Variation in cardiovascular care completion is well documented. However, less is known about differences originating from earlier, intermediate stages such as ordering or scheduling of testing or referrals, despite their role as key prerequisites for care access. To examine the care cascades for coronary artery disease (CAD) after emergency department (ED) visits and to identify the specific stages at which variation emerges for CAD testing and cardiology referrals. This was a retrospective cohort study using data and metadata from electronic health records from a large multicenter health system. Participants were adult patients with established primary care and no history of ischemic heart disease or cardiology care who presented to an ED from January 1, 2020, to June 30, 2022, and underwent a troponin test, a proxy for clinically suspected myocardial ischemia. Variation in cardiovascular follow-up care (CAD testing and cardiology referrals) was identified and analyzed. Analyses were restricted to patients with above-median electrocardiogram (ECG)-derived ischemia risk scores to enrich for higher likelihood of benefit from cardiovascular follow-up. Receipt of an order for CAD testing (stress tests, coronary computed tomography angiography) or cardiology referral, scheduling of the service, and completion within 6 months. Outcomes were compared by insurance type, race and ethnicity, language, and sex using multivariable logistic regression adjusted for demographic characteristics, clinical factors, and ECG-derived cardiovascular risk. Among 16 475 patients with an ED visit (median [IQR] age, 67.4 [54.9-77.9] years; 36% female and 64% male individuals) and elevated cardiovascular risk, marked variation in follow-up care emerged. Compared to commercially insured patients, those with Medicare dual or disabled coverage had lower adjusted odds of completing CAD testing (adjusted odds ratio [aOR], 0.45; 95% CI, 0.36-0.56) and cardiology referrals (aOR, 0.47; 95% CI, 0.39-0.57); similar patterns were seen for Medicaid coverage. Patients whose primary language was not English were less likely to complete either service (CAD testing aOR, 0.77; 95% CI, 0.61-0.98; referral aOR, 0.75, 95% CI, 0.61-0.92), and female patients had lower adjusted odds of completing CAD testing (aOR, 0.86; 95% CI, 0.77- 0.96). Adjusted differences by race and ethnicity were modest. Variation was primarily associated with ordering differences and with additional scheduling barriers for select groups. Once scheduled, completion rates exceeded 75%, without differences between groups. This retrospective cohort study found that among patients who visited the ED with elevated ischemic risk, attrition in follow-up care was concentrated early in care cascades and most pronounced among those with noncommercial health insurance. This stepwise analytic framework offers a novel, reproducible approach for health systems to identify where and for whom care gaps arise, which can enable targeted interventions to improve equity and efficiency.
Patient-facing large language model (LLM) outputs for inflammatory bowel disease (IBD) must be decision-relevant, readable, and verifiable. In a cross-sectional benchmark using a guideline-derived question set, five publicly available LLMs provided answers to 20 single-intent patient IBD questions, mapped to prespecified decision-critical domains across the care pathway (100 model-question responses). Queries were conducted from January 17-24, 2026, via official web interfaces under default settings (privacy mode; new chat per prompt). Two blinded raters evaluated informational quality and completeness (using DISCERN, EQIP, and the Global Quality Scale), transparency proxies (based on JAMA benchmark criteria), and readability through the Automated Readability Index, Flesch Reading Ease, Gunning Fog Index, Flesch-Kincaid Grade Level, Coleman-Liau Index, and SMOG. Overall differences were assessed using within-question paired Friedman tests with Holm adjustment, and effect size was quantified with Kendall's W. Interrater agreement was high [DISCERN ICC(A,1) = 0.842; EQIP ICC(A,1) = 0.760; GQS weighted κ = 0.812; JAMA weighted κ = 0.936]. Median DISCERN scores ranged from 43.5 to 57.5, and EQIP scores ranged from 67.5 to 77.5, while transparency remained limited (JAMA median 0-1/4). Readability consistently failed to meet patient targets, with grade-level indices exceeding sixth grade and Flesch Reading Ease medians ranging from 15 to 36 (compared to a target of ≥80 for "easy" readability). All 10 outcomes varied significantly across models (Holm-adjusted P < 0.001; W = 0.238-0.702). Under default settings, publicly available LLMs exhibit variable informational quality for IBD but consistently poor transparency and readability. Patient-facing deployment should mandate provenance, currency, and disclosure fields, as well as outputs targeted to appropriate grade levels.
Apolipoprotein B (apoB) is a superior marker of residual atherosclerotic cardiovascular disease risk in patients treated with lipid-lowering therapy (LLT) compared with low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C). The cost-effectiveness of LDL-C, non-HDL-C, and apoB goals has not been established. To determine the relative cost-effectiveness of intensifying LLT for primary prevention based on LDL-C, non-HDL-C, and apoB goals. This economic evaluation used a computer simulation model to evaluate the cost-effectiveness of intensifying LLT with high-intensity statins or ezetimibe according to LDL-C, non-HDL-C, or apoB goals. A cohort of 250 000 statin-eligible and atherosclerotic cardiovascular disease-free US adults was constructed from 2005 to 2016 National Health and Nutrition Examination Survey participants (N = 4149). Individuals commenced the simulation after lipid screening and received statin therapy based on 2018 American Heart Association/American College of Cardiology guidelines. Model inputs were derived from national survey data, pooled longitudinal cohort studies, and published literature. Uncertainty was explored with traditional and probabilistic sensitivity analysis. Lipid-lowering therapy was intensified if individuals did not achieve treated LDL-C level less than 100 mg/dL, non-HDL-C level less than 118 mg/dL, or apoB level less than 78.7 mg/dL. Lifetime quality-adjusted life-years (QALYs) and costs (in 2025 US dollars), discounted 3.0% annually. The primary outcome was the incremental cost-effectiveness ratio. Strategies were considered cost-effective if they cost less than $120 000 per QALY gained. Compared with an LDL-C goal, 965 QALYs (95% uncertainty interval [UI], -3551 to 5341 QALYs) would be gained with a non-HDL-C goal, alongside a $2.1 million (95% UI, -$94.2 million to $92.0 million) reduction in costs. Compared with a non-HDL-C goal, 1324 QALYs (95% UI, -2602 to 5669 QALYs) would be gained with an apoB goal, alongside a $40.2 million (95% UI, -$43.6 million to $134 million) increase in costs, yielding an incremental cost-effectiveness ratio of $30 300 per QALY gained. At a willingness-to-pay threshold of $120 000 per QALY gained, an apoB goal was optimal in 65% of probabilistic analyses and a non-HDL-C goal was optimal in 25%. The cost of apoB testing was marginal; higher costs reflected longer life expectancy and prolonged preventive treatment. The results of this computer simulation study suggest that apoB can be used as a cost-effective marker to guide primary prevention LLT and improve population health.
Prepregnancy care and counseling optimize maternal health before conception to improve outcomes for mothers and infants. In the US, 66.4% of reproductive-aged women have at least 1 modifiable risk factor for adverse pregnancy outcomes. For all individuals desiring pregnancy, recommended interventions include folic acid supplementation; cessation of tobacco, alcohol, cannabis, and opioids; immunizations against hepatitis B virus, varicella, and rubella; and screening for syphilis and HIV. Folic acid use before pregnancy is associated with reduced fetal neural tube defects (relative risk [RR], 0.67; 95% CI, 0.52-0.87). Maternal tobacco smoking is associated with increased risks of stillbirth (summary RR [sRR], 1.46; 95% CI, 1.38-1.54), neonatal death (sRR, 1.22; 95% CI, 1.14-1.30), and perinatal death (sRR, 1.33; 95% CI, 1.25-1.41). Screening for and treatment of syphilis and HIV prior to and during pregnancy decrease rates of fetal and neonatal infection. Prepregnancy immunizations against hepatitis B virus, varicella, and rubella decrease neonatal infection and mortality. Individuals using tobacco, alcohol, cannabis, and opioids should receive counseling and treatment prior to pregnancy (eg, buprenorphine or methadone for opioid use disorder). For individuals with chronic disease, routine health examinations and contraceptive care in the year before conception can optimize pregnancy timing and are associated with decreased risk of severe maternal morbidity. Compared with planned pregnancies, unintended pregnancies are associated with increased risk of postpartum depression (15.7% vs 9.6%; adjusted odds ratio [aOR], 1.51; 95% CI, 1.40-1.70), preterm birth (9.4% vs 7.7%; aOR, 1.21; 95% CI, 1.12-1.31), and low infant birth weight (7.3% vs 5.2%; aOR, 1.09; 95% CI, 1.02-1.21). Weight loss prior to conception is recommended for individuals with a body mass index of 25 or greater because overweight and obesity are associated with increased risk of gestational diabetes, gestational hypertension, and cesarean delivery. Among patients with pregestational diabetes (type 1 or 2), hemoglobin A1c of less than 6.5% is associated with a decreased risk of fetal anomaly compared with hemoglobin A1c of 6.5% or greater. Cardiovascular complications such as hypertension and heart failure occur in 15% of pregnancies and are more common among those with preexisting cardiovascular disease. These patients should receive counseling on maternal and neonatal risk, monitoring, and medication management by specialists in cardiology and maternal fetal medicine. Prepregnancy counseling and care reduce maternal morbidity and neonatal morbidity and mortality. Primary care-based discussion of reproductive goals, immunizations, screening for infections and substance use, and risk-reducing interventions such as folate supplementation can optimize outcomes in individuals contemplating pregnancy.
Transcatheter tricuspid valve replacement (TTVR) demonstrated superior outcomes over medical therapy in patients with severe tricuspid regurgitation (TR) in the Edwards EVOQUE Transcatheter Tricuspid Valve Replacement: Pivotal Clinical Investigation of Safety and Clinical Efficacy Using a Novel Device II (TRISCEND II) randomized clinical trial, and received regulatory approval in the US in 2024. Contemporary real-world data on its effectiveness and safety remain limited. To evaluate 30-day clinical, echocardiographic, and health status outcomes of TTVR in real-world use. Retrospective cohort study of all consecutive patients who underwent TTVR in the US from February 2024 through March 2025 in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. Patients had symptomatic, severe TR despite optimal medical therapy and TTVR was deemed appropriate by a heart team. Statistical analysis was conducted from September 2025 to February 2026. Device-enabled TTVR. Thirty-day event rates (all-cause death, stroke, bleeding, new cardiac implantable electronic device [CIED] implantation, heart failure hospitalizations), TR reduction, and changes in health status (New York Heart Association [NYHA] functional class and Kansas City Cardiomyopathy Questionnaire Overall Summary [KCCQ-OS] score) are reported. Subgroup analyses examined the impact of baseline CIED status on outcomes. Among 1034 attempted procedures at 82 centers (mean [SD] age, 77.1 [10.6] years; 69.1% female; 73.2% NYHA functional class III/IV), a valve was successfully implanted in 1017 patients (98.4%). Mild or less TR was achieved in 98.4% of patients post procedure and in 97.7% at 30 days. At 30 days, all-cause mortality was 3.1%; stroke, 0.2%; bleeding, 7.9%; new CIED, 15.9% in CIED-naive patients; and heart failure hospitalization, 3.1%. There were significant improvements in NYHA functional class (class I/II, 82.7%; P < .001) and mean KCCQ-OS score (22.4 points; P < .001) from baseline to 30 days. There were no significant differences in 30-day mortality (P = .47), heart failure hospitalization (P > .99), and functional outcomes (P = .55) when patients were stratified by baseline CIED status. Early US real-world experience with TTVR confirms safety and effectiveness in patients with severe TR. Thirty-day outcomes are consistent with the TRISCEND II pivotal trial, demonstrating acceptable safety, near-complete TR elimination, and significant health status improvements in an older, comorbid population. Rates of new CIED implantation and bleeding were lower than randomized clinical trial experience.
This Medical News article is an interview with Katie Berlacher, MD, MS, an associate professor of medicine at the University of Pittsburgh Medical Center and chair of this year’s American College of Cardiology Scientific Sessions.
Clonal hematopoiesis of indeterminate potential (CHIP) is linked to an increased incidence of cardiovascular and malignant diseases. To determine whether CHIP is associated with cardiotoxic effects in patients with breast cancer receiving trastuzumab. Analyses of human cohorts with complementary animal experimentation were performed using a nationwide population-based cohort (UK Biobank), 1 tertiary referral center (Seoul National University Hospital [SNUH]), and a controlled laboratory setting. UK Biobank participants were enrolled between 2006 and 2010, and SNUH patients were enrolled from January 2004 to March 2024. Data were analyzed from March 2021 to February 2026. Incident heart failure (HF) in the UK Biobank cohort and trastuzumab-related cardiotoxic effects in the SNUH cohort were the main outcome measures. Trastuzumab-related cardiotoxic effects were defined using established clinical criteria (European Society of Cardiology [ESC], Canadian Trastuzumab Working Group, and Cardiac Review and Evaluation Committee [CREC]). Fine-Gray competing risk models were used to account for death and myocardial infarction; multivariable models were adjusted for age and cardiovascular risk factors in both cohorts, with additional adjustment for anthracycline use in the SNUH cohort. Changes in left ventricular ejection fraction (LVEF) were assessed in Tet2-deficient bone marrow chimeric mice following trastuzumab exposure. Overall, 15 729 patients with breast cancer from the UK Biobank cohort (mean [SD] age, 58.8 [7.3] years; 107 [0.68%] male) and 454 female patients with breast cancer who received trastuzumab from the SNUH cohort (mean [SD] age, 52.0 [9.6] years) were included. The corresponding 2-year cumulative incidence values for trastuzumab-related cardiotoxic effects were 15.7% vs 5.0% by ESC criteria (Gray test P = .001), 19.9% vs 10.8% by Canadian criteria (P = .01), and 20.9% vs 11.3% by CREC criteria (P = .02). Using the ESC definition, CHIP positivity (variant allele frequency ≥1.0%) was associated with cardiotoxic effects in multivariable competing risk analysis (adjusted subdistribution hazard ratio, 1.91; 95% CI, 1.32-2.76). Tet2-deficient mice demonstrated a significant LVEF reduction following trastuzumab treatment (effect size, -4.2%; 95% CI, -7.91 to -0.49; P = .03); other experimental groups showed no significant change. In this cohort study, the presence of CHIP was associated with increased susceptibility to trastuzumab-related cardiotoxic effects.
Heart failure (HF) affects more than 64 million individuals worldwide, and acute HF is associated with 1-year mortality rates of 23.6% in North America and Europe. Cardiac dyssynchrony from conduction system disease may cause HF progression, particularly in patients with left ventricular (LV) systolic dysfunction. Electrical dyssynchrony in HF most commonly presents as left bundle-branch block and affects 20% to 30% of patients with reduced LV ejection fraction (LVEF). Cardiac resynchronization therapy, which includes biventricular pacing and conduction system pacing, restores synchronous ventricular contraction and is recommended for patients with symptomatic HF despite optimal medical therapy, LVEF of 35% or less, and left bundle-branch block. Delayed referral for device therapy in this population is associated with worse clinical outcomes. Resynchronization should also be considered for patients requiring chronic ventricular pacing, typically due to symptomatic bradycardia because right ventricular pacing for atrioventricular block may result in ventricular dyssynchrony and increased risk of LV systolic dysfunction. Biventricular pacing uses 2 leads to stimulate the right ventricle and LV simultaneously; conduction system pacing uses a single lead to stimulate the His bundle or left bundle branch. An individual patient-level meta-analysis of 5 randomized clinical trials (N = 3872) reported biventricular pacing was associated with lower all-cause mortality compared with medical therapy or implantable cardioverter-defibrillator over a median follow-up of 23.7 months (13.7% vs 20.8%; hazard ratio, 0.66 [95% CI, 0.57-0.77]). A meta-analysis of 7 small randomized clinical trials, including 408 patients with HF and LVEF of 40% or less, reported that compared with biventricular pacing, conduction system pacing was associated with improvement in LVEF (mean difference, 2.06%; P = .03). An observational study of 1778 patients with LVEF of 35% or less undergoing cardiac resynchronization therapy reported conduction system pacing was associated with lower rates of HF hospitalization (12% vs 19%; hazard ratio, 0.67 [95% CI, 0.52-0.86]). A trial of 249 patients without HF undergoing permanent pacing for atrioventricular block-related bradycardia reported lower rates of pacing-induced cardiomyopathy, defined as a decrease in LVEF of at least 10% to less than 50% after conduction system pacing vs right ventricular pacing (6% vs 15%; P = .01). Cardiac dyssynchrony due to conduction system disease occurs in 20% to 30% of patients with HF and systolic dysfunction. Cardiac resynchronization therapy restores synchronous ventricular activation in patients with HF, reduced LVEF, and left bundle-branch block, or in those requiring chronic ventricular pacing, and may improve LV function, decrease HF hospitalizations, and reduce mortality.
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Underweight and obesity represent opposite ends of the nutritional risk spectrum that negatively affect children's health worldwide. Both conditions have been associated with increased mortality in pediatric patients receiving extracorporeal membrane oxygenation (ECMO) support. To investigate the association of underweight and obesity status with pediatric ECMO outcomes using body mass index (BMI) z scores. This retrospective cohort analysis used data from the Extracorporeal Life Support Organization (ELSO) database from January 1, 2019, to December 31, 2023. Participants included all pediatric patients from international ECMO centers aged 29 days to 18 years who received ECMO support during the study period. Data were analyzed from July 1, 2024 to June 30, 2025. BMI or weight for length. Survival to hospital discharge. A total of 8885 children undergoing their first ECMO run during the study period were included. The median age was 1.9 years (IQR, 0.4-10.7 years), the median weight was 11 kg (IQR, 6-36 kg), and 4773 patients (53.7%) were male. Among the cohort, 6443 patients (72.5%) had a normal weight (z scores -2 to 2), 1458 (16.4%) had underweight (z score <-2), and 984 (11.1%) had obesity (z score >2). Overall hospital survival occurred in 5453 patients (61.2%) but was significantly lower in patients with underweight (849 [58.2%]) and obesity (565 [57.4%]) compared with normal weight (4020 [62.4%]; P < .001). In multivariable logistic regression, having underweight (odds ratio [OR], 1.34; 95% CI, 1.09-1.66; P = .005) and obesity (OR, 1.25; 95% CI, 1.00-1.56; P = .04) were associated with increased hospital mortality. This pattern persisted across subgroup analyses based on age and diagnosis leading to ECMO cannulation. Severe obesity (BMI z score >3) was not associated with mortality. In this cohort study of children receiving ECMO, 1 in 4 had an abnormal BMI, which was associated with increased hospital mortality. Prospective studies are warranted to further elucidate and define the association of nutritional status and clinical outcomes in this population.
Chronic lymphocytic leukemia (CLL) and its immunosuppressive treatment has been suggested to be associated with increased risk of skin cancer. However, detailed long-term evidence of this association is lacking, including whether an increased skin cancer incidence translates into increased risk of skin cancer-specific metastasis and death in patients with CLL. To assess the overall risk of skin cancer, skin cancer subtypes, and skin cancer-specific metastasis and death among patients with CLL compared with individuals without CLL (controls). This nationwide population-based matched cohort study analyzed Danish registry data from January 1990 to December 2020. Follow-up began at CLL diagnosis and continued until an event of interest, death, emigration, or study end. Patients with prior skin cancer or immunosuppression were excluded. Patients with CLL were matched 1:5 with controls based on birth year, sex, geographic region, educational level, income, marital status, and Charlson Comorbidity Index score. Data were analyzed from June to September 2025. Absolute risks and risk differences for overall skin cancer, basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, melanoma, cutaneous lymphoma, and skin cancer-specific metastasis and death. All risks were estimated using multivariable cause-specific Cox proportional hazards regression models with death from other causes as a competing risk. Among the 8352 patients with CLL included in the study (median age, 70.7 years [IQR, 62.2-78.3 years]; 4902 [58.7%] male), the absolute 10-year risk of skin cancer was 13.5% (95% CI, 12.7%-14.3%) compared with 6.9% (95% CI, 6.6%-7.2%) among 41 760 controls (median age, 70.7 years [IQR, 62.2-78.2 years]; 24 510 [58.7%] male), resulting in an absolute risk difference (ARD) of 6.6 percentage points (pp) (95% CI, 5.7-7.4 pp; P < .001). Patients with CLL had an increased risk of most skin cancer subtypes compared with controls, with the most common being basal cell carcinoma (8.6% [95% CI, 7.9%-9.2%] vs 5.4% [95% CI, 5.2%-5.7%]; ARD, 3.2 pp [95% CI, 2.4-3.8 pp]; P < .001) and squamous cell carcinoma (4.7% [95% CI, 4.2%-5.2%] vs 1.4% [95% CI, 1.3%-1.6%]; ARD, 3.3 pp [95% CI, 2.8-3.8 pp]; P < .001). Patients with CLL, compared with controls, had a higher risk of both skin cancer metastasis (0.7% [95% CI, 0.4%-0.9%] vs 0.1% [95% CI, 0.1%-0.2%]; ARD, 0.6 pp [95% CI, 0.3-0.7 pp]; P < .001) and skin cancer-specific death (0.3% [95% CI, 0.2%-0.4%] vs 0.1% [95% CI, 0.1%-0.1%]; ARD, 0.2 pp [95% CI, 0.1-0.3 pp]; P = .004). All-cause mortality among patients with CLL was 56.3% (95% CI, 55.3%-57.2%) compared with 39.3% (95% CI, 38.8%-39.8%) among controls (ARD, 17.0 pp; 95% CI, 16.0-18.0 pp; P < .001). This cohort study found that patients with CLL had an increased risk of developing skin cancer, mainly basal cell carcinoma and squamous cell carcinoma. Skin cancer-specific metastasis and death were also more frequent among patients with CLL, although the absolute risk remained low given markedly higher all-cause mortality.
Several integrative indices at the neighborhood level have been developed in the US, but direct comparisons across these indices for the prevalence of cardiovascular-kidney-metabolic (CKM) conditions are limited. Moreover, it is not known whether certain indices better capture place-based variability in CKM conditions or provide additional information when compared with a single measure of income. To determine how much variability is explained by neighborhood indices in the prevalence of CKM conditions at the census tract level and the incremental value of each index when added to median household income. This cross-sectional study of US national surveillance data (Behavioral Risk Factor Surveillance System and American Community Survey) included all census tracts with complete data for exposures, covariates, and outcomes from 2010 to 2022. Analyses were completed between October 2024 and July 2025. Seven neighborhood indices available at the census tract level (Area Deprivation Index, Child Opportunity Index, Environmental Justice Index, Neighborhood Deprivation Index, Social Deprivation Index, Social Vulnerability Index, Structural Racism Effect Index) and median household income at the census tract level from the American Community Survey. The primary outcome was prevalence of CKM conditions (coronary heart disease [CHD], stroke, and chronic kidney disease [CKD]) at the census tract level. Differences in the exposures and outcomes were visualized by mapping index scores, median household income, and prevalences of CKM conditions for all census tracts. To assess index agreement, pairwise correlations were computed with Spearman rank correlation coefficients, and to assess the incremental variability explained by each index when added to median household income, change in r2 was calculated. Of the 65 476 US census tracts included, median (IQR) prevalence was 5.9% (4.7%-7.4%) for CHD, 3.3% (2.6%-4.1%) for stroke, and 2.9% (2.5%-3.4%) for CKD. The indices and income were modestly to highly correlated (range, 0.46-0.94), with some discordance in how each measure classified census tracts by quartiles of index scores. All indices and income were significantly associated with CKM condition prevalence at the census tract level in multivariable linear regression models, adjusted for median population size and age. The r2 values of the indices with CHD, stroke, and CKD ranged from 0.379 (SE = 0.033) for the correlation between the Environmental Justice Index and stroke to 0.688 (SE = 0.002) for the correlation between the Structural Racism Effect Index and stroke. Additionally, the improvement in variability for CHD, stroke, and CKD (change in r2) explained by the addition of each index to income ranged from 0.014 (SE = 0.001) for the correlation between the Environmental Justice Index and CHD to 0.195 (SE = 0.002) for the correlation between Structural Racism Effect Index and stroke. In this cross-sectional study, there were similar associations across neighborhood indices and income with the prevalence of CKM conditions. These findings inform how different place-based measures can be applied in public health research and policy.
Many adults fail to achieve guideline-directed low-density lipoprotein cholesterol (LDL-C) goals on statin monotherapy, requiring additional nonstatin lipid-lowering medication. Enlicitide, an oral proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor, lowered LDL-C by 60% compared with placebo; its efficacy compared with other oral nonstatin therapies has yet to be examined. This study assessed the efficacy of enlicitide, a novel oral PCSK9 inhibitor, vs other oral nonstatin therapies. In this phase 3, randomized, double-blind, active-comparator trial, statin-treated adults aged ≥18 years with LDL-C ≥55 mg/dL and a previous major atherosclerotic cardiovascular disease (ASCVD) event, or LDL-C ≥70 mg/dL if at intermediate to high risk for a first event, were randomized in 2:1:1:2 fashion to 20 mg enlicitide (n = 101), 180 mg bempedoic acid (n = 50), 10 mg ezetimibe (n = 50), or 180 mg bempedoic acid plus 10 mg ezetimibe (n = 100) once daily for 56 days. The primary endpoint was mean percentage change in LDL-C from baseline to day 56; secondary endpoints included mean percentage changes in apolipoprotein B (ApoB) and non-high-density lipoprotein cholesterol (nonHDL-C). Safety endpoints included overall adverse events (AEs) and discontinuations due to AEs. Among 301 randomized participants (mean age 64.4 years, 37% female, 98% receiving moderate- to high-intensity statin), 298 (99.0%) completed the trial. The mean percentage change in LDL-C from baseline to day 56 was -64.6% (95% CI: -68.3% to -60.9%) with enlicitide, -6.3% (95% CI: -13.5% to 0.8%) with bempedoic acid, -27.8% (95% CI: -32.3% to -23.4%) with ezetimibe, and -36.5% (95% CI: -40.8% to -32.2%) with bempedoic acid plus ezetimibe; enlicitide was superior to each comparator (all P < 0.001). Reductions in ApoB and nonHDL-C were also greater with enlicitide (all P < 0.001). Proportions of participants with AEs and discontinuations due to AEs were similar across treatment arms. In statin-treated adults with a history of a major ASCVD event or at increased risk for a first event, enlicitide achieved greater reductions in LDL-C, ApoB, and nonHDL-C than other oral nonstatin therapies, demonstrating its potential role as an important add-on option when LDL-C goals are not met with the use of statins alone. (A Study to Evaluate the Efficacy and Safety of Enlicitide Decanoate [MK-0616, Oral PCSK9 Inhibitor] Compared With Ezetimibe or Bempedoic Acid or Ezetimibe and Bempedoic Acid in Adults With Hypercholesterolemia [MK-0616-018] [CORALreef AddOn; NCT06450366).
Familial hypercholesterolemia is a common genetic disorder associated with premature cardiovascular disease. Genetic cascade screening is recommended but remains underused due to privacy laws that prevent clinicians from directly contacting at-risk relatives. To examine whether implementing a web-based communication platform in a patient-mediated genetic cascade screening program for familial hypercholesterolemia increases uptake compared with usual care. This open-label, multicenter, implementation randomized clinical trial (CATCH) was conducted between November 1, 2020, and October 31, 2023, at 7 cardiovascular prevention or lipid clinics across Switzerland, representing French-, German-, and Italian-speaking regions. Adults aged 16 years or older with genetically confirmed familial hypercholesterolemia and at least 1 eligible first-degree relative living in Switzerland participated. A total of 87 index patients with 359 eligible first-degree relatives were randomized by family cluster (1:1) to the intervention or usual care arm. A secure web-based platform allowing participants to send preprepared electronic messages (email or text) to their relatives, linking them directly to participating centers for genetic testing. The primary outcome was cascade screening uptake, defined as the proportion of eligible first-degree relatives undergoing genetic testing within 6 months. The secondary outcome was new cases identified. Among 221 adults screened across multiple families, 87 (39.4%) had genetically confirmed familia hypercholesterolemia (median [IQR] age, 49.2 [16.4-83.7] years; 46 [52.9%] female; median [IQR] highest low-density lipoprotein cholesterol, 289.58 [139.00-498.07] mg/dL); 43 were randomized to the usual care arm, and 44 were randomized to the intervention arm. Among the 359 eligible relatives (median family size, 4), 99 (27.6%) underwent genetic testing. Uptake was higher in the intervention arm (30.4%; 95% CI, 22.0%-40.4%) than in usual care arm (16.7%; 95% CI, 10.1%-26.3%), yielding an odds ratio of 2.18 (95% CI, 1.06-4.51; P = .03). New case identification was also greater (17.0% vs 8.1%; odds ratio, 2.32; 95% CI, 1.07-5.05; P = .03). Newly identified patients were often untreated or had modifiable risk factors. In this randomized clinical trial of patient-mediated genetic cascade screening supported by a web-based platform, participation in genetic testing and detection of familial hypercholesterolemia was increased compared with usual care. These results suggest that the use of digital communication tools enhanced the reach and effectiveness of genetic screening programs within privacy-regulated health systems. ClinicalTrials.gov Identifier: NCT04419090.
Psoriasis is a chronic immune-mediated disease associated with cardiovascular, metabolic, musculoskeletal, psychiatric, hepatic, kidney, and pulmonary comorbidities. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are approved by the US Food and Drug Administration for type 2 diabetes, obesity, cardiovascular risk reduction, chronic kidney disease, obstructive sleep apnea, and metabolic dysfunction-associated steatohepatitis-conditions common in psoriasis. Emerging evidence suggests GLP-1 RAs and dual glucose-dependent insulinotropic polypeptide/GLP-1 agonists may improve psoriatic skin disease, partly through immune modulation. If confirmed in larger randomized clinical trials, GLP-1-based therapies may offer an opportunity to address both cutaneous disease and cardiometabolic comorbidities. This primer from the US National Psoriasis Foundation Medical Board sought to provide an evidence-informed narrative synthesis and practical considerations to introduce dermatologists to GLP-1 RAs for psoriasis treatment. GLP-1 RAs have been associated with reductions in Psoriasis Area and Severity Index (PASI) scores, particularly in patients with obesity or type 2 diabetes. Studies report relative PASI reductions ranging from approximately 40% to 80% with parallel quality-of-life gains, although most of these studies are small (7-48 patients), short term (≤6 months), and lack a control group. Semaglutide and liraglutide have been associated with reductions in C-reactive protein, interleukin-6, lipids, and visceral adiposity. In small, translational cohorts, PASI improvement has been correlated with reductions in superficial adiposity and dermal γδ T-cell density. GLP-1 RAs combine safely with methotrexate, cyclosporine, and biologics. Adverse effects are mainly transient gastrointestinal symptoms; pancreatitis and gallbladder events are rare. Early data show both metabolic and immunomodulatory benefits. This review found that GLP-1-based therapies target shared metabolic and inflammatory pathways in psoriasis. Current evidence supports consideration of adjunctive use in selected patients with metabolic comorbidities, although definitive conclusions await larger randomized clinical trials.
The management of patients with coronary artery disease requiring percutaneous coronary revascularisation has undergone a significant transformation over the past several decades. With the increasing use of early invasive strategies, the role of pretreatment with oral antiplatelet agents has evolved. Additionally, the introduction of novel agents such as cangrelor has had a significant impact on the management of thrombotic risk. In this review, we summarise the current evidence on the role of pretreatment with antiplatelet agents across the spectrum of coronary artery disease, from non-ST-segment elevation acute coronary syndromes and ST-segment elevation myocardial infarction to stable coronary artery disease. We also highlight data on novel parenteral agents, both available and in development.
Timely prescription of quadruple guideline-directed medical therapies (GDMTs) for patients with heart failure with reduced ejection fraction (HFrEF) is associated with improved morbidity and mortality, yet contemporary estimates of time to quadruple therapy (TTQ) and the factors associated with its achievement remain unknown. To characterize TTQ and factors associated with TTQ in HFrEF. This was a retrospective cohort study including patients with incident HFrEF from the Veterans Health Administration database during the January 1, 2020, to December 31, 2023, period. Study data were analyzed from November 2024 to December 2025. Primary factors included race and ethnicity, sex, and copay status (priority group). Secondary factors included clinical characteristics. The main outcome included quadruple therapy according to pharmacy fill data-concurrent use of evidence-based β-blockers, renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors. TTQ was defined as the first date that all 4 medication classes overlapped, based on dispense date and days' supply. Among 52 850 patients with incident HFrEF (median [SD] age, 71.8 [11] years; 51 473 male [97%]; 10 791 Black [20%]; 2528 Hispanic [5%]; 35 867 White [68%]; 3664 other [7%]), 11 217 (21.2%) achieved quadruple therapy over a median (IQR) follow-up of 2.9 (1.9-3.9) years. The median (IQR) TTQ was 197 (49-528) days. After adjustment, Black patients (hazard ratio [HR], 1.22; 95% CI, 1.15-1.30), Hispanic patients (HR, 1.21; 95% CI, 1.09-1.33), and those from other racial or ethnic groups (HR, 1.11; 95% CI, 1.02-1.20) had higher rates of quadruple therapy than White patients. There was no difference in TTQ in females vs males (HR, 0.97; 95% CI, 0.86-1.09). Prescription copays (priority groups 2-8) were associated with an 8% lower rate of achieving quadruple therapy (HR, 0.92; 95% CI, 0.87-0.96) than no prescription copay (priority group 1). Rates of quadruple therapy were higher among veterans with an outpatient HFrEF diagnosis vs inpatient (22.2% vs 14.2%), with diabetes vs without diabetes (23.6% vs 19.3%), and without chronic kidney disease vs with chronic kidney disease (22.5% vs 18.1%). Results of this cohort study suggest that opportunities exist to improve both the rate and timeliness of quadruple therapy as only 21.2% of patients with HFrEF achieved it, with a median follow-up of 2.9 years and TTQ of 6 months. Medication copays represent a modifiable barrier, providing a potential target for interventions to enhance TTQ.
In individuals with heterozygous familial hypercholesterolemia (HeFH), it is uncertain whether and to what extent the reduction in low-density lipoprotein cholesterol (LDL-C) with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor therapy is dependent on the residual functional activity of the LDLR gene carrying the pathogenic variant. To evaluate the reduction in LDL-C achieved with PCSK9 inhibition according to FH genotype in a large cohort of patients with HeFH. This nonrandomized clinical trial reports on a predefined, pooled subanalysis of participants with HeFH requiring additional lipid-lowering therapy in the open-label worldwide phase 3 study of the PSCK9 inhibitor lerodalcibep. This study included participants randomized to 5 phase 3 studies with the plasma PSCK9 inhibitor lerodalcibep and who participated in the open-label extension study from December 2020 to May 2025. Data were analyzed from March 2025 to February 2026. All participants received lerodalcibep 300 mg subcutaneously monthly for 72 weeks. The co-primary efficacy end points were LDL-C reduction at weeks 48 and 72. Secondary and exploratory end points included LDL-C response according to FH genotype and the achievement of currently recommended LDL-C goals. Among 703 included participants (mean [range] age, 53.8 [18-80] years; 372 male [52.9%]), 86 (12.2%) were Black, South Asian, or multiracial and 617 (87.8%) were White; 217 participants (72.3%) had atherosclerotic cardiovascular disease (ASCVD) or were at very high risk for ASCVD and 195 participants (27.7%) were at high risk for ASCVD. Despite most participants receiving treatment with statins or ezetimibe, the mean (SD) baseline LDL-C was 144.9 (61.9) mg/dL. Mean (SD) reductions in LDL-C associated with lerodalcibep were 50.3% (28.9%) and 50.3% (28.7%) (mean [SD] absolute change, -72.6 [50.5] mg/dL and -71.8 [48.0] mg/dL) at weeks 48 and 72, respectively. Of 740 participants (92.5%) who underwent genetic testing, monogenic FH-causing variants were found in 455 participants (61.5%), including 432 participants (95.7%) with the LDLR pathogenic variant. LDL-C reduction with lerodalcibep was independent of LDLR variant functional activity. More than 70% of participants achieved both a reduction in LDL-C of at least 50% and their ASCVD risk-based LDL-C goal. These findings suggest that lerodalcibep was associated with significantly and consistently reduced LDL-C in patients with HeFH, with response found to be independent of LDLR function of the pathogenic variant. These findings support that LDL-C reductions in patients with HeFH with PCSK9 inhibition are predominantly mediated by upregulation of the unaffected wild-type LDLR. ClinicalTrials.gov Identifier: NCT04798430.
This cross-sectional study examines trends in prescribing nonstatin lipid-lowering therapy in the US from 2019 to 2024 vs statin prescribing.