<div><h4>Oral Anticoagulation Use and Left Atrial Appendage Occlusion in LAAOS III.</h4><i>Connolly SJ, Healey JS, Belley-Cote EP, Balasubramanian K, ... Yusuf S, Whitlock RP</i><br /><b>Background</b><br />LAAOS III (Left Atrial Appendage Occlusion Study III) showed that left atrial appendage (LAA) occlusion reduces the risk of ischemic stroke or systemic embolism in patients with atrial fibrillation undergoing cardiac surgery. This article examines the effect of LAA occlusion on stroke reduction according to variation in the use of oral anticoagulants (OACs).<br /><b>Methods</b><br />Information regarding OAC use was collected at every follow-up visit. Adjusted proportional hazards modeling, including using landmarks of hospital discharge, 1 and 2 years after randomization, evaluated the effect of LAA occlusion on the risk of ischemic stroke or systemic embolism, according to OAC use. Adjusted proportional hazard modeling, with OAC use as a time-dependent covariate, was also performed to assess the effect of LAA occlusion, according to OAC use throughout the study.<br /><b>Results</b><br />At hospital discharge, 3027 patients (63.5%) were receiving a vitamin K antagonist, and 879 (18.5%) were receiving a non-vitamin K antagonist oral anticoagulant (direct OAC), with no difference in OAC use between treatment arms. There were 2887 (60.5%) patients who received OACs at all follow-up visits, 1401 (29.4%) who received OAC at some visits, and 472 (9.9%) who never received OACs. The effect of LAA occlusion on the risk of ischemic stroke or systemic embolism was consistent after discharge across all 3 groups: hazard ratios of 0.70 (95% CI, 0.51-0.96), 0.63 (95% CI, 0.43-0.94), and 0.76 (95% CI, 0.32-1.79), respectively. An adjusted proportional hazards model with OAC use as a time-dependent covariate showed that the reduction in stroke or systemic embolism with LAA occlusion was similar whether patients were receiving OACs or not.<br /><b>Conclusions</b><br />The benefit of LAA occlusion was consistent whether patients were receiving OACs or not. LAA occlusion provides thromboembolism reduction in patients independent of OAC use.<br /><br /><br /><br /><small>Circulation: 21 Sep 2023; epub ahead of print</small></div>

<div><h4>Mental Health Conditions Among Children and Adolescents With Congenital Heart Disease: A Danish Population-Based Cohort Study.</h4><i>Miles KG, Farkas DK, Laugesen K, Sørensen HT, Kasparian NA, Madsen N</i><br /><b>Background</b><br />Despite the known mental health burden among children with congenital heart disease (CHD), the literature is constrained by a lack of comparison cohorts and population-based follow-up data. We examined the incidence of mental health conditions among children with CHD, relative to 3 comparison cohorts.<br /><b>Methods</b><br />This population-based cohort study identified all children with CHD (<18 years of age; n=16 473) in Denmark from 1996 to 2017, through linkage of individual-level data across national registries. This allowed for complete follow-up of the population. Comparison cohorts included children from the general population (n=162 204), siblings of children with CHD (n=20 079), and children with non-CHD major congenital anomalies (n=47 799). Mental health conditions were identified using inpatient and outpatient hospital discharge codes, prescription data, and data on use of community-based psychology, psychiatry, and psychotherapy services. We computed cumulative incidence by 18 years of age, incidence rates, and adjusted hazard ratios (aHRs) using Cox regression. aHRs accounted for sex, year of CHD diagnosis, parental mental health, and socioeconomic status. All estimates were stratified by age, sex, and CHD complexity.<br /><b>Results</b><br />The cumulative incidence of mental health conditions by 18 years of age in the CHD cohort was 35.1% (95% CI, 34.0%-36.1%), corresponding to aHRs of 1.64 (95% CI, 1.58-1.71), 1.41 (95% CI, 1.30-1.52), and 1.02 (95% CI, 0.98-1.07) compared with the general population, sibling, and major congenital anomaly cohorts, respectively. Mental health incidence rates showed prominent peaks in early childhood and adolescence. Males and children with severe or single-ventricle CHD demonstrated higher incidence rates of mental health conditions relative to females and children with mild or moderate CHD, respectively. Compared with the general population and sibling cohorts, incidence rates and aHRs in the CHD cohort were highest for severe stress reactions, attention deficit/hyperactivity disorder, intellectual disability, and autism spectrum disorder. Compared with children in the major congenital anomaly cohort, the aHRs were close to 1.<br /><b>Conclusions</b><br />More than one-third of children with CHD were diagnosed or treated for a mental health condition by 18 years of age. Mental health conditions began early in life and were most prominent among males and children with severe or single-ventricle heart disease.<br /><br /><br /><br /><small>Circulation: 18 Sep 2023; epub ahead of print</small></div>

<div><h4>Cardiovascular Events After Aortic Root Repair in Patients With Marfan Syndrome.</h4><i>David TE, Park J, Tatangelo M, Steve Fan CP, Ouzounian M</i><br /><b>Background</b><br />The usefulness of aortic valve sparing operations to treat aortic root aneurysm in patients with Marfan syndrome (MS) remains controversial.<br /><b>Objectives</b><br />The purpose of this study was to evaluate the occurrence of cardiovascular events in patients with MS who have undergone valve-preserving aortic root replacement.<br /><b>Methods</b><br />Patients with MS who had aortic valve sparing operations (reimplantation of the aortic valve or remodeling of the aortic root) from 1988 through 2019 were followed prospectively for a median of 14 years. Pertinent data from clinical, echocardiographic, computed tomography, and magnetic resonance images of the aorta were collected and analyzed.<br /><b>Results</b><br />There were 189 patients whose mean age was 36 years, and 67% were men. Ten patients presented with acute type A dissection and 29 had mitral regurgitation. There were 52 patients at risk at 20 years. Mortality rate at 20 years was 21.5% (95% CI: 14.7%-30.8%); advancing age and preoperative aortic dissections were associated with increased risk of death by multivariable analysis. At 20 years, the cumulative incidence of moderate or severe aortic insufficiency was 14.5% (95% CI: 9.5%-22.0%), reoperation on the aortic valve was 7.5% (95% CI: 3.9%-14.7%), and new distal aortic dissections was 19.9% (95% CI: 13.9%-28.5%). Remodeling of aortic root was associated with greater risk of developing aortic insufficiency and aortic valve reoperation than reimplantation of the aortic valve.<br /><b>Conclusions</b><br />Aortic valve sparing operations provide stable aortic valve function and low rates of valve-related complications during the first 2 decades of follow-up but aortic dissections remain problematic in patients with MS.<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 12 Sep 2023; 82:1068-1076</small></div>

<div><h4>Mechanisms of benefits of sodium-glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction.</h4><i>Pandey AK, Bhatt DL, Pandey A, Marx N, ... Pandey A, Verma S</i><br /><AbstractText>For decades, heart failure with preserved ejection fraction (HFpEF) proved an elusive entity to treat. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently been shown to reduce the composite of heart failure hospitalization or cardiovascular death in patients with HFpEF in the landmark DELIVER and EMPEROR-Preserved trials. While improvements in blood sugar, blood pressure, and attenuation of kidney disease progression all may play some role, preclinical and translational research have identified additional mechanisms of these agents. The SGLT2 inhibitors have intriguingly been shown to induce a nutrient-deprivation and hypoxic-like transcriptional paradigm, with increased ketosis, erythropoietin, and autophagic flux in addition to altering iron homeostasis, which may contribute to improved cardiac energetics and function. These agents also reduce epicardial adipose tissue and alter adipokine signalling, which may play a role in the reductions in inflammation and oxidative stress observed with SGLT2 inhibition. Emerging evidence also indicates that these drugs impact cardiomyocyte ionic homeostasis although whether this is through indirect mechanisms or via direct, off-target effects on other ion channels has yet to be clearly characterized. Finally, SGLT2 inhibitors have been shown to reduce myofilament stiffness as well as extracellular matrix remodelling/fibrosis in the heart, improving diastolic function. The SGLT2 inhibitors have established themselves as robust, disease-modifying therapies and as recent trial results are incorporated into clinical guidelines, will likely become foundational in the therapy of HFpEF.</AbstractText><br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 07 Sep 2023; epub ahead of print</small></div>

<div><h4>Predictors of 5-Year Mortality in Patients Managed With a Magnetically Levitated Left Ventricular Assist Device.</h4><i>Nayak A, Hall SA, Uriel N, Goldstein DJ, ... Wang A, Mehra MR</i><br /><b>Background</b><br />In advanced heart failure patients implanted with a fully magnetically levitated HeartMate 3 (HM3, Abbott) left ventricular assist device (LVAD), it is unknown how preimplant factors and postimplant index hospitalization events influence 5-year mortality in those able to be discharged.<br /><b>Objectives</b><br />The goal was to identify risk predictors of mortality through 5 years among HM3 LVAD recipients conditional on discharge from index hospitalization in the MOMENTUM 3 pivotal trial.<br /><b>Methods</b><br />This analysis evaluated 485 of 515 (94%) patients discharged after implantation of the HM3 LVAD. Preimplant (baseline), implant surgery, and index hospitalization characteristics were analyzed individually, and as multivariable predictors for mortality risk through 5 years.<br /><b>Results</b><br />Cumulative 5-year mortality in the cohort (median age: 62 years, 80% male, 65% White, 61% destination therapy due to transplant ineligibility) was 38%. Two preimplant characteristics (elevated blood urea nitrogen and prior coronary artery bypass graft or valve procedure) and 3 postimplant characteristics (hemocompatibility-related adverse events, ventricular arrhythmias, and estimated glomerular filtration rate <60 mL/min/1.73 m<sup>2</sup> at discharge) were predictors of 5-year mortality. In 171 of 485 patients (35.3%) without any risk predictors, 5-year mortality was reduced to 22.6% (95% CI: 15.4%-32.7%). Even among those with 1 or more predictors, mortality was <50% at 5 years (45.7% [95% CI: 39.0%-52.8%]).<br /><b>Conclusions</b><br />Long-term survival in successfully discharged HM3 LVAD recipients is largely influenced by clinical events experienced during the index surgical hospitalization in tandem with baseline factors, with mortality of <50% at 5 years. In patients without identified predictors of risk, long-term 5-year mortality is low and rivals that achieved with heart transplantation, even though most were implanted with destination therapy intent. (MOMENTUM 3 IDE Clinical Study Protocol, NCT02224755; MOMENTUM 3 Pivotal Cohort Extended Follow-up PAS, NCT03982979).<br /><br />Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 29 Aug 2023; 82:771-781</small></div>

<div><h4>Atrial pacing minimization in sinus node dysfunction and risk of incident atrial fibrillation: a randomized trial.</h4><i>Kronborg MB, Frausing MHJP, Malczynski J, Riahi S, ... Nielsen JC, DANPACE II Investigators </i><br /><b>Background:</b><br/>and aims</b><br />High percentages of atrial pacing have been associated with an increased risk of atrial fibrillation. This study aimed at evaluating whether atrial pacing minimization in patients with sinus node dysfunction reduces the incidence of atrial fibrillation.<br /><b>Methods</b><br />In a nationwide, randomized controlled trial, 540 patients with sinus node dysfunction and an indication for first pacemaker implantation were assigned to pacing programmed to a base rate of 60 bpm and rate-adaptive pacing (DDDR-60) or pacing programmed to a base rate of 40 bpm without rate-adaptive pacing (DDD-40). Patients were followed on remote monitoring for 2 years. The primary endpoint was time to first episode of atrial fibrillation longer than 6 min. Secondary endpoints included longer episodes of atrial fibrillation, and the safety endpoint comprised a composite of syncope or presyncope.<br /><b>Results</b><br />The median percentage of atrial pacing was 1% in patients assigned to DDD-40 and 49% in patients assigned to DDDR-60. The primary endpoint occurred in 124 patients (46%) in each treatment group (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.76-1.25, P=0.83). There were no between-group differences in atrial fibrillation exceeding 6- or 24 hours, persistent atrial fibrillation, or cardioversions for atrial fibrillation. The incidence of syncope or presyncope was higher in patients assigned to DDD-40 (HR 1.71 95% CI 1.13-2.59, P=0.01).<br /><b>Conclusions</b><br />Atrial pacing minimization in patients with sinus node dysfunction does not reduce the incidence of atrial fibrillation. Programming a base rate of 40 bpm without rate-adaptive pacing is associated with an increased risk of syncope or presyncope.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 28 Aug 2023; epub ahead of print</small></div>

<div><h4>Catheter Ablation in End-Stage Heart Failure with Atrial Fibrillation.</h4><i>Sohns C, Fox H, Marrouche NF, Crijns HJGM, ... Sommer P, CASTLE HTx Investigators</i><br /><b>Background</b><br />The role of catheter ablation in patients with symptomatic atrial fibrillation and end-stage heart failure is unknown.<br /><b>Methods</b><br />We conducted a single-center, open-label trial in Germany that involved patients with symptomatic atrial fibrillation and end-stage heart failure who were referred for heart transplantation evaluation. Patients were assigned to receive catheter ablation and guideline-directed medical therapy or medical therapy alone. The primary end point was a composite of death from any cause, implantation of a left ventricular assist device, or urgent heart transplantation.<br /><b>Results</b><br />A total of 97 patients were assigned to the ablation group and 97 to the medical-therapy group. The trial was stopped for efficacy by the data and safety monitoring board 1 year after randomization was completed. Catheter ablation was performed in 81 of 97 patients (84%) in the ablation group and in 16 of 97 patients (16%) in the medical-therapy group. After a median follow-up of 18.0 months (interquartile range, 14.6 to 22.6), a primary end-point event had occurred in 8 patients (8%) in the ablation group and in 29 patients (30%) in the medical-therapy group (hazard ratio, 0.24; 95% confidence interval [CI], 0.11 to 0.52; P<0.001). Death from any cause occurred in 6 patients (6%) in the ablation group and in 19 patients (20%) in the medical-therapy group (hazard ratio, 0.29; 95% CI, 0.12 to 0.72). Procedure-related complications occurred in 3 patients in the ablation group and in 1 patient in the medical-therapy group.<br /><b>Conclusions</b><br />Among patients with atrial fibrillation and end-stage heart failure, the combination of catheter ablation and guideline-directed medical therapy was associated with a lower likelihood of a composite of death from any cause, implantation of a left ventricular assist device, or urgent heart transplantation than medical therapy alone. (Funded by Else Kröner-Fresenius-Stiftung; CASTLE-HTx ClinicalTrials.gov number, NCT04649801.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 27 Aug 2023; epub ahead of print</small></div>

<div><h4>New-onset atrial fibrillation in chronic coronary syndrome: the CLARIFY registry.</h4><i>Gautier A, Picard F, Ducrocq G, Elbez Y, ... Tendera M, Steg PG</i><br /><b>Background:</b><br/>and aims</b><br />Data on new-onset atrial fibrillation (NOAF) in patients with chronic coronary syndromes (CCS) are scarce. This study aims to describe the incidence, predictors and impact on cardiovascular outcomes of NOAF in CCS patients.<br /><b>Methods</b><br />Data from the international (45 countries) CLARIFY registry (prospeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease) were used. Among 29,001 CCS outpatients without previously reported AF at baseline, patients with at least one episode of AF/flutter diagnosed during 5-year follow-up were compared with patients in sinus rhythm throughout the study.<br /><b>Results</b><br />The incidence rate of NOAF was 1.12 [95% confidence interval (CI) 1.06-1.18] per 100 patient-years (cumulative incidence at 5 years: 5.0%). Independent predictors of NOAF were increasing age, increasing body mass index, low estimated glomerular filtration rate, Caucasian ethnicity, alcohol intake and low left ventricular ejection fraction, while high triglycerides were associated with lower incidence. NOAF was associated with a substantial increase in the risk of adverse outcomes, with adjusted hazard ratios of 2.01 (95% CI 1.61-2.52) for the composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, 2.61 (95% CI 2.04-3.34) for cardiovascular death, 1.64 (95% CI 1.07-2.50) for non-fatal myocardial infarction, 2.27 (95% CI 1.85-2.78) for all-cause death, 8.44 (95% CI 7.05-10.10) for hospitalization for heart failure and 4.46 (95% CI 2.85-6.99) for major bleeding.<br /><b>Conclusions</b><br />Among CCS patients, NOAF is common and is strongly associated with worse outcomes. Whether more intensive preventive measures and more systematic screening for AF would improve prognosis in this population deserves further investigation.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 27 Aug 2023; epub ahead of print</small></div>

<div><h4>Pulsed Field or Conventional Thermal Ablation for Paroxysmal Atrial Fibrillation.</h4><i>Reddy VY, Gerstenfeld EP, Natale A, Whang W, ... Mansour M, ADVENT Investigators</i><br /><b>Background</b><br />Catheter-based pulmonary vein isolation is an effective treatment for paroxysmal atrial fibrillation. Pulsed field ablation, which delivers microsecond high-voltage electrical fields, may limit damage to tissues outside the myocardium. The efficacy and safety of pulsed field ablation as compared with conventional thermal ablation is not known.<br /><b>Methods</b><br />In this randomized, single-blind, noninferiority trial, we assigned patients with drug-refractory paroxysmal atrial fibrillation in a 1:1 ratio to undergo pulsed field ablation or conventional radiofrequency or cryoballoon ablation. The primary efficacy end point was freedom from a composite of initial procedural failure, documented atrial tachyarrhythmia after a 3-month blanking period, antiarrhythmic drug use, cardioversion, or repeat ablation. The primary safety end point included acute and chronic device- and procedure-related serious adverse events.<br /><b>Results</b><br />A total of 305 patients were assigned to undergo pulsed field ablation, and 302 were assigned to undergo thermal ablation. At 1 year, the primary efficacy end point was met (i.e., no events occurred) in 204 patients (estimated probability, 73.3%) who underwent pulsed field ablation and 194 patients (estimated probability, 71.3%) who underwent thermal ablation (between-group difference, 2.0 percentage points; 95% Bayesian credible interval, -5.2 to 9.2; posterior probability of noninferiority, >0.999). Primary safety end-point events occurred in 6 patients (estimated incidence, 2.1%) who underwent pulsed field ablation and 4 patients (estimated incidence, 1.5%) who underwent thermal ablation (between-group difference, 0.6 percentage points; 95% Bayesian credible interval, -1.5 to 2.8; posterior probability of noninferiority, >0.999).<br /><b>Conclusions</b><br />Among patients with paroxysmal atrial fibrillation receiving a catheter-based therapy, pulsed field ablation was noninferior to conventional thermal ablation with respect to freedom from a composite of initial procedural failure, documented atrial tachyarrhythmia after a 3-month blanking period, antiarrhythmic drug use, cardioversion, or repeat ablation and with respect to device- and procedure-related serious adverse events at 1 year. (Funded by Farapulse-Boston Scientific; ADVENT ClinicalTrials.gov number, NCT04612244.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 27 Aug 2023; epub ahead of print</small></div>

<div><h4>Complete or Culprit-Only PCI in Older Patients with Myocardial Infarction.</h4><i>Biscaglia S, Guiducci V, Escaned J, Moreno R, ... Campo G, FIRE Trial Investigators</i><br /><b>Background</b><br />The benefit of complete revascularization in older patients (≥75 years of age) with myocardial infarction and multivessel disease remains unclear.<br /><b>Methods</b><br />In this multicenter, randomized trial, we assigned older patients with myocardial infarction and multivessel disease who were undergoing percutaneous coronary intervention (PCI) of the culprit lesion to receive either physiology-guided complete revascularization of nonculprit lesions or to receive no further revascularization. Functionally significant nonculprit lesions were identified either by pressure wire or angiography. The primary outcome was a composite of death, myocardial infarction, stroke, or any revascularization at 1 year. The key secondary outcome was a composite of cardiovascular death or myocardial infarction. Safety was assessed as a composite of contrast-associated acute kidney injury, stroke, or bleeding.<br /><b>Results</b><br />A total of 1445 patients underwent randomization (720 to receive complete revascularization and 725 to receive culprit-only revascularization). The median age of the patients was 80 years (interquartile range, 77 to 84); 528 patients (36.5%) were women, and 509 (35.2%) were admitted for ST-segment elevation myocardial infarction. A primary-outcome event occurred in 113 patients (15.7%) in the complete-revascularization group and in 152 patients (21.0%) in the culprit-only group (hazard ratio, 0.73; 95% confidence interval [CI], 0.57 to 0.93; P = 0.01). Cardiovascular death or myocardial infarction occurred in 64 patients (8.9%) in the complete-revascularization group and in 98 patients (13.5%) in the culprit-only group (hazard ratio, 0.64; 95% CI, 0.47 to 0.88). The safety outcome did not appear to differ between the groups (22.5% vs. 20.4%; P = 0.37).<br /><b>Conclusions</b><br />Among patients who were 75 years of age or older with myocardial infarction and multivessel disease, those who underwent physiology-guided complete revascularization had a lower risk of a composite of death, myocardial infarction, stroke, or ischemia-driven revascularization at 1 year than those who received culprit-lesion-only PCI. (Funded by Consorzio Futuro in Ricerca and others; FIRE ClinicalTrials.gov number, NCT03772743.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 26 Aug 2023; epub ahead of print</small></div>

<div><h4>Global Effect of Modifiable Risk Factors on Cardiovascular Disease and Mortality.</h4><i>Global Cardiovascular Risk Consortium, Magnussen C, Ojeda FM, Leong DP, ... Ziegler A, Blankenberg S</i><br /><b>Background</b><br />Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking.<br /><b>Methods</b><br />We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality.<br /><b>Results</b><br />Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6).<br /><b>Conclusions</b><br />Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 26 Aug 2023; epub ahead of print</small></div>

<div><h4>Ferric Carboxymaltose in Heart Failure with Iron Deficiency.</h4><i>Mentz RJ, Garg J, Rockhold FW, Butler J, ... Hernandez AF, HEART-FID Investigators</i><br /><b>Background</b><br />Ferric carboxymaltose therapy reduces symptoms and improves quality of life in patients who have heart failure with a reduced ejection fraction and iron deficiency. Additional evidence about the effects of ferric carboxymaltose on clinical events is needed.<br /><b>Methods</b><br />In this double-blind, randomized trial, we assigned ambulatory patients with heart failure, a left ventricular ejection fraction of 40% or less, and iron deficiency, in a 1:1 ratio, to receive intravenous ferric carboxymaltose or placebo, in addition to standard therapy for heart failure. Ferric carboxymaltose or placebo was given every 6 months as needed on the basis of iron indexes and hemoglobin levels. The primary outcome was a hierarchical composite of death within 12 months after randomization, hospitalizations for heart failure within 12 months after randomization, or change from baseline to 6 months in the 6-minute walk distance. The significance level was set at 0.01.<br /><b>Results</b><br />We enrolled 3065 patients, of whom 1532 were randomly assigned to the ferric carboxymaltose group and 1533 to the placebo group. Death by month 12 occurred in 131 patients (8.6%) in the ferric carboxymaltose group and 158 (10.3%) in the placebo group; a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12; and the mean (±SD) change from baseline to 6 months in the 6-minute walk distance was 8±60 and 4±59 m, respectively (Wilcoxon-Mann-Whitney P = 0.02; unmatched win ratio, 1.10; 99% confidence interval, 0.99 to 1.23). Repeated dosing of ferric carboxymaltose appeared to be safe with an acceptable adverse-event profile in the majority of patients. The number of patients with serious adverse events occurring during the treatment period was similar in the two groups (413 patients [27.0%] in the ferric carboxymaltose group and 401 [26.2%] in the placebo group).<br /><b>Conclusions</b><br />Among ambulatory patients who had heart failure with a reduced ejection fraction and iron deficiency, there was no apparent difference between ferric carboxymaltose and placebo with respect to the hierarchical composite of death, hospitalizations for heart failure, or 6-minute walk distance. (Funded by American Regent, a Daiichi Sankyo Group company; HEART-FID ClinicalTrials.gov number, NCT03037931.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 26 Aug 2023; epub ahead of print</small></div>

<div><h4>Significance of lipids, lipoproteins, and apolipoproteins during the first 14-16 months of life.</h4><i>Nielsen ST, Lytsen RM, Strandkjær N, Rasmussen IJ, ... Tybjærg-Hansen A, Frikke-Schmidt R</i><br /><b>Background:</b><br/>and aims</b><br />The aims of this study were to investigate lipid parameters during the first 14-16 months of life, to identify influential factors, and to test whether high concentrations at birth predict high concentrations at 2- and 14-16 months.<br /><b>Methods</b><br />The Copenhagen Baby Heart Study, including 13,354 umbilical cord blood samples and parallel venous blood samples from children and parents at birth (n = 444), 2 months (n = 364), and 14-16 months (n = 168), was used.<br /><b>Results</b><br />Concentrations of lipids, lipoproteins, and apolipoproteins in umbilical cord blood samples correlated highly with venous blood samples from newborns. Concentrations of low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (HDL) cholesterol, apolipoprotein B, and lipoprotein(a) increased stepwise from birth to 2 months to 14-16 months. Linear mixed models showed that concentrations of LDL cholesterol, non-HDL cholesterol, and lipoprotein(a) above the 80th percentile at birth were associated with significantly higher concentrations at 2 and 14-16 months. Finally, lipid concentrations differed according to sex, gestational age, birth weight, breastfeeding, and parental lipid concentrations.<br /><b>Conclusions</b><br />Lipid parameters changed during the first 14-16 months of life, and sex, gestational age, birth weight, breastfeeding, and high parental concentrations influenced concentrations. Children with high concentrations of atherogenic lipid traits at birth had higher concentrations at 2 and 14-16 months. These findings increase our knowledge of how lipid traits develop over the first 14-16 months of life and may help in deciding the optimal child age for universal familial hypercholesterolaemia screening.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 26 Aug 2023; epub ahead of print</small></div>

<div><h4>Temporal trends of cause-specific mortality after diagnosis of atrial fibrillation.</h4><i>Wu J, Nadarajah R, Nakao YM, Nakao K, ... Camm AJ, Gale CP</i><br /><b>Background:</b><br/>and aims</b><br />Reports of outcomes after atrial fibrillation (AF) diagnosis are conflicting. The aim of this study was to investigate mortality and hospitalisation rates following AF diagnosis over time, by cause, and by patient features.<br /><b>Methods</b><br />Individuals aged ≥16 years with a first diagnosis of AF were identified from the UK Clinical Practice Research Datalink-GOLD dataset from Jan 1, 2001 to Dec 31, 2017. The primary outcomes were all-cause and cause-specific mortality and hospitalisation at 1 year following diagnosis. Poisson regression was used to calculate rate ratios (RRs) for mortality and incidence rate ratios (IRRs) for hospitalisation and 95% confidence intervals (CIs) comparing 2001/02 and 2016/17, adjusted for age, sex, region, socioeconomic status and 18 major comorbidities.<br /><b>Results</b><br />Of 72 412 participants, mean (SD) age was 75.6 (12.4) years and 44 762 (61.8%) had ≥3 comorbidities. All-cause mortality declined (RR 2016/17 vs 2001/02 0.72; 95% CI 0.65-0.80), with large declines for cardiovascular (RR 0.46; 95% CI 0.37-0.58) and cerebrovascular mortality (RR 0.41; 95% CI 0.29-0.60) but not for non-cardio/cerebrovascular causes of death (RR 0.91; 95% CI 0.80-1.04). By 2016/17 deaths from dementia (67, 8.0%), outstripped deaths from acute myocardial infarction, heart failure and acute stroke combined (56, 6.7%, p < 0.001). Overall hospitalisation rates increased (IRR 2016/17 vs 2001/02 1.17; 95% CI, 1.13-1.22), especially for non-cardio/cerebrovascular causes (IRR 1.42; 95% CI 1.39-1.45). Older, more deprived, and hospital-diagnosed AF patients experienced higher event rates.<br /><b>Conclusions</b><br />After AF diagnosis, cardio/cerebrovascular mortality and hospitalisation has declined, whilst hospitalisation for non-cardio/cerebrovascular disease has increased.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.<br /><br /><small>Eur Heart J: 25 Aug 2023; epub ahead of print</small></div>

<div><h4>Atrial fibrillation progression after cryoablation versus radiofrequency ablation: the CIRCA-DOSE trial.</h4><i>Andrade JG, Deyell MW, Khairy P, Champagne J, ... Macle L, CIRCA-DOSE Study Investigators</i><br /><b>Background:</b><br/>and aims</b><br />Atrial fibrillation (AF) is a chronic, progressive disorder. Persistent forms of AF are associated with increased rates of thromboembolism, heart failure, and death. Catheter ablation modifies the pathogenic mechanism of AF progression. No randomized studies have evaluated the impact of the ablation energy on progression to persistent atrial tachyarrhythmia.<br /><b>Methods</b><br />346 patients with drug-refractory paroxysmal AF were enrolled and randomized to contact-force guided radiofrequency ablation (CF-RF ablation, n = 115), 4-minute cryoballoon ablation (CRYO-4, n = 115), or 2-minute cryoballoon ablation (CRYO-2, n = 116). Implantable cardiac monitors placed at study entry were used for follow-up. The main outcome was the first episode of persistent atrial tachyarrhythmia. Secondary outcomes included atrial tachyarrhythmia recurrence, and arrhythmia burden on implantable monitor.<br /><b>Results</b><br />At a median of 944.0 (interquartile range [IQR], 612.5-1104) days, 0 of 115 patients (0.0%) randomly assigned to CF-RF, 8 of 115 patients (7.0%) assigned to CRYO-4, and 5 of 116 patients (4.3%) assigned to CRYO-2 experienced an episode of persistent atrial tachyarrhythmia (P = 0.03). A documented recurrence of any atrial tachyarrhythmia ≥30 seconds occurred in 56.5%, 53.9%, and 62.9% of those randomised to CF-RF, CRYO-4, and CRYO-2, respectively (P = 0.65). Compared to the pre-ablation monitoring period, AF burden was reduced by a median of 99.5% (IQR 94.0-100.0%) with CF-RF, 99.9% (IQR 93.3-100.0%) with CRYO-4, and 99.1% (IQR 87.0-100.0%) with CRYO-2 (P = 0.38).<br /><b>Conclusions</b><br />Catheter ablation of paroxysmal AF using radiofrequency energy was associated with fewer patients developing persistent AF on follow-up.<br /><br />© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.<br /><br /><small>Eur Heart J: 25 Aug 2023; epub ahead of print</small></div>

<div><h4>Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity.</h4><i>Kosiborod MN, Abildstrøm SZ, Borlaug BA, Butler J, ... Petrie MC, STEP-HFpEF Trial Committees and Investigators</i><br /><b>Background</b><br />Heart failure with preserved ejection fraction is increasing in prevalence and is associated with a high symptom burden and functional impairment, especially in persons with obesity. No therapies have been approved to target obesity-related heart failure with preserved ejection fraction.<br /><b>Methods</b><br />We randomly assigned 529 patients who had heart failure with preserved ejection fraction and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or higher to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The dual primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in the 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level.<br /><b>Results</b><br />The mean change in the KCCQ-CSS was 16.6 points with semaglutide and 8.7 points with placebo (estimated difference, 7.8 points; 95% confidence interval [CI], 4.8 to 10.9; P<0.001), and the mean percentage change in body weight was -13.3% with semaglutide and -2.6% with placebo (estimated difference, -10.7 percentage points; 95% CI, -11.9 to -9.4; P<0.001). The mean change in the 6-minute walk distance was 21.5 m with semaglutide and 1.2 m with placebo (estimated difference, 20.3 m; 95% CI, 8.6 to 32.1; P<0.001). In the analysis of the hierarchical composite end point, semaglutide produced more wins than placebo (win ratio, 1.72; 95% CI, 1.37 to 2.15; P<0.001). The mean percentage change in the CRP level was -43.5% with semaglutide and -7.3% with placebo (estimated treatment ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). Serious adverse events were reported in 35 participants (13.3%) in the semaglutide group and 71 (26.7%) in the placebo group.<br /><b>Conclusions</b><br />In patients with heart failure with preserved ejection fraction and obesity, treatment with semaglutide (2.4 mg) led to larger reductions in symptoms and physical limitations, greater improvements in exercise function, and greater weight loss than placebo. (Funded by Novo Nordisk; STEP-HFpEF ClinicalTrials.gov number, NCT04788511.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 25 Aug 2023; epub ahead of print</small></div>

<div><h4>Bleeding and Ischemic Risks of Ticagrelor Monotherapy After Coronary Interventions.</h4><i>Mendieta G, Mehta S, Baber U, Angiolillo DJ, ... Gibson CM, Mehran R</i><br /><b>Background</b><br />In TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention), among high-risk patients undergoing percutaneous coronary intervention (PCI), ticagrelor monotherapy vs continuation of dual antiplatelet therapy (DAPT) with aspirin and ticagrelor after completing a 3-month course of DAPT was associated with reduced bleeding, without an increase in ischemic events.<br /><b>Objectives</b><br />This investigation sought to study the clinical benefit of ticagrelor monotherapy vs DAPT by simultaneously modeling its associated potential bleeding benefits and ischemic harms on an individual patient basis.<br /><b>Methods</b><br />Multivariable Cox regression models for: 1) Bleeding Academic Research Consortium type 2, 3, or 5 (BARC-2/3/5); and 2) cardiovascular death, nonfatal myocardial infarction, and nonfatal ischemic stroke (major adverse cardiac and cerebrovascular event [MACCE]) were developed using stepwise forward variable selection. The coefficients in the BARC-2/3/5 and MACCE models were used to calculate bleeding and ischemic risk scores, respectively, for each patient (excluding the coefficient for randomized treatment).<br /><b>Results</b><br />In the total study group (N = 7,119), BARC-2/3/5 occurred in 391 (5.5%) patients, and MACCE occurred in 258 (3.6%). There was a consistent reduction in bleeding events associated with ticagrelor monotherapy compared with DAPT across both bleeding and ischemic risk strata (P interaction = 0.54 and 0.11, respectively). Importantly, this benefit associated with ticagrelor monotherapy was not offset by an increase in MACCE at any level of bleeding or ischemic risk.<br /><b>Conclusions</b><br />Three months after PCI, discontinuing aspirin and maintaining ticagrelor monotherapy reduces bleeding in both higher-bleeding risk and lower-bleeding risk patients compared with continued DAPT. This benefit does not appear to be offset by greater ischemic risk. (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention [TWILIGHT]; NCT02270242).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 22 Aug 2023; 82:687-700</small></div>

<div><h4>Omitting Radiotherapy after Breast-Conserving Surgery in Luminal A Breast Cancer.</h4><i>Whelan TJ, Smith S, Parpia S, Fyles AW, ... Levine MN, LUMINA Study Investigators</i><br /><b>Background</b><br />Adjuvant radiotherapy is prescribed after breast-conserving surgery to reduce the risk of local recurrence. However, radiotherapy is inconvenient, costly, and associated with both short-term and long-term side effects. Clinicopathologic factors alone are of limited use in the identification of women at low risk for local recurrence in whom radiotherapy can be omitted. Molecularly defined intrinsic subtypes of breast cancer can provide additional prognostic information.<br /><b>Methods</b><br />We performed a prospective cohort study involving women who were at least 55 years of age, had undergone breast-conserving surgery for T1N0 (tumor size <2 cm and node negative), grade 1 or 2, luminal A-subtype breast cancer (defined as estrogen receptor positivity of ≥1%, progesterone receptor positivity of >20%, negative human epidermal growth factor receptor 2, and Ki67 index of ≤13.25%), and had received adjuvant endocrine therapy. Patients who met the clinical eligibility criteria were registered, and Ki67 immunohistochemical analysis was performed centrally. Patients with a Ki67 index of 13.25% or less were enrolled and did not receive radiotherapy. The primary outcome was local recurrence in the ipsilateral breast. In consultation with radiation oncologists and patients with breast cancer, we determined that if the upper boundary of the two-sided 90% confidence interval for the cumulative incidence at 5 years was less than 5%, this would represent an acceptable risk of local recurrence at 5 years.<br /><b>Results</b><br />Of 740 registered patients, 500 eligible patients were enrolled. At 5 years after enrollment, recurrence was reported in 2.3% of the patients (90% confidence interval [CI], 1.3 to 3.8; 95% CI, 1.2 to 4.1), a result that met the prespecified boundary. Breast cancer occurred in the contralateral breast in 1.9% of the patients (90% CI, 1.1 to 3.2), and recurrence of any type was observed in 2.7% (90% CI, 1.6 to 4.1).<br /><b>Conclusions</b><br />Among women who were at least 55 years of age and had T1N0, grade 1 or 2, luminal A breast cancer that were treated with breast-conserving surgery and endocrine therapy alone, the incidence of local recurrence at 5 years was low with the omission of radiotherapy. (Funded by the Canadian Cancer Society and the Canadian Breast Cancer Foundation; LUMINA ClinicalTrials.gov number, NCT01791829.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 17 Aug 2023; 389:612-619</small></div>

<div><h4>Subcutaneous Implantable Cardioverter-Defibrillators in Patients With Congenital Heart Disease.</h4><i>Waldmann V, Marquié C, Bessière F, Perrot D, ... Probst V, Marijon E</i><br /><b>Background</b><br />Very few data have been published on the use of subcutaneous implantable cardioverter-defibrillators (S-ICDs) in patients with congenital heart disease (CHD).<br /><b>Objectives</b><br />The aim of this study was to analyze outcomes associated with S-ICDs in patients with CHD.<br /><b>Methods</b><br />This nationwide French cohort including all patients with an S-ICD was initiated in 2020 by the French Institute of Health and Medical Research. Characteristics at implantation and outcomes were analyzed in patients with CHD.<br /><b>Results</b><br />From October 12, 2012, to December 31, 2019, among 4,924 patients receiving an S-ICD implant in 150 centers, 101 (2.1%) had CHD. Tetralogy of Fallot, univentricular heart, and dextro-transposition of the great arteries represented almost one-half of the population. Patients with CHD were significantly younger (age 37.1 ± 15.4 years vs 50.1 ± 14.9 years; P < 0.001), more frequently female (37.6% vs 23.0%; P < 0.001), more likely to receive an S-ICD for secondary prevention (72.3% vs 35.9%; P < 0.001), and less likely to have severe systolic dysfunction of the systemic ventricle (28.1% vs 53.1%; P < 0.001). Over a mean follow-up period of 1.9 years, 16 (15.8%) patients with CHD received at least 1 appropriate shock, with all shocks successfully terminating the ventricular arrhythmia. The crude risk of appropriate S-ICD shock was twice as high in patients with CHD compared with non-CHD patients (annual incidences of 9.0% vs 4.4%; HR: 2.1; 95% CI: 1.3-3.4); however, this association was no longer significant after propensity matching (especially considering S-ICD indication, P = 0.12). The burden of all complications (HR: 1.2; 95% CI: 0.7-2.1; P = 0.4) and inappropriate shocks (HR: 0.9; 95% CI: 0.4-2.0; P = 0.9) was comparable in both groups.<br /><b>Conclusions</b><br />In this nationwide study, patients with CHD represented 2% of all S-ICD implantations. Our findings emphasize the effectiveness and safety of S-ICD in this particularly high-risk population. (S-ICD French Cohort Study [HONEST]; NCT05302115).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 15 Aug 2023; 82:590-599</small></div>

<div><h4>Right Atrial Function Role in Tricuspid Regurgitation-Related Systemic Venous Congestion.</h4><i>Tafciu E, Niro L, Iseppi M, Fanti D, ... Rossi A, Ribichini FL</i><br /><AbstractText>Tricuspid regurgitation (TR) is a frequent valvular pathology and when significant, may cause systemic venous congestion (SC). The right atrium (RA) is an intermediate structure between the tricuspid valve and the venous system and its role in SC is not yet defined. A total of 116 patients with a measurable TR effective regurgitant orifice area (EROA) and regurgitant volume (RVol) were selected from 2020 to 2022. SC was estimated by echocardiography using inferior vena cava diameter and estimated right atrial pressure (eRAP) and by clinical congestive features. TR grade was mild in 23 patients (20%), moderate in 53 patients (46%), and severe in 40 patients (34%). There was a significant decrease in RA function measured by strain with increasing TR severity (p <0.001). There was a marked difference in RA strain between the groups with eRAP >10 and ≤10 mm Hg (25 ± 11% vs 11 ± 7%, p <0.0001). Variables independently associated with inferior vena cava diameter were RA strain (β -0.532, p <0.001), RA volume indexed (β 0.249, p = 0.002), RVol (β 0.229, p = 0.005) and EROA (β 0.185, p = 0.016), and independently associated with eRAP >10 mm Hg were EROA (odds ratio [OR] 1.024, 95% confidence interval [CI] 1.002 to 1.046), RVol (OR 1.039, 95% CI 1.007 to 1.072) and RA strain (OR 0.863, 95% CI 0.794 to 0.940). The addition of RA strain to models containing EROA or RVol significantly improved the power of the model. RA strain was independently associated with the presence of 3 or more congestive features. In conclusion, echocardiographic and clinical signs of SC are frequent in higher degrees of TR, and RA function seems to play a key role in modulating the downstream effect of TR.</AbstractText><br /><br />Copyright © 2023 Elsevier Inc. All rights reserved.<br /><br /><small>Am J Cardiol: 09 Aug 2023; 204:320-324</small></div>

<div><h4>Heart Rate Response Predicts 6-Minutes Walking Distance in Pulmonary Arterial Hypertension.</h4><i>Lu D, Cheng CY, Zhu XJ, Li JY, ... Sun K, Jing ZC</i><br /><AbstractText>Because the 6-minute walking test (6MWT) is a self-paced submaximal test, the 6-minute walking distance (6MWD) is substantially influenced by individual effort level and physical condition, which is difficult to quantify. We aimed to explore the optimal indicator reflecting the perceived effort level during 6MWT. We prospectively enrolled 76 patients with pulmonary arterial hypertension and 152 healthy participants; they performed 2 6MWTs at 2 different speeds: (1) at leisurely speed, as performed in daily life without extra effort (leisure 6MWT) and (2) an increased walking speed, walking as the guideline indicated (standard 6MWT). The factors associated with 6MWD during standard 6MWT were investigated using a multiple linear regression analysis. The heart rate (HR) and Borg score increased and oxygen saturation (S<sub>p</sub>O<sub>2</sub>) decreased after walking in 2 6MWTs in both groups (all p <0.001). The ratio of difference in HR before and after each test (ΔHR) to HR before walking (HR<sub>at rest</sub>) and the difference in SpO<sub>2</sub> (ΔSpO<sub>2</sub>) and Borg (ΔBorg) before and after each test were all significantly higher in both groups after standard 6MWT than after leisure 6MWT (all p <0.001). Multiple linear regression analysis revealed that ΔHR/HR<sub>at rest</sub> was an independent predictor of 6MWD during standard 6MWT in both groups (both p <0.001, adjusted R<sup>2</sup> = 0.737 and 0.49, respectively). 6MWD and ΔHR/HR<sub>at rest</sub> were significantly lower in patients than in healthy participants (both p <0.001) and in patients with cardiac functional class III than in patients with class I/II (both p <0.001). In conclusion, ΔHR/HR<sub>at rest</sub> is a good reflector of combined physical and effort factors. HR response should be incorporated into 6MWD to better assess a participant\'s exercise capacity.</AbstractText><br /><br />Copyright © 2023 Elsevier Inc. All rights reserved.<br /><br /><small>Am J Cardiol: 07 Aug 2023; 204:207-214</small></div>

<div><h4>Selective Inhibition of Na1.8 with VX-548 for Acute Pain.</h4><i>Jones J, Correll DJ, Lechner SM, Jazic I, ... White PF, VX21-548-101 and VX21-548-102 Trial Groups</i><br /><b>Background</b><br />The Na<sub>V</sub>1.8 voltage-gated sodium channel, expressed in peripheral nociceptive neurons, plays a role in transmitting nociceptive signals. The effect of VX-548, an oral, highly selective inhibitor of Na<sub>V</sub>1.8, on control of acute pain is being studied.<br /><b>Methods</b><br />After establishing the selectivity of VX-548 for Na<sub>V</sub>1.8 inhibition in vitro, we conducted two phase 2 trials involving participants with acute pain after abdominoplasty or bunionectomy. In the abdominoplasty trial, participants were randomly assigned in a 1:1:1:1 ratio to receive one of the following over a 48-hour period: a 100-mg oral loading dose of VX-548, followed by a 50-mg maintenance dose every 12 hours (the high-dose group); a 60-mg loading dose of VX-548, followed by a 30-mg maintenance dose every 12 hours (the middle-dose group); hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. In the bunionectomy trial, participants were randomly assigned in a 2:2:1:2:2 ratio to receive one of the following over a 48-hour treatment period: oral high-dose VX-548; middle-dose VX-548; low-dose VX-548 (a 20-mg loading dose, followed by a 10-mg maintenance dose every 12 hours); oral hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. The primary end point was the time-weighted sum of the pain-intensity difference (SPID) over the 48-hour period (SPID48), a measure derived from the score on the Numeric Pain Rating Scale (range, 0 to 10; higher scores indicate greater pain) at 19 time points after the first dose of VX-548 or placebo. The main analysis compared each dose of VX-548 with placebo.<br /><b>Results</b><br />A total of 303 participants were enrolled in the abdominoplasty trial and 274 in the bunionectomy trial. The least-squares mean difference between the high-dose VX-548 and placebo groups in the time-weighted SPID48 was 37.8 (95% confidence interval [CI], 9.2 to 66.4) after abdominoplasty and 36.8 (95% CI, 4.6 to 69.0) after bunionectomy. In both trials, participants who received lower doses of VX-548 had results similar to those with placebo. Headache and constipation were common adverse events with VX-548.<br /><b>Conclusions</b><br />As compared with placebo, VX-548 at the highest dose, but not at lower doses, reduced acute pain over a period of 48 hours after abdominoplasty or bunionectomy. VX-548 was associated with adverse events that were mild to moderate in severity. (Funded by Vertex Pharmaceuticals; VX21-548-101 and VX21-548-102 ClinicalTrials.gov numbers, NCT04977336 and NCT05034952.).<br /><br />Copyright © 2023 Massachusetts Medical Society.<br /><br /><small>N Engl J Med: 03 Aug 2023; 389:393-405</small></div>

<div><h4>Combination Lipid-Lowering Therapy in Patients Undergoing Percutaneous Coronary Intervention.</h4><i>Lee SJ, Joo JH, Park S, Kim C, ... Nam CM, Hong MK</i><br /><b>Background</b><br />The RACING (randomized comparison of efficacy and safety of lipid-lowering with statin monotherapy versus statin/ezetimibe combination for high-risk cardiovascular diseases) trial examined the effects of combination therapy with moderate-intensity statin and ezetimibe in patients with atherosclerotic cardiovascular disease compared with high-intensity statin monotherapy.<br /><b>Objectives</b><br />This observational study was conducted to evaluate the impact of 2 treatment strategies used in the RACING trial in clinical practice.<br /><b>Methods</b><br />After stabilized inverse probability of treatment weighting, a total of 72,050 patients who were prescribed rosuvastatin after drug-eluting stent implantation were identified from a nationwide cohort database: 10,794 patients with rosuvastatin 10 mg plus ezetimibe 10 mg (combination lipid-lowering therapy) and 61,256 patients with rosuvastatin 20 mg monotherapy. The primary endpoint was the 3-year composite event of cardiovascular death, myocardial infarction, coronary artery revascularization, hospitalization for heart failure treatment, or nonfatal stroke in accordance with the RACING trial.<br /><b>Results</b><br />Combination lipid-lowering therapy was associated with a lower occurrence of the primary endpoint (11.6% vs 15.2% for those with high-intensity statin monotherapy; HR: 0.75; 95% CI: 0.70-0.79; P < 0.001). Compared with high-intensity statin monotherapy, combination lipid-lowering therapy was associated with fewer discontinuations of statin (6.5% vs 7.6%; HR: 0.85; 95% CI: 0.78-0.94: P < 0.001) and a lower occurrence of new-onset diabetes requiring medication (7.7% vs 9.6%; HR: 0.80; 95% CI: 0.72-0.88; P < 0.001).<br /><b>Conclusions</b><br />In clinical practice, combination lipid-lowering therapy with ezetimibe and moderate-intensity statin was associated with favorable clinical outcomes and drug compliance in patients treated with drug-eluting stent implantation. (CONNECT DES Registry; NCT04715594).<br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 01 Aug 2023; 82:401-410</small></div>

<div><h4>Mechanisms of Aortic Dilation in Patients With Bicuspid Aortic Valve: JACC State-of-the-Art Review.</h4><i>Rodríguez-Palomares JF, Dux-Santoy L, Guala A, Galian-Gay L, Evangelista A</i><br /><AbstractText>Bicuspid aortic valve is the most common congenital heart disease and exposes patients to an increased risk of aortic dilation and dissection. Aortic dilation is a slow, silent process, leading to a greater risk of aortic dissection. The prevention of adverse events together with optimization of the frequency of the required lifelong imaging surveillance are important for both clinicians and patients and motivated extensive research to shed light on the physiopathologic processes involved in bicuspid aortic valve aortopathy. Two main research hypotheses have been consolidated in the last decade: one supports a genetic basis for the increased prevalence of dilation, in particular for the aortic root, and the second supports the damaging impact on the aortic wall of altered flow dynamics associated with these structurally abnormal valves, particularly significant in the ascending aorta. Current opinion tends to rule out mutually excluding causative mechanisms, recognizing both as important and potentially clinically relevant.</AbstractText><br /><br />Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 01 Aug 2023; 82:448-464</small></div>

<div><h4>Postapproval Study of a Subcutaneous Implantable Cardioverter-Defibrillator System.</h4><i>Gold MR, El-Chami MF, Burke MC, Upadhyay GA, ... Weiss R, S-ICD System Post Approval Study Investigators</i><br /><b>Background</b><br />The subcutaneous implantable cardioverter-defibrillator (S-ICD) was developed to avoid complications related to transvenous implantable cardioverter-defibrillator (TV-ICD) leads. Device safety and efficacy were demonstrated previously with atypical clinical patients or limited follow-up.<br /><b>Objectives</b><br />The S-ICD PAS (Subcutaneous Implantable Cardioverter-Defibrillator System Post Approval Study) is a real-world, multicenter, registry of U.S. centers that was designed to assess long-term S-ICD safety and efficacy in a diverse group of patients and implantation centers.<br /><b>Methods</b><br />Patients were enrolled in 86 U.S. centers with standard S-ICD indications and were observed for up to 5 years. Efficacy endpoints were first and final shock efficacy. Safety endpoints were complications directly related to the S-ICD system or implantation procedure. Endpoints were assessed using prespecified performance goals.<br /><b>Results</b><br />A total of 1,643 patients were prospectively enrolled, with a median follow-up of 4.2 years. All prespecified safety and efficacy endpoint goals were met. Shock efficacy rates for discrete episodes of ventricular tachycardia or ventricular fibrillation were 98.4%, and they did not differ significantly across follow-up years (P = 0.68). S-ICD-related and electrode-related complication-free rates were 93.4% and 99.3%, respectively. Only 1.6% of patients had their devices replaced by a TV-ICD for a pacing need. Cumulative all-cause mortality was 21.7%.<br /><b>Conclusions</b><br />In the largest prospective study of the S-ICD to date, all study endpoints were met, despite a cohort with more comorbidities than in most previous trials. Complication rates were low and shock efficacy was high. These results demonstrate the 5-year S-ICD safety and efficacy for a large, diverse cohort of S-ICD recipients. (Subcutaneous Implantable Cardioverter-Defibrillator [S-ICD] System Post Approval Study [PAS]; NCT01736618).<br /><br />Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.<br /><br /><small>J Am Coll Cardiol: 01 Aug 2023; 82:383-397</small></div>