Catapano AL, Mikhailova E, Navar AM
… +10 more, Banka P, Corral P, Saxena M, Steg PG, Verma S, Kordahi AY, Mendizabal G, Zhu P, Ballantyne CM, CORALreef AddOn Investigators
J Am Coll Cardiol
· 2026 Mar · PMID 42017875
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BACKGROUND: 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...BACKGROUND: 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. OBJECTIVES: This study assessed the efficacy of enlicitide, a novel oral PCSK9 inhibitor, vs other oral nonstatin therapies. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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).
The first Tricuspid Valve Academic Research Consortium publication standardized definitions of disease etiology and severity, as well as standardized endpoints for trials to address the knowledge gaps related to identifi...The first Tricuspid Valve Academic Research Consortium publication standardized definitions of disease etiology and severity, as well as standardized endpoints for trials to address the knowledge gaps related to identification and management of patients with tricuspid regurgitation. Based on randomized trials comparing transcatheter tricuspid valve intervention with optimal medical therapy, transcatheter edge-to-edge repair and tricuspid valve replacement were approved by the U.S. Food and Drug Administration and received CE Mark. These technologies represent a major step forward for patients with severe symptomatic tricuspid regurgitation and transcatheter tricuspid valve intervention. This second chapter of the Tricuspid Valve Academic Research Consortium focuses on defining specific trial design and endpoint options for comparisons of emerging technologies, tricuspid valve surgery, and medical therapy.
Recent trials have shown that glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dual gastric inhibitory polypeptide/GLP-1 RAs improve symptoms and functional capacity in patients with heart failure (HF) with pres...Recent trials have shown that glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dual gastric inhibitory polypeptide/GLP-1 RAs improve symptoms and functional capacity in patients with heart failure (HF) with preserved ejection fraction and obesity, with or without type 2 diabetes. These studies enrolled modest sample sizes and had few worsening HF events or cardiovascular (CV) deaths, limiting definitive conclusions regarding those endpoints. At the same time, the benefits of these drugs on major adverse CV and kidney outcomes in patients with obesity, diabetes, and chronic kidney disease raise questions about placebo-controlled designs in future HF trials. This article explores scientific, practical, and ethical considerations surrounding the design of future incretin-based therapy trials in HF. We highlight the current gaps in evidence and emphasize the need for event-driven outcome trials in HF. The use of placebo ensures methodologic rigor but may raise ethical concerns in the context of cardiometabolic benefit with GLP-1 RAs. Abandoning placebo, however, risks incomplete safety and efficacy data and premature therapeutic extrapolation. Such studies are essential to define the efficacy, durability, and safety of incretin-based therapy across the HF spectrum and to clarify whether improvements in patient-reported outcomes are bolstered by other benefits. To support balanced decision making, we introduce a structured framework outlining when placebo remains appropriate, when active comparison may be required, and how trial design features can address the ethical and operational challenges unique to incretin-based HF research. Ethically robust, clinically focused, and methodologically rigorous trials remain the only means to inform guideline recommendations and insurance coverage. The HF population is too large, too vulnerable, and too costly to remain without definitive evidence guiding the use of these therapies.
Cardiovascular disease (CVD) is highly prevalent in patients receiving hemodialysis and is the leading cause of mortality in this population. Cardiovascular randomized clinical trials frequently exclude patients with kid...Cardiovascular disease (CVD) is highly prevalent in patients receiving hemodialysis and is the leading cause of mortality in this population. Cardiovascular randomized clinical trials frequently exclude patients with kidney failure or on hemodialysis for a variety of reasons, and the current practice is generally to apply guidelines for the management of CVD in patients without kidney failure to patients on hemodialysis. However, the benefits seen in patients without kidney failure have not always translated to those receiving hemodialysis, because the etiology of vascular disease differs, drug metabolism varies, the risk for individual outcomes is different, and the patients are subject to higher all-cause mortality risk. There are several barriers to conduct cardiovascular outcome trials in patients receiving hemodialysis and more efforts are needed to bridge the evidence gap for this population. In this narrative review, we discuss the current state of cardiovascular outcome trials in patients receiving hemodialysis, the barriers that have hindered clinical trial conduct, the potential opportunities in studying this population, and the solutions as well as future directions to improve the evidence derived from clinical trials in patients on hemodialysis.
Khan S, Sajjad U, Fawaz S
… +18 more, Butt H, Simpson R, Ibrahim A, Robertson C, Kelly P, Mohdnazri SR, Tang K, Cook CM, Demir OM, O'Kane P, Spratt JC, Brilakis ES, Karamasis GV, Shun-Shin M, Al-Lamee R, Keeble TR, Davies JR, ORBITA-CTO Investigators
J Am Coll Cardiol
· 2026 Mar · PMID 41999379
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BACKGROUND: Percutaneous coronary intervention for coronary chronic total occlusion (CTO PCI) is offered for symptom and quality of life improvement, despite the absence of blinded randomized evidence. OBJECTIVES: The ai...BACKGROUND: Percutaneous coronary intervention for coronary chronic total occlusion (CTO PCI) is offered for symptom and quality of life improvement, despite the absence of blinded randomized evidence. OBJECTIVES: The aim of this study was to assess the efficacy of CTO PCI in the first randomized, placebo-controlled trial of CTO PCI. METHODS: ORBITA-CTO is a multicenter, randomized, blinded trial comparing CTO PCI with a placebo procedure. Patients had angina attributable to a single-vessel CTO, without bystander coronary disease. Angina symptoms were recorded daily using the ORBITA app. After dual-injection coronary angiography, patients were randomized to either CTO PCI or placebo. Blinding was maintained using auditory isolation and deep conscious sedation. Antianginal medications were stopped at randomization and reintroduced on a patient-initiated protocol. At the 6-month follow-up, assessments were repeated. The primary efficacy outcome was the angina symptom score, an ordinal scale combining the daily symptom burden assessed by the ORBITA app, antianginal use, and over-ride events. Secondary outcomes were symptom and quality of life questionnaires and blinding fidelity. RESULTS: Between October 19, 2021 and October 21, 2025, 50 patients were randomly assigned to CTO PCI (n = 25) or placebo (n = 25). One patient randomized to PCI was withdrawn during the procedure because of a complication. All 50 patients were included in the primary analysis. Compared with placebo, CTO PCI resulted in an immediate and sustained improvement in the angina symptom score (OR: 4.38; 95% credible interval [CrI]: 1.57-12.69; probability of benefit [Pr{Benefit}] = 0.996), arising from a clear reduction in the number of episodes of angina (OR: 4.38; 95% CrI: 1.55-11.78; Pr[Benefit] = 0.997). This resulted in an additional 30.6 days free of angina (95% CrI: 11.1-50.7; Pr[Benefit] >0.999). Improvements were also observed with the Seattle Angina Questionnaire in angina frequency (+10.7; 95% CrI: 1.4-20.2; Pr[Benefit] = 0.988), physical limitation, quality of life, and summary score and Canadian Cardiovascular Society class. Blinding of patients, staff, and researchers was maintained. CONCLUSIONS: In patients with symptomatic single-vessel CTO, CTO PCI improves angina beyond placebo. (A Placebo-controlled Trial of Chronic Total Occlusion Percutaneous Coronary Intervention for the Relief of Stable Angina [ORBITA-CTO]; NCT05142215).
Hamatani Y, Claggett BL, Desai AS
… +9 more, Lewis EF, Jhund PS, Lam CSP, Martinez FA, Zannad F, Pfeffer MA, McMurray JJV, Solomon SD, Vaduganathan M
J Am Coll Cardiol
· 2026 Jun · PMID 41995644
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BACKGROUND: The 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ-23) is formally qualified by the Food and Drug Administration as a valid patient-reported outcome measure for use in heart failure (HF) clinical tria...BACKGROUND: The 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ-23) is formally qualified by the Food and Drug Administration as a valid patient-reported outcome measure for use in heart failure (HF) clinical trials. However, its length may increase respondent burden. The 12-item version (KCCQ-12) provides a more efficient alternative but was originally developed and validated in HF with reduced left ventricular ejection fraction (LVEF), and its performance relative to the KCCQ-23 has not been evaluated in HF with mildly reduced or preserved LVEF (HFmrEF/HFpEF). OBJECTIVE: The purpose of this study is to examine the interchangeability of KCCQ-12 and KCCQ-23 in patients with HFmrEF/HFpEF. METHODS: We conducted a participant-level pooled analysis of 4 randomized clinical trials (TOPCAT, PARAGON-HF, DELIVER, and FINEARTS-HF), including adults with HFmrEF/HFpEF. All trials collected the KCCQ-23 at baseline and follow-up visits. In this study, the KCCQ-12 overall summary scores (OSS) were derived from individual items of the KCCQ-23 OSS. Both scores ranged from 0 (worst) to 100 (best). We assessed concordance between KCCQ-12 OSS and KCCQ-23 OSS and compared prognostic discrimination and treatment-related changes. RESULTS: Of 18,216 participants (mean age: 72 ± 9 years; female: 46%; NYHA functional class II: 72%; mean LVEF: 55 ± 8%; median N-terminal pro-B-type natriuretic peptide levels: 987 [IQR: 517-1,781] pg/mL), baseline KCCQ-23 OSS was 65.5 ± 21.4, and KCCQ-12 OSS was 64.1 ± 21.7. Baseline KCCQ-12 OSS strongly correlated with KCCQ-23 OSS (Spearman ρ = 0.987), consistent across major subgroups and follow-up visits (all Spearman ρ > 0.980). Prognostic discrimination for cardiovascular death and HF hospitalization was comparable (C index: 0.583 for KCCQ-23 vs 0.586 for KCCQ-12). Treatment effects of HF drugs on KCCQ-OSS were similar across the 2 instruments in each trial and at each time point (all the differences between KCCQ-23 and KCCQ-12 were <1 point on a 0-100 scale). CONCLUSIONS: In patients with HFmrEF/HFpEF, the KCCQ-12 closely parallels the KCCQ-23, demonstrating comparable prognostic performance and treatment responsiveness. These findings support the KCCQ-12 as a lower-burden alternative for use in HF clinical trials. (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist; NCT00094302; Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin Receptor Blocker Global Outcomes in HF with Preserved Ejection Fraction; NCT01920711; Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure; NCT03619213; Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients with Heart Failure; NCT04435626).
BACKGROUND: Drug-eluting stents (DESs) are recommended treatment for coronary in-stent restenosis (ISR) but are not used in >20% of cases. OBJECTIVES: The aim of the SELUTION4ISR (SELUTION SLR 014 In-stent Restenosis) tr...BACKGROUND: Drug-eluting stents (DESs) are recommended treatment for coronary in-stent restenosis (ISR) but are not used in >20% of cases. OBJECTIVES: The aim of the SELUTION4ISR (SELUTION SLR 014 In-stent Restenosis) trial was to assess the safety and effectiveness of a novel sirolimus drug-eluting balloon (DEB). METHODS: After successful lesion predilation, patients with ISR were randomly assigned to the SELUTION Sustained Limus Release (MedAlliance) DEB or a control strategy of usual care, including any approved DES or balloon angioplasty (BA) on the basis of operator selection prerandomization. Randomization to selected BA control treatment was limited to 20% of patients. The primary outcome was target lesion failure (TLF) (cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization) assessed at 1 year in the per protocol group (all treated eligible patients with complete primary endpoint follow-up). Noninferiority was established if the upper limit of the 2-sided 95% credible interval was smaller than 10%. A sequential secondary hypothesis test was performed comparing DEB with DES in patients with single-layer ISR. RESULTS: From July 2020 to July 2024, 418 patients were randomly assigned to the DEB group (n = 210) or the control group (n = 208), with 390 patients per protocol (DEB, 197; control, 193 [154 DES; 39 BA]). TLF occurred in 32 (16.2%) of 197 patients in the DEB group and in 28 (14.5%) of 193 patients in the control group (difference: 1.7%; 95% credible interval: -5.5% to 8.9%; posterior probability of noninferiority: 98.80%). In the secondary hypothesis test, TLF occurred in 22 (14.2%) of 155 patients in the DEB group and in 9 (6.5%) of 138 patients in the DES control group (difference: 7.7%; 95% credible interval: 0.6%-14.6%, posterior probability for noninferiority: 76.07%). TLF according to operator selected control was higher for DEB compared with DES (15.3% vs 7.1%; difference: 8.1%; 95% credible interval: 1.4%-15.0%) and lower for DEB compared with BA (23.6% vs 43.6%; difference: 23.7%; 95% credible interval: -41.4% to -1.5%; P = 0.0026). CONCLUSIONS: The sirolimus DEB was noninferior to a usual care control strategy including 80% repeat DES but not noninferior to DES for single-layer ISR for TLF at 12 months. There was significant interaction on the basis of operator selection of DES vs BA. (SELUTION SLR 014 In-stent Restenosis [SELUTION4ISR]; NCT04280029).
Bu F, Wu R, Ostropolets A
… +18 more, Aminorroaya A, Chen HY, Chai Y, Dhingra LS, Falconer T, Hsu JC, Kim C, Lau WCY, Man KKC, Minty E, Morales DR, Nishimura A, Thangraraj P, Van Zandt M, Yin C, Khera R, Hripcsak G, Suchard MA
J Am Coll Cardiol
· 2026 Jun · PMID 41984016
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BACKGROUND: Glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2Is) have established cardiovascular benefits for patients with type 2 diabetes mellitus (T2DM), with si...BACKGROUND: Glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2Is) have established cardiovascular benefits for patients with type 2 diabetes mellitus (T2DM), with similar class-level effectiveness found in previous studies. However, real-world comparative effectiveness assessments of individual agents remain limited. OBJECTIVES: The goal of this study was to compare the cardiovascular effectiveness of individual GLP-1RAs and SGLT2Is. METHODS: We conducted a multinational, retrospective, new-user active-comparator cohort study using 10 U.S. and non-U.S. administrative claims and electronic health record databases. The study included 1,245,211 adults with T2DM receiving metformin who initiated second-line therapy with 1 of 6 GLP-1RAs (albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide) or 1 of 4 SGLT2Is (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin). Empagliflozin (393,499; 31.6%), semaglutide (235,585; 18.9%), dapagliflozin (208,666; 16.8%), and dulaglutide (207,348; 16.8%) were most commonly used. A secondary subgroup analysis included 316,242 patients with established cardiovascular diseases (CVDs). Primary outcomes were 3-point major adverse cardiovascular events (MACEs) (acute myocardial infarction, stroke, sudden cardiac death) and 4-point MACE (adding hospitalization/emergency room visit with heart failure). Secondary outcomes included the individual components. HRs were estimated for pairwise agent comparisons while on-treatment (per-protocol) and over total follow-up using Cox proportional hazards models, with propensity score adjustments, negative control calibration, and prespecified study diagnostics to guard against potential confounding. Random-effects meta-analysis produced summary HR estimates across data sources that passed diagnostics. RESULTS: Across the study cohort, individual GLP-1RAs and SGLT2Is demonstrated broadly similar cardiovascular effectiveness, both within and across drug classes. For example, semaglutide and empagliflozin showed comparable risks for 3-point MACE (meta-analytic HR: 1.05; 95% CI: 0.79-1.39) and 4-point MACE (meta-analytic HR: 0.95; 95% CI: 0.81-1.12), with consistent findings in the CVD subgroup. Study diagnostics confirmed adequate equipoise, covariate balance, and statistical power to detect similarity in HRs between 0.8 and 1.2 for commonly used agents. CONCLUSIONS: In this large-scale real-world study, individual GLP-1RAs and SGLT2Is exhibited largely comparable cardiovascular benefits, including in patients with established CVD. These findings align with network meta-analytic estimates from major cardiovascular outcome trials and broadly support current treatment guidelines. Clinical choices should be guided by relevant factors such as safety, adherence, tolerability, cost, and patient preference, where further work is needed.
Zhang Y, Zhang S, Wang Y
… +4 more, Spatz ES, Krumholz HM, Lu Y, Chen K
J Am Coll Cardiol
· 2026 May · PMID 41984014
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BACKGROUND: Although long-term exposure to fine particulate matter (particles ≤ 2.5 μm in diameter [PM]) has been linked to adverse cardiovascular outcomes, evidence remains limited regarding the effects of PM at concent...BACKGROUND: Although long-term exposure to fine particulate matter (particles ≤ 2.5 μm in diameter [PM]) has been linked to adverse cardiovascular outcomes, evidence remains limited regarding the effects of PM at concentrations below current regulatory standards on hypertension-related hospitalization. OBJECTIVES: In this study, we examined the association between long-term exposure to PM concentrations below the U.S. Environmental Protection Agency annual standard of 9 μg/m and the risk of hypertension-related hospitalization among Medicare beneficiaries aged ≥65 years across the contiguous United States from 2017 to 2022 using a causal inference approach. METHODS: We constructed a national cohort of more than 26 million older adults from the Medicare database residing in ZIP codes where annual PM concentrations consistently remained below 9 μg/m throughout the study period. To address unmeasured confounding, we used a double-negative control approach. Secondary analyses compared the main findings with results from conventional quasi-Poisson regression models and examined effect modification by population subgroups. RESULTS: Each 1-μg/m increase in the annual PM concentration was associated with a 2.8% (95% CI: 2.5-3.2) increase in hypertension-related hospitalization among all beneficiaries, comparable with estimates from conventional quasi-Poisson regression models. Greater vulnerability was observed among women, residents of the Midwest and Northeast, those living in rural or suburban areas, and individuals in more socioeconomically deprived neighborhoods. CONCLUSIONS: These findings suggest that even PM exposures below current regulatory thresholds in the United States may contribute to increased hypertension risk, emphasizing the need to reconsider existing air quality standards to better protect public health.
Li Y, Yan F, Yu L
… +7 more, Xu J, Wu T, Cao J, Zhang Y, Wang L, Zhou M, Yin P
J Am Coll Cardiol
· 2026 May · PMID 41984013
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BACKGROUND: Visual acuity (VA) impairment and cardiovascular disease (CVD) are major global health burdens. Although impaired VA is linked to elevated all-cause mortality risk, its association with CVD mortality, particu...BACKGROUND: Visual acuity (VA) impairment and cardiovascular disease (CVD) are major global health burdens. Although impaired VA is linked to elevated all-cause mortality risk, its association with CVD mortality, particularly in older population, remains inadequately explored and inconsistent. OBJECTIVES: This study aimed to quantify the burden of VA impairment and investigate its association with CVD mortality in a large cohort of Chinese older adults. METHODS: This multicenter cohort study used data from the Basic Public Health Services in China. A total of 2,517,662 participants 65 years of age or older from 4 cities (Zaozhuang, Luzhou, Zunyi, and Shenzhen) were included between 2017 and 2023. Presenting visual acuity of the better-seeing eye (BVA) was measured using a standard logarithmic tumbling E chart. Mortality data were ascertained via linkage to the China Population Death Information Registration System, with follow-up through December 31, 2024. Cox proportional hazards models were used to estimate HRs and 95% CIs for the association between VA and mortality, with adjustments for demographic, lifestyle, clinical and geographic factors. Stratified analysis, competing risk analysis, dose-response analysis, and extensive sensitivity analyses were performed to further investigate the relationship. RESULTS: Among the 2.52 million participants (mean age: 70.67 years), 42.5% had VA impairment. Over a mean follow-up of 4.99 years (accumulating 12,560,718.9 person-years), 348,501 deaths occurred, including 153,758 CVD deaths. In the fully adjusted model, each 1-logMAR unit increase in BVA (greater visual impairment) was associated with a 3% higher risk of all-cause mortality (HR: 1.03; 95% CI: 1.03-1.04) and a 3% higher risk of CVD mortality (HR: 1.03; 95% CI: 1.02-1.03). A graded association was observed when VA was categorized by quartiles, with the worst quartile (Q4) showing significantly elevated risks for all-cause (HR: 1.25; 95% CI: 1.24-1.26) and CVD mortality (HR: 1.30; 95% CI: 1.28-1.32) compared to the best quartile (Q1). Stratified analysis indicated that the association was stronger in younger participants (65-70 years). Dose-response analysis revealed a significant nonlinear association, with mortality risk rising steeply at lower levels of impairment and plateauing at higher levels. Competing risk and sensitivity analysis confirmed the robustness of these findings. CONCLUSIONS: Beyond its traditional ocular role, VA impairment emerges as a sentinel marker of cardiovascular vulnerability and a functional barometer of biological aging. Situating cardiovascular risk within the broader landscape of functional aging and prioritizing holistic functional preservation could be pivotal for promoting longevity and achieving healthy aging goals.
BACKGROUND: Screening for atrial fibrillation (AF) may lead to earlier detection and initiation of preventive measures. Current AF screening approaches using a guideline age-based threshold of ≥65 years have shown limite...BACKGROUND: Screening for atrial fibrillation (AF) may lead to earlier detection and initiation of preventive measures. Current AF screening approaches using a guideline age-based threshold of ≥65 years have shown limited yield. OBJECTIVES: In an AF screening trial, we assessed whether the screening effect was larger among individuals at elevated AF risk using validated clinical and electrocardiogram (ECG)-based artificial intelligence (AI) risk models. METHODS: VITAL-AF was a cluster-randomized trial of patients aged ≥65 years treated at 1 of 16 primary care practices affiliated with Massachusetts General Hospital. Patients randomized to a screening practice were screened using a single-lead ECG. Among VITAL-AF participants without prevalent AF with at least one 12-lead ECG within 3 years before enrollment, we estimated AF risk using 3 validated models derived outside of VITAL-AF: the Cohorts of Heart and Aging Research in Genomic Epidemiology-AF (CHARGE-AF) clinical score, an AI-based model using a 12-lead ECG alone (ECG-AI), and a model combining ECG-AI and CHARGE-AF (CH-AI). Two-year incident AF discrimination was assessed by the time-dependent area under the receiver-operating characteristic curve (AUROC) and average precision. AF screening effect was defined as the difference in 2-year incident AF diagnosis rate (per 100 person-years) in screening vs control across AF risk deciles. RESULTS: Of 30,630 VITAL-AF participants without prevalent AF, 16,937 had pretrial ECG and clinical data. Each score discriminated 2-year AF risk according to AUROC (CHARGE-AF: 0.711 [95% CI: 0.671-0.749]; ECG-AI: 0.784 [95% CI: 0.743-0.819]; CH-AI: 0.788 [95% CI: 0.754-0.824]) and average precision (0.0952 [95% CI: 0.0836-0.112]; 0.132 [95% CI: 0.113-0.157]; 0.133 [95% CI: 0.117-0.159]). An AF screening effect was observed in the top decile of CH-AI (AF diagnosis rate in screening 10.07/100 person-years [95% 8.28-11.87] vs 7.76 [95% 6.30-9.21] in control, P < 0.05), corresponding to a difference in AF diagnosis rate of 2.32/100 person-years (95% CI: 0.01-4.63) and number-needed-to-screen of 43 per year. CONCLUSIONS: Use of ECG-based AI and clinical factors identified individuals at particularly high risk for AF who may benefit from screening. Findings suggest a trade-off between increasing AF screening efficiency and decreasing population coverage (ie, restriction of the screening pool). Future studies are needed to determine whether a risk-based approach is optimal or whether consideration of additional clinical- and systems-level factors (eg, access, health care system engagement) can further refine AF screening strategies. (Screening for Atrial Fibrillation Among Older Patients in Primary Care Clinics [VITAL-AF]; NCT03515057).