular disease (ASCVD) risk reduction. Apo C-III, an apolipoprotein on the surface of triglyceride-rich lipoproteins (TRLs), impairs clearance of TRLs through both lipoprotein lipase dependent and independent pathways, thereby resulting in increased concentrations of triglycerides. Apo C-III has also been shown to have pro-atherogenic effects when bound to high-density lipoprotein (HDL) particles. Classical and genetic epidemiology studies provide support for the concept that apo C-III is associated with an increased risk of ASCVD events. Drug efficacy of agents that silence APOC3 mRNA has been studied in populations with varying hypertriglyceridemia severity, including those with familial chylomicronemia syndrome, multifactorial chylomicronemia syndrome/severe hypertriglyceridemia, and mixed hyperlipidemia. Randomized controlled trials have reported significant reductions in TG and non-HDL cholesterol levels among these patients treated with APOC3 inhibitors. Upcoming clinical outcomes trials seek to establish a role for APOC3 inhibitors to reduce risk of ASCVD.

Use of Aspirin and Initial Cardiovascular and Bleeding Risk in Patients with Chronic Kidney Disease

Background: Despite the high cardiovascular risk in patients with chronic kidney disease (CKD), the role of aspirin in primary prevention remains unclear. This study aimed to investigate the association between aspirin initiation in adults with CKD without prior cardiovascular disease (CVD) and the first cardiovascular and bleeding events using Korean nationwide cohort data. Methods: Among individuals aged 40–79 years with an estimated glomerular filtration rate between 15 and 59 mL/min/1.73 m2 who underwent routine health examinations between 2011 and 2016, 15,861 individuals who were newly prescribed aspirin at a dose of 100 mg/day were matched with 79,305 aspirin non-users by propensity score matching. The primary efficacy outcome was a composite of nonfatal atherosclerotic CVD or cardiovascular death. The primary safety outcome was hospitalization due to intracranial or gastrointestinal bleeding. Results: During a mean follow-up of 6.9±2.9 years, the incidence rates for the primary efficacy outcome in aspirin users and non-users were 8.0 and 9.0 per 1,000 person-years, respectively. Aspirin therapy initiation was not associated with the primary efficacy outcome (hazard ratio [HR], 0.93; 95% confidence intervals [CI], 0.86-1.04). However, the primary safety outcome of major bleeding was more frequent in aspirin users than in non-users (6.7 versus 4.7 per 1,000 person-years). The HR for this outcome in aspirin users versus non-users was 1.45 (95% CI, 1.32-1.59). Conclusions: No association was observed between aspirin use and the risk of nonfatal atherosclerotic CVD or cardiovascular death in patients with CKD stages G3 and G4 without prior CVD. Aspirin use was associated with higher risk of major bleeding.

Factors associated with lipid lowering therapy in the multi-ethnic study of atherosclerosis.

Lipid-lowering therapy (LLT) plays a central role in managing atherosclerotic cardiovascular disease (ASCVD) risk, but its underuse is reported in over 40% of the qualified population in the United States. Studies on factors, particularly actionable factors associated with guideline-directed LLT are limited. This study evaluated participants from the Multi-Ethnic Study of Atherosclerosis (MESA) on their qualification for LLT at exam 5 (2010-2012) according to the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guideline on cholesterol management. Participants were categorized as on-LLT or off-LLT at the following exam (2016-2018). Multi-variable relative risk (RR) models were used to analyze between LLT usage and factors prior to 2013, including age, gender, race/ethnicity, education level and medical insurance, income, smoking, body mass index (BMI), diabetes, hypertension, and presence of coronary artery calcium (CAC). Among the 2114 participants qualified for LLT at exam 5 with an average age of 70.7, 1,129 (53.4%) were on LLT while 985 (46.6%) were off LLT at exam 6. Black participants were less likely to be on LLT compared to the reference white participants (RR 0.80, 95% confidence interval CI 0.71-0.90). Higher BMI showed borderline significant association with LLT. Comorbidities of diabetes and hypertension were positively associated with LLT use (RR 1.39 and 1.23, 95% CI 1.27-1.52 and 1.10-1.36, respectively). CAC score > 0 as an indicator of subclinical ASCVD was strongly associated with LLT too, independent of other demographic or comorbidity factors (RR 1.38, 95% CI 1.21-1.56). This study identifies key factors influencing LLT use among MESA participants. Black participants were less likely to be on LLT, highlighting healthcare disparities. CAC presence was strongly associated with LLT use, suggesting that CAC measurement could be an actionable factor to improve adherence to LLT guidelines.

Primary prevention of cardiovascular diseases among women in a South Asian population: a descriptive study of modifiable risk factors

ObjectiveThe aim of this study was the assessment of modifiable risk factors of cardiovascular diseases (CVD) among women versus men at a newly developed preventive cardiology clinic of a large...

Learning health system linchpins: information exchange and a common data model.

To demonstrate the potential for a centrally managed health information exchange standardized to a common data model (HIE-CDM) to facilitate semantic data flow needed to support a learning health system (LHS). The Rhode Island Quality Institute operates the Rhode Island (RI) statewide HIE, which aggregates RI health data for more than half of the state's population from 47 data partners. We standardized HIE data to the Observational Medical Outcomes Partnership (OMOP) CDM. Atherosclerotic cardiovascular disease (ASCVD) risk and primary prevention practices were selected to demonstrate LHS semantic data flow from 2013 to 2023. We calculated longitudinal 10-year ASCVD risk on 62,999 individuals. Nearly two-thirds had ASCVD risk factors from more than one data partner. This enabled granular tracking of individual ASCVD risk, primary prevention (ie, statin therapy), and incident disease. The population was on statins for fewer than half of the guideline-recommended days. We also found that individuals receiving care at Federally Qualified Health Centers were more likely to have unfavorable ASCVD risk profiles and more likely to be on statins. CDM transformation reduced data heterogeneity through a unified health record that adheres to defined terminologies per OMOP domain. We demonstrated the potential for an HIE-CDM to enable observational population health research. We also showed how to leverage existing health information technology infrastructure and health data best practices to break down LHS barriers. HIE-CDM facilitates knowledge curation and health system intervention development at the individual, health system, and population levels.

Polygenic Risk Scores and Extreme Coronary Artery Calcium Phenotypes (CAC=0 and CAC≥1000) in Adults ≥75 Years Old: The ARIC Study.

Coronary artery calcium (CAC) is heterogeneous in older age and is incompletely explained by traditional atherosclerotic cardiovascular disease risk factors. The extremes of subclinical atherosclerosis burden are strongly associated with either a low or high 10-year risk of incident atherosclerotic cardiovascular disease, respectively. However, the genetic underpinnings of differences in arterial aging remain unclear. We sought to determine the independent association of 2 polygenic scores for coronary heart disease (CHD) with CAC in adults ≥75 years of age. There were 1865 ARIC (Atherosclerosis Risk in Communities) participants who underwent genetic testing at visit 1 (1987-1989) and CAC scans at visit 7 (2018-2019). In the primary analysis, an externally derived multi-ancestry polygenic CHD risk score was calculated for both White and Black participants. Results were confirmed using a separate ARIC-derived polygenic CHD risk score, including ≥6 million variants computed for White participants. We used multivariable logistic regression models to assess the association of polygenic CHD risk with CAC, after adjusting for baseline, time-averaged lifestyle, traditional risk factors, and local ancestry principal components. In the primary analysis, the average age was 80.6 years old, 61.6% were women, and the median CAC score was 246 (189 participants with CAC=0, 364 participants with CAC≥1000). Compared with persons below the 20th percentile of polygenic CHD risk, persons with polygenic-CHD risk above the 80th percentile had 82% lower odds of having CAC=0 (odds ratio, 0.18 [95% CI, 0.09-0.37]) and had >4-fold higher odds of CAC≥1000 (odds ratio, 4.77 [95% CI, 2.88-7.88]). On a continuous scale, each SD increment increase in the polygenic risk score was associated with a 78% higher CAC score. Results were nearly identical using a second confirmatory polygenic CHD risk score in White participants. Polygenic CHD risk is robustly associated with a lower prevalence of CAC=0 and a higher prevalence of CAC≥1000 in adults ≥75 years of age, beyond lifestyle and traditional risk factors. These results suggest a heritable contribution to distinct healthy and unhealthy arterial aging phenotypes that persist throughout the life course.

Guideline-directed antihypertensive medication use among young adult participants with uncontrolled hypertension at enrollment in the MyHEART study.

Hypertension is a major risk factor for heart disease, heart failure and stroke. Lifestyle changes are recommended as first-line treatment for management of high blood pressure for young adults, when 10-year atherosclerotic cardiovascular disease risk score is < 10%. If lifestyle changes alone do not control blood pressure, then providers have access to four classes of first-line blood pressure lowering agents to treat hypertension, when other contra-indications are not present. This is a cross-sectional, retrospective, secondary analysis performed of the MyHEART trial on study participants at enrollment to determine they were prescribed anti-hypertensive medication. Of those prescribed medications, we aimed to determine the frequency first-line medications including thiazide or thiazide-like diuretics, angiotensin converting-enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers were prescribed. This analysis categorized participants into four medication status categories: no antihypertensive medication, prescribed only first-line antihypertensives, prescribed only non-first-line antihypertensives, and prescribed a combination of first-line and non-first-line antihypertensives. Participant clinical and sociodemographic factors by medication use were evaluated. Linear regression models were fit to determine the association between antihypertensive medication and blood pressure. At enrollment, 157/311 (50.5%) participants were not on antihypertensives. Of the 154 on antihypertensives, reported use included monotherapy 97/154 (63.0%), combined therapy 57/154 (37.0%), only first-line antihypertensive 111/154 (72.0%), and only non-first-line antihypertensives 21/154 (13.6%), and combination of first-line and non-first-line antihypertensives 22/154 (14.2%). Antihypertension medication use varied based on age (p < 0.001), sex (p = 0.008), race (p = 0.001), body mass index (BMI) kg/m2 (p = 0.016), anxiety and/or depression (p = 0.048), diabetes (p = 0.007), and sodium intake (p = 0.042). Participants with only first-line medications had lower in-office systolic (-4.66 mmHg, CI -8.31 to -1.02, p = 0.013) and diastolic (-3.51 mmHg, CI -6.30 to -0.71, p = 0.015), and lower ambulatory diastolic (-2.12 mmHg, CI -4.15 to -0.09, p = 0.041) blood pressure than those without antihypertensives. Among MyHEART study participants, all of which had uncontrolled hypertension, 50.5% were not on an antihypertensive at enrollment. This finding supports the call to improve management of blood pressure earlier in life to potentially contribute to the reduction of long-term cardiovascular disease. Of the participants who were prescribed blood pressure medication, providers prescribed guideline-based antihypertensive therapy the majority of the time, however, this study indicates there may be an opportunity to increase the use of first-line, guideline-based antihypertensives, regardless of age, sex, or type of hypertension to lower long-term cardiovascular risk. https://www. gov Identifier: NCT03158051, registered 5-15-2017. IRB approval obtained: IRB # 2017 - 0372.

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 (&lt;5%) or borderline (5-&lt;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&gt;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 4137570: Atherosclerotic Cardiovascular Disease Risks in Children: An electronic health record data analytics approach

Background and Aims: There is little data on atherosclerotic cardiovascular disease (ASCVD) risk conditions, factors, and tiers in the pediatric population. This study aimed to develop and validate electronic health record (EHR) data analytic algorithms to attain the prevalence of 24 risk conditions, 7 factors, and 4 tiers in children in a rural community. Methods: This study included all the 495,902 subjects from 0 to 18 years at the Geisinger Medical Center from 2004 to 2022. The demographic and clinical data were collected using ICD-10 codes, clinical and laboratory data, and a dual-coded computational algorithm was developed based on the AHA guideline to derive the ASCVD risk conditions, factors, and tiers. To validate the EHR algorithms, the algorithm (rater 1) and a clinician (rater 2) extracted and analyzed the data from 40 randomly selected subjects from this cohort. Kendall’s coefficient of concordance (W) and Gwet’s agreement coefficient were used to evaluate algorithm and clinician agreement within the ASCVD tiers, conditions and factors, respectively. Results: High concordance was observed between algorithmic and clinician raters for risk tiers (W=80%), conditions (80-97%), and factors (49% for blood pressure, and 92% to 97% for the rest of the risk factors). In this cohort, the median age was 3.9 years, 51.0% were male, 80.6% were Non-Hispanic/Latino, and 88.1% were White. Overall, 15.5% (N = 76,945) were at-risk, 7.0% (N = 34,530) at moderate risk, and 4.2% (N = 20,761) at high risk for ASCVD, respectively. The most prevalent risk conditions were obesity (9.1%, N = 45,074), chronic inflammatory conditions (6.8%, N = 33,685), severe obesity (2.7%, N = 13,442), insulin resistance with comorbidities (2.7%, N = 13,397), and hypertension (2.1%, N = 10,436). The most prevalent risk factors were elevated BMI (27.4%, N = 135,904), blood pressure (12.5%, N = 62,015), and fasting lipid profile (8.7%, N = 43,100). Conclusion: Our EHR data analytics algorithm is in high agreement with the clinician rater. The high, moderate, and at-risk ASCVD risk tiers are prevalent in a large contemporary pediatric cohort at Geisinger. Both ASCVD risk conditions and factors are also prevalent, especially obesity, diabetes, hypertension, and hyperlipidemia. These findings suggest the further application and refinement of these algorithms to design innovative approaches for ASCVD risk reduction and prevention in children.

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: &lt;0.001; female: &lt;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 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 &amp; 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 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 (&lt;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 4138221: Ezetimibe plus statin combination vs. double dose statin for patients with dyslipidemia and ASCVD risk: A Systematic Review and Meta-Analysis

Background: Dyslipidemia is a major risk factor for Atherosclerotic Cardiovascular Disease (ASCVD). Statin is a crucial intervention to fix dyslipidemia and reduce the ASCVD risk. Still, there are several regimens to achieve blood lipid level targets, including increasing the statin dose or adding ezetimibe to the statin used. However, the best option between the two regimens is still a matter of debate. Research Question: We aim to evaluate the efficacy and safety of Ezetimibe plus any type of statin versus a double dose of the same statin in patients with ASCVD risk. Methods: A systematic review and meta-analysis based on randomized controlled trials (RCTs) obtained from PubMed, Embase Cochrane, Scopus, and WOS till December 2023. We used the random-effects model to report dichotomous outcomes using odds ratio (OR) and continuous outcomes using mean difference (MD), with a 95% confidence interval (CI). Results: Forty-seven studies with a total of 18592 patients were included. Ezetimibe plus statin was associated with a decrease in low-density lipoprotein (LDL) levels [MD: -13.69 with 95% CI (-15.64, -11.74), P &lt;0.01], and more patients achieving their targeted LDL levels [OR: 2.89 with 95% CI (2.40, 3.47), P &lt;0.01]. However, there was no significant difference between the two groups regarding any adverse events [OR: 0.98 with 95% CI (0.89, 1.08), P =0.62], and the composite endpoint of cardiovascular death, major coronary events, or nonfatal stroke [OR: 0.72 with 95% CI (0.39, 1.32), P = 0.29], although there was a trend towards better results for patients with the combination regimen. Conclusion: Ezetimibe plus statin combination led to more reduced LDL levels and more patients achieving their goal levels than double dose statin, without a significant difference in the rate of any adverse events occurrence. More RCTs are mandatory to assess the effect of both regimens on major clinical events such as stroke, coronary events, and death.

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 &gt; 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) &gt; 50 mg/dL. Individuals with Lp(a) &gt; 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) &lt;50 mg/dL (HR=0.37, 95% CI: 0.25-0.55), but borderline significant for participants with Lp(a) &gt; 50 mg/dL (HR=0.41, 95% CI: 0.16-1.02). Individuals with Lp(a) &gt; 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 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 &gt; 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 &gt; 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 &gt; 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 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 (&lt;75th percentile), and Lp(a) levels, in nmol/L, as &lt;125 or ≥125. Participants were then stratified into four groups: Group-1: Low TyG with Lp(a), &lt;125, Group-2: Low TyG with Lp(a) ≥125, Group-3: High TyG with Lp(a) &lt;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. &lt;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 &lt;0.001). Compared to Group-1 (low TyG with Lp(a) &lt;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.