Shapiro, Michael D.

Abstract Aims Routine aspirin use for primary prevention yields modest cardiovascular benefit but increases bleeding risk in average-risk adults. Whether individuals with elevated lipoprotein(a) [Lp(a)] levels or high-risk LPA variants derive greater benefit remains uncertain. Methods and results Following Cochrane and PRISMA guidelines, we systematically searched PubMed/MEDLINE, Embase, and Cochrane Central for studies of adults without ASCVD, elevated Lp(a) (≥50 mg/dL), high-risk LPA genotypes, or elevated genetic risk scores, comparing aspirin vs. no aspirin use. Random-effects meta-analyses using restricted maximum-likelihood (REML) estimation with Hartung–Knapp–Sidik–Jonkman (HKSJ) adjustment were used to pool hazard ratios (HR) and 95% confidence intervals (CI). In six studies, 6628 participants were included. Pooled random effects showed no significant reduction in major adverse cardiovascular events (MACE) with aspirin (HR = 0.60; 95% CI 0.31–1.17; P = 0.1) or clinical bleeding events (HR = 1.24; 95% CI 0.83–1.87; P = 0.18). Subgroup analyses showed a nonsignificant reduction MACE among elevated Lp(a) (HR = 0.63; 95% CI 0.16 to 2.49; P = 0.284) and statistically significant reduction among LPA rs3798220 carriers (HR = 0.37; 95% CI 0.19 to 0.71; P = 0.003), though this finding was not consistent in the sensitivity analyses. Conclusion Among adults without ASCVD but with elevated Lp(a) or high-risk LPA genotypes, aspirin use did not confer a statistically significant cardiovascular benefit and was associated with numerically higher bleeding risk. The apparent reduction seen in rs3798220 carriers was inconsistent and likely reflects small-sample bias.

Introduction: Apolipoprotein B (ApoB) and coronary artery calcium score (CAC) are well-established risk factors for coronary heart disease (CHD). However, the interaction between these risk factors on CHD risk has not been well-studied. We investigated the association between ApoB levels and CAC with CHD risk. Methods: We analyzed 4,649 participants from the Multiethnic Study of Atherosclerosis cohort (median follow-up 13.9 years) without baseline CHD or statin use. High ApoB was defined as ≥120 mg/dL. Participants were divided into 6 groups; group 1: CAC = 0 with normal ApoB, group 2: CAC = 0 with high ApoB, group 3: CAC 1-99 with normal ApoB, group 4: CAC 1-99 with high ApoB, group 5: CAC ≥100 with normal ApoB, group 6: CAC ≥100 with high ApoB. CHD was defined as myocardial infarction, resuscitated cardiac arrest, or CHD death. Survival analysis using Kaplan-Meier and multivariable Cox proportional hazard models were performed to assess the relationship between ApoB, CAC, and time to first CHD event. Results: In an adjusted model, high ApoB, CAC (1-99), and CAC (≥100) were independently associated with CHD (HR: 1.48; 95% CI: 1.04, 2.11; HR: 2.54; 95% CI: 1.78, 3.64; and HR: 4.41; 95% CI: 3.08, 6.31, respectively). Compared to group 1 (CAC 0 with normal ApoB), CAC 0 and high ApoB (group 2) was not associated with increased risk of CHD (HR: 1.15; 95% CI: 0.59, 2.23). However, a statistically significant greater risk of CHD was observed in those with CAC 1-99 and normal ApoB (group 3) (HR: 2.12; 95% CI: 1.37, 3.28), CAC 1-99 and high ApoB (group 4) (HR: 4.12; 95% CI: 2.42, 7.00), CAC ≥100 and normal ApoB (group 5) (HR: 4.20; 95% CI: 2.78, 6.34), CAC ≥100 and high ApoB (group 6) (HR: 5.72; 95% CI: 3.40, 9.63). Conclusions: In this analysis, ApoB and CAC are independently associated with CHD risk. Individuals with high ApoB and CAC ≥100 had the highest risk of CHD. In contrast, individuals with CAC = 0 and high ApoB had no significant increase in CHD risk compared to individuals with normal ApoB levels. These findings suggest that ApoB and CAC may be complementary tools for CHD risk stratification in the context of primary prevention.

Background: Nationally, many ASCVD patients fail to achieve an LDL-C <70 mg/dL, and uptake of both statin and non-statin therapies is low. The degree to which this varies across health systems is less clear. Methods: A cross sectional analysis was performed where lipid levels and lipid lowering therapies (LLT) were assessed using electronic health record data in patients with a previous diagnosis of ASCVD. The data was obtained across 14 US healthcare systems between 1/1/2021-12/31/2022. Proportions of patients with an active prescription of any statin, high intensity statin, ezetimibe, PCSK9i, and combination therapy (two or more agents) within 395 days of the most recent LDL-C value (index date) was evaluated overall and by participating site. Additionally, the proportion of patients with an LDL-C <70 mg/dL at the index date was also assessed. Results: Across 14 health systems, 1,118,623 patients with ASCVD were identified (median 61,840 per health system, range 8,161-182,315). Overall, 675,776 (60.4%) had an LDL-C level in the past year (range 39.1% - 70.8%). Of those with a lipid level, achievement of LDL-C <70 mg/dL ranged from 34.6-47.2%. In total, 42.6% were on any statin, 20.1% were on a high intensity statin, 4.3% on ezetimibe, and 1.2% on a PCSK9i. Only 2.9% were on combination therapy of a statin with ezetimibe or a PCSK9i. Variability was seen across health systems in utilization of each of these therapies, however even in the highest performing health systems, LLT uptake and achievement of LDL-C < 70mg/dL remained low ( Figure). Conclusion: Variability in utilization of LLT in ASCVD patients between health systems suggests that system-level factors may impact achieving guideline-based LDL-C goals. Despite the variability, the highest proportion of patients achieving an LDL-C <70mg/dL remained under 50% indicating the need for aggressive implementation efforts.

Introduction: Guidelines are increasingly recommending a goal LDL-C <55 mg/dL in persons with atherosclerotic cardiovascular disease (ASCVD). The proportion and characteristics of US adults with ASCVD with an LDL-C <55 mg/dL remains unclear. Aims: To evaluate lipid management in ASCVD patients and factors associated with achieving an LDL-C <55mg/dL. Methods: Using electronic health record data from 8 US health systems, we evaluated LDL-C levels and treatment patterns in persons with prevalent ASCVD seen as outpatients between 1/1/2021-12/31/2021 with an LDL-C level within the prior year. Multivariable logistic regression modeling with generalized estimating equations was used to evaluate factors associated with an LDL-C <55 mg/dL. Results: Among 178,240 eligible ASCVD patients, 43.5% (77,472) had an LDL- C <70 mg/dL and 22.0% (39,270) had an LDL-C <55 mg/dL. Older age was associated with higher odds of LDL-C <55 mg/dL (OR 1.10 per 10 years, 95% CI 1.07-1.13), while female sex (OR 0.71, 95% CI 0.68-0.64) Black race (OR 0.77, 95% CI 0.70-0.86), and non-coronary artery disease forms of ASCVD including peripheral artery disease (PAD, OR 0.61, 95% CI 0.58-0.64) and cerebrovascular disease (CeVD, OR 0.72, 95% CI 0.66-0.79) were associated with lower odds of LDL-C <55 mg/dL in multivariable modeling. Overall, while 75.0% were on a statin, only 36.9% were on a high-intensity statin, 5.7% were on ezetimibe, and 1.7% were on a PCSK9i. Combination therapy was rare: only 4.2% were on a statin+ezetimibe, 0.5% on statin+PCSK9i, and 0.3% on all three. Conclusions: Less than a quarter of US patients with ASCVD achieve an LDL <55 mg/dL. Achieving this goal is even less common among younger adults, women, Black persons, and those with PAD and CeVD. Current therapeutic regimens often fail to use high-intensity statins, and markedly underutilize combinations of statins with ezetimibe and/or PCSK9 inhibitors.

Abstract Whether initiation of statins could increase survival free of dementia and disability in adults aged ≥75 years is unknown. PREVENTABLE, a double‐blind, placebo‐controlled randomized pragmatic clinical trial, will compare high‐intensity statin therapy (atorvastatin 40 mg) with placebo in 20,000 community‐dwelling adults aged ≥75 years without cardiovascular disease, disability, or dementia at baseline. Exclusion criteria include statin use in the prior year or for >5 years and inability to take a statin. Potential participants are identified using computable phenotypes derived from the electronic health record and local referrals from the community. Participants will undergo baseline cognitive testing, with physical testing and a blinded lipid panel if feasible. Cognitive testing and disability screening will be conducted annually. Multiple data sources will be queried for cardiovascular events, dementia, and disability; survival is site‐reported and supplemented by a National Death Index search. The primary outcome is survival free of new dementia or persisting disability. Co‐secondary outcomes are a composite of cardiovascular death, hospitalization for unstable angina or myocardial infarction, heart failure, stroke, or coronary revascularization; and a composite of mild cognitive impairment or dementia. Ancillary studies will offer mechanistic insights into the effects of statins on key outcomes. Biorepository samples are obtained and stored for future study. These results will inform the benefit of statins for increasing survival free of dementia and disability among older adults. This is a pioneering pragmatic study testing important questions with low participant burden to align with the needs of the growing population of older adults.

BACKGROUND The United States (US)‐Mexico border is a socioeconomically underserved area. We sought to investigate whether stroke‐related mortality varies between the US border and nonborder counties. METHODS AND RESULTS We used death certificates from the Centers for Disease Control and Prevention Wide‐Ranging Online Data for Epidemiologic Research database to examine stroke‐related mortality in border versus nonborder counties in California, Texas, New Mexico, and Arizona. We measured average annual percent changes (AAPCs) in age‐adjusted mortality rates (AAMRs) per 100 000 between 1999 and 2018. Overall, AAMRs were higher for nonborder counties, older adults, men, and non‐Hispanic Black adults than their counterparts. Between 1999 and 2018, AAMRs reduced from 55.8 per 100 000 to 34.4 per 100 000 in the border counties (AAPC, −2.70) and 64.5 per 100 000 to 37.6 per 100 000 in nonborder counties (AAPC, −2.92). The annual percent change in AAMR initially decreased, followed by stagnation in both border and nonborder counties since 2012. The AAPC in AAMR decreased in all 4 states; however, AAMR increased in California’s border counties since 2012 (annual percent change, 3.9). The annual percent change in AAMR decreased for older adults between 1999 and 2012 for the border (−5.10) and nonborder counties (−5.01), followed by a rise in border counties and stalling in nonborder counties. Although the AAPC in AAMR decreased for both sexes, the AAPC in AAMR differed significantly for non‐Hispanic White adults in border (−2.69) and nonborder counties (−2.86). The mortality decreased consistently for all other ethnicities/races in both border and nonborder counties. CONCLUSIONS Stroke‐related mortality varied between the border and nonborder counties. Given the substantial public health implications, targeted interventions aimed at vulnerable populations are required to improve stroke‐related outcomes in the US‐Mexico border area.

Background: Ischemia with no obstructive coronary artery disease (INOCA) is common and has an adverse prognosis. We set out to describe the natural history of symptoms and ischemia in INOCA. Methods: CIAO-ISCHEMIA (Changes in Ischemia and Angina over One Year in ISCHEMIA Trial Screen Failures With INOCA) was an international cohort study conducted from 2014 to 2019 involving angina assessments (Seattle Angina Questionnaire) and stress echocardiograms 1 year apart. This was an ancillary study that included patients with a history of angina who were not randomly assigned in the ISCHEMIA trial. Stress-induced wall motion abnormalities were determined by an echocardiographic core laboratory blinded to symptoms, coronary artery disease status, and test timing. Medical therapy was at the discretion of treating physicians. The primary outcome was the correlation between the changes in the Seattle Angina Questionnaire angina frequency score and changes in echocardiographic ischemia. We also analyzed predictors of 1-year changes in both angina and ischemia, and we compared CIAO participants with ISCHEMIA participants with obstructive coronary artery disease who had stress echocardiography before enrollment, as CIAO participants did. Results: INOCA participants in CIAO were more often female (66% of 208 versus 26% of 865 ISCHEMIA participants with obstructive coronary artery disease, P <0.001), but the magnitude of ischemia was similar (median 4 ischemic segments [interquartile range, 3–5] both groups). Ischemia and angina were not significantly correlated at enrollment in CIAO ( P =0.46) or ISCHEMIA stress echocardiography participants ( P =0.35). At 1 year, the stress echocardiogram was normal in half of CIAO participants, and 23% had moderate or severe ischemia (≥3 ischemic segments). Angina improved in 43% and worsened in 14%. Change in ischemia over 1 year was not significantly correlated with change in angina (ρ=0.029). Conclusions: Improvement in ischemia and angina were common in INOCA but not correlated. Our INOCA cohort had a degree of inducible wall motion abnormalities similar to concurrently enrolled ISCHEMIA participants with obstructive coronary artery disease. Our results highlight the complex nature of INOCA pathophysiology and the multifactorial nature of angina. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02347215.