Milvexian vs apixaban for stroke prevention in atrial fibrillation: The LIBREXIA atrial fibrillation trial rationale and design.

BACKGROUND: Direct oral anticoagulants are the standard of care for stroke prevention in eligible patients with atrial fibrillation and atrial flutter; however, bleeding remains a significant concern, limiting their use. Milvexian is an oral Factor XIa inhibitor that may offer similar anticoagulant efficacy with less bleeding risk. METHODS: LIBREXIA AF (NCT05757869) is a global phase III, randomized, double-blind, parallel-group, event-driven trial to compare milvexian with apixaban in participants with atrial fibrillation or atrial flutter. Participants are randomly assigned to milvexian 100 mg or apixaban (5 mg or 2.5 mg per label indication) twice daily. The primary efficacy objective is to evaluate if milvexian is noninferior to apixaban for the prevention of stroke and systemic embolism. The principal safety objective is to evaluate if milvexian is superior to apixaban in reducing the endpoint of International Society of Thrombosis and Hemostasis (ISTH) major bleeding events and the composite endpoint of ISTH major and clinically relevant nonmajor (CRNM) bleeding events. In total, 15,500 participants from approximately 1,000 sites in over 30 countries are planned to be enrolled. They will be followed until both 430 primary efficacy outcome events and 530 principal safety events are observed, which is estimated to take approximately 4 years. CONCLUSION: The LIBREXIA AF study will determine the efficacy and safety of the oral Factor XIa inhibitor milvexian compared with apixaban in participants with either atrial fibrillation or atrial flutter. TRIAL REGISTRATION: ClinicalTrials.gov NCT05757869.

Milvexian: An Oral, Bioavailable Factor XIa Inhibitor.

Direct oral anticoagulants have a dose-dependent increased bleeding risk which limits use in certain populations. Studies in both animals and humans with inherited variations in factor XI levels provide a theoretical basis for a drug target capable of addressing current unmet needs. Milvexian is an oral factor XIa inhibitor that has the potential to provide robust anticoagulant effect without increased bleeding compared with current standard of care. Several key studies in the preclinical, phase I, and phase II stages have reported promising safety data in venous thromboembolism and stroke prevention without compromising hemostasis. The planned phase III trials will examine the efficacy of milvexian for prevention of thrombotic events in patients with acute stroke, acute coronary syndrome, and atrial fibrillation.

Using large language models to assess public perceptions around glucagon-like peptide-1 receptor agonists on social media.

BACKGROUND: The prevalence of obesity has been increasing worldwide, with substantial implications for public health. Obesity is independently associated with cardiovascular morbidity and mortality and is estimated to cost the health system over $200 billion dollars annually. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a practice-changing therapy for weight loss and cardiovascular risk reduction independent of diabetes. METHODS: We used large language models to augment our previously reported artificial intelligence-enabled topic modeling pipeline to analyze over 390,000 unique GLP-1 RA-related Reddit discussions. RESULTS: We find high interest around GLP-1 RAs, with a total of 168 topics and 33 groups focused on the GLP-1 RA experience with weight loss, comparison of side effects between differing GLP-1 RAs and alternate therapies, issues with GLP-1 RA access and supply, and the positive psychological benefits of GLP-1 RAs and associated weight loss. Notably, public sentiment in these discussions was mostly neutral-to-positive. CONCLUSIONS: These findings have important implications for monitoring new side effects not captured in randomized control trials and understanding the public health challenge of drug shortages.

Obesity is a global public health burden that increases heart disease risk. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of medications originally developed for diabetes but are now used to improve lifespans in those with heart disease and increase weight loss. To better understand how the public views this type of drug, over 390,000 discussions from the social media platform Reddit were analyzed using computer software. Topics of discussion included experiences with weight loss, side effects of different GLP-1 RAs, and concerns about drug access and supply. The results showed a mainly neutral-to-positive view of these medications. The findings may help identify new side effects not previously seen in clinical trials and highlight future directions for research and public health efforts.

Artificial Intelligence in Cardiovascular Disease Prevention: Is it Ready for Prime Time?

PURPOSE OF REVIEW: This review evaluates how Artificial Intelligence (AI) enhances atherosclerotic cardiovascular disease (ASCVD) risk assessment, allows for opportunistic screening, and improves adherence to guidelines through the analysis of unstructured clinical data and patient-generated data. Additionally, it discusses strategies for integrating AI into clinical practice in preventive cardiology. RECENT FINDINGS: AI models have shown superior performance in personalized ASCVD risk evaluations compared to traditional risk scores. These models now support automated detection of ASCVD risk markers, including coronary artery calcium (CAC), across various imaging modalities such as dedicated ECG-gated CT scans, chest X-rays, mammograms, coronary angiography, and non-gated chest CT scans. Moreover, large language model (LLM) pipelines are effective in identifying and addressing gaps and disparities in ASCVD preventive care, and can also enhance patient education. AI applications are proving invaluable in preventing and managing ASCVD and are primed for clinical use, provided they are implemented within well-regulated, iterative clinical pathways.

Artificial Intelligence in Cardiovascular Care-Part 2: Applications: JACC Review Topic of the Week.

Recent artificial intelligence (AI) advancements in cardiovascular care offer potential enhancements in effective diagnosis, treatment, and outcomes. More than 600 U.S. Food and Drug Administration-approved clinical AI algorithms now exist, with 10% focusing on cardiovascular applications, highlighting the growing opportunities for AI to augment care. This review discusses the latest advancements in the field of AI, with a particular focus on the utilization of multimodal inputs and the field of generative AI. Further discussions in this review involve an approach to understanding the larger context in which AI-augmented care may exist, and include a discussion of the need for rigorous evaluation, appropriate infrastructure for deployment, ethics and equity assessments, regulatory oversight, and viable business cases for deployment. Embracing this rapidly evolving technology while setting an appropriately high evaluation benchmark with careful and patient-centered implementation will be crucial for cardiology to leverage AI to enhance patient care and the provider experience.

Artificial Intelligence for Cardiovascular Care-Part 1: Advances: JACC Review Topic of the Week.

Recent artificial intelligence (AI) advancements in cardiovascular care offer potential enhancements in diagnosis, treatment, and outcomes. Innovations to date focus on automating measurements, enhancing image quality, and detecting diseases using novel methods. Applications span wearables, electrocardiograms, echocardiography, angiography, genetics, and more. AI models detect diseases from electrocardiograms at accuracy not previously achieved by technology or human experts, including reduced ejection fraction, valvular heart disease, and other cardiomyopathies. However, AI's unique characteristics necessitate rigorous validation by addressing training methods, real-world efficacy, equity concerns, and long-term reliability. Despite an exponentially growing number of studies in cardiovascular AI, trials showing improvement in outcomes remain lacking. A number are currently underway. Embracing this rapidly evolving technology while setting a high evaluation benchmark will be crucial for cardiology to leverage AI to enhance patient care and the provider experience.

Treatment effect of canagliflozin for patients on therapy for heart failure: Pooled analysis of the CANVAS program and CREDENCE trial.

BACKGROUND: Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that has been shown to reduce cardiovascular events in diabetic patients with and without heart failure (HF). Whether the clinical benefits and safety profile of canagliflozin are different in those on a beta blocker and an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (BB + RAASi) is unknown. METHODS: We pooled participants with HF at baseline from the CANVAS Program and CREDENCE trial and assessed major adverse cardiovascular events and its components; hospitalization for heart failure (HHF); HHF or CV death; all-cause mortality; a renal composite; and a combined renal and CV composite. RESULTS: Of 14,543 participants, 2113 had HF at baseline, and 1280 were on BB + RAASi. In those with a history of HF, participants on BB + RAASi therapy were more likely to have coronary atherosclerotic disease (82 vs 72%, p < 0.001), history of myocardial infarction (42 vs 29%, p < 0.001), higher mean body mass index (34 vs 32 kg/m2, p < 0.001), and lower mean estimated glomerular filtration rate (67 vs 70 mL/min/1.73 m2, p < 0.01). They were also more likely to be on insulin, a statin, antithrombotic agent, and a diuretic (all p < 0.001). In unadjusted analysis and when adjusted for selected baseline factors, there was no heterogeneity in canagliflozin treatment effect except for HHF/CV death in those on baseline BB + RAASi vs. those not on baseline BB + RAASi (Pheterogeneity = 0.02). CONCLUSION: Canagliflozin mostly improved CV and kidney outcomes in participants with a history of HF irrespective of use of BB + RAASi at baseline, with possible greater benefit on HHF/CV death in participants on BB + RAASi.

Association of Coronary Artery Calcium Detected by Routine Ungated CT Imaging With Cardiovascular Outcomes.

BACKGROUND: Coronary artery calcium (CAC) is a strong predictor of cardiovascular events across all racial and ethnic groups. CAC can be quantified on nonelectrocardiography (ECG)-gated computed tomography (CT) performed for other reasons, allowing for opportunistic screening for subclinical atherosclerosis. OBJECTIVES: The authors investigated whether incidental CAC quantified on routine non-ECG-gated CTs using a deep-learning (DL) algorithm provided cardiovascular risk stratification beyond traditional risk prediction methods. METHODS: Incidental CAC was quantified using a DL algorithm (DL-CAC) on non-ECG-gated chest CTs performed for routine care in all settings at a large academic medical center from 2014 to 2019. We measured the association between DL-CAC (0, 1-99, or ≥100) with all-cause death (primary outcome), and the secondary composite outcomes of death/myocardial infarction (MI)/stroke and death/MI/stroke/revascularization using Cox regression. We adjusted for age, sex, race, ethnicity, comorbidities, systolic blood pressure, lipid levels, smoking status, and antihypertensive use. Ten-year atherosclerotic cardiovascular disease risk was calculated using the pooled cohort equations. RESULTS: Of 5,678 adults without ASCVD (51% women, 18% Asian, 13% Hispanic/Latinx), 52% had DL-CAC >0. Those with DL-CAC ≥100 had an average 10-year ASCVD risk of 24%; yet, only 26% were on statins. After adjustment, patients with DL-CAC ≥100 had increased risk of death (HR: 1.51; 95% CI: 1.28-1.79), death/MI/stroke (HR: 1.57; 95% CI: 1.33-1.84), and death/MI/stroke/revascularization (HR: 1.69; 95% CI: 1.45-1.98) compared with DL-CAC = 0. CONCLUSIONS: Incidental CAC ≥100 was associated with an increased risk of all-cause death and adverse cardiovascular outcomes, beyond traditional risk factors. DL-CAC from routine non-ECG-gated CTs identifies patients at increased cardiovascular risk and holds promise as a tool for opportunistic screening to facilitate earlier intervention.

Aortic Root Thrombosis in patients with HeartMate 3 left ventricular assist device support.

BACKGROUND: Aortic root thrombosis(ART) is a complication of continuous-flow left ventricular assist device therapy. However, the incidence and related complications of ART in HeartMate 3 (HM3) patients remain unknown. METHODS: Patients who underwent HM3 implantation from November 2014 to August 2020 at a quaternary academic medical center were included. Demographics and outcomes were abstracted from the medical record. Echocardiograms and contrast-enhanced computed tomography studies were reviewed to identify patients who developed ART and/or moderate or greater aortic insufficiency (AI) on HM3 support. RESULTS: The study cohort included 197 HM3 patients with a median postimplant follow-up of 17.5 months. Nineteen patients (9.6%) developed ART during HM3 support, and 15 patients (7.6%) developed moderate or greater AI. Baseline age, gender, race, implantation strategy, and INTERMACS classification were similar between the ART and no-ART groups. ART was associated with an increased risk of death, stroke, or aortic valve (AV) intervention (subhazard ratio [SHR] 3.60 [95% confidence interval (CI) 1.71-7.56]; p = 0.001) and moderate or greater AI (SHR 11.1 [CI 3.60-34.1]; p < 0.001) but was not associated with a statistically significantly increased risk of death or stroke on HM3 support (2.12 [0.86-5.22]; p = 0.10). Of the 19 patients with ART, 6 (31.6%) developed moderate or greater AI, necessitating more frequent AV interventions (ART: 5 AV interventions [3 surgical repairs, 1 surgical replacement, 1 transcatheter replacement; 26.3%]; no-ART: 0). CONCLUSIONS: Nearly 10% of HM3 patients developed ART during device support. ART was associated with increased risk of a composite end-point of death, stroke, or AV intervention as well as moderate or greater AI.

Impact of Periprocedural Adverse Events After PCI and CABG on 5-Year Mortality: The EXCEL Trial.

BACKGROUND: The relative risks for different periprocedural major adverse events (MAE) after percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) on subsequent mortality have not been described. OBJECTIVES: The aim of this study was to assess the association between periprocedural MAE occurring within 30 days postprocedure and early and late mortality after left main coronary artery revascularization by PCI and CABG. METHODS: In the EXCEL (Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization) trial, patients with left main disease were randomized to PCI vs CABG. The associations between 12 prespecified nonfatal MAE and subsequent 5-year all-cause and cardiovascular death in 1,858 patients were examined using logistic regression. RESULTS: One or more nonfatal MAE occurred in 111 of 935 patients (11.9%) after PCI and 419 of 923 patients (45.4%) after CABG (P < 0.0001). Patients with MAE were older and had more baseline comorbidities. Within 5 years, all-cause death occurred in 117 and 87 patients after PCI and CABG, respectively. Experiencing an MAE was a strong independent predictor of 5-year mortality after both PCI (adjusted OR: 4.61; 95% CI: 2.71-7.82) and CABG (adjusted OR: 3.25; 95% CI: 1.95-5.41). These associations were present within the first 30 days and between 30 days and 5 years postprocedure. Major or minor bleeding with blood transfusion ≥2 U was an independent predictor of 5-year mortality after both procedures. Stroke, unplanned revascularization for ischemia, and renal failure were significantly associated with mortality only after CABG. CONCLUSIONS: In the EXCEL trial, nonfatal periprocedural MAE were strongly associated with early and late mortality after both PCI and CABG for left main disease.

Outflow Graft Narrowing of the HeartMate 3 Left Ventricular Assist Device.

BACKGROUND: In patients with the HeartMate 3 (HM3, Abbott) left ventricular (LV) assist device (LVAD), outflow graft narrowing has been reported as a result of accumulation of biodebris either internal or external to the graft. This study describes the prevalence, imaging findings, and clinical outcomes associated with HM3 LVAD outflow graft narrowing. METHODS: A single-center retrospective cohort study was performed in patients who received an HM3 LVAD between November 2014 and July 2019. All patients with a computed tomographic (CT) angiogram or a CT scan with intravenous contrast sufficient to evaluate the outflow graft lumen were included. Narrowing was defined as a hypodensity of ≥3 mm. RESULTS: Of 165 HM3 LVAD recipients, 46 (28%) had qualifying imaging. Outflow graft narrowing was present in 33% (15/46). One patient had complete obstruction requiring emergency surgery, whereas 14 patients had a median hypodensity of 4.5 mm (interquartile range, 3.3-5.8 mm). The presence of outflow graft narrowing was significantly associated with a longer duration of LVAD support (588.2 ± 277.5 days vs 131.5 ± 170.9 days; P < .0001). One-year survival after identification of narrowing was 93%, with death occurring in 1 patient with complete obstruction. LV unloading (mean percent decrease in LV end-diastolic diameter at time of CT imaging vs pre-LVAD) was 16.7% vs 17.7% in patients with and without narrowing, respectively (P = .86). CONCLUSIONS: Among patients with adequate imaging, one-third have evidence of narrowing. Outflow graft narrowing secondary to biodebris was more likely to be found in HM3 LVAD recipients with longer duration of LVAD support. There was no significant difference in LV unloading between patients with and without narrowing.

Clinical and economic burden of obstructive hypertrophic cardiomyopathy in the United States.

AIMS: Obstructive hypertrophic cardiomyopathy (oHCM) is a disease of the cardiomyocyte in which dynamic left ventricular outflow track obstruction may lead to heart failure, valvular disease, and sudden death. Little is known about healthcare resource utilization (HRU) and costs associated with oHCM. This study investigated the clinical and economic burden of oHCM in patients with or without symptoms associated with oHCM. METHODS: We used the US IBM MarketScan Commercial and Medicare Supplemental database to identify patients with oHCM (January 2009-March 2019). Control patients without cardiomyopathy were matched to each patient with oHCM based on age, sex, region, and index year (3:1 ratio). One-year HRU and cost data were compared between all oHCM, symptomatic oHCM, and asymptomatic oHCM subgroups, and their respective controls. RESULTS: Among 11,401 eligible patients with oHCM (mean age 57 years, 42% female), 5,667 (50%) were symptomatic (23% chest pain, 57% dyspnea, 29% fatigue, 17% syncope). oHCM was associated with significant increases in all-cause hospitalizations, hospital days, outpatient visits, and total healthcare costs (mean ± standard deviation: $26,929 ± 77,720 vs. $6,808 ± 25,712, p<.001) compared with matched controls. These differences were driven mainly by the clinical and economic burden of symptomatic oHCM, which was associated with significant increases in 1-year hospitalization rates (38.0 vs. 6.9%), hospital days (3.7 ± 9.9 vs. 0.4 ± 3.0), and total healthcare costs ($43,586 ± 103,756 vs. $6,768 ± 27,618; all p<.001). Adjustment for comorbidities had minimal impact on these differences. LIMITATIONS: The use of claims data relies on International Classification of Diseases (ICD-9 and ICD-10) diagnosis codes, which might be inaccurate. Only commercially insured patients were included. CONCLUSION: In a real-world population, oHCM was associated with substantial increases in HRU and incremental costs of ∼$20,000/year when compared with matched controls-a difference that increased to ∼$35,000/year among symptomatic patients. Further studies are warranted to understand the potential impact of specific therapies on HRU and the economic burden of oHCM.

PLAIN LANGUAGE SUMMARYObstructive hypertrophic cardiomyopathy (oHCM) is a medical condition in which the heart muscle becomes abnormally thick and can cause partial blockage of blood flow out of the heart. Some patients experience symptoms (such as shortness of breath, chest pain, and fatigue) from this condition while others do not. Little is known about the healthcare resource utilization (HRU) and costs associated with oHCM, and if there are any differences between patients with oHCM who experience symptoms versus those who are asymptomatic. Therefore, we performed a study to investigate the clinical and economic burden of oHCM in patients with or without symptoms associated with oHCM. Based on insurance claims data, ∼50% of all patients with diagnosed oHCM are symptomatic. Symptomatic patients experience nearly 8 times as many hospitalizations and cost the healthcare system >$35,000 per year more than matched controls. In contrast, asymptomatic patients with oHCM have a much smaller difference in HRU and costs (∼$3,600/year) compared with matched controls. The results of this study suggest that effective therapies for oHCM may provide economic value, even if the impact of therapy is limited solely to the relief of symptoms.

Prognostic Importance of Health Status Versus Functional Status in Heart Failure and Secondary Mitral Regurgitation.

OBJECTIVES: This study sought to understand the extent to which health status and exercise capacity are independently associated with long-term outcomes in patients with heart failure (HF) and secondary mitral regurgitation (MR). BACKGROUND: Secondary MR in patients with HF leads to impaired health status (Kansas City Cardiomyopathy Questionnaire Overall Summary Score [KCCQ-OS]) and exercise capacity (6-minute walk distance [6MWD]), both of which improve after transcatheter mitral valve repair (TMVr). METHODS: The study used data from the COAPT trial (N = 604) to examine the association of baseline KCCQ-OS and 6MWD with 2-year mortality and HF hospitalization, adjusting for treatment arm and patient factors. We also examined the association of change in KCCQ-OS and 6MWD from baseline to 1 month with risk of outcomes from 1 month to 2 years. Interactions of KCCQ-OS and 6MWD with treatment assignment were explored. RESULTS: Mean baseline KCCQ-OS was 53 ± 23 points, and 6MWD was 240 ± 125 meters. In models including both measures, greater baseline 6MWD (but not KCCQ-OS) was associated with reduced 2-year mortality (HR per 125 meters: 0.75, 95% CI: 0.61-0.92). When stratified by treatment group, both baseline KCCQ-OS and 6MWD were independently associated with HF hospitalization in patients treated with medical therapy, whereas only KCCQ-OS was associated with HF hospitalization in patients treated with TMVr. In separate analyses, 1-month improvements in KCCQ-OS and 6MWD were each associated with lower subsequent risk of mortality and HF hospitalization, independent of treatment group. CONCLUSIONS: Among patients with HF and severe secondary MR, assessment of both health status and exercise capacity provide complementary prognostic information for patients with HF and severe secondary MR-both before and after TMVr. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial]; NCT01626079).