Baseline Atherosclerotic Cardiovascular Disease Research Articles

Effectiveness and safety of empagliflozin: final results from the EMPRISE study.

Limited evidence exists on the comparative safety and effectiveness of empagliflozin against alternative glucose-lowering medications in individuals with type 2 diabetes with the broad spectrum of cardiovascular risk. The EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) cohort study was designed to monitor the safety and effectiveness of empagliflozin periodically for a period of 5 years with data collection from electronic healthcare databases. We identified individuals ≥18 years old with type 2 diabetes who initiated empagliflozin or dipeptidyl peptidase-4 inhibitors (DPP-4i) from 2014 to 2019 using US Medicare and commercial claims databases. After 1:1 propensity score matching using 143 baseline characteristics, we identified four a priori-defined effectiveness outcomes: (1) myocardial infarction (MI) or stroke; (2) hospitalisation for heart failure (HHF); (3) major adverse cardiovascular events (MACE); and (4) cardiovascular mortality or HHF. Safety outcomes included lower-limb amputations, non-vertebral fractures, diabetic ketoacidosis (DKA), acute kidney injury (AKI), severe hypoglycaemia, retinopathy progression, and short-term kidney and bladder cancers. We estimated HRs and rate differences (RDs) per 1000 person-years, overall and stratified by age, sex, baseline atherosclerotic cardiovascular disease (ASCVD) and heart failure. We identified 115,116 matched pairs. Compared with DPP-4i, empagliflozin was associated with lower risks of MI/stroke (HR 0.88 [95% CI 0.81, 0.96]; RD -2.08 [95% CI (-3.26, -0.90]), HHF (HR 0.50 [0.44, 0.56]; RD -5.35 [-6.22, -4.49]), MACE (HR 0.73 [0.62, 0.86]; RD -6.37 [-8.98, -3.77]) and cardiovascular mortality/HHF (HR 0.57 [0.47, 0.69]; RD -10.36 [-12.63, -8.12]). Absolute benefits were larger in older individuals and in those with ASCVD/heart failure. Empagliflozin was associated with an increased risk of DKA (HR 1.78 [1.44, 2.19]; RD 1.59 [1.08, 2.09]); decreased risks of AKI (HR 0.62 [0.54, 0.72]; RD -2.39 [-3.08, -1.71]), hypoglycaemia (HR 0.75 [0.67, 0.84]; RD -2.46 [-3.32, -1.60]) and retinopathy progression (HR 0.78 [0.63, 0.96)]; RD -9.49 [-16.97, -2.10]); and similar risks of other safety events. Empagliflozin relative to DPP-4i was associated with risk reductions of MI or stroke, HHF, MACE and the composite of cardiovascular mortality or HHF. Absolute risk reductions were larger in older individuals and in those who had history of ASCVD or heart failure. Regarding the safety outcomes, empagliflozin was associated with an increased risk of DKA and lower risks of AKI, hypoglycaemia and progression to proliferative retinopathy, with no difference in the short-term risks of lower-extremity amputation, non-vertebral fractures, kidney and renal pelvis cancer, and bladder cancer.

Abstract MP28: Declines in Plasma Levels of Nonnutritive Sweetener Erythritol Are Related to Two-Year Improvements in Atherosclerotic Cardiovascular Disease Risk Estimates Among Adults With Overweight and Obesity

Background: A potential adverse relationship between the consumption of low-calorie sweeteners and cardiovascular disease (CVD) risk has been proposed. High levels of circulating erythritol, a sugar alcohol (polyol) used as one of the non-nutritive sweeteners, have been recently linked to increased risks of major adverse cardiovascular events. However, associations of temporal changes in plasma erythritol and other polyols with cardiometabolic risk remain unclear. Hypothesis: We tested whether changes in plasma levels of non-nutritive sweetener erythritol and other polyols in response to weight-loss dietary interventions were associated with improved atherosclerotic cardiovascular disease (ASCVD) risk estimates and atherogenic lipoproteins among adults with overweight and obesity. Methods: This study included 804 adults (mean BMI: 32.7 [SD 3.9] kg/m 2 ) without diabetes or unstable CVD at baseline who participated in a 2-year intervention of weight-loss diets, the POUNDS Lost trial. Metabolomic profiling was performed to measure plasma erythritol and its precursor erythronate, other sugar alcohols, and low-calorie sweeteners at baseline and 6 months after randomization. The primary outcome was the change in 10-year ASCVD risk scores calculated by the validated pooled cohort equations. Two-year changes in lipid profiles and cholesterol [Chol] in lipoprotein subfractions defined by the presence or absence of apolipoprotein CIII (apoCIII) were analyzed as secondary outcomes. Results: The mean estimated value of the 10-year ASCVD risk was 4.0% at baseline; 16% of the participants were at intermediate or high ASCVD risk (score ≥7.5%). Higher levels of erythritol (per 1 SD increment: β 1.1% [SE 0.2%], p <.0001) and erythronate (β 1.3% [0.2%], p <.0001), as well as other sugar alcohols, such as mannitol-sorbitol, myoinositol, arabitol-xylitol ( p <.0001 for all), and low-calorie sweetener saccharin ( p = 0.02), but not acesulfame ( p =0.8), were related to a higher ASCVD risk at baseline after adjusting for BMI. There was large variability in the changes in metabolite levels across participants; greater decreases in erythritol in response to the interventions were significantly related to greater reductions in ASCVD risk estimates at 6 months (per 1 SD reduction: β -0.2% [SE 0.1%]; p =0.023) and at 2 years (β -0.3% [0.1%]; p = 0.015) after adjusting for covariates, including BMI, the initial metabolite levels, and baseline ASCVD risk. The 6-month decrease in erythritol was associated with long-term (2-year) improvements in atherogenic lipids, including Chol in VLDL+LDL with apoCIII ( p <0.05). Conclusions: Higher plasma levels of erythritol and other sugar alcohols were associated with greater 10-year ASCVD risk scores among adults with overweight and obesity. Weight-loss diet-induced decreases in erythritol levels were related to improved ASCVD risk and atherogenic lipid profiles.

Nurse-Led Strategy to Improve Blood Pressure and Cholesterol Level Among People With HIV

Despite higher atherosclerotic cardiovascular disease (ASCVD) risk, people with HIV (PWH) experience unique barriers to ASCVD prevention, such as changing models of HIV primary care. To test whether a multicomponent nurse-led strategy would improve systolic blood pressure (SBP) and non-high-density lipoprotein (HDL) cholesterol level in a diverse population of PWH receiving antiretroviral therapy (ART). This randomized clinical trial enrolled PWH at 3 academic HIV clinics in the US from September 2019 to January 2022 and conducted follow-up for 12 months until January 2023. Included patients were 18 years or older and had a confirmed HIV diagnosis, an HIV-1 viral load less than 200 copies/mL, and both hypertension and hypercholesterolemia. Participants were stratified by trial site and randomized 1:1 to either the multicomponent EXTRA-CVD (A Nurse-Led Intervention to Extend the HIV Treatment Cascade for Cardiovascular Disease Prevention) intervention group or the control group. Primary analyses were conducted according to the intention-to-treat principle. The EXTRA-CVD group received home BP monitoring guidance and BP and cholesterol management from a dedicated prevention nurse at 4 in-person visits (baseline and 4, 8, and 12 months) and frequent telephone check-ins up to every 2 weeks as needed. The control group received general prevention education sessions from the prevention nurse at each of the 4 in-person visits. Study-measured SBP was the primary outcome, and non-HDL cholesterol level was the secondary outcome. Measurements were taken over 12 months and assessed by linear mixed models. Prespecified moderators tested were sex at birth, baseline ASCVD risk, and trial site. A total of 297 PWH were randomized to the EXTRA-CVD arm (n = 149) or control arm (n = 148). Participants had a median (IQR) age of 59.0 (53.0-65.0) years and included 234 males (78.8%). Baseline mean (SD) SBP was 135.0 (18.8) mm Hg and non-HDL cholesterol level was 139.9 (44.6) mg/dL. At 12 months, participants in the EXTRA-CVD arm had a clinically significant 4.2-mm Hg (95% CI, 0.3-8.2 mm Hg; P = .04) lower SBP and 16.9-mg/dL (95% CI, 8.6-25.2 mg/dL; P < .001) lower non-HDL cholesterol level compared with participants in the control arm. There was a clinically meaningful but not statistically significant difference in SBP effect in females compared with males (11.8-mm Hg greater difference at 4 months, 9.6 mm Hg at 8 months, and 5.9 mm Hg at 12 months; overall joint test P = .06). Results of this trial indicate that the EXTRA-CVD strategy effectively reduced BP and cholesterol level over 12 months and should inform future implementation of multifaceted ASCVD prevention programs for PWH. ClinicalTrials.gov Identifier: NCT03643705.

Association of Alkaline Phosphatase with Cardiovascular Disease in Patients with Dyslipidemia: A 6-Year Retrospective Study.

Serum alkaline phosphatase (ALP) activity has been associated with atherosclerotic cardiovascular disease (ASCVD). We aimed to investigate the association of ALP with ASCVD in patients with dyslipidemia. We conducted a retrospective cohort study including consecutive adults with dyslipidemia followed-up for ≥3 years (from 1999 to 2022) in the outpatient Lipid Clinic of Ioannina University General Hospital, Greece. The primary endpoint was the association between baseline ALP and incident ASCVD after adjusting for traditional risk factors (i.e., sex, age, hypertension, diabetes, smoking, and dyslipidemia), baseline ASCVD, and lipid-lowering treatment. ALP levels were stratified by tertiles as follows: low: <67 U/L, middle: 67-79 U/L, high: ≥79 U/L. Overall, 1178 subjects were included; 44% were males, and their median age was 57 years (range: 49-65). During a 6-year median follow-up (interquartile range: IQR: 4-9), 78 new ASCVD events (6.6%) occurred. A statistically significant association between baseline ALP levels and incident ASCVD was demonstrated (Odds Ratio, OR: 6.99; 95% Confidence Interval, CI: 2.29-21.03, p = 0.001). Subjects in the highest ALP tertile had the highest odds for ASCVD when compared with those in the lowest tertile (OR: 2.35; 95% CI: 1.24-4.41, p = 0.008). The present study indicates an association between ALP and the development of ASCVD in patients with dyslipidemia, which underscores the potential of ALP as a predictive tool or a therapeutic target in the realm of ASCVD prevention within this population.

Cardiorenal effectiveness of empagliflozin vs. glucagon-like peptide-1 receptor agonists: final-year results from the EMPRISE study

BackgroundNo randomized clinical trials have directly compared the cardiorenal effectiveness of empagliflozin and GLP-1RA agents with demonstrated cardioprotective effects in patients with a broad spectrum of cardiovascular risk. We reported the final-year results of the EMPRISE study, a monitoring program designed to evaluate the cardiorenal effectiveness of empagliflozin across broad patient subgroups.MethodsWe identified patients ≥ 18 years old with type 2 diabetes who initiated empagliflozin or GLP-1RA from 2014 to 2019 using US Medicare and commercial claims databases. After 1:1 propensity score matching using 143 baseline characteristics, we evaluated risks of outcomes including myocardial infarction (MI) or stroke, hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE – MI, stroke, or cardiovascular mortality), a composite of HHF or cardiovascular mortality, and progression to end-stage kidney disease (ESKD) (in patients with chronic kidney disease stages 3–4). We estimated hazard ratios (HR) and rate differences (RD) per 1,000 person-years, overall and within subgroups of age, sex, baseline atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF).ResultsWe identified 141,541 matched pairs. Compared with GLP-1RA, empagliflozin was associated with similar risks of MI or stroke [HR: 0.99 (0.92, 1.07); RD: -0.23 (-1.25, 0.79)], and lower risks of HHF [HR: 0.50 (0.44, 0.56); RD: -2.28 (-2.98, -1.59)], MACE [HR: 0.90 (0.82, 0.99); RD: -2.54 (-4.76, -0.32)], cardiovascular mortality or HHF [HR: 0.77 (0.69, 0.86); RD: -4.11 (-5.95, -2.29)], and ESKD [0.75 (0.60, 0.94); RD: -6.77 (-11.97, -1.61)]. Absolute risk reductions were larger in older patients and in those with baseline ASCVD/HF. They did not differ by sex.ConclusionsThe cardiovascular benefits of empagliflozin vs. cardioprotective GLP-1RA agents were larger in older patients and in patients with history of ASCVD or HF, while they did not differ by sex. In patients with advanced CKD, empagliflozin was associated with risk reductions of progression to ESKD.

Association Between Cardiovascular Event Type and Smoking Cessation Rates Among Outpatients With Atherosclerotic Cardiovascular Disease: Insights From the NCDR PINNACLE Registry.

It is unclear how the type of an atherosclerotic cardiovascular disease (ASCVD) event potentially influences patients' likelihood of smoking cessation. Using 2013 to 2018 data from the US based National Cardiovascular Data Registry Practice Innovation and Clinical Excellence outpatient cardiac registry, we identified patients who were current smokers at a clinic visit and followed them over time for a subsequent ASCVD event. Self-reported smoking status was assessed at each consecutive visit and used to determine smoking cessation after each interim ASCVD event (myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, stroke/transient ischemic attack, peripheral artery disease). We constructed separate multivariable Cox models with nonproportional hazards to examine the association of each interim ASCVD event with smoking cessation, compared with not having an interim ASCVD event. We estimated the relative association of ASCVD event type with smoking cessation using contrast tests. Analyses were stratified by presence versus absence of ASCVD at baseline. Across 530 cardiology practices, we identified 1 933 283 current smokers (mean age 62±15, male 54%, ASCVD at baseline 50%). Among the 322 743 patients who had an interim ASCVD event and were still smoking, 41 336 (12.8%) quit smoking by their first subsequent clinic visit, which was higher among those with baseline ASCVD (13.4%) as compared with those without baseline ASCVD (11.5%). Each type of ASCVD event was associated with an increased likelihood of smoking. Patients who had an myocardial infarction, underwent coronary artery bypass graft (hazard ratio, 1.60 [95% CI, 1.55-1.65]), or had a stroke or transient ischemic attack were more likely to quit smoking as compared with those who underwent elective percutaneous coronary intervention or had a new diagnosis of peripheral artery disease (hazard ratio, 1.20 [95% CI, 1.17-1.22]). Only 13% of patients reported smoking cessation after an ASCVD event, with the type of event being associated with the likelihood of smoking cessation, prompting the need for patient-centered interventions.

Incorporating longitudinal history of risk factors into atherosclerotic cardiovascular disease risk prediction using deep learning

It is increasingly clear that longitudinal risk factor levels and trajectories are related to risk for atherosclerotic cardiovascular disease (ASCVD) above and beyond single measures. Currently used in clinical care, the Pooled Cohort Equations (PCE) are based on regression methods that predict ASCVD risk based on cross-sectional risk factor levels. Deep learning (DL) models have been developed to incorporate longitudinal data for risk prediction but its benefit for ASCVD risk prediction relative to the traditional Pooled Cohort Equations (PCE) remain unknown. Our study included 15,565 participants from four cardiovascular disease cohorts free of baseline ASCVD who were followed for adjudicated ASCVD. Ten-year ASCVD risk was calculated in the training set using our benchmark, the PCE, and a longitudinal DL model, Dynamic-DeepHit. Predictors included those incorporated in the PCE: sex, race, age, total cholesterol, high density lipid cholesterol, systolic and diastolic blood pressure, diabetes, hypertension treatment and smoking. The discrimination and calibration performance of the two models were evaluated in an overall hold-out testing dataset. Of the 15,565 participants in our dataset, 2170 (13.9%) developed ASCVD. The performance of the longitudinal DL model that incorporated 8 years of longitudinal risk factor data improved upon that of the PCE [AUROC: 0.815 (CI 0.782–0.844) vs 0.792 (CI 0.760–0.825)] and the net reclassification index was 0.385. The brier score for the DL model was 0.0514 compared with 0.0542 in the PCE. Incorporating longitudinal risk factors in ASCVD risk prediction using DL can improve model discrimination and calibration.

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 (&gt;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&lt;0.001 and adjusted HR = 1.34, p&lt;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&lt;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.

SAT658 Tirzepatide Reduces The Predicted Risk Of Developing Atherosclerotic Cardiovascular Disease: A Post-hoc Analysis Of The Surmount-1 Trial

Abstract Disclosure: E.R. Hankosky: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. H. Wang: Other; Self; Eli Lilly &amp; Company. N.M. Lisa: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. H. Kan: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. F. Wang: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. N.N. Ahmad: Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. A. Stefanski: Grant Recipient; Self; Eli Lilly &amp; Company. Employee; Self; Eli Lilly &amp; Company. Stock Owner; Self; Eli Lilly &amp; Company. W. Garvey: Consulting Fee; Self; Eli Lilly &amp; Company, Novo Nordisk, Boehringer Ingelheim, Pfizer, Inc., Fractyl Laboratories, Merck. Grant Recipient; Self; Eli Lilly &amp; Company, Novo Nordisk, Pfizer, Inc. Background: Tirzepatide (TZP) resulted in substantial and sustained body weight reduction among participants with obesity or overweight in SURMOUNT-1, a phase 3 randomized clinical trial. Using predictive modelling, the current study assessed the impact of TZP treatment on the 10-year risk of developing atherosclerotic cardiovascular disease (ASCVD) among SURMOUNT-1 participants. Methods: The American College of Cardiology/American Heart Association (ACC/AHA) risk engine was applied to data from SURMOUNT-1 participants free of ASCVD at baseline. ASCVD risk scores were calculated at baseline, 24, and 72 weeks. The model inputs were age, total cholesterol, high density lipoprotein, systolic blood pressure, hypertension treatment, diabetes, and smoking status. Mean percent change in the 10-year risk score from baseline to week 72 was compared between TZP groups and placebo (PBO) using Mixed Model for Repeated Measures (MMRM), adjusted for baseline risk scores and country; risk scores were analyzed on log-scale. Since the risk score was low in the overall SURMOUNT-1 population, a subgroup analysis was conducted in participants with higher ASCVD risk at baseline (score≥7.5%, ACC/AHA intermediate-to-high risk). Results: A total of 2461 participants (TZP 5 mg, n=614; 10 mg, n=616; 15 mg, n=609; PBO, n=622) were included (mean age=45 years; female=68%; White=70%). At baseline, the median 10-year predicted risk score ranged from 1.5%–1.6% and did not differ across treatment groups. Median absolute risk scores for TZP 5/10/15 mg and PBO groups were 1.4%, 1.2%, 1.3%, and 1.6% at week 24, and 1.3%, 1.2%, 1.1%, and 1.7% at week 72, respectively. At week 72, MMRM-estimated relative change in risk from baseline was -16.4%, -23.5%, -22.4%, and 12.7% for TZP 5/10/15mg and PBO, leading to significantly greater reduction for TZP groups compared to PBO (TZP 5 mg: -25.8%; 10 mg: -32.1%; 15 mg: -31.1%; p≤0.001). Among 272 participants (TZP 5 mg, n=83; 10 mg, n=66; 15 mg, n=55; PBO, n=68) with intermediate-to-high baseline ASCVD risk, median risk scores for TZP 5/10/15 mg and PBO groups were: baseline: 11.3%, 10.5%, 10.9%, 10.1%; week 72: 11.3%, 9.0%, 10.3%, 11.7%, respectively. MMRM-estimated relative risk reduction at week 72 was -10.3%, -20.6%, -16.1%, and 6.4% for TZP 5/10/15 mg and PBO groups, respectively. Consistent with the primary analysis, relative risk reduction was significantly greater in TZP groups compared to PBO (TZP 5 mg = -15.7%; 10 mg = -25.3%; 15 mg = -21.1%; p≤0.01). Conclusion: TZP treatment significantly reduced the 10-year predicted risk of developing ASCVD compared to PBO, though the magnitude of reduction in absolute risk scores was small due to low baseline risk in the overall population. Among participants with higher ASCVD risk at baseline, TZP treatment resulted in larger absolute reductions in risk along with significant relative risk reduction consistent with the primary analysis. Presentation: Saturday, June 17, 2023

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.

Predictive value of ASCVD risk score for mortality and major adverse cardiovascular events in the year following a COVID-19 infection among US Veterans

BackgroundMorbidity and mortality following COVID-19 infection may be influenced by baseline atherosclerotic cardiovascular disease (ASCVD) risk, yet limited data are available to identify those at highest risk. We examined the association between baseline ASCVD risk with mortality and major adverse cardiovascular events (MACE) in the year following COVID-19 infection. MethodsWe evaluated a nationwide retrospective cohort of US Veterans free of ASCVD who were tested for COVID-19. The primary outcome was absolute risk of all-cause mortality in the year following a COVID-19 test among those hospitalized vs. not stratified by baseline VA-ASCVD risk scores. Secondarily, risk of MACE was examined. ResultsThere were 393,683 Veterans tested for COVID-19 and 72,840 tested positive. Mean age was 57 years, 86% were male, and 68% were white. Within 30 days following infection, hospitalized Veterans with VA-ASCVD scores >20% had an absolute risk of death of 24.6% vs. 9.7% (P ≤0.0001) for those who tested positive and negative for COVID-19 respectively. In the year following infection, risk of mortality attenuated with no difference in risk after 60 days. The absolute risk of MACE was similar for Veterans who tested positive or negative for COVID-19. ConclusionsVeterans without clinical ASCVD experienced an increased absolute risk of death within 30 days of a COVID-19 infection compared to Veterans with the same VA-ASCVD risk score who tested negative, but this risk attenuated after 60 days. Whether cardiovascular preventive medications can lower the risk of mortality and MACE in the acute period following COVID-19 infection should be evaluated.

A phase II trial modifying metabolic syndrome and cardiovascular risk for patients with prostate cancer on ADT using a risk factor modification program and continuous Fitbit monitoring (ProTrio).

TPS273 Background: Prostate cancer is a disease of older age, and there is significant overlap with age-related illnesses. Androgens play a critical role in prostate cancer but also have been linked to cardiovascular (CV) disease, metabolic syndrome, bone health, and frailty. ADT is associated with an increased risk of CV events primarily due to increased rates of diabetes, dyslipidemia, and adverse changes in body composition. We assume that prostate cancer and age-related illnesses share biology with therapeutic implications in a subset of men. The ProTrio trial will test the hypothesis that a 16-week digital risk factor modification program will improve 10-year atherosclerotic cardiovascular disease (ASCVD) risk score as compared to usual care in men with potentially lethal prostate cancer receiving ADT. Methods: This single center, open-label, randomized phase II trial is evaluating a 16-week digital risk factor modification program, which includes an exercise prescription (150 minutes of titrated cardiovascular exercise and resistance exercise 2 times a week) with support via a smart phone application (Moving Analytics) and Fitbit, in patients with prostate cancer who are receiving ADT compared to usual care with Fitbit monitoring. Eligible patients are men receiving ADT +/- an androgen signaling inhibitor for at least 3 months prior to enrollment. The study will enroll to two cohorts: (1) distant metastatic disease and (2) biochemically recurrent or regional lymph node disease. Patients will be stratified according to their baseline ASCVD risk score. The primary endpoint is the difference in ASCVD risk score post-intervention. Secondary endpoints include difference in metabolic severity index z-score, PSA velocity, 6-minute walk, 5X Sit-to-Stand, body composition, physical activity measured by Fitbit, and health-related quality of life. Up to 100 patients will be enrolled in each cohort. A clinically relevant improvement in ASCVD score reduction is 2.5%. With 44 men per arm, after 12% dropout, we can detect an improvement of 2.5% vs. 0% at a 2-sided 5% significance level with 80% power assuming a standard deviation (SD) of 4.125%. A sample size adjustment is planned based on the SD of the first cohort to reach 44 patients. Each cohort will undergo futility analysis once half the men are enrolled. The study is enrolling at MD Anderson Cancer Center. Clinical trial information: NCT05054296 .

Implementation of risk enhancers in ASCVD risk estimation and hypolipidemic treatment eligibility: A sex-specific analysis

ObjectiveSex-specific data are limited regarding eligibility for hypolipidemic treatment. We aim to explore the sex-specific clinical utility of high-sensitivity C-reactive protein (hsCRP) and carotid ultrasound as risk modifiers for hypolipidemic treatment in primary prevention of atherosclerotic cardiovascular disease (ASCVD). MethodsWe aimed to explore these sex-specific trends in two pooled contemporary independent Greek cohorts (Athens Vascular Registry n = 698, 50.9% women and Menopause Clinic n = 373, 100% women) of individuals without overt ASCVD. Baseline ASCVD risk was estimated using the Systematic COronary Risk Evaluation-2 (SCORE2) tools. The presence of carotid plaque and hsCRP ≥2 mg/L were integrated as risk modifiers. ResultsMen had increased odds to achieve target LDL-C levels based on ASCVD risk (23.8% vs. 17.7%, OR: 1.45 95% CI: 1.05–2.00, p = 0.023, for men vs. women). Additionally, considering carotid plaque or high hsCRP levels did not change this association but reduced on-target LDL-C rate in both sexes. Women had decreased odds of being eligible for hypolipidemic treatment by ASCVD risk estimation (11.5% vs. 26.4%, p < 0.001) compared with men. The addition of carotid plaque presence or high hsCRP levels and their combination resulted in a higher relative increase in hypolipidemic treatment eligibility in women (from 11.5% to 70.9% vs. 26.4% to 61.4% for carotid plaque, from 11.5% to 38.5% vs. 26.4% to 50.8% for hsCRP and from 11.5% to 79.1% vs. 26.4% to 75% for their combination, all for women vs. men, pforinteraction < 0.001 for all) than men. ConclusionsImplementation of carotid plaque and hsCRP levels increases hypolipidemic treatment eligibility more prominently in women than in men. The impact on clinical outcomes in these untreated patients merits further investigation.

Aspirin With or Without Statin in Individuals Without Atherosclerotic Cardiovascular Disease Across Risk Categories

BackgroundThe effects of aspirin in adults without atherosclerotic cardiovascular disease (ASCVD), stratified by statin use across different ASCVD risks, remain uncertain. ObjectivesThe purpose of this study was to examine the effects of aspirin in adults without ASCVD, stratified by statin use across different ASCVD risks. MethodsWe searched databases through March 2022 and selected randomized controlled trials of aspirin without ASCVD and follow-up of ≥1 year. We used random-effects models and estimated relative and absolute risks for cardiovascular outcomes, major bleeding, and mortality over 5 years. We calculated absolute risk differences assuming constant relative risks (RRs) across statin use and ASCVD risks. The Cholesterol Treatment Trialists Collaboration, and the ASCEND (A Study of Cardiovascular Events in Diabetes) trial were used to estimate baseline risks. ResultsIn 16 trials [171,215 individuals; median age, 64 (Q1-Q3: 60-65) years], aspirin vs control reduced myocardial infarction (MI) [RR: 0.85 (95% CI: 0.77-0.95)] but increased major bleeding [RR: 1.48 (95% CI: 1.32-1.66)]. Aspirin did not reduce mortality. Statin vs no statin was associated with lower bleeding and MI risk; the bleeding and MI risk were proportional to ASCVD risk. For every 10,000 adults, aspirin reduced MI (very low risk: 3 events as monotherapy or 1 event with statin; very high risk: 49 events as monotherapy or 37 events with statin) and increased major bleeding (very low risk: 21 events as monotherapy or 20 events with statin; very high risk: 98 events as monotherapy or 94 events with statin) proportional to baseline ASCVD risk. ConclusionsIn adults without ASCVD, concomitant statin appeared to significantly reduce absolute risk reduction for MI associated with aspirin without influencing bleeding risk. The anticipated absolute risk of major bleeding with aspirin exceeds absolute MI benefits for every level of ASCVD risk.

Abstract 13954: Cardiovascular Imaging Markers and Atherosclerotic Cardiovascular Disease in Lung Cancer Survivors

Introduction: Lung cancer survivors have heightened risk of atherosclerotic cardiovascular disease (ASCVD) due to shared risk factors. Chest computed tomography (CT) is routinely performed for cancer staging and radiotherapy (RT) planning. However, the extent of coronary artery calcium (CAC) and thoracic aortic calcium (TAC) is not routinely evaluated for ASCVD risk assessment. Methods: We evaluated the extent of CAC and TAC from chest CTs obtained for routine care prior to RT in a cohort of lung cancer survivors from 2007 to 2021 at a single academic health system that serves a large multiracial community. The demographics, baseline cardiovascular risk factors and baseline ASCVD (the composite of myocardial infarction, cerebrovascular disease, or peripheral arterial disease) were compared between survivors with and without CAC or TAC. The primary end point was incident ASCVD. Results: The cohort studied 603 subjects, including 19% non-Hispanic Whites, 33% non-Hispanic Blacks and 32% Hispanics. Mean age was 65±11 years, with 45% women. CAC was present in 72% of subjects and TAC in 85%. Individuals with CAC had higher prevalence of hypertension (75% vs 57%, p&lt;0.001), diabetes (41% vs 20%, p&lt;0.001) and hyperlipidemia (49% vs 26%, p&lt;0.001). Survivors with CAC had a higher prevalence of baseline ASCVD (33% vs 18%, p=0.001). Survivors with TAC yielded similar findings. In individuals without prior ASCVD, 10-year ASCVD risk score was higher in survivors with CAC (20%±21% vs 12%±13%, p=0.009) or with TAC (19%±20% vs 8%±8%, p=0.007). In a median follow-up time of 15 months, the new development of ASCVD appeared higher in survivors with CAC (23% vs 14%, p=0.04, Figure A) and with TAC (22% vs 8%, p=0.01, Figure B). Conclusions: In a large cohort of multiracial lung cancer survivors, presence of CAC or TAC based on routine chest CT at baseline is associated with a higher burden of ASCVD risk and predicts a higher risk of the new development of ASCVD during follow- up.

Abstract 11309: Lipoprotein(a) and the Pooled Cohort Equations for Risk Prediction: The Multi-Ethnic Study of Atherosclerosis

Introduction Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) but is not included in the ACC/AHA ASCVD Risk Estimator based on the Pooled Cohort Equations (PCE). Methods We evaluated the association between Lp(a) &gt;50 mg/dL and risk for cardiovascular disease (CVD) events using multivariable Cox proportional hazards models stratified by ASCVD risk category in individuals free of baseline ASCVD with elevated Lp(a) in the Multi-Ethnic Study of Atherosclerosis (MESA). We then evaluated actual versus PCE-predicted risk by comparing 10-year CVD event rates in those with Lp(a) &gt;50 mg/dL versus Lp(a) ≤50 mg/dL using Poisson regression with adjustment for the components of the PCE by strata of risk (&lt;5%, 5-7.5%, 7.5-20%, ≥20%). We then evaluated the change in the C-index and continuous net reclassification improvement (NRI) with the addition of Lp(a) to the PCE. Results: In participants with borderline risk (5-7.5%), elevated Lp(a) was associated with greater risk for CVD events (HR 2.59, 95% CI 1.41, 4.78). Among patients with elevated Lp(a), the greatest discrimination of risk was present in those with borderline (5-7.5%) predicted risk, where the PCE significantly underestimated risk (observed rate: 8.9% for Lp(a) &gt;50 mg/dL vs 4.1% for Lp(a)≤50 mg/dL, risk ratio 2.54, 95% CI 1.35-4.62, Figure ). In this group, addition of Lp(a) to the PCE resulted in C-index improvement of 0.063. The continuous NRI with the addition of Lp(a) for CVD was 0.0386 (95% CI -0.0115, 0.1087) overall, but 0.3142 (95% CI 0.0350, 0.6083) among those at borderline predicted risk. Conclusions: The PCE underestimates risk in individuals with borderline predicted risk and elevated Lp(a). The addition of Lp(a) to the PCE improves risk prediction in individuals with borderline risk, for whom the greatest opportunity to guide treatment decisions exists.

Comparative Effectiveness of Empagliflozin vs Liraglutide or Sitagliptin in Older Adults With Diverse Patient Characteristics

Limited evidence is available on the comparative effectiveness of empagliflozin vs alternative second-line glucose-lowering agents in patients with type 2 diabetes (T2D) receiving routine care who have a broad spectrum of cardiorenal risk. To evaluate the association of empagliflozin with cardiovascular outcomes relative to liraglutide and sitagliptin, stratified by age, sex, baseline atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and chronic kidney disease (CKD). This retrospective comparative effectiveness cohort study used deidentified Medicare claims data from August 1, 2014, to September 30, 2018, with follow-up from drug initiation until treatment changes, death, or gap in Medicare enrollment (>30 days). Data analysis was performed from October 1, 2021, to April 30, 2022. Medicare fee-for-service beneficiaries older than 65 years with T2D were included. A total of 45 788 patients (22 894 propensity score-matched pairs initiating treatment with either empagliflozin or liraglutide) were included in cohort 1, and 45 624 patients (22 812 propensity score-matched pairs initiating treatment with either empagliflozin or sitagliptin) were included in cohort 2. Empagliflozin vs liraglutide (cohort 1) or empagliflozin vs sitagliptin (cohort 2). Primary outcomes were (1) modified major adverse cardiovascular events (MACEs), including a composite of myocardial infarction, stroke, and all-cause mortality, and (2) hospitalization for heart failure (HHF). Hazard ratios (HRs) and rate differences (RDs) per 1000 person-years were estimated, adjusting for 143 baseline covariates using 1:1 propensity score matching. Among 45 788 patients in cohort 1, the mean (SD) age was 71.9 (5.1) years; 23 396 patients (51.1%) were female, 22 392 (48.9%) were male, and 38 049 (83.1%) were White. Among 45 624 patients in cohort 2, the mean (SD) age was 72.1 (5.1) years; 21 418 patients (46.9%) were female, 24 206 (53.1%) were male, and 37 814 (82.9%) were White. Relative to patients initiating liraglutide, those initiating empagliflozin had a similar risk of the modified MACE outcome (HR, 0.90; 95% CI, 0.79-1.03) and a reduced risk of HHF (HR, 0.66; 95% CI, 0.52-0.82). Across subgroups, empagliflozin was associated with a lower risk of the modified MACE outcome in patients with a history of ASCVD (HR, 0.83; 95% CI, 0.71-0.98) and HF (HR, 0.77; 95% CI, 0.60-1.00) compared with liraglutide, and potential heterogeneity in estimates was observed by sex (male: HR, 0.85 [95% CI, 0.71-1.01]; female: HR, 1.16 [95% CI, 0.94-1.42]; P = .02 for homogeneity). However, reductions in the risk of HHF were observed across most subgroups (eg, ASCVD: HR, 0.66 [95% CI, 0.51-0.85]; HF: HR, 0.66 [95% CI, 0.49-0.88]). Compared with sitagliptin, empagliflozin was associated with reduced risks of the modified MACE outcome (HR, 0.68; 95% CI, 0.60-0.77) and HHF (HR, 0.45; 95% CI, 0.36-0.56), which were consistent across all subgroups. Absolute benefits of empagliflozin vs sitagliptin were larger in patients with a history of ASCVD (modified MACE: RD, -17.6 [95% CI, -24.9 to -10.4]; HHF: RD, -16.7 [95% CI, -21.7 to -11.9]), HF (modified MACE: RD, -41.1 [95% CI, -59.9 to -22.6]; HHF: RD, -50.4 [95% CI, -67.5 to -33.9]), or CKD (modified MACE: RD, -26.7 [95% CI, -41.3 to -12.3]; HHF: RD, -31.9 [95% CI, -43.5 to -20.8]). In this comparative effectiveness study of older adults, empagliflozin was associated with a lower risk of HHF (relative to both liraglutide and sitagliptin) and the modified MACE outcome (relative to sitagliptin), with larger absolute benefits in patients with established cardiorenal diseases. These findings suggest that older adults with T2D might benefit more from empagliflozin vs liraglutide or sitagliptin with respect to the risk of HHF; with respect to the risk of MACEs, empagliflozin might be preferable to liraglutide only in patients with cardiovascular disease history and to sitagliptin across all patient subgroups.

Predictive value of 10-year atherosclerotic cardiovascular disease risk equations from the China-PAR for new-onset lower extremity peripheral artery disease.

Lower extremity peripheral artery disease (LEPAD) is a common and serious health-threatening disease. The aim of this study was to evaluate the predictive value of 10-year atherosclerotic cardiovascular disease (ASCVD) risk equations from the Prediction for ASCVD Risk in China (China-PAR) project for incident LEPAD after 6.75 ± 0.13 years of follow-up. A total of 3,595 Chinese participants without baseline ASCVD or LEPAD from a community-based cohort were enrolled in our study. The mean (interquartile range) baseline 10-year China-PAR ASCVD risk was 4.35% (2.24–8.44%), and the incidence of new-onset LEPAD during 6.75 ± 0.13 years was 4.23%. In univariable logistic regression analysis, 10-year China-PAR ASCVD risk was significantly associated with LEPAD incidence (odds ratio [OR] for each 1% increase in the risk score = 1.06, 95% confidence interval [CI]: 1.03–1.08, P < 0.001). After adjusting confounders, the relationship remained significant (OR: 1.09, 95% CI: 1.05–1.1. P < 0.001). Participants with the highest risk (≥10%) had significantly increased risk compared to those with the lowest risk (<5%) (OR = 2.65, 95% CI: 1.15–6.07, P = 0.022). Further interaction analyses showed no evidence of heterogeneity according to sex, age, body mass index (BMI), smoking, drinking, hypertension, diabetes mellitus, dyslipidemia, renal function, waist circumference, and family history. In conclusion, 10-year China-PAR ASCVD risk independently predicted the risk of new-onset LEPAD in a Chinese community-based population, indicating the importance of polyvascular diseases (PVDs) and the intrinsic interactions of its components.

Carotid ultrasonography improves residual risk stratification in guidelines-defined high cardiovascular risk patients

Abstract Background The clinical value of carotid atherosclerosis markers for residual risk stratification in high atherosclerotic cardiovascular disease (ASCVD) risk patients is not established. Purpose In the present study we aimed to derive and validate optimal values of markers of carotid subclinical atherosclerosis improving risk stratification in guidelines-defined high ASCVD risk patients. Methods We consecutively analysed high or very high ASCVD risk patients from a cardiovascular (CV) prevention registry (n=751, derivation cohort) and from the Atherosclerosis Risk in Communities (ARIC) study (n=2,897, validation cohort). Baseline ASCVD risk was defined using the 2021 European Society of Cardiology (ESC) guidelines (clinical ESCrisk). Intima-media thickness (IMT) excluding plaque, average maximal (avg.maxWT), maximal wall thickness (maxWT) and number of sites with carotid plaque were assessed. As endpoint of the study was defined the composite of CV death, acute myocardial infarction (MI) and revascularization after a median of 3.4 years in both cohorts and additionally for 16.7 years in the ARIC cohort. Results MaxWT &amp;gt;2.00mm and avg.maxWT &amp;gt;1.39mm provided incremental prognostic value, improved discrimination and correctly reclassified risk over the clinical ESCrisk both in the derivation and the validation cohort (p&amp;lt;0.05 for net reclassification index, integrated discrimination index and Delta Harrell's C index). MaxWT &amp;lt;0.9mm predicted very low probability of CV events (negative predictive value = 97% and 92% in the derivation and validation cohort, respectively). These findings were additionally confirmed for very long-term events in the validation cohort. Conclusion Integration of carotid ultrasonography in guidelines-defined risk stratification may identify very high risk patients in need for further residual risk reduction or at very low probability Funding Acknowledgement Type of funding sources: None.

Prediction of Cardiovascular Events by Pulse Waveform Parameters: Analysis of CARTaGENE.

BackgroundWaveform parameters provide approximate data about aortic wave reflection. However, their association with cardiovascular events remains controversial and their role in cardiovascular prediction is unknown.Methods and ResultsWe analyzed participants aged between 40 and 69 from the population‐based CARTaGENE cohort. Baseline pulse wave analysis (central pulse pressure, augmentation index) and wave separation analysis (forward pressure, backward pressure, reflection magnitude) parameters were derived from radial artery tonometry. Associations between each parameter and major adverse atherosclerotic events (MACE; cardiovascular death, stroke, myocardial infarction) were obtained using adjusted Cox models. The incremental predictive value of each parameter compared with the 10‐year atherosclerotic cardiovascular disease score alone was assessed using hazard ratios, c‐index differences, continuous net reclassification indexes, and integrated discrimination indexes. From 17 561 eligible patients, 2315 patients had a MACE during a median follow‐up of 10.1 years. Central pulse pressure, forward pressure, and backward pressure, but not augmentation index and reflection magnitude, were significantly associated with MACE after full adjustment. All parameters except forward pressure statistically improved MACE prediction compared with the atherosclerotic cardiovascular disease score alone. The greatest prediction improvement was seen with augmentation index and reflection magnitude but remained small in magnitude. These 2 parameters enhanced predictive performance more strongly in patients with low baseline atherosclerotic cardiovascular disease scores. Up to 5.7% of individuals were reclassified into a different risk stratum by adding waveform parameters to atherosclerotic cardiovascular disease scores.ConclusionsSome waveform parameters are independently associated with MACEs in a population‐based cohort. Augmentation index and reflection magnitude slightly improve risk prediction, especially in patients at low cardiovascular risk.